JPH0466872B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [] [In the formula, R ₀ represents a lower alkyl group, R ₁ represents a hydrogen atom or a hydroxyl group-protecting group, R ₂ represents a hydrogen atom or an amino group-protecting group, and R ₃ represents a hydrogen atom or a carboxyl group-protecting group. . R ₄ and R ₅ are hydrogen atoms,
represents a lower alkyl group, an aralkyl group or a substituted lower alkyl group, or R ₄ and R ₅ represent an alkylene chain or an alkylene chain bonded to each other via an oxygen atom, a sulfur atom or a lower alkyl substituted nitrogen atom, and the adjacent nitrogen Together with atoms, it represents a 4- to 7-membered cyclic amino group. However, with R ₄
R ₅ is never a lower alkyl group at the same time. ] The present invention relates to a novel β-lactam compound represented by the above, a pharmacologically acceptable salt thereof, and a method for producing the same. In the above general formula [], examples of the lower alkyl group for R ₀ include methyl, ethyl, n-propyl,
Examples include alkyl groups having 1 to 3 carbon atoms such as isopropyl, and a preferred example is methyl. The hydroxyl group-protecting group in R ₁ or the amino group-protecting group in R ₂ is preferably, for example, tert
- lower alkoxycarbonyl groups such as butyloxycarbonyl, e.g. 2-ethyloxycarbonyl iodide, halogenoalkoxycarbonyl groups such as 2,2,2-trichloroethyloxycarbonyl, e.g. benzyloxycarbonyl, p-
Aralkyloxycarbonyl groups such as methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trialkylsilyl groups such as trimethylsilyl, tert-butyldimethylsilyl. As a protecting group for carboxyl group in R ₃ ,
Suitable examples include methyl, ethyl, isopropyl,
Straight-chain or branched lower alkyl groups such as tert-butyl, e.g. 2-ethyl iodide,
halogen lower alkyl groups such as 2,2,2-trichloroethyl, e.g. lower alkoxymethyl groups such as methoxymethyl, ethoxyethyl, isobutoxymethyl, e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl,
Lower aliphatic acyloxymethyl groups such as pivaloyloxymethyl, e.g. 1-methoxycarbonyloxyethyl, 1-lower alkoxycarbonyloxyethyl groups such as 1-ethoxycarbonyloxyethyl, e.g. benzyl, p-methoxybenzyl, o - an aralkyl group such as -nitrobenzyl, p-nitrobenzyl, a benzhydryl group or a phthalidyl group. R ₄ and R ₅ are the same or different from each other, and the lower alkyl group is a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.; For example, a phenyl group such as benzyl, substituted benzyl, phenethyl or an alkyl group having 1 to 3 carbon atoms substituted with a substituted phenyl group is substituted with a substituted lower alkyl group such as a hydroxyl group, a di-lower alkylamino group, a carbamoyl group, etc. Examples include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, and n-propyl. In addition, R ₄ and R ₅ represent an alkyl chain or an alkylene chain bonded to each other via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom,
Examples of a 4- to 7-membered cyclic amino group together with the adjacent nitrogen atom include azetidino group, piperidino group, pyrrolidino group, monophorino group, thiomorpholino group, N-methylpiperazino group, and the like. The carboxylic acid compound in which R ₃ is a hydrogen atom in the general formula [] can be converted into a pharmacologically acceptable salt form, if necessary. Such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium, and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, but sodium salts and It is a potassium salt. It is known that carbapenem compounds such as thienamycin (US Pat. No. 3,950,357; J. Am. Chem. Soc., 100 , 313 (1978)) exhibit excellent antibacterial activity. As a result of intensive research aimed at carbapenem compounds that are excellent as antibacterial agents, the present inventors discovered that the compound represented by the general formula [] has a strong antibacterial effect or can be a precursor thereof, The invention has been completed. That is, the β-lactam compound represented by the general formula [] is carbapenem (1-azabicyclo[3,2,0]hept-2-en-7-one-2
-carboxylic acid) derivatives, with the general formula at the 3rd position A novel compound having various 2-aminocarbonylpyrrolidin-4-ylthio groups shown in It has been found that these compounds have strong antibacterial activity and are useful as pharmaceuticals, or are important intermediates for compounds exhibiting antibacterial activity. The method for producing the compound of the present invention will be described in detail below. General formula [] [In the formula, R ₀ and R ₁ have the same meanings as above.
R ₇ represents a carboxyl group protecting group. ] Reactive ester of alcohol represented by and general formula [ ] [In the formula, R ₂ , R ₄ and R ₅ have the same meanings as above. ] By reacting a mercaptan represented by the general formula [ ] in an inert solvent in the presence of a base. [In the formula, R ₀ , R ₁ , R ₂ , R ₄ , R ₅ and R ₇ have the same meanings as above. ] A β-lactam compound represented by the following can be produced. Here, the reactive ester of alcohol refers to, for example, substituted or unsubstituted aryl sulfonic acid ester, lower alkanesulfonic acid ester, halogeno lower alkanesulfonic acid ester, or diarylphosphoric acid ester of alcohol [ ], or halogenated Indicates a halide that is an ester with hydrogen. Furthermore, as substituted or unsubstituted arylsulfonic acid esters,
For example, benzenesulfonic acid ester, p-toluenesulfonic acid ester, p-nitrobenzenesulfonic acid ester, p-bromobenzenesulfonic acid ester, etc., and lower alkanesulfonic acid ester include, for example, methanesulfonic acid ester,
Ethanesulfonic acid ester, etc., halogeno lower alkanesulfonic acid ester, such as trifluoromethanesulfonic acid ester, diarylphosphoric acid ester, such as diphenylphosphoric acid ester, etc.; , for example, chlorine, bromine, iodide, etc. Suitable examples of such alcohol reactive esters include p-toluenesulfonic acid ester, methanesulfonic acid ester, and diphenylphosphoric acid ester. R ₇ corresponds to the protecting group for R ₃ above, and similar examples can be given as suitable protecting groups. Inert solvents used in this reaction include dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, etc., and bases include potassium carbonate, sodium hydrogen carbonate, triethylamine,
Mention may be made of diisopropylethylamine. The raw material mercaptan [] needs to be in an amount sufficient for the reaction to proceed sufficiently, and a large excess amount can be used, but it can usually be carried out using 1 to 1.5 equivalents relative to the reactive ester of the alcohol []. . The reaction temperature is carried out in the range of -78℃ to 60℃,
A range of -40°C to 40°C is suitable. In addition, after the reaction is completed, the resultant can be taken out by ordinary organic chemical methods. Next, from the compound represented by the general formula [] obtained in this way, according to a known method,
By performing a reaction in which the hydroxyl protecting group in R ₁ is removed, the amino group in R ₂ is removed, and the carboxyl group is removed in R ₇ in combination as necessary, the general formula [] A β-lactam compound represented by can be obtained. The method for removing protecting groups varies depending on the type, but
It is removed by generally known methods. For example, in the above general formula [], a compound in which the hydroxyl group protecting group in R ₁ and/or the amino group protecting group in R ₂ is a halogenoalkoxycarbonyl group or an aralkyloxycarbonyl group, and the carboxyl group protecting group R ₇ is a halogenoalkyl group. ,
The protecting group of a compound having an aralkyl group or benzhydryl group can be removed by subjecting it to an appropriate reduction reaction. For such a reduction reaction, when the protecting group is a halogenoalkoxycarbonyl group or a halogenoalkyl group, reduction with an organic solvent such as acetic acid, tetrahydrofuran, or methanol and zinc is suitable; In the case of a benzhydryl group, a catalytic reduction reaction using a catalyst such as platinum or palladium-carbon is suitable. The solvents used in this catalytic reduction reaction include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetic acid, or these organic solvents, and water or buffers such as phosphoric acid and morpholinopropanesulfonic acid. A mixed solvent with a liquid is suitable. The reaction temperature ranges from 0°C to 100°C, but preferably from 0°C to 40°C. Moreover, hydrogen pressure can be carried out under normal pressure or increased pressure. Further, when the protecting group is an o-nitrobenzyloxycarbonyl group or an o-nitrobenzyl group, the protecting group can also be removed by photoreaction. In addition, after the reaction is completed, the resultant can be taken out by ordinary organic chemical methods. The compound represented by the above general formula [] is represented by the following formula There are optical and stereoisomers based on the asymmetric carbons at positions 4, 5, 6 and 8, and these isomers are all shown in a single formula for convenience, as shown in However, the scope of the description of the present invention is not limited thereby. However, regarding the steric structure at the 5th and 6th positions, the carbon atom at the 5th position preferably has an S coordination (5S, 6S) coordination,
Examples include compounds with (5S, 6R) coordination.
Regarding the 8-position, a compound having R coordination can be selected as a suitable one. Regarding the 4-position, there are isomers of α-configuration and β-configuration, with β-configuration being preferred. When producing isomers having such coordination, corresponding isomers can be used in the starting material compound []. Furthermore, regarding the 2′-substituted pyrrolidin-4′-ylthio group, the [2′S, 4′S] coordination, [2′S, 4′R] coordination,
There are four types of isomers: [2′R, 4′S] coordination and [2R′, 4′R] coordination, and they are represented by a single formula in general formulas such as [] However, they are not limited in any way. Among them, preferable steric configurations include compounds with [2'S, 4'S] coordination and [2'R, 4'R] coordination. The compound of the present invention represented by the general formula [] is 3
various 2-aminocarbonylpyrrolidine-4 at the position
- A group of novel carbapenem derivatives having a lower alkyl group at the 4-position and an ylthio group.These compounds exhibit excellent antibacterial activity and are useful as pharmaceuticals, or are compounds that exhibit these activities. It is an important intermediate. Examples of the compound having the general formula [] obtained by the present invention include the compounds described below. (1) 3-[2-aminocarbonylpyrrolidine-4
-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-
Hept-2-en-7-one-2-carboxylic acid (2) 3-[(2-N-methylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-
(1-Hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-
2-Carboxylic acid (3) 3-[(2-N-ethylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-
(1-Hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-
2-Carboxylic acid (4) 3-[(2-N-n-propylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0 ]-hept-2-ene-7-
1-2-carboxylic acid (5) 3-[(2-N-isopropylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0 ]-hept-2-ene-7-
1-2-carboxylic acid (6) 3-[(2-N-n-butylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2 ,0]hept-2-en-7-one-2-carboxylic acid (7) 3-[(2-N-isobutylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl )-1-Azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid (8) 3-[(2-(2-hydroxyethyl)aminocarbonyl)pyrrolidin-4-ylthio] -4
-Methyl-6-(1-hydroxyethyl)-1-
Azabicyclo[3,2,0]-hept-2-en-7-one-2-carboxylic acid (9) 3-[(2-(2-N,N-dimethylaminoethyl)aminocarbonyl)pyrrolidine-4- ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-2-carboxylic acid (10) 3-[(2- (aminocarbonylmethyl)aminocarbonyl)pyrrolidin-4-ylthio]-
4-methyl-6-(1-hydroxyethyl)-1
-Azabicyclo[3,2,0]-hept-2-
En7-one-2-carboxylic acid (11) 3-[(2-benzylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-
(1-Hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-
2-Carboxylic acid (12) 3-[(2-(2-hydroxyethyl)methylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2 ,0]-hept-2-en-7-one-2-carboxylic acid (13) 3-[(2-(2-hydroxyethyl)ethylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6- (1-Hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid (14) 3-[(2-(2-N,N-dimethylaminoethyl ) methylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0]-hept-2-en-7-one-2-carboxylic acid (15) 3-[(2-benzylmethylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl) -1-Azabicyclo[3,2,0]-hept-2-ene-7-
1-2-carboxylic acid (16) 3-[(2-benzylethylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0] Hept-2-en-7-one-2-carboxylic acid (17) 3-[(2-(1-pyrrolidinylcarbonyl))pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl )-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid (18) 3-[(2-(1-piperidinylcarbonyl))pyrrolidin-4-ylthio] -4-Methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-
1-2-carboxylic acid (19) 3-[(2-(1-morpholinylcarbonyl))pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3, 2,0]-hept-2-ene-7-
1-2-carboxylic acid (20) 3-[(2-(1-thiomorpholinylcarbonyl))pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3 ,2,0]-hept-2-ene-7
-one-2-carboxylic acid (21) 3-[(2-(1-N-methylpiperazinecarbonyl))pyrrolidin-4-ylthio]-4-
Methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-2-carboxylic acid (22) 3-[(2-(1-N- Ethylpiperazinylcarbonyl))pyrrolidin-4-ylthio]-4
-Methyl-6-(1-hydroxyethyl)-1-
Azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid (23) 3-[(2-(2-N,N-diethylaminoethyl)aminocarbonyl)pyrrolidine-4-
ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid (24) 3-[(2-( 2-N,N-dimethylaminoethyl)ethylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0]Hept-2-en-7-one-2-carboxylic acid (25) 3-[(2-(2-N,N-diethylaminoethyl)ethylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl- 6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0]Hept-2-en-7-one-2-carboxylic acid (26) 3-[(2-(3-N,N-dimethylaminopropyl)aminocarbonyl)pyrrolidine-4
-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]
Hept-2-en-7-one-2-carboxylic acid (27) 3-[(2-(3-N,N-diethylaminopropyl)aminocarbonyl)pyrrolidine-4
-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]
Hept-2-en-7-one-2-carboxylic acid (28) 3-[(2-(3-hydroxypropyl)aminocarbonyl)pyrrolidin-4-ylthio]
-4-methyl-6-(1-hydroxyethyl)-
1-Azabicyclo[3,2,0]hept-2-
En-7-one-2-carboxylic acid (29) 3-[(2-(2-hydroxy-1-methylethyl)aminocarbonyl)pyrrolidine-4-
ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid (30) 3-[(2-( 2-hydroxypropyl)aminocarbonyl)pyrrolidin-4-ylthio]
-4-methyl-6-(1-hydroxyethyl)-
1-Azabicyclo[3,2,0]hept-2-
En-7-one-2-carboxylic acid (31) 3-[(2-(2-aminocarbonylethyl)
(aminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid (32) 3-[(2-(1-azetidinecarbonyl))
pyrrolidin-4-ylthio]-4-methyl-6
-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-
2-Carboxylic acid (33) 3-[2-aminocarbonylpyrrolidinyl-4-ylthio]-4-ethyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0]-hept-2-en-7-one-2-carboxylic acid (34) 3-[(2-N,N-dimethylaminocarbonyl)pyrrolidin-4-ylthio]-4-ethyl-6-(1- hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7
-one-2-carboxylic acid (35) 3-[(2-(1-piperidinecarbonyl))
pyrrolidin-4-ylthio]-4-ethyl-6
-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-
2-Carboxylic acid As mentioned above, stereoisomers exist in this exemplified compound, and although a single name has been given, this is not intended to be limiting in any way. However, preferred carbapenem skeletons include those having (4R, 5S, 6S, 8R) and (4R, 5S, 6R, 8R) coordinations. As for the pyrrolidinylthio group which is a substituent at the 3-position, preferable examples include those having (2'S, 4'S) and (2'R, 4'R) coordination. The compound [] which is a raw material compound has the general formula [] [In the formula, R ₀ , R ₁ and R ₇ have the same meanings as above. ] For example, benzenesulfonyl chloride, p-toluenesulfonyl chloride,
Substituted or unsubstituted arylsulfonylating agents such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, and p-bromobenzenesulfonyl chloride; lower classes such as methanesulfonic anhydride, methanesulfonyl chloride, and ethanesulfonyl chloride; Alkanesulfonylating agents, e.g. halogeno-lower alkanesulfonylating agents such as trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, diarylphosphonylating agents such as diphenylchlorophosphate, or, e.g. triphenylphosphine dichloride, Treated in the presence of a halogenating agent such as triphenylphosphine dibromide or oxalyl chloride and a base such as triethylamine, diisopropylethylamine or N-dimethylaminopyridine in an inert solvent such as methylene chloride, acetonitrile, dimethylformamide, or tetrahydrofuran. It can be manufactured by The compound represented by the above general formula [] can be prepared by a known method (for example, JP-A-58-26887).
Alternatively, it can be produced according to a known method, and for example, compound [Va] can be produced by the method shown in the following scheme. [In the formula, R ₀ and R ₇ have the same meanings as above,
R ₆ represents a protecting group for the amide NH group, and Y represents a t-butyldimethylsilyl group. ] Compounds 2a~ and 2b~ are (3R, 4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone 1~ (Chemical and Pharmacy Euthetical Bulletin (Chem.Pharm.Bull) Volume 29, Nos. 2899-2909
(1981)) in the presence _of diethylaluminum chloride _{and zinc .} has the same meaning as above;
X represents a halogen atom. ] It is obtained as a mixture by reacting the halogeno fatty acid ester represented by the following in a solvent such as ethers such as tetrahydrofuran, dioxane and diethyl ether, aromatic hydrocarbons such as benzene and toluene, or in a mixed solvent of these and hexane. It will be done. Separation and purification of each isomer (2a~ and 2b~) can be performed by silica gel column chromatography. Compounds 3a to 3a can be obtained by a conventional protection reaction of the nitrogen atom of an amide group (e.g., silylation reaction, tetrahydropyranylation reaction), and the protecting group R ₆ is a tri-lower group such as trimethylsilyl, t-butyldimethylsilyl, etc. Mention may be made of cyclic ethers such as alkylsilyl groups, 2-tetrahydropyranyl, and the like. Compounds 4a - can be obtained by a commonly used deprotection reaction of a carboxylic acid, such as alkaline hydrolysis, solvation reaction with an acid such as trifluoroacetic acid, or catalytic reduction. Compound [Va] can be produced from Compound 4a to Compounds 5a to 6a to 7a by a known method (for example, JP-A-58-26887). Compound [Va] can be led to the corresponding isomer of compound [] according to the method described above. Furthermore, the isomer of the 4-position carbon of the compound [Va] (e.g. 4α-methyl form) and the corresponding isomer of the compound [] can be produced in the same manner as the above method by using compounds 2b~. can. On the other hand, raw material mercaptan [] can be produced by various methods, but for example, by the method shown below, 2'S-configured mercaptan can be produced using trans-4-hydroxy-L-proline 8~ as a raw material compound. Mercaptans [a], [b], and [c] having the following positions can be produced. [In the formula, R ₄ , R ₅ and R ₇ have the same meanings as above. R ₈ represents an amino group-protecting group, and R ₉ represents a thiol group-protecting group. [Step A] This can be easily achieved by a commonly used protection reaction of the amino group of various known amino acids, such as a method of reacting with arylmethyloxycarbonyl chloride etc. in the presence of a base, or S-acyl- Examples include a method using 4,6-dimethyl-2-mercaptopyrimidine and the like. Step B Various known methods for obtaining esters from carboxylic acids are possible, and for example, this can be achieved by reacting carboxylic acids 9 to 9 with various alkyl halides or aralkyl halides in the presence of a base. Step C Various known methods for converting a hydroxyl group into a protected thiol group are possible; for example, after deriving the hydroxyl group into an active ester, various thiolating reagents such as thioacetic acid, thiobenzoic acid, trityl mercaptan, etc. and a base can be used. This can be achieved by reacting in the presence of This step can also be obtained by reacting an alcohol derivative with a thiolating reagent such as thioacetic acid in the presence of triphenylphosphine and diethyl azodicarboxylate in an inert solvent such as tetrahydrofuran. Step D Various known methods for converting esters into carboxyl groups are possible, such as alkaline hydrolysis, an acid method using trifluoroacetic acid, hydrobromic acid, etc., or a reductive method using zinc. be able to. Step E Various known methods for converting carboxylic acid into an amide group are possible, but for example, the carboxylic acid group is converted into an active ester derivative using a halogenating agent, an acylating agent, etc., and the general formula [In the formula, R ₄ and R ₅ have the same meanings as above. ] This is achieved by a method of treating with an amine represented by: Step F Various known deprotection methods for thiol protecting groups are possible. For example, when the thiol protecting group is an acyl group, it can be removed by a method such as alkaline hydrolysis. Step G Various known oxidation reactions for converting hydroxyl groups into carbonyl groups are possible, and this can be achieved, for example, by oxidation reactions such as chromic acid-sulfuric acid in acetone. Step H Various known reduction reactions for converting a carbonyl group into a hydroxyl group are possible, but for example, by treatment with sodium borohydride etc., a mixture of Compounds 10- and 16-, in which the steric hydroxyl groups of 10-- are different, is obtained. be able to. Although the production ratio of 10~ and 16~ differs depending on the conditions, each compound can be obtained as a single compound by purification such as recrystallization or chromatography. Isomerization of the 4-position hydroxyl group can be achieved through the above steps G and H, but it can also be achieved by a method that involves steps I and J described below. IJ process Alcohol derivative is converted into triphenylphosphine,
This can be achieved by reacting with formic acid in an inert solvent such as tetrahydrofuran in the presence of diethyl azodicarboxylate to give a formyloxy derivative 20~, and then removing the formyl group by a method such as alkaline hydrolysis. I can do it. K step Various commonly used methods for deprotecting amino groups are possible, including methods using acids such as trifluoroacetic acid and hydrobromic acid, reductive methods using zinc or lithium-liquid ammonia, etc. Alternatively, it can be achieved by catalytic reduction or the like. In addition, in the production of 2′R mercaptan, cis-4-hydroxy-
It can be produced using D-proline in accordance with the method for producing the 2'S isomer described above, that is, by combining the various reactions described in the production of the 2'S isomer. Among the novel β-lactam compounds of the present invention represented by the general formula [], compounds in which R ₁ , R ₂ and R ₃ are hydrogen atoms include Staphylococcus aureus, Staphylococcus epidermides, Streptococcus It has excellent antibacterial activity against a wide range of pathogenic bacteria, including Gram-positive bacteria such as C. pyrogiens and Streptococcus fuecalis, and Gram-negative bacteria such as Escherichia coli, Proteus mirabilis, Selassia marsetuscens, and Pseudomonas aeruginosa. It is a useful compound as an antibacterial agent. moreover,
It is a unique compound that has excellent antibacterial activity against β-lactamase-producing bacteria. Other compounds of the present invention are important synthetic intermediates for synthesizing compounds exhibiting antibacterial activity as described above. Further, although the compounds of the present invention differ depending on each compound, they are generally characterized by high physicochemical stability and excellent solubility in water. The administration form for using the compound of the present invention as an antibacterial agent for treating bacterial infections includes, for example, oral administration in tablets, capsules, powders, syrups, etc., or parenteral administration in intravenous injection, intramuscular injection, rectal administration, etc. An example is administration. The dosage varies depending on the symptoms, age, body weight, dosage form, number of administrations, etc., but it is usually about 1 day per day for adults.
Administer 100 to 3000 mg once or in divided doses.
The amount can be reduced or increased as necessary. In addition, the compound of the present invention can be used as Z-7-
(L-amino-2-carboxyethylthio)-2-
It can also be administered in combination with a dipeptidase inhibitor such as sodium (2,2-dimethylcyclopropanecarboxamide)-2-heptenoate (compound group described in JP-A-56-81518). Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is of course not limited to these in any way. The meanings of the abbreviations used in the following Examples and Reference Examples are as follows. PNZ: p-nitrobenzyloxycarbonyl group PMZ: p-methoxybenzyloxycarbonyl group PMB: p-methoxybenzyl group PNB: p-nitrobenzyl group Ph: phenyl group Ac: acetyl group Ms: methanesulfonyl group tBu: t-butyl Group Me: Methyl group Et: Ethyl group (TBDMS): t-butyldimethylsilyl group Example 1 (a) (4R, 5R, 6S, 8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-
1-Azabicyclo[3,2,0]-hept-3,
7-Dione-2-carboxylate (61 mg) was dissolved in dry acetonitrile (6 ml) and diisopropylethylamine (72
mg), then diphenyl chlorophosphate (55
mg) and stirred for 2.5 hours, then [2S, 4S]-1
-p-nitrobenzyloxycarbonyl-2-
(1-pyrrolidinylcarbonyl)-4-mercaptopyrrolidine (77 mg) was added, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography. -p-
Nitrobenzyl-3-(1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolidinylcarbonyl)pyrrolidin-4-ylthio]-4
-Methyl-6-(1-hydroxyethyl)-1-
Azabicyclo[3,2,0]-hept-2-en-7-one-2-carboxylate (51mg)
I got it. IR ^film _nax (cm ^-1 ): 1760, 1710, 1640, 1525, 1440,
1350, 1210, 1110 NMRδ (CDGl ₃ ): 1.30 (3H, d, J = 7.0Hz),
1.34 (3H, d, J = 6.5Hz), 5.21 (2H.s), 5.20 and 5.44 (2H, ABq, J = 14Hz), 7.50 (2H,
d, J=8.5Hz), 7.64 (2H, d, J=8.5Hz),
8.20 (4H, d, J = 8.5Hz) (b) (4R, 5S, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-[1-p-nitrobenzyloxycarbonyl-2 -(1-pyrrolidinylcarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-
7-one-2-carboxylate (50 mg) was mixed with tetrahydrofuran (3.9 ml) and ethanol (0.6
10% dissolved in morpholinopropanesulfonic acid buffer (PH = 7.0, 3.9 ml) and hydrogenated at room temperature for 1 hour under normal hydrogen pressure and then washed with water.
Palladium-carbon (60 mg) was added and hydrogenated under atmospheric hydrogen pressure for 4.5 hours at room temperature. After passing through the catalyst, tetrahydrofuran and ethanol were distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the aqueous layer was again distilled off the organic solvent under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the part eluted with 2% tetrahydrofuran aqueous solution (4R, 5S, 6S, 8R, 2'S, 4'S) -
3-[2-(1-pyrrolidinylcarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo[3,
2,0]-hept-2-en-7-one-2-
Carboxylic acid was obtained. UV ^H ₂ ^O _{nax on} : 297 NMRδ (D ₂ O): 1.20 (3H, d, J = 7.0Hz), 1.28
(3H, d, J=6.5Hz), 1.95 (6H, m), 3.46
(6H, m), 3.72 (1H, dd, J=6.5Hz and 12
Hz), 4.02 (1H, guintet, J=6.5Hz) Example 2 (a) (4R, 5R, 6S, 8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-
1-azabicyclo[3.2.0]-hept-3,7-
Dione-2-carboxylate (116 mg) was dissolved in dry acetonitrile (1.4 ml) and diisopropylethylamine (87
mg) and then diphenyl chlorophosphate (90 mg) and stirred for 1.5 hours [2S, 4S]
-1-p-nitrobenzyloxycarbonyl-
2-(2-hydroxyethyl)methylaminocarbonyl-4-mercaptopyrrolidine (96mg)
Add a solution of dry acetonitrile (1.6 ml) of
The mixture was stirred as it was for 14 hours. The reaction solution was diluted with ethyl acetate, washed with 0.1M phosphate buffer (PH=7.0), dried over magnesium sulfate and sodium carbonate, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography and purified with (4R, 5S,
6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3
-[4-(1-p-Nitrobenzyloxycarbonyl-2-(2-hydroxyethyl)methylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl-1-azabicyclo[3.2.0 ]-hept-2-en-7-one-2-carboxylate (148 mg) was obtained. IR ^film (cm ^-1 ): 3400 (br), 1700, 1633, 1513,
1422, 1398, 1340, 1205 NMRδ (CDCl ₃ ): 1.28 (3H, d, J = 7.3Hz) 1.37
(3H, d, J=5.9Hz) 2.01 (1H, m) 2.62 (1H,
m) 2.9-3.2 (3H, m) 3.2-3.9 (9H, m) 3.99
(1H, m) 4.1-4.4 (9H, m) 5.21 (2H, s)
5.37 (2H, m) 7.49 (2H, d, J = 8.9Hz) 7.65
(2H, d, J=8.9Hz) 8.23 (2H, d, J=8.9
Hz) (b) (4R, 5S, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-(2-hydroxyethyl) ) Methylaminocarbonyl(pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2
-En-7-one-2-carboxylate (148 mg) was dissolved in tetrahydrofuran (15 ml) and water (15 ml), 10% palladium on carbon (592 mg) was added, and the mixture was hydrogenated at room temperature under normal pressure of hydrogen for 5.5 hours. After filtering the catalyst, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with methylene chloride, the aqueous layer was again distilled off under reduced pressure to remove the organic solvent, and the residual liquid was subjected to polymer chromatography (CHP-
20P), the parts eluted with 1% to 2% tetrahydrofuran aqueous solution (4R, 5S, 6S,
8R, 2′S, 4′S)-3-[(2-(2-hydroxyethyl)methylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2 .0] -Hept-
2-en-7-one-2-carboxylic acid was obtained. IR ^KBr (cm ^-1 ): 3410 (br), 1740, 1640, 1590,
1370 NMRδ (D ₂ O): 1.17 (3H, d, J = 7.3Hz) 1.24
(3H, d, J=6.6Hz) 1.96 (1H, m) 2.9~3.2
(4H, m) 3.2-3.6 (5H, m) 3.6-3.9 (3H,
m) 4.03 (1H, m) 4.1-4.3 (2H, m) UV ^H2O (nm): 297 The following compounds can be synthesized in a similar manner to ^the methods described in _Examples 1 and 2. (1) (4R, 5S, 6S, 8R, 2′S, 4′S) −3− [2−
Aminocarbonylpyrrolidin-4-ylthio]
-4-methyl-6-(1-hydroxyethyl)-
1-Azabicyclo[3,2,0]-hept-2
-en-7-one-2-carboxylic acid (2) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-N-methylaminocarbonyl)pyrrolidine-
4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]
-hept-2-en-7-one-2-carboxylic acid (3) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-N-ethylaminocarbonyl)pyrrolidine-
4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]
-hept-2-en-7-one-2-carboxylic acid (4) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-N-(isopropylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo[3,
2,0]hept-2-en-7-one-2-carboxylic acid (5) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(2-hydroxyethyl)aminocarbonyl)
pyrrolidin-4-ylthio]-4-ethyl-6
-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-
2-Carboxylic acid (6) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(2-N,N-dimethylaminoethyl)aminocarbonyl)pyrrolidin-4-ylthio]-
4-methyl-6-(1-hydroxyethyl)-1
-Azabicyclo[3,2,0]-hept-2-
En-7-one-2-carboxylic acid (7) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(aminocarbonylmethyl)aminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-
one-2-carboxylic acid (8) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-benzylaminocarbonyl)pyrrolidine-4
-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-
Hept-2-en-7-one-2-carboxylic acid (9) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(2-N,N-dimethylaminoethyl)methylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2 -en-7-one-2-carboxylic acid (10) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(1-azetidylnylcarbonyl))pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0]-hept-2-en-7-one-2-carboxylic acid (11) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(1-morpholinylcarbonyl))pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0]-hept-2-en-7-one-2-carboxylic acid (12) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(1-thiomorpholinylcarbonyl))pyrrolidin-4-ylthio]-4-methyl-6-(1-
hydroxyethyl)-1-azabicyclo[3,
2,0]-hept-2-en-7-one-2-
Carboxylic acid (13) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(1-N-methylpiperazinylcarbonyl))
pyrrolidin-4-ylthio]-4-methyl-6
-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-
2-Carboxylic acid (14) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-(1-pyrrolidinylcarbonyl))pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0] hept-2-en-7-one-2-carboxylic acid (15) (4R, 5S, 6S, 8R, 2′S, 4′S)-3-[(2
-benzylmethylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0]-hept-2-en-7-one-2-carboxylic acid (16) (4R, 5S, 6S, 8R, 2′R, 4′S)-3-[2
-(1-pyrrolidinylcarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0] Hept-2-en-7-one-2-carboxylic acid reference example 1-1 Trans-4-hydroxy-L-proline (6.55 g) and triethylamine (7.5 ml) were dissolved in water (15 g).
ml) and added Sp-nitrobenzyloxycarbonyl-4,6-dimethyl-2 at room temperature.
- A solution of mercaptopyrimidine (15.95 g) in dioxane (35 ml) was added dropwise, stirred at room temperature for 1.5 hours, and left overnight. Add 2N to the reaction solution under ice cooling.
Add sodium hydroxide (30ml), extract with ether, and remove the ether layer with 1N sodium hydroxide (20ml).
After washing with , the alkaline aqueous layers were combined, acidified with hydrochloric acid using 2N-hydrochloric acid water (100 ml), and extracted with ethyl acetate. The ethyl acetate layer was sequentially washed with 2N hydrochloric acid, dried with sodium sulfate, and the solvent was distilled off. The resulting crude crystals were purified by repulping with ethyl acetate to obtain trans
(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline was obtained. mp 134.3~135.5℃ IR ^Nujol _nax (cm ^-1 ): 3300 (br), 1738, 1660, 1605,
1520, 1340, 1205, 1172, 1070, 965 Reference example 1-2 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (15.0 g) and triethylamine (13.5 ml) were dissolved in dry dimethylformamide (150 ml), and p-methoxybenzyl chloride ( 12.66
ml) was added dropwise and stirred at 70°C for 10 hours. The reaction solution was diluted with ethyl acetate (500ml), washed with water, dried with mirabilite,
The solvent was distilled off and the residue was crystallized from ether to give trans-1-(p-nitrobenzyloxycarbonyl).
-4-Hydroxy-L-proline-p-methoxybenzyl ester was obtained. mp 83~85℃ IR ^film _nax (cm ^-1 ): 3430, 1735, 1705, 1510, 1340,
1245, 1160 Reference example 1-2 trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline-p
-Methoxybenzyl ester (8.6 g) and triphenylphosphine (7.86 g) were dissolved in dry tetrahydrofuran (20 ml), and a solution of diethyl azodicarboxylate (5.22 g) in dry tetrahydrofuran (5 ml) was cooled with ice under a nitrogen stream. Drip and leave it as is.
After stirring for 30 minutes, thioacetic acid (2.28 g) was added dropwise, and the mixture was stirred for 1 hour under ice cooling and then for 3 hours at room temperature.
Concentrate the reaction solution. The residue was subjected to silica gel column chromatography to give cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L
-Proline-p-methoxybenzyl ester was obtained. IR ^film _nax (cm ^-1 ): 1740 (sh), 1715, 1520, 1405,
1348, 1120 NMRδ ( _CDCl3 ): 2.31 (3H, s), 3.79 (3H, s),
5.10 (2H, s), 5.24 (2H, s), 7.49 (2H, d,
J=9.0Hz), 8.18 (2H, d, J=9.0Hz) Reference example 1-4 cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline-p-
Methoxybenzyl ester (9.76g), anisole (4.32g) with trifluoroacetic acid (35ml)
Stir at room temperature for 30 minutes. It was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain cis-1-
(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline was obtained. mp 107~109℃ IR ^Nujol _nax (cm ^-1 ): 1725, 1685, 1660 (sh), 1340,
1180, 1110 Reference example 1-5 cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline (160
mg) was dissolved in dry methylene chloride (2 ml), 1 drop of dimethylformamide was added thereto, oxalyl chloride (0.1 ml) was added, and the mixture was stirred at room temperature for 1 hour.
After distilling off the solvent under reduced pressure, a solution of tetrahydrofuran (2 ml) was prepared, and the solution was added dropwise to a solution of pyrrolidine (60 mg) in tetrahydrofuran (3 ml) under ice cooling.
Stir for hours. The reaction solution was diluted with ethyl acetate, washed with water, dried with mirabilite, and the solvent was distilled off. The residue was subjected to silica gel chromatography (2S, 4S)-1-
(p-nitrobenzyloxycarbonyl)-2-
(1-pyrrolidinylcarbonyl)-4-acetylthiopyrrolidine was obtained. IR ^film (cm ^-1 ): 1705, 1640, 1516, 1430, 1342,
1110 NMRδ ( _CDCl3 ): 2.31 (3H, s) 4.03 (2H, dd,
J=6Hz, J=8Hz) 4.53 (1H, t, J=8
Hz) 5.19 (2H, s) 7.48 (2H, d, J = 9Hz)
8.18 (2H, d, J=9Hz) Reference example 1-6 (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(1-pyrrolidinylcarbonyl)-4-acetylthiopyrrolidine (48 mg) was dissolved in methanol (3 ml), and 1N-NaOH (0.12
ml) was stirred at room temperature for 15 minutes. Then 1N−HCl
(0.14ml) and concentrated under reduced pressure. The concentrated solution was diluted with ethyl acetate, washed with water, dried with mirabilite, and the solvent was distilled off to give (2S, 4S)-1-(p-nitrobenzyloxycarbonyl)-2-(1-pyrrolidinylcarbonyl)-
4-Mercaptopyrrolidine was obtained. IR ^film (cm ^-1 ): 1708, 1645, 1520, 1440, 1405,
1350, 1170, 1115 NMRδ (CDCl ₃ ): 1.90 (1H, d, J = 8Hz) 2.97
(3H, s) 3.08 (3H, s) 5.19 (2H, s) 7.48
(2H, d, J=9Hz) 8.15 (2H, d, J=9
Hz) The following thioacetates were obtained in the same manner as in Reference Example 1-5 using the respective corresponding amines.

【table】

[Table] Reference example 2-1 trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline 3.10
g, 1.10 g of triethylamine was dissolved in 40 ml of dry tetrahydrofuran, and 1.20 g of ethyl chloroformate was dissolved in 10 ml of dry tetrahydrofuran at -25°C to -35°C.
Add the solution dropwise and stir for 50 minutes, then -25℃ to 40℃
10 ml of concentrated ammonia water was added dropwise. The temperature was gradually raised to room temperature, and after further stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Add 20 ml of water and 50 ml of ether to the residue, collect the white crystals obtained after cooling with ice, wash them sequentially with cold water and cold ether, and dry under reduced pressure to obtain trans-1-(p-
Nitrobenzyloxycarbonyl)-4-hydroxy-L-prolinamide was obtained. mP 163.3~164.0℃ IR ^Nujol _nax (cm ^-1 ): 3460, 3370, 3200, 1687, 1640,
1621, 1539, 1341, 1180, 1078 Reference example 2-2 A suspension of 2.32 g of trans-1-(P-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolinamide and 1.67 g of triethylamine in 40 ml of dry tetrahydrofuran at room temperature contains 1.89 g of methanesulfonyl chloride in dry tetrahydrofuran 10
ml solution was added dropwise, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Add 30 ml of water and 30 ml of ether to the residue, collect the white crystals obtained after cooling with ice, wash them sequentially with cold water and cold ether, and dry under reduced pressure to obtain trans-1-
(P-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolinamide was obtained. mP 149.5~151℃ IR ^Nujol _nax (cm ^-1 ): 3400, 3225, 1715, 1675, 1520,
1340, 1170, 1135 Reference example 2-3 642 thioacetic acid under a nitrogen stream in a suspension of 374 mg of 50% sodium hydride in 13 ml of dry dimethylformamide.
Add 14 ml of dry dimethylformamide solution of
Stir for 25 minutes at room temperature, add 975 mg of sodium iodide to this solution, and then add a solution of 2.52 g of trans-1-(P-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolinamide in 12 ml of dry dimethylformamide. The mixture was heated and stirred at 70°C for 6 hours. The reaction solution was poured into cold brine and extracted with benzene. The extract was washed successively with a 10% aqueous sodium sulfite solution and brine, dried with mirabilite, and the solvent was distilled off. The resulting crude crystals were purified by repulping with a mixed solvent of tetrahydrofuran and benzene. -1-(P-nitrobenzyloxycarbonyl)-4-thioacetoxy-L-prolinamide was obtained. mP 168.5~169.5℃ IR ^Nujol _nax (cm ^-1 ): 3350, 3180, 1715, 1690, 1638,
1510, 1330, 1100 [α] ³⁰ _D −23° (c=0.334, DMF) Reference example 2-4 From (2s, 4s)-1-(P-nitrobenzyloxycarbonyl)-2-carbamoyl-4-acetylthiopyrrolidine (950 mg), (2s, 4s)-1-( P-nitrobenzyloxycarbonyl)-2-aminocarbonyl-4-mercaptopyrrolidine was obtained. mP 158-162℃ Reference example 3-1 A solution of dimethyl sulfoxide (0.35 ml) in dry methylene chloride (1 ml) was added to a solution of oxalyl chloride (0.2 ml) in dry methylene chloride (5 ml) at -60 to -70°C.
After 10 minutes, a dry methylene chloride solution (10 ml) of trans-1-(P-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline P-methoxybenzyl ester (860 mg) was added dropwise to -50
It was added dropwise at a temperature below 0.degree. C. and stirred for 15 minutes. Next, triethylamine (1.01 g) was added dropwise, warmed to room temperature, diluted with methylene chloride, washed with dilute hydrochloric acid, dried with sodium sulfate, evaporated the solvent, and the residue was subjected to silica gel column chromatography. -nitrobenzyloxycarbonyl)-4-osiso-L-proline P
-Methoxybenzyl ester IR ^film _nax (cm ^-1 ): 1762, 1740, 1710, 1512, 1345,
1245, 1155 NMRδ ( _CDCl3 ): 3.78 (3H, s), 3.95 (2H, s),
5.08 (2H, s), 6.85 (2H, d, J=9Hz),
8.12 (2H, d, J=9Hz) Reference example 3-2 1-(P-nitrobenzyloxycarbonyl)-
Dissolve 4-oxo-L-proline P-methoxybenzyl ester (650 mg) in ethanol (45 ml) and add sodium borohydride (86 mg) at room temperature.
Add in two parts. After 30 minutes, it was concentrated under reduced pressure at below 30°, the concentrated solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain cis-1-(P-nitro benzyloxycarbonyl)-4-hydroxy-
L-proline P-methoxybenzyl ester and trans-1-(P-nitrobesidyloxycarbonyl)-4-hydroxy-L-proline P-
Methoxybenzyl ester was obtained. Trans form: IR and NMR were consistent with the spectrum data of the compound of Reference Example 1-2. Cis body: IR ^film _nax (cm ^-1 ): 3400 (br), 1725, 1515
,
1405, 1350, 1250, 1170, 1120 NMRδ ( _CDCl3 ): 3.78 (3H, s), 5.08 (2H, s),
6.82 (2H, d, J = 9Hz), 8.12 (2H, d, J =
9Hz) Reference example 3-3 Using cis-1-(P-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline P-methoxybenzyl ester (610 mg), trans-1- (P-nitrobenzyloxycarbonyl)-
4-acetylthio-L-proline was obtained. IR ^film _nax (cm ^-1 ): ~3000, 1700, 1515, 1430, 1400
,
1345, 1205, 1165 NMRδ ( _CDCl3 ): 2.32 (3H, s), 5.20 (2H, br,
s), 7.42 (2H, d, J=9Hz), 8.12 (2H, d,
J=9Hz) Reference example 3-4 (a) [2s,4R]-1-(P- Nitrobenzyloxycarbonyl)-2-aminocarbonyl-4-acetylthiopyrrolidine (132 mg) was obtained. IR ^film _nax (cm ^-1 ): 3300 (br), 1700 (sh), 1685, 1
512,
1430, 1400, 1345, 1175, 1115 [α] ³⁰ _D +7.36° (c = 0.625, acetone) (b) Thioacetate derivative obtained in (a) above (100 mg)
[2s,
4R]-1-(P-nitrobenzyloxycarbonyl)-2-aminocarbonyl-4-mercaptopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 1700, 1685, 1515, 1435, 1400,
1342, 1118 NMRδ ( _CDCl3 ): 2.26 (1H, d, J = 7Hz), 5.22
(2H, s), 8.11 (2H, d, J = 8.5Hz) Reference example 4-1 Cis-1-P-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-P-methoxy obtained from cis-4-hydroxy-D-proline in the same manner as in Reference Examples 1-1 and 1-2. The benzyl ester (166 mg) and triphenylphosphine (202 mg) are dissolved in dry tetrahydrofuran (1.5 ml) and then formic acid (27 mg) is added.
plus diethyl azodicarboxylate (134mg)
was added under a nitrogen stream at room temperature, and after stirring for 30 minutes, the solvent was distilled off. The residue was purified by silica gel chromatography to give trans-1-P-nitrobenzyloxycarbonyl-4-formyloxy-D-proline-
P-methoxybenzyl ester was obtained. IR ^film _nax (cm ^-1 ): 1720, 1515, 1402, 1342, 1245,
1165, 1120 NMRδ ( _CDCl3 ): 3.76 (3H, s), 4.50 (2H, t,
J=8Hz), 5.08 (2H, s), 5.15 (2H, ABq,
J=16Hz), 5.41 (1H, m), 7.97 (1H, s) Reference example 4-2 trans-1-P-nitrobenzyloxycarbonyl-4-formyloxy-D-proline-P
-Methoxybenzyl ester (215mg) was dissolved in tetrahydrofuran (1.1ml) and 1N-NaOH water was added.
Add 0.93ml, stir for 10 minutes, dilute with ethyl acetate, and wash with saturated saline. After drying the Glauber's salt, the solvent was distilled off. The residue was purified by thin layer chromatography to give trans-1-P-nitrobenzyloxycarbonyl-4
-Hydroxy-D-proline-P-methoxybenzyl ester was obtained. IR ^film _nax (cm ^-1 ): 3425 (br), 1735, 1705, 1510,
1400, 1340, 1240, 1162 NMRδ ( _CDCl3 ): 2.33 (2H, m), 3.58 (2H, d,
J=3.5Hz), 3.73 (3H, s), 5.03 (2H, s),
5.07 (2H, ABq, J = 18Hz), 6.73 (2H, d, J
= 9Hz), 6.77 (2H, d, J = 9Hz), 8.00 (2H,
d, J=8.5Hz), 8.07 (2H, d, J=8.5Hz) Reference example 4-3 (a) trans-1-P-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-P
- using methoxybenzyl ester (110 mg),
[2R, 4R]-1-P-nitrobenzyloxycarbonyl-2-aminocarbonyl- by the same method as Reference Examples 1-3, 1-4 and 2-1
40 mg of 4-acetylthiopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 1685, 1515, 1400, 1340 1110 [α] ³⁰ _D +39.6° (c = 0.293, DMF) (b) Thioacetate derivative obtained in (a) above (40 mg)
[2R,
4R]-1-P-nitrobenzyloxycarbonyl)-2-aminocarbonyl-4-mercaptopyrrolidine was obtained. IR ^Nujol _nax (cm ^-1 ): 3200, 1710, 1655, 1512, 1340,
1115 Reference example 5 (a) Cis-4-hydroxy-D-proline (300
mg) to Reference Examples 1-1, 1-2, 1-3, 1-
By the same method as 4 and 2-1 [2R, 4S]
-1-P-nitrobenzyloxycarbonyl-
2-Aminocarbonyl-4-acetylthiopyrrolidine (82 mg) was obtained. IR ^film _nax (cm ^-1 ): 1705 (sh), 1685, 1520, 1425,
1402, 1342, 1122 [α] ³⁰ _D −6.92° (c = 0.665, acetone) (b) Thioacetate derivative obtained in (a) above (66 mg)
[2R,
4S]-1-P-nitrobenzyloxycarbonyl)-2-aminocarbonyl-4-mercaptopyrrolidine was obtained. IR ^CHCl _3nax (cm ^-1 ): 1695 (sh), 1682, 1515, 1395,
1340, 1115 Reference example 6-1 trans-1-P-nitrobenzyloxycarbonyl-4-hydroxy-L-proline (500mg)
and P-nitrobenzyl bromide (383 mg),
Trans-1- by the same method as Reference Example 1-2
P-nitrobenzyloxycarbonyl-4-hydroxy-L-proline-P-nitrobenzyl ester was obtained. IR ^CHCl _3nax (cm ^-1 ): 3380 (br), 1750, 1705, 1520,
1425, 1400, 1342, 1160 NMRδ ( _CDCl3 ): 2.20 (3H, m), 3.67 (2H, d,
J=3Hz), 4.60 (2H, t, J=8Hz), 5.15
(2H, s), 5.23 (2H, ABq), 7.47 (4H, d,
J=8.5Hz), 8.15 (4H, d, J=8.5Hz) Reference example 6-2 From trans-1-P-nitrobenzyloxycarbonyl-4-hydroxy-L-proline-P-nitrobenzyl ester, cis-1-P-nitrobenzyloxycarbonyl was obtained by the same method as in Reference Examples 1-3 and 1-6. -4-Mercapto-L
-Proline-P-nitrobenzyl ester was obtained. IR ^film _nax (cm ^-1 ): 1700, 1685, 1600, 1510, 1430,
1400, 1340, 1105 Reference example 6-3 (a) Dissolve cis-1-P-nitrobenzyloxycarbonyl-4-mercapto-L-proline-P-nitrobenzyl ester (115 mg) in dry tetrahydrofuran (3 ml), add triethylamine (30 mg), and cool on ice. Add ethyl chloroformate (28.5 mg) dropwise, stir for 10 minutes, dilute with ethyl acetate, wash sequentially with dilute hydrochloric acid and water, and dry with mirabilite. The solvent was distilled off to obtain cis-1-P-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline-P-nitrobenzyl ester (133 mg). IR ^film _nax (cm ^-1 ): 1755, 1710, 1610, 1525, 1405,
1350, 1160, 1015, 850 (b) Dissolve the ester derivative (133 mg) obtained in (a) above in a tetrahydrofuran-water (1:) mixture (5 ml), add 1N-NaOH water (0.26 ml), and dissolve at room temperature. After stirring for 2.5 hours, 1N-HCl (0.3ml) was added.
Extracted with ethyl acetate, washed with water, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel thin layer chromatography to give cis-1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-
Got proline. IR ^film _nax (cm ^-1 ): 1700, 1520, 1400, 1340, 1165,
1145 NMRδ ( _CDCl3 ): 1.30 (3H, t, J=7Hz), 4.28
(2H, q, J=7Hz), 5.24 (2H, s), 7.50
(2H, d, J=9Hz), 8.17 (2H, d, J=9
Hz) Reference example 6-4 (a) Cis-1-P-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline (72 mg) was dissolved in dry tetrahydrofuran (3
After adding triethylamine (40 mg), ethyl chloroformate (41 mg) was added dropwise under ice-cooling, and after stirring for 15 minutes, methylamine (40%) aqueous solution (1.5 ml) was added dropwise, and then 15 minutes Stir for minutes. The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid and water, and dried with mirabilite. Evaporate the solvent, [2S, 4S]-1-P-
Nitrobenzyloxycarbonyl-2-methylaminocarbonyl-4-ethoxycarbonylthiopyrrolidine was obtained. IR ^Nujol _nax (cm ^-1 ): 3290, 1705, 1660, 1520, 1425,
1405, 1345, 1180, 1160 NMRδ (CDCl ₃ ): 1.30 (3H, t, J = 8Hz), 2.80
(3H, d, J = 5Hz), 4.27 (2H, q, J = 8
Hz), 5.22 (2H, s), 7.48 (2H, d, J=9
Hz), 8.18 (2H, d, J = 9Hz) (b) The methylaminocarbonyl derivative (82 mg) obtained in (a) above was added to a methanol/water (1:1) mixture (4
ml), add 0.25 ml of 1N-NaOH,
After stirring at room temperature for 30 minutes, add 0.27 ml of 1N-HCl.
Extracted with ethyl acetate, washed with water, dried with mirabilite, and then distilled off the solvent to give [2S, 4S]-1-P-nitrobenzyloxycarbonyl-2-methylaminocarbonyl-
4-Mercaptopyrrolidine was obtained. IR ^Nujol _nax (cm ^-1 ): 3280, 1710, 1650, 1510, 1340,
1165 NMRδ ( _CDCl3 ): 2.79 (3H, a, J=5Hz), 4.27
(2H, t, J=8Hz), 5.23 (2H, s), 7.50
(2H, d, J=9Hz), 8.20 (2H, d, J=9
Hz) The following thiocarbonates were obtained in the same manner as in Reference Example 6-4(a) using the respective corresponding amines.

[Table] The following mercaptan was obtained in the same manner as in Reference Example 1-6 or 6-4(b).

[Table] Reference example 8-1 (a) Trans-4-hydroxy-L-proline (10 g) and S-P-methoxybenzyloxycarbonyl in the same manner as in Reference Example 1-1 using 4,6-dimethyl-2-mercaptopyrimidine (23.2 g) trans-1-(p-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline was obtained. IR ^film _nax (cm ^-1 ): 3400 (br), 1692, 1430, 1355,
1245, 1170, 1122 NMRδ ( _CDCl3 ): 2.23 (2H, m), 3.73 (3H, s),
5.00 (2H, s), 6.78 (2H, d, J=9Hz),
7.20 (2H, d, J = 9Hz) (b) Using the proline derivative (0.57g) obtained in (a) above and benzylamine (0.215g), Reference Example 2-
Trans-1-P-methoxybenzyloxycarbonyl-4-hydroxy-L-benzylprolinamide was obtained in the same manner as in Example 1. IR ^Nujol _nax (cm ^-1 ): 3375, 3300, 1665, 1248, 1165,
1120, 1025 NMRδ ( _CDCl3 ): 3.76 (3H, s), 4.35 (4H, m),
4.96 (2H, s), 6.79 (2H, d, J=9Hz),
7.20 (5H, s) (c) Benzylprolinamide obtained in (b) above (0.5
[2S,4S]-1-P-methoxybenzyloxycarbonyl-2-benzylaminocarbonyl- by the same method as in Reference Example 1-3 using
4-Acetylthiopyrrolidine was obtained. IR ^Nujol _nax (cm ^-1 ): 3280, 1690, 1675, 1240 NMR δ (CDCl ₃ ): 2.27 (3H, s), 3.82 (3H, s),
4.42 (2H, d, J=6Hz), 5.05 (2H, s),
6.87 (2H, d, J = 8Hz), 7.23 (2H, d, J =
8Hz), 7.28 (5H, s) Reference example 8-2 (a) [2S,4S]-1-P-methoxybenzyloxycarbonyl-2-benzylaminocarbonyl-4-acetylthiopyrrolidine (177 mg) and anisole (86 mg) were dissolved in 0.5 ml of trifluoroacetic acid and stirred at room temperature for 30 minutes. did. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium bicarbonate and water, and dried with sodium sulfate. The solvent was distilled off, the residue was subjected to silica gel thin layer chromatography, and [2S, 4S]-
2-benzylaminocarbonyl-4-acetylthiopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 3325, 1690, 1510, 1400, 1350,
1120, 950 NMRδ ( _CDCl3 ): 2.28 (3H, s), 3.83 (2H, m),
4.42 (2H, d, J = 6Hz), 7.32 (5H, s) (b) Thioacetate derivative obtained in (a) above (40mg)
was subjected to the same treatment as in Reference Example 1-6 to obtain [2S,
4S]-2-benzylaminocarbonyl-4-mercaptopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 3250, 1685, 1610, 1510, 1132 Reference example 9-1 20 ml of dry tetrahydrofuran was added to 1.33 g (20 mM) of activated zinc, and then a 15% n-hexane solution (8.8 ml) of diethylaluminium chloride was added under ice-cooling and nitrogen flow, and (3R, 4R)- 4
-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone
(1) A solution of 1.49g (5.2mM) and benzyl-α-bromopropionate 3.73g (15.3mM) dissolved in 13.3ml of dry tetrahydrofuran was added dropwise over 30 to 40 minutes, and then stirred for an additional hour. Under ice cooling, add 2.8 ml of pyridine, then 13.2 ml of water, 26.5 ml of ethyl acetate and 13.2 ml of 1N hydrochloric acid, and filter through Celite. The liquid was washed with water, the organic layer was dried with sodium sulfate, the solvent was distilled off, and the resulting oily residue was subjected to silica gel column chromatography to obtain 4-(1-benzyloxycarbonyl)ethyl-3-[(R)- A mixture of 1-(t-butyldimethylsilyloxy)ethyl]-2-acetidinone was obtained. Separation of isomers was performed using 1.5% isopropanol/n-
This was achieved by Rover column chromatography (silica gel) eluting with hexane to give (2a) and (2b) as oils. Isomer (2b) IR ^film _nax (cm ^-1 ): 1755, 1460, 1377, 1252, 1100,
835 NMRδ ( _CDCl3 ): 0.06 (6H, s), 0.87 (9H, s),
1.16 (3H, d, J = 6.5Hz), 1.19 (3H, d, J
= 7.0Hz), 3.71 (1H, dd, J = 2 and 10Hz),
5.14 (2H, s), 7.35 (5H, s) Isomer (2a) NMRδ (CDCl ₃ ): 0.06 (6H, s), 0.87 (9H, s),
1.08 (3H, d, J = 6.5Hz), 1.18 (3H, d, J
= 7.0Hz), 3.91 (1H, dd, J = 2.2 and 5.5
Hz), 4.17 (2H, q, J=6Hz), 5.12 (2H,
s), 7.35 (5H, s) Reference example 9-2 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyl-dimethylsilyloxy)ethyl]-2-azetidinone (2a) (200
mg) was dissolved in dry dimethylformamide (2 ml) and added to triethylamine (126 mg), then t
-Butyldimethylsilyl chloride (151 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and purified by silica gel chromatography to obtain 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy). ) ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone (3a) was obtained. IR ^film _nax (cm ^-1 ): 1750, 1465, 1325, 1255, 835 Reference example 9-3 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone (184 mg) was dissolved in methanol 4
ml and stirred with 10% palladium-carbon (20 mg) under normal pressure hydrogen gas for 2 hours. The catalyst was removed, the liquid was concentrated under reduced pressure, and 4-(1-carboxy)
Ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone (4a) was obtained. IR ^film _nax (cm ^-1 ): 1740, 1465, 1330, 1255, 1043,
837 Reference example 9-4 4-(1-carboxy)ethyl-3-[(R)-1
-(t-butyldimethylsilyloxy)ethyl]-
From 1-(t-butyldimethylsilyl)-2-azetidinone (170 mg), JP-A-58-26887 No. 64
~ By the method described on page 65 (4R, 5R, 6S, 8R)
-P-nitrobenzyl-4-methyl-6-(1-
hydroxyethyl)-1-azabicyclo[3,2,
0]-hepto-3,7-dione-2-carboxylate was obtained. IR ^film _nax (cm ^-1 ): 3450 (br), 1770 (sh), 1750, 1
605,
1520, 1350, 1217, 1180 For the 4S-methyl form, the compound (2b) obtained in Reference Example 9-1 was used, and the above-mentioned Reference Example 9-2,
It can be synthesized by the same method as 9-3 and 9-4. In addition, for those in which the 4-position is other than a methyl group, by replacing benzyl-α-bromopropionate with a corresponding halogeno fatty acid ester such as benzyl-α-bromo-n-butyrate in Reference Example 9-1. Can be synthesized. Reference example 10 (a) Cis-4-hydroxy-D-proline (300
mg), Reference Examples 1-1, 1-2, 1-3, 1
-4 and 2-1 [2R,
4S]-1-P-nitrobenzyloxycarbonyl-2-pyrrolidinecarbonyl-4-acetylthiopyrrolidine (66 mg) was obtained. IR ^film _nax (cm ^-1 ): 1695, 1635, 1515, 1430, 1395,
1340, 1115 (b) Thioacetate derivative obtained in (a) above (60 mg)
[2R,
4S]-1-P-nitrobenzyloxycarbonyl-2-pyrrolidinecarbonyl-4-merkabutopyrrolidine was obtained. IR ^CHCl _3nax (cm ^-1 ): 1700, 1640, 1520, 1422, 1345,
1120

Claims (1)

[Claims] 1. General formula [In the formula, R ₀ represents a lower alkyl group, R ₁ represents a hydrogen atom or a hydroxyl group-protecting group, R ₂ represents a hydrogen atom or an amino group-protecting group, and R ₃ represents a hydrogen atom or a carboxyl group-protecting group. . R ₄ and R ₅ are hydrogen atoms,
represents a lower alkyl group, an aralkyl group or a substituted lower alkyl group, or R ₄ and R ₅ represent an alkylene chain or an alkylene chain bonded to each other via an oxygen atom, a sulfur atom or a lower alkyl substituted nitrogen atom, and the adjacent nitrogen Together with atoms, it represents a 4- to 7-membered cyclic amino group. However, with R ₄
R ₅ is never a lower alkyl group at the same time. ] A β-lactam compound represented by these and a pharmacologically acceptable salt thereof. 2 Whether R ₄ and R ₅ are both hydrogen atoms or R ₄ and
The β-lactam compound and pharmacologically acceptable salt according to claim 1, wherein R ₅ represents an alkylene chain bonded to each other and together with the adjacent nitrogen atom represents a 4- to 7-membered cyclic amino group. 3. The compound according to claim 1 or 2, and a pharmacologically acceptable salt thereof, wherein the β-lactam compound represented by the general formula has a (5S, 6S, 8R) conformation. 4. The compound according to claim 1 or 2, wherein the β-lactam compound represented by the general formula has a conformation (4R, 5S, 6S, 8R), and a pharmacologically acceptable salt thereof . 5 General formula A compound according to claim 1 or 2 and a pharmacologically acceptable salt thereof. 6 Claim 1, wherein R ₀ is a methyl group,
A compound according to item 2, 3 or 5 and a pharmacologically acceptable salt thereof. 7. The compound and pharmacologically acceptable salt thereof according to claim 6, wherein R ₄ and R ₅ are bonded together and together with the adjacent nitrogen atom form a pyrrolidinyl group. 10 formula A compound according to claim 1 represented by: and a pharmacologically acceptable salt thereof. 11 General formula [In the formula, R ₀ represents a lower alkyl group, R ₁ represents a hydrogen atom or a hydroxyl group-protecting group, R ₂ represents a hydrogen atom or an amino group-protecting group, and R ₃ represents a hydrogen atom or a carboxyl group-protecting group. . R ₄ and R ₅ are hydrogen atoms,
represents a lower alkyl group, an aralkyl group or a substituted lower alkyl group, or R ₄ and R ₅ represent an alkylene chain or an alkylene chain bonded to each other via an oxygen atom, a sulfur atom or a lower alkyl substituted nitrogen atom, and the adjacent nitrogen Together with atoms, it represents a 4- to 7-membered cyclic amino group. However, with R ₄
R ₅ is never a lower alkyl group at the same time. ] In producing the β-lactam compound represented by the general formula [In the formula, R ₀ represents a lower alkyl group, R ₁ represents a hydrogen atom or a hydroxyl group-protecting group, and R ₇ represents a carboxyl group-protecting group. ] Reactive ester of alcohol represented by and general formula [In the formula, R ₂ , R ₄ and R ₅ have the same meanings as above. ] The mercaptan represented by is reacted in the presence of a base to form the general formula [In the formula, R ₀ , R ₁ , R ₂ , R ₄ , R ₅ and R ₇ have the same meanings as above. ] Produce a β-lactam compound represented by R ₁ ,
When a β-lactam compound in which R ₂ and/or R ₃ is a hydrogen atom is desired, a reaction for removing the carboxyl group protecting group R ₇ , a reaction for removing the hydroxy protecting group in R ₁ , and an amino acid reaction for R ₂ . A method for producing a β-lactam compound and a pharmacologically acceptable salt thereof, which comprises subjecting the group to a reaction for removing a protecting group in an appropriate combination as necessary. 12 Claims in which R ₄ and _{R 5 simultaneously} represent _a hydrogen atom or an alkylene chain bonded to each other, and together with the adjacent nitrogen atom represent a 4- to 7-membered cyclic amino group The manufacturing method according to item 11. 18. The production method according to claim 11 or 12, in which R ₀ is a methyl group.