JPS60104088A - Novel beta-lactam compound and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R0 is lower alkyl; R1 is H, or hydroxyl-protecting group; R2 is H, or amino-protecting group; R3 is H, or carboxyl-protecting group; R4 and R5 are H, lower alkyl, aralkyl, substituted lower alkyl, or R4 and R5 are linked each other to form alkylene chain or alkylene through O, etc., or R4 and R5 together with neighboring N show cyclic amino of 4-7-membered ring) and its salt. EXAMPLE:( 4S,5R,6S,8R,2'S,4'S )-3-[ 4-( 2-Dimethylcarbamoyl ) pyrrolidinylthio]-4- methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid. USE:An important intermediate for a compound exhibiting antibacterial activity. Having high physical and chemical stability and improved solubility. PREPARATION:A compound shown by the formula II (R7 is carboxyl-protecting group) is reacted with a mercaptan shown by the formula III in the presence of a base to give a compound shown by the formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (IJ [wherein, Ro represents a lower alkyl group, K represents a hydrogen atom or a hydroxyl group-protecting group, R2 represents a hydrogen atom or an amino group-protecting group, and R3 represents a protecting group for a hydrogen atom or a carboxyl group.

R4 and R6 represent a hydrogen atom, a lower alkyl group, an aralkyl group, or a substituted lower alkyl group, or R4 and R6 are an alkylene chain or an oxygen atom that are bonded to each other,
Represents an alkylene chain via a sulfur atom or a lower alkyl substituted nitrogen atom, and together with the adjacent nitrogen atom, 4 to 7
Represents a membered cyclic amino group. ] A new β expressed as
-Relates to lactam compounds, pharmacologically acceptable salts thereof, and methods for producing the same.

In the general formula CI], the lower alkyl group of Ro is,
Examples include alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, and isopropyl;
A suitable example is a methyl group.

The protecting group for the hydroxyl group or the protecting group for the amino group in R2 is preferably a lower alkoxycarbonyl group such as tert-butyloxycarbonyl, such as 2-ethyloxycarbonyl iodide, 2,2.
Norogenoalkoxy carbonyl groups such as 2-1-lichloroethyloxycarbonyl, e.g. benzyl 2-oxycarbonyl, P-methoxybenzyloxycarbonyl, 0-
Aralkyloxycarbonyl groups such as nitrobenzyloxycarbonyl, P-nitrobenzyloxycarbonyl, trialkylsilyl groups such as trimethylsilyl, tert-butyldimethylsilyl.

The carboxyl group-protecting group in 2. 2.2-1-IJ Halogeno lower alkyl groups such as dichlorotyl, e.g. lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl, isobutoxymethyl, e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyl Lower aliphatic acyloxymethyl groups such as oxymethyl, e.g. 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, etc.
- lower alkoxycarbonyloxyethyl groups, such as benzyl, P-methoxybenzyl, 0-nitrobenzyl,
It is an aralkyl group such as P-nitrobenzyl, a benzhydryl group or a phthalidyl group.

R4 and R6 are the same or different from each other, examples of lower alkyl groups include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, and n-butyl; examples of aralkyl groups include, for example. Phenyl group or substitution such as benzyl, substituted benzyl, phenethyl.

An alkyl group having 1 to 3 carbon atoms substituted with a phenyl group,
Examples of substituted lower alkyl groups include methyl substituted with hydroxyl group, di-lower alkylamino group, carbamoyl group, etc.
Examples include lower alkyl groups having 1 to 4 carbon atoms such as ethyl and n-propyl.

In addition, when R4 and R represent an alkylene chain bonded to each other or an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and together with the adjacent nitrogen atom represent a 4- to 7-membered cyclic amino group,
Examples include azetidino group, piperidino group, pyrrolidino group, morpholino group, thiomorpholino group, and N-methylpiperazino group.

The carboxylic acid compound in which 3 in general formula CI) is a hydrogen atom can be converted into a pharmacologically acceptable salt form, if necessary. Examples of 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. Sodium and potassium salts.

Chenamycin (U.S. Pat. No. 3,950,357,
J, Am, Chem, Soc,, 100, 31
It is known that carbapenem compounds such as 3 (197B)) exhibit excellent antibacterial activity.

The present inventors have also conducted extensive research with the aim of finding carbapenem compounds that are excellent as antibacterial agents.As a result, we have found that the compound represented by the general formula CI) has a strong antibacterial effect, or may be a precursor thereof. The present invention has been completed.

That is, the β-lactam compound represented by the general formula [I] belongs to carbapenem (1-azabicyclo(3,2,O)hept-2-en-7-one-2-carphonic acid) derivatives, and - It is a novel compound having various 2-carbamoylpyrrolidin-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 (II) [In the formula, R6 and Ni have the same meanings as above. R
7 represents a carboxyl group protecting group. ] Reactive ester of alcohol represented by the general formula (1
11) [In the formula, R3, R4 and 6 have the same meanings as above. ] By reacting a mercaptan represented by the following in an inert solvent in the presence of a base, the general formula [) [wherein Ro, R□, R2, R,, R6 and R7]
has the same meaning as above. ] A β-lactam compound represented by the following can be produced.

Examples of reactive esters of alcohol include:

For example, it is a substituted or unsubstituted arylsulfonic acid ester, lower alkanesulfonic acid ester, halogeno lower alkanesulfonic acid ester or diarylphosphoric acid ester of alcohol (II), or an ester with hydrogenated water or hydrogen. Indicates a halide. Further, examples of substituted or unsubstituted arylsulfonic acid ester include benzenesulfonic acid ester,
Examples of lower quaternary alkanesulfonic acid esters include pt-ruenesulfonic acid ester, P-nitrobenzenesulfonic acid ester, p-bromobenzenesulfonic acid ester, methanesulfonic acid ester, ethanesulfonic acid ester, and halogen ester. Examples of lower alkanesulfonic acid esters include trifluoromethanesulfonic acid esters, examples of diarylphosphoric acid esters include diphenylphosphoric acid esters, and examples of halides include chlorine, bromine, and iodide. be able to.

Suitable examples of such reactive esters of alcohol include p-torenine sulfonic acid ester, methanesulfonic acid ester, and diphenylphosphoric acid ester.

R7 corresponds to the protecting group for R3, and similar examples can be given as suitable protecting groups.

The inert groove used in this reaction, dioxane as a medium,
Examples of the base include dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, and the like, and examples of the base include potassium carbonate, sodium bicarbonate, triethylamine, and diisopropylethylamine.

The raw material mercaptan [mJ] needs to be in an amount sufficient for the reaction to proceed sufficiently, and can be used in large excess;
This can be done using 1.5 equivalents.

The reaction temperature is carried out in the range 4 of -78°C to 60'C, preferably in the range 1 of -40°C to 40°C.

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 (IV3) obtained in this manner, a reaction for removing the protecting group for the hydroxyl group in the nitric acid, a reaction for removing the protecting group for the amino group in R2, a reaction for removing the protecting group for the amino group in R2, and a reaction for removing the protecting group for the amino group in R2 according to known methods. The β-lactam compound represented by the general formula (1) can be obtained by appropriately combining the reactions for removing the protecting group R7 as necessary.

The method for removing the protecting group varies depending on the type and class, but it is removed by a generally known method.

For example, in the above general formula (IV), a compound in which the protecting group for the hydroxyl group in 2 is a halogenoalkoxycarbonyl group or an aralkyloxycarbonyl group, and the protecting group for the carboxyl group R7 is a halogenoalkyl group. , an aralkyl group, or a benzhydryl group, the protecting group can be removed by subjecting the compound 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; When the group is a benzhydryl group, the solvents used in the catalytic reduction reaction include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or acetic acid, or these organic solvents, water or phosphoric acid, A mixed solvent with a buffer such as morpholinopropanesulfonic acid is suitable.

The reaction temperature is 0°C to 100°C.
A range of 0.degree. C. to 40.degree. C. is suitable. Moreover, hydrogen pressure can be carried out under normal pressure or increased pressure.

Further, when the protecting group is an 0-nitrobenzyloxycarbonyl group or an 0-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.

As shown in the following formula, the compound represented by the general formula CI) has optical isomers and stereoisomers based on the asymmetric carbon atoms at the 4-, 5-, 6-, and 8-positions, and these isomers are all shown in a single formula for convenience, but this does not limit the scope 1 of the description of the present invention.

However, for the 5th and 6th positions, preferably,
Compounds having (5R, (35) coordination, and (5R16R) coordination) which have carbon atom coordination at the 5th position can be mentioned.

Regarding the 8th position, a compound having coordination can be selected as a preferred one. Also, for the 4th place, α−
There are isomers with the configuration and β-configuration, and the preferred one is β-configuration.
- Can mention placement.

When producing an isomer having such a coordination, each corresponding isomer can be used in the raw material compound (II).

Furthermore, 4 of the 2'-substituted pyrrolidin-4'-ylthio group
There are isomers of species, and although they are represented by a single formula in general formulas such as general formula (1), they are not limited in any way. Among them, the preferred steric configurations are (2" y 4' S ) coordination, (2'R, 4'R
) configuration position can be mentioned.

The uninvented compounds represented by the general formula CI) are a group of novel carbapenem derivatives having various 2-carbamoylpyrrolidin-4-ylthio groups at the 3-position and a lower alkyl group at the 4-position. These compounds exhibit excellent bacteriolytic activity and are useful compounds as pharmaceuticals, or are important intermediates for compounds exhibiting such activity.

Examples of the compound having the general formula (h) obtained by the present invention include the compounds listed in 4 below.

fl+3-(2-carbamoylpyrrolidin-4-ylthiocou-4-methyl-6-(nee-hydroxyethyl)-1
-Azabicyclo[3,2゜0]-hept-2-en-7
-one-2-carboxylic acid +21 3-((2-N-methylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(neehydroxyethyl)-1-azabicyclo(3,2,0)-hept-2 -en-7-one-2-carboxylic acid +31 3-[(2-N-ethylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,O ) hept-2-en-7-one-2-carboxylic acid +41 3-((2-N-n-propylcarbamoyl)
pyrrolidin-4-ylthio]-4-methyl-6-(1-
hydroxyethyl)-1-azabicyclo(a $2 T
o)-Hept-2-en-7-one-2-carboxylic acid +51 3- ((2-N-isopropylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo(3,2,O
)-hept-2-en-7-one-2-carboxylic acid +61 3-((2-N-n-butylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1- Azabicyclo[3,2,0)hept-2-en-7-one-2-carboxylic acid +71 3-((2-N-isobutylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl )-1-azabicyclo[3,2,O]hept-2-en-7-one-2-carboxylic acid (813-((2-N,N-dimethylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6 -(1-hydroxyethyl)-1-azabicyclo(3,2,0)-
Hept-2-en-7-one-2-carboxylic acid (913-((2-N N-diethylcar]cumoyl)
pyrrolidin-4-ylthiocou-4-methyl-6-(1-
hydroxyethyl)-1-azabicyclo[3,2,01
-hept-2-en-7-one-2-carboxylic acid α■ 3 ((2N N-di-n-propylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(
1-hydroxyethyl)-1-azabicyclo[3,2,
0]hept-2-en-7-one-2-carboxylic acid Ofhept-2-en-7-one-2
-carboxylic acid fi3-((2-NN-G-n-buty/
I/f) /I/bamoyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1
-Azabicyclo[3,2,0)hept-2-ene-
7-one-2-carboxylic acid α31 3-((2-′)isobutylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3.2,0)hept- 2-en-7-one-2-carboxylic acid (1413-((2-methylethylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2.0 )〕〕
Hept-2-en-7-one-2-carboxylic acid (151 3-[(2-n-butylmethylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(
3,2,0)-hept-2-en-7-one-2-
Carboxylic acid α61 3-((2-n-methylethylcarbamoyl)
pyrrolidin-4-ylthiocou-4-methyl-6-(1-
hydroxyethyl)-1-azabicyclo(3,2,
0) Hept-2-en-7-one-2-carboxylic acid αη 3-[(2-(2-hydroxyethyl)carbamoyl)pyrrolidin-4-ylthio]-4-methyl-6-
(1-hydroxyethyl)-1-azabicyclo(3,
2,0)-hept-2-en-7-one-2-carboxylic acid decoy 3-((2-(2-N,N-dimethylaminoethyl)carbamoyl)pyrrolidin-4-ylthiocou 4-methyl-6- (1-hydroxyethyl)-
1-Azabicyclo (3,2.

0]-hept-2-en-7-one-2-carboxylic acid Q91 3-((2-(carbamoylmethyl)carbamoyl)pyrrolidin-4-ylthiocou 4
-Methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,0)-hept-2-ene 7-one-2
-Carboxylic acid @ 3-((2-benzylcarbamoyl)pyrrolidine-
4-ylthiocou 4-methyl-〒-(1-hydroxyethyl)-niazabicyclo(3,2,0)-hept-2
-En-7-one-2-carboxylic acid (Incorporated) 3-((2-(2-hydroxyethyl)methylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1- Azabicyclo[3,2,0)-hept-2-en-7-one-2-carboxylic acid (2) 3-((2-(2-hydroxyethyl)ethylcarbamoyl)-4-methyl-6-( l-hydroxyethyl)-1
-azabicyclo(3,2,0]heft-2-ene-7-
on-2-carboxylic acid (23) 3-((2-(2-N
,N-dimethylaminoethyl)methylcarbamoyl)pyrrolidin-4-ylthiocou4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.

21O]-hept-2-en-7-one-2-carboxylic acid (241 3-((2-benzylmethylcarbamoyl)
pyrrolidin-4-ylthiocou-4-methyl-6-(1-
hydroxyethyl)-1-azabicyclo(3,2,
O]-hept-2-en-7-one-2-carboxylic acid 3-[, (2-benzyl ethylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo(3,2,0
]Hept-2-en-7-one-2-carboxylic acid (a) 3-((2-(1-pyrrolidinecarbonyl))
pyrrolidin-4-ylthiocou-4-methyl-6-(1-
hydroxyethyl)-1-azabicyclo(3,2.03
Hept-2-en-7-one-2-carboxylic acid @3-[(2-(1-piperidinecarbonyl))pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo( 3,2,O)-
Hept-2-en-7-one-2-carboxylic acid (281 3-((2-(1-morpholinecarbonyl)
)pyrrolidin-4-ylthio) -4-uthyl-6-(
1-hydroxyethyl)-1-azabicyclo(3+2*
0)-hept-2-en-7-one-2-carboxylic acid@3-((2-(1-thiomorpholinecarbonyl))pyrrolidin-4-ylthio)-4-methyl-6-(1-hydroxyethyl )-niazabicyclo(3,2.0)-
Hept-2-en-7-one-2-9urubonic acid■ 3-((2-(1'-N-methylpiperazinecarbonyl))pyrrolidin-4-ylthiocou-4-methyl-6
-(1-hydroxyethyl)-1-azabicyclo[3
,2,O)-hept-2-en-7-one-2-carboxylic acid (31) 3-((2-(1-N-ethylpiperazinecarbonyl))pyrrolidin-4-ylthiocou 4-
Methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,01hept-2-en-7-one-
2-・carboxylic acid (32) 3-((2-(2-N,N
-diethylaminoethyl)carbamoyl)pyrrolidine-
4-ylthiocou 4-methyl-6-(l-hydroxyethyl)-1-azabicyclo(3,2.

0] hept-2-en-7-one-2-carboxylic acid (33), 3-((2-(2-N
, N-dimethylaminoethyl)ethylcarbamoyl)pyrrolidin-4-ylthiocou4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo[3.

2,0]Hept-2-en-7-one-2-carboxylic acid (34) 3-((2-(2-N,N-diethylaminoethyl)ethylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6 -(1-hydroxyethyl)
-i-Azabicyclo [3.

2,0]Hept-2-en-7-one-2-carboxylic acid (35) 3-((2-(3-N,N-dimethylaminoprobyl)carbamoyl)pyrrolidin-4-ylthiocou-4-methyl- 6-(nihydroxyethyl)-1-
Azabicyclo(3,2゜0)hept-2-en-7-one-2-carboxylic acid (36) 3-((2-(3-N,N-diethylaminopropyl)carbamoyl)pyrrolidin-4-ylthiocou 4- Methyl-6-(1-hydroxyethyl)-
1-Azabicyclo[3,2°O]hept-2-ene-7
-one-2-carboxylic acid (3,7) 3-[(2-(3-hydroxypropyl)carbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-niazabicyclo(3, 2,01hept'-2-en-7-one-2-
Carboxylic acid (38) 3-((2-(2-hydroxy-1-methylethyl)carbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(neehydroxyethyl)-1-azabicyclo(3,2゜0) Hept-2-en-7-one-2-carboxylic acid (39) 3-((2-(2-hydroxypropyl)carbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)- 1-Azabicyclo[
3,2,0) hept-2-en-7-one-2-carboxylic acid (40,) 3-((2-(2-carbamoylethylcarbamoyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1 -hydroxyethyl)-niazabicyclo(
3,2,03Hept-2-en-7-one-2-carboxylic acid (41) 3-C (2-(l-azetidinecarbonyl))pyrrolidin-4-ylthiocou-4-methyl-6
-(1-hydroxyethyl)-1-azabicyclo(3
,2,O) Hept-2-en-7-one-2-carboxylic acid (42) 3-(2-carbamoylpyrrolidin-4-ylthio]-4-ethyl-6-(1-hydroxyethyl)-
1-Azabicyclo (3,2.

0]-hept-2-en-7-one-2-carboxylic acid (43) 3-((2 N,N-dimethylcarbamoyl)
pyrrolidin-4-ylthio]-4-ethyl-6-(1-
hydroxyethyl)-1-azabicyclo I:3,2
, 03-hept-2-en-7-one-2-carboxylic acid (44) 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 they are given a single name, they are not limited in any way by this. It's not a thing. However, preferred carbapenem skeletons include (4R, 5, 6S, 8k),
(4k.

Examples include those having 5R, 5R, 8R) coordination. In addition, the pyrrolidinylthio group which is a substituent at the 3-position is preferably (2'S).

``S) + (2'R, 4'R) coordination.

Compound [I[], which is a raw material compound, is represented by the general formula [■] [where Ro, R, and 7 have the same meanings as described above. ] The compound represented by is substituted with a substituted or unsubstituted aryl compound such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, pt-toluenesulfonic anhydride, P-nitrobenzenesulfonic anhydride, P-bromobenzenesulfonyl chloride, etc. Sulfonylating agents, such as methanesulfonic anhydride, methanesulfonyl chloride, ethanesulfonyl chloride, etc.; A halogenating agent such as a lower alkanesulfonylating agent such as phosphine dichloride, triphenylphosphine dibromide, or oxalyl chloride and triethylamine, diisopropylethylamine, N-dimethylamino in an inert solvent such as methylene chloride, acetonitrile, dimethylformamide, or tetrahydrofuran. It can be produced by treatment in the presence of a base such as pyridine.

The compound represented by the above general formula (Vl) can be prepared by a known method (
For example, the compound (Va) can be produced by the method shown in the following scheme.

2° 7a [In the formula, Ro and 7 have the same meanings as above, R6
represents a protecting group for the amide NH group, and Y represents a t-butyldimethylsilyl group. ] Compounds 2a and 2b are (3R,
4R)-4-aceI xy-3-[4l-1-(L-butyldimethylsilyloxy)ethylcou-2-azetidinone 1 (Chemical and Pharmaceutica/Niichi Bretin (Chem, Pharm, Bull) Second
9, pp. 2899-2909 (1981))
Particularly, in the presence of diethylaluminum chloride and zinc, the general formula % formula % [wherein R6 and R7 have the same meanings as above, and X represents a halogen atom. ] Halogeno fatty acid esters represented by and ethers such as tetrahydrofuran, dioxane, diethyl ether,
Aromatic ashing such as benzene and toluene, in solvents such as hydrogen,
Alternatively, they can be obtained as a mixture by reacting them with hexane in a mixed solvent.

Separation of each isomer (2a and 2b).

The preparation can be performed by silica gel column chromatography.

Compound 3a is obtained by the usual protection reaction of the nitrogen atom of the amide group (
For example, silyl L reaction, tetrahydropyranylation reaction)
Examples of the protecting group R6 include trimethylsilyl, tri-lower, lower-level alkylsilyl groups such as [-butyldimethylsilyl], cyclic groups such as 2-tetrahydropyranyl, and ethers.

Compound 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.

The production of compound (Va) from compound 4a via compounds 5a, 5a, and 7a can be carried out according to known methods (for example, JP-A-58-26887).

Compound (Va 3) was prepared from compound (I) according to the previously described method.
I) can lead to the corresponding isomer.

In addition, isomers (e.g. 4α-methyl form) of the 4-position carbon of compound CVa) and the corresponding compound (I
The isomer of I) can be produced in a similar manner to the above method by using compound 2b.

On the other hand, raw material mercaptan (I[) can be produced by various methods, but for example, by the method shown below, it is possible to produce mercaptan (I[) with 2'S coordination using trans-4-hydroxy-L-proline 8 as a raw material compound. Surumercaptan C■
a]t (mb), [l[c] can be produced.

SO 田廁 類0 19 (l[b) it [11C] [In the formula, R4, R6 and ni7 have the same meanings as above. R8 represents an amino group-protecting group, and R9 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-4゜Examples include a method using 6-dimethyl-2-mercaptopyrimidine and the like.

Step B Various known methods for obtaining esters from carbonic acids are possible; for example, in the presence of a base, carboxylic acid 9
This can be achieved by reacting with various aralkyl halides or aralkyl halides.

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 azodicarboxylene-1 in an inert solvent such as tetrahydrofuran.

Step D Various known methods for converting esters into carboxyl groups are possible; for example, alkaline hydrolysis, an acid method using trifluoroacetic acid, hydrobromic acid, etc., or a reductive method using zinc. can.

Step E Various known methods are possible for converting carboxylic acid into an amide group. For example, converting a carboxylic acid group into an active ester derivative using a halogenating agent, an acylating agent, etc.
General formula [wherein, R4, R, 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 methods such as alkaline hydrolysis.

Step C 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 hydroxyl groups of 10 and 16 differ in stereo can be obtained. .

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.

1. Step J The alcohol derivative is reacted with formic acid in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate to form a formyloxy derivative 20, and then the formyl group is converted by a method such as alkaline hydrolysis. This can be achieved by removing the .

K step Various commonly used deprotection methods for amino groups are possible, including methods using acids such as trifluoroacetic acid and hydrobromic acid, and reductive methods using zinc or lithium-liquid ammonia. Alternatively, this can be achieved by catalytic reduction or the like.

In addition, in the production of zf R-mercaptan Cl1l), cis-4-hydroxy-D-
It can be produced using 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 CI), the compounds in which R1, R2 and 3 are water or hydrogen atoms are Staphylococcus aureus, Staphylococcus eidermizois, Streptococcus pyrogiens. It has excellent antibacterial activity against a wide range of pathogenic bacteria, including Durum-positive bacteria such as Streptococcus fuecalis, Escherichia coli, Proteus O mirabilis, Selassia marcescens, and Pseudomonas aeruginosa, and is useful as an antibacterial agent. It is a useful compound. Furthermore, 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.

In addition, although the compounds of the present invention vary depending on each compound,
Characteristics include generally high physicochemical stability and excellent solubility in water.

Dosage forms for using the compound of the present invention as an antibacterial agent to treat bacterial infections include, for example, tablets, capsules,
Examples include oral administration using powders, syrups, etc., and parenteral administration via intravenous injection, intramuscular injection, rectal administration, etc.

The dosage varies depending on symptoms, age, body weight, dosage form, number of administrations, etc., but it is usually about 100 to 30 doses per day for adults.
Administer 00■ once or in divided doses. The amount can be added or increased as necessary.

In addition, the compound of the present invention may be treated with sodium z-7-(L-amino-2-carpoxyedylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoate, etc., if necessary. Dipeptidase inhibitor (Unexamined Japanese Patent Publication No. 5
It can also be administered in combination with the compounds described in Publication No. 6-81518).

Next, the present invention will be explained in more detail with reference to examples and reference examples, but the present invention is not limited by these examples.

The meanings of the abbreviations used in the following Examples and Reference Examples are as follows.

PNZ: P-nitrobenzyloxy carbonyl group PMZ
; p-methoxybenzyloxycarbonyl group PMB: p
-methoxybenzyl group PNB: p-nitrobenzyl group Ph: phenyl group AC niacetyl group MS: methanesulfonyl group tBu: t-butyl group Me: methyl group Et: ethyl group (TBDMS): t-butyldimethylsilyl group Example 1 a) (4' * 5 Rp 6 Sr 8 k) P
=trobenzyl-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3゜2IO]-hept-
3,7-Sion-2-carboxylene) (53■) was dissolved in dry acetonitrile (5-), diisopropylethylamine (57■) was added under water cooling in a nitrogen stream, and then diphenylchlorophosphate (43η) was added.2. 5
After stirring for an hour (2S, 453-1-P-nitrobenzyloxycarbonyl-2-dimethylcarbamoyl-4
- Add mercaptopyrrolidine (57■) and leave it as >1
Stir for hours.

The reaction solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography, (4K, 5R, (
iS, 8R.

2'S e 4'S )-p-nitrobenzyl-3-(
4-(1-p-nitrobenzyloxycarbonyl-2-
dimethylcarbamoyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,O)-hept-2-en-7-one-2-carboxylate (35■) I got it.

IR”m (Cal 1): 1760,1705,1
645,1520ax 1402.1342,1135.111ONMRδ(C
DCJ3): 1.30 (3H, d, J-7, OH.

1.35 (3H, d, J-6°5f (su.

2.99 (3H, 8).

3.02 (3H, d, J-15H).

5°21 (2H, S), 5.20 and 5.43 (2H
, ABq, J-14Hz).

7-51 (2H*dJ"", 5Hz) e7.64
(2H, d, J-8, 5H.

8.20 (4H, d, J-3, 5HQ b) (4, 51L, 65.8, 2'S, 4'5
)-P-nitrobenzyl-3-(4-(1-P-nitrobenzyloxycarbonyl-2-dimethylcarbamoyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3 ,2,0]hept-2-en-7-one-2-carboxylate (25η
) with tetrahydrofuran (1°9m/) and ethanol (
Dissolve morpholinopropanesulfone in 8M buffer solution (pH=7.0, 1.9 mq and hydrogen under normal pressure).
1゜thipalladium, which was hydrogenated for an hour, filtered and washed with water.
Carbon (30η) was added and hydrogenation was carried out at room temperature for 3 hours under hydrogen pressure.

After filtering off the catalyst, tetrahydrofuran and ethanol are distilled off under reduced pressure, the residual liquid is washed with ethyl acetate, the aqueous layer is again distilled off under reduced pressure to remove the organic solvent, and the residual liquid is subjected to polymer chromatography (CHP 20P). and from the portion eluted with water (4R, 5, (3S, 8R).

“S+””) 3 [4(2-dimethylcarbamoyl)
pyrrolidinylthio)-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,0)hept-2-en-7-one-2-carboxylic acid was obtained.

Uv □nm=296 NMg S ex, -o): t, Ut (91/JI
J= v, Q-12-3゜t'-x'/ (3H, a
, )=b, 5Hz).

I11N, Tane).

L, 9'I (U■劃) Yo, 0 too (yo H, S).

Example 2 a) (4R,5R=,6S,8R)-P-di)lobenzyl-4-methyl-6-(1-hydroxyethyl)-1
-Azabicyclo[3゜2,O]-hepto-3,7-sion-2-carboxylate (61T9) was dissolved in dry acetonitrile (6-), diisopropylethylamine (72"f) was added under water cooling in a nitrogen stream, and then After adding diphenylchlorophosphate (55■) and stirring for 2.5 hours, (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)
-4-Mercaptopyrrolidine (77 ml) 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 remaining 4'5)-
p-Nitrobenzyl-3-(1-P-nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2 ,0)-
hept-2-en-7-one-2-carboxylate (
51■) was obtained.

I Rf 11m1 fIllax (clI): 1760, 171o, 164
o, 1525°1440.1350,1210.111
ONMRδ (CDCI!,): 1.30 (3H, d
, J+=7. QHz).

1.34 (3H, d, J-6, 5H2).

5.21 (2H, 1), 5.20 and 5.44 (2
H, AB (1, J-14H.

7.50 (2H, d, J-8, 5HQ.

7.64 (2H, d, J=8.5Hz).

8.20(4H,d,J-8,5Hz)b) (4K
, 5R, 6S, sR, 2'S, 4'5) -P-nitrobenzyl-3-(1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)pyrrolidin-4-ylthiocou 4-methyl- 6-(l-hydroxyethyl)-1-azabicyclo[3°2.0]-hept-2-en-7-one-2-carboxylate (50r
n9) in tetrahydrofuran (3,9rnl)! : 10% palladium dissolved in ethanol (0°6 ml), hydrogenated under morpholinopropanesulfonic acid buffer (PH = 7.0, 3.9 rnl) and normal hydrogen pressure at room temperature for 1 hour, and then washed with water. Add carbon (60”f),
Hydrogenation was carried out at room temperature for 4.5 hours under normal hydrogen pressure. After filtering off 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 under reduced pressure to remove the organic solvent, and the residual liquid was subjected to polymer chromatography (CIIP-20P). From the part eluted with 2% tetrahydrofuran aqueous solution (4R, 5R, 65, 8
, 2'S , 4'S) -3-(2-(1-pyrrolidinecarbonyl)pyrrolidin-4-ylthiocou-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,03- Hept-2-7-one-2-carboxylic acid was obtained.

Uvm"a'X nm" 297 NMSjK DJ): 1. ho (1,a-'7
1otlJ.

1, z>ON, or J=4. tHz).

Shi9su (Kou, Go), '3A-&(btt, →.

a, 1''(1'',tAd,:r=4),'5 K
R・) u”4z), %ol (%H, Iuζ and mouse.

J-b, 5 The following compounds can be synthesized in the same manner as described in Examples 1 and 2.

fi+ (4R, 5R, 65, 8R, 2'S, 4'5)
-3-(2-Carbamoylpyrrolidin-4-ylthiocou-4-methyl-6-(l-hydroxyethyl)-1-azabicic O(3,2°0)-hept-2-en-7-one-2-carvone Acid (21(4R,5 to 65,8R,2'S,4'5)-
3-((2-N-methylcarbamoyl)pyrrolidine-4
-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,0)-hept-2-
En-7-one-2-carboxylic acid +31 (4R, 5R, 65, 8, 2'S, 4'5)
-3-((2-N-ethylcarbamoyl)pyrrolidine-
4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0)-hept-2
-En-7-one-2-carboxylic acid +41 (4, 5R, 65, 8R, 2'S, 4'5)
-3-((2-N-isopropylcarbamoyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,0)hept-2-ene-7- On-2-carboxylic acid +51 (4R, 5R, 65, 8R, 2'S, 4'5)
-3-((2-(2-hydroxyethyl)carbamoyl)pyrrolidin-4-ylthio]-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo(3,2,0
)-hebdo-2-en-7-one-2-carboxylic acid +6
1 (4, 5R, 68, 8R, 2'S, 4'5)-3
-((2-(2-N,N-dimethylaminoethyl)carbamoyl)pyrrolidin-4-ylthio]-4-methyl-
6-(1-hydroxyethyl)-1-azabicyclo[3
,2゜0]-hept-2-en-7-one-2-carboxylic acid +71 (4R, 5R, 65, 8, 2'S, 4'5)
-3-((2-(carbamoylmethyl)carbamoyl)
pyrrolidin-4-ylthio]-4-methyl-6-(1-
hydroxyethyl)-1-azabicyclo[3,2,03
-hept-2-en-7-one-2-carboxylic acid +81 (4R,5 to 68,8R,2'S,4'5)
-3-((2-benzylcarbamoyl)pyrrolidine-4
-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2,0)-hept-2-
En-7-one-2-carboxylic acid +91 (4R, 5K, 6S, 8R, 2'
S,4S)-3-((2-(2-human,oxyethyl)methylcarbamoyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-
1-azabicyclo[3,2,O]-hef-1--2-en-7-one-2-carboxylic acid QOI (41L, 51L, 6S, 8, 2'S,
4'5)-3-((2-(2-N,N-dimethylaminoether)methylcarbamoyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1
-Azabicyclo[3゜2.0]-hept-2-con-7
-one-2-carboxylic acid Co., Ltd. (4, 5R, aS +8Rt2'S +4'
5) -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 α2 (4R,5R,68,8R,2'S,45)3-
((2-(1-morpholinecarbonylpyrrolidine-4-
ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2.0)-hept-2-en-7-one-2-carboxylic acid (13 (in 4, 51L, OS ,8R,2'S,4'S
)-a-((2-(1-thiomorpholinecarbonylmethyl-6-(1-hydroxyethyl)-1-azabicyclo(3,2.0)-hept-2-en-7-one-2
-carlebonic acid circle (4fL, 51L, 5s, 8P=, 2'S, 4'
S)-3-((2-(1-N-methylpiperazinecarbonyl))pyrrolidin-4-ylthio]-4-mef
-6-(1-hydroxyethyl)-1-azabicyclo(3,2,O)-hept-2-en-7-one-2
-carboxylic acid (Is (4, 5, 68.8.2'
S,4'S)-3-((2-(1-pyrrolidinecarbonylpyrrolidin-4-ylthio-2-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo(3,2,0
1hept-2-en-7-one-2-carboxylic acid (161 (4 to 5, 65,8R, 2'S, 4'5)
-3-((2-benzylmethylcarbamoyl)pyrrolidin-4-ylthiotsu-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0)-hept-2-en-7-one- 2-carboxylic acid 0η (4, 5, 6S, 8, 2'S, 4'R)-
3-((2-dimethylcarbamoyl)pyrrolidine-4-
ylthio2-4-methyl-〇-(1-hydroxyethyl)-1-azabicyclo(3,2,0)hept-2-en-7-one-2-carboxylic acid (18) (4k+ 5' r 65r 8 R+
2"t4")-3-((2-dimethylcarbamoyl)pyrrolidin-4-ylthio-2-4-methyl-6-(
1-hydroxyethyl)-1-azabicyclo[3,2,
0) Hept-2-en-7-one-2- is a rubonic acid <1'l) (4R,51'-,65,811-,2'
R,4'R)-3-((2-dimethylcarbamoyl)pyrrolidin-4-ylthiotsu-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo(3+2*O)hept-2-ene-7- One-2-carboxylic acid (4) (4k+ 5 R* 6 S* 8 R+ 2
'k+ 4'')-3-(2-(1-pyrrolidinecarbonyl)pyrrolidin-4-ylthio-2-4-methyl-6
-(1-hydroxyethyl)-1-azabicyclo(3,
2, O]Hept-2-en-7-one-2-carboxylic acid Reference Example 1-1
), triethylamine (7,5m/>) in water (15rn
S-P-nitrobenzyloxycarbonyl-4°6-dimethyl-2-mercaptopyrimidine (15,959) in dioxane (35n
/) Add the solution dropwise and stir for 1.5 hours at room temperature.
- I installed it at night. Add 2N sodium hydroxide (30n/) to the reaction solution under water cooling, extract with ether, transfer the ether layer to I. After washing with 6L of sodium monohydroxide (20rnt), add an alkali water shield, and add 2N hydrochloric acid (100m/). The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with 2N hydrochloric acid, dried with sodium sulfate, and the solvent was distilled off.
Trans 1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline was obtained.

m, P, 134.3-135.5°C HLNuj” (ai 1): 3300(1)r)
, 1738, 1660° mλX 1605.1520, 1340, 1205° 1172.
1070.965 Reference Example 1-2 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (15°OF) triethylamine (13.5m/) was dissolved in dry dimethylformamide (150rnt). , under nitrogen flow, P-
Methoxybenzyl chloride (12,66d) was added dropwise, and the mixture was stirred at 70°C for 10 hours. The reaction solution was diluted with ethyl acetate (5
The residue was crystallized from ether to give trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-
Proline-P-methoxybenzyl ester was obtained.

m, P, 83-85℃ HL'''m(c+m 1): 3430,1735,
1705,1510°ax 1340.1245.1160 Reference example 1-3 trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-florin-P-methoxybenzyl ester (8,6F), triphenylphosphine (
7.86 g) was dissolved in dry tetrahydrofuran (20d), a solution of diethyl azodicarbonate (5,22j') in dry tetrahydrofuran (5-) was added dropwise under water cooling and a nitrogen stream, and the mixture was stirred for >30 minutes. Thioacetic acid (2
, 28F) was added dropwise under water cooling for 1 hour, then at room temperature for 3 hours.
Stir for an hour and concentrate the reaction solution. The residue was subjected to silica gel column chromatography to obtain cis-1-(P-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline-P-methoxybenzyl ester.

IR”1m (cm 1): 1740 (ah), 17
15.1520°ax 1405.1348.112O NMRδ (CDCr3): 2.31 (3H, 8),
3.79 (3H, s).

5.10 (2) 111) #5.24 (2H1m) 1
7.49 (2H, d, J=9.0H2).

8.18 (2H, d, J-9, QHz) Reference Example 1-4 cyx-1-(P-nitrobenzyloxycarbonyl)-
4-acetylthio-L-7” lolin-P-methoxybenzyl ester (9,7611), anisole (4,32
F) was stirred with trifluoroacetic acid (35-) for 30 minutes at room temperature. The residue was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline.

m, P, 107-109℃ IRNuj” (cm 1): 1725,1685
．． 1660 (lh).

ax 1340.1180.1110 Reference Example 1-5 cis-1-'(p-nitrobenzyloxycarbonyl)
-4-Acetylthio-zoroline (180 µ) was dissolved in dry tetrahydrofuran (2 rnl), dimethylamine hydrochloride (48 η), N,N-dimethylaminopyridine (78'9), dicyclohexylcarbodiimide (1
52■) were added one after another, and the mixture was stirred overnight.

Insoluble materials were removed, the furnace solution was diluted with ethyl acetate, diluted with dilute hydrochloric acid,
Washed sequentially with water, dried with Glauber's salt, distilled off the solvent, and subjected the residue to silica gel chromatography.25.48)-1-
(P-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine was obtained.

IR”'m(CI+1): 1705,1650,
1515,1400゜ax 1340.11l1 05Nδ (CDCJ3): 2.32 (3H, Su, 2
゜97 (3H, Su.

3.11 (3H, Su, 5.21 (2H, Su.

8.18 (2H, d, J = 8° 5H [α), +5.21° (c-0,379 acetone) Reference Example 1-43 (25,45)-1-(p-nitrobenzyloxycarbonyl IN-NaO is dissolved in methanol (4mZ).
)l (Q.1-) was stirred at room temperature for 15 minutes.

After that, IN-HO2 (0, IIJ) was added 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,48)-1-(P-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-
4-Mercaptopyrrolidine was obtained.

IRfil-(011 1): 1705,1650
, 1515, 1400.

m13 (1340, 1165.1105 NMRδ (CDC, /, B): 1-90 (IHrd
eJ-8”)+2,97(3)1,B),3.08(
3H.

5, 19 (2H, l).

7,48(2)1,d,J=gHz) 18,15(2
H, d, J-9Hz) The above thioacetates were prepared in the same manner as in Reference Example 1-5 using the respective corresponding amines at a concentration of 9%.

1'NZ Reference Example 2-1 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline a,ioy, triethylamine 1.1o LI was dried in tetrahydrofuran 4o
A solution of 1.20 F of ethyl chloroxate in dry tetrahydrofuran was added dropwise at -25°C to -35°C, and after stirring for 50 minutes, 10rnt of concentrated ammonia water was added dropwise at -25°C to -40'C. . The humidity was gradually raised to room temperature, and after further stirring for 1 hour, the reaction solution was concentrated under reduced pressure. After adding 20 m of water and 50 m of ether to the residue and cooling with water, the resulting white crystals were separated, washed successively with cold water and cold ether, and dried under reduced pressure to give trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy- L-prolinamide was obtained.

m, p. 163.3~164.0℃IRNu"'(
Ql 1): 3460, 3370, 3200.16
87°5hx 1640.1621.1539.1341.

1180.1078 Reference Example 2-2 5-1-(P-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolinamide 2.32F,
) A suspension of 1.671 ethylamine in 40 ml of dry tetrahydrofuran A 10-ml solution of methanesulfonyl chloride 1.89 F in dry tetrahydrofuran was added dropwise at room temperature, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure.

After adding 30 ml of water and 30 ynl of ether to the residue and cooling with water, the resulting white crystals were separated, washed successively with cold water and cold ether, and dried under reduced pressure to give trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy. -L-
Prolinamide was obtained.

m, p. 149.5-151℃ IR2101 (♂1): 3400, 3225, 17
15,1675°1520.1340,1170.11
35 Reference Example 2-3 This NZ ] l' NZ 50 To a suspension of 374 η of sodium thihydride in dry dimethylformamide 13-, a solution of 642 g of thioacetic acid in 14 ml of dry dimethylformamide EF' was added under a nitrogen stream, and the mixture was stirred at room temperature for 25 minutes. Then add sodium iodide 9751 to this solution.
r9 was added and then trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L
- A solution of 2.52 F of prolinamide in dry dimethylformamide 12 was added, and 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 sodium chloride, and the solvent was distilled off. The resulting crude crystals were repulfed using a mixed solvent of tetrahydrofuran and benzene. Tecis-1-(
P-nitrobenzyloxycarbonyl)-4-thioacetoxy-L-prolinamide was obtained.

m, p, 168.5~169.5° CIRNu"'(
cm”): 3350, 3180, 1715, 16
90°ax 1638.1510,1330,1100[α]D-2
3 (C-0,334, DMF) Reference Example 2-4 From (28,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-acetylthiopyrrolidine (950■), Reference Example 1 (25,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-mercaptopyrrolidine was obtained in the same manner as in -6.

m, P, 158~162°C Reference Example 3-1 LNZ LNZ Dry chlorination of dimethyl sulfoxide (0,35mZ) in a solution of oxalyl chloride (0,21n) in dry methylene chloride (5mJ) at -60~-70°C Methylene solution (1-)
was added dropwise, and after 10 minutes, a dry methylene chloride solution (I Qm/) of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline P-methoxybenzyl ester (860 μm) was added to -50 It was added dropwise at a temperature below 0.degree. C. and stirred for 15 minutes. Next, triethylamine (1°0I
F) was added dropwise, warmed to room temperature, diluted with methylene chloride,
Washing with dilute hydrochloric acid water, drying with Glauber's salt, evaporation of the solvent, and subjecting the residue to silica gel column chromatography to obtain 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline P-methoxybenzyl ester 1K'''In (CI+1): 1762,1740
, 1710, 1512°ax 1345.1245.1155 NMRδ (C:DCI!2i): 3.78 (3H,
s), 3.95 (one 2H.

5.08 (2H#a) m6.85c2H#deJ-9H
2) 1 8.12 (2H, d, J-9Hz) Reference Example 3-2 Group 1-(p-nitrobenzyloxycarbonyl)-4-oxo-proline P-methoxybenzyl ester (
650 η) in ethanol (45 m/), hydrogenated at room temperature, and added sodium boron (86 η) in two portions. After 30 minutes, concentrate under reduced pressure at 30° or higher), dilute the concentrated solution with ethyl acetate, wash with water, dry with sodium sulfate, remove the solvent, and apply the residue to silica gel column chromatography.
cis-1-(P-nitrobenzyloxycarbonyl)-
4-hydro$-L-proline P-methoxybenzyl ester and trans-1-(P-nitrobenzyloxycarbonyl)-4-hydroxy-proline P-methoxybenzyl ester were obtained.

Trans form: IR and NMR were consistent with the spectral data of the compound of Reference Example 1-2.

film-1.

Cis body; IkL (am), 3400 (br), 1
725.

ax 1515, 1405, 1350, 1250.

1170, 112O NMRδ (CDCI!s): 3.7B (3H,S)
.

5, 08 (28, S), 6.82 (2H.

d, J-=9HQ+ 8, 12 (2H.d, J-9Hz) Example 3-3 Cis-1-(P-nitrobenzyloxycarbonyl)-
Reference Examples 1-3 and 1- were prepared using 4-hydroxy-L-7'loline P-methoxybenzyl ester (610).
Ridranth-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline was obtained in the same manner as in Example 4.

IR”m (Cal 1) knee 3000.1700,1
515.1430゜ax 1400.1345,1205,1165NMRJ(C
DCj73): 2.32 (3H, l), 5.20 (
2H, br.

+7'2 (2HtdJ=9H") +s -12 (2
H1dI J-9Hz) Reference example 3-4! 'NZ f'NZ NZ Re trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline (180■)
(2S, 4
RJ-1-(p-nitrobenzyloxycarbonyl)-
2-dimethylcarbamoyl-4-acetylthiopyrrolidine (100'P) was obtained.

IR””n (C1l 1): 1700, 1655,
1515,1400°ax 1340.1115 (α), +32.8° (c-0,375, acetone) b
) From the thioacetate derivative (80"V) obtained by soil distribution, (25,4JL]-
1-(p-nitrobenzyloxycarbonyl) -2-
Dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

IR”m (Cal 1): 1700, 1650, 1
510,1420°ax 1400.1340,112O NMRδ (3 in cax): 1.77(1)1. d,
J-7H.

2.97 (31-1, Su, 3.16 (31-1゜su, 5
．． 22(2H,I) 1 8.16(2H,dJ-8,5H2) Reference Example 3-5 a) Trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline (180η)
(2S, 4
R)-1-(p-nitrobenzyloxycarbonyl)-
2-Carbamoyl-4-acetylthiopyrrolidine (13
2 miles).

Ik''''rn (Cal 1): 3300 (br)
, 1700 (Sh).

ax 1685.1512, 1430, 1400°1345.
1175.1115 [α] 30+7°36° (c-0,625, acetone)
b) Thioacetate derivative obtained by overlaying (100m9)
From (2S *4R
)-t-(p-nitrobenzyloxycarbonyl)-2
-Carbamoyl-4-mercaptopyrrolidine was obtained.

IR”m (am 1): 1700,16B5,15
15,1435゜l1x 1400.1342.1118 NMRδ(CDCal3): 2.2(3(IH, d
,J,,,7H.

5.22 (2H, S).

8.11 (28, d, J = 13,5flQ Reference example 4-
1 Reference example 1-1 from cis-4-hydroxy-D-proline
and cis-1-P- obtained by the same method as 1-2
Nitrobenzyloxycarbonyl-4-hydroxy-D
7'loline-P-methoxybenzyl ester (166η
), triphenylphosphine (202■) was dissolved in dry detrahydrofuran (1,5i), and then formic acid (2
Furthermore, diethyl azodicarbonate (1341 rq) was added at room temperature under a nitrogen stream, and after stirring for 30 minutes, the solvent was distilled off.

The residue was purified by silica gel chromatography, trans-1-P-nitrobenzyloxycarbonyl-4-formyloxy-D-pro! J-P-methoxybenzyl ester.

[ilm-1.

1R (Cll), 1720, 1515, 140
2,1342.

ax 1245, 1165.112O NMRa (CDC: l!3): 3.76 (3B, s
), 4.50 (2H, t.

J = 8) 1ri, 5.08 (2) 1, S) 15, 15
(2H,AB(1,J-1(iHz).

5, 41 (IH, m), 7.97 (IH, r Reference example 4
-2 5-1-P nitrobenzyloxycarbonyl-
4-Formyloxy-D-proline-P-methoxybenzyl ester (215119) was dissolved in tetrahydrofuran (
1.1 m/) l force) and I N - NaOH
After adding 0.93 g of water and stirring for 10 minutes, the mixture was diluted with ethyl acetate, saturated, washed with brine, and dried with sodium sulfate, followed by evaporation of the solvent. The residue was purified by thin layer chromatography and trans-1-P-
Nitrobenzyloxycarbonyl-4-hydroxy-D
-Proline-P-methoxybenzyl ester was obtained.

I R f 1 1 m<♂1) : 3425(br
), 1735, 1705.

ax 1510, 1400, 1340, 1240.

162 NMRa(Cl)Cj'3): 2.33(2)1,
m).

3,58 (2H, d, J = 3.5H.

3.73 (3H, Su, 5.03 (2H, Su.

5, 07 (2H.AB (1, J-1sf-1t) #6
, 73 (2H, d, J = 9Hl).

6, 77 (2H, d, J = 9Hz).

8,00 (2H, d, J=8.5Hz).

8,07 (2H, d.J=8.5) L Reference Example 4-3 a) trans-1-P-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-P-methoxybenzyl ester (1 1 0mg) [2k.

4R]-1-p-nitrobenzyloxycarbonyl-2
-dimethylcarbamoyl-4-acetylthiopyrrolidine was obtained.

11L"'m (Cll 1): 1705, 1650
, 1515.

ax 1435, 1340, 1115 [αJD-7.
38 (C-0°210, AZ ton) b) Using the thioacetate derivative (42) obtained in a) above, [2K,4R)-1-P-nitro Benzyloxycarbonyl-2-dimethylcarbamoyl-
4-Mercaptopyrrolidine was obtained.

IR""" (Ql 1): 1710, 1660,
1525,1440゜ax 1347.1180.1122 Reference Example 4-4 This NZ 1) Trans-1-P-nitrobenzyl, t+dicarbonyl-4-hydroxy-D-proline-P-methoxybenzyl ester (110K) Reference Examples 1-3.1-4 and 2-
[2K.

4RJ-1-p-nitrohensyloxycarbonyl-2
-Carbamoyl-4-acetylthiopyrrolidine 40 ml was obtained.

IRfthl” (am 1): 1685, 1515
, 1400.134Dax 11O [α), +39.6°(c-0,29a, DMF
) b) Thioacetate derivative obtained above (40■)
Using the same method as Reference Example 1-6, (2, 4K
)-1-p-nitrohensyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine was obtained.

IR"j0'(C1l-1): 3200,1710
, 1655°ax 1512.1340.1115 Reference example 5-1 ↓NZ Lys cis-4-hydroxy-D-proline (300η)
From, Reference Examples 1-1.1-2.1-3.1-4 and 1
(2R, 481-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine (45η)) was obtained in the same manner as in -5.

IR"" (CI+1): 1700, 1650,
1520°ax 1400.1345.1120 [α) D-29.6° (C stomach 0.215, acetone)
b) From the thioacetate derivative (30η) obtained in a) above, C2 was converted to 48)- by the same method as in Reference Example 1-6.
1-(P-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

IR”m (0111): 1710,1655,15
20,1430°ax 1405.1347.1122 Reference Example 5-2! NZ Lys cis-4-hydroxy-D-proline (300mq
) to Reference Examples 1-1.1-2.1-3.1-4 and 2
'(2, 48)-1-P-nitrobenzyloxycarbonyl-2-carbamoyl-4 by the same method as in -1.
-Acetylthiopyrrolidine (82■) was obtained.

11L"m (Cal") 2 1705 (Ih)
, 16B5, 1520°ax 1425.1402, 1342.1122 [α]D-6
゜92° (c-o, eas, acetone) b) From the thioacetate derivative (66■) obtained by soil distribution, Reference Example 1-6
In the same manner as (2, 45)-1-p-nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine was obtained.

■, CJIC; J3 (-1): 1695 (Sh),
1682,1515°flaX 1395.1340.1115 Reference Example 6-1 1'NZ J? NZ tonx-1-p-nitrobenzyloxycarbonyl-
Yolitrans-1-P-nitrobenzyloxycarbonyl-4-hydroxy-L was prepared in the same manner as in Reference Example 1-2 using 4-hydroxy-L-proline (sooq) and p-nitrobenzylbromide (3831Iv). -Proline-P-nitrobenzyl ester is obtained.

IkCI(013(♂1): 3380(br), 1
750.1705°ax 1520.1425,1400,1342°16O NMRδ(CDCal3): 2.20(3)1. m
), 3.67 (2H, J.

J-3H Rit 4.60 (2H, t, J-8H.

5.15 (2B, Su 15-23 (2H).

ABq).

7.47(4)1. d, J-8, 5) 1ri #8.15
(4H, d, J s-3, 5H1) Reference example 6-2 HOHS trans-1-P-nitrobenzyloxycarbonyl-
4-Hydroxy-L-proline-p-nitrobenzyl ester color, cis-1-P-nitrobenzyloxycarbonyl-
4-mercapto-proline-P-nitrobenzyl ester color.

film-1.

1R (cm), 1700, 1685, 1600,
1510°ax 1430.14 (Jo, 1340.1105 Reference example 6-
3 1 & NZ J? NZ lys cis-1-P-nitrobenzyloxycarbonyl-
4-Mercapto-L-proline-P-nitrobenzyl ester (IIS) was dissolved in dry tetrahydrofuran (3tn
After adding triethylamine (30 µ), ethyl chloroformate (28,5 µ) was added dropwise under water cooling, and 1
After stirring for 0 minutes, dilute with ethyl acetate, wash sequentially with dilute hydrochloric acid and water, and dry with sodium sulfate.

mtJl, distilled off, cis-1-P-nitrobenzyloxycarbonyl-4-ethoxycarboxylic acid L
-Florin-P-nitrobenzyl ester (133■)
I got it.

11L”rn (Cal 1): 1755, 1710
, 1610, 1525゜ax 1405.1350, 1160.1015゜50 b) The ester derivative (133■) obtained in a) above was dissolved in a tetrahydrofuran-water (1:1) mixture (5rnl), and I N -NaOH Add water (0.26 ml),
After stirring at room temperature for 2.5 hours, INHCJ (Q.3-) was added, extracted with vinegar and 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 obtain cis-1.
-P-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline was obtained.

film-1.

IR (cm), 1700, 1520, 1400,
1340°ax 1165.1145 NMKδ (CDCJ3): 1.30 (3H, t
, J-7Hz).

4-28(2H*'l, J=7H2)+5.24(2)
1,8) 1 7.50(2H, cl, J-91(z) +8.17(
2HtdtJ-9H Reference Example 6-4 00 Lysis-1-P-nitrobenzyloxycarbonyl-4
- Ethoxylponylthioni L-proline (72■) was dissolved in dry tetrahydrofuran (3i), triethylamine (40~) was added thereto, ethyl chloroformate (41'9) was added dropwise under water cooling, and after stirring for 15 minutes, Methylamine (40%) aqueous solution (1.5 mZ) was added dropwise, and the mixture was further stirred for 15 minutes.

The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid and water, and dried with mirabilite. The solvent was evaporated and [2S.

453-1-p-nitrobenzyloxycarbonyl-2
-Methylcarbamoyl-4-ethoxycarbonylthiopyrrolidine was obtained.

,, Nujol (cm 1): 321jO-17
05,1660+ax 1520.1425.1405°1345.1180.116O NMKδ (C1) CI! , ): 1.30 (3H,
t, J-8H1)? 2.80 (3H, d, J-5Hz)
14.27 (2H, (IJ-8Hz) 15.22 (
2)1. vinegar.

7.48 (28, d, J-9Hz).

8.18 (2H, d, J = 9H2) b) Methylcarbamoyl derivative (82~) obtained by soil distribution
Add methanol/water (1:1) solution a (4 mt) + c to b> 25 mZ of IN-NaOH, stir at room temperature for 30 minutes, add 0.27 ml of -HCJ to 1, and dilute with ethyl acetate. After extraction, washing with water and drying with sodium sulfate, the solvent was distilled off [2S.

48)-1-p-nitrobenzyloxycarbonyl-2
-Methylcarbamoyl-4-mercaptopyrrolidine was obtained.

1RNu”1 (Cal 1): 32B0,1710
, 1650°ax 1510.1340.1165 NMKδ (CDCj73): 2.79 (3n, ci
, j=5iiz)+4.27(2)1. t, J=43
)1z).

5.23 (211,su.

7.5o(2)1. d, J=e5it,).

8.20 (21 (, d, J, = 9H1) Below Reference Example 6-
The following thiocarbonates were obtained in the same manner as in Example 4 using the corresponding amines.

1 f'NZ The following mercaptan was obtained in the same manner as in Reference Example 1-6 or 6-4b).

■lS Reference Example 8-1 ”) l-ran
trans-1-(p-methoxybenzyloxycarbonyl) using the same method as in Reference Example 1-1 using
-4~Hydroxy-L-proline was obtained.

1355.1245, 1170.1122NMRδ(C
DCI! 3): 2.23 (2H, m), 3.73 (
3H.

Su, 5.00 (2H, Su.

6.78 (28, d, J=9Hz).

7.20 (2H, d, J = 9Hsb) Using the proline derivative (0,57F) obtained by dispensing and benzylamine (0,2159), trans-1 was prepared in the same manner as in Reference Example 2-1. -P-methoxybenzyloxycarbonyl-4-hydroxy-L-benzylprolinamide was obtained.

""m"a'x.'(01"): 3375,3
300,1665°124B, 1165.1120°025 NMRδ (CDCj',): 3.76 (30,
4.35 (4) 1゜m), 4.96 (2H, S.

a, 'y9 (2H, d, J-9Hz).

7.20 (5H, SuC) Benzylprolinamide (0,5F) obtained in b) above
), use the same LGC as in Reference Example 1-3. ) [25
, 45)-1-P-)toxybenzyloxycarbonyl-2-benzylcarbamoyl-4-acetylthiopyrrolidine was obtained.

IR: 4"(Ql"): 3280, 1690,
1675°24O NMRa (CDCZ'8): 2-27 (3H
* ' ) *3-82 (3H+su.

4.42(2)1. d, J-(iHz).

5.05(2)1. vinegar.

6.87 (2H1dJ-81-1.

7.23(2)1. d, J=8H.

7.28 (5M, Reference Example No. 8-2 MZ H Su(23,45)-1-p-methoxybenzyloxycarbonyl-2-benzylcarbamoyl-4-acetylthiopyrrolidine (177■) and anisole (86■ ) was dissolved in 0.54% trifluoroacetic acid and stirred at room temperature for 30 minutes.The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium bicarbonate and water, and dried with Glauber's salt.The solvent was distilled off, and the residue was filtered with silica gel. Subjected to layer chromatography, (25,43)-2
-Benzylcarbamoyl-4-acetylthiopyrrolidine was obtained.

1K”1m (CI+ 1): 3325,1690,
1510,1400°ax 1350.1120.95O NMRδ(CIX:l!3): 2.28(31(,
S), 3.83(24(.

m), 4.42(zl(+dtJ-ef(z) I
7.32(5)11fi) b) The thioacetate derivative (40~) obtained in a) above was subjected to the same treatment as in Reference Example 1-6 to obtain (25,451-2
-Benzylcarbamoyl-4-mercaptopyrrolidine was obtained.

film-1.

IKm, X (cm) -3250+1685,181
L1510.1132 Reference Example 9-1 (1) Add 20 ml of dry tetrahydrofuran to 1.33 f (20 sM) of activated zinc, then add 15% diethylaluminum chloride in Lee's xane solution (8.8 ml). Cooled with water, added under a nitrogen stream, and added thereto (3R,4R)-4-acetoxy-3-[(8)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone + 111.4
A solution of benzyl α-bromopropionate 3,7:1 (15,3 mM) in dry tetrahydrofuran 13,3 was added dropwise over a period of 30 to 40 minutes, followed by an additional hour. Stir.

While cooling with water, add 2.8 m of pyridine, then 13.2 m/h of water, 26.5 m/h of ethyl acetate and 13.2 m of IN-hydrochloric acid, and filtrate over Celite.

The r solution was washed with water, the elA layer was dried with mirabilite, and the solvent was distilled off.
The resulting oily residue was subjected to silica gel column chromatography to obtain a mixture of 4-(1-bar-2-acetidinone).

Separation of isomers was achieved by Rover column chromatography (silica gel) eluting with 1.5% isopropanol/n-hexane to give (2a) and (2b) as oils.

Isomer (2a) IR”'m (cm 1): 1755,1460,1
377.1252°ax 1100.835 NM艮δ(CDCI!3): 0.06(6)1. 0.137 (9H, I) 11.16 (3H, d, J=
J, 5) 1x).

1.19 (3H, d, J=7.0t(Z).

3.71 (114, dd, J-2 and IQH,
5.14(2)1. fi).

7.35(5t(,S)NiRδ(CDC1!,): 0.06(61(,
S), 0.87(91(,1)11.08(3H,d,
J=5.5Hz).

1.18 (3H, d, J=7.0H1).

3.91 (IH, ddsJ-2, 2 and 5.5H).

4.17 (2H, (1, J-6H2).

5.12 (28,5) 17.35 (5) 1. S) Reference Example 9-2 (2S4-(1-benzyloxycarbonyl)dia) (20
0 ■) in dry dimethylformamide (2-),
After adding triethylamine (12611v), [-butyldimethylsilyl chloride (151η) 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.
-(1-benzyloxycarbonidimethylsilyl)-2
-Azetidinone (3,a) was obtained.

, kf4.1. m (CI+-1): 1750,1
465. ．． 1325,1255゜35 Reference Example 9-3 (4S4-(1-benzyloxycarbonyl)ersilyl)-
2-Azetidinone (184η) was dissolved in methanol 4- and stirred with 10% palladium-carbon (20μ) under atmospheric pressure hydrogen gas for 2 hours. The catalyst was removed, and the furnace liquid was concentrated under reduced pressure to obtain (chill)-1-(t-butyldimethylsilyl)-2-azetidinone (411).

IR”” (Ql ”): 1740,1465,1
330,1255°ax 1043.837 Reference Example 9-4 (From 4-1-(t-butyldimethylsilyl)-2-azetidinone (170'f), JP-A-58-26887, pages 64-65 (4R, 5R, O5
,8R)-P-nitrobenzyl-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo[3,2゜0
]-hept-3,7-thion-2-carboxylate was obtained.

1R”m (011”): 3450 (br), 177
0 ($11).

ax 1750.1605.1520.1350.

1217.1180 The 4S-methyl compound was obtained using the compound (2b) obtained in Reference Example 9-1, and the above ε Reference Examples 9-2.9-3 and 9.
-4 can be synthesized by the same method. In addition, for those in which the 4-position is other than a methyl group, synthesis is performed by replacing benzyl-α-bromopropionate with a corresponding halogeno fatty acid ester such as benzyl-α-bromo-n-butyrate in Reference Example 9-1. be able to.

Reference example? From the nose book NZ lys cis-4-hydroxy-〇20 phosphorus (300■), Reference examples 1-1.1-2.1-3.1-4 and 2-
[2R,48]-1-p-nitropenzyloxycarbonyl-2-pyrrolidinecarbonyl-4-acetylthiopyrrolidine (66■) was obtained in the same manner as in Example 1.

IR”m (CIll 1): 1695, 1635
, 1515.

ax 1430.1395, 1340°1115 b) From the thioacetate derivative (60"r) obtained above, [2, 45)-
1-p-nitrobenzyloxyluponyl-2-pyrrolidinecarbonyl-4-mercaptopyrrolidine was obtained.

1 Now zλ* Hi45a + 120 Threat to correct proceedings (voluntary) February 1, 1985 Patent Application No. 212857 2 Title of the invention Novel β-lactam compound and its manufacturing method 8, Person making the amendment Relationship to the case Patent applicant address: 2-40-4 Doshomachi, Higashi-ku, Osaka City, “Detailed Description of the Invention” column 5 of the specification to be amended, contents of Supplementary iH (IJ) ni [Cal]〈Moyle〈
Let's call it "aminocarbonyl".

(2) In the following parts of the same book, all references to "ncarbonyl" shall be replaced with "nylcarbonyl."

(8) "Hept-2" in the first line of page 54 of the same book is changed to "hept-2-ene."

(4) "Carbonate" in lines 4 to 8 from the bottom of page 68 of the same book is changed to "carpeptaxylate."

(5) “Carbonate” in the third line from the bottom of page 84 of the same book
is called "carboxylate".

(6) "2a" on page 110, line 4 of the same book is changed to "2b".

(7) "2b" in the 7th line from the bottom of the same page of the same book is changed to "2a".

that's all

Claims (1)

[Scope of Claims] (1) General formula [In the formula, Ro is a lower alkyl group, R is a hydrogen atom or a protecting group for a hydroxyl group, R2 is a hydrogen atom or a protecting group for an amino group, and R3 is a hydrogen atom or a protecting group for an amino group. Indicates a carboxyl group protecting group. R4 and R6 represent a hydrogen atom, a lower alkyl group, an aralkyl group, or a substituted lower alkyl group, or R4 and R6 represent an alkylene chain bonded to each other or alkylene via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom. The chain represents a 4- to 7-membered cyclic amino group together with adjacent nitrogen atoms. ] A β-lactam compound represented by these and a pharmacologically acceptable salt thereof. (21Ro, the β-lactam compound and pharmacologically acceptable salt thereof according to claim 1, wherein R2 and R3 are hydrogen atoms. (3) General formula [wherein, Ro represents a lower alkyl group] , R1 represents a protecting group for a hydrogen atom or a hydroxyl group, R2 represents a protective group for a hydrogen atom or an amino group, R3 represents a protective group for a hydrogen atom or a carboxyl group, R4 and R6 represent a hydrogen atom, a lower alkyl group, an aralkyl group. or a substituted lower alkyl group, or R4 and R6 represent an alkylene chain bonded to each other or an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and together with the adjacent nitrogen atom, a 4- to 7-membered ring is formed. represents a cyclic amino group.] In producing a β-lactam compound represented by
General Formula [In the formula, Ro represents a lower alkyl group, k□ represents a hydrogen atom or a hydroxyl group-protecting group, and R7 represents a carboxyl group-protecting group. ] A reactive ester of alcohol represented by the general formula [wherein R3, R, and R5 have the same meanings as above. ] In the general formula C, Ro, R1, R2, R4, R6 and R7 have the same meanings as above. ] A β-lactam compound represented by is produced, k□, R2
and/or when a β-lactam compound in which R3 is a hydrogen atom is desired, the protective group of the carboxyl group is removed in step 7, the hydroxyl group is removed in step 2, and the amino acid is removed in 2 A process for producing the above-mentioned β-lactamated compound and its pharmacological pestle and salts, which comprises subjecting the group to a reaction for removing a protective group in an appropriate combination as necessary.