JPH06220058A - Production of carbapenem and penem production - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an antimicrobial agent by reacting specific two compounds in the presence of a metal salt. CONSTITUTION:A compound of formula I [R<1> is H or carboxyl-protecting group; R<2> and R<3> are H, lower alkyl, group of formula C(CH3)(R<5>)OR<6> (R<5> is H or methyl; R<6> is H or OH-protecting group), etc.; R<4> is (substituted) lower alkyl, (substituted) aryl, etc.; X is S or CHR<7> (R<7> is H, lower alkyl, etc.); (k) is 1 or 2] is reacted with a compound of the formula ASH [A is (substituted) lower alkyl, (substituted) alicyclic heterocyclic ring-substituted lower alkyl or (substituted) aromatic heterocyclic ring] in the presence of a salt of a metal belonging to the group II to III to give the objective compound of formula II.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing carbapenems and penem derivatives which are known as excellent antibacterial agents.

[0002]

2. Description of the Related Art One of the methods for synthesizing a carbapenem derivative is to oxidize a sulfur atom bonded to a carbon at the 2-position to form an s-oxide, and then to perform an addition elimination reaction with a required mercaptan to obtain a desired 2-position substituent. There is a way to do it. However, in the conventional method using an organic base, sulfenic acid produced in the substitution reaction gives various double products and the reaction yield may be low (for example, mercaptan and 4-chlorosulfinyl described in JP-A 1-25780). Addition-elimination reaction with group (A
→ The yield of B) is 22%).

[0003]

[Chemical 2]

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention, in the presence of a metal salt belonging to Group II or Group III of the periodic table instead of an organic base, present a sulfinyl derivative (1a; k = 1) or a sulfonyl derivative (1b). As a result of various studies on addition-elimination reaction between k = 2) and a mercaptan derivative, it was found that this reaction can be performed in high yield. As a result, it became possible to replace the substituent at the 2-position of the naturally-occurring carbapenem antibiotic with a desired substituent. Furthermore, they have found that the addition-elimination reaction using this metal salt proceeds in good yield even with a penem antibiotic, and completed the present invention.

[0005]

In the present invention, a compound having the general formula (1) is reacted with a compound having the formula ASH (2) in the presence of a metal salt belonging to Group II or Group III of the periodic table. A method for producing a carbapenem or a penem derivative, which comprises leading to a compound having the formula (3).

[0006]

[Chemical 3]

In the above formula, R ¹ represents a hydrogen atom or a protecting group for a carboxyl group. R ² and R ³ are independently a hydrogen atom, a lower alkyl group, a formula —C (CH ₃ ) (R ⁵ ) OR ⁶ group (wherein R ⁵ is a hydrogen atom or a methyl group, and R ⁶ is a hydrogen atom or a hydroxyl group; A protecting group) or a combination of the formulas = C
A (CH ₃ ) CH ₂ OR ⁶ group (R ⁶ has the same meaning as described above) is shown. R ⁴ is a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a substituent It represents an aliphatic cyclic alkyl group which may have a group, an aromatic heterocyclic group which may have a substituent, or an aromatic heterocyclic group substituted lower alkyl group which may have a substituent. X represents a sulfur atom or a —CHR ⁷ — group (R ⁷ represents a hydrogen atom or a linear or branched lower alkyl group or a linear or branched lower alkoxy group). A is a lower alkyl group which may have 1 or 2 substituents, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and a resin which may have a substituent. A cyclic heterocyclic group, an alicyclic heterocyclic-substituted lower alkyl group which may have a substituent, and an aromatic heterocyclic group which may have a substituent are shown. k represents 1 or 2.

The protecting group for the carboxyl group of R ¹ is
A protecting group for a carboxyl group commonly used in the synthesis of β-lactam derivatives, preferably a lower alkyl group such as methyl, ethyl, t-butyl, benzyl, diphenylmethyl, 4-
Aralkyl groups such as nitrobenzyl and 2-nitrobenzyl, alkenyl groups such as allyl, 2-chloroallyl and 2-methylallyl, 2,2,2-trichloroethyl, 2,
Examples thereof include halogenated alkyl groups such as 2,2-tribromoethyl and 2- (trimethylsilyl) ethyl groups.

Further, examples of the protecting group for the carboxy group of R ¹ include a protecting group for the carboxy group which is hydrolyzed in vivo, and examples thereof include acetoxymethyl, t-butylcarbonyloxymethyl and 1- (acetoxy) ethyl. Acyloxyalkyl group, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Isopropoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, (1-
Alkyl or cycloalkyloxycarbonyloxyalkyl groups such as methylcyclohexyl) oxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl or 3- An example is a phthalidyl group. The lower alkyl group represented by R ² , R ³ and R ⁴ and the lower alkyl group which may have a substituent are:
Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl, and the substituent thereof is, for example, a hydroxyl group or a protected hydroxyl group (the protecting group is a hydroxyl group represented by R ⁶ described later). , And an amino group or a protected amino group.

The protected amino-protecting group is not particularly limited, and general amino-protecting groups can be used.
For example, an acyl group such as formyl, acetyl, chloroacetyl, propionyl or benzoyl or t-butoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl. And substituted oxycarbonyl such as 2-nitrobenzyloxycarbonyl and allyloxycarbonyl.

The lower alkenyl group which may have a substituent represented by R ⁴ is, for example, ethenyl, 1-propenyl, 2
-Propenyl or 1-butenyl group can be mentioned, and the substituent thereof can be, for example, a protected amino group. The protecting group of the protected amino group has the same meaning as described above.

The aryl group which may have a substituent represented by R ⁴ includes, for example, a phenyl group, a 1-naphthyl group, or a 2-naphthyl group, which has 1 or 2 substituents which are the same or different. The substituent may be a straight chain or branched chain alkyl group such as methyl, ethyl, propyl or i-propyl group, or a straight chain or branched chain lower group such as methoxy, ethoxy or i-propoxy group. Alkoxy group, hydroxyl group, halogen atom such as fluorine, chlorine or bromine, cyano group, nitro group, alkoxycarbonyl group such as methoxycarbonyl group or ethoxycarbonyl group or -CONR ⁸ R ⁹ group (in the formula, R ⁸ and R ⁹ Are each independently methyl, ethyl,
i-Propyl, or a linear or branched alkyl group such as a butyl group or a phenyl group, or R ⁸ and R
⁹ together form the formula (CH ₂ ) _M (Y) _L (CH ₂ ) _N
A group (in the formula, M and N are the same or different and each represents 0 to 5 (wherein M + N is 2 or more), L represents 0 or 1, and Y represents an oxygen atom).

Examples of the aralkyl group which may have a substituent represented by R ⁴ include linear or molecular chain aralkyl groups such as benzyl, 2-phenethyl, 3-phenylpropyl and 4-phenylpentyl. The substituent of the aryl moiety of is the same as the substituent of the aryl group.

The alicyclic cyclic alkyl group which may have a substituent represented by R ⁴ is, for example, a cyclohexyl, cyclopentyl or cyclobutyl group, and the substituent is the same as the substituent of the aryl group.

The aromatic heterocyclic group represented by R ⁴ which may have a substituent is, for example, 2-pyridyl, 3-pyridyl, 2-
Pyrimidinyl, 2-imidazolyl, 3-thiazolyl, 2
Examples thereof include -thienyl and 2-furyl groups, and the substituents on the aromatic heterocyclic group are the same as the substituents on the aryl group.

The aromatic heterocycle-substituted lower alkyl group which may have a substituent represented by R ⁴ is, for example, 2-pyridylmethyl, 2-imidazolylmethyl, 3-isothiazolylmethyl, 2-thienylmethyl, or 2 Examples thereof include a-(2-furyl) ethyl group, and the substituent of the aromatic heterocyclic group is the same as the substituent of the aryl group.

The hydroxyl-protecting group represented by R ⁶ is a hydroxyl-protecting group commonly used in the synthesis of carbapenem derivatives,
For example, trimethylsilyl, triethylsilyl, tert
-Butyldimethylsilyl, silyl groups such as t-butyldiphenylsilyl, benzyl, 4-nitrobenzyl, 2-
Aralkyl groups such as nitrobenzyl and 4-methoxybenzyl; benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, allyloxycarbonyl, 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl, 2,
2,2-trichloroethyloxycarbonyl, 2,2
Substituted oxycarbonyl groups such as 2-tribromoethyloxycarbonyl, tert-butyloxycarbonyl, diphenylmethyloxycarbonyl, 2- (trimethylsilyl) ethyloxycarbonyl; tetrahydropyranyl, methoxymethyl, 1-ethoxyethyl, 2- (trimethylsilyl) ) Examples include ether groups such as ethyloxymethyl and chloroacetyl groups.

Examples of the straight chain or branched lower alkyl group represented by R ⁷ include methyl, ethyl, propyl, isopropyl, butyl, and s-butyl. The alkyl moiety of the lower alkoxy groups straight or branched chain represented by R ⁷ include the same lower alkyl groups straight or branched chain represented by R ^7, preferably a methoxy, ethoxy Is.

The lower alkyl group which may have 1 or 2 substituents represented by A includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl, and the substitution thereof. The group is, for example, a hydroxyl group or a protected hydroxyl group (the protecting group is the above-mentioned R
^It has the same meaning as the hydroxyl-protecting group represented by ⁶ . ), An amino group, a protected amino group (the protecting groups have the same meanings as described above), a -C (= NR ¹⁰ ) NR ¹¹ R ¹² group or a -NR ¹³ C (= NR ¹⁴ ) R ¹⁵ group. Can be given.

R in the -C (= NR ¹⁰ ) NR ¹¹ R ¹² group
¹⁰ , R ¹¹ and R ¹² are a hydrogen atom; an amino group-protecting group (having the same meaning as described above); a lower alkyl group such as methyl or ethyl; and R ¹¹ and R ¹² together. Form a ring via an adjacent nitrogen atom-(C
H ₂ ) _n -group (n represents 2, 3, 4, 5 or 6)
Alternatively, — (CH ₂ ) _p — group (p is 2 or 3) in which R ¹⁰ and R ¹¹ are taken together to form a ring through an adjacent nitrogen atom.
Indicates. ) Is given.

R in the -NR ¹³ C (= NR ¹⁴ ) R ¹⁵ group
¹³ , R ¹⁴ is a hydrogen atom; a lower alkyl group such as a methyl, ethyl or propyl group, or an amino-protecting group (the protecting group has the same meaning as the above-mentioned amino-protecting group), R ¹⁵
Is a hydrogen atom; a lower alkyl group such as methyl, ethyl or propyl group, an amino group or a protected amino group (the protecting group has the same meaning as the above-mentioned protecting group for amino group), R ¹³ and R ¹⁴ , R ¹⁴ and R ¹⁵ , or R ¹³ and R ¹⁵ may be taken together to form a ring to form — (CH ₂ ) _p — (p has the same meaning as described above).

The aryl group which may have a substituent represented by A has the same meaning as the aryl group which may have a substituent which is represented by R ⁴ .

The aralkyl group which may have a substituent represented by A has the same meaning as the aralkyl group which may have a substituent which is represented by R ⁴ .

The alicyclic heterocyclic group which may have a substituent represented by A is a substituted or non-substituted one having a nitrogen atom, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group or a carbonyl group in the ring carbon chain. Substituted 4- to 8-membered rings such as azetidinyl, pyrrolidinyl, oxopyrrolidinyl, piperidyl, oxopiperidyl, morpholinyl, tetrahydropyrimidinyl, thiazolidinyl, oxazolinidyl, hexahydropyrimidinyl, imidazolidinyl, octahydroazocinyl, pyrazolidinyl, or pyrazolo. A triazolium group may be mentioned, and the substituent bonded to the ring carbon atom of the alicyclic heterocycle is, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-
A linear or branched lower alkyl group such as butyl, t-butyl, pentyl, isopentyl; a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl; eg methoxymethyl, ethoxymethyl, propoxymethyl Lower alkoxyalkyl groups such as, isopropoxymethyl, butoxymethyl, methoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 4-ethoxybutyl; for example methoxycarbonylmethyl, ethoxycarbonylmethyl, t-
Alkoxycarbonylalkyl groups such as butoxycarbonylmethyl, benzyloxycarbonylethyl, methoxycarbonylpropyl; eg cyanomethyl, cyanoethyl, 3-cyanopropyl, 2-cyanopropyl, 4-
Cyano lower alkyl groups such as cyanobutyl; eg trifluoromethyl, 2-fluoroethyl, 2,2,2-
Trifluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl, 2-fluoropropyl,
Halogeno lower alkyl group such as 4-chlorobutyl, 3-fluorobutyl; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec
A linear or branched lower alkoxy group such as -butoxy or t-butoxy; a hydroxyl group; an amino group, a protected amino group (the protecting group has the same meaning as the above-mentioned protecting group for the amino group) ; such as fluorine, chlorine, bromine, halogen atom such as iodine; cyano group, azido group; for example acetoxy, propionyloxy, butyryloxy, lower aliphatic acyloxy groups such as iso-butyryloxy carboxy group; -CONR ^{10 'R 11 ′} (R ^{10 ′} , R ^{11 ′} : hydrogen atom, C ₁ -C ₄ alkyl); for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t- Lower alkoxycarbonyl groups such as butoxycarbonyl;
A linear or branched lower alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio; for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl A straight chain or branched lower alkylsulfinyl group; a straight chain or branched lower alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl or isobutylsulfonyl; Nitro group or -COB group [In the formula, B represents any one of (4) to (12).

[0025]

[Chemical 4]

In the formula, R ²⁰ is a hydrogen atom, an amino group-protecting group, a lower alkyl group or a substituted lower alkyl group (wherein the substituent is a hydroxyl group, a protected hydroxyl group, a carboxy group, a protected carboxy group or a cyano group). , A lower alkoxy group, a lower alkylsulfonyl group, a —NHCOR ²³ group (R ²³ represents a hydrogen atom or a lower alkyl group), —NR ²⁴ R
²⁵ groups, -CONR ²⁴ R ²⁵ groups, -OCONR ²⁴ R ²⁵ groups (R
²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group. ) Is shown. ), COR ²⁶ group (R ²⁶
Represents a lower alkyl group which may have 1 or 2 substituents) or -C (= NR ¹⁶ ) R ¹⁷ group (R ¹⁶ and R ¹⁷ have the same meanings as described below), and R ²¹ and R ²² is a lower alkyl group,
It represents a hydroxyl group or a protected hydroxyl group, and 1 represents 2 or 3.

[0027]

[Chemical 5]

In the formula, R ²⁷ represents a hydrogen atom or a lower alkyl group. R ²⁸ and R ²⁹ are the same or different and each is a hydrogen atom, a lower alkyl group, an amino group-protecting group, or -C (=
NR ¹⁶ ) R ¹⁷ group (R ¹⁶ and R ¹⁷ have the same meanings as described below). e represents 0, 1 or 2. f is 0
Or 1 is shown.

[0029]

[Chemical 6]

In the formula, D represents an imidazolyl or triazolyl group. g represents 0, 1 or 2.

[0031]

[Chemical 7]

In the formula, R ²⁰ has the same meaning as described above. q, r, s, t and u represent 0, 1 or 2.

[0033]

[Chemical 8]

In the formula, R ³⁰ represents a lower alkyl group or a hydroxyl group or a lower alkyl group having a protected hydroxyl group. W represents a nitrogen-containing aromatic heterocyclic group which may have a lower alkyl group as a substituent. v represents 1, 2, or 3.

[0035]

[Chemical 9]

In the formulas (9) to (12), Q, Q ¹ , Q ² and Q ³ each independently represent CH or N. R ³¹ represents a hydrogen atom, a lower alkyl group or an amino group-protecting group. R ³² is a hydrogen atom, a lower alkyl group or —NR ²⁸ R
²⁹ (R ²⁸ and R ²⁹ have the same meanings as described above.)
Indicates. a and b represent 1, 2 or 3.

The protecting group for the amino group of R ²⁰ , R ²⁸ , R ²⁹ and R ³¹ has the same meaning as the protecting group for the amino group in the alkyl group represented by R ⁴ having the protected amino group as a substituent. is there.

R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R
^{26, R 27, R 28,} R 29, R 30, lower alkyl and substituted lower alkyl group R ²⁰ of R ³¹ and R ^32, lower alkylsulfonyl-substituted lower alkyl group R ^20, the hydroxyl group or the protection of R ³⁰ The lower alkyl group having a hydroxyl group and the lower alkyl group of the nitrogen-containing aromatic heterocyclic group which may have a lower alkyl group as a substituent of W are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- Butyl and t-butyl are mentioned.

A hydroxyl-protecting group of a lower alkyl group substituted with a protected hydroxyl group of R ^20, a protected hydroxyl-protecting group of R ²¹ and R ²² , and a lower alkyl group having a protected hydroxyl group of R ^30. The hydroxyl-protecting group of has the same meaning as the hydroxyl-protecting group represented by R ⁶ .

The protecting group for the carboxy group of the protected carboxy-substituted lower alkyl group for R ^{20 has} the same meaning as the protecting group for the carboxy group represented by R ¹ .

The alkoxy group of the lower alkoxy-substituted lower alkyl group for R ²⁰ is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or t-butoxy.

The lower alkyl group having 1 or 2 substituents represented by R ²⁶ has the same meaning as the lower alkyl group optionally having 1 or 2 substituents represented by A.

The nitrogen-containing aromatic heterocyclic group of W is, for example, pyridine, pyrrolidine, pyridazine, pyrazine, pyrrole, imidazole, triazole or tetrazole which may have a lower alkyl group as a substituent. ] Is given.

The substituent bonded to the ring nitrogen atom of the alicyclic heterocyclic group is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,
A linear or branched lower alkyl group such as pentyl or isopentyl; a formula —CR ¹⁷ (= NR ¹⁶ ) group (wherein R ¹⁶ is a hydrogen atom; a lower alkyl group such as a methyl group or an ethyl group, or Amino group-protecting group (the protecting group has the same meaning as defined above), R ¹⁷ is a hydrogen atom; a lower alkyl group such as methyl, ethyl, or propyl; an amino group or a protected amino group (the protecting group). Has the same meaning as above)); Formula -CONR ¹⁸ R ¹⁹ group (in the formula, R ¹⁸ and R ¹⁹ are the same or different and each is a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl and isopropyl). Or a protecting group for an amino group (which represents the above-mentioned protecting group for an amino group).

The alicyclic heterocyclic-substituted alkyl group which may have a substituent represented by A has the alicyclic heterocyclic group which may have a substituent represented by A as a substituent. Examples thereof include methyl, ethyl, isopropyl and butyl groups.

The aromatic heterocyclic group which may have a substituent represented by A has the same meaning as the aromatic heterocyclic group which may have a substituent which is represented by R ⁴ .

Specific examples of the compounds having the general formulas (1) and (3) of the present invention include the compounds shown in Table 1 and Table 2, respectively, but the present invention is limited to these compounds. It is not something that will be done. Note that Equation 1 is used for Table 1 and Equation 3 is used for Table 2.

[0048]

[Chemical 10]

[0049]

[Chemical 11]

[0050]

[Chemical 12]

[0051]

[Chemical 13]

[0052]

[Chemical 14]

[0053]

[Chemical 15]

[0054]

[Chemical 16]

[0055]

[Chemical 17]

[0056]

[Chemical 18]

[0057]

[Chemical 19]

[0058]

[Chemical 20]

According to the method of the present invention, the compound represented by the formula (1) is added with 1 to 20 times mol of the compound of the formula (2) in the presence of a metal salt belonging to Group II or Group III of the periodic table. It is carried out by reacting with the indicated mercaptan in an organic solvent.

The Group II metal salts used in this reaction include Group II metal halides such as magnesium chloride, magnesium bromide, magnesium iodide, and calcium bromide; II such as magnesium bromide-ether complexes. Complexes of Group II metals with ethers; Complexes of Group II metal halides or their ethers with triethylamine, diisopropylethylamine, 1-ethylpiperidine, 1,5-diazabicyclo [5,4,0]- Mixtures with organic bases such as undecene-5,1,4-diazabicyclo [2,2,2] octane or 1,5-diazabicyclo [4,3,0] nonene-5 It is prepared by suspending a metal halide or its ether complex and adding an organic base (the ratio of the metal salt to the organic base is 10: 1. 1)); General formula (13)
Group II metal amides represented by R ³³ R ³⁴ NMetal-X (13) [wherein R ³³ and R ³⁴ are independently a linear or branched lower alkyl such as methyl, ethyl or isopropyl group] A group, an aliphatic cyclic alkyl group such as cyclohexyl or cyclopentyl, a trialkylsilyl group such as a phenyl group or a trimethylsilyl group, or R ³³ and R ³⁴ are taken together to form a-(CH ₂ ) _d -group ( d wherein represents a 4 or 5) or _{- (CH 2) 2 O (} CH 2) 2 - represents a group, metal is II metals of, X is denotes chlorine, bromine, a halogen atom such as iodine.

Group II metal alcoholate represented by the general formula (14): R ³⁵ --O--Metal--X (14) [wherein R ³⁵ is methyl, ethyl, isopropyl, t
A linear or branched lower alkyl group such as a butyl group, an aliphatic cyclic alkyl group such as a cyclohexyl or cyclopentyl group, or a phenyl group, Metal
Represents a Group II metal, and X represents a halogen atom such as chlorine, bromine or iodine. [R ³⁵ OH corresponding to the solvent used in the reaction
Is dissolved and reacted with a Grignard reagent such as methyl magnesium bromide or phenyl magnesium bromide]]; an alkali metal amide such as lithium bistrimethylsilylamide, lithium diisopropylamide, or sodium bistrimethylsilylamide or potassium t-butoxide. Or Group II metal halide suspended in the solvent used in the reaction with an alkali metal alcoholate such as lithium ethoxide or
Examples thereof include a mixture prepared in addition to an ether complex of a Group II metal halide.

The Group III metal salt used in this reaction is, for example, the compound represented by the formula (15).

R ³³ R ³⁴ N—Al (R ³⁵ ) ₃ (15) [wherein R ³³ and R ³⁴ have the same meanings as described above,
R ³⁵ represents lower alkyl such as methyl and ethyl groups. Preferred group II or group III metal salts are magnesium bromide, ether complexes; magnesium bromide ether complexes with diisopropylethylamine, 1-ethylpiperidine or 1,5-diazabicyclo [5,4,0] undecene-5. Mixture; bromomagnesium cyclohexyl isopropylamide, bromomagnesium diisopropylamide, bromomagnesium diethylamide or bromomagnesium hexamethyldisilazide; bromomagnesium t-butoxide; mixture of lithium diisopropylamide or lithium bistrimethylsilylamide with magnesium bromide ether complex; diethyl Aluminum diisopropylamide, and the like.

The solvent used in the reaction according to the present invention is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane and tetrahydrocarbon. Halogenated hydrocarbons such as carbon chloride, ethers, 1,
Ethers such as 2-dimethoxyethane, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-
Pyrrolidone, amides such as hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide, preferably hydrocarbons, halogenated hydrocarbons, ethers, and amides, particularly preferably , Ethers.

The reaction temperature will differ depending on the starting compounds (1) and (2) and the type of solvent used, but it is usually from -70 ° C to 6 ° C.
It is 0 ° C., and preferably 0 ° C. to 30 ° C. The reaction time varies depending on the reaction temperature and the like, but is 10 minutes to 48 hours when the sulfinyl derivative (1a) is used, and 10 minutes to several days when the sulfonyl derivative (1b) is used.

Sulfinyl derivative (1
The a) is synthesized by oxidizing the compound represented by the formula (16) by a known method using a peroxide such as m-chloroperbenzoic acid, peracetic acid or t-butyl hydroperoxide.

[0067]

[Chemical 21]

When t-butyl peroxide is used, vanadyl acetylacetonate [VO (aca
c) ₂ ] etc. are used. Further, in order to remove the acidic substance derived from peroxide generated in this reaction, the oxidation reaction can be carried out in the presence of an alkali metal carbonate or its aqueous solution.

The sulfonyl derivative (1b) used as a starting material can also be synthesized by further oxidizing the sulfinyl derivative (1a) by the above method or by directly oxidizing the compound represented by the formula (16).

Furthermore, when the compound of the formula (16) used as a starting material for these oxidation reactions is X ₂ of the formula (16), CH ₂ is preferable to a natural product (for example, SM
Schmitt et al, J. Org. Chem, 1980 , 45, 1142) Further, X represented by the formula (16) is CH ₂ or CH (CH ₃ )
In the case of, the method described in the literature [eg S. Oida et al, Tetr
ahedron Lett., 25, 2793 (1984); BG Christensen e
T al, Heterocycles 21 , 29 (1984)].

When X represented by the formula (16) is a sulfur atom, it is synthesized (for example, S. Oida et al, Chem, Pharm).
Bull, 29 3158 (1981); A. Yoshida et al. Chem Phar
m Bull 31 768 (1983)) Can be obtained.

[0072]

The compound having the general formula (3) obtained by the method of the present invention has a protecting group R ^{1 for} a carboxy group, and optionally R ^{2 at} the 6-position, a protecting group for a hydroxyl group in R ³ and a group in A. By removing the protection by a conventional method, it is possible to lead to a carbapenem or a penem derivative having excellent antibacterial activity.

[0073]

【Example】

Example 1 (1R, 5S, 6S) -2-[(2S, 4S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio] -1-methyl-
6-[(R) -1-trimethylsilyloxyethyl]-
1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0074]

[Chemical formula 22]

(2S, 4S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4
A solution of 68 mg (0.19 mmol) of mercaptopyrrolidine in 2 ml of tetrahydrofuran was cooled in an ice bath, and 0.19 ml (0.19 mmol) of a 1M bromomagnesium isopropylcyclohexyl tetrahydrofuran solution was added dropwise over 2 minutes. The compound of Reference Example 5 was stirred at the same temperature for 10 minutes.
1 ml of a solution of 100 mg (0.16 mmol) of tetrahydrofuran was added. After stirring at the same temperature for 15 minutes, ice water was added, the reaction solution was diluted with ethyl acetate, and washed successively with an ammonium chloride aqueous solution and saturated saline. The solvent was evaporated and the obtained residue was subjected to column chromatography using 10 g of silica gel and eluted with ethyl acetate to obtain 94 mg (78%) of the target compound as a foamy substance.

IR spectrum (film) cm ⁻¹ : 1773, 1711,
1655, 1522, 1345, 1142, 845 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.13 (4.5H,
s), 0.14 (4.5H, s), 1.25-1.29 (6H, m), 1.89-2.00 (1H, m),
2.67-2.80 (1H, m), 2.94 (1.5H, s), 2.98 (1.5H, s), 3.00
(1.5H, s), 3.11 (1.5H, s), 3.22-3.27 (1H, m), 3.30-3.40
(1H, m), 3.46-3.57 (1H, m), 3.60-3.76 (1H, m), 4.02-4.3
0 (3H, m), 4.72 (0.5H, t, J = 8Hz), 4.76 (0.5H, t, J = 8Hz),
5.07 (0.5H, d, J = 14Hz), 5.22 (1H, s), 5.25 (1H, d, J = 14H
z), 5.30 (0.5H, d, J = 14Hz), 5.46 (1H, d, J = 14Hz), 7.44 (1
H, d, J = 9Hz), 7.52 (1H, d, J = 9Hz), 7.65 (2H, d, J = 9Hz), 8.
20 (1H, d, J = 9Hz), 8.21 (3H, d, J = 9Hz) Mass spectrum (m / z): 754 (M ⁺ (C ₃₅ H ₄₃ N ₅ O ₁₁ SSi) −CH
₃ ) Example 2 (1R, 5S, 6S) -2-[(2S, 4S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio] -1-methyl-
6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid
4-nitrobenzyl ester

[0077]

[Chemical formula 23]

A) Using the compound of Reference Example 6 under the same conditions as in Example 1, the target compound was obtained as a foamy substance in a yield of 86%.

B) Reference example 10 under the same conditions as in example 1
The target compound was obtained as a foamy substance in a yield of 83% by using the compound of.

C) 50 mg (0.071 mmo) of the compound of Reference Example 8
l), (2S, 4S) -2-dimethylcarbamoyl-1-
25 mg of diisopropylethylamine was added to a suspension of 30 mg (0.086 mmol) of (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine and 76 mg (0.294 mmol) of magnesium bromide ether complex in tetrahydrofuran.
1 (0.144 mmol) was added and the mixture was stirred for 94 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 40 mg (69%) of the target compound.

D) Under the same conditions as in Example 1, using the compound of Reference Example 8 and the above mercaptan, the target compound was adjusted to 78%.
It was obtained in a yield of.

E) Reference example 14 under the same conditions as in Example 1
The target compound was prepared using the above compound and the above mercaptan.
Obtained in a yield of 3%.

F) Reference example 15 under the same conditions as in Example 1
A reaction is carried out using the above compound and the above mercaptan,
After purification by silica chromatography, a fraction containing the target compound was obtained in a yield of 87%. This fraction, which contains impurities that cannot be separated by silica gel column chromatography, has a purity of 83.5% according to the area ratio by liquid chromatography.
showed that.

G) 18 μl of ice-cooled diisopropylamine
75 μl of 1.6 M n-butyllithium hexane solution was added to 1 ml of toluene solution (1 (0.13 mmol)) and stirred for 10 minutes, and 125 μl (0.12 mmol) of 0.97 M diethylaluminum chloride hexane solution was added and stirred for 20 minutes at the same temperature. The diethylaluminum diisopropylamide solution thus prepared was added to an ice-cooled solution of 43 mg (0.12 mmol) of the above mercaptan in 2 ml of tetrahydrofuran, and the mixture was stirred at the same temperature for 15 minutes, and further 68 mg (0.10 mmol) of the compound of Reference Example 6 was added. A 1 ml solution of tetrahydrofuran was added and stirred for 1 hour and 45 minutes. A saturated ammonium chloride aqueous solution and ethyl acetate were added to remove the precipitate. The organic layer was collected, washed successively with water and saturated brine, and the solvent was evaporated.
The residue was subjected to column chromatography using 10 g of silica gel and eluted with benzene-ethyl acetate (1: 3) to obtain a fraction containing 60 mg (yield 74%) of the desired product. This fraction was analyzed by liquid chromatography and the area ratio of the purity was 5
It showed 6%.

IR, NM of the target compounds of the above a) to g)
The R and mass spectrum data are shown below.

IR spectrum (film) cm ⁻¹ : 1775, 1713,
1657, 1522, 1345, 1142, 837 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.07-0.09 (6
H, m), 0.85 (4.5H, s), 0.87 (4.5H, s), 1.23-1.29 (6H, m),
1.88-2.00 (1H, m), 2.67-2.81 (1H, m), 2.94 (1.5H, s), 2.
98 (1.5H, s), 2.99 (1.5H, s), 3.11 (1.5H, s), 3.23-3.41
(2H, m), 3.46-3.57 (1H, m), 3.61-3.78 (1H, m), 4.03-4.3
2 (3H, m), 4.73 (0.5H, t, J = 8Hz), 4.77 (0.5H, t, J = 8Hz),
5.07 (0.5H, d, J = 13Hz), 5.22 (1H, s), 5.25 (1H, d, J = 13H
z), 5.30 (0.5H, d, J = 13Hz), 5.45 (1H, d, J = 13Hz), 7.45 (1
H, d, J = 9Hz), 7.52 (1H, d, J = 9Hz), 7.65 (2H, d, J = 9Hz), 8.
20 (1H, d, J = 9Hz), 8.21 (3H, d, J = 9Hz) Mass spectrum (m / z): 754 (M ⁺ (C ₃₈ H ₄₉ N ₅ O ₁₁ SSi) -C ₄ H ₉ ) Example 3 (1R, 5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2-
[(2S, 4S) -2- [4- [2- (4-nitrobenzyloxycarbonyloxy) ethyl] piperazine-1
-Ylcarbonyl] -1-[(4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio]]-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0087]

[Chemical formula 24]

A) Under the same conditions as in Example 1, the compound of Reference Example 6 and (2S, 4S) -4-mercapto-2- [4-
[2- (4-nitrobenzyloxycarbonyloxy)
Ethyl] piperazin-1-ylcarbonyl] -1- (4
-Nitrobenzyloxycarbonyl) pyrrolidine was used to obtain the target compound in a yield of 86%. When this was recrystallized from toluene, crystals having an mp of 134 to 136 ° C. were obtained.

B) Under the same conditions as in c) of Example 2, the target compound was obtained with a yield of 60% using the compound of Reference Example 8 and the above mercaptan.

IR spectrum (KBr) cm ⁻¹ : 1773, 1750, 17
09, 1653, 1522, 1345, 1260, 1146, 837 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.06-0.09
(6H, m), 0.85 (4.5H, s), 0.86 (4.5H, s), 1.22-1.29 (6H,
m), 1.84-1.99 (1H, m), 2.38-2.81 (7H, m), 3.23-3.77 (8
H, m), 4.04-4.32 (5H, m), 4.73 (1H, dt, J = 14Hz, 8Hz), 5.0
7 (0.5H, d, J = 14Hz), 5.22 (1H, s), 5.26 (2H, s), 5.25 (1H,
d, J = 14Hz), 5.30 (0.5H, d, J = 14Hz), 5.45 (1H, d, J = 14Hz),
7.44 (1H, d, J = 9Hz), 7.52 (1H, d, J = 9Hz), 7.56 (2H, d, J = 9
Hz), 7.65 (2H, d, J = 9Hz), 8.17-8.26 (6H, m) Example 4 (1R, 5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2-
[(S) -1- [N- (4-Nitrobenzyloxycarbonyl) acetimidoyl] pyrrolidin-3-ylthio] -1-carbapene-2-em-3-carboxylic acid 4
-Nitrobenzyl ester

[0091]

[Chemical 25]

A) Under the same conditions as in Example 1, the compound of Reference Example 6 and (S) -3-mercapto-1- [N- (4-
Nitrobenzyloxycarbonyl) acetimidoyl]
The target compound was obtained with a yield of 79% using pyrrolidine.
This was recrystallized from isopropyl ether-ethyl acetate to give crystals having an mp of 171 to 172.5 ° C.

B) 101 mg (0.148 mmo) of the compound of Reference Example 6
l), 106 mg (0.328 mmol) of the above mercaptan and 155 mg (0.600 mmol) of magnesium bromide ether complex in 4 ml of tetrahydrofuran were stirred for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the solvent was evaporated. The residue was subjected to column chromatography using 5 g of silica gel and eluted with hexane-ethyl acetate (1: 1) to obtain the desired product containing a small amount of impurities. This was further subjected to column chromatography using 5 g of silica gel, and ethyl acetate-methylene chloride (1:
Elution with 3) gave 74 mg of the desired compound (yield 64%).

C) Under the same conditions as in c) of Example 2, the target compound was obtained in a yield of 39% using the compound of Reference Example 8 and the above mercaptan.

IR spectrum (KBr) cm ^-1 : 1769, 1694, 16
75, 1567, 1520, 1345, 1242, 839 NMR spectrum (270MHz, CDCl ₃ ): 0.08 (3H, s), 0.09 (3
H, s), 0.87 (9H, s), 1.22-1.31 (6H, m), 1.96-2.16 (1H,
m), 2.29 (0.75H, s), 2.32 (2.25H, s), 2.35-2.51 (1H, m),
3.23-3.35 (2H, m), 3.44-4.05 (5H, m), 4.24-4.32 (2H,
m), 5.22 (2H, s), 5.24 (1H, d, J = 14Hz), 5.45 (1H, d, J = 14H
z), 7.56 (2H, d, J = 9Hz), 7.65 (2H, d, J = 9Hz), 8.19 (2H, d, J
= 9Hz), 8.21 (2H, d, J = 9Hz) Mass spectrum (m / z): 781 (M ⁺ , C ₃₇ H ₄₇ N ₅ O ₁₀ SSi) Example 5 (1R, 5S, 6S) -6- [(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2- [2
-(4-Nitrobenzyloxycarbonyl) aminoethylthio] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0096]

[Chemical formula 26]

A) Under the same conditions as in Example 1, using the compound of Reference Example 6 and 2- (4-nitrobenzyloxycarbonyl) aminoethylmercaptan, the target compound was obtained as a foamy substance in a yield of 92%. Was given.

B) Under the same conditions as in b) of Example 4, the target compound was obtained in a yield of 83% using the compound of Reference Example 6 and the above mercaptan.

C) Under the same conditions as in b) of Example 4, the target compound was obtained in a yield of 81% using the low-polarity s-oxide of Reference Example 11 and the above mercaptan. Reference example 11
When the highly polar S-oxide of is used, the target compound is 8
Obtained in a yield of 9%.

D) Using the compound of Reference Example 8 and the above mercaptan under the conditions of c) of Example 2, the target compound was obtained in 87
Obtained in% yield.

E) Reference example 12 under the conditions of c) of Example 2
The target compound was prepared using the above compound and the above mercaptan.
Obtained in a yield of 6%.

F) To a suspension of ice-cooled magnesium bromide ether complex 91 mg (0.352 mmol) in tetrahydrofuran 2 ml was added 1.5M lithium diisopropylamide / tetrahydrofuran complex cyclohexane solution 0.14 ml (0.21 mmol), and the mixture was stirred at the same temperature for 10 minutes. did. To this was added a solution of 55 mg (0.207 mmol) of 2- (4-nitrobenzyloxycarbonyl) aminoethylmercaptan in 2 ml of tetrahydrofuran, and the mixture was stirred for 10 minutes with ice cooling, and then the low polarity s of Reference Example 11 was obtained.
-Oxide (102 mg, 0.174 mmol) was added and the mixture was further stirred for 15 minutes. A saturated aqueous ammonium chloride solution and ethyl acetate were added, and the mixture was partitioned with water. The organic layer was collected, washed with water and saturated saline, and then the solvent was distilled off. The obtained residue was subjected to column chromatography using 15 g of silica gel and eluted with ethyl acetate-hexane (1:19) to obtain the target compound 1
04 mg (84%) were obtained as a foam.

IR spectrum (film) cm ⁻¹ : 1771, 1723, 16
07, 1522, 1347, 1140 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.07 (3H, s), 0.
08 (3H, s), 0.86 (9H, s), 1.22-1.28 (6H, m), 2.93 (1H, do
ft, J = 13Hz, 7Hz), 3.11 (1H, d of t, J = 13Hz, 7Hz), 3.26
(1H, dd, J = 3Hz, 5Hz), 3.30-3.60 (3H, m), 4.22-4.31 (2H,
m), 5.20 (2H, s), 5.25 (1H, d, J = 14Hz), 5.35 (1H, dull t,
J = 6Hz), 5.47 (1H, d, J = 14Hz), 7.50 (2H, d, J = 9Hz), 7.66
(2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz), 8.21 (2H, d, J = 9Hz) Mass spectrum (m / z): 714 (M ⁺ C ₃₃ H ₄₂ N ₄ O ₁₀ SSi) Example 6 (1R, 5S, 6S) -6-[(R) -t-butyldimethylsilyloxyethyl] -1-methyl-2- (4-nitrobenzylthio) -1-carbapene-2- M-3-
Carboxylic acid 4-nitrobenzyl ester

[0104]

[Chemical 27]

A) Using the compound of Reference Example 6 and 4-nitrobenzyl mercaptan under the conditions of Example 1, the target compound was obtained in a yield of 81%. Recrystallization from ethyl acetate-isopropyl ether gave crystals having an mp of 150.5 to 151 ° C.

B) Under the conditions of Example 4b, the target compound was obtained in a yield of 88% using the compound of Reference Example 6 and the above mercaptan.

IR spectrum (KBr) cm ⁻¹ : 1773, 1711, 16
05, 1522, 1345, 1140 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.06 (3H, s),
0.08 (3H, s), 0.85 (9H, s), 1.24 (3H, d, J = 5Hz), 1.26 (3H,
d, J = 6Hz), 3.25 (1H, dd, J = 2Hz, 5Hz), 3.30 (1H, dof q, J =
10Hz, 6Hz), 4.11-4.23 (3H, m), 4.25 (1H, quint, J = 5Hz),
5.25 (1H, d, J = 14Hz), 5.46 (1H, d, J = 14Hz), 7.52 (2H, d, J =
8Hz), 7.65 (2H, d, J = 8Hz), 8.20 (2H, d, J = 8Hz), 8.21 (2H,
d, J = 8Hz) Mass spectrum (m / z): 627 ( M + (C 30 H 37 N 3 O 8 SSi)) Example 7 (1R, 5S, 6S) -6 - [(R)-1- t-Butyldimethylsilyloxyethyl] -1-methyl-2-phenylthio-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0108]

[Chemical 28]

Under the same conditions as in Example 4b, using the compound of Reference Example 6 and thiophenol, the target compound was obtained as crystals in 72% yield. Recrystallization from ethyl acetate-hexane gave crystals with mp 149 to 150 ° C.

IR spectrum (KBr) cm ⁻¹ : 1768, 1694, 16
07, 1335, 1136, 839 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.06 (6H, s),
0.84 (9H, s), 0.95 (3H, d, J = 7Hz), 1.17 (3H, d, J = 6Hz), 3.
06 (1H, d of q, J = 10Hz, 7Hz), 3.19 (1H, dd, J = 2Hz, 5Hz),
4.19 (1H, dd, J = 2Hz, 10Hz), 4.25 (1H, d of q, J = 5Hz, 6Hz),
5.33 (1H, d, J = 14Hz), 5.50 (1H, d, J = 14Hz), 7.37-7.43 (3
H, m), 7.51-7.57 (2H, m), 7.69 (2H, d, J = 8Hz), 8.22 (2H,
d, J = 8Hz) Mass spectrum (m / z): 568 ( M + (C 29 H 36 N 2 O 6 SSi)) Example 8 (1R, 5S, 6S) -2- [2- (2H-1 , 3,
4,5,6,7-Hexahydro-1-azepinyl) carbonylphenylthio] -1-methyl-6-[(R) -1
-T-Butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0111]

[Chemical 29]

Using the compound of Reference Example 6 and 2- (2H-1,3,4,5,6,7-hexahydro-1-azepinyl) carbonylphenyl mercaptan under the same conditions as in Example 1, a yield of 95% was obtained. The target compound was obtained at a rate. This compound was the same as the compound of Reference Example 9 including physical constants.

Example 9 (1R, 5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -2-ethylthio-1-
Methyl-1-carbapene-2-em-3-carboxylic acid
4-nitrobenzyl ester

[0114]

[Chemical 30]

Under the same conditions as in Example 1, the target compound was obtained as crystals in a yield of 83% using the compound of Reference Example 6 and ethyl mercaptan. Recrystallization from isopropyl ether gave crystals with mp 121-121.5 ° C.

IR spectrum (KBr) cm ^-1 : 1757, 1700, 152
2, 1499, 1339, 1215, 1144, 839 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.07 (3H, s),
0.08 (3H, s), 0.86 (9H, s), 1.25 (3H, d, J = 7Hz), 1.26 (3H,
d, J = 6Hz), 1.34 (3H, t, J = 7Hz), 2.86 (1H, d of q, J = 12Hz,
7Hz), 2.90 (1H, d of q, J = 12Hz, 7Hz), 3.23 (1H, dd, J = 3H
z, 6Hz), 3.35 (1H, d of q, J = 9Hz, 7Hz), 4.20 (1H, dd, J = 3H
z, 9Hz), 4.26 (1H, q, J = 6Hz), 5.25 (1H, d, J = 14Hz), 5.46
(1H, d, J = 14Hz), 7.66 (2H, d, J = 9Hz), 8.21 (2H, d, J = 9Hz) Mass spectrum (m / z): 520 (M ⁺ (C ₂₅ H ₃₆ N ₂ O ₆ SSi)) Example 10 (1R, 5S, 6S) -2-[(2S, 4S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio] -1- Methyl-
6-[(R) -1-hydroxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0117]

[Chemical 31]

(I) 467 mg (0.843 m) of the compound of Reference Example 4
mol), 80% m-chloroperbenzoic acid 201 mg (0.93
2 mmol) was used and the reaction treatment was carried out in the same manner as in Reference Example 5 to obtain crude S
-464 mg of oxide are obtained. This was used for the next reaction without chromatographic purification.

(Ii) (2S, 4S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine 347 mg (0.982 mmol)
Was cooled with ice in 3 ml of tetrahydrofuran, 0.97 ml (0.97 mmol) of 1M bromomagnesium isopropylcyclohexyl tetrahydrofuran solution was added dropwise over 4 minutes, and the mixture was further stirred for 10 minutes. To this solution was added the crude S-oxide obtained in (i) 464 mg of tetrahydrofuran 2
ml solution was added and stirred for another 30 minutes. After adding a saturated ammonium chloride aqueous solution and water, the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and concentrated. The oily residue was subjected to column chromatography using 50 g of silica gel and eluted with methanol-ethyl acetate (1: 9) to obtain 365 mg of the target compound (yield 62% from the compound of Reference Example 4) as a foamy substance. .

IR spectrum (film) cm ^-1 : 3500-3300, 1
771, 1707, 1649, 1522, 1345, 1140, 855 NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.25 (1.5H, d, J
= 7Hz), 1.28 (1.5H, d, J = 7Hz), 1.34 (3H, d, J = 6Hz), 1.86-
1.99 (1H, m), 2.40-3.20 (1H, broad), 2.67-2.81 (1H, m),
2.94 (1.5H, s), 2.99 (3H, s), 3.11 (1.5H, s), 3.23-3.29
(1H, m), 3.34-3.76 (3H, m), 4.04-4.29 (3H, m), 4.73 (0.5
H, t, J = 8Hz), 4.78 (0.5H, t, J = 8H), 5.07 (0.5H, d, J = 14H
z), 5.21 (1H, s), 5.22 (0.5H, d, J = 14Hz), 5.23 (1H, d, J = 1
4Hz), 5.48 (1H, d, J = 14Hz), 7.43 (1H, d, J = 8Hz), 7.51 (1
H, d, J = 8Hz), 7.64 (2H, d, J = 8Hz), 8.20 (1H, d, J = 9Hz), 8.
17-8.22 (3H, m) Example 11 (5S, 6S) -2-[(2S, 4S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio] -6 -[(R) -1-
t-Butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0121]

[Chemical 32]

Under the same conditions as in Example 1, the target compound was foamed in a yield of 89% using the mercaptan used in Example 1 and the crude S-oxide purified by the column chromatography described in Reference Example 13. Obtained as a substance.

IR spectrum (film) cm ⁻¹ : 1779, 1709,
1657, 1522, 1345, 1136, 837 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.08-0.09 (6H,
m), 0.87 (4.5H, s), 0.88 (4.5H, s), 1.23-1.27 (3H, m),
1.90-2.03 (1H, m), 2.65-2.79 (1H, m), 2.93 (1.5H, s), 2.
97 (1.5H, s), 2.99 (1.5H, s), 3.10 (1.5H, s), 3.03-3.30
(3H, m), 3.49-3.71 (2H, m), 4.07-4.30 (3H, m), 4.72 (1H,
dt, J = 14Hz, 8Hz), 5.07 (0.5H, d, J = 14Hz), 5.23 (1H, s), 5.
25 (1H, d, J = 14Hz), 5.30 (0.5H, d, J = 14Hz), 5.44 (1H, d, J =
14Hz), 7.44 (1H, d, J = 9Hz), 7.52 (1H, d, J = 9Hz), 7.64 (2H,
d, J = 9Hz), 8.19-8.24 (4H, m) Example 12 (5R, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -2-[(2S, 4S) -2-
Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio] -penem-3
-Carboxylic acid 4-nitrobenzyl ester

[0124]

[Chemical 33]

Under the same conditions as in Example 1, using the compound of Reference Example 16 and the mercaptan used in Example 1, 81% was obtained.
The target compound was obtained as a foamy substance in a yield of.

IR spectrum (film) cm ⁻¹ : 1788, 1711,
1657, 1522, 1345, 1117, 839 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.04 (3H, s),
0.07 (3H, s), 0.83 (9H, s), 1.25 (3H, d, J = 6Hz), 1.91-2.0
5 (1H, m), 2.67-2.85 (1H, m), 2.93 (1.5H, s), 2.97 (1.5H,
s), 2.99 (1.5H, s), 3.09 (1.5H, s), 3.46-3.60 (1H, m),
3.69-3.80 (2H, m), 4.22-4.40 (2H, m), 4.68-4.79 (1H, m),
5.07 (0.5H, d, J = 14Hz), 5.21 (1H, d, J = 14Hz), 5.23 (1H,
s), 5.31 (0.5H, d, J = 14Hz), 5.41 (1H, d, J = 14Hz), 5.69 (1
H, s), 7.44 (1H, d, J = 9Hz), 7.52 (1H, d, J = 9Hz), 7.61 (2H,
d, J = 9Hz), 8.19-8.24 (4H, m) Example 13 (5R, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -2- [2- (4- Nitrobenzyloxycarbonyl) aminoethylthio] -penem-
3-carboxylic acid 4-nitrobenzyl ester

[0127]

[Chemical 34]

A) Reference example 16 under the same conditions as in Example 1
The target compound was obtained as a foamy substance in a yield of 76% by using the compound of 2) and 2- (4-nitrobenzyloxycarbonyl) aminoethyl mercaptan.

B) Reference Example 1 under the same conditions as in Example 4b
Using the compound of 6 and the above mercaptan, the target compound was obtained in a yield of 86%.

IR spectrum (film) cm ⁻¹ : 1788, 1725,
1607, 1522, 1347, 1119 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.04 (3H, s),
0.07 (3H, s), 0.83 (9H, s), 1.24 (3H, d, J = 6Hz), 3.04-3.2
4 (2H, m), 3.53 (2H, q, J = 6Hz), 3.73 (1H, dd, J = 1Hz, 4Hz),
4.26 (1H, d of q, J = 4Hz, 6Hz), 5.18-5.27 (1H, m), 5.20 (2
H, s), 5.21 (1H, d, J = 14Hz), 5.42 (1H, d, J = 14Hz), 5.67 (1
H, d, J = 1Hz), 7.50 (2H, d, J = 9Hz), 7.62 (2H, d, J = 9Hz), 8.
20 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz) Mass spectrum (m / z): 661 (M ⁺ (C ₃₁ H ₃₈ N ₄ O ₁₀ S ₂ Si) -t-
Bu) Example 14 (5S, 6S) -6-[(R) -1-Trimethylsilyloxyethyl] -2-[(S) -1- [N- (4-nitrobenzyloxycarbonyl) acetimidoyl] pyrrolidine -3-ylthio] -1-carbapene-2-em-
3-carboxylic acid 4-nitrobenzyl ester

[0131]

[Chemical 35]

I. (5S, 6S) -6-[(R) -1-hydroxyethyl] -2- [2- (4-nitrobenzyloxycarbonyl) aminoethylthio] -1-carbapene-2 derived from thienamycin in two steps. -M-
3-carboxylic acid 4-nitrobenzyl ester (SMSc
hmitt et al, J. Org Chem., 1980 , 45, 1142) 140 mg
To a solution of (0.239 mmol) in 2 ml of tetrahydrofuran, 0.233 ml (1.65 mmol) of triethylamine and 0.147 ml (1.19 mmol) of trimethylsilyl chloride were added and stirred for 9 hours. Since the raw material does not disappear, triethylamine 0.167 ml (1.20
mmol) and trimethylsilyl chloride 0.148 ml (1.20 mmol)
Was added and stirred for 1 hour. The reaction solution was diluted with ethyl acetate and washed with ice water and saturated saline. The solvent was evaporated, the residue was subjected to column chromatography using 10 g of silica gel, and eluted with ethyl acetate-methylene chloride (15:85) to obtain 130 mg (83%) of trimethylsilyl derivative as crystals. Mp when recrystallized from ethyl acetate-hexane
Crystals at 165 to 168 ° C were obtained.

IR spectrum (KBr) cm ⁻¹ : 1773, 1738, 16
94, 1607, 1518, 1341, 1140 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.14 (9H, s),
1.28 (3H, d, J = 6Hz), 2.91-3.18 (3H, m), 3.16 (1H, dd, J = 2H
z, 6Hz), 3.27-3.49 (3H, m), 4.11-4.26 (2H, m), 5.20 (2H,
s), 5.25 (1H, d, J = 14Hz), 5.15-5.30 (1H, m), 5.48 (1H, d,
J = 14Hz), 7.50 (2H, d, J = 9Hz), 7.66 (2H, d, J = 9Hz), 8.21
(2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz) ii. Using 130 mg of the trimethylsilyl derivative obtained in i, the same reaction and post-treatment as in Reference Example 5 were carried out to obtain 137 mg of crude S-oxide.

IR spectrum (film) cm ⁻¹ : 1786, 1721, 1
607, 1522, 1349, 1252, 1053 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.13 (9H, s),
1.25 (1.5H, d, J = 6Hz), 1.26 (1.5H, d, J = 6Hz), 3.03-3.38
(4.5H, m), 3.52-3.85 (2.5H, m), 4.20-4.45 (2H, m), 5.20
(1H, s), 5.22 (1H, s), 5.26 (0.5H, d, J = 14Hz), 5.30 (0.5
H, d, J = 14Hz), 5.43 (0.5H, d, J = 14Hz), 5.47 (0.5H, d, J = 14
Hz), 5.62-5.70 (1H, m), 7.51 (2H, d, J = 9Hz), 7.62 (1H, d,
J = 9Hz), 7.65 (1H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz), 8.23 (2
H, d, J = 9 Hz) iii, 137 mg of S-oxide obtained in ii and (S) -3
-Mercapto-1- [N- (4-nitrobenzyloxycarbonyl) acetimidoyl] pyrrolidine 84 mg (0.2
6 mmol) was reacted under the same conditions as in Example 1 and post-treated to obtain 126 mg of the target compound (yield 87% from the trimethylsilyl derivative) as crystals. Recrystallization from ethyl acetate-hexane gave crystals with mp 95-96 ° C. This compound is a compound described in the literature (A. Yoshida et al, Tetrahe
dron Lett., 25 , 2793 (1984)) coincided with the physical constant.

IR spectrum (KBr) cm ⁻¹ : 1783, 1700, 167
6, 1557, 1520, 1349, 1239, 845 NMR spectrum (CDCl ₃ ) δppm: 0.14 (2.2
5H, s), 0.15 (6.75H, s), 1.2
9 (3H, d, J = 6Hz), 1.96-2.17
(1H, m), 2.29 (0.75H, s), 2.
32 (2.25H, s), 2.30-2.51 (1
H, m), 3.06-3.31 (3H, m), 3.
45-4.07 (5H, m), 4.15-4.27
(2H, m), 5.23 (2H, s), 5.24
(1H, d, J = 14 Hz), 5.48 (1H, d,
J = 14 Hz), 7.56 (2H, d, J = 9H
z), 7.65 (2H, d, J = 9 Hz), 8.2
0 (2H, d, J = 9Hz), 8.22 (2H, d,
J = 9 Hz) Example 15 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(S) -3- (4-Nitrobenzyloxycarbonyl) aminopyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(R) -1-
Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0136]

[Chemical 36]

Under the same conditions as ii in Example 10, (2
S, 4S) -4-Mercapto-2-[(S) -3- (4
-Nitrobenzyloxycarbonyl) aminopyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine was used to obtain the target compound as a powdery substance in a yield of 60%. The physical constant of this compound was the same as that of the synthetic intermediate 45 (a) of the compound of Example 45 described in EP-518558.

Example 16 (1R, 5S, 6S) -2-[(RS) -2-oxo-
4-Pyrrolidinylthio] -6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0139]

[Chemical 37]

Under the same conditions as in Example ii, using 4-mercapto-2-oxopyrrolidine, the target compound was obtained as a powdery substance in a yield of 59%. This compound had a physical constant consistent with the synthetic intermediate of the compound of Example 11 described in JP-A-2-49783.

Reference Example 1 (R) -2-[(3S, 4S) -3-[(R) -1-
(Trimethylsilyloxy) ethyl] -2-oxo-4
-Azetidinyl] thiopropionic acid S-2-diethylcarbamoylphenyl ester

[0142]

[Chemical 38]

(R) -2-[(3S, 4S) -3-
[(R) -1-t-Butyldimethylsilyloxyethyl] -2-oxo-4-azetidinyl] thiopropionic acid S-2-diethylcarbamoylphenyl ester (Example 1 of JP-A-5-201986) 1.002 g
To a solution of (2.03 mmol) in 20 ml of tetrahydrofuran was added 5 ml of 2N hydrochloric acid, and the mixture was heated at 50 ° C for 3 hours. After cooling, the reaction solution was diluted with ethyl acetate and partitioned with water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the solvent was evaporated. 10 ml of the resulting desilylated product is tetrahydrofuran
Dissolve in, add 0.60 ml (4.30 mmol) of triethylamine and 0.53 ml of trimethylsilyl chloride, and stir at room temperature for 80 minutes, 40
Stir at 100C for 100 minutes. After cooling, the reaction solution was diluted with ethyl acetate, washed twice with ice water and further washed with saturated saline, and the solvent was evaporated. The residue was subjected to column chromatography using 50 g of silica gel and ethyl acetate-hexane (3: 2-
742 mg (81%) of the title compound as a foam, eluting with 4: 1).
Got

IR spectrum (film) cm ⁻¹ : 3250, 1760,
1700, 1625 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.12 (9H, s),
1.03 (3H, t, J = 7Hz), 1.23 (3H, d, J = 6Hz), 1.25 (3H, t, J = 7H
z), 1.22-1.31 (3H, m), 2.95-3.12 (4H, m), 3.25-3.85 (2
H, m), 3.90 (1H, dd, J = 2Hz, 4Hz), 4.14 (1H, quint, J = 6Hz),
6.07-6.18 (1H, brs), 7.32-7.35 (1H, m), 7.41-7.51 (3H,
m) Mass spectrum (m / z): 450 ( M + (C 22 H 34 N 2 O 4 SSi)) Reference Example 2 (1R, 5S, 6S) -2- (2- diethylcarbamoyl-phenylthio) -1- Methyl-6-[(R) -1-trimethylsilyloxyethyl] -1-carbapene-2-
M-3-carboxylic acid 4-nitrobenzyl ester

[0145]

[Chemical Formula 39]

8 ml of methylene chloride containing 492 mg (1.09 mmol) of the compound of Reference Example 1 and 0.46 ml (3.30 mmol) of triethylamine.
The solution was cooled with a salt-ice bath, 797 mg (3.27 mmol) of 4-nitrobenzyloxyoxalyl chloride was added, and the mixture was reacted at the same temperature for 15 minutes. Further isopropanol 0.25 ml
(3.27 mmol) was added and the mixture was stirred for 10 minutes at the same temperature to decompose excess acid chloride. Dilute the reaction mixture with ethyl acetate and add 2 to water.
It was washed twice with saturated saline. The solvent was evaporated, the obtained residue was suspended in toluene, and the insoluble material was removed by filtration.
Toluene was distilled off, 784 mg (4.40 mmol) of dipropylethylphosphonite was added to the residue, and the mixture was stirred at room temperature for 140 minutes. The excess reagent was distilled off, the residue was dissolved in 65 ml of xylene, and the mixture was heated under reflux for 3 hours. The solvent was distilled off, and the residue was silica gel 5
It was subjected to column chromatography using 0 g and eluted with ethyl acetate-hexane (1: 2) to obtain the desired product containing a small amount of impurities. This was further purified under the same conditions to obtain 535 mg (78%) of the title compound, which was recrystallized with isopropyl ether to give colorless crystals with an mp of 202 to 203 ° C.

IR spectrum (KBr) cm ⁻¹ : 1761, 1695, 16
30, 1342, 1207 NMR spectrum (270MHz, CDCl ₃ ) δppm; 0.10 (9H, s),
1.01 (3H, t, J = 7Hz), 0.95-1.20 (6H, m), 1.20 (3H, d, J = 6H
z), 3.06 (2H, q, J = 7Hz), 3.05-3.28 (3H, m), 3.45-3.80 (1
H, brs), 4.18-4.25 (2H, m), 5.27 (1H, d, J = 14Hz), 5.47 (1
H, d, J = 14Hz), 7.32-7.65 (4H, m), 7.68 (2H, d, J = 9Hz), 8.
21 (2H, d, J = 9Hz) Mass spectrum (m / z): 625 (M ⁺ (C ₃₁ H ₃₉ N ₃ O ₇ SSi)) Reference example 3 (1R, 5S, 6S) -2- (2- Diethylcarbamoylphenylthio) -1-methyl-6-[(R) -1-t
-Butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0148]

[Chemical 40]

When the reaction and treatment were carried out in the same manner as in Reference Example 2 using the compound of Example 1 of JP-A-5-201968, 80% was obtained.
The title compound was obtained in a yield of 1, and was recrystallized from isopropyl ether to give crystals having an mp of 166 to 166.5 ° C.

IR spectrum (nujol) cm ⁻¹ : 1762, 1693,
1633, 1340, 1210 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.06 (6H, s),
0.84 (9H, s), 1.01 (3H, t, J = 7Hz), 0.93-1.20 (6H, m), 1.1
6 (3H, d, J = 6Hz), 3.00-3.30 (3H, m), 3.07 (2H, q, J = 7Hz),
3.40-3.90 (1H, m), 4.21-4.33 (2H, m), 5.28 (1H, d, J = 14H
z), 5.44 (1H, d, J = 14Hz), 7.27-7.65 (4H, m), 7.67 (2H, d,
J = 9Hz), 8.21 (2H, d, J = 9Hz) Mass spectrum (m / z): 667 (M ⁺ (C ₃₄ H ₄₅ N ₃ O ₇ SSi)) Reference example 4 (1R, 5S, 6S) − 2- (2-Diethylcarbamoylphenylthio) -1-methyl-6-[(R) -1-hydroxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0151]

[Chemical 41]

To a solution of 1.072 g (1.71 mmol) of the compound of Reference Example 2 in 30 ml of methanol-methylene chloride (2: 1) was added 41 mg (0.195 mmol) of hydrate of citric acid, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated and the resulting residue was washed with silica gel 25
Column chromatography using g and eluting with ethyl acetate gave 970 mg (quantitative yield) of colorless foam.

IR spectrum (neat) cm ⁻¹ : 3600 to 3200 (b
r), 1771,1707,1612,1345,1207 NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.00 (3H, t, J =
7Hz), 0.94-1.15 (6H, m), 1.30 (3H, d, J = 6Hz), 3.05 (2H,
q, J = 7Hz), 3.10-3.28 (3H, m), 3.45-3.80 (1H, brs), 4.20
(1H, quint, J = 7Hz), 4.25 (1H, dd, J = 2Hz, 9Hz), 5.27 (1H,
d, J = 14Hz), 5.48 (1H, d, J = 14Hz), 7.31-7.65 (4H, m), 7.6
7 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz) Mass spectrum (m / z): 553 (M ⁺ (C ₂₈ H ₃₁ N ₃ O ₇ S)) Reference example 5 (1R , 5S, 6S) -2- (2-Diethylcarbamoylphenylsulfinyl) -1-methyl-6-[(R)
-1-Trimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0154]

[Chemical 42]

122 mg (1.45 mmol) of sodium bicarbonate was added to a solution of 304 g (0.486 mmol) of the compound of Reference Example 2 in 6 ml of methylene chloride, and further 105 mg (0.487 mmol) of 3-chloroperbenzoic acid having a purity of 80% was added with stirring under ice cooling. And stirred at the same temperature for 1 hour. The reaction solution was diluted with methylene chloride and washed with ice-cooled dilute aqueous sodium hydrogen carbonate. The solvent was evaporated and the obtained residue was subjected to column chromatography using 25 g of silica gel and eluted with ethyl acetate-hexane (2: 1) to give 260 mg (83%) of the title compound as a foamy substance.

IR spectrum (film) cm ⁻¹ : 1788, 1734,
1630, 1522, 1061 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.08 (5.4H,
s), 0.10 (3.6H, s), 1.04-1.27 (12H, m), 2.98-3.53 (5.6
H, m), 3.67 (0.4H, d of q, J = 11Hz, 7Hz), 4.16-4.23 (1H,
m), 4.26 (0.6H, dd, J = 10Hz, 3Hz), 4.34 (0.4H, dd, J = 10Hz,
3Hz), 5.35 (0.4H, d, J = 14Hz), 5.38 (0.6H, d, J = 14Hz) 5.4
6 (0.4H, d, J = 14Hz), 5.50 (0.6H, d, J = 14Hz), 7.27-7.36 (1
H, m), 7.50-7.73 (4H, m), 7.84-7.90 (0.4H, m), 8.15-8.2
6 (2.6H, m) Mass spectrum (m / z): 641 (M ⁺ (C ₃₁ H ₃₉ N ₃ O ₈ SSi)) Reference Example 6 (1R, 5S, 6S) -2- (2-diethylcarbamoylphenyl Sulfinyl) -1-methyl-6-[(R)
-1-tert-Butyldimethylsilyloxyethyl] -1-
Carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0157]

[Chemical 43]

By reacting and treating the compound of Reference Example 3 in the same manner as in Reference Example 5, the title compound was obtained as a foamy substance in a yield of 87%.

IR spectrum (nujol) cm ⁻¹ : 1788, 1735,
1630, 1523, 1058 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.03-0.06 (6H, m),
0.83 (4.5H, s), 0.84 (4.5H, s), 1.05-1.27 (12H, m), 2.98
-3.56 (5.5H, m), 3.59 (0.5H, d of q, J = 10Hz, 7Hz), 4.20-
4.38 (1H, m), 4.30 (0.5H, dd, J = 11Hz, J = 3Hz), 4.39 (0.5H,
dd, J = 11Hz, 3Hz), 5.34 (0.5H, d, J = 14Hz), 5.38 (0.5H, d, J
= 14Hz), 5.45 (0.5H, d, J = 14Hz), 5.49 (0.5H, d, J = 14Hz),
7.29-7.36 (1H, m), 7.50-7.71 (4H, m), 7.85-7.89 (0.5H,
m), 8.15-8.25 (2.5H, m ) mass spectrum (m / z): 683 ( M + (C 34 H 45 N 3 O 8 SSi)) Reference Example 7 (1R, 5S, 6S) -2- ( 2-Diethylcarbamoylphenylsulfinyl) -1-methyl-6-[(R)
-Hydroxyethyl] -1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester

[0160]

[Chemical 44]

A solution of 554 mg (1.00 mmol) of the compound of Reference Example 4 in 10 ml of methylene chloride was ice-cooled, and 1.5 ml of 1M aqueous sodium bicarbonate solution (1.
5 mmol), 80% m-chloroperbenzoic acid 215 mg (1.00 mmo
l) were sequentially added, and the mixture was stirred at the same temperature for 90 minutes. Aqueous sodium sulfite solution was added to the reaction solution and stirred for 10 minutes to terminate the reaction. The reaction mixture was diluted with methylene chloride, washed with ice-cold aqueous sodium hydrogen carbonate, and concentrated. The residue was subjected to column chromatography using 50 g of silica gel and eluted with ethyl acetate to give 145 mg (25%) of the less polar title compound and S-.
96 mg (17%) of the highly polar title compound, which is an isomer due to the coordination of the oxide, was obtained as a foam.

IR spectrum (film) cm ⁻¹ : low polar S-oxide, 3500-3300, 1786, 1732, 1624, 1522, 1200, 10
61; Highly polar S-oxide, 3500-3300, 1786, 1734, 162
4, 1522, 1198, 1061 NMR spectrum (270MHz, CDCl ₃ ) δppm: low polarity S-oxide, 1.02-1.11 (6H, m), 1.24 (6H, t, J = 7Hz), 3.01 (1H, d of
q, J = 10Hz, 7Hz), 3.12 (2H, q, J = 7Hz), 3.18-3.30 (1H, m),
3.32 (1H, dd, J = 3Hz, 6Hz), 3.39-3.52 (1H, m), 4.19 (1H, q
uint, J = 6Hz), 4.28 (1H, dd, J = 3Hz, 10Hz), 5.38 (1H, d, J = 1
4Hz), 5.52 (1H, d, J = 14Hz), 7.33 (1H, dd, J = 1Hz, 8Hz), 7.
58 (1H, d of t, J = 1Hz, 8Hz), 7.66 (1H, d of t, J = 1Hz, 8H
z), 7.70 (2H, d, J = 9Hz), 8.16 (1H, dd, J = 1Hz, 8Hz), 8.24
(2H, d, J = 9Hz); high polarity S-oxide, 0.83 (3H, d, J = 7H
z), 1.09 (3H, t, J = 7Hz), 1.18 (3H, t, J = 7Hz), 1.28 (3H, d,
J = 6Hz), 3.18 (2H, q, J = 7Hz), 3.20-3.35 (1H, m), 3.40-3.
53 (1H, m), 3.47 (1H, dd, J = 3Hz, 6Hz), 3.70 (1H, d of q, J =
10Hz, 7Hz), 4.25 (1H, quint, J = 6Hz), 4.38 (1H, dd, J = 3Hz, 1
0Hz), 5.34 (1H, d, J = 13Hz), 5.48 (1H, d, J = 13Hz), 7.28-
7.32 (1H, m), 7.48-7.56 (2H, m), 7.65 (2H, d, J = 9Hz), 7.8
5-7.91 (1H, m), 8.22 (2H, d, J = 9Hz) Mass spectrum (m / z) :; High polarity S-oxide, 551 (M
⁺ (C ₂₈ H ₃₁ N ₅ O ₈ S) -H ₂ O) Reference Example 8 (1R, 5S, 6S) -2- (2-Diethylcarbamoylphenylsulfonyl) -1-methyl-6-[(R)-
1-t-butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0163]

[Chemical formula 45]

A solution of 157 mg (0.235 mmol) of the compound of Reference Example 3 in 3 ml of methylene chloride was cooled in an ice bath, and 78 mg (0.93 m) of sodium bicarbonate was added.
mol) and 78% (0.52 mmol) of 80% m-chloroperbenzoic acid were sequentially added. After stirring at the same temperature for 20 minutes and further at room temperature for 3.5 hours, an aqueous sodium sulfite solution was added and the reaction was terminated by stirring for 10 minutes. The reaction mixture was diluted with methylene chloride, washed with aqueous sodium hydrogen carbonate, and concentrated. The residue is silica gel 15
Column chromatography using g and eluting with ethyl acetate-hexane (4: 6) gave 148 mg (90%) of the title compound as a foam.

IR spectrum (film) cm ⁻¹ : 1794, 1748,
1636, 1524, 1320, 1266, 1161 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.03 (3H, s),
0.05 (3H, s), 0.83 (9H, s), 1.06 (3H, t, J = 7Hz), 1.16 (3H,
d, J = 6Hz), 1.20-1.43 (6H, m), 3.01-3.19 (2H, m), 3.24-
3.84 (4H, m), 4.19-4.28 (1H, m), 4.42-4.52 (1H, m), 5.39
(2H, s), 7.25-7.34 (1H, m), 7.48-7.65 (2H, m), 7.62 (2H,
d, J = 9Hz), 8.11 (1H, d, J = 8Hz), 8.21 (2H, d, J = 9Hz) Mass spectrum (m / z): 700 (M ⁺ (C ₃₄ H ₄₅ N ₃ O ₉ SSi) ) +1) Reference example 9 (1R, 5S, 6S) -2- [2- (2H-1,3,3
4,5,6,7-Hexahydro-1-azepinyl) carbonylphenylthio] -1-methyl-6-[(R) -1
-T-Butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0166]

[Chemical formula 46]

Example 9 of JP-A-5-202068
The compound of above was treated in the same manner as in Reference Example 2 to obtain the title compound, which was reconstituted with isopropyl ether to give mp
Crystals of 210 to 211 ° C. were obtained.

IR spectrum (KBr) cm ⁻¹ : 1757, 1700, 16
32, 1341, 1212, 1138 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.06 (6H, s),
0.85 (9H, s), 0.95-1.08 (3H, m), 1.16 (3H, d, J = 6Hz), 1.4
0-1.85 (8H, m), 3.04-3.34 (5H, m), 3.45-3.65 (1H, brs),
4.20-4.36 (2H, m), 5.29 (1H, d, J = 14Hz), 5.46 (1H, d, J = 14
Hz), 7.30-7.65 (4H, m), 7.68 (2H, d, J = 9Hz), 8.22 (2H, d,
J = 9 Hz) Mass spectrum (m / z): 693 ( M + (C 36 H 47 N 3 O 7 SSi)) Reference Example 10 (1R, 5S, 6S) -2- [2- (2H-1,3 ，
4,5,6,7-Hexahydro-1-azepinyl) carbonylphenylsulfinyl] -1-methyl-6-
[(R) -1-t-butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4
-Nitrobenzyl ester

[0169]

[Chemical 47]

The compound obtained in Reference Example 9 was treated and treated in the same manner as in Reference Example 5 to give the title compound as a foamy substance. Yield 89%.

IR spectrum (film) cm ⁻¹ : 1790, 1734,
1628, 1524, 1347, 1061 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.03, 0.04, 0.
05,0.06 (total 6H, each s), 0.75 (1.5H, d, J = 7Hz), 0.83
(4.5H, s), 0.84 (4.5H, s), 1.13 (1.5H, d, J = 6Hz), 1.16 (1.
5H, d, J = 6Hz), 1.28 (1.5H, d, J = 7Hz), 1.44-1.80 (8H, m),
3.00 (0.5H, d ofq, J = 10Hz, 7Hz), 3.11-3.37 (3.5H, m), 3.
41-3.50 (1H, m), 3.60-3.77 (1H, m), 4.19-4.31 (1.5H, m),
4.38 (0.5H, dd, J = 10Hz, 3Hz), 5.33 (0.5H, d, J = 14Hz), 5.
40 (0.5H, d, J = 14Hz), 5.46 (0.5H, d, J = 14Hz), 5.49 (0.5H,
d, J = 14Hz), 7.27-7.32 (0.5H, m), 7.36 (0.5H, dd, J = 7Hz, 1H
z), 7.48-7.60 (1.5H, m), 7.63-7.73 (2.5H, m), 7.93-7.9
6 (0.5H, m), 8.15 (0.5H, dd, J = 8Hz, 1Hz), 8.22 (1H, d, J = 9H
z), 8.23 (1H, d , J = 9Hz) Mass Spectrum (m / z): 709 ( M + (C 36 H 47 N 3 O 8 SSi)) Reference Example 11 (1R, 5S, 6S) -6- [(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2-phenylsulfinyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0172]

[Chemical 48]

Using the compound of Example 7, the reaction was carried out in the same manner as in Reference Example 5, and silica gel column chromatography (ether-methylene chloride = 1: 19 to 1: 4) was carried out for separation and purification to give a low polarity with a yield of 62%. S-oxide as crystals,
Furthermore, highly polar S-oxide was obtained as a foam in a yield of 30%.

Crystals of repolarized low polar S-oxide from ethyl acetate-hexane were obtained with mp of 150-151 ° C.

IR spectrum Low polarity S-oxide (KBr)
cm ^-1 : 1796, 1715, 1528, 1335, 1044, 839; High polarity S
-Oxide (film) cm ^-1 : 1788, 1730, 1524, 1319, 12
73,1047,837 NMR spectrum (270MHz, CDCl ₃ ) δppm: low polarity S-oxide 0.06 (3H, s), 0.07 (3H, s), 0.73 (3H, d, J = 7Hz), 0.8
5 (9H, s), 1.18 (3H, d, J = 6Hz), 3.27 (1H, dd, J = 3Hz, 5Hz),
3.90 (1H, d of q, J = 11Hz, 7Hz), 4.23 (1H, d of q, J = 5Hz, 6
Hz), 4.41 (1H, dd, J = 3Hz, 11Hz), 5.36 (1H, d, J = 14Hz), 5.
56 (1H, d, J = 14Hz), 7.46-7.53 (3H, m), 7.66 (2H, d, J = 9H
z), 7.72-7.78 (2H, m), 8.24 (2H, d, J = 9Hz); High polarity S-
Oxide 0.04 (3H, s), 0.05 (3H, s), 0.83 (9H, s), 1.15
(3H, d, J = 6Hz), 1.39 (3H, d, J = 7Hz), 3.16 (1H, d of q, J = 1
0Hz, 7Hz), 3.39 (1H, dd, J = 3Hz, 4Hz), 4.16 (1H, dd, J = 3Hz, 1
0Hz), 4.26 (1H, d of q, J = 4Hz, 6Hz), 5.40 (1H, d, J = 14H
z), 5.49 (1H, d, J = 14Hz), 7.51-7.58 (3H, m), 7.68 (2H, d, J
= 9Hz), 7.68-7.73 (2H, m), 8.23 (2H, d, J = 9Hz) Mass spectrum (m / z): low and high polarity S-oxide
584 (M ⁺ (C ₂₉ H ₃₆ N ₂ O ₇ SSi)) Reference Example 12 (1R, 5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2 -Phenylsulfonyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0176]

[Chemical 49]

Reaction was carried out using the highly polar compound of Reference Example 11 under the same conditions as in Reference Example 5 to obtain the title compound as a foamy substance in a yield of 87%.

IR spectrum (film) cm ⁻¹ : 1796, 175
0, 1524, 1316, 1264, 1161, 1079, 837 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.03 (3H, s),
0.05 (3H, s), 0.84 (9H, s) 1.16 (3H, d, J = 6Hz), 1.19 (3H, d,
J = 7Hz), 3.40 (1H, d of q, J = 11Hz, 7Hz), 3.46-3.52 (1H,
m), 4.23 (1H, d of q, J = 4Hz, 6Hz), 4.44 (1H, dd, J = 4Hz, 11
Hz), 5.45 (2H, s), 7.51-7.58 (2H, m), 7.60-7.68 (3H, m),
8.00 (2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz) Mass spectrum (m / z): 543 (M ⁺ (C ₂₉ H ₃₆ N ₂ O ₈ SSi) -tB
u) Reference Example 13 (5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -2-phenylsulfinyl-
1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0179]

[Chemical 50]

(5S, 6S) -6-[(R) -1-t-
Butyldimethylsilyloxyethyl] -3-phenylthio-1-carbapene-2-em-3-carboxylic acid 4-
Nitrobenzyl ester (Tetrahedron Lett. 25 2793
(1984)), and post-reaction treatment was carried out in the same manner as in Reference Example 5. Separation and purification by silica gel column chromatography using ethyl acetate-hexane (4: 6) as an elution solvent gave low-polar S-oxide (yield 43%) as crystals, and further high-polar S-oxide (yield 48%). Obtained as a foam. Recrystallization of the low polarity S-oxide from i-propyl ether gave crystals with mp 111.5-114 ° C.

IR spectrum Low polarity S-oxide (KBr)
cm ^-1 : 1786, 1723, 1607, 1526, 1323, 1206, 1044, 83
7; High polarity S-oxide (film) cm ^-1 : 1790, 1723, 1
607,1524, 1322, 1269, 1044, 837 NMR spectrum (270MHz, CDCl ₃ ) δppm: low polarity S-oxide 0.05 (3H, s), 0.06 (3H, s), 0.85 (9H, s), 1.17 (3H , d, J
= 6Hz), 2.55 (1H, dd, J = 9Hz, 18Hz), 3.08 (1H, dd, J = 3Hz, 5H
z), 3.51 (1H, dd, J = 11Hz, 18Hz), 4.18 (1H, d of q, J = 5Hz,
6Hz), 4.37 (1H, ddd, J = 3Hz, 9Hz, 11Hz), 5.37 (1H, d, J = 14H
z), 5.54 (1H, d, J = 14Hz), 7.48-7.54 (3H, m), 7.65 (2H, d,
J = 9Hz), 7.70-7.77 (2H, m), 8.24 (2H, d, J = 9Hz); High polarity S-oxide 0.05 (3H, s), 0.06 (3H, s), 0.84 (9H, s) , 1.1
8 (3H, d, J = 6Hz), 2.80 (1H, dd, J = 11Hz, 19Hz), 3.29 (1H, d
d, J = 8Hz, 19Hz), 3.34 (1H, t, J = 3Hz), 4.17-4.30 (2H, m),
5.40 (1H, d, J = 14Hz), 5.49 (1H, d, J = 14Hz), 7.49-7.55 (3
H, m), 7.68 (2H, d, J = 9Hz), 7.70-7.76 (2H, m), 8.23 (2H,
d, J = 9Hz) Mass spectrum (m / z): low polarity S-oxide 570 (M ⁺ (C
₂₈ H ₃₄ N ₂ O ₇ SSi)) Reference Example 14 (1R, 5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2- [2
-(4-Nitrobenzyloxycarbonyl) aminoethylsulfinyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0182]

[Chemical 51]

The same reaction as in Reference Example 5 was carried out using the compound of Example 5 to obtain the title compound as a foamy substance in a yield of 92%.

IR spectrum (film) cm ⁻¹ : 1786, 1721,
1607, 1522, 1347, 1254, 1048 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.07 (3H, s), 0.
09 (3H, s), 0.86 (9H, s), 1.23 (1.5H, d, J = 6Hz), 1.24 (1.5H,
d, J = 6Hz), 1.39 (1.5H, d, J = 7Hz), 1.40 (1.5H, d, J = 7Hz),
3.12-3.45 (3H, m), 3.60-3.92 (3H, m), 4.29 (1H, q, J = 6H
z), 4.34 (0.5H, dd, J = 3Hz, 10Hz), 4.46 (0.5H, dd, J = 3Hz, 1
0Hz), 5.14-5.46 (2H, m), 5.23 (2H, s), 5.68-5.77 (1H,
m), 7.51 (1H, d, J = 9Hz), 7.52 (1H, d, J = 9Hz), 7.61 (1H, d,
J = 9Hz), 7.66 (1H, d, J = 9Hz), 8.20-8.24 (4H, m) Mass spectrum (m / z): 705 (M ⁺ (C ₃₃ H ₄₂ N ₄ O ₁₁ SSi) -C
H ₃ ) Reference Example 15 (1R, 5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2-ethylsulfinyl-1-methyl-1-carbapene-2 -M-3-carboxylic acid 4-nitrobenzyl ester

[0185]

[Chemical 52]

Using the compound of Example 9 and in the same manner as in Reference Example 5,
The reaction treatment gave the title compound as a foam in 92% yield.

IR spectrum (film) cm ⁻¹ : 1784, 1715,
1524, 1333, 1055, 837 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.08 (3.6H, s),
0.09 (2.4H, s), 0.86 (9H, s), 1.24 (3H, d, J = 6Hz), 1.39
(3H, d, J = 7Hz), 1.41 (1.8H, t, J = 7Hz), 1.44 (1.2H, t, J = 7H
z), 2.93-3.10 (2H, m), 3.38 (0.6H, dd, J = 3Hz, 5Hz), 3.41
(0.4H, dd, J = 3Hz, 5Hz), 3.61 (0.6H, d of q, J = 10Hz, 7Hz),
3.85 (0.4H, d of q, J = 10Hz, 7Hz), 4.23-4.34 (1.6H, m),
4.42 (0.4H, dd, J = 3Hz, 10Hz), 5.27 (0.4H, d, J = 14Hz),
5.32 (0.6H, d, J = 14Hz), 5.41 (0.6H, d, J = 14Hz), 5.44 (0.4
H, d, J = 14Hz), 7.63 (1.2H, d, J = 9Hz), 7.66 (0.8H, d, J = 9H
z), 8.23 (2H, d, J = 9Hz) Mass spectrum (m / z): 479 (M ⁺ (C ₂₅ H ₃₆ N ₂ O ₇ SSi) -tB
u) Reference example 16 (5R, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -2-ethylsulfinyl-penem-3-carboxylic acid 4-nitrobenzyl ester

[0188]

[Chemical 53]

Ice-cooled (5R, 6S) -6-[(R)-
1-t-Butyldimethylsilyloxyethyl] -2-ethylthio-penem-3-carboxylic acid 4-nitrobenzyl ester 1.039 g (1.98 mmol) in 20 ml of methylene chloride was added with 469 mg of 80% m-chloroperbenzoic acid in small portions. 5
Added in minutes. After stirring at the same temperature for 30 minutes, 8 more
0% m-chloroperbenzoic acid 88 mg (total 557 mg, 2.58 m
mol) was added and stirred for 15 minutes. The reaction solution was diluted with methylene chloride and washed with dilute aqueous sodium hydrogen carbonate. The residue obtained by concentrating the organic layer was subjected to column chromatography using 50 g of silica gel and eluted with ethyl acetate-hexane (4: 6) to give 202 mg (19 mg of low-polar S-oxide as a foam substance.
%), A mixture of low-polarity and high-polarity S-oxides (ratio 1: 3), 336 mg (31%), and further 72 mg (7%) of high-polarity S-oxide as a foam.

In Examples 12 and 13, the three fractions thus separated by column chromatography were used again as S-oxide as a combined raw material.

IR spectrum (film) cm ⁻¹ : low polarity S-oxide 1796, 1701, 1524, 1323, 1063; high polarity S-oxide 1794, 1702, 1524, 1321, 1063 NMR spectrum (270 MHz, CDCl ₃ ) δppm : Low polarity S-oxide 0.05 (3H, s), 0.08 (3H, s),
0.84 (9H, s), 1.26 (3H, d, J =
6Hz), 1.44 (3H, t, J = 7Hz),
3.10 (2H, q, J = 7Hz), 3.92 (1
H, dd, J = 1 Hz, 3 Hz), 4.28 (1H,
d of q, J = 3 Hz, J = 6 Hz), 5.2
6 (1H, d, J = 14Hz), 5.38 (1H, d,
J = 14 Hz), 5.73 (1H, d, J = 1H
z), 7.62 (2H, d, J = 9 Hz), 8.2
3 (2H, d, J = 9Hz); high polarity S-oxide 0.04
(3H, s), 0.07 (3H, s), 0.82 (9H, s), 1.26 (3H, d, J = 6Hz),
1.44 (3H, t, J = 7Hz), 3.13 (2H, d of q, J = 4Hz, J = 8Hz), 3.90
(1H, dd, J = 2Hz, 4Hz), 4.27 (1H, d of q, J = 4Hz, J = 6Hz),
5.22 (1H, d, J = 14Hz), 5.41 (1H, d, J = 14Hz), 5.85 (1H, d, J = 2
Hz), 7.59 (2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz) Reference Example 17 (1R, 5S, 6S) -2-[(2S, 4S) -2-dimethylcarbamoyl-1 -(4-Nitrobenzyloxycarbonyl) -4-pyrrolidinylthio] -1-methyl-
6-[(R) -1-hydroxylethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0192]

[Chemical 54]

55 mg (0.071 m) of the compound of Example 1
mol) in a solution of 2 ml of methanol in citric acid-hydrate 8
mg (0.039 mmol) was added, and the mixture was stirred at room temperature for 35 minutes. The residue obtained by distilling off the solvent is 5 g of silica gel.
Was subjected to column chromatography using, and eluted with methanol-ethyl acetate = 1: 9 to obtain 42 mg of the title compound.
(84%) was obtained as a glassy material. This substance had the same physical constant as that of the compound described in Example 10.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07D 499/88 // A61K 31/40 7431-4C 31/43 ADZ 7431-4C C07B 61/00 300

Claims (1)

[Claims] 1. The formula: Method for producing carbapenem or penem derivative having R ^{1 in the} above formula, R ¹ represents a hydrogen atom or a protecting group for a carboxyl group. R ^2, R ³ are independently a hydrogen atom, a lower alkyl group, the formula ^{_{-C (CH 3) (R 5}} ) OR 6 group (wherein R ⁵
Is a hydrogen atom or a methyl group, R ⁶ is a hydrogen atom or a hydroxyl-protecting group) or R ² and R ³ are taken together to form a formula ═C (CH ₃ ) CH ₂ OR ⁶ group (R ⁶ is as described above). The same meaning is shown). R ⁴ is a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a substituent It represents an aliphatic cyclic alkyl group which may have a group, an aromatic heterocyclic group which may have a substituent, or an aromatic heterocyclic substituted lower alkyl group which may have a substituent. X represents a sulfur atom or a —CHR ⁷ — group (R ⁷ represents a hydrogen atom or a linear or branched lower alkyl group or a linear or branched lower alkoxy group). A is a lower alkyl group which may have 1 or 2 substituents, an aryl group which may have a substituent,
An aralkyl group which may have a substituent, an alicyclic heterocyclic group which may have a substituent, an alicyclic heterocyclic substituted lower alkyl group which may have a substituent, and a substituent Represents an aromatic heterocyclic group. k represents 1 or 2.