JPH0249783A - 1-methylcarbapenem derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R<1> is lower alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, group of formula II [m is 0-2, n is 0-3; R<2> is H, (substituted) lower alkyl or alkanoyl], etc., substituted with carbamoyloxy or carbamoyl group}, its salt or its ester. EXAMPLE:(1R,5S,6S)-2-(2-carbamoyloxyethylthio-6-[(1R)-1-hydroxyethyl]-1- methylcarbapen-2-em-3-carboxylic acid sodium salt. USE:An antibacterial agent effective against Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, etc. It is stable to dehydropeptidase 1 and has high recovery in urine. PREPARATION:The objective compound can be produced by reacting a compound of formula IV with alkanesulfonic acid anhydride, etc., in the presence of a base, reacting the resultant compound of formula V with a mercaptan of formula HS-R<1> and removing the protecting group R<3> from the produced compound of formula VI.

Description

[Detailed Description of the Invention] [Purpose] Chenamycin derivatives have poor antibacterial activity, but they are degraded by dehydropeptidase 1, which is an inactivating enzyme for Chenamycin derivatives present in the human body. A loss of activity and a low urinary recovery rate have been reported (H, Kropp et al.).

Eight microb, Agents, Che
mother, 22, 62 (1982
): S, R, Norrby et al.
1bid, 23 +300 (1983)).

The inventors conducted various studies to solve this drawback of chenamycin derivatives, and a new carbapenem derivative (1) was found.
The present invention was completed based on the discovery that chenamycin has stronger antibacterial activity than chenamycin derivatives, is stable against dehydropeptidase 1, and has a high urinary recovery rate.

〔composition〕

The present invention is 1-methylcarbapenem derivatives having the formula and salts thereof and esters thereof.

In the formula, R1 is a lower alkyl group substituted with carbamoyloxy or carbamoyl.

Cycloalkyl group, aralkyl group, aryol group.

represents a heteroaryl group, a heteroaralkyl group, or an alkylheteroaralkyl group, or R1 is (CH2).

2, and n is 0, 1.2 . or 3, and R2 represents a hydrogen atom, a lower alkyl group with or without a substituent, or an alkanoyl group. ) Preferred R1 is carbamoyloxy substituted alkyl such as 2-carbamoyloxyethyl, 1-carbamoyloxy-2-propyl, 2-carbamoyloxypropyl, 3-carbamoyloxypropyl 3 or 3-carbamoyloxycyclobutyl. groups; carbamoyloxy-substituted cycloalkyl groups such as 2-carbamoyloxycyclopentyl or 4-carbamoyloxycyclohexyl; carbamoyloxy-substituted aralkyl groups such as 4-carbamoyloxyhenthyl or 2-carbamoyloxyphenethyl; 3-carbamoyloxyphenyl; carbamoyloxy-substituted aryl groups such as; carbamoyloxy-substituted heteroaryl groups such as 4-carbamoyloxy-2-thienyl or 3-carbamoyloxy-2-furyl; carbamoyloxy-substituted heteroaralkyl groups such as 4-carbamoyloxy-2thenyl; or 5-carbamoyloxymethylfurfuryl; a carbamoyloxy-substituted alkylheteroaralkyl group such as 4-carbamoyloxymethylfurfuryl; carbamoylmethyl, 2-carbamoylethyl, ■-carbamoylethyl, 3-carbamoylpropyl or 1-carbamoyl- Carbamoyl-substituted alkyl groups such as 2-propyl; 2-carbamoylcyclopropyl, 2-carbamoylcyclobutyl,
Carbamoyl-substituted cycloalkyl groups such as 3-carbamoylcyclopentyl, 2-carbamoylcyclopentyl or 4-carbamoylcyclohexyl; carbamoyl-substituted aralkyl groups such as 4-carbamoylbenzyl; carbamoyl-substituted aryl groups such as 4-carbamoylphenyl; Rubamoyl = Carbamoyl substituted heteroaryl group such as 2-thiazolyl or 4-carbamoyl 2-thienyl: 4-carbamoylthenyl 4-carbamoyl substituted heteroaryl group such as 4-carbamoylfurfuryl≠substituted heteroaralkyl group or 4-carbamoyl/-1 -Lua(coz)- is pyrrolidin-2-one-4-yl, ■-methylpyrrolidin-2-one-4-yl, 1=ethylpyrrolidine-
2-one-4-yl, 1-propylpyrrolidin-2-one-4-yl, ■-acetylpyrrolidin-2-one-4-yl, pyrrolidin-2-one-3-yl, ■-methylpyrrolidin-2-one- 3-yl, 1-ethylpyrrolidine-
2-one-3-yl, 1-acetylpyrrolidin-2-one 3-yl, piperidin-2-one-4-yl 1-methylpiperidin-2-one-4-yl 11-acetylpiperidin-2-one-4 -yl, piperidin-2-one-5
yl 1-methylbiperidin-2-one-5-ylpiperidin-2-one-3-yl, 1-methylpiperidin-2
-one-3-yl azetidin-2-one-3-yl,
1-methylazetidin-2-one-3-yl, hexamethyleneimin-2-one-6-yl, 7zetidin-2-one-4-methyl 1-methylazetidin-2-one-4-
Methyl azetidin-2-one-4-ethyl, 1-methyl azetidin-2-one-4-ethyl, pyrrolidine-2-
one-5-methyl11-methylpyrrolidin-2one-5
-Methyl 1-acetylpyrrolidin-2-one 5-methyl and 1-ethylpyrrolidin-2-one-5-methyl. Preferred substituted or unsubstituted lower alkyl groups for R2 include, for example, methyl, ethyl, propyl, or butyl, and the preferred positions thereof! The IA group is
For example, halogen atom, hydroxy group, alkoxy group, amino group, alkanoylamino group, alkanoyloxy group, alkaryl group, carboxyl group, orkoxycarbonyl group, cyano group, -CONR6R7 group (R6,R
) or a -3(0)jR8 group (RQ represents a lower alkyl group, and j represents 0, 1 or 2), which are the same or different and represent a hydrogen atom or a lower alkyl group.

Preferred substituent halogen atoms of the alkyl group having R2 substituents include, for example, fluorine or chlorine atoms,
Alkoxy groups include, for example, methoxy or ethoxy, alkanoyl groups of alkanoylamino, alkanoyloxy and alkanoyl groups include, for example, formyl, acetyl or propionyl, and alkoxycarbonyl groups include, for example, methoxycarbonyl or ethquinocarbonyl. , -CONl16R7%
is, for example, carbamoyl, methylcarbamoyl or dimethylcarbamoyl, and the -5(0)jR' group is, for example, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methanesulfonyl or ethanesulfonyl.

Suitable alkanoyl groups for R2 include, for example, formyl, acetyl or propionyl.

Examples of the salt of compound (1) include inorganic salts or ammonium salts such as lithium, sodium, potassium, calcium, and magnesium, and salts with organic bases such as I-liethylamine, diisopropylamine, cyclohen-1-enylamine, and the like. preferred are sodium and potassium salts.

The ester of compound (1) is an ester that is metabolized and hydrolyzed in vivo, and the ester residue is -C
I'191? "0COOR" group, -CR9R"0CO
R'' group (R9゜Rro is the same or different and represents a hydrogen atom or an alkyl group, such as 52, for example, methyl.

Mention may be made of ethyl, propyl, isopropyl or butyl. R114 Alkyl group; cycloalkyl group, alkenyl group, cycloalkenyl group, or alkynyl group optionally substituted with an alkyl group: Aralgyl group or cycloalkylalkyl optionally substituted with an alkyl group, alkoxy group, or siloxy group Indicates the group,
The alkyl group of R11 is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl,
t-butyl, pentyl or 3-pentyl,
The cycloalgyl group of the cycloalkyl group and cycloal-tolualkyl group which may be substituted with an alkyl group of R is, for example, cycloprobyl, nocrophthyl, cyclopentyl, cyclohquinol, ncrohebutyl, menthyl,
3-vinanyl or adamantyl, R1+
an alkyl group (optionally interchangeable alkenyl groups include, for example, allyl, butenyl, pentenyl, R
Examples of the cycloalkenyl group optionally substituted with a 1+ alkyl group include cyclohexenyl and cyclopentenyl, and examples of the alkynyl group optionally substituted with an R-th alkyl group include propargyl, butynyl, and pentynyl.

Examples of the aralgyl group which may be substituted with an alkyl group, alkoxy group, or acyloxy group for R1+ include hensyl and phenethyl; examples of the alkoxy group as a substituent include methoxy and ethoxy; and examples of the acyloxy group include acetoxy and propionyl. Examples include oxy and biwa hydroxy.

The alkyl group of the cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group and aralkyl group substituted with an alkyl group in R11 is, for example, methyl ethyl.
Propyl isopropyl methyl or isobutyl, and the cycloalkylalkyl group of l'lll is, for example, cycloalkylmethyl, -cycloalkylethyl, 2-cycloalkylethyl or 1-cycloalkylpropyl. ), (R12 and l'l13 are the same or different and are a hydrogen atom, an alkyl group, an aryl group, or R+2 and [?1
3 together represent an alkylene group. The alkyl groups mentioned are, for example, methyl, ethyl, propylisopropyl, butyl or S-butyl, the aryl groups mentioned are, for example, phenyl, and the alkylene groups are, for example, -(CHz)3- or (C)12. ) 4- can be mentioned. ) or phthalidyl group.

Suitable ester residues are acetoxymethyl, -acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-(pivaloyloxy)ethyl, 1-(pivaloyloxy)propyl, 2-pivaloyloxy)propyl, isobutyryloxymethyl, 1-(isobutyryloxy)ethyl, 1-(isobutyryloxy)propylbonyloxymethyl 11-(cyclohexanecarbonyloxy)ethyl, 1-(cyclo-,xanecarbonyloxy)propyl, (1-methylcyclohexane) -1-yl)carbonyloxymethyl 1-C (1-methylcyclohexan-1-yl)carbonyloxyethyl,
Cyclobencune carbonyloxymethyl, 1-(cyclobencune carbonyloxy)ethyl, 1-(cyclobencune carbonyloxy)propyl, (1-methylcyclobencun-1-yl)carbonyloxymethyl, 1
- ((1-Methylcyclobencun-1-yl)carbonyloxyethyl, cyclobutanecarbonyloxymethyl.1-(cyclobutanecarbonyloxy)ethyl, cyclopropanecarbonyloxymethyl51-(cyclopropanecarbonyloxy)ethyl 5 Cyclohebutanecarbonyloxymethyl 1-(cyclohebutanecarbonyloxy)ethyl, ■-(cyclohexylmethylcarbonyloxy)ethyl, 1-(cyclobenthylmethylcarbonyloxy)ethyl, 1-(cyclophthylmethylcarbonyloxy) Ethyl 21-(cyclopropylmethylcarbonyloxy)ethyl, methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl,
Ethoxycarbonyloxymethyl 11-(ethoxycarbonyloxy)ethyl, isopropoxycarbonyloxymethyl.

1-(isopropoxycarbonyloxy)ethyl.

1-(isopropoxycarbonyloxy)propyl 1-
(Ethoxycarbonyloxy)propyl, t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, cyclohexyloxycarbonyloxymethyl 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyl) oxy)propyl, 2-cyclohexylcarbonyloxy)propyl, cyclopentyloxycarbonyloxymethyl, ■(cyclopentyloxycarbonyloxy)ethyl, ■-(cyclopentyloxycarbonyloxy)propyl, cycloptyloxyluponyloxymethyl, 1-( cyclobutyloxycarbonyloxy)
Ethyl, cycloheptyloxycarbonyloxymethyl 1-(cycloheptyloxycarbonyloxymethyl)ethyl, menthyloxycarbonyloxymethyl 1-(menthyloxycarbonyloxy)ethyl, 3-binanyloxycarbonyloxymethyl, 1-(3-binanyloxycarbonyloxymethyl) Nyloxycarbonyloxy)ethyl, 1-(cyclohexylmethoxylponyloxy)ethyl, 1-(2
-cyclohexylethoxycarbonyloxy)ethyl,
■-(cyclopentylmethoxycarbonyloxy)ethyl, 1-(cyclobutylmethoxycarbonyloxy)ethyl, 1(cyclopropylmethoxycarbonyloxy)
Ethyl, 2-cyclohexenyloxylponyloxydimethyl, L, (2-cyclohexenyloxylponyloxy)ethyl 14-pivaloyloxyhensyl,
3-Methoxy-4-pivaloyloxyhensyl 4-acetoxybenzyl, 4. Acetoxy-3-methoxyhensyl 3-methyl-1-buten-3-ylcarbonyloxymethyl, phthalidyl, 5-methyl-2-oxo-13
-dioxolen-4-ylmethyl or 5-phenyl, 2
-oxo-13-dioxolen-4-ylmethyl, particularly preferred ester residues include acetoxomethyl, 1. acetoxyethylpivaloyloxymethyl,
1-(pivaloyloxy)ethyl, isobutyryloxymethyl, 1-(isophthyryloxy)ethyl, (1-methylcyclohexan-1-yl)calun-1zonyloxymethyl, (1-methylcyclopencun-1-yl) ) carbonyloxymethyl, cyclohexanecarbonyloxymethylto(cyclohexanecarbonyloxy)ethyl.

1-((1methylcyclohexane=1-yl)carbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(isopropoquinecarbonyloxy)ethyl,
1-(t-butoxycarbonyloxy)ethyl, ■-
(cyclohexyloxycarbonyloxy)ethyl, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclohexylmethoxycarbonyloxy)ethyl, (IR
2S, 5R)-(ρ)menthyloxycarbonyloxymethyl, 1-[(11?, 2S.

517)-(N) Menthyloxycarbonyloxymethyl, 5-methyl-2-oxo-1,3-dio; tosolen-4ylmethyl or phthalidyl.

Compounds having the formula (1,1) exist in various isomers based on their asymmetric carbon atoms. Formula (1) represents one or a mixture of these isomers. Among these isomers, preferred are Examples include compounds in which the (IR, 5S, 6S) coordination and the hydroxyl group at the 2-position of the 6-position substituent are in the R coordination.

The 1-methylcarbapenem derivative having the general formula (1) can be produced by the method shown below (method he).

Method A: R3 represents a protecting group for a carboxy group, such as an alkyl group such as methyl ethyl or L-butyl;
Aralkyl groups such as hensyl, diphenylmethyl, 4-nitrohenzyl or 2-nitrohensyl; alkenyl groups such as allyl, 2-chlorolyl or 2-methylallyl; 2.2.2-1-lichloroethyl2,
2-dibromoethyl b s< ha 2,2.2-Tribromoethyl and other helochelialkyl groups or 2-trimethylsilylethyl 7;

R4 is an alkanesulfonyl group such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl;
Arylsulfonyl groups such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl; dialkylphosphoryl groups such as dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl or diethylphosphoryl or diphenylphosphoryl or ditolylphosphoryl; represents a diarylphosphoryl group.

This synthesis method uses a compound having formula (2) in the presence of a base.

Alkanesulfonic anhydride, arylsulfonic anhydride 1
A dialkylphosphoryl halide or diarylphosphoryl halide is reacted to produce a compound having the formula (3), and the resulting compound (3) is reacted with a mercaptan having the formula (4) in the presence of a base without isolation. formula(
5), and the carboxyl group protecting group R
The target compound having general formula (1) is produced by subjecting it to the removal reaction of step 3.

Examples of the alkanesulfonic anhydride used in the reaction to obtain compound (3) from compound (2) include methanesulfonic anhydride, ethanesulfonic anhydride, and arylsulfonic anhydride such as benzenesulfonic anhydride and p-toluenesulfonic anhydride. Examples of acid dialkylphosphoryl halides include dimethylphosphoryl chloride, diethylphosphoryl chloride, and examples of diarylphosphoryl halides include diphenylphosphoryl chloride and diphenylphosphoryl bromide. Among these reagents, 11-toluenesulfonic anhydride is particularly suitable. Or diphenylphosphoryl chloride is suitable. There is no particular limitation on the volume used, as long as it does not take part in this reaction; for example, methylene chloride,
Examples include halogenated hydrocarbons such as 1,2-dichloroethane and chloroform; nitriles such as acetonitrile, or amides such as N,)1-dimethylformamide and N,N-dimethylacetamide. The base used is not particularly limited as long as it does not affect other parts of the compound, especially the β-lactam ring.
Suitable examples include organic bases such as triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine.

The reaction temperature is not particularly limited, but in order to suppress side reactions, it is desirable to conduct the reaction at a relatively low temperature, usually between 20°C and 4°C.
It is carried out at around 0°C. The reaction time varies mainly depending on the reaction temperature and the type of reaction reagent, but is from 10 minutes to 5 hours.

The thus obtained compound (3) can be treated with a mercaptan of formula (4) in the reaction mixture in the presence of a base without sh+. The base used in this step is not particularly limited, but suitable examples include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium carbonate.

The reaction temperature is not particularly limited, but it is usually carried out at -20°C to room temperature. Reaction time is 30 minutes to 108 hours.

After the reaction is completed, the target compound (5) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding a water-immiscible organic solvent to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water, and then distilling off the solvent. The obtained target compound can be prepared by a conventional method if necessary.
Further purification can be carried out, for example, by recrystallization, reprecipitation or chromatography. Further, if desired, the target compound (5) can be subjected to the next reaction for removing the carboxyl group without being isolated. Obtained compound (5)
is a carboxyl group protecting group R3 according to a conventional method if necessary.
can be converted into a carboxylic acid derivative by removal treatment. Removal of protecting groups differs depending on the type, but -
removed by any method best known in the art. Preferably, the reaction is performed using a compound having the formula (5) in which the substituent R3 is a halogenoalkyl group, an aralkyl group, a benzhydryl group, etc., which can be removed by a reduction treatment.
, 5 by contacting the compound with a reducing agent.

As the reducing agent used in this reaction, zinc and acetic acid are preferred when the protecting group for the carboxy group is a halogenoalkyl group such as 2,2-dibromoethyl or 2,2.2-trichloroethyl. When the protecting group is for example an aralkyl group such as benzyl, 4-nitrobenzyl or a benzhydryl group, hydrogen and a catalytic reduction catalyst such as palladium on carbon or an alkali metal sulfide such as sodium or potassium sulfide are suitable. be.

The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, tetrahydrofuran, dio:1-san, etc. Ether neck: A mixed solvent of water and a fatty acid such as acetic acid and an organic solvent such as chlorine is suitable. The reaction temperature is usually around O'C to room temperature, and the reaction time varies depending on the raw material compound and the type of reducing agent, but is usually 5 minutes to 12 hours.

After the reaction is completed, the target compound of the reaction for removing the protecting group of the carboxy group is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing the waste precipitated from the reaction mixture by distilling off the solvent.

The target compound thus obtained can be purified, if necessary, by conventional methods such as recrystallization, preparative 7'Iv layer chroma i-graph, E, Kara J, chroma I-graph, etc. . Also, if necessary, as the salt (
It can also be front-mounted.

On the other hand, the 1-methylethylhabefum derivative having formula (1) of the present invention can also be produced by the method shown below (R method).

Method: where )73 is as defined above, R5 is an alkyl group such as methyl, ethyl, propyl or isopropyl; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoroethyl Diku 1 Choroethyl 1 Trifluoroethyl or halogenoalkyl like trifluoroethyl, t%? -acetylamino, ethyl group; 2
-Acetylaminohinyl group, phenyl or (7-aryl group such as yonaphthyl, which may have a substituent, and these 7-aryl groups: have 1 to 3 substituents that are the same or different as shown below) The substituents that may be used are: fluorine, chlorine bromine, methyl, ethyl, propyl, isopropyl.

Notoxo 1 engineering 1-)-shi, propokine, isobu I:!
Bo・1-shi, ,,/ l-xysulfonyl, etquincarbonyl [butquincarbonyl, 21・ro, glacial acid'I
A heteroaryl group such as birinol or pyrimidinyl, which includes the Masiano group or which may have a substituent, and these heteroaryl groups have 1 to 3 substituents that are the same or different as shown below. The substituent may be fluorine, chlorine, bromine, methylethyl, propyl or isopropyl.

The compound having formula (6) in this synthesis method is
No. 2-30781. The reaction of producing a compound having the general formula 5) by reacting the compound forming second (6) with a mercaptan in the presence of a base is carried out in an inert solvent. The solvent to be used is not particularly limited as long as it does not participate in this reaction; for example, tetrahydrofuran 1
7 Setonitrile Examples include dimethylformamide, dimethylsulfur oxide, water, or a mixed solvent thereof. The base to be used is not particularly limited as long as it does not affect other parts of the compound, especially the β-lactam ring, but diisopropylethylamine, triedylamintomethylpiperidine, 4-dimethylaminopyridine, etc. and inorganic bases such as potassium carbonate and sodium bicarbonate. There is no particular limitation on the reaction temperature, but in order to suppress side reactions, it is desirable to conduct the reaction at a relatively low temperature, and the reaction temperature is usually 120°C to 40°C. The reaction time varies mainly depending on the reaction temperature and the type of reaction reagent, but is usually 15 minutes to 75 hours. After completion of the reaction, the target compound 5) of this reaction can be collected from the reaction mixture according to a conventional method.

A compound having 21) can be obtained by subjecting the compound having 25) to the carboxyl protecting group removal reaction described in Method A. The compound having the general formula 1) thus obtained by Method A or Method A can be converted into its salts and esters by methods and techniques known in the field of β-lactam antibiotics.

The 1-methylcarbapenem derivative having formula 1) of the present invention exhibits excellent antibacterial activity with a broad spectrum,
It has β-lactamase inhibitory activity. Furthermore, although chenamycin-based compounds are easily metabolized by mammals, they also show limited stability against dehydropeptidase 1, an enzyme known to catalyze the inactivation of chenamycin, and It also has excellent properties such as medium recovery rate. As for antibacterial activity, its activity was measured by the agar plate dilution method, and it was found that, for example, Staphylococcus aureus, Bacillus subtilis, and other Durham-positive bacteria, Escherichia coli, Shigella, Klebsiella pneumoniae, M. mutaris, Serratia, and Enterobacter-1 Pseudomonas aeruginosa It showed potent activity against a wide range of pathogenic bacteria, including Gram-negative bacteria such as Bacteroides fragilis and anaerobes such as Bacteroides fragilis.

Such compounds are therefore useful as antibacterial agents to treat cell infections caused by these pathogens.

Dosage forms for that purpose include, for example, tablets.

Examples include oral administration using capsules, granules, powders, syrups, etc., and parenteral administration via intravenous injection, intramuscular injection, etc. The dosage varies depending on age, body weight, symptoms, etc., as well as the mode of administration and the number of administrations, but it is usually administered to adults at about 100 mg to 3000 mg per day, either once or in several divided doses.

-Gubutsuko (IR, 51'1.6S) -6-((IR)-1-hydroxyethyl)1-methyl-2-oxo-1-carbabenam-3-carboxylic acid 4-nitrohensyl ester (2
50 mg) 'i: Mini dry acetonitrile ml) diisopropylethylamine (126 μj
) and diphenylphosphoryl chloride (150 μl) were added, and the mixture was stirred at 0 to 5°C for 1 hour. Next, while cooling with water, diisopropylethylamine (1 μl) and 2-carbamoyloxyethyl mercaptan (100 mg) were added to
After stirring at 5°C for 7 hours, it was left in the refrigerator overnight. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was dissolved in tetrahydrofuran (20 ml).
), 0.1M phosphate buffer (pH 7, 1, 20ml
) was dissolved in a mixture of 10χ palladium-carbon catalyst (3
31 mg) at room temperature for 2.5 hours.

After the reaction: Insoluble matter was removed using Celite, the liquid was washed with diethyl ether, the aqueous layer was concentrated under reduced pressure, and applied to a column of Diaion IP-20AG (manufactured by Mitsubishi Chemical Industries, Ltd.). The eluted portion was concentrated under reduced pressure and lyophilized to obtain the crude target compound. Furthermore, using an 0-bar column (manufactured by Merck & Co., Ltd., Rikurobesop RP-8 size B),
The portion eluted with 2x methanol water was concentrated under reduced pressure and lyophilized to obtain the target compound (58+++g) as a colorless powder.

Nuclear magnetic resonance spectrum 71/ (270MHz, D2
0) δppm 0.99 (3+l, d, J=7.3
3) 1z) , 1.10 (3H, d, J=6.5
91(Z), 2.75 (18d L, J=14
．． 29.6.2311z), 2.99 (Ill
dt, J=14.29.6.23Hz) 3.20~
3.34 (211, m), 3.98 ~ 4.10 (48
m) Carbapen-2-M-3-carbon sodium (IR,5R,6S)-6-((IR)-1-hydroxyethyl)
3-carboxylic acid 4-di-lohendyl ester (250
mg) in total dry acetonitrile (5 ml),
Under water cooling, diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl) were added.
Stirred at 0-5°C for 1 hour. Next, under water cooling, diisopropylethylamine (144 μm) and mercaptoacetamide (75 mg) were added, stirred at 0 to 5° C. for 2 hours, and then left in a refrigerator overnight. Dilute the reaction solution with ethyl acetate,
The ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was dissolved in tetrahydrofuran (20 ml), 0.1 M phosphate buffer; overnight (pH 7, I, 20 ml) and mixed with 10'4 palladium-carbon. Catalyst (331mg
) for 25 hours at room temperature. After the reaction, insoluble materials were removed using Celite, the reactor solution was washed with diethyl ether, and the aqueous layer was depressurized and washed with Diaion HP-2.
The mixture was attached to a column of 0AG (manufactured by Mitsubishi Chemical Industries, Ltd.), and the portion eluted with water was concentrated under reduced pressure and lyophilized to obtain the crude target compound. Furthermore, using a Roper column (Merck & Co., Ltd. "A Licropressop RP-8, size B), the portion eluted with water was concentrated under reduced pressure and lyophilized to obtain the target compound as a colorless powder (
56 mg) was obtained.

Nuclear magnetic resonance spectrum (270MHz, 020) δp
pm 0.99 (3Hd J=7.33Hz), 1.
10 (3B, d, J・6.231(z), 3.13~3
．． 25 (LH, m), 3.27 (IH, dd, J=6
．． 23,2.57Hz), 3.33(IH,d,
J=5.75Hz), 3.43 (ltl, d,
J=5.75Hz), 3.99 (111dd
J=9.16 2.57tlz), 3.99-4.1
1(11!, m)bon7sodium(IR,5R,6S)-6-((IR)-1-hydroxyethyl]j-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4- Nitrohensyl ester (250
mg) Dissolve in completely dry acetonitrile (5 ml), add diisopropylethylamine (126 μm) and diphenylphosphoryl chloride (150 μl) under water cooling, and add
Stirred at 5°C for 1 hour. Next, diisopropylethylamine (144 μm) and 5-carbamoyloxymethylfurfuryl mercaptan (155 mg) were added under water cooling, and the mixture was stirred at 0 to 5°C for 2.5 hours and then left in the apparatus overnight. In the same manner as in Example 1, the desired compound (9 m
g) was obtained.

Ultraviolet absorption spectrum λmax nm: 301 Tylcarbapen-2-M-3-carboxylic acid (IR, 5R, 6S)-6-((11?L1-hydroxyethyl)1-methyl-2-oxo-1-carbabenam- 3-carboxylic acid 4-nitrobenzyl ester (250
mg) Dissolved in dry acetonitrile (5 ml), added diisopropylethylamine (126/Jl) and diphenylphosphoryl chloride (150 μm) under water cooling,
Stirred at 0-5°C for 1 hour. Next, diisopropylethylamine (144 μI) and 4-carbamoylbenzyl mercaptan (138 mg) were added under water cooling, and the mixture was heated at 0 to 5°C.
It was left in the refrigerator for 2.5 hours and then overnight. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was mixed with 0.0% tetrahydrofuran (20ml).
It was dissolved in a mixture of 1M phosphate buffer (pH 7, 1, 20ml) and hydrogenated for 2 hours at room temperature in the presence of a 10χ palladium-carbon catalyst (331mg). After the reaction, the insoluble materials were removed using Celite, the liquid was washed with diethyl ether, the aqueous layer was bound under reduced pressure, and the insoluble matter was washed with Diaion 11P.
-208G (manufactured by Mitsubishi Chemical Industries, Ltd.) column, and the portion eluted with 5x acetone water was concentrated under reduced pressure and lyophilized to obtain the crude target compound. Furthermore, add this to a Rover column (manufactured by Merck & Co., Ltd., Ricroprep RP-8° size B)
From the part eluted with 10x methanol water using
Concentrate under reduced pressure and freeze-dry to obtain the target compound (36,
3 mg) was obtained.

Nuclear magnetic resonance (270MHz, D20)
6 ppm 0.94 (311, d, J=7.33H
z), 1.07 (3H, d, J=6.23Hz
), 3.06~3.20 (2H, m), 3.72~
4.07 (4th day, m), 7.32, 7.58 (4842
B2. J=8.43Hz) 1 tylcarbapene-2-M-3-carbond (
IR,5R,65)-6-[(IR)-1-hydroxyethyl]1-methyl-2-oxo-1-carbapenam-
3-carboxylic acid 4-nitrobenzyl ester 250m
g) in dry acetonitrile (3 ml), diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl) were added under water cooling, and 0 to 5
Stirred at °C for 1 hour. Next, under water cooling, a dry acetonitrile solution (2 ml) of diisopropylethylamine (144 μm) and 4-carbamoylphenylmercaptan (127 mg) was added, and the mixture was left in the refrigerator for 3 days. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed twice with brine and dried over anhydrous maggotium sulfate.

The solvent was distilled off, and the resulting crude product was mixed with tetrahydrofuran (20 ml) and 0.1M phosphate buffer (pH 7, 1, 2).
0ml) and hydrogenated for 2 hours at room temperature in the presence of IOX palladium-carbon catalyst (331mg). After the reaction, the insoluble matter was removed using Celite, the reactor solution was washed with diethyl ether, the aqueous layer was concentrated under reduced pressure, and it was applied to a column of Diaion 1 (P-20AG (manufactured by Mitsubishi Chemical Industries)). The crude target compound was obtained from the portion eluted with 5χ acetone water, concentrated under reduced pressure and lyophilized.
8, size B), the portion eluted with lOx methanol water was concentrated under reduced pressure and lyophilized to obtain the target compound (14 mg) as a colorless powder.

Ultraviolet absorption spectrum λ,, Xnm: 315,227 Nuclear magnetic resonance spectrum C21C21O, 020) δppm
Q, '78 (3H, d, J=7.33tlz), 1.
05 (3H, d, J=6.23Hz), 2.88-3.
02 (IH, m), 3.22 (l) 1. dd, J=6.
05, 2.74Hz), 3.98-4.07 (2H, m
), 7.44, 7.62 (4H, A2B2.J=8.
43Hz) Ram (IR,5R,65)-6-((IR)-1-hydroxyethyl]1-methyl-2-oxo-1-carbabenam-3-carboxylic acid 4-nitrobenzyl ester (250
mg) in dry acetonyl chloride (3 ml), diisopropylethylamine (126 μl)) and diphenylphosphoryl chloride (150 μl) were added under water cooling, and
Stir at ~5°C for 1 hour. Next, under water cooling, diisopropylethylamine (144 μm) and 4-carbamoyl-
A dry acetonitrile solution (2 ml) of 2-mercaptothiazole (131 mg) was added and the mixture was left in the refrigerator for 3 days. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the resulting crude product was mixed with tetrahydrofuran (20 ml) and 0.1 M phosphate buffer (pH 7.1,
The mixture was dissolved in a mixed solution of 20 ml) and hydrogenated for 2 hours at room temperature in the presence of a 10x palladium-carbon catalyst (331 mg). After the reaction, the mixture was treated and purified in the same manner as in Example 5 to obtain the target compound (4 mg) as a colorless powder.

Ultraviolet absorption spectrum λ□, nm: 308 Carbaben-2-M-3-carbon'sodium (111,5
R,6S)-6~ ((III)-1-hydroxyethyl]1-methyl-2-oxo-1-carbabenam-3-
Carboxylic acid 4-nitrohensyl ester (250mg)
Dissolve in completely dry acetonitrile (5 ml) and cool with water.
Add diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μm) and heat at 0-5°C.
The mixture was stirred for 1 hour. Next, under water cooling, diisopropylethylamine (144 μl) and 3-mercaptopropionamide (87 mg) were added, and the mixture was left at 0 to 5° C. for 2.5 hours and then left in the refrigerator overnight. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was dissolved in a mixture of tetrahydrofuran (20 ml) and 0.1 FI phosphate buffer (p) (17.1.20 ml).
Hydrogenation was carried out at room temperature for 2 hours in the presence of χ palladium-carbon catalyst (331 mg). After the reaction, the reaction mixture was treated and purified in the same manner as in Example 5 to obtain the target compound (23.4 mg) as a colorless powder.

Ultraviolet absorption spectrum λ□, nm: 302 nm nuclear magnetic resonance spectrum (270 MHz, 020) δppm
1.011.02 (3H, d X2.J=7.33,6
．． 96Hz), 1.11, 1.12 (311°d x2
．． J=6.22, 6.60Hz), 2.34-2.52
(2Lm), 2.72-3.02 (21m) 3.21
~3.35 (2H, m), 3.98 ~ 4.12 (2H,
m) Example 8 (III 5S, 6S)-2-C(IR)
-1-carbamoyl enalthio)-6-((IIIL1
-hydroxyethyl)thorium (IR,5R,6S)-6-[(IR)-1-hydroxyethyl]1-methyl-2-oxo-1-carbabenam-3-carboxylic acid 4-nitrobenzyl ester (250
mg) To a completely dry acetonitrile (5 ml) solution was added diisopropylethylamine (126 μm) and diphenylphospho 1-norchloride (150 μl) under water cooling, and
Stirred at 5°C for 1 hour. Next, diisopropylethylamine (144 μm) and (2R)-2-mercaptopropionamide (87 mg) were added at the same temperature, stirred for 5 hours, and then left in the refrigerator overnight. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. (The crude product obtained by distilling off the container was dissolved in a mixture of tetrahydrofuran (20 ml) and 0.1 M phosphate buffer (pt+7.1.20 ml)), and 10 g of palladium-carbon catalyst (331 mg) was dissolved. Hydrogenation was carried out for 2.5 hours at room temperature in the presence of. After the reaction, insoluble materials were removed using Celite, and the aqueous layer was concentrated under reduced pressure and applied to a column of Diaion IIP-20AG (manufactured by Mitsubishi Chemical Industries, Ltd.), and the portion eluted with water was concentrated under reduced pressure and freeze-dried. The crude target compound was obtained. Furthermore, using a Rover column (manufactured by Merck & Co., Ltd., Ricrobresov RP-8, size B),
The portion eluted with 2x methanol water was concentrated under reduced pressure and lyophilized to obtain the target compound (65 mg) as a colorless powder.

Nuclear magnetic resonance spectrum (270Mtlz, D2o)
δppm 0.98 (311,d, J=7.33H
z) , ], 11 (311,d, J=6.2
3) 1z) , 1.30 (311°d, J=7.33
11z), 3.13-3.24 (III, m), 3.2
6 (Ill, dd, J=6.23, 2.5711z)
, 3.70 (ill, q, J・7.3311z) ,
4.01-4.11 (2H, m) Example 9 (IR, 5S, 6S)-2-((Is)-
1-carno\moylethylthio)-6-((IR)-1
-Hydroxethyl 1-methylcarbapen-2-m-
Hydrofuran (20 ml), 0.1 M phosphate buffer (
2.5 at room temperature in the presence of 1 oz palladium-carbon catalyst (331 mg).
Hydrogenated for hours. After the reaction, the reaction mixture was treated and purified in the same manner as in Example 8 to obtain the target compound (26 mg) as a colorless powder.

(IR,5R,6S)-6-[(1)ILI-hydroxyethyl]1-methyl-2-oxo-1-carbabenam-3-carboxylic acid 4-nitrohensyl ester (250
mg) Dissolved in dry acetonitrile (5 ml), added diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl) under water cooling, and diluted with 0
Stir at ~5°C for 1 hour. Next, diisopropylethylamine (144 μl) and (2S)-2-mercaptopropionamide (87 mg) were added at the same temperature, stirred for 1.5 hours, and then left in the refrigerator overnight. The reaction solution was diluted with ethyl acetate, washed twice with brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was subjected to tetranuclear magnetic resonance spectrum (270MHz, 020) δp
pm 1.00 (3) 1. d, J=7.32)1z
), 1.10 (3L d, J=6.23)1z
), 1.29 (3) 1°d, J=7.33Hz)
, 3.12-3.24 (LH, m), 3.25 (III
dd J=6.23, 2.5611z), 3.70
(1)1. q, J=7.33), 3.99 (IH, dd
J=9.16, 2.56tlz), 4.00 ~ 4.1
2(III, m)carnisu(IR,5R,6S)-6-C(IR)-1-hydroxyethyl]1-methyl-2-oxo-1-carbabenamyl 3-carboxylic acid 4-nitrohen Silester (25
0 mg) was dissolved in dry acetonitrile (3 ml), and diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl) were added under water cooling.
Stir at ~5°C for 1 hour. Then, under water cooling, diisopropylethylamine (288 μm) and 3-mercapto-2
A dry acetonitrile solution (2 ml) of a mixture of -pyrrolidinone and trifluoromethanesulfonic acid (1:1) (222 mg) was added and left in the refrigerator for 3 days. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed with hydrogen carbonate, water, saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was dissolved in a mixture of tetrahydrofuran (20 ml) and O,LM phosphate buffer (pH 7, 1° 20 ml), and the solution was dissolved in the presence of a 10χ palladium-carbon catalyst (331 mg). , 2 at room temperature
Hydrogenated for hours. After the reaction, the insoluble materials were removed using Celite, the liquid was washed with diethyl ether, the aqueous layer was concentrated under reduced pressure, and applied to a column of Diaion HP-20AG (manufactured by Mitsubishi Chemical Industries, Ltd.). The eluted portion was concentrated under reduced pressure and lyophilized to obtain the crude target compound.

This product was further concentrated under reduced pressure using a Roper column (manufactured by Merck & Co., Ltd., Licropressop RP-8, size B) from the portion eluted with 3χ methanol water, and lyophilized to obtain the target compound (35 mg) as a colorless powder. Ta.

Nuclear magnetic resonance spectrum (270MHz, 020) δ
ppm 1.00 (3H, d, J=7.33Hz)
, 1.11 (3H, d, J=6.60Hz) ,
1.86-1.98 (IN, m), 2.40-2.
55 (III, m), 3.18 - 3.39 (4) 1 m
), 3.71 (IH, dd, J=9.16, 6.60t
lz), 4.02 to 4.12 (21(.

m) Forcibly (IR,5R,65)-6-((IR)-1-hydroxyethyl]1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (250
mg) in dry acetonitrile (5 ml), diisopropylethylamine (126 μm) and diphenylphosphoryl chloride (150 μm) were added under water cooling, and
Stir at ~5°C for 1 hour. Then, under water cooling, diisopropylethylamine (144μI) and 4-mercapto-2
-Pyrrolidinone (97 mg) was added, and after stirring at 0-5°C for 7 hours, it was left in the refrigerator overnight. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was dissolved in a mixture of tetrahydrofuran (20 ml) and 0.1 phosphoric acid buffer (pH 7.1, 20 ml), and the solution was dissolved in the presence of a lOx palladium-carbon catalyst (331 mg). , hydrogenated for 2.5 hours at room temperature. After the reaction, insoluble materials were removed using Celite, the reactor solution was washed with diethyl ether, and the aqueous layer was concentrated under reduced pressure.
It was attached to a column of 20AG (manufactured by Mitsubishi Chemical Industries, Ltd.), and the portion eluted with water was concentrated under reduced pressure and lyophilized to obtain a crude target compound. Furthermore, using a Roper column (manufactured by Merck & Co., Ltd., Likloprep RP-8, size B), the portion eluted with 3x methanol water was concentrated under reduced pressure and lyophilized to obtain the target compound (91 mg) as a colorless powder. pyrrolidone ring 4
The isomer ratio S:R for positional coordination is approximately 1:1.

Ultraviolet absorption spectrum λmax nm: 300 Nuclear magnetic resonance spectrum (270MHz, 020) δppm
1.02゜1.03 (3H, d x2.J=7.33,
6.96Hz), 1.10 (3tl, d, J-6,60
Hz), 2.12, 2.22 (IH, dd X2 J=
17.594.40Hz.

J=17.59, 4.03Hz), 2.74, 2.77
(IH, dd x2.J=17.59°9, 1611z
, J= 17.59.9.16Hz) 3.07~3
．． 29 (3H, m), 3.64-3.73 (li
t, m), 3.84-3.96 (it(, m), 4.0
0 to 4.12 (2H, m) Example 12 1R5S 6S -2-2-oxo-3-
A dry dimethylformamide solution of 2-oxo-13-dioxolen-4-ylmethyliodite (66 mg) was added to Pyro-1-Dinola L, and the mixture was stirred at room temperature for 80 minutes and at 30-40°C for 4.5 hours. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed four times with brine and dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was collected using a Roper column (Liclopresop 5i60, manufactured by Merck Co., Ltd., size A), and the target compound (2"7. 4 mg) was obtained.

(IR,55,65)-2-(2-oxo-3-pyrrolidinylthio)6-((IR)-1-hydroxyethyl)
Dry dimethylformamide (0.4 ml) was added to sodium -1-methylcarbapen-2-em-3-carboxylate (47.6 mg), and then 5-methyl-2-oxo-1,3-dioxolen-4yl 5-Methyl nuclear magnetic resonance spectrum prepared by heating refluxing methyl bromide and sodium iodide in acetone (270 Mtl
z, DMSO-d6) δppm: 1, 13 (3
B, d, J=7.3211z), 1.15
(311,d, J=6.3511z), 1.84
~1.98 (III, m), 2.17 (31
1,s), 2.50-2.65 (18,m).

3.12-3.45 (411, m), 3.77-4.
06 (2H, m), 4.14 (IIIdd, J=9.
27.2.44Hz), 5.08(2H,s)um(IR,5R,6S)-6-((IR)-1-hydroxyethyl)1-methyl-2-oxo-1-carbapenam-3- Carboxylic acid 4-nitrobenzyl ester (2,9
3g) t-1 Dissolved in dry acetonitrile (50ml) and diisopropylethylamine (1.45ml) under water cooling.
) and diphenylphosphoryl chloride (1.70ml) were added and stirred at 0-5°C for 30 minutes. Next, the reaction solution was cooled to -20°C and diisopropylethylamine (1,4
5ml) and 4-mercapto-2-pyrrolidinone (1
, 35 g) in acetonitrile (5 ml), and
After stirring at °C for 3 hours, the mixture was incubated overnight under the same conditions. The reaction solution was diluted with ethyl acetate and washed twice with brine. Insoluble matter generated during the separation operation was separated. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a foamy crude product containing 4-nitrobenzyl ester. Tetrahydrofuran (150 ml) was added to this to remove a small amount of insoluble matter, and the liquid was added with 0.1 M phosphate buffer (pH 7,
1,150ml) and 10% palladium on carbon catalyst (
1.5 g) at room temperature for 2.5 hours.

Thereafter, the same operation as in Example 11 was performed to obtain the target compound (1.05 g) as a colorless powder. Regarding the configuration of the 4-position of the pyrrolidine ring, the isomer ratio SIR is approximately 9=1.

1597, 1393.1296 Nuclear magnetic resonance spectrum (270Mtlz, 020)
δppm: 1.03 (3H, d, J=7.3Hz
), 1.10 (311,d, J=6.211z
), 2.12 (0.9tl, dd, J=17
．． 9. '4.4Hz), 2.22 (0,Ill
, dd, J=17.94.4Hz), 2.74
．． 2.77 (IH, dd x 2. J=17.9.8
．． 4tlz), 3.08-3.24(2tl, m)
, 3.26 (Ill, dd, J=5.9. 2.6Hz
), 3.69 (11 (, dd, J = 11.4, 6.61
(z), 3.84-3.93 (ill, m), 4.
02-4.11 (211, m) Example 14 R5S 6S -2-4S-2-oxo-4pyro1dinyl o -+1-hydroxyethyl -1-methylcarbapen-2-em-3-carbo 2
1j'' fL intermittent In the same manner as in Example 13, (IR, 5R, 6S)
-6((IR)-1-Hydroxyethyl]-1-methyl-2-oxotocarbapenam-3-carboxylic acid 4-nitrobenzyl ester (330 mg) was converted into a crude product containing p-nitrobenzyl ester of the target compound. The product was prepared and subjected to column chromatography using silica gel (50 g).The portion eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give a colorless powder (260 mg).
I got it. Ethyl acetate (10 ml) was added to this, and after cooling on ice, the unmelted portion was removed. The furnace liquid was concentrated under reduced pressure, and isopropyl ether was added, and the solidified portion was weighed and dried. p-nitrobenzyl ester of the target compound (15
0 mg) was obtained in powder form.

Nuclear magnetic resonance spectrum (270M) lz, DMSO-
d6) δppm: 1.16 (3H, d, J=6.0H
z), 1.18 (3H, d, J=7.3) 1z), 2.
02 (LH, dd, J=17.1.4.911z)
, 2.72 (LH, dd, J=17.1, 8.
3tlz) 3.12-3.48 (3H, m), 3.74
(IH, dd, J=10.7, 6.3Hz).

3.94-4.05 (2H, m), 4.24 (
IH, dd, J=9.8.2.9Hz), 5.0
6 (LH, d, J=4.9Hz), 5.30.5
．． 46 (2H, AB, J=14.2Hz), 7
．． 71 (2H, d, J = 8.8Hz), 8.23 (2H
, d, J = 8.8 Hz) The thus obtained powder of 4-nitrobenzyl ester (100 mg) was added to Example 1.
The target compound (55
mg) was obtained in powder form.

Nuclear magnetic resonance spectrum (270MHz, D20) δ
ppm: 1.03 (31(, d, J=7.31(
z), 1.10 (38, d, J=6.211z
), 2.12 (IH, dd, J=17.9, 4.4
Hz), 2.74 (1B, dd, J=17.9, 8.
4Hz), 3.08~3.24 (211, m)
, 3.26 (III, dd, J=5.9.2.
611z) 3.69 (18, dd, J=11.4, 6.
6Hz), 3.84-3.93 (IH, i).

4.02-4.11 (2H, m) Example 15 R5S 6S -2-4) 1-2-Oxyl-4-pyroidinylthio-6-IR-1-hydroxyethyl■ Methylcarbapen-2-em -3-Carbo 2jkL
L upper blade] In the same manner as in Example 11, (IP, 5R, 6S)
-6((IR)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylic acid p-
A crude product containing p-nitrobenzyl ester of the target compound was prepared from nitrobenzyl ester (300 mg), and this was chromatographed using silica gel (50 g). A colorless powder (270 mg) was obtained from the portion eluted with ethyl acetate/methanol (4/1). This powder is the p-nitrobenzyl ester of the target compound with an isomer ratio of about 1:1 about the 4-position of the pyrrolidine ring.

A portion (100 mg) of the powder obtained here was taken and ethyl acetate (10 ml) was added. The ethyl acetate insoluble portion was counted and recrystallized using a methanol-isopropanol mixed solvent. Colorless needle crystals (30 mg) of p-nitrohensyl ester of the target compound having a reverse coordination with respect to the compound of Example 14 at the 4-position of the pyrrolidine ring were obtained. Further, this product was recrystallized with ethanol to obtain colorless plate-like crystals having a mp of 219 to 221°C, and X-ray analysis revealed that the 4-position of the pyrrolidine ring was R-coordinated.

Nuclear magnetic resonance spectrum (DMSO-d6, 270MHz
) δppm1,16 (311,d, J=6.3Hz
), 1.17 (3tl, d, J=7.3tl
z), 2.13 (IH, dd, J=17.L
4.4+12), 2.79 (IH, dd, J=
17. L 7.8tlz), 3.10(l)1. dd
, J=10.8, 3.4Hz), 3.16~3.35(
IHm), 3.40-3.51 (Lli, m), 3.7
0 (18, dd, J=10.7, 7.3Hz), 3
．． 95-4.12 (2H, m), 4.25 (l
tl, dd, J=9.3.2.5)1z).

5.07 (IHd, J=5.411z), 5.30,5
．． 46(2HAB, J=14.21(z)7.71(2
H, d, J=8.81+z), 8.23(2tl, d
, J=8.811z) The thus obtained crystals (20 mg) of p-nitrobenzyl ester of the target compound were added to Example 11.
A hydrogenation reaction was carried out in the same manner as above to obtain a powdered target compound (11 mg) having a reverse coordination at the 4-position of the pyrrolidine ring to that of the compound of Example 14.

Nuclear magnetic resonance spectrum (270MHz, D20) δ
ppm: 1,02(311,d, ,l'7.31
1z), 1.10 (3+I, d, 16.61
(z), 2.22 (LH, dd, J= 17.6
．． 4.4H7,), 2.77 (lil, dd
, J=11.6.8.411z) 3.08~3.25
(2H, m), 3.25 (IH, dd, J=
5.9.2.611z), 3.68(LH, dd,
J=11.4, 6.4tlz), 3.84-3.96(
IH. Sodium chloride (100 mg) was dried N, N
- QJi) in dimethylacetamide (3 ml), and under water cooling, pivaloyloxymethyl iodite (80 μm) was added and stirred. After about 5 minutes, the solution became homogeneous. After stirring for another 10 minutes under the same conditions, the reaction solution was mixed with ethyl acetate (5
0n+l) and washed twice with saline (50 ml).

The ethyl acetate layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off. The residue was chromatographed using a Roper column (Merck Licropress RP-8, size B).

Methanol was distilled off under reduced pressure from the portion eluted with 60% methanol-water, and sodium chloride was added to the remaining aqueous layer, followed by extraction with ethyl acetate. The ethyl acetate extract layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound (110
mg) was obtained.

Ultraviolet absorption spectrum λn+ax nm(ε): 3
23 (10760) 1699° (IR, 5S, 6S) -2 obtained in Example 13
-(2-oxonuclear magnetic resonance spectrum 270M1lz
, CDCh) δppm: 1.23 (9H,S) 1
．． 29 (3H, d, J=7.311z), 1.
35 (3H, d, J=6.2Hz), 1.95
(LH, br s), 2.33 (Itl, d
d, J=17.6.6.211z).

2.79 (IH, dd, J=17.6, 8.811z)
, 3.22-3.34 (2H, m) 3.38 (LH,
dd, J=4.8.9.9Hz), 3.80 (
IH, dd, J= 10.3°7.0)1z), 3
．． 95-4.05 (IH, m), 4.20-4.27 (
2H, m).

5.79 (LH, bs), 5.83, 5.97 (2tl
, AB, J=5.5Hz) Oxymethyl ester yl) Carbonyloxymethyl yoquid was used to carry out the same reaction procedure to obtain the target compound.

Nuclear magnetic resonance spectrum (270MH2, CDCl:I)
δppm: 1, 18 (3B, S) 1.29 (
3H, d, J=7.3Hz), 1.35 (3H
, d, J=6.2Hz), 1.25-1.75 (9H
, m), 2.00 to 2.08 (2H, m), 2.33
(IH, dd, J=17.6.6.2Hz), 2
．． 79 (ill, dd, J=17.6.8.8
Hz).

3.21-3.33 (2H, m), 3.38 (IH, d
d, J=9.9, 4.811z).

3.79 (111, dd, J=9.9, 7.0Hz),
3.95-4.05 (IH, m).

4.21 to 4.30 (2H, m), 5.78 (IH,
br s), 5.87, 5.96 (21(, 8B, J=
5.5Hz).

Instead of the piparoyloxymethyl iodite used in Example 16, (1-methylcyclohexane-1-thyl esultanol) The target compound (62 mg) in the form of a colorless powder was obtained from the portion eluted with water.

(IR, 5S, 6S)-2-( obtained in Example 13
2-Oki-he4-pyrrolidinylthio)-6-((IR)
Sodium -1-hydroxyethyl-1-methyl-1-carbapen-2-em-3carboxylate (54 mg) was suspended in dry N,N-dimethylacetamide (2 ml), and 1-(cyclohexyloxycarbonyloxy) was suspended in dry N,N-dimethylacetamide (2 ml). ) Ethyl iodite (50 μl) was added and stirred. After about 10 minutes, a homogeneous solution was obtained. After stirring for another 15 minutes at room temperature, the reaction solution was diluted with ethyl acetate (50 ml) and diluted with brine ( 50 ml) twice.The ethyl acetate layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure.
P8, size B) was used for chromatographic purification. 65% ME nuclear magnetic resonance spectrum (270 MI (Z, CDCl:l
) δppm: 1.28 (38, d, J=7.0Hz)
, 1.33.1.36 (3tl, d x2.J=6.
2tlz), 1.59.1.61 (311,d
x2. J=5.5Hz), 1.2~1.6 (
6tL m) 1.7 ~ 2.0 (5H, m), 2.33
(IH, dd, J=17.6, 6.211z), 2.7
9 (IH, dd, J=17.6, 8.8Hz), 3.2
4 ~ 3.33 (211, n+), 3.35 ~ 3.42
(II, m), 3.76 to 3.85 (1) 1. m)
3.94 ~ 4.05 (LH, m), 4.19 ~ 4
．． 27(2)1. m), 4.59 to 4.70 (lit
, m).

5.69(1)1. br s), 6.88 (IH, q,
J=5.5Hz) Example 19 1 used in Example 18
-(Cyclohexyloxycarbonyloxy)ethyl iodite, 1-(cyclopentyloxycarbonyloxy)ethyl iodite, 1-(cyclohexylmethoxycarbonyloxy)ethyl iodite, or 1-(isopropoxy) carbonyloxy)
Ethyl iodite, (IR, 2S, 5R) - (1)
-menthyloxycarbonyloxymethyl iodite,
A similar reaction procedure was carried out using cyclohexyloxycarbonylmethyl iodide or cyclopentyloxycarbonylmethyl iodide, and the following (1) was carried out.
Compounds (6) to (6) were obtained.

2, J=6.211z), 1.58, 1.60 (3H,
dX2. J=5.511z), 1.65-1.95
(8H, m), 2.33 (IH, dd, J=
17.6.6.2tlz), 2.79(III, d
d, J=17.6.8.8tlz), 3.23 to 3.
32 (2H, m), 3.38°3.39 (IH, ddx
2. J=4.8, 9.9Hz), 3.68 ~ 3.87
(LH, m).

3.96-4.07 (ill, m), 4.19-4.
27(2)1. m), 5.08 ~ 5, 16 (LH,
m), 5.66 (1)1. brs), 6
．． 87 (ltl, q, J=5.5Hz) Laso and No Σ” and nuclear magnetic resonance spectra (270MIIz, CDCl+)
δppm: 1.28129 (3) 1. dX2. J=7.
31(z), 1.33.1.35(3t(,d
23 (10975) Infrared absorption spectrum v,,Xc
m-': 1766.1700.1269 Nuclear magnetic resonance spectrum (270MIIZ, CDCl:l) δppm:
0.95-1.26 (511, m), 1.28.
1.29 (311,d x 2. J=7.3Hz)
1.33.1.35 (311, d x 2. J・6.
211z), 1.59.1.6N3)1. d x2,
J=5.9.5.5)1z)+1.64~1.76(6
H,m), 1.87(It(,brs), 2.33
(LH, dd, J=17.6.6.21h),
2.79 (lft, dd, , J=17.68.
8tlz), 3.24-3.35 (2H, m), 3.3
7-3.42 (1) 1. mL3.75-3.87 (II
I, m), 3.95-4.06 (3H, m), 4.20
~4.28 (21hm), 5.73 (111,br s
), 6.86.6.87 (III, q X2J=5.
9,5.511z nuclear magnetic resonance spectrum (270Mtlz, CDC13
) δppm: 1.26 to 1.36 (12H, m),
1.59.1.61 (3H, d x 2. J=5
．． 5Hz) 1.80 (1) 1. br t J=3.7
Hz), 2.33 (LH, dd, J=17.6, 6.2
Hz), 2.79 (IH, dd, J=17.6, 8.8
)1z), 3.24 to 3.34 (2H.

m), 3.35 to 3.42 (LH, m), 3.76
~3.87 (Ill, m), 3.95 ~ 4.07 (il
l, m), 4.19 - 4.28 (28m), 4.82
~4.99 (III, m), 5.63 (ltl, br
s), 6.88 (111, q, J = 5.5t (z) propoxycarbonyloxy) ethyl ester ≦ (fuyu L and (IR Nuclear magnetic resonance spectrum (270MH2, CDCl:l)
δppm: 0.78 (3H, d, J=7.01lz
), 0.89 (3H, d, J=7.0Hz),
0.92 (31d, J=7.311z), 1.
29 (3H, d, J=7.311z), 1.
35 (311, d, J=6.2Hz), 0.95
~1.55 (5H, m), 1.63 ~ 1.73 (211
, m), 1.88-2.03 (111, m), 2.
08-2.18 (1) 1. m), 2.34 (IH, dd
, J=17.2°6.2Hz), 2.79(111,d
d, J=17.2,8.8tlz), 3.22~3
．． 34 (2H, m), 3.39 (IH, dd, J=9.
5.4.8tlz), 3.74-3.86(LH,
m), 3.96-4.06 (IH, m), 4.18-4
．． 28 (2H, m).

4.56 (111, dt, J=10.6, 4.4Hz)
, 5.70 (IH, br s), 5.89° 5.91 (
2H, 8B, J = 5.911z) UV absorption spectrum λ, 1laXnlTl (ε): 323 -pyridinylthio)6- ((IR)-1-hydroxyethyl]
Dry dimethylacetamide (2 ml) was added to sodium -1-methyl-1carbapen-2-em-3-carboxylate (50 mg), and 5-methyl-2-oxo-1,3-
Dioxolen-4-ylmethyl bromide (55mg)
A dry dimethylacetamide solution (1 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour.

The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was eluted with 50% methanol and water using a Rover column (Liclopresop RP-8, size B, manufactured by Merck) to obtain the target compound (colorless powder).
50 mg) was obtained.

Ultraviolet absorption spectrum λmax nm (ε): 321
．． 1 Infrared absorption spectrum νmax Cm-': 182
0,1772170L 1627 Nuclear magnetic resonance spectrum (270MHz, CDC13)
δpp11.30 (3H, d, J=7.33Hz)
, 1.36 (3tl, d, J=6.2211z
), 1.80(LH,br s), 2.21
(311,S), 2.35(IH,dd, J=1
7.58.6.0411z), 2.81(IH, dd,
J=17.58.8.80Hz), 3.25-3.43
(3H, m), 3.73-4.05 (2H, m) 4.
17~4.32 (2H, m) 4.96.5.05 (2t
1. AB, J=13.93Hz), 5.59(ltl,
br s) Example 21. Using the compound of Example 13 as a starting material, pivaloyloxymethyl iodite used in Example 16 was replaced with 1-(isobutyryloxy)ethyl iodite, 1-(cyclohexanecarbonyloxy)ethyl iodite, 1 -(pivaloyloxy)ethyl iodite, 1-(acetoxy)ethyl iodite or cyclo, the same reaction operation as in Example 16 was carried out using xanecarbonyloxymethyl iodite, and the following compounds (1) to f51 were obtained. The compound was obtained.

Example 21 1701.1064 nuclear magnetic resonance spectrum (270MHz, CDC13)
δppm1.15-1.21 (6H, m), 1
．． 29 (311, d, J=7.311z), 1
．． 351.36 (3H, d x 2. J=6.2)
1z), 1.55, 1.57 (311, dx2,
J = 5.5 Hz), 2.28-2.38 (l
ft, m), 2.50-2.64 (IH.

m) 2.74-2.84 (IH, m), 3.2
3-3.32C2tl, m), 3.353.42(
1tlm), 3.75-3.82 (III, m),
3.97-4.05 (ltl, m) 4.20-4.27
(2H, m), 5.58 (11 (, br s)
, 6.97.6.99 (IL q X 2.
J=5.5Hz) (211m) 5.87(1,tl
, br s), 6.93-7.01 (III
, m) haloyloxy) ethyl ester chlorohexane (luponyloxy) ethyl ester nuclear magnetic resonance spectrum (270 Mllz, CDCh) δ
ppm1.11-1.97 (19N, m), 2.25
-2.40 (211, m), 2.75-2.84 (l
it m), 3.19-3.31 (2i1.m),
' 3.35-3.42 (ltl, m) 3.76-3.
82 (Ill, m), 3.95-4.04 (IH, i
+1), 4.20-4.30 (acetoxy)ethyl ester Example 22 (IRS The reaction operation was carried out in the same manner as in 11 to obtain the target compound.

Example 23 Using the compound of Example 22 as a starting material, the reaction operation was carried out in the same manner as in Example 16 or 18 to obtain the following compound.

Ultraviolet absorption spectrum λl,l□8 nm: [1] (IR S S 1-Methyloxobipivaloyloxymethylesulfluoromene sulfone - methoxyhensylthio) Pyrrolidineone (979■) was dissolved in anisole (4 m) ), and under cooling with water, trifluoroacetic acid (20 ml), trifluorometachloride, and sulfonic acid (0.41 ml) were added, and the mixture was stirred at room temperature for 30 minutes.

The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel (developing agent: ethyl acetate/
Purification with methanol (10/1) gave the title compound (728 mg) as an oil.

Nuclear magnetic resonance spectrum (60Mllz, CDCl
3) δppm1.75-3.05 (31(,+n)
, 3.30-4.04 (311, m), 8.12 (
It (br s), 9.32 (1tLbr s) Reference 4
24-Mercapto-2-pyrrolidinone (1) 4-Acetylthio-2-pyridinone 4-hydroxy-2-pyrrolidinone (3 g) was suspended in tetrahydrofuran (2QOml), triphenylphosphine (15.6 g) was added, and the mixture was heated to room temperature. The mixture was stirred for 5 minutes. It was then cooled to -20°C and diluted with diethyl azujirupoxylate (9.3ml) in tetrahydrofuran. The solution (9 ml) was heated to -20'~12゛C.
It was dripped. After stirring for 10 minutes at 0-5°C using an ice-water bath, it was cooled again to -20°C, and thioacetic acid (4.2 m
1) was added dropwise at -20° to 18°C, and stirred again at 0-5°C for 2 hours using an ice-water bath. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography using silica gel (developing agent: ethyl acetate/methanol-10/1), and further purified by column chromatography using silica gel (developing agent: acetonitrile/benzene-2). /1) to obtain the title compound (2.45 g) as colorless crystals.

Nuclear magnetic resonance spectrum (90MIIz, CDCI
:l) δppm :2.00~4.44(511,
m), 2.31 (3H, s), 7.13 (LH, b
r 5) (2) 4-mercapto-2-pyrrolidinone (1
) 4-acetylthio-2-pyrrolidinone (1,8
Dissolve 2g) in methanol (30ml) and add sodium methoxide to 28χ methanol under water cooling. night) night (2,
3ml) was added dropwise and stirred for 30 minutes. Then, IN hydrochloric acid (12 ml) was added under water cooling, and the mixture was concentrated to dryness under reduced pressure.

Ethyl acetate (50 ml) was added to the powdery residue to extract the soluble portion. The ethyl acetate extract was dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure to yield the title compound (
1.35 g) was obtained.

Nuclear magnetic resonance spectrum (270MIIz, CDCl+)
δppm: 1.95 (IH, d, J=7.0tl
z) 2.30 (01, dd, J=17.2゜6
．． 6Hz) 2.80 (LH, dd J=17.2
, 7.1Hz) 3.31 (IH, ddd, J.9.
9,5.2,0.8Hz) 3.59-3.73(I
Hm), 3.80 (LH, ddd, J = 9.9, 7.3
．． 0.7tlz) 6.13(III, br
s).

Claims (1)

[Claims] 1. A 1-methylcarbapenem derivative having the formula ▲ Numerical formula, chemical formula, table, etc. ▼, a salt thereof, and an ester thereof. In the formula, R^1 represents the following group substituted with carbamoyloxy or carbamoyl, lower alkyl group, cycloalkyl group, aralkyl group, aryl group, heteroaryl group, heteroaralkyl group, or alkylheteroaralkyl group, or R^1▲There are mathematical formulas, chemical formulas, tables, etc.▼Group (In the formula, m represents 0, 1 or 2, n represents 0, 1, 2, or 3, R^2 is a hydrogen atom, a substituent represents a lower alkyl group or alkanoyl group with or without .