JPH0321543B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides an intermediate for producing a 2-penem-3-carboxylic acid compound in which the 6-substituent is 6-substituted, which is different from the acylamino group. This invention relates to novel compounds that can be used and methods for producing the novel compounds.

[Conventional technology]

Since the discovery of penicillin, a large number of two-ring thiaza compounds having a β-lactam structure have become known.
A summary of early work can be found at EHFlynn.
"Cephalosporins and Penicillins", Academic
Press, New York and London, 1972. For more recent developments, see J.Cs.
Ja′szbere′nyi et al., Progr.Med.Chem., Volume 12,
1975, pp. 395-477, PGSammes, Chem.
According to Rev.1976, Vol. 76 No. 1, pp. 113-155,
And in June 1976, the
by various authors at the International Symposium of the Chemical Society (later published by J. Elks, “Recent
Advances in the Chemistry of β-lactam
antibiotics”, The Chemical Society,
Burlington House, London, 1977).

In addition to the usual penam and cefem compounds with acylamino groups in the 6- and 7-positions, respectively, compounds unsubstituted in these positions, such as 3-carboxy-2,2-dimethylpenam (JPCClayton, J.Chem Soc., 1969, 2123) and 3-methyl-4-carboxy-3-cephem (K. Ku¨hlein, Liebigs Ann., 1974 p. 369 and D.
Bormann, Complete Journal, p. 1391) has also become publicly known. 3-carboxy-2,2-dimethylpenam compounds containing a 6α-chlorine atom or a 6α-bromine atom instead of the usual 6β-acylamino group are manufactured by I.McMillan.
and RJ Stoodley, Tetrahedron Lett.1205 (1966)
and J.Chem.Soc.C 2533 (1968), while the corresponding 6α-hydroxy-, 6α-acetoxy- and 6α-phenoxyacetoxy-
2,2-dimethylpenam-3-carboxylic acid is D.
Hauser and HPSigg, Helv.Chimica Acta50,
1327 (1967). However, none of these compounds is known to have any antibiotic activity, or at least any significant antibiotic activity.

6-acylamino-2-penem-3-carboxylic acid compounds having antibiotic activity and having a 2-penem ring system are described in German Patent Application No. 2,655,298.

No 2-penem-3-carboxylic acid compounds having a substituent other than the acylamino group in the 6-position and which are effective against penicillin-sensitive and penicillin-resistant microorganisms have hitherto been published.

The 2-penem ring system has the formula It is systematically expressed as 7-oxo-4-thia-
It can be named 1-azabicyclo[3,2,0]hept-2-ene. From now on, for simplicity, “2
-penem" and is derived from penem, using the following numbering standard in penicillin chemistry:

2-penem-3-carboxylic acid compounds can be prepared in a variety of ways using novel intermediates. The present invention is 2
- A novel intermediate for producing penemcarboxylic acid compounds and a method for producing the same.

[Summary of the invention]

The object of the present invention is the formula (In this formula, R is an organic group bonded to a ring carbon atom through a hydrogen atom or a carbon atom, and R _b
and R _c are both organic groups bonded to a ring carbon atom through a hydrogen atom or a carbon atom,
The two groups R _b and R _c may be bonded to each other, A is a lower alkylene group with 2 or 3 carbon atoms between the two heteroatoms, and n is 0 or 2. ), stereoisomers thereof, mixtures of these stereoisomers, and starting materials for the production of compounds represented by formula ().

[Specific explanation]

An organic radical _{R a} bonded to a ring carbon atom through a carbon atom is in particular a saturated or unsaturated, optionally substituted, aliphatic, cycloaliphatic, cycloaliphatic substituted aliphatic, aromatic or aryl Substituted aliphatic hydrocarbon residues having up to 18, preferably up to 10 carbon atoms or optionally substituted, having up to 10 carbon atoms, nitrogen atoms, oxygen atoms and/or Heterocyclic radicals, heterocyclic substituted lower alkyl radicals or heterocyclic substituted lower alkenyl radicals with up to 4 ring heteroatoms from the group consisting of sulfur atoms, in particular optionally substituted lower alkyl radicals or lower alkenyl groups, optionally functionally modified carboxy groups or optionally substituted cycloalkyl groups, cycloalkenyl groups, cycloalkyl lower alkyl groups, cycloalkyl lower alkenyl groups,
Cycloalkenyl lower alkyl group, phenyl group,
It is a phenyl lower alkyl group or a phenyl lower alkenyl group. The substituents of such groups are, for example, optionally functionally modified. for example hydroxyl or mercapto groups, optionally etherified or esterified, e.g. hydroxyl groups,
Lower alkoxy groups, such as methoxy or ethoxy groups, lower alkanoyloxy groups, such as acetoxy or propionyloxy groups, hydroxysulfonyloxy groups present in salt form, halogen atoms, such as chlorine or bromine atoms, or lower alkylthio groups, such as methylthio groups. Carboxyl groups which are functionally modified, such as carboxyl groups, lower alkoxycarbonyl groups, such as methoxycarbonyl or ethoxycarbonyl groups, carbamoyl or cyano groups, but also nitro groups, sulfo groups present in salt form, in some cases Amino groups which are substituted, such as lower alkyl groups, such as methyl or ethyl groups, or mono- or di-substituted acyl groups, such as lower alkanoyl groups, such as acetyl groups, or lower alkylene groups, such as 1, It is an amino group di-substituted with a 4-butylene group or a 1,5-pentylene group.

Lower alkyl radicals R _a contain up to 7, especially up to 4 carbon atoms, for example methyl, ethyl,
It is a propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group or pentyl group. A substituted lower alkyl group R _a is in particular a substituted methyl, ethyl or propyl group, the substituent being especially in the 1-position, but also in the 2-position.
- or 3-position, such as hydroxy lower alkyl groups such as hydroxymethyl, hydroxyethyl or hydroxypropyl, lower alkoxy lower alkyl groups such as lower alkoxymethyl, lower alkoxyethyl or lower alkoxypropyl groups such as methoxymethyl a methoxyethyl or methoxypropyl group, a lower alkanoyloxy lower alkyl group such as a lower alkanoyloxymethyl group, a lower alkanoyloxyethyl group or a lower alkanoyloxypropyl group such as acetoxymethyl, propionyloxymethyl, acetoxyethyl or acetoxypropyl hydroxysulfonyloxy lower alkyl groups present in the form of salts, e.g. alkali metal salts e.g. sodium salts or ammonium salts e.g. hydroxysulfonyloxymethyl, hydroxysulfonyloxyethyl or hydroxysulfonyloxypropyl groups, halo Lower alkyl groups such as halomethyl, haloethyl or halopropyl groups such as chloroethyl or bromoethyl or chloropropyl or bromopropyl groups, lower alkylthio lower alkyl groups such as methylthiomethyl, methylthioethyl, methylthiopropyl or
tert-butylthiomethyl group, lower alkoxycarbonyl lower alkyl group such as lower alkoxycarbonylmethyl group or lower alkoxycarbonylethyl group such as methoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylmethyl or ethoxycarbonylethyl group, cyano lower alkyl group, e.g. a cyanomethyl group or a cyanoethyl group, a sulfo-lower alkyl group in which the sulfo group is present in the form of a salt, for example an alkali metal salt, e.g. a sodium salt, or an ammonium salt;
Examples are sulfomethyl, sulfoethyl or sulfopropyl groups, or optionally protected eg acetylated amino lower alkyl groups such as aminomethyl, aminoethyl or aminopropyl groups.

Lower alkenyl R _a has 2 to 7, especially 2 to 4 carbon atoms and is, for example, vinyl, allyl or 2- or 3-butenyl. A substituted lower alkenyl group can have the same substituents as a substituted lower alkyl group.

Carboxyl radicals R _a , optionally functionally modified, can be free or esterified or amidated carboxyl radicals, such as lower alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl groups, aryl Substituted lower-alkoxycarbonyl groups, such as benzyloxycarbonyl groups,
p-Nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl, aryloxycarbonyl, such as phenoxy optionally substituted, for example by a halogen atom, such as a chlorine atom, by a lower alkoxy group, such as a methoxy group, or by a nitro group; Carbonyl groups, such as phenoxycarbonyl, o-, m- or p-chlorophenoxycarbonyl, pentachlorophenoxycarbonyl, o-, m- or p-methoxyphenoxycarbonyl or p-nitro A phenoxycarbonyl group, an aminocarbonyl group or a substituted aminocarbonyl group, such as an aminocarbonyl group mono- or di-substituted with a lower alkyl group, such as a methyl group or an ethyl group.

The cycloalkyl group R _a is, for example, 3 to 7 carbon atoms
, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, while cycloalkyl lower alkyl group R _a
has, for example, 4 to 7 carbon atoms and is, for example, cyclopropylmethyl, cyclobetylmethyl, cyclopentylmethyl or cyclohexylmethyl.

Cycloalkenyl group R _a has a corresponding cycloalkyl group with one or optionally two C-C double bonds, e.g. cyclohexenyl group e.g. 1-
A cyclohexenyl group or a cyclohexadienyl group, such as a 1,4-cyclohexadienyl group.

The cycloalkyl-lower alkenyl group or the cycloalkenyl lower alkyl group R _a is, for example, a cyclohexylvinyl group or a cyclohexylallyl group and a cyclohexenylmethyl group or a 1,4-cyclohexadienylmethyl group, respectively.

A phenyl group or a phenyl lower alkyl group such as a benzyl group or a 1- or 2-phenylethyl group R _a is optionally preferably an aromatic group such as a lower alkyl group such as a methyl or ethyl group, a lower alkoxy group such as a methoxy group. or a halogen atom, such as a fluorine atom or a chlorine atom,
Alternatively, the phenyl lower alkyl group may be substituted with a hydroxyl group, a hydroxysulfonyloxy group, a carboxy group, a sulfo group, or an amino group at the α-position.

Heterocyclic group or heterocyclic-substituted lower alkyl group
In R _a the heterocyclic group is bonded through a carbon atom and is preferably an aromatic group, such as a pyridyl group such as a 2-, 3- or 4-pyridyl group, a thienyl group such as a 2-thienyl group or a furyl group such as a 2- a furyl or corresponding pyridyl lower alkyl group, thienyl lower alkyl group or furyl lower alkyl group, especially a pyridylmethyl group,
a thienylmethyl group or a furylmethyl group,
The heterocyclic substituted lower alkyl group may be substituted at the α-position, for example, by a hydroxyl group, a hydroxysulfonyloxy group, a carboxy group, a sulfo group or an amino group.

A phenyl lower alkenyl group or a heterocyclically substituted lower alkenyl group R _a is a lower alkenyl group substituted in the same manner as the corresponding lower alkyl group, such as a phenylvinyl group or a furylallyl group.

Lower alkylene group A is especially ethylene group and 1,2
-propylene radicals, but also 1,3-propylene radicals or 1,2-, 2,3- or 1,3-butylene radicals.

The organic radicals R _b and R _c are in particular lower alkyl groups such as methyl, ethyl, n-propyl or isopropyl, optionally substituted phenyl or phenyl lower alkyl groups such as benzyl or When used together, it is preferably a lower alkylene group having 3 to 6 carbon atoms, such as a 1,4-butylene group or a 1,5-pentylene group.

The present invention particularly provides that R is a hydrogen atom or R _a ,
R _a is a lower alkyl group, a lower alkenyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkanoyloxy-lower alkyl group, in some cases such as a lower alkyl group, a lower alkoxy group, a halogen atom and/or a nitro An aryl lower alkoxycarbonyloxy lower alkyl group substituted with a group or a hydroxysulfonyloxy lower alkyl group existing in the form of a salt, where A is an ethylene group or a 1,2-propylene group, and the group R _b Each of R _c is a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a phenyl group, or, when together, a lower alkylene group having up to 6 carbon atoms, such as a 1,5-pentylene group or a 1,5-pentylene group. It relates to a compound represented by the formula () which is a 4-butylene group and n is 0 or 2, a stereoisomer of the compound represented by the formula (), and a mixture of these stereoisomers.

The present invention particularly relates to R a hydrogen atom or a radical R _a in which R _a is a lower alkyl group having up to 4 carbon atoms, such as a methyl, ethyl, propyl or butyl group, a hydroxy lower alkyl group having up to 4 carbon atoms, Alkyl groups, especially 1-hydroxy-lower alkyl groups, such as hydroxymethyl, 1-hydroxyethyl or 1-hydroxypropyl groups, lower alkenyl groups having up to 4 carbon atoms, lower alkyl groups and lower alkoxy groups both containing carbon atoms Lower alkoxy lower alkyl groups having up to 4 atoms, especially 1
- lower alkoxy lower alkyl groups, such as methoxymethyl, 1-methoxyethyl or 1-methoxypropyl groups, lower alkanoyloxy lower alkyl groups in which both the lower alkanoyloxy group and the lower alkyl group have up to 4 carbon atoms, especially 1-Lower alkanoyloxy-lower alkyl groups, such as acetoxymethyl, propionyloxymethyl or 1-acetoxyethyl groups, phenyl lower alkoxycarbonyloxy lower alkyl optionally substituted with e.g. halogen atoms and/or nitro groups groups, especially the corresponding 1-
phenyl lower alkoxycarbonyloxy lower alkyl group, the lower alkyl group containing up to 4 carbon atoms, hydroxysulfonyloxy lower alkyl group present in salt form, especially 1-hydroxysulfonyloxy lower alkyl group, both in salt form hydroxysulfonyloxymethyl, 1-hydroxysulfonyloxyethyl or 1 _{- hydroxysulfonyloxypropyl} group present in is an alkyl group or, when R _b and R _c are bonded, is a lower alkylene group having 3 to 6 carbon atoms, such as a 1,5-benzene group or a 1,4-butylene group, and A is an ethylene group. or a 1,2-propylene group and n can be 0 or 2, stereoisomers of the compound represented by the formula (), and mixtures of these stereoisomers.

The present invention particularly provides that R is a hydrogen atom or a group R _a
and R _a is a lower alkyl group having up to 4 carbon atoms, in particular a methyl group, a lower alkenyl group having up to 4 carbon atoms or having up to 4 carbon atoms,
The 1-hydroxy group may optionally be an acyl group, such as an acyl group of an organic carboxylic or sulfonic acid, such as an optionally substituted lower alkanoyl group, such as an acetyl or trifluoroacetyl group, or A phenyl-lower alkoxycarbonyl group substituted with a halogen atom and/or a nitro group, such as an optionally substituted phenylalkoxycarbonyl group, which can be protected with a p-nitrobenzyloxycarbonyl group, for example. a 1-hydroxy lower alkyl group, especially a 1-hydroxyethyl group, in which both the groups R _b and R _c are lower alkyl groups, especially a methyl group, or R _b and R _c taken together lower alkylene radicals having up to 6 carbon atoms, especially 1,5-pentylene radicals, where A is ethylene radical or 1,2-propylene radical n
is 0 or 2, stereoisomers of the compound represented by formula (), and mixtures of these stereoisomers.

A compound represented by the formula () is a compound represented by the formula () [In this formula, A has the meaning described under formula ()] A compound represented by the formula R _b -(C=O)-R _c () [In this formula, R _b and R _c are having the meaning given under formula () or a derivative thereof in the presence of an acid reagent, if desired, can be obtained according to the method described above, and R is hydrogen. Introducing a group R _a into a compound of formula () which is an atom and, if desired, can be obtained according to the method described above, converts a compound of formula () where n is 0 into a compound of formula () where n is 2 and/or, if desired, by separating the isomer mixture obtainable according to the above-described method into individual isomers.

The carbonyl compound of formula () is preferably a monovalent organic group in which both groups R _b and R _c are monovalent organic groups, in particular lower alkyl groups having up to 4 carbon atoms, such as methyl or ethyl groups or carbon atoms.
Aryl groups or aryl lower alkyl groups having up to 10 ketones, especially lower alkanones such as acetone, such as phenyl or benzyl groups, or if R _b and R _c taken together are divalent organic radicals. , cyclic ketones, especially cycloalkanones such as cyclohexanone, or optically active ketones or aldehydes such as acetic acid.

Derivatives of carbonyl compounds of formula () are acetals or enol ethers, more particularly acetone dimethyl ketanol.

Acid reagents include strong acids and weak acids of the precipitated type, such as mineral acids such as sulfuric acid or hydrochloric acid, organic acids such as p
- toluenesulfonic acid or Lewis acids such as boron trifluoride etherate, copper sulfate or iron chloride.

The water formed during the reaction of the compound of the formula () with the carbonyl compound of the formula () can be removed from the reaction mixture, for example by cofluoro-distillation in a conventional manner with the aid of a water separator.

Suitable solvents for this purpose are aromatic hydrocarbons such as benzene or toluene.

The reaction is preferably carried out at elevated temperatures, e.g.
°C to about 150 °C, more particularly at the boiling temperature of the particular reaction mixture.

Both the enantiomer of the compound represented by formula () and its racemic mixture or diastereoisomeric mixture can be used in the above reaction. In the reaction described above, the configuration of the chirality centers remains unchanged.

Compounds of formula () having an additional center of chirality in A can form diastereoisomeric mixtures. Such diastereoisomeric mixtures are for example represented by () (4R,
S)-acyloxyazetidinone and the enantiomer of 2-mercaptopropan-1-ol, e.g. (2R)-
It can be obtained by reaction with 2-mercaptopropan-1-ol.

If desired, such diastereoisomeric mixtures can be processed individually according to the reactions described above to form the enantiomers of formula () without changing the configuration using conventional methods. can be separated into its enantiomers.

The organic group R _a has the formula () where R is a hydrogen atom
The compound represented by the formula () can be obtained, for example, according to the method described above, and R is a hydrogen atom.
The organic group R a can be converted to R by treating the compound represented by with a suitable metallizing reagent and then with a reactive compound corresponding to the organic group R described above _.
can be introduced into a compound represented by formula () where is a hydrogen atom.

Suitable metallating reagents include substituted and unsubstituted alkali metal amides, alkali metal hydrides or alkali metal lower alkyl compounds, where the alkali metal is sodium or especially lithium, such as sodium or lithium amides, lithium bis- Trimethylsilylamide, sodium hydride, lithium hydride and preferably lithium diisopropylamide and butyllithium.

Reactive compounds corresponding to the above-mentioned organic radicals R _a are, for example, compounds of the formula in which X is a nucleophilic leaving group, such as a halogen atom, such as a chlorine, bromine or iodine atom, or a sulfonyloxy group, such as a mesyloxy or tosyloxy group. A compound represented by R _a −X or a group in which R′ _a and R _a ″ are mutually independently combined with a carbinol residue derived from a hydrogen atom or a carbonyl group to form a group R _a Carbonyl compounds, especially ketone or aldehyde compounds, corresponding to the group R _a of the formula R' _a -(C=O)-R _a ″. R′ _a and R _a ″ are each independently preferably a hydrogen atom or a lower alkyl group.

Suitable solvents for the metallization reaction must not contain active hydrogen atoms, for example hydrocarbons such as hexane, benzene, toluene or xylene, weakly polar ethers such as diethyl ether, tetrahydrofuran or dioxane or acid amides such as hexamethyl. It is a phosphoric acid triamide.

The metallated intermediate does not need to be isolated and can be reacted with a reactive compound corresponding to the organic group _{R a} following the metallation reaction. Said metallization reaction is about -
It is carried out at a temperature of 100°C to about +100°C, preferably -30°C or less. The subsequent reactions can be carried out at the same temperature, optionally during gentle heating up to 100°C.

The enantiomer of the compound represented by formula () and its racemic mixture or diastereoisomer mixture may be used in the metalation reaction.

Reactive compounds corresponding to the organic group R _a generally attack the substrate stereospecifically. When (4S)-acetidinone represented by formula () is used as a starting material, (3R,4S)-4 _- R a -azetidinone is mainly obtained. When using (4R)-azetidinone, (3S,4R)-
Azetidinone is mainly obtained. What is therefore obtained are primarily trans compounds.

In the reaction with a ketone or aldehyde of the formula R′ _a -(C=O)-R _a ″, one more center of chirality is formed in the 1-position of the side chain, usually with the (R,S)-configuration. Threo-trans compounds can be distinguished from ectro-trans compounds according to the position of the hydroxyl group.

Diastereoisomeric mixtures of threo-trans and erythro-trans compounds can be separated into the individual enantiomers using conventional methods, for example by fractional crystallization, chromatography or similar methods.

In the compound represented by the formula () obtained according to the above method and in which R _a is an organic group R _a substituted at the 1-position with a hydroxyl group, e.g. It can be protected or substituted in a manner such as by etherification or esterification.

Suitable protecting groups are acyl groups of organic carboxylic or sulfonic acids, in particular optionally substituted lower alkanoyl groups such as acetyl, trifluoroacetyl, optionally substituted benzyl- or Phenyl-lower alkanoyl groups, such as benzoyl groups, optionally substituted lower alkoxycarbonyl groups or phenyl lower alkoxycarbonyl groups, such as p-nitrobenzyloxycarbonyl groups, and also 2-oxacycloalkyl groups, such as 2-tetrahydropyranyl. or an optionally substituted silyl or stannyl group, such as a trimethylsilyl group. Hydroxyl protecting groups can be introduced in a manner known per se, for example by treatment with reactive derivatives such as acid anhydrides such as acid halides or ketenes, halides or corresponding unsaturated compounds.

Conversion of a compound represented by the formula () where the index n is 0 to a compound represented by the formula () where n is 2 can be carried out using a reagent that converts a sulfide group into a sulfone group, especially hydrogen peroxide or an organic peracid. , in particular with aliphatic percarboxylic acids, such as peracetic acid, perbenzoic acid, chloroperbenzoic acid, such as m-chlorobenzoic acid or monoperphthalic acid, or oxidized inorganic acids or their salts, such as nitric acid, chromic acid, permanganic acid. This is carried out by treatment with potash or alkali metal hypochlorites, such as sodium hypochlorite, or by oxidation by anodic oxidation. The oxidation is preferably carried out in suitable inert solvents, such as halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, alcohols such as methanol or ethanol, ketones such as acetone, ethers such as diethyl ether, dioxane or tetrahydrofuran, amides such as dimethylformamide, Sulfones such as dimethylsulfone, liquid organic carboxylic acids such as acetic acid or in water or mixtures of these solvents, especially water-containing mixtures such as aqueous acetic acid, at room temperature or with cooling or gentle heating;
i.e. about -20°C to about +90°C, preferably about 18°C
Perform at ~30°C. The oxidation may also be carried out stepwise, first at low temperatures, i.e. from about -20°C to about 0°C, until the sulfoxide stage is reached, optionally with isolation of the sulfoxide stage, and then in a second stage to form the sulfone, i.e. 1 expressed by the formula (),
It is also possible to oxidize the sulfoxide to form 1-dioxide, preferably at higher temperatures, such as room temperature.

Any excess oxidizing reagent that may still remain in the finishing can be destroyed by reduction, in particular treatment with reducing reagents such as thiosulfates, such as sodium thiosulfate.

The starting material represented by the formula () is e.g. (In this formula, Ac is an acyl group.)
Reacting with a hydroxy lower alkyl mercaptan represented by A-OH in the presence of a suitable base,
-S-A in the resulting compound if desired
Compounds of formula () are prepared by converting the -OH group into a different -S-A-OH group and/or separating the resulting isomer mixture into individual isomers.

In the compound represented by formula (), Ac represents an acyl group of an organic carboxylic acid or sulfonic acid, in particular an optionally substituted lower alkanoyl group such as an acetyl group, a trifluoroacetyl group or a formyl group, or an optionally substituted lower alkanoyl group. One example is a substituted benzoyl group, such as a benzoyl group.

Hydroxy-lower alkyl mercaptans contain 2 or 3 carbon atoms between two heteroatoms and are, for example, 3-mercaptopropanol or especially 2-mercaptoethanol or 2-mercaptopropan-1-ol.

Suitable bases are strong organic or inorganic bases such as 1,5-diazabicyclo[5,5,0]undec-5-ene or alkali metal or alkaline earth metal hydroxides, especially sodium hydroxide. The latter base is preferably added in concentrated aqueous solution.

Suitable solvents are weakly polar solvents such as tetrahydrofuran or dioxane or relatively strong polar solvents such as dimethylformamide, dimethylsulfoxide or alcohols such as methanol or ethanol. The above reaction is preferably carried out in the presence of water at a temperature of about -20°C to about 100°C, preferably -10°C to room temperature.

In the reaction of the acyloxyazetidinone represented by the formula () with the hydroxy lower alkyl mercaptan, a racemic (4R,S) mixture is obtained.
In this reaction, if A is a HS-A-OH compound containing a chirality center, such as (2R)-2-mercaptopropan-1-ol protected at the hydroxyl group, the diastereoisotope of the compound represented by formula () can be obtained. A mixture of isomers is obtained.

The resulting diastereoisomeric mixture can be separated into its enantiomers, if desired, as described below.

The compound represented by formula () and the above (2R)-
2-Mercaptopropan-1-ols are new and they, together with their preparation, form another subject of the invention.

In the reaction with acyloxyazetidinone of formula (2R)-2-mercaptopropan-1-ol is optionally protected at the hydroxyl group by a hydroxyl protecting group customary in cephalosporin or penicillin chemistry. do. Particularly suitable as hydroxy-protecting groups are silyl groups, such as trimethylsilyl, or acyl groups, such as acetyl.

(2R)-2-Mercaptopropan-1-ol is produced by esterification of the hydroxyl group of (S)-lactic acid ester with an acid residue of an organic acid, such as a mesyl group, in the presence of an organic base such as triethylamine. By reaction with a suitable thio salt of the resulting compound, such as potassium thioacetate, the configuration of the esterified lactate ester at the hydroxyl group is reversed, and the esterified hydroxyl group is replaced by the substituted thio group. By subsequent reduction with a suitable reducing agent such as lithium aluminum hydride, (2R)-
2-Mercaptopropan-1-ol is produced.

The compound represented by formula () and its production method are known.

The present invention also relates to the formula (In this formula, A and R _a have the above meanings,
n is 0 or 2) in the presence of a suitable solvolysis agent, a group in which R has the meaning under formula ()
solvolysis of a compound of formula () in which R _a and A, R _b and R _c have the meanings given under formula (), and n has the value 0 or 2; can be obtained by the method of
preparation by conversion of a compound of formula () in which n is 2 into a compound of formula () in which n is 2 and/or, if desired, separation of the compound obtained by the above process into individual isomers. Regarding.

Suitable solvolysis reagents are, for example, organic acids such as lower alkane carboxylic acids such as glacial acetic acid or formic acid, anhydrides of lower alkane carboxylic acids such as acetic anhydride or sulfonic acids such as p-toluenesulfonic acid, mineral acids such as sulfuric acid or hydrochloric acid, lower alkanols such as Methanol or ethanol or lower alkanediols such as ethylene glycol.

The solvolysis reagents mentioned above are added undiluted or diluted with water. The solvolysis described above can also be carried out in pure water.

Said solvolysis with an acid reagent is preferably carried out in an aqueous solution of this reagent at a temperature of about -20°C to about 150°C.
It is preferably carried out at room temperature to 110°C.

Sulfide (n=0) or sulfone (n=2) represented by formula () can be solvolyzed. In the case of solvolysis of the sulfide, the oxidation to form the sulfone is subsequently carried out in a manner known per se.
For example, as described above.

Physicochemical methods, especially fractional crystallization, are suitable for separating the diastereoisomeric mixtures obtained according to the invention. However, it is also possible to use chromatographic methods, in particular solid-liquid chromatography. Easily volatile diastereoisomeric mixtures can also be separated by distillation or gas chromatography.

One method of separating the racemate consists of chromatography on an optically active adsorption layer, such as cane sugar, or by dissolving the racemate in an optically active solvent and dissolving the less easily dissolved The enantiomer can be crystallized or the difference in reactivity of the optical enantiomer with a biological material such as a microorganism or isolated enzyme can be used, or the racemate can be dissolved and the method described above. One of the optical antipodes crystallizes out by inoculating a small amount of the optically active product obtained in .

The compound represented by formula () can be converted into a 6-substituted 2-penem-3-carboxylic acid compound, for example, as shown in the following reaction scheme and as explained in the examples.

The following reaction scheme represents the reaction steps leading to the product of formula ().

_-SO2 -A- in the compound represented by formula ()
The OH group is a nucleophilic leaving group, and will be referred to as w in the following.

Reaction formula () and () and () and ()
In the compound represented by, z is an oxygen atom,
a sulfur atom or, especially when R ₁ is a hydrogen atom,
It is a methylidene group optionally substituted with one or two substituents Y and convertible by oxidation into an oxo group z. The substituent Y of this methylidene group can be an organic group, for example one of the organic groups listed under R ₁ , such as the optionally substituted lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group mentioned above. esterified groups, including phenyl groups or phenyl lower alkyl groups and especially functionally modified carboxyl groups, for example esterified with optically active alcohols such as 1-menthol. It is one of the carboxyl groups. This methylidene group preferably carries one of the substituents mentioned above. The carbomethoxymethylidene group z is of special interest. The latter can be used to produce optically active compounds represented by formulas (), (), (), and ().

In the compound represented by formula (), X ₀ is a reactively esterified hydroxyl group, particularly a halogen atom or an organic sulfonyloxy group. In the compound represented by formula ()
is one of the phosphonio groups or phosphono groups customary in Wittig condensation reactions, especially triarylphosphonio groups such as triphenylphosphonio groups or tri-lower alkylphosphonio groups such as tributylphosphonio groups or two lower alkyl groups such as ethyl groups. In the case of esterified phosphono groups, the signal X 1 also includes strong basic cations, in particular suitable metal ions such as alkali metal ions such as lithium, sodium or potassium ions. The group X is preferably on the one hand a triphenylphosphonio group and on the other hand a diethylphosphono group together with an alkali metal ion, for example a sodium ion.

6 which can be produced from the compound represented by formula ()
-Substituted-2-penem-3-carboxylic acid compounds are particularly of the formula (In this formula, R _a is an organic group bonded to a ring carbon atom through a carbon atom, and R ₁ is a hydrogen atom or an organic group bonded to a ring carbon atom through a carbon atom, or is etherified. a mercapto group, and R ₂ is a group ^A ₂ which together with a hydroxyl group or a carbonyl group -C(=O)- forms a protected carboxyl group) and a salt-forming group. Salts of such compounds.

2-penem compounds can exhibit valuable pharmacological properties. R _a and R ₁ have the above meanings,
R ₂ is combined with a hydroxyl group or a carbonyl group,
Preferably a compound of formula () with an etherified hydroxyl group R ^A ₂ forming an esterified carboxy group that can be easily cleaved under pharmacological conditions or such a compound with a salt-forming group. Pharmacologically acceptable salts of exhibit antibacterial activity. They include, for example, Gram-positive and Gram-negative microorganisms such as Staphylococcus aureus and penicillin-resistant Staphylococcus aureus, Escherichia coli, Proteus vulgaris. vulgavis), Pseudomonas aeruginosa and Pseudomonas aeruginosa
aeruginosa) R. In a disk test using a compound of the formula () according to the present invention and the above-mentioned microorganisms in a 0.5% solution on paper (diameter 6 mm), an inhibition zone of about 12 to 33 mm is observed.

Penicillin V, tested in the same manner at the same time, has an inhibition zone diameter of 29-33 mm for penicillin-sensitive Staphylococcus aureus microorganisms and an inhibition zone of approximately 9-12 mm for penicillin-resistant microorganisms. Neither penicillin V nor penicillin G is effective against Pseudomonas aeruginosa.

Antibacterial activity in vitro can also be observed in the agar dilution test (according to Fricsson), with MIC values for Gram-positive and Gram-negative cocci.
MIC values of 0.06 to 8 mcg/ml and 2 to 128 mcg/ml for Gram-negative bacilli such as enteric bacilli Pseudomonas and Haemophilus are obtained.

In the body, Staphylococcus pyogenes
Subcutaneous administration of compounds according to the invention in systematic infection of mice with Streptococcus pyogenes Aronson gives ED ₅₀ values of about ≦1 for about 50 mg/Kg.

Particular mention should be made of the effectiveness against Pseudomonas aeruginosa.

The aforementioned compounds inhibit β-lactamases and act synergistically in combination with other β-lactam antibiotics.

These compounds or their pharmacologically acceptable salts, alone or in combination with other fungicidal substances,
For example, they can be used in the form of antibiotically active preparations for the treatment of infections of the corresponding systemic systems or organs, as dynamic feed additives, for food preservation or as fungicides.

The production of a compound represented by formula () from a compound represented by formula () is disclosed in European Patent Publication No.
It is described in No. 791002587.

The following examples are intended to illustrate the invention. The following abbreviations are used:

TCL = thin layer chromatogram on silica gel.

Example 1 4-(2-Hydroxyethylthio)-2-oxoazetidine 4-acetoxyazetidin-2-one (K .
Clauss et. and stir the mixture for 60 minutes at 0°C. The mixture is neutralized with 2 ml of trifluoroacetic acid and evaporated to dryness in a vacuum rotary evaporator. The residue is dried in a high vacuum, 100 g of sodium sulphate is added to it and extracted twice with several 200 ml portions of methylene chloride and then twice with 200 ml portions of chloroform. The combined extracts are filtered and concentrated by evaporation. The viscous residue is purified and used later.

TLC: R _f = 0.12 (ethyl acetate); Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3580,
3380, 1770cm ^-1 .

Example 2 (1) (4R)- and (4S)-4-((2R)-1-hydroxyprop-2-ylthio)-2-azetidine diazabicyclo[5,4,0] in 6 ml of tetrahydrofuran at -20°C. -undec-5-ene 3.6ml
4-acetoxyazetidine-2 in 12 ml of dry tetrahydrofuran for 30 minutes with stirring.
2.58 g (20 mmol) of -one and 2.76 g (30 mmol) of (2R)-2-mercaptopropan-1-ol. The reaction mixture was heated to −20°C.
Stir for another 30 minutes at −40°C and add 0.5 ml of trifluoroacetic acid to it. The mixture was then concentrated in a 11 mm, 25 °C rotary evaporator to remove the residue.
EtoAc/Toluene 2 on Merck silica gel 150g:
1 (20 sections, 100 ml each). A 1:1 mixture of the two diastereoisomeric designations of the compound is obtained.

(2) Starting material (2R)-2-mercaptopropane-
1-ol is produced as follows.

(2・1) (2S)-2-Methylsulfonyloxypropionic acid ethyl ester 15.5 ml of methanesulfonyl chloride was dissolved in 400 ml of dry ether at room temperature with constant stirring.
-Lactic acid ethyl ester 23.6g (22.9ml, 0.2mol)
and triethylamine (21.8 ml, 10.3 mol) dropwise so that the temperature does not exceed 30°C. The reaction mixture is then stirred for an additional 60 minutes at 25°C. The formed precipitate was removed by filtration, and the solution was then diluted with 250 ml of aqueous 1N HCl and 250 ml of water.
Wash with ml. The organic phase is dried over sodium sulfate, the mixture is filtered and the solvent is removed in a rotary evaporator. 32.4 g of the residue is distilled under high vacuum 0.05 mm. Boiling point 75℃/0.05mm.

R _f value: 0.60 (EtoAc).

NMR spectrum (CDCl ₃ ), ppm: 5.2, 1H,
q, J=7.5Hz; 4.35, 2H, q, J=8Hz; 3.2,
3H, S; 1.7, 3H, d, J=7.5Hz; 1.35, 3H,
t, J = 8Hz.

[α] ²⁰ _D : -65° (undiluted).

(2・2) (2R)-2-Acetylthiopropionic acid ethyl ester In a 1000 ml sulfonated flask at room temperature, 17.1 g of solid potassium thioacetate was dissolved in 200 ml of dry tert-butanol ( 2S)
-Add to a solution of 19.6 g of 2-methylsulfonyloxypropionic acid ethyl ester. The reaction mixture is refluxed for an additional 15 minutes. When the reaction mixture has cooled, 1000 ml of ether are added and the mixture is washed twice with 600 ml of water each time. The organic phase is dried over sodium sulfate and, after filtration, the solvent is removed on a rotary evaporator. Distill with a residue of 11 mm. The product is 11
It has a boiling point of 90-95℃ in mm.

R _f value: 0.63 (EtoAc).

Infrared spectrum (in CH ₂ Cl ₂ ), cm ^-1 : 2970,
1732, 1695, 1180.

NMR spectrum (in CDCl ₃ ), ppm: 4.2,
3H, m; 2.3, 3H, S; 1.45, 3H,, d, J=7.5
Hz; 1.25, 3H, t, J = 7Hz.

[α] ²⁰ _D : -48° (undiluted).

(2・3) (2R)-2-mercaptopropane-1-
In a 750 ml sulfonation flask with a mechanical stirrer, a solution of 14.1 g of acetylthiopropionic acid ethyl ester in 40 ml of dry tetrahydrofuran was heated for 30 minutes at a bath temperature of 75°C (reflux) to lithium hydride in 160 ml of dry tetrahydrofuran. 12.16 g of aluminum are added dropwise to the mixture and the reaction mixture is refluxed for a further 60 minutes. After the mixture has cooled, 160 ml of 2N aqueous HCl are added dropwise, with constant stirring, at a bath temperature of 0° C., such that the internal temperature does not exceed 30° C. After stirring for 1 hour at room temperature, the mixture is passed through a fine glass filter and the residue is washed with 700 ml of tetrahydrofuran.
The combined liquids are concentrated in a rotary evaporator at 25° C. and 11 mm. Then add 500 ml of methylene chloride to the residue,
The mixture is dried with 200 g of sodium sulfate.
The solution is concentrated again by evaporation at 25° C. and 11 mm to produce a liquid residue. The residue is distilled at 11 mm. The pure product obtained is 11
mm and has a boiling point of 56℃.

R _{f value} : 0.15 ( _CH2Cl2 ).

Infrared spectrum (in CH ₂ Cl ₂ ), cm ^-1 : 3570,
2920, 2860, 1450, 1390, 1055, 1025.

NMR spectrum (in CDCl ₃ ), ppm: 3.3−3.9,
2H, m; 3.3, 1H, m; 2.2, 1H, Broad S;
1.45, 1H, d, J = 7.5Hz; 1.3, 3H, d, J =
7Hz.

[α] ²⁰ _D : −10.4° (undiluted).

[α] ²⁰ _D : -25° (CHCl ₃ , C=12).

Example 3 (4R)- and (4S)-4-((2R)-1-hydroxyprop-2-ylthio)-2-azetidinone 243 mg diazabicyclo[5,4,0]undec-5-ene in 0.8 ml tetrahydrofuran (1.6 mmol) solution at −30°C for 15 min with stirring.
258 mg (2 mmol) of 4-acetoxyazetidin-2-one in 1.2 ml of dry tetrahydrofuran
and 319 mg (2.4 mmol) of 1-acetoxy-(2R)-2-mercaptopropane. The mixture is then stirred for 30 minutes at 0°C. Add 25 ml of EtoAc and convert the mixture to 1N aqueous
Wash with 25 ml of HCl and 25 ml of saturated aqueous _NaHCO3 solution;
The organic phase is dried, filtered and the liquid is concentrated by evaporation of the solvent in vacuo to give a mixture of diastereoisomeric acetates. Mix that mixture with methanol 20
1.5 ml of 10% aqueous K ₂ CO ₃ solution are added to it, the whole is stirred at room temperature for 150 minutes, then 120 μ of trifluoroacetic acid are added and the mixture is concentrated in a vacuum rotary evaporator. The residue was dried in high vacuum at room temperature and then purified on 12 g of Merck silica gel using toluene/EtoAc 1:2 (20 sections, 8 ml each).
Apply to chromatography. A mixture of the two named compounds is obtained.

(2) Starting material 1-acetoxy-(2R)-2-mercaptopropane can be obtained as follows.

(2R)- produced according to (2.3) of Example 2
A mixture of 920 mg of 2-mercaptopropan-1-ol and 1.12 g of acetic anhydride is refluxed for 30 minutes at a bath temperature of 130°C. 11 mm, liquid residue when concentrated in vacuo at 25 °C
1.4g is produced. Merck silica gel the residue
70g, using methylene chloride (15 divisions, 50% each)
ml) chromatography.

R _f value: 0.5 (Toluene/EtoAc2:1).

Infrared spectrum (in CH ₂ Cl ₂ ), cm ^-1 : 2950,
1735, 1230.

NMR spectrum (in CDCl ₃ ), ppm: 4.1,
2H, d, J=7Hz; 3.2, 1H, m; 2.1, 3H,
S; 1.65, 1H, d, J=7Hz; 1.35, 3H, d,
J=7Hz.

Example 4 (4R)- and (4S)-4-(2R)-1-hydroxyprop-2-ylthio)-2-azetidinone 304 mg diazabicyclo[5,4,0]undec-5-ene (2 258 mg (2 mmol) of 4-acetoxyazetidin-2-one and 401 mg (2 mmol) of 1-trimethylsilyloxy-(2R)-2-mercaptopropane in 1.2 ml of dry tetrahydrofuran were prepared with stirring at -30°C for 15 minutes. 2.4 mmol). The mixture is then stirred for 30 minutes at 0°C. Add 25ml of EtoAc and mix the mixture.
20 ml of 0.1N aqueous HCl solution and _{3 ml} of saturated aqueous NaHCO solution
The organic phase is dried over sodium sulfate and the solvent is concentrated by evaporation in vacuo to give the diastereoisomeric trimethylsilyl ether. This ether is dissolved in 20 ml of methanol, 1 ml of 2N aqueous HCl solution is added and the mixture is stirred for 60 minutes at room temperature. Solid _NaHCO3 168mg
(2 mmol) after addition, the mixture is concentrated in a vacuum rotary evaporator and the residue is dried in a high vacuum. Merck
Chromatography on 12 g of silica gel with toluene/EtoAc 1:2 (20 sections, 8 ml each) gives a mixture of the two title compounds.

(2) Starting material 1-trimethylsilyloxy-
(2R)-2-mercaptopropane can be obtained as follows.

1.53 ml of triethylamine and 920 mg of (2R)-2-mercaptopropan-1-ol prepared according to (2.3) of Example 2 and 1.36 mg of trimethylchlorosilane in 10 ml of dry benzene with stirring for 15 minutes at 0°C. Add to the mixture with ml. The mixture is stirred for a further 15 minutes at room temperature and 15 minutes at 60°C, then cooled and the precipitate that forms is separated. The excess residue is washed with 10 ml of benzene and the combined liquors are removed in an 11 mm, 25° C. rotary evaporator. Ball-tube distillation of the residue at 11 mm, 100 °C yields the pure liquid product.

Infrared spectrum (in CH ₂ Cl ₂ ), cm ^-1 : 2950,
1080, 875, 845.

NMR (in benzene-d), ppm: 3.35, 2H,
m; 2.8, 1H, m; 1.4, 1H, d, J=7Hz;
1.15, 3H, d, J = 7Hz; 0.9H, S.

Example 5 (4R)-4-((2R)-1-hydroxyproper-
2-ylthio)-2-azetidinone and (4S)
-4-((2R)-1-Hydroxyprop-2-ylthio)-2-azetidinone The diastereoisomeric mixture can be separated by chromatography. Merck silica gel
400g EtoAc/Toluene 2:1 (20 categories, 300 each
ml) and EtoAc (10 sections, 300 ml each).
3.2g divided into parts. Category 10-11 is pure 4
Contains 410 mg of the (S) isomer.

R _f value: 0.18 (EtoAc).

NMR spectrum (in CDCl ₃ ), ppm: 7.2,
1H, Broad S; 4.90, 1H, dd, J=3Hz, J
=5Hz; 2.6-4.0, 5H, m; 1.26, 3H, d, J
=7Hz.

Categories 12-17 contain both diastereoisomers;
Sections 18-30 contain 400 mg of pure 4(R) compound.

R _f value: 0.15 (EtoAc).

NMR spectrum (in CDCl ₃ ), ppm: 7.0,
1H, Broad S; 5.0, 1H, dd, J=3Hz, J
=5Hz; 2.5-3.8, 5H, m; 1.35, 3H, d, J
=7Hz.

Example 6 2,2-dimethyl-9-oxo-3-oxa-6-thia-1-azabicyclo[5,2,0 ^1,7 ]
-nonane 15 g of 4-(2-hydroxyethylthio)-2-oxoazetidine obtained according to Example 1 are dissolved in 100 ml of ethanol-free methylene chloride and 26.2 g of acetone dimethyl ketal are dissolved therein at -10°C.
(30.5ml, 0.25mol). 2 ml of boron trifluoride etherate are added with stirring at -10°C and the mixture is stirred for 30 minutes at -10°C and for 2 hours at room temperature. The mixture is diluted with 150 ml of methylene chloride and washed with 350 ml of ice-cold aqueous saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered, freed from the solvent in a vacuum rotary evaporator and then dried under high vacuum. The solid residue is recrystallized from ether/n-hexane. The melting point of the racemic compound is 67-68℃.

R _f :0.5 (ethyl acetate).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 1750,
1345, 1240, 1080cm ^-1 .

Example 7 (7R,5R)-2,2,5-trimethyl-9
-oxo-3-oxa-6-thia-1-azabicyclo[5,2,0 ^1,7 ]nonane (4R)-4-((2R)-1 obtained according to Example 5
166 mg of -hydroxyprop-2-ylthio)-2-azitidinone are dissolved in a mixture of 1 ml of dry, ethanol-free methylene chloride and 0.31 ml of acetone dimethyl acetal. 20μ of boron trifluoride ethyl etherate are added with stirring at -10°C and the mixture is stirred for 30 minutes at -10°C and 150 minutes at room temperature. Mix that mixture with methylene chloride
Dilute with 10 ml and wash with saturated aqueous _NaHCO3 solution,
The organic phase was dried over sodium sulfate and filtered.
The liquid is concentrated by evaporation of the solvent to obtain 225 mg of amorphous residue. The pure title compound is produced by chromatography on 7 g of Merck silica gel with toluene/EtoAc 4:1 (20 sections, 3.5 ml each).

Melting point: 87°C (n-hexane).

_Rf : 0.57 (EtoAc).

NMR spectrum (in CDCl ₃ ), ppm: 5.17,
1H, dd, J=3Hz, J=5Hz; 2.4-4.6, 5H,
m; 1.77, 3H, S; 1.50, 3H, S; 1.47, 3H,
d, J = 7Hz.

[α] ²⁰ _D : +131° (CHCl ₃ , C=1).

Example 8 (7S,5R)-2,2,5-trimethyl-9-
Oxo-3-oxa-6-thia-1-azabicyclo[5,2,0 ^1,7 ]nonane The compound of pure title above is obtained according to Example 5 in a manner analogous to Example 7 (4S) −4−((2R)−
Obtained from 166 mg of 1-hydroxyprop-2-ylthio)-2-azetidinone.

Melting point: 54°C (n-hexane).

_Rf : 0.57 (EtoAc).

NMR spectrum (in CDCl ₃ ), ppm: 5.17,
1H, dd, J=3Hz, J=5Hz; 2.4-4.6, 5H,
m; 1.75, 3H, S; 1.47, 3H, S; 1.15, 3H,
d, J = 7Hz.

[α] ²⁰ _D : -133° (CHCl ₃ , C=1).

Example 9 2,2-dimethyl-trans-8-(1-hydroxyethyl)-9-oxo-3-oxa-6-
Thia-1-azabicyclo[5,2,0 ^1,7 ]nonane n- in n-hexane at -65°C under nitrogen atmosphere
11.0 g of diisopropylamine in 200 ml of dry tetrahydrofuran within 15 minutes while stirring 55 ml (0.11 mol) of a 2.0 M solution of butyllithium.
(15.5 ml, 0.11 mol) is added dropwise to the solution and the mixture is stirred for 15 minutes at -65°C. 2,2-dimethyl-9-oxo-3-oxa-6-thia-1-azabicyclo[ ^5,2,0,1,7 ] obtained according to Example 6 in 80 ml of dry tetrahydrofuran.
A solution of 18.7 g (0.1 mol) of nonane is added dropwise within 15 minutes with stirring at -65°C, and the mixture is stirred for a further 10 minutes at -65°C. Then -65℃
Then 17 ml (0.3 mol) of acetaldehyde in 80 ml of dry tetrahydrofuran are added dropwise over 15 minutes. Allow the temperature of the mixture to rise slowly to 0°C and stir at 0°C for 1.5 hours. Pour the reaction mixture onto 1 kg of ice and add 2.5 kg of methylene chloride.
Extract with The organic phase is dried over sodium sulfate, filtered and the solvent is removed in a vacuum rotary evaporator. The residue was chromatographed on 1 Kg of Merck silica gel using toluene/ethyl acetate (2:1) as eluent (500 ml sections).
20 pieces). After evaporation of the solvent, a mixture of a compound with the designation erythro-trans (2 parts) and a compound with the designation threo-trans (1 part) is obtained.

_Rf : 0.4 (ethyl acetate).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3550,
1740, 1220, 1080 cm ^-1 .

Example 10 2,2-dimethyl-trans-8-allyl-9
-Oxo-3-oxa-6-thia-1-azabicyclo[5,2,0 ^1,7 ]nonane of butyllithium in n-hexane at -70°C.
Add 1.8 ml of the 2N solution to a solution of 0.35 g (0.5 ml, 3.5 mmol) diisopropylamine in 5 ml dry tetrahydrofuran. After 10 minutes, 2,2-dimethyl-9-oxo-3-oxa-6-thia-1-azabicyclo[5,2,
0 ^1,7 ] Add nonane (0.56 g, 3 mmol) solution. After a further 10 minutes, 1.1 g (0.8 ml, 9 mmol) of allyl bromide are added and the mixture is stirred at 0° C. for 2 hours. The mixture was diluted with 100ml of EtoAc and 1N
Wash with 20 ml of NaH ₂ PO ₄ solution and then with 20 ml of water;
The organic phase is dried over sodium sulfate. After evaporating the solvent in vacuo, transfer the residue to Merck silica gel.
Chromatography on 25 g (triene/EtoAc 9:1) gives the pure title compound.

R _f value: 0.5 (Toluene/EtoAc 1:1) NMR spectrum (CDCl ₃ ), ppm: 2.3-6.3,
8H, m; 1.7, 3H, S; 1.45, 3H, S.

Example 11 2,2-dimethyl-trans-8-(1-p-nitrobenzyloxycarbonyloxyethyl)
-9-oxo-3-oxa-6-thia-1-azabicyclo[5,2,0 ^1,7 ]nonane 21.6 g (0.1 mol) of solid chloroformic acid p-nitrobenzyl ester at -10°C without ethanol 2,2-dimethyl- in 200 ml of methylene chloride
Add trans-8-(1-hydroxyethyl)-9-oxo-3-oxa-6-thia-1-azabicyclo[5,2,0 ^1,7 ]nonane 17.4 g (75 mmol) solution at -10°C. Then 12.2 g (0.1 mol) of solid 4-N',N'-dimethylaminopyridine are introduced into the solution in small portions within 30 minutes. The reaction mixture is stirred for an additional hour at room temperature and then refluxed for 6 hours. After cooling, the mixture is diluted with 1.5 parts of methylene chloride and washed with 1 part of cold aqueous NaCl solution. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in a vacuum rotary evaporator. Merck residue
Chromatograph on 1Kg of SiO ₂ using toluene/ethyl acetate (9:1) as eluent (20 500ml sections). When the solvent is removed, erythro-
A racemic mixture of compounds designated as trans and threo-trans is obtained.

R _f :0.4 (trans/ethyl acetate 1:1).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 1760,
1750, 1610, 1530, ^{1355cm -1} .

Example 12 2,2-dimethyl-trans-8-(1-p-nitrobenzyloxycarbonyloxyethyl)
-9-Oxo-3-oxa-6-thia-1-azabicyclo[5,2,0 ^1,7 ]nonane-6-dioxide m-chloroperbenzoic acid (90%) at -10°C 19.4
g (0.1 mol) in small portions over 30 minutes in 200 ml of dry methylene chloride.
Dimethyl-trans-8-(1-p-nitrobenzyloxycarbonyloxyethyl)-9-oxo-
3-oxa-6-thia-1-azabicyclo[5,
2,0 ^1,7 ] Add to 16.4g of nonane solution.

The mixture was then stirred at 0°C for 1 hour,
Dilute with 1.5 methylene chloride and wash with saturated aqueous sodium bicarbonate solution, 10% sodium bisulfite solution and again with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the solvent is evaporated off in a vacuum rotary evaporator. The amorphous residue consists of a racemic mixture of the erythro-trans and threo-trans designated compounds and is used directly further.

_Rf : 0.6 (EtoAc).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 1780,
1750, 1610, 1325, 1135 ^{cm -1} .

Example 13 trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-(2-hydroxyethylsulfonyl)-2-oxoazetidine Crude 2,2-dimethyl-trans-8-(1-p-nitrobenzyl oxycarbonyloxyethyl)-
9-Oxo-3-oxa-6-thia-1-azabicyclo[5,2,0 ^1,7 ]nonane 6-dioxide
17.7 g (40 mmol) was dissolved in 260 ml of glacial acetic acid,
Dilute with 60ml of water. The mixture was refluxed for 105 minutes,
Remove the solvent in a vacuum rotary evaporator and dry in a high vacuum. The residue is dissolved in 60 ml of methylene chloride and crystallized at -20°C. pure erythro
The compound represented by trans can be obtained by further recrystallizing the above crystals.

R _f value: 0.35 (EtoAc).

Melting point 152℃.

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3570,
3370, 1790, 1750, 1520, 1350cm ^-1 .

NMR spectrum (in DMSO-d/100MC),
ppm: 9.1, 1H, S; 8.3-7.6, 4H, m; 5.3,
2H, S; 5.5−5.0, 1H, 5.1, 1H, dd, J=4
Hz, J=6.5Hz; 4.9, 1H, d, J=2.5Hz; 3.7−
39, 3H, m; 3.3-3.4, 2H, m; 1.5, d, 3H,
J=6.6Hz.

The mother liquor was concentrated by evaporation and the residue was sent to Merck.
Chromatograph on 600 g of SiO ₂ using toluene/ethyl acetate (2:1) as eluent. The sections with an R _f value of 0.4 (EtoAc) are combined and the solvent is removed in a vacuum rotary evaporator. The pure amorphous threo-trans designation compound has an R _f value of 0.4.
(EtoAc).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3570,
3370, 1790, 1750, 1520, 1350cm ^-1 .

NMR spectrum (in DMSO-d/100MC),
ppm: 9.1, 1H, S; 8.4-7.6, 4H, m; 5.3,
2H, S; 5.5−5.0, 1H, 5.1, 1H, dd, J=5
Hz, J=6.5Hz; 4.0, 1H, d, J=2.5Hz; 3.9−
37, 3H, m; 3.33, 2H, m; 1.45, 3H, d, J
=6.5Hz.

The following examples illustrate the further processing of the compounds obtained according to Examples 1 to 13.

Example 14 Threo-trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-(cis
-β-methoxycarbonyl vinyl mercapto)
-2-Oxoazetidine 4.73 g (24 mmol) of cis-β-methoxycarbonylvinyl isouronium chloride in 100 ml of 95% ethanol from 48 ml of 1.0 N aqueous sodium hydroxide solution with stirring under nitrogen atmosphere for 5 minutes.
Add dropwise to the solution that has been cooled to -15℃,
The internal temperature is maintained at -10℃ by external cooling. −10℃
After stirring for another 5 minutes, add 60ml of 95% ethanol.
of threo-trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-(2-hydroxyethylsulfonyl)-2-oxoazetidine (8.1 g (20 mmol)) at -10°C within 5 minutes. Add dropwise and then heat the mixture at 2°C.
Stir for 80 minutes. After adding 1 part of methylene chloride, the mixture was washed twice with 500 ml of saturated aqueous NaCl solution each time, and the organic phase was dried over sodium sulfate,
Filter and remove in a vacuum rotary evaporator. The solid residue is chromatographed on 300 g of Merck SiO ₂ using toluene/ethyl acetate (2:1) as eluent. After evaporation of the solvent in vacuo, crystallization from methylene chloride/n-hexane gives the pure title compound.

_Rf : 0.6 (EtoAc).

Melting point 164.5-165.5℃.

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3500,
1790, 1760, 1710, 1530, 1360 cm ^-1 .

NMR spectrum (in DMSO-d/100MC),
ppm: 8.8, 1H, S; 8.3-7.6, 4H, dd; 7.5,
1H, d, J = 10Hz; 6.0, 1H, d, J = 10Hz;
5.3, 2H, S; 5.1, 1H, d, J=2.5Hz; 5.2−
5.0, 1H, m; 3.6, 3H, S; 3.5, 1H, dd, J
=6Hz, J=2.5Hz; 1.35, 3H, d, J=6.5Hz.

Example 15 Erythro-trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-
(cis-β-methoxycarbonylvinylmercapto)-2-oxoazetidine The title compound is obtained as described in Example 14 from the corresponding erythro-trans starting material.

R _f value: 0.6 (EtoAc).

Melting point 135-137.5℃.

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3400,
1790, 1760, 1710, 1530, 1360 cm ^-1 .

NMR spectrum (in DMSO-d/100MC),
ppm: 8.8, 1H, S; 8.3-7.6, 4H, m; 7.5,
1H, d, J = 10Hz; 6.0, 1H, d, J = 10Hz;
5.3, 2H, S; 5.05, 1H, d, J=2.5Hz; 5.2−
5.0, 1H, m; 3.65, 3H, S; 3.55, 1H, dd,
J=2.5Hz, J=5Hz; 1.4, 3H, d, J=6.5Hz.

Example 16 2-threo-trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-
(cis-β-methoxycarbonylvinylmercapto)-2-oxoazetidinyl]-2-hydroxyacetic acid acetonyl ester threo-trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-(cis- β
-methoxycarbonylvinylmercapto)-2-
A mixture of 2.25 g (50 mmol) of oxoazetidine and 2 g of glyoxylic acid acetonyl ester was mixed with 5 ml of N,N-dimethylformamide and 10 g of toluene.
ml and dissolved at 30 °C in a 3Å molecular sieve.
Stir for 15 hours. After the mixture has cooled, it is filtered, the residue is washed several times with ethyl acetate, and the combined liquids are freed from the solvent in a vacuum rotary evaporator. The residue was then concentrated by evaporation several times with dimethylformamide in vacuo (0.02 mmHg) at a bath temperature of 55 °C and then chromatographed on 120 g of Merck SiO ₂ using toluene/ethyl acetate (2:1) as eluent. Apply to graphie. The sections containing the product are combined and the solvent is removed in a vacuum rotary evaporator. For an amorphous viscous substance, R _f =0.6
(EtoAc).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3500,
1780, 1760, 1740, 1530 ^{cm -1} .

Example 17 2-[erythro-trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-
4-(cis-β-methoxycarbonylvinylmercapto)-2-oxoazetidinyl]-2-hydroxyacetic acid acetonyl ester The corresponding named compound is obtained from the erythro-trans starting material according to the description in Example 16. . Amorphous, viscous substance R _f =0.6 (EtoAc).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3500,
1780, 1760, 1740, 1530 ^{cm -1} .

Example 18 2-[threo-trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4
-(cis-β-methoxycarbonylvinylmercapto)-2-oxoazetidinyl]-2-triphenylphosphoranylidene acetic acid acetonyl ester -10°C, 0.43 ml of thionyl chloride under nitrogen atmosphere
(6 mmol) of 2-[threo-trans-3-] in 25 ml of dry tetrahydrofuran with stirring.
(1-p-nitrobenzyloxycarbonyloxyethyl)-4-(cis-β-methoxycarbonylvinylmercapto)-2-oxoazetidinyl]-
2-hydroxyacetic acid acetonyl ester 2.7g
(5 mmol) to the solution and then at -10° C. 0.83 ml (6 mmol) of triethylamine are added dropwise over 2 minutes. The mixture was stirred for a further 30 minutes at 0°C, 150 ml of ice-cold methylene chloride was added, and the mixture was then dissolved in 0.1N aqueous HCl.
Wash with 50 ml and then 50 ml of saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and the solvent is removed on a vacuum rotary evaporator. The amorphous solid residue is used directly.

The above amorphous solid residue (2.8 g, 5 mmol) was dissolved in a mixture of 2.9 g (12 mmol) of triphenylphosphine and 4 ml of tetrahydrofuran.
Leave at room temperature under nitrogen atmosphere for an hour. The mixture is diluted with 100 ml of methylene chloride and washed twice with 30 ml of 10% aqueous sodium carbonate solution each time. The organic phase is dried over sodium sulphate, filtered and the solvent is removed in a vacuum rotary evaporator. Merck the residue
Chromatograph on 100 g of SiO ₂ using toluene/ethyl acetate (3:1) as eluent. The amorphous solid residue has an R _f value of 0.5 (EtoAc)
have.

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 1755,
1695, 1630, 1525 cm ^-1 .

Example 19 2-[erythro-trans-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-
4-(cis-β-methoxycarbonylvinylmercapto)-2-oxoazetidinyl]-2-triphenylphosphoranylidene acetic acid acetonyl ester The correspondingly named compound is also the starting material for erythro-trans as described in Example 18. It can also be obtained from

Amorphous solid.

R _f =0.5 (EtoAc).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 1755,
1695, 1630, 1525 cm ^-1 .

Example 20 Trio-trans-6-(1-p-nitrobenzyloxycarbonyloxyethyl)penem-3
-Carboxylic acid acetonyl ester 2-[threo-trans-3-(1-p-
(nitrobenzyloxycarbonyloxyethyl)
-4-(cis-β-methoxycarbonylvinylmercapto)-2-oxoazetidinyl]-2-triphenylphosphoranylidene acetic acid acetonyl ester
Add 1.96 g (2.5 mmol) to the solution and introduce a stream of O ₃ in O ₂ (0.33 mmol O ₃ per minute) for 15 minutes into the mixture at this temperature. Excess O ₃ was then removed by introducing nitrogen and then 2 ml dimethyl sulfide.
Add. Stir the mixture at 10°C for 10 minutes,
Diluted with 50 ml of ice-cold methylene chloride, washed twice with 25 ml of 10% aqueous potassium bicarbonate solution each time, dried the organic phase over sodium sulfate, concentrated by evaporation in a vacuum rotary evaporator, and concentrated the solid residue to a high concentration. Dry in vacuo for 2 minutes and add methylene chloride (freshly filtered through Alox).
Dissolve in 60ml. The solution was then refluxed under a nitrogen atmosphere for 90 minutes, after cooling concentrated by evaporation in a vacuum rotary evaporator and the residue was chromatographed on 25 g of Merck SiO ₂ using toluene/ethyl acetate (3:1) as eluent. Apply to graphie. Concentration of the combined fractions by evaporation yields the pure amorphous title compound.

R _f value = 0.55 (EtoAc).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 1795,
1750, 1745, 1720, 1530, 1350cm ^-1 .

NMR spectrum (acetone-d/100Mc),
ppm: 8.3-7.6, 4H, m, 7.6, 1H, S, 5.95,
1H, d, J = 2.5Hz; 5.3, 2H, S; 5.4-5.1,
1H, m; 4.8, 2H, S; 4.2, 1H, dd, J=6
Hz, J=2.5Hz; 2.1, 2H, S; 1.45, 3H, d,
J=6.5Hz.

Example 21 Erythro-trans-6-(1-p-nitrobenzyloxycarbonyloxyethyl)penem-
3-Carboxylic acid acetonyl ester The correspondingly labeled compounds are also obtained using the erythro-trans starting compound as starting material according to the description in Example 20.

Melting point 154-156°C R _f =0.55 (EtoAc).

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 1795,
1745, 1720, 1530, 1350 ^{cm -1} .

NMR spectrum (acetone-d/100Mc),
ppm: 8.4-7.6, 4H, m, 7.6, 1H, S; 5.8,
1H, d, J = 2.5Hz; 5.35, 2H, S; 5.25, 1H,
dd, J=6.5Hz, J=3.5Hz; 4.80, 2H, S; 3.8,
1H, m; 2.1, 3H, S; 1.5, 3H, d, J = 6.5
Hz.

Example 22 Threo-trans-6-(1-hydroxyethyl)penem-3-carboxylic acid acetonyl ester Threo-trans-6-(1-p-nitrobenzyloxy (carbonyloxyethyl)penem-3-carboxylic acid acetonyl ester 0.936g
(2 mmol) solution is hydrogenated over 800 mg of 10% pd/c catalyst for 2.5 hours at room temperature. strain the mixture;
The liquid is concentrated by evaporation and the residue is
Merck SiO ₂ 40g on toluene/eluent
Chromatograph using ethyl acetate (2:1). The solvent of the combined sections is removed in a vacuum rotary evaporator and the residue is crystallized by adding methylene chloride/ether.

R _f value: 0.6 (EtoAc).

Melting point 115-116℃.

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3580,
1790, 1725, 1720, ^{1560, 1175cm -1} .

NMR spectrum (in acetone-d/100Mc),
ppm; 7.6, 1H, S; 5.85, 1H, d, J=2Hz;
4.8, 1H, S; 4.4, 1H, m; 4.4-4.0, 1H,
S; 3.85, 1H, dd, J=7Hz, J=2Hz; 2.15,
3H, S; 1.3, 3H, d, J = 6.5Hz.

Example 23 Erythro-trans-6-(1-hydroxyethyl)penem-3-carboxylic acid acetonyl ester The corresponding title compound is also obtained from the erythro-trans starting compound as described in Example 22.

R _f value: 0.4 (EtoAc).

Melting point 120-121.5℃.

Infrared spectrum (CH ₂ Cl ₂ ): absorption band 3580,
1790, 1725, 1720, ^{1560, 1175cm -1} .

NMR spectrum (in acetone-d/100Mc),
ppm: 7.55, 1H, d, J=1Hz; 5.8, 1H, d,
J=2Hz; 4.8, 2H, S; 4.4, ~4.0, 1H, S;
4.4～4.2, 1H, m; 4.0, 1H, m; 2.15, 3H,
S; 1.35, 3H, d, J = 6.5Hz.

Example 24 Threo-trans-6-(1-hydroxyethyl)penem-3-carboxylic acid 10 ml of aqueous 0.1 NaOH solution at 0°C under nitrogen atmosphere
0.271 of threo-trans-6-(1-hydroxyethyl)penem-3-carboxylic acid acetonyl ester in 40 ml of acetonitrile and 10 ml of water for 15 minutes.
g (1 mmol) dropwise to the solution. The mixture was stirred for another 30 min at 0°C and then swollen with a weakly acidic cation exchanger (Merck) 6.
Stir with g for 5 minutes at 0℃, filter, and concentrate by evaporation in vacuo to a volume of about 20 ml, 20 cm x 20 cm.
Chromatographed on 10 Antec gel dodecyltrichlorosilane TLC plates with water. Elution with acetonitrile/H ₂ O (3:1) and lyophilization of the solution gives the sodium salt of the named compound in the form of an amorphous solid.

R _f value: 0.4 ( _H2O , Antec gel dodecyltrichlorosilane TLC plate).

Infrared spectrum (KBr): 1750cm ^-1 .

NMR spectrum (in D ₂ O/100Mc), ppm:
7.25, 1H, S; 5.95, 1H, d, J=2Hz; 4.45,
1H, m; 4.15, 1H, dd, J=6Hz, J=2Hz;
1.48, 3H, d, J = 6.5Hz.

12 mg of the pure sodium salt described above are dissolved in 0.5 ml of water and the resulting solution is applied to an ion exchange column (strongly acidic ion exchanger I, Merck) containing 0.5 g of washed resin. Elute with water to neutrality and lyophilize the acidic fraction to obtain the pure title compound. The compound is recrystallized from hot acetonitrile.

Melting point: 230°C (dislocation at 155-156°).

R _f value: 0.1 (glacial acetic acid/toluene/water 5:5:1).

Infrared spectrum (KBr): 3480, 1795,
1670, 1545, 1435, 1255, 1165 ^{cm -1} .

UV spectrum (in ethanol): λ _nax
260nm (ε3850), 311nm (ε6400).

Example 25 Erythro-trans-6-(1-hydroxyethyl)penem-3-carboxylic acid The corresponding sodium salt of the designation is obtained from the starting compound of erythro-trans as described in Example 24.

Amorphous solid.

R _f = 0.4 (H ₂ O, Antec gel dodecyltrichlorosilane TLC plate).

Infrared spectrum (KBr): 1750cm ^-1 .

NMR spectrum (in D ₂ O/100Mc), ppm:
7.3, 1H, S; 5.9, 1H, d, J=2Hz; 4.4,
1H, m; 4.2, 1H, dd, J=4Hz, J=2Hz;
1.52, d, J = 6.5Hz.

The pure named compounds are obtained in a similar manner.

Melting point 230℃ (transition at 147-151℃).

R _f value 0.1 (glacial acetic acid/toluene/water 5:5:1).

Infrared spectrum (KBr): 3510, 1785,
1670, 1550, 1435, 1260, 1180, 1035, 835 cm ^-1 .

UV spectrum (in ethanol): λ _nax
260nm (ε3650), 311nm (ε6300).

Example 26 The following compounds are obtained in a similar manner to the previous examples using the corresponding starting materials and passing through the corresponding intermediates.

6-ethyl-2-(2-aminoethylthio)-2- in racemic and optically active form
Penem-3-carboxylic acid, 6-hydroxymethyl-2-penem-3-carboxylic acid, 6-hydroxymethyl-3-methyl-2-penem-3-carboxylic acid, 6-hydroxymethyl-2-(3-amino propyl)-2-penem-3-carboxylic acid, 6-hydroxymethyl-2-(3-acetylaminopropyl)-2-penem-3-carboxylic acid, 6-hydroxymethyl-2-ethylthio-2-penem-3 -carboxylic acid, 6-hydroxymethyl-2-(2-aminoethylthio)-2-penem-3-carboxylic acid, 6-hydroxymethyl-2-(2-acetylaminoethylthio)-2-penem-3- Carboxylic acid, 6-(1-hydroxyethyl)-2-methyl-2-
Penem-3-carboxylic acid, 6-(1-hydroxyethyl)-2-(3-aminopropyl)-2-penem-3-carboxylic acid, 6-(1-hydroxyethyl)-2-(3-acetylamino propyl)-2-penem-3-carboxylic acid, 6-(1-hydroxyethyl)-2-ethylthio-
2-penem-3-carboxylic acid, 6-(1-hydroxyethyl)-2-(2-aminoethylthio)-2-penem-3-carboxylic acid, 6-(1-hydroxyethyl)-2-(2 -acetylaminoethylthio)-2-penem-3-carboxylic acid, 6-(2-hydroxyprop-2-yl)-2-penem-3-carboxylic acid, 6-(2-hydroxyprop-2-yl) -2-methyl-2-penem-3-carboxylic acid, 6-(2-hydroxyprop-2-yl)-2-
(3-aminopropyl)-2-penem-3-carboxylic acid, 6-(2-hydroxyprop-2-yl)-2-
(3-acetylaminopropyl)-2-penem-3
-carboxylic acid, 6-(2-hydroxyprop-2-yl)-2-ethylthio-2-penem-3-carboxylic acid, 6-(2-hydroxyprop-2-yl)-2-
(2-Aminoethylthio)-2-penem-3-carboxylic acid, 6-(2-hydroxyprop-2-yl)-2-
(2-acetylaminoethylthio)-2-penem-
3-carboxylic acid, 6-hydroxymethyl-2-(1-methyl-1H-
Tetrazol-5-ylthiomethyl)-2-penem-3-carboxylic acid, and salts thereof.

Example 27 6-(1-hydroxyethyl) as active substance
-2-penem-3-carboxylic acid sodium salt
Dry ampoules or vials containing 0.5 g are produced as follows.

Composition (per ampoule or vial) Active substance 0.5 g Mannitol 0.05 g A sterile aqueous solution of the active substance and mannitol is lyophilized under aseptic conditions in a 5 ml ampoule or vial, the ampoule or vial is closed and tested. do.

Example 28 6-(1-hydroxyethyl) as active substance
A dry ampoule or vial containing 0.25 g of -2-penem-3-carboxylic acid is prepared as follows.

Composition (per ampoule or vial) Active substance 0.25 g Mannitol 0.025 g A sterile aqueous solution of the active substance and mannitol is lyophilized under aseptic conditions in a 5 ml ampoule or a 5 ml vial and the ampoule or vial is sealed;
inspect.

Claims (1)

[Claims] 1 The following formula (): (wherein A is a lower alkylene group having 2 or 3 carbon atoms between two heteroatoms) stereoisomers of the compound represented by the formula () and the compound represented by the formula (), and the stereoisomers of these stereoisomers. blend. 2 The following formula (): 2. A compound according to claim 1, wherein A is a lower alkylene group having 2 or 3 carbon atoms between two heteroatoms. 3. The compound according to claim 1, which is 4-(2-hydroxyethylthio)-2-oxoazetidine. 4. The compound according to claim 1, which is (4R)-4-[(2R)-1-hydroxyprop-2-ylthio]-2-azetidinone. 5. The compound according to claim 1, which is (4S)-4-[(2R)-1-hydroxyprop-2-ylthio]-2-azetidinone.