BE897351A - CARBAPENEM DERIVATIVES, THEIR PREPARATION AND THEIR USE AS DRUGS - Google Patents

Abstract

The invention relates to compounds of formula (I), in which R1 signifies hydrogen or a methyl group and R2 signifies hydrogen or an optionally substituted saturated or unsaturated hydrocarbon residue. These compounds can be used therapeutically as drugs.

Description

       

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  Carbapenem derivatives, their preparation and their use as medicaments. Invention of: Ching Pong MAK and Hans FLIRI Claiming the priority of patent applications filed in SWITZERLAND on July 26, 1982 under number 4539/82, on September 24, 1982 under number 5654/82 and on December 31, 1982 under number 7648 / 82 on behalf of SANDOZ SA

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   The present invention relates to 6- (1-fluoroethyl) -et6- (l'-fluoro-1'-methylethyl) -carba- penemes, their preparation process and their use in chemotherapy.



   European Patent No. 1628 describes a large number of carbapenem derivatives having antibiotic activity, but makes no mention of the fluoroalkylated compounds of the present invention and of their advantageous antibiotic properties.



   The invention relates more particularly to the compounds of formula 1
 EMI2.1
 in which} - R-) represents hydrogen or a methyl group and R2 represents hydrogen or a lower alkyl group, a lower alkenyl group or a cycloalkyl group each of which may be unsubstituted or mono or poly-substituted by an amino group , mono or di- (lower alkyl) -amino, lower acylamino, carboxy, lower alkoxycarbonyl or carbamoyl;

   a group of formula IIc (CH2) p-R7IIC in which R7 represents a phenyl group "or a

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 5 or 6-membered sturated or unsaturated heterocycle containing 1 or more heteroatoms chosen from 0, Set / or N and which may be unsubstituted or mono or poly substituted by a fluorine, chlorine, bromine atom, an amino group, mono or di-lower alkyl) -amino, hydroxy, lower alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, guanidino, nitro, cyano, lower acylamino, carboxy, alkoxycarbonyl or carbamoy le and p means 0,1, 2 or 3;

   or a group corresponding to one of the formulas
 EMI3.1
 in which
 EMI3.2
 R4, R5 and R6 may be the same or different and 1 each represents hydrogen or a lower alkyl group or R4 and R6 and / or R5 and one of the CH2 groups may form a ring, as well as
 EMI3.3
 RS and R6 in formula II and R4 and R5 in formulas and IIb, these rings being able to be unrelated or mono or poly substituted by an alkyl, hydroxy, carboxyoudi- (lower alkyl) -amino group m means 2 or 3, and n means 1, 2 or 3

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 with the condition that when R-) represents hydrogen and the group which contains it has the R configuration, R2 is other than an acetylaminoethyl group;

   or protected forms and / or physiologically hydrolyzable and acceptable esters of these compounds; in the form of free acids or salts or in the form of amphoteric ions.



  The compounds of the invention can be prepared A) by introducing a -S-R2 group into a compound of formula III
 EMI4.1
 in which R-j and R2 have the meanings given above, R8 represents an eliminable group R3 represents a protective group or a physiologically hydrolysable and acceptable ester group or B) by exchanging the OH group in a compound of formula IV
 EMI4.2
 in which R., R and R3 have the meanings given above, or a precursor of this compound, by a fluorine atom and, where appropriate,

   by eliminating the protective group from the compound thus obtained or by converting the compound thus obtained into another physiologically hydrolysable and acceptable ester and / or in its protected form ------------------- -----------

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 and isolating the compound thus obtained in the form of free acid or salt or in the form of an amphoteric ion.



   Process A) can be carried out according to the usual methods, for example in an inert solvent such as an aromatic hydrocarbon, for example benzene, or acetonitrile, and preferably at reduced temperatures, for example at around 0 ° C. .



   Process B) can be carried out according to the usual methods, for example using a dialkylamino-sulfuryl trifluoride such as diethylamino-sulfuryl trifluoride quest.



   The removal of the protective groups is carried out according to the usual methods, as well as the isolation and the purification of the products obtained.



   The preparation and interconversion of esters, protected forms and salts is also carried out according to the usual methods.



   Processes for the preparation of carbapenems in their various forms are also described in the literature, for example in the publications of European patent applications Nos 1628, 10316, 17992,
37080.37081, 388869.50334, 33209, 44142, 60612, 61231, 44170.59478, 58317, and may if necessary be used in a similar manner for the preparation of the compounds of the invention.



   The starting materials of formula III are new and can be prepared by introducing the group R8 into a compound of formula V
 EMI5.1
 

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 in which Ri, R and R8 have the meanings given above.



   As an example of groups R8 which can be eliminated, mention may be made of those formed by the reaction of the hydroxy group with a phosphoric acid ester chloride, for example, with diphenyl chlorophosphate or with 1 sulfonic acid, for example with p-acid. -sulfonic toluene.



   The compounds of formula IV can be prepared analogously to that described for process A) mentioned above, from compounds of formula Va
 EMI6.1
 The process is conventional and includes the introduction of the Rg group and then of the -S-R2 group.



   The compounds of formula V are also new and can, for example, be prepared according to the following reaction schemes or in a manner analogous to the methods described in the reaction schemes mentioned above.
 EMI6.2
 

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 EMI7.1
 



  S CH2-C / J if CH 1 If a) j OH "OH CH3-C CH2-C 1 / f} - \? OH OH CH-C ---. --CH-.



  - d) N t 2 --------- OH CH - C -..-- CH.



  ) 1.



  OH CH3-C f) i 'R ..' NH 01 / J Y

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 EMI8.1
 F 1 CH? - 1 --- 2-H, R 1 CH-C ------- CH-COOH h) NU F 1., CH2-CO-CH2-COGR3 RI Of F 2 CH 3- U CH 2-0 C 0 0 R3 NH VI CH3-1 j) "--HFF t 1 k) OH el 3 R

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 EMI9.1
 REACTIONAL DIAGRAM 2: OH 1 CH - C --.----- CH. l RI 0 Si + OH 1 3 R CH 3-CH CO. CPI CH - C -----. . . -. . . l P'1 FN 'Si bi Si C) 2 F, 1 1 CH ------ p-CHCO. . -C -, ---, - CH. .



  R, --- R1 1). oh oh as in diagram 1 reaction 1 Y "" --- t-- (step j), - N - L - COOR "0 e) ii) F '-" Ri NL - CCOR RI

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The reactions indicated in these diagrams can be carried out according to the usual methods for the type of reaction concerned. The cyclization can for example be carried out in an inert solvent such as an aromatic hydrocarbon, for example benzene, in the presence of a catalyst based on a transition metal. Mention may be made of rhodium-n acetate or copper acetylacetonate as examples of catalyst based on a transition metal.



   The compounds of formula V and Va can exist in the following tautomeric forms
 EMI10.1
 
 EMI10.2
 The remaining products are either known r u 1 or can be prepared in a known intermediate method and / or as described below in the examples.



   Carbapenems such as those of the present application contain 2 centers of chirality in the cycle (5 and 6)
 EMI10.3
 
They can be present in the various configurations, as 6R, 5R, 6S, 5S, 6S, 5R or 6R, 5S isomers or as mixtures thereof. When the starting products used have a particular configuration, the final products obtained will have the same configuration, while the starting products

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 mixed will produce mixed end products. Thus the configuration of these compounds does not change during the reactions such as A) or B) described above. The mixtures of isomers can be separated according to the usual methods such as fractional crystallization.



   It is known that the biological activity can be attributed to the compounds, in which position 5 has the R configuration.



   There is another center of chirality when R-j represents hydrogen and it remains unchanged during the reactions, such as A) described above.



  However, in reactions such as ion), where fluorine is introduced, the inversion occurs. Consequently, by fluorination of an 8-R-hydroxy starting product, an 8-S-fluoro end product is obtained and vice versa.



   The compounds of formula 1 in free form or in the form of an easily separable ester can be used as chemotherapeutic agents, in particular as antimicrobial agents as indicated by their inbibitatory action on various bacteria, (for example Pseudomonas aeroginosa, Enterobacter cloacae,
 EMI11.1
 Enterobacter Streptoçoccus Aerococcus tococcuspyogenes, agglomerans, Staphylococcus epiidermiidiis, coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Klebsiella pneumoniae, Serratia marcescens and Salmone'la typhimurium), for example a series of tests, for example a series of tests, 0, 001 and 50 1g / ml, and by in vivo tests in 1 smile, at doses included,

   for example between about 0, 1 and 100 mg / kg.

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   The compounds of the invention also exert an inhibiting effect on ss-lactamases at concentrations of between 0.1 and 10 μg / ml.



  The enzymatic activity of preparations of ss-lactemases of gram-positive and pram-negative bacteria can be tested using nitrocefine as the chromogenic substrate (Publication by CH 0'Callaghan et al., In Novel method for detection of -tactamases by using a chromogenic cephalosporin substrate; Antimicrobial Agents and Chemotherapy, Vo. 1, NO 4, 283-288 / 1972). The inhibition of s-lactamases is determined in a 0.1 M phosphate buffer solution (pH = 7) using the same substrate.

   The enzymes are preincubated with the inhibitors at 25 ° C. and at appropriate concentrations or the inhibitors and the substrate (nitrocefine) are simultaneously added and the inhibition of the hydrolysis of the substrate caused by the inhibitors is measured by comparison with non-hydrolysis. -inhibited. The activity is expressed in% inhibition or in IC50 (= concentration of the inhibitor, which inhibits 50% of the enzyme). This inhibition effect is also apparent in the marked synergy demonstrated with other lactam antibiotics on bacteria producing lactamases. The compounds of the invention are stable with respect to the lactamases.



   The compounds of the invention can therefore be used in chemotherapy, in particular as active antibacterial antibiotics.



   For this use, the appropriate daily dose is between approximately 1 and 6 g, advantageously administered in divided doses 2 to 4 times per day, the daily doses containing approximately 250 to 3000 mg, or in the form of delayed release.

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   The compounds in free form can be used in this form or in the form of a chemotherapeutically acceptable salt, these forms having the same type of activity as the free forms. Suitable salts include the alkali and alkaline earth metal and ammonium or amino acid salts.



   The compounds can be combined with usual chemotherapeutically acceptable vehicles or diluents, and can be administered in the form of tablets, capsules or in parenteral form.



  Such compositions are also part of the present invention.



   The lower alkyl groups contain from 1 to 6 (for example from 1 to 4) carbon atoms, in particular 1 or 2 carbon atoms. Of the same
 EMI13.1
 way, the alkenyl and alkynile groups contain from 2 to 4 carbon atoms, in particular from 2 to 3 carbon atoms. Cycloalkyl groups preferably contain 3 to 6 carbon atoms.



  By lower acylaminoalkyl group is meant for example -CHCH. NH. CO. CH, -CH - CH; NH. CO. CH2. C6H5 NH. CO. CH2CH2. NH2 -
 EMI13.2
 

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Heterocycles like R7 include, for example
 EMI14.1
 and morpholino
The protective groups are those usually used in antibiotic chemistry to protect the OH and COOH groups. They include the groupesp-nitro-
 EMI14.2
 benzyl, p-nitrobenzyloxycarbonyl, dimethylsilyl and trimethylsilyl.



  Physiologically t-butyl-hydrolyzable and acceptable ester groups (also known as easily separable ester groups) are those which are hydrolyzable under physiological conditions to give bases which themselves are physiologically acceptable; such esters. include acetoxymethyl, 1-acetoxyethyl, 1-ethoxycarbonyloxyethyl, 5-indanyl or preferably pivaloyloxymethyl,
 EMI14.3
 hexanoyloxymethyl, phthalidyl, ethoxycarbonylmethoxymethyl or 3-ethoxycarbonyl-1-acetonyl.



   Certain protecting groups can also be physiologically hydrolyzable and acceptable groups and vice versa.

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 EMI15.1
 



  The preferred substituents are R1 = a) H b) CH3 R2 = a) a lower alkyl group or optionally mono or disubstituted by an amino, mono or di- (lower alkyl) -amino, acylamino, carboxy group; b) - (CH2) p-R7 c) II, lia or II b preferably lia R4, R5, R6 = a) H, an alkyl group, in particular a methyl group b) closed rings R7 = a) heterocycles individual as listed above b) a methyltetrazolyl group, morpholino p = 0, 1, 2,3 or preferably 0 or 2 m = 2 or 3 preferably 2 n = -1, 2, or 3 preferably 1
The combinations of these meanings and of the preferred forms are particularly advantageous. Mention may be made, as examples, of the compounds in which R'j represents hydrogen or a methyl group;

     R2 represents a lower alkyl group, or optionally mono or disubstituted by an amino, alkylamino, dialkylamino, acylamino, carboxy, imino, alkylimino and / or a heterocycle group, for example a methyltetrazolyl or morpholino group.



   Examples of groups of particular compounds of formula I are those in which R1 represents hydrogen and R2 represents hydrogen,

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 a lower alkyl, lower alkenyl, or cycloalkyl group which may be substituted by an amino, mono or di- (lower alkyl) -amino, acylamino group
 EMI16.1
 lower, carboxy, alkoxycarbonyl or carbamoyl, nitrogen being able. be part of the ring when the cycloalkyl group is substituted by an amino or mono or di- group;

   or a group of formula II or IIa, in which R3, R4 and R5 may be the same or different and represent hydrogen or a lower alkyl group, m and n have the meanings given above and the carboxy group in position 2 is under free or protected form or in the form of an easily separable ester or in the form of a salt having an organic or inorganic cation (Group of compounds PI (2)).



   Another group is that in which R 1 represents hydrogen or a methyl group, R 2 represents hydrogen, a lower alkyl group, a lower alkenyl group, or a cycloalkyl which may be substituted by an amino group, mono or
 EMI16.2
 di-carboxy, alkoxycarbonyl which can be part of the ring when the cycloalkyl group is substituted by an amino or mono or di- (lower alkyl) -amino group; a group of formula - (CHp) p-Ry, in which p signifies 0, 1, 2 or 3 and R7 represents a phenyl group or a 5 or 6-membered saturated or unsaturated heterocycle containing one or more heteroatoms chosen from 0, S and / or N;

   or a group of formula II or III, in which R4'RS and R6 can

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 be the same or different and represent hydrogen or a lower alkyl group, m and n have the meanings given above and the carboxy group in position 2 is in free or protected form or in the form of ester-easily separable or in the form of a salt having an organic or inorganic cation. (Group of compounds P3).



   Particularly preferred compounds are (5RS, 6RS) -1-aza-6- (1 (RS) -fluoroethyl) - 3- (N-dimethyl-N'-methylamidinomethylthio) -7-oxobicyclo L3 acid. 2. 0] hept-2-ene-2-carboxylic acid and acid (5RS. 6RS) -
 EMI17.1
 1-aza-6- thio)
The following examples illustrate the invention in which the temperatures are expressed in degrees celcius.
 EMI17.2
 

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 EMI18.1
 



  EXAMPLE 1 (5RS, 6RS) -1-aza-6-n benzyloxycarbonyl) 2.



  4-nitrobenzyl 2-ene-2-carboxylate (process a) To an ice-cooled solution of 90 mg of (5RS, 6RS) -1-aza-3, bicyclo [3. 2.0) 4-nitrobenzyl heptane-2-carboxylate in 20 ml of anhydrous acetonitrile, 0.06 ml of diisopropylamine and then 0.06 ml of diphenyl chlorophosphate are added. After 15 minutes at 0, 0.06 ml of diisopropylamine is again added and then 73 mg of 4-nitrobenzyloxycarbonylcysteamine in 5 ml of anhydrous acetonitrile. Stirring is continued for 1 hour at 0, then the ethyl acetate and aqueous saturated with NaCl are distributed. organic to dryness, the residue is chromatographed on a gel of: ethyl acetate / -, ether. diisopropyl = 9/1).



  RM), 1 7 (dq, 13 1 6 id, 1, J = 13, - 7Hz); 5, 2ó (d, 1, J 5, J = 5 Hz); 7, 2, J = 9riz); 7.68 (d, = 9 Hz); 8, (d, 4, J Removal of the protective groups to obtain the (5RS, 6RS) -3- 6- [1 carboxylic acid can be carried out as follows: Hydrogenation is carried out for 30 minutes at ambient temperature and under a hydrogen pressure of 3 bars a suspension of 50 mg of (5RS, 6RS) -1-aza-6- [3- aminoethyl ') 4-nitrobenzyl and palladium xylate on

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 EMI19.1
 10% carbon in 20 ml of tetrahydrofuran and 10 of water, in the presence of 5 ml of a 0.5 M buffer solution of 3-morpholino-propane-sulfonic acid (pH 7). After filtering the catalyst and washing the residue with water, the filtrates are combined, the overall phase is extracted with ethyl acetate and the aqueous phase is lyophilized.

   The lyophilisate thus obtained is purified by chromatography on XAD 2 (eluent: water).



  The fractions exhibiting extinction in the ultraviolet at 300 nm are combined and lyophilized, which
 EMI19.2
 gives the title product. UV spectrum (pH 7 buffer): Ji mex = 295 nm (= 8000).



  EXAMPLE 2 (5RS, 6RS) -3-! ne 4-nitrobenzyl 2-carboxylate a) To an ice-cooled solution of 150 mg of (5RS6RS) methylethyl) 2. 0-heptane-2-carboxylate of (2-acetylaminoethylthio) -1-aza-6- (1- 4-nitrobenzyl in 10 ml of anhydrous acetonitrile, 0.11 ml of N-ethyldiisopropylamine is added, then 0.13 ml of diphenyl chlorophosphate. After 15 minutes at 0, another 0.22 ml of N-ethyldiisopropylamine is added.
 EMI19.3
 then 70 mg of N-acetylcysteamine in 5 ml anhydrous. The mixture is stirred again for 1 hour at 0 and the residue is distributed again, between acetate and a saturated aqueous solution of Nacl. The organic phase is dried over MgSO4 and evaporated to dryness.

   The residue is chromatographed on silica gel (ethyl acetate / acetone = 7/3).

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   EXAMPLE 3 (5RS, 6Rs) -3- (2-acetylaminoethylthio) -1-aza-6- (1-fluro-1-methylethyl) -7-oxobicyclo [3.2.0] hept-2- ene-2-carboxylate 4-nitrobenzyl (process b)
 EMI20.1
 To a cooled solution 0.12 ml of diethylamino-sulfuryl trifluoride 75 mg of potassium fluoride in 5 ml of anhydrous dichloromethane is added a solution of 150 mg of (5RS, 6SR) - 3-methylethyl) 4-nitrobenzyl xylate in 5 ml of anhydrous dichloromethane. The mixture is stirred for 15 minutes at -780 and then mixed with water. After adding dichloromethane, the phases are separated, the organic phase is washed with a saturated NACI solution, dried over MgSO4 and evaporated to dryness.

   The residue is chromatographed on silica gel (ethyl acetate / acetone = 7/3), this yes gives the compound
 EMI20.2
 of the title. F = 206-2100.



   Analogously to the examples above, or retort described above, the following compounds of formula I can be prepared:
 EMI20.3
 

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 EMI21.1
 (Configuration: 6RS, 5RS R3 = H: 8RS):
 EMI21.2
 Ex. Rl.



  "" "s'ico-chimtjUes.



  4 5 Ma-CHCH-.



  2 - "'02 - Ct-2C" 2- 7 Na N == N 8 Na - aCHNN -. / 1 CH3 9 Na - "- CH n-x295 10 .-.



  K (CH-) ,, N -CF OXNa 12 / .. -C \ 3 QNH 14 H? 2'N 3) ru / 3 'CH 15 H-CHLCH n-ax-294 -, NH' '' 2-23 17 - "-" - c- -. -oeo. - / ..



  17 3] 18 - "- //: -" KCL

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 EMI22.1
 , 02 - 19 \, CH Y 20 - "- '2-- CH 21 -" --- L / = \ e 22-CLrA /)'.



  \ LZ /)
 EMI22.2
 EXAMPLE (5 R, 6R) -3- ì-oxobicyclo [3. of 4-nitrobenzyl The product is obtained by proceeding in a manner analogous to that described in Example 1.



  EXAMPLE 24 Sodium salt of the acid, no thio) -1-aza-E [1 2. 0Jhept- 2-ene-2-carboxyl The product is obtained by proceeding in a manner analogous to that described in Example 1. max rlax 298.



  EXAMPLE (+) - R) -f1uoroêthy1] -3- oxycarbonyl) -2- bi 2. 0] -hept-3-ene-2-carboxylate To a solution 4 mg dioxo-6-carboxylate of 4-nitrobenzyl formamide is added with stirring 0.506 ml of diisopropylethylamine and 0.486 ml of diphenyl chlorophsphate. The reaction mixture is allowed to stand

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 for 30 minutes at -30 and mixed with 0.404 ml of diisopropylamine. Then a solution of 1.016 g of N- (4-nitrobenzyloxycarbonyl) -D-cysteine in 4 ml of anhydrous dimethylformamide is added dropwise, the mixture is stirred for 30 minutes at -30 and diluted with 200 ml of dichloromethane.

   The organic solution is washed successively with 140 ml of 0.1 M phosphate buffer each, pH 8.4, pH 6.9 and pH 8.4, and dried with Na SO 4.



  This solution can be used for the preparation of optical isomers.



   [The racemic can be obtained by filtration
 EMI23.1
 of the dichloroethane solution concentrating under vacuum up to approximately 20 ml and by chromatography the residue on silica gel (benzene / ethyl acetate = 3/1). The Rf 0.30 fractions under UV light (benzene / ethyl acetate = 2/1) are collected and dried.



   For the preparation of the isomer, the dichloromethane solution is evaporated to dryness, the residue is washed with 20 ml of chloroform and dried. The filtrate is evaporated until a syrup is obtained and it is chromatographed on silica gel (eluent: benzene / ethyl acetate = 3/1). The fractions are combined and evaporated to dryness under reduced pressure. We treat
 EMI23.2
 the residue washes it with 10 ml of chloroform. A pale yellow amorphous powder is obtained; [aj = + 27.9 (c = 0.5 in the JD with 5 ml of chloroform, filtered and ondichloromethane). For further purification, this powder is dissolved in 20 ml of dichloromethane and filtered.

   The filtrate is concentrated to approximately 1 ml and is then treated with 1- 2 ml of chloroform, which
 EMI23.3
 2 3 gives an amorphous, pale yellow powder; [a] - = + 290 D (c = 0.5 in dichloromethane).

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 EMI24.1
 



  NMR SPECTRUM Examples: Spectra: 2, 1, 49 (d, 3, J = 20 Hz) j. (d, 3, J = 20 Hz); 2 ,. (s, 3); 2.87- (CDCt) 3.53 (m, 7); 4.10 Hz, 2.7); 5.25 (d, 13.7 Hz); 5.52 (d, 1, J = 13.7 Hz); 5.89 z r, 1); 7.67 (d, 2, J = 8 Hz); 8, 24 (d, 2, J 4 1, 52 (dd, 3, J = 25 and 6 Hz); 2, 7-3, 6 (m, 7); 4, 26 (tm, (CDC) 7 Hz ); 4, 98 (dq, 1, J = 48 and 7 Hz); 5, (s, 2); 5, 26 (d, 1, J = 13, 5 Hz); 552 (d, 1, J = 13.5 Hz); 7.53 (d, 2, J Hz); 7.68 (d, 2, J = 9 Hz); 8.25 (d, 4, J = 9 Hz).



  5 (d, 3, J = 5 Hz); 1.74 (d, 3, J = 22,; 2.00 (s, 3); (D20); 3, J = 17.9 Hz); 3, 23 (dd, 1, J = 17, 5 and 9, 5 H; 3, 42 (t, 2, J = 6, 65 (dd, 1, J 17, 5 and 9, 5 Hz); 3, 42 (t, 2, J = 6.5 H; 3.65 (dd, 1, J = 01 and 2.5 Hz); 4.5 and 2.5 Hz).



  6 1, 42 (dd, 3, J = 24 and 7 Hz); 2, 4, J = 4.5 Hz): 2.60 (t, (CDC! = 7.5 Hz); 2.94-3.10 (m, 2) DMSO-d6) = 4.5 Hz) ; 3.66 (ddd, 1, J = 25.6 and 2.5 Us), 23 (td, 1, J = 2.5 Hz); 5.03 (dq, 1, J = 49 6 Hz); 5.27 (d, 1, J = 14 Hz); 5.45 (d, 1.14 Hz); 6.88 (1r, 1); (d, 2, J 9,; 8, 20 (d, 2, J 9, 5 Hz).



  758 (dd, 3, J = 25 and 6.5 Hz) 3.06-3.76 (m, 11) 12 (D 4); 4.48 (td, 9 and 3 Hz) 5.28 (dm, 1, J = 52 Hz).



  8 43 (dd, 3, J = 26 6.5 Hz); 2.59 (s, 3) (dd, 1, J = 18 9 Hz); 3, 02 1, J = 18 and 9, Hz); 3, 56 (ddd, 1, J 27, 5; 4, 09 (ld, 5 and 2, 8 Hz); 5, 12 3 d. 1 1, in

  <Desc / Clms Page number 25>

 
 EMI25.1
 10 1 45 (dd, 3, J = 25 and 6.5 Hz); 2.90-3.03 (m, 12); 3.07-3.57 O) (m, 6); 3.67 (ddd, 1, J = 28.5 and 2 Hz); 4.29 (td, 1, J = 9 and 2.5 Hz); 5.14 (dm, 1, J = 49 Hz).



  11 41 (dd, 3, J = 6 and 25 Hz); 2.80-3.65 (m, 5); 3.75-3.97 (m, (DO); 4.29 (dt, l, J = 8.5 Hz); 5.11 (m, 1, J 6, 7.5, and 48.8 Hz) ; 12 1, 46 (dd, 3, J = 24 and 7 Hz); 3, 10-3 57 (m, 11); 3, (CDCI- / J = 24, 6and 2, 5 Hz); 4, 15 (d, J = 12.5 Hz); 4.27 (d, 1, J DMSO-d6) 12.5 Hz); 4.33 (td, 1, J = 5 Hz); 5.05 (dm, 1, J 49 Hz); 5.29 (d, 1, J = 14 Hz); 5.51 (d, 1, J = 14 Hz); 770 2, J = 9 Hz); 8.28 (d, 2, J = 9 Hz); 8, 1).



  13 1, 46 (dd, 3, J 25 ônd; 3, 12 (s, 3); 3, 15 (s, 3); 3, 25 (DyO) (dd, 1, J = 18 and 9 Hz); 3.32 (dd, 1, J = is and 10 Hz); 3.



  (s,; 3, 71 (ddd, 1, J = 27, 5 and 2, 8 Hz); 4, 01 12, 5; 4, 09 (d, 1, J 12, 5 Hz); 4, 35 5 and 2.8 Hz); 5, 25 (dm, 1, J = 49 14 1, 44 (cd, 3, J = 25 and 6, 5; 3 J. (d, 2, J = 9, 3, 17 (DO) 3); 3 , 30 (s, 3); 3 J1 (ddd, 1, J = 28, 5 and 2.5 Hz); 00 (s, 2); 4, 31 (td, 1, J = 9, 5 and 2, 5 Hz); 5.15 (dm, 1, J = 49 Hz).



  16 0.70-1 5 (m, 3); 1, 22-1, 60 (m,; 1, 52 (dd, 3, J = 25 and (CDCI) 7 Hz). 00 (m, 2): 3. 8 J = 9, and 2, 5 Hz) ; 5.02 (dm, 1, J = Hz); 5.26 (d, J = 12.5 Hz); 5.52 (d,; 7.68 (d, 2, J = 9 Hz); 8.26 (d, 2, J 9 Hz).



  17 0.8-1.02 (m, 3); 1, 20-1, (m, 6); 1.51 (d, 3, = 25 Hz); (CDCI (d, 3, J = 21.5 Hz); 2, (t, 2, J = 7 Hz) (dd, l, 16 und 7 33 (dd, l ,. J = 16 and 8 Hz); = le and 3 Hz) 4.32 (dt ,. 1, J 3 Hz); 27 (d, l, J; lr = width

  <Desc / Clms Page number 26>

 
 EMI26.1
 5.55 (d, 1, J = 14; 7.70 (d, 2, J = 9 Hz); 8.26 (d, 2, J 9 Hz).



  18 1.51 (dd, 3, J = 5 and 7 Hz); 2.0-2, (m, 2); 2, 64-3 /) (m, (CDC) 1); 3J10-3, (m, 5); 4.0-4.9 (m, 2.5); 5, 1-5, 64 (m, 6, 5); 7, 34-7, 67 (m, 6); 8, 04-8, 36 (m, 6).



  19 1, 20-1, 37 (m, 3); 50 (dd, 3, 1 = 24 and 8 Hz); 2, 62-3, 56 (COC) 6); 3, (m, 1); 4.80-5.32 (m, 1); 5.22 (s, 2); 5.28 (d, 1, J = 14.5 Hz); 5.54 (d, 1, J = 14.5 Hz); 7.52 (d, 2, J = 9 Hz); 7, 70 (d, 2, J = 9 8, 26 (d, 4, J 20 1, 48 (d, 3, J = 21, 5 Hz); 1.56 (d, 3, J = 21, 5 Hz); 2, (s, 3); 70-3, 53 (m, 5); 4.25 (td, 1, J 2, 5 Hz); 431 3 3 = 7; 5.28 (d, 1 , J = 13.5 Hz); 5, (d, 1, J =; 7.68 (d, 2, J Hz); 8.28 (d, 2, Hz).



  21 1, (dd, 3, J = 5 and 6.5 Hz); 2.56 (s, 3); 2, (CDC!)) (Td, 1, J = 2.5 Hz); 4.30-4; (m, 2); 5.12 (dm, 1, J = 49 Hz); 5.27 (d, 1, J = 14.5 Hz); 5.49 (d, 1,; 7.67 (d, 2, J = 9 Hz); 8.27 (d, J = 9 Hz).



  72 1.45 (dd, 3, J = 24 and 6.5 Hz); 3.11 (s, 3); 3.23 (s, 3); 3, 30- (CDCI! /; 3, 71 (ddd, 1, J = 25, 5. 2, 5; 4, 26 (s, 2); DMSO-d 10 and 2, 5; 5, 04 (dru , 1, J = 48 Hz); 30 (d, 1, J = 15 Hz); 5, 50 (d, 1,. 1 15 Hz); 7.72 (d, 2, J = 9 Hz); 8 , 25 (d, 2, J = 9 Hz); 9, 03 (br, 9, 75 (1 r, 1).



  23 1, 57. (dd, 3, J = 23, 5 and 6, Hz); 2.0 (s, 3); 2, 87-3, 74 (CDCI / 4, = 9 and 2.7 Hz); 5.02 (dm, 1, J = 49 Hz); 5, Aceton-dJ; 5 ,, (d, 1, J = 16 Hz); 6.78 (li, 72 (d, 6 2, J = 9 Hz); 8.28 (d, 2, J = 9 Hz).



  The required starting materials can be prepared as follows: lr

  <Desc / Clms Page number 27>

 
 EMI27.1
 A) (5RS, 6RS) -1-aza-3, bicyclo [3. 2. 0-4-nitrobenzylheptane-2-carboxylate (for 4, 6-8, 10-16, 18, 19, 21): [1-step reaction scheme g) to k)] a) (3RS, 4RS) - 3-
3yl benzyl acetate
To a solution cooled to -780 of 1.5 ml of diethylamino-su1furyl trifluoride in 4 ml of anhydrous dichloromethane is added a solution of 2.52 g of (3SR, 4RS) -3- [1 (SR) -hydroxyethyl] Benzyl -2-oxoazetidine-4yl-acetate (prepared analogously to that described by DG Melillo et al. In Tetrahedron Letters 21, 2783 [1980J) in 4 ml of anhydrous dichloromethane.

   The mixture is stirred for 5 minutes at -780 and mixed with an excess of cold saturated NaHCO3 solution.



  After further adding dichloromethane, the phases are separated, the organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel (cyclohexane / ethyl acetate- 2/1), which gives the title compound. 40-43 '.



  Specters:
 EMI27.2
 !. (CHCi) 3'ei, = 2, 5 63 (d I, J, 5 C2 5, 97 E 3 b) Acid (3RS, 4RS) -3- thyn-2-cxoazêtid-ineb) Acid (¯3RS , 4RS) -3- [-I (RS) -fluo-i-o'fthyll-2-oxoazÉtiJ-ire--: 1764-yl-acetic
Hydrogenation is carried out for 30 minutes, under a hydrogen pressure of 10 bars, a mixture of 700 mg of corresponding benzyl ester and 50 mg of 10% palladium on carbon in 50 ml of ethanol. By filtration and concentration of the filtrate to dryness, the compound is obtained
 EMI27.3
 of the title.

   F = ze

  <Desc / Clms Page number 28>

 
 EMI28.1
 Spectra JR RM '(-DC! RMN (CDC. 00) 5 9 5 Cu (ddd, 5, 53), c) [' 3RS, 4RS) -3-EI (RS) -fluoroethyll-2-oxoazé-tidine- 4yl] -2-oxo-butyrate A solution of 352 mg of acid (3RS, 4RS) -3El (RS) -fluoroethyl} in 15 ml of anhydrous tetrahydrofuran is stirred for 5 hours at room temperature. with 359 carbonytdiimidazole. A solution of 995 mg of mono-4-nitrobenzyl malonate in 15 ml of anhydrous tetrahydrofuran anhydrous magnesium ethanolate is mixed during this time and the mixture is stirred for one hour at room temperature. The two solutions are combined and stirred for 16 hours at room temperature. The mixture is diluted with 1 and washed with a 0.1 N solution of HC1.

   The aqueous phase is again extracted with ethyl acetate, the extracts are combined, dried and evaporated to dryness. 0n on gel of what gives the title. F = 115-118.



  Specters:! CL). - ,. '350 IL, -1, 2 s, 10, 4, 2 R'-) 7 66 -5, 9 (ded, J -' I '.



  J, 93 S,; * "J &num;}.) J = 9 Hz).

  <Desc / Clms Page number 29>

 
 EMI29.1
 d) S3RS, 4RS) -3- ylJ of 4-nitrobenzyl
To an ice-cooled solution of 469 mg of (3RS, 4RS) -3- [l (RS) -fluoroethyl] -
 EMI29.2
 2-oxoazetidine-4-yl-4-nitrobenzyl and 374 mg of 4-carboxy-benzene-sulfonyl azide in (2-oxo) butytate of 15 ml of ethyl acetate is added in part 0.67 ml of triethylamine. After removing the cooling bath, stirring is continued at room temperature. The precipitate which is filtered is filtered. formed and the filtrate is washed once with a saturated NaHCO3 solution and dried over MgSO4. The title compound is obtained by removing the solvent. F = 138-141.



  Specters
 EMI29.3
 IR B) '),, 35, p.M-j (CDCI): 1145 (dd, 3, J = 23, 7 Hz); 3.; 3, J = 18.10 Hz); 03/04 03.06 (drJ, 1, J = IB, 1.5 Hz) i 3 L 2; 98; 5, 2); (,, 1); 7.9 Hz); 8, 2, J 9 Hz). e) (5RS, cyclo [3. e-2-carboxylate) A suspension of (3RS, 4RS) -3- 2-oxoazetidine-4-yl- of 4-: 34nitrobenzyl and 2 is heated for 5 minutes under an argon atmosphere. mg of rhodium-II acetate in 5 ml of anhydrous benzene After cooling to room temperature, the catalyst is filtered and the filtrate is evaporated to dryness The title compound is obtained in the form of a colorless foam.

  <Desc / Clms Page number 30>

 
 EMI30.1
 



  Specters:! C) D'-i3 3, i 21 1, 7 is, 5, -7, 5 2, 9Àel R.'N) 2 (dd, 5,, = IS, 2 EC, J = SJ = 125 58 (d , 2, J = 9; E29 B) (5RS, 6RS) -1-aza-3, bicyclo [3.20.0 4-nitrobenzylheptane-2-carboxylate (for examples 2, 5, 9, 17 and 20 ): [(scheme L nel 1 steps a) to k)] a) 2-oxo-3-trans- (1-hydroxy-1-methylethyl) -4- s silyl) azetidine To a solution of 10, 1 9 of diisopropylarmne in 500 ml of anhydrous tetrahydrofuran is added to - 75 ml of a 1 N solution of n-butyllithium in hexane. After 20 minutes, 20 g of 1-tert are added. butyidimethyl-2-oxo-4- 2-y1-methyl) -azêtidi 20 minutes, The reaction mixture is diluted with 500 ml of saturated NHCI solution and extracted with ethyl acetate. By drying and concentrating the extracts, the title compound is obtained.



  NMR--) (s, 15); 098 0 80-2, jl? 4 (s, 3); il 2): 2. 34 I. 0 3-300 3} (s, 1); 3, 1). b) butyldimethylsilylazetidine The mixture is heated for ') hour at reflux 28 9 of 2-oxo-3-trans-silyldiithianne-2-yl-nethyl) -1-azetidine, 23, 65 9 of red mercuric oxide and 43 g of

  <Desc / Clms Page number 31>

 mercuric chloride in 400 ml of 95% methanol. After filtration of the mercury salts, the filtrate is concentrated and the residue is distributed between ethyl acetate and a saturated NH4Cl solution. By drying and concentrating the organic phase, the title compound is obtained
 EMI31.1
 as a colorless oil.



  NHN) (d, J, J = 2 Hz) 53; 3J28; 3J P6 c) L1-tert-butyldimethylsilyl-2-oxo-3-trans- (1-hydroxy-1-methyl-ketic acid) The mixture is heated to reflux with trimethylsilyl-1-tert. Hutyldiethylsilylaz2tidine-4-yl-methylJ-ketone in 120 ml methanol with 10 ml of 30% hydrogen peroxide. After concentration to dryness, the residue is taken up in ethyl acetate; extracted twice with 5% aqueous NaHCO 3, and the aqueous phase is again extracted with ethyl acetate. We cover the phase
 EMI31.2
 aqueous with ethyl acetate, the pH is adjusted to 3.5 with HCl half-concentrated and after separation of the ethyl acetate phase is extracted again 2 times with acetate ethyl.

   After drying and removing the solvent from the combined ethyl acetate extracts, the title compound is obtained in the form of a colorless oil.
 EMI31.3
 



  Rr'ù'l ')' f '. r (cdJ, 9) J = 's9 C; 3, and i t'G and Hz).

  <Desc / Clms Page number 32>

 
 EMI32.1
 d) [1-tert-butyldimethylsilyl-2-oxo-3-hydroxy-1-methylethyl) benzyl 5 g of butyldimethylsilyl-2-oxo-3-trans-ethyl) azetidine-4-yl] -acetic acid are rapidly mixed , benzyl alcohol and 300 mg of 4-dimethylaminopyndine in (30 ml of anhydrous dichloromethane with a solution of 4 g of dicyclohexylcarbodiimide and the mixture is further stirred for 2 hours at room temperature. After addition of 50 ml of ether and 50 ml diisopropyl ether is filtered, the residue is washed carefully with ether and the filtrate is evaporated to dryness. The residue is chromatographed on a small quantity of silica gel, which gives the title compound in the form colorless oil.
 EMI32.2
 



  R 6 2 r.



  31 1lc-2 and 4 (cd, '2etIGHr) 2,.,) 1), 7H 3 l, 10 e) [4-yl] -acetate To an ice-cooled solution of 3.7 g of 1- tert. butyl dimethylsilyl-2-oxo-3- (COC) benzyl acetate in 130 ml of a 9/1 mixture of methanol and water is added 6.6 ml of concentrated HCl.



  This mixture is stirred for 30 minutes at 00 and for 3 1/2 to 25 hours. The solution is concentrated and the residue is taken up in ethyl acetate, then it is washed once with an aqueous solution of Nail, it is dried over Mecs04 and evaporated to dryness, which gives 1

  <Desc / Clms Page number 33>

 
 EMI33.1
 composed of the title RMK 34 4 3, f li). 1 1 8 6, 3 and 3 7 7, f) [(CDC14-yl] -benzyl acetate
To a solution cooled to -78 of 3 ml of diethylamino-sulfuryl trifloride and 1.7 g of potassium fluoride in 80 ml of dichloromethane is added
 EMI33.2
 a solution of 3.29 of [methylethyl) benzyl in this mixture is stirred for 15 minutes at -78 and mixed with water.



  After further adding dichioromethane, the phases are separated and the organic phase is washed with a saturated NaCl solution, dried over MgSO and evaporated to dryness. The residue is chromatographed on gel
 EMI33.3
 of silica which gives Specters: td, 3, i = 21, 5 3 1, J, 2 e-, 4, c7 Fiz 2 t 9 k 21). - 5 C2, 2) l, 5 <, 'g) 2- (Acetoxoazetidine-4-yl] -acetic acid
Hydrogenate for 3 1/2 hours under a hydrogen pressure of 1 bar a mixture of 1 g of [(3RS, 4RS) -3- (1-flouro-1-methylethyl) -2-oxoazetidine-4-yl} benzyl acetate and 0.5 g of 10% palladium on carbon in 80 ml of methanol. By filtration and concentration to dryness of the filtrate, the title compound is obtained. F = 118-122.

  <Desc / Clms Page number 34>

 
 EMI34.1
 



  R'- " </ DSO-d) 3 52 2 257 2 and 54 J = 23, 3, and 2 .. j and 2, it h) [(CDC. 2-oxo: 4-nitrobenzyl butyrate
700 mg of [(3RS, 4RS) 3- (1-fluro1-1methylethyl) -2-oxoazetidine-4-yl] acetic acid are dissolved in 20 ml of tetrahydrofuran, mixed at -200 with 600 mg of carbonyldiimidazole and shakes for 3 hours at +200. Meanwhile, we put in
 EMI34.2
 sus-ension 900 mg of malonate suspension and 420 mg 900 mg of. 4-nitrobenzyl malonate of magnesium ethanolate in 20 ml of tetrahydrofuran and the mixture is stirred for 3 hours at room temperature. The two solutions are combined and stirred overnight. The mixture is then poured onto ether and extracted with a 1N solution of HC1 and water.

   By drying the organic phase, then chromatography on a residue column to obtain the title compound.
 EMI34.3
 



  J S),. 5 358 02, 5). 16 53), 23 8 10 2-and 5 02 e, 2 "; 7 2, J Hz i) (3RS, 4RS} (2-oxo-3-diazo) -4-nitrobenzylbutyrate A solution cooled by the gel (1-fluoro-1-methylethyl) -2-oxoazetidine-4-yl- = 4-nitrobenzyl and 0.17 9 of 4-carboxy-benzenesulfonyl azide in 20 ml of acetonitrile is added 0 , 34 ml of triethylamine. After removing the cooling bath, the mixture is stirred for another 30 minutes at room temperature. 100 mol of ethyl acetate are added to the mixture, the mixture is washed with a 5% NaHCO 2 solution and then with water and dried over MgS04.

   By removing the solvent, the

  <Desc / Clms Page number 35>

 
 EMI35.1
 composed of the title. j) (5RS, 6RS) [3. of 4-nitrobenzyl A suspension of 0.19 g of (3RS, 4RS) -3-oxoazetidine-4-yl- of 4-nitrobenzyl and 20 mg of rhodium-II acetate is heated for 10 minutes at 800 argon atmosphere. in 100 ml of benzene.



  The mixture is cooled to ambient temperature, the catalyst is filtered and the filtrate is evaporated to dryness, which gives the title compound.



  C) (5RS, 6RS) -1-aza-3, [3. of 4-nitrobenzyl (for examples 2, b) ii) e) ii)] a) 1-tert-butyldinethylsily methylethyl) -azetidine-4-y'L] - 4-nitrobenzyl butyrate Is dissolved in 20 ml of tetrahydrofuran 1.2 g of 1-tert-butyldimethylsilyl-2-oxo-3-trans-aZetidine-4-yl-acetic acid, 1 g of carbonyldiimidazole is mixed with -20 and stirred for 3 hours to 20. Meanwhile, 1.9 g of magnesium 4-nitrobenzyl malonate 7 are suspended in 30 ml of tetrahydrofuran and the mixture is stirred for hours at room temperature. The subsequent reaction and the extraction are carried out in a similar manner to that described in B) h).



  R 32 t 3 = 18 and 9'4177 4-, FJ2: and 4 Flz); and 7, 3 7 H \ J = 9 H =).

  <Desc / Clms Page number 36>

 
 EMI36.1
 



  1 b) 2-oxo-3- b (2-oxo) 4-nitrobenzyl butyrate
To a solution cooled by. ice 1.4 g of 1-tert. butylidmethylsilyl-2-oxo-3- (trans) - (1-hydroxy-1-methylethyl) azetidine-4-yl- (2-oxo) 4-nitrobenzyl butyrate in 60 ml of a 9/1 mixture of methanol and of water, 2 ml of concentrated HCl are added. The mixture is stirred for 30 minutes
 EMI36.2
   00 and for 5 1/2 to 25 hours. The subsequent processing is carried out in a similar manner to that described in Example B) e).



  -RMN. (CDCI3) (s, 3) 35 (s, 3): 2, 32 (d, 1, J and 8, 6 Hz); 3.06 (d. 5 Hz); 3.60 (5.2); 3, 1, J = 6, 5 2.; 7.57 (d, 2, J = 9 Hz); 8, 27 (d, 2, J = 9 Hz). c) 3-: 1, 25diazo) 4-butyrate butyrate
To an ice-cooled solution of 0.45 g of 2-oxo-3- (trans) - (1-hydroxy-1-methylethyl) azetidine-4-yl- (2-oxo) butyrate of 4-nitrobenzyl and 0.33 g of 4-carboxy-benzene-sulfonyl azide in 30 ml of acetonitrile, the following is added
 EMI36.3
 0, ml of triethylGine. then processes analogously to that described in Example B) R '(CDC) CB, 3 L 1 and 6, 3, -7 e K z);

   3, and J = 3, <3-'é d) (5RS, 6SR) -l-aza-3, L [3. of 4-nitrobenzyl
67 A 0.4 g suspension of 3- (1-hydroxy-1-methylethyl) -2-oxoazetidine-4-yl (2-oxo-3-diazo) butyrate of 4 is heated for 10 minutes under an argon atmosphere. -nitrobenzyl and 40 mg of rhodium-II acetate in 250 ml of anhydrous benzene. Then treated analogously to that described in Example B) j).

  <Desc / Clms Page number 37>

 
 EMI37.1
 



  L-9 Ijzf, 1, and: d, 1 FCIN (C 0 c 1 0 3); i, 1-6 s, 3 ') 21 3 - 0' 6 9,,, and 7, 16 d, ')' 1, '7 \' 326 1); 51.-1 i s, nP- (d, 2, 9 e) (5RS, 6RS) -1-aza-3, [3. 2. 0] heptane-2-carboxylate of 4-nitrobenzyl A solution cooled to -78 3 ml of diethylamino-sulfuryl trifloride and 170 mg of fluoride of 8 ml of dichloromethane is added a solution of 0.35 g of (5RS , 6RS) -t-aza-3, [3. 2. O] -heptane-2-carboxyl of 4-nitrobenzyl in ì dichloromethane The mixture is stirred and mixed with water. Then treated analogously to example B) f). F = 132-135.



  Rt. 1 and. , 7. 7 e t et 1-iz, ', 36 fdi, 1, J = 21-ex 2, 2 Hz; "7- C 5 ', D) - D) [(3RS, 4RS) -3- (I-fluoro-lr ,, ethylét. Hvl) -2-oxoazéùid-ine --- yi-il- 2oxo-butyrate 4-nitrobenzyle 2 mi a) (3RS, 4RS) -1-tert-butyldimethylsilyl-3- 2-oxo-azetidine-4-yl- (2-oxo) To a solution cooled to 14.4 ril of dimethylamino-sulfuryl potassium fluoride in 500 ml of dichloromethane is added a solution of 18 9 of (3SR, 4RS) -1-tert. oxoazetidine-4-yl (2-oxo) butyrate of 4-nitrobenzyl 400 ml of dichloromethane.

   Then treated analogously to that B) f) (eluent: dichloromethane / ethyl acetate = IR spectrum: 1740, 1520 cm '\

  <Desc / Clms Page number 38>

 
 EMI38.1
 b) [2-oxo-butyrate
To an ice-cooled solution of 5.8 9 of [(3RS, 4RS) -1-tert.butyldimethylsilyl-3- (1-fluoro-1methylethyl) -2-oxoazetidine-4-yl] -2-oxo- 4nitrobenzyl butyrate in 250 ml of a 9/1 mixture of methanol and water 8.3 ml of concentrated HCl are added. The mixture is stirred for 30 minutes at 00 and for 5 hours at 25. The methanol is removed by distillation and the product is crystallized.
 EMI38.2
 



  E) (5RS, methylethyl) of 4-
6SR) -3- (2-acetylaminoethylthio) -1-aza-6- (1-hydroxy-1-nitrobenzyl (for Example 3)
To an ice-cooled solution of 300 mg of (5RS, 6SR) -1-aza-3,7-dioxo-6- (1-hydroxy-1-methylethyl) bicyclo [3. 2.0] 4-nitrobnezyl heptane-2-carboxylate in 20 ml of anhydrous acetomtnte, 0.22 ml of N-ethyldiisopropylamine and then 0.26 ml of diphenyl chlorophosphate are added. After 15 minutes at 0 another 0.22 ml of N-ethyldiisopropylamine is added.
 EMI38.3
 then 140 mg of N-acetylcysteamine in 5 ml of acetonitrile. Stirring is continued for 1 hour at 0 and the reaction mixture is distributed between ethyl acetate and a saturated NaCl solution.



  The organic phase is dried over MgSO4, evaporated to dryness and the residue is chromatographed on silica gel (ethyl acetate / acetone = 7/3).
 EMI38.4
 



  RM. ) 35 6-5, - '.



  3, = 9 and 2, 7 1, J 5, 92 2, j = 9i-2,): ci .. 2, 39 Hz 1 = 9 and 2, 7, 3,.



  J) 8 6 F) 1 heptan2-2-4-nitrobenzyl carboxylate (for examples 23 and 24) a) 6 (R) - [1- (S) fluoroethyl] penicillanic acid methyl ester
10 ml of diethlamino-sulfuryl trifloride are added

  <Desc / Clms Page number 39>

 
 EMI39.1
 to -780 a suspension of potassium in 200 ml of dichloromethane is then added to this suspension a solution of 12.5% of methyl ester of (R) hydroxyethyl acid]. After 45 minutes and the mixture is stirred for an hour at ambient temperature.



  The reaction mixture is extracted twice with water, dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (dichloromethane), which gives the title compound in the form of an oil.



  RMj \ ') 3. 6.5 Hz); C5 55 28. 1 3, 5 and 3-% 1- (d ', 52 5 and!), B) (3R) - 4-acetoxy-3-U carbony1-propene -') - y1) -2- oxoazêti di To a solution of 7.1 g of methyl ester of acid (I-IS) fl. uo ril of acetate n- in 200 of ethyl is added 21, 7 9 of mercuric acetate and the mixture is stirred for 1 hour at 100. After cooling the filter mixture, you evaporate to dryness and evaporate three times with toluene. The residue is taken up in acetate and the part is washed, the filtrate is washed 3 times with 400 ml of water, dried over MgSO, concentrated and the title compound is crystallized. F = 94-970.



  Spectrum IfCHCI): 1770, 1720 cm '\ c) Methyl ester of acid Slf1uor e th)'. D -''- t-robêD-ZYl 2-pxo- --tl-:: i1: 12- benz azetidine-l-ylJacétique To a solution of 6.59 of the product obtained under b) and 8.77 g of 3-methyl-4-tr-imêthy1s'i1y1buty) -atede (prepared according to the method of K. Itoh et al., In Chem. Comm.

  <Desc / Clms Page number 40>

 



  1977.500) in 30 ml of nitromethane is slowly added to -200 and under an argon atmosphere 9.2 ml of trimethylsilyl-trifluormethanesulfonate. After 15 minutes lawn removes the cooling bath and the mixture is stirred for another 2 hours at room temperature. The mixture is diluted with 100 ml of ethyl acetate, it is extracted with a buffer solution (pH7) and dried over MgSO4 before evaporating to dryness. Chromatography on silica gel (dichloromethane / ether = 10/1), which gives the title compound as an oil.
 EMI40.1
 



  NMR! 3): 1, 3, J = 24 and, 7 Hz); it (s,; 2, 20 (s, 3); 1, J = and S,; 2, 56 (dd, 1, J = 15; 3, 13 (ddd, 1, 3 =, 5, 5, 5 and 2.5 Hz-, (s, 2), 95 8 7.52 (d, 2, J = 9 2, J = 9fi] (C'- ;. 753 d) -4 4-nitrobenzyl butyrate A- 780m pass through one of isopropylidene acid methyl ester- [3 (R) - (1- (S) fluoroethyl) -4 (R) - [2- (4-nitrobenzyloxycarbonylmethyl) allyl-2-oxoazetidine -1-yl] acetic acid in 10 ml of dichloromethane until the solution turns blue, then nitrogen is added until the color disappears. After the addition of 1 μl of sulphide
 EMI40.2
 dimethyl, the mixture is heated to room temperature and stirred for 2 hours. Dichloromethane is removed and the residue is dissolved in 5 ml of methanol and after adding a drop of triethylamine, the mixture is stirred for 30 minutes.

   After removing the solvent, the residue is mixed with 200 ml of ether, extracted 3 times with water, dried over MgSO4 and concentrated.



  By chromatography on silica gel, the compound is obtained

  <Desc / Clms Page number 41>

 
 EMI41.1
 of the title in the form of an oil.



  RN 5 3.07 3 J = 27.3 and 2 = 7.5 and 2.7 Hz); 5, Oj; 5, 30 2, J = 9 Hz) 2 2, = 9 Hz). e) 4-3 dine-4 4-nitrobenzyl diazobutyrate To a solution of 100 mg of 4- [3 (S) fluorethyl) -2oxoazetidine-4 and 77 mg of azide is added dropwise, with stirring and cooling with ice 0.31 ml of triethylamine and the mixture is further stirred for 15 minutes at room temperature. The mixture is then diluted with 40 ml of ethyl acetate, washed once with a 5% solution of bicarbonate and twice with 1! water, you are dried over MgS04 and concentrated, which gives the title compound.
 EMI41.2
 



  2 Pzi; 3 10 1, J 25 F-. z); 17 Ic'et 1 J lo and 5 "z; 1.,. 22 1, l, = -F .., R '.'.), 7 5. 5 35.



  J IR (CHC),).



  17 2? 5 c -nf) (5R, 4-nitrobenzyl 2-carboxylate For 15 minutes and with stirring, degassification is carried out by vigorous passage of argon a solution of 100 mg of acid 4- [3 (R) - (1- (S ) fluorethyl) -2-oxoazetidine-4 (R) -yl] -3-oxo-2-diazobutyrate 4-nitrobenzyl in 20 ml of benzene A catalytic amount of rhodium-n acetate is added and the flask is placed of reaction in a bath preheated to 80. After 15 minutes at 80, the filtrate is concentrated and the filtrate is concentrated, which gives the title compound.

  <Desc / Clms Page number 42>

 
 EMI42.1
 



  (, -Ic 18 and).



  2, Hz) (dd, C 5 22 J = 7 and 2, C-92; 30 5, 16-5, 50 (m, 2, 5); 7, 56 2, J = 9 Hz) 8, 30 ( d, 2, J = 9 Hz).



  G) Iodhydrate!, 3, i 7 Hzi; 2, 5î (c! D,), J = guanidine (for example 10) a) N, N, N ', N'-tetramethyl-S-methylisothio-urea iodide
While cooling with ice, 30 g of tegramethylthiourea are added to 100 ml of methyl iodide and 200 ml of dichlormethane and the mixture is then stirred for 3 hours in the dark and at room temperature. After adding 500 ml of ether the title compound which has precipitated (F = 170 '") can be used directly for the following reaction. B) N, N, N', N'-tetramethyl-N'- lodhydrate (2-mercapto) ethyl-guanidine
A solution of 2.27 g of cysteamine hydrochloride in 20 ml of anhydrous dimethylformamide is mixed at room temperature with 2.77 ml of triethylamine and the mixture is stirred for 2 hours.

   The precipitate is removed and the filtrate is mixed with 4.48 g of N, N, N ', N'-tetramethyl-S-methylisothiourea iodide. After 2 hours with stirring at room temperature, 100 ml of diisopropyl ether are added to the mixture and the resulting brown oil is decanted. This oil is digested in 10 ml of isopropanol after which the title compound crystallizes. After filtration, the residue is washed once with isopropanol and once with diisopropyl ether, then it is dried, which gives the
 EMI42.2
 composed-of the title. F = 950.



  R): 2,, ''),; 3,, C-D

  <Desc / Clms Page number 43>

 (CDCH) N, N, N ', nonafluorobutanesulfonate - trmethylmercaptoacetamidine (for Example 12) a) &gamma; -tritylthio-N-methylacetamide
To a solution of 26.55 g of sodium in 1800 ml of ethanol is added 288.8 g of triphenylmethane-thiol. Then while cooling with ice, a solution of
 EMI43.1
 m, 8 g of N-methylchloracetamide in 1000 ml of ethanol, which causes the formation of a gray-white precipitate. When the addition is complete, the mixture is further stirred at room temperature for 45 nm and the mixture is concentrated to half its volume. The precipitate is filtered, washed with isopropanol, water and more isopropanol and dried, to give the title compound. F = 200-210.
 EMI43.2
 



  CD e'1 R '): 2.,. 5Hz) r. '))) B) Ci-tri thjo-Nm & th) 0n stirred for 6 hours at 325 9 (CDCN-methylacetamide and 400 9 of the Lawesson reagent in 4000 ml of toluene. After concentration at approximately 1300mil, the insoluble products are eliminated and the residue is washed with ethyl acetate.



  The original filtrate and the ethyl acetate phase are combined and evaporated to dryness. The oily residue is crystallized, usually with a little ethanol, which gives the title compound, more product can be obtained by chromatography.
 EMI43.3
 spelling of the mother liquor on silica gel.



  P '', r ,,,,) ...,. 'U) ..,: r).' I52J '., 0,') c) Iodhydrate of the ester of a-tritylthio acid
N'N-methylthio-acetimide
For 20 hours at room temperature, 136% of γ-tritylthio-N-methylthioacetamide are stirred in the dark in 800 ml of methyl iodide. 1500 ml of ethyl acetate are then added, the mixture is filtered and it is washed thoroughly twice with acetate.

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 EMI44.1
 ethyl, which gives the title compound. F =. ) '7 o)! ''



  2 2 4, /% 1 1% 1 ci7. d) a-tritylthio-N, N iodhydrate,
On a bath of. carbon snow. dimethylamine is stirred in a suspension of 170 g of S-methyl ester of omega-gamma; -tritylthio N-methylthioacetimide in 750 ml of anhydrous dichloromethane at room temperature (about 200 mil ); the solution which then becomes clear is stirred for a further 3 hours at room temperature. It is evaporated to dryness and the residue is crystallized by trituration with ethyl acetate. By wire-
 EMI44.2
 tration and drying gives the title compound.

   F R '\ J-I,'. '.. .. \ p D: 21 2 2 e) N, N, N nonafluorobutanesulfonate' - trimethy1n) ercapto- acetamidine
It is divided between a 6N solution of NaO and ether 10g of gamma iodhydrate; -tritylthio-N, N, N ', - trimethylacetamidine, which gives the free base, then dissolved in 100 ml of methanol.



  During this time, a solution of 4.29 of silver nitrite in 500 ml of methanol and 2.5 ml of pyridine is prepared. The solutions are combined and stirred for 90 minutes at room temperature. The resulting brown-black precipitate is filtered and washed thoroughly with methanol and ether. It is then suspended in 400 ml of anhydrous dichloromethane to which a drop of pyridine is added and H2S is passed for about 20 minutes to 0. After filtrate! on sintered glass, the filtrate is concentrated, it is mixed with toluene and it is evaporated again to dryness. By drying under high vacuum, the residue is taken up in about 100 ml of a 1N HCl solution and

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 EMI45.1
 it is extracted 3 times with ethyl acetate.

   10 g of potassium nonafluorobutanesulfonate are added and the mixture is extracted 5 times with dichloromethane. After concentrating the combined extracts, the title compound is crystallized. F = 60-65 (decomposition).



  ! ) 2) r.



  IR. l.


    

Claims (11)

 EMI46.1   CLAIMS 1. A 6- (1'-fluoroethyl) - l'-methyléthyl) -carbapénème, acid (1 (R) -f1uoroéthyl) -3- aCétaminoéthylthio) 2. 0Jhept-2-ene-carb0- (Cxylic .  2. A compound of formula 1  EMI46.2  in which R-) represents hydrogen or a methyl group and R2 represents hydrogen or a lower alkyl group, a lower alkenyl group or a cycloalkyl group each of which may be unsubstituted or mono or poly-substituted by an amino group, mono or di- (lower alkyl) -amino, lower acylamino, carboxy, lower alkoxycarbonyl or carbamoyl;  a group of formula IIc (CH) p-Ry Ile in which R7 represents a phenyl group or a 5- or 6-membered saturated or unsaturated heterocycle containing 1 or more heteroatoms chosen from 0, S and / or N and which may  EMI46.3  be non or mono or po '8 Vil u-1 to cu L 1 It c by a fluorine, chlorine, bromine atom, an amino group, mono or di- (lower alkyl) -amino, hydroxy, lower alkoxy , mercapto, alkylthio, phenyl-  <Desc / Clms Page number 47>  thio, sulfamoyl, guanidion, nitro, cyano, lower acylamino, carboxy, alkoxycarbonyl  EMI47.1  or carbamoyl and 0, 1, 2 or 3;  or a group corresponding to one of the formulas  EMI47.2  in which  EMI47.3  R4'RS can be the same or different and R, 4, R 5 and R each represents hydrogen or a lower alkyl group or R4 and R6 and / or RS and one of the CH groups can form a ring, as well as R5 and R6 in formula II and R4 and R5 in formulas 11a and IIb, these rings possibly being unsubstituted or mono or poly substituted by an alkyl, hydroxy, carboxy or di- (alkyl-inferor) amino group m signifies 2 or 3, and  EMI47.4  n means 1,2 or 3 with the proviso that when R-) represents hydrogen and the group containing it has the R configuration, Ruz is other than an acetylaminoethyl group;  or protected forms and / or physiologically hydrolyzable and acceptable esters of cos compounds; in the form of free acids or salts or in the form of amphoteric ions.  <Desc / Clms Page number 48>    3. A compound according to claim 2, characterized in that RI represents hydrogen or a methyl group; R2 represents a lower alkyl group, optionally mono or disubstituted by an amino, alkylamino, dialkylamin, acylamino, carboxy, imino, alkylimino and / or heterocycle group, for example a methyltetrazolyl group or. morpholino.  4. A compound according to claim 3, characterized in that it is chosen from acid  EMI48.1  (5RS, 6RS) -1-aza-6-methylamidinomethyl 2-carboxylic acid and (5RS, 6RS) -1-aza-6-fluoroethyl) bicyclo [3. 2. 0Jhept-2-ene-2-carboxylic, form (1 (RS) -fluoroethyl) -3- (N-dimethyl-N'-protected Or in the form of a physiologically hydrolysable and acceptable ester; in the form of free acid , or salt or ions. amphoteric.  5. A compound according to claim 2, characterized in that Rl represents hydrogen and R2 represents hydrogen, a lower alkyl, lower alkenyl, cycloalkyl group which can be substituted by an amino group, mono or di- (alkyl- lower) -amino, lower acylamino, carboxy, lower alkoxycarbonyl or carbamoyl nitrogen which may be part of the ring when a cycloalkyl group is substituted by an amino or mono or di- (lower alkyl) -amino group;  or a group of formula II or IIa, in which R4, Rc and R6 may be the same or different and represent hydrogen or a lower alkyl group and m and n have the meanings given above, the carboxy group in position 2 is form  <Desc / Clms Page number 49>  free or in the form of a protected or easily separable ester or in the form of a salt formed with an organic or inorganic cation.  6. A compound according to claim 2, characterized in that R1 represents hydrogen or a methyl group, R2 represents hydrogen, a lower alkyl, lower alkenyl, cycloalkyl group which may be substituted by an amino group, mono or di - (lower alkyl) -amino, lower acylamino, carboxy, lower alkoxycarbonyl or carbamoyl, nitrogen can be part of the ring when a cycloalkyl group is substituted by an amino or mono or di- (lower alkyl-) -amino group a group of formula- (CH2) p-R7, in which p signifies 0, 1, 2 or 3 and R7 represents a phenyl group or a 5 or 6-membered saturated or unsaturated heterocycle containing 1 or more heteroatoms chosen from 0, S and / or N;  or a group of formula II or III, in which R4, R5 and R6 may be the same or different and represent hydrogen or a lower alkyl group, m and n have the meanings given above and the carboxy group in positions 2 is under free form or in the form of a protected or easily separable ester or in the form of a salt with an organic or inorganic cation.  7. A process for the preparation of a compound according to claim 1, characterized in that a hydroxy group is exchanged in a 6- (t'-hydroxyethyl) or 6- (1'-hydroxy-1'-métthy1êthy1) "corresponding carbapenem with fluorine.  <Desc / Clms Page number 50>    8. A process for the preparation of a compound according to claim 2, characterized in that it is prepared A) by introducing a group -S-R2 into a compound of formula III  EMI50.1  in which R1 and R2 have the meanings given above, R8 represents an eliminable group R3 represents a protective group or a physiologically hydrolysable and acceptable ester group or B) by exchanging the OH group in a compound of formula IV  EMI50.2    EMI50.3  in which R, and the meanings 1 2 3 R3 have given above, or a precursor of this compound, by a fluorine atom and, where appropriate,  by eliminating the protective group from the compound thus obtained or by converting the compound thus obtained into another physiologically hydrolysable and acceptable ester and / or in its protected form and by isolating the compound thus obtained in the form of free acid or of salt or in the form of an amphoteric ion.  <Desc / Clms Page number 51>    9. A compound according to any one of claims 1 to 6, or optionally in the form of a salt: * or in the form of an amphoteric ion acceptable from a chemotherapeutic point of view, in combination with a chemotherapeutically acceptable diluent or vehicle. , for use as a medicine.  10. A chemotherapeutic composition, characterized in that it comprises a compound according to  EMI51.1  any one of claims 1 to 6 or optionally in the form of a salt or an ion acceptable from a chemotherapeutic point of view, in association with a chemotherapeutic diluent or vehicle  EMI51.2  rapically ll. A compound of formula or V as defined above. 12. N, N'-trimethylmercaptoacetamidine and its salts.  11 Products and processes in substance as described above with reference to the examples cited.