JP2752143B2 - Carbapenem derivatives - Google Patents

Description

[Object] The present invention relates to a thienamycin derivative (1).

Although thienamycin derivatives have excellent antibacterial activity, they have been reported to be degraded by dehydropeptidase I in the human body and lose their activity, resulting in low urine recovery (H. Kropp et al., Antimierob, Angents.Chemot
her., 22 , 62, (1982); SR Norrby et al., ibid., 23 , 300.
(1983)).

The present inventors have found that the novel carbapenem derivative (1) has excellent antibacterial activity and is also stable against dehydropeptidase I, and completed the present invention.

〔Constitution〕

The present invention uses the formula And a salt thereof.

In the formula, R ¹ represents a hydrogen atom or a methyl group.

l, m and n independently represent 0, 1, 2 or 3;
m + n represents 2 to 6.

Y is a direct single bond, an oxygen atom, a sulfur atom or = NR ₈
(R ₈ represents a hydrogen atom, an alkyl group or an alkanoyl group).

R ² is a hydrogen atom, an alkyl group which may have a substituent, a halogen atom, a hydroxy group, an alkoxy group, an amino group,
Alkanoylamino group, alkanoyloxy group, alkanoyl group, carboxyl group, alkoxycarbonyl group,
A cyano group, a —S (O) jR ⁹ group (j represents 0.1 or 2; R ⁹ represents an alkyl group) or a —CONR ⁶ R ⁷ group (R ₆ and R ₇ independently represent a hydrogen atom, An alkyl group which may have a substituent,
An alkenyl group, an alkynyl group or a cycloalkyl group, or an alkylene group which may have a substituent in which R ⁶ and R ⁷ are bonded, and the alkylene group is an oxygen atom,
A sulfur atom or NRNR ₈ (R ₈ may be a hydrogen atom, an alkyl group or an alkanoyl group).

R ³ and R ⁴ independently represent an alkyl group which may have a substituent, an alkenyl group, an alkynyl group, an aralkyl group, or a cycloalkylalkyl group, or
One of R ^{3 and} R ⁴ represents an alkylene group which may have a substituent by bonding to R ^2, and the alkylene group is an oxygen atom, a sulfur atom or a ＝ NR ⁸ group (R ⁸ is a hydrogen atom , An alkyl group or an alkanoyl group).

R ⁵ represents a hydrogen atom, an anionic charge or a carboxyl-protecting group. When R ⁵ is a carboxyl protecting group, a counter ion is present.

The halogen atom for R ² is, for example, a fluorine, chlorine or bromine atom.

Alkoxy groups include, for example, methoxy, ethoxy or propoxy.

The alkanoylamino group includes, for example, acetylamino or propionylamino.

The alkanoyloxy group includes, for example, acetoxy or propionyloxy.

Examples of the alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl.

The alkanoyl group for R ² and R ⁸ includes, for example, formyl, acetyl, or propionyl.

The alkyl group for R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and R ⁹ includes, for example, methyl, ethyl, propyl or butyl.

The alkenyl group for R ³ , R ⁴ , R ⁶ and R ⁷ includes, for example, allyl, butenyl or pentenyl.

Alkynyl groups include, for example, propargyl, butynyl or pentynyl.

The cycloalkyl group for R ⁶ and R ⁷ is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The aralkyl group in R ⁵ and R ⁴ is, for example, benzyl or phenethyl.

Examples of the cycloalkylalkyl group include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cyclopropylethyl.

One of R ³ and R ⁴ is bonded to R ² to form an oxygen atom,
An alkylene group which may be bonded via a sulfur atom or NRNR ⁸ (R ⁸ represents a hydrogen atom, an alkyl group or an alkanoyl group) is, for example,-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(C
H ₂ ) ₄ -,-(CH ₂ ) ₅ -,-(CH ₂ ) ₂ O-,-(CH ₂ ) ₂ O
CH ₂ -,-(CH ₂ ) ₂ O (CH ₂ ) ₂ -,-(CH ₂ ) ₂ NR ⁸ -,-
(CH ₂ ) ₂ NR ⁸ CH ₂ −, − (CH ₂ ) ₂ NR ⁸ (CH ₂ ) ₂ −, − (C
H ₂ ) ₂ S−, − (CH ₂ ) ₂ SCH ₂ − and − (CH ₂ ) ₂ S (C
H ₂ ) _2- .

R ⁶ and R ⁷ combine to form an oxygen atom, a sulfur atom, or = NR ₈
(R ₈ represents a hydrogen atom, an alkyl group or an alkanoyl group), for example, an alkylene group via-(C
H ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(CH ₂ ) ₄ -,-(CH ₂ )
₅ −, − (CH ₂ ) ₂ OCH ₂ −, − (CH ₂ ) ₂ O (CH ₂ ) ₂ −, −
(CH ₂ ) ₂ NR ⁸ CH ₂ −, − (CH ₂ ) ₂ NR ⁸ (CH ₂ ) ₂ −, − (C
H _{2) 2} SCH ₂ - and _{- (CH 2) 2 S (} CH 2) 2 - and the like.

The substituent of the alkyl group having the substituents of R ² , R ³ , R ⁴ , R ⁶ and R ⁷ is a hydroxyl group, a cyano group, a carbamoyloxy group, an azide group, a carboxyl group, a nitro group, an oxo group,
Halogen atom, alkoxy group, alkanoyl group, alkanoyloxy group, alkanoylamino group, alkoxycarbonyl group, -NR ¹⁰ R ¹¹ group, -CONR ¹² R ¹³ group (R ¹⁰ , R ¹¹ ,
R ¹² and R ¹³ independently represent a hydrogen atom, an alkyl group or an alkanoyl group. ^{_{), - SO 2 NR 14 R}} 15 groups, -S
(O) _k R ¹⁶ group (R ¹⁴ , R ¹⁵ and R ¹⁶ independently represent an alkyl group; k represents 0, 1 or 2), —NHSO ₂ R
¹⁷ , -N = CR ¹⁸ NR ¹⁹ R ²⁰ group, -NR ²¹ CR ²² = NR ²³ group or -C (= NH) NR ²⁴ R ²⁵ group (R ^{17 to} R ²⁵ independently represent a hydrogen atom or an alkyl group Is shown.).

R ⁶ and R ⁷ are bonded to substituents of the alkylene group which may have either of the alkylene group which may have a substituent and R ³ or R ⁴ to bond to a substituent and R ² Is an alkyl group, an alkoxy group, a halogen atom, a hydroxyl group, a cyano group,
A carbamoyl group or an oxo group;

Of the above substituents, a halogen atom, an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkanoylamino group and an alkoxycarbonyl group are
The meaning is as described above.

The carboxy protecting group for R ⁵ may be an ester group removed by treatment with a chemical reducing agent under mild conditions or catalytic reduction, for example, an alkyl group such as methyl, ethyl or t-butyl; benzyl, diphenylmethyl Aralkyl groups such as, 4-nitrobenzyl or 2-nitrobenzyl; alkenyl groups such as allyl, 2-chloroallyl or 2-methylallyl; 2,2,2-trichloroethyl, 2,2-dibromoethyl or 2,2 A halogenoalkyl group such as 2,2-tribromoethyl or 2-
Or trimethylsilylethyl groups; or those which are hydrolyzed under physiological conditions include, for example, pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, methoxymethyl or 2-oxo-5-methyl-1,3- Dioxolen-4-ylmethyl;

Examples of the salt of compound (1) include non-toxic acid addition salts, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid, methanesulfonic acid, and ethane. Sulfonic acid, sulfonic acid salt such as benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, tartaric acid, citric acid, maleic acid, succinic acid, acetic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, apple And salts with organic acids such as acids. The compound of formula (1) in an acid addition salt can be written as:

 In the above formula, X Represents an anion of an acid. Counter ion X
Is selected to give the acid addition salt. Acidic groups
Is a basic group R^Two, R^ThreeOr R^FourWhen present in the group,
The present invention also includes base salts or acid salts of these functional groups.
For example, in the case of a basic group,
Metal salts such as sodium salts, potassium
Salt, calcium salt, ammonium salt, triethyl alcohol
Trialkylamines such as min, procaine, diben
With organic bases such as zylamine or phenethylamine
And salts of

Preferred compounds having formula (1) are those wherein R ¹ is hydrogen or methyl, and those wherein l is 0.1,2. m + n is 2,
A compound which is 3,4,5 or 6.

Y is a direct single bond, an oxygen atom, a sulfur atom or = NR ⁸
(R ⁸ is a hydrogen atom, methyl, ethyl, formyl, acetyl).

R ² represents a hydrogen atom, a fluorine atom, a hydroxy, methoxy, ethoxy, amino, acetylamino, acetoxy, formyl, acetyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, —CONR ⁶ R ⁷ group (R ⁶ and R ⁷
Are independently a hydrogen atom, an alkyl group which may have a substituent, allyl, propargyl,-(CH ₂ ) ₃ -,-(C
H ₂ ) ₄ ,-(CH ₂ ) ₅ -,-(CH ₂ ) ₂ OCH ₂ -,-(CH ₂ ) _{2
O (CH 2) 2 -,} - (CH 2) 2 NR 8 (CH 2) 2 - (R 8 is a hydrogen atom, methyl, formyl or acetyl), - (CH
_{2) 2} SCH ₂ -, or _{- (CH 2) 2 S (} CH 2) 2 - is. ), - S (O) jR 9 (j is 0, 1 or 2, R ⁹ is methyl or ethyl), methyl, compound is ethyl or propyl.

The substituent of the alkyl group of R ³ and R ⁴ is a hydroxyl group, cyano,
Carbamoyloxy, carboxyl, nitro, fluorine atom, chlorine atom, methoxy, ethoxy, acetyl, formyl, acetoxy, acetylamino, formylamino, methoxycarbonyl, ethoxycarbonyl, -NR ¹⁰ R ¹¹ groups (R ¹⁰ and R ¹¹ Independently a hydrogen atom, methyl or ethyl.), -CONR ¹² R ¹³ (R ¹² and R ¹³ are each independently a hydrogen atom, methyl or ethyl.) SO ₂ NR ¹⁴ R ¹⁵ (R ¹⁴ and R ¹⁵ Are each independently a hydrogen atom, methyl or ethyl). −S (O) tR ¹⁶ (t is 0,1
Or 2 and R ¹⁶ is methyl), —NHSO ₂ R ¹⁷ (R
¹⁷ is methyl or ethyl), -N = CR ¹⁸ NR ¹⁹ R ²⁰
Or —NR ²¹ CR ²² NRNR ²³ groups (R ^{18 to} R ²³ are each independently a hydrogen atom, methyl or ethyl), —C (＝ NH) NR ²⁴
A compound wherein R ²⁵ groups (R ²⁴ and R ²⁵ are each independently a hydrogen atom, a methyl group or an ethyl group;

R ³ and R ⁴ independently of one another are methyl, ethyl, propyl,
Allyl, propargyl, benzyl, _{cyclopropylmethyl, - (CH 2) 2 -} , - (CH 2) 3 -, - (CH 2) 4, - (CH
₂ ) ₅ -,-(CH ₂ ) ₂ -O-,-(CH ₂ ) ₂ -OCH ₂ -,-
_{(CH 2) 2 -O- (CH} 2) 2 -, - (CH 2) 2 -NR 8 -, - (C
H ₂ ) ₂ NR ⁸ CH ₂ —, — (CH ₂ ) ₂ NR ⁸ — (CH ₂ ) ₂ — (R ₈ is a hydrogen atom, methyl, ethyl, formyl, acetyl),
-(CH ₂ ) ₂ -S-,-(CH ₂ ) ₂ SCH _2- and-(CH ₂ ) ₂
A compound which is -S- (CH ₂ ) _2- . A substituent of an alkylene group in which R ⁶ and R ⁷ may be bonded to each other and which may have a substituent and an alkylene group which may have a substituent in which one of R ³ and R ⁴ is bonded to R ² ; Is a compound which is a methyl, ethyl, fluorine atom, hydroxyl group or oxo group.

The compound having the formula (1) has various isomers based on its asymmetric carbon. Formula (1) shows one or a mixture of these isomers. Specific compounds having the formula (1) include, for example, the compounds described below.

The compound having the formula (1) can be produced by the following method (Method A).

R ²⁴ represents a protecting group for a carboxy group, for example, an alkyl group such as methyl, ethyl or t-butyl; an aralkyl group such as benzyl, diphenylmethyl, 4-nitrobenzyl or 2-nitrobenzyl;
Alkenyl group such as 2-chloroallyl or 2-methylallyl; halogenoalkyl group such as 2,2,2-trichloroethyl, 2,2-dibromoethyl or 2,2,2-tribromoethyl or 2-trimethylsilylethyl group Is raised.

R ²⁵ is an alkanesulfonyl group such as, for example, methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl,
Arylsulfonyl groups such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl; dialkylphosphoryl groups such as dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl or dipentylphosphoryl or such as diphenylphosphoryl or ditolylphosphoryl Shows a diaryl phosphoryl group.

X 'represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or a fluorosulfonyloxy group.

In the present synthesis method, a compound having the formula (3) is added in the presence of a base.
A compound having the formula (4) is produced by reacting an alkanesulfonic anhydride, an arylsulfonic acid anhydride, a dialkylphosphoryl halide or a diarylphosphoryl halide, and the compound (4) obtained is reacted with the compound of the formula (4) in the presence of a base without isolation. (5) reacting mercaptan having to produce a compound of formula (6), to produce the desired compound of formula (1) is subjected to removal of the protecting group R ²⁴ of the carboxy group if desired Things.

Examples of the alkanesulfonic anhydride used in the reaction for obtaining the compound (4) from the compound (3) include methanesulfonic anhydride and ethanesulfonic anhydride, and examples of the arylsulfonic acid include benzenesulfonic anhydride and p-toluenesulfonic anhydride. Examples of the acid and dialkyl phosphoryl halide include, for example, dimethyl phosphoryl chloride, diethyl phosphoryl chloride, and examples of the diaryl phosphoryl halide include diphenyl phosphoryl chloride and diphenyl phosphoryl bromide. Of these reagents, p-toluenesulfonic anhydride Or diphenyl phosphoryl chloride is preferred. The solvent used is not particularly limited as long as it does not participate in the reaction.Examples include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform, nitriles such as acetonitrile, and N, N-dimethylformamide. And amides such as N, N-dimethylacetamide. The base to be used is not particularly limited as long as it does not affect the other parts of the compound, especially the β-lactam ring, but preferably triethylamine, diisopropylethylamine, 4-
Organic bases such as dimethylaminopyridine can be mentioned.

Although the reaction temperature is not particularly limited, it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually from -20 ° C to 40 ° C.
Performed at about ° C. The reaction time mainly varies depending on the reaction temperature and the type of the reaction reagent, but is 10 minutes to 5 hours.

The compound (4) thus obtained can be treated without isolation of the reaction mixture with a marcaptan having the formula (5) in the presence of a base. The base used in this step is not particularly limited, but is preferably an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as potassium carbonate or sodium carbonate.

Although the reaction temperature is not particularly limited, it is usually carried out at -20 ° C to room temperature. The reaction time is 30 minutes to 5 days.

After completion of the reaction, the target compound (6) of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent of the reaction mixture or the reaction mixture is distilled off, and the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
Purification can also be performed by subjecting the reaction mixture to reprecipitation directly. If desired, the desired compound (6)
Can be subjected to the following reaction for removing a protecting group of a carboxy group without isolation. The obtained compound (6) can be converted to a carboxylic acid derivative by performing a process of removing the protecting group R ²⁴ of the carboxy group in a conventional manner as needed. The removal of the protecting group depends on its type, but is generally done by methods known in the art. Suitably, the reaction is carried out with a substituent R ²⁴ of a compound having the formula (6)
Can be achieved by contacting a compound such as a halogenoalkyl group, an aralkyl group, a benzhydryl group or the like, which is a protecting group that can be removed by a reduction treatment, with a reducing agent. When the protecting group for the carboxy group is a halogenoalkyl group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl, zinc and acetic acid are preferred as the reducing agent used in this reaction. Wherein the protecting group is e.g.
For aralkyl or benzhydryl groups such as nitrobenzyl, hydrogen and catalytic reduction catalysts such as palladium on carbon or alkali metal sulfides such as sodium or potassium sulfide are preferred. 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 the reaction.Methanol, alcohols such as ethanol, tetrahydrofuran, ethers such as dioxane, acetic acid And mixed solvents of these organic solvents and water. The reaction temperature is usually from 0 ° C. to around room temperature, and the reaction time is usually from 5 minutes to 12 hours, depending on the type of the starting compound and the reducing agent.

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

The target compound thus obtained can be purified, if necessary, by a conventional method, for example, recrystallization, preparative thin-layer chromatography, column chromatography and the like. Further, the carboxy group of the compound obtained by the reaction for removing the above protecting group can be converted into an ester group which is hydrolyzed under physiological conditions by a known method. R ⁵ is pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, methoxymethyl, 2
In the case of a physiologically hydrolyzable ester such as -oxo-5-methyl-1,3-dioxolen-4-ylmethyl, the compound of formula (1) is hydrolyzed in vivo under physiological conditions. Therefore, it can be directly administered to patients without deprotection.

Further, the compound having the formula (1) is prepared by the following method (B
Method).

R ²⁶ is an alkyl group such as methyl, ethyl, propyl or isopropyl; a halogeno such as fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl or trifluoroethyl. Alkyl group; 2-acetylaminoethyl group; 2-acetylaminovinyl group; aryl groups which may have a substituent such as phenyl or naphthyl; The substituent, which may have a substituent, is fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, nitro, Hydroxyl if It is a cyano group.
Or a heteroaryl group such as pyridyl or pyrimidinyl which may have a substituent, these heteroaryl groups may have the same or different 1 to 3 substituents shown below, and the substituent is fluorine. , Chlorine, bromine, methyl, ethyl, propyl or isopropyl.

The compound having the formula (7) in this synthesis method is disclosed in
-30781. Can be synthesized.

The reaction of reacting a compound having the formula (7) with a mercaptan (5) in the presence of a base to produce a compound having the general formula (6) is performed in an inert solvent. The solvent to be used is not particularly limited as long as it does not participate in this reaction, and examples thereof include tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, water and a mixed solvent thereof. The base used is not particularly limited as long as it does not affect the other parts of the compound, particularly the β-lactam ring. Examples of the base include diisopropylethylamine, triethylamine, N-methylpiperidine, and 4-dimethylaminopyridine. Organic bases and inorganic bases such as potassium carbonate and sodium bicarbonate. The reaction temperature is not particularly limited, but it is preferable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, and it is usually carried out at -20 ° C to 40 ° C. The reaction time depends mainly on the reaction temperature and the type of the reaction reagent, but is usually from 5 minutes to 5 days. After completion of the reaction, the target compound (6) of this reaction can be collected from the reaction mixture according to a conventional method.

A compound having the formula (1) can be obtained by subjecting the compound having the formula (6) to a reaction for removing a protecting group for a carboxy group described in the method A as necessary.

Each of the raw materials having the formula (5) is a novel compound and can be produced by the following method.

R ²⁷ represents a protecting group for a thiol group, for example, 4-methoxybenzyl, triphenylmethyl, benzhydryl,
Aralkyl groups such as 3,4-dimethoxybenzyl and di (4-methoxyphenyl) methyl; alkanoyl groups such as acetyl, pyropionyl and pivaloyl; aromatic acyl groups such as o-toluoyl, p-toluoyl and benzoyl. Can be

X represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or a fluorosulfonyloxy group.

R ² , R ³ , R ⁴ , l, m, n, and X ′ have the same meaning as described above.

The starting compound (8) used in the present synthesis method can be produced according to various well-known methods generally used. In this synthesis method, a compound having the formula (8) is reacted with a compound having the formula (9) in the presence of a base, or, when R ³ is a methyl group, by reacting with formalin and reacting sodium cyanoborohydride. Alternatively, it can also be achieved by reacting with formalin and hydrogenating it under a palladium-carbon catalyst or heating in formalin and formic acid. The solvent used is not particularly limited as long as it does not participate in the reaction.Examples include N, N-dimethylformamide, amides such as N, N-dimethylformamide, methylene chloride,
Examples include halogenated hydrocarbons such as 2-dichloroethane and chloroform, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, and mixed solvents of these organic solvents and water. Examples of the base used include an inorganic base such as sodium hydrogencarbonate and sodium carbonate or an organic base such as triethylamine and diisopropylethylamine. The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually at about -20 ° C to 100 ° C. The reaction time varies depending on the reaction temperature and the type of the reaction reagent, but is 10 minutes to 2 days.

The compound (12) can be produced by reacting the obtained compound (10) with a compound having the formula (11). The solvent used is not particularly limited as long as it does not participate in the present reaction. Examples thereof include methylene chloride, 1,2-dichloroethane, and halogenated hydrocarbons such as chloroform;
Benzene, toluene, aromatic hydrocarbons such as xylene, tetrahydrofuran, dioxane, ethers such as diethyl ether, N, N-dimethylformamide,
Examples include amides such as N, N-dimethylacetamide, nitriles such as acetonitrile, and mixed solvents of these organic solvents and water. Although the reaction temperature is not particularly limited, it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, and it is usually carried out at -20 ° C to 180 ° C. The reaction time varies mainly depending on the reaction temperature and the type of the reaction reagent, but is 10 minutes to 3 days. The obtained compound (12) after performing the process of removing the protecting group R ²⁷ of the thiol group mercaptan compound (5) can be produced. The removal of the protecting group depends on its type, but is generally done by methods known in the art. Suitably when R ²⁷ is an aralkyl group, in the presence of trifluoroacetic acid, anisole
This is achieved by reacting trifluoromethanesulfonic acid. When the protecting group is an alkanoyl group or an aromatic acyl group, hydrogen chloride or hydrogen bromide may be used in an alcohol such as methanol or ethanol, or in water, water or hydrated ether such as hydrated tetrahydrofuran or hydrated dioxa, or a mixture thereof. It can be removed in a solvent. Although the reaction temperature is not particularly limited, it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, and it is usually carried out at -20 ° C to 200 ° C. The reaction time varies depending on the type of the protecting group, but is usually 10 minutes to 24 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing the solvent from the reaction mixture.

Mercaptan compound (5) thus obtained
Can be further purified by reprecipitation and column chromatography. X ′ in the formula (5) varies depending on the type of the reagent used in the reaction for removing the protecting group in the formula (12).

〔effect〕

The carbapenem-3-carboxylic acid derivative having the formula (1) according to the present invention exhibits an excellent antibacterial activity having a broad spectrum and a β-lactamase inhibitory activity. Furthermore, although thienamycin compounds are easily metabolized by mammals, they show excellent stability against dehydropeptidase I, which is known as an enzyme that catalyzes the inactivation of thienamycin. It has excellent properties. Antibacterial activity was measured by agar plate dilution method, for example, Staphylococcus aureus, Gram-positive bacteria such as Bacillus subtilis, Escherichia coli, Shigella, Klebsiella pneumoniae, deformed bacteria, Serratia, Enterobacter, Pseudomonas aeruginosa Gram-negative bacteria and Bacteroides,
It showed strong activity against a wide range of pathogenic bacteria including anaerobic bacteria such as fragilis.

Accordingly, such compounds are useful as antibacterial agents for treating bacterial infections caused by these pathogenic bacteria. Dosage forms for that purpose include, for example, oral administration by tablets, capsules, granules, powders, syrups and the like or parenteral administration by intravenous injection, intramuscular injection and the like. , Symptoms, etc., and the dosage form and number of administrations.
0 mg to 3000 mg is administered once or in several divided doses.

Example 1 (1R, 5S, 6S) -2-[(2S, 4S) -2-carbamoyl-
1,1-dimethylpyrrolidinium-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1-
Carbapen-2-M-3-carboxylate (1) (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) -1,1-dimethylpyrrolidium
Fluorosulfonate (520mg) with anisole (1.45m
l), trifluoroacetic acid (5.14 ml) under ice-cooling,
Trifluoromethanesulfonic acid (0.13 ml) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes. The solvent was distilled off, and the residue was washed by repeating decantation with dimethyl ether, dried under reduced pressure, and obtained as oily (2S, 4S) -2-carbamoyl-4-mercapto-1,1-dimethylpyrrolidine. The sodium salt (420 mg) was obtained.

(2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (400 m
g) was dissolved in dry acetonitrile (4 ml), diisopropylethylamine (0.20 ml) and diphenylphosphoryl chloride (0.24 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Then, diisopropylethylamine (0.46
ml) and a solution of the salt obtained in (1) in dry acetonitrile (3 ml) were added dropwise, and the mixture was stirred at the same temperature for 7 hours and then left under ice cooling for 2 days. The solvent is distilled off, and washing is performed by repeating decantation with diethyl ether,
The crude product obtained by drying under reduced pressure was dissolved in a mixture of tetrahydrofuran (30 ml) and 0.1 M phosphate buffer (pH 7.0, 30 ml), and the mixture was dissolved in the presence of a 10% palladium-carbon catalyst (555 mg). Hydrogenated at room temperature for 2.5 hours. After the reaction, the insolubles were removed using Celite, the solution was washed with diethyl ether, the aqueous layer was concentrated under reduced pressure, and Diaion HP-20AG was used.
(Mitsubishi Kasei Kogyo Co., Ltd.), and the mixture was concentrated under reduced pressure and lyophilized from a portion eluted with 5% acetone water to obtain a crude target compound as a yellow powder. Further, 5% using a Roper column (Licroprep RP-8, size B, manufactured by Merck) and
From the portion eluted with 10% aqueous methanol, concentration under reduced pressure and lyophilization gave the target compound (100 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.33 Hz), 1.10 (3H, d, J = 6.23 Hz), 2.
20−2.31 (1H, m), 2.87−3.22 (2H, m), 3.10 (3H, s),
3.14 (3H, s), 3.28 (1H, dd, J = 2.78,6.05Hz), 3.67-3.
73 (1H, m), 3.86-4.08 (4H, m), 4.22 (1H, dd, J = 7.50,
Example 2 (1R, 5S, 6S) -2-[(2S, 4S) -2-carbamoyl-
1- (2-fluoroethyl) -1-methylpyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-
Carboxylate (1) (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) -1- (2-fluoroethyl)-
1-methylpyrrolidinium fluorosulfonate (1.
11g) was suspended in anisole (2.83 ml), trifluoroacetic acid (10.0 ml) and trifluoromethanesulfonic acid (0.25 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure to give an oily (2S, 4S) -2-carbamoyl-4-mercapto-1-mer.
(2-Fluoromethyl) -1-methylpyrrolidinium salt (927 mg) was obtained.

(2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (720 m
g) was dissolved in dry acetonitrile (7 ml), diisopropylethylamine (0.37 ml) and diphenylphosphoryl chloride (0.44 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Then, diisopropylethylamine (0.88
ml) and a solution of the salt obtained in (1) in dry acetonitrile (5 ml) were added dropwise and left at the same temperature for 2 days. The solvent was distilled off, the residue was washed by repeating decantation with diethyl ether, and the crude product obtained by drying under reduced pressure was treated with tetrahydrofuran (55 ml), 0.1 M phosphate buffer (pH 7.0, 55 ml). ) And hydrogenated at room temperature for 2 hours in the presence of 10% palladium-carbon (1 g). After the reaction, the insolubles were removed using Celite, the solution 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 Kasei Kogyo).
The mixture was concentrated under reduced pressure and lyophilized from a portion eluted with a% acetone water to obtain a crude compound as a yellow powder. Further, using a rover column (Licroprep RP-8, size B, manufactured by Merck), the portion eluted with 2% aqueous methanol was concentrated under reduced pressure and lyophilized to obtain the target compound (40 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.03 (3H, d, J = 7.33 Hz), 1.10 (3H, d, J = 6.59 Hz), 2.
27-2.35 (1H, m), 2.92-3.12 (2H, m), 3.19 (3H, s),
3.29 (1H, dd, J = 2.75,6.05Hz), 3.67-3.78 (2H, m), 3.
91−4.09 (5H, m), 4.37 (1H, dd, J = 7.50,10.81Hz), 4.6
9-4.91 (2H, m) Example 3 (1R, 5S, 6S) -2-[(2S, 4S) -1,1-dimethyl-2-
Methylcarbamoylpyrrolidinium-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-
1-carbapene-2-m-3-carboxylate (1) (2S, 4S) -1,1-dimethyl-2-methylcarbamoyl-4- (4-methoxybenzylthio) -pyrrolidinium fluorosulfonate (280 mg) was suspended in anisole (0.744 ml) and cooled under ice-cooling. , Trifluoroacetic acid (2.64 ml), and trifluoromethanesulfonic acid (0.
132 ml), and the mixture was stirred for 2 hours under ice cooling. The solvent was distilled off, and the residue was decanted with diethyl ether for 2 hours.
Wash by repeating and drying under reduced pressure to give an oily crude (2
(S, 4S) -1,1-dimethyl-2-methylcarbamoyl-4
-A mercaptopyrrolidinium salt (230 mg) was obtained.

(2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (225m
g) was dissolved in dry acetonitrile (3 ml), and diisopropylethylamine (108 μl) and diphenylphosphoryl chloride (129 μl) were simultaneously added under ice-cooling.
Stirred for hours. Then, under ice-cooling, diisopropylethylamine (118 μl) and a solution of the salt obtained in (1) in dry acetonitrile (2 ml) were added, and the mixture was added at 0 to 5 for 2 hours in a refrigerator.
Left for 8 hours. The reaction solution was poured into diethyl ether, washed by decantation, and the obtained crude product was treated with tetrahydrofuran (20 ml), 0.1 M phosphate buffer (pH 7.0, 20
dissolved in a mixture of 10% palladium-carbon catalyst (25%).
4 mg) at room temperature for 2.5 h. After the reaction,
The insolubles were removed using Celite, the solution was washed with diethyl ether, and the aqueous layer was concentrated under reduced pressure.
The mixture was applied to a column of HP-20AG (manufactured by Mitsubishi Kasei Kogyo Co., Ltd.), and the crude target compound was obtained by lyophilization from a portion eluted with 5% acetone water. Further, the target compound (9.0 mg) was obtained by concentration under reduced pressure and freeze-drying from portions eluted with 10% and 15% methanol water using a Roper column (Licroprep RP-8, size B, manufactured by Merck).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.33 Hz), 1.10 (3H, d, J = 6.59 Hz), 2.
19 ~ 2.31 (1H, m), 2.63 (3H, s), 2.82 ~ 3.23 (2H, m),
3.05 (3H, s), 3.12 (3H, s), 3.29 (1H, dd, J = 6.22Hz.J
= 2.93Hz), 3.70 (1H, dd, J = 12.46Hz, J = 5.13Hz), 3.83
4.24.20 (5H, m) Example 4 (1R, 5S, 6S) -2-[(2S, 4S) -1,1-dimethyl-2-
(N, N-dimethylcarbamoyl) pyrrolidinium-4-
Ilthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapene-2-em-3-carboxylate (1) (2S, 4S) -1,1-dimethyl-2-N, N-dimethylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (350 mg) was suspended in anisole (0.669 ml), Under ice cooling, trifluoroacetic acid (3.3 ml) trifluoromethanesulfonic acid (0.12 ml)
Was added and stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was washed by decantation with n-hexane,
Further, the resultant was similarly washed by decantation using diethyl ether. The solvent was distilled off under reduced pressure to give an oily crude (2S, 4
S) -1,1-Dimethyl-2-N, N-dimethylcarbamoyl-4-mercaptopyrrolidinium salt (316 mg) was obtained.
This was used for the next reaction without further purification.

(2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (326m
g) was dissolved in dry acetonitrile (4 ml), and diisopropylethylamine (164 μl) and diphenylphosphoryl chloride (196 μl) were simultaneously added under ice-cooling.
Stirred for hours. Then, a solution of diisopropylethylamine (248 ml) and the salt obtained in (1) (418 mg) in dry acetonitrile (3 ml) was added under ice cooling, and the mixture was added at 0 to 5 ° C. for 1 hour.
It was left in the refrigerator for 2 days. The reaction solution was treated in the same manner as in Example 1 (2), and the resulting crude product was dissolved in a mixture of tetrahydrofuran (20 ml) and 0.1 M phosphate buffer (pH 7.0, 20 ml), and 10% palladium was added. -Hydrogenation was carried out at room temperature for 2 hours in the presence of a carbon catalyst (400 mg), followed by reduction and treatment and purification in the same manner as in Example 1 (2) to obtain the desired compound (101 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.03 (3H, d, J = 7.33 Hz), 1.11 (3H, d, J = 6.22 Hz), 2.
19 (1H, quintet, J = 7.20 Hz), 2.83 (3H, s), 2.90 to 3.18
(2H, m), 3.01 (3H, s), 3.10 (3H, s), 3.12 (3H, s), 3.
29 (1H, dd, J = 6.23, 2.56 Hz), 3.74 to 3.91 (2H, m), 3.96
-4.11 (3H, m), 4.76 (1H, t, J = 7.70 Hz) Example 5 (1R, 5S, 6S) -2-[(3S) -1,1-dimethylpyrrolidinium-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-M-
3-carboxylate (1) (3S) -1,1-dimethyl-3- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (453 mg) was suspended in anisole (1.40 ml), and trifluoroacetic acid (4.97 ml) was added under ice cooling. Then, trifluoromethanesulfonic acid (0.249 ml) was added, and the mixture was stirred under ice cooling for 2 hours.
The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure.
An oily crude (3S) -1,1-dimethyl-3-mercaptopyrrolidinium salt (250 mg) was obtained.

(2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (250 m
g) was dissolved in dry acetonitrile (2 ml), and diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl) were simultaneously added under ice-cooling.
Stirred for hours.

Then, diisopropylethylamine (145 μl under ice cooling)
1) and a solution of the salt obtained in (1) in dry acetonitrile (4 ml) were added, and the mixture was allowed to stand at 0 to 5 ° C. for 2 hours and in a freezer for 2 nights. The reaction solution was poured into diethyl ether, washed by decantation, and the obtained crude product was dissolved in tetrahydrofuran (20 ml) and 0.1 M phosphate buffer (pH 7.0, 20 ml).
Room temperature in the presence of 10% palladium-carbon catalyst (300 mg)
Hydrogenated for 2.5 hours. After the reaction, insolubles were removed using Celite, and the solution was washed with diethyl ether.
The aqueous layer was concentrated under reduced pressure, applied to a column of Diaion HP-20AG (manufactured by Mitsubishi Kasei Kogyo), and lyophilized from the portion eluted with 5% acetone water to obtain a powdery crude target compound. Furthermore, the target compound (90 mg) was obtained by concentration under reduced pressure and freeze-drying from a portion eluted with 10% and 15% methanol water using a rover column (Licroprep RP-8, size B, manufactured by Merck).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.33 Hz), 1.09 (3H, d, J = 6.59 Hz), 1.
96 ~ 2.14 (1H, m), 2.52 ~ 2.70 (1H, m), 3.00 (3H, s),
3.09 (3H, s), 3.04 ~ 3.18 (1H, m), 3.28 (1H, dd, J = 2.7
5Hz, J = 6.05Hz), 3.38-3.67 (3H, m), 3.80 (1H, dd, J =
7.70 Hz, J = 12.46 Hz), 3.91 to 4.11 (3H, m) Example 6 (5R, 6S) -2-[(3S) -1,1-dimethylpyrrolidinium-3-ylthio] -6- [ (1R) -1-Hydroxyethyl] -1-carbapene-2-em-3-carboxylate (5R, 6S) -6-[(1R) -1-hydroxyethyl]
-2-oxo-1-carbapenam-3-carboxylic acid 4
-Nitrobenzyl ester (348 mg) was dissolved in dry acetonitrile (4 ml) and diisopropylethylamine (183 µl) and diphenylphosphoryl chloride (218
μl) was added at the same time, followed by stirring at the same temperature for 1 hour. Then, a solution of the crude (3S) -1,1-dimethyl-3-mercaptopyrrolidinium salt (338 mg) obtained in Example 5 (1) in dry acetonitrile (4 ml) and diisopropylethylamine (209 μl) were added under ice cooling. The mixture was left at the same temperature for 1 hour and in a refrigerator for 2 nights. The reaction solution was poured into diethyl ether and washed by decantation. The obtained crude product was treated with tetrahydrofuran (30 ml) and a 0.1 M phosphate buffer (pH 7.0, 30
ml), and hydrogenated at room temperature for 2.5 hours in the presence of 10% palladium-carbon catalyst (400 mg). After the reaction, the insolubles were removed using Celite, the solution was washed with diethyl ether, and the aqueous layer was concentrated under reduced pressure.
The mixture was applied to an AG (manufactured by Mitsubishi Kasei Kogyo) column, and the target compound eluted with water was freeze-dried to obtain a powdery crude target compound. Furthermore, the target compound (60 mg) was obtained from the part eluted with 5% aqueous methanol using a rover column (Licroprep RP-8 size B manufactured by Merck) under reduced pressure and freeze-dried.

Nuclear magnetic resonance absorption spectrum (270 MHz, D ₂ O) δ ppm: 1.09 (3H, d, J = 6.23 Hz), 2.01 to 2.18 (1H, m), 2.53 to
2.72 (1H, m), 2.89 to 3.04 (2H, m), 3.01 (3H, s), 3.09
(3H, s), 3.23 (1H, dd, J = 6.05,2.75Hz), 3.36-3.67
(3H, m), 3.85 (1H, dd, J = 12.64,8.24Hz), 3.93-4.09
(3H, m) Example 7 (1R, 5S, 6S) -2- [1,1-dimethylpiperidinium-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylate (1) 1,1-dimethyl-4- (4-methoxybenzylthio) piperidinium fluorosulfonate (3.0 g)
Was suspended in anisole (8.9 ml), trifluoroacetic acid (31.6 ml) and trifluoromethanesulfonic acid (1.6 ml) were added under ice cooling, and the mixture was stirred for 3 hours under ice cooling. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether. Drying under reduced pressure gave an oily crude 1,1-dimethyl-4-mercaptopiperidinium salt (2.4 g).

(2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (250 m
g) was dissolved in dry acetonitrile (2 ml), and diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl) were simultaneously added under ice-cooling.
Stirred for hours. Then, a solution of diisopropylethylamine (288 μl) and the salt obtained in (1) (245 mg) in dry acetonitrile (4 ml) was added under ice cooling, and the mixture was added at 0 to 5 ° C. for 50 minutes.
Left in freezer for 2 days. The reaction solution was poured into diethyl ether, washed by decantation, and the obtained crude product was dissolved in tetrahydrofuran (20 ml) and 0.1 M phosphate buffer (pH 7.0, 20 ml) to obtain a 10% palladium-carbon catalyst ( (331 mg) in the presence of hydrogen at room temperature for 2 hours, followed by treatment after reduction and purification in the same manner as in Example 5 (2) to obtain the desired compound (11.3 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 6.96 Hz), 1.10 (3H, d, J = 6.23 Hz), 1.
70, 1.93 (2H, m), 2.03 to 2.20 (2H, m), 2.97 (6H, s), 3.
11 to 3.48 (7H, m), 4.01 to 4.12 (2H, m) Example 8 (5R, 6S) -2- [1,1-dimethylpiperidinium-4-
Ilthio] -6-[(1R) -1-hydroxyethyl]-
1-carbapene-2-m-3-carboxylate A solution of the crude 1,1-dimethyl-4-mercaptopiperidinium salt (368 mg) obtained in Example 7 (1) in dry acetonitrile (3 ml) and diisopropylethylamine (360 μm)
Using l), the reaction and treatment were conducted in the same manner as in Example 6 to obtain the desired compound (24 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.09 (3H, d, J = 6.23 Hz), 1.74 to 1.93 (2H, m), 2.02 to
2.16 (2H, m), 2.86 to 3.43 (8H, m), 2.96 (6H, s), 3.97
~ 4.08 (2H, m) Example 9 (1R, 5S, 6S) -2-[(2S, 4S) -2- (N, N-dimethylcarbamoyl) -1-ethyl-1-methylpyrrolidinium-4 -Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-
Carboxylate (1) (2S, 4S) -2- (N, N-dimethylcarbamoyl) -1-ethyl-1-methyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (560 mg) was added to anisole (1.39 ml). Suspended under ice cooling,
Trifluoroacetic acid (4.94 ml) and trifluoromethanesulfonic acid (248 μl) were added, and the mixture was stirred for 2 hours under the same conditions. The solvent was distilled off, and the residue was washed by repeating decantation twice with diethyl ether, dried under reduced pressure, and obtained as an oily crude (2S, 4S) -2- (N, N-dimethylcarbamoyl) -1-. Ethyl-1-methyl-4-mercaptopyrrolidinium salt (460 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.21 (3H, t, J = 7.33 Hz), 2.14 (1H, dt, J = 14.29 Hz, 7.
15Hz), 2.82 (3H, s), 2.98 (3H, s), 3.00 (3H, s), 2.86
-3.94 (m, 6H), 4.69 (1H, t, J = 7.15 Hz) (2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo -1-Carbapenam-3-carboxylic acid 4-nitrobenzyl ester (301 m
g) was dissolved in dry acetonitrile (4 ml), and diisopropylethylamine (152 μl) and diphenylphosphoryl chloride (181 μl) were simultaneously added under ice-cooling, followed by stirring for 1 hour under ice-cooling. Then, a solution of diisopropylethylamine (174 μl) and the salt obtained in (1) (366 mg) in dry acetonitrile (4 ml) was added under ice cooling, and the mixture was allowed to stand at 0 to 5 ° C. for 1 hour and in a refrigerator for 2 days. The reaction solution was poured into diethyl ether, washed by decantation, and the obtained crude product was dissolved in tetrahydrofuran (25 ml) 0.1 M-phosphate buffer (pH 7.0, 25 ml), and 10% palladium-carbon catalyst ( (340 mg) in the presence of hydrogen at room temperature for 2.5 hours, followed by treatment after reduction and purification in the same manner as in Example 1 (2) to obtain the desired compound (127 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 6.96 Hz), 1.10 (3H, d, J = 6.22 Hz), 1.
22 (3H, t, J = 7.32Hz), 2.12-2.25 (1H, m), 2.82 (3H,
s), 2.83-3.50 (5H, m), 3.00 (3H, s), 3.05 (3H, s),
3.65 (1H, dd, J = 12.45Hz, 5.13Hz), 3.85 (1H, dd, J = 12.
45Hz, 8.42Hz), 3.91 ~ 4.12 (3H, m), 4.68 ~ 4.75 (1H,
m) Example 10 (5R, 6S) -2-[(2S, 4S) -1-ethyl-1-methyl-2- (N, N-dimethylcarbamoyl) pyrrolidinium-4-ylthio] -6-[(1R ) -1-Hydroxyethyl] -1-carbapene-2-em-3-carboxylate Crude (2S, 4S) -1-ethyl-1-methyl-2-N, N-dimethylcarbamoyl-4 obtained in Example 9- (1)
-The reaction and treatment were conducted using a mercaptopyrrolidinium salt (580 mg) in the same manner as in Example 6 to obtain the desired compound (55 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.10 (3H, d, J = 6.59 Hz), 1.23 (3H, t, J = 7.15 Hz), 2.
17 ~ 2.30 (1H, m), 2.83 (3H, s), 2.83 ~ 3.07 (2H, m),
3.00 (3H, s), 3.01 (3H, s), 3.05 (3H, s), 3.24 (1H, d
d, J = 6.04, 2.75 Hz), 3.27 to 4.18 (7H, m), 4.72 (1H, t, J
= 8.06 Hz) Example 11 (5R, 6S) -2-[(2S, 4S) -1,1-dimethyl-2-
(N, N-dimethylcarbamoyl) pyrrolidinium-4-
Ilthio] -6-[(1R) -1-hydroxyethyl]-
1-carbapene-2-m-3-carboxylate (5R, 6S) -6-[(1R) -1-hydroxyethyl]
-2-oxo-1-carbapenam-3-carboxylic acid 4
-Nitrobenzyl ester (218 mg) was dissolved in dry acetonitrile (3 ml), and diisopropylethylamine (126 µl) and diphenylphosphoryl chloride (132
μl) was added at the same time, followed by stirring at the same temperature for 1 hour. Next, a dry acetonitrile solution of the crude (2S, 4S) -1,1-dimethyl-2-N, N-dimethylcarbamoyl-4-mercaptopyrrolidinium salt (243 mg) obtained in Example 4 (1) ( 2ml) and diisopropylethylamine (144μl)
Was added under ice-cooling and left at the same temperature for 5 hours in a freezer for 2 days. The reaction solution was treated in the same manner as in Example 9, and the obtained crude product was dissolved in a mixture of tetrahydrofuran (15 ml) and 0.1 M phosphate buffer (pH 7.0, 15 ml), and a 10% palladium-carbon catalyst was dissolved. (200 mg) at room temperature for 2 hours,
The same treatment after reduction and purification as in Example 6 were carried out to obtain the desired compound (56 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.10 (3H, d, J = 6.23 Hz), 2.17 to 2.28 (1H, m), 2.79 to
3.04 (3H, m), 2.83 (3H, s), 3.00 (3H, s), 3.11 (3H,
s), 3.12 (3H, s), 3.24 (1H, dd, J = 6.05,2.75Hz), 3.76
~ 3.96 (2H, m), 3.97 ~ 4.12 (3H, m), 4.76 (1H, t, J = 7.
Example 12 (1R, 5S, 6S) -2-[(2S, 4S) -1,1-dimethyl-2-
(4-morpholinocarbonyl) pyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylate (1) (2S, 4S) -1,1-dimethyl-4- (4-methoxybenzylthio) -2- (4-morpholinocarbonyl)
Using pyrrolidinium fluorosulfonate (446 mg), the reaction and treatment were carried out in the same manner as in Examples 4 (1) and (2).
The target compound (16 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.32 Hz), 1.10 (3H, d, J = 6.59 Hz), 2.
16 ~ 2.28 (1H, m), 2.90 ~ 3.18 (2H, m), 3.10 (3H, s),
3.15 (3H, s), 3.29 (2H, dd, J = 6.23,2.93Hz), 3.43 ~ 3.
65 (8H, m), 3.76 ~ 3.93 (2H, m), 3.96 ~ 4.12 (3H, m),
4.76 (1H, t, J = 7.69Hz) Example 13 (1R, 5S, 6S) -2-[(2S, 4S) -1,1-dimethyl-2-
(1-pyrrolidinocarbonyl) pyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylate (1) (2S, 4S) -1,1-dimethyl-4- (4-methoxybenzylthio) -2- (1-pyrrolidinocarbonyl)
Using pyrrolidinium fluorosulfonate (472 mg), the reaction and treatment were conducted in the same manner as in Examples 4 (1) and (2).
The target compound (24 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 6.96 Hz), 1.10 (3H, d, J = 6.23 Hz), 1.
65 ~ 1.84 (4H, m), 2.14 ~ 2.24 (1H, m), 2.92 ~ 3.04 (1
H, m), 3.10 (3H, s), 3.12 (3H, s), 3.20 ~ 3.57 (5H,
m), 3.74-4.11 (6H, m), 4.47-4.63 (1H, m) Example 14 (1R, 5S, 6S) -2-[(2S, 4S) -2-carbamoyl-
1-ethyl-1-methylpyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylate (1) (2S, 4S) -2-carbamoyl-4-p-methoxybenzylthio-1-ethyl-1-methyl-pyrrolidinium fluorosulfonate (450 mg) was suspended in anisole (1.2 ml), and the suspension was added under ice cooling. Fluoroacetic acid (4.2m
l), trifluoromethanesulfonic acid (0.11 ml) was added dropwise, and the mixture was stirred at the same temperature for 90 minutes. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether, dried under reduced pressure, and obtained as an oily (2S, 4S) -2-carbamoyl-4-mercapto-1-ethyl-1-methylpyrrolyl. The dinium salt (370 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.20 (3H, t, J = 7.32 Hz), 2.13-2.25 (1H, m), 2.80-
3.92 (6H, m), 2.98 (3H, s), 4.11-4.17 (1H, m) (2) Using the salt (340 mg) obtained in (1), react in the same manner as in Example 9 (2). , Treatment, target compound (120m
g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 6.96 Hz), 1.10 (3H, d, J = 6.23 Hz), 1.
23 (3H, t, J = 7.33 Hz), 2.21-2.35 (1H, m), 2.88-3.25
(2H, m), 3.04 (3H, s), 3.26-4.08 (8H, m), 4.22 (1H,
dd, J = 7.32, 10.26 Hz) Example 15 (5R, 6S) -2-[(2S, 4S) -2-carbamoyl-1-
-Ethyl-1-methylpyrrolidinium-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-carbapene-2-em-3-carboxylate (Using the salt (530 mg) obtained in Example 14 (1), reaction and treatment were carried out in the same manner as in Example 11 to obtain the desired compound (205 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.09 (3H, d, J = 6.60 Hz), 1.24 (3H, t, J = 7.33 Hz), 2.
26 ~ 2.38 (1H, m), 2.84 ~ 3.07 (2H, m), 3.03 (3H, s),
3.24 (1H, dd, J = 6.05, 2.93Hz), 3.27 to 4.06 (8H, m), 4.
22 (1H, dd, J = 10.26,7.33 Hz) Example 16 (5R, 6S) -2-[(2S, 4S) -2-carbamoyl-1,1
-Dimethylpyrrolidinium-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-carbapene-
2-M-3-carboxylate (5R, 6S) -6-[(1R) -1-hydroxyethyl]
-2-oxo-1-carbapenam-3-carboxylic acid-4
-Nitrobenzyl ester (400 mg) was dissolved in dry acetonitrile (5 ml), and diisopropylethylamine (210 μl) and diphenylphosphoryl chloride (2
50 μl) were added simultaneously, and the mixture was stirred for 1 hour under ice cooling. Next, a dry acetonitrile solution (5 ml) of the crude (2S, 4S) -2-carbamoyl-1,1-dimethyl-4-mercaptopyrrolidinium salt (447 mg) obtained in Example 1 (1) and diisopropylethylamine (240 μl) ) Was added under ice cooling, and the mixture was allowed to stand under ice cooling for 4 hours and in a refrigerator for 2 days. The reaction solution was poured into diethyl ether and washed by repeating decantation. The obtained crude product was dissolved in tetrahydrofuran (30 ml) and 0.1 M phosphate buffer (pH 7.0, 30 ml), and 10% palladium was added. -Hydrogenation at room temperature for 2.5 hours in the presence of a carbon catalyst (450mg). After the reaction, the insolubles were washed with celite, and the aqueous layer was concentrated under reduced pressure.
The mixture was applied to a column of 20AG (Mitsubishi Kasei Kogyo) and lyophilized from the portion eluted with water to obtain a powdery crude target compound. In addition, a rover column (Merck Licroprep RP-8)
Using size B), the target compound (208 mg) was obtained by concentration under reduced pressure from the portion eluted with 5% aqueous methanol and freeze-drying.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.09 (3H, d, J = 6.59 Hz), 2.23 to 2.36 (1H, m), 2.86 to
3.04 (3H, m), 3.10 (3H, s), 3.15 (3H, s), 3.23 (1H, d
d, J = 5.86, 2.57 Hz), 3.73 (1H, dd, J = 12.09, 5.50 Hz),
3.90 ~ 4.08 (4H, m), 4.22 (1H, dd, J = 9.16,7.69Hz) Example 17 (1R, 5S, 6S) -2-[(2S, 4S) -2-ethylcarbamoyl-1-ethyl -1-methylpyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylate (1) (2S, 4S) -2-Ethylcarbamoyl-1-ethyl-1-methyl-4-p-methoxybenzylthiopyrrolidinium fluorosulfonate (1.23 g) was suspended in anisole (3.06 ml), and ice was suspended. Under cooling, trifluoroacetic acid (10.86 ml), trifluoromethanesulfonic acid (544μ)
l) was added, and the mixture was stirred for 2 hours under the same conditions. The solvent was distilled off, the residue was washed with diethyl ether by repeating decantation three times, dried under reduced pressure, and obtained as an oily crude (2S, 4S) -2-ethylcarbamoyl-1-ethyl-
1-methyl-4-mercaptopyrrolidinium salt (0.96
g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.96 (3H, t, J = 7.33 Hz), 1.21 (3H, t, J = 7.33), 2.13
2.22.26 (1H, m), 2.95 (3H, s), 2.73 to 4.16 (9H, m) (2) Example 1 was performed using the salt (304 mg) obtained in 1.
The reaction and treatment were carried out in the same manner as (2) to obtain the desired compound (69 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.95 (3H, t, J = 7.32 Hz), 1.02 (3H, d, J = 7.33 Hz), 1.
10 (3H, d, J = 6.58 Hz), 1.22 (3H, t, J = 7.33 Hz), 2.12 to
2.34 (1H, m), 2.76 to 2.97 (1H, m), 2.99 (3H, s), 3.03
Example 18 (5R, 6S) -2-[(2S, 4S) -2-ethylcarbamoyl-1-ethyl-1-methylpyrrolidinium-4-ylthio] -6-[( 1R) -1-Hydroxyethyl] -1-carbapene-2-em-3-carboxylate Same as Example 16 except that the crude (2S, 4S) -2-ethylcarbamoyl-1-ethyl-1-methyl-4-mercaptopyrrolidinium salt (440 mg) obtained in Example 17 (1) was used. To give the target compound (80 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.95 (3H, t, J = 7.32 Hz), 1.09 (3H, d, J = 6.59 Hz), 1.
23 (3H, t, J = 7.33 Hz), 2.13 to 2.37 (1H, m), 2.76 to 3.05
(3H, m), 2.98 (3H, s), 3.09 (2H, q, J = 7.33Hz), 3.23
(1H, dd, J = 6.05, 2.75 Hz), 3.22 to 4.18 (8H, m) Example 19 (1R, 5S, 6S) -2-[(2S, 4S) -1-ethyl 1-methyl-2- Methylcarbamoylpyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylate Using (2S, 4S) -1-ethyl-1-methyl-2-methylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidinium fluososulfonate (986 mg), Examples 1 (1), (2 The reaction and treatment were carried out in the same manner as in the above) to obtain the desired compound.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.33 Hz), 1.10 (3H, d, J = 6.59 Hz), 1.
21 (3H, t, J = 7.33 Hz), 2.11 to 2.33 (1H, m), 2.62 (3H,
s), 2.77 ~ 2.90 (1H, m), 2.98 (3H, s), 3.00 ~ 4.23 (10
H, m) Example 20 (1R, 5S, 6S) -2-[(2S, 4S) -1,1-dimethyl-2-
Ethylcarbamoylpyrrolidinium-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-
1-carbapene-2-m-3-carboxylate (1) (2S, 4S) -1,1-dimethyl-2-ethylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (1.27 g) was added to anisole (3.2
Trifluoroacetic acid (11.56m) under ice-cooling.
l) and trifluoromethanesulfonic acid (580 μl) were added and the mixture was stirred for 2 hours under the same conditions. The solvent was distilled off, and the residue was washed by repeating decantation three times with diethyl ether, dried under reduced pressure, and obtained as an oily crude (2S, 4S) -1,1.
-Dimethyl-2-ethylcarbamoyl-4-mercaptopyrrolidinium salt (802 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.96 (3H, t, J = 7.33 Hz), 2.18 (1H, dt, J = 14.66, 7.33)
Hz), 2.79 ~ 2.98 (1H, m), 3.03 (3H, s), 3.06 (3H, s),
3.10 (2H, q, J = 7.33 Hz), 3.46 to 3.92 (3H, m), 4.06 (1
(H, t, J = 7.33 Hz) (2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4 -Nitrobenzyl ester (674m
g) in dry acetonitrile (10 ml),
Diisopropylethylamine (340 μl) and diphenylphosphoryl chloride (405 μl) were added simultaneously, and the mixture was stirred under ice cooling for 1 hour. Then, under ice-cooling, diisopropylethylamine (390 µl) and dry acetonitrile (8 ml) of the salt (790 mg) obtained in (1) were added, and the mixture was added at 0 to 5 ° C for 2 hours.
It was left in the refrigerator for 2 days. The reaction solution was poured into diethyl ether and washed by decantation. The obtained crude product was dissolved in tetrahydrofuran (30 ml) 0.1M-phosphate buffer (pH 7.0, 30 ml), and 10% palladium-carbon catalyst (650 mg) ) In the presence of) at room temperature for 2 hours
The same post-reduction treatment and purification as in (2) were performed to obtain the desired compound (289 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.95 (3H, t, J = 7.15 Hz), 1.02 (3H, d, J = 7.33 Hz), 1.
10 (3H, d, J = 6.23 Hz), 2.17 to 2.30 (1H, m) 2.81 to 3.18
(2H, m), 3.05 (3H, s), 3.10 (2H, q, J = 7.33Hz), 3.11
(3H, s), 3.28 (1H, dd, J = 6.05,2.76Hz), 3.69 (1H, dd,
J = 12.09, 5.49 Hz), 3.84 to 4.16 (5H, m) Example 21 (1R, 5S, 6S) -2-[(2S) -1,1-dimethyl-2-pyrrolidinium methyltto] -6 -[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-ene-3-carboxylate (1) (2S) -1,1-dimethyl-4- (4-methoxybenzylthiomethyl) pyrrolidinium fluorosulfonate (1.1 g), anisole (3.3 ml), trifluoroacetic acid (11.6 ml), trifluoromethanesulfonic acid ( 581
The reaction, treatment, and purification were carried out in the same manner as in Example 7 (1) using the above-mentioned (μl) to obtain an oily crude (2S) -1,1-dimethyl-4-mercaptomethylpyrrolidinium salt (666 mg).

(2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (150 m
g) was dissolved in dry acetonitrile (3 ml), diisopropylethylamine (76 μl) and diphenylphosphoryl chloride (90 μl) were added simultaneously under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Then, a solution of diisopropylethylamine (87 μl) and the salt (148 mg) obtained in (1) in dry acetonitrile (2 ml) was added under ice cooling, and the mixture was allowed to stand at 0 to 5 ° C. for 2 hours and in a refrigerator for 1 day. The reaction solution was poured into cooled (−78 ° C.) diethyl ether, washed by decantation, and the obtained crude product was treated with tetrahydrofuran (13 ml).
It was dissolved in 0.1 M phosphate buffer (pH 7.0, 13 ml), hydrogenated at room temperature for 2 hours in the presence of 10% palladium-carbon catalyst (210 mg), passed through celite, concentrated, and the residue was concentrated. Was applied to a CHP-20P (manufactured by Mitsubishi Chemical Corporation) column, and from the portion eluted with 5% -acetone water, a crude product was obtained by concentration and freeze-drying, and then Dowex 50W-X4 (manufactured by Dow Chemical Company) From the part attached to the column and eluted with water,
A crude product was obtained by concentration and freeze-drying. Further, the product was applied to a row bar column RP-8 (manufactured by Merck), and the target compound (45 mg) was obtained from a portion eluted from 8% aqueous methanol.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.04 (3H, t, J = 7.33 Hz), 1.11 (3H, d, J = 6.60 Hz), 1.
70 ~ 2.08 (3H, m), 2.35 ~ 2.56 (1H, m), 2.70 (1H, dd, J
= 13.18, 10.99Hz), 2.77 (3H, s), 3.4 (3H, s), 3.08-
3.60 (6H, m), 4.04 to 4.09 (2H, m) Example 22 (1R, 5S, 6S) -2-[(2R) -1,1-dimethyl-2-pyrrolidinium methylthio] -6- [ (1R) -1-Hydroxyethyl] -1-methyl-1-carbapen-2-ene-3-carboxylate Using (2R) -1,1-dimethyl-4- (4-methoxybenzylthiomethyl) pyrrolidinium fluorosulfonate (0.94 g), the reaction and treatment were carried out in the same manner as in Examples 21 (1) and (2). The compound (70 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.01 (3H, d, J = 7.33 Hz), 1.10 (3H, d, J = 6.23 Hz), 1.
69 ~ 2.08 (3H, m), 2.28 ~ 2.45 (1H, m), 2.79 (3H, s),
2.94 ~ 3.12 (2H, m), 3.07 (3H, s), 3.18 ~ 3.64 (5H,
m), 4.01 to 4.11 (2H, m) Example 23 (1R, 5S, 6S) -2-[(2S, 4S) -2-carbamoyl-
1- (2-hydroxyethyl) -1-methylpyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3
-Carboxylate (2S, 4S) -2-carbamoyl-1- (2-hydroxyethyl) -4- (4-methoxybenzylthio) -1-
Methylpyrrolidinium fluorosulfonate (0.37
Using g), the reaction and treatment were conducted in the same manner as in Examples 7 (1) and (2) to obtain the desired compound (17 mg).

Example 24 (1R, 5S, 6S) -2- (1-Methyl-quinuclidium-3)
-Ylthio) -6-[(1R) -1-hydroxyethyl]
-1-Methyl-1-carbapene-2-ene-3-carboxylate (1) 3- (4-methoxybenzylthio) -1-methylminuclidium fluorosulfonate (1.08 g),
Using anisole (3.12 ml), trifluoroacetic acid (15 ml), and trifluoromethanesulfonic acid (278 μl), the reaction, treatment, and purification were performed in the same manner as in Example 7 (1) to obtain an oily crude product.
Mercapto-1-methylquinuclidium salt (880 mg) was obtained.

(2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (268m
g) was dissolved in dry acetonitrile (3 ml), and diisopropylethylamine (135 μl) and diphenylphosphoryl chloride (160 μl) were simultaneously added under ice-cooling.
Stirred for hours. Then, a solution of diisopropylethylamine (185 μl) and the salt obtained in (1) (271 mg) in dry acetonitrile (2 ml) was added under ice-cooling, and the reaction and treatment were carried out in the same manner as in Example 21 (2) to give the desired compound (35 mg). I got

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.32 Hz), 1.10 (3H, d, J = 6.60 Hz), 1.
66 ~ 2.32 (5H, m), 2.80 (3H, s), 2.98 ~ 3.36 (7H, m),
3.57 to 3.73 (2H, m), 4.00 to 4.12 (2H, m) Example 25 (1R, 5S, 6S) -2-[(6S, 8S) -1,4-dimethyl-5-
Oxo-4-aza-1-azoniabicyclo [4.3.0] non-8-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-
Carboxylate (1) (6S, 8S) -1,4-dimethyl-8- (4-methoxybenzylthio) -5-oxo-4-aza-1-azoniabicyclo [4.3.0] nonane fluorosulfonate (8
41 mg), anisole (2.17 ml), trifluoroacetic acid (7.
70 ml) and trifluoromethanesulfonic acid (386 μl), reacted, treated and purified in the same manner as in Example 7 (1) to give an oily crude (6S, 8S) -1,4-dimethyl-8-mercapto-5-yl.
Oxo-4-aza-1-azoniabicyclo [4.3.0] nonane salt (700 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 2.18 (1H, dt, J = 13.92, 9.16 Hz), 2.85 (3H, s), 2.86
~ 3.04 (1H, m), 3.16 (3H, s), 3.51 ~ 3.90 (6H, m), 3.9
8 (1H, dd J = 12.09, 7.69 Hz), 4.26 (1H, t, J = 8.61 Hz) (2) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1- Methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester (362m
g) was dissolved in dry acetonitrile (5 ml), and diisopropylethylamine (183 μl) and diphenylphosphoryl chloride (218 μl) were simultaneously added under ice-cooling.
Stirred for hours. Then, under ice cooling, diisopropylethylamine (209 μl) and a solution of the salt obtained in (1) (420 mg) in dry acetonitrile (3 ml) were added, and the reaction, treatment, reduction reaction and treatment were carried out in the same manner as in Example 20 (2). Target compound (195m
g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.33 Hz), 1.10 (3H, d, J = 6.59 Hz), 2.
23 ~ 2.37 (1H, m), 2.86 (3H, s), 2.96 ~ 3.14 (2H, m),
3.20 (3H, s), 3.31 (1H, dd, J = 5.86,2.93Hz), 3.47-3.
80 (4H, m), 3.83 to 4.12 (5H, m), 4.34 (1H, t J = 7.88H
z) Example 26 (1R, 5S, 6S) -2-[(2RS, 4S) -1,1-dimethyl-2
-Methoxycarbonylpyrrolidinium-4-ylthio]
-6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylate (2S, 4S) -1,1-dimethyl-4- (4-methoxybenzylthio) -2-methoxycarbonylpyrrolidinium
Using fluorosulfonate, Example 1 (1),
The reaction and treatment were carried out in the same manner as in (2) to obtain the desired compound.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02, 1.03 (3H, d, J = 7.33 Hz), 1.10 (3H, d, J = 6,23H)
z), 2.27 ~ 2.45 (1H, m), 2.83 ~ 3.32 (3H, m), 3.01 ~ 3.
14 (3H, s), 3.19,3.22 (3H, s), 3,53 ~ 3.77 (1H, m), 3.
69 (3H, s), 3.88 to 4.12 (4H, m), 4.48 (0.5H, dd, J = 11.
35,7.69Hz), 4.65 (0.5H, dd, J = 10.44,8.61Hz) Example 27 (1R, 5S, 6S) -2-[(2R, 4S) -1,1-dimethyl-2-
(N, N-dimethylcarbamoyl) pyrrolidinium-4-
Ilthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapene-2-em-3-carboxylate Example 4 (1), using (2R, 4S) -1,1-dimethyl-N, N-dimethylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate
The reaction and treatment were carried out in the same manner as in (2) to obtain the desired compound.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.33 Hz), 1.10 (3H, d, J = 6,22 Hz), 2.
28 ~ 2.41 (1H, m), 2.68 ~ 2.80 (1H, m), 2.82 (3H, s),
3.01 (3H, s), 3.03 (3H, s), 3.05-3.16 (1H, m), 3.18
(3H, s), 3.29 (1H, dd, J = 6.23,2.94Hz), 3.50 ~ 3.58
(1H, m), 4.01 to 4.18 (4H, m), 4.91 (1H, dd, J = 7.69,6.
Example 23 (1R, 5S, 6S) -2-[(2R, 4S) -2-carbamoyl-
1,1-dimethylpyrrolidinium-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1-
Carbapen-2-M-3-carboxylate Using (2R, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) -1,1-dimethylpyrrolidinium fluorosulfonate, the reaction and treatment were conducted in the same manner as in Examples 1 (1) and (2). Thus, the target compound was obtained.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.03 (3H, d, J = 6.96 Hz), 1.10 (3H, d, J = 6,22 Hz), 2.
28 ~ 2.41 (1H, m), 2.74 ~ 2.88 (1H, m), 3.02 (3H, s),
3.07-3.18 (1H, m), 3.22 (3H, s), 3.29 (1H, dd, J = 6.2
3,2.57Hz), 3.52 ~ 3.63 (1H, m), 3.98 ~ 4.17 (4H, m),
4.39 (1H, t, J = 8.06Hz) Example 29 (1R, 5S, 6S) -2-[(2S, 4S) -2-cyclopropylcarbamoyl-1,1-dimethylpyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylate (2S, 4S) -2-cyclopropylcarbamoyl-1,1-
Example 3 using dimethyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate
The reaction and treatment were carried out in the same manner as (1) and (2) to obtain the desired compound.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.37 to 0.42 (2H, m), 0.59 to 0.64 (2H, m), 1.01 (3H,
d, J = 7.32 Hz), 1.09 (3H, d, J = 6.23 Hz) 2.17 to 2.29 (1
H, m), 2.47 ~ 2.55 (1H, m), 2.80 ~ 3.13 (2H, m), 3.05
(3H, s), 3.09 (3H, s), 3.28 (1H, dd, J = 6.05,2.75H
z), 3.69 (1H, dd, J = 12.09, 6.05 Hz), 3.84 to 4.10 (5H,
m) Example 30 (1R, 5S, 6S) -2- (1,1-dimethylazetidinium-
3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylate 1,1-dimethyl-4- (4-methoxybenzylthio)
Using azetidinium fluorosulfonate, the reaction and treatment were carried out in the same manner as in Example 5 (1) and (2) to obtain the target compound.

Example 31 (1R, 5S, 6S) -2- (4,4-dimethylmorpholinium-
2-ylmethylthio] 6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-
Carboxylate 4,4-dimethyl-2- (4-methoxybenzylthio)
Using methylmorpholinium fluorosulfonate, the reaction and treatment were carried out in the same manner as in Examples 5 (1) and (2) to obtain the desired compound.

Example 32 (1R, 5S, 6S) -2-[(6S, 8S) -5-oxo-1-methyl-4-aza-1-azoniabibicyclo [4.3.0] non-8-ylthio-6 -[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylate Using (6S, 8S) -5-oxo-8- (4-methoxybenzylthio) -1-methyl-4-aza-1-azoniabicyclo [4.3.0] nonane fluorosulfonate,
The reaction and treatment were conducted in the same manner as in Example 25 to obtain the desired compound.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.02 (3H, d, J = 7.33 Hz), 1.09 (3H, d, J = 6.23 Hz), 2.
23 ~ 2.37 (1H, m), 2.94 ~ 3.27 (2H, m), 3.19 (3H, s),
3.30 (1H, dd, J = 6.23,2.94Hz), 3.45 to 3.93 (5H, m), 3.
96 ~ 4.13 (4H, m), 4.32 (1H, t, J = 8.24Hz) Example 33 (1R, 5S, 6S) -2-[(2S, 4S) -1,1-dimethyl-2-
Isopropylcarbamoylpyrrolidinium-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylate The target compound was obtained in the same manner as in Example 3 from (2S, 4S) -1,1-dimethyl-2-isopropylpropylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate.

Example 34 (1R, 5S, 6S) -2-[(2S, 4S) -2- (1-azetidinocarbonyl) -1,1-dimethylpyrrolidinium-4-
Ilthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapene-2-em-3-carboxylate (2S, 4S) -2- (1-azetidinocarbamoyl)-
The target compound was obtained in the same manner as in Example 3 from 1,1-dimethyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate.

Example 35 (1R, 5S, 6S) -2-[(2S, 4S) -1,1-dimethyl-2-
(2-fluoroethylcarbamoyl) pyrrolidinium-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylate (2S, 4S) -1,1-dimethyl-2- (2-fluoroethylcarbamoyl) -4- (4-methoxybenzylthio)
The target compound was obtained in the same manner as in Example 20 from pyrrolidinium fluorosulfonate.

Reference Example 1 (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) -1,1-dimethylpyrrolidinium fluorosulfonate (1) (2S, 4R) -1-tert-butoxycarbonyl-
4-Hydroxy-2-pyrrolidinecarboxylic acid Sodium hydroxide (27.3 g) was dissolved in water (380 ml),
Under ice cooling, (2S, 4R) -4-hydroxy-2-pyrrolidinecarboxylic acid (85 g) was added at 3 to 5 ° C. Tetrahydrofuran (570 ml) was added at the same temperature, and then di-tert-butoxycarbonate (141.5 g) in tetrahydrofuran (19
0 ml) was added at 3-5 ° C, followed by stirring at 50-55 ° C for 2 hours. The reaction solution was cooled, adjusted to pH 3 to 4 using conc. Hydrochloric acid, added with ammonium chloride, extracted with tetrahydrofuran, dried, and the solvent was distilled off to obtain the title compound (128 g) as a colorless powder.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.44 (9H, s), 1.96 to 2.45 (2H, m), 2.36 to 2.72 (2H,
m), 4.24 to 4.66 (2H, m), 5.04 to 5.60 (2H, brs) (2) (2S, 4R) -1-tert-butoxycarbonyl-
2-carbamoyl-4-hydroxypyrrolidine (2S, 4R) -1- (tert-butoxycarbonyl) -4
-Hydroxy-2-pyrrolidinecarboxylic acid (58 g) was dissolved in dry tetrahydrofuran (850 ml), triethylamine (38.2 ml) was added at -15 to -20 ° C, and then ethyl chloroformate (26.3 ml) in dry tetrahydrofuran (24 ml) was added.
0 ml) was added dropwise at -15 to -20 ° C. After stirring at the same temperature for 35 minutes, 28% aqueous ammonia (258 ml) was added at -15 to -20 ° C, and the mixture was left overnight at room temperature. Then, ammonium chloride was added, the mixture was extracted with tetrahydrofuran, dried, the solvent was distilled off, and the residue was crystallized by adding ether, followed by washing with excess ether to obtain the title compound as colorless crystals (49.7 g).

mp146-8 ° C. Nuclear magnetic resonance spectrum (60 MHz, DMSO-d ₆ ) δ ppm: 1.38 (9H, s), 1.65 to 2.24 (2H, m), 3.00 to 3.66 (2H,
m), 3.76 to 4.49 (3H, m), 6.78 (1H, br s), 7.23 (1H, br
s) (3) (2S, 4R) -1- (tert-butoxycarbonyl) -2-carbamoyl-4-methanesulfonyloxypyrrolidine (2S, 4R) -1- (tert-butoxycarbonyl) -2
-Carbamoyl-4-hydroxypyrrolidine (5.0 g) was dissolved in dry tetrahydrofuran (250 ml), methanesulfonyl chloride (1.85 ml) was added under ice cooling, and then triethylamine (3.31 ml) was added. After stirring at 0-5 ° C for 1 hour, brine was poured, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is subjected to chromatography using silica gel (developing agent).
Purification with ethyl acetate / methanol = 9/1) gave the title compound (5.5 g) as colorless crystals.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.43 (9H, s), 2.10 to 2.68 (2H, m), 3.12 (3H, s), 3.1
0 to 3.40 (1H, br s), 3.73 (2H, d, J = 4.0Hz), 4.32 (1H,
t, J = 7.0Hz), 5.26 (1H, t, J = 4.0Hz), 6.68 (1H, br
s), 7.30 (1H, brs) (4) (2S, 4S) -1- (tert-butoxycarbonyl) -2-carbamoyl-4- (4-methoxybenzylthio) pyrrolidine p-methoxybenzylmercaptan (1.18 g) ) Was dissolved in dry dimethylformamide (25 ml), 55% sodium hydride (330 mg) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. (2S, 4R) -1- (tert-butoxycarbonyl) -2-carbamoyl-4-methanesulfonyloxypyrrolidine (2.14 g) was added, and the mixture was stirred at room temperature for 3 hours.
The reaction solution was poured into saline and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate,
The solvent was distilled off. The residue was chromatographed on silica gel (developing agent cyclohexane / ethyl acetate = 2 /
Purification in 3) gave the title compound as an oil (1.94 g).

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.43 (9H, s), 1.80 to 3.42 (5H, m), 3.70 (2H, s), 3.7
8 (3H, s), 4.18 (1H, t, J = 7.0Hz), 5.96 (1H, brs), 6.
35 (1H, br s), 6.79,7.21 (4H, A 2 B 2, J = 9.0Hz) (5) -a (2S, 4S) -2- carbamoyl-4- (4
-Methoxybenzylthio) pyrrolidine (2S, 4R) -1- (tert-butoxycarbonyl) -2
-Carbamoyl-4- (4-methoxybenzylthio) pyrrolidine (1.92 g) was dissolved in ethyl acetate (25 ml), and a 4N solution of hydrogen chloride in dioxane (26.2 ml) was added under ice-cooling.
The mixture was stirred at ５5 ° C. for 2 hours and at room temperature for 30 minutes. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate to make it weakly alkaline, then extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound as a powder (1.36
g) was obtained.

mp 120-121 ° C. Nuclear magnetic resonance spectrum (60 MHz, DMSO-d ₆ ) δ ppm: 1.58 to 3.40 (7H, m), 1.67 (2H, s), 1.78 (3H, s), 6.4
3 (1H, br s), 6.78,7.22 (4H, A 2 B 2, J = 9.0Hz), 7.31 (1
H, brs) (5) -b (2S, 4S) -2-carbamoyl-4- (4
-Methoxybenzylthio) pyrrolidine hydrochloride (2S, 4S) -1-tert-butoxycarbonyl-2-carbamoyl-4- (4-methoxybenzylthio) pyrrolidine (91gg) was dissolved in ethyl acetate (2l) and cooled on ice. Lower 4N−
Ethyl hydrogen chloride solution (620 ml) was added, and the mixture was stirred at room temperature for 4.5 hours. The precipitate was collected, washed with diethyl ether and dried in vacuo to give the title compound (63 g).

mp192-195 ℃ Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.75 to 1.90 (1H, m), 2.54 to 2.62 (1H, m), 3.04 to 3.11
(1H, m), 3.28 to 3.41 (2H, m), 3.64 (2H, s), 3.65 (3H,
s), 4.22 (1H, t , J = 8.06Hz), 6.80,7.15 (4H, A 2 B 2, J =
8.79Hz) (6) -a (2S, 4S) -2-carbamoyl-4- (4
-Methoxybenzylthio) -1-methylpyrrolidine (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) pyrrolidine (0.6 g) was dissolved in dry dimethylformamide (4.5 ml), and dissolved in ice under ice-cooling. Methyl chloride (0.0
7 ml), and the mixture was stirred at 0 to 5 ° C for 5 minutes and at room temperature for 20 minutes.
The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified using a row bar column (Licroprep Si60, size B, manufactured by Merck) in ethyl acetate /
From the portion eluted with methanol = 9/1, the crystalline title compound (252 mg) having a mp. 113-114 ° C was obtained.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.58 to 3.36 (6H, m), 2.35 (3H, s), 3.68 (2H, s), 3.7
8 (3H, s), 5.95 (1H, br s), 6.84,7.23 (4H, A 2 B 2, J = 9.
0 Hz), 7.20 (1H, brs) (6) -b (2S, 4S) -2-carbamoyl-4- (4
-Methoxybenzylthio) -1-methylpyrrolidine The compound (1 g) obtained in Reference Example (5) b was suspended in acetonitrile (20 ml), and sodium hydrogen carbonate (0.29
g) was dissolved in water (3 ml) and added dropwise. Then, a 35% aqueous formaldehyde solution (0.34 ml) was added dropwise under ice cooling, and the mixture was stirred at 10 ° C. for 20 minutes, and sodium cyanoborohydride (0.25 ml) was added.
g) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Acetic acid (0.55 ml) was added dropwise to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 20 minutes, diluted with acetate (100 ml), and mixed with a 1N aqueous solution of sodium hydroxide: saturated saline 1: 1 and then. After washing with a saturated saline solution, the ethyl acetate layer was dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (Wako Gel C-100, manufactured by Wako Pure Chemical Industries, Ltd.), and the portion eluted with chloroform: methanol 95: 5 was the same as that obtained in Reference Example (6) a. The title compound (0.92 g) having mp, infrared absorption spectrum and nuclear magnetic resonance spectrum was obtained.

(7) (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) -1,1-dimethylpyrrolidinium fluorosulfonate (2S, 4S) -2-carbamoyl-4- (4-methoxybenzyl) Thio) -1-methylpyrrolidine (320 mg) was dissolved in dry methylene chloride (7 ml), methyl fluorosulfonate (0.123 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes and at room temperature for 2 hours. The solvent was distilled off, and the residue was washed with diethyl ether by repeating decantation and dried under reduced pressure to obtain the title compound (525 mg) as an oil.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 2.01 to 3.68 (5H, m), 3.02 (3H, s), 3.03 (3H, s), 3.6
5 (3H, s), 3.68 (2H, s), 4.07 (1H, dd, J = 7.70, 8.43H
z), 6.81,7.16 (4H, A 2 B 2, J = 8.79) REFERENCE EXAMPLE 2 (2S, 4S) -2- carbamoyl-4- (4-methoxybenzylthio) -1- (2-fluoroethyl) - 1-methylpyrrolidinium fluorosulfonate (1) (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) -1- (2-fluoroethyl) pyrrolidine (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) ) Pyrrolidine (1.2 g) was dissolved in dry dimethylformamide (12 ml), and the solution was cooled with ice to give 1-bromo-2-.
Add fluoroethane (0.4 ml), sodium iodide (3.83 g) and sodium hydrogen carbonate (0.38 g), and add
Stirred at 0 ° C. for 20 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, washed with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel chromatography (Silica Gel 60K070, manufactured by Katayama Chemical Industry Co., Ltd.) to extract the title compound (83
8 mg).

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.55 to 3.40 (8H, m), 3.69 (2H, s), 3.79 (3H, s), 4,4
7 (2H, td, J = 60,47.0Hz), 47.8 (1H, brs), 7.02 (4H, A
_{2 B 2, J = 9.0Hz)} , 6.95~7.50 (1H, br s) (2) (2S, 4S) -2- carbamoyl-4- (4-methoxybenzylthio) -1- (2-fluoroethyl) −
1-Methylpyridinium fluorosulfonate (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) -1- (2-fluoroethyl) pyrrolidine (630 mg) was dissolved in dry methylene chloride (12 ml). Then, methyl fluorosulfonate (0.17 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 5 hours. The solvent was distilled off, and the residue was washed with diethyl ether by repeating decantation and dried under reduced pressure to obtain the title compound as an oil (850 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O)) δ ppm: 1.84 to 4.73 (10H, m), 3.18 (3H, s), 3.65 (3H, s), 3.
68 (2H, s), 6.79-7.19 (4H, m) Reference Example 3 (2S, 4S) -1,1-dimethyl-2-methylcarbamoyl-
4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (1) (2S, 4R) -1- (tert-butoxycarbonyl) -2-methylcarbamoyl-4-hydroxypyrrolidine (2S, 4R) -1- (tert-butoxycarbonyl) -4
To a solution of -hydroxy-2-pyrrolidinecarboxylic acid (15.03 g) in dry tetrahydrofuran (250 ml) at -40 ° C was added triethylamine (9.91 ml), followed by a solution of ethyl chloroformate (6.82 ml) in dry tetrahydrofuran (30 ml). C. to -40.degree. C. and stirred at the same temperature for 1 hour. 40%
-Methylamine aqueous solution (16.82 ml) was added at -30 ° C, the temperature was gradually raised, and the reaction was carried out at room temperature for 1 hour. A small amount of saline was added, extracted three times with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the title compound (12.76 g) as a colorless oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.44 (9H, s), 1.89 to 2.45 (2H, m), 2.81 (3H, d, J = 5.
0Hz), 3.23 ~ 3.71 (3H, m), 4.12 ~ 4.68 (2H, m), 6.70
(1H, brs) (2) (2S, 4R) -1- (tert-butoxycarbonyl) -4-methanesulfonyloxy-2-methylcarbamoylpyrrolidine (2S, 4R) -1- (tert-butoxycarbonyl)- 2
-Methylcarbamoyl-4-hydroxypyrrolidine (1
1.29 g) in dry tetrahydrofuran (120 ml)
Under ice-cooling, triethylamine (7.11 ml) was added, and then methanesulfonyl chloride (3.93 ml) was added. 0-5 ° C
After stirring for 30 minutes at 15 ° C for 30 minutes,
The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the title compound as colorless crystals (11.58 g).

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.00 to 2.85 (2H, m), 2.81 (3H, d, J = 5.
0Hz), 3.03 (3H, s), 3.41 ~ 5.42 (4H, m), 6.75 (1H, br
s) (3) (2S, 4S) -1- (tert-butoxycarbonyl) -4- (4-methoxybenzylthio) -2-methylcarbamoylpyrrolidine 4-methoxybenzylmercaptan (5.70 ml) was dried in tetrahydrofuran (100 ml)
Under ice-cooling, 55% sodium hydride (1.80 g) was added, and the mixture was stirred at 0 to 5 ° C for 30 minutes. (2S, 4R) -1- (ter
A solution of (t-butoxycarbonyl) -4-methanesulfonyloxy-2-methylcarbamoylpyrrolidine (11.00 g) in dry dimethylformamide (80 ml) was added. At 34 ° C
After stirring for 4.5 hours, the reaction solution was poured into saline and extracted with ethyl acetate. The extract was washed with saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography on silica gel (eluent, ethyl acetate / n-hexane = 5/1) to give the title compound as an oil (4.35 g)
was gotten.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.42 (9H, s), 1.80 to 4.40 (6H, m), 2.81 (3H, d, J = 5.
0Hz), 3.70 (2H, s), 3.79 (3H, s), 6.39 (1H, br s), 6.
_{87,7.26 (4H, A 2 B 2} J = 9.0Hz) (4) (2S, 4S) -4- (4- methoxybenzyl) -2-methylcarbamoyl-pyrrolidine (2S, 4S) -1- (tert- Butoxycarbonyl) -4
-(4-Methoxybenzylthio) -2-methylcarbamoylpyrrolidine (4.00 g) was dissolved in ethyl acetate (50 ml), a 4N-hydrogen chloride dioxane solution (52.5 ml) was added under ice cooling, and the mixture was added at 0 to 5 ° C for 30 minutes. And stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate to make it slightly alkaline, and then extracted with ethyl acetate. The aqueous layer was further saturated with ammonium chloride and extracted with tetrahydrofuran. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is subjected to column chromatography using silica gel (developing agent ethyl acetate / methyl alcohol =
Purification by 5/1) gives the title compound as colorless crystals (2.34 g). Melting point 53-54 ° C. Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.42 to 3.89 (6H, m), 2.74 (3H, d, J = 5.0 Hz), 3.66 (2
H, s), 3.76 (3H , s), 6.79,7.17 (4H, A 2 B 2, J = 9.0Hz),
7.03 to 7.75 (2H, m) (5) (2S, 4S) -4- (4-methoxybenzylthio) -1-methyl-2-methylcarbamoylpyrrolidine (2S, 4S) -4- (4-methoxybenzylthio) ) -2
-Methylcarbamoylpyrrolidine (1.00 g) was dissolved in dry dimethylformamide (6 ml), methyl iodide (244 μl) and sodium hydrogen carbonate (300 mg) were added under ice-cooling, and the mixture was stirred at 0 to 5 ° C. for 1 hour, and then cooled to room temperature. And left overnight. The reaction solution was poured into brine, extracted with ethyl acetate, washed with brine,
It was dried over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is purified by column chromatography using silica gel (developing agent: ethyl acetate / methanol = 10/1) to obtain the title compound (222 mg) as colorless crystals.

82-84 ° C Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.45 to 3.91 (6H, m), 2.31 (3H, s), 2.80 (3H, d J = 5.
0Hz), 3.66 (2H, s), 3.77 (3H, s), 6.81,7.20 (4H, A ₂ B ₂
J = 9.0 Hz), 6.85-7.60 (1H, m) (6) (2S, 4S) -1,1-dimethyl-2-methylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (2S , 4S) -4- (4-Methoxybenzylthio) -1
-Methyl-2-methylcarbamoylpyrrolidine (210m
g) in dry dichloromethane (30 ml),
Methyl fluorosulfonate (280 μl) was added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 5 hours. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether and dried under reduced pressure to obtain the title compound (281 mg) as a colorless powder.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.95 to 2.43 (2H, m), 2.62 (3H, s), 2.61 to 3.88 (3H,
m), 3.03 (3H, s), 3.10 (3H, s), 3.65 (3H, s)), 3.68
(2H, s), 4.12 (1H, t, J = 8.06Hz), 6.83,7.12 (4H, A ₂ B ₂
J = 8.61 Hz) Reference Example 4 (2S, 4S) -1,1-dimethyl-2- (N, N-dimethylcarbamoyl) -4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (1) (2S, 4R) -1- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) -4-hydroxypyrrolidine (2S, 4R) -1- (tert-butoxycarbonyl) -4
-Hydroxy-2-pyrrolidinecarboxylic acid (5.8 g) was dissolved in dry tetrahydrofuran (85 ml), triethylamine (3.84 ml) was added at -15 to -20 ° C, and then ethyl chloroformate (2.63 ml) in dry tetrahydrofuran (25 ml). )
Was added at the same temperature, and the mixture was stirred for 2 hours. 50% dimethylamine (19.75 ml) was added at -20 to -25 ° C, and the mixture was stirred under ice-cooling for 3 hours and left at room temperature overnight. The reaction solution was poured into concentrated hydrochloric acid (30 ml) and ice, extracted with ethyl acetate, washed with brine, and dried. The solvent was distilled off, and the residue was purified by column chromatography using silica gel (developing agent: ethyl acetate / methanol = 9/1) to obtain 429 mg of the title compound.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.42 (9H, s), 1.86 to 2.34 (2H, s), 2.58 to 2.95 (1H,
m), 2.97 (3H, s), 3.10 (3H, s), 3.43-3.74 (2H, m),
4.36 to 5.00 (2H, m) (2) (2S, 4R) -1- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) -4-methanesulfonyloxypyrrolidine (2S, 4R) -1 -(Tert-butoxycarbonyl) -2
-(N, N-dimethylcarbamoyl) -4-hydroxypyrrolidine (993 mg) in dry tetrahydrofuran (20 ml)
Methanesulfonyl chloride (297μ)
l) was added, followed by triethylamine (537 μl). After stirring at 0 to 5 ° C for 1 hour and at room temperature for 1 hour, the mixture was treated and purified in the same manner as in Reference Example 1- (3) to give the title compound (1.05 g) as a colorless oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.43 (9H, s), 2.15 to 2.60 (2H, m), 2.97 (3H, s), 3.0
7 (3H, s), 3.10 and 3.13 (3H, s), 3.83 (2H, d, J = 4.0H
z), 4.63-5.03 (1H, m), 5.15-5.46 (1H, m) (3) (2S, 4S) -1- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) -4 − (4
-Methoxybenzylthio) pyrrolidine 4-methoxybenzylmercaptan (532 mg) was dissolved in dry dimethylformamide (10 ml), and 55% under ice-cooling.
Sodium hydride (151 mg) was added, and the mixture was stirred at room temperature for 30 minutes. (2S, 4R) -1- (tert-butoxycarbonyl)-
2- (N, N-dimethylcarbamoyl) -4-methanesulfonyloxypyrrolidine (1.05 g) was added, and the mixture was added at room temperature for 30 minutes.
And stirred at 40 ° C. for 6 minutes. The reaction solution was treated and purified in the same manner as in Reference Example 1 (4) to give the title compound (385 g) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.35 & 1.38 (9H, s), 1.55-3.37 (5H, m), 2.93 (3H,
s), 3.00 (3H, s), 3.68 (2H, s), 3.77 (3H, s), 4.30 ~
4.75 (1H, m), 6.85,7.25 (4H, A 2 B 2, J = 9.0Hz) (4) (2S, 4S) -2- (N, N- dimethylcarbamoyl) -4- (4-methoxybenzyl Thio) pyrrolidine (2S, 4S) -1- (tert-butoxycarbonyl) -2
-(N, N-dimethylcarbamoyl) -4- (4-methoxybenzylthio) pyrrolidine (385 mg) was added to ethyl acetate (1
4N hydrogen dioxane solution (1m2) under ice-cooling.
l) was added and stirred at room temperature for 1.5 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate to make it weakly alkaline, then extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography using silica gel (developing agent: ethyl acetate / methanol = 1/2) to obtain the title compound (163 g) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.21 to 1.78 (2H, m), 2.09 to 3.98 (5H, m), 2.94 (6H,
s), 3.64 (2H, s), 3.74 (3H, s), 6.81,7.21 (4H, A ₂ B ₂ , J
= 9.0Hz) (5) (2S, 4S) -2- (N, N-dimethylcarbamoyl) -4- (4-methoxybenzylthio) -methylpyrrolidine (2S, 4S) -2- (N, N-dimethyl) Carbamoyl) -4
-(4-methoxybenzylthio) pyrrolidine (163 mg)
Was dissolved in dry dimethylformamide (1.5 ml), and sodium hydrogen carbonate (84 mg) and methyl iodide (41 µm) were added under ice-cooling.
l) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Distill off the solvent,
The residue was transferred to a rover column (Merck Licroprep Si6).
Using 0, size A), the title compound (45 mg) was obtained as an oil from the portion eluted with ethyl acetate / methanol = 3/1.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.56 to 2.18 (2H, m), 2.20 to 3.60 (4H, m), 2.34 (3H,
s), 2.96 (3H, s), 3.10 (3H, s), 3.70 (2H, s), 3.78 (3
H, s), 6.82,7.22 (4H , A 2 B 2, J = 9.0Hz) (6) 1- (tert- butoxycarbonyl) -4-hydroxy proline methyl ester 1-(tert-butoxycarbonyl) -4- Hydroxyproline (11.5g) is dried in dimethylformamide (100m
l) and 55% sodium hydride (2.2 g)
C. and stirred at room temperature for 1.5 hours. The mixture was cooled again at 0 to 5 ° C, methyl iodide (3.42 ml) was added, and the mixture was left overnight at room temperature. The reaction solution was poured into saturated saline and extracted with ethyl acetate.
Washed and dried. The solvent was distilled off, and the residue was purified by column chromatography using silica gel (developing agent: benzene / ethyl acetate = 1/1) to obtain the title compound (6.1 g) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.41 (9H, s), 1.78 to 2.84 (3H, m), 3.58 (2H, d, J = 4.
0 Hz), 3.71 (3H, s), 4.18 to 4.62 (2H, m) (7) (2S, 4R) -1- (tert-butoxycarbonyl) -4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine 1- ( (tert-Butoxycarbonyl) -4-hydroxyproline methyl ester (6.1 g) was dissolved in dry tetrahydrofuran (120 ml), methanesulfonyl chloride (2.02 ml) was added under ice cooling, and then triethylamine (3.
65 ml) was added. After stirring at 0 to 5 ° C. for 1 hour and at room temperature for 1 hour, brine was poured, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the title compound (8.13 g) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.47 (9H, s), 1.74 to 2.85 (2H, m), 3.08 (3H, s), 3.7
9 (3H, s), 3.81 (2H, d, J = 4.0Hz), 4.15-4.65 (1H,
m), 5.12-5.41 (1H, m) (8) (2S, 4S) -1- (tert-butoxycarbonyl) -4- (4-methoxybenzylthio) -2-methoxycarbonylpyrrolidine 4-methoxybenzylmercaptan ( 3.51 ml) dry dimethylformamide (60 ml)
And 55% sodium hydride (1.11 g) was added thereto under ice-cooling, followed by stirring at room temperature for 30 minutes. (2S, 4R) -1- (tert-
(Butoxycarbonyl) -4-methanesulfonyloxy-
A solution of 2-methoxycarbonylpyrrolidine (8.13 g) in dry dimethylformamide (20 ml) was added dropwise, and the solution was added at room temperature for 15 minutes.
And stirred at 40 ° C. for 4 hours. The reaction solution was poured into saline, extracted with ethyl acetate, washed with water and dried, and the solvent was distilled off. The residue is purified by column chromatography on silica gel (developing agent: benzene / ethyl acetate = 15/1) to give the title compound (6.849) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.40 (9H, s), 1.71 to 3.48 (5H, m), 3.71 (3H, s), 3.7
8 (2H, s), 4.01 ~ 4.45 (1H, m), 6.85,7.25 (4H, A ₂ B ₂ , J
= 9.0 Hz) (9) (2S, 4S) -4- (4-methoxybenzylthio) -2-methoxycarbonylpyrrolidine (2S, 4S) -1- (tert-butoxycarbonyl) -4
-(4-Methoxybenzylthio) -2-methoxycarbonylpyrrolidine (5.22 g) was dissolved in ethyl acetate (14 ml), and 4N hydrogen chloride ethyl acetate (27.3 ml) was added under ice-cooling.
Stirred at room temperature for 1 hour. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the title compound (3.3 g) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.56 to 3.32 (6H, m), 3.67 (2H, s), 3.72 (3H, s) 3.78
(3H, s), 3.70 to 3.99 (1H, m) (10) (2S, 4S) -4- (4-methoxybenzylthio) 2-methoxycarbonyl-1-methylpyrrolidine (2S, 4S) -4- ( 4-methoxybenzylthio) -2
-Methoxycarbonylpyrrolidine (3.3 g) was dissolved in dry dimethylformamide (30 ml), and sodium hydrogen carbonate (1.18 g) and methyl iodide (0.876 ml) were added under ice-cooling.
Stirred at room temperature for 5 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography using silica gel (developing agent: ethyl acetate / benzene = 1/2) to give the title compound (968 mg) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.64 to 3.34 (6H, m), 2.37 (3H, s), 3.70 (2H, s), 3.8
1 (3H, s), 3.88 (3H, s), 6.83,7.23 (4H, A ₂ B ₂ J = 9.0H
z) (11) (2S, 4S) -2- (N, N-dimethylcarbamoyl) -4- (4-methoxybenzylthio) -1-methylpyrrolidine (2S, 4S) -4- (4-methoxybenzylthio) ) -2
-Methoxycarbonyl-1-methylpyrrolidine (378m
g) was dissolved in methanol (3.84 ml), 1N sodium hydroxide (1.92 ml) was added, and the mixture was stirred at room temperature for 3 hours. Reaction solution
The mixture was neutralized with 1N hydrochloric acid (1.92 ml), the solvent was distilled off, and the residue was dried to obtain crude (2S, 4S) -2-carboxy-4- (4-methoxybenzylthio) -1-methylpyrrolidine. . This was suspended in acetonitrile (7.3 ml), N, N'-carbonyldiimidazole (318 mg) was added, and the mixture was stirred at 40 ° C for 1 hour. After returning to room temperature, a solution of dimethylamyl (559 mg) in tetrahydrofuran (3.7 ml) was added, and the mixture was allowed to stand at room temperature overnight. The solvent and excess dimethylamine were distilled off, brine was added to the residue, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was used in Reference Example 4
Purification in the same manner as (5) gives the title compound as an oil (382 mg)
was gotten.

(12) (2S, 4S) -2- (N, N-dimethylcarbamoyl) -4- (4-methoxybenzylthio) -1,1-dimethylpyrrolidinium fluorosulfonate (2S, 4S) -2- (N , N-Dimethylcarbamoyl) -4
-(4-Methoxybenzylthio) -1-methylpyrrolidine (190 mg) was dissolved in methylene chloride (3.8 ml), and methyl fluorosulfonate (139 µl) was added under ice-cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off, and the residue was washed with hexane by repeating decantation, and dried under reduced pressure to obtain the title compound (356 mg) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, D ₂ O) δ ppm: 1.58 to 4.58 (12H, m), 3.07 (6H, s), 3.84 (3H, s), 3.
90 (2H, s), 6.90,7.25 (4H, A 2 B 2, J = 9.0Hz) Reference Example 5 (3S) -1,1-dimethyl-3- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (1) (3R) -1-tert-butoxycarbonyl-3-
Methanesulfonyloxypyrrolidine (3R) -1-tert-butoxycarbonyl-3-hydroxypyrrolidine (25 g) was added to dry tetrahydrofuran (250 g).
ml), and triethylamine (16.91 ml) was added under ice cooling, and then methanesulfonyl chloride (9.36 ml) was added. After stirring at 0 to 5 ° C for 30 minutes and at 15 ° C for 30 minutes,
Brine was poured, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Removal of the solvent gave the title compound (31.0 g) as a colorless oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.48 (9H, s), 1.91 to 2.45 (2H, m), 3.04 (3H, s), 3.2
6 to 3.82 (4H, m), 6.1 to 6.44 (1H, m) (2) (3S) -1-tert-butoxycarbonyl-3-
(4-Methoxybenzylthio) pyrrolidine 4-methoxybenzylmercaptan (16.86 ml) was dissolved in dry dimethylformamide (200 ml), and the solution was dissolved under ice cooling.
% Sodium hydride (5.32 g) was added and the mixture was stirred at room temperature for 30 minutes. A solution of (3R) -1-tert-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (31.00 g) in dry dimethylformamide (50 ml) was added. After stirring for 30 minutes under ice cooling, the mixture was left overnight at room temperature. The reaction solution was poured into brine, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography using silica gel (developing agent, n-hexane / ethyl acetate = 5/1) to give the title compound (28.00) as a pale brown oil.
g) was obtained.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.50-2.35 (2H, m), 2.81-3.88 (5H,
m), 3,70 (2H, s), 3.79 (3H, s), 6.83,7.27 (4H, A ₂ B ₂ , J
= 9.0 Hz) (3) (3S) -3- (4-methoxybenzylthio) pyrrolidine hydrochloride (3S) -1-tert-butoxycarbonyl-3- (4-
(Methoxybenzylthio) pyrrolidine (27.50 g) was dissolved in ethyl acetate (100 ml), 4N-hydrogen chloride in ethyl acetate (106 ml) was added under ice cooling, and the mixture was stirred at 0 to 5 ° C. for 30 minutes and at 25 ° C. for 2 hours. . The mixture was diluted with diisopropyl ether (200 ml), and the precipitated crystals were filtered to give the title compound (20.84 g) as colorless crystals. 125-126 ° C Nuclear magnetic resonance spectrum (60 MHz, D ₂ O) δ ppm: 1.52 to 2.53 (2H, m), 2.91 to 3.70 (5H, m), 3.63 (2H,
s), 3.67 (3H, s ), 6.80,7.16 (4H, A 2 B 2, J = 9.0Hz) (4) (3S) -3- (4- methoxybenzylthio) -
1-Methylpyrrolidine (3S) -3- (4-methoxybenzylthio) pyrrolidine hydrochloride (900 mg) was obtained by neutralizing with sodium hydrogen carbonate. (3S) -3-p-methoxybenzylthiopyrrolidine (750 mg) was dissolved in dry acetonitrile (15 ml), and a 35% formaldehyde solution (1.44 ml) was added at room temperature. Subsequently, sodium cyanoborohydride (338 mg) was added, and the mixture was stirred for 15 minutes, and then neutralized with acetic acid, and further stirred for 2.5 hours. The reaction solution was poured into ethyl acetate (200 ml), washed with a 2N aqueous solution of potassium hydroxide and brine, dried over potassium carbonate, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (developing agent ethyl acetate / methyl alcohol = 3 /
Purification in 1) gave the title compound (349 mg) as a colorless oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.40 to 3.49 (7H, m), 2.33 (3H, s), 3.69 (2H, s), 3.7
8 (3H, s), 6.86,7.25 (4H, A 2 B 2 J = 9.0Hz) (5) (3S) -1,1- dimethyl-3- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (3S) -3- (4-Methoxybenzylthio) -1-methylpyrrolidine (340 mg) was added to dry dichloromethane (20 m
l) and melt under ice-cooling with methyl fluorosulfonate (118
μl) and stirred at the same temperature for 30 minutes and at room temperature for 3.5 hours.
The solvent was distilled off, the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure to obtain the title compound (500 mg) as a colorless powder.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.86 to 2.05 (1H, m), 2.34 to 2.56 (1H, m), 2.90 (3H,
s), 3.01 (3H, s), 2.98 ~ 3.73 (5H, m), 3.65 (3H, s),
3.67 (2H, s), 6.82,7.17 (4H, A 2 B 2, J = 8.62Hz) Referential Example 6 1,1-dimethyl-4- (4-methoxybenzylthio) piperidinium fluorosulfonate (1) 4-Methanesulfonyloxy-1-methylpiperidine 4-Hydroxy-1-methylpiperidine (10 g) was dissolved in dry tetrahydrofuran (100 ml), triethylamine (13.3 ml) was added under ice cooling, and then methanesulfonyl chloride ( 7.4 ml) was added. After stirring at 0 to 5 ° C for 2 hours and further at room temperature for 1.5 hours, the mixture was poured into brine, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the title compound (12.74 g) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.74 to 2.90 (8H, m), 2.28 (3H, s), 3.00 (3H, s), 4.7
3 (1H, m) (2) 4- (4-Methoxybenzylthio) -1-methylpiperidine 4-methoxybenzylmercaptan (10.9 ml) was dissolved in dry dimethylformamide (55 ml), and 55% hydrogenated under ice cooling. Sodium (3.4 g) was added, and the mixture was stirred at room temperature for 30 minutes.
A solution of 4-methanesulfonyloxy-1-methylpiperidine (12.6 g) in dry dimethylformamide (63 ml) was added. After stirring for 30 minutes under ice cooling, the mixture was left overnight at room temperature. The reaction solution was poured into brine, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (developing agent,
Purification with ethyl acetate / methanol = 1/4) gave the title compound (9.01 g) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.40 to 3.05 (9H, m), 1.23 (3H, s), 3.69 (2H, s), 3.7
8 (3H, s), 6.82,7.23 (4H, A 2 B 2, J = 9.0Hz) (3) 1,1- dimethyl-4- (4-methoxybenzylthio) piperidinium fluorosulfonate 4- (4-methoxy (Benzylthio) -1-methylpiperidine (8.95 g) was dissolved in dry methylene chloride (300 ml), methyl fluorosulfonate (2.9 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes and at room temperature for 2.5 hours. The solvent was distilled off, the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure to obtain the title compound (12.76 g) as a colorless powder.

Nuclear magnetic resonance spectrum (270 MHz, DMSO-d ₆ ) δ ppm: 1.75 to 1.93 (2H, m), 2.02 to 2.15 (2H, m), 2.80 to 2.84
(1H, m), 3.05 (3H, s), 3.06 (3H, s), 3.24 ~ 3.97 (4H,
m), 3.74 (3H, s ), 3.78 (2H, s), 6.88,7.26 (4H, A 2 B 2, J
Reference Example 7 (2S, 4S) -2- (NN-dimethylcarbamoyl) -1-
Ethyl-1-methyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (1) (2S, 4S) -1-ethyl-4- (4-methoxybenzylthio) -2-methoxycarbonylpyrrolidine (2S, 4S) -4- (4-methoxy) obtained in Reference Example 4 (9) (Benzylthio) -2-methoxycarbonylpyrrolidine (1.2 g) was dissolved in dry dimethylformamide (12 ml), and sodium hydrogen carbonate (358 mg) and ethyl iodide (0.41 ml) were added thereto under ice-cooling. 3 at 45-50 ℃
Stirred for hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography using silica gel (developing agent: ethyl acetate / benzene = 1/4) to give the title compound as an oil (904 mg)
was gotten.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.03 (3H, t, J = 7.0 Hz), 2.72 to 3.43 (H, m), 3.70 (5
H, s), 3.78 (3H , s), 6.84,7.25 (4H, A 2 B 2, J = 9.0Hz) (2) (2S, 4S) -2- (N, N- dimethylcarbamoyl) -1- Ethyl-4- (4-methoxybenzylthio)
Pyrrolidine (2S, 4S) -1-ethyl-4-((4-methoxybenzylthio) -2-methoxycarbonylpyrrolidine (883m
g) was dissolved in methanol (8.6 ml), 1N-sodium hydroxide (4.3 ml) was added, and the mixture was stirred at room temperature for 2 hours. 1N-hydrochloric acid (4.3 ml) was added for neutralization, and the reaction solution was concentrated under reduced pressure.
To dryness.

The obtained crude product was suspended in dry acetonitrile (18 ml), N, N'-carbonyldiimidazole (694 mg) was added, the mixture was stirred at 40 ° C for 1 hour, and dimethylamine (1.89 ml) was added.
Of tetrahydrofuran (10 ml) was added. The reaction solution was left at room temperature overnight, and then concentrated under reduced pressure. Brine was added to the residue, extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was eluted with a row bar column (manufactured by Merck, Licroprep Si60, size B) with ethyl acetate / methanol = 10/1 to obtain the title compound (795 mg) as an oil. .

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.01 (3H, t, J = 7.0 Hz), 1,57 to 3.73 (8H, m), 2.91 (3
H, s), 3.16 (3H, s), 3.70 (2H, s), 3.78 (3H, s), 6.83,
_{7.27 (4H, A 2 B 2} , J = 9.0Hz) (3) (2S, 4S) -2- (N, N- dimethylcarbamoyl) -1-ethyl-1-methyl-4- (4-methoxybenzylthio ) Pyrrolidinium fluorosulfonate (2S, 4S) -2- (N, N-dimethylcarbamoyl) -1
-Ethyl-4- (4-methoxybenzylthio) pyrrolidine (438 mg) was dissolved in methylene chloride (10 ml), and methyl fluorosulfonate (128 µl) was added under ice-cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure to obtain the title compound as an oil.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.12 (3H, t, J = 7.15 Hz), 196 to 2.08 (1H, m), 2.62 to
3.51 (6H, m), 2.79 (3H, s), 2.93 (3H, s), 2.95 (3H,
s), 3.65 ((3H, s), 3.68 (2H, s), 4.55 to 4.60 (1 H, m)) Reference Example 8 (2S, 4S) -1,1-dimethyl-4- (4-methoxybenzylthio) -2- (4-morpholinocarbonyl) pyrrolidinium fluorosulfonate (1) (2S, 4S) -4- (4-methoxybenzylthio) -2-methoxycarbonyl-1-methylpyrrolidine (2S, 4S) -4- (4-methoxy) obtained in Reference Example 4 (9) (Benzylthio) -2-methoxycarbonylpyrrolidine (2.25 g) was dissolved in acetonitrile (42 ml), 35% formalin (3.43 ml) was added at room temperature, and sodium cyanoborohydride (804 mg) was added three times for about 5 minutes. And stirred at room temperature for 30 minutes. The reaction solution was cooled on ice, acetic acid (1.3 ml) was added, and the mixture was stirred at room temperature for 40 minutes. 1N-Sodium hydroxide (40 ml) and brine were added to the reaction solution, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate.
The solvent was distilled off, and the residue was purified in the same manner as in Reference Example 4 (10) to give the title compound (1.31 g) as an oil. This was in agreement with that obtained in Reference Example 4 (10) by infrared absorption spectrum, nuclear magnetic resonance spectrum, and thin-layer chromatography.

(2) (2S, 4S) -4- (4-methoxybenzylthio) -1-methyl-2- (4-morpholinocarbonyl)
Pyrrolidine (2S, 4S) -4- (4-methoxybenzylthio) -2
-Methoxycarbonyl-1-methylpyrrolidine (1.31
g) was dissolved in methanol (11 ml), 1N sodium hydroxide (5.32 ml) was added, and the mixture was stirred at room temperature for 2 hours. Reaction solution
The mixture was neutralized with 1N hydrochloric acid (5.32 ml), the solvent was distilled off, and the residue was dried. Crude (2S, 4S) -2-carboxy-4- (4-methoxybenzylthio) -1-methylpyrrolidine (1.5 g) ) Got. This (500 mg) was suspended in acetonitrile (10 ml), N, N'-carbonyldiimidazole (278 mg) was added, and the mixture was stirred at 40 ° C for 1 hour. The mixture was returned to room temperature, morpholine (187 μl) was added, the mixture was stirred at room temperature for 2 hours, and left overnight. The solvent and excess morpholine were distilled off, and the residue was added with brine, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was eluted with cyclohexane / ethyl acetate / methanol = 3/1/1 using a rover column (Licroprep Si60, size B, Merck) to obtain the title compound (418 mg) as an oil. Was done.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.50 to 3.33 (6H, m), 2.31 (3H, s), 3.64 (8H, br
s), 3.70 (2H, s ), 3.78 (3H, s), 6.82,7.21 (4H, A 2 B 2,
J = 9.0 Hz) (2) (2S, 4S) -1,1-dimethyl-4- (4-methoxybenzylthio) -2- (4-morpholinocarbonyl)
Pyrrolidinium fluorosulfonate (2S, 4S) -4- (4-methoxybenzylthio) -1
-Methyl-2- (4-morpholinocarbonyl) pyrrolidine (392 mg) was dissolved in methylene chloride (8 ml), and the mixture was cooled with ice.
Methyl fluorosulfonate (106 μl) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure to obtain the title compound (446 mg) as an oil.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.80 to 2.03 (1H, m), 2.67 to 3.90 (12H, m), 2.98 (3H,
s), 3.07 (3H, s), 3.65 (3H, s), 3.68 (2H, s), 4.61 (1
H, dd, J = 8.06,6.23Hz), 6.82,7.17 (4H, A ₂ B ₂ , J = 8.61H
z) Reference Example 9 (2S, 4S) -1,1-dimethyl-4- (4-methoxybenzylthio) -2- (1-pyrrolidinocarbonyl) pyrrolidinium fluorosulfonate (1) (2S, 4S) -4- (4-methoxybenzylthio) -1-methyl-2- (1-pyrrolidinocarbonyl)
Pyrrolidine Crude (2S, 4S) -2-carboxy-4- (4-methoxybenzylthio) -1-methylpyrrolidine (500 mg) obtained in Reference Example 8 (2), N, N'-carbonyldimidazole (278 mg) ), Pyrrolidine (178 μl) instead of morpholine
Was used for the reaction, treatment and purification in the same manner as in Reference Example 8 (2) to give the title compound (440 mg).

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.58 to 2.78 (6H, m), 2.30 (3H, s), 2.90 to 3.80 (8H,
m), 3.70 (2H, s ), 3.78 (3H, s), 6.84,7.24 (4H, A 2 B 2, J
= 9.0Hz) (3) (2S, 4S) -1,1-dimethyl-4- (4-methoxybenzylthio) -2- (1-pyrrolidinocarbonyl)
Pyrrolidinium fluorosulfonate (2S, 4S) -4- (4-methoxybenzylthio) -1
-Methyl-2- (1-pyrrolidinocarbonyl) pyrrolidine (418 mg) and methyl fluorosulfonate (118 µl) were reacted, treated and purified in the same manner as in Reference Example 8 (3) to give the title compound as an oil (472 mg). Was.

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.68 to 1.85 (4H, m), 1.94 to 2.10 (1H, m), 2.69 to 3.85
(7H, m), 2.99 (3H, s), 3.03 (3H, s), 3.65 (3H, s), 3.
67 (2H, s), 4.41 (1H, dd, J = 8.06,6.60Hz), 6.81,7.17
(4H, A ₂ B ₂ , J = 8.62 Hz) Reference Example 10 (2S, 4S) -2-carbamoyl-4-p-methoxybenzylthio-1-ethyl-1-methylpyrrolidinium
Fluorosulfonate (1) (2S, 4S) -2-carbamoyl-1-ethyl-
4- (4-Methoxybenzylthio) pyrrolidine (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) pyrrolidine (1000 mg) was dissolved in dry dimethylformamide (10 ml), and the solution was iodinated under ice-cooling. Ethyl (0.362 ml) and sodium hydrogen carbonate (315 mg) were added, and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (Katayama Chemical Industries, silica gel 60K070) to obtain the crystalline title compound (560 mg) from the portion eluted with ethyl acetate.

mp124-125 ℃ Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ + D ₂ O) δ ppm: 1.08 (3H, t, J = 7.33), 1.86 to 1.96 (1H, m), 2.38 to 2.
76 (4H, m), 3.99 to 3.18 (3H, m), 3.70 (2H, s), 3.80 (3
H, s), 6.84,7.21 (4H , A 2 B 2, J = 8.79Hz) (2) (2S, 4S) -2- carbamoyl -4-p-methoxybenzyl-thio-1-ethyl-1-methyl - Pyrrolidinium fluorosulfonate (2S, 4S) -carbamoyl-4-p-methoxybenzylthio-1-ethylpyrrolidine (1.44 g) was dissolved in dry methylene chloride (30 ml), and methyl fluorosulfonate (0.43 ml) was cooled on ice. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was washed with diethyl ether by repeating decantation and dried under reduced pressure to obtain an oily target compound (2.0 g).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.12 (3H, t, J = 7.33), 2.06 to 2.18 (1H, m), 2.63 to 3.
83 (6H, m), 2.92 (3H, s), 3.64 (3H, s), 3.65 (2H, s),
4.02~4.09 (1H, m), 6.82,7.16 (4H, A 2 B 2, J = 8.42Hz) Reference Example 11 (2S, 4S) -2- ethyl-1-ethyl -
1-methyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (1) (2S, 4R) -1-tert-butoxycarbonyl-
To a solution of 2-ethylcarbamoyl-4-hydroxypyrrolidine (2S, 4R) -1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylic acid (23.13 g) in dry tetrahydrofuran (350 ml) at -25 ° C was added triethylamine (15.25). ml), and a solution of ethyl chloroformate (10.48 ml) in dry tetrahydrofuran (50 ml) was added at −25 ° C., followed by stirring at the same temperature for 30 minutes. A 70% ethylamine aqueous solution (24.15 ml) was added at -22 ° C, and the temperature was gradually raised.
The reaction was completed when the temperature rose to 0 ° C. A small amount of saline was added, extracted three times with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the title compound (23.60 g) as a colorless oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.10 (3H, t, J = 7.5 Hz), 1.44 (9H, s), 1.80 to 4.65 (1
0H, m), 6.64 (1H, brs) (2) (2S, 4R) -1-tert-butoxycarbonyl-
2-ethylcarbamoyl-4-methanesulfonyloxypyrrolidine (2S, 4R) -1-tert-butoxycarbonyl-2-ethylcarbamoyl-4-hydroxypyrrolidine (23.20
g) was dissolved in dry tetrahydrofuran (250 ml), and triethylamine (13.81 ml) was added under ice cooling, and then methanesulfonyl chloride (7.65 ml) was added. At 0-5 ° C
After stirring for 30 minutes, brine was poured, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the title compound as colorless crystals (26.54 g).

mp 138 ~ 140 ℃ Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.12 (3H, t, J = 7.5 Hz), 1,48 (9H, s), 2.05 to 4.59 (7
H, m), 3.03 (3H, s), 5.07 ~ 5.43 (1H, m), 6.58 (1H, br
s) (3) (2S, 4S) -1-tert-butoxycarbonyl-
2-Ethylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidine 4-methoxybenzylmercaptan (11.31 ml) was dissolved in dry dimethylformamide (150 ml), and cooled under ice-cooling.
5% sodium hydroxide (3.57 g) was added, and the mixture was stirred at 0 to 5 ° C for 30 minutes. (2S, 4R) -1-tert-butoxycarbonyl-
2-Ethylcarbamoyl-4-methanesulfonyloxypyrrolidine (26.00 g) in dry dimethylformamide (10
0 ml) solution was added. After stirring at room temperature for 2 hours, the reaction solution was poured into saline and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography using silica gel (developing agent, n-hexane / ethyl acetate = 1/1) to give the title compound (17.00 g) as colorless crystals.

mp 92-94 ° C Nuclear magnetic resonance spectrum (60 Hz, CDCl ₃ ) δ ppm: 1.10 (3H, t, J = 7.5 Hz), 1.43 (9H, s), 1.85 to 3.96 (7
H, m), 3.69 (2H, s), 3.78 (3H, s), 4.18 (1H, t, J = 7.5H
z), 6.35 (1H, br s), 6.86,7.24 (4H, A 2 B 2, J = 9.0Hz) (4) (2S, 4S) -2- ethylcarbamoyl-4-
(4-methoxybenzylthio) pyrrolidine (2S, 4S) -1-tert-butoxycarbonyl-2-ethylcarbamoyl-4- (4-methoxybenzylthio)
Pyrrolidine (13.00 g) is dissolved in ethyl acetate (100 ml) and, under ice-cooling, 4N-ethyl acetate solution of hydrogen chloride (41.19 ml)
Was added and stirred at room temperature for 3 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Further, the aqueous layer was extracted with tetrahydrofuran saturated with ammonium chloride. After the extract was washed with saline and dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue is purified by column chromatography using silica gel (developing agent: ethyl acetate / methyl alcohol = 87/13) to give the title compound (8.00 g) as pale brown crystals.

mp.67-68 ℃ Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.10 (3H, t, J = 7.5 Hz), 1.50 to 2.20 (1H, m), 2.16 (1
H, s), 2.23 to 3.96 (7H, m), 3.69 (2H, s), 3.78 (3H,
s), 6.86,7.25 (4H, A 2 B 2, J = 9.0Hz), 7.53 (1H, br s) (5) (2S, 4S) -2- ethyl-1-ethyl-4- (4- (Methoxybenzylthio) pyrrolidine (2S, 4S) -2-Ethylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidine (1.00 g) was dissolved in dry dimethylformamide (8 ml), and ethyl iodide (301 μl) was added under ice-cooling. ) And sodium hydrogen carbonate (314 mg) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into brine, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is purified by column chromatography using silica gel (developing agent: ethyl acetate) to give the title compound (982 mg) as colorless crystals.

mp.60 ~ 61 ℃ Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.06 (3H, t, J = 7.5 Hz), 1.14 (3H, t, J = 7.5 Hz), 1.56
~ 3.90 (10H, m), 3.69 (2H, s), 3.80 (3H, s), 6.82,7.2
_{0 (4H, A 2 B 2} , J = 9.0Hz), 7.30 (1H, br s) (6) (2S, 4S) -2- ethyl-1-ethyl-1-methyl-4- (4-methoxy Benzylthio)
Pyrrolidinium fluorosulfonate (2S, 4S) -2-ethylcarbamoyl-1-ethyl-
4- (4-methoxybenzylthio) pyrrolidine (910 m
g) in dry dichloromethane (35 ml),
Add methyl fluorosulfonate (233 μl) and add
Stir for 3.5 hours. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure to give the target compound as a pale brown oil (1.20 g).
I got

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.93 (3H, t, J = 7.33 Hz), 1.12 (3H, t, J = 7.33 Hz), 1.
95 ~ 2.26 (1H, m), 2.56 ~ 4.50 (9H, m), 2.88 (3H, s),
3.65 (3H, s), 3.69 (2H, s), 6.83,7.18 (4H, A 2 B 2 J = 8.
Reference Example 12 (2S, 4S) -1-ethyl-1-methyl-2-methylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (1) (2S, 4S) -1-ethyl-4- (4-methoxybenzylthio) -2-methylcarbamoylpyrrolidine (2S, 4S) -4- (4-methoxybenzylthio) -2
-Methylcarbamoylpyrrolidine (2.25 g) was dissolved in dry dimethylformamide (20 ml), and ethyl iodide (0.71 ml) and sodium hydrogen carbonate (742 mg) were added thereto under ice-cooling, and the mixture was added at 0 to 5 ° C for 1 hour and further at room temperature. Stir for 5 hours. The reaction solution was poured into brine, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is subjected to column chromatography using silica gel (developing agent).
Purification with ethyl acetate) gave the title compound (1.87) as colorless crystals.
g) is obtained.

mp.68 ~ 70 ℃ Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.02 (3H, t, J = 7.0 Hz), 1.58 to 3.91 (8H, m), 2.80 (3
H, d, J = 5.0Hz), 3.67 (2H, s), 3.78 (3H, s), 6.85,7.21
_{(4H, A 2 B 2 J} = 9.0Hz), 7.10~7.60 (1H, br s) (2) (2S, 4S) -1- ethyl-1-methyl-2-methylcarbamoyl-4- (4-methoxy Benzylthio)
Pyrrolidinium fluorosulfonate (2S, 4S) -1-ethyl-4- (4-methoxybenzylthio) -2-methylcarbamoylpyrrolidine (700m
g) in dry dichloromethane (30 ml),
Add methyl fluorosulfonate (187 μl) and add 4
Stirred for hours. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure to obtain a colorless oily target compound (950 mg).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.12 (3H, t, J = 7.33 Hz), 2.02 to 2.20 (1H, m), 2.58 to
4.50 (7H, m), 2.60 (3H, s), 2.87 (3H, s), 3.65 (3H,
s), 3.68 (2H, s ), 6.82,7.17 (4H, A 2 B 2, J = 8.80Hz) Reference Example 13 (2S, 4S) -1,1- dimethyl-2-ethylcarbamoyl-4- (4 -Methoxybenzylthio) pyrrolidinium fluorosulfonate (1) (2S, 4S) -2-ethylcarbamoyl-4-
(4-Methoxybenzylthio) -1-methylpyrrolidine (2S, 4S) -2-ethylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidine (2.36 g) was dissolved in acetonitrile (42 ml) and 35% -formaldehyde Liquid (3.43ml), sodium cyanoborohydride (804mg)
Was added and stirred at room temperature for 40 minutes, acetic acid (1.3 ml) was added, and the mixture was further stirred at room temperature for 40 minutes. After adding 1N-sodium hydroxide aqueous solution to make the mixture basic, the mixture was poured into saline and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography using silica gel (developing agent: ethyl acetate) to give the title compound (1.93 g) as colorless crystals.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.12 (3H, t, J = 7.5 Hz), 1.50 to 2.20 (1 H, m), 2.31 (3
H, s), 2.36 to 3.88 (7H, m), 3.67 (2H, s), 3.78 (3H,
s), 6.83,7.21 (4H, A 2 B 2 J = 9.0Hz), 7.20 (1H, br s) (2) (2S, 4S) -1,1- dimethyl-2-ethylcarbamoyl-4- (4 -Methoxybenzylthio) pyrrolidinium fluorosulfonate (2S, 4S) -2-ethylcarbamoyl-4- (4-methoxybenzylthio) -1-methylpyrrolidine (987m
g) in dry dichloromethane (40 ml),
Methyl fluorosulfonate (264 μl) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was washed by repeating decantation with diethyl ether, and dried under reduced pressure to obtain the target compound as a colorless oil (1.332 g).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.94 (3H, t, J = 7.33 Hz), 1.95 to 2.20 (1H, m), 2.60 to
2.98 (1H, m), 2.96 (3H, s), 3.00 (3H, s), 3.02 to 3.70
(5H, m), 3.64 (3H, s), 3.67 (2H, s), 3.97 (1H, t, J =
7.88Hz), 6.81,7.01 (4H, A 2 B 2 J = 8.80Hz) Reference Example 14 (2S) -1,1-dimethyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (1) (2S) -1-tert-butoxycarbonyl-2-
(4-methoxybenzylthio) pyrrolidine (2S) -1-tert-butoxycarbonyl-2-hydroxymethylpyrrolidine obtained by methanesulfonylation of (2S) -1-tert-butoxycarbonyl-2-methanesulfonyloxymethylpyrrolidine ( 12.16 g), 4-methoxybenzylmercaptan (7.3 ml) and 55% sodium hydride (2.3 g) were used for the reaction, treatment and purification in dry dimethylformamide (100 ml) in the same manner as in Reference Example 5 (2). The title compound (13.93 g) was obtained as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.20 to 4.15 (9H, m), 1.45 (9H, s), 3.70 (2H, s), 3.7
8 (3H, s), 6.82,7.25 (4H, A 2 B 2, J = 9.0Hz) (2) (2S) -2- (4- methoxybenzylthio) pyrrolidine (2S) -1-tert-butoxycarbonyl -2- (4-
Methoxybenzylthiomethyl) pyrrolidine (5 g) and a 4N solution of hydrogen chloride in ethyl acetate were reacted, treated and purified in the same manner as in Reference Example 5 (3) to give the title compound (2.51 g) as colorless crystals.

mp 124 ~ 126.5 ℃ Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.45 to 2.20 (4H, m), 2.25 to 3.96 (6H, m), 3.76 (5H,
s), 6.85,7.32 (4H, A 2 B 2 J = 9.0Hz) (3) (2S) -2- (4- methoxybenzylthio) -
1-Methylpyrrolidine (2S) -2- (4-methoxybenzylthiomethyl) pyrrolidine (2 g), 35% formalin (3.6 ml), sodium cyanoborohydride (848 mg) in acetonitrile (44 ml) The reaction, treatment and purification were conducted in the same manner as for 5 (4) to give the title compound (883 mg) as an oil.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.40 to 3.22 (9H, m), 2.26 (3H, s), 3.68 (2H, s), 3.7
8 (3H, s), 6.83,7.25 (4H, A 2 B 2, J = 9.0Hz) (4) (2S) -1,1- dimethyl-2- (4-methoxybenzyl thiomethyl) pyrrolidinium fluorosulfonate ( 2S) -2- (4-methoxybenzylthiomethyl)-
Using 1-methylpyrrolidine ('40 mg) and methyl fluorosulfonate (243 µl), the reaction, treatment and purification were carried out in dichloromethane (22 ml) in the same manner as in Reference Example 5 (5) to obtain the title compound (1.0 g) as crystals. .

mp 150-153 ℃ Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.60 to 2.02 (3H, m), 2.26 to 3.51 (6H, m), 2.64 (3H,
s), 2.85 (3H, s ), 3.64 (5H, s), 6.82,7.19 (4H, A 2 B 2, J
= 8.79Hz) Reference Example 15 (2R) -1,1-dimethyl-4- (4-methoxybenzylthiomethyl) pyrrolidinium fluorosulfonate Reference Example 14 using (2R) -1-tert-butoxycarbonyl-2-hydroxymethylpyrrolidine as a starting material
The oily title compound was obtained in the same manner as in (1), (2), (3) and (4).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.64 to 2.00 (3H, m), 2.25 to 3.48 (6H, m), 2.64 (3H,
s), 2.85 (3H, s ), 3.64 (5H, s), 6.82,7.19 (4H, A 2 B 2, J
Reference Example 16 (2S, 4S) -2-carbamoyl-1- (2-hydroxyethyl) -4- (4-methoxybenzylthio) -1-methylpyrrolidinium fluorosulfonate (1) (2S, 4S) -2-carbamoyl-1- (2-hydroxyethyl) -4- (4-methoxybenzylthio)
Pyrrolidine (2S, 4S) -2-carbamoyl-4- (4-methoxybenzylthio) pyrrolidine (0.5 g) obtained in Reference Example 1 (5) was dissolved in dry dimethylformamide (5 ml), and cooled under ice-cooling. -Add ethanol iodide (0.175 ml) and sodium bicarbonate (0.16 g) and add 2 hours at room temperature at the same temperature.
The mixture was stirred at 40 ° C. for 19 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Distill off the solvent,
The residue was purified by silica gel chromatography (Wako Pure Chemical Industries, Ltd., Wakogel C-100) from the portion eluted with 95: 5 ethyl acetate: methanol to give the crystalline title compound (0.46).
5g) was obtained.

mp101.5 ~ 102.5 ℃ Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.69 (1H, brs), 1.92 to 1.99 (1H, m), 2.55 to 2.72 (3
H, m), 2.82 ~ 2.92 (1H, m), 3.12 ~ 3.18 (3H, m), 3.67
(2H, t, J = 4.03Hz), 3.71 (2H, s), 3.80 (3H, s), 5.42
(1H, br s), 6.85,7.21 (4H, A 2 B 2, J = 8.8Hz), 7.35 (1
H, brs) (2) (2S, 4S) -2-carbamoyl-1- (2-hydroxyethyl) -4- (4-methoxybenzylthio)
-1-Methylpyrrolidinium fluorosulfonate (2S, 4S) -2-carbamoyl-1- (2-hydroxyethyl) -4- (4-methoxybenzylthio) pyrrolidine (0.38 g) in dry methylene chloride (7.5 ml) Dissolved in
Methyl fluorosulfonate (0.108 ml) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 2 hours. The solvent was distilled off, and the residue was washed with diethyl ether by repeating decantation, and dried under reduced pressure to give an oily target compound (0.39%).
6g).

Reference Example 17 3- (4-methoxybenzylthio) -1-methylquinuclidium fluorosulfonate (1) 3- (4-methoxybenzylthio) quinuclidine 3-methanesulfonyloxyquinuclidine obtained by methanesulfonylation of 3-quinuclidinol (3.7
g), 4-methoxybenzyl mercaptan (3.0 ml), 55
Reference Example 6 (2) using% sodium hydride (0.942 g)
Reaction, treatment and purification were carried out in the same manner as in the above to give the title compound as an oil (1.
74g).

Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ ) δppm:
1.02 to 2.31 (5H, m), 2.33 to 3.41 (7H, m), 3.67
(2H, s) 3.82 (3H , s), 6.86,7.26 (4H, A 2 B 2, J = 9.0Hz) (2) 3- (4- methoxybenzylthio) -1-methyl-quinuclidine indium fluorosulfonate 3 -(4-methoxybenzylthio) quinuclidine (75
6 mg) and methyl fluorosulfonate (271 μl) in dichloromethane (5 ml) in the same manner as in Reference Example 6 (3).
Treatment and purification gave the title compound as an oil (1.078 g).

Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 1.63 to 2.16 (5H, m), 2.70 (3H, s), 2.76 to 3.77 (7H,
m), 4.63 (5H, s ), 6.80,7.15 (4H, A 2 B 2, J = 8.61Hz) Reference Example 18 (6S-8S) -1,4- dimethyl-8- (4-methoxybenzylthio) -5-oxo-4-aza-1-azoniabicyclo [4.3.0] nonane fluorosulfonate (1) (2S, 4S) -1- (2-hydroxyethyl)-
4- (4-methoxybenzylthio) -2-methylcarbamoylpyrrolidine (2S, 4S) -4- (4-methoxybenzylthio) -2
-Methylcarbamoylpyrrolidine (2.80 g) is dissolved in dry dimethylformamide (18 ml), and under ice-cooling, 2-iodoethanol (934 μl) and sodium hydrogen carbonate (1.01 g)
Was added thereto, followed by stirring at 40 ° C. for 24 hours. The reaction solution was poured into brine, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography using silica gel (developing agent: ethyl acetate / methanol = 15/1) to obtain the title compound (2.22 g) as colorless crystals.

mp88 ~ 89.5 ℃ Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.66 to 2.05 (2H, m), 2.50 to 2.91 (4H, m), 2.82 (3H,
d, J = 4.77Hz), 3.07 ~ 3.21 (3H, m), 3.56 ~ 3.75 (2H,
m), 3.69 (2H, s ), 3.80 (3H, s), 6.84,7.20 (4H, A 2 B 2, J
= 8.79Hz), 7.42 (1H, brs) (2) (2S, 4S) -1- (2-methanesulfonyloxyethyl) -4- (4-methoxybenzylthio) -2-
Methylcarbamoylpyrrolidine (2S, 4S) -1- (2-hydroxyethyl) -4-
(4-Methoxybenzylthio) -2-methylcarbamoylpyrrolidine (2.13 g) was added to dry tetrahydrofuran (45 m
l), triethylamine (1.06 ml) was added under ice-cooling, and then methanesulfonyl chloride (584 μl) was added. After stirring at 0 to 5 ° C for 30 minutes, the precipitated crystals were filtered, washed with tetrahydrofuran, and the mother liquor was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound as an oil (2.50 g)
was gotten.

Nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.55 to 4.10 (8H, m), 2.81 (3H, d, J = 5.0 Hz), 3.05 (3
H, s), 3.70 (2H, s) 3.80 (3H, s), 4.18-4.49 (2H, m),
_{6.87,7.26 (4H, A 2 B 2} , J = 9.0Hz), 7.55 (1H, br s) (3) (6S, 8S) -8- (4- methoxybenzylthio) -4-methyl-5-oxo 1,4-diazabicyclo [4.3.0] nonane (2S, 4S) -1- (2-methanesulfonyloxyethyl) -4- (4-methoxybenzylthio) -2-methylcarbamoylpyrrolidine (2.64 g) was dried. Dissolve in dimethylformamide (30 ml), add 55% sodium hydride (347 mg) under ice-cooling, add 0 to 5 ° C for 30 minutes, and further add 30% at 30 ° C.
Stirred for hours. The reaction solution was poured into brine, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (developing agent, acetonitrile / methanol = 5 /
Purification in 1) gave the title compound (1.75 g) as an oil.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.88 to 2.01 (1H, m), 2.59 (1H, dt J = 13.18, 8.06H)
z), 2.75-2.98 (3H, m), 2.94 (3H, s), 3.00-3.24 (3
H, m), 3.30 (1H, t J = 8.06 Hz), 3.48 to 3.62 (1H, m), 3.
70 (2H, s), 3.80 (3H, s), 6.84,7.33 (4H, A 2 B 2 J = 8.80
Hz) (4) (6S, 8S) -1,4-dimethyl-8- (4-methoxybenzylthio) -5-oxo-4-aza-1-azoniabicyclo [4.3.0] nonanefluorosulfonate (6S, 8S ) -8- (4-Methoxybenzylthio) -4
-Methyl-5-oxo-1,4-diazabicyclo [4.3.0]
Nonane (1.71 g) was dissolved in dry dichloromethane (60 ml), and methyl fluorosulfonate (461 μl) was added under ice-cooling, followed by stirring at room temperature for 2 hours. Dilute with ether, filter the crystals, and dry under reduced pressure to give the title compound as colorless crystals (2.09 g)
I got

mp 208 ~ 210 ℃ Nuclear magnetic resonance spectrum (270 MHz, DMSO-d ₆ ) δ ppm: 2.16 to 2.33 (1H, m), 2.79 to 2.95 (1H, m), 2.89 (3H,
s), 3.23 (3H, s), 3.38 (1H, br s), 3.56 to 4.02 (6H,
m), 3.74 (3H, s), 3.80 (2H, s), 4.37 (1H, t, J = 8.30H)
z), 6.90,7.26 (4H, A 2 B 2 J = 8.79Hz) fluorosulfonate compound starting material used in Reference Example 19 Example 26 to 32 were each synthesized in the same manner as in Reference Example described above .

((2S, 4S) -1,1-dimethyl-4- (4-methoxybenzylthio) -2-methoxycarbonylpyrrolidinium
Fluorosulfonate (raw material of Example 26) Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 2.16 to 2.29 (1H, m), 2.74 to 2.92 (1H, m), 3.05 (3H,
s), 3.12 (3H, s), 3.38 ~ 3.73 (3H, m), 3.65 (3H, s),
3.66 (3H, s), 3.68 (2H, s), 4.32 (1H, dd, J = 10.99,7.6
9Hz), 7.82,7.16 (4H, A 2 B 2, J = 8.61Hz) (2R, 4S) -2- carbamoyl-4- (4-methoxybenzylthio) -1,1-dimethyl pyrrolidinium fluorosulfonate ( Raw materials of Example 28) Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 2.19 to 2.30 (1H, m), 2.57 to 2.70 (1H, m), 2.93 (3H,
s), 3.15 (3H, s), 3.30 (1H, dd, J = 12.09, 7.51 Hz), 3.4
7 to 3.60 (1H, m), 3.66 (3H, s), 3.69 (2H, s), 3.77 (1
H, dd, J = 12.99,8.06Hz), 4.26 (1H, t, J = 8.43Hz), 6.8
2,7.18 (4H, A ₂ B ₂ , J = 8.61 Hz) (2R, 4S) -1,1-dimethyl-2-N, N-dimethylcarbamoyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate ( Raw material of Example 27) Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 2.17 to 2.29 (1H, m), 2.46 to 2.58 (1H, m), 2.78 (3H,
s), 2.94 (3H, s), 2.98 (3H, s), 3.10 (3H, s), 3.26 (1
H, dd, J = 12.09, 6.96Hz), 3.51 to 3.63 (1H, m), 3.65 (3
H, s), 3.69 (2H, s), 3.84 (1H, dd, J = 12.09, 8.62Hz),
4.75 (1H, dd, J = 7.69,6.96Hz), 6.82,7.17 (4H, A 2 B 2, J
= 8.78 Hz) (2S, 4S) -2-cyclopropylcarbamoyl-1,1-dimethyl-4- (4-methoxybenzylthio) pyrrolidinium fluorosulfonate (raw material of Example 29) Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 0.26 to 2.66 (4H, m), 2.00 to 3.65 (6H, m), 2.96 (3H,
s), 2.98 (3H, s), 3.65 (3H, s), 3.68 (2H, s), 3.92 (1
H, t, J = 7.86Hz) , 6.81,3.17 (4H, A 2 B 2, J = 8.80Hz) (6S, 8S) -5- oxo-8- (4-methoxybenzylthio) -1-methyl - 4-aza-1-azoniabicyclo [4.3.0] nonane fluorosulfonate (raw material of Example 32) Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm: 2.10 to 2.24 (1H, m), 2.73 to 2,90 (1H, m), 3.65 (3H,
s), 3.67 (2H, s), 3.36 to 3.85 (7H, m), 4.18 ((1H, t, J
= 8.43Hz), 6.82,7.17 (4H, A 2 B 2, J = 8.79Hz)

Claims (1)

(57) [Claims] (1) Expression Or a salt thereof. In the formula, R ¹ represents a hydrogen atom or a methyl group. l, m and n each independently represent 0, 1, 2 or 3, and m + n represents 2 to 6. Y is a direct single bond, an oxygen atom, a sulfur atom or NRNR ⁸ (R
⁸ represents a hydrogen atom, an alkyl group or an alkanoyl group). R ² is a hydrogen atom, an alkyl group which may have a substituent a, a halogen atom, a hydroxy group, an alkoxy group, an amino group,
Alkanoylamino group, alkanoyloxy group, alkanoyl group, carboxyl group, alkoxycarbonyl group,
Cyano, -S (O) jR ⁹ group (j represents 0, 1 or 2; R ⁹ is an alkyl group) or -CONR ⁶ R ⁷ group (R ^6, R
⁷ are each independently a hydrogen atom, a substituent an alkyl group optionally having a a, alkenyl group, alkynyl group or cycloalkyl group, or R ⁶ and and R ⁷ are bonded to substituents b
Represents an alkylene group which may have an oxygen atom, a sulfur atom or NRNR ⁸ (R ⁸ is a hydrogen atom,
An alkyl group or an alkanoyl group). R ³ and R ⁴ each independently represent an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group or a cycloalkylalkyl group which may have a substituent a, or one of R ^{3 and} R ⁴ is R ² And an alkylene group which may have a substituent b, which is bonded to an oxygen atom, a sulfur atom or an NRNR ⁸ group (R ⁸ represents a hydrogen atom, an alkyl group or an alkanoyl group) You may. R ⁵ represents a hydrogen atom, an anionic charge or a carboxyl-protecting group. When R ⁵ is a carboxyl protecting group, a counter ion is present. In the above, the substituent a is a hydroxyl group, a cyano group, a carbamoyloxy group, an azide group, a carboxyl group, a nitro group,
Oxo group, halogen atom, alkoxy group, alkanoyl group, alkanoyloxy group, alkanoylamino group, alkoxycarbonyl group, -NR ¹⁰ R ¹¹ group, -CONR ¹² R ¹³ group (R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are And each independently represents a hydrogen atom, an alkyl group or an alkanoyl group.), -SO ₂ NR ¹⁴ R
¹⁵ groups, -S (O) _k R ¹⁶ groups (.k showing the R ^14, R ¹⁵ and R ¹⁶ independently of one another represent alkyl groups is 0, 1 or _{2.), - NHSO 2 R} 17 group, - N = CR ¹⁸ NR ¹⁹ R ²⁰ groups, -NR ²¹ C
R ²² = NR ²³ or —C (＝ NH) NR ²⁴ R ²⁵ (R ^{17 to} R ²⁵ independently represent a hydrogen atom or an alkyl group), and the substituent b is an alkyl group, an alkoxy group, It represents a halogen atom, a hydroxyl group, a cyano group, a carbamoyl group or an oxo group.