CH643265A5 - Antibacterial penem compounds - Google Patents

Abstract

Penem compounds of the formula I are described. The definitions of the substituents X, Y and Z can be taken from Patent Claim 1. They can be obtained by cyclisation of compounds of the formula II in which R<''> is an ester protective group, followed by removal of this protective group in cases where Z denotes hydrogen. The compounds have a good activity as antibacterial agents. <IMAGE>

Description

         

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 gig are 1 or 2 and wherein RA and RB are independently hydrogen or (lower) alkyl; or
EMI3. 1
 wherein n is an integer from 1-6 and RC Cl-C4-alkyl, phenyl or
EMI3. 2nd
 means, where is 1 or 2. 



   6.  A pharmaceutical mixture containing, as an active component, a compound according to claims 1-5 or a pharmaceutically acceptable salt or a physiologically cleavable ester thereof, together with a pharmaceutically acceptable carrier or diluent. 



   7.  A process for the preparation of a compound of formula I, wherein Z represents an ester protecting group and X and Y are as defined in claim 1, characterized in that a compound of formula
EMI3. 3rd
 wherein Q is phenyl or (lower) alkyl, R "is an ester protecting group, is cyclized, working in an inert organic solvent at a temperature from just above room temperature to the reflux temperature of the solvent. 



   8th.  A process for the preparation of a compound of the formula I in which Z is hydrogen and X and Y are as defined in claim 1, characterized in that a compound of the formula I in which Z is an ester protecting group is prepared by the process according to claim 7 and in the compound obtained cleaves the ester protecting group. 



   The present invention relates to new 2-substituted and 2,6-disubstituted penem compounds with strong antibiotic activity, to a pharmaceutical mixture containing such a compound and to a process for the preparation of these compounds. 



   The penem ring system has the formula
EMI3. 4th
 and can be systematically called 7-oxo-4-thia-1-azabicyclo [3. 2nd 0] hept-2-enes.  For simplicity, it is referred to as 2-penem in the present description and the numbering used is as follows:
EMI3. 5

The present invention accordingly relates to the new penem compounds of the formula
EMI3. 6
 wherein the substituents Z, X and Y have the meaning given in claim 1, and their pharmaceutically acceptable salts. 



   The compounds of formula I wherein Z is hydrogen (and their pharmaceutically acceptable salts and physiologically hydrolyzed esters) are effective antibacterial agents.  The remaining compounds are useful intermediates for the production of the biologically active penems. 



   The substituent groups mentioned for the 2- and 6-position of the Penem ring system can be described in more detail as follows: (a) Halogen includes chlorine, bromine, fluorine and iodine.  Preferred halogen substituents are chlorine and fluorine; (b) (Lower) alkyl includes both a straight-chain and a branched-chain saturated aliphatic hydrocarbon group with 1-6 C atoms including, e.g. B.  Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.  Preferred (lower) alkyl substituents have 14 C atoms and in particular 1-2 C atoms; (c) (Lower) aliphatic means an acyclic straight-chain or branched-chain saturated or unsaturated hydrocarbon radical with 1-6 C atoms inclusive. 

  The unsaturated radicals can contain one or more double or triple bonds, but either a double or a triple bond is preferred.  Examples of (lower) aliphatic radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isobutyl, vinyl, I propenyl, 2-propenyl, isopropenyl, 2-methyl -2-propenyl, ethynyl and 2-propynyl.  The most preferred aliphatic radicals are (lower) alkyl as in (b); (d) (Lower) cycloaliphatic means an alicyclic saturated or unsaturated hydrocarbon radical with 3-8 ring carbon atoms, preferably 3-6 carbon atoms.  The unsaturated ring may contain one or more (preferably one) double bond (s). 

  Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclopentenyl, 1,3-cyclohexadienyl and cyclohexenyl; (e) (Lower) cycloaliphatic (lower) aliphatic stands for cycloaliphatic-aliphatic radicals with 3-8 C atoms (preferably 3-6) in the cycloaliphatic ring and 1-6 C atoms (preferably 1 and in particular 1-2) in the aliphatic part.  Examples include cyclopropylmethyl, cyclopropylethyl, cyclopropylpentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cy



  clopentenylethyl, cyclopropylethenyl, cyclopropylethynyl, etc.  The most preferred radicals of this type are cycloalkyl-alkyl, in which the cycloalkyl part contains 3-6 C atoms and the alkyl part contains 1-2 C atoms; (f) (Lower) alkoxy includes C1-C6 alkoxy radicals in which the alkyl part corresponds to the definition of (b).  Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, etc.  Ct-C4-alkoxy and in particular C1-C2-alkoxy are preferred; (g) (Lower) alkylthio includes C1-C6-alkylthio residues, in which the alkyl part corresponds to the definition of (b).  Examples are methylthio, ethylthio and n-butylthio; (h) (Lower) alkylamino comprises C1-C6-alkylamino groups, in which the alkyl part corresponds to the definition of (b). 



  Examples are methylamino, ethylamino, n-propylamino and n-butylamino; (i) Di (lower) alkylamino stands for C1-C6-alkylamino, in which the alkyl part corresponds to the definition of (b).  Examples are dimethylamino and diethylamino; d) (lower) alkanoyloxy represents radicals of the formula (lower)
EMI4. 1
 wherein the alkyl is as defined in (b); (k) (Nieder) alkanoylamino stands for residues of the formula (Nieder)
EMI4. 2nd
 wherein the alkyl is as defined in (b); (1) Carb (lower) alkoxy stands for
EMI4. 3rd
 alkoxy, wherein (lower) alkoxy is as defined under (f); (m) Halogen (lower) alkyl represents alkyl radicals in which one or more hydrogen atoms have been replaced by a halogen atom; (n) sulfo (lower) alkyl represents (CH2) nSO3H, where n is 1-6;

  ; (o) carboxy (lower) alkyl represents- (CH2) nCOOH, where n is 1-6; (p) Phenyl (lower) alkyl stands for
EMI4. 4th
 wherein n is 1-6; (q) (lower) alkylamino (lower) alkyl represents dCH2) nNH- (lower) alkyl, wherein n is 1-6 and alkyl corresponds to the definition of (b); (r) Di (lower) alkylamino (lower) alkyl stands for
EMI4. 5
 wherein n is 1-6 and each alkyl is as defined in (b); (s) (Nieder) alkanoyl stands for
EMI4. 6
 wherein each alkyl corresponds to the definition of (b); (t) N- (lower) alkylcarbamoyl stands for
EMI4. 7
 wherein alkyl corresponds to the definition of (b); (u) N, N-Di (lower) carbamoyl stands for
EMI4. 8th
 wherein each alkyl corresponds to the definition of (b); (v) amino (lower) alkyl represents (CH2) nNH2, where n is 1-6;

  ; (w) hydroxyamino (lower) alkyl represents - (CH2) nNHOH, where n is 1-6; (x) (lower) alkylsulfinyl stands for
EMI4. 9
 wherein (lower) alkyl is as defined under (b); and (y) (lower) alkenyl stands for a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group, containing a double bond and including 2-6 C atoms, e.g. B.  Vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl. 

 

   The term heterocyclic or heterocyclyl as used in the present description encompasses both heteromonocyclic and heterobicyclic radicals of aromatic character as well as corresponding partially or completely saturated radicals, these heterocyclic radicals containing at least one heteroatom such as oxygen, sulfur or nitrogen and via one Ring carbon atom are bound to the Penem ring carbon.  The preferred heterocyclic groups are either 5- or 6-membered monocyclic groups or 6,6- or 5,6-bicyclic groups fused together. 

  Illustrative examples of such heterocyclic groups are the following:
EMI4. 10th
  
EMI5. 1

The given definition for the expression heterocyclic or heterocyclyl also applies to heterocyclyl- (lower) alkyl, heterocyclyl-thio- (lower) alkyl, heterocyclyloxy and heterocyclylthio, these designations standing for dCH2) n-heteroeyelyl, - (CH2) nS-heterocyclyl , -O-heterocyclyl or  -S-heterocyclyl, where n is 1-6 (preferably 1 or 2). 



   Since an asymmetric carbon atom is present in the 2-substituted compound of the formula I, such compounds can either be in the form of a racemic mixture (R, S form) or as a right-hand or  left-rotating (round S-shape) optically active isomer.  Compounds are preferred in which the configuration of the 5-carbon atom corresponds to that of natural penicillin (SR configuration).  Substituents in the 5 and 6 positions of the 2,6-disubstituted penem can be in the cis or trans position with respect to one another.  If the penem-6 substituent contains an asymmetric carbon atom, the resulting isomers can be identified as isomers A, B, C and D (see Example 58 for stereochemistry).  The preferred isomer in such compounds is that of type B. 

  The different optical and geometric isomers can be separated in conventional separation processes. 



   The present invention comprises the compounds of the formula I in the form of isomeric mixtures and also in the form of individually separated and worked up isomers. 



   The pharmaceutically usable salts are non-toxic carboxylic acid salts, e.g. B.  non-toxic metal salts of sodium, potassium, calcium, aluminum and magnesium, the ammonium salts and salts with non-toxic amines such as trialkylamines (triethylamine), procaine, dibenzylamine, N benzyl-ss-phenethylamine, l-ephenamine, N, N'-dibenzyl ethylenediamine, N -Alkylpiperidin and other amines, which were previously common for the formation of salts of penicillins and cephalosporins.  In the presence of a basic group, the present invention also encompasses the pharmaceutically acceptable acid addition salts thereof, e.g. B. 



  Salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid or with suitable organic carboxylic acids or sulfonic acids such as trifluoroacetic acid, p-toluenesulfonic acid, maleic acid, acetic acid, citric acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid, mandelic acid.  Compounds containing an acid group and a basic group may also be in the form of internal salts, e.g. B. 



  a hermaphrodite.  The salts described above can be prepared in a conventional manner, as is customary for the formation of salts of ss-lactam antibiotics such as penicillins and cephalosporins. 



   The term ester protecting group stands for an easily cleavable group, as is common in the chemistry of ss-lactams and peptides.  Many such groups are known which protect the carboxyl group during subsequent chemical reactions and which can later be split off in a conventional manner to give the free carboxylic acid.  Known ester protecting groups are 2,2,2-trichloroethyl, tertiary alkyl radicals with F6 carbon atoms, tertiary alkenyls with 5-7 carbon atoms, tertiary alkynyl groups with 5-7 carbon atoms, alkoxymethyl, alkanoylmethyl with 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilyl, ss-trimethylsilyl-ethyl, and the like. 



   The choice of an ester protecting group depends on the subsequent reaction conditions and the group must remain bound in these reactions.  The choice of a suitable protective group is no problem for the person skilled in the art. 



  For use as a chemical intermediate, the most preferred ester is the p-nitrobenzyl ester, which can be easily cleaved off by catalytic hydrogenation.  A preferred alternative for the preparation of compounds containing functional groups which can be reduced under such conditions is ss-trimethylsilylethyl ester, which can be eliminated by treatment with fluoride ions.  Easily cleavable ester protecting groups, which are physiologically cleavable esters, also include. H.  those esters from penicillin and cephalosporin chemistry which are broken down in the organism. 

  Examples of such physiologically cleavable esters are indanyl, phthalidyl, methoxymethyl, glycyloxymethyl, phenylglycyloxymethyl, thienylglycyloxymethyl or acyloxymethyl of the formula
EMI6. 1
 wherein Y 'is C1-C4 alkyl or phenyl.  Particularly preferred esters of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl. 



   The compounds of formula I can exist at various stages of solvation and both the anhydrous and the solvated (including hydrates) forms are encompassed by the present invention. 



   With regard to the compounds of formula I, the preferred compounds are those in which Y is hydrogen or (lower) alkyl, optionally substituted (preferably on the a-carbon) by hydroxy.  More preferred are compounds of the group mentioned, in which Y is hydroxy, ethyl or a-hydroxyethyl.  Finally, most preferred are compounds of the formula I in which Y is hydrogen or α-hydroxyethyl.  Finally, within this group, compounds in which Y represents a-hydroxyethyl are most preferred. 



   A preferred embodiment of the present invention consists in compounds of the formula I in which the substituent X is a substituted (lower) aliphatic, (lower) cycloaliphatic or (lower) cycloaliphatic- (lower) aliphatic radical or a ring-substituted phenyl, phenyl (lower) alkyl, represents a heterocycle, heterocyclyl (lower) alkyl or heterocyclylthio (lower) alkyl, the substituents for the aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenylalkyl, heterocyclic, heterocyclyl-alkyl and heterocyclyl-thioalkyl radicals mentioned
EMI6. 2nd
 represent in which R1 represents hydrogen, (lower) alkyl or phenyl and R2 and R3 independently of one another hydrogen, (lower) alkyl, phenyl or benzyl. 

  In this class the preferred compounds are those in which Y is hydrogen, ethyl or a-hydroxyethyl, especially those in which Y is hydrogen or a-hydroxyethyl and most preferred are compounds in this class in which Y is a-hydroxyethyl. 



   A further preferred embodiment of the present invention consists of compounds of the formula I in which X is a substituted (lower) aliphatic, (lower) cycloaliphatic or (lower) cycloaliphatic (lower) aliphatic radical or a ring-substituted phenyl, phenyl (lower) alkyl, represents heterocyclic, heterocyclyl (lower) alkyl or heterocyclylthio (lower) alkyl group, the substituents of the aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl-, phenylalkyl-, heterocyclic, heterocyclyl-alkyl or heterocyclyl-thio Radicals are -CORf, where Rf is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, -NHNH2,

   -NR17NR18, -NHOR19, -SR, -O (CH2) n- A-Re or -NReRg, wherein Rl7, Ri8, Re and Rg (lower) alkyl, R19 hydrogen or (lower) alkyl, AO, S, NH or NCH3 and n represent an integer from 1-6.  Within this class, the preferred compounds are those in which Y is hydrogen, ethyl or a-hydroxyethyl, especially those in which Y is hydrogen or a-hydroxyethyl and most preferably those in which Y is a-hydroxyethyl.   



   Another preferred embodiment of the present invention consists of compounds of the formula I in which X is:
EMI7. 1
 where n is an integer of 16, preferably 1; (b) - (CH2) nNHOH, where n is an integer from 1-6, preferably 14; (c) - (CH2) nPO (O-Cl-C6-alkyl) 2, where n is an integer from 1-6, preferably 14 and alkyl is preferably methyl, ethyl or isopropyl;
EMI7. 2nd
 wherein n is an integer from 1-6, preferably 14 and alkyl is preferably methyl or ethyl;
EMI7. 3rd
 wherein n is an integer from 1-6, preferably 14;

  ;
EMI7. 4th
 wherein n and m are independently 1 or 2 and RA and RB are independently hydrogen or (lower) alkyl; or
EMI7. 5
 wherein n is an integer from 1-6, preferably 14 and Rc Cl-C4-alkyl (preferably methyl or ethyl), phenyl or
EMI7. 6
 where m is 1 or 2. 



   In this class of compounds, preference is given to those in which Y is hydrogen, ethyl or a-hydroxyethyl, in particular those in which Y is hydrogen or a-hydroxyethyl and most preferred are compounds in which Y is a-hydroxyethyl. 



   Important compounds in the production of the substances according to the invention are the compounds of the formulas
EMI7. 7
 wherein Y is hydrogen or as defined for formula I, wherein Q is phenyl or (lower) alkyl, R "is an easily removable ester protecting group, X 1 or 2 and M is Cu (II), Pb (II) or Hg (II) if x is 2 or represent Ag (I) when x is 1;
EMI7. 8th
 wherein Y corresponds to the definition for compounds of the formula (I), in which Q is phenyl or (lower) alkyl, R "is an easily removable ester protecting group and T
EMI7. 9
 represent and wherein X corresponds to the definition in compounds of formula I. 



   In the intermediates of the formulas III, IIIa and IV, Q is preferably phenyl, R "is preferably p-nitrobenzyl and X and Y are preferably those substituents which have been mentioned as preferred in connection with the compounds of the formula I.  Reactive functional groups such as mercapto, amino and hydroxy in substituents Y and X can be protected by conventional protecting groups during the conversion of the intermediates into biologically active end products. 



   The invention also relates to the methods described in claims 7 and 8.  However, the compounds of the formula I can also be prepared by other syntheses. 



   The different synthetic routes, which also include the methods according to the invention, can be divided into three main
Methods are classified which differ in when the substituent is in the 6-position, i.e. H.  Y is introduced. 



  In process I, the 6-substituent is already introduced in the starting product; in process II, the substituent Y is introduced at the end of the synthesis and in process III the substituent Y is introduced in the middle of the synthesis process.  Each of the three main processes can in turn be different again, depending on the time of introduction of the desired 2-substituent, i. H.  X.  In general, the substituent Y is preferably introduced in the middle of the synthesis process and the substituent X is preferably introduced by acylation of mercaptide intermediates III or IIIa, which processes have been found to be most suitable. 



   The steps of process I can be seen from the following reaction scheme:
Method I (Variation 1): Early introduction of the 2-substituent
EMI8. 1
  
Method I (Variation 2): Late introduction of the 2-substituent
EMI9. 1
  
Method I (Variation 3): Late introduction of the 2-substituent
EMI10. 1

In process Ia, the vinyl ester (Y = H or a radical as defined for compounds I) containing the desired 6-substituent for optionally 1-substituted 4-acetoxy-2-azetidinone by cycloaddition with chlorosulfonyl isocyanate (CSI) followed by reduction with an organic Reducing agents such as sodium sulfite converted.  The CSI reaction is generally carried out in an inert organic solvent such as diethyl ether at a temperature of 0 ° C. or below. 

  The reduction step can be carried out in an aqueous or an aqueous-organic reaction mixture at a temperature of 0 ° C or below and at a slightly basic pH.   



   After the formation of 4-acetoxy-2-azetidinone as follows, process I can be continued in three different directions.  In the first case (variation 1) the azetidinone with a thiol acid
EMI11. 1
 wherein X corresponds to the definition of compounds I, or a salt thereof in a suitable solvent (e.g. B.  aqueous or aqueous-organic).  The removal of the acetoxy group results in the introduction of the desired 2-substituents in the azetidinone at this point.  The exchange reaction is preferably carried out at room temperature or below and at a slightly basic pH (approx.  7.5).  If Y is not hydrogen, the cis and trans isomers of the resulting azetidinone are preferably separated (e.g. B.  by chromatography). 

  Variations 2 and 3 consist of the conversion of 4-acetoxy-2-azetidinone into 4-acetylthio-2-azetidinone and  4-Tritylthio-2-azetidinone by nucleophilic exchange reaction with thioacetic acid or triphenylmethyl mercaptan (or a salt thereof such as the sodium salt). 



   The 4-thio-azetidinone is first used with a glyoxylate ester
EMI11. 2nd
 wherein R "is an easily removable ester protecting group such as p-nitrobenzyl or trimethylsilylethyl, or a reactive oxo derivative thereof such as one
Hydrate, in an inert organic solvent (e.g. B. 



   Benzene, toluene, xylene and the like) and preferably at elevated temperature (e.g. B.  50 C to the most preferred reflux temperature) implemented.  If a hydrate of the
When ester is used, the resulting water can be removed azeotropically or by molecular sieves.  The hydroxyester product is obtained as a mixture of epimers which can be separated by chromatography or can be used directly in the next reaction step. 



   The conversion of the hydroxy ester to the corresponding chloro ester takes place by reaction with a chlorinating agent (e.g. B.    STOCK, POCI3, PCIS and the like) in an inert organic solvent (e.g. B.  Tetrahydrofuran, diethyl ether, methylene chloride, dioxane and the like) in the presence or absence of a base, preferably an aliphatic tertiary amine (e.g. B.  Triethylamine) or a heterocyclic tertiary amine (e.g. B.  Pyridine or collidine). 



  The reaction is preferably carried out at a temperature of approx.  - 10 C to room temperature.  The chlorester will keep it as a mixture of epimers, which can optionally be worked up before use in the next reaction step. 



   The phosphorane intermediate can be reacted with the chloroester with a suitable phosphine (preferably triphenylphosphine or tri (lower) alkylphosphine such as
Triethylphosphine or tri-n-butylphosphine) in an inert organic solvent such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (e.g. B.  Hexane, cyclohexane, benzene, toluene and the like) can be obtained in the presence of a base, preferably an organic tertiary amine such as triethylamine, pyridine or 2,6-lutidine.  The reaction takes place preferably at temperatures from room temperature to
Reflux temperature of the solvent system. 



   At this stage, the process again divides into two directions.  In variation 1 (in which the 2-substituent has already been introduced), the phosphorane intermediate is converted to the desired penem by thermal cyclization in an inert organic solvent at a temperature from above room temperature to the reflux temperature of the solvent system.  The cyclization is suitably carried out under reflux conditions.  Suitable organic solvents are aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. B.  Benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (e.g. B.  Methylene chloride, chloroform, carbon tetrachloride), ether (diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane), carbocyclic acid amides (e.g. B.  Dimethylformamide), di-C 1-C6-alkyl sulfoxides (e.g. B. 

  Dimethyl sulfoxide) or a Cl-C6 alkanol (e.g. B.  Methanol, ethanol, t-butanol) or mixtures thereof. 



   In variations 2 and 3, the phosphorane becomes a heavy metal mercaptide of the formula
EMI11. 3rd
 implemented in which Q is preferably phenyl or (lower) alkyl, x 1 or 2 and M is Cu (II), Pb (II) or Hg (II) if x is 2 or Ag (I) if x is list.  Mercaptide formation takes place by reaction of the phosphorane with a salt of Hg (II), Pb (II), Cu (II) or AG (I) or with (methoxycarbonyl) mercury (II) acetate in a solvent containing methanol and in the presence of a organic or inorganic base such as aniline, pyridine, collidine, 2,6-lutidine, an alkali metal carbonate and the like.  The preferred base is pyridine.  The reaction can take place at room temperature or alternatively with cooling or heating.  

  The anion (A) of the heavy metal salt can be any anion which gives a soluble salt in the chosen solvent, e.g. B. 



  NO3, CH3COO, BF4, F, ClO4, NO2, CNO, etc. 



  The mercaptide intermediate is then reacted with an acylating agent which does the rest
EMI11. 4th
 can introduce where X represents the desired Penem-2 substituent.  The acylating agent
EMI11. 5
 can the acid
EMI11. 6
 or a reactive functional derivative thereof, such as an acid halide (preferably acid chloride), acid azide, acid anhydride, mixed acid anhydride, active ester, active thioester, etc.  The acylation takes place in an inert solvent, (e.g. B.  a halogenated hydrocarbon such as methylene chloride or an ether such as dioxane, tetrahydrofuran or diethyl ether) and, if an acid derivative is used, in the presence of an acid acceptor such as tri (lower) alkylamine (e.g. B.  Triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6-lutidine. 

  If the free acid is used, the acylation is carried out in the presence of a suitable condensing agent, e.g. B.  a carbodiimide such as N, N'-dicyclohexylcarbodiimide.  The acylation of the mercaptide can be carried out in a wide temperature range, but is preferably carried out at from -20 to + 25 C.     After acylation, the resulting phosphorane is cyclized to give the desired penem ester. 



   The formation of the phosphorane via the mercaptide intermediate (variations 2 and 3) generally resulted in a purer end product than after the conventional preparation according to variant 1. 



   Once the carboxyl protected penem is formed, the protecting group can be removed in a conventional manner (e.g. B.  by hydrolysis, hydrogenation or photolysis) to give the desired deblocked penem.  The
Method II (Variation 1): Early introduction of the 2-substituent cleavage of the p-nitrobenzyl ester takes place, for. B.  by catalytic hydrogenation in the presence of a noble metal catalyst such as palladium or rhodium, including derivatives thereof such as oxides, hydroxides or halides, the catalyst preferably being contained on a carrier such as activated carbon or diatomaceous earth.  A non-reducible aqueous or non-aqueous inert solvent such as water, ethanol, methanol, ethyl acetate, tetrahydrofuran, diethyl ether or dioxane is used. 

  The hydrogenation can take place at atmospheric pressure or elevated pressure and is preferably carried out at room temperature for 1-5 hours, depending on the solvent and catalyst used. 



  If an equivalent part by weight of a base such as an alkali metal or alkaline earth metal hydroxide or an amine is used during the hydrogenation, the product can be isolated in the form of a carboxylic acid salt.  The elimination of the ss-trimethylsilyl ethyl ester, another protective group etc.  is preferably carried out by treatment with a fluorine ion source.  Further ester protecting groups can also be split off in a conventional manner. 



   In a second main process (Process II), the reaction corresponds to the following scheme:
EMI12. 1
  
EMI13. 1

Procedure II (variation 2): late introduction of the 2-substituent
EMI13. 2nd
  
EMI14. 1

Procedure II (variation 3): late introduction of the 2-substituent
EMI14. 2nd
  
EMI15. 1

As can be seen from the reaction scheme, Process II is essentially the same as Process I (although Y must be H) up to the thermal cyclization step which provides the desired 2-substituted penem.  At this point, however, a 6-substituent is optionally introduced, the 2-penem with a suitable electrophile in an inert organic solvent (e.g. B.  Tetrahydrofuran, diethyl ether, dimethoxyethane and the like) and in the presence of a strong base. 

  In this process the 2-penem can be in the form of the free acid (obtained by deblocking as described above) in the presence of approx.  2 equivalents of base or on the other hand as a 2-penemester and in the presence of approx.  1 equivalent base can be implemented.  Any ester which is inert to anion chemistry (the reaction involves anion formation with the base followed by reaction of the electrophile with the penem anion) can be used, e.g. B.  (Lower) alkyl such as methyl, ethyl, n-propyl or t-butyl, phenyl, trichloroethyl, methoxymethyl, silyl such as trimethylsilyl or t-butyldimethylsilyl, and the like.  Penemesters with an activated methylene group such as p-nitrobenzyl are not suitable and when using 2-penemesters of this type, deblocking must be carried out first and the use is in the form of the free acid or after conversion to a suitable ester. 

  The type of base used is not critical and strong bases such as sodium hydride, phenyllithium or butyllithium are common.  However, a lithium disilyl amide or a lithium dialkyl amide such as lithium dicyclohexyl amide (LDCA), lithium diethyl amide, lithium dimethyl amide or lithium di-isopropyl amide (LDA) is preferred. 



   The electrophile is chosen so that the desired Y substituent is formed by reaction with the anion and can e.g. B.  a halogen (e.g. B.  Br2, 12), an alkyl halide (e.g. B. 



  CH3I) or a similar halide such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl (lower) alkyl, heterocyclic, heterocyclic thio, heterocyclic thio (lower) alkyl or heterocyclic (lower) alkyl, halide, tosylate or mesylate (e.g. . B.    CH3CH20-
EMI15. 2nd
   OCH2CH, CH20SO2CH3, etc. ) an epoxy
EMI15. 3rd
 Episulfide
EMI15. 4th
 an aldehyde (e.g. B.  CH3CHO, C6H5CH2CHO), a ketone (e.g. B.  CH3COCH3,
EMI15. 5
  an ester (e.g. B.  CH3CH2COOCH3 or C6H5COCH3). 



  Representative examples of other suitable electrophiles are the following: CH2 = CH-CH2-BR
EMI16. 1

EMI16. 2nd

The most preferred electrophile is acetaldehyde, which forms the hydroxyethyl 6-substituent.  The introduction of the 6-substituent by this method is preferably carried out with cooling (e.g. B.  -80 to 0 C) according to the general method described in Canadian Journal of Chemistry, 50 (19), 31963201 (1972).    



   After formation of the desired 2,6-penem, any ester protecting group can be split off as described, the desired deblocked product being obtained. 

 

   The third main process (process III) follows the following scheme:
Procedure III (Variations 1 and 2):
EMI16. 3rd
  
EMI17. 1
  
EMI18. 1
 B = protective group for the ring nitrogen
The 4-tritylthio-2-azetidinone from Process III is formed as described in Process II (Variation 3).  The ring nitrogen of the azetidinone is then removed in a conventional manner by an easily removable protective group such as triorganosilyl (e.g. B.  Trimethylsilyl or t-butyldimethylsilyl), methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl or the like protected.  The introduction of the desired Y substituent in the 1-position of the azetidinone is then carried out by reacting a suitable electrophile with the N-protected azetidinone in the presence of a strong base (reaction conditions as described in connection with process II). 

  From this point in time, the process is divided into two, depending on the time when the azetidinone is unblocked. 



   In one process, the N-protected intermediate is deblocked in a conventional manner (e.g. B.  by acid hydrolysis) and then via ester formation, chlorination of the hydroxy ester, conversion of the chloro ester to phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide with
EMI19. 1
 Thermal cyclization of the resulting phosphorane to the 2,6-Penemester and removal of the carboxyl protecting group to the desired 2,6-Penem transferred.  The reaction conditions for these steps are as described for Process II (Variation 3). 



   A further process route comprises the steps for converting the N-protected azetidinone to the heavy metal mercaptide and acylating the mercaptide with the rest
EMI19. 2nd
 Removal of the N-protecting group, reaction of the deblocked azetidinone with the glyoxylate ester, chlorination, reaction of the chloroester with the phosphine to form the phosphorane, cyclization of the phosphorane to form the penemester and removal of the carboxyl protecting group to form the 2,6-penem.  The reaction conditions for these steps correspond to those already described. 



   In the preparation of the 2-penem or 2,6-penem compounds by the process described, free functional groups in substituents X or Y which do not take part in the reaction can be temporarily protected, this being done in a conventional manner like free amino groups by acylation, tritylation or silylation, free hydroxyl groups, e.g. B.  by etherifying or esterifying, mercapto groups by esterifying and free carboxyl or sulfo groups, e.g. B.  through esters like silylation. 



  After the reaction has ended, these groups can be split off individually or simultaneously in a conventional manner. 



   Furthermore, it is possible in compounds of the formula I to modify the 2 and / or 2,6 substituents in a conventional manner during or after completion of the reaction steps, other substituents being obtained which also correspond to the present invention.  So z. B.  Carbonyl groups are reduced to alcohol groups, unsaturated aliphatic groups can be halogenated, amino groups can be alkylated or acylated, nitro groups can be converted to hydroxyamino and amino groups, and hydroxyl groups can be etherified or esterified, etc. 



   The penem compounds in the form of free acids can be converted to pharmaceutically usable salts thereof or to easily cleavable esters thereof (in particular physiologically cleavable esters).  Salts can be formed by reacting the free acid with a stoichiometric proportion of a suitable non-toxic acid or base in an inert solvent, followed by isolating the desired salt, such as by lyophilization or precipitation.  Esters (in particular physically cleavable esters) can be prepared in an analogous manner to the esters of penicillins and cephalosporins.  Obtained mixtures of isomers can also be separated into the individual isomers in a conventional manner. 

  Mixtures of diastereomeric isomers can e.g. B.  fractional crystallization, adsorption chromatography (column or thin film) or other suitable separation methods.  Racemates can be separated into the two antipodes in a conventional manner, e.g. B.  by forming a mixture of diastereomeric salts with optically active salt-forming reagents, separating the diastereomeric salts and converting the salts into the free compounds, or by fractional crystallization from optically active solvents. 



   In the process for the preparation of the compounds of formula I in which a compound of formula
EMI19. 3rd
 wherein Q is phenyl or (lower) alkyl, R "represent an easily cleavable ester group in an inert organic solvent at a temperature from just above room temperature to the reflux temperature of the solvent, and if Z is hydrogen, the cleavable ester group is optionally cleaved any other protecting groups present are removed in a conventional manner and if Y is hydrogen the product can be converted to another desired product wherein Y is not hydrogen by reacting the product with a corresponding electrophilic reagent in an inert solvent and in the presence of a strong base . 



   The penem compounds of the present invention in the form of the free acid and pharmaceutically acceptable salts and physiologically cleavable esters thereof have been found to be effective broad spectrum antibacterial agents which are useful in the treatment of infectious diseases in humans and animals as described by gram-negative and gram-positive organisms.  The compounds are also valuable as additives in animal feed and as a means of treating mastitis in cattle. 



   The 2-penem acids (and physiologically cleavable esters and pharmaceutically acceptable salts thereof) of the present invention (i.e. H.  Compounds of the general formula I, in which Y = H) have antibacterial activity and can also be used as intermediates (preferably in their carboxyl-protected form) for the preparation of the 2,6-disubstituted penems I by anion formation and reaction with an electrophile. 

 

   The active compounds of the present invention can be formulated as pharmaceutical mixtures which, in addition to the active component, contain a pharmaceutically acceptable carrier or diluent.  The compounds can be administered both orally and parenterally.  The pharmaceutical preparations can be in solid form such as capsules, tablets or dragees or in liquid form such as solutions, suspensions or emulsions.  In the treatment of bacterial infections in humans, the active compounds of the present invention can be administered orally or parenterally in a proportion of 5-200 mg / kg / day and preferably 5-20 mg / kg / day in divided doses, i.e. H.  three or four times a day. 

  The administration takes place in dose units, contain z. B.  125, 250 or 500 mg of the active component together with a suitable physiologically usable carrier or diluent. 



   In the following examples for the production of the starting products and end products of the present invention, all temperatures are given in degrees Celsius.  For the sake of simplicity, various abbreviations have been used which have the following meaning: CSI chlorosulfonyl isocyanate ether, diethyl ether (unless otherwise stated, Celite trademark by Johns
Manville Products
Corporation for
Diatomaceous earth PNB p-nitrobenzyl m. p. 

  Melting point LAH lithium aluminum n-BuLi n-butyllithium MIBK methyl isobutyl ketone Et C2H5 Tr-C (C6H5) 3 Me CH3 THF tetrahydrofuran Ph phenyl DMF dimethylbenzamethyltramethylhexamethylchloride Ac CH3CO Ms CH3SO2- DMAP 4-dimethylaminopyridine Py pyridine LDA lithium diisopropylamide
Example I
2 '- (2'-Diethylphosphono-1'-ethyl) -penem-3-carboxylic acid
EMI20. 1

A mixture of 11.2 g (50 mmol) of 1 and 10 ml of 5N NaOH was bathed for 15 minutes at room temperature with cooling on the ice and then stirred for 15 minutes at room temperature.  The mixture was extracted with ether and the extract was discarded. 

  The aqueous solution was acidified with 5N HC1 and extracted with CH2Cl2, after which 10.0 g (95%) of an oil 2 were obtained after drying and removal of the solvent, NMR 6 (CDCl3), 4.1 (4H, m), 1, 8-2.9 (4H, m) 1.2 (6H, t). 



   To a 2.26 g (10.76 mmol) 2 solution cooled on the ice bath, 2.74 g (1.88 ml, 21.5 mmol) of oxalyl chloride was added dropwise.  The mixture was left at room temperature for 6 hours and then concentrated to dryness.  The traces of (COC1) 2 were removed azeotropically with benzene to give 2.4 g (quantitative yield) of the crude 3. 
EMI20. 2nd




  1800; 1735 cm NMR â 4.3 (4H, m), 3.0-3.7 (2H, m) 2.0-3.0 (2H, m), 1.4 (6H, m).  The product was treated with H2S / TEA in a conventional manner to give 1.9 g (80%) of Oil 4 in an estimated purity of 80%.  NMR: 84.1 (4H, q), 2.7-3.5 (2H, m), 1.7-2.5 (2H, m) 1.33 (6H, t). 
EMI20. 3rd




   To 1.9 g (8.4 mmol) 4 were added 10 ml of an I M solution of NaHCO3 under nitrogen, followed by addition of 0.813 g (6.3 mmol) 5 in 3 ml of H2O.  The pH of the mixture was brought to 7-8 by adding NaHCO3.  After standing for 4 h, the mixture was extracted with CHCl3, whereupon, after drying and concentrating, 1.05 g (56.4% based on 5) of solid 6 of mp.  64-67 C were obtained.  NMR 8 7.7 (NH), 5.3 (1H, q), 4.2 (4H) 3.8 (1H q) 3.5 (1H, q), 2.63.2 (2H, m) , 1.7-2.4 (2H, m), 1.3 (6H).   
EMI21. 1




   A mixture of 260 mg (0.88 mmol) of 6 and 198 mg (0.88 mmol) of p-nitrobenzylglyoxylate was refluxed in 6 ml of benzene in a Dean-Stark apparatus for 16 h, after which 453 mg of a heavy one were removed after the benzene had been removed Oil 7 were obtained.  NMR 8 8.3 (2H, d), 7.6 (2H, d), 5.3-5.7 (4H), 4.9 (OH), 4.2 (4H, 3.55 (1H, g), 3.4 (1H, g), 2.5-3.2 (2H, m), 1.7-2.5 (2H, m), 1.3 (6H). 
EMI21. 2nd




   504 mg (0.88 mmol) of crude 7 were dissolved in 0.9 ml of an IM solution of pyridine in THF.  For this purpose, 0.9 ml of a 1M solution of SOCl2 in THF was added dropwise while cooling in an ice bath, and the mixture was stirred in the cold for 15 min and at room temperature for 40 min.  Then 10 ml of benzene was added and the solids were filtered off, after which the filtrate was concentrated in vacuo to give 463 mg (quantitative yield) of crude 8.  NMR 8 8.3 (2H, d), 7.6 (2H, d), 6.1 (1H, s), 5.7 (1H, m), 5.3 (2H, d), 4.2 (4H, 1.8-3.6 (6H, m), 1.3 (6H). 
EMI21. 3rd
  



   To a solution of 463 mg (0.88 mmol) of the crude 8 in 4 ml THF were added 236 mg (0.9 mmol) triphenylphosphine and 96 mg (0.9 mmol) 2,6-lutidine and the mixture was added at room temperature left to stand for 65 h. 



  Then it was filtered, the filtrate was concentrated and the remaining oil was chromatographed on a silica gel column with ethyl acetate-2% EtOH as eluent to give 203 mg (30.6%) of an oil 9 which crystallized on standing.  M.p.  126-128 "C.    
EMI22. 1




   A solution of 470 mg (0.635 mmol) 9 in 30 ml toluene was refluxed for 5 hours, after which 167 mg (56%) of 10 were obtained in the form of an oil after concentration and chromatography on silica gel-ethyl acetate.  IR: 1795, 1710 cm-l.     NMR Åa 8.3 (2H, d), 7.7 (2H, d), 5.7 (1H, m), 5.38 (2H, d), 4.1 (4H), 1.8-3 , 8 (6H), 1.35 (6H). 
EMI22. 2nd




   To a solution of 59 mg (0.126 mmol) of 10 in 3 ml THF and 1 ml ether was added 9 mg (0.107 mmol) NaHCO3, 1 ml water and 60 mg 10% Pd / Celite and the mixture was stirred at 206.78 kPa hydrogenated for 2 h.  The product was isolated in a conventional manner to give 36 mg (86%) of 11 as an oil.  IR (CH Cl3) 1798, 1730, 1710 cm 1.     NMR 8 9.0 (CO2H), 5.6 (1H, m), 4.4 (4H), 3.6 (1H, q), 3.15 (1H, qY, 1.7-3.0 ( 4H, m), 1.3 (6H). 



   Example 2
6-acetoxymethyl-2-methylpenem-3-carboxylic acid
EMI22. 3rd

Production of 1,3-diacetoxypropene 1 (see  L. W.  McTeer US 2,866,813, CA 53 9063) CH2 = CH-CHO
EMI22. 4th
 AcOCH2CH = CH-OAc +
Cat. 



  CH2 = CH-CH (OAc) 2
Preparation of the catalyst: A solution of 6.2 g of boric acid and 12.6 g of oxalic acid in 44 ml of water was concentrated to dry, to give the solid catalyst. 



   Procedure: 140 g (2.5 mol) acrolein were mixed with 256 g (2.5 mol) acetic anhydride at r. t.  mixed.  A portion of 5 ml of this mixture was placed in a 1 liter Erlenmeyer flask and treated with a few drops of catalyst made by dissolving 1.0 g of the solid catalyst in 5 ml of acetic anhydride.  A vigorous exothermic reaction started and the temperature was maintained at 40-60 by cooling with an ice bath, after which the remainder of the acrolein-acetic anhydride mixture was added to the flask in 10 15 ml portions, each followed by a few drops of catalyst.  The resulting mixture was distilled to remove the unreacted starting product, followed by 1,1-diacetoxy-propene.  

  51.6 g (13.06%) of the desired product were obtained, b. p. 



  54-57 "C / 1.2mm.  NMR 8 (ppm, CDCl3) 7.4 (H, d, J = 12), 5.3-5.8 (H, m), 4.5 (2H, d, J = 7), 2.16 ( 3H, s), 2.05 (3H, s). IR: vC = O 1770.1750, vC = O 1680.   
EMI23. 1




  Method:
16.92 g (0.12 mol) of CSI were added dropwise to 18.96 g (0.12 mol) of cooled 1 (ice salt bath, -15 "C.). 



  The pale yellow mixture was held at 5 "for 5 hours, the color turning deep yellow.  The mixture was then dissolved in 20 ml of ethyl acetate, cooled to -30 ° C. and added dropwise to a cooled mixture (ice salt bath) of 3.4 ml of water, 17.0 g of ice, 0.3 g of NaHCO3 and 3.4 g of Na2SO3.  After the addition, the resulting mixture was stirred vigorously for 20 min and the pH was kept at 7-8 by further addition of NaHCO3.  The phases were separated, the aqueous phase was extracted with 2 × 50 ml of ethyl acetate and the combined organic phases were dried over Na2 SO4: NaHCO3, 1: 1.  It was then filtered and concentrated in vacuo to give 17.4 g of an oil. 



  This was distilled in a high vacuum (0.01-0.05 mm) on a hot air bath (temperature 55-85 ") to remove 1.  The undistilled pale brown oil was cooled, taken up in ether and filtered through Celite activated carbon, whereupon 5.28 g (22%) of a 4: 1 mixture of 2a and 2b were obtained in the form of a colorless oil.  NMR: 7.25 (H, NH), 6.0 (0.25H, d, J = 4.3), 5.8 (0.75H, d, J = 15), 4.5 (0.5H , d, J = 6.5), 4.4 (1.5H, d, J = 4.5), 3.8 (0.25H, m), 3.5 (0.75H, m), 2 , 13 (3H, s), 2.1 (3H, s). IR: v ,,, 1780.1740.    
EMI23. 2nd




  Method:
Sodium thioacetate was prepared by adding 2.22 ml (2.363 g) of thioacetic acid to a solution of 31.0 ml of 1M NaHCO3 under nitrogen.  This was then added to a cooled solution of 5.2 g (25.9 mmol) of 2 in 20 ml of water and stirred for 4 hours at room temperature.  Then 20 ml of acetone were added and the mixture was concentrated in vacuo and extracted with methylene chloride.  The extract was dried and concentrated to give 5.6 g of a mixture of isomers (83.14%) of 3a and 3b.  The NMR of the crude oil showed the presence of one trans and two cis compounds in the mixture. 

  A 550 mg sample was chromatographed on silica gel (30 g, 10% H2O) and eluted with benzene ether methanol to give 200 mg of a mixture of 3a and 3b in a 7: 1 ratio, followed by 150 mg of an unknown cis -Connection (a 5.5, d, J = 4.3) to which structure 3c has been assigned.  NMR: 6.78 (H, NH), 5.52 (0.17H, d, J = 4.3), 5.18 (0.83H, d, J = 1.5), 4.37 (2H , d, J = 4.5), 3.45 (H, m), 2.35 (3H, s), 2.05 (3H, s).  IR: vC = O 1765, 1740, 1600 cm- '.    
EMI23. 3rd
  



  Method:
A mixture of 2.17 g (10 mmol) of crude 3 and 2.5 g (11 mmol) of p-nitrobenzylglyoxylate in 200 ml of benzene was refluxed under a Dean-Stark water collector for 20 h, followed by concentration in vacuo, whereby 3.4 g of the crude 4 were obtained in the form of an oil.  This oil was used without further processing.    



     NMR: # 7.5-8.5 (4H), 5.2-5.8 (4H), 3.4-5.1 (4H), 2-2.4 (6H). 



     IR: # c = 0 1665, 1740, 1730, 1700.    
EMI24. 1




  Method:
To a chilled solution of 3.3 g (7.75 mmol) of the crude 5 and 0.67 g (8.5 mmol) of pyridine in 20 ml of benzene was added dropwise 1.01 g (8.5 mmol) of thionyl chloride in 10 ml Benzene was added and the mixture was stirred at said temperature for 15 minutes and at room temperature for 15 minutes.  The benzene solution was decanted off and the remaining solid was washed three times with 15 ml of benzene.  The combined benzene solutions were concentrated to give 1.90 g of the crude 5 (55%).  NMR: # 7.5-8.5 (4H), 6.12 and 6.2 (1H), 5.66 (1H, m), 5.4 (2H, d, J. 6), 4.3-4.7 (2H, m), 3.63 (H, m) 2.4 (3H, d), 2.1 (3H, s).  IR: # c = 0 1765, 1740, 1730, 1700.    
EMI24. 2nd




  Method:
A mixture of 1.90 g (4.27 mmol) of the crude 5, 1.572 g (6 mmol) triphenylphosphine and 0.642 g (6 mmol) 2,6-lutidine in 20 ml dioxane was heated to 55 during 18 h. 



  After cooling, filtering and concentrating, 3.8 g of a crude dark oil were obtained.  This was chromatographed on silica gel to give 1.2 g (42%) of 6. 
EMI24. 3rd




  Method:
A solution of 1.20 g (1.79 mmol) of the crude 6 in 15 ml of toluene was refluxed for 5 hours.  After cooling and concentrating, an oil was obtained which, after chromatography on SiO2 and 30 g and elution with benzene, gave 0.4 g (57%) of 7. 



   Analysis for Cl7Hl6N207S Calculated: C, 52.04, H, 4.11, N, 7.14 Found: C 51.77, H, 4.08 N, 7.30. 



   The cis and trans isomers were separated by careful chromatography on 60 g of silica gel and elution with benzene.  Cis-isomer: # (ppm, CDCl3): 7.5-8.5 (4H, aromatic), 5.67 (1H, d, J = 5, H-5), 5.28 (2H, AB quartet, Benzyl), 4.33 (2H, d, AcOC112), 4.20 (1H, dt, H-6), 2.31 (3H, s. 

  CH3), 2.0 (3H, s, CH3CO).    # c = 0 1770, 1740, 1730 cm-l.     Trans isomer: 8 (ppm, CDCl3): 7.5-8.5 (4H, aromatic), 5.53 (1H, d, J = 2, H-5), 5.30 (2H, AB-quartet) , Benzyl), 4.32 (2H, d, AcOCH2), 4.27 (1H, dt, J = 5, J-2, H-6), 2.31 (3H, s, CH3), 2.0 (3H, s, CH3CO).    # c = 0 1770, 1740, 1730 cm-1. 
EMI25. 1




  Method:
To a solution of 119 mg (0.3 mmol) of trans-7 in 15 ml of ethyl acetate and 7 ml of water were added 25.2 mg (0.3 mmol) of NaHCO3 and 110 mg of Pd / C and the hydrogenation was carried out for 4.5 h at 206.78 kPa.  The mixture was filtered, the phases were separated, the aqueous phase washed with ether and lyophilized to give 40 mg of solid 8 (48%).    # c = 0 1765, 1740, 1600 cm-1.    # (ppm, D2O): 5.52 (1H, H-5), 4.85 (2H, AcOCH2), 4.0 (1H, H-6), 2.65 (3H, CH3), 2.40 (3H, CH3CO). 
EMI25. 2nd


 

  Method:
Cold 1N HCl was added to a solution of 100 mg of crude trans-8 in 2 ml of cold water and then extracted with CHC13.  The extract was dried over Na2SO4 and concentrated to give 30 mg of a pale yellow solid.  M.p.  111-113 with decomposing.  IR: # c = 0 1780, 1750, 1680.     (Neat).  IR: (KBr): vC = O 1775 (Strong), 1745, 1670. 



   Treatment of the cis-paranitrobenzyl-6-acetoxymethyl-2-methyl-penem-3-carboxylate by the above method gave the cis-sodium salt and the free acid. 



   Example 3
Potassium 6- (2'-hydroxyisopropyl) -2-methylpenem-3-carboxylate (anion method)
EMI25. 3rd
  
A solution of 116 mg (0.627 mmol) of acid 1 in 4 ml of THF freshly distilled over LAH was added dropwise at −78 ° C. to 2 ml of a solution of LDA in THF (from diisopropylamine, 70.7 mg, 98 l, .0.699 mmol, and n-BuLi 1 6M, 0.440 ml, 0.704 mmol, stirred at -78 C for 30 min).  The mixture was stirred for 5 min, followed by sequential addition of 70.7 mg (98 L, 0.699 mmol) of diisopropylamine and 0.440 ml, (0.704 mmol) of 1.6M n-BuLi at -78 C.     The mixture was then stirred at -78 ° C. for 10 min and 5 ml of acetone were added quickly. 

  The mixture was allowed to react with the acetone for 10 minutes, then acidified to pH 2 with 1% HC1, diluted with 40 ml of ethyl acetate and washed with 3 x 20 ml of brine.  After drying over Na2SO4 and removal of the solvent, the crude residue 3a was obtained, which was taken up in CH2Cl2 (crude yield 90 mg).  The crude acid was dissolved in cold MIBK (2 ml) and treated dropwise with potassium 2-ethylhexanoate.  Two samples of the potassium salt (36.4 mg, 26%) were obtained as a cis and trans mixture, with predominance of the trans isomer. 



     8 (ppm, DMSOd6) 5.60 (1H, d, J5-6cis = 4, H-5), 5.55 (1H, d, J5-6 trans = 2, 11-5), 3.93 (1H d, J65 ds = 4, H-6), 3.62 (1H, d, J6-5 trans = 2, H-6), 3.50 (b. s. , OH), 2.34 (3H, s, CH3), 1.47, 1.40 (6H, 2s, 2CH3), 1.35, 1.32 (6H, 2s, 2CH3).    # c = 0 (Nujol Mull) 1765, 1582, vou 3600-3100 UV (EtOH) #max 257 (8 = 3920), 300 (± = 4020). 



   Example 4
Potassium 6-hydroxybenzyl-2-methylpenem-3-carboxylate (anion method)
EMI26. 1

A solution of 100 mg (0.540 mmol) of acid 1 in 6 ml of anhydrous T11F (distilled over LAH) was added dropwise to a cold (-78) solution of LDA in 2 ml of THF made from 84 l (60.6 mg, 0.599 mmol) diisopropylamine and 0.380 ml (0.608 mmol) 1.6 M n-BuLi.  The mixture was stirred for 5 minutes, after which 84 liters (60.6 mg, 0.599 mmol) of diisopropylamine and 0.380 ml (0.608 mmol) of 1.6 M n-BuLi were added in succession.  The mixture was then stirred at -78 for 7 min and treated rapidly with 300 l of benzaldehyde. 

  The mixture was allowed to react at -78 for 20 min, brought to pH 2 with 1% HCl, diluted with ethyl acetate (40 ml) and with 1: 1 H2O saline (3> <x 20 20 ml) and once 20 ml of saline solution. After drying over Na2SO4, removal of the solvent, a residue was obtained, which was dissolved in 2 ml of MIBK.

  It was then treated dropwise with potassium 2-ethylhexanoate to give 35 mg of 4b in a 20% yield as a diastereomeric mixture. a: (ppm, DMSOd6) 7.95 (5H, s, H-aromatic), 5.57 (d, J5-6 trans = 1.5, H-5), 5.45 (d, J5-6 trans = 1.5, H-5) 5.35 (d, J5-6 cis = 4, H-5), 5.0 (m, CH hydroxybenzyl), 4.25 (dd, J65 cis = 4, J6- CH hydroxybenzyl = 10, H-6), 3.90 (m, H-6), 3.65 (bs, OH), 2.35 (3H, 2s, CH3) ## c = 0 (Nujolmull) 1760, 1590, #OH 3600-3100. UV (H2O) #max 252 (# = 5,100), 296 (# = 3,300).



   Example 5 Potassium 6-thiomethyl-2-methylpenem-3-carboxylate (anion method)
EMI26.2
  
A solution of 100 mg (0.540 mmol) of acid 1 in 5 ml of anhydrous THF (distilled over LAH) was added dropwise to a cold solution of LDA in 2 ml of THF, made from 84 liters (60.6 mg, 0.599 mmol) of diisopropylamine and 0.380 ml (0.608 mmol) of 1.6 M n-butyllithium. The mixture was stirred for 7-8 minutes, followed by addition of 84 liters (60.6 mg, 0.599 mmol) of diisopropylamine and 0.380 ml (0.608 mmol) of 1.6 M n-butyllithium. The mixture was then stirred at -78 'for 7 min and treated rapidly with 300 l of excess methylthiomethylsulfonate.

  The mixture was allowed to react at -78 for 5 min, then brought to pH 2 with 1% HCl, diluted with 40 ml of ethyl acetate and washed with 1: 1 H2O saline (3 x 20 ml) and 20 ml of brine.



   The organic solution was dried over Na2SO4, whereupon a residue was obtained after removal of the solvent, which was dissolved in 2 ml of MIBK (cold). This cold solution was treated dropwise with potassium 2-ethylhexanoate. 40 mg of 4c were obtained in a yield of 28% as an 8: 3 mixture of the cis and trans isomers (decomp.) 115-120 C. # (ppm, DMSOd6) 5.85 (1H, d, J5-6 cis = 4, H-5), 5.57 (1H, d, J5-6 trans = 1.5. H-5), 4.87 (1H, d, J6-5 cis = 4, H-6), 4.72 (1H, d, J65 trans = 1.5, H-6), 3.42 (bs, OH), 2.37 (s, SCH3), 2.33 (s, CH3), 2.25 (s, SCH3). # c = 0 (Nujolmull) 1770, 1600, UV (H2O) Ämax 252 (± = 4200), 297 (± = 3700).



  Manufacturing 6
1- (p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone
EMI27.1

90 ml of a methanol suspension of 13.8 g (0.05 mmol) of triphenylmethyl mercaptan were degassed in a nitrogen stream for 0.5 h. The mixture was cooled to 0 and 2.4 g (0.05 mol), 50% oil dispersion) of sodium hydride were added in portions. The resulting solution was stirred for 5 minutes and 7.7 g (0.059 mol) of 4-acetoxyazetidinone in 55 ml of water was added rapidly. The 4-triphenylmethylmercaptoazetidinone (2) was precipitated immediately. The mixture was then stirred at room temperature for 4 hours, after which the solid was filtered off and then washed with water and dissolved in methylene chloride.

  The methylene chloride solution was washed with dilute HCl, water and an aqueous solution of sodium bicarbonate and again with water and brine and dried over MgSO4 (89.8, mp: 146.5-147.5 C)
Analysis for Q2H19NOS Calculated: C, 76.49, H, 5.54, N, 4.05, S, 9.28 Found: C, 7.54, H, 5.60, N, 4.00, S, 9.36.



     # (ppm, CDCl3) 7.60-7.10 (15H, m, H-trityl), 4.62 (1H, bs, NH), 4.40 (1H, dd, J4-3 trans = 3.0 , J4-3 cis = 5, H-4), 3.24 (1H, ddd, Jgem = 15, J3-4 cis = 5, J3 NH = 1.8, H-3) 2.81 (1H, ddd , Jgem = 15, J3-4 trans = 3.0, J3 NH = 1.2, H-3) # c = 0 (CHCl3) 1760, #NH 3340.
EMI27.2


 

   4.54 g (0.02 mol) of p-nitrobenzylglyoxylate hydrate and 6.90 g (0.02 mol) of azetidinone 2 were refluxed in benzene over a Dean-Stark condenser filled with 3 molecular sieve for 24 h. Two 454 mg (2 mmol) glyoxylates were added with a reflux period of 18 hours after each addition. The mixture was diluted with ether, washed with 5% aqueous HCl, water, aqueous 5% NaHCO3, water and brine. After drying over MgSO4, 12 g was obtained in quantitative yield. A small fraction of the epimeric mixture was chromatographed on a silica gel plate (CH2Cl2 ether 6: 4).



   Isomer A: Rf = 0.87, m.p. = 170.5-171.5.



     8 (ppm, CDCl3) 8.07 (2H, d, J = 9, Hm aromatic), 7.45 (part of d, Ho aromatic), 7.40-7.00 (15H, m, trityl), 5 , 25 (2H, s, CH2-PNB), 4.75 (1H, s, HCO), 4.37 (1H, dd, J3-4 trans = 3, J3-4 cis = 4, H-3), 2.83 (1H, dd, Jgem = 16, J4-3 cis = 4, H-4), 2.10 (1H, dd, Jgem = 16, J4-3 trans = 3, H-4), 1, 42 (bs, OH) ## c = 0 (CHCl3) 1770, 1760 (shoulder), VNO2 1525, voH 3475. Isomer B:

  Rf = 0.75, m.p. = 152-153. 8 (ppm), CDCl3), 8.13 (2H, d, J = 9, Hm aromatic), 7.47 (2H, d, J = 9, Ho aromatic), 7.40-7.00 (15H, m, trityl), 5.30 (3H, s, CH2-PNB, HCO), 4.45 (1H, t, J = 3.5, H-4), 2.90-2.70 (2H, AB Part of ABX, H-4), 1.55 (bs, OH). vC = O (CHCl3) 1767, 1755 (shoulder), VNO2 1525, voH 3500.
EMI28.1




   150 ml of a cold (- 15 ') solution of 12 g azetidinone 3 (21.7 mmol) in THF (dried over molecular sieves) was treated with 1.9 g (24.1 mmol, 1.94 ml) pyridine and dropwise with 2 , 86 g (24 mmol, 1.88 ml) of thionyl chloride were treated under a nitrogen atmosphere. The mixture was stirred at -15 for 45 min, after which the precipitate formed was filtered off and washed with benzene.

  After removal of the solvent, a residue was obtained, which was taken up in benzene and treated with 11.7 g of activated carbon (94%, crystallized from chloroform). 8 (ppm, CDCl3) 8.17 (2H, d, J = 8, Hm aromatic), 7.67-7.00 (17H, m, Ho aromatic, Tr-H), 5.80 (s, HC- Cl), 5.37, 5.33 (2s, HC-Cl, CH2-PNB), 4.81 (1H, m, H-4), 3.27-2.40 (2H, m, H-3 ) vC = O (KBr film) 1785, 1770 # NO2 1525.
EMI28.2




   A solution of 11.6 g (20.2 mmol) of chloroazetidinone 4 in 100 ml of THF (distilled over LAH) was mixed with 7.86 g (30.0 mmol) of triphenylphosphine and 2.36 g (2.56 ml, 22, 0 mmol) 2,6-lutidine treated. The mixture was refluxed for 72 h, after which the residue was filtered off and washed with ether. The organic solution was washed with 2% aqueous HCl and 5% aqueous bicarbonate solution and dried over MgSO4. After removing the solvent, a residue was obtained which was purified over 200 g of silica gel. The desired phosphorane was eluted with 30.40 and 50% ether benzene (11.4 g, 70.4%, mp 201-202).



   Analysis for C49H40N2O5SP Calculated: C, 73.57, 11, 5.04, N, 3.50, S, 4.01 Found: C, 73.58, H, 4.91, N, 3.44, S, 3.87.



     vC = O (CHC13) 1740, v phosphorane (1620, 1610), VNo2 1525.
EMI28.3




   1.6 g (2 mmol) of 4-tritylmercaptoazetidinone 5 were dissolved in 20 ml of CH2Cl2 and the solvent was cooled to 55-60. The phosphorane 5 was dissolved in 32 ml of preheated methanol at 55-60. Immediately after preparing this methanolic solution of 6, this was made with a preheated (55-60) mixture of methanolic 0.15 M silver nitrate solution (16 ml, 1.2 Aq.) And 174 mg (178 l, 2.2 mm 01, 1 , 1 eq.) Treated with pyridine. The heating bath was then removed, the mixture was stirred at room temperature for 2 h and then at 0 C for 1 h.

  The silver mercaptide 6 was filtered off, washed twice with cold methanol (0) and three times with ether (1.12 g, 84.5%, mp .: 130-135, dec.). vC = O (CHC13) 1795, 1725 (shoulder, v phosphorane (1620, 1605), # NO2 1530.



  Manufacturing 7
1 - (p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone
EMI29.1

A solution of 1.796 g (3.0 mmol) of phosphorane 7 in 3 ml of chloroform was diluted with 90 ml of methanol, cooled to 0 C under nitrogen and successively with 0.51 g (3.0 mmol) of silver nitrate and 0.33 g ( 2.4 mmol) treated with potassium carbonate. The reaction mixture (protected from light) was stirred at 0 C for 15 min, then the cooling bath was removed and stirring was continued for 3 h. The reaction mixture was cooled to -10 C, stirred for 1 h and filtered, and the silver mercaptide was washed successively with cold methanol and ether; 1.91 g mp 138-145 "C dec., 96%.

  IR (Nujol) cm- ': 1748, 1620, and 1605. An analytical sample was obtained by preparative TLC (ethyl acetate); M.p .: 140-5 C, dec. Calculated for C30H24N2OsSPAg: C, 54.31, H, 3.65, N, 4.22, S, 4.83. Found: C, 54, 11, H, 3.48, N, 3.92, S, 4.62.



  Preparation 8 1 - (p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone
A. Use of aniline as a base
EMI29.2

A solution of 1.8 g (3.0 mmol) of phosphorane 7 in 4 ml of chloroform was diluted with 90 ml of methanol, cooled to -15 C under nitrogen and successively with 0.56 g (3.3 mmol) of silver nitrate and 1 5 ml (16.5 mmol) of aniline treated. The reaction mixture (protected from light) was stirred at -15 C for 0.5 h and then the cooling bath was removed and stirring continued for 24 h.



  The reaction mixture was cooled to -10 C and stirred for 1 h and then filtered, the silver mercaptide was washed successively with cold methanol and ether; 1.55 g, m.p. 114115 C, dec., 77.9%. IR (Nujol) cm identical to the compound from Example 7.



   Silver 1 - (paranitrobenzyl-2'-triphenylphosphoranylidene 2'-acetate) -2-azetidinone-4-thiolate.



   B. Use of 4-dimethylaminopyridine (DMAP) as base
EMI29.3

A solution of 17.96 g (30 mmol) of the above S-acetylphosphorane in methanol and dichloromethane (1: 2, 450 ml) was flushed with nitrogen for 5-10 min, cooled to 5 C and successively with 5.35 g (31.5 mmol) silver nitrate and 3.85 g (31.5 mmol) 4-dimethylaminopyridine. The cooling bath was removed and the solution was vigorously refluxed for 2 hours and then stirred at room temperature for 1 hour. The colored reaction mixture was then treated with activated carbon, filtered and evaporated. The residue was redissolved in a minimal portion of dichloromethane and added dropwise to 300 ml of cold methanol with stirring.

  The precipitated silver salt was filtered off, washed with ether and dried (18.1 g (91%), IR (CHCl3) #max: 1745 (C = O from the ss-lactam) and 1607 cm-1 (C = O from the ester) .



   Silver 1- (paranitrobenzyl-2'-triphenylphosphoranylidene 2 "acetate) -2
C. Use of diazabicycloundecene (DBU) as a base
EMI30.1
    36.0 g (0.060 mol) of the above-mentioned S-acetylphosphorane were dissolved in 120 ml of methylene chloride. The solvent was evaporated to give an oil. This resulting oil was dissolved in 240 ml of warm methanol (35 C) and quickly treated with 420 ml of a methanolic solution of 10.68 g (0.0628 mol) of silver nitrate. The resulting solution (or suspension) was stirred at room temperature for 5 min, cooled in an ice bath and a solution of 8.96 ml (0.060 mol) of DBU in 20 ml of methanol was added for 5 min.

  The mixture was stirred for 5 min, the solid was filtered off, washed with cold methanol (0 ° C.) and ether and dried in vacuo; 37.0 g (93%), IR (Nujol Naill) vmax (c = o) and 1600 cm-1 (phosphorane)
D. Use of pyrrolidine as base
Silver 1 - (paranitrobenzyl-2'-triphenylphosphoranylidene 2 "acetate) -2-azetidinone-4-thiolate
EMI30.2

To a cold (0 C) solution of 4-acetylthio-1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (0.60 g, 1.0 mmol) in CH2Cl2 (2 ml) 4 ml of MeOH, a solution of AgNO3 in MeOH (0.14N, 7.86 ml, 1.1 mmol) and a solution of pyrrolidine (0.92 ml, 1.1 mmol) in 2 ml of MeOH were added. The cooling bath was removed and the reaction mixture was stirred for 1.75 h, cooled to -10 ° C, stirred for 0.25 h and filtered.

  The solid was washed with cold MeOH and dried in vacuo; 0.548 g, mp 115 C, 82.4%. IR (Nujol) #max: 1755 (C = O) and 1600 cm-1 (aromatic) production 9
Mercury (II) - (2'-triphenylphosphoranylidene-2'-acetate) 2-azetidinone-4-thiolate
EMI30.3

A solution of 2.4 g (3 mmol) I in 15 ml dichloromethane was cooled to 5 C and treated with a solution of 0.525 g (1.65 mmol) mercury acetate in 15 ml methanol. After stirring at 5 C for 2 h, the solvent was evaporated and the residue redissolved in dichloromethane and washed with cold water.



  The organic solution was evaporated after drying over MgSO4 and treatment with activated carbon, leaving a foam which crystallized after shaking with ether. Yield: 1.73 g (91%) mp 123-127 C, IR (CHCI3) 1745 cm- '(vC = O, B-lactam) 1608 cm-l (phenyl)
Example 10
2-methylpenem-3-p-nitrobenzyl carboxylate (from the mercaptide intermediate)
EMI31.1

A solution of 262 mg (0.2 mmol) II, 35 mg (0.44 mmol) acetyl chloride and 2 drops of pyridine in 10 ml dichloromethane was stirred at 5 C for 1 h. The excreted mercury chloride was then filtered off and the filtrate was washed successively with cold dilute hydrochloric acid, sodium hydroxide and brine.

  The organic solution was treated with hydrogen sulfide at 5 ° C. for 2 minutes and then stirred at the same temperature for a further 10 minutes in order to precipitate out the last traces of mercury salts. Activated carbon was added to the black mixture and then filtered through Celite. After the clear, clear filtrate had been evaporated, 193 mg (80.7%) III were obtained in the form of a foam. IR (CHCI3) 1755 (vC = O p-lactam) 1692 (vscoca3 1620 (phenyl).
EMI31.2




   75 mg (0.126 mmol) of phosphorane III in 10 ml of toluene were refluxed under nitrogen for 2.5 h. After evaporating off the solvent and working up the residue, 25 mg of a crystalline derivative (63%) were obtained, the physical and spectral data of which corresponded to the desired product.



   Product IV can be subjected to catalytic hydrogenation (30% Pd on Celite) to produce the corresponding 3-carboxylic acid product.



   Example 11
2-aminomethylpenem-3-carboxylic acid (from the mercaptide intermediate)
EMI31.3

A solution of 1.25 g (1.99 mmol) of silver mercaptide 1 in 15 ml of dichloromethane was cooled to 0 C under a nitrogen atmosphere and treated dropwise with a 2M solution of azidoacetylchlovide in dichloromethane (1.13 ml, 2.26 mmol). The reaction mixture was stirred at 0 C for 1 h, the cooling bath was removed and stirring was continued for 5 h. The reaction mixture was then filtered through Celite and the solid obtained was washed with 35 ml dichloromethane.

  The filtrate and the washing solutions were combined, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to give an orange syrup which was purified by column chromatography (3 g silica gel 60, eluate; ether-2% ethyl acetate (200 ml) , Ether-6% ethyl acetate (200 ml) and ether-20% ethyl acetate (500 ml), fraction size: 10 ml). The pooling and concentration of fractions 49-80 resulted in a yellow powder; 0.73 g, mp 61-70, 60.8%.
EMI32.1




   A solution of 0.593 g (0.93 mmol) of phosphorane 2 in 20 ml of toluene was heated at 105 C for 1 h, cooled to 23 C and evaporated to a semi-crystalline compound which was purified by column chromatography (12 g of silica gel 60, eluate: benzene (100 ml), benzene-2% ether (100 ml) and benzene-4% ether; fraction size: 10 ml). The pooled and evaporated fractions 18-26 gave a yellow syrup which crystallized on standing; 0.18 g, m.p .: 127-128 C, 53.7%.

  NMR (CDCl3), 6 8.22 (2H, d, JHo, Hm = 8.8 Hz, Ho from p-nitrobenzyl), 7.60 (2H, d, JHm, Ho = 8.8 Hz, Hm from p -Nitrobenzyl), 5.71 (1H, dd, J5-6 cis = 3.6 Hz, J5.6 trans = 2.1 Hz, H-5), 5.33 (2H, center of ABq, yes, b = 14.0Hz, CH2 of p-nitrobenzyl), 4.58 (2H, center of ABq, yes, b = 15.0Hz, CH2 on C-2), 3.88 (1H, dd, J6.5 cis = 3.6 Hz, J gem = 16.5 Hz, H-6 cis) and 3.55 (1H, dd, J6.5 trans = 2.1 Hz, Jgem = 16.5 Hz, H-6 trans). IR (nujol) cm-1; 2115 and 2090 (N3), 1780 (c = 0 from ss-lactam) and 1685 (c = o from p-nitrobenzyl ester).



   An analytical sample was prepared by preparative T.L.C.



  receive; 127-128 C, calculated for C14H11N5O5S: C, 46.54, H, 3.07, N, 19.37, S, 8.87, found: C, 46.43, H, 3.08, N , 19.37, S, 8.90.
EMI32.2




   6 ml of ether, 6 ml of water and 0.18 g of 30% palladium on Celite were added in succession to a solution of 0.18 g (0.5 mmol) of Penem 3 in 6 ml of tetrahydrofuran. The reaction mixture was hydrogenated at 206.78 kPa and 23 C for 2.5 h and filtered through Celite, the filter was washed with water and filtrates and washing solutions were combined, washed with ether-THF and lyophilized, whereby 30 mg (30%) of Compound 4 were obtained. (The water and ether insoluble compound was dissolved in chloroform and the organic solution was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 77 mg (42.8%) of the starting product 3).

  NMR (DMSO d-6) 6: 5.7 (dd, J5 6 cis = 3.5 Hz, J5-6 trans = 1.5 Hz, H-5). IR (Nujol) cm- ': 1775 (c = o from ss-lactam) and 1615, 1585. UV.



     # H2O / max m: (# = 2320) and 307 (# = 2685).



   Product 4 was obtained from intermediate 3 in the following manner:
EMI32.3

To a solution of 2.4 g (6.89 mmol) of Penem 3 in tetrahydrofuran-ether-water mixture (1: 1: 1, 165 ml) was added 4.8 g of 30% palladium on diatomaceous earth. The reaction mixture was hydrogenated at 45 psi and 23 C for 2.5 h and filtered through Celite. The filtrate and washings were combined, washed twice with ether, centrifuged and filtered several times to give a clear solution which was lyophilized; 0.622 g, 45%. Crystallization of the compound was induced by the addition of 0.8 ml of water, the suspension was centrifuged and the water was removed leaving an orange solid.

  This solid was washed twice with water and after drying a pale yellow solid was obtained: 0.273 mg, 19.8% UV # H2O / max: 307 (# = 4318) and 257 (e = 2650). 1.2 g (50%) of the crude starting product were obtained. 50 mg of the compound were purified by column chromatography (Sephadex G10, column size: 1.6 x 100 cm, flow rate: 10 ml / h, eluent: distilled water, fraction volume: 1.5 ml, detector: refractive index), UV # H2O / max : 307 (# = 3597) and 255 (# = 2424).



   The stability of the compound in aqueous solution was determined as follows:
UV: 6 h 307 (# = 3545) and 255 (# = 2773) 21 h 307 (# = 3457) and 255 (# = 2411)
UV: 28 h 307 (8 = 3337) and 254 (8 = 2398)
46 h 307 (± = 3259) and 254 (e = 2398) 70 h 307 (# = 3076) 94 h 307 (# = 2842) 170 h 307 (± = 1900)
A sample of compound 4 was kept at 23 C for 3 days and then the UV spectrum was recorded
H20 men: UV X: 307 (± = 3055) and 255 (± = 2008).



   Max
Compound 4 was converted to two further 2-penem derivatives as described below.
EMI33.1




   A suspension of 50 mg (0.25 mmol) of Compound 4 in 0.5 ml of distilled water was treated with an equivalent (21 mg) of sodium bicarbonate, followed by the addition of 21.8 mg (0.024 ml) of ethyl acetimidate. The reaction mixture was stirred at 23 C for 20 min and lyophilized to give 52 mg of a yellow solid. NMR (D20) 6: 5.7 (m, H-5) and 2.23 (b.s., CH3 from amidine). IR (KBr) cm-1: 1772 (c = o from f3 lactam). W # D2O / max m: 305 (# = 3116) and 253 (# = 2525).

  Compound 5 was placed on a column (Sephadex G10, column size: 1.6 x 100 cm-1, eluent: H2O, detector: IR, fraction size: 1.6 ml) and lyophilization of the corresponding fractions gave 23 mg 45% of a pale yellow Powder.



     UV # H2O / max m: 303 (# = 2960) and 248 (# = 2885).
EMI33.2




   A suspension of 50 mg (0.25 mmol) of compound 4 in 0.5 ml of distilled water was treated with 21 mg (0.25 mmol) of sodium bicarbonate and stirred for 1.5 min, after which a mixture of 126 mg (1, 5 mmol) sodium bicarbonate and 164 mg (1.5 mmol) ethyl formimidate hydrochloride was added. The reaction mixture was stirred at 23 C for 10 min and lyophilized, whereby an orange colored powder was obtained.



     UV # H2O / max m #: 304 (# = 2300).



   Example 12 Sodium 2-hydroxyaminopropylpenem-3-carboxylate
EMI34.1

21.6 g (0.134 mol) of ester 1 were added to 320 ml of a cold 5% aqueous solution of sodium hydroxide. The resulting mixture was stirred at room temperature for 2 h and then concentrated to 250 ml and acidified with concentrated HCl. The mixture was then extracted four times with 200 ml of ethyl acetate each time and the organic extracts were dried over sodium sulfate. After concentrating on the rotary evaporator, an oil was obtained. Yield 13.2 g (75%).
EMI34.2




   A solution of 13.2 g (0.1 mol) of acid 2 in 25 ml of SOCl2 was stirred at 30 C for 2 h. After evaporation of the thionyl chloride, the residue was distilled in vacuo T = 7678 C (P = 0.2 mm Hg). Yield 8.8 g (58.3%) as a colorless liquid: NMR (CDCl3) 6 ppm 2.40 (2H, m, ss-CH2), 3.15 (2H, t, α-CH2), 4, 50 (2H, t, γ-CH2), IR (neat): 1550 cm-1 (# NO2), 1790 cm-1 (# C = O, acid chloride).
EMI34.3




   A solution of 19.46 g (0.128 mol) 3 in 200 ml methylene chloride was quickly added to a cold (0-10) stirred solution of 36 ml (0.256 mol) triethylamine in 500 ml methylene chloride, which was saturated with H2S at 0-5 was.



  The mixture was stirred at -10 C for 1 h and then a stream of nitrogen was bubbled through the solution to eliminate excess 1125. The mixture was washed with 10% HCl, the organic extract was approx.



  150 ml concentrated and mixed with 10.9 g sodium bicarbonate and 500 ml water. The pH was brought to about 7.5 with NaHCO3 or HCl. The resulting mixture was cooled to 0 ° C. and 16.8 g (0.13 mol) of 4-acetoxy-2-azetidinone in 20 ml of water were added with vigorous stirring. After 4 h the mixture was extracted with ethyl acetate, the extracts were washed with 10% HCl, saturated NaHCO3, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2; eluent: ether, then ether-ethyl acetate 5%) to give an oil which crystallized in ethyl acetate-hexane, giving 4 (3.5 g, 12.5%) as a white powder received.
EMI35.1




   A mixture of 1.09 g (5 mmol) of azetidinone 4 and 1.2 g (5.25 mmol) of p-nitrobenzyl glyoxylate hydrate in 100 ml of benzene was heated to reflux temperature in the Dean-Stark apparatus using 4 -Molecular sieves and during 18 h. After evaporation of the solvent, the glyoxylate adduct 5 (2.1 g) was obtained as an oil.
EMI35.2




   2.1 g of azetidino glyoxylate 5 were dissolved in 50 ml of tetrahydrofuran, and 0.57 ml (7 mmol) of pyridine were added. The mixture was cooled to 0 C and 0.5 ml (7 mmol) SOC12 was slowly added. The mixture was then at 0 C
6 stirred for 1 h and filtered to dryness before evaporation. Filtration of this product over silica gel with C112C12 gave a foam; Yield 1.9 g (85%).
EMI35.3




   5.5 g (0.02 mol) of triphenylphosphine and 2.4 ml (0.02 mol) of 2,6-lutidine were added to a solution of 6.2 g (14 mmol) of chloroazetidinone in 300 ml of THF. The mixture was heated to 45 C over 20 h. Lutidine hydrochloride was filtered off and washed with ether, the filtrate was evaporated and the residue was chromatographed on a silica gel column and eluted with dichloromethane and dichloromethane-ethyl acetate (1: 1). Evaporation of the eluent gave a white solid (2.9 g, 30%).
EMI36.1




   2.0 g (3 mmol) of phosphorane 7 in 150 ml of toluene were refluxed for 2.5 h. Evaporation of the solvent gave an oil which was chromatographed on a silica gel column and worked up with dichloromethane and dichloromethane-ethyl acetate (9: 1) as the eluent. Evaporation of the solvent gave a syrup which crystallized in ethyl acetate hexane as a white solid (0.82 g, 40.7%).
EMI36.2




   To a solution of 50 mg (0.127 mmol) of ester 8 in a tetrahydrofuran-ether mixture (2: 3, 25 ml) were added 10 ml of water, 10 mg (0.127 mmol) of sodium bicarbonate and 50 mg of 30% palladium on diatomaceous earth. The reaction mixture was hydrogenated at 344.64 kPa for 3 h and 25 ° C. Filtered through Celite and washed with ether. The aqueous solution was lyophilized, whereby 30 mg of a yellow powder which was highly hygroscopic was obtained.



   Example 13
6-ethyl-2-aminomethylpenem-3-carboxylic acid (cis and trans isomers)
EMI36.3
 a. Silver-cis- and trans-3-ethyl-1. (P-nitrobenzyl.2'.triphenylphosphoranylidene-2'-acetate) -2-azetidinone.4.thiolate.



   A solution of 1.88 g (3.0 mmol; example 1, structure 7) cis- and trans-3-ethyl-1 - (p-nitrobenzyl-2'-phosphoranylidene-2'-acetate) -4-acetylthio- 2-azetidinone in 4 ml of chloroform was diluted with 90 ml of methanol, cooled to 0 C and treated successively with 0.51 g (3.0 mmol) of finely powdered silver nitrate and 0.33 g (2.4 mmol) of potassium carbonate. The mixture was stirred vigorously at 0 C for 15 min and then at room temperature for 3 h and at -10 C for 1 h. The excreted silver mercaptide was filtered off, washed with methanol and with ether and dried in vacuo. The desired compound was obtained in the form of a gray solid, mp 112-135 "C d. VC = O 1750, 1620, 1605.

 

   b. Cis- and trans-3-ethyl-l- (p-nitrobenzyl-2'-phosphoranylidene-2'-acetate) -4-azidoacetylthio-2-azetidinone.



   A solution of 1.31 g (2 mmol) of said crude mercaptide in 15 ml dichloromethane was cooled to 0 and treated under nitrogen with a 2M solution of azidoacetyl chloride in dichloromethane (1.13 ml, 2.26 mmol).



  The mixture was stirred at 0 for 1 h and at room temperature for 5 h. The insoluble silver salts were filtered off, washed through Celite and with dichloromethane. The combined filtrates were washed with dilute sodium bicarbonate solution and water, dried and concentrated. The oily residue was purified by column chromatography over 35 g of silica gel and elution with ether-ethyl acetate. The appropriate fractions were evaporated to give a mixture of cis and trans acylated compounds in the form of a semi-solid; 0.62 mg # (CDCl3): 2105, 1760, 1690, 1621 cm-1 c.

  Cis- and trans-p-nitrobenzyl-2-azidomethyl-6-ethylpenem-3-carboxylates
A solution of 0.60 g of the above crude phosphorane in 30 ml of toluene was left to stand at 105 for 1 h, cooled and evaporated, leaving an oily residue which was column chromatographed over 20 g of silica gel and by elution with increasing proportions of ether in benzene was worked up. The appropriate fractions were concentrated to give the cis and trans isomers.



   cis isomer: 6 (ppm, CDCl3): 8.25 (2H, d, J = 8.8, Ho from paranitrobenzyl), 7.65 (2H, d, Hm), 5.93 (1H, d, J = 4.1, H-5), 5.38 (2H, AB quartet, J = 14.0, benzyl), 4.68 (2H, AB quartet, J = 15, O, CH3-N3), 3, 4 (1H, m, H-6), 2.0 (2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3), trans isomer: # (ppm, CDCl3): 8.18 (2H, d, J = 8.8, Ho), 7.59 (2H, d, Hm), 5.52 (1H, d, J = 1.4, H-5), 5.33 (2H, AB quartet, J = 14.0, benzyl), 4.58 (2H, AB quartet, J = 15.0, CH2-N3), 3.7, (1H, dt, J = 1.4, J = 7.4 H-6), 1.9 (2H, m, CH2CH3), 1.1 (3H, t, J 7.4, CH2CH3).



   d. Trans-2-aminomethyl-6-ethylpenem-3-carboxylic acid
A mixture of 0.20 g (0.5 mmol) of said transp-nitrobenzyl ester, 6 ml of THF, 6 ml of ether, 12 ml of water and 0.20 g of 30% palladium on Celite was at 23 for 2.5 h and with hydrogenated to initially 30 psi hydrogen pressure. The catalyst was filtered off through Celite and washed with water. The combined filtrates were washed with ether THF and lyophilized to give 12 mg of the crude trans acid. Chromatography on a column with Sephadex G-10, elution with water gave the pure trans acid (6 mg) in the form of a hygroscopic powder. # c = 0 1775, 1615 cm-1. #max = 2.0 (2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3).



   e. cis-2-aminomethyl-6-ethylpenem-3-carboxylic acid
Reduction of the cis-p-nitrobenzyl ester as described above for the trans ester gave the cis acid in the form of a yellowish hygroscopic powder (13%). vC = O 1775, 1615 cm-1. #max 304 (e = 3563). 8 (ppm, D2O-DMSO): 5.75 (1H, d, J = 4.0, H-5), 2.0 (2H, m, CH2CH3), 1.1 (3H, t, J = 7 , 4 CH2CH3).



   Example 14
The following compounds could be obtained using the same procedure as in Example 13:
EMI37.1

EMI37.2


 <tb> acylating agent <SEP> Y <SEP> X <SEP> Z
 <tb> CH3COCl <SEP> -CH3 <SEP> CH3 <SEP> Well, <SEP> H
 <tb> Ac2O <SEP> -CH3 <SEP> -CH3 <SEP> Well, <SEP> H
 <tb> CH3CO2SO2CH3 <SEP> -CH3 <SEP> -CH3 <SEP> Well, <SEP> H
 <tb> C2H5COCl <SEP> -CH3 <SEP> -C2H5 <SEP> Well, <SEP> H
 <tb> CH2COC1 <SEP> -CH3 <SEP> -CH2 <SEP> Well, <SEP> H
 <tb> OCH2COCI <SEP> -CH3 <SEP> -CH20 <SEP> Well, <SEP> H
 <tb> LCOCl <SEP> -CH3 <SEP> < <SEP> Well, <SEP> H
 <tb> QCOC1 <SEP> C113 <SEP> 23 <SEP> Well, H
 <tb> (CF3CO) 2O <SEP> -CH3 <SEP> -CF3 <SEP> Well
 <tb> C2H502C-COCI <SEP> -CH3 <SEP> -CO2Et <SEP> Well
 <tb> <SEP> cOCl
 <tb> N \ N <SEP> -CH3 <SEP> Well,

    <SEP> H
 <tb> <SEP> CH3 <SEP> CH3
 <tb> FcH2 <SEP> COC <SEP> 1 <SEP> -CH3 <SEP> CH <SEP> 2 <SEP> \ <SEP> Well,
 <tb> N <SEP> NS
 <tb> N3 (CH2) 2COCI <SEP> -CH3 <SEP> - (CH2) 2NH2 <SEP> H
 <tb> N3 (CH2) 3COCI <SEP> CH3 <SEP> - (CH2) 3NH2 <SEP> H
 <tb> NC (CH2) 2COCI <SEP> -CH3 <SEP> - (CH2) 3NH2 <SEP> H
 <tb>
EMI38.1


 <tb> acylating agent <SEP> (continued) <SEP> Y <SEP> X <SEP> Z
 <tb> O2N (CH2) 3COCl <SEP> -CH3 <SEP> - (CH2) 3NHOH <SEP> Well, <SEP> H
 <tb> N3 (CH2) 4COCI <SEP> -CH3 <SEP> - (CH2) 4NH2 <SEP> H
 <tb> N3 (CH2) 2OCH2COCl <SEP>.-CH3 <SEP> -CH2O (CH2) 2NH2 <SEP> H
 <tb> N3 (CH2) 2SCH2COCl <SEP> -CH3 <SEP> -CH2S (CH2) 2NH2 <SEP> H
 <tb> AcHN (CH-) 2C02CO? Et <SEP> -CH3 <SEP> - (CH2) 2NHAc <SEP> Well, <SEP> H
 <tb> CH3COCl <SEP> -C2H5 <SEP> -CH3 <SEP> Well, <SEP> H
 <tb> C2H5COCI <SEP> -C2H5 <SEP> -C2H5 <SEP> Well, <SEP> H
 <tb> CH2COCI <SEP> -C2H5 <SEP> -CH2 <SEP> Well,

    <SEP> H
 <tb> OCH2COCI <SEP> -C2H5 <SEP> -CH20 <SEP> Well, <SEP> H
 <tb> n <SEP> cocl <SEP> -C2H5 <SEP> ff <SEP> Well, <SEP> H
 <tb> N3 (CH2) 2COCI <SEP> -C2H5 <SEP> - (CH2) 2NH2 <SEP> H
 <tb> N (CH7) 3COCI <SEP> -C2H5 <SEP> - (CH2) 3NH2 <SEP> H
 <tb> O2N (CH2) 3COCI <SEP> -C2H5 <SEP> - (CH2) 3NHOH <SEP> Well, H
 <tb> N3 (CH2) 4COCI <SEP> -C2H5 <SEP> - (CH2) 4NH2 <SEP> H
 <tb> CHRCOCI <SEP> iso-C3H7 <SEP> -CH3 <SEP> Well, <SEP> H
 <tb> C2H5COCI <SEP> iso-C3H7 <SEP> -C2H5 <SEP> Well, <SEP> H
 <tb> n <SEP> cocl <SEP> iso-C3H7 <SEP> < <SEP> Well, <SEP> H
 <tb> <SEP> COCl <SEP> \, <SEP> S
 <tb> · <SEP> iso-C3H7 <SEP> lol <SEP> Well, H
 <tb> <SEP> O <SEP> O
 <tb> C <SEP> cccl <SEP> iso-C3H7 <SEP> y <SEP> Well, H
 <tb> II <SEP> il <SEP> iSO-C3H7 <SEP> I <SEP> Well, <SEP> H
 <tb> CH2COCI <SEP> iso-C3H7 <SEP> -CH2 <SEP> Well,

    <SEP> H
 <tb> N3CH2COCl <SEP> iso-C3H7 <SEP> -CH2NH2 <SEP> H
 <tb> N3 (CH2) 2COCI <SEP> iso <SEP> C3H7 <SEP> - (CH2) 2NH2 <SEP> H
 <tb> N3 (CH2) 3COCl <SEP> iso <SEP> C3H7 <SEP> - (CH2) 3NH2 <SEP> H
 <tb> O2N (CH2) 3COCl <SEP> iso-C3H7 <SEP> - (CH2) 3NHOH <SEP> Well, <SEP> H.
 <tb>



   Example 15 ice and trans.6.acetoxymethyl.2-aminomethylpenem-3-carboxylic acid
EMI38.2
 a) 3-acetoxymethyl-4-tritylthio-2-azetidinone (cis and trans isomers)
A solution of 4.7 g (25 mmol) of a mixture of ice and trans.4.Aeetoxy-3-acetoxymethyl.2-azetidinone (Example 2, structure 25) in 200 ml of water quickly became a vigorously stirred solution of Sodium triphenylmethylmer captid (from triphenylmethyl mercaptan, 55.2 g; and
Sodium hydride, 9.6 g, in methanol, 300 ml). The mixture was stirred at room temperature for 4 h and the
Solids were filtered off, washed with water and in
Dichloromethane dissolved.

  The solution was diluted with
Hydrochloric acid, water, an aqueous solution of sodium bicarbonate and water, dried and concentrated, whereby 85% of a solid was obtained, which was used in the next reaction without working up.



   b) ice and trans-3-acetoxymethyl-1 - (p-nitrobenzyl-2'-hydroxy-2'-acetate) -4-tritylthio-2-azetidinone
A solution of 8.0 g (20 mmol) of said azetidinone and 4.54 g (20 mmol) of p-nitrobenzylglyoxylate in 100 ml of benzene were refluxed on a Dean-Stark apparatus with a 3-molecular sieve. After 24 h, a second amount of 4.54 g of p-nitrobenzyl glyoxylate was added and the mixture was refluxed for a further 24 h. The mixture was diluted with ether, washed with 5% aqueous hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water.



  After drying and concentration in vacuo, 100% of the crude isomeric mixture was obtained in the form of an oil.

 

   c) ice and trans-3-acetoxymethyl-1- (p-nitrobenzyl-2'-chloro-2'-acetate) -4-tritylthio-2-azetidinones
A solution of 12.2 g (20 mmol) of the azetidinones from part b) and 1.9 g (24 mmol) of pyridine in 150 ml of dry THF was cooled to -15 'and dropwise with 2.86 g (24 mmol) of thionyl chloride treated under nitrogen. The mixture was stirred at -15 for 45 min, the precipitate was filtered off and washed with benzene and the filtrates were concentrated to give a semi-solid (95%).



   d) ice and trans-3.acetoxymethyl-1. (p.nitrobenzyl-2'-tri-phenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinones
A mixture of 12.6 g (20 mmol) of the azetidinones from step c), 7.8 g (30 mmol) of triphenylphosphine and 2.6 ml (22 mmol) of 2,6-lutidine in 100 ml of THF was applied over 80 h Reflux temperature heated. The insoluble solid was filtered off and washed with ether, the filtrates were washed with 2% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate solution and water, dried and concentrated. The residue was dissolved in benzene, slowly
250 g of silica gel was filtered and the silica gel was increasing
Portions of ether eluted in benzene.

  Concentration of the corresponding fractions resulted in a mixture of the compounds mentioned (65%). vC = O 1740, Vc = p3 1620, 1610, # NO2 1525 cm- '.



   e) Silver-cis- and -trans-3-acetoxymethyl-l- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2.azetidinone-4-thiolate
8.5 g (10 mmol) of the crude azetidinones from step d) were dissolved in hot methanol at 55-60. A hot solution of 2.04 g (12 mmol) of silver nitrate and 0.87 g (11 mmol) of pyridine in 80 ml of methanol was added. The mixture was allowed to cool to room temperature and after 2 h was stirred for a further 1 h at 0. The silver mer captid was filtered off, washed with ice-cold methanol and then with ether (5.7 g, 82%, melting point with decomposition). # c = 0 1745, 1740, 1625 cm-1.



   f) cis and trans-3-acetoxymethyl-4azidoacetylthio- l- (p nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone
1.4 g (2 mmol) of the silver mercaptide from steps) in
15 ml of dichloromethane was treated as in Example 13 with azidoacetyl chloride (2.3 mmol), 0.78 g of a yellow
Powder were obtained.



   g) cis and trans-6-acetoxymethyl-2-azidomethylpenem 3-carboxylic acid p-nitrobenzyl ester
A solution of 0.70 mg of said crude phosphorane in 35 ml of toluene was kept at 105 for 1 h, cooled and concentrated to give an oil which was
25 g of silica gel was chromatographed, followed by elution with increasing proportions of ether in benzene. The appropriate fractions were concentrated to give the cis and trans isomers of the desired compound.



   cis isomer: 6 (ppm, CDCl3),: 8.5-7.5 (4H, aromatic), 5.67 (1H, d, J = 5, H-5), 5.31 (2H, AB- Quartet, CH2-Benzyl), 4.50 (2H, AB-Quartet, CH2N3), 4.33 (2H, d, AcOCH2), 4.26 (1H, dt, H-6) 2.0 (3H, s , CHl).



  trans isomer: 6 (ppm, CDCl3): 8.5-7.5 (4H, aromatic), 5.62 (1H, d, J = 2, H-5), 5.33 (2H, AB-quartet) , CH2-benzyl), 4.40 (1H, dt, H-6), 4.50 (2H, AB-quartet, CH2N3), 4.27 (2H, d, AcOCH2), 2.0 (3H, s , CH3).



   h) trans-6-acetoxymethyl-2-aminomethylpenem-3-car bonic acid
Hydrogenation of the above trans isomer by the method of Example 13 gave the desired compound.



     # c = 0 1775, 1740, 1616 cm-1. #max 304 (# = 3192).



   i) cis-6-acetoxymethyl-2-aminomethylpenem-3-carboxylic acid
Hydrogenation of the corresponding cis isomer as described in Example 13 gave the desired compound in the form of an unstable hygroscopic semi-solid.



   Example 16
The following compounds were made according to the general procedure of Example 15:
EMI39.1

EMI39.2


 <tb> <SEP> acylating agent <SEP> Y <SEP> X <SEP> Z
 <tb> <SEP> CH3COCl <SEP> -CH2OAc <SEP> -CH3 <SEP> H
 <tb> <SEP> C2H5COCI <SEP> -CH2OAc <SEP> -C2H5 <SEP> H
 <tb> <SEP> Lcoci <SEP> -CH2OAc <SEP> -n <SEP> H
 <tb> <SEP> COC1 <SEP> -CH2OAc <SEP> 43
 <tb> <SEP> COCl <SEP> -CH2OAe <SEP> U <SEP> H
 <tb> <SEP> N3 (CH2) 2COCI <SEP> -CH2OAc <SEP> - (CH2) 2NHt <SEP> H
 <tb> <SEP> N3 (CH2) 3COCI <SEP> -CH2OAc <SEP> - (CH2) 3NH, <SEP> H
 <tb> <SEP> N3 (CH2hCOCI <SEP> -CH2OAc <SEP> - (CH2) 4NH,

    <SEP> H
 <tb> <SEP> O2N (CH2) 3COCI <SEP> -CH2OAc <SEP> - (CH2) 3NHOH <SEP> H
 <tb> <SEP> CH3COCI <SEP> - (CH2) 2OAc <SEP> H3 <SEP> H
 <tb> <SEP> LCOCl <SEP> - (CH2) 2OAc <SEP> 11
 <tb> N3CH2COCI <SEP> - (CH2) 2OAc <SEP> -CH2NH2 <SEP> H
 <tb> N3 (CH2) 2COCI <SEP> - (C112) 2OAc <SEP> - (CH2) 2NHo <SEP> H
 <tb> N3 (C112) 3COCl <SEP> - (CH2) 2OAc <SEP> - (CH2) 3NH2 <SEP> H
 <tb>
EMI40.1


 <tb> Ac! <SEP> agent <SEP> (continued) <SEP> Y <SEP> x <SEP> Z
 <tb> <SEP> CH3
 <tb> CH3COCl <SEP> -CH-OAc <SEP> -CH3 <SEP> H
 <tb> <SEP> CH3
 <tb> N3CH2COCI <SEP> -CH-OAc <SEP> -CH2NH2 <SEP> H
 <tb>
Example 17 ice and trans-6- (1'-hydroxy-1'-ethyl) -2-methylpenem-3-carboxylic acid, sodium salts
EMI40.2

To a solution of 100 mg (0.54 mmol) of 2-methylpenem-3-carboxylic acid in 8 ml of THF was added 0.08 ml (0.57 mmol) of diisopropylamine at 0 and 0.75 ml (1.20 mmol) of n- Butyllithium given at -78 '.

  After stirring at -78 'for 2 minutes, 0.5 ml of freshly distilled acetaldehyde was added and stirring was continued for a further 10 minutes. The reaction mixture was quenched with a saturated solution of ammonium chloride (10 ml) and washed with ethyl acetate. The aqueous phase was acidified with 18 ml of 0.1N hydrochloric acid and extracted with 3 × 20 ml of ethyl acetate. Concentration of the dried ethyl acetate phases gave 49 mg of an oil which was dissolved in methyl isobutyl ketone and treated with an excess of sodium methylhexanoate in the same solvent. Addition of ether resulted in precipitation of the desired compound in the form of a white amorphous solid (25 mg). 6 (ppm, D2O): 5.6-5.83 (1H, m, H-5, ice and trans-), 2.27 (3H, s, CH3), 1.22 and 0.90 (3H, 2d , CH3).



   Example 18 cis-6- (1 '-hydroxy-I' -ethyl) -2-methylpenem-3-carboxylic acid sodium salt (isomer D)
100 mg of 2-methylpenem-3-carboxylic acid were treated with LDCA and acetaldehyde as described in Example 17. 58 mg of the residue obtained after concentration of the dry ethyl acetate phases was extracted with ether and the ether solution was concentrated to 48 mg of an oil.



  This oil was converted into sodium salt with sodium methylhexanoate as described in Example 17. This gave 29 mg of a white solid, which was identified as cis.6- (1'-hydroxy-l'-ethyl) -2-methyl-penem-3-carboxylic acid, sodium salt, contaminated with a small part of sodium 5-methyl-1 , 3-thiazole-4-carboxylate. 6 (ppm, DMSO-d6): 5.5 (1H, d, J = 4.1, H-5), 2.22 (3H, s, CH3), 1.02 (3H, d, J = 5 , 5, CH3).



   Example 19 cis- and trans-6- (2'-hydroxy-2'-propyl) -2-ethylpenem-3-carboxylic acids, potassium salts
EMI40.3

Using the same procedure as in Example 3 for the 2-methylpenem-3-carboxylic acid, but using an equimolar fraction of 2-ethylpenem-3-carboxylic acid, a mixture of the potassium salts resulted. 8 (ppm, DMSOd6): 5.60 and 5.56 (1H, 2d, J = 4 and J = 2, H-5), 3.92 and 3.60 (1H, 2d, J = 4 and J = 2, H-6), 2.88 and 2.86 (2H, 2q, CH2-CH3), 1.47, 1.41, 1.36 and 1.32 (6H, 4s, CH3), 1.2 and 1.4 (3H, 2t, CH2CH3). Xmas 257 (& = 3705) and302 (± = 3815).



   Example 20 cis and trans-6- (1'-hydroxy-1'-ethyl) -2-methoxymethylpenem-3-carboxylic acid, sodium salts
To a solution of 2-methoxymethylpenem-3-carboxylic acid (see preparation 6; 116 mg, 0.55 mmol) in 10 ml THF was added 0.08 ml (0.57 mmol) diisopropylamine at 0 and 0.75 ml (1, 20 mmol) of n-butyllithium at -78.



  After stirring at -78 'for 2 minutes, 0.5 ml of freshly distilled acetaldehyde was added and stirring was continued for a further 10 minutes. The reaction mixture was then quenched with 10 ml of a saturated solution of ammonium chloride and washed with ethyl acetate. The aqueous phase was acidified with 18 ml of 0.1N hydrochloric acid and extracted 3 times with 10 ml of ethyl acetate. Concentration of the dry ethyl acetate phases gave 53 mg of an oil which was converted into the sodium salts of the desired compound as described in Example 17. White amorphous hygroscopic powder (21 mg) 6 (ppm, D2O): 5.7-5.85 (1H, m, H-5, cis and trans-), 3.38 (3H, 2s, OCH3), 1 , 22 and 0.92 (3H, 2d, CH3).



     vC = O 1770, 1600 cm-l.



   Example 21 cis and trans-6-acetyl-2-methylpenem-3-carboxylic acid, sodium salts
EMI40.4

To a solution of 100 mg (0.54 mmol) of 2-methylpenem-3-carboxylic acid in 10 ml of THF was added 0.08 ml (0.57 mmol) of diisopropylamine at 0 and 0.75 ml (1.20 mmol)
Butyllithium given at -78 '. After stirring at -78 'for 2 min, 1 ml of ethyl acetate was added and stirring was continued for a further 10 min. The reaction mixture was then quenched with 10 ml of a saturated solution of ammonium chloride and washed with ethyl acetate. The aqueous phase was carefully acidified at 0 with 0.1N hydrochloric acid and extracted quickly with 3 × 20 ml of ethyl acetate. Concentration of the dry extracts gave 36 mg of an oil, which was converted to the desired compound as described in Example 17.

 

   6 (ppm, D2O): 5.90-6.10 (1H, 2d, J = 4, J = 2, H-5), 3.8 (1H, m, H-6 ice and trans-), 2.34 and 2.27 (3H, 2s, CH3), 2.12 and 2.0 (3H, 2s, CH3).



   Example 22
The following compounds were prepared according to the general procedures in Examples 3-5 and 17-21.
EMI40.5
  
EMI41.1


 <tb>



  x <SEP> Y <SEP> Z
 <tb> <SEP> OH
 <tb> <SEP> I
 <tb> H3 <SEP> -CH-C6H4-OCH3 <SEP> K
 <tb> <SEP> OH
 <tb> -CH3 <SEP> -CH-nBu <SEP> Well
 <tb> <SEP> 0
 <tb> <SEP> II
 <tb> -CH3 <SEP> -C- <SEP> Well
 <tb> -CH3 <SEP> -CH2OH <SEP> Well
 <tb> <SEP> OH
 <tb> -CH3 <SEP> -CHCF3 <SEP> Well
 <tb> -C2Hs <SEP> -SCH3 <SEP> K
 <tb> <SEP> OH
 <tb> -C2H5 <SEP> -C-CH3 <SEP> Well
 <tb> <SEP> 0
 <tb> <SEP> II
 <tb> -C2H5 <SEP> -C-CH3 <SEP> Well
 <tb> <SEP> OH
 <tb> -C6H5 <SEP> -CH-CH3 <SEP> Well
 <tb> <SEP> OH
 <tb> -C6H5 <SEP> -C (CH3) 2 <SEP> K
 <tb> <SEP> 0
 <tb> <SEP> II
 <tb> -C6Hs <SEP> -C-CH3 <SEP> Well
 <tb> <SEP> OH
 <tb> t3 <SEP> -CH <SEP> CH3 <SEP> Well
 <tb> <SEP> O <SEP> OH
 <tb> -CH2OCH3 <SEP> -C (CH3) 2 <SEP> K
 <tb> <SEP> OH
 <tb> -CH2OCH3 <SEP> -C- <SEP> K
 <tb> <SEP> 0
 <tb> <SEP> II
 <tb> -CH2OCH3 <SEP> -C-CH3 <SEP> Well
 <tb> <SEP> 0
 <tb> <SEP> I <SEP> I
 <tb> -CH2OCH3 <SEP> -C- <SEP> Well
 <tb> <SEP> OH
 <tb> -CH2SCH3 <SEP>

   -CHCH3 <SEP> Well
 <tb> <SEP> C113 \ <SEP> / O <SEP> OH
 <tb> <SEP> CEi2C <SEP>) <SEP> -C- (CH3) 2 <SEP> K
 <tb>
Example 23
The following compounds were prepared according to the general procedure from Example 3:
EMI41.2

EMI41.3


 <tb> x <SEP> Y <SEP> Z
 <tb> <SEP> OH
 <tb> <SEP> I
 <tb> -H <SEP> -CHCH3 <SEP> Well
 <tb> <SEP> OH
 <tb> -H <SEP> -CH- <SEP> K
 <tb> <SEP> OH
 <tb> -H <SEP> -CH-C6H4OCH3 <SEP> Well
 <tb> <SEP> OH
 <tb> -H <SEP> -CH-n-C3H7 <SEP> Well
 <tb> <SEP> OH
 <tb> -H <SEP> -CH-CF3 <SEP> Well
 <tb> -H <SEP> -CH2OH <SEP> Well
 <tb> <SEP> 0
 <tb> <SEP> 11
 <tb> -H <SEP> -C-CH3 <SEP> Well
 <tb> <SEP> 0
 <tb> <SEP> 11
 <tb> -H <SEP> -C- <SEP> Well
 <tb> -H <SEP> -SCH3 <SEP> K
 <tb> <SEP> OH
 <tb> -CHCH3 <SEP> Well
 <tb> <SEP> OH
 <tb> <SEP> CW <SEP> -CH- <SEP> K
 <tb> <SEP> 0
 <tb> <SEP> II
 <tb> -C-CH3 <SEP> Well
 <tb> <SEP> OH
 <tb> -CH-CH3 <SEP> Well
 <tb> <SEP> OH
 <tb> -CH20 <SEP> -CH-CH3

    <SEP> Well
 <tb> <SEP> OH
 <tb> -CH20 <SEP> -CH- <SEP> K
 <tb> <SEP> OH
 <tb> -CH20 <SEP> -CH (CH3) 2 <SEP> K
 <tb>
Example 24 2- (4'-Phthalimido-1'-butyl) -penem-3-carboxylic acid
EMI41.4
  
EMI42.1

A solution of 10.65 g (40.2 mmol) 1 was added dropwise to a solution of triethylamine hydrosulfide, prepared by passing H2S gas through 200 ml of methylene chloride with 8.8 ml (63.7 mmol) of triethylamine dissolved therein (Gabriel Ber. 41, 2010) in 75 ml methylene chloride at 0 C over 30 min. The mixture was stirred at 0 for 15 minutes and then at room temperature for 2 hours. The organic solution was diluted with 125 ml of methylene chloride and washed twice with 15 ml of 1N HCl, 2 x 15 ml of water and brine.

  After drying over MgS04 and evaporation of the solvent was obtained
10.5 g (100%) of 2 in the form of a white solid. M.p .:) 93-94 C. NMR (CDCl3) 8 7.5-8 (4H, m), 4.47 (1H, broad, s), 3.5-3.9 (2H, m), 2 , 5-2.9 (2H, m), 1.4-1.9 (4H, m).



   Analysis for C13H13NO3S:
Calculated: C, 59.29, H, 4.97, N, 5.32, S, 12.17
Found: C, 58.92, H, 4.91, N, 5.42, S, 12.31.
EMI42.2




   A suspension of 3.34 g (11.6 mmol) 2 in a solution of 11.6 ml of 1 M sodium bicarbonate was stirred at room temperature under nitrogen for 15 min. 1.5 g (11.6 mmol) 3 was added and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was then diluted with water and extracted with methylene chloride. The organic phase was dried and concentrated in vacuo, where
3.82 g of a solid 4 were obtained; 95-96 C, IR (CHCl3) 1775.1710 cm-1.NMR 6 7.9 (4H, d, J = 2 Hz), 7.05 (1H, broad, s), 5.25 (111 , dd, Jcis = 5 Hz, Jtrans = 3 Hz), 3.5-3.0 (2H, m), 1.5-2.0 (4H, m).



   Analysis for C16H16N2O4S:
Calculated: C, 57.62, H, 4.85, N, 8.43, S, 9.64,
Found: C, 57.43, H, 4.82, N, 8.44, S, 9.71.
EMI42.3
  
EMI43.1




   30 ml of a solution of 3.0 g (9.04 mmol) of 4 and 2.22 g (9.8 mmol) of p-nitrobenzylglyoxalate in benzene was refluxed in the Dean-Stark apparatus with 3A molecular sieve for 21 h. After evaporation of the solvent, 5.4 g of 5 was obtained in the form of an oil (100%). IR (neat) 3200-3600, 1770.1710, 1525 cm- '. NMR (CDCl3) o 8.21 (2H, d, J = 9 Hz), 7.75 (4H, d, J = 2 Hz), 7.52 (2H, d, J = 9 Hz), 5.52 (1H, broad), 5.32 (3H, 2s), 4.55 (1H, broad s), 3.5-3.7 (2H, m), 3.45 (1H, dd, Jgem = 15 Hz , Jcis = 5 Hz), 3.02 (1H, dd, Jgem = 15 Hz, Jtrans = 3 Hz), 2.4-2.9 (2H, m), 1.4-2.0 (4H, m ).
EMI43.2




   4.9 g (9.05 mmol) of glyoxalate 5 were treated with 15 ml of thionyl chloride at 0 C and left at 0 C for 0.5 h and room temperature for 1 h. The excess thionyl chloride was distilled off with benzene in vacuo to give 6 as a yellow syrup (5.0 g, 100%). NMR (CDCl3) # 8.2 (2H, d, J = 9 Hz), 7.72 (4H, broad s), 7.60 (2H, d, J = 9 Hz), 6.1 (1H, broad s), 5.505.85 (1H, m), 5.32 (2H, 2s), 3.4-4.0 (2H, m), 3.1-3.3 (1H, m), 2.8 -3.05 (1H, m), 2.50-2.85 (2H, m), 1.5-1.9 (4H, m).
EMI43.3




   A solution of 21.6 g (38.8 mmol) 6 in 85 ml of tetrahydrofuran (distilled over LAH) was mixed with 10.2 g (38.8 mmol) of triphenylphosphine and 5.0 ml (42.9 mmol) of 2.6- Treated lutidine at 40 C for 18 h. The mixture was diluted 1: 1 with benzene ether (30 ml), washed with water, 1N HCl, saturated NaHCO3, brine and dried over MgSO4. After evaporation of the solvent was obtained
7 a dark brown oil. This was poured over 700 g of silica gel and eluted with benzene ether, 1 5.0 g (53%) 7 in
Form of a thick oil were obtained. N MR (CDCl3) 6 8.2 (2H, d, J = 9 Hz), 7.8 (8H, d, J = 2 Hz), 7.52 (16H, broad s), 5.2 (1H, broad s), 4.78 (1H, 2s), 4.30-4.52 (1H, m), 3.5-3.8 (2H, m), 2.8-3.5 (2H, m ), 2.1-2.9 (4H, m), 1.5-1.9 (4H, m).
EMI44.1




   A solution of 5.0 g (6.4 mmol) of phosphorane 7 in 35 ml of toluene was refluxed for 3 hours. After evaporation of the solvent, a residue was obtained, which was added to 100 g of silica gel in a column. Elution with benzene followed by ether gave 600 mg of the ester 8 in the form of an oil. IR (neat) 1790, 1710, 1520 cm-1 NMR (CDCl3) # 8.22 (2H, d, J = 9 Hz), 7.82 (4H, d, J = 2 Hz), 7.65 (2H , d, J = 9 Hz), 5.69 (1H, dd, Jcis = 4 Hz, Jtrans = 2 Hz), 5.35 (2H, 2s), 4.12 (111, dd, Jgem = 16 Hz, Jcis = 4 Hz), 3.50 (1H, dd, Jgem = 16 Hz, Jtrans = 2 Hz), 3.1-3.8 (2H, m), 2.5-3.0 (2H, m) , 1.4-2.0 (4H, m).
EMI44.2




   A two phase mixture of ester 8 (196 mg, 0.39 mmol) in 2 ml ether, 4 ml tetrahydrofuran and 32 mg (0.39 mmol) sodium bicarbonate in 2 ml water was made up to 190 mg 30% palladium on diatomaceous earth in a Parr device hydrogenated at 40 psi H2. After 4.5 h the mixture was filtered through Celite and the filter was washed with water and tetrahydrofuran.

 

  The filtrate and washing solutions were combined and the organic phase was separated. The aqueous solution was washed with ether, acidified with 1N hydrochloric acid (3 × 0.4 ml) and after each addition of acid with 4> <x 2 ml of ethyl acetate extracted. The organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated to give 67 mg (47%) of acid 9 as a yellow solid. IR (Nujol) 1775, 1705, 1690 cm-1. NMR (DMSO) o 7.92 (4H, s), 5.71 (1H, dd, Jcis-4 Hz, Jtrans = 2 Hz), 3.90 (1H, dd, Jgem = 16 Hz, Jcis = 4 Hz ), 3.47 (1H, dd, Jgem = 16 Hz, Jtrans = 2 Hz), 3.3-4.3 (3H, m), 2.7-3.05 (2H, m), 1.5 -2.0 (4H, m).



   Example 25
Sodium 2- (acetonylmethyloxime) -penem-3-carboxylate
EMI44.3
  
2.0 g (4.54 mmol) of Ketal 1 was treated at 0 with 20 ml of 95% TFA for 15 min. The mixture was diluted with brine and extracted 4 times with 30 ml of methylene chloride. The methylene chloride extracts were with water-saline (3> <x) and washed with saline and dried over MgSO4 (1.44 g, 80%).



   6 (ppm, CDCl3) 8.27 (2H, d, J = 9, Hm aromatic), 8.60 (2H, d, J = 9, Ho aromatic), 5.70-5.25 (m, CH2- PNB, HCO, H-4,
EMI45.1
 4.75, (1H, bs, OH), 3.76 (center of ABq, CH2-CO), 3.47 (part of a dd, J3 cis = 5, H-3), 3.05 (2H, 2dd, Jgem = 15, J3-4 trans = 3, H-3), 2.30, 2.28 (1.67 H, 2s, CH3), 1.98 (1.33 H, s, CH3) # c = 0 (CHCl3) 1780, 1755, vNo2 1525.
EMI45.2




   50 ml of a methylene chloride solution of ketone 2 (1.44 g, 3.63 mmol) were treated at 0 under nitrogen with 334 mg (1.1 eq.) Methoxylamine hydrochloride.



   367 mg (0.51 ml, 1 eq.) Of triethylamine were then added dropwise to the mixture, which was stirred at room temperature for 18 hours. The reaction mixture was then diluted with methylene chloride, washed with water brine (2 times), brine and dried over MgSO4 (1.52 g, 98%).



   6 (ppm, CDCl3) 8.12 (2H, d, J = 8, Hm aromatic), 8.40 (2H, d, J = 8, Ho aromatic), 5.50-5.05 (4H, m, CH2-PNB), H-4, HCO), 3.80-3.60 (m, OCH3, part of H-3 cis, part of OH), 3.55-2.70 (m, part of H- 3 cis, H-3 trans, CH2CO, part of OH), 1.97, 1.90, 1.88 (3H, 2s, CH3) # c = 0 (CHCl3) 1170, 1750, 1690.
EMI45.3




   A cold (-15 C) solution of 1.52 g (3.57 mmol) of azetidinone 3 in 20 ml of T11F (distilled over LAH) was added dropwise with 325 mg, (0.332 ml, 4.10 mmol, 1.15 eq. ) Pyridine and 488 mg (0.299 ml, 4.10 mmol, 1.15 Aq.) Thionyl chloride added under nitrogen. The mixture was stirred at -15 for 15 min, after which the solid was filtered off and washed with benzene. The resulting solution was evaporated, the residue was taken up in benzene and treated with activated carbon (1.2 g, 76%).



     # (ppm, CDCl3), 8.23 (2H, d, Hm aromatic), 7.80 (2H, d, Ho aromatic), 6.12, 6.08 (1H, 2s, HC-Cl), 5, 75-5.55 (1H, m, H-4), 5.40, 5.30 (2H, 2s, CH2-PNB), 3.95-3.80 (3H, 3s, OCH3), 3.80 -2.95 (4H, m, 2H-3, CH2-CO), 2.00-1.85 (3H, 4s, CH3). # c = 0 (CHCl3) 1790, 1765 (shoulder), 1700, # NO2 1530.
EMI45.4
  



   A solution of chlorazetidinone 4 (1.2 g, 2.70 mmol) in 20 ml T11F (distilled over LAH) was added with 1.06 g (4.05 mmol, 1.5 eq.) Triphenylphosphine and 318 mg (0.346 ml , 2.97 mmol, 1.1 Aq.) 2,6-lutidine. The mixture was stirred under nitrogen at room temperature for 4 days, diluted with ethyl acetate, washed with 2% aqueous HCl, H2O, 2% aqueous NaHCO3, water and brine. The solution was then dried over MgSO4 and the solvent evaporated. The crude 5 was column chromatographed on 10 parts by weight of silica gel (ethyl acetate, 770 mg, 45%).



     # c = 0 (CHCl3) 1755, 1695, # 1630-1610, # NO2 1525.
EMI46.1




   700 mg (1.05 mmol) of phosphorane 5 were refluxed in toluene for 4.5 h. After evaporation of the toluene, a residue was obtained, which was added to a silica gel column (1:15) (4% ether-petroleum). 6 was obtained in the form of a crystalline solid (251 mg, 62%, mp 116-125).



   Analysis for C17H17N3O6S Calculated: C, 52.17, H, 4.38, N, 10.74 Found: C, 51.15, H, 4.18, N, 10.33.



  6 (ppm, CDCl3) 7.70 (2H, d, Hm aromatic), 7.12 (2H, d, Ho aromatic), 5.00 (2H, s, CH2PNB), 4.85 (1H, m, H -5), 3.75-2.70 (7H, m, CH30, CH2, H-6), 1.77, 1.72, 1.65 (3H, s, CH3).



     # c = 0 (CHCl3) 1787, 1742, 1705, NO2 1530.



   UV (EtOH) #max 318 (± = 8420), 262 (8 = = 12.539).
EMI46.2




   A mixture of 151 mg (0.386 mmol) of ester 6 in 20 ml of THF, 40 ml of ether and 32 mg (0.381 mmol) of NaHCO3 in 20 ml of water was shaken in a Parr hydrogenator at 35 psi 112 for 3 hours using 200 mg 30% Pd on Celite as a catalyst. The catalyst was filtered off and washed with water and ether. The resulting aqueous mixture was washed three times with 60 ml of ether and lyophilized (32 mg, 30%).



     8 (ppm, DMSO) 5.50 (m, H-5), 3.75 (s, OCH3), 0.77 (s, CH3). vC = O (Nujolmull) 1770, 1600, 1400.



   UV (H2O) Xma, 300 (± = 2,800), 255 (± = 2,400).



   Example 26
The following 2-penem compounds could be prepared by acylating l- (p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone with the corresponding acylating agents, followed by cyclization and deblocking.

  The general reaction scheme is as follows:
EMI46.3
  
EMI47.1
 for variation 1: use of RCO2H + iBuCOCl for variation 2: use of HCI + PCl5 + RCO2H
EMI47.2


 <tb> <SEP> acylating agent <SEP> method <SEP> product
 <tb> <SEP> CH20CONH- (CH2) 4-C02H <SEP> 1 <SEP> 2- (4-aminobutyl) penem
 <tb> <SEP> 3-carboxylic acid
 <tb> <SEP> CH3
 <tb> <SEP> CH2OCONH-C <SEP> H-CO2H <SEP> 1 <SEP> 2- (1.Aminoethyl) -penem
 <tb> <SEP> (both <SEP> D <SEP> and <SEP> L) <SEP> 3-carboxylic acid
 <tb> <SEP> CH2CH3
 <tb> <SEP> CH2OCONH-C <SEP> H-COIH <SEP> 1 <SEP> 1 <SEP> 2 (1st aminopropyl) penem
 <tb> <SEP> (both <SEP> D <SEP> and <SEP> L) <SEP> 3-carboxylic acid
 <tb> <SEP> CH3
 <tb> <SEP> CH-CH3
 <tb> CH2OCONH-C <SEP> H-CO2H <SEP> 1 <SEP> 2- (1-amino-2-methyl
 <tb> (both <SEP> D <SEP> and <SEP> L) <SEP> propyl) -penem-3-carbon
 <tb> <SEP> acid
 <tb> <SEP> CH2OCONH-CH-CO2H <SEP> 1 <SEP>

   2- (1-aminobenzyl) penem
 <tb> <SEP> (both <SEP> D <SEP> and <SEP> L) <SEP> 3-carboxylic acid
 <tb> <SEP> ICH2
 <tb> <SEP> CH2OCONH-C <SEP> H-CO2H <SEP> 1 <SEP> 2- (l-amino-2-phenylethyl)
 <tb> <SEP> (both <SEP> D <SEP> and <SEP> L) <SEP> penem-3-carboxylic acid
 <tb> <SEP> CH2OCH2-NO2 <SEP> P
 <tb> <SEP> CH2OCONH-C <SEP> H-CO2H <SEP> 1 <SEP> 2- (l-amino-2-hydroxy
 <tb> <SEP> (both <SEP> D <SEP> and <SEP> L) <SEP> ethyl) -penem-3-carbon
 <tb> <SEP> acid
 <tb> <SEP> CH2C02CH2-NO2-P
 <tb> <SEP> CH2OCONH-C <SEP> H-CO2H <SEP> 1 <SEP> 2- (l-amino-2-carboxyethyl)
 <tb> <SEP> (both <SEP> D <SEP> and <SEP> L) <SEP> penem-3
 <tb> <SEP> CH2CONH2
 <tb> <SEP> CH2OCONH-C <SEP> H-C02H <SEP> 1 <SEP> 2- (i-amino-2-carbamoyl
 <tb> <SEP> (both <SEP> D <SEP> and <SEP> L) <SEP> ethyl) -penem-3-carbon
 <tb> <SEP> acid
 <tb> <SEP> CH2CH2SCH3
 <tb> <SEP> CH2OCONH-C <SEP> H-CO2H <SEP> 1 <SEP> 2- (l <SEP> -Amino-3 <SEP>

   -methylthio
 <tb> <SEP> (both <SEP> D <SEP> and <SEP> L <SEP> propyl) -penem-3-carbon
 <tb> <SEP> acid
 <tb>
EMI48.1


 <tb> Av! <SEP> licrungsmlttcl <SEP> (continued) <SEP> method <SEP> product
 <tb> <SEP> (CH2) 4NHC02CH2
 <tb> CH2OCONH-C <SEP> H-CO2H <SEP> 1 <SEP> 2- (1,5-diaminopentyl)
 <tb> (both <SEP> D <SEP> and <SEP> L) <SEP> penem-3-carboxylic acid
 <tb> <SEP> ICH3
 <tb> C112OCON <SEP> CH2CO2H <SEP> 1 <SEP> 2 - [(methylamino) methyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> INCH3
 <tb> CH2OCON <SEP> CH2CH2CO2H <SEP> 1 <SEP> 2- [2- (methylamino) ethyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> C113
 <tb> CH2OCON <SEP> CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (methylamino) propyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> CH3
 <tb> CH2OCON <SEP> CH2CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [4- (methylamino) butyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> C2H5
 <tb> CH2OCON <SEP> CH2CO2H <SEP>

   1 <SEP> 2 - [(ethylamino) methyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> c211s
 <tb> CH2OCON <SEP> CH2CH2CO2H <SEP> 1 <SEP> 2- [2- (ethylamino) ethyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> lc2H5
 <tb> CH2OCON <SEP> CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (ethylamino) propyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> lC2H5
 <tb> CH2OCON <SEP> CH2CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [4- (ethylamino) butyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> I
 <tb> <SEP> I
 <tb> CH2OCON <SEP> CH2CO2H <SEP> 1 <SEP> 2 - [(phenylamino) methyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> I
 <tb> CH2OCON <SEP> CH2CH2CO2H <SEP> 1 <SEP> 2- [2- (phenylamino) ethyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> I
 <tb> CH2OCON <SEP> CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (phenylamino) propyl]
 <tb> <SEP> penem-3 <SEP> carboxylic acid
 <tb> <SEP> I
 <tb> CH2OCON <SEP> CH2CH2CH2CH2CO2H <SEP> 1 <SEP> 1- [4- (phenylamino) butyl]
 <tb>

    <SEP> penem-3-carboxylic acid
 <tb> CH3CONHCH2CO2H <SEP> 1 <SEP> 2 - [(acetylamlno) methylj
 <tb> <SEP> penem-3-carboxylic acid
 <tb> CH3CONHCH2CH2CO2H <SEP> 1 <SEP> 2- [2- (acetylamino) ethyl]
 <tb> <SEP> penem-3 <SEP> carboxylic acid
 <tb> CH3CONHCH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (acetylamino) propyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> CH3CONHCH2CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [4- (acetylamino) butyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> C6HsCONHCH2CO2H <SEP> 1 <SEP> 2 - [(benzoylamino) methyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> C6H5CONHCH2CH2CO2H <SEP> 1 <SEP> 2- [2- (benzoylamino) ethyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> C6H5CONHCH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (Benzoylamino) -pro
 <tb> <SEP> pyl] -penem-3-carboxylic acid
 <tb> Acylating agent (continued) Method Product C6H5CONHCH2CH2CH2CH2CO2H 1 2 - [(4-Benzoylamino) butyl] penem-3-carboxylic acid # CH2OCONHCH2CONHCH2CO2H 1

   2 - [(Glycinamido) methyl] penem-3-carboxylic acid CH2oCoNHCH2CONHCH2CH2CO2H 1 2- [2- (Glycinamido) ethyl] penem-3-carboxylic acid # CH2OCONHCH2CONHCH2CH2CH2CO2H 1 2- [3- (Glycinamido) propyl] pen 3-carboxylic acid CH2oCoNHCH2CONHCH2CH2CH2- 1 2- [4- (glycinamido) butyl] CH2CO2H penem-3-carboxylic acid H2NCONHCH2CO2H 1 2- (ureidomethyl) -penem-3 carboxylic acid H2NCONHCH2CH2CO2H 1 2- (2-urepenem # - carboxylic acid H2NCONHCH2CH2CH2CO2H 1 2- (3-ureidopropyl) -penem
3-carboxylic acid H2NCONHCH2CH2CH2CH2CO2H 1 2- (4-ureidobutyl) -penem
3-carboxylic acid CH3NHCONHCH2CO2H 1 2 - [(methylcarbamoylamino) methyl] -penem3 -carboxylic acid CH3NHCONHCH2CH2CO2H 1 2- [2- (methylcarbamoylami

   no) -methyl] -penem-3-carboxylic acid CH3NHCONHCH2CH2CH2CO2H 1 2- [3- (methylcarbamoylamino) propylj-penein-3-carboxylic acid CH3NHCONHCH2CH2CH2CH2CO2H 1 2- [4- (methylcarbamoylamino) butyl] -penem-3CH-carboxylic acid NHCHON [(Phenylcarbamoylamino) methyl] -penem-3-carboxylic acid NHCONHCH2CH2CO2H 1 2- [2- (Phenylcarbamoylamino) ethyl] -penem-3-carboxylic acid NHCONHCH2CH2CH2CO2H 1 2- [3- (Phenylcarbamoylamino) propyl] -penem-3-carboxylic acid #CH2H2H2H2CH2CH2CH2CO2H2 1 2- [4- (phenylcarbamoylamino) butyl] -penem-3-carboxylic acid CH3CONHCONHCH2CO2H 1 2 - [(acetylcarbamoylamino) methyl) -penem-3-carboxylic acid CH3CONHCONHCH2CH2CO2H 1 2- [2- (acetylcarbamoylamino) 3-ethyl] -penem carboxylic acid CH3CONHCONHCH2CH2CH2CO2H 1

   2- [3- (Acetylcarbamoylamino) propyl] -penem-3-carboxylic acid CH3CONHCONHCH2CH2CH2CH2CO2H 1 2- [4- (Acetylcarbamoylamino) butyl] -penem-3-carboxylic acid # CONHCONHCH2CO2H 1 2 - [(Benzoylcarbamoylamino-3-) methyl] -pen carboxylic acid CONHCONHCH2CH2CO2H 1 2- [2- (benzoylcarbamoylamino) - ethyl] -penem-3-carboxylic acid CONHCONHCH2CH2CH2CO2H 1 2- [3- (benzoylcarbamoylamino) propyl] -penem-3-carboxylic acid # CONHCONHCH2CH2CHlCHcarbOoyl butyl] penem-3-carboxylic acid CH3OCONHCONHCH2CO2H 1 2 - [(Carbomethoxycarbamoyl amino) -methyl] penem-3-carboxylic acid CH3OCONHCONHCH2CH2CO2H 1 2- [2- (Carbomethoxycarba moylamino) ethyl] penem-3-carboxylic acid 1 2 CH3OCONHCONHCH2CH2CH2CO2H - [3- (Carbomethoxycarba

   moylamino) -propyl] -penem-3-carboxylic acid CH3OCONHCONHCH2CH2CH2CH2CO2H 1 2- [4- (Carbomethoxycarba moylamino) -butyl] -penem-3-carboxylic acid (CH3) 3Si (CH2) 2OCONHCONHCH2CO2Hethyl-carbonyl (methyl-trimethyl) ] -penem-3-carboxylic acid (CH3) 3Si (CH2) 20CONHCONHCH2- 1 2- [2- (2-trimethylsilyl CH2CO2H ethyloxycarbonylcarbamoyl amino) ethyl] -penem-3-carboxylic acid
EMI50.1


 <tb> Acx <SEP> ungsl <SEP> tcl <SEP> (continued) <SEP> method <SEP> product
 <tb> (CH3) 3Si (CH2) 2OCONHCON11CH2- <SEP> 1 <SEP> 2- [3- (2-trimethylsilylethyl
 <tb> CHoCH2CO2H <SEP> oxycarbonylcarbamoylamino)
 <tb> <SEP> propyl] -penem-3-carboxylic acid
 <tb> (CH3) 3Si (CH,) 2OCONHCONHCH2- <SEP> 1 <SEP> 2- [4- (2-trimethylsilylethyl
 <tb> CH2CH2CH2CO2H <SEP> oxycarbonylcarbamoylamino)
 <tb> <SEP> butyl] -penem-3 <SEP>

   -carboxylic acid
 <tb> CH3S2CNHCH2CO2H <SEP> 1 <SEP> 2 - [(methylthiothiocarbonyl
 <tb> <SEP> amino) methyl] -penem-3-carboxylic acid
 <tb> CH3S2CN <SEP> HCH2CH2CO2H <SEP> 1 <SEP> 2- [2- (Methylthiothiocarbo
 <tb> <SEP> nylamino) ethyl] -penem-3-carboxylic acid
 <tb> CH3S2CNHCH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (Methylthiothiocarbo
 <tb> <SEP> nylamino) -propyl] -penem-3-carboxylic acid
 <tb> CH3S2CNHCH2CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [4- (Methylthiothiocarbo
 <tb> <SEP> nylamino) -butyl] -penem-3-carboxylic acid
 <tb> CH3SO2NHCH2CO2H <SEP> 1 <SEP> 2 - [(methanesulfonylamino)
 <tb> <SEP> methyl] -penem-3-carboxylic acid
 <tb> CH3SO2NHCH2CH2CO2H <SEP> 1 <SEP> 2- [2- (methanesulfonylamino)
 <tb> <SEP> ethyl] -penem-3-carboxylic acid
 <tb> CH3SO2NHCH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (methanesulfonylamino)
 <tb> <SEP> propyl] -penem-3-carboxylic acid
 <tb> CH3SO2NHCH2CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [4- (methanesulfonylamino)
 <tb> <SEP>

   butyl] -penem-3-carboxylic acid
 <tb> SO2NHCH2CO2H <SEP> 1 <SEP> 2 - [(benzenesulfonylamino)
 <tb> <SEP> methyl] -penem-3-carboxylic acid
 <tb> <SEP> S
 <tb> <SEP> i <SEP> I
 <tb> H3CNHCNHCH2CH2CO2H <SEP> 1 <SEP> 2- [2- (N-methylthiocarbamoyl
 <tb> <SEP> S <SEP> amino) ethyl] -penem-3-carboxylic acid
 <tb> <SEP> I <SEP> I
 <tb> H3CNHCNHCH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (N-methylthiocarbamoyl
 <tb> <SEP> S <SEP> amino) -propyl] -penem-3-carboxylic acid
 <tb> <SEP> II
 <tb> H3CNHCNHCH2CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [4- (N-methylthiocarbamoyl
 <tb> <SEP> S <SEP> amino) -butyl] -penem-3-carboxylic acid
 <tb> <SEP> II
 <tb> NHCNHCH2CO2H <SEP> 1 <SEP> 2 - [(N-phenylthiocarbamoyl
 <tb> <SEP> S <SEP> amino) methyl] -penem-3-carboxylic acid
 <tb> <SEP> II
 <tb> NHCNHCH2CH2CO2H <SEP> 1 <SEP> 2- [2- (N-phenylthiocarbamoyl
 <tb> <SEP> S <SEP> amino) ethyl] -penem-3-carboxylic acid
 <tb> <SEP> II
 <tb> NHCNHCH2CH2CH2CO2H <SEP> 1 <SEP>

   2- [3- (N-phenylthiocarbamoyl
 <tb> <SEP> S <SEP> amino) -propyl] -penem-3-carboxylic acid
 <tb> <SEP> II
 <tb> NHCNHCH2CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [4- (N-phenylthiocarbamoyl
 <tb> <SEP> amino) -butyl] -penem-3 <SEP> carboxylic acid
 <tb> <SEP> K <SEP> NHCH2CO2H <SEP> 1 <SEP> 2 - [(guanylamino) methyl]
 <tb> <SEP> 1 <SEP> N <SEP>, <SEP>, <SEP> penem-3-carboxylic acid
 <tb> <SEP> AOo
 <tb> HO
 <tb> <SEP> ^ <SEP> NI <SEP> H <SEP> CH <SEP> CO <SEP> H <SEP> 1 <SEP> 2- [2- (guanylamino) ethyl]
 <tb> <SEP> 2 <SEP> 2 <SEP> 2 <SEP> 2 <SEP> penem-3-carboxylic acid
 <tb> N
 <tb> 110
 <tb> <SEP> N <SEP> 1I <SEP> NHCH <SEP> CH <SEP> CH <SEP> CO <SEP> H <SEP> 1
 <tb> <SEP> P <SEP> penem-3-carboxylic acid
 <tb> <SEP> HO¯ <SEP>
 <tb> <SEP> II <SEP> L <SEP> L <SEP>.

   <SEP> butyl] -penem3 <SEP> carboxylic acid
 <tb> <SEP> N
 <tb> <SEP> AOz
 <tb> HO <SEP> Ha2CH2 <SEP> CH <SEP> 2CH2CO2 <SEP> 11 <SEP> 1
 <tb>
EMI51.1


 <tb> acylating agent <SEP> (continued) <SEP> method <SEP> product
 <tb> <SEP> 1 <SEP> .3
 <tb> <SEP> 1 <SEP> 2 - [(acetimidoylamino)
 <tb> <SEP> NCH <SEP> CO <SEP> methyl] -penem-3-carboxylic acid
 <tb> H3C <SEP> 2 <SEP> 2
 <tb> <SEP> - <SEP> CH <SEP> 2 <SEP> a <SEP> 2CO2lE <SEP> 1 <SEP> 2- [2- (acetimidoylamino) <SEP> äthy1-penein-3 <SEP> carboxylic acid
 <tb> <SEP> - <SEP> CH <SEP> 2 <SEP> CH <SEP> CO <SEP> 2 <SEP> H <SEP> 1 <SEP> 2- [3- (acetimidoylamino)
 <tb> <SEP> 2 <SEP> L <SEP> 2 <SEP> propyl] -penem-3-carboxylic acid
 <tb> <SEP> n <SEP> - <SEP> CH <SEP> 2 <SEP> CH2 <SEP> OH <SEP> 2CH2CO2H <SEP> 1 <SEP> 2- [4- (acetimidoylamino)
 <tb> <SEP> c.

   <SEP> L <SEP> L <SEP> butyl] -penem-3-carboxylic acid
 <tb> <SEP> 0 <SEP> 0
 <tb> I <SEP> í <SEP> 1 <SEP> 2 - [(Forrnimidoylamino)
 <tb> ii <SEP> N-CH2CO2H <SEP> methyl] -penem.3-carboxylic acid
 <tb> <SEP> g1 <SEP> -ch2CH2CO2H <SEP> 1 <SEP> 2 <SEP> 1 <SEP> 2- [2- (formimidoylamino)
 <tb> <SEP> ethyl] -penem-3-carboxylic acid
 <tb> <SEP> -CH <SEP> OH <SEP> 2OH <SEP> 2CO2H <SEP> 1 <SEP> 2- [3- (formimidoylamino)
 <tb> <SEP> propyU-penem-3-carboxylic acid
 <tb> <SEP> 2 <SEP> OH <SEP> 2 <SEP> OH <SEP> 2OH2 <SEP> OH <SEP> 2CO2 <SEP> H <SEP> 1 <SEP> 2- [4- (formimidoylamino)
 <tb> <SEP> butyl] -penem-3-carboxylic acid
 <tb> O2NCH2CO2H <SEP> 1 <SEP> 2 - [(hydroxyamino) methyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> O2NCH2CH2CO2H <SEP> 1 <SEP> 2- [2- (hydroxyamino)
 <tb> <SEP> ethyl] -penem-3-carboxylic acid
 <tb> O2NCH2CH2CH2CH2co2H <SEP> 1 <SEP> 2- [4- (hydroxyamino) -bu
 <tb> <SEP> tyl] -penem-3-carboxylic acid
 <tb> <SEP>

   OCH3
 <tb> (CH3) 3Si (CH2) 2OCON-CH2CO2H <SEP> * <SEP> 1 <SEP> 2 - [(methoxyamino)
 <tb> <SEP> OCH3 <SEP> methyl] -penem-3-carboxylic acid
 <tb> (CH3) 3Si (CH2) 2OCON-CH2CH2CO2H <SEP> * <SEP> 1 <SEP> 2- [2- (methoxyamino)
 <tb> <SEP> OCH3 <SEP> ethyl] -penem-3-carboxylic acid
 <tb> (CH3) 3Si (CH2) 2OCON <SEP> CH2CH2CH2CO2H <SEP> * <SEP> 1 <SEP> 2- [3- (methoxyamino)
 <tb> <SEP> OCH3 <SEP> propyl] -penem-3-carboxylic acid
 <tb> <SEP> (CH3) 3Si (CH2) 20CON <SEP> CH2CH2CH2CH2C02H <SEP> * 1 <SEP> 2- [4- (methoxyamino)
 <tb> <SEP> INCH2 <SEP> butyl] -penem-3-carboxylic acid
 <tb> <SEP> (CH3) 3Si (CH2) 2OCON <SEP> CH2CO2H <SEP> * 2 <SEP> 2 - [(hydrazino) methyl]
 <tb> <SEP> penem-3 <SEP> carboxylic acid
 <tb> <SEP> NH2
 <tb> <SEP> (CH3) 3Si (CH2) 2OCON <SEP> CH2CH2CO2H <SEP> * 2 <SEP> 2- [2- (hydrazino)
 <tb> <SEP> ethyl] -penem-3-carboxylic acid
 <tb>
EMI52.1


 <tb> <SEP> c <SEP> lirungniitil <SEP> (continued) <SEP> method <SEP> product
 <tb>

    <SEP> NR2 <SEP> * 2 <SEP> 2- [3- (Hydrazino) -pro
 <tb> (CH3) 3Si (CH2) 2OCON <SEP> CH2CH2CH2CO2H <SEP> pyl] -penem-3-carboxylic acid
 <tb> <SEP> INCH2
 <tb> (CH3) 3Si (CH2) 20CON <SEP> CH2CH2CH2CH2CO2H <SEP> * 2 <SEP> 2- [4- (hydrazino) butyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> N (CH3) 2
 <tb> (CH3) 3Si (CH2) 2OCONCH2CO2H <SEP> * 2 <SEP> 2 - [(2,2-dimethylhydra
 <tb> <SEP> zino) -methyl] -penem-3
 <tb> <SEP> N (C113) 2 <SEP> carboxylic acid
 <tb> (CH3) 3Si (CH2) 2OCON <SEP> CH2CH2CO2H <SEP> * 2 <SEP> 2- [2- (2,2-dimethylhy
 <tb> <SEP> drazino) -ethyl] -penem
 <tb> <SEP> N (CH3) 2 <SEP> 3-carboxylic acid
 <tb> (CH3) 3Si (CH2) 20CON <SEP> CH2CH2CH2C02H <SEP> * 2 <SEP> 2- [3- (2,2-dimethylhydra
 <tb> <SEP> zino) -propyl] -penem-3
 <tb> <SEP> N (CH3) 2 <SEP> carboxylic acid
 <tb> (CH3), Si (CH2) 20CON <SEP> CH2CH, CH2CH2C02H <SEP> * 2 <SEP> 2- [4- (2,2-dimethylhy
 <tb> <SEP> drazino) -butyl] -penem
 <tb> <SEP> 3-carboxylic acid
 <tb> * Use of

   Trimethylsilylethyl instead of PNB in azetidinone intermediate and deblocking with F-.



     CH3CONHNHCH2CO2H * 2 2 - [(2-acetylhydrazino)
CH3CONHNHCH2CH2CO2H * 2 methyl] -penem-3-carboxylic acid
2- [2- (2-acetylhydrazino) ethyl] -penem-3-carboxylic acid
CH3CONHNHCH2CH2CH2CO2H * 2 2- [3- (2-acetylhydrazino) propyl] -penem-3-carboxylic acid
CH3CONHNHCH2CH2CH2CH2CO2H * 2 2- [4- (2-acetylhydrazino) butyl] -penem-3-carboxylic acid (CH3) 2NCH2CO2H 2 2 - [(dimethylamino) -methyl] - penem-3-carboxylic acid (CH3) 2NCH2CH2CO2H 2 2- [2 - (Dimethylamino) ethyl] penem-3-carboxylic acid (CH3) 2NCH2CH2CH2CO2H 2 2- [3- (dimethylamino) propyl] -penem-3-carboxylic acid (CH3) 2NCH2CH2CH2CH2CO2H 2 2- [4- (dimethylamino) -bu tyl] -penem-3-carboxylic acid
EMI52.2


 <tb> <SEP> CH3
 <tb> CH3CON <SEP> CH2CO2H <SEP> 1 <SEP> 2 - [(N-methylacetamido)
 <tb> <SEP> methyl] -penem3 <SEP> carboxylic acid
 <tb> <SEP> C113
 <tb> CH3CON <SEP> CH2CH2CO2H <SEP> 1 <SEP>

   2- [2- (N-methylacetamido)
 <tb> <SEP> ethyl] -penem-3-carboxylic acid
 <tb> <SEP> CH3
 <tb> <SEP> I
 <tb> CH3CON <SEP> CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [3- (n-methylacetamido)
 <tb> <SEP> propyl] -penem-3-carboxylic acid
 <tb> <SEP> CH3
 <tb> CH3CON <SEP> CH2CH2CH2CH2CO2H <SEP> 1 <SEP> 2- [4- (N-methylacetamido)
 <tb> <SEP> butyl] -penem-3-carboxylic acid
 <tb>
EMI53.1


 <tb> Acylicrunasmittel <SEP> (continued) <SEP> method <SEP> product
 <tb> <SEP> 0
 <tb> - <SEP> CO <SEP> H <SEP> 1 <SEP> 2 - [(phthalimido) methyl]
 <tb> <SEP> 2 <SEP> 2 <SEP> 2 <SEP> penem-3-carboxylic acid
 <tb> <SEP> 0
 <tb> <SEP> CH <SEP> OH <SEP> CO <SEP> H <SEP> 1 <SEP> 2- [2- (phthalimido) ethyl]
 <tb> <SEP> 2 <SEP> 2 <SEP> 2 <SEP> 2 <SEP> penem-3-carboxylic acid
 <tb> <SEP> -o
 <tb> <SEP> 1- <SEP> CH2OH2CH2CO2 <SEP> H <SEP> 1 <SEP> 2- [3- (phthalimido) propyl]
 <tb> / <SEP> L <SEP> r <SEP> penem-3-carboxylic acid
 <tb> <SEP> -0
 <tb> <SEP>

   -CHOH <SEP> OH2CH2CO <SEP> H <SEP> H <SEP> 1 <SEP> 2- [4- (phthalimido) butyl] 2 <SEP> penem-3-carboxylic acid
 <tb> <SEP> o
 <tb> CH2OCONHCH2CH2OCH2CO2H <SEP> 1 <SEP> 2 - [(2-aminoethoxy) methyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> CH2oCoNHCH2CH2SCH2CO2H <SEP> 1 <SEP> 2 - [(2-aminoethylthio) methyl]
 <tb> <SEP> penem-3-carboxylic acid
 <tb> <SEP> C02CH2
 <tb> CH2OCONHCH2CH2N <SEP> CH2CO2H <SEP> 1 <SEP> 2 - [(2-aminoethylamino)
 <tb> <SEP> methyl] -penem-3-carboxylic acid
 <tb> <SEP> CH3
 <tb> CH2OCONHCH2CH2N <SEP> CH2CO2H <SEP> 2 <SEP> 2- [N- (2-aminoethyl) -N-methyl
 <tb> <SEP> amino] -methylpenem-3-carboxylic acid
 <tb> CH2OCONH <SEP> OH <SEP> CO <SEP> H <SEP> 1 <SEP> 2- (p-aminobenzyl) -penem-3
 <tb> <SEP> 22 <SEP> carboxylic acid
 <tb> <SEP> x = r
 <tb> <SEP> // <SEP> 1 <SEP> 1 <SEP> 2- (o-aminobenzyl) -penem-3
 <tb> CH2OCONHn <SEP> carboxylic acid
 <tb> CH <SEP>, OCONH- (CO, H <SEP> 1 <SEP> 2- (p-aminophenyl) -penem-3 <SEP> 2

    <SEP> I <SEP> \ = / <SEP> 2 <SEP> carboxylic acid
 <tb> <SEP> CO- <SEP> B
 <tb> <SEP> 1 <SEP> H <SEP> 1 <SEP> 2- (m-aminophenyl) -penem-3
 <tb> 1 <SEP> OCONHX <SEP> carboxylic acid
 <tb>
EMI54.1


 <tb> Acylated gauze <SEP> (continued) <SEP> method <SEP> product
 <tb> <SEP> c02
 <tb> <SEP>> <SEP> 1 <SEP> 2- (o-aminophenyl) -penem-3
 <tb> <SEP> CH <SEP> 2OCONH <SEP> m <SEP> 1 <SEP> 2- (o-aminophenyl) -penem-3 <SEP> <SEP> carboxylic acid
 <tb> <SEP> C0I <SEP> 20CONHCH <SEP> 2 <SEP> XCO <SEP> 1 <SEP> 2- [E- (aminomethyl) phenyl]
 <tb> <SEP> CO <SEP> B
 <tb> <SEP> L
 <tb> <SEP> 1 <SEP> \\ <SEP> 1 <SEP> 2- [m- (aminomethyl) phenyl]
 <tb> <SEP> CH <SEP> 2oCoNHCH2 <SEP> penem-3-carboxylic acid
 <tb> <SEP> CO2H <SEP> 1 <SEP> 2- [o- (aminoinethyl) phenylj.
 <tb>



    <SEP> CH <SEP> OCONHCH,
 <tb> <SEP> 2 <SEP> Z <SEP> ¯ <SEP> penem-3-carboxylic acid
 <tb>
Example 27
The 2-penem products below in the form of triethylamine salts were treated with (CH3) 3N # SO3 in
Source material
EMI54. 2nd
 Exp.  A n = 1 exp. Bn = 2 exp. Cn = 3 exp. Dn = 4
Example 28 The following 2-penem products can be obtained from CH2Cl2 at 0.  Addition of sodium 2-ethylhexanoate in 1-butanol to the reaction solution resulted in precipitation of the specified products in the form of the disodium salts. 



   product
EMI54. 3rd

On 1 B. n = 2 C. n = 3
D. n = 4 benen starting products can be obtained by the following procedure. 
EMI54. 4th
  
EMI55. 1




  Starting material product
EMI55. 2nd

Exp.  A n = 1 A.  n = 1 exp.  B n = 2 B.  n = 2 exp.  C n = 3 C.  n = 3 exp.  D n = 4 D.  n = 4
Example 29 The following 2-penem products can be obtained from the specified starting products by the following procedure
EMI55. 3rd
   Base product product
EMI56. 1

Exp.  A n = 1
Exp. Bn = 2
Exp. Cn = 3
Exp. Dn = 4
Example 30 The following 2-penem products can be obtained from the following
A.  n = 1
B.  n = 2 C. n = 3
D.  n = 4 starting products can be obtained by the following procedure:
EMI56. 2nd
  
EMI57. 1
 m = 0-2 Z = - (CH2) 2Si (CH3) 3
R = H, CH3 B = -O (CH2) 2Si (CH3) 3 starting product
EMI57. 2nd

Exp. AR = H, m = 0
Exp.  B R = H, m = 1
Exp. CR = Hin = 2
Exp.  D R = CH3, m = 0
Exp.  E R = CH3, m = 1
Exp. 

  F R = CH3, m = 2
The use of H2NO (CH2) 2Si (CH3) 3 instead of H2NOCH3 in the above process resulted in the formation of the following products:
EMI57. 3rd
   ExpAm = 0, R = H Exp.  B m = 1, R = H Exp. Cm = 2, R = H Exp. Dm = 0, R = CH3
A.  R = H, m = 0
B.  R = H, m = 1
C.  R = H, m = 2 D. R = CH3, m = 0
E.  R = CH3, m = 1
F.  R = CH3, m = 2. 



   Exp.  Em = 1, R = CH3
Exp.  F m = 2, R = CH3. 



   The use of (CH3) 3Si- (CH2) 2OCONHNH2 instead of H2NO (CH2) 2Si (CH3) 3 in the above procedure gave the following products:
EMI57. 4th
      Exp.  A m = 0, R = H
Exp. Bm = 1, R = H Exp.  C m = 2, R = H
Exp.  D m = 0, R = CH3
Exp.  Em = 1, R = CH3
Exp. Fm = 2, R = CH3. 



   The use of (CH3) 2NNH2 instead of H, NO (CH2) 2Si (CH3) 3 in the above procedure gave the following products:
EMI58. 1
 Exp.  A m = 0, R = H Exp.  B m = 1, R = H Exp. Cm = 2, R = H Exp. Dm = 0, R = CH3 Exp.  Em = 1, R = CH3 Exp. Fm = 2, R = CH3. 



   Example 31
The use of (CH3) 3Si (CH2) 2OCON-NH2 instead of H2NO (CH2) 2Si (CH3) 3 in the above procedure resulted in the following products:
EMI58. 2nd
   ExpAm = 9, R = 11 Exp.  B m = 1, R = H Exp.  C m = 2, R = H Exp.  D m = 0, R = CH3 Exp.  E m = 1, R = CH3 Exp.  F m = 2, R = CH3. 
EMI58. 3rd




   A solution of 1.1 g (1.6 mmol) I and 0.16 ml (1.6 mmol) H in 30 ml methylene chloride was cooled in an ice bath and added dropwise with a 1M solution of pyridine in methylene chloride (1.7 ml, 1.7 mmol) was added.  The resulting reaction mixture was stirred at room temperature for 1 h and then filtered through Celite and washed with methylene chloride.  The filtrate and washings were combined and washed successively with 5 ml of 1N HCl, 5 ml of water, 5 ml of 1M NaHCO3 and brine, and dried over MgSO4 and concentrated in vacuo to give 900 mg (87%) III as an amorphous solid .  This product was used in the next step without refurbishment.  IR (CHCl3) 1755, 1690 cm-1. 



  NMR (CDCl3) # 8.22 (2H, d, J = 9 Hz), 7.55 (15H, m), 6.72 (2H, d, J = 9 Hz), 5.7 (1H, m) , 5.0 (2H, 2s), 3.55 (2H, 2s), 2.8 (4H, m).   
EMI59. 1




   A mixture of 1.3 g (2 mmol) III and 0.65 ml (3 mmol) IV was heated to 80 C for 4 h.  The reaction mixture was diluted with 10 ml of methylene chloride and washed twice with 5 ml of water.  The organic phase was dried over MgSO4 and concentrated in vacuo to give 1.4 g (90%) V as an amorphous solid. 



  This product was used in the next step without cleaning.  IR (CHCl3) 1755, 1690 cm-1.  NMR (CDCl3) #
8.25 (2H, d, J = 9 Hz), 7.55 (15H, m), 6.8 (2H, d, J = 9 Hz),
5.7 (1H, m), 5.1 (2H, 2s), 4.72 (2H, dq, J = 12 Hz, J = 6 Hz),
2.6 (4H, m), 1.4 (6H, s), 1.28 (6H, s). 
EMI59. 2nd




   A solution of 1.6 g (2.06 mmol) V in 60 ml of toluene was heated to reflux temperature for 5 h. 



   The solvent was removed in vacuo and the remaining oil was chromatographed on a silica gel column (30 g).  Elution was carried out with benzene followed by ether, the non-polar material being washed out first, followed by elution with ethyl acetate VI, 620 mg (62%) as a white solid, mp.  83-84 C from ether.  IR (CHCl3) 1790, 1710 cm-1 NMR (CDCl3) # 8.2 (2H, d, J = 9 Hz), 7.6 (2H, d, J = 9 Hz), 7.5 (2H, s ), 5.65 (1H, dd, Jtrans = 4 Hz, Jcis = 2 Hz), 5.22 (2H, 2s), 4.75 (2H, dq J = 12 Hz, J = 6 Hz), 3, 85 (1H, dd, Jgem = 15 Hz, Jtrans = 4 Hz), 3.5 (1H, dd, Jgem = 15 Hz, Jcis = 2 Hz), 2.8-3.3 (2H, m), 1 , 4 (6H, s), 1.28 (6H, s). 
EMI59. 3rd




   34 mg (0.4 mmol) of sodium bicarbonate, 4 ml of water and 200 mg of 30% Pd / Celite were added to a solution of 200 mg (0.4 mmol) of VI in 8 ml of tetrahydrofuran and 4 ml of ether, followed by 2 hours at 40 psi was hydrogenated.  The mixture was filtered and the phases were separated, after which the aqueous phase, after washing with 2 × 5 ml of methylene chloride, was cooled with ice, acidified with 1 ml of 1N HCl and extracted 5 × with 5 ml of chloroform.  The organic extracts were dried over MgSO4 and concentrated in vacuo to give 76 mg (52%) VII in the form of an oil.  IR (CHCl3) 1790, 1710 cm-1.  NMR (CDCl3) # 9.5 (1H, wh), 5.65 (1H, dd, Jtrans = 4 Hz, Jcis = 2Hz), 4.72 (2H, dq J = 12 Hz, J = 6Hz, 4, 2-5.1 (2H, m), 3.4-4.1 (2H, m), 2.7-3.4 (2H, m), 1.35 (6H, s), 1.25 ( 6H, s). 



   Example 32
EMI60. 1

To a cooled mixture of 1.324 g (2 mmol) 1 and 0.54 g (2.2 mmol) (crude) 2 in 15 ml CH2Cl2 was added dropwise 2.2 ml (2.2 mmol) of a 1M solution of pyridine in CH2Cl2 given.  The mixture was stirred at room temperature for 1 h and then filtered through Celite.  The filtrate was washed successively with 0.5N HCl, H2O, 0.5M NaHCO3 and brine.  The mixture was then dried over MgS4 and filtered through Celite / activated carbon, 0.9 g of an oil remaining after evaporation.  This oil was chromatographed on SiO2 (10% H2O) and eluted with ethyl acetate to give 0.5 g (32.8%) 3.  NMR # (ppm, CDCl3) 7.08-8.4 (m, 19H), 4.8-5.8 (3H, m), 4.1 (4H, q), 3.3-4.2 ( 2H, m), 2.7 (2H, m), 1.9 (2H, m), 1.3 (6H, t). 
EMI60. 2nd


 

   0.4 g (0.52 mmol) 3 in 35 ml of toluene was refluxed for 4 h and concentrated to dryness to give an oil containing 3,4 and 3P = 0.  Chromatography on SiO2 (10% H2O) and elution with ethyl acetate gave 0.1 g of pure 4, followed by 0.15 g of 3 and 4. 



  NMR # (ppm, CDCl3), 8.3 (2H, d), 7.67 (2H, d), 5.7 (H, q), 5.33 (2H, d), 4.2 (4H, q), 3.83 (H, q), 3.4 (H, q), 2.9 (2H, m), 1.9 (2H, m), 1.3 (6H, t).  IR (neat) 1790 cm-1 (ss-lactam) 1710 cm-1 (ester).   
EMI61. 1




   A mixture of 0.1 g (0.207 mmol) 4, 0.1 g 30% Pd / Celite and 17 mg (0.207 mmol) NaHCO3 in 10 ml THF, 5 ml ether and 5 ml water was at an initial pressure of 40 psi during Hydrogenated for 2 h.  After filtration through Celite, the phases were separated, the basic aqueous phase was washed with ethyl acetate and acidified with 1N HCl. 



  Then it was extracted with CH2C12 and dried over MgSO4.  CH2Cl2 solution was concentrated to give 48 mg of 5 (66.5%). 



  IR spectrum 61790 (ss-lactam) 61700
EMI61. 2nd
 Example 33
EMI61. 3rd

A mixture of 1.07 g (1.66 mmol) 1 and 0.42 g (3 mmol) 2 in 3 ml CH2Cl2 was heated to 80 over 5 h. 



  The crude oil was chromatographed on SiO2 (3% H2O) and eluted with ether, ether-ethyl acetate (1: 1) and ethyl acetate: 5% EtOH to give 1.0 g (82%) of 3.  This oil crystallized on standing, mp.  (Ather) 138-140.  NMR # (ppm, CDCl3) 8.2 (2H, d), 7.0-8.0 (17H, m), 4.6-5.5 (3H, m), 3.8 (3H, s ), 3.6 (3H, s), 1.5-3.5 (6H, m). 
EMI61. 4th
  



   0.5 g (0.69 mmol) 3 in 30 ml toluene was refluxed for 4 h.  After evaporating to dryness, chromatographed on SiO2 (3% H2O) and eluted with Et2O: EtOAc (1: 1) followed by EtOAc: 10% EtOH to give 0.18 g (58%) of 4.  NMR 8 (ppm, CDCl3), 8.25 (2H, d), 7.6 (2H, d), 5.65 (H, q), 5.3 (2H, d), 3.8 (3H, s), 3.6 (3H, s), 2.7-3.6 (2H, m), 1.5-2.5 (4H, m).    
EMI62. 1




   A mixture of 50 mg (0.112 mmol) 4, 9.125 mg NaHCO3 and 50 mg 30% Pd / Celite in 5 ml THF, 2.5 ml Et2O and 2.5 ml water was hydrogenated at an initial pressure of 40 psi for 2 h.  After filtration through Celite, the phases were separated and the basic aqueous phase was washed well with EtOAc and lyophilized under high vacuum, giving 28 mg 5 (75.9%, hygroscopic).  IR (KBr) 1770 cm-1 (ss-lactam), 1610 cm- (-COO-). 



   Example 34 (1'R, 5R6R) and (1'S, 5S, 6S) 6- (1'-hydroxy-1'-ethyl) -2-methylpenem-3-carboxylic acid (isomer D) (illustrated from most preferred methods for Introduction of the 6-substituent in the middle of the synthesis)
EMI62. 2nd

A.  Preparation of 4-tritylthio-2-azetidinone intermediates
1.    1- (trimethylsilyl) -4-tritylthio-2-azetidinone
EMI62. 3rd

A solution of 345 mg (1 mmol) of 4-tritylthio-2-azetidinone, 80 mg (0.5 mmol) of 1,1,1, 3,3,3-hexamethyldisilazane and 55 mg (0.5 mmol) of chlorotrimethylsilane in 20 ml of dichloromethane was heated to reflux temperature for 18 h. 



  After concentration of the reaction mixture, the desired compound was obtained in pure form.  6 (ppm, CDC13): 7.32 (15H, m, aromatic), 4.22 (1H, dd, H-4), 2.67 (1H, dd, J = 4.1, J = 16, H) -3), 2.22 (1H, dd, J = 2.2, J = 16, H-3), 0.3 (9H, s, CH3). 



  2nd  1- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone
EMI62. 4th

1.62 ml (11.6 mmol) of triethylamine were added dropwise over 5 min to a cooled (0) and stirred solution of 3.5 g (10.1 mmol) of 4-tritylthio-2-azetidinone and 1.68 g (12 , 7 mmol) of chloro-t-butyldimethylsilane in 35 ml of DMF.  The reaction mixture was stirred at room temperature for 18 h and then diluted with 250 ml of water and 200 ml of ether.  The organic phase was washed 3 times with 50 ml of water, dried and concentrated to give 4.33 g of an oil.  After recrystallization from pentane, 4.1 g (89%) of the desired compound were obtained in the form of a white solid. 

  M.p.  113-114.    8 (ppm, CDC13): 745 (15H, m, aromatic), 4.2 (1H, dd, H-4), 2.63 (1H, dd, J = 4, J = 16, H-3), 2.13 (1H, dd, J = 2, J = 16, H-3), 1.0 (9H, s, t-Bu), 0.35 (6H, s, Me).    vC = O 1735 cm-1. 



   Analysis for C28H33NOSSi Calculated: C, 73.15, 11, 7.24, N, 3.05, S, 6.97 Found: C, 73.27, 11, 7.32, N, 2.97, S, 6.94.    



   3rd    1-methoxymethyl-4-tritylthlo-2-azetidinone
EMI63. 1

A solution of 1.38 g (4.0 mmol) of 4-tritylthio-2-azetidinone in 10 ml of THF was added to a well-stirred suspension of 200 mg of 50% sodium hydride (4.1 mmol), washed with pentane) in 10 ml T11F given at -15.  12 drops of methanol were added to the mixture and stirring continued at -15 'for 0.5 h.  0.58 g (4.6 mmol) of methoxymethyl bromide was added to the mixture, which was stirred for 2 hours, diluted with ether, washed with water and brine, and dried and concentrated to give 1.72 g of an oil. 

  Recrystallization from pentane gave a white solid (1.41 g) mp.    72-76.     6 (ppm, CDCl3), 7.3 (15H, m, aromatic), 4.4 (3H, m, NCH2O and H-4), 3.22 (3H, s, CH3), 2.76 (2H, m, H-3).    



   4th 1- (methoxyethoxymethyl) -4-tritylthio-2-azetidinone
EMI63. 2nd

To a suspension of 322 mg (1 mmol) of tetrabutylammonium bromide and 70 mg (85%, 1.1 mmol) of potassium hydroxide in 10 ml of dichloromethane, cooled to 5, 345 mg (1 mmol) of 4-tritylthio-2 were stirred vigorously -azetidi- non and 187 mg (1.5 mmol) methoxyethoxymethyl chloride added.  The mixture was stirred at room temperature for 2 hours, the solvent was evaporated and the residue was partitioned between water and ethyl acetate.  The dried organic phase was concentrated to give 415 mg of a viscous oil. 

  After purification by column chromatography on silica gel and elution with ether (5%) dichloromethane, the desired compound (206 mg, 48%) was obtained as an oil.     6 (ppm, CDCl3), 7.30 (15H, m, aromatic), 4.57 (2H, AB quartet, N-CH2O), 4.46 (1H, dd, H-4), 3.50 (4H , s, OCH2CH2O), 3.30 (3H, s, CH3), 2.75 (2H, m, H-3).    



   5. 1- (2'-Tetrahydropyranyl) -4-tritylthio-2-azetidinone
EMI63. 3rd

1.6 ml (1, 6M, 2.56 mmol) of n-butyllithium was added dropwise to a solution of 863 mg (2.5 mmol) of 4-tritylthio-2-azetidinone in THF at -78 '.  After stirring for 15 minutes, 560 mg (4.7 mmol) of 2-chlorotetrahydropyran was added to the reaction mixture, which was left to stand for 1.5 hours.  The reaction solution was then diluted with ethyl acetate, washed with brine, dried and concentrated to leave 635 mg of an oil.  After column chromatography on silica gel and elution with dichloromethane ether, a mixture of the isomeric desired compounds was obtained, contaminated with little starting product.  6 (ppm, CDCl3), 7.28 (15H, m, aromatic), 4.4 (H, dd, H-4), 2.9-2.2 (2H, m, H-3), 4, 1-3.2 and 2.2-0.7 (tetrahydropyranyl). 

 

   B.  Preparation of 3- (1'-hydroxy-1'-ethyl) -1-methoxy-methyl-4-tritylthio-2-azetidinone
EMI63. 4th
  a) (1'-S, 3S, 4R and 1'R, 3R, 4S) isomer (isomer C)
A solution of lithium diisopropylamide was prepared in 5 ml THF at -78 C from 1.0 ml (1, 6M, 1.6 mmol) n-butyllithium and 0.25 ml (1.84 mmol) diisopropylamine. 



  After 30 minutes, a solution of 491 mg (1.42 mmol) of 1-methoxymethyl-4-tritylthio-2-azetidinone in 6 ml of THF was added dropwise and the solution was stirred for 15 minutes.  3.0 ml of acetaldehyde was added dropwise, followed by 30 ml of water after 20 minutes.  The mixture was brought to pH 3 with 2% HCl and extracted 5 times with 20 ml of ethyl acetate.  The combined organic phases were washed with brine, dried and concentrated to give an oil which crystallized after treatment with ether: 440 mg, 80%, mp.  188.5-189 C.    



     IHmr (CDCl3) 87.3- (1511, m, aromatic), 4.37 (2H, ABq, N-CH2O), 4.32 (1H, d, J = 2, H-4), 3.17 ( 3H, s, OCH3), 3.32-2.70 (2H, m, H-3 and H-5) and 1.12 ppm (3H, d, J = 7, CH3). 



   Analysis for C26H27NO3S Calculated: C, 72.02, H, 6.28, N, 3.23, S, 7.39 Found: C, 71.99, H, 6.02, N, 3.21, S, 7.40. 



   b) (1'S, 3S, 4R and 1'R, 3R, 4S) and (1'R, 3S, 4R and l'S, 3R, 4S) (isomers C and B)
A solution of 0.482 mmol lithium diisopropylamide was prepared in -78 C 3 ml dry ether from 0.191 ml butyllithium of a 2.52 M solution in hexane (0.482 mmol) and 0.067 ml (0.482 mmol) diisopropylamine. 



  After 20 min, a solution of 0.171 g (0.439 mmol) of 4R and 4S) -methoxymethyl-4-tritylthio-2-azetidinone in a mixture of 1 ml of dry ether and 1 ml of dry THF was added dropwise and the resulting clear solution was added to - 78 C stirred for 15 min.  A solution of 0.96 ml of tetrabutylammonium fluoride (0.5 M solution in THF, 0.48 mmol) was then added, whereupon a precipitate formed with a pale pink color.  After 5 min at -78 C, the reaction mixture was quenched with freshly distilled acetaldehyde (0.2 ml, excess) and stirring continued for 15 min.  The mixture was worked up by adding a saturated solution of ammonium chloride and extracting with 2 × 25 ml of ethyl acetate. 

  The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 0.228 g of an oil which was chromatographed on 10 g of silica gel.  A mixture of benzene and ethyl acetate (6: 4) gave 0.106 g (62%) of the substrate and a mixture of the two isomeric alcohols, which were separated by chromatography on thick-film plates (same solvent system).  The alcohol with the higher Rf value (0.033 g, 17%) was identical to the isomer (isomer C) mentioned: mp.  188.5-189 C (ether dichloromethane); the alcohol with the low Rf value (0.030 g, 16%) (isomer B) was obtained as an oil, which crystallized from hexane with difficulty: mp. 



  94-95 C.  IR (CH2Cl2) #max: 3600 (OH), 1760 cm t (C = O); lHmr (CDCl3) 6: 6.9-7.5 (15H, m, aromatic), 4.2 (2H, center of ABq, J = 11.5, CH2-O-CH3), 4.28 (1H, d, J = 2.0, 4-H), 3.65 (1H, broad sextet center, H-1 '), 3.3 (1H, dd, J3.4 trans = 2.5, J3.1 = 5.5, H3), 3.15 (3H, s, O-CH3), 1.55 (1H, broad s, OH-1 '), 1.05 (3H, d, J = 6.5, H-2 '). 



   Analysis for C26H27NO3S Calculated: C, 72.02, H, 6.28, N, 3.23, S, 7.39 Found: C, 71.77, 11, 6.36, N, 3.15, S, 7.43. 



   C.  Preparation of trans-3-acetyl-1-methoxymethyl-4-tritylthio-2-azetidinone
EMI64. 1

Lithium diisopropylamide was prepared under nitrogen at -78 ° C in a conventional manner from diisopropylamine (0.34 ml, 2.4 mmol) and n-butyllithium (1.1 ml of a 2.2 M solution in hexane, 2.4 mmol) in 3 ml THF.  A solution of 1-methoxymethyl-4-tritylthio-2-azetidinone (0.78 g, 2 mmol) in 3 ml THF was added dropwise and after stirring for 20 min at -78 C, 0.53 g (6 mmol) ethyl acetate added and stirring continued at -78 C for 0.75 h.  The reaction mixture was diluted with ether and washed with ammonium chloride solution, water and brine, dried and concentrated to give 0.7 g of an oil. 

  The mixture was worked up by chromatography on 20 g of silica gel, elution with increasing proportions of ether in benzene, whereupon the desired compound was obtained from the corresponding fractions as a colorless oil (0.32 g, 37%).  ÚHmr (DCDl3) 6: 7.7-6.8 (15H, aromatic), 4.85 (1H, d, J = 2, H-4), 4.5 (2H, s, N-C112-O) , 3.9 (1H, d, J = 2, H-3), 3.22 (3H, s, CH3) and 2.0 ppm (3H, s, CH3); IR #max: 1770, 1710 cm-1. 



   D.  Preparation of trans-3-acetyl-l - (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone
EMI64. 2nd

Diisopropyllithium amide was prepared in a conventional manner from 0.18 ml (1.24 mmol) of diisopropylamine and 0.78 ml of n-butyllithium (1.6 M solution in hexane, 1.24 mmol) in 8 ml of THF.  A solution of 0.46 g (1 mmol) of 1- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone in 8 ml of THF was added dropwise at -78 ° C.  After stirring for 5 min, 1 ml of ethyl acetate was added and the mixture was stirred at -78 C for 3 h.  The mixture was then acidified to pH 6 with cold 0.5 N hydrochloric acid and extracted twice with 20 ml of ethyl acetate. 

  The combined organic phases were dried and concentrated to give 0.5 g of an oil which crystallized from pentane: 200 mg, 40%, mp.    122-124 C.  IR #max: 1750, 1710 cm-1. 



     lHmr (CDCl3) b: 8-7.1 (15H, m, aromatic), 4.83 (1H, d, J = 2, H-4), 3.38 (1H, d, J = 2, H = 3), 1.80 (3H, s, CH3), 0.92 (9H, s, Bu) and 0.3 ppm (6H, s, CH3). 



   E.  Preparation of trans -1- (t-butyldimethylsilyl) -3- formyl -4- tritylthio -2- azetidinone
EMI65. 1

To a cooled (-78 C) solution of 0.34 ml (2.4 mmol) diisopropylamine in 5 ml tetrahydrofuran was added dropwise a solution of 1.6 ml (2.4 mmol) 1.5 M n-BuLi under nitrogen .  After stirring for 30 min, a solution of 1.0 g (2.18 mmol) of 1- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone in 5 ml of tetrahydrofuran was added dropwise and the mixture was stirred for a further 30 min.  0.8 ml (9.9 mmol) of ethyl formate was added to the cooled solution and stirred for 10 minutes.  The reaction mixture was then washed successively with 5 ml of cold 1N hydrochloric acid, 6 ml of 1M sodium bicarbonate, 10 ml of water and brine. 

  The organic phase was dried over MgSO4, concentrated and recrystallized from pentane, 810 mg (76%) formate as a white solid of mp. 



  132-133 C were obtained.    IR (CHC13) Xmax: 1760, 1715 cm-1.  ÚHmr (CDCl3) #: 9.0 (1H, d, J = 1.25 Hz), 7.30 (15H, m), 4.7 (1H, d, J = 1.5 Hz) and 3.5 ppm (1H, t, J = 1.5 Hz). 



  Note: a) diisopropylamine was distilled over CaH and stored over KOH b) tetrahydrofuran was distilled over LAH and stored over molecular sieve 3 c) ethyl formate was stirred with KrCO3 at room temperature and then distilled over P2O5 d) n-BuLi was titrated with 1N hydrochloric acid. 



   F.  Preparation of l- (t-butyldimethylsilyl) -3- (l'-hydroxy l'-ethyl) -4-tritylthio-2-azetidinone (4 isomers)
EMI65. 2nd

3.4 ml (1.6 M, 5.44 mmol) of n-butyllithium were added over 5 min to a solution of 0.847 ml (6.23 mmol) of diisopropylamine in 30 ml of THF and kept at -78 ° C.  After 0.5 h, a solution of 2.0 g (4.4 mmol) of 1- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone in 20 ml of THF was added, after which 10 ml of acetaldehyde was added after 15 minutes and then after a further 15 min, 100 ml of water was added. 

  The mixture was brought to pH 5-6 with dilute hydrochloric acid and extracted 3 × with 30 ml of ethyl acetate.     The organic phases were washed with brine, dried and concentrated, leaving an oil which, after thin-layer chromatography, was a mixture of the 4 isomers (denoted by isomers A, B, C and D in decreasing order of polarity). 



   Recrystallization of the oily residue in ethyl acetate-pentane gave the isomers B and C as white solids and the isomers A and D remained in the mother liquor.  The four pure compounds were obtained by preparative chromatography (Waters, 500) of the solids and mother solutions obtained.  The relative proportions were: A, 17%; B, 32%; C, 39%; D, 12%.  In the reaction mentioned, using ether instead of THF and quenching after 1 min at -78 C gave relative proportions of A, B, C and D of: 12.9, 30, 38, 18.2% .  In ether when the reaction came to 20 C in 2 h before quenching, the proportions were: 13.4, 24.6, 44 and 18%. 

  The addition of one molar equivalent of anhydrous magnesium bromide to the reaction mixture gave fractions of: 19.2, 19.7, 30.1 and 31%. 



   Isomer A: This isomer has a cis stereochemistry at C3-C4.  It is a racemic mixture of (1'S, 3R, 4R) and (1'R, 3S, 4S) enantiomers.  Compounds that were later derived from compound A are each referred to as isomer A.  They consist of enantiomeric mixtures and have the same configuration at C1, C3 and C4. 



  Compounds derived from Compound A via a reaction that has an inversion of configuration are referred to as Isomer D when the inversion is on and as Isomer C when the inversion is at C3. 



  M.p.  152-153 C.       1Hmr (CDC13) 6: 8.0-6.8 (15H, m, aromatic), 4.30 (1H, d, J = 5.5, H-4), 3.78 (1H, m, H- 1 '), 3.10 (1H, dd, J = 5.5, J = 10.11-3), 1.22 (3H, d, J = 6.5, CH3), 0.95 (9H, s, Bu), 0.27 (6H, 2s, CH3). 



   Analysis for C30H37NO2Si Calculated: C, 71.52, 11, 7.40, N, 2.78, S, 6.36 Found: C, 71.28, 11, 7.41, N, 2.48, S, 6.19.    



   Isomer B: This isomer has trans stereochemistry at C3-C4.  It is a racemic mixture consisting of the (1'R, 3S, 4R) and (1'S, 3R, 4S) enantiomers.  Compounds with the same configuration at C1, C3 and C4 are referred to below as isomer B; IR (CHC13) vrnax: 1745 cm- (C = O), m.p.    158-159 C; ÚHmr (CDCl3) 6: 7.60-7.10 (15H, m, aromatic), 4.02 (1H, d, J = 0.8, H-4), 3.32 (1H, dd, J = 3.0, J = 0.8, H-3), 3.55-3.15 (1H, m, H-1 '), 0.88 (12H, CH3, and t-Bu), 0.16 (6H, s, CH3). 

 

   Isomer C: This isomer has trans stereochemistry at C3-C4.  It is a racemate formed from (1'S, 3S, 4R) and (1'R, 3R, 4S) enantiomers.  Compounds with the same configuration at C1, C3 and C4 are referred to as isomer C.  M.p.  134-136 C; ÚHmr (CDCl3) #: 7.60-7.10 (15H, m, aromatic), 4.32 (1H, d, J = 1.8, H-4), 3.02 (1H, dd, J = 2.7, J = 1.8, H-3), 3.02-2.5 (1H, dq, J = 2.7, J = 6, H-1 '), 1.02 (3H, i.e. , J = 6, CH3), 0.95 (9H, s, t-Bu), 0.27 (6H, s, CH3); IR (CHC13) v ,,,: 1735 cm- '(C = 0).    



   Isomer D: This isomer has cis stereochemistry at C3-C4.     It is a racemate formed from the (1'R, 3R, 4R) and (l'S, 35 45) enantiomers.     Compounds with the same configuration at C1, C3 and C4 are referred to as isomer D.  M.p.  171-172 C; Hmr (CDCl3): 7.80-6.90 (15H, m, aromatic), 4.70 (1H, d, J = 4.5, H-4), 3.02 (1H, dd, J = 4 , 5, J = 0.5, H-3), 2.39 (1H, dq, J = 0.5, J = 6.5, H-1 '), 1.0 (3H, d, J = 6.5, CH3), 0.97 (9H, s, t-Bu), 0.32 (6H, s, CH3). 



   Analysis for C30H37NO2SSi Calculated: C, 71.52, H, 7.40, N, 2.78, S, 6.36 Found: C, 71.27, H, 7.43, N, 2.51, S, 6.31. 
EMI66. 1




  2-trans isomers
A solution of 1.0 g (2 mmol) of trans-3-acetyl-1- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone in 30 ml of THF was added dropwise under nitrogen to a cooled, stirred suspension (0 C, 0 , 38 g) sodium borohydride (10 mmol) in 120 ml THF.  The ice bath was removed and the mixture was stirred at room temperature for 4 hours.  Then it was poured into ice-cooled 1N hydrochloric acid (pH 6), stirred for 15 min and extracted 3 times with ether.  The combined ether extracts were dried and concentrated to 1.04 g of an oil which, after recrystallization from pentane, gave the desired compounds as a 70:30 mixture of the C and B isomers.  M.p. 



  119-121 C, 84%. 
EMI66. 2nd




   A suspension of 4.78 g (15 mmol) copper (I) iodide in
50 ml ether was cooled to 0 C and treated under nitrogen with 25 ml (50 mmol) of a 1.9 M solution of methyl lithium.  The brown solution was stirred at 0 C for 10 min and then cooled to -60 C and added dropwise with 2.43 g (5.0 mmol) of trans-II - (t-butyl-dimethylsilyl) -3-formyl-4- tritylthio-2-azetidinone in a mixture of
10 ml tetrahydrofuran / 40 ml ether treated.  After stirring for a further 3 h, the solution was warmed to -40 ° C. and carefully treated with a 1 M solution of ammonium chloride. 

  The mixture was filtered through Celite and the organic phase was washed with 3 × 5 ml of a 1 M solution of ammonium chloride and with brine and dried over sodium sulfate.  Filtration and on
Isomer B narrow gave an alcohol, Isomer B, which crystallized from warm pentane and gave 1.6 g (65%), mp. 



  160-161 C.  JR (CHCl3) #max: 1730 cm-1.    ÚHmr (CDCl3) #: 7.32 (15H, m), 4.05 (1H, s), 3.4 (1H, d, J = 3 Hz), 3.25-3.55 (1H, m) , 1.6 (1H, s), 0.9 (12H, s) and 0.1 ppm (6H, s). 



  Note: a) tetrahydrofuran and ether was distilled over LAH b) methyl lithium was titrated with 1N hydrochloric acid c) copper (I) iodide was purified by continuous extraction with anhydrous tetrahydrofuran in a Soxhlet extractor for 18 h and then in the excicator (P205) dried for 18 h. 
EMI66. 3rd




   0.1 ml (0.1 mmol) of methyl magnesium iodide was added dropwise to a cooled (0 C) and stirred solution of 25 mg (0.05 mmol) of trans-1- (t-butyldimethylsilyl) -3-formyl- 4-tritylthio- 2-azetidinone added in 2 ml of THF.  The solution was stirred at 0 C for 1.5 h, poured onto an ammonium chloride solution, acidified with 1N hydrochloric acid and extracted with ether.  Drying and concentrating the organic extracts gave an oil consisting of the starting product and a small proportion of a mixture of the two trans compounds with dominant isomer B. 



   F.  Preparation of (1'S, 3S, 4R- and 1'R, 3R, 4S) -l- (t-butyldimethylsilyl) -3- (1'-trimethylsilyloxy-1'-ethyl) -4-tritylthio2-azetidinone (isomer C)
EMI67. 1

A solution of 15 mg (0.3 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4- tritylthio-2-azetidinone and 35 mg (0.30 mmol) of azidotrimethylsilane in 6 ml of dry THF were stirred at room temperature until the starting product had disappeared (15 min). 



  Working up the reaction mixture by column chromatography (silica gel, CH2C12) gave the desired compound as a white solid (128 mg, 74%), mp.    144146 C. 



  ÚHmr (CDCl3) #: 7.10-7.60 (15H, m, aromatic), 4.30 (1H, d, J = 1.5, H-4), 2.25-2.89 (2H, m, H-3, H-1 '), 0.82-1.07 (12H, m, t-Bu, H-2'), 0.27 (6H, s, CH3), 0.10 (9H , s, -O-Si (CH3) 3). 



  IR (CHC13) vrnax: 1736 cm-1 (C = O). 



   G.  Preparation of (l'S, 3R, 4R and 1'R, 3S, 4S) -1 '- (t-butyldimethylsilyl) -3- (1'methoxymethoxyether-1'-ethyl) -4-tritylthio-2- azetidinone (isomer A). 
EMI67. 2nd




   approx.  12.5 ml of n-butyllithium (1.6M solution in hexane, 20 mmol, just enough to obtain a permanent pink color) were added dropwise to a solution of (1'S, 3R, 4R and 1'R, 3S, 4S) - 1- (t-Butyldimethylsilyl) -3- (1'-hydroxy-1 'ethyl) -4-tritylthio-2-azetidinone (isomer A, 10.1 g, 20 mmol) in 100 ml THF at -78 ° C.  After stirring for 15 min, a solution of 2 ml (24 mmol) of bromomethoxymethyl ether in 30 ml of T11F was added dropwise.  The mixture was stirred at -78 for 1 h and at room temperature for 2 h and poured into 200 ml of ammonium chloride solution. 

  The extraction was carried out 3 times with 200 ml of ethyl acetate, followed by washing with brine, drying over sodium sulfate and concentration to give the desired compound, which was chromatographed on silica gel and eluted with increasing proportions of ether in benzene (10.4 g, 95% ).  ÚHmr (CDCl3) 6: 7.1-7.5 (15H, m, aromatic), 4.47 (1H, d, H-4), 4.23 (2H, ABq, J = 7.0 CH2-O ), 3.1-3.4 (2H, m, H-3 and H-1 '), 3.23 (3H, s, O-CH3), 1.37 (3H, d, J = 6.5 , CH3), 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CH3). 



   H.  Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-formyloxy-1'-ethyl) -4-tritylthio-2-azetidinone ( Isomer C)
EMI67. 3rd

A solution of 50 mg (0.1 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4 -tritylthio-2-azetidinone (isomer C), 100 mg (0.4 mmol) of p-bromobenzenesulfonyl chloride and 24 mg (0.2 mmol) of dimethylaminopyridine in 3 ml of DMF were stirred at room temperature until the starting product disappeared (0.5 h ). 

 

  Then the reaction mixture was diluted with water and extracted with ether.  The organic extracts were washed with brine, dried over MgSO4 and concentrated.  The desired compound was purified by column chromatography.  ÚHmr (CDCl3) 6: 7.80 (1H, s, CHO), 7.20-7.66 (15H, m, aromatic), 3.90-4.36 (1H, m, H-1 '), 4.07 (1H, d, J = 3, H-4), 3.22 (1H, broad s, H-3), 1.18 (3H, d, J = 6.5, H-2 ') , 1.0 (9H, s, t-Bu), 0.31 (6H, s, di-CH3). 



   I.  Preparation of (1'R, 3S, 4R and l'S, 3R, 4S) -1 '- (t-butyldimethylsilyl) -3- (1'-acetoxy-1' -ethyl) -4-tritylthio-2-azetidinone ( Isomer B)
EMI67. 4th
  
A solution of 13.85 g (27.5 mmol) (1'R, 3S, 4S and 1'S, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone in 75 ml pyridine, 50 ml acetic anhydride (prepared at 0) was stirred at room temperature for 40 h.  The reagents were evaporated (the last traces were removed azeotropically 3 times with toluene), leaving an almost white solid.  The crude derivative was recrystallized from ether-petroleum ether to give the pure desired compound (97.5%). 



  ÚHmr (CDCl3): 7.64-7.03 (1 5H, m, 11 aromatic), 4.60 (1H, m, J = 6, H-1 '), 3.92 (1H, d, J = 2, H-4), 3.55 (1H, dd, J = 2, J = 6, H-3), 1.79 (3H, s, CH3CO), 0.98 (3H, d, J = 6 , CH3), 0.88 (9H, s, t-butyl), 0.12 (6H, s, CH3).  IR (CHCl3) v max: 1775, 1740 cm-1 (C = O). 



   J.  Preparation of 1- (t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarbonyl) - 1'-ethyl) -4-tritylthio-2-azetidinone (4 isomers)
EMI68. 1
   Isomer C.  8.8 ml of n-butyllithium from a 1.6M solution in
Hexane (14 mmol, just enough to give a permanent pink color) was added dropwise to a solution of isomer C of 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1 'ethyl) -4-tritylthio- 2-Azetinone (6.55 g, 13 mmol) in 70 ml THF at -78 C added.  After stirring for 15 min, a solution of 3.2 g (14.8 mmol) of paranitrobenzyl chloroformate in 30 ml of THF was added dropwise.  The mixture was stirred at -78 C for 1 h and poured into 100 ml of ammonium chloride solution.  Extraction with 3 x 100 ml ethyl acetate, washing with brine, drying and concentration gave 11 g of crude product. 

  The pure desired compound was obtained by chromatography on 220 g of silica gel, elution with increasing proportions of ether in benzene.  93%, mp.  118-119 C (ether).  ÚHmr (CDCl3) #: 8.35-7 (19H, m, aromatic), 5.12 (2H, s, benzyl), 4.08 (1H, d, J = 1.8, H-4), 4 -3.5 (1H, dq, J = 6.5, J = 2, H-1 '), 3.10 (1H, dd, J = 2, J = 1.8, H-3), 1, 2 (3H, d, J = 6.5, CH3), 1.0 (9H, s, Bu) and 0.30 ppm (6H, 2s, CH3).  IR (CHC13) vrnax: 1745 cm (C = O). 



   Analysis for C38H42N206SiS Calculated: C, 66.83, H, 6.20, N, 4.10, S, 4.69 Found: C, 66.90, H, 6.26, N, 4.11, S, 4.59. 



    Isomer B.  The isomer B of l- (t-butyldimethylsilyl) 3- (1'hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone, treated as described above, gave pure isomer B of l- (t-butyldimethylsilyl) -3- (1'-Paranitrobenzyldioxycarbonyl -'- ethyl) 4-tritylthio-2-azetidinone in the form of a foam, 95%.     ÚHmr (CDCl3) a: 8.32-6.90 (19H, m, aromatic), 5.1 (2H, s, benzyl), 4.65-4.20 (1H, m, H-1 '), 3.97 (1H, d, J = 1.5, H-4), 3.58 (1H, dd, J = 1.5, J = 5.8, H-3), 1.1 1.1 (3H, d, CH3), 0.7 (9H, s, Bu) and 0.2 ppm (6H, s, CH3).  IR (film) #max: 1755, 1740 cm-1 (C = O). 



    Isomer A.  The isomer A of l- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone, treated as described above, gave pure isomer A of butyldimethylsilyl) -3- (1'-Paranitrobenzyldioxycarbonyl-1 'ethyl-4-tritylthio-2-azetidinone in the form of an oil.  95%.     'Hmr (CDCl3) a: 8.3-6.7 (19H, m, aromatic), 4.95 (2H, ABq, benzyl), 4.53 (1H, p, J = 7.5, J = 7 , 5, H-1 '), 4.31 (1H, d, J = 6, H-4), 3.32 (1H, dd, J = 6, J = 7.5, H-3), 1 , 44 (3H, d, J = 6.5), 0.95 (9H, s, t-Bu) and 0.2 ppm (6H, 2s CH3). 



    Isomer D.  In the same way, isomer D of 1- (t-butyldimethylsilyl) -3- (1'-hydroxy- 1 'ethyl) -4-tritylthio-2-azeidinone gave the pure isomer D of 1- (t-butyldimethylsilyl) - 3 (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-tritylthio-2-aze tidinone, 90%.     ÚHmr (CDCl3) a: 8.3-6.7 (19H, m, aromatic), 5.20 (2H, ABq, benzyl), 4.72 (1H, d, J = 5, H-4), 3 , 50 (1H, dq J = 6.5, J = 0.5, H-1 '), 2.85 (1H, dd, J = 0.5, J = 5, H-3), 1.03 (3H, d, J = 6.5, CH3), 1.0 1.0 (9H, s, t-Bu) and 0.35 ppm (6H, s, CH3).  M.p.  130-132 C. 



   Analysis Calculated: C, 66.83, 11, 6.20, N, 4.10, S, 4.70 Found: C, 66.56, 11, 6.28, N, 3.96, S, 4, 89.    



   K.  Preparation of 1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer C)
EMI68. 2nd

A solution of 2.0 g (4 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) 4- tritylthio-2-azetidinone (isomer C) in 80 ml dichloromethane was treated at 5 C with 0.99 g (8.6 mmol) methanesulfonyl chloride and 0.87 g (8.6 mmol) triethylamine.  After stirring at the same temperature for 1 h under nitrogen, the solution was washed with brine, dried over MgSO4 and concentrated to dryness.  After recrystallization from ether-petroleum ether, 1.9 g (81.9%) of mesylate were obtained. 

  M.p.  120-122 C.    ÚHmr (CDCl3) #: 7.13-7.61 (15H, m, aromatic), 4.50 (1H, d, J = 2, H-4), 3.62 (1H, dq, J = 6, 5, 2, H-1 '), 2.96 (1H, dd, J = 2.2, H-3), 2.84 (3H, s, methanesulfonyl), 1.22 (3H, d, J = 6.5, H-2 '), 0.99 (9H, s, Si-t-Bu) and 0.30 ppm (6H, s, Si (CH3) 2).     IR #max (CHCI3): 1746 (C = 0),
1343 and 1180 cm-1 (SO2). 



   L.  Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-trityl thio-2-azetidinone (isomer B)
EMI69. 1

A solution of 5.03 g (10 mmol) (1'R, 3S, 4R and 1'S, 3 R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) - 4-tritylthio-2-azetidinone (isomer B), 2.52 g (22.0 mmol) methane sulfonyl chloride and 2.23 g (22.0 mmol) trithylamine in 200 ml CH2C12 was stirred at 5 C for 1 h .  Then the solution was washed with brine, dried over MgSO4 and concentrated to give a residue which crystallized as a white festolf when poured into ether.  (5.40 g, 93%).  M.p.  127-131 C. 



     1Hmr (CDCl3) #: 7.20-7.63 (15H, m, aromatic), 4.51 (1H, dq, J = 5.0-6.2, H-1 '), 4, 10 (1H , d, J = 2.0, H-4), 3.60 (1H, dd, J = 5.0-2.0, H-3), 2.03 (3H, s, -CH3), 1 , 01 (3H, d, J = 6.2, H-2 '), 0.90 (9H, s, t-Bu), 0.12 (6H, s, -CH3).     IR (CHCl3) vrnaz: 1745 cm-1 (C = 0)
M.  Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-p bromobenzenesulfonyloxy-1'-ethyl-1- (t-butyldimethyl) -4tritylthio-2-azetidinone (isomer C)
EMI69. 2nd

A solution of 2.5 g (5 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4 -tritylthio-2-azetidinone (isomer C) in 100 ml of dry THF was cooled to -78 ° C. and treated with 2.38 ml (6 mmol) of 2.52M butyllithium / hexane. 

  After 3-4 minutes, 1.53 g (6 mmol) of p-bromobenzenesulfonyl chloride, dissolved in THF, were added dropwise.  The solution was stirred at -78 C for 3 h and then allowed to warm to room temperature.  The solvent was then evaporated off and the desired product was purified by column chromatography (silica gel, CH2Cl2) (3.36 g 94.6%).  M.p.  142-144 C. 



     1Hmr (CDCl3) #: 7.68 (4H, S, benzenesulfonyl), 7.28-7.60 (15H, m, aromatic), 4.59 (1H, d, J = 1.8, H-4) , 3.68 (1H, dq, J = 6.2, H-1 '), 2.99 (1H, dd, J = 1.8.2.0 H-3), 1.18 (3H, d , J = 6.2, H-2 '), 1.08 (9H, s, t-Bu), 0.40 and 0.38 (6H, 2S, -CH3). 



  IR (CHCl3) v max: 1749 cm-1 (C = 0). 



   N.  Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -3- (1 'methoxymethyl-1'-ethyl) -4-trythio-2-azetidine (isomer A)
EMI69. 3rd

A cold (0 C) HMPA-H2O solution (116 ml-13 ml) of isomer A of 1- (t-butyldimethylsilyl) -3- (1'-methoxy-methyl-1'-ethyl) -4-tritylthio- 2-azetidinone (11 g, 20 mmol) was treated with 2.7 g (42 mmol) sodium azide.  The cooling bath was removed and the mixture was stirred for 30 minutes.  Then it was poured into 1.3 liters of cold water and dried.  The desired compound was recrystallized from ethyl acetate / hexane, 7.2 g (83%) of a white solid with mp.  of 173-174 C were obtained. 

 

     tHmr (CDCl3) a: 7.10-7, (15H, m, aromatic), 4.85 (2H, ABq, J = 7.4, O-CH2-O), 4.53 (1H, d, J = 5.2 H-4), 4.42 (1H, s, NH) L, 4.15 (1H, m, H-1 '), 3.5 (1H, m, H-3), 3, 47 (3H, s, O-CH3), 1.5 (3H, d, J = 6, CH3) IR (KBr) vrnax: 3400-3500 (NH) and 1760 cm-1 (C = O).    



   O.  Preparation of (1'S, 3S, 4R and 1'R, 4S) -3 (1'-methyloxymethyloxy-1'ethyl) -4-trytilthio-2-azetidinone (isomer C)
EMI69. 4th
  
A cold solution of 5.03 g (10 mmol) (1'S, 3S, 4R and 1'R, 3r, 4S) -1 - (t-butyldimethylsilyl) -3- (1 '-hydroxy-1' -ethyl) - 4-tritylthio-2-azetidinone in 50 ml of THF (distilled over LAH) was added dropwise with a 1.6M solution of n-butyllithium in hexane (13.0 ml) until the color changed to pink.  A solution of bromomethyl methyl ether (1.49 g, 0.97 ml, 1.19 mmol) in 20 ml of THF was added dropwise.  The mixture was stirred at -78 C for 30 min and then stirred at 0 C for 3 h.  Then it was poured into ice-cooled ammonium chloride solution and extracted with ether. 

  The ether extracts were combined, washed with water, dried over MgS4 and concentrated, using crude (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1 '-methoxymethyloxy -l '-ethyl) -4-tritylthio-2-azetidinone (5.83 g, 100%) was obtained, which was deblocked as follows:
A cold (ice bath) solution of the named derivative (5th 83 g, 10 mmol) in HMPA-H2O (90 ml-10 ml) was treated with 1.365 g (21 mmol) sodium azide.  The cooling bath was removed and the mixture was stirred at room temperature for 2 hours.  Then it was slowly poured into 900 ml of ice-cold water and stirred for 30 min. 

  The precipitate was filtered off and dissolved in methylene chloride, the solution was washed with water and brine and dried over MgSO4 to give 3.0 g (69.3%) of the desired compound from ethyl acetate-hexane.  M.p.  172-172.5 C IR (CHC13) vmax: 3400 (n-H) and 1760 cm-1 (C = O).    1Hmr (CDCl3) #: 7.67-7.12 (15H, m, H aromatic), 4.63 (2H, center of ABq, J = 6, O-CH2-O), 4.49 (1H, s , NH), 4.40 (1H, d, J = 3, H-4), 4.25-3.80 (1H, m, h-1 ').  3.35-3.15 and 3.26 (4H, s + m, CH3 and H-3) and 1.30 ppm (3H, d, J = 6, CH3). 



   P.  Preparation of (1'R, 3S, 4Rund 1'S, 3R, 4S) -3- (1'-Formyloxy-l '-ethyl) -4-tritylthio-2-azetidinone (isomer B)
EMI70. 1

A solution of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-p bromobenzenesulfonyloxy-1'-ethyl) -1- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone (isomer C ) in 3 ml of DMF was heated to 50 C for 48 h and then heated to 100 C for 4 h.  The reaction mixture was then diluted with H20 and extracted with ether.  The ethereal extracts were washed with brine, dried over MgSO4 and evaporated. 

  The desired compound was obtained in the form of white crystals (2 mg, 4.8%) after working up by column chromatography (silica gel, 5% CH3CN-CH2CL2).    M.p.  131-132 C.  1Hmr (CDCl3) #: 8.07 (1H, s, CHO), 7.24-7.56 (15H, m, aromatic), 5.23 (1H, dq, J = 6.4, 7, H- 1 '), 4.38 (1H, dm, J = 2.4, H-4), 4.25 (1H, s, NH), 3.20 (1H, dd, J = 7, 2, 4, H-3), 1.43 (3H, d, J = 6.4, H-2 '). 



     IR (CHC13) v max: 3400 (NH, 1765 (C = O), 1725 cm-1 (C = O).    



   Q.  Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-l'-ethyl) -4-tritylthio-2-azetidinone (isomer B)
EMI70. 2nd

5.77 g (10.57 mmol) of the pure derivative (1'R, 3S, 4R and 1'S, 3R, $ S) -1- (t-butyldimethylsilyl) -3- (l'-acetoxy-1'-ethyl ) -4-tritylthio-2-azetidinone were dissolved in warm HMPT water (60 ml, 10 ml).  The solution was cooled to room temperature and 1.2 g of NaN3 were added.  The mixture was then stirred for 45 min (the course of the reaction was monitored by tlc) and slowly poured into stirred cold water (800 ml).  The mixture was further stirred for 20 minutes, after which the crystalline solid was separated and washed with water. 

  After redissolving in CH2C12, washing with water (twice) and brine and drying over MgSO4, the solvent was evaporated, leaving a foam which crystallized from ether-petroleum ether (4.90 g, 96.5%, mp.  143-144.5 ').  IR in (CH2Ck) v max: 3395 (N-H), 1772, 1738 cm-1 (C = O).    1Hmr (CDCl3) #: 7.9-6.8 (15H, m, H aromatic), 5.12 (1H, center of dq, J = 6.5 7.5 H-1 '), 4.33 ( 1H, d, J = 2.8 H-4), 4.20 (1H, bs, NH), 3.17 (1H, ddd, J3-1, = 7.5, J3-NH = 1, H- 3), 2.1 (3H, s, CH3CO), 1.35 (3H, d, J-6.5, CH3). 



   R.  Preparation of 3- (1'-hydroxy-1'-ethyl) -4-trithylthio-2-azetidinone.  Mixture of the 4 isomers
EMI70. 3rd
  
A solution of 0.74 mmol of lithium diisopropylamide was prepared in 5 ml of dry tetrahydrofuran at -78 C from 0.103 ml (0.75 mmol) of diisopropylamine and 0.29 ml of BuLi (2.52M in hexane).  After 30 min at -78 C, a solution of 0.292 g (6.99 mmol) (R and S) -l-trimethylsilyl-4-tritylthio-2-azetidinone in 2 ml of dry tetrahydrofuran was added dropwise.  After 5 minutes, an excess of 0.2 ml of freshly distilled acetaldehyde was added. 



  After 20 min at -78 C, a complete disappearance of the starting product could be demonstrated by tlc and the reaction mixture was quenched by adding a saturated solution of ammonium chloride.  Extraction with 2 x 25 ml of ethyl acetate, washing the combined organic phases with saturated NH4Cl, brine and drying over magnesium sulfate gave a yellow oil after evaporation of the solvent.     Filtration of this oil on silica gel (10 g, eluting with C6h6: EtOAc, 6: 4) gave a mixture of the alcohols (0.215 g, 80%).  This mixture ('Hmr) could not be separated by either hplc or tlc. 



  a: Acetylation
Acetylation of an aliquot of the mixture 0.065 with excess acetic anhydride (1.0 ml) and 1.4 ml pyridine gave a mixture of the acetates.  hplc analysis indicated four components2: a) 34: 6%, b) 17.4%, c) 30.1%, d) 17.9%.  Compound a) was identical to isomer B by direct comparison (hplc) 4. 



  b: t-butyldimethylsilyl derivatives
0.121 g (0.34 mmol) of the mixture of alcohols was treated with 0.117 g (0.776 mmol) of t-butyldimethylchlorosilane and 0.10 ml (7.14 mmol) of triethylamine in 1 ml of dry dimethylformamide for 36 hours at room temperature.  After dilution with ethyl acetate, the solution was washed with saturated ammonium chloride solution and dried over anhydrous magnesium sulfate.  Evaporation gave 0.716 g of an oil containing 4 components (HPLC).  a = 3.7%, b = 60.6%, c = 31.1%, d = 4.6% (the identity of the individual compounds was not established) 4. 



  Note: 'Butyllithium and lithium hexamethyldisilazane were ineffective
2In increasing polarity
3Acetylation of the product from l-t-butyldimethylsilyl-4tritylthio-2-azetidinone gave the following ratio: d = 29.5, c = 24.1%, b = 33.8%, a = 12.6%
4Reaction of a mixture of the alcohols derived from (R and S) l- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone gave the following proportions: a = 5.2%, b = 41.3%, c = 48%, d = 4.6%. 



   S.  Preparation of (1'R, 3S, 4R and l'S, 3R, 4S) -3- (1'- benzoxy-1'-ethyl) 4-tryithylthio-2-azetidinone (isomer B)
EMI71. 1

A solution of 35 mg, (2 mmol) ('S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonyloxy-l'-ethyl) -4-tritylthio-2-azetidinone (isomer C) and 432 mg (3 mmol) of sodium benzoate in 10% H2O-DMF (10 ml) was heated to 90 C for 7.5 h.  Then the reaction mixture was diluted with H20 and extracted with ethyl acetate.  The organic phases were washed with brine, dried over MgSO4 and evaporated. 

  The residue was purified by column chromatography (silica gel, 5% CH3CN-CH3Cl) and gave the desired compound as a white solid (108 mg, 23.2%) mp.  158 C.    lHmr (CDC13) 6: 7.03-8.25 (20H, m, aromatic), 5.32 (1H, dq, J = 6.1.9, H-1.9, 4.40 (1H, i.e. , J = 2.5, H-4), 4.30 (1H, s, NH), 3.40 (111, dd, J = 9, 2.5, H-3), 1.50 (3H, d, J = 6.1-H-2 ').  IR (CHCl3) v max: 3400 (N-H), 1765 (C-O), 1715cm-1 (C = O). 



   T.  Preparation of 3- (1 '-paranitrobenzyldioxycarbonyl-1' ethyl) -4-tritylthio-2-azetidinone (4 isomers)
EMI71. 2nd
  Isomer C a) A solution of isomer C of l- (t-butyldimethylsilyl) -3- (1 '-paranitrobenzyldioxycarbonyl-1' -ethyl) -4-tritylthio2-azetidinone (1.3 g) in a mixture of 5 ml of TFA, 5 ml of water, 20 ml of dichloromethane and 30 ml of methanol were stirred at room temperature for 2 days.  The solution was diluted with water and the aqueous phase was extracted with dichloromethane.  The combined organic phases were then washed with sodium bicarbonate and water, dried and concentrated to an oil. 

  Recrystallization from ether gave the desired pure compound (902 mg) from the mp.  78-80 C.    tHmr (CDCI3): 8.25-6.75 (19H, m, aromatic), 5.21 (2H, s, benzyl), 5.05 (1H, m, H-1 '), 4.40 (1H , s, NH), 4.27 (1H, d, J = 2.8, H-4), 3.37 (1H, dd, J = 5.3, 2.8, H-3) and 1, 37 ppm (3H, d, J = 6.5, CH3).  IR CHCl3) vmax: 3390 (N-H), 1765 and 1745 (shoulder) (C = O) and 1525 cm- '(NO2). 

 

   b) A cold (0 C) 1 HMPT-H2O solution (90 ml-19 ml) of isomer C of 1- (t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarboxy-1'-ethyl) -4 -trythylthio-2-azetidinone (9.11 g, 13.3 mmol) was treated with 1.82 g (27.9 mmol) sodium azide.  The cooling bath was removed and the mixture was stirred for 30 min and then poured into 1 liter of water and extracted 5 times with 200 ml of ether.  The ether fractions were used and washed 5 times with 200 ml of water and brine and dried over MgSO4.  When diluted with water, the desired compound crystallized out and was filtered off and recrystallized from ether, 7.22 g, 89%, mp.  78-80 C. 



   Isomer B Isomer B of 3- (1'-parannitrobenzyldioxycarbonyl-1'-ethyl) -4-tritylthio-2-azetidinone was prepared for isomer C as described above, 92%, mp.  155.5-156 C (ether). 



     IHmr (CDCl3) 6: 8.25-6.80 (19H, m, aromatic), 5.20 (2H, s, benzyl), 4.95 (1H, m, H-1 '), 4.35 ( 1H, d, J = 2.9, H-4), 4.17 (1H, s, NH), 3.20 (1H, dd, J = 10.8, J = 2.9, H-3) and 1.40 ppm (3H, d, J = 7.5, CH3).  IR (CHCl3) v max: 3480, 3390 (N-H), 1772, 1750 (C = O) and 1525 cm-1 (NO2). 



   Analysis for C32H28N206S Calculated: C, 67.59, H, 4.96, N, 4.93, S, 5.64 Found: C, 67.48, H, 4.98, N, 4.92, S, 5.67 Isomer A Isomer A of 3- (1'-paranitrobenzyldioxycarbonyl-l'-ethyl) -4-tritylthio-2-azetidinone was prepared as described for isomer C; M.p.  205-206 C.    1Hmr (CDCl3) #: 8.2-6.7 (19H, m, aromatic), 5.22 (2H, ABq, benzyl), 5.57-4.87 (1H, m, H-1 '), 4.65 (1H, NH), 4.50 (1H, d, J = 6.5, H-4), 3.65 (1H, dd, J = 6.5, 12, JN-H = 1, H-3) and 1.52 ppm (3H, d, J = 7.5). 



   Isomer D Isomer D of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-tritylthio-2-azetidinone was prepared as for isomer C; 1Hmr (CDCl3) 6: 8.15-6.70 (19H, m, aromatic), 5.23 (2H, ABq, benzyl), 5.20 (1H, m, H-1 '), 4.75 ( 1H, NH), 4.52 (1H, d, J = 5.5, H-4), 3.42 (1H J = 3.3 3, H-3 and 1.5 ppm (3H, d, J = 6.5, CH3).  (J value for H-3 measured after D20 exchange). 



   U.  Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-methanesulfonyloxy-1 'ethyl) -4-tritylthio-2-azetidinone (isomer B)
EMI72. 1

A solution of 4.95 g (8.5 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1 'ethyl) - 4-tritylthio-2-azetidinone (isomer B) and 1.11 g (17.0 mmol) sodium azide in 50 ml 10% H2O-HMPA was stirred at room temperature for 30 min.  Then the solution was diluted with 250 ml of water and extracted with ether.  The organic extracts were washed with brine, dried over MgSO4 and evaporated.  Recrystallization of the residue (ether-petroleum ether) gave 3.33 g (83.8%) of the desired compound of mp. 130-131 C.    



     1Hmr (CDCl3) #: 7.20-7.62 (15H, m, aromatic), 4.97 (1H, dq, J = 6.4, 6.1, H-1 '), 4.56 (1H , d, J = 2.8, H-4), 4.22 (1H, m, NH), 3.27 (1H, dd, J = 6.1, 2.8, H-3), 3, 0 (3H, s, -CH3), 1.63 (3H, d, J = 6.4, H-2 ').  IR (Nujol) v max: 3195 (n-H), 1768cm-1 (C = O). 



   V.  Preparation of (1'S, 3S, and 1'R, 3R, 4S) -3- (l'-methanesulfonyloxy-1 '-ethyl) -4-tritylthio-2-azetidinone (isomer C)
EMI72. 2nd

A solution of 2.85 g (4.9 mmol) (1'S, 3S, 4R and 1'R, 3 R, 4S) -1 - (t-butyldimethylsilyl) -3- (1 "-methanesulfonyloxy-1 ethyl) - 4-tritylthio-2-azetidinone (isomer C) in 25 ml of 10% aqueous HMPA was treated with 0.65 g (10 mmol) of sodium azide and stirred at 25 C for 0.5 h.  After dilution of the solution with 250 ml of water, the product was crystallized, the crude mesylate was redissolved in dichloromethane, washed with brine, dried over MgSO4 and evaporated. 

  After shaking with ether, the desired compound was obtained in the form of white crystals of mp.  155-160 C.  1.80 g, 78.6%. 



  1Hmr CDCl3) 6: 7.43 (15H, m, aromatic), 5.02 (1H, dq, J = 6.9.4.9, H-1 '), 4.55 (1H, s, NH) , 4.95 (1H, d, J = 3, H-4), 3.33 (1H, dd, J = 4, 9, 3, H-3), 1.51 (3H, d, J = 6 , 9, H-2 ').  IR vmax: 3395 (N-H), 1768cm-1 (C = O). 



   Analysis for C25H25NO4S Calculated: C, 64.22, H, 5.39, N, 3.00 Found: C, 63.93, H, 5.39, N, 3.24. 



   W.  Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1-p-bromobenzenesulfonyloxy-1 '-ethyl) -4-tritylthio-2-azetidinone (isomer C)
EMI72. 3rd

A solution of 1.42 g (2 mmol) (1'S, 3S, 4R and 1'R, 3 R, 4S) -3- (1'-p-bromobenzenesulfonyloxy-1'-ethyl) -1 - (t-butyldimethylsilyl ) -4-tritylthio-2-azetidino (isomer C) and 0.865 g (6 mmol) of sodium benzoate in 40 ml of 10% H2O-HMPA was stirred at room temperature for 1 h.  Then the solution was diluted with 100 ml H20 and extracted with ether.   



  The ether extracts were washed with brine, dried over MgSO4 and evaporated.  The crude crystalline compound was shaken with a small volume of ether and filtered off (0.92 g, 77%).  125-126 C. 



     1Hmr (CDCl3) #: 7.80 (4H, s, benzenesulfonyl), 7.30-7.65 (15H, m, aromatic), 5.13 (1H, dq, J = 6.5, 4.0 H) -1 '), 4.50 1H, d, J = 2.9, H-4), 4.40 (1H, s, NH), 3.40 (1H, dd, J = 4.0, 2, 9, H-3), 1.50 (3H, d, J = 6.5, H-2 ').     IR (CHCl3) vrnax: 3400cm-1, (N-H); 1770cm-1 (C = O). 



   X.  Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1 'hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer B)
EMI73. 1

To a warm solution of 5 ml (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-p-bromobenzenesulfonyloxy-1'-ethyl) -1- (t-butyldimethylsilyl) -4-tritylthio -2-azetidinone (isomer C) in HMPA (5 ml) was added dropwise 1 ml H20.  The reaction mixture was kept at 90 ° C. for 20 h, then diluted with ether and washed 4 × with brine. 



  The organic solution was dried over MgSO4, evaporated and the crude compound obtained was worked up by column chromatography (silica gel, 15% CH3CN CH2Cl2).  A white solid (122 mg, 44.5%) mp was obtained.  187-189 C, which was identical to a sample of the desired compound, prepared by another method. 



   Y.  Preparation of 3- (1'-hydroxy-1'-ethyl) -4-trithylthil-2-azetidinone
EMI73. 2nd

The two isomers (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1 'hydroxy-l'-ethyl) -4-tritylthio-2-azetidinone (isomer C) and (1'R, 3S 4R and 1'S, 3R, 4S) -3- (1'-hydroxy-1'ethyl) -4-tritylthio-2-azetidinone (isomer B) were prepared in the same way. For example, a solution of 1.0 g (2nd mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (l'hydroxy-1'ethyl) -4-tritylthio-2-azetidinone (isomer C) and 0.865 mg (6 mmol) of sodium benzoate in 40 ml of 10% H2O-DMF at room temperature for 18 h.  Then the reaction mixture was diluted with H20 and extracted with ether.  The organic extracts were washed with brine, dried over MgSO4 and evaporated. 

  The crude compound was recrystallized from cold ether to give 0.47 g (61%) mp.  134-135 C.  'Hmr (CDCl3) 6: 7.12-7.56 (15H, m, aromatic), 4.48 (1H, s, NH), 4.28 (1H, d, J = 2.8, H-4 ), 2.94 (1H, dq, J = 6.5 6.2, H-1 '), 3.06 (1H, dd, J = 6.2, 2.8, H-3), 2, 18 (1H, s, -OH), 1.30 (3H, d, J = 6.5, H-2 ').  IR (CHCl3) v max: 3400 (n-H), 1760 cm (C = O).    



   In the same way, (1'R, 3S, and 1'S, 3R, 4S) - 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1-ethyl) -4-tritylthio-2azetidinone (isomer B) mp .  190-192 C.    1Hmr (CDCl3) #: 7.10-7.55 (15H, m, aromatic), 4.45 (1H, d, J = 2.5, H-4), 4.28 (1H, s, NH) , 4.10 (1H, dq, J = 6.4 5.3, H-1 '), 3.08 (1H, dd, J = 5.3, 2.5, H-3), 1.50 (1H, s, -OH), 1.30 (3H, d, J = 6.4, H-2 ').     IR (CHC13) vrnax: 3400 (N-H), 1760 cm-1 ^ (C O).    



   Z.  Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -3- (1 'methoxymethyl-1'-ethyl) -1- (paranitrobenzyl) -2 "-hydroxy-2" acetate) -4-tritylthio -2-azetidinone (isomer A)
EMI73. 3rd

A mixture of 7.5 g (17.3 mmol) of isomer A of methoxymethyl-1'-ethyl) -4-tritylthio-2-azetidinone, 4.7 g (20.8 mmol) of paranitrobenzylglyoxylate hydrate and 300 ml of toluene was added refluxed for 1 h in a Dean-Stark apparatus with 3 molecular sieve.  The solution was cooled in ice and 0.24 ml (1.7 mmol) of triethylamine was added dropwise.  

  Then the mixture was stirred for 1 hour, washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give 10.5 g (94%) of the desired compound as a foam.  1Hmr (CDCl3) 6: 8.25-6.84 (19H, m, aromatic), 5.24 (2H, s, benzyl), 4.67-4.83 (3H, m, O-CH2 and H- 4), 4.34-4.55 (1H, m, H-2 "S), 4.02 (1H, m, H-1 '), 3.54 (1H, m, H-3), 3 , 40 (3H, s, O-CH3), 1.38 (3H, d, J = 6.5, CH3).  IR (KBr) vmax: 3360 (OH), 1770 (C = 0 from p-lactam), 1735 (C = O from ester) and 1605 cm - (aromatic). 



   AA.  Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1 'methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" acetate) -4-tritylthio- 2-azetidinone (isomer C)
EMI74. 1

A solution of 1.73 g (7.11 mmol) of hydrogenated paranitrobenzyl glyoxylate in 90 ml of toluene was refluxed in a Dean Stark apparatus with 3-molecular sieve for 2 h.  3.0 g (6.93 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'Methoxymethyloxy-1'-ethyl) -4-tritylthio-2-azetidinone were added to the boiling solution was added and the mixture was refluxed for a further 2 h.  The mixture was then cooled to room temperature, 70 mg (97 l, 0.69 mmol) of triethylamine were added and the mixture was stirred for a further 2 h. 

  The reaction mixture was diluted with ether, washed with 1% aqueous HCl, water, 1% aqueous NaHCO3, water and brine, dried over MgSO4 and concentrated to the desired compound (4.60 g, 100%).  IR (CHCl3) vmax: 3530-3100 (O-H), 1750 (C = O) and 1525cm-1 (NO2).  1Hmr (CDCl3) 6: 8.22, 8.18 2H, 2d, J = 8, Hm aromatic), 7.67-7.0 (17H, m, H-aromatic), 5.3 (2H, bs, CH2 PNB), 5.30-5.02 (m, H-2 "), 4.89-4.52 (m, H-1 'and OH), 4.63, 4.59 (1H, 2d J = 2, H-4), 4.33, 4.30 (2H, 2 center of 2 ABq, J = 7, J = 7, O-CH2-O), 4.1-3.67 (1H, m, H-1 '), 3.2 (1H, H-3), 3.1, 3.6 (3H, 2s, CH3-O), and 1.15 ppm (3H, d, J = 6.5, CH3).    



   BB.  Preparation of (1'R, 3S, 4R and IS, 3R, 4S) -3- (1'-acetoxy-1 '-ethyl) - 1 - (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4tritylthio- 2-azetidinone
EMI74. 2nd
  Isomer B
A solution of hydrated p-nitrobenzylglyoxylate (shaken with ether) (1.82 g, 30 mmol) was refluxed in benzene in a Dean-Stark apparatus with 3 molecular sieve for 2 h.  Then 10.88 g (25.2 mmol) (1'R, 3S, 4Rund 1'S, 3R, 4S) -3- (1 '-acetoxy-1' -ethyl) -4-tritylthio-2-azetidinone were added and the mixture was refluxed for another 1 h.  The solution was then cooled to room temperature and 0.35 ml (2.5 mmol) of triethylamine was added.  The mixture was then stirred for 2 h, the course of the reaction being followed by tlc. 

  Evaporation of the solvent gave a white foam in quantitative yield (100%, mixture of epimers).  Alternatively, the solution can be washed with acid and base. 



  IR (CH3Cl2) v max: 3520 (OH), 1775, 1745cm-1 (C = O).  1Hmr (CDCl3) #: 8.3 8.18 (2H, 2d, J = 8, Ho aromatic), 7.80-6.90 (17H, m, H aromatic), 5.28, 5.17 ( 2H, 24, CH2-PNB), 4.89 (0.67H, d, J = 7.2, CHO), 4.80 (center of m, H-1 '), 4.38 (0.33H, 2d, J = 8.8, CHO), 4.22 (D. 33H, d, J4-3 = 2.5, H-4), 4.09 (0.67H, d, J4-3 = 2.1 H-4) 3.65 (D. 67h, dd, H3-1 = 5.8, J3-4 = 2.1, H-3), 3.47 (0.33H, dd, J3-1 = 5.5, J3-4 = 2.5 , H-3), 3.33 (0.33, d, J = 8.8, OH), 3.23 (0.67H, d, J = 7.5OH), 1.88, 1.86 ( 3H, 2s, CH3CD), 1.10, 1.06 (3H, 2d, J = 5.8, 6.3, CH3). 



   CC.  Preparation of 3- (1'-paranitrobenzylcarbonyl-1 '-ethyl) -l - (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio- 2-azetidinone (4 isomers)
EMI74. 3rd
  Isomer C
A mixture of 1.70 g (0.3 mmol) of isomer C of paranitrobenzyldioxycarbonyl-1'-ethyl) -4-tritylthio-2-azetidinone, 815 mg (3.6 mmol) of paranitrobenzylglyoxylate hydrate and 50 ml of toluene was added during 7 Days refluxed in a Dean Stark apparatus with 3A molecular sieve.  The cooled solution was then washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give 2.1 g of the desired compound as an epimeric mixture at C-2. 



  Working up was carried out by chromatography on silica gel.  In an alternative, the desired compound could be made using a catalytic portion of triethylamine.  Less polar epimer at C-2 ": 1Hmr (CDCl3) ô: 8.25-6.80 (23H, m, aromatic), 5.30 and 3.12 (4H, 2s, benzyl), 4.65 (1H , d, J = 9, H-2 "), 4.45 (1H, d, J = 2.5, H-4), 4.45-4.0 (1H, m, H-1 '), 3.50 (1H, d, J = 9, "2-OH), 3.28 (1H, dd, J = 2.5, J = 2.5, H-3) and 1.23 ppm (3H, d, J = 6.5, CH3).  IR (CHC13) vrnax: 3530 to 3200 (D-H), 1765, 1750 (C = O) and 1525 cm-1 (NO2). 

  More polar isomer anC-2 ": 1Hmr (CDCl3) Ï: 8.25-6.85 (23H, m, aromatic), 5.25 and 5.08 (4H; 2s, benzyl), 5.05 (1H, d, J = 7, H-2 "), 4.35 (1H, d, J = 2.5, H-4), 4.40-4.05 (1H, m, H-1 '), 3 , 42 (1H, J = 7.2 "-OH), 3.33 (1H, dd, J = 2.5, 2.5, H-3), 1.23 (3H, d, J = 6, 5, CH3). IR (CHCl3) v max: 3520 to 3200 (O-H), 1755 (C = O) and 1525 Cm-1 (NO2). 



   Isomer B
A mixture of 1.74 g (7.66 mmol) of hydrated paranitrobenzylglyoxylate and 3.63 g (6.38 mmol) (1'r, 3S, 4R and 1'S, 3R, 4S) -3- (1 '-paranitrobenzyldioxycarbonyl- 1'-ethyl) -4-tritylthio-2-azetidinone was refluxed in 70 ml of toluene in a Dean-Stark apparatus with 3-molecular sieve for 3 h.  The solution was cooled to room temperature and 64.5 mg (89 ml, 0.639 mmol) of triethylamine were added.  The mixture was then stirred for 4 h, diluted with ether and washed with 2% aqueous HCl, water, 2% aqueous NaHCO3, water and brine.  After drying and concentration, 5.02 g (100%) of the pure desired compound were obtained.  The two epimers were separated by preparative silica gel chromatography. 

  Less polar epimer at C-2 ": IR (CHC13) vmax 3500 (O-H), 1772, 1750 (C = O) 1525 cm-l (NO2).  1Hmr (CDCl3) 8: 8.30-8.0 and 7.65-6.80, (23H, m, aromatic), 5.27 and 5.13 (4H, 2s, benzyl), 4.71 (1H , m, J = 6.5, 6.5, H-1 '), 4.28 (1H, d, J = 2.2, H-4), 4.23 (1H, d, J = 8, 7, H-2 "), 3.50 (1H, dd, J = 2.2, 6.5, H-3), 3.28 (1H, d, J = 8.7, OH) and 1, 18ppm (3H, d, J = 6.5, CH3).  More polar epimer: IR (CHC13) vrnax: 3480 (O-H), 1772, 1750 (C = O) and 1525 cm-1 (NO2). ÚHmr (CDCl3) o: 8.35-6.90 (23H, m, aromatic), 5.15 (4H, benzyl), 4.72 (1H, d, J = 7.5, H-2 "O) , 4.90-4.50 (1H, m, J = 6.5, 6.5, H-1 '), 4.10 (1H, d, J = 2, H-4), 3.68 (1H , dd, J = 2, 6, 5, H-3), 3.28 (1H, d, J = 6.5, OH) and 1.15 ppm (3H, d, J = 6.5 CH3). 



   Isomer A
The isomer A of 3- (1'-paranitrobenzyldioxycarbonyl-
1'-ethyl) -4-tritylthio-2-azetidinone likewise gave a mixture of isomer A of 3- (l'-paranitrobenzyldioxycar bonyl-l'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" acetate) -4 tritylthio-2-azetidinones.    IHmr (CDCl3) Ï: 8.3-6.7 (23H, m, aromatic), 5.17 (1H, d, J = 7.5, H-2 "O), 4.90-4.50 ( 1H, m, J = 6.5, 6.5, (1H, 2d, J = 6, H-4.2 epimers), 4.32 and 3.96 (1H, 2s, H-2 ", 2 epimers ), 3.68 (1H, dd, J = 6, 6, H-3) and 1.47 ppm (3H, 2d, J = 6.5, CH3, 2 epimers). 



   Isomer D
The isomer D of 3- (1'-paranitrobenzyldioxycarbonyl-l'-ethyl) -4-tritylthio-2-azetidinone likewise gave a mixture of isomer D of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" acetate) -4-tritylthio-2-azetidinone.  1Hmr (CDCl3) o: 8.30-6.60 (23H, m, aromatic), 5.20 (4H, m, benzyl), 4.83 (1H, 2D, J = 5, H = 4), 5 , 50-4.30 (2H, m, H-1 'and H-2 "), 3.48 (1H, m, H-3),
3.15 (1H, m, O-H), 1.37 and 1.30 ppm (3H, 2d, CH3). 



   DD.  Preparation of (1'S, 3S 4R and 1'R, 3R, 4S) -3- (1 'methanesulfonyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy2" -acetate) -4-tritylthio-2- azetidinone (isomer C) (epimers at C2 ". 
EMI75. 1




   A solution of 9.72 g (42.6 mmol) of paranitrobenzyl glyoxylate hydrate in 350 ml of benzene was refluxed for 2 hours, the water being collected azeotropically in a Dean-Stark trap.  16.62 g (35.5 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio-2- were added to the solution. Azetidinon given and refluxed for a further 0.5 h.  The reaction mixture was then cooled to room temperature, treated with 0.5 ml (3.5 mmol) of triethylamine and stirred for 3 hours until the reaction was complete. 

  After evaporation of the solvent, a white foam was obtained, which was used as such in the next step.  1Hmr (CDCl3) ô: 8.12 (2H, d, J = 9, Hm aromatic), 7.28 (17H, part of d, Ho aromatic, trityl), 5.28 (2H, s, -CH2-PNB ), 4.88 (0.5H, s, H-1 "), 4.62 (1.5H, m, H-2" and H4-), 4.00 (2H, m, H-1'- OH), 3.15 (1H, m, H-3), 2.73 (3H, s, mesylate) and 1.30 ppm (3H, d, J = 6Hz, H-2 '), IRvmax: 3520 ( OH), 1775 (C = O) and 1765 cm- '(C = O).    



   EE. Preparation of ('S, 3R, $ R and 1'R, 3S 4S) -3- (1 methoxymethyl-1'-ethyl) -1- (paranitroibenzyl-2 "-chloro-2" -acetate) -4-tritylthio -2-azetidinone (isomer A)
EMI75. 2nd

1.1 ml (14.2 mmol) of pyridine was added dropwise to a solution of isomer A of 3- (1'-methoxymethyl-1'-ethyl) -1 (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4- trityl hio-2-azetidinone (7 g, 10.9 mmol) in 350 ml THF, cooled to -15 C, added.  Immediately thereafter, 1.0 ml (14.0 mmol) of thionyl chloride was added dropwise and the mixture was stirred at -15 C for 0.5 h.  

  The precipitate was filtered off and washed with benzene, the combined filtrates were evaporated, the residue was dissolved in fresh benzene and the solution was treated with activated carbon, filtered and concentrated, leaving the desired compound in the form of an oil (6.5 g, 90%) .    IHmr (CDCl3) o: 6.65-8.35 (19H, m, aromatic), 5.24 (2H, s, benzyl), 3.43 (3H, s, OCH3) and 1.42 ppm (3H, d, J = 6, CH3). 



   FF.  Preparation of (1'S, 3S, 4R and l'R, 3R, 4S) -3- (1 'ethoxymethyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chlor" acetate) -4-tritylthio-2- azetidinone (isomer C)
EMI76. 1

A cold (ice-MeOH bath) solution of 4.25 g (6.62 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methoxy-methyloxy-1 '- ethyl) - 1 -paranitrobenzyl-2 "-hydroxy-2" -acetate) -4- tritylthio-2-azetidinone in 60 ml THF (distilled over LAH) was added dropwise with 0.696 ml (8.61 mmol) pyridine and 0.530 ml ( 8.61 mmol) thionyl chloride treated.  The mixture was stirred at -15 C for 30 min, after which the precipitate was filtered off and washed with benzene. 



  The THF-benzene solution was evaporated and the residue was again dissolved in benzene.  The resulting solution was treated with activated carbon, whereupon the activated carbon was filtered off on a Celite filter and the benzene evaporated to give 4.86 g (100%) of the desired compound.  IR (CHCl3) vrnax: 1770 (C = 0) and 1525 cm- (NO2).  1Hmr (CDCl3) ô: 8.15, 8.12 (211, 2d, H-aromatic), 7.70-7.00 (17H, m, H-aromatic), 5.62, 5.02 (1H, 2s, H-2 "), 5.27 (2H, s, CH2-PNB), 4.7 (1H, d, H-4), 4.7-3.7 (m, O CH2-O. H-1 '), 3.5-2.8 (m, H-3), 3.12, 3.08 (3H, 2s, O-CH3) and 1.30-0.96 ppm (3H, m , CH3). 



   GG.  Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1 'acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4tritylthio-2 -azetidinone
EMI76. 2nd
  Isomer B
A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4 -tritylthio-2-azetidinone (from 10.88 g of NH) in THF (distilled over LAH) was at -15 C (ice-methanol bath) and under nitrogen with 2.19 g (2.24 ml, 27, 7 mmol) of pyridine and 3.3 g (2.02 ml, 27.7 mmol) of thionyl chloride.  The mixture was stirred at -15 for 20 min, the salt was filtered off and washed with benzene.  After evaporation of the solvents, a residue was obtained, which was taken up in benzene and treated with activated carbon. 

  The suspension was filtered through Celite and a foam was obtained after evaporation of the solvent. 



  IR (CH2Cl2) vmax: 1780, 1740cm-1 (C = O).    1Hmr (CDCl3) #: 8.17, 8, 21 (2H, 2d, J = 8, Ho aromatic), 7.76-6.88 (17H, m, H aromatic), 5.31, 5.16 , 5.12, 4.73 (3H, CH2-PNB, CHCI), 5.12-4.55 (1H, m, H-1 '), 4.35-4.25 (1H, m, H- 4), 3.80-3.45 (1H, m, H-3), 1.90 (3H, s, CH3CO), 1.12-1.07 (3H, J = 6.6, CH3). 



   HH.  Preparation of 3- (1 '-paranitrobenzyldioxycarbonyl1'-ethyl) -1- (paranitrobenzyl-2 "-chlor-2" -acetate) -4-trithylthio-2azetidinone (mixture of epimers at C2 ")
EMI76. 3rd
  Isomer C
58 mg (0.73 mmol) of pyridine was added dropwise to a solution of isomer C of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" acetate) 3tritylthio- 2-azetidinone (470 mg, 0.6 mmol, mixed epimers at C-2 ") in 15 ml THF, cooled to -15 C. 



  Immediately thereafter, 86.5 mg (0.73 mmol) of thionyl chloride was added dropwise to the mixture and this was stirred at '15 C for 0.5 h.  The precipitate was filtered off and washed with benzene.  The combined filtrates were concentrated, the residue was dissolved in fresh benzene and the solution treated with activated carbon, filtered and concentrated, the desired compound remaining as oil.  530 mg, 100% 1Hmr (CDCl3) o: 8.7-6.8 (23H, m, aromatic), 5.53 (111, s, H-2 "), 5.30 and 5.17 (4H, 2s, benzyl), 4.52 (1H, d, J = 2, H-4), 4.20-3.70 (1H, m, H-1 '), 3.31 (1H, dd, H- 3), 1.27 and 1.21 ppm (3H, 2d, J = 6.5).     IR (CHC13) vmax:

  : 1780, 1750 (C = O) and 1525 cm-1 (NO2), isomer B isomer B of 3- (1-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-chlor-2" -acetate ) -4-trithylthio-2 azetidinone (mixture of the C-2 "epimers) was obtained for the isomer C in quantitative yield as described above. 



     lHmr (CDCl3) o: 8.25-6.90 (23H, m, aromatic), 5.40-5.0 (4H, m, benzyl), 5.40-4.45 (1H, m, H- 1 '), 4.82 and 4.57 (1H, 2s, H-2 "), 4.36 and 4.31 (1H, 2d, J = 2.5, H-4), 3.63 (1H , m, J = 2.5, J = 6.5, H-3), 1.25 and 1.18 ppm (3H, 2d, J = 6.5, CH3). IR (CHCl3) vmax: 1780, 1750 (C = O) and 1525cm-1 (NO2). 



   Isomer A Isomer A of 3- (1 '-paranitrobenzyldioxycarbonyl- 1' ethyl) - 1 '- (paranitrobenzyl-2' 'chloro-2 "acetate) -4-tntylthio-2-azetidinone (mixture of C-2" -Epimers).    lHmr (CDCl3) o: 8.30-6.80 (23H, m, aromatic), 5.45-4.80 (1H, m, H-1 '), 5.18 and 5.21 (4H, 2s , Benzyl), 4.87 (1H, 2d, H-4), 4.22 and 3.87 (1H, 2s, H-2 "), 4.05-3.40 (1H, m H-3) , 1.57 and 1.50 ppm (3H, 2d, CH3). 



   Isomer D Isomer D of 3- (1 "-paranitrobenzyldioxycarbonyl-1'-ethyl) -1 '- (paranitrobenzyl-2" -chloro-2 "acetate) -4-tritylthio-2azetidinone (mixture of C-2" epimers ).    sHmr (CDCl3) o: 8.30-6.70 (23H, m, aromatic), 5.32-5.10 (4H, m, benzyl), 5.48 and 5.30 (1H, 2s, H- 2 "), 4.82 (1H, d, J = 5, H-4), 5.30-5.20 (1H, m, H-1 '), 3.15 (1H, m, H-3 ), 1.40 and 1.30 ppm (3H, 2d, J = 6.5, CH3).  IR (CHC13) vrnax: 1780, 1750 (C = O) and 1525 cm-1 (NO2). 



   II.  Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chlor-2" -acetate) -4 -tntylthio-2-azetidinone (isomer C) (epimers at C-2 ")
EMI77. 1

To a cold solution of 24.0 g (35.5 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonyloxy-1'-ethyl) -1- (paranitrobenzyl- 2 "-hydroxy-2" acetate) -4-tritylthio-2-azetidinone in 350 ml of dry tetrahydrofuran, 3.65 g (46.2 mmol) of pyridine and 5.5 g (46.2 mmol) of thionyl chloride were added dropwise.  After stirring for 45 min, 100 ml of ether were added, as a result of which the hydrochloride salt was separated out, which was subsequently filtered off.  The filtrate was concentrated and the residue was dissolved in 200 ml of benzene and treated with activated carbon. 

  After evaporation of the solvent, an almost white foam was obtained, which was used as such in the next step.    IHmr (CDCl3) o: 8.18 (2H, d, J = 9, Hm aromatic), 7.72 (17H, m, part of d, Ho aromatic, trityl), 5.57 and 5.12 (1H, s, H-2 "), 5.28 (2H, s, -CH2PNB), 4.73 (1H, 2d, H-4), 3.21 (1H, 2dq, H-3), 2.78 ( 3H, 2s, mesylate) and 1.21 ppm (3H, 2d, H-6H2; H-2 ').     IR vmax: 1779cm-1 (C = O). 



   YY.  Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -3- (1 'methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio -2-azetidinone (isomer A)
EMI77. 2nd

A mixture of isomer A of 6.6 g (10 mmol) of 3- (1 'methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" acetate) -4-tritylthio-2-azetidinone , 3.3 g (12.5 mmol) of triphenylphosphine, 1.3 ml (11 mmol) of 2,6-lutidine and 140 ml of dioxane were heated to reflux temperature for 2 days.  The solution was diluted with ether, washed with dilute acid (5% HCl) 3 water, dilute sodium bicarbonate solution and brine, dried and concentrated.  The residue was purified by chromatography on silica gel and eluted with 10% ether in benzene.  The concentration of the corresponding fractions gave 1.4 g (13.7%) of the desired compound in the form of a foam.  

  IR (KBr) vmax: 1750 (C = O) and 1660-1650cm-1 (C = C, aromatic). 



   KK = Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1 'methoxymethyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenyl-phosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (isomer C)
EMI77. 3rd

A solution of 4.86 g (6.62 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methoxymethyloxy-1'-ethyl) -1- (paranitrobenzyl- 2 "-chloro-2" acetate) -4-tritylthio-2-azetidinone in 100 ml of dioxane (distilled over LAH) and containing 2.60 g (9.93 mmol) of triphenylphosphine and 770 mg (0.837 ml, 7.20 mmol) 2,6-lutidine was heated to reflux temperature for 4 h and kept in the heating bath (100 C) for 16 h.  The mixture was diluted with ether, washed with 1% aqueous HCl, water, 10% aqueous NaHCO3, water and brine and dried over MgSO4. 



  The solution was then concentrated and the residue was filtered through 65 g of silica gel in a column (5%, 10% and 20% ether-benzene) to give 2.8 g (48%) of the desired compound.  IR (CHC13) vrnax: 1795 (C = 0), 1620 and 1605 (phosphorane) and 1515 cm-1 (NO2). 



   LL.  (1'R, 3S, 4Rund 1'S, 3R, 4S) -3- (1 '-acetoxy-1' -ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4tritylthio-2-azetidinone (Isomer B)
EMI78. 1

A solution of crude (1'R, 3S, 4R and 1'S, 3R, 4S) -3 (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chlor-2" -acetate) 4- tritylthio-2-azetidinone in 100 ml of dioxane (freshly distilled over LAH) was treated with 2.97 g (3.23 ml, 27.72 mmol) of 2,6-lutidine and 9.91 g (37.8 mmol) of triphenylphosphine . 



  The mixture was refluxed on the oil bath (130) for 18 h.  Then the solvent was evaporated and the residue was dissolved in methylene chloride.  The resulting solution was washed successively with dilute HCl, H2O, dilute aqueous NaHCO3, H2O and brine.  After drying and evaporating the solvent, the desired compound was obtained as a solid, which was shaken with ether and filtered (14.6 g, 65.9%).  IR (CH3Cl2) vmax: 1750 (C = O) and 1620, 1610 cm- '(phosphorane). 



   MM.    3- (1'-Paranitrobenzyldioxycarbonyl-1 '-ethyl) -1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone
EMI78. 2nd
 Isomer B
A mixture of 4.96 g (6.22 mmol, mixture of the epimers at C-2 ") (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-paranitrobenzyl-dioxycarbonyl- 1 ' -ethyl) - 1 - (paranitrobenzyl-2 "-chloro" acetate) -4-tritylthioazetidinone (isomer B), 2.47 g (9.42 mmol) triphenylphosphine and 740 mg (0.80 ml, 6.91 mmol 2,6-Lutidine was refluxed in dioxane (freshly distilled over LAH) for 30 h.  The solution was diluted with ether and ethyl acetate, washed with 5% aqueous HCl, water, 10% aqueous NaCHO3, water and brine and dried over MgSO4. 

  After evaporation of the solvent, a residue was obtained which was placed on a silica gel column and eluted with 10% ether-benzene, ether and ethyl acetate.  3.1 g (49%) of the desired compound were obtained as a crystalline solid, mp. 



     189-190 (ether).     IR (CHCl3) vmax: 1750 (C = 0), 1620, 1605 (phosphorane) and 1522 cm '(NO2).    



  Isomer C
The isomer C of 3- (1'-paranitrobenzyldioxycarbonyl-l'-ethyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-tritylthio-2-azetidinone was prepared for isomer B as described.  IR CHCl3) vmax: 1750 (C 0), 1610, 1620 (Phsophoran) and 1520 cm-1 (NO2).  l Hmr (CDCl3) o: 8.6-6.7 (H, aromatic, 5.22 and 4.95 (benzyl), 4.70 (H-4), 2.6 (H-3), 1, 19 and 1.07 ppm (CH3). 



  Isomer D
A mixture of isomer D of 3- (l'-p-nitrobenzyldioxycarbonyl-1-ethyl) -1- (p-nitrobenzyl-2 "-chloro-2" acetate) -4-tritylthio-2-azetidinone (4,598 g, 4.45 mmol), purity 77%, mixture of the epimers at C-2 "), 1.425 g (5.44 mmol, Aldrich) triphenylphosphine and 0.63 ml (580 mg, 5.40 mmol, anachemia) 2 , 6-lutidine in 65 ml of dioxane (distilled over LAH) was gently heated to reflux temperature for 41 h under nitrogen, the reaction being followed by tlc (benzene: ether = 3: 1).  The dark reaction mixture was cooled, diluted with EtOAc and washed successively with 0.1 NHCl, water, 2% NaHCO3 and brine. 

  After drying over Na2SO4 and evaporation of the solvents, 4.18 g of a dark-colored oil was obtained, which was worked up by column chromatography (SiO2, 88 g; eluted with 10-25% ether in benzene), yield 1.108 g (1.08 mmol, yield 24.3%) of the desired compound in the form of a yellow foam.    1 Hmr (CDCI3) 6: 1.08 (d, J = 6 Hz, 1'-CH3).     IR (neat) vmax: 1745 cm-1 1 (s, C = O).    



     
NN.  Preparation of (1'S, 33S, and 1'R, 3R 4S) -3- (1'-methanesulfonyloxy-1 '-ethyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2". acetate) -4-tritylthio-2-azetidinone (isomer C)
EMI78. 3rd
  
A solution of 24.7 g (35.5 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1 '-methanesulfonyloxy-I' -ethyl) - l. (paranitrobenzyl-2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinone, 11.2 g (42.7 mmol) triphenylphosphine and 4.2 g (39.1 mmol) 2,6- Lutidine in 350 ml dry dioxane was refluxed under nitrogen for 19 h.  The solvent was evaporated and the crude product dissolved in ethyl acetate and washed successively with dilute HC1, NaHCO3 and brine. 

  It was then purified by column chromatography on silica gel (8.5 × 12 cm) and eluted with 10% ether dichloromethane (1.5 1) and then ether (1.5 1), giving 12.36 g (40%) of the phosphorane were.    IHmr (CDCl3) b: 2.53 and 2.93 ppm (3H, 2s, mesylate).  IR vmax: 1749 and 1620 cm- (C = O).    



   00.  Manufacture of (1'R, 3S, 4R and 1'S.  3R 4S) -3 (l'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (IsomerB)
EMI79. 1

A solution of 4.43 g (5.00 mmol) of the phosphorane (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl- 2 "-triphenylphosphoranylidene-2" acetate) -4-trityl thio-2-azetidinone in 10 ml of methanol and 60 ml of THF was treated with 1% aqueous NaOH (1 eq. , 200 mg in 20 ml H2O) treated.  The reaction was followed with tlc *.  The mixture was diluted with ether-ethyl acetate and washed with HCl, H2O, aqueous NaHCO3, H20 and brine.  After evaporation of the solvents, a residue was obtained, which was recrystallized from benzene ether (3.7 g, 87.7%). 



   169.5-170.5 C.  IR (CH2CI2) vrnax: 1745 (C = 0) and
1620 cm- '(phosphorane).  * Heating the mixture increased the reaction rate. 



   PP.  Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -Silver-3 (1'-methoxymethyl-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2 -azetidinone-4-thiolate (isomer A)
EMI79. 2nd
    Silver 3- (l'-methoxymethyl-l '-ethyl) -l - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -3-tritylthio-2-azetidinone (isomer A) was prepared as described for the isomer C of the paranitrobenzyldioxy-carbonyl derivative.  Yield 50%.  IR (neat) vrnas: 1745 cm-1 (C = O). 



   QQ.  Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -Silber2- (1'-methoxymethyloxy-l'-ethyl) - l- (paranitrobenzyl-2 "-triphenylphosphoranyliden-2" -azetidinone-4-thiolate (Isomer C)
EMI79. 3rd

887 mg (1.0 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1 'methoxymethyloxy-1' -ethyl) - 1 - (paranitrobenzyl-2 '' -triphenyl-phosphoranylidene- 2 "acetate) -4-tritylthio-2-azetidinone was dissolved in 30 ml of hot (40 C) methanol, treated with 103 mg (0.105 ml, 1.3 mmol) of pyridine and, after cooling, with a 0.1 5M solution of Silver nitrate (8.7 ml (1.3 mmol) treated in methanol.  The mixture was stirred at 23 C for 1 h, cooled in an ice bath and stirred for 20 min.  

  The salt was filtered and washed 3 times in succession with cold methanol and ether.  (671 mg, 87%).  IR (CHCl3) vmax: 1745 (C = O), 1605 (phosphorane) and 1520cm-1 (NO2). 



   RR.  Preparation of silver 3- (1'-paranitrobenzyldioxy-carbonyl-l 1 '-ethyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone-4-thiolate
EMI80. 1
  Isomer B
1.02 g (1 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-Paranitrobenzylcarbonyldioxy- 1 '-ethyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranyliden-2" acetate) -4-trithio-2-azetidinone were dissolved in 3 ml of CH2Cl2 and diluted with 20 ml of hot (55 C) MeOH.  The hot solution was treated with 120 ml (117 mg, 1.48 mmol) of pyridine and then with a hot 0.15N methanolic solution of silver nitrate (8 ml, 1.2 mmol). 

  The mixture was stirred at room temperature for 15 min and then at 0 C for 2 h and then concentrated on a rotary evaporator to a 10% solution.  The mercaptide was filtered and washed twice with cold (- 15 C) methanol and 3 times with ether.  (917 mg, 100%).  IR (Nujolmull) vrnax: 1745 (C = 0), 1600 (phosphorane) and 1517 cm1 (NO2).    



   Isomer C
Silver 3- (1'-paranitrobenzyldioxycarbonyl-1 '-ethyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -triphenylphosphoranylidene-2 "-acetate) -2-azetidinone-4-thiolate, isomer C was as above described for isomer B.  IR (Nujol) vmax: 1745 (C = 0) and 1600 cm-1 (phosphorane). 



    Isomer D
A solution of 145 mg (0.142 mmol) of isomer D of
3- (1 '-p-Nitrobenzylcarbonyldioxy-1' -ethyl) - 1 - (p-nitrobenzyl2 "-triphenylphophanyliden-2" -acetate) -4-tritylthio-2-azetidinone was prepared by dissolving in 5 ml CH2CI2, evaporating the CH2Cl2 at 55-60 and addition of 4 ml MeOH.  To the solution was added a hot solution of AgNO3 in MeOH (0.15M, 1.14 ml, 0.17 mmol, 1.2 eq), followed by pyridine (14 l, 0.17 mmol, 1.2 eq. ).  The silver mercaptide began to excrete immediately, whereupon the mixture was stirred at room temperature for 2 h and at 0 C for 1 h.  The mercaptide was filtered off and washed with ice-cooled MeOH and ether. 

  Yield 99 mg (0.11 mmol, 78%) of the desired compound in the form of a brown colored solid.  IR (nujol) vmax: 1750 cm-l (s, C = 0).    



   SS.  Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -Silver-3 (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2 -azetidinone-4-thiolate (isomer B)
EMI80. 2nd

A solution * of 1 g (1.19 mmol) (1'R, 3S, 4Rund 1'S, 3 R, 4S) -3- (1 '-Hydroxy-1' -ethyl) - 1 - (paranitrobenzyl-2 "- triphenylphosphoranylidene-2 "acetate) -4-trityhlthio-2-azetidinone in 10 ml of MeOH was treated with 124 l (121.3 mg, 1.53 mmol) of pyridine and at 10 C with a 0.1 5M solution of silver nitrate in MeOH (15 ml, 2.25 mmol - or until no further precipitation of the silver mercaptide occurred).  The mixture was stirred for 1 h and rotated on the rotary evaporator to approx.  10% concentration concentrated. 

  The solvent was filtered off, the filter cake was washed with MeOH and 3 × with ether and dried under high vacuum.  (954 mg, 100%).  IR (Nujolmull) vmax: 3500-3400 (O-H), 1752 (C = 0), 1595 (phosphorane) and 1525 cm-l (NO2). 



   * The crystalline material was first dissolved in C112C12. 



   TT.  Preparation of (1'R, 3R, 4R and 1'S, 3S, 4S) -4-acetylthio-3- (1'-p-nitrobenzyldioxycarbonyl-1 'ethyl) - 1 - (p-nitro benzyl-2 "-triphenylphosphoranylidene -2 "acetate) -2-azetidinone (isomer D)
EMI80. 3rd

To a stirred solution of 85 mg (0.095 mmol) of silver 3- (1'-paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone-4-thiolate (isomer D) in 5 ml of CH2Cl2 containing 30 l ( 0.37 mmol, Fisher) pyridine was added at 0-5 C 20 l (0.28 mmol) CH3COCI and the mixture was stirred at 0-5 C for 30 min. 

  The precipitate was filtered off and washed with CH2CI2, the filtrate and the washing solutions were combined, washed successively with brine, dilute HCl, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to give 75 mg (0.091 mmol) (crude yield 95%) desired compound were obtained in the form of a syrup. 



  1Hmr ((CDCI3) 6: 2.33 (s, -SOCOCH3).  IR (neat) vrnas: 1750 (ss-lactam, ester), 1695 (thioester), 1520 and 1350cm-1 (-NO2). 



   UU.  Preparation of (1'R, 5R, 6R and 1'S, 5S, 6S) -cis-p nitrobenzyl-2-methyl-6- (1'-p-nitrobenzyldioxycarbonylmethylpenem-3-carboxylate) (isomer D)
EMI81. 1

A solution of 74 mg (0.09 mmol) of the above acetylthioazetidinone in 30 ml of toluene was refluxed under nitrogen for 7 hours.  After evaporation of the solvent, the residue was purified by hplc (SiO2; eluent, benzene: ether = 3: 1), giving 24 mg (0.044 mmol), 49% yield, of the penem ester as a syrup. 



      (Note: This oil could be recrystallized from Thf ether or CH2Cl ether).  1Hmr (CDCl3) #: 1.40 (3H, d, J = 6.5 Hz, l'-CH3), 2.38 (3H, s, 2-CH3), 4.07 (1H, dd, J5, 6 4 Hz, J6.1 = 9Hz, 6-H), 5.05-5.30, 5.345.59 (2H, AB type, 3-CO2CH2-Ar), 5.30 (2H, s, 1'- OCH2-CH2-Ar), 5.1-5.6 (1H, m, l'-H), 5.68 (1H, d, J5.6 = 4 Hz, 5-H), 7.49-7 , 64-8.18-8.33 (4H, A2'B2 ', l'-aromatic, Hs), 7.53-7.68-8.18-8.33 (4H, A2'B2', 3rd -aromatic, ms).  IR (neat) vmax: 1780 (ss-lactam), 1750 (-OCO2-), 1710 (ester) 1520 and 1350 cm-1 (-NO2). 



   VV. Preparation of (1'R, 5R, 6R and 1'S, 5S, 6S) potassium and sodium 6- (1'-hydroxyethyl) -2-methylpenem-3-carboxylate (isomer D)
EMI81. 2nd

A solution of the aforementioned Penem ester (24 mg, 0.044 mmol) in 5 ml of THF was mixed with 10 ml of ether, 5 ml of water, 1.00 ml (0.05 molar pH 7.00, Fisher) and phosphate buffer
50 mg 30% Pd-Celite (Engelhard) mixed. 

  The mixture was hydrogenated at 241.25 kPa for 21.5 h at room temperature, whereupon after removal of the catalyst (via Ce lite), the aqueous phase was separated off, washed with ether and lyophilized, 12 mg of the desired product being in the form of the sodium and potassium salts were obtained as a white powder.  lHmr (D20) #: 1.23 (3H, d, J = 6 Hz, 1'-CH3), 2.27 (3H, s, 2-CH3), 3.85 (1H, dd, J5.6 = 4Hz,
J6.1 = 9 Hz, 6-H), 4.3 (1H, m, 1'-H) and 5.65 ppm (1H, d, J5.6 = 4 Hz, 5-H).  IR (Nujol) vmax: 1755 (ss-lactam) and
1570 cm-1 (-CO2-).  UV (H2O) Smax: 297 (2300, calc.  as K
Salt), 258 (1900, calc.  as K salt).  

  This product was iden
Method A: table with a sample of the compound mentioned, prepared by aldol condensation of acetaldehyde with the dianion of 2-methylpenem-3-carboxylic acid 1Hmr, IR, UV). 



   Example 35 (1'S, 5R, 6S and 1'R, 5S, 6R) -6-1; -Hydroxy-l'-ethyl) -2methylpenem-3-carboxylic acid (isomer C)
EMI81. 3rd

EMI81. 4th
   Method B:
EMI82. 1
 Method A:
1) (1'S, 3s, 4R and 1'R, 3R, 4s) -4-acetylthio-3- (1'-parani, trobenzyldioxycarbonyl-1-'ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranyliden-2" - acetate) -2-azetidinone (isomer C)
EMI82. 2nd

A cold (ice-MeOH bath) solution of 1.14 g (1.30 mmol) (I'S, 3S, 4R and l'R, 3R, 4S) -silver-3- (l'-paranitrobenzyl-dioxycarbonyl -1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone-4-thiolate (isomer C) in 60 ml of CH2CL2 was treated with 0.6 ml (0.74 mmol ) Pyridine and treated dropwise with 236 mg (0.213 ml, 3.00 mmol) acetyl chloride. 

  The reaction mixture was stirred at - 15 C for 1 h, the precipitate formed was filtered off and washed with ether.  The filtrate was washed with 2% aqueous HCl, water, 2% aqueous NaHCO3, water and brine and dried over MgSO4.  The residue after evaporation of the solvents was shaken with ether.  (895 mg, 83.7%, m.p. 



  184-185 C, dec. ). IR (CHCL3) Vmax: 1755, 1695 (C = O), 1620 and 1605 cm-1 (phosphorane). 



   Analysis for C42H36N3O11SSi Calculated: C, 61.38, H, 4.42, N, 5.11, S, 3.90 Found: C, 61.26, H, 4.49, N, 4.88, S, 4.26
2) (1'S, 5R, 6S and 1'R, 5S, 6R) -paranitrobenzyl-2-methyl6- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -enem-3-carboxylate (isomer C)
EMI82. 3rd

A solution of 855 mg (1.04 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -4-acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl- 2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone (isomer C) in 60 ml of toluene was heated to reflux temperature for 4.5 h.  After evaporation of the solvents, the residue was chromatographed on 10 g of silica gel in a column and eluted with 1% ether in benzene to give 393 mg (69.6%) of the desired compound.  M.p.  157-158 C (CHCl3 ether). 

  IR (CHCL3) vmax 1785, 1745, 1710 (C = O) and 1525cm-1 (NO2). ÚHmr (CDCL3) #: 8.30-7.2 (8H, m, H-aromatic), 5.46 (1H, d, J = 1.8, H-5), 5.40-5.0 ( 5H, m, zCH2 PNB and H-1 ') 3.95 (1H, dd, J = 1.8, J = 5.4, H-6), 2.35 (3H, s, CH3) and 1, 43 ppm (311, d, J = 5.4, CH3). 



   Analysis for C24H21N3O10S Calculated: C, 53.04, H, 3.89, N, 7.73 Found: C, 52.76, H, 3.86, N, 7.69. 



   3) (1'S, 5R, 6S and 1'R, 5S, 6R) -6- (1'-hydroxy-1'-ethyl) -2- inethyl-penem-3-carboxylic acid (isomer C)
EMI83. 1

A mixture was prepared from 206 mg (0.379 mmol) (1'S, 5R, 6S and 1'R, 5S, 6R) -paranitrobenzyl-2-methyl-6- (1'paranitrobenzyldioxycarbonyl-1'-ethyl) -penem-3- carboxylate, THF ether-H2O (30 inl, 40 inl, 20 ml), a 0.05M PH 7 buffer solution (7.64 ml, 0.382 mmol) and 500 mg 30% Pd on Celite and at 42 psi in a Parr- Apparatus hydrogenated for 16 h.  The catalyst was filtered off and washed with water. 

  The aqueous phase was washed 3 times with ether, brought in portions with cold 1% aqueous HCl to pH 2.5 and with 15> <x 20 20 inl of ethyl acetate extracted between each addition of HC1. The ethyl acetate extracts were combined and washed 3 times with 30 inl saline. After evaporation of the solvent and shaking of the residue with ether, 57 mg (65.6%) of the desired compound were obtained. IR (KBr) vmax: 3580-3300 (O-H), 1755 and 1660cm-1 (C = O). UV (EtOH) #max: 311 (# 6538), 262 (# 3672) .1Hmr (DMSO-d6) #: 5.57 (1H, d, J = 1.7, H-59.4.02 (1H , m, H-1 '), 3.75 (1H, dd, J = 1.7, J = 3.5, H-6), 2.23 (3H, s, CH3) and 1.23 ppm ( 3H, d, CH3).



  Method B
1) Silver (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'paranitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone-4-thiolate (Isomer C)
EMI83.2

1 g (143 mmol) of isomer C of 1 '- (t-butyldimethylsilyl) 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-tritylthio-2azetidinone were dissolved by stirring in 12 ml of hot (40 C) methanol. A solution of 0.59 g of silver nitrate in 12 ml of methanol was added, followed by 0.13 ml of pyridine. The mixture was stirred vigorously at room temperature for 1 h and at 0 C for 2 h. The silver mercaptide formed was filtered off and washed with ether, 352 mg (46%).



  IR vmax: 1735 cm-1 (C = O).



   2) (1'S, 3S, 4R and 1'R, 3R, 4S) -4-acethylthio-1- (t-butyldimethylsily) -3- (1 '- paranitrobenzyldioxycarbonyl-1'-ethyl) -2azetidinone (isomer C)
EMI83.3

To a solution of 880 mg of isomer C of silver 1- (t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone-4-thiolate in 40 ml dichloromethane, stirred at 0 C. 0.57 ml of pyridine and then dropwise 0.49 ml of acetyl chloride were added.

  The mixture was stirred at 0 for 0.5 h, the solids were filtered off and the filtrates were diluted with ether, washed with aqueous hydrochloric acid (2%), water, sodium bicarbonate (2%) and brine, dried and concentrated to 610 mg the desired compound was obtained in the form of an oil. ÚHmr (CDCL3) #: 8.2 and 7.48 (4H, 2d, aromatic), 5.40 (111, d, J = 2.2, H-4) , 5.2 (211, s, benzyl), 5.3-4.9 (1H, in, H-1 '), 3.42 (1H, dd, J = 2, H-3), 2.32 (3H, s, CH3), 1.40 (3H, d, J = 6.5, CH3), 0.95 (911, s, t-Bu) and 0.2 ppm (6H, CH3).



   3) (1'S, 3S; $ R and 1'R, 3R, 4S) -4-acetylthio-3- (1'paranitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone (isomer C)
EMI83.4
  
1.4 g of isomer C of said S-acetyl-Nt-butylmethylsilyl-azetidinone derivative were dissolved in a mixture of 0.5 ml TFA, 0.5 ml water, 3 ml methanol and 2 ml dichloromethane and at room temperature for 48 h stirred. The solution was diluted with 100 ml of water and extracted 4 × with 20 ml of dichloromethane. The combined organic extracts were washed with sodium bicarbonate (2% and brine, dried and concentrated to leave the desired compound as an oil.



  The purification was carried out by chromatography over 30 g of silica gel, elution with 5% ether in benzene and gave 650 mg.



  After recrystallization from benzene, a white solid was obtained. 1Hmr (CDCL3) 6: 8.15 and 7.45 (4H, 2d, aromatic), 6.18 (1H, NH), 5.19 (2H, m, H-4 and H-1 '), 3, 35 (1H, dd, J = 2.5, 4.5, H-3), 2.34 (3H, s, CH3) and 1.42 ppm (3H, d, J = 6.5, CH3). IR vmax: 1780, 1750, 1695 cm-1 (C = O).



   4) (1'S, 3S, 4R and 1'R, 3R, 4S9-4-acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1 '-ethyl) - I - (paranitrobenzyl-2 "-hydroxy-2" -acetate) -2-azetidinone (epimers at C-2 ") (isomer C)
EMI84.1

A mixture of 750 mg of isomer C of 4-acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1 '-ethyl) -2-azetidinone, 525 mg of paranitrobenzylglyoxylate hydrate and 50 ml of benzene was in a Dean-Stark apparatus for 3 days refluxed with a 3 molecular sieve. A second portion of 52 mg glyoxylate was added and refluxing continued for an additional 2 days.

  Then the mixture was diluted with ether, washed with hydrochloric acid (2%), water, sodium bicarbonate (2%) and water, dried and concentrated to leave 975 mg of an oily residue. Chromatography on silica gel, elution with benzene ether (85:15) gave the pure desired compounds.



     lHmr (CDCL3) 6: 8.25-6.75 (8H, m, aromatic), 5.30 and 5.12 (4H, 2s, benzyl), 5.05-4.70 (1H, H-2 " ), 4.45 4.35 (1H, 2d, H-4), 4.50-4.10 (1H, m, H-1 '), 3.30 (1H, m, H-2) and 1 , 25 ppm (3H, 2d, CH3).



   5) (1'S, 3S, 4R and 1'R, 3R, 4S) -4-acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-tri phenylphosphoranyliden-2" - acetate) -2-azetidinone (isomer C)
EMI84.2

577 mg (1 mmol) of isomer C of 4-acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "hydroxy-2" acetate) -2-azetidinone were dissolved in 10 ml of anhydrous THF and mixed with 95 mg (1.2 mmol) of pyridine. The solution was cooled to 0 and 143 mg (1.2 mmol) of thionyl chloride were slowly added. The mixture was stirred at 0 for 30 min, diluted with a little ether and the insoluble salts were filtered off and washed with ether.

  The combined filtrates were concentrated to give the crude mixture of the epimers of the C-2 "chlorine compound. After dissolving in 20 ml THF, 314 mg (1.2 mmol) triphenylphosphine and 129 mg (1.2 mmol) 2,6-Lutidine added and stirred for 4 days at 45 C. The solids were filtered off, washed with benzene and the combined filtrates were concentrated to an oil whose spectral data and tlc behavior were identical to a sample of the desired compound prepared by Acylation of the corresponding silver thiolate.



   The desired Penem product can be produced by reacting the compound mentioned according to the method from steps 2 and 3 in Example 35 (Method A).



   Example 36 (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxy-1'-ethyl) -2-methylpenem-3-carboxylic acid (isomer B)
EMI84.3
   Method A
EMI85.1
 Method B
EMI85.2
 Method A
1) (1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1 '-ethyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate ) -2-azetidinone (isomer B)
EMI85.3

A solution of 917 mg (1.03 mmol) (1'R, 3S, 4R and
1'S, 3R,

   4S) -Silber-3- (1'-paranitrobenzyldioxycarbonyl-1 'ethyl) - 1' -paranitrobenzyl-2 "-triphenylphosphoranyliden-2" acetate) -2-azetidinone-4-thiolate (isomer B) in 20 ml CH2CL2 was added - 15 C (ice-MeOH bath) with 242 #l (247 mg,
3.13 mmol) pyridine and treated dropwise with 142 # 1 (157 mg (2.0 mmol) acetyl chloride. The mixture was stirred for 15 min at -15 C and the solids were filtered off and washed with ether. The organic solution was washed with 2% aqueous HCl, water, 2% aqueous Na11CO3, water and brine and dried over MgSO4.

  The residue was recrystallized from ether after evaporation of the solvents. (710 mg, 80%, mp. 183-185 C) IR (CHCl3) vmax: 1755, 1695 (C = O), 1620,
1605 (phosphorane) and 1625 a-1 (NO2).



   2) (1'R, 5R, 6S and 1'S, 5R, 6R) -paranitrobenzyl-2-methyl-6- (1'paranitrobenzyldioxycarbonyl-1'-ethyl) -penem-3carboxylate (isomer B)
EMI86.1

A solution of 650 mg (0.791 mmol) (1'R, 3S, 4R and 1 'S, 3R, 4S) -4-acetylthio-3- (1' -paranitrobenzyldioxycarbonyl- 1'-ethyl) -1- (paranitrobenzyl- 2 "-triphenylphosphoranyliden2" acetate) -2-azetidinone was refluxed in toluene for 7 hours. The concentrated solution after evaporation of the solvent was added to a silica gel column (10 times the weight) and the desired compound (0.5% ether-benzene to 2% ether-benzene) was obtained as a white solid.



  329 mg, 77%, mp 134-135 C. CH2CL2 ether). IR (CHCL3) vmax: 1785, 1745, 1705 (C = O) and 1525 cm-1 (NO2). 1Hmr (CDCL3) 6: 8.20 (2H, d, Ho aromatic), 7.60 (2H, d, Hm aromatic), 5.55 (1H, d, J = 1.5, Hs), 5, 5-4.75 (5H, m, 2CH2-PNB, H-1 '), 3.86 (1H, dd, J = 7.8, J = 1.5, H-6), 2.38 (3H , s, CH3) and 1.50 ppm (3H, d, J = 6.3, CH3).



   Analysis for C24H21N3010S Calculated: C, 53.04, H, 3.89, N, 7.73, S, 5.90 Found: C, 53.05, 11, 3.98, N, 7.63, S, 6.02.



   3) (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxy-1'-ethyl) -2methyl-penem-3-carboxylic acid (isomer B)
EMI86.2

A mixture of 65 mg (0.12 mmol) (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-2-methyl-6- (1'-paranitrobenzyldioxycarbonyl-1'.ethyl) -penem -c -3-carboxylate (isomer B), 0.05M pH 7 buffer solution (1.06 eq.), H2O-THF ether (10 ml, 10 ml, 25 ml) was in a Parr hydrator with 200 mg 30 % Pd on Celite shaken at 344.64 kPa hydrogen for 16 h. The catalyst was filtered off and washed with small volumes of water. The aqueous phase was washed 3 times with ether, acidified in portions with 1% cold aqueous HCl, extracted with ethyl acetate between the additions of HCl and saturated with brine and extracted thoroughly with ethyl acetate.

  The ethyl acetate extracts were combined, washed 5+ with brine and dried over MgSO4. After evaporation of the solvent, a solid was obtained which was shaken with methylene chloride. (19.4 mg, 71%). IR (Nujol) v max: 3500 (O-H), 1785, 1672 cm-1 (C = O). UV (EtOH) #max: 260 (± 3450), 309 (± 6400). lHmr (DMSOd6) 6: 5.54 (1H, d, J = 1.5, H-5), 3.88 (1H, m, H-1 '), 4.2--3.5 (2h, bs, OH), 3.65 (1H, dd, J = 6.5, J = 1.5, H-6), 2.28 (3H, s, CH3) and 1.15 ppm (3H, d, J = 6, CH3).



  Method B
1) (1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (1'-trimethylsilyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranyliden-2 "acetate) -2-azetidinone (isomer B)
EMI86.3

A suspension of 505 mg (0.715 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -silver-3- (1'-hydroxy-1'-ethyl) -1- (paranitro benzyl-2 "- triphenylphosphoranylidene-2 '"acetate) -2-azetidinone-4-thiolate in 25 ml THF was cooled to -15 C (ice-MeOH bath), dropwise with 289 mg (398 # 1, 2.86 mmol) triethylamine , 310 mg (362 1, 2.85 mmol) of trimethylchlorosilane and treated with 50 mg (0.734 mmol) of imidazole and stirred for 3 h at −15 ° C. and for 16 h at room temperature.

  The IR spectrum of an aliquot showed the absence of hydroxyl groups. The mixture was cooled to −15 ° C., diluted with 20 ml of CH 2 Cl 2, treated with 226 mg (231 ltl, 2.86 mmol) of pyridine and 168 mg (152 1, 2.14 mmol) of acetyl chloride, while stirring for 0.5 h, diluted with ether, washed with dilute aqueous HCl, water, 5% aqueous NaHC03, water and brine and dried. The solvent was removed on a rotary evaporator and the residue was purified by filtration on a silica gel column (1:10, 3% -10% ether in benzene), taking in 360 mg (84.2%) of the desired compound in a mixture with a small portion of the desilylated derivative (30 mg, 7.8%) were obtained.

  IR (liquid film) vrnax: 1750, 1790 (C = 0), 1620 (phosphorane) and 1518 cm-1 (NO2).



   2) (1'R, 3S, 4R and 1'S, 3R, 4S) 4-acetylthio-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-22-triphenylphosphoranylidene-2 "acetate ) -2-azetidinone (isomer B)
EMI87.1

A solution of 360 mg (0.504 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (1'-trimethylsilyloxy-1'-ethyl) -1 (paranitrobenzyl-2 "- triphenylphoranylidene-2 "acetate) -2azetidinone was treated with 3 drops of TFA and stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate, washed with water, dilute aqueous NaHCO3, water and brine and dried over MgSO4. After evaporating off the solvent, the desired compound was obtained. (334 mg, 100%). IR (CHCL3) vmax: 1755, 1690 (C = O), 1620, 1605 (phosphorane and 1520 cm (NO2).



   3) (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-2-methyl6- (1'-hydroxy-1'-ethyl) -penem-3-carboxylate (isomer B)
EMI87.2

A solution of 410 mg (0.638 mmol) (1'R, 3S, 4r and 1'S, 3R, 4S) -4-acethylthio-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 " triphenylphosphoranylidene-2 "acetate) -2-azetidinone in 40 ml of toluene was refluxed for 7 hours. The toluene was partially evaporated, the residue was applied to a silica gel column (1-12-fold) (3%, 4% and 5% ether in benzene) to give 151 mg (65%) of the desired compound as a white solid (mp 161-161.5 C).

  IR (CDCL3) vmax: 3600, 350-3400 (OH), 1780.1608 (C = O) and
1525 cm-1 (NO2). 1Hmr (CDCL3) #: 8.20 (2H, d, J = 7, Ho aromatic), 7.60 (2H, d, aromatic), 5.57 (1H, d, J = 2, H-5), 5.29 (2H, center of ABq, J = 15, CH2-PNB), 4.2 (1H, dq, J = 7, J = 6, H-1 '), 3.67 (IH, dd, J = 7, J = 2, H-6), 2.33 (3H, s, CH3) and 1.33 ppm (3H, d, J = 6, CH3).



   Analysis for C16H16N2O6S Calculated: C, 52.74, 11, 4.43, N, 7.69, S, 8.80 Found: C, 52, 67, H, 4.41, N, 7.71, S, 8.96.



   4) (1'R, 5R, 6S and 1'S, 5S, 6R) -6 - (- Hydroxy-1'-ethyl) -2methyl-penem-3-carboxylic acid (isomer B)
EMI87.3

A mixture of 89 mg (0.244 mmol) (1 ', 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-6- (1'-hydroxy-1'-ethyl) -2-methylpenemem-3-carboxylate, THF-H2O ether (15 ml, 10 ml, 30 ml), 5.06 ml (0.253 mmol) 0.05M pH 7 buffer solution and 250 mg 30% Pd on Celite was added in a Parr apparatus for 3.5 h Hydrogenated 310.14 kPa. After working up as described above, 32 mg (57%) of the desired compound were obtained.



   Example 37 (1'S, 5R, 6R and 1'R, 5S, 6S) -6- (1'-hydroxy-1'-ethyl) -2methylpenem-3-carboxylic acid (isomer A)
EMI87.4

1) (1'S, 3R, 4R and 1'R, 3S, 4S) -4-acetylthio-3- (1'-methoxymethoxy-1'-ethyl-1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" - acetate) -2-azetidinone (isomer A)
EMI87.5
  
The isomer A of 4-acetylthio-3- (1'-methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone was as described for isomer C of paranitrobenzyl-dioxycarbonyl -Derivative manufactured, yield 85%. IR (neat) vrnas: 1750 and 1690 cm-1 (C = O).



     2) (1 'S, 3R, 4S and 1'R, 3S, 4S) -4-acetylthio-3- (1'-hydroxy1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene2" -acetate) - 2-azetidinone (isomer A)
EMI88.1

500 mg (0.68 mmol) of isomer A of 4-acetylthio-3- (1 'methoxymethoxy-1' -ethyl) - 1 - (paranitrobenzyl-2 "-triphenyl-phosphoranylidene-2" -acetate) -2-azetidinone added to a cooled (0 C) solution of 50 ml trifluoroacetic acid and 10 ml water and stirred for 15 min in ice and 3 h at room temperature. The reaction mixture was concentrated, dichloromethane was added and the solution was washed with sodium bicarbonate, water and brine, dried and concentrated to give 450 mg (96%) of the desired compound. IR (neat) #max: 3400 (OH), 1745 and 1690 cm-1 (C = O).



   3) (1'S, 5R, 6R and 1'R, 5S, 6S) -paranitrobenzyl-6- (1'-hydroxy-1'-ethyl) -2-methyl-penem-3-carboxylate (isomer A)
EMI88.2

Preparation as described for isomer C of the paranitrobenzyl-dioxycarbonyl derivative, yield 45%. 1Hmr (CDCL3) 6: 7.93 (4H, ABq, aromatic), 5.68 (1H, d, J = 4.0, H-5), 5.33 (2H, ABq, benzyl), 4.3 (1H, m, H-1 '), 3.8 (1H, dd, J = 4.0, H-6), 2.41 (3H, s, CH3), 2.31 (1H, s, OH ) and 1.42 ppm (3H, d, J = 6, CH3). IR (CHC13) vrnax: 3100-3600 (OH), 1780 and 1710 cm- '(C = O).



   4) (1'S, 5R, 6R and 1'R, 5S, 6S) -6- (1'-hydroxy-1'-ethyl) -2-methyl-penem-3-carboxylic acid (isomer A)
EMI88.3

A mixture of 82 mg (0.2 mmol) of the isomer A of paranitrobenzyl 6- (1'-hydroxy-1'-ethyl9-2-methyl-penem-3 carboxylate, 400 mg 30% palladium on Celite, 10 ml THF, 25 ml of ether, 10 ml of water and 4 ml of buffer (0.05M, pH = 7, Fisher SO-B-108) were hydrogenated in a Parr apparatus with an initial pressure of 45 psi for 4 h, the catalyst was filtered off through Celite and The filtrates were washed with ether and the aqueous phase was acidified with cold hydrochloric acid (0.25M) and extracted 5 times with 10 ml of ethyl acetate, the combined organic extracts were washed with brine, dried and concentrated.

  The foam-like residue was shaken in ether to give 20 mg (44%) of a white solid. IR (Nujol) vmax: 3500 (OH), 1765 and 1665 cm-1 (C = O). UV (EtOH) #max: 301 (# 5922), 260 (# 4280).



   Example 38 (1'R, 5R, 6S and 1'S, 5S, 6R) -2-aminomethyl-6- (1'-hydroxy-1'-ethyl) -penem-3-carboxylic acid (isomer B)
EMI88.4
    (1'R, 3S, 4R and 1 'S, 3R, 4S) -4-azidoacetylthio-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate ) -2-azetidinone (isomer B)
EMI89.1

A cold (ice-MeOH bath) suspension of 970 mg (1.37 mmol, from 1 g of the corresponding trityl) (1'R, 3S, 4R and 1'S, 3R, 4S) -silver-3- (1'- Hydroxy-1'-ethyl) -1- (paranitro-benzyl-2 "-triphenylphosphoranylidene-2" acetate) -azetidinone-4-thiolate in 40 ml of THF was added dropwise with 0.695 ml (595 mg, 5.48 mmol) of trimethylchlorosilane, 0.765 ml (555 mg, 5.49 mmol) of triethylamine and 50 mg (0.734 mmol) of imidazole.

  The mixture was stirred under nitrogen for 17 h, cooled to -15 C (ice-MeOH bath) and 406 mg (3.40 mmol) of azidoacetyl chloride were added. Then the mixture was stirred for 30 min (the course of the reaction was monitored by tlc). The solid was filtered off and washed with ether, the filtrate was diluted with ether, washed with 1% aqueous HCl, water, 1% aqueous NaHCO3, water and brine and dried over MgSO4.



  The residue after removal of the solvents was taken up in 50 ml of moist CH2C12 and treated with 3 drops of TFA (cleavage of the TMS ether was followed by tlc). The methylene chloride solution was then washed with 1% aqueous NaHCO3, water and brine and dried over MgSO4. The residue was placed on a silica gel column (8 times the weight) and eluted with benzene ether 1: 1, ether and ethyl acetate-ether 1: 1 to give 565 mg (69.8%) of the desired compound. IR (film) Vmax: 3500-3200 (O-H), 2100 (N3), 1755, 1609 (C = O), 1620-1605 (phosphorane) and 1518 cm-1 (NO2).



   (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-2-azidomethyl-6- (1'-hydroxy-1'-ethyl) -penem-3-carboxylate (isomer B)
EMI89.2

A solution of 500 mg (0.731 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -4-azidoacetylthi0-3- (1 - hydroxy-l'-ethyl) - I- (paranitrobenzyl-2 "-triphenylhosphoranylidene-2" acetate) -2-acetidine in 100 ml of toluene was refluxed under nitrogen for 30 min. The solution was concentrated in vacuo and the residue was poured onto 5 g of silica gel in a column (3.5-4% ether-benzene) to give 193 mg (65.1%) of the desired compound as a yellowish solid.



     IHmr (CDC13) 6: 8.13 (2H, d, Ho aromatic), 7.52 (2H, d, Hm aromatic), 5.59 (1H, d, J = 1.8, H-5), 5 , 27 (2H, center of ABq, J = 13.5, CH2-PNB), 4.50 (2H, center of ABq, J = 16, CH2-N3), 4.15 (1H, m, H-1 '), 3.73 (1H, dd, J = 6.3, J = 1.8, H-6) 1.92 (1H, d, J = 4, OH) and 1.33 ppm (3H, d , J = 6.3, CH3). IR (CHC13) vrnax: 2110 (N3), 1785, 1705 (C = O) and 1520 cm- '(NO2).



   (1'R, 5R, 6S and 1'S, 5S, 6R) -2-aminomethyl-6- (1'-hydroxy-l'-ethyl) -penem-3-carboxylic acid (isomer B)
EMI89.3

A solution of 25 mg (0.062 mmol) of 1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-2-azidomethyl-6- (1'-hydroxy-1'-ethyl) -penem-3-carboxylate in THF ether water (6 ml, 6 ml, 15 ml) was hydrogenated in a Parr apparatus for 2.5 h at 275.71 kPa hydrogen and with 100 mg 10% Pd on activated carbon. The catalyst was filtered off and washed with small parts of water. The aqueous phase was washed 3 times with ether and lyophilized to give 11 mg (73%) of the desired compound. 1Hmr (D2O) 6: 5.75 (1H, d, J = 2, H-5), 4.30 (1H, center of m, J = 6.5, H-1 '), 4.02 (1H , dd, J = 6.5, J = 2, H-6) and 1.37 ppm (3H, d, J = 6.5, CH3).

  IR (Nujolmull) Vmax. 35502450 (O-H, N-H), 1765 (C = O) and 1600 cm-1 (CO2) UV (H2O) #max: 309 (± 3650), 255 (± 2815).



   Example 39 (1'R, 5R, 6S and 1'S, 5S, 6R) -2- (4-aminobutyl) -6- (1'-hydroxyethyl) -penem-3-carboxylic acid (isomer B)
EMI90.1
  (1'R, 3S, 5R and 1'S, 3R, 4S) -4- (6-azidobutanoylthio) -3- (1'-hydroxyethyl) -1- (paranitrobenzyl-2 "-triphenylphosphorus anylidene-2" acetate) - 2-azetidinone
EMI90.2

A solution of 3.03 g (4.28 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -silver-3- (1'-hydroxyethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene- 2 "acetate) -2-azetidinone-4-thiolate in 55 ml of dry THF and under a nitrogen atmosphere was cooled to -25 ° C. and successively with 2.39 ml (17.12 mmol) of triethylamine, 2.18 ml (17.12 mmol) of trimethylchlorosilane and 0.10 g (1.47 mmol) of imidazole.

  The reaction mixture was stirred at -25 C for 0.25 h, the cooling bath was removed and stirring was continued for 16 h. It was then cooled to 0 ° C. and diluted with 55 ml of CH2Cl2 and finally treated successively with 0.73 ml (9.0 mmol) of pyridine and with a solution of 1.36 g (8.56 mmol) of 4-aminobutanoyl chloride in 10 ml of CH2Cl2. The reaction mixture was stirred at 0 C for 1 h and filtered through Celite. The filter was washed with 25 ml of CH 2 Cl 2, the filtrate and washing solutions were combined and diluted with 300 ml of EtOAc.

  The organic solution was washed with 1N HC1, H2O, saturated NaHCO3 and H20 and dried over anhydrous MgSO4 and evaporated in a rotary evaporator to 3.83 g of an orange syrup. This syrup was dissolved in 75 ml of CH2Cl2 and 4 ml of water and treated with 0.2 ml of TFA, whereupon the reaction mixture was stirred at 23 ° C. for 1.5 h, washed with NaHCO3 and H20 and dried over anhydrous Na2SO4 and to 3.4 g an orange syrup. This syrup was worked up by column chromatography (silica gel G 60, 80 g; eluent: EtOAc in CH2Cl2 10 to 75%). Evaporation of appropriate fractions gave an Ö1. 2.14 g 67.7%.



   Analysis for C37H36N507SP Calculated: C, 61.23, 11, 5.00, N, 9.65, S, 4.42 Found: C, 61.17, H, 5.10, N, 10.02, S, 3.71 (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-2- (6-azido butyl) -6- (1'-hydroxyethyl) -penem-3-carboxylate
EMI90.3

A solution of 2.04 g (2.81 mmol) (1'R, 3S, and 1'S, 3R, 4S) -4- (â-azidobutynoylthio) -3- (1'-hydroxy-1'-ethyl) - 1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone in 310 ml of toluene-CH2Cl2 (30: 1) was refluxed in a nitrogen stream over 9 h (the CH2CI2 was removed at the beginning of the reflux).

  The reaction mixture was cooled to 23 ° C. and the toluene was removed in vacuo, leaving an orange residue which was purified by column chromatography (silica gel G 60.45 g; eluent: ether in petroleum ether, 1: 1 to 9: 1). The appropriate fractions were combined and concentrated to a syrup, which was recrystallized from ether-petroleum ether.



     0.443 g, mp 85 C, 35.2%.



   Analysis for C19H21N5O6S
Calculated: C, 51.00, H, 4.73, N, 15.65, S, 7.17
Found: C, 51.05, H, 4.86, N, 15.86, S, 7.19.



   The fractions corresponding to unreacted starting material were cyclized as described above, an additional 0.276 mg (21.9%) of the desired compound being obtained. #max: 2100 (N3), 1770 (C = O, ss-lactam) 1 and 1705 cm-1 (C = O, PNB ester). UV (H20 23 C) #max: 268 (g 13757), 316 (# 9826). ÚHmr (CDCl3) #:

  : 1.36 (d, JH-2 "-H-1" = 6.3 Hz, 3H, methyl), 1.52-1, 77 (m, 4H, H-2 ', H-3'), 2.57-3.00 (m, 2H, H-4 '), 3.00-3.42 (m, 2H, H-1'), 3.72 (dd, JH-6-H-5 = 1.6 Hz, JH-6-H-1 "= 6.4 Hz, H-6), 4.02-4.42 (m, 1H, H-1"), 5.32 (ABq, Ja.h = 13.6 Hz, 2H, CH2 of PNB ester), 5.60 (d, JH-5-H-6 = 1.6 Hz, 1H, H-5), 7.61 (d, JHm-Ho = 8.8 Hz, 2H, Hm from PNB ester) and 8.21 ppm (d, JHo-Hm = 8.8 Hz, 2H, Ho from PNB ester).



   (1'R, 5R, 6S and 1'S, 5S, 6R) -2- (4-aminobutyl) -6 - (- hydroxyethyl) -penem-3-carboxylic acid
EMI91.1

To a solution of 0.54 g 1.21 mmol) (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-2- (6-azidobutyl) -6- (1'-hydroxy-ethyl) - penem-3-carboxylate in 50 ml of dimethoyethane, 50 ml of ether, 50 ml of water and 0.54 g of 10% palladium were added to activated carbon. The reaction mixture was hydrogenated at 310.18 kPa hydrogen at 23 C for 3. The mixture was then filtered through Celite and the filtrate was diluted with ether, whereupon the aqueous phase was separated off, washed with ether and lyophilized. The crude desired compound was purified by hplc.

  IR (KBr) vrnax: 1760 (C = O, ss-lactam) and 1565 cm-1 (C-O, carboxylate). lHmr (D2O) 6: 1.32 (d, JCH3-HI S = 6.4 Hz, 3H, CH3), 1.45-1.85 (m, 4H, H-1 ', H-3'), 2.50-3.20 (m, 4H, H-1 ', H-4'), 3.84 (dd, JH-6-H-1 "= 6.1 Hz, JH-6-H-5 = 1.4 Hz, 1-H, H-6), 4.00-4.45 (m, 1H, H-1 "-) and 5.62 ppm (d, JH-5-H-6 = 1 , 4 Hz, 1H, H-5). UV (H2O) #max: 260 (# 4240), 302 (e 5480).



   Example 40 (1 "R, 5R, 6S and 1'S, 5S, 6R) -2- (trans-3'-amino-l'-cyclobutyl) -6- (1" -hydroxy-1 "-ethyl) -penem- 3-carboxylic acid (isomer B)
EMI91.2
  (1 "R, 3S, 4R and 1" S, 3R, 4S) -4- (trans-3'-azidocyclobutanoylthio) -3- (1 "-hydroxy-1" -ethyl) -1- (paranitrobenzyl-2 " -triphenylphosphoranylidene-2 '' 'acetate) -2-azetidinone
EMI91.3

A solution of 1.01 g (1.43 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -silver-3- (1'-hydroxyethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene- 2 "acetate) -2-azetidinone-4-thiolate in 25 ml dry T11F was cooled to -40 ° C. under a nitrogen atmosphere and successively with 0.80 ml (5.74 mmol) triethylamine, 0.726 ml (5.72 mmol) trimethylchlorosilane and treated with 0.10 g (1.47 mmol) of imidazole.

  The reaction mixture was warmed to -15 C while stirring for 3 h, the cooling bath was removed and stirring was continued for a further 18 h. The reaction mixture was then cooled to -15 C and diluted with 25 ml CH2Cl2, whereupon it was treated with 0.15 ml (1.85 mmol) pyridine and 0.274 g (1.72 mmol) trans-3-azidocyclobutanoyl chloride. The cooling bath was removed and the solution was stirred for 1 h and treated with 0.15 ml (1.85 mmol) of pyridine and 0.274 g (1.72 mmol) of trans-3-azidocyclobutanoyl chloride.



  The mixture was then stirred at 23 ° C. for 1 h and filtered through Celite, the filtrate was diluted with 100 ml of EtOAc, washed with 1N HCl, H2O, saturated NaHCO3 and H2O, dried over MgSO4 and on a rotary evaporator to 1.47 g of an orange syrup evaporated. 2 ml of water and 0.2 ml of TFA were added to a solution of the syrup in 50 ml of CH2C12. The reaction mixture was stirred at 23 C for 2 h, washed with saturated NaHCO3 and water, dried over Na2SO4 and concentrated to 1.1 g of an orange syrup. This syrup was purified by column chromatography (silica gel G 60, 20 g; eluent: EtOAc ether 35% to 70%). Evaporation of the appropriate fractions gave the desired compound in the form of an oil. 0.77 g, 74.4%.

  IR (neat) vrnax: 3440 (011), 2100 (N3), 1755 (C = O, beta-lactam), 1735 (C = O), 1680 (C = O) and 1625 cm-1 (aromatic).



   (1 "R, 5R, 6S and 1" S, 5S, 6R) -paranitrobenzyl-2- (trans-3'azidocyclobutyl) -6- (1 "-hydroxy-1" -ethyl) -penem-3-carboxylate
EMI91.4
  
A solution of 2.27 g (3.14 mmol) (1 "R, 3S, 4R and 1" S, 3R, 4S-4- (trans-3'-azidocyclobutanoylthio) -3- (1 "-hydroxy-1 "-ethyl) -1- (paranitrobenzyl-2 '' '- triphenylphosphoranyliden2"' - acetate) -2-azetidinone in 40 ml CHCl3 was diluted with 300 ml toluene and refluxed under nitrogen for 6 h.



  The first 60 ml of the solution (CHCl3 + toluene) were separated in a Dean-Stark trap. The reaction mixture was cooled to 23 ° C. and the solvent was removed in vacuo, leaving an orange syrup which was purified by column chromatography (silica gel
G 60, 35 g, eluent: ether-benzene, 0 to 6%). Evaporation of the appropriate fractions gave the desired compound. 0.38 g, mp 134135 C, 27.3%.



   Analise for C19H19N5O6S Calculated: C, 51.24 H, 4.30 N, 15.73, S, 7.20 Found: C, 50.98, H, 4.20, N, 15.83, S, 7, 10 IR (KBr) #max 2110 (N3), 1765 (C = O, beta-lactam), 1690 (C = O PNB ester), 1510 (NO2) and 1355 cm-1 (NO2). ÚHmr (CDCl3) #: 1.36 (d, JCH3-H-1 "= 6.3 Hz, 3H, CH3), 2.0-2.75 (m, 4H, H-2 ', H-4' ), 3.67 (dd, JH-6-H-5 = 1.5 Hz, JH-6-H-1 "= 6.5 Hz, 1H, H-6), 3.8-4.55 ( m, 3H, H-1 ', H-3' and H-1 "-), 5.30 (ABq, Ja-b = 13.6Hz, 2H, CH2-Ph-NO2), 5.60 (d, JH-5-H-6 = 1.5 Hz, 1H, H-5), 7.59 (d, JHo-Hm = 8.8 Hz, 2H, HO from PNB). UV (CHCl3, 23 C) # max: 266 (± 13050) and 322 ppm (e 10008).



  The unreacted phosphorane was mixed with Ph3P-O isolated and cyclized as described, an additional 0.145 g (10.4%) of the desired compound being obtained. Total yield 37.7%. (1 "R, 5R, 6S and 1" S, 5S, 6R) 2- (trans-3'Amino-1'-cyclobutyl) -6- (1 "-hydroxyethyl) -penem3-carboxylic acid
EMI92.1

To a solution of 0.33 g (0.74 mmol) (1 "R, 5R, 6S and 1" S, 5S, 6R) -paranitrobenzyl-2- (trans-3'-azidocyclobutyl) -6 (1 "- hydroxyethyl) -penem-3-carboxylate in 40 ml of dimethoxyethane, 40 ml of ether and 0.33 g of 10% palladium on activated carbon were added, the reaction mixture was hydrogenated at 310.18 kPa hydrogen for 3 h and filtered through Celite washed with water and the filtrate and washings were combined and diluted with ether.

  The aqueous phase was separated, washed with ether and lyophilized, 0.20 g, 95%, UV (H20, 23 C) #max: 258 (# 2725) and 306 (± 3613). The crude product was shaken with water and the white solid was filtered and dried over P205 under high vacuum for 5 h.



  84 mg, 40%. ÚHmr (D2O) #: 1.34 (d, JH-2 "-H-1" = 6.3 Hz, 3H, H-2 "-), 2.3-2.7 (m, 4H, H- 2 ', H-4'), 3.90 (dd, JH-6-H-5 = 1.5 Hz, JH-6-H-1 "= 6.1 Hz, 1H, H-6) and 5 , 68 (d, JH-5-H-6 = 1.5 Hz, 1H, H-5). UV (H2O, 23 C) #max '258 (# 4738) and 306 (# 6318).



  The filtrate was purified by hplc, 58 mg. UV (H20, 23 C) #max: 257 (± 3580) and 306 (± 5033).



   Example 41
Following the general procedure of Example 34, the following 2,6-disubstituted penem compounds were prepared using the electrophiles mentioned.
EMI92.2


 <tb> electrophile <SEP> product
 <tb> <SEP> n <SEP> s
 <tb> <SEP> 0
 <tb> <SEP> C02H
 <tb> <SEP> L
 <tb> CH3I <SEP> CH3
 <tb> <SEP> cH <SEP> 2OSO <SEP> 2 <SEP> CH <SEP> CH3CH2 <SEP> 3
 <tb> <SEP> CH3CE2CE2Q5O2 <CH3 <SEP> CH3CH2CH2
 <tb> <SEP> CH2 <SEP> = <SEP> CH-CH2-Br <SEP> CH2 <SEP> = <SEP> CHCH2
 <tb> <SEP> HC <SEP> ¯ <SEP> C-CH2Br <SEP> HC <SEP> = <SEP> CCH2
 <tb> <SEP> ·
 <tb>
EMI93.1


 <tb> electrophile
 <tb> ogOS02 <CH3 <SEP> X
 <tb> CH2Br <SEP> i2:

  : CH2
 <tb> cH
 <tb> <SEP> c3
 <tb> CH2cH2cEI2Oso2g <SEP> 3
 <tb> CH = <SEP> CHCH2Br <SEP> wi
 <tb> C <SEP> CCH2Br <SEP> CCH2
 <tb> Over <SEP> XL
 <tb> <SEP> Br <SEP> ·
 <tb> C113C <SEP> H-CH3
 <tb> CH3OCH2Cl <SEP> CH30CH2
 <tb> CH3SCH2CI <SEP> CH3SCH2- <SEP> (E)
 <tb> aC1 <SEP> ÇL
 <tb> CH30CH2CH2C1 <SEP> CH3OCH2CH2
 <tb> CH3SCH2CH2C1 <SEP> CH3SCH2CH2- <SEP> (E)
 <tb> HCHO <SEP> HIGH2- <SEP> (i)
 <tb> a can be oxidized to
EMI93.2

0 b can be oxidized to CH3SCH2CH2 and CH3S02CH2CH2c OH protected by
EMI93.3
  
EMI94.1


 <tb> <SEP> electrophile
 <tb> CH3CH2CHO <SEP> OH
 <tb> <SEP> CH3CH2CH- <SEP> Hw
 <tb> <SEP> HIGH2CH2- <SEP> (i)
 <tb> <SEP> OH
 <tb> CH3CH-CH2- <SEP> (D
 <tb> <SEP> HSCH2CH2
 <tb> <SEP> s <SEP> SH
 <tb> / D <SEP> CH3C <SEP> H-CH2- <SEP> often
 <tb> <SEP> Co <SEP> ·
 <tb> OCH2C1 <SEP> OCH2
 <tb> CH2OCH2Cl <SEP> CH2OCH2
 <tb> OCH2CH2Cl <SEP> OCH2CH2
 <tb> CH2OCH2CH2Cl <SEP>

   CH2OCH2CH2
 <tb> SCH2Cl <SEP> $ SCH2- <SEP>
 <tb> CH2SCH2CI <SEP> CH2SCH2- <SEP> h
 <tb> SCH2CH2C1 <SEP> SCH2CH2- <SEP> n
 <tb> CH2SCH2CH2C1 <SEP> CH2SCH2CH2- <SEP> 0
 <tb> <SEP> Of
 <tb> e-I <SEP> o
 <tb> od SH protected by
EMI94.2
   can be oxidized to HO3SCH2CH2 can be oxidized to
EMI94.3

0 g can be oxidized to SCH2 and SO2CH2
0 h can be oxidized to CH2S CH2 and CH2S02CH2
0 o can be oxidized to SCH2CH- and So2CH2CH2-
0 j can be oxidized to # CH2SCH2CH2- and # CH2SO2CH2CH2-
EMI95.1


 <tb> electrophile
 <tb> S <SEP>
 <tb> <SEP> j <SEP> SH
 <tb> CH2CHO <SEP> 0
 <tb> <SEP> OH
 <tb> CH <SEP> = <SEP> CH-CHO <SEP> 1llA · oc
 <tb> <SEP> 0
 <tb> <SEP> II
 <tb> CH3CH2CO2CH3

    <SEP> CH3CH2C <SEP>
 <tb> &num; ci <SEP> ¸
 <tb> <SEP> S <SEP> S
 <tb> <SEP> II
 <tb> CH3C-SC2HS
 <tb> <SEP> ci <SEP> ·
 <tb> C1 <SEP> pro
 <tb> <SEP> o
 <tb> <SEP> 4 / <SEP> / 9 / \
 <tb> <SEP> o
 <tb> <SEP> ·
 <tb> C02CH3 <SEP> PI
 <tb> <SEP> k <SEP> can <SEP> oxidized Become <SEP> <SEP> too
 <tb> <SEP> 3H <SEP> O
 <tb> <SEP> S02CH3 <SEP> ¸
 <tb> Moci
 <tb> 5 <SEP> WC1 <SEP> n <SEP> Oe
 <tb>
EMI96.1


 <tb> <SEP> electrophile
 <tb> <SEP> 0
 <tb> <SEP> CH <SEP> = <SEP> CHCO2CH3 <SEP> · y ·
 <tb> <SEP> 1: 1
 <tb> <SEP> OH
 <tb> <SEP> CC-CH- <SEP> Q
 <tb> <SEP> C-CO2CH3 <SEP> II
 <tb> <SEP> C <SEP> C-C
 <tb> <SEP> SH
 <tb> <SEP> CHS
 <tb> <SEP> OH
 <tb> <SEP> CHO
 <tb> <SEP> C02 <SEP> CR3 <SEP> ML
 <tb> <SEP> 2 <SEP> 3
 <tb> <SEP> 0
 <tb> <SEP> .Ml <SEP> ·
 <tb> <SEP> o
 <tb> <SEP> ¹
 <tb> <SEP> l, d <SEP> Br
 <tb> <SEP> Br <SEP> ·
 <tb> <SEP> for
 <tb> <SEP> Br
 <tb>.

   <SEP> e.g.
 <tb> <SEP> y% Ür
 <tb>
EMI97.1


 <tb> electrophile
 <tb> MMr <SEP> MM
 <tb> N \ Br
 <tb> <SEP> .o.
 <tb>



  B-r <SEP> ÄI
 <tb> <SEP> N- <SEP> ar <SEP> 0:
 <tb> <SEP> / N <SEP> I
 <tb> <SEP> o
 <tb> <SEP> o
 <tb> <SEP> II <SEP> II
 <tb> C2HSOC-CI <SEP> C2H5OC
 <tb> <SEP> O <SEP> 0
 <tb> <SEP> II <SEP> II
 <tb> C2H5OC <SEP> CH2Br <SEP> C2H5OC <SEP> w \
 <tb> N¯C-CH2C1 <SEP> NC
 <tb> <SEP> 0
 <tb> FCH2CH2CO2CH3
 <tb> 02N-CH2CI <SEP>,
 <tb> <SEP> HONH <SEP> ¯
 <tb> 3 <SEP> 0CH2C1 <SEP> S <SEP> o-¹
 <tb> <SEP> o
 <tb> (PNB-0) 2P <SEP> 2 <SEP> 3 <SEP>
 <tb> <SEP> NH,
 <tb> CH3CHO
 <tb>
EMI98.1
  
EMI99.1
  
EMI100.1

EMI100.2


 <tb> <SEP> electrophile
 <tb> <SEP> NRR ' <SEP>
 <tb> CH2CHo <SEP> s <SEP> R, <SEP> R ' <SEP> = <SEP> H, <SEP> CH3
 <tb> <SEP> J <SEP> a,
 <tb> <SEP> e
 <tb> <SEP> / al, <SEP> e
 <tb> <SEP> R, <SEP> R0, <SEP> R ' <SEP> = <SEP> H, <SEP> CH
 <tb> <SEP> RR ' <SEP> N <SEP> < <SEP> 3
 <tb> <SEP> CH3CC1 <SEP> CH <SEP> 3o
 <tb>
Example 42 (1'S, 5R, 6S and 1'R, 5S,

   6R) -beta-trimethylsilylethyl-6 (1'acetoxy-1'-ethyl) -2-methylpenem-3-carboxylate (isomer C)
EMI100. 3rd

3- (1'-Hydroxy-1'-ethyl) -1- (beta-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" acetate) -4-tritylthio-2-azetidinone
EMI101. 1

To a solution of 185 mg (1.84 mmol) of diisopropylamine in 5 ml of tetrahydrofuran was added 1.3 ml (2.0 mmol) of n-butyllithium with stirring at -78 ° C.  After 5 min, a solution of 1.27 g (1.67 mmol) of 1- (beta-trimethylsilylethyi-2'-triphenylphosphoranylidene-2 'acetate) 4-tritylthio-2-azetidinone in 15 ml of tetrahydrofuran was added dropwise over the course of 20 min added while stirring. 

  After 2 minutes, 1 ml of freshly distilled acetaldehyde was added and the solution was stirred for 5 minutes.  12.6 ml of 0.3M hydrochloric acid was added to the mixture and this was allowed to warm to 23 ° C.  Then 20 ml each of water and ethyl acetate were added, the mixture was shaken and separated.  The organic phase was washed with water and saturated sodium chloride solution (20 ml), dried and the solvent was removed in vacuo to give 1.37 g of a crude product.  This product was poured from methylene chloride onto 7 g of silica gel and dry onto 28 g of silica gel column.  The column was eluted with 100 ml ether and then with ether / ethyl acetate 1: 1 (50 ml).  The first 20 ml of the fractions were discarded. 



  The rest was combined and the solvent was removed in vacuo to give 1.03 g of product. 



  This product was poured from ether onto a 50 g silica gel column (wet).  The column was eluted with 680 ml ether and with 200 ml ethyl acetate.  Later fractions were combined (largest spot with low Rf on tlc) and the solvent was removed in vacuo to give partially purified desired compound, 440 mg (33%).  IR vrnax: 3400 (OH) and 1750 cm-1 (beta-lactam and ester).    lHmr (CHC13) 6: Resolution too poor to recognize signals other than aromatic and trimethylsilyl signals. 



      Silver 3- (1'-hydroxy-1 '-ethyl) -1- (beta-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate
EMI101. 2nd

A solution of 425 mg (2.5 mmol) of silver nitrate, 79 mg (1.0 mmol) of pyridine and 10 ml of water was added to a solution of the above compound (403 mg, 0.50 mmol) in 10 ml of ether.  The mixture was stirred vigorously for 1 h, the precipitate was filtered off and washed with water and ether to give 267 mg (80%) of the desired mercaptide.  IR vmax: 3400 (OH) and 1750 cm- '| (beta-lactam and ester). 



   4-Acetylthio-3- (1'-acetoxy-1'-ethyl) -1- (beta-trimethylsilyl ethyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone
EMI101. 3rd

A solution of 70 mg (0.88 mmol) of acetyl chloride in 1 ml of methylene chloride was added dropwise to a solution of 267 mg (0.40 mmol) of said silver mercaptide and 70 mg (0.88 mmol) of pyridine in 5 ml of methylene chloride at 0 ° C given.  The mixture was stirred at 0 C for 1.5 h and then at 23 C for 15 min.  The precipitate was filtered off and the solution was washed with 0.1M HCl and 0.1M sodium bicarbonate (10 ml each).  The solvent was removed in vacuo to give the desired compound.  153 mg (59%). 

  IR vmax: 3450 (OH), 1750 (beta-lactam and ester) and 1690 cm-1 (thioester).    ÚHmr (CDCl3) #: 7.5-8.2 (m, 15H, Ph), 5.85 (br, 1H, H-4), 3.0-5.0 (undissolved, 4H, OCH, OCH2 , H-3), 2.0-2.6 (3 singles, 6H, OAc, SAc), 0.9-1.7 (m, 5H, CH3, CH2Si) and 0.20 ppm (s, 9H, SiMe3). 



   (1'S, 5R, 6S and 1'R, 5S, 6R) -beta-trimethylsilylethyl-6 (l'-acetoxy-l'-ethyl) -2-methylpenem-3-carboxylate (isomer C)
EMI102. 1

A solution of 150 mg (0.23 mmol) of said phosphorane in 15 ml of toluene was heated to the reflux temperature for 2 h.  The solution was mixed with 1 g of silica gel and the solvent was removed in vacuo. 



  The silica gel was placed on a 4 g silica gel column (dry) and eluted with ether.  The first 5 ml fraction (single spot with high Rf value) after evaporation of the solvent gave 65 mg (76%) of the desired compound in the form of a waxy solid.  IR vmax: 1790 (beta-lactam) 1740 (ester) and 1700 cm-1 (OAc).  IHmr (CDCl3) 6: (d, J = 2 Hz, 1H, H-5), 5.4 (m, 1H, H-1 '), 4.3 (m, 2H, OCH2), 3.90 ( q, J = 2 Hz, 4 Hz, 1H, H-7), 2.37 (s, 3H, 2-CH3), 2.11 (s, 3H, OAc), 1.42 (d, J = 6 , 5, Hz, 3H, 2'-CH3), 1.1 (m, 2H, CH2Si) and 0.05 ppm (s, 9H, SiMe3).  The product turned out to be a single isomer. 



   Example 43 (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-amino-1'-ethyl) -2-methyl-penem-3-carboxylic acid
EMI102. 2nd
 Method A (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-Azido-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4 -trityl- thio-2-azetidinone (isomer B)
EMI102. 3rd

A solution of 12.36 g (13.4 mmol) (1'S, 3S, 4R and 1 'R, 3R, 4S) -3- (1-methanesulfonyloxy-1' -ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-tritylthio2-azetidinone (isomer C) in 135 ml of 10% H2O-HMPA was heated to 85 ° C. in the presence of 1.75 g (27.0 mmol) of sodium azide.  

  The solution was then poured into 1 liter of cold water and the reaction product which crystallized out was filtered off.  After redissolving in dichloromethane, washing with brine and drying over MgSO4, the azidophosphorane was obtained as a yellow foam after evaporation of the solvent, 11.5 g (98.9%).  It was used as such in the next step. 



  IR #max (CHC13): 2100 (N3), 1740 and 1610 cm-1 (C = O). 



   (1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (1'-azido-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2 -azetidinone (isomer B)
EMI102. 4th
  
A cooled solution (5 C) of 8.9 g (10.25 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1 "Azido-1'-ethyl) -1 - ( paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone in 30 ml of dichloromethane was treated with a solution of 2.12 g (6.66 mmol) of mercury acetate in 30 ml of methanol.  After stirring at 5 C for 0.5 h and at room temperature for 1.5 h, the solvent was evaporated and the crude mercury salt redissolved in dichloromethane and washed with dilute NaHCO3 and brine. 

  After drying over MgSO4, the solution was cooled to 5 C and treated directly with 1.66 g (21 mmol) of pyridine and dropwise with 1.65 g (21 mmol) of acetyl chloride.  The reaction mixture was then stirred at 0 C for 1 h, the mercury chloride which had separated out was filtered off and the filtrate was washed successively with dilute HCl, NaHCO3 and brine.  The organic solution was then saturated with hydrogen sulfide at 5 ° C. in order to remove any remaining impurities from mercury onto mercury sulfide. 



  The crude thioester obtained after evaporation of the solvent was purified on a silica gel column (8.5 x 9 cm) and the elution was carried out with 500 ml dichloromethane and 15% acetonitrile dichloromethane: 5.1 g (74.6%).    IHmr (CDCl3) 6: 3.70 (1H, m, H-1 '), 2.98 (1H, m, H-3), 2.33 and 2.20 (3H, 2s, acetyl), 1, 28 (3H, d, J = 6.2 Ha, H-2 ').       IR #max (CHCl3): 2115 (N3), 1758, 1693 and 1620 cm-1 (C = O). 



   (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-6- (1'-azido-1 '-ethyl) -2-methyl-penem-3-carboxylate (isomer B)
EMI103. 1

A solution of 5.1 g (13.1 mmol) (1'R, 5R, 6S and 1'S, 5S, 6R) -4-acetylthio-2- (1'azido-1'-ethyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone in 100 ml of toluene was refluxed under nitrogen for 2 h. 

  The solvent was evaporated and the reaction mixture was chromatographed on a silica gel column (7 × 5 cm).     The azido-penem was eluted with dichloromethane (a further elution with 10% ether dichloromethane allowed the recovery of 1.82 g of unreacted phosphorane): 1.21 g (40.6%), mp.  132-134 C.    ÚHmr (CDCl3) #: 8.21 (2H, d, Hm, aromatic), 7.60 (2H, d, Ho aromatic), 5.51 (1H, d, J = 1.6 Hz, H-5) , 5.33 (2H, ABq, H-benzyl), 3.92 (1H, dq, J = 8.6 Hz, H-1 '), 3.67 (1H, dd, J = 1,6,8 Hz, H-6), 2.37 (3H, s, CH3), 1.46 (3H, d, J = 6.4 Hz, H-2 ').  IR #max (CDCl3): 2123 (N3), 1788 and 1712 cm-1 (C = O). 



   (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-amino-1'-ethyl) -2-methyl-penem-3-carboxylic acid (isomer B)
EMI103. 2nd

A solution of 440 mg (1.13 mmol) (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-6- (1'-azido-1'-ethyl) -2-methylpenem-3 carboxylate THF ether water (1: 1: 1) (120 ml) was hydrogenated at 50 psi hydrogen for 1 h in the presence of 440 mg 10% Pd on activated carbon.  The catalyst was filtered off, the filtrate was extracted with ether and the aqueous phase was lyophilized. 

  The 100 mg of crude amino acid obtained were purified by hplc: 19.5 mg 1 Hinr (D2O) 6: 5.69 (1H, d, J = 0.9 Hz, H-5), 3.94 (2H, m, H -6, H-1 '), 2.28 (3H, s, CH3), 1.50 (3H, d, J = 6.4 Ha, H-2').     IR vmax (Nujol): 1767, 1576 cm-1 (C = O).    UV (H2O) #max: 300 m (# 5326). 



  Method B (1'R, 3S, 4S and l'S, 3R, 4S) -3- (1'-azido-1'-ethyl) -4-trityl-thio-2-azetidinone (isomer B)
EMI103. 3rd

A solution of 1.75 g (3 mmol) of 1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1 '-methanesulfonyloxy-l' ethyl) -4-tritylthio -2-azetidinone (isomer C) and 0.39 g (6 mmol) sodium azide in 15 ml 10% H2O: HMPA was heated to 75-80 C under nitrogen for 3 h.  Then the reaction mixture was diluted with ethyl acetate and washed several times with brine.  The organic phase was dried over MgSO4 and concentrated, leaving an oil which crystallized spontaneously. 

  After shaking in ether and filtering, 951 mg (76.5%) of the desired azido compound were obtained in the form of a white solid, mp.  185-190 C, decomposition.  ÚHmr (CDCl3) 6: 7.23-7.78 (15H, m, aromatic), 4.43 (1H, d, J = 3, H-4), 4.37 (1H, s, NH), 3 , 89 (1H, dq, J = 7, 6.5, H-1 '), 3.16 (1H, dd, J = 7, 3, H-3), 1.50 (3H, d, J = 6.5, H-2 ').     IR vmax (CHCl3): 3410 (n-H), 2123 (N3) and 1765 cm-1 (C = O). 



   (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-amino-1'-ethyl) -4-triylthio-2-azetidinone (isomer B)
EMI104. 1

A suspension of 1.0 g (2.41 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-azido-1'-ethyl) -4-tritylthio-2-azetidione (Isomer B) and 100 mg of platinum oxide in 100 ml of ethyl acetate were hydrogenated at 50 psi of hydrogen for 1 h.  Since the reaction was incomplete, 200 mg of platinum oxide were added and the mixture was hydrogenated for a further hour.  Finally 200 mg of platinum oxide were added and the reaction was continued for 2.5 hours.  Total catalyst: 500 mg, total time: 4.5 h.  The catalyst was then filtered off and the solvent was evaporated and the crude amine recrystallized from ether: 700 mg (80%).  M.p.  128-130 C. 



  'Hmr (CDCl3) 6: 7.13-7.63 (15H, m, aromatic), 4.40 (1H, d, J = 2.5, H-4), 4.30 (1H, broad, H -1), 3.30 (1H, dq, J = 5.1, 6.3, H-1 '), 3.03 (1H, dd, J = 5.1, 2.5, H-3) , 1.20 (3H, d, J = 6.3, H-2 ') and 1.01.80 ppm (2H, broad, NH2). 



   (1'R, 3S, 4Rund 1'S, 3R, 4S) -3- (1 '-p-nitrobenzyloxycarbonylamino-l' -ethyl) -4-tritylthio-2-azetidinone (isomer B)
EMI104. 2nd

A solution of 1.00 g (2.57 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-amino-1'-ethyl) -4-tritylthio-2-azetidinone (Isomer B) in 100 ml dichloromethane was cooled to 5 C and treated with 0.61 g (2.83 mmol) of p-nitrobenzyl chloroformate and 0.22 g (2.83 mmol) of pyridine.  After stirring at 5 C for 45 min and at room temperature for 2.25 h, the reaction mixture was washed with dilute HCl, brine, dried over MgSO4 and concentrated to dryness.  The crude carbamate was recrystallized from ether: 1.03 g (70.5%). 

  M.p.  147-150 C.  ÚHmr (CDCl3) 6: 7.10-8.33 (19H, m, aromatic), 5.23 (2H, s, benzyl), 5.08 (1H, NH), 4.40 (1H, s, NH ), 4.29 81H, d, J = 2.2, H-4), 4.10 (1H, dq, J = 8, 6, H-1 '), 3.18 (1H, dd, J = 2.2, 8, H-3) and 1.23 ppm (3H, d, J = 6, H-2 ').     IR vmax (CHCl3): 3395 (N-H), 1765 and 1724 cm-1 (C = O). 



     (1'R, 5R, 6S and 1'S, 5S, 6R) -p-nitrobenzyl-2-methyl-6- (l "- p-nitrobenzyloxycarbonylamino-1'-ethyl) -penem-3-carboxylate (isomer B)
EMI104. 3rd

The desired product was prepared from (1'R, 5R, 6S and 1'S, 5S, 6R) -3- (1 '-p-nitrobenzyloxycarbonylamino-1'- ethyl) -4-tritylthio-2-azetidinone (isomer B) in conventional way; M.p.  108-110 C.  ÚHmr (CDCl3) 6: 7.50-8.40 (8H, m, aromatic), 5.58 (1H, d, J = 1.20, H-5), 5.35 (2H, ABq, benzyl ester) , 5.20 (2H, s, benzyl carbamate), 4.90 (1H, broad NH), 4.20 81H, dq, J = 6.8, H-1 '), 3.80 (1H, dd, J = 1.2, 8.0, H-6), 2.40 (3H, s, CH3), 1.40 (3H, d, J = 6, CH3).  

  IR #max: 3435 (n-H), 1777 and 1717 cm- '(C = O). 



   The p-nitrobenzyl ester could be catalytically hydrogenated to the corresponding carboxylic acid as in the procedure of Example 43 (Procedure A). 



   Example 44 6-Dimethylaminomethyl-2-methylpenem-3-carboxylic acid
EMI104. 4th
    1 - (t-butyldimethylsilyl) -3-dimethylaminomethyl-4-trityl-thio-2-azetidinone (cis and trans)
EMI104. 5
  
To a solution of dimethylamine (18.5 ml of a 2N solution in methanol, 36.9 mmol) in 80 ml of methanol was added dropwise a solution of hydrochloric acid in methanol (2.5 ml of a 5N solution in methanol) followed by 3.0 g (6.16 mmol) trans-1 - (t-butyldimethylsilyl) -3-formyl-4-tritylthio-2-azetidinone and 0.27 g (4.31 mmol) sodium cyanoborohydride.  The mixture was stirred at room temperature for 3.5 h, poured onto ice-hydrochloric acid (pH 2) and basified with sodium hydroxide (1N NaOH, pH = 9). 

  The mixture was extracted with ether and the ether phase was washed with brine, dried and concentrated to give 3.0 g of the desired compound as a crude oil. 



   cis and trans-3-dimethylaminomethyl-4-tritylthio-2-azetidinone
EMI105. 1

A solution of 3.0 g (6 mmol) of the crude compound mentioned in 16 ml of hexamethylphosphoric triamide (HMPT), containing 10% water, was cooled to 5 ° C. and treated with 0.78 g (12 mmol) of sodium azide.  The mixture was stirred at room temperature for 1.5 h, water was poured onto ice and extracted 5 times with 30 ml of ether.  The organic phases were extracted with 1N HCl and the acidic extracts washed well with ether to remove HMPT.  The acidic phase was then made basic with 1N NaOH and extracted with dichloromethane. 

  Then the organic phase was washed with brine, dried and concentrated to give 1.5 g (62.5%) of the desired compound as an amorphous white solid.  The mixture of the two isomers was separated on Waters Prep 500 by elution with methanol (5%), ammonia (0.2%), ethyl acetate (95%).  Trans isomer: 1.0 g, m.p.  129-131 C (pentane).    8 (ppm, CDCl3): 6.8-7.8 (15H, m, aromatic), 4.5 (1H, NH), 4.28 (111, d, J = 2.5, H-4), 3.35 (1H, m, H-3), 2.75-2.1 (2H, m, H-1 '), 2.3 (6H, s, CH3). 



   Cis isomer: 0.5 g, m.p.  132-133 C (ether pentane). 6 (ppm, CDC13): 7.7-6.7 (15H, m, aromatic), 4.72 (111, NH), 4.5 (1H, d, J = 5.3, H-4), 3.5 (1H, m, H-3), 2.85-2.35 (2H, m, H-1 '), 2.31 (6H, s, CH3).    



   The cis-trans ratio can be varied by changing the reaction conditions. 



   cis- and trans-6-dimethylaminomethyl-2-methylpenem3-carboxylic acid
This compound was prepared from cis- and trans-3-dimethylaminomethyl-4-tritylthio-2-azetidinone by the procedure of Example 58. 



      (ppin, CDCl3): 5.5 (111, d, J = 1.3), 3.7 (111, dt, J = 1.3, J = 8), 2.8 (2H, d, J = 8), 2.35 (6H, s), 2.3 (3H, s). 



   Example 45
2-aminoacetoxymethyl-penem-3-carboxylic acid (via mercaptide intermediate)
EMI105. 2nd
    4-Azidoacetoxyacetylthio -1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone
EMI105. 3rd

A chilled (ice-MeOH bath) solution of 586 mg (0.954 mmol) of 4-hydroxyacetylthio-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone in 15 ml
Methylene chloride was added sequentially with 240 mg (2.01 mmol) of azidoacetyl chloride and dropwise with
Treated 226 mg (231 ml, 3.0 mmol) pyridine in 10 ml methylene chloride.  After the addition had ended, the disappearance of the starting product was detected by tlc.  The mixture was diluted with ether, washed successively with dilute HCl, water, dilute aqueous sodium bicarbonate solution, water and saline. 

  Then it was dried over sodium sulfate and the residue on a
Silica gel column (10 g) purified, eluting with 20% ether in benzene, ether and 30% ethyl acetate in ether.  To
Concentration of the appropriate fractions gave the desired compound as a foam.  533 mg, 80.1%. IR Vrnax: (CHCl3): 1763, 1702 (C = O), 1625 (C = O # 3), 1522 (NO2) and 2110 cm-1 (N3). 



      Paranitrobenzyl-2-azidoacetoxymethylpenem-3-carboxy-lat
EMI106. 1

A solution of 533 mg (0.764 mmol) of phosphorane was refluxed in 90 ml of toluene for 0.5 h with a catalytic portion of hydroquinone.  The solvent was evaporated and the concentrated solution was applied to a silica gel column (10 g).  (Benzene: ether, 48: 2).  236 mg (73.7%) of the desired compound were obtained as Ö1. 

  This oil was found to be unstable at room temperature, which is why it was stored at -78 C until use.  ÚHmr (CDCl3) b: 8.21 (2H, d, Hm aromatic), 7.57 (2H, d, Ho aromatic), 5.68 (1H, dd, J5-6 trans = 2, H-5), 5.43 (2H, center of ABq, J = 16, CH2-PNB), 5.39 (2H, CH2O), 3.93 (2H, s, CH2-N3), 3.72 (part of dd, J6 -5 cis = 4, H-6), and 3.50 ppm (1H, dd, Jgem = 17, J6-5trans = 2, H-6). IR #max (CHCl3): 1795, 1755, 1710 (C = O), 1525 (NO2), 2110 cm-1 (N3).    



   2-aminoacetoxymethylpenem-3-carboxylic acid
EMI106. 2nd

A mixture of 219 mg (0.522 mmol) of said ester in 16 ml of THF, 30 ml of ether and 16 ml of water was in the Parr hydrator for 2.25 h at 344.64 kPa hydrogen and with 240 mg 10% Pd on activated carbon as Catalyst shaken.  The catalyst was filtered off and washed with water and ether.  The aqueous phase was washed 3 times with 30 ml of ether and lyophilized.  The crude powder was purified on a reverse phase hplc column to give 8 mg (6.7%) of the desired compound as a white powder.  ÚHmr (D2O) #: 5-72 (1H, dd, J5-6 cis = 3.5, J5 6 trans = 2, H-5), 5.37 (2H, center of ABq, J = 13.5, CH2-O), 3.96 (2H, s, CH2-NH2), 3.87 (1H, dd, Jgem = 16.5, J6-5 cis = 3.5 H-6) and 3.49 Nmr ( 1H, dd, Jgem = 16.5, J6-5trans = 2, H-6). 

  IR vrnax (Nujol): 1775, 1755 and 1600 cm- (C = O). UV (H2O) # max306 (# 4900), 256 (# 3000). 



  Manufacturing 46
Silver 1- (beta-trimethylsilylethyl-2'-triphenylphoshoranylidene-2'-acetate) -2-azetidinone-4-thiolate
EMI106. 3rd
 di-beta-trimethylsilylethyl fumarate
EMI106. 4th

To a cold (-10 C) solution of 4.73 g (0.04 mmol) 2-trimethylsilylethanol in 20 ml ether (H.     Gerlach Helv. 



  Chim.  Acta 60, 3039 (1977)) and 5.66 ml (0.07 mol) of pyridine were added dropwise under nitrogen over a period of 15 minutes to 3.78 ml (0.035 mol) of fumaryl chloride, dissolved in 10 ml of ether.  The black mixture was stirred at -10 C for 5 min and then at room temperature for 10 min.  Activated carbon was added and the reaction mixture was filtered through Celite.  The filtrate was washed with sodium bicarbonate 1% saline (1: 1, 150 ml).  The aqueous phase was extracted with 30 ml ether, the ether solutions were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a brown solid. 

 

  This compound was purified on silica gel (30 g, 4 × 5 cm) and with 300 ml of benzene as the eluent, giving 4.855 g (77%) of an oil which crystallized on standing: mp.  33-34 C.    



   Analysis for C14H28O4Si2 Calculated: C, 53.12, H, 8.91 Found: C, 53.35, H, 8.91 ÚHmr (CDCL3) #: 6.78 (2H, s, C = CH), 4, 26 (4H, m, CH2-O), 1.03 (4H, m, CH2-Si) and 0.06 ppm (18H, s, (CH3) 3Si).     IR (CHCL3) #max: 1710 (C = 0 from ester), 1643 (C = C), 1267, 1258, 862 and 840 cm-1 (Si-C). 



   Trimethylsilylethylglyoxylate hydrate
EMI107. 1

A solution of 37 g (0.117 mmol) of the-beta-trimethylsilylethyl fumarate in 1.1 liters of methylene chloride was ozonized at -78 C until a blue color remained.  The excess ozone was purged with nitrogen and 2.57 ml (0.351 mol) of dimethyl sulfide were added.  The solution was then allowed to warm up slowly to 23 ° C, whereupon the reaction mixture was made up to 2 liters with carbon tetrachloride and washed with a 1% aqueous solution of sodium carbonate (500 ml).  The organic phase was dried over sodium sulfate, filtered on Celite and concentrated (25 C) to give 43.9 g of the desired compound (97%). 

  IR (neat) vmax: 3450 (-OH), 1740 (ester, 1255, 860 and 840 cm-1 (Si-C). 



   1 - (beta-Trimethylsilylethyl-2'-hydroxy-2'-acetate) -4-trityl thio-2-azetidinone
EMI107. 2nd

4,000 g (11.6 mmol) of trimethylsilylethylglyoxylate hydrate and 4.8 g (24.96 mmol) of the 4-tritylthio-2-azetidinone were refluxed in 25 ml of benzene in a Dean-Stark apparatus under nitrogen for 24 hours.  The solvent was removed in vacuo, the product was chromatographed on silica gel (450 g, 8.5 x 14.5 cm) and eluted with ethyl acetate: methylene chloride (1:19) until the desired compound appeared (approx.  1.5 liters) and then with ethyl acetate: methylene chloride (1: 9, 2 liters). 

  The fractions with the desired compound were combined and evaporated to dryness to give 5.415 g (89%) of the desired compound.    ÚHmr (CDCl3) #: 7.80-6.70 (15H, m, trityl), 5.23 and 4.90 (1H, 2s, HCO), 4.50-4.10 (3H, m, H- 3 and O-CH2), 2.60 (2H, m, H-2), 0.95 (2H, m, CH2-Si) and 0.1 ppm (9H, s, Si-CH3).    IR (CHCl3) #max: 3520 (-OH), 1765 (C = O from beta-lactam), 1740 (C = O from ester), 1595 (CH, aromatic), 1257, 860 and 840 cm-1 (C -Si). 



   1- (beta-trimethylsilylethyl-2'-chloro-2'-acetate) -4-tritylthio2-azetidinone
EMI107. 3rd

A solution of 0.74 ml (10.37 mmol) of thionyl chloride in 9 ml of dry THF was added dropwise with stirring to a solution of 4.9 g (9.37 mmol) of 1- (beta-trimethylsilylethyl-2'-hydroxy- 2'-acetate) -4-tritylthio-2-azetidinone, 0.84 ml (10.38 mmol) pyridine and 40 ml dry THF at -15 C under nitrogen.  The mixture was stirred at -15 C for 2 h.  The precipitate was filtered off through Celite and washed with 50 ml of benzene, the filtrate was concentrated in vacuo at 30 C and the residue was dissolved in 100 ml of benzene, treated with activated carbon and filtered through Celite. 

  After evaporation of the solvent, a residue was obtained, which was purified by silica gel (100 g, 4.7 x 11 cm): hexane-benzene (1: 1, 400 ml), ether-benzene (1: 19.1 liters).  Evaporation of the appropriate fractions gave 4.64 g of the desired compound (92%). 



     IHmr (CDCl3) Ï: 7.30 (15H, m, aromatic), 5.77 and 5.43 (1H, 2s, CH-Cl), 4.7 to 4.2 (3H, m, H-4 and C112-O), 2.85 to 2.50 (2H, m, H-3), 1.15 (2H, m, CH2-Si) and 0.06 ppm (9H, s, Si-CH3).  IR (neat) vrnax: 1760 (C = 0), 860 and 840 cm-l (C-Si). 



      1 - (beta-Trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone
EMI107. 4th

A solution of 4.12 g (7.568 mmol) of the chlorazetidinone in 20 ml of dioxane was treated with 2.209 g (8.424 mmol) of triphenylphosphine and 0.98 ml (8.424 mmol) of 2,6-lutidine.  The mixture was refluxed for 3.5 h, the cooled solution was filtered and the white solid obtained was washed with THF.  The filtrate was evaporated to dryness, the residue was purified on silica gel (200 g, 4 x 31 cm) using ethyl acetate-hexane (3: 7, 1 liter, 7: 3, 1 liter), whereby 4.836 g (83% ) of the desired phosphorane were obtained.  IR (film) vrnax: 1755 (C = O), 1615 (phosphorane), 850 and 830 cm- | (Si-C). 



   Analysis for C47H46NO3PSSi Calculated: C, 73.89, 11, 6.07, N, 1.81 Found: C, 72.18, H, 6.08, N, 1.83
Silver 1st (beta. trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate
EMI108. 1

7.64 g (10 mmol) of 1- (beta-trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone were dissolved in 60 ml of ether.  An aqueous solution of silver nitrate (0.5M, 80 ml, 40 mmol) was added, followed by a rapid (1 min) solution of 3 ml (12.58 mmol) tributylamine and 0.154 ml trifluoroacetic acid (0.2 mmol) in 20 ml ether.  The mixture was stirred for 19 min, the precipitate was filtered, rinsed with 200 ml of ether, shaken with 70 ml of water, filtered and rinsed with 100 ml of ether. 

  The light brown solid was dried in vacuo (water jet vacuum 10 min and vacuum pump 65 min) and gave 6.42 g of the desired compound.  IR (CHCl3) vmax 1862 (C = 0), 1630 (phosphorane), 860 and 840 cm-1 (Si-C). 



   Example 47
6-formamidomethyl-2-methylpenem-3-carboxylic acid, sodium and potassium salts
EMI108. 2nd
 trans-1 (t-butyldimethylsilyl) -3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone
EMI108. 3rd

A solution of 8.0 g (16.36 mmol) of trans-1- (t-butyldimethylsilyl) -3-hydroxymethyl-4. tritylthio-2-azetidinone in 50 ml dichloromethane was treated at 5 C with 1.4 ml (18 mmol) methanesulfonyl chloride in 10 ml dichloromethane and 2.5 ml (18 mmol) triethylamine.  The mixture was stirred further under nitrogen for 1 h, after which the solution was washed successively with cold 1N HCl, 1M sodium bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuo.  The residue (mixture of hydroxy and mesylate compound) was treated a second time as mentioned to give 90 g (97%) of the mesylate as an amorphous solid.  

  This product was used as such in the next step without further processing.  An analytical sample was recrystallized from methylene chloride, mp.  167-168 C.    IR (pure) vrnsx: 1755 cm- 1.  IHmr (CDC13) o: 7.3 (15H, m), 4.4 (1H, d, J = 2 Hz), 3.9 (1H, dd, J = 8 Hz, 4Hz), 3.2 (2H , bs), 2.8 (3H, s), 0.95 (9H, s) and 0.3 ppm (6H, s). 



   trans-3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone and trans-3- (azidomethyl) -4-tritylthio-2-azetidinone
EMI108. 4th
  
A solution of 21.0 g (37.0 mmol) of trans-l- (t-butyldimethylsilyl) -3-methanesulfonylmethyl-4-tritylthio-2-azetidinone in 90 ml of HMPA was cooled in an ice bath and 2.7 g (41 , 2 mmol) of sodium azide in 10 ml of H2O.  The reaction mixture was stirred at room temperature for 1 h, diluted with ethyl acetate, washed 5 times with 100 ml of H20, dried over MgSO4 and concentrated in vacuo. 



  The trans-3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone was diluted with 90 ml HMPA, treated at room temperature with 2.7 g (41.2 mmol) sodium azide in 10 ml H20, heated to 60 C for 2 h and with shaken cold water.  The crude azide was diluted with benzene ether (5: 1) and washed 5 times with 20 ml of water.  After evaporation of the solvent and recrystallization from ether, 18.0 g (77%) of the azide were obtained as a white solid.  An analytical sample was recrystallized from C112C12 / ether, mp.  174-175 C. 



   Analysis for C23H20N4OS Calculated: C, 68.97, 11, 5.03, N, 13.99 Found: C, 68.78, 11, 5.00, N, 14.16
IR (Nujol) vmax: 2100, 1765 cm-1, ÚHmr (CDCl3) 6: 7.35 (15H, m), 4.75 (1H, bs), 4.4 (1H, d, J = 2 Hz) and 3.1-3.7 ppm (3H, m).     trans-3-aminomethyl-4-tritylthio-2-azetidinone
EMI109. 1

To a solution of 10.0 g (47.5 mmol) of trans-3-azidomethyl-4-tritylthio-2-azetidinone in 500 ml of dry methanol was added 19.0 g of ammonium chloride and 1.0 g of zinc powder and the suspension was added to Room temperature stirred for 5 h. 

  Then the reaction mixture was filtered and evaporated, the residue was partitioned between 1N hydrochloric acid and benzene, the aqueous phase was made basic with 1M sodium bicarbonate and extracted with methylene chloride.  The extracts were washed with brine, dried over MgSO4 and concentrated in vacuo.  The crude amine was recrystallized from ether to give 14.05 g (79%).  M.p.  139-9 C. 



   Analysis for C23H22N2OCl # 1 / 4CH2Cl2 Calculated: C, 70.56, 11, 5.73, N, 7.08 Found: C, 70.68, 11, 5.94, N, 7.27
IR (CHCl3) vrnax: 3400 and 1760 cm-1.  ÚHmr (CDCl3) 6: 7.35 (15H, m), 5.15 (1H, m), 4.3 (1H, bs), 2.7-3.5 (3H, m) and 1.3 ppm (2H, m). 



   trans-3-phthalimidomethyl-4-tritylthio-2-azetidinone
EMI109. 2nd

A solution of 13.9 g (37.2 mmol) of trans-3-aminomethyl-4-tritylthio-2-azetidinone and 8.3 g (37.9 mmol) of N-carb ethoxyphthalimide in 200 ml of benzene was applied over 15 h Reflux temperature heated.  The solvent was removed in vacuo and the residue recrystallized from ether to give 17.4 g (93%) of the desired compound.     M.p.  172-173 C. 



   Analysis for C31H24N203S Calculated: C, 73.78, 11, 4.79, N, 5.55 Found: C, 73.92, H, 4.87, N, 5.49
IR (C11C13) #max: 1770 and 1715 cm Ú. ÚHmr (CDCl3) 6: 7.8 (4H, m), 7.3 (15H, m), 4.45 (111, d, J = 2 Hz), 3.3-4.1 (3H, m) and 3.3-4.6 ppm (1H, m).    



   trans-3-phthalimidomethyl-1 - (paranitrobenzyl-2'-hydroxy-2'-acetate) -4-tritylthio-2-azetidinone
EMI109. 3rd

A mixture of 17.4 g (34.52 mmol) of trans-3-phthalimidomethyl-4-tritylthio-2-azetidinone, 9.4 g (41.4 mmol) of paranitrobenzyl glyoxylate hydrate and 4.8 ml (34.5 mmol ) Trit ethylamine in 250 ml of tetrahydrofuran was stirred at room temperature for 20 h.  The reaction mixture was concentrated in vacuo and the residue with activated carbon
Treated with benzene.  After evaporation of the solvent, he kept 25 g (quantitative) of the crude hydroxyglyoxylate as an amorphous solid.  This was used in the next step without cleaning.  IR (CHCl3) max 1770 and 1715 cm-1. 



  ÚHmr (CDCl3) o: (2H, d, J = 9 Hz), 7.55 (3H, d, J = 9 Ha),
7.3 (19H, m), 5.0-5.4 (2H, bs), 4.3-5.0 (2H, m) and 2.8-3.8 ppm (4H, m).    



   trans-3-phthalimidomethyl-1 - (paranitrobenzyl-2'chlor-2'-acetate) -4-tritylthio-2-azetidinone
EMI110. 1

A 1M solution was added dropwise to a solution of 25 g (35 mmol) of trans-3-phthalimidomethyl-1 - (paranitrobenzyl-2'-hydroxy-2'-acetate) -4-tritylthio-2-azetidinone cooled in an ice bath in 150 ml of tetrahydrofuran of thionyl chloride in tetrahydrofuran (46 ml, 46 mmol) followed by a 1M solution of pyridine in tetrahydrofuran (46 ml, 46 mmol).  The reaction mixture was stirred at room temperature for 20 min, diluted with 50 ml of petroleum ether and filtered through Celite / activated carbon.  The solvent was evaporated in vacuo to give 26 g (quantitative) of the chlorazetidinone as an amorphous solid. 



  This was used in the next step without refurbishment.  IR (CHCl3) vrnax: 1775 and 1720 cm-1.    1Hmr (CHCl3): 8.12 (2H, d, J = 9 Hz), 7.60 (2H, d, J = 9 Hz), 7.3 (19 H, m), 5.25 (2H, m ), 4.7-5.4 (1H, m), 4.55 (1H, bs) and 3.3-4.0 ppm (3H, m).    



   trans-3-phthalimidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-trityltlsio-2-azetidinone
EMI110. 2nd

A mixture of 26 g (35.5 mmol) of trans-3-phthalimidomethyl-1 - (paranitrobenzyl-2'-chloro-2'-acetate) -4-tritylthio-2azetidinone, 10.25 g (39.1 mmol) of triphenylphosphine and 4.6 ml (39.1 mmol) of 2,6-lutidine in 200 ml of dioxane was heated to 100 ° C. over 20 hours.  The reaction mixture was filtered through Celite and evaporated, the residue was chromatographed on a silica gel column (350 g) and eluted with benzene and benzene / ether (1: 1) to give 21 g (62%) of the phosphorane as a white solid. 

  IR (CHC13) max 1750 and 1710 cm 1.     1Hmr (CDCl3) o: 7.4 (38H, m), 4.8-5.4 (3H, m), 4.6 (2H, m) and 3.7 ppm (1H, bs). 



      trans-3-phthalimidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone
EMI110. 3rd

A cooled (ice bath) suspension of 18.02 g (18.83 mmol) of trans-3-phthalimidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-aze- tidinone in 30 ml of tetrahydrofuran, 30 ml of water and 30 ml of acetone was treated dropwise with 4.97 g (20.7 mmol) of sodium sulfide in acetone / water 1: 1 (30 ml) and heated at reflux temperature for 8 h.  The reaction mixture was diluted with water, acidified with 1N HCl and extracted with dichloromethane.  

  The organic extracts were washed with brine and evaporated in vacuo to give 17.1 g (88%) of the desired compound as an amorphous pale yellow solid.     This was used in the next step without refurbishing.  IR (pure) vmax: 3150-3600, 1750 and 1700 cm-l.     1Hmr (CDCl3) 6:

   7.4 (38H, m) and 3.3-5.5 ppm (8H, m).     trans-3-phthalisoimidomethyl-1 - (paranitrobenzyl-2'-triphenyl-phosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone
EMI110. 4th
  
A solution of 17.1 g (17.54 mmol) of trans-3-phthalimido domethyl-1 - (paranitrobenzyl-2 '-triphenylphosphoranyliden2'-acetate) -4-tritylthio-2-azetidinone in 125 ml of dichloromethane was added dropwise at room temperature Treated 3.62 g (17.54 mmol) of N, N'-dicyclohexylcarbodiimide in 30 ml of dichloromethane.  The solution was filtered through Celite and evaporated to give 18.23 g (quantitative) of the desired compound as an oil.  This was used in the next step without refurbishing. 

  IR (neat) vrnax: 2 2110, 1755 and 1710 cm- '.  iHmr (CDCI3) 6: 7.5 (38H, m), 4.6-5.3 (4H, m) and 3.9 ppm (2H, bs). 



   trans-3-aminomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone
EMI111. 1

A solution of 5.9 g (6.16 mmol) of trans-3-phthalisoimi domethyl) - 1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone in 40 ml of tetrahydrofuran was added Cooled to -20 ° C. and treated dropwise under nitrogen with 0.2 times (6.16 mmol) hydrazine and stirring continued for 30 min.  The reaction mixture was acidified with 1N HCl, washed with ether, the aqueous phase was made basic with 1M sodium bicarbonate solution and extracted with methylene chloride.  The organic extracts were washed with brine, dried over MgSO4 and evaporated. 

  The residue was purified on a silica gel column (60 g), eluting with ether and ethyl acetate, to give 3.38 g (66%) of the aminophosphorane as an amorphous solid.  IR (CHC13) vmax: 1730, 1710 cm 1 lHmr (CDCI3) 6: 6.5-8.1 (34H, m), 3.8-5.3 (6H, m) and 0.9-1.9 ppm (2H, m).    



   trans-3-formamidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio. 2-azetidinone
EMI111. 2nd

To a cooled (ice bath) solution of 5.0 g (6.04 mmol) of trans-3- (aminomethyl) -1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone in 50 ml of dichloromethane, a solution of acetic acid / formic anhydride (600 mg, 6.8 mmol) in 5 ml of dichloromethane was added dropwise under nitrogen, followed by a solution of 1 ml (7 mmol) of triethylamine in 2 ml of dichloromethane, followed by Was stirred for a further 30 min.  The solution was washed successively with 1N HCl, water, 1M sodium bicarbonate solution and brine. 

  The organic phase was dried over MgSO4, evaporated and the residue was purified on a silica gel column (50 g).  Elution was performed with ether and ethyl acetate and gave 2.0 g (39%) of the formamide as an amorphous solid.  IR (CHCl3) vmax: 1740, 1685 and 1620 cm Hmr (CDC13) 6: 6.68.2 (35H, m), and 2.5-5.3 ppm (7H, m).    



     trans-silver-3-forinamidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate
EMI111. 3rd

A solution of 550 mg (0.64 mmol) of trans-3-formamidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranyliden2'-acetate) -4-tritylthio-2-azetidinone in 10 ml of dichloromethane was evaporated to dryness and with 20 ml hot methanol diluted.  The solution was stirred at 60 C and with a preheated (60 C) solution of 0.1 5M silver nitrate in 5.7 ml (0.86 mmol) of methanol followed by a solution of 1.5M pyridine in methanol (0.57 ml , 0.86 mmol) treated.  The creamy solution was stirred at room temperature for 30 minutes and then stirred in an ice bath for 2 hours. 

  The solid was filtered, washed with cold methanol and ether and dried to give 300 mg (65%) of the silver salt as a beige solid.  This was used in the next step without further processing. 



      trans-4-acetylthio-3-formamidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone
EMI112. 1

To a cooled (ice bath) solution of 800 mg (1.11 mmol) of trans-silver-3-formamidomethyl-1- (paranitro benzyl-2 '. triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate in 10 ml of dichloromethane was dropwise added a solution of 1M acetyl chloride in dichloromethane (1.33 ml, 1.33 mmol) under nitrogen, followed by a solution of 1M pyridine in dichloromethane (1.33 ml, 1.33 mmol).  The solution was stirred in the cooling bath for 1 h and then filtered through Celite.  The filtrate was washed successively with 1N HCl, water, 1M sodium bicarbonate solution and brine and the organic phase was dried over MgSO4 and evaporated. 

  The residue was purified on a silica gel column (5.0 g) and eluted with ethyl acetate and 10% methanol in ethyl acetate to give 450 mg (62%) of the desired compound.  IR (CHCl3) vmax: 1755, 1685 and 1620 cm-1.  ÚHmr (CDCl3): 8.18 (2H, d, J = 9 Hz), 7.0-8.0 (20H, m), 6.75 (2H, d, J = 9 Hz), 6.3 ( 1H, m), 5.5 (1H, m), 5.2 (2H, bs), 4.9 (1H, bs), 3.6 (1H, m), 3.0 (1H, m) and 2.2 ppm (3H, two s). 



   Paranitrobenzyl-6-formamidomethyl-2-methylpenem-3carboxylate
EMI112. 2nd

A solution of 450 mg (0.686 mmol) of trans-4-acetylthio-3-formamidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone in 10 ml of toluene was heated at reflux temperature for 12 h.  After concentration and working up on a silica gel column and elution with ether and 10% methanol in ether, 100 mg (39%) of the penem were obtained as an amorphous solid.  IR (CHCl3) #max: 1780 and 1690 cm-1. ÚHmr (CDCl3) #: 8.2 (2H, d, J = 9Hz), 8.2 (1H, s), 7.6 (2H, d, J = 9 Hz), 6.9 (1H, m) , 5.55 (1H, s), 5.35 (2H, 2s), 3.3-4.1 (3H, m) and 2.33 ppm (3H, s). 



     6-Formamidomethyl-2-methylpenem-3-carboxylic acid sodium and potassium salts
EMI112. 3rd

A mixture of 80 mg (0.21 mmol) of paranitrobenzyl-6 formamidomethyl-2-methylpenem-3. carboxylate, 100 mg 30% palladium on Celite, 10 ml tetrahydrofuran, 25 ml ether and 4.46 ml (0.223 mmol) 0.05M buffer solution pH 7 was hydrogenated in a Parr apparatus with an initial pressure of 310.18 kPa hydrogen for 3 h .  The catalyst was filtered off through Celite and washed with water. 

 

  The filtrate and washings were combined and the phases were separated.  The aqueous phase was 3 times with
15 ml ether washed and lyophilized.  The solid obtained was purified by hplc to give 18 mg of a mixture of the potassium and sodium salts. 



     Uv (H2O) #max: 229 (± 4933), 259 (e 4094).  IR (Nujol) Vmax: 3100-3650 and 1755 cm-l.       lHmr (D2O) 8: 8.15 (1H, s), 5.53 (1H, d, J = 1.4 Hz), 4.0 (1H, m), 3.74 (2H, d, J = 5 Hz), 3.25-4.25 (1H, m) and 2.27 ppm (3H, s). 



   Example 48 (1'S, 5R, 6S and 1'R, 5S, 6R) -6- (1'-hydroxy-1'-propyl) -2methyl-penem-3-carboxylic acid, sodium salt (isomer C)
EMI112. 4th
 trans-1-t-butyldimethylsilyl-3-propionyl-4-tritylthio-2azetidinone
EMI112. 5
   Method:
37.50 ml (1.6M / hexane, 60 mmol) of n-BuLi was added dropwise under nitrogen to a cooled (dry ice / acetone bath) and stirred solution of 8.50 ml (60 mmol) diisopropylamine in 200 ml of dry THF.  The mixture was stirred in the cold and 22.9 g (50 mmol) of 1-t-butyldimethylsilyl-4-tritylthio-2-azetidinone in 100 ml of dry THF were added.  After 15 min, 40 ml of methyl propionate were added and the reaction mixture was kept at -78 C for 4 h. 

  The cooling bath was then removed and the temperature was allowed to rise to 0 C (approx.  40 min).  Then it was poured onto ice / HCl (pH 6) and extracted with ether.  The phases were separated and the aqueous phase was extracted with ether, whereupon the combined extracts were washed with water and brine and dried over Na2SO4.  After evaporation in vacuo, an oil was obtained in quantitative yield.  This consisted of a mixture of the starting product and the desired compound and was used as such in the next step.  IR (pure) vrnax.    
EMI113. 1




  1750 cm - '(be ta-lactam).    



   1-t-Butyldimethylsilyl-3- (1'-hydroxy-1'-propyl) -4-tritylthio-2-azetidinone
EMI113. 2nd
 Method:
A solution of 26 g (50 mmol) of 1-t-butyldimethylsilyl3-propionyl-4-tritylthio-2-azetidinone and 7.6 g (200 mmol) of sodium borohydride in 400 ml of THF was stirred at room temperature for 18 h.  Then it was poured onto ice / HCl (1N) (pH 6) and extracted with ether.  The acidic phase was extracted several times with ether and the combined ether solutions were washed with brine, dried over Na2SO4 and evaporated to an amorphous solid (25.0 g).  This crude product was chromatographed on silica gel (400 g) and first eluted with CH2C12 to give 10.8 g of 1-t-butyldimethylsilyl-4-tritylthio-2-azetidinone. 

  Elution with 20% ether in CH2Cl2 gave 10.3 g of the desired compound as a mixture of the two isomers trans alcohols.  These were separated by hplc (Water Associates, System 500) using 10% EtOAc in CH2C12 as the eluent.  Isomer C, white solid, 3.8 g mp  (Petroleum ether) 134-136 C.  ÚHmr (CDCl3) 6: 7.1-7.8 (15H, m, STr), 4.35 (H, d), 3.1 (H, dd), 2.5 (H, m), 0, 7-1.7 (5H, m), 0.97 (9H, s) and 0.25 ppm (6H, s). 



   Analysis for C31H39NO2SSi Calculated: C, 71.91, H, 7.59, N, 2.71 Found: C, 71.51, H, 7.60, N, 2.96
Isomer B, white solid, 5.4 g.  M.p.  (Pentane-petroleum ether) 97-99 C.    IHmr (CDCI3) 6: 7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 0, 7-1.7 (5H, m), 0.85 (9H, s) and 0.1 ppm (6H, s).  97-99 C.    lHmr (CDCl3) 6: 7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 0, 7-1.7 (5H, m) 0.85 (9H, s) and 0.1 ppm (6H, s). 

  Total yield of these two alcohols (based on recovered starting product) was 67.5%.    



   (1'S, 3S, 4R and 1'R, 3R, 4S) -1-t-butyldimethylsilyl-3- (1'paranitrobenzyldioxycarbonyl- 1'-propyl) -4-tritylthio-2-azetidinone (isomer C)
EMI113. 3rd
 Method:
To a cooled (dry ice-acetone bath) solution of 3.1 g (6 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1-t-butyldimethylsilyl-3- (1 '-hydroxy- 1 '-propyl) -4-tritylthio-2-azetidinone (isomer C) in 20 ml of dry THF, a solution of 1.6M n-BuLi / hexane (4.88 ml, 7.8 mmol) was added dropwise under nitrogen and stirred at -78 C for 25 min. 



  Then 1.56 g (7.2 mmol) of paranitrobenzyl chloroformate in 10 ml of dry THF was added and the resulting mixture was stirred at -78 C for 4 h.  The mixture was then diluted with ether and washed with NH4Cl solution and brine, the organic phase was dried over Na2SO4 and evaporated to dryness, giving 4.2 g of the desired compound (quantitative yield).    1Hmr (CDCl3) 6: 8.2 (2H, d), 7.0-7.7 (17H, m), 5.13 (2H, s), 4.05 (H, d), 3.75 ( H, dt), 3.25 (dd), 0.55-1.8 (5H, m), 0.9 (9H, s) and 0.25 ppm (6H, d). 



   (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-Paranitrobenzyldioxy carbonyl-1'-propyl) -4-tritylthio-2-azetidinone (isomer C)
EMI113. 4th
   Method:
To a cooled (ice bath) solution of 4.2 g (6 mmol) (1'S, 3S, 4R and 1 'R, 3R, 4S) -1-t-butyldimethylsilyl-3- (l' -paranitrobenzyldioxycarbonyl-1 ' -propyl) -4-tritylthio-2-azetidinone (isomer C) in 40 ml of HMPT, containing 10% H2O, 0.78 g (12 mmol) of sodium azide were added.  The mixture was stirred at room temperature for 1 h, diluted with 100 ml of water and extracted with benzene: petroleum ether (1: 1) (4 x 15 ml). 

  The organic phase was washed 6 times with 30 ml of water and then with brine, dried over Na2SO4 and evaporated to dryness to give 3.5 g of a solid (quantitative yield).  This was treated with pentane and filtered to give 3.4 g of a pale yellow solid.  M.p.    84-86 C.  ÚHmr (CDCl3) #: 8.2 (2H, d), 7-7.7 (17H, n), 5.2 (2H, s), 4.95 (H, dt), 4.4 (NH) , 4.25 (H, d), 3.4 (H, dd), 1.7 (2H, m) and 0.95 ppm (3H, t). 



   (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-paranitrobenzyldioxycarbonyl-1 '-propyl) - 1 - (paranitrobenzyl-2 "-hydro y-2" -hydroxy-2 "acetate ) -4-tritylthio-2-azeidinone (isomer C)
EMI114. 1
 Method:
To a solution of 3.2 g (5.5 mmol) (1'S, 3S, 4R and 1 'R, 3 R, 4S) -3- (1' -paranitrobenzyldioxycarbonyl-1 '-propyl) -4-tritylthio-2 -azetidinone (isomer C) and 1.362 g (6 mmol) of paranitrobenzylglyoxylate hydrate in 50 ml of dry THF, a catalytic portion (4 drops) of TEA and Na, SO4 (to adsorb the H2O formed) was added. 

  The resulting mixture was stirred at room temperature for 6 h, filtered and evaporated to dryness to give 4.35 g of an amorphous solid (quantitative yield).  1Hmr (CDCl3) 6: 8.25 (4H, dd), 7-7.9 (19H, m), 5.28 (2H, s), 5.1 (2H, s), 4.8 (H, d), 4.4 (H, dd), 4.1 (H, dt), 3.4 (H, m), 1.1-1.8 (2H, m) and 0.8 ppm (3H, t). 



   (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-paranitrobenzyldioxycarbonyl-1 '-propyl) -1- (paranitrobenzyl-2 "-chlor-2" -acetate) -4tritylthio-2- azetidinone (isomer C)
EMI114. 2nd
 Method:
To a chilled (ice / saline / bath) solution of said glyoxylate (4.35 g, 5.5 mmol) in 30 ml of dry THF was added 7 ml (7 mmol) of 1M py / THF, followed by dropwise addition of 7 ml (7 mmol) 1M SOCl2 / THF.  The mixture obtained was stirred at the temperature mentioned for 1 h, then diluted with 30 ml of benzene and stirred in the cold (ice / water bath) for 30 min and filtered through Celite activated carbon. 

  The filtrate was evaporated to dryness to give 3.8 g of an amorphous solid (85.3%).  1Hmr (CDCl3) â: 8.15 (4H, d), 6.75-7.7 (19H, m), 5.65 (H, s) 5.2 (2H, s), 5.1 (2H , s), 4.5 (H, m), 3.85 (H, m), 3.4 (H, m), 1.25-2.0 (2H, m) and 0.9 ppm (3H , t). 



   (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-Paranitrobenzyldioxycarbonyl- 1 '-propyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranyliden-2" -acetate) -4- tritylthio-2-azetidinone (isomer C)
EMI114. 3rd
 Method:
1.197 g (5 mmol) of 3P and 9.54 g (5 mmol) of lutidine were added to a solution of 3.7 g (4.568 mmol) of the chlorine compound mentioned in 35 ml of dioxane.  The mixture was heated in an oil bath at 100 C for 3 days, then was cooled, diluted with ether and washed successively with 1N HCl, 1M NaHCO3 and brine.  To
Drying over Na2SO4 and filtering through Celite / activated carbon, the filtrate was evaporated to dryness to give 3.6 g of an oil.  

  This was chromatographed on 120 g of silica gel and eluted with benzene, benzene ether and gave 1.45 g of the desired compound as an amorphous solid (31%).    



  IR (pure) Vmax: 1750 cmt (wide). 



   (1'S, 3S, 4R and 1'R, 3R, 4S) -4-acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1 '-propyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) - 2-azetidinone (isomer C)
EMI115. 1
 Method:
A hot solution of 0.3 g (1.76 mmol) of AgNO3 in 10 ml of MeOH was added to a hot (60 ° C.) solution of the above-mentioned phosphorane (1.4 g, 1.35 mmol) in 40 ml of MeOH while stirring. followed by 0.107 g (0.11 ml, 1.76 mmol) pyridine.  The silver mercaptide began to excrete immediately, the mixture was stirred at room temperature for 15 minutes and then at 0 ° C. for 2 hours.  Then it was filtered, the solid was washed with cold MeOH and ether to give 1.2 g (quantitative yield).  M.p.  113-115 C (d). 

  IR (Nujol) vmax: 17401760 cm- I (broad).  This solid was used as such.  To a chilled (ice bath) solution of said mercaptide (1.2 g, 1.35 mmol) in 15 ml of CH2Cl2 was added 0.118 g (0.107 ml, 1.5 mmol) of acetyl chloride in 2 ml of CH2Cl2, followed by 0.119 g (0.122 ml, 1.5 mmol) pyridine in 2 ml CH2C12.  The mixture was stirred at 0 C for 30 min. After filtering through Celite to remove the silver salt, the filtrate was washed successively with HCl (0.5N), H2O, NaHCO3 (0.5M) and brine.  The CH2C12 solution was dried over MgSO4 and evaporated to dryness to give 0.94 g of the desired compound as an amorphous solid.  (83.4%).  IR (pure) vrnax: 1750 cm l (wide). 



   (1'S, 5R, 6S and 1'R, 5S, 6R) -paranitrobenzyl-6- (1'-para-nitrobenzyldioxycarbonyl-1'-propyl) -2-methylenem-3-carboxylate (isomer C)
EMI115. 2nd
 Method:
A solution of 0.4 g (1.077 mmol) of said phosphorane in 35 ml of toluene was heated to the reflux temperature and 5 ml of the toluene was distilled off.  The yellow solution was then refluxed for 7.5 h, then concentrated to dryness to give 0.76 g of a thick oil.  This was chromatographed on silica gel (ACT 1.30 g) and eluted with benzene and benzene / ether to give 0.32 g (53.4%) of the desired compound as a solid.  M.p.  (Pentane) 160-162 C.       tHmr (CDCl3) 6: 7.3-8.4 (8H, m, aromatic), 5.4 (H, d), 5.3 (4H, benzyl, m), 5.0 (H, dt), 4.0 (H, dd), 2.35 (6H, s), 0.8 (2H, dq) and 1.0 ppm (3H, t). 



   (1'S, 5R, 6S and 1'R, 5S, 6R) -6- (1'-hydroxy-l'-propyl) -2-methyl-penem-3-carboxylic acid (isomer C) sodium salt
EMI115. 3rd
 Method:
A mixture of 48 mg (0.086 mmol) of the above ester and 100 mg of 30% Pd-Celite in 10 ml of THF, 20 ml of Et2O, 10 ml of H2O and 2 ml of phosphate buffer (pH 7) was at an initial pressure of 344.64 kPa during Hydrogenated for 23 h. 



  Then it was filtered through Celite and the phases were separated.  The organic phase was washed twice with 5 ml of water and the combined water phases were washed twice with 10 ml EtOAc.  Then the aqueous phase was lyophilized, whereby 30 mg of the desired compound was obtained in the form of a white salt.  IR (KBr) vmax: 1750 (beta-lactam) and 1600-1650 cm '(broad, -CO2-).  UV Xmas: 258 (g 1105) and 305 (± 1244). 



   Example 49 (1'R, 5R, 6S and 1'S, 5S, 6R). 6- (1'-hydroxy-1'-propyl) -2-methyl-penem-3-carboxylic acid, sodium and potassium salts (isomer B)
EMI116. 1
  (1'R, 3S, 4R and 1'S, 3R, 4S) -1-t'-butyldimethylsilyl-3- (1'-formyloxy-l'-propyl) -4-tritylthio-2-azetidinone (isomer B)
EMI116. 2nd

4-Dimethylaminopyridine (DMAP) was manufactured according to a) H. C.  Brown and co-workers.  Org.  Synth.  Collect.  Volume 5.977 (1973) and b) Helmet Vorbruggen and co-workers.  Appl. 



  Chem.  Int.  Ed. , 17, 569 (1978). 



  Method:
To a cooled (0 C) solution of 3.612 g (7 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -1-t-butyldimethylsilyl-3- (1'-hydroxy-1'-propyl) -4-tritylthio-2-azetidinone (isomer B) in 50 ml CH2Cl2 was added 4.48 ml (35 mmol) Et3N, 0.63 ml (16.8 mmol) HCO2H and 0.854 g (7 mmol) DMAP, followed by Dropwise addition of 7.14 g (70 mmol) of acetic anhydride.  The clear yellow solution was stirred at −40 ° C. and concentrated to a milky mixture.  This was poured onto ice / HCl (1N, pH 6) and the phases were separated.  The CH2C12 solution was washed with 1M NaHCO3 and brine. 

  The mixture was then dried over Na2SO4 and evaporated to dryness to give 3.8 g of a solid residue which was treated with pentane and filtered to give 3.7 g of a white solid (96.8%).  M.p.    125-127 "C.     IR (neat) vmax: 1720
EMI116. 3rd
 1750 cm-1 (beta-lactam).    IHmr (CDCI3) ô: 7.1
EMI116. 4th
 6.8-7.7 (15H, m), 4.8 (H, m), 4.05 H, d, J = 1.5), 3.7 (H, m, J = 1.5, J = 7), 1.4 (2H, m), 0.95 (9H, s), 0.8 (3H, t) and 0.1 ppm (6H, s). 



   Analysis for C32H39NO3SSi Calculated: C, 70.42, H, 7.20, N, 2.57 Found: C, 70.20, H, 7.33, N, 2.73 (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-formyloxy-1'-propyl) - 4tritylthio. 2nd azetidinone (isomer B)
EMI116. 5
 Method:
0.91 g (14 mmol) of NaN3 were added to a cooled (ice bath) solution of 3.7 g (6.77 mmol) in 40 ml of HMPT containing 10% H2O.  The mixture was stirred at room temperature for 1.5 h, poured onto 200 ml of ice water and extracted 4 times with 40 ml of ether.  The ether solution was diluted with petroleum ether and washed with water and brine to remove HMPT. 

 

  The mixture was then dried over Na2SO4 and evaporated to dryness, giving 2.92 g of a thick colorless oil.  (Quantitative yield).    lHmr (CDCI3) ô: 8.1
EMI116. 6
 S), 7.1-7.7 (15H, m, -STr), 5.23 (H, m, J = 7), 4.38 (H, d, J = 2.5), 4.3 (H, -NH), 3.35 (H, dd, J = 2.5, J = 7), 1.75 (2H, m) and 1.0 ppm (3H, t). 



   (1'R, 3S, 4Rund 1'S, 3R, 4S) -3- (1'-formyloxy-l'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio-2 -azetidinone (isomer B)
EMI116. 7
   Method:
A mixture of 2.9 g (6.77 mmol) of 3- (1t-formyloxy-1'-propyl) -4-tritylthio-2-azetidinone (isomer B), 1.59 g (7 mmol) of PNB glyoxylate, 5 drops of Et3N and 5.0 g of Na2SO4 (anhydrous) in 50 ml of THF were stirred at room temperature for 18 h.  After filtering and evaporating to dryness, an amorphous solid was obtained in quantitative yield (4.33 g). 

  IHmr (CDCl3) ô: 8.2 (2H, d), 7.1-7.8 (18H, m), 5.2 (2H, d), 4.9 (H, m), 4.65 and 4.3 (H, 4.65 (1/2 H, s), 4.3 (1 / 2H, s)), 4.2-4.3 (H, d, 1 / 2H at 4.2, 1 / 2H at 4.3), 3.65 (H, m), 1.4 (2H, m) and 0.8 ppm (3H, t). 



     (1'R, 3S, 4Rund 1'S, 3R, 4S) -3- (1'-formyloxy-1'-propyl) -1 (paranitrobenzyl-2 "-chloro-2" -acetate) -4-tritylthio-2- azetidinone (isomer B)
EMI117. 1
 Method:
To a cooled (ice / salt bath) solution of 4.3 g (6.77 mmol) of said glyoxylate and 8 ml (8 mmol) of 1M Py / THF in 30 ml of dry THF was added dropwise a solution of 8 ml (8 mmol) 1M SOCl2 / Py.  The resulting solid mixture was stirred at said temperature for 1 hour, then diluted with 30 ml of benzene and stirred for a further 20 minutes. 

  It was then filtered through Celite / activated carbon and the filtrate was evaporated to dryness to give 4.1 g of an amorphous solid (92%).     IR (neat) vmax: 1720
EMI117. 2nd

EMI117. 3rd
 and 1780 cm-1 (beta-lactam).  ÚHmr (CDCl2) ô: 8.25 (2H, d), 7.8
EMI117. 4th
 7-7.75 (17H, m), 5.25 (2H, d), 5.0 (H, m), 4.6 (H, s), 4.4 (H, d), 3.7 (H, m), 1.6 (2H, m) and 0.9 ppm (3H, t). 



   (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-formyloxy-1'-propyl) -1 (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate). 4- tritylthio-2-azetidinone (isomer B)
EMI117. 5
 Method:
A mixture of 4.0 g (6.07 mmol) of the chlorine compound mentioned, 1.834 g (7 mmol) of 3P and 0.749 g (7 mmol) of lutidine in 40 ml of dioxane was heated to 100 ° C. in an oil bath for 2 days.  It was then cooled, diluted with ether and washed successively with a cold solution of 1N HCl, 1M NaHCO3 and brine.  The organic solution was dried over Na2SO4 and filtered over Celite / activated carbon. 

  After concentration to dryness, an oil was obtained which was chromatographed on silica gel (200 g) and eluted with benzene and benzene / ether, giving 2.60 g of the desired compound as an amorphous solid.  (48.45%). IR (pure) Vmax:
EMI117. 6
 and 1750-1760 cm-1 (-CO2PNB and beta-lactam). 



   (1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (1'-formyl-oxy-l'-propyl) -l- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone (isomer B)
EMI117. 7
   Method:
A warm (60 "C) solution of 8.7 ml (1.3 mmol) 0.15M AgNO3-CH30H was added to a mixture of 0.88 g (1 mmol) of said phosphorane and 0.103 g (1.3 mmol) Pyridine in 5 ml of MeOH warmed to 60 ° C.  The mixture was stirred at room temperature for 15 min and at 0 C for 2 h.  It was then filtered and washed with cold MeOH to give 0.53 g of the silver mercaptide as a yellow solid (71%) which was used as such. 

  To a cooled (ice bath) mixture of 0.53 g (0.71 mmol) of said mercaptide and 0.079 g (1 mmol) of pyridine in 10 ml of CH2Cl2 was added dropwise 0.079 g (1 mmol) of CH3COCl in 5 ml of CH2Cl2.  After stirring at 0 C for 1 h, the mixture was filtered, the filtrate was washed well with a cold solution of 0.5M HCl, 0.5M NaHCO3 and brine.  After drying over Na2SO4 and evaporation to dryness, 0.43 g of an oil was obtained.  (3%).    IR (pure) vrnax: 170> 1760 cm-l
EMI118. 1
 and beta-lactam). 



   (1'R, 3S, 4R and 1'S, 3R, 4S) and acetylthio-3- (1'-hydroxy-1 '-propyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2- azetidinone (isomer B)
EMI118. 2nd
 Method:
1.0 g (1.45 mmol) of the mentioned formate in 10 ml of THF were mixed with HCl / MeOH (10 ml, prepared from 2 ml of conc.  HCl and diluted with MeOH to a volume of 24 ml).  The mixture was left at room temperature for 0.5 h then basified with 1M NaHCO3, extracted with EtOAc, washed with brine and dried over Na2SO4.  It was then evaporated to dryness to give 0.9 g of the crude desired compound. 

  This was chromatographed on silica gel and eluted with ether and ether: EtOAc (1: 1), giving 0.6 g of the pure desired compound as an amorphous solid (62.5%).  1Hmr (CDCl3) ô: 8.25 (2H, d), 7.3-8.1 (17H, m, aromatic), 5.6 (Hin), 5.2 (2H), 4.9 (H) , 4.4 (H, m), 2.3 (3H, SAc), 1.5 (2H, m) and 0.9 ppm (3H, t). 



   (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-6- (1'-hydroxy-1'-propyl) -2-methylpenem-3-carboxylate (isomer B)
EMI118. 3rd
 Method:
0.2 g (0.3 mmol) of the above phosphorane in 45 ml of toluene was heated to the reflux temperature and 5 ml of toluene was distilled off.  The resulting solution was refluxed for 6 hours, then cooled and evaporated to dryness to give 0.2 g of an oil.  This was chromatographed on silica gel and eluted with ether and gave 0.1 g of the desired compound as a white solid.  (87%).  M.p.  (Pentane) 133-135 C.  tHMR (CDCl3) ô: 8.3 (2H, d), 7.6 (2H, d), 5.6 (H, d), 5.35 (2H, d), 4.15 (H, m) , 3.8 (H, m), 2.4 (3H, s, CH3), 2.2 (H, OH), 1.7 (2H, m) and 1.05 ppm (3H, t). 



   (1'R, 5R, 6S and 1'S, 5S, 6R) -6-1 '- (hydroxy-l'-propyl) -2-methyl-penem-3-carboxylic acid (isomer B), mixed K- and Na- Salts
EMI118. 4th
 Method:
A mixture of 0. 07 g (0.185 mmol) of the named ester, 150 mg of 30% Pd-Celite and 4 ml of buffer solution (pH 7) in 15 ml of THF, 25 ml of Et2O and 15 ml of deionized water were at an initial pressure of 358.43 kPa for 4 h hydrated.  It was then filtered through Celite and the phases were separated, the aqueous phase was washed with ethyl acetate and then lyophilized to give 91 mg of a solid.    IR (KBr) vmax 1780 (beta-lactam) and 1650 cm-1 (broad, -CO2-).  UV H2O # max: 255 (# 983) and 300 (# 1092). 

 

   Example 50 (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxy-2'-phenylethyl) -2-methylpenem-3-carboxylic acid (isomer B)
EMI119. 1
 trans-1 - (t-butyldimethylsilyl) -3-phenylacetyl-4-tritylthio-2-azetidinone
EMI119. 2nd

18.32 g (4G mmol) of 1-t-butyldimethylsilyl-4-triylthio-2-azetidinone in 100 ml of dry THF was added dropwise under nitrogen to a cooled (-78 C) LDA solution (prepared under nitrogen at -78 C) by dropwise addition of 101.25 ml (162 mmol) of 1.6M n-BuLi to 22.95 ml (162 mmol) of diisopropylamine in 150 ml of dry THF and stirring at -78 ° C. for 30 min). 

  The mixture was stirred at -78 ° C for 30 minutes and 15.66 g (15.12 ml, 93.6 mmol) of ethylphenylacetate in 50 ml of dry THF were added and the reaction mixture was stirred at -78 ° C for 2 hours.  Then it was poured onto ice / 1N HCl (pH 5-6) and extracted several times with ether, whereupon the ether solution was washed with brine and dried over Na2SO4.  The mixture was then evaporated to dryness, giving 33.7 g of a solid.  This was dissolved in 10 ml of ether and shaken with 200 ml of pentane, the solid was filtered off and washed several times with pentane, 18.3 g of a white solid (79.6%) being obtained.  M.p.  141-143 C.    IHmr (CDC13) 6: 7.0-7.6 (20H, m), 4.8 (H, d), 3.7 (H, d), 3.53 (H, s), 3.43 ( H, s), 1.5 (9H, s) and 0.3 ppm (6H, s). 



   1 - (t-butyldimethylsilyl) -3- (1'-hydroxy-2'-phenylethyl) -4tritylthio-2-azetidinone (2 trans diastereomers)
EMI119. 3rd

28.8 g (50 mmol) of trans-1- (t-butyldimethylsilyl) -3-phenyl-acetyl4-tritylthio-2-azetidinone and 0.5 g (0.25 mmol) of NaBH4 in 200 ml of THF were at room temperature for 18 h touched.  The mixture was poured onto ice / 1N HCl and extracted with CH2, the CH2Cl2 solution was washed with brine and dried over Na2SO4. 



  Evaporation gave 27.7 g of an amorphous solid.  23.0 g of which were chromatographed on silica gel and eluted with hexane: ether to give 14.4 g of an almost white solid which was a mixture of (1'R, 3S, 4R and 1'S, 3R, 4S) and ( 1'S, 3S, 4R and 1'R, 3R, 4S) isomers in a ratio of 1: 1 (60%).    1Hmr (CDCl3) #: 7-7.7 (20H, m), 4.37 (1 / 2H, d), 4.18 (1 / 2H, d), 3.3-3.8 (H, m ), 3.45 (1 / 2H, dd), 3.1 (1 / 2H, dd), 2.7 (2H, m), 0.87 (9H, d) and 0.25 ppm (6H, s ). 



   1 - (t-Butyldimethylsilyl) -3- (1'-formyloxy-2'-phenylethyl) -4 tritylthio-2-azetidinone
EMI119. 4th
 isomer B
EMI119. 5
 Isomer C
To a chilled (-40 C) solution of the above mixture of alcohols (14.4 g, 24.0 mmol) in 250 ml CH2Cl2 was added 15.93 ml (125 mmol) Et3N, 2.24 ml (59.76 mmol) HCO2H and 3.04 g (24.9 mmol) DMAP.  After stirring for 5 minutes, 2.35 ml (249 mmol) of acetic anhydride was added dropwise.  The clear solution was stirred at -40 C for 15 min, resulting in a white cloudy mixture.  This was kept at -40 C for a further 45 min (total time 1 h), then poured onto ice / IN HCl and the phases were separated. 

  The CH2Cl2 solution was washed well with cold 1N HCl, H2O, 1M NaHCO3 and brine, dried over MgSO4 and evaporated to give 14.0 g of an amorphous solid.  This was separated by hplc (Water Associates, System 500) and gave: Isomer B 6.0 g, mp.  172-173 C and isomer C 6.0 g mp. 



  188-189 C.     Total yield of the pure compound 12.0 g (73.2%).  1Hmr (CDCl3) 6: 6.8-7.7 (21H, m), 5.05 (H, ddt), 4.05 (CH, d), 3.65 and 3.75 (H, two doublets) , 2.7-2.9 (2H, d), 0.88 (9H, s) and 0.2 ppm (6H, s).  Isomer B: 1Hmr (CDCl3) 6: 7.75 (H, s), 6.9-7.5 (20H, m), 4.3 (H, ddt), 3.95 (H, d), 3 , 37 (H, dd), 2.95 (H, s), 2.85 (H, s), 0.9 (9H, s) and 0.2 ppm (6H, s). 



   3- (1 '-formyloxy-2'-phenylethyl) -4-tritylthio-2-azetidinone (1'R, 3S, 4Rund 1'S, 3R, 45-enantiomers)
EMI120. 1
 Isomer B
To a chilled (ice bath) solution of 5.9 g (9.375 mmol) of the above formate in HMPT containing 10% water (50 ml) was added 1.3 g (20 mmol) of NaN3.  The mixture was stirred at room temperature for 1.5 h, poured onto 300 ml of ice water and extracted three times with 100 ml of ether.  The ether solution was washed well with water and brine, dried over Na2SO4 and concentrated to leave a solid residue.  This was treated with petroleum ether and filtered to give 4.4 g of a white solid (92%) mp.  169171 C. 



   Analysis for C31H27N03S Calculated: C, 75.43, H, 5.51, N, 2.84 Found: C, 75.04, H, 5.64, N, 2.78
1Hmr (CDCl3) 6: 7.9 (H, s), 7.1-7.6 (20H, m), 5.4 (H, m), 4.6 (H, NH), 4.2 ( H, d), 3.3 (H, dd), 3.15 (H, s) and 3.0 (H, s). 



   3- (1'-Formyloxy-2'-phenylethyl) - 1 - (paranitrobenzyl-2 "hydroxy-2" acetate) -4-tritylthio-2-azetidinone (1'R, 3S, 4R and 1'S, 3R, 4S -Enantiomers)
EMI120. 2nd

A solution of 2.37 g (10.16 mmol) of PNB glyoxylate in 100 ml of dry benzene was refluxed in the Dean-Stark apparatus (with molecular sieve 3) for 2 h.  Then the above N-H compound (4.2 g, 8.537 mmol) was added and refluxing was continued for an additional 1 h.  Then it was cooled to room temperature, 0.12 ml (0.85 mmol) of Et3N was added and the mixture was stirred at room temperature for 1.5 h. 



  The mixture was then evaporated to dryness, giving the desired compound in quantitative yield and as a mixture of two isomeric alcohols.  1Hmr (CDCl3) 6: 8.0-8.3 (2H, two doublets), 7.5 and 7.6 (H, two singlets), 7.0-7.4 (20H, m), 5.25 (2H, d), 4.9 (H, OH), 4.25 and 4.35 (H, two doublets), 3.5-4.5 (H, m, broad), 3.1-3, 3 (H, m) and 2.9 ppm (2H, m). 



   3- (1'-Formyloxy-2'-phenylethyl) - 1 - (paranitrobenzyl-2 "chloro-2" acetate) -4-tritylthio-2-azetidinone (1'R, 3S, 4Rund 1'S, 3R, 4S enantiomers )
EMI120. 3rd

To a chilled (ice / salt bath) solution of 6.0 g (8.537 mmol) of said glyoxylate in 30 ml of dry THF was added 10 ml (10 mmol) of a 1M solution of pyridine in THF, followed by dropwise addition of an IM Solution of thionyl chloride in THF (10 ml, 10 mmol).  After 1 h at the temperature mentioned, the mixture was diluted with 30 ml of benzene and stirring was continued in the cold for 30 min.  

  The mixture was then filtered through Celite / activated carbon and evaporated to dryness, giving 6.0 g of an amorphous solid (98%).    1Hmr (CDCl3) b: 8.2 (2H, m), 7-7.7 (23H, m), 5.8 (H, s), 5.25 (2H, s), 4.35 (H, d), 3.5-4.0 (H, m), 3.3 (H, m) and 2.9 ppm (2H, d). 



   3- (1 '-formyloxy-2'-phenylethyl) - 1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-tritylthio-2-azetidinone (1'R, 3S, and 1'S, 3R, 4S enantiomers)
EMI121. 1
 in a mixture of 6.0 g (8.333 mmol) of the chlorine compound mentioned, 2.489 g (0.5 mmol) of 3P and 1.0165 g (1.1 ml, 9.5 mmol) of lutidine in 50 ml of dioxane was applied during 18 h Heated to 110 ° C.  Then it was cooled and filtered through Celite, the filtrate was diluted with ethyl acetate and washed with cold 1N HCl, H2O, 1M NaHCO3 and brine.  The mixture was then dried over Na2SO4 and concentrated to give 8.0 g of a crude product. 

  This was chromatographed on silica gel and eluted with ether: hexane (1: 1) and ether to give 4.0 g of the desired compound.  M.p.  (Needles from ether) 235-237 C (d).    (51%).     IR (film) vrnax: 1720, 1750 cm1.    



      4-Acetylthio-3- (1 '-formyloxy-2'-phenylethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone (1'R, 3S, 4Rund 1'S, 3R , 4S enantiomers)
EMI121. 2nd

To a refluxing solution of 3.6 g (3.8 mmol) of said phosphorane and 0.33 g (4.2 mmol) of pyridine in 30 ml of CH2C12 and 30 ml of MeOH, a 0.15M AgNO3 / MeOH solution ( 28 ml, 4.2 mmol). 



  The mixture was stirred at room temperature for 2.15 h, then was brought to about  Concentrated 10 ml, cooled and filtered to give the silver mercaptide as a yellow solid (2.3 g, 77%).  This mercaptide and 0.277 g (3.5 mmol) of pyridine in 20 ml of ice-cooled CH2Ck was treated dropwise with 0.27 g (3.5 mmol) of CH3COCl in 5 ml of CH2Cl2.  The mixture was stirred at room temperature for 3 hrs, filtered through Celite and the filtrate was washed with cold 1N HCl, H2O 1M NaHCO3 and brine.  The mixture was then dried over MgSO4 and evaporated to dryness to give 1.0 g of an amorphous solid (89.8%).    1Hmr (CDCl3) #: 8.2 (2H, d), 7.0-8.0 (23H, m), 4.5-5.7 (4H, m), 2.6-3.3 (3H , m), and 2.3 ppm (2H, d, SAc). 



      4-acetylthio-3- (1'-hydroxy-2'-phenylethyl) -1 - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone (1'R, 3S, 4R and 1S, 3R, $ S diene diomers)
EMI121. 3rd

A solution of 1.8 g (2.416 mmol) of said phosphorane in 10 ml of THF was treated with 10 ml of 1N HCl / MeOH and the mixture was stirred at room temperature for 4 hours.  It was then evaporated to remove methanol, diluted with cold water, basified with 1M NaHCO3 and extracted with CHCl3.  The CHCl3 solution was dried over MgSO4 and evaporated to give 1.65 g of an amorphous solid. 

  This was chromatographed on silica gel and eluted with ether: ethyl acetate and gave 1.30 g of the desired compound (75%).  1Hmr (CDCl3) 6: 8.2 (2H, d), 6.7-8.0 (22H, m), 4.0-6.0 (5H, m), 2.5-3.5 (3H , m) and 2.2 ppm (3H, SAc). 



      Paranitrobenzyl-6- (1'-hydroxy-2'-phenylethyl) -2-methyl-penem-3-carboxylate (1'R, 5R, 6R enantiomers)
EMI122. 1

A solution of 1.2 g (1.67 mmol) of said phosphorane in 80 ml of toluene was heated to the reflux temperature, whereupon 10 ml were distilled off and whereupon the mixture was refluxed for a further 6 hours.  The mixture was then evaporated to dryness and the crude product was chromatographed on silica gel. 

  The desired compound was obtained by eluting the column with ether to give 0.65 g of an amorphous solid (89%).    lHmr (CDCl3) b: 8.2 (2H, d), 7.6 (2H, d), 5.4 (H, d), 5.2-5.4 (2H, d), 4.0- 4.5 (H, m), 3.7-4.0 (H, dd), 3.0 (2H, d) and 2.3 ppm (3H, s). 



   6- (1'-Hydroxy-2'-phenylethyl) -2-methylpenem-3-carboxylic acid (1'R, 5R, 6S and 1'S, 5S, 6R enantiomers)
EMI122. 2nd

A mixture of 0.33 g (0. 75 mmol) paranitrobenzyl ester, 17.4 ml 0.05M buffer solution (pH 7), 30 ml THF, 30 ml Et2O, 60 ml H2O dist.  and 0.69 g of 30% Pd / Celite was hydrogenated at an initial pressure of 344.64 kPa for 24 hours. 



  Then it was filtered through Celite and the organic phase was washed with water, the combined aqueous phases were washed several times with EtOAc and then lyophilized for 18 h, whereby the desired compound was obtained as a yellow colored salt.  This was treated with a small portion of water, acidified with cold 1N HC1 and extracted with CHCI3.  The CHCl3 solution was dried over MgSO4 and evaporated to a solid residue.  This was treated with ether and filtered to give 30 mg of a white solid.  (13.2%), m.p.  165167 C.     IR (Nujol) vmax: 3580 (OH, S), 1660 and 1760 cm-l.    



  UV (MeOH) arnas: 310 (± 5490) and 254 (± 4880). 



   Example 51 (4'R, 5R, 6S and 4'S, 5S, 6R) 6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylic acid ( Isomer C)
EMI122. 3rd
 A.  Production of
EMI122. 4th
  (4'R, 3S, 4R and 4'S, 3R, 4S) and (4'S, 3S, 4R and 4'R, 3R, 4S) l- (t-butyldimethylsilyl) -3- (2 ', 2'-dimethyl- 1 ', 3'-dioxolane 4'-yl) -4-tritylthio-2-azetidinone (isomer C and isomer B) ethyl-O- (2-methoxy-2-propyl) glycolate1)
EMI122. 5

To a solution of 15.6 g (0.150 mol, freshly distilled) ethyl glycolate and 16.4 g (0.216 mol, 95% purity) 2) 2 methoxypropene in 150 ml CH2Cl2 were added 3 drops (35 mg, 0.23 mmol) of phosphorus oxychloride was added and the mixture was stirred at 0-5 C for 15 min and then at room temperature for 1.5 h.  

  It was then quenched with 30 drops of pyridine, stirred for 45 min and the solvent was evaporated.  The residue was diluted with 150 ml of pentane and dried over K2CO3.  After filtration, the solvent was evaporated, leaving 27.89 g (0.158 mol, 100%, 94% purity) of the desired compound as a colorless oil.    lHmr (CCl4) 6: 1.25 (3H, t, J = 7 Hz, -CH2CH3), 1.28 (6H, s, Me2), 3.12 (3H, s, -OCH3), 3.88 ( 2H, s, OCH2CO-), 4.10 (2H, q, J = 7 Hz, -CH2CH3).     IR (pure) Vrnax: 1760 and 1735 cm- | (Ester). 



     1) J.     Meinwald and co-workers. , Tet.  Lett. , 4327 (1978)
2) M. S.  Newman and M. C.  Vander Zwan, J.  Org.  Chem. , 38, 2910 (1973). 



   (3S, 4R and 3R, 4S) 1- (t-butyldimethylsilyl) -3- (1'-keto-2 '(2 "-methoxy-2" -isopropyloxy) -1'-ethyl) -4-tritylthio-2 -azetidinone
EMI123. 1

90 ml of n-butyllithium (1.6M in hexane, 0.144 mol) were added to a stirred solution of 18.5 ml (0.134 mol) of diisopropylamine in 400 ml of THF (freshly distilled over LAH) at -78 ° C. and under nitrogen.  After 30 minutes, a solution of 50.0 g (0.109 mol) of 1- (t-butyldimethylsilyl) 4-tritylthio-2-azetidinone in 100 ml of THF was added dropwise over 10 minutes and the mixture was stirred for 5 minutes.  To this pink colored solution was added 23.94 g (0.136 mol) of ethyl O- (2-methoxy-2-propyl) glycolate and the mixture was stirred for 1 hour.  After removing the dry ice bath, 200 ml of NH4Cl solution and 100 ml of saline were added. 

  The aqueous phase was extracted 3 × with 100 ml Et2O, the combined organic extracts were washed with brine, dried over Na2SO4 and evaporated, giving 60.95 g (0.103 mol, crude yield 94.6%) of the desired compound in the form of an orange Ols were obtained.  This crude product was used as such in the next reaction. 

  A pure sample was obtained by column chromatography (SiO2, eluent: 2% Et20 in benzene).  1Hmr (CDCl3) 8: 0.30 (6H, s, Si-CH3), 0.95 (9H, s, t-Bu), 1.12 (3H, s, CH3), 1.15 (3H, s , CH3), 3.15 (3H, s, OCH3), 3.57 (1H, A from AB, Jgern = 17Hz), 3.77 (1H, d, J = 1.6 Hz, H-3), 3.97 (1H, BvonAB, Jgem = 17 Hz), 4.83 (iH, d, J = 1.6Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs).  IR (neat) vmax: 1750, 1725, 1710 cm-l (C = O).  tlc, Rf0.53 (benzene, Et2O = 4: 1), Rf0.61 (hexane: EtOAc = 2: 1).    



   (3S, 4R and 3R, 4S) 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-2'-methoxyisopropyloxyethyl) -4-tritylthio-2-azetidinone (mixture of epimers at C- 1 ')
EMI123. 2nd

A solution of 60.95 g (0.103 mol) of 1- (t-butyldimethylsilyl) -3- (1'-keto-2 '- (2 "-methoxy-2" -isopropyloxy) -1'-ethyl) -4tritylthio- 2-azetidinone in 100 ml of THF was diluted with 350 ml of absolute EtOH and 4.88 g (0.156 mol) of NaBH4 at 0 ° C. were added to this solution.  The mixture was stirred at room temperature for 2 h and quenched by slowly adding 280 ml of saline.  The mixture was extracted 3 times with 150 ml Et2O and the extracts were washed with brine, dried over Na2SO4 and evaporated to a yellow residue which was redissolved in 500 ml CH2Cl2. 

  After drying over Na2SO4 and evaporation, 57.1 g (0.0966 mol, crude yield 93.8%) of the desired compound were obtained in the form of a yellow foam.    IHmr (CDCl4) 6: 0.17 (s, SiCH3), 0.80,0.87 (2s, Si-tBu), 1.22, 1.25 (2s, CH3), 3.03 (s, OCH3 ), 4.32 (d, J = 2Hz, H-4), 7.0-7.7 (m, aromatic Hs). 



  IR (neat) vmax: 3460 (OH), 1745 (C = 0), 1595 (aromatic). 



  Rf 0.47 and 0.42 (hexane: EtOAc = 2: 1).  The crude product was used in the next step without working up. 



     (4'R, 35, 4R and 4'S, 3R, 4S) and (4'S, 3S, 4R and 4'R, 3R, 4S) l- (t-butyldimethylsilyl) -3- (2 ', 2'-dimethyl- 1 ', 3'-dioXolan-4'-yl) -4-tritylthio-2-azetidinone (isomer C and isomer B)
EMI123. 3rd

A solution of 57.1 g (0.0966 mol, crude) (3S, 4R and 4R, 4S) 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-2'-methoxyisopropyloxyethyl) -4-tritylthio- 2-azetidinone (mixed diastereomers at C- 1 ') in 500 ml of CH2Cl2 was treated at room temperature with 200 mg of p-toluenesulfonic acid monohydrate and 20 ml of 2,2-dimethoxypropane and then stirred for 1 h. 

  It was then washed with saturated NaHCO3 and brine, dried over Na2SO4 and evaporated to give 49.64 g (0.0888 mol, crude yield 91.9%) of a mixture of the desired compounds (isomer B and isomer C) as a yellow foam .  This was purified by HPLC (Waters 500 silica gel, eluent: hexane: EtOAc = 9: 1) and recrystallized, 14.28 g (25.5 mmol), 26.4%) of the desired compound (isomer C) in the form of white crystals were obtained. 



  M.p.  146-147 C (pentane).  'Hmr (CCl4) µ: 0.27 (6H, s, Si-CH3), 0.95 (9H, s, Si-tBu), 1.15 (6H, s, di-Me), 2.5- 2.9 (1H, m, H-4 '), 2.97 (1H, t, J = 1.8 Hz, H-3), 3.25-3.9 (2H, m, H-5' ), 4.27 (1 H, d, J = 1.8 Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs).  IR (Nujol) vrnax: 1750 (C = 0) and 1595 cm-1 (aromatic).  Rf 0.45 (hexane: EtOAc = 4: 1) and 14.50 g (25.9 mmol, 25.94%) of the desired compound (isomer B) as white crystals.  M.p.  144-145 C (Et20 pentane).    



  'Hmr (CCl4) b: 0.02 (6H, s, SiMe), 0.833 (9H, s, Si-tBu), 1.13, 1.18 (6H, 2s, diMe), 2.5-2, 8 (1H, m, H-4 '), 3.3-4.1 (2H, m, H-5'), 3.48 (1H, dd, J3-4 = 1.5Hz, J3-4 = 5.0 Hz, H-3), 3.93 (1H, d, J3.4 = 1.5 Hz, H-4), 7.1-7.7 (iSH, m, aromatic Hs). 



  IR (Nujol) vmax: 1650 (C = 0) and 1595 cm-1 (aromatic). 



  Rf 0.37 (hexane: EtOAc = 4: 1). 



   Analysis for C33H41 So3SSi Calculated: C, 70.80 H, 7.38 N, 2.50, S, 5.73 (isomer C) Found: C, 70.23, H, 7.30, H, 7.3 -, N, 2.41, S, 5.53 (isomer B) C, 70.52, H, 7.31, N, 2.40, S, 5.05
B.  Preparation of the penem product (isomer C) (4'R, 3S, 4Rund4'S, 3R, 4S) 3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -4 -tritylthio-2-azetidinone (isomer C)
EMI124. 1

To a stirred solution of 14.3 g (25.6 mmol) (4'R, 3S, 4R and 4'S, 3R, 4S) 1- (butyldimethylsilyl) -3- (2 ', 2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -4-tritylthio-2-azetidione (isomer C) in 230.4 ml hexamethylphosphoric triamide slowly became a solution of 2.50 g for 20 min at 0-5 C (38, 4 mmol, 1.5 eq. ) Sodium azide in 25.6 ml of H2O added. The mixture was stirred at room temperature for 2 hours and then poured into 2.5 liters of cold water. 

  The white precipitate formed was filtered off, washed with H2O and dried, 11.26 g (25.3 mmol) (crude yield 98.8%) of the desired compound being obtained as a white solid.  A pure product could be obtained by recrystallization from CH2-Cl2-Et2O.  M.p. 



  192-193 C (dec).  'Hmr (CDCl3) 8: 1.33, 1.37 (6H, 2s, di-Me), 3.27 (1H, t, J = 3 Hz, H-3), 3.8-4.4 ( 3H, m, H-4 'and H-5'), 4.40 (1H, d, J = 3 Hz, H-4), 4.47 (1H, br, NH, D20 exchange) and 7, 1-7.7 ppm (15H, m, aromatic Hs).  IR (Nujol) vmax: 3220 (NH), 1760 (C = 0) and 1950 cm-1 (aromatic): Rf0.31 (hexane: EtOAc = 3: 2). 



   (4'R, 3S, 4Rund4'S, 3R, 4S) 3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-hydroxy- 2 "acetate) -4-tritylthio-2-azetidinone (mixture of epimers at C-2") (isomer C)
EMI124. 2nd

A suspension of 6.57 g (28.95 mmol, 1.15 eq. ) p Nitrobenzylglyoxylate hydrate in 500 ml of benzene was refluxed in a Dean-Stark apparatus for 2 h.  After evaporation of the solvent, p-nitrobenzylglyoxylate was obtained as an oil.  A mixture of this oil with 11.2 g (25.2 mmol) (4'R, 3S, and 4'S, 3R, 4S 3- (2 ', 2'-dimethyl-1', 3'-dioxolane-4'- yl) -4-tritylthio-2-azetidinone (isomer C) in 350 ml THF (distilled over LAH) was treated with 289 mg (2.86 mmol) triethylamine at room temperature and under nitrogen for 18 h (overnight). 

  After evaporation of the solvent, the residue was dissolved in 200 ml of CH2C12, and washed successively with brine containing 1N HCl (2.9 ml), saturated NaHCO3 and brine, dried over Na2SO4 and evaporated after adding 30 ml of Et2O, 17.2 g (26.3 mmol, crude yield 100%, purity 95.8%) of the desired compound were obtained as white foam: Rf 0.40 and 0.30 (benzene: Et20 = 3: 2).  The isomers were separated by hplc (SiO2, eluent benzene: Et2O = 3: 2) and purified by recrystallization from CH2Cl2-Et2O.  Isomer I: Rf 0.40 (benzene: Et2O = 3: 2). 

  M.p.  153-154 C.    'Hmr (CDCl3) #: 1.20 (6H, s, di-Me), 3.1 (2H, m, H-3 and (OH), 3.5-4.2 (3H, m, H- 4 'and H-5'), 4.55 (1H, d, J = 2 Hz, H-4), 5.12 (1H, br, H-2 "), 5.30 (2H, s, OCH2Ar ) and 7.1-8.3 ppm (19H, m, aromatic Hs).  IR (Nujol) vrnax: 3370 (OH), 1775 (beta-lactam) and 1745 cm-1 (ester). 



   Analysis for C36H34N208S Calculated: C, 66.04, H, 5.23, N, 4.28 Found: C, 65.85, H, 5.64, N, 4. 11
Isomer II: Rf 0.30 (benzene: Et2O = 3: 2).  M.p.  164-165 C.    

 

     tHmr (CDCl3) 8: 1.17 (6H, s, di-Me), -3.2 (2H, m, H-3 and (OH), 3.4-4.0 (3H, m, H- 4 'and H-5'), 4.57 (1H, d, J = 2 Hz, H-4), 5.23 (1H, br, -2 "), 5.27 (2H, s, -OCH2Ar ) and 7.1-8.3 ppm (19H, m, aromatic Hs).  IR (Nujol) vmax: 3340 (OH), 1765 (beta-lactam) and 1740 cm-l (ester). 



   Analysis for C36H34N208S Calculated: C, 66.04, H, 5.23, N, 4.28, S, 4.90 Found: C, 66.01, H, 5.34, N, 4.28, S, 4.75 (4'R, 3S, 4R and 3'S3R4S) 3- (2 ',' 2-Dimethyl-1 ', 3'-dioxolan-4'-yl) - 1 - (p-nitrobenzyl-2 "-chlor-2" acetate) -4-tritylthio-2azetidinone (mixture of epimers at C-2 ") (isomer C)
EMI125. 1

To a stirred solution of 17.13 g (25.07 mmol), mixture of the epimers at C-2 ") (3'R, 3S, 4R and 4'S, 3R ,, 4S) 3- (2 ', 2'- Dimethyl-1 ', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "- hydroxy-2" acetate) -4-tritylthio-2-azetidinone (isomer C) in 250 ml of THF 2.84 ml (35.1 mmol) of pyridine at -15 C under nitrogen and then immediately afterwards 2.20 ml (30.1 mmol, anachemia) of thionyl chloride were added. 

  The mixture was stirred at -15 C for 20 min and then the precipitate formed was filtered off, washed with benzene, the filtrates and washing solutions were combined and evaporated.  The residue was dissolved in 250 ml of benzene, treated with activated carbon, filtered and evaporated to give 17.94 g (26.65 mmol, crude yield 100%, purity 94.1%) of the crude desired compound as a white foam.  Rf 0.76 (benzene: Et2O = 3: 2), 'Hmr (CDCI3) 8: 1.20 (6H, s, diMe), 3.17 (1H, m, H-3), 3.4-3 , 9 (3H, m, H-4 'and H-5'), 4.67, 4.72 (1H, 2d, J = 2.5 Hz, H-4), 5.30 (2H, s, OCH2Ar), 5.83 (s, H-2 ") and 7.1-8.3 ppm (19H, m, aromatic Hs). 

  IR (pure) vmax: 1770cm-1 (beta-lactam and ester).  This product was used in the next step without cleaning. 



   (4'R, 3S, 4Rund4'S, 3R, 4S) 3- (2 ',' 2-Dimethyl-1 ', 3'-dioxolan-4'-yl) - 1 - (p-nitrobenzyl-2 "- triphenylphosphoranylidene-2 "acetate) -4-tritylthio-2-azetidinone (isomer C)
EMI125. 2nd

A mixture of 17.87 g (25.0 mmol), purity 94.1% mixture of the epimers at C-2 ") (4'R, 3S, 4R and 4'S, 3R ,, 4S) 3- (2 ', 2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "- chloro-2" acetate) -4-tritylthio-2-azetidinone (isomer C), 7 , 27 g (27.5 mmol) of triphenylphosphine and 3.19 ml (27.5 mmol) of 2,6-lutidine in 350 ml of dioxane (distilled over LAH) were refluxed under nitrogen for 40 h. 

  After removal of the solvent in vacuo, 29.5 g of a dark oil were obtained, which was purified by column chromatography (SiO2 330 g, eluent 20-50% Et2O in benzene), giving 10.5 g of a yellow solid.  This solid was rinsed with Et2O to give 7.49 g (8.33 mmol, 33.3% yield) of the desired compound as pale yellow crystals.  'Hmr (CDCL3) 8: 1.07 (s, di-Me) and 7.1-8.2 ppm (m, aromatic Hs).  IR (Nujol) Vmax: 1760 cm- '(CO).  An analytical sample was obtained by recrystallization from CH2Cl2-Et2O.  M.p.  231-232 C.    



   Analysis for C54H 47N207PS Calculated: C, 72.14, H, 5.27, N, 3.12, S, 3.57 Found: C, 72.18, H, 5.43, N, 2.98, S , 3.41
Rf 0.17 (benzene: Et2O = 1: 1). 



   (4'R, 3S, 4R and 4'S, 3R, 4S) silver-3- (2 ', 2'-dimethyl-1', 3 'dioxolan-4'-yl) - 1 - (p-nitrobenzyl-2 " -triphenylphosphoranyli- 2-acetate) -2-azetidinone-4-thiolate (isomer C)
EMI125. 3rd

A solution of 319 mg (0.355 mmol) (4'R, 3S, 4R and 4'S, 3R, 4S) 3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -1 - (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2azetidinone (isomer C) in 10 ml of CH2C12 was evaporated to an oily residue which was redissolved in 8 ml of hot methanol (60 ° C) .  A hot solution of AgNO3 in MeOH (0.15M, 4.0 ml, 0.60 mmol) was added to this solution at 60 C and then 29 l (0.36 mmol) pyridine.    



  The mixture was stirred at room temperature for 5 h and then at 0 C for 1 h.  The precipitate was filtered off, washed with ice-cold methanol and then cold Et2O to give 255 mg (0.334 mmol) (yield 94.1%) of the desired compound as a brown solid. 



  IR (nujol) v max: 1750cm-1 (s, CO). 



      (4'R, 3S, 4Rund4'S, 3R, 4S)) 3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) -1-) p-nitrobenzyl-2 " -triphenylphosphoranyliden-2 "acetate) -4-acetylthio-2-azetidinone (isomer C)
EMI126. 1

To a solution of 254 mg (0.333 mmol) (4'R, 3S, 4R and 4'S, 3R, 4S) silver-3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl ) - 1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2azetidinone-4-thiolate (isomer C) in 15 ml of CH2Cl2, containing 100 l (1.24 mmol).  3.72 eq. ) Pyridine was 71 L (1.0 mmol, 3.0 eq. ) Acetyl chloride added. 

  The mixture was stirred at 0-5 C for 40 min, after which the precipitate was filtered through Celite, the filtrate was washed successively with brine containing 1N HCl (1.25 ml), saturated NaHCO3 and brine, dried over Na2SO4 and evaporated 200 mg of an oil were obtained, which, recrystallized from Et2O, gave 155 mg (0.222 mmol, yield 66.7%) of the desired compound in the form of white crystals.    tHmr (CDCl3) 6: 1.23 (s, di-Me), 2.20, 2.33 (2s, -SAc) and 7.2-8.3 ppm (m, aromatic Hs).  IR (Nujol) vmax: 1750 (beta-lactam and ester) and 1690 cm-l (thioester).  An analytical sample was obtained by recrystallization from CH2ClrEt2O. 



  M.p.  177-178 C. 



   Analysis for C37H35N2O8PS Calculated: C, 63.60, H, 5.05, N, 4.01, S, 4.59 Found: C, 63.34, H, 5.32, N, 3.83, S, 4.31
Rf 0.62 (EtOAc). 



   (4'R, 5R, 6S and 4'S, 4S, 6R) -p-nitrobenzyl-6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -2-methylpenem -3-carboxylate (isomer C)
EMI126. 2nd

A suspension of 443 mg (0.634 mmol) (4'R, 3S, 4R and 4'S, 3R, 4S) (3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) - (p-nitrobenzyl-2 "-triphenylphosphoranylidene. 2 "acetate) -4-acetylthio-2-azetidinone (isomer C) in 70 ml of toluene was heated to reflux temperature under nitrogen for 6 h. 

  After evaporation of the solvent, a white solid was obtained, which was worked up by column chromatography (SiO2 10 g, eluent 10% Et2O in benzene), giving 247 mg (0.587 mmol, yield 92.7%) of the desired compound in the form of a white solid .    IHmr (CDCl3) 8: 1.42 (6H, s, di-Me), 2.38 (3H, s, 2-CH3), 3.8-4.5 (4H, m, H-6, H- 4 'and H-5'), 5.02-5.255.33-5.57 (2H, AB type, -OCH2-Ar), 5.57 (1H, d, J = 1.8 Hz, H-5 ) and 7.52-7.67-8.12-8.27 ppm (4H, A2'B2 ', aromatic Hs).  IR (Nujol) vmax: 1760 (beta-lactam) and 1700 cm-1 (ester).  An analytical sample was obtained by recrystallization from CH2Cl2-Et2O.  M.p.  167-168 C. 

  UV (EtOH) #ma: 265 (# 14,000) and 314m (# 10,000). 



   Analysis for C19H20N2O7S Calculated: C, 54.28, H, 4.79, N, 6.66, S, 7.63 Found: C, 54.15, H, 4.78, N, 6.54, S, 7.64 (benzene-Et2O = 1: 1). 



   (4'R, 5R, 6S and 4'S, 55, 6R) 6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylic acid ( Isomer C)
EMI126. 3rd

A solution of 195 mg (0.464 mmol) (4'R, 5R, 6S and (4'S, 5S, 6R) p-nitrobenzyl-6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4yl) -2-methylpenem-3-carboxylate (isomer C) in 20 ml THF was mixed with 20 ml Et2O, 20 ml H2O, 39 mg (0.46 mmol) NaHCO3 and 200 mg 10% Pd / C (Engelhard).  This mixture was hydrogenated at 241.24 kPa for 4 h and at room temperature.  After filtering off the catalyst through Celite, the aqueous phase was washed twice with EtOAc, saturated NaCl, acidified with 1N HCl (0.47 ml) and extracted three times with 20 ml EtOAc. 

  The extracts were washed with brine, dried over Na2SO4 and concentrated to give 94 mg of a yellow solid, which was rinsed with pentane to give 89 mg (0.31 mmol, yield 67%) of the desired compound as a yellow solid.  M.p.  132-133 C.  Rf 0.60 (acetone: HOAc = 5: 0.7).  'Hmr (CDCl3) 8: 1.37, 1.43 (6H, 2s, di-Me), 2.36 (3H, s, 2-CH3), 3.9-4.6 (4H, m, H -6, H-4 'and H-5'), and 5.59 ppm (1H, d, J = 1.7 Hz, H-5).  IR (Nujol) vmax: 1760 (beta-lactam) and 1660 cm-1 (CO2H).  UV (EtOH) Xmax: 309 (± 6300) and 263m (# 3800).    

 

   Example 52 (4'S, 5R, 6S and 4'R, 5S, 6R) 6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -2-methylpenem-3- carboxylic acid (isomer B)
EMI127. 1
  (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) -4-tritylthio-2-azetidinone (isomer B )
EMI127. 2nd

The desired compound was prepared as described in Example 51 for isomer C from 14.4 g (25.8 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) 1- (t-butyldimethylsilyl) -3- ( 2 ', 2'-dimethyl-1', 3'-dioxolan-3'-yl) -4-tritylthio-2-azetidinone (isomer B), yield 10.8 g 24.3 mmol, 94.1% .  M.p.  155 C (CH2Cl2-Et2O).  Rf 0.24 (hexane: EtOAc = 2: 1). 

  Hmr (CDCl3) #: 1.37, 1.40 (6H, 2s, di-Me), 3.23 (1H, dd, J3-4) 2.5 Hz, J3-4 '= 5 Hz, H- 3), 3.7-4.5 (4H, m, H-4 ', H-5', NH), 4.50 (1H, d, J = 2.5 Hz, H-4) and 7, 1-7.6 ppm (15H, m, aromatic Hs).  IR (Nujol) 3170 (NH) and 1745 cm- '(C = O). 



   Analysis for C27H27NO3S Calculated: C, 72.78, H, 6.11, N, 3.14, S, 7.20 Found: C, 72.16, H, 6.11, N, 3.14, S, 7.17 (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) - 1 - (p-nitrobenzyl -2 "-hydroxy-2" -acetate) -4-trityltlsio- 2-azetidinone (mixture of epimers at C-2 ") (isomer B)
EMI127. 3rd

The compound mentioned was prepared as described in Example 51 for isomer C from 10.8 g (24.3 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -4-trityl-thio-2-azetidinone (isomer B), yield 15.8 g, 24.1 mmol), 99.3%, yellow foam, Rf- Values 0.29 and 0.22 (benzene: Et20 = 1: 1).    IHmr (CDCL3) #:

   1.28, 1.34 (2s, di-Me), 3.4-4.4 (m, H-3, H-4 ', H-5', H-2 ", OH), 4.39 , 4.53 (2d, J = 2 Hz, H-4), 5.15, 5.25 (2s, OCH2Ar) and 7.1-8.3 ppm (m, aromatic Hs).  IR (neat) vrnax: 3440 (br, OH), 1760 (C = 0.1520, 1350 cm-1 (NO2). 



   (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-Dimethyl-1', 3 'dioxolan-4'-yl) -l - (p-nitrobenzyl-2 "-chloro -2 "acetate) -4-trityl thio-2-azetidinone (mixture of epimers at C-2") (isomer B)
EMI127. 4th

The compound mentioned was prepared for isomer C as described in Example 51 from 14.9 g (22.8 mmol, mixture of the epimers at C-2 ") (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) - 1 - (p-nitrobenzyl-2 "hydroxy -" - acetate) -4-tritylthio-2-azetidinone (isomer B) , Yield 14.1 g, 20.9 mmol, 91.9%, yellow foam, Rf value 0.52 (benzene: Et2O = 3: 2).  'Hmr (CDCl3) a:

  : 1.30-1.38 (6H, 2s, di-Me), 3.44.5 (4H, m, H-3, H-4 ', H-5'), 4.57 (1H, i.e. , 5 = 3 Hz, H-4), 5.13 (s, H-2 "), 5.27 (s, OCH2Ar) and 7.1-8.3 ppm (19H, m, aromatic Hs).  IR (neat) vrnax: 1780 cm '(beta-lactam, ester). 



   (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "- triphenylphosphoranilidene-2 "acetate) -4-tritylthio-2-azetidinone (isomer B)
EMI128. 1

The compound mentioned was described in Example 51 for isomer C and was prepared from 14.0 g (20.8 mmol, mixture of the epimers at the C-2 ") (4'S, 3S, 4Rund3'R, 3R, 4S) -3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-chloro-2" acetate) -4-tritylthio-2-azetidinone (isomer B) produced.  Yield 4.64 g, 5.16 mmol, 24.8%, mp.  190-195 C (dec. , CH2C12 Et2O).  'Hmr (CDCl3) #: 1.12, 1.20, 1.27, 1.35 (4s, di-Me) and 7.0-8.1 ppm (m, aromatic Hs).  IR (CH2Cl3) vrnax: 1750 cm-1 (beta-lactam, ester). 



   Analysis for C54H47N207PS Calculated: C, 72.14, H, 5.27, N, 3.12, S, 3.57 Found: C, 71.90, H, 5.57, N, 3. 07, S, 3.56 Rf 0.21 (benzene: Et2O = 1: 1). 



   (4'S, 3S, 4R and 4'R, 3S, 4R) silver-3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranilidene-2" acetate) -2-azetidinone-4-thiolate (isomer B)
EMI128. 2nd

The compound mentioned was prepared as described in Example 51 for isomer C from 1.00 g (1.12 mmol) (4'S, 3S, 4R and 4'R, 3S, 4R) 3- (2 ', 2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -1- (p-nitro-benzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (isomer B), yield 580 mg, 0.760 mmol, 67.8%, m.p.  129-135 C (dec. ), IR (Nujol) vmax:

   1745 cm-l (beta-lactam, ester) (4'S, 3S, 4Rund 4'R, 3R, 4S) -3- (2 ', 2'-Dimethyl- I', 3'-dioxolan-4'- yl) - 1 - (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-acetylthio-2-azetidinone (isomer B)
EMI128. 3rd

The compound mentioned was prepared as described in Example 51 for isomer C from 2.46 g (3.22 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) silver-3- (2 ', 2'-dimethyl- 1 ', 3'-dioxolan4'-yl) - 1 - (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer B), yield after working up by column chromatography (SiO2 32 g, eluent 10% -50% EtOAc in CH2Cl2 = 1: 1).  'Hmr (CDCl3) #: 1.23, 1.27, 1.30 (3s, di-Me), 2.22, 2.33 (2s, SAc) and 7.3-8.3 ppm (m, aromatic Hs). 

  IR (neat) vmax: 1755 (beta-lactam, ester) and 1695 cm-1 (thioester). 



   (4'S, 5R, 6S and 4'R, 5S, 6R) p-nitrobenzyl-6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -2-methylpenem-3 carboxylate ismer B)
EMI128. 4th

The compound mentioned was prepared as described in Example 51 for isomer C from 200 mg (0.286 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-dimethyl-1', 3 '-dioxolan4'-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-acetylthio-2-azetidinone (isomer B), yield 64 mg, 0.15 mmol, 53%.  M.p.  151-152 C (CH2Cl2 / Et2o).  Rf 0.67 (benzene: Et2O = 1: 1).    IHmr (CDCl3) #: 1.28, 1.38 (6H, 2s, di Me), 2.30 (3H, s, 2-CH3), 3.64.4 (4H, m, H-6, H -4 ', H-5'), 5.00-5.19-5.28-5.46 (4H, ABq, -OCH2Ar), 5.47 (1H, d, J = 1.5 Hz, H -5) and 7.42-7.55-8.05-8.15 ppm (4H, A2'B2 ', aromatic Hs). 

  IR (neat) vmax: 1785 cm-1 (beta-lactam) and 1710 cml (ester).  UV (EtOH) #max: 266 (8 13,300) and 314 m (# 9.7000).    



   Analysis for C19H20N207S Calculated: C, 54.28, H, 4.79, N, 6.66, S, 7.63 Found: C, 54.00, H, 4.75, N, 6.68, S, 7.61 (4'S, 5R, 6S and 4'R, 5S, 6R) 6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylic acid (Isomer B)
EMI129. 1

Said compound was prepared as described in Example 51 for isomer C from 79 mg (0.19 mmol) (4'-S, 5R, 6S and 4'R, 5S, 6R) p-nitrobenzyl-6- (2 ', 2'-dimethyl1 ', 3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylate (isomer B), yield after recrystallization from CH2Cl2-pentane 9 mg, 0.032 mmol, 17%.  Rf 0.54 (acetone: HOAc = 5: 0.5). 1Hmr (CDCl3) #: 1.35, 1.44 (6H, 2s, di-Me), 2.37 (3H, s, 2-CH3), 3.6-4.5 (4H, m, H- 6, H-4 ', H-5') and 5.56 ppm (1H, brs, H5). 

  IR (neat) vmax: 1785 cm-l (beta-lactam).  UV (EtOH) Aerax: 307 (E 4300) and 262 m (E 3700). 



   Example 53 (1'R, SR, 6S and 1'S, 5S, 6R) 6- (1'-Hydroxy-2'methoxy methoxy-2'-ethyl) -2-ethyi) -2-inethylpenem-3-carboxylic acid (isomer C)
EMI129. 2nd
    (1'R, 3S, 4Rund 1'S, 3R, 4S) 3- (1 ', 2'-Dihydroxyäthil) -1- (p-nitrobenzyl-2 "-triphenylphosphoranyliden-2" -acet t) -4-acetylthio-2 -azetidinone (isomer C)
EMI129. 3rd

A solution of 472 mg (0.676 mmol) (4'R, 3S, 4R and 4'S, 3R, 4S) 3- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl) -1 - (p-nitro-benzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio2-azetidinone (isomer C) in 1.0 ml of trifluoroacetic acid and 0.1 ml of water was left to stand at room temperature for 30 minutes.  The mixture was added dropwise to a cold solution of 2.5 g NaHCO3 in 50 ml water and extracted 3 times with 20 ml CH2C12.  

  The extracts were washed with saturated NaHCO3 and brine, dried over Na2SO4 and evaporated to give 458 mg (0.695 mmol, crude yield 100%, purity 97.3%) of the crude desired compound as a yellow foam.    1Hmr (CDCl3): 2.20, 2.32 (2s, SAc) and 7.2-8.3 ppm (m, aromatic Hs).  IR (neat) vmax: 3420 (OH), 1745 (beta-lactam, ester) and 1690 cm-l (thioester).  Rf 0.16 (EtOAc). 



   (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-Hydroxy-2'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate ) -4-acetylthio-2-azetidinone (isomer C)
EMI129. 4th
  
To a solution of 291 mg (0.430 mmol, purity 97.3%) (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1 ', 2'-dihydroxyethyl) 1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4acetylthio-2-azetidinone (isomer C) and 55.2 mg (0.442 mmol, 4 drops) of bromomethyl methyl ether in 8 ml of CH2Cl2 were 58.8 mg (0.483 mmol) at 0 C, 5 Drop) N, N'-dimethylaniline added and the mixture was stirred at room temperature for 20 h.  Another 2 drops of bromomethyl methyl ether and 2 drops of N, N'-dimethylaniline were added and stirring was continued for 4 hours. 



  The mixture was then diluted with CH2Cl2 and washed successively with 1N HCl, saturated NaHCO3 and brine, dried over Na2SO4 and evaporated. 



  The crude residue was worked up by hplc (SiO2), eluent EtOAc), whereby 31 mg (0.186 mmol, yield 42.2%) of the desired compound were obtained as oil. 



     lHmr (CDCl3) â: 2.20, 2.32 (2s, SAc), 3.30 (s, OCH3), 4.52 (s, -OCH2O- and 7.4-8.3 ppm (m, aromatic Hs).  IR (neat) vmax: 3420 (OH), 1755 (br, beta-lactam and ester) and 1690 cm- '(thioester). 



   (1'R, SR, 6S and 1'S, 5S, 6R) p-nitrobenzyl-6- (1'-hydroxy-2'-methoxymethoxy-2'-ethyl) -2-methylpenem-3-carboxylate
EMI130. 1

A solution of 167 mg (0.238 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-Hydroxy-2'-methoxymethoxy-1'-ethyl) -1- (pnitrobenzyl-2 " -triphenylphosphoranyliden-2 "acetate) -4-acetylthio-2-azetidinone (isomer C) in 30 ml of toluene was heated to reflux temperature under nitrogen for 8 h.  Evaporation of the solvent in vacuo gave an oily residue which was purified by hplc (SiO2, eluent EtOAc) and gave 68 mg (0.16 mmol, yield 67%) of the desired compound as an oil. 

  Rf 0.61 (EtOAc), 0.15 (benzene: Et2O = 1: 1).    1Hmr (CDCl3) 8: 2.38 (3H, s, 2-CH3), 3.35 (1H, br, OH), 3.40 (3H, s, OCH3), 3.6-3.8 (2H , m, H-2 '), 3.90 (1H, dd, J6-5 = 2 Hz, J6-1' = 4 Hz, H-6), 4.18 (1H, m, H-1 ') , 4.67 (2H, s, -OCH2O-), 5.03-5.275.38-5.62 (2H, ABq, OCH2Ar), 5.65 (1H, d, J = 2 Hz, H-5) and 7.55-7.70-8.15-8.30 ppm (4H, A2'B2 ', aromatic Hs).  IR (neat) vmax: 3450 (OH), 1785 (beta-lactam), 1710 (ester) and 1520 cm- '(NO2).  UV (EtOH) #max: 266 (± 13,000) and 313m (# 9100). 



   Analysis for Cl8H20N208S Calculated: C, 50.94, H, 4.75, N, 6.60 Found: C, 51.13, H, 4.77, N, 6.36 (1'R, 5R, 6S and 1'S, 5S, 6R) 6- (1'-hydroxy-2'-methoxy-methoxy-2'-ethyl) -2-methylpenem-3-carboxylic acid (isomer C)
EMI130. 2nd

A solution of 51 mg (0.12 mmol) (1'R, 5R, 6S and 1'S, 5S, 6R) p-nitrobenzyl-6- (1'-hydroxy-2'-methoxymethoxy-2 'ethyl) -2- methylpenem-3-carboxylate (isomer C) in 10 ml THF was mixed with 10 ml Et2O, 10 ml H2O, 10 mg (0.12 mmol) NaHCO3 and 50 mg Engelhard) 10% Pd / C.  The mixture was then hydrogenated at room temperature and 220.57 kPa for 3 h, whereupon after filtering off the catalyst over Celite, the aqueous phase was separated off and washed 3 × with Et2O and saturated with NaCl. 

  The aqueous phase was acidified at 0 C with 1.2 ml 0.1N HCl and immediately extracted 3 times with 15 ml EtOAc.  The extracts were washed with brine, dried over Na2SO4 and evaporated to give 22 mg of a yellow solid which was rinsed with a small portion of Et2O, giving 20 mg (0.069 mmol, yield 58%) of the desired compound as a pale yellow Solid were obtained.  'Hmr (DMSO-d6) â: 2.28 (3H, s, 2-CH3), 3.27 (3H, s, OCH3), 3.49 (2H, d, J = 6.2 Hz, 2' -H), 3.87 (iH, dd, J6-5 = 1.7Hz, J6-1 '= 3.3 Hz, 6-H), 4.58 (2H, s, -OCH2O-) and 5, 55 ppm (1H, d, J = 1.7 Hz, 5-H). 

  IR (KBr) vmax: 3410 (OH), 1755 (beta-lactam) and 1655 cm¯l (CO2H). 



  UV (EtOH) #max: 308 (# 6800) and 262m (# 4200).     M.p. 



  137-138 C (dec. ). 



   Example 54 (1'S, 5R, 6S and 1'R, 5S, 6R) 6- (1'-hydroxy-2'-methoxymethoxy-2'-ethyl) -2-methylphenem-3-carboxylic acid (isomer B)
EMI131. 1
    (1'S, 3S, 4Rund 1'R, 3R, 4S) 3- (1 ', 2'-Dihydroxyäthyl) -l- (pnitrobenzyl-2 "-triphenylphosphoranyliden-2" -acetate) -4-acetylthio-2-azetidinone ( Isomer B)
EMI131. 2nd
 Said compound was prepared as described in Example 53 for isomer C from 1.03 g (1.47 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-dimethyl- 1 ', 3'-dioxolan-4'-yl) - 1 - (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) 4-acetylthio-2-azetidinone (isomer B), yield 970 mg, 1.47 mmol, 100%, yellow foam.  Hmr (CDCl3) a: 2.20, 2.32 (2s, -SAc) and 7.3-8.2 ppm (m, aromatic Hs). 

  IR (neat) vrnax: 3410 (OH), 1750 (beta-lactam, ester) and 1690 cm-1 (thioester).  Rf 0.16 (EtOAc). 



   (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (l'-Hydroxy-2'-methoxymethoxy-1 '-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate ) -4-acetylthio-2-azetidinone (isomer B)
EMI131. 3rd

The compound mentioned was prepared as described in Example 53 for isomer C from 485 mg (0.736 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1 ', 2'-dihydroxyethyl) -1-) p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetyithio-2-azetidinone (isomer B), yield 205 mg, 0.292 mmol, 39.6%, oil.    1HMR (CDCl3) â: 2.22, 2.33 (2s, SAc), 3.32 (s, OCH3), 4.57 (s, -OCH2O-) and 7.2-8.3 ppm (m, aromatic Hs).  IR (neat) vmax: 3420 (OH), 1755 (beta-lactam, ester) and 1690 (thioester) Rf.  0.32 (EtOAc). 



   (1'S, 5R, 6S and 1'R, 5S, 6R) p-nitrobenzyl-6- (l '-hydroxy-1' -methoxymethoxy-2'-ethyl) -2-methylpenem-3-carboxylate
EMI131. 4th

The compound mentioned was prepared as described in Example 53 for isomer C from 205 mg (0.292 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-hydroxy-2'-methoxymethoxy-oxy- 1'-ethyl) - 1 - (p-nitrobenzyl-2 "-triphenylphosphoranyli den-2" -acetate) -4-acetylthio-2-azetidino (isomer B) and 10 mg (0.09 mmol) of hydroquinone, yield 38 mg , 0.090 mmol, 31%, m.p.  152-154 C, Rf 0.23 (benzene: Et2O = 1: 1). 

 

     IHmr (CDCl3) a: 2.37 (3H, s, 2-CH3), 3.40 (3H-s, OCH3), 3.4-3.9 (3H, m, H-6, H-2 " ), 4, 15 (1H, m, H-l '), 4.67 (2H, s, -OCH2O-), 5.10-5.27-5.39-5.56 (2H, ABq, - OCH2Ar), 5.67 (1H, d, J = 1.5 Hz, H-5) and 5.55-5.16-8.15-8.27 ppm (4H, A2'B2 ', aromatic H3 ).  IR (CH2Cl2 mull) vmax: 3370 (OH), 1785 (beta-lactam) and 1700 cm-1 (ester).  UV (THF EtOH = 1: 1) #max: 265 (± 10400) and 314 m (± 7800). 



   (1'S, 5R, 6S and 1'R, 5S, 6R) 6- (1'-hydroxy-2'-methoxy-methoxy-2'-ethyl) -2-methylphenem-3-carboxylic acid (isomer B)
EMI132. 1

Said compound was prepared as described in Example 53 for Isomer C from 36 mg (0.085 mmol) (1'S.  5R, 6S and 1'R, 5S, 6R) p-nitrobenzyl-6- (l'-hydroxy-2'-methoxymethoxy-2'-ethyl) -2-methylphenem-3-carboxylate (isomer B), yield 7, 5 mg, 0.026 mmol, 30%, yellowish crystals.  'Hmr (CDCL3) a: 2.36 (3H, s, 2-CH3), 3.39 (3H, s, OCH3), 3n6-3.9 (3H, m, H-6, H-2') , 4.15 (1H, m, H-1 '), 4.66 (2H, s, OCH2O) and 5.67 ppm (1H, d, J = 1.4 Hz, H-5). 

  IR (CH2Cl2) #max: 1785 (beta-lactam) and 1675 cm-1 (CO2H). 



  UV (EtOH) #max: 308 (± 2900) and 263 m (± 2900). 



   Example 55 2-Benzimidoylaminomethylpenem-3-carboxylic acid
EMI132. 2nd

To a suspension of 0.38 g (0.0015 mol) of sodium 3benzyl-1,2,4-oxadiazol-5-one-4-acetate (I) l in 10 ml of methylene chloride, containing 2 drops of DMF, 0 were obtained at room temperature , 13 ml (0.0015 mol) of oxalyl chloride were added, the mixture foaming.     The reaction mixture was stirred at room temperature for 1 h, the NaCl formed was filtered off and the filter cake was washed several times with small parts of methylene chloride. 



  The solution of acid chloride (II) was used directly.  1.  K.    Takacs and K.  Harsanyi, Ber.  103: 2330 (1970). 
EMI132. 3rd
  



   A solution of 1.0 g (0.0015 mol) of (III) and 0.12 ml (0.015 mol) of pyridine in 10 ml of methylene chloride was cooled to 4 C under nitrogen, the acid chloride (II) solution became the solution of (III) was added and the reaction mixture was stirred at 4 C for 5 min, and then further stirred at room temperature for 1.5 h.  The thick precipitate formed in the reaction mixture was filtered off, the filtrate was diluted to a volume of 70-90 ml with methylene chloride and the organic phase was then washed successively with 70 ml of 0.1N HCl, 80 ml of 1% sodium bicarbonate and 80 ml of water. 

  The methylene chloride phase was dried over magnesium sulfate, the solvent was removed in vacuo and the remaining oil was chromatographed on Mallinckrodt SilicAR CC-7 silica gel using chloroform as eluent, whereby 0.4 g (30.5%) of (IV) as Oil were obtained.  IR and NMR spectra were consistent with (IV).    
EMI133. 1




   A solution of 0.4 g (0.00045 mol) IV in 50 ml toluene was refluxed for 4 hours.  The solvent was evaporated in vacuo and the residue chromatographed on Mallinckrodt SilicAR CC-7 silica gel using 5% ethyl acetate in methylene chloride as the eluent to give 0.15 g (66.6%) of V as an oil which solidified .  IR and NMR spectra were consistent with V. 



   Analysis for C23H18N407S Calculated: C, 55.86, H, 3.67, N, 11.33 Found: C, 56.17, H, 3.76, N, 11.23
EMI133. 2nd

A solution of 0.135 g (0.00027 mol) of V in 40 ml of tetrahydrofuran and 40 ml of anhydrous diethyl ether was poured into a slurry of 10% palladium on activated carbon in 40 ml of water under nitrogen.  The resulting mixture was hydrogenated in a Parr apparatus at room temperature and an initial pressure of 358.42 kPa for 3.5 hours.  The hydrogen uptake was 31.02 kPa.  The catalyst was filtered off, the filter cake was washed with water, further diethyl ether was added to the filtrate and the phases were separated. 

  The aqueous phase was extracted 3 times with diethyl ether, then the aqueous phase was evaporated to dryness and the residue obtained was chromatographed by hplc to give 0.050 g (58%) of the desired penemic acid, decomposition mp.  156-173 C.     IR and NMR spectra were consistent with the desired product. 



   Analysis for C15H15N303S. 1.5H20 Calculated: C, 52.31, H, 5.27, N, 12.20 Found: C, 51.64, H, 4.95, N, 12.31
Example 56
2-phenylimidoylaminomethylpenem-3-carboxylic acid
EMI133. 3rd

Using the same procedure as in Example 55 and using an equimolar fraction of sodium 3-phenyl1,2,4-oxadiazol-5-one-4-acetate as the starting product instead of the sodium 3-benzyl-1, 2.4 used therein -oxadiazoi-5- on-4-acetate, the compound mentioned was obtained. 



  Biological data
Representative compounds of the present invention have been subjected to in vitro antibiotic screening against a large number of microorganisms.  Samples of the specified compounds were examined after dissolving in water and diluting with a nutrient medium and gave the minimum inhibitor concentrations (MIC) given below in μg / ml against the specified microorganisms, incubation at 37 ° C. overnight. 



     M. l. C.     in llg / ml organism compound (example no. )
1 Streptococcus pneumoniae 125 A9585 Streptococcus pyogenes> 125 A9604 Staphylococcus aureus 1 A9537 M. I. C.     in llg / ml M. l. C.     in llg / ml organism compound (example no. ) Organism connection (example no. )
1 2 3 Staph aureus + 50% serum 8 5 A9537 Escherichia coli 32 63 Staphylococcus aureus 32 A15119 A9606 Escheriehia coli 32 63 Staphylococcus aureus 4 A20341-1 A15097 lo Klebsiella pneumoniae 63 125 Streptococcus faecalis 125 Abs130ischerichia8> 125 A15130 Ascherichia 8 A20468 A15119 Proteus mirabillis 63 63 Escherichia coli 2 15 A9900 A20341-1 Proteus vulgaris 63 32
Klebsiella pneumoniae 125 A9716 A15130 Proteus

   morganii 63 125
Klebsiella species 4 A15153 A20468 20 Providencia stuartii 32 63
Proteus mirabilis 8 A21205 A9900 Serratia marcescens 125 63 Proteus mirabilis 63 A20019 A9716 Enterobacter cloacae 125 125
Proteus morganii 6325 A9659 A15153 Enterobacter cloacae> 125 125
Proteus rettgeri 32 A9656 A21203 Pseudomonas aeruginosa> 125> 125
Serratia marcescens 63 A9843A
A20019 30 Pseudomonas aeruginosa> 125> 125 A21213
Enterobacter cloacae 16 A21213
A9659 Hemophilus influenzae -
Enterobacter cloacae 16 A9833
A9656 Haemophilus influenzae
Pseudomonas aeruginosa 12535 A21522
A9843A Bacteroides fragilis - Pseudomonas aeruginosa> 125 A20931
A21213 Bacteroides fragilis -
Hemophilus influenzae - A20929
A9833
Haemophilus influenzae - M. I. C.     in <RTI

    ID = 134.10> llg / ml
A21522
Bacteroides fragilis - organism compound (example no.) A20931 55 4 5
Bacteroides fragilis
A20929 Streptococcus pneumoniae 1 0.5
A9585
Streptococcus pyogenes 4 4 M.LC. in g / ml 50 A9604 50 aureus 8 4
Organism Compound (Example No.) A9537
2 3 Staph aureus + 50% serum> 63> 63
A9537
Streptococcus pneumoniae 1 155 Staphylococcus aureus 4 9
A9585 A9606
Streptococcus pyogenes 2 4 Staphylococcus aureus 125 63
A9604 A15097
Staphylococcus aureus 8 2 Streptococcus faecalis 125 125 A9537 60 A20688
Staph aureus + 50% serum> 63> 63 Escherichia coli> 125 63
A9537 A15119
Staphylococcus aureus 4 4 Escherichia coli> 125 125
A9606 A20341-1
Staphylococcus aureus 8 3265 Klebsiella pneumoniae> 125

   63
A15097 A15130
Streptococcus faecalis 63 125 Klebsiella species> 125> 125
A20688 A20468 M.I.C. in zg / ml Serratia marcescens 32 63
A20019 Organism Compound (Example No.) Enterobacter cloacae 63 63
4 5 A9659
5 Enterobacter cloacae 63 63 Proteus mirabilis 63 63 A9656 A9900 Pseudomonas aeruginosa 16 32 Proteus vulgaris 63 32 A9843A A9716 Proteus morganii 125 125 10 M.I.C.

   in g / ml A15153 Providencia stuartii 125 32 Organism Compound (Example No.) A21205 Serratia marcescens> 125 63 12 (5) 12 (6) A20019 15 Pseudomonas aeruginosa 32> 125 Enterobacter cloacae> 125 125 A21213 A9659 Hemophilus influenzae Enterobacter cloacae> 125 125 A9833 A9656 Haemophilus influenzae - Pseudomonas aeruginosa -> 125 20 A21522 A9843A Bacteroides fragilis - Pseudomonas aeruginosa -> 125 A20931 A21213 Bacteroides fragilis - Hemophilus influenzae - - A20929 A9833 25 Haemophilus influenzae - - in g / ml A21522 Bacteroides fragilis - - organism compound (Example No.) A20931 12 Bacteroides fragilis - - 30 A20929 Streptococcus pneumoniae 0.016
A9585
Streptococcus pyogenes 0.06 M.I.C.

   in Rg / ml A9604 35 Staphylococcus aureus 0.13 organism compound (Example No.) A9537
11 (5) 11 (6) Staph aureus + 50% serum 4
A9537 Streptococcus pneumoniae 1 2 Staphylococcus aureus 8 A9585 40 A9606 Streptococcus pyogenes 2 4 Staphylococcus aureus 125 A9604 A15097 Staphylococcus aureus 4 4 Streptococcus faecalis 63 A9537 A20688 Staph aureus Staphylia coli 329 A2537 A45 Escherichia coli 3215 A45 Escherichia coli 3215 A45 Escherichia coli 325 A9537 coli 1255 Escherichia col 63 A9606 A20431-1 Staphylococcus aureus 63 63 Klebsiella pneumoniae 8 A15097 soA15130 Streptococcus faecalis> 63 125 Klebsiella species> 125 A20688 A20468 Escherichia coli 16 16 Proteus mirabilis 1 A15119 A9900 Escherichia coli> 63 125559716ote1 vul morganii 1 A15130 A15153 Klebsiella species> 63> 125

   Proteus rettgeri 2 A20468 60 A21203 Proteus mirabilis 8 16 Serratia marcescens 1 A9900 A20019 Proteus vulgaris 63 32 Enterobacter cloacae 2 A21559 A9659 Proteus morganii 16 3265 Enterobacter cloacae 1 A15153 A9656 Proteus rettgeras20I. in Clglml Bacteroides fragilis - -
A20929 Organism compound (example no.) Pseudomonas aeruginosa - -
12 A20599
5 Pseudomonas aeruginosa - - Pseudomonas aeruginosa 125 A9925 A21213 Pseudomonas aeruginosa - - Hemophilus influenzae 125 A20229 A9833 Proteus species - Haemophilus influenzae - 10A20543 A21522 Proteus mirabilis - - 16 Bacteroides fragilis - Aiden16 B20920531I5 A916A20931 Fragile A2716 A20921 Fragile A2716

   in llg / ml M.I.C. in llg / ml organism compound (example No.) organism compound (example No.)
32 18 24 20 25 Streptococcus pneumoniae 0.25 0.25 0.016 Streptococcus pneumoniae 2 A9585 A9585 Streptococcus pyogenes 8 2 0.25 Streptococcus pyogenes 16 A9604 25 A9604 Staphylococcus aureus 8 4 0.03 Styphylococcus aureus 32 A9537 A9537% Serum aure 32 63 63 Staph aureus + 50% serum> 63 A9537 A9537 Staphylococcus aureus 16 4 16 30 Staphylococcus aureus> 125 A9606 A9606 Staphylococcus aureus 63 16> 125 Staphylococcus aureus> 125 A15097 A15097 Streptococcus faecalis A125 12568 12568686868686868 coli 63 4 63 Escherichia coli 63 A15119 A15119 Escherichia coli> 125 16> 125 Escherichia coli> 125 <RTI

    ID = 136.8> A20341-1 A20341-1 Klebsiella pneumoniae 125 32> 125 40 Klebsiella pneumoniae> 125 A15130 A15130 Klebsiella species> 125 125> 125 Klebsiella species> 125 A20468 A20468 Proteus mirabilis 63 16 32 Proteus mirabilis 63 A9900 45 A9900 Proteus vulgaris 16 - Proteus vulgaris A9555 A9716 Proteus morganii 125 32 32 Proteus morganii 125 A15153 A15153 Proteus rettgeri 63 32 - 50 Proteus rettgeri 125 A21203 A21203 Serratia marcescens 63 32 16 Serratia marcescens> 125 A20019 A20019 Aobacteraco 1259> 125obacteracoobacteria 55 A9659 Enterobacter cloacae 125 63 125 Enterobacter cloacae> 125 A9656 A9656 Pseudomonas aeruginosa 125 125> 125 Pseudomonas aeruginosa 125 A9843A A9843A Pseudomonas aeruginosa 125 125> 125 60 Pseudomonas aeruginosa 125 A21213 A21213 Hemophilus influenzae <RTI

    ID = 136.10> - - - Hemophilus influenzae A9833 A9833 Haemophilus influenzae - - - Haemophilus influenzae A21522 65 A21522 Bacteroides fragilis - - - Bacteroides fragilis A20931 A20931 M.I.C. in pg / ml Bacteròides fragilis
A20931 Organism Compound (Example No.) Bacteroides fragilis
25 A20929 Bacteroides fragilis - 5 A20929 Pseudomonas aeruginosa M.LC. in pgjml A20599 Pseudomonas aeruginosa - organism compound (example no.) A9925 10 33 34 Pseudomonas aeruginosa Streptococcus pneumoniae .00 .25 A20229 A9585 Proteus species A20543 streptococcus pyogenes .13 2 Proteus mirabilis 6315 A9604 Acusote A3716 Staphylus555 aureus + 50% 16 63
Serum A9537 20 Staphylococcus aureus 125 4
M.I.C.

   in g / ml A9606 Staphylococcus aureus> 125 16 organism compound (example no.)
31 A15097
Streptococcus faecalis 125 125 Streptococcus pneumoniae 6325 A20688 A9585 Escherichia coli 16 4 Streptococcus pyogenes 125 A15119 A9604 Escherichia coli> 125 16 Staphylococcus aureus 32 A20341-1 A9537 30 Klebsiella pneumoniae 125 32 Staph aure37 A 12537 serum aure37 + 1251 serum aure37 +151% Seri aureus> 125 A20468 A9606 Proteus mirabilis 8 16 Staphylococcus aureus 6335 A9900 A15097 Proteus vulgaris 63 16 A9555 Streptococcus faecalis 63 Proteus morganii 32 32 A20688 A15153 Escherichia coli 63 40 Proteus rettgeri 1620 A32111i12021 322 A15119i12021 322 A15119201 A21 pneumoniae> 125 Enterobacter cloacae 125 32 A15130 A9659 Klebsiella species 6345Enterobacter cloacae

   63 63 A20468 A9656 Proteus mirabilis 125 Pseudomonas aeruginosa 125 125 A9900 A9843A Proteus vulgaris> 125 Pseudomonas aeruginosa 125 125 A9555 50A21213 Proteus morganii 125 Hemophilus influenzae A15153. A9833 Proteus rettgeri 125 Haemophilus influenzae A21203 A21522 Serratia marcescens 125 Bacteroides fragilis A20019 A20931 Enterobacter cloacae 125 Bacteroides fragilis A9659 A20929 Enterobacter cloacae 32 A9656 60 Pseudomonas aeruginosa 125 M.I.C. in pg / ml A9843A organism compound (example No.) Pseudomonas aeruginosa 125 35 36 40 A21213 Hemophilus influenzae - 65 Streptococcus pneumoniae 32 .25 .004 A9833 A9585 32 .25 .008 Haemophilus influenzae - Streoptococcus pyogenes 125 1 .004 A21522 A9604 125 .008 MIC

   in g / ml Streptococcus faecalis 2 32 4
A20688 Organism Compound (Example No.) Escherichia coli 2 8 2
35 36 40 A15119
5 Escherichia coli 8 8 2 Staphylococcus aureus - - .008 A20341-1 A9537> 125 2 .008 Klebsiella pneumoniae 8 16 4 Staph aureus + 50% - - .06 A15130 Serum A9537> 63 8 .06 Klebsiella species 63 32 4 Staphylococcus aureus - - .06 10 A20468 A9606> 125 4 .06 Proteus mirabilis 2 2 4 Staphylococcus aureus - - .06 A9900 A15097> 125 8 .25 Proteus vulgaris 4 2 2 Streptococcus faecalis> 125 63 .5 A21559 A20688> 125 63 5 15 Proteus morganii 8 2 4 Escherichiacoli> 125 16 .13 A15153 A15119> 125 16 .25 Proteusrettgeri 2 2 4 Escherichiacoli> 125 16 <.25 A21203 A20341-1> 125 16 .13 Serratiamarcescens 8 16 4 Klebsiella pneumoniae> 125 16 <.25

   20A20019 A15130> 125 16 .5 Enterobacter cloacae 8 32 4 Klebsiella species> 125 16 .5 A9659 A20468> 125 16 .5 Enterobacter cloacae 32 1 16 Proteus mirabilis> 125 32 <.25 A9656 A9900> 125 16 .25 25 Pseudomonas aeruginosa 63 2 16 Proteus vulgaris> 125 16 <.25 A9843A A21559> 125 16 .25 Pseudomonas aeruginosa - - Proteus morganii> 125 32 1 A21213 A15153> 125 16 1 Hemophilus influenzae - - Proteus rettgeri> 125 16 <.25 30 A9833 A21203> 125 16 .5 Haemophilus influenzae - - Serratia marcescens> 125 16 .5 A21522 A20019> 125 16 .5 Bacteroides fragilis - - Enterobacter cloacae> 125 32 4 A20931 A9659> 125 - 2 35 Bacteroides fragilis - - Enterobacter cloacae> 125 16 .5 A20929 A9656> 125 - .5 Pseudomonas aeruginosa> 125> 125 16 A9843A> 125 - 16 MICin g / ml Pseudomonas

   aeruginosa> 125> 125 125 A21213> 125 - 63 40 organism compound (example no.) Haemophylus influenzae - - -43 A9833 - - - Streptococcus pneumoniae> 63 Haemophylus influenzae - - - A9585 A21522 - - - 45 Bacteroides fragilis - - - Streoptococcus pyogenes> 63 A20931 - - - A9604 Bacteroides fragilis Staphylococcus aureus> 63 A20929 - - - A9537
50 Staph aureus + 50%> 32 M.I.C in g / ml Staphylococcus aureus> 63
A9606 Organism Compound (Example No.) Staphylococcus aureus> 63
37 38 3955A15097 Streptococcus faecalis> 63 Streptococcus pneumoniae .03 .03 .016 A20688 A9585 Escherichia coli> 63 Streptococcus pyogenes .06 .5 .03 A15119 A9604 Escherichia coli> 63
Staphylococcus aureus .5 .03 .06 60 A20341-1 A9537 Klebsiella

   pneumoniae> 63 Staph aureus + 50% 4 .25 .13 A15130
Serum A9537 Klebsiella species> 63
Staphylococcus aureus 1 .25 .13 A20468 A9606 65 Proteus mirabilis> 63
Staphylococcus aureus 2 .5 .25 A9900 A15097 Proteus vulgaris> 63
A21559 M.I.C. in Fg / ml Enterobacter cloacae 8
A9656 Organism Compound (Example No.) Pseudomonas aeruginosa 63
43 A9343A
5 Pseudomonas aeruginosa> 63 Proteus morganii> 63 A21213 A15153 Hemophilus influenzae Proteus rettgeri> 63 A9833 A21203 Haemophilus influenzae Serratia marcescens> 63 lot21522 A20019 Bacteroides fragilis Enterobacter cloacae> 63 A20931 Aides699999999509 in llg / ml A9843A Pseudomonas aeruginosa> 63

   Organism Compound (Example No.) A21213 47 48 49 50 Hemophilus influenzae - 20 A9388 Streoptococcus pneumoniae .5> 125 1 32 Haemophilus influenzae - A9585 A21522 Streptococcus pyogenes .5> 125 16 32 Bacteroides fragilis - A9604 A20931 25 Staphylococcus 32 125 Bacteroides fragilis - A9537 A20929 Staphaureus + 50% 32> 63> 63 63
Serum A9537 M.I.C. in zg / ml Staphylococcus aureus 16> 125 32> 125
30 A9606 Organism Compound (Example No.) Staphylococcus aureus 32> 125> 125> 125
45 A15097
Streptococcus aureus> 63> 125> 125> 125 Streptococcus pneumoniae 2 A15097 A9585 35Escherichiacoli 32> 125> 125> 125 Streptococcus pyogenes 16 A15119 A9604 Escherichia coli 32> 125> 125> 125 Staphylococcus aureus 32 A20341-1 A9537

   Klebsiella pneumoniae 63> 125> 125> 125 Staphaureus + 50%> 3240A15130 Serum A9537 Klebsiella species 63> 125> 125> 125 Staphylococcus aureus 2 A20468 A9606 Proteus mirabilis 32> 125> 125> 125 Staphylococcus aureus 8 A9900 A150gar 4is 32 125> 125> 125 Streptococcus faecalis 63 A21559 A20688 Proteus morganii 63> 125> 125> 125 Escherichia coli 2 A15153 A15119 Proteusrettgeri 32> 125> 125> 125 Escherichia coli 32 50 A21203 A20341-1 Serratiamarcescens 63> 125> 125> 125 Klebsiella 8 A20019 A15130 Enterobactercloacae 63> 125> 125> 125 Klebsiella species> 63 A9659 A20468 55 Enterobacter cloacae 63> 125> 125

   > 125 Proteus mirabilis 4 A9656 A9900 Pseudomonas aeruginosa> 63> 125> 125> 125> 125 Proteus vulgaris 16 A9843A A21599 Pseudomonas aeruginosa> 63> 125> 125> 125 Proteus morganii 8 60A21213 A15153 Hemophilus influenzae - - - Proteus rettophilus influenz 8 - 98 - - - Serratiamarcescens 8 A21522 A20019 65 Bacteroides fragilis Enterobacter cloacae 8 A20931 A9659 Bacteroides fragilis - - - -
A20929 M.I.C. in llg / ml M.I.C. in llg / ml organism compound (example No.) organism compound (example No.)
51 52 53 54 55 56
5 Streptococcus pneumoniae 63 16 4 32 Streptococcus pneumoniae .5 .25 A9585 A9585 Streptococcus pyogenes 63 32 4 32 Streptococcus pyogenes .5 .25 A9604

   A9604 Staphylococcus aureus> 63 63> 8 63 1O Staphylococcus aureus .5 .25 A9537 A9537 Staphaureus + 50%> 32> 32> 32> 32 Staphaureus + 50% 16 16 Serum A9537 Serum A9537 Staphylococcus aureus> 63 63 63> 63 Staphylococcus 32 16 A9606 15 A9606 Staphylococcus aureus> 63 63> 63> 63 Staphylococcus aureus> 63> 125 A15097 A15097 Streptococcus faecalis> 63 63> 63> 63 Streptococcus faecalis> 63 125 A20688 A20688 Escherichia coli> 63> 63 63 63 2oEscherichia coli A15119 A15119 Escherichia coli> 63> 63 63 63 Escherichia coli> 63> 125 A20341-1 A20341-1 Klebsiella pneumoniae> 63> 63 63> 63 Klebsiella pneumoniae> 63 125 A15130 25 A15130 Klebsiella species> 63> 63> 63>

   63 Klebsiella species> 63> 125 A20468 A20468 Proteus mirabilis 63> 63> 63 63 Proteus mirabilis 63 63 A9900 A9900 Proteus vulgaris> 63> 63> 63> 63 30Proteus vulgaris 63 125 A21559 A21559 Proteus morganii> 63> 63> 63> 63 Proteus morganii 63 63 A15153 A15153 Proteus rettgeri> 63 63 32 63 Proteus rettgeri 63 63 A21203 35 A21203 Serratia marcescens> 63> 63> 63 63 Serratia marcescens 63 125 A20019 A20019 Enterobacter cloacae> 63> 63 63> 63 Enterobacter cloacae> 63 12596599 Enterobacter cloacae> 63> 63 63 63 40 Enterobacter cloacae 63 125 A9656 A9656 Pseudomonas aeruginosa 63 63 63 63 Pseudomonas aeruginosa 63 63 A9843A A9843A Pseudomonas aeruginosa 63 63 63 63 Pseudomonas aeruginosa 63 125 A21213 45 A21213 Hemophilenz influophil A9833 Haemophilus influenzae - - - - Haemophilus influenzae - A21522

   A21522
Bacteroides fragillis - - - - 50 Bacteroides fragilis - A20931 A20931
Bacteroides fragilis - - - - Bacteroides fragilis - A20929 A20929
Representative compounds of the present invention were also tested in vivo in mice and 50% of the treated test animals were determined against a letha PD50 values (dose of the compound in mg / kg, 60 ml to protect infection from microorganisms).

 

  S. aureus A9537 Compound Number of Infectious Number of Administered PD50 render Organisms (mg / kg / men of S. aureus art treat
A9537 from example 7.8 x 105 2 IM 0.12 game 40 from example 6.6 x 105 2 IM 7.7 game 36 from example 8.6 x 105 2 IM 1.0 game 37 from example 8 x 105 2 IM> 5 game 56 from example 8 x 105 2 IM 0.04 game 39
The blood level of representative compounds of the present invention was determined in mice after intramuscular administration and the measured values were as follows: * Blood levels in mice in pg / ml after intramuscular administration of 40 mg / kg body weight compound minutes after administration
10 20 30 45 60 90 120 from Example 40 44.7 34.4 23.7 17.6 9.8 3.6 1 * Average from 6 mice


      

Claims (8)

 PATENT CLAIMS 1. Compound of the formula EMI1.1  wherein Z represents hydrogen or an ester protecting group; X (a) is a radical of the formula (i) -ORa, in which Re is hydrogen; (ii) -ORb, wherein Rb represents optionally substituted lower alkyl or optionally ring-substituted phenyl or a heterocycle, one or more substituents in the alkyl group being halogen, hydroxy, oxo, carboxy, carb (lower) alkoxy, carbamoyl, (lower) alkoxy, amino Represent (lower) alkylamino, di (lower) alkylamino, (lower) alkanoylamino or optionally substituted phenyl or a heterocycle, and wherein the substituents on the phenyl or heterocyclic ring are one or more radicals from the group hydroxyl, (lower) alkoxy, halogen, (Lower) alkyl, halogen (lower) alkyl, methanesulfonyl, oxo,  (Lower) alkylthio, amino, (lower) alkylamino, di (lower) alkylamino, (lower alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl); or (iii ) -OCORC, wherein Re represents amino, (lower) alkylamino, di (lower) alkylamino or optionally substituted (lower) alkyl, the substituents being as described under (ii);  or (b) a substituted (lower) aliphatic, (lower) cycloaliphatic or (lower) cycloaliphatic- (lower) aliphatic radical or a ring-substituted phenyl, phenyl (lower) alkyl, a heterocycle, heterocycyl (lower) alkyl, or heterocyclylthio (lower ) -alkyl, where substituents for the aliphatic, cycloaliphatic, phenyl or heterocyclic groups mentioned are the following EMI1.2  wherein R1 is hydrogen, (lower) alkyl or phenyl and R2 and R3 are independently hydrogen, (lower) alkyl, phenyl or benzyl; ; (ii) -ORd, wherein Rd is amino, (lower) alkylamino, di (lower) alkylamino, substituted (lower) alkyl, (lower) alkenyl or optionally ring-substituted phenyl, phenyl- (lower) alkyl, a heterocycle or heterocycyl (lower ) alkyl, and the substituents in alkyl, phenyl and heterocyclic groups are as defined under (a) (ii); (iii) -O (CH2) nORr, where n is an integer from 1-6 and Re is optionally substituted (lower) alkyl or optionally ring-substituted phenyl or a heterocycle, the substituents in the alkyl, phenyl or heterocyclic groups as under ( a) (ii) are defined; ; (iv) -OCORr ', where Rrt is amino, (lower) alkylamino, di (lower) alkylamino and has the meaning of Re, provided that Rrt cannot be unsubstituted (lower) alkyl; (v) -OSO3H; EMI1.3   (vii) -OSO2Rr, wherein R has the meaning given under (b) (iii); EMI1.4  wherein Re represents (lower) alkyl; (ix) S (O) nRd, where n is 0, 1 or 2 and Re for the case that n is 0 EMI1.5  means where R4 is hydrogen or (lower) alkyl and R5 and Re independently of one another are hydrogen or (lower) alkyl, provided that Rd cannot be unsubstituted phenyl; ; (x) -CORf, wherein Rf is amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) alkylamino (lower) alkyl, -NHNH2, -NR17NR18, -NHOR19, -S-R17> -O (CH2) nA-Re or -NReRg, wherein R17, R18 and Re are (lower) alkyl, R19 is hydrogen or (lower) alkyl, A is oxygen, sulfur, NH or NCH3 and n is the one mentioned under (b) (iii) Has meaning; (xi) PO (ORw) 2, wherein Rw is hydrogen or (lower) alkyl; ; (xii) -NHRh, where Rh is optionally substituted phenyl, an optionally substituted heterocyclic group, -CH = NH, -SO3H, -OH, (lower) alkoxy, amino, (lower) alkylamino, di (lower) alkylamino, -NHCOCH3, -CS2CH3, EMI1.6 EMI1.7  in which R7 and R8 independently of one another denote (lower) alkyl, phenyl or phenyl (lower) alkyl, EMI 1.8  wherein Rg means (lower) alkyl, phenyl or phenyl (lower) alkyl, or EMI1.9  wherein Ri amino (lower) alkyl, -NR2, (lower) alkylamino, di (lower) alkylamino, EMI1.10 EMI 1.11  in which Rlo denotes (lower) alkyl or optionally substituted phenyl or a heterocyclic group,  where the substituents in phenyl and heterocycle are defined under (a) (ü), EMI1.12  by amino, (lower) alkylamino or di (lower) alkylamino; (xiv) -NRjRk, wherein Rj (lower) alkyl and Rk (lower) alkyl, (lower) alkoxy, a heterocyclic group, amino, or EMI1.13  means, where Ri has the meaning given under (b) (xii) or together with the nitrogen Rj and Rk EMI2.1  , provided that when Rk is amino or -CH2CH2NH2, then Rj is methyl and also provided that Rj and Rk cannot both be (lower) alkyl; ; (xv) -NRj'Rk ', where Rj' (lower) alkoxy and Rk '(lower) alkyl, a heterocyclic group, amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) alkylamino (lower) alkyl or EMI2.2  means in which Ri has the meaning given under (b) (xii) or together with the nitrogen, Rj 'and Rk' EMI2.3  mean; (xvi) N0 + RiRmRn, wherein R1, Rm and Rn independently of one another (lower) alkyl or together with the nitrogen EMI2.4  represent; (xvii) -N = CH-Rx, wherein Rx is (lower) alkyl or optionally ring-substituted phenyl or a heterocycle, the substituents in the phenyl or in the heterocyclic ring being defined as under (a) (ii); ; (xviii) -N = CRxRy, wherein Ry is (lower) alkyl or optionally ring-substituted phenyl or a heterocyclic ring, the substituents in phenyl and heterocycle being as defined under (a) (ii) and wherein Rx as under (b) ( xvii) is defined; (xix) = N-Rp, where Rp is hydroxy, (lower) alkoxy, amino, di (lower) alkylamino or or EMI2.5  represents; EMI2.6  wherein n is an integer from 1-6 and Rt5 and R16 independently of one another are hydrogen or (lower) alkyl;  and Y is hydrogen or a radical from one of the following groups (a) an optionally substituted (lower) aliphatic, (lower) cycloaliphatic or (lower) cycloaliphatic (lower) aliphatic group, where one or more substituents are hydroxy, (lower) alkoxy, optionally substituted phenyloxy, optionally substituted heterocyclyloxy, optionally substituted (lower) alkylthio, optionally substituted phenylthio, optionally substituted heterocyclylthio, mercapto, amino, (lower) alkylamino, di (lower) alkylamino, (lower) alkanoyloxy, (lower) alkanoylamino, optionally substituted phenyl, optionally substituted heterocyclic group, carboxy, carb (lower) alkoxy, carbamoyl, N- (lower) alkylcarbamoyl, N, N-di (lower) alkylcarbamoyl, halogen, cyano, oxo, thioxo, -S03H, -OSO3H, - SO2- (lower) alkyl, (lower) alkylsulfinyl, nitro,  Phosphono or EMI2.7    (ORe), in which Re and Re have the meaning given and in which the substituents in (lower) alkylthio represent one or more of halogen, hydroxy, (lower) alkoxy, amino, (lower) alkanoylamino or optionally substituted phenyl or a heterocyclic group and the substituents in phenyl or heterocyclic group one or more of hydroxy, (lower) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, amino, (lower) alkanoylamino, (lower) alkanoyloxy, Are carboxy, carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl; ; (b) -ORe, in which Re denotes optionally substituted (lower) alkyl or (lower) alkanoyl or optionally substituted phenyl or a heterocyclic group, where one or more substituents in alkyl and alkanoyl, halogen, hydroxy, (lower) alkoxy, (lower ) alkylamino, di (lower) alkylamino, amino, oxo, (lower) alkanoylamino or optionally substituted phenyl or a heterocyclic group and one or more substituents in phenyl or the heteroclylic group hydroxy, (lower) alkoxy, halogen, (lower) alkyl , Halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, (lower) alkylamino, di (lower) alkylamino, amino, (lower) alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo (lower ) mean alkyl; (c) S (O) R ,, where n is 0, 1 or 2; (d) halogen;  and (e) optionally substituted phenyl or heterocyclic group, in which one or more substituents are hydroxy, (lower) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, amino, (lower) alkylamino, Are di (lower) alkylamino, (lower) alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl; or a pharmaceutically acceptable salt thereof, provided that when Y is hydrogen, X cannot be -CH20CH2CH20CH3.    2. A compound according to claim 1, wherein Y is hydrogen.  3. A compound according to claim 1, wherein Y is C1-C6 alkyl optionally substituted by hydroxy.  4. A compound according to claim 1, wherein Y is a-hydroxyethyl.  5. A compound according to claims 1-4, wherein X is EMI 2.8  wherein n is an integer from 1-6; (b) - (CH2) nNHOH, where n is an integer from 1-6; (c) - (CH2) nPO (O-C, -C6-alkyl) 2, where n is an integer from 1-6; EMI2.9  wherein n is an integer from 1-6; EMI2.10  wherein n is an integer from 1-6; EMI 2.11  where n and m are independent  gig are 1 or 2 and wherein RA and RB are independently hydrogen or (lower) alkyl; or EMI3.1  wherein n is an integer from 1-6 and RC Cl-C4-alkyl, phenyl or EMI3.2  means, where is 1 or 2.  6. A pharmaceutical mixture containing as an active component a compound according to claims 1-5 or a pharmaceutically acceptable salt or a physiologically cleavable ester thereof, together with a pharmaceutically acceptable carrier or diluent.  7. A process for the preparation of a compound of formula I, wherein Z is an ester protecting group and X and Y are as defined in claim 1, characterized in that a compound of formula EMI3.3  wherein Q is phenyl or (lower) alkyl, R "is an ester protecting group, is cyclized, working in an inert organic solvent at a temperature from just above room temperature to the reflux temperature of the solvent.  8. A process for the preparation of a compound of the formula I in which Z is hydrogen and X and Y are as defined in claim 1, characterized in that a compound of the formula I in which Z is an ester protecting group is prepared by the process in accordance with claim 7 and splits off the ester protecting group in the compound obtained.  The present invention relates to new 2-substituted and 2,6-disubstituted penem compounds with strong antibiotic activity, to a pharmaceutical mixture containing such a compound and to a process for the preparation of these compounds.  The penem ring system has the formula EMI3.4  and can be systematically called 7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene. For simplicity, it is referred to as 2-penem in the present description and the numbering used is as follows: EMI3.5 The present invention accordingly relates to the new penem compounds of the formula EMI3.6  wherein the substituents Z, X and Y have the meaning given in claim 1, and their pharmaceutically acceptable salts.  The compounds of formula I wherein Z is hydrogen (and their pharmaceutically acceptable salts and physiologically hydrolyzed esters) are effective antibacterial agents. The remaining compounds are useful intermediates for the production of the biologically active penems.  The substituent groups mentioned for the 2- and 6-position of the Penem ring system can be described in more detail as follows: (a) Halogen includes chlorine, bromine, fluorine and iodine. Preferred halogen substituents are chlorine and fluorine; (b) (Lower) alkyl includes both a straight chain and a branched chain saturated aliphatic hydrocarbon group with 1-6 C atoms included, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc. Preferred (lower) alkyl substituents have 14 carbon atoms and in particular 1 -2 C atoms; (c) (Lower) aliphatic means an acyclic straight-chain or branched-chain saturated or unsaturated hydrocarbon radical with 1-6 C atoms inclusive. The unsaturated radicals can contain one or more double or triple bonds, but either a double or a triple bond is preferred. Examples of (lower) aliphatic radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isobutyl, vinyl, I propenyl, 2-propenyl, isopropenyl, 2-methyl -2-propenyl, ethynyl and 2-propynyl. The most preferred aliphatic radicals are (lower) alkyl as in (b); (d) (Lower) cycloaliphatic means an alicyclic saturated or unsaturated hydrocarbon radical with 3-8 ring carbon atoms, preferably 3-6 carbon atoms. The unsaturated ring may contain one or more (preferably one) double bond (s). Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclopentenyl, 1,3-cyclohexadienyl and cyclohexenyl; (e) (Lower) cycloaliphatic (lower) aliphatic stands for cycloaliphatic-aliphatic radicals with 3-8 C atoms (preferably 3-6) in the cycloaliphatic ring and 1-6 C atoms (preferably 1 and in particular 1-2) in the aliphatic part. Examples include cyclopropylmethyl, cyclopropylethyl, cyclopropylpentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cy ** WARNING ** End of CLMS field could overlap beginning of DESC **.