JPH06199860A - Carbapenem derivative - Google Patents

Abstract

PURPOSE:To provide a novel compound having a wide antibacterial spectrum and useful as an antibiotic. CONSTITUTION:A compound of formula I [R<1> is H, methyl; R<2> is H, (substituted) lower alkyl, hydrolyzable ester residue of formula: -C(=NH)R<0> (R<0> is H, lower alkyl), etc.; A is group of formula II (l is 0, 1; R<3> is H, lower alkyl, etc.; R<4> is H, lower alkyl, etc.; R<5> is H, halogen, etc.,), etc.; R<10> is H, hydrolyzable ester residue]. For example, (1R,5R,6S)-2[(2S,4S)-2-(3-aminoazetin-1-ylcarbonyl) pyrrolidin-4-ylthio]-6[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3 -carboxylic acid hydrochloride. The compound of formula I is synthesized from a compound of formula III (R<11> is carboxy-protecting group) through a compound of formula IV (A' us A, etc.; R<13> is R<2>, etc.,), etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a carbapenem derivative (1) which is an excellent antibacterial agent.

[0002]

BACKGROUND OF THE INVENTION Thienamycin derivatives have excellent antibacterial activity, but they are degraded by dehydropeptidase I, which is an inactivating enzyme of thienamycin derivatives in the human body, and lose their activity, resulting in a low urinary recovery rate. (H. Kropp et al., Antimicrob. Agents, Chemothe
r., 22 62, (1982); SR Norrby et al., ibid., 23,300 (198
3)).

[0003]

DISCLOSURE OF THE INVENTION The present inventors have conducted various studies to solve this drawback of thienamycin derivatives, and the novel carbapenem derivative (1) has a stronger antibacterial activity than the thienamycin derivatives, and dehydropeptidase I. The present invention has been completed by discovering that it is stable against urine and has a high recovery rate in urine.

[0004]

The present invention is based on the formula

[0005]

[Chemical 4]

And a pharmaceutically acceptable salt thereof.

In the formula, R ¹ represents a hydrogen atom or a methyl group, R ² represents a hydrogen atom, a lower alkyl group having a substituent or not, a lower alkenyl group, a lower alkynyl group or --C (═NH) R. Group ⁰ (in the formula, R ⁰ represents a hydrogen atom or a lower alkyl group), and R ¹⁰ represents a hydrogen atom or an ester residue that undergoes hydrolysis in vivo.
A represents any group represented by the following general formula or

Expression

[0009]

[Chemical 5]

(In the formula, l represents 0 or 1, and R ³ is a hydrogen atom, a lower alkyl group having a substituent or not, a lower alkenyl group, a lower alkynyl group or -C (= N
H) represents an R ⁶ group (in the formula, R ⁶ represents a hydrogen atom, a lower alkyl group with or without a substituent, a cycloalkyl group or a cycloalkyl lower alkyl group), and R ⁴
Represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkynyl group with or without a substituent, R ⁵ represents a substituent on the ring, and a hydrogen atom independently of each other,
A halogen atom, a lower alkyl group with or without a substituent, a hydroxy group, a carboxy group, a carbamoyl group, an amino group, a cyano group or a carbamoyloxy group is shown. )

[0011]

[Chemical 6]

(In the formula, m represents 0 or 1, R ⁵ has the same meaning as described above, R ⁷ represents a hydrogen atom or a lower alkyl group, and R ⁸ represents a hydrogen atom or a substituent. Or a lower alkyl group, a lower alkenyl group which does not have,
A lower alkynyl group or -C (= NH) R ⁶ group (wherein,
R ⁶ has the same meaning as described above. In the explanation of the formula (1), the lower alkyl group for R ⁰ in R ² includes, for example, methyl, ethyl and propyl, and R ² and R ³ in the groups represented by the general formulas and
The lower alkyl group for R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl or t-butyl may be mentioned.

Examples of the lower alkenyl group for R ² , R ³ , R ⁴ and R ⁸ include allyl and 2-methylallyl. Examples of the lower alkynyl group of R ² , R ³ , R ⁴ and R ⁸ include propargyl and 2-methylpropargyl.

The substituent of the lower alkyl group having a substituent of R ² is hydroxy group, carboxy group, carbamoyl group,
Carbamoyloxy group, cyano group, halogen atom (eg, fluorine, chlorine, bromine atom), oxo group, alkoxy group (eg, methoxy, ethoxy, propoxy), amino group, lower alkylamino group, di-lower alkyl Examples thereof include an amino group (lower alkylamino group, lower alkyl group in di-lower alkylamino group has the same meaning as lower alkyl group in R ² ).

The substituent of the lower alkyl group having a substituent of R ³ is a hydroxy group, a carboxy group, a carbamoyl group,
Carbamoyloxy group, cyano group, sulfamoyl group,
Ureido group, sulfo group, alkoxy group, alkoxycarbonyl group, alkanoyl group, alkanoylamino group, alkanoyloxy group, halogen atom, amino group, lower alkylamino group, di-lower alkylamino group, alkylthio group, alkylsulfinyl group, alkylsulfonyl Group, alkyl-substituted carbamoyl group, dialkyl-substituted carbamoyl group, alkyl-substituted carbamoyloxy group, dialkyl-substituted carbamoyloxy group. Examples of the alkoxy group as the substituent of the lower alkyl group having a substituent of R ³ include methoxy, ethoxy and propoxy, and examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl. Examples of the alkanoyl group include acetyl and propionyl, examples of the alkanoylamino group include acetylamino and propionylamino, and examples of the alkanoyloxy group include acetoxy and propionyloxy. Examples of the halogen atom include fluorine, chlorine and bromine atoms. The lower alkylamino group is
Examples include methylamino and ethylamino groups, and examples of the di-lower alkylamino group include dimethylamino and diethylamino. Examples of the alkylthio group include methylthio, ethylthio and propylthio, and examples of the alkylsulfinyl group include methylsulfinyl and ethylsulfinyl. Examples of the alkylsulfonyl group include methylsulfonyl and ethylsulfonyl. Examples of the alkyl-substituted carbamoyl group include methylcarbamoyl and ethylcarbamoyl, and the dialkyl-substituted carbamoyl group includes dimethylcarbamoyl and
Examples include diethylcarbamoyl. Examples of the alkyl-substituted carbamoyloxy group include methylcarbamoyloxy and ethylcarbamoyloxy, and examples of the dialkyl-substituted carbamoyloxy group include dimethylcarbamoyloxy and diethylcarbamoyloxy. Examples of the substituent of the alkyl group having a substituent of R ⁴ and R ⁵ include a hydroxy group, an amino group, a carbamoyl group, a carboxy group, a halogen atom and an alkoxy group, and the halogen atom includes a fluorine, chlorine and bromine atom. Examples of the alkoxy group include methoxy, ethoxy, and propoxy.

Examples of the substituent of the lower alkyl group having a substituent of R ⁶ include a halogen atom and an alkoxy group, the halogen atom includes chlorine, bromine and fluorine atoms, and the alkoxy group includes methoxy, ethoxy and propoxy. .

Examples of the cycloalkyl group represented by R ⁶ include cyclopropyl, cyclobutyl and cyclopentyl. R ⁶
Examples of the cycloalkyl lower alkyl group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and cyclopentylmethyl.

The substituent of the lower alkyl group having a substituent of R ⁸ is a halogen atom, a hydroxy group, a carbamoyl group,
Examples thereof include a carbamoyloxy group, methoxy group, ethoxy group, cyano group, amino group and carboxy group, and examples of the halogen atom include chlorine, bromine and fluorine atoms.

Examples of the ester residue of R ¹⁰ which is hydrolyzed in vivo include an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a phthalidyl group and a 2-oxo-1,3-dioxolen-4-ylmethyl group. The above acyloxyalkyl group is, for example, pivaloyloxymethyl, isobutyryloxymethyl, 1-
(Isobutyryloxy) ethyl, acetoxymethyl, 1
Examples include-(acetoxy) ethyl, 1-methylcyclohexylcarbonyloxymethyl and 1-methylcyclopentylcarbonyloxymethyl. The alkoxycarbonyloxyalkyl group is, for example, t-butoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Isopropoxycarbonyloxy) ethyl, 1- (t
Examples include -butoxycarbonyloxy) ethyl, 1- (cyclohexylcarbonyloxy) ethyl and 1- (cyclopentylcarbonyloxy) ethyl.

If necessary, the compound (1) of the present invention can be converted into a pharmacologically acceptable salt.

Examples of the pharmacologically acceptable salts include mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate and nitrate; methanesulfonate and ethanesulfone. Acid salts, benzene sulfonates, sulfonates such as p-toluene sulfonate; oxalates, tartrates, citrates, maleates, succinates, acetates, benzoates, mandelate salts. , Pharmacologically acceptable acid addition salts such as organic acid salts such as ascorbate, lactate, gluconate, malate, or lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, etc. Examples thereof include inorganic salts or ammonium salts, triethylamine salts, diisopropylamine salts, salts with organic bases such as cyclohexylamine salts.

Preferred R ¹ is a hydrogen atom or a methyl group, and a methyl group is particularly preferred.

Preferred R ² is a hydrogen atom, an alkyl group with or without a substituent, an alkenyl group, an alkynyl group or a —C (═NH) R ⁰ group, and a preferred alkyl group is methyl, ethyl or A propyl group, a suitable substituent thereof is a hydroxy group, a carboxy group, a carbamoyl group, a carbamoyloxy group, a cyano group, a fluorine atom, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, A preferred R ⁰ is a hydrogen atom or a methyl group, a preferred alkenyl group is an allyl group, and a preferred alkynyl group is a propargyl group.

Preferred R ¹⁰ is a hydrogen atom or an ester residue which undergoes hydrolysis in vivo, and preferred ester residues include 2-oxo-1,3-dioxolen-4-ylmethyl and pivaloyl. And oxymethyl, 1-methylcyclohexylcarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl and 1- (cyclohexylcarbonyloxy) ethyl groups.

In the group in which A is of the formula; preferred l
Is 0 or 1.

Preferred R ³ is a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group, which may or may not have a substituent, and the preferred alkyl group is a methyl, ethyl or propyl group. Suitable substituents are hydroxy group, carboxy group, carbamoyl group,
Carbamoyloxy group, cyano group, sulfamoyl group,
Sulfo group, methoxy group, methoxycarbonyl group, acetyl group, acetylamino group, acetoxy group, fluorine atom, ureido group, amino group, methylamino group, dimethylamino group, methylthio group, methylsulfinyl group, methylsulfonyl group, methylcarbamoyl Group, a dimethylcarbamoyl group, a methylcarbamoyloxy group, a dimethylcarbamoyloxy group, a preferable alkenyl group is allyl, a preferable alkynyl group is a propargyl group, and a preferable R ³ is —C (═NH) R ⁶ In the group, preferred R ⁶ is hydrogen atom, methyl, ethyl, chloromethyl, methoxymethyl, cyclopropyl, cyclopropylmethyl,
Preferred R ⁴ is a hydrogen atom, an alkyl group with or without a substituent, the preferred alkyl group is a methyl, ethyl or propyl group, a preferred substituent of the alkyl group is a hydroxy group, a carboxy group, Carbamoyl group, amino group, methoxy group, or fluorine atom, suitable R
⁵ is a hydrogen atom, an alkyl group, a hydroxy group, a carbamoyl group, a cyano group, a carboxy group, a hydroxymethyl group, a methoxymethyl group, an aminomethyl group, a carbamoylmethyl group or a fluoromethyl group, a suitable alkyl group is methyl. It is a base.

Suitable compound (1) in which A has a group represented by the formula is as follows: 1 is 0 or 1, R ¹ is hydrogen atom or methyl group, R ² is hydrogen atom, methyl group, fluoro group. A methyl group, a formimidoyl group or an acetimidoyl group, wherein R ³ is a hydrogen atom, a methyl group, an ethyl group, a 2-carbamoyloxyethyl group, a 2-hydroxyethyl group, a 2-fluoroethyl group, a 2-aminoethyl group. Group, carboxymethyl group, carbamoylmethyl group, allyl group, propargyl group, formimidoyl group, acetimidoyl group, α-methoxyacetimidoyl group, α-
It is a chloroacetimidoyl group, an α-cyclopropylacetimidoyl group or a cyclopropylimidoyl group, and R ⁴ is a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyethyl group, a carbamoylmethyl group or a 2-fluoroethyl group. And R ⁵ is a hydrogen atom, a methyl group, a carbamoyl group, a cyano group, a carboxy group, a hydroxymethyl group,
A compound which is a fluoromethyl group or an aminomethyl group and R ¹⁰ is a hydrogen atom. As a particularly preferred compound (1) in which A has a group represented by the general formula, l is 0, R is
¹ is a methyl group, R ² is a hydrogen atom, a methyl group, a fluoromethyl group or an acetimidoyl group, and R ³ is a hydrogen atom, a 2-carbamoyloxyethyl group, a methyl group, an ethyl group, 2-hydroxyethyl. A group, a 2-fluoroethyl group, a carboxymethyl group, a carbamoylmethyl group, a formimidoyl group or an acetimidoyl group, and R ⁴ is a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyethyl group, a carbamoylmethyl group, A compound which is a 2-fluoroethyl group and R ⁵ and R ¹⁰ are hydrogen atoms.

In the group represented by the general formula of A, m is 0, R ¹ is preferably a hydrogen atom or a methyl group, and R ² is preferably a hydrogen atom, a methyl group, a fluoromethyl group or a formimide. It is an yl group or an acetimidoyl group, preferable R ⁵ has the same meaning as described above, and preferable R ⁷ is a hydrogen atom, a methyl group, an ethyl group or a propyl group. Preferred R ¹⁰ is a hydrogen atom, and preferred R ⁸ is a hydrogen atom, a lower alkyl group with or without a substituent, a lower alkenyl group, a lower alkynyl group, —C
(= NH) R ⁶ group, wherein R ⁶ is a hydrogen atom, a lower alkyl group with or without a substituent, a cycloalkyl group or a cycloalkyl lower alkyl group, a suitable lower alkyl group is methyl, An ethyl or propyl group, the preferred substituents of which are a fluorine atom, a chlorine atom, a hydroxy group, a carbamoyl group, a carbamoyloxy group, a methoxy group, an ethoxy group, a cyano group, an amino group and a carboxy group, and a preferred lower alkenyl group. The group is allyl, the preferred alkynyl group is propargyl group, -C (= N
H) A preferred lower alkyl group for R ⁶ in R ⁶ is a methyl, ethyl or propyl group, preferred substituents for which are a fluorine atom, a chlorine atom, a methoxy group and an ethoxy group, and a preferred cycloalkyl group for R ^9. The group is cyclopropyl and the preferred cycloalkylalkyl group is the cyclopropylmethyl or cyclopropylethyl group.

As a preferred compound (1) having a group represented by A as m, m is 0, R ¹ is a hydrogen atom or a methyl group, and R ² is a hydrogen atom, a methyl group or a fluoromethyl group. , A formimidoyl group or an acetimidoyl group, R ⁵ is a hydrogen atom, R ⁷ is a hydrogen atom, a methyl group, an ethyl group, or a propyl group, and R
⁸ is a hydrogen atom, methyl group, ethyl group, 2-carbamoyloxyethyl group, 2-hydroxyethyl group, 2-fluoroethyl group, carboxymethyl group, carbamoylmethyl group, formimidoyl group, acetimidoyl group, α- A compound which is a methoxyacetimidoyl group, an α-chloroacetimidoyl group, an α-cyclopropylacetimidoyl group or a cyclopropylimidoyl group, and R ¹⁰ is a hydrogen atom. As a particularly preferred compound (1) in which A has a group represented by the formula, m is 0, R ¹ is a methyl group, R ² is a hydrogen atom, a methyl group, a fluoromethyl group, a formimidoyl group or Is an acetimidoyl group, and R
⁵ is a hydrogen atom, R ⁷ is a hydrogen atom, a methyl group, an ethyl group, R ⁸ is a hydrogen atom, a methyl group, an ethyl group, 2
A carbamoyloxyethyl group, a 2-fluoroethyl group, a carboxymethyl group, a carbamoylmethyl group, a formimidoyl group or an acetimidoyl group, and R ¹⁰
Is a compound in which is a hydrogen atom.

Formula (1) represents one or a mixture of isomers. Among these isomers, preferred is that the 1-position is the R-coordination, the 5- and 6-positions are the same coordination as thienamycin (5S, 6S) -coordination and the hydroxyl group of the 6-position substituent. The compound in which the α-coordinate has is R-coordination can be given.

Examples of suitable compound (1) are shown below.

[0032]

[Chemical 7]

[0033]

[Chemical 8]

[0034]

[Chemical 9]

[0035]

[Chemical 10]

[0036]

[Chemical 11]

[0037]

[Chemical 12]

[0038]

[Chemical 13]

[0039]

[Chemical 14]

The carbapenem derivative having the general formula (1) can be produced by the method (method A) shown below.

Method A

[0042]

[Chemical 15]

In the above formula, R ¹¹ 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. An alkenyl group such as allyl, 2-chloroallyl or 2-methylallyl; 2,2,2-trichloroethyl, 2,2-dibromoethyl or 2,2,2-
A halogenoalkyl group such as tribromoethyl or 2
A trimethylsilylethyl group.

R ¹² is an alkanesulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl; arylsulfonyl such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl. A group; a dialkylphosphoryl group such as dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl or dipentylphosphoryl or a diarylphosphoryl group such as diphenylphosphoryl or ditolylphosphoryl. A 'and R ¹³ show that also contains the protecting group when the protecting group in or A and R ² or as defined as A and R ² are needed. The protecting group is a usual protecting group for hydroxyl group, imino group, amino group and carboxy group, and representative examples thereof include p-nitrobenzyloxycarbonyl and p-nitrobenzyl.

In this synthetic method, a compound having the formula (3) is produced by reacting a compound having the formula (2) with an alkanesulfonic anhydride, an arylsulfonic anhydride, a dialkylphosphoryl halide or a diarylphosphoryl halide in the presence of a base. Then, the compound having the formula (4) is reacted in the presence of a base without isolation of the obtained compound (3) to produce a compound having the formula (5), and removal of the protecting group R ¹¹ for the carboxy group. It is intended to produce the target compound having the general formula (1) by subjecting it to a reaction, or after its removal reaction, and converting it into an ester that is hydrolyzed in vivo, if necessary.

Examples of the alkanesulfonic anhydride used in the reaction for obtaining the compound (3) from the compound (2) include anhydrous methanesulfonic acid, trifluoromethanesulfonic anhydride, ethanesulfonic anhydride, and arylsulfonic anhydride. Examples of benzenesulfonic acid, p-trienesulfonic anhydride, dialkylphosphoryl halides include dimethylphosphoryl chloride, diethylphosphoryl chloride, and examples of diarylphosphoryl halides include diphenylphosphoryl chloride and diphenylphosphoryl bromide. Among them, p-toluenesulfonic anhydride or diphenylphosphoryl chloride is particularly preferable. The solvent used is not particularly limited as long as it does not participate in this reaction, and for example, methylene chloride, 1,
Examples thereof include halogenated hydrocarbons such as 2-dichloroethane and chloroform, nitriles such as acetonitrile, and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. The base used is not particularly limited as long as it does not affect other parts of the compound, particularly the β-lactam ring, but preferably triethylamine, diisopropylethylamine, 4-
An organic base such as dimethylaminopyridine can be used.

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

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

The reaction temperature is not particularly limited, but is usually -2.
It is carried out at 0 ° C to room temperature. Reaction time is 30 minutes to 108
It's time.

After completion of the reaction, the target compound (5) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography. If desired, the desired compound (5) can be subjected to the next reaction for removing the protective group of the carboxy group without isolation. The obtained compound (5) can be converted into a carboxylic acid derivative by removing the protecting group R ^{11 for} the carboxy group, if necessary, according to a conventional method. Removal of the protecting group R ¹¹ will depend on its type, but will generally be done by methods known in the art. Suitably the reaction is of formula (5)
It is achieved by contacting with a reducing agent a compound in which the substituent R ^{11 in the} compound having R is a protecting group that can be removed by a reduction treatment such as a halogenoalkyl group, an aralkyl group and a benzhydryl group. As the reducing agent used in this reaction, zinc and acetic acid are preferable when the protecting group of the carboxy group is a halogenoalkyl group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl. Where the protecting group is an aralkyl group such as benzyl, 4-nitrobenzyl or a benzhydryl group, hydrogen and catalytic reduction catalysts such as palladium-carbon or alkali metal sulfides such as sodium sulfide or potassium sulfide are preferred. Is. The reaction is carried out in the presence of a solvent, the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, tetrahydrofuran, ethers such as dioxane, acetic acid. Fatty acids such as and mixed solvents of these organic solvents and water are preferred. The reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 5 minutes to 12 hours, depending on the kinds of the raw material compound and the reducing agent.

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

If desired, the desired compound thus obtained can be purified by a conventional method such as recrystallization, preparative thin film chromatography, column chromatography and the like. If necessary, it can be converted into an ester that is hydrolyzed in vivo by a conventional method,
It can also be purified as a pharmacologically acceptable salt by a conventional method.

When A'and R ¹³ contain a protecting group for a hydroxyl group, an imino group, an amino group, and a carboxy group (for example, p-nitrobenzyloxycarbonyl group or p-nitrobenzyl group), the above-mentioned carboxy group can be used. The protecting group can be removed simultaneously with the removal of the protecting group (when R ¹¹ is a p-nitrobenzyl group).

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

[0055]

[Chemical 16]

Method B; wherein R ¹¹ has the same meaning as defined above, R ¹⁴ is an alkyl group such as methyl, ethyl, propyl or isopropyl; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl A halogenoalkyl group such as difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl or trifluoroethyl; 2-acetylaminoethyl group; 2-acetylaminovinyl group; phenyl or naphthyl which may have a substituent. Aryl groups such as
These aryl groups are the same or different 1 to 1 shown below.
It may have 3 substituents. The substituents are fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl,
Methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, carbamoyl, mono- and di-substituted alkylcarbamoyl (the alkyl group represents, for example, methyl, ethyl, propyl group), nitro, hydroxyl group or cyano group. Or a heteroaryl group such as pyridyl or pyrimidinyl which may have a substituent, and these heteroaryl groups are the same or different 1 to 3 shown below.
May have one substituent, the substituent is fluorine, chlorine,
Examples include bromine, methyl, ethyl, propyl or isopropyl.

The compound having the formula (6) in this synthetic method is disclosed in JP-A-62-30781.
The reaction of reacting the compound of formula (6) with mercaptan in the presence of a base to produce the compound of general formula (5) is carried out in an inert solvent. The solvent used is not particularly limited as long as it does not participate in this reaction, for example, tetrahydrofuran, acetonitrile, dimethylformamide,
Examples thereof include dimethyl sulfoxide, 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, but it may be, for example, diisopropylethylamine, triethylamine, N-methylpiperidine or 4-dimethylaminopyridine. Examples of such organic bases include inorganic bases such as potassium carbonate and sodium bicarbonate. Although the reaction temperature is not particularly limited, it is preferably carried out at a relatively low temperature in order to suppress side reactions, and is usually carried out at -20 ° C to 40 ° C. The reaction time varies depending mainly on the reaction temperature and the type of reaction reagent, but is usually 15 minutes to 75 hours. After completion of the reaction, the target compound (5) of this reaction can be collected from the reaction mixture according to a conventional method.

If necessary, the compound having the formula (5) can be prepared by subjecting it to the removal reaction of the protecting groups for A'and R ¹³ described in Method A, and the removal reaction of the protecting group of the carboxy group. The compound having the formula (1) can be obtained by converting into an ester that is hydrolyzed in the body. The compound having the general formula (1) thus obtained by Method A or Method B is converted into a pharmacologically acceptable salt by a method or technique known in the field of β-lactam antibiotics. can do.

The raw material mercaptan (4) used is described in JP-A-2-28180, JP-A-2-3687, JP-A-4-211083, JP-A-3-131545 and JP-A-4-142286. It can be manufactured according to the described method.

[0060]

INDUSTRIAL APPLICABILITY The carbapenem-3-carboxylic acid derivative having the formula (1) of the present invention exhibits an excellent antibacterial action having a broad spectrum and has β-lactamase inhibitory activity. Furthermore, thienamycin compounds are easily metabolized by mammals, but show excellent stability against dehydropeptidase I, which is known as an enzyme that catalyzes the inactivation of thienamycin, and also have an excellent recovery rate in urine. It has the property Regarding the antibacterial action, when its activity was measured by the agar plate dilution method,
Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis,
It showed potent activity against a wide range of pathogens including Gram-negative bacteria such as Escherichia coli, Shigella, Klebsiella pneumoniae, morphobacterium, Serratia, Enterobacter, Pseudomonas aeruginosa and anaerobic bacteria such as Bacteroides fragilis.

Accordingly, such compounds are useful as antibacterial agents for treating bacterial infections by these pathogens.
Examples of dosage forms for that purpose include oral administration by tablets, capsules, granules, powders, syrups and the like, or parenteral administration by intravenous injection, intramuscular injection, etc. Depending on the medical condition, the administration form and the number of administrations, about 100 mg to 3000 mg per day is usually administered to an adult once or in several divided doses.

Hereinafter, the compounds of the present invention will be described in more detail with reference to Reference Examples and Examples.

The nuclear magnetic resonance spectra in the examples and reference examples were measured using tetramethylsilane as an internal standard unless otherwise specified for the measurement in D ₂ O.

[0064]

【Example】

Example 1 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(3-Aminoazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-
3-carboxylic acid hydrochloride

[0065]

[Chemical 17]

(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (278 mg) in dry acetonitrile (4
diphenyl phosphate chloride (16 ml) under ice cooling.
7 μl) and diisopropylethylamine (140 μl
1) was added dropwise at the same time, and the mixture was stirred at the same temperature for 1 hour. Then, (2S, 4S) -4-mercapto-2- [3- (4
-Nitrobenzyloxycarbonylamino) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (430 mg) in dry acetonitrile (4 ml) and diisopropylethylamine (134 μl) were simultaneously added dropwise under ice cooling, After stirring at the same temperature for 2 hours, the mixture was left overnight under ice cooling. The reaction solution was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel. The fractions eluted with ethyl acetate: methanol (98: 2) were combined and concentrated to give a powder. Shaped (1R, 5S, 6S) -2-
[(2S, 4S) -2- [3- (4-Nitrobenzyloxycarbonylamino) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio] -6-[( 1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (2
24 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1772,1713,1659,1608,1522,1453,1403,1347 Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ + D ₂ O) δppm:
1.06-1.27 (6H, m), 1.66-1.89 (1H, m), 2.64-2.85 (1H, m), 3.
08-3.37 (2H, m), 3.41-4.59 (11H, m), 5.07-5.52 (6H, m), 7.5
1-7.78 (6H, m), 8.23 (6H, d, J = 8.79Hz) (2) Dissolve the compound (216mg) obtained in (1) in tetrahydrofuran: water (3: 2,10ml) to obtain 10%. Palladium carbon catalyst (250 mg) and 1N-hydrochloric acid (239 µ
1) was added and hydrogenation was carried out at room temperature for 1.5 hours. The catalyst was removed by filtration, the filtrate was washed with ether, the aqueous layer was concentrated under reduced pressure, and the residue was subjected to column chromatography (Nacalai Tesque, Cosmo Seal 75C ₁₈ -PRE.
(P, 18 ml), the fraction containing the desired compound was concentrated and freeze-dried from the fraction eluted from water to obtain the target compound (46 mg) in the form of powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 297. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1756,1661,15
96,1486,1462,1391,1287,1180 Nuclear magnetic resonance spectrum (270MHz, D ₂ O, internal standard sodium trimethylsilylpropionate-d ₄ ) ppm: 1.21 (3H,
d, J = 7.32Hz), 1.29 (3H, d, J = 6.35Hz), 1.95-2.12 (1H, m),
2.90-3.05 (1H, m), 3.29-3.51 (3H, m), 3.72-3.83 (1H, m), 3.
97-4.10 (1H, m), 4.13-4.86 (8H, m) Example 2 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(3-acetimidoylaminoazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0069]

[Chemical 18]

(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (0.55 g) in dry acetonitrile (10
(ml) solution under ice-cooling under diphenyl phosphate chloride (0.
35 ml) and diisopropylethylamine (0.29 ml) were simultaneously added dropwise, and the mixture was stirred at the same temperature for 50 minutes. Then, (2S, 4S) -4-mercapto-2- [3- (N
-4-Nitrobenzyloxycarbonylacetimidoylamino) azetidin-1-ylcarbonyl] -1-
A solution of (4-nitrobenzyloxycarbonyl) pyrrolidine (0.82 g) in dry acetonitrile (10 ml) and diisopropylethylamine (0.24 ml) were simultaneously added dropwise under ice cooling, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 1 hour. did. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with water and brine in this order. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Merck silica gel 6).
0 9385 200 ml) and eluted with ethyl acetate: methanol (95: 5) to obtain amorphous (1R, 5S, 6S) -2-[(2S, 4S) -2
-[3- (N-4-Nitrobenzyloxycarbonylacetimidoylamino) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio] -6-[(1R)- 1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.
77 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1773,1709,1607,1549,1522,1448,1346,1225 Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.27,
1.28 (3H, d × 2, J = 7.33Hz), 1.36 (3H, d, J = 6.35Hz), 1.47-2.
28 (3H, m), 2.19,2.22 (3H, s × 2), 2.50-2.83 (1H, m), 3.26-
3.52 (3H, m), 3.59-3.78 (1H, m), 3.70-4.84 (9H, m), 5.06-5.
51 (6H, m), 7.48-7.66 (6H, m), 8.19-8.23 (6H, m) (2) The compound (0.77g) obtained in (1) was added to tetrahydrofuran-water (2: 1, 15ml). , 10% palladium carbon catalyst (0.77 g) was added, and hydrogenation was carried out at room temperature for 2 hours. The catalyst was removed by filtration, the filtrate was washed with ether, and the aqueous layer was concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography (Cosmo Nacalai Tesque seal 75C ₁₈ -PREP100ml), 4% acetonitrile - from fractions eluted with water, concentrated fractions containing the desired compound, by freeze drying, A powdery title compound (0.13 g) was obtained.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 30
0 Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1755,1633,15
91,1463,1389,1286,1262 Nuclear magnetic resonance spectrum (270MH
z, D ₂ O, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3H, d, J = 6.84Hz), 1.30 (3H, d, J =
6.35Hz), 1.64-1.74 (1H, m), 2.25-2.35 (3H, m), 2.58-2.70
(1H, m), 2.98-3.04 (1H, m), 3.20 (1H, dddJ = 12.21,5.86,
2.44Hz), 3.34-3.45 (1H, m), 3.44 (1H, dd, J = 6.35,2.44H
z), 3.73-3.88 (2H, m), 4.03-4.10 (1H, m), 4.19-4.37 (3H,
m), 4.41-4.90 (3H, m) Example 3 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(3-Formimidoylaminoazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0073]

[Chemical 19]

(1R, 5R, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-oxo-1
-Carbapenam-3-carboxylic acid 4-nitrobenzyl ester (0.12 g) and (2S, 4S) -4-mercapto-2- [3- (N-4-nitrobenzyloxycarbonylformimidoylamino) azetidine-1- Iylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (0.17 g) was treated, treated and purified in the same manner as in Example 2 to give the title compound in powder form (19 m
g) was obtained.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 301 Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1754,1645,1
592,1463,1388,1319,1289,1262.Nuclear magnetic resonance spectrum (270MHz, D ₂ O, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3
H, d, J = 7.22Hz), 1.30 (3H, d, J = 6.33Hz), 1.66-1.76 (1H, m),
2.61-2.75 (1H, m), 3.01-3.13 (1H, m), 3.20-3.30 (1H, m), 3.
35-3.48 (2H, m), 3.76-3.98 (2H, m), 4.04-4.13 (1H, m), 4.20
-4.56 (4H, m), 4.61-4.88 (2H, m), 7.87,7.88 (1H, s × 2) Example 4 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(3-Aminoazetidin-1-ylcarbonyl) -1-
Methylpyrrolidin-4-ylthio] -6-[(1R)-
1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0076]

[Chemical 20]

(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (0.
70 g) in dry acetonitrile (14 ml) solution under ice-cooling (2S, 4S) -4-mercapto-1-methyl-2.
-[3- (4-Nitrobenzyloxycarbonylamino) azetidin-1-ylcarbonyl] pyrrolidine (0.
A solution of 42 g) in dry acetonitrile (10 ml) and diisopropylethylamine (0.18 ml) were simultaneously added dropwise, and the mixture was allowed to stand at the same temperature for 2 days. The reaction solution is concentrated under reduced pressure,
The residue was diluted with ethyl acetate and washed successively with water and brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Merck & Co., Inc. silica gel 60 9385 100 ml) and eluted with acetonitrile: methanol (95: 5) to give an amorphous form. (1R, 5S, 6S)
-2-[(2S, 4S) -1-methyl-2- [3- (4
-Nitrobenzyloxycarbonylamino) azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.25 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1771,1723,1641,1608,1522,1455,1347 Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O), δppm:
1.27,1.28 (3H, d × 2, J = 7.33,6.84Hz), 1.36 (3H, d, J = 5.86H
z), 1.85-2.04 (1H, m), 2.33,2.37 (3H, s × 2), 2.67-2.80 (2
H, m), 3.03-3.39 (4H, m), 3.65-3.73 (1H, m), 3.90-3.95 (1H,
m), 4.10-4.83 (6H, m), 5.09-5.52 (4H, m), 7.47-7.67 (4H,
m), 8.15-8.26 (4H, m) (2) The compound (0.25 g) obtained in (1) was dissolved in tetrahydrofuran: water (6: 5, 5.5 ml) to obtain a 10% palladium carbon catalyst (0.25 g). ) Was added and hydrogenation was performed at room temperature for 90 minutes. The catalyst was removed by filtration, the filtrate was washed with ether, and the aqueous layer was concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography (Nacalai Tesque Cosmo Seal 7
5C ₁₈ -PREP 25 ml), and the fraction containing the desired compound was concentrated and freeze-dried from the fraction eluted with 5% acetonitrile-water to give the title compound (0.05 g) as a powder. .

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 301 Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1755,1641,15
98,1462,1386,1284,1255 Nuclear magnetic resonance spectrum (270MH
z, D ₂ O, internal standard sodium trimethylsilylpropionate −d ₄ ) 1.21 (3H, d, J = 7.33Hz), 1.30 (3H, d, J = 6.35Hz),
1.75-1.85 (1H, m), 2.46,2.47 (3H, s × 2), 2.79-2.89 (1H,
m), 2.97-3.07 (1H, m), 3.22-3.53 (4H, m), 3.90-4.06 (2H,
m), 4.13-4.29 (4H, m), 4.35-4.44 (1H, m), 4.54-4.84 (1H, m) Example 5 (1R, 5S, 6S) -2-[(2S, 4S) -2 −
(3-acetimidoylaminoazetidin-1-ylcarbonyl) -1-methylpyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0080]

[Chemical 21]

(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (5
95 mg) in a solution of dry acetonitrile (10 ml) under ice-cooling (2S, 4S) -4-mercapto-1-methyl-2.
-[3- (N-4-Nitrobenzyloxycarbonylacetimidoylamino) azetidin-1-ylcarbonyl] pyrrolidine (435 mg) in dry acetonitrile (4
ml) solution and diisopropylethylamine (174 μl)
Was added dropwise at the same time, the mixture was reacted at the same temperature for 20 minutes, then left at room temperature for 3 hours and then left in the refrigerator overnight. The reaction solution was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel. The fractions eluted with methylene chloride: ethyl acetate: methanol = 2: 2: 1 were combined and concentrated. And powder (1R, 5S, 6S)
-2-[(2S, 4S) -1-methyl-2- [3- (N
-4-Nitrobenzyloxycarbonylacetimidoylamino) azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em -3
-Carboxylic acid 4-nitrobenzyl ester (464m
g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ^-1 :
1771,1690,1607,1549,1521,1455,1378,1346 Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ + D ₂ O) δppm ：
1.16 (6H, d, J = 6.83Hz), 1.59-1.74 (1H, m), 2.11 (3H, s), 2.2
9 (3H, br-s), 2.54-3.19 (3H, m), 3.27 (1H, dd, J = 6.35,2.44H
z), 3.32-4.27 (8H, m), 4.42-4.60 (2H, m), 5.11-5.49 (4H,
m), 7.60,7.61 (2H, d × 2, J = 8.79Hz), 7.70,7.72 (2H, d × 2, J
= 8.79Hz), 8.16-8.28 (4H, m) (2) The compound (453mg) obtained in (1) was dissolved in tetrahydrofuran: water (2: 1, 21ml), and 10% palladium-carbon catalyst (500mg) was added. Was added and hydrogenation was carried out at room temperature for 1.5 hours. The catalyst was removed by filtration, the filtrate was washed with ether, the aqueous layer was concentrated under reduced pressure, and the residue was eluted with 8% acetonitrile-water by reverse-phase column chromatography (Nacalai Tes Co., Cosmosil 75C ₁₈ -PREP 40 ml). From the fractions obtained, the fraction containing the desired compound was concentrated and freeze-dried to obtain the title compound (166 mg) as a powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 301 Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1757,1633,15
92,1462,1386,1335,1284,1256 Nuclear magnetic resonance spectrum (270MHz, D ₂ O, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.21 (3
H, d, J = 6.83Hz), 1.30 (3H, d, J = 6.35Hz), 1.64-1.78 (1H, m),
2.27 (3H, s), 2.29 (3H, s), 2.63-2.85 (2H, m), 3.01-3.21 (2
H, m), 3.27-3.46 (2H, m), 3.75-3.88 (1H, m), 4.00-4.10 (1H,
m), 4.15-4.96 (6H, m) Example 6 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(3-Formimidoylaminoazetidin-1-ylcarbonyl) -1-methylpyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0084]

[Chemical formula 22]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester (0.35 g)
And (2S, 4S) -4-mercapto-1-methyl-2-
[(3- (N-4-nitrobenzyloxycarbonylformimidoylamino) azetidin-1-ylcarbonyl] pyrrolidine (0.22 g) was subjected to the same reaction, treatment and purification as in Example 5 to give a powder. Title compound (17m
g) was obtained.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 302 Example 7 (1R, 5S.6S) -2-[(2S, 4S) -2-
[3-azetidinylaminocarbonyl] pyrrolidine-4
-Ilthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0087]

[Chemical formula 23]

(1R, 5R.6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester (0.80 g)
And (2S, 4S) -4-mercapto-2- [1- (4-
Example 4 from nitrobenzyloxycarbonyl) azetidin-3-ylaminocarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (0.95 g).
The reaction, treatment and purification were carried out in the same manner as in, to obtain the title compound (86 mg) as a powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 301. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1754,1590,1
450,1389,1287,1264. Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3H,
d, J = 7.25Hz), 1.30 (3H, d, J = 6.36), 1.83-1.93 (1H, m), 2.72
-2.82 (1H, m), 2.88 (1H, dd, J = 11.64,5.19Hz), 3.34-3.48 (3
H, m), 3.65-3.82 (4H, m), 4.04 (1H, t, J = 11.67Hz), 4.19-4.2
9 (2H, m), 4.34 (1H, dd, J = 9.02,5.98Hz), 4.40-4.48 (1H, m) Example 8 (1R, 5S.6S) -2-[(2S, 4S) -2 −
(3-aceimidoylaminoazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R)
-1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid hydrochloride

[0090]

[Chemical formula 24]

The compound (0.40) obtained in Example 2- (2)
g) was dissolved in cold water (20 ml), 1N-hydrochloric acid (0.88 ml) was added and freeze-dried to obtain the target compound (400 mg) as a colorless powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 296. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1760,1664,1
630,1585,1463,1378,1286,1148 Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.01 (3
H, d, J = 7.17Hz), 1.09 (3H, d, J = 6.37Hz), 1.76-1.86 (1H, m),
2.07 (3H, s), 2.70-2.82 (1H, m), 3.10-3.30 (3H, m), 3.55 (1
H, dd, J = 12.9,6.54Hz), 3.78-3.96 (2H, m), 4.00-4.17 (3H,
m), 4.26-4.67 (4H, m) Example 9 (1R, 5S.6S) -2-[(2S, 4S) -2-
(3-Dimethylaminoazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid

[0093]

[Chemical 25]

(1) (1R, 5R.6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-
A solution of em-3-carboxylic acid 4-nitrobenzyl ester (1.43 g) in dry acetonitrile (25 ml) was cooled with (2S, 4S) -2- (3-dimethylaminoazetidin-1-ylcarbonyl)-. 4-mercapto-1-
A solution of (4-nitrobenzyloxycarbonyl) pyrrolidine (0.98 g) in dry acetonitrile (20 ml) and diisopropylethylamine (0.418 ml) were added dropwise at the same time,
The mixture was stirred at the same temperature for 2 hours. After leaving it in the refrigerator overnight, the reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel, and the fractions eluted with ethyl acetate / methanol = 75/25 were combined and concentrated to give a powder (1R , 5S.6S) -2-[(2S, 4S)-
2- (3-Dimethylaminoazetidin-1-ylcarbonyl) -1- (4-nitrobenzyloxycarbonyl)
Pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-
Obtained em-3-carboxylic acid 4-nitrobenzyl ester (1.16 g).

Infrared absorption spectrum (KBr) ν _max c
m- ¹ : 1774, 1712, 1663, 160
7, 1522, 1456, 1404, 1346 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ +
D ₂ O) δppm: 1.26 (3H, d, J = 7.11Hz), 1.36 (3H, d, J = 6.13H
z), 2.00-2.18 (1H, m), 2.10,2.14,2.25,2.28 (6H, s × 4), 2.
51-2.73 (1H, m), 2.86-4.56 (13H, m), 5.08-5.54 (4H, m), 7.5
0 (2H, d, J = 8.57Hz), 7.65 (2H, d, J = 8.57Hz), 8.23 (4H, d, J =
8.57Hz) (2) The compound (0.75 g) obtained in (1) was dissolved in a mixed solvent of tetrahydrofuran (21 ml) and water (14 ml), 10% palladium-carbon catalyst (0.75 g) was added, and the mixture was stirred at room temperature for 1. Hydrogenation was carried out for 5 hours. The catalyst was removed by filtration, the filtrate was washed with ether, the aqueous layer was concentrated under reduced pressure, and the residue was subjected to reverse-phase column chromatography (Nacalai Tesque, Cosmo Seal 75C ₁₈ -PREP.25g) to give 7% aqueous acetonitrile. Fractions containing the desired compound were concentrated and lyophilized from the more eluted fractions to obtain the target compound (171 mg) in powder form.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 299. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1757,1653,1
599,1462,1385,1284,1259,1150. Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3
H, d, J = 7.22Hz), 1.30 (3H, d, J = 6.40Hz), 1.83-1.92 (1H, m),
2.41 (3H, s), 2.45 (3H, s), 2.78-2.89 (1H, m), 3.26 (1H, dd, J
= 12.14,4.90Hz), 3.34-3.73 (4H, m), 3.89-4.06 (2H, m), 4.1
9-4.33 (5H, m) 4.43-4.54 (1H, m). Example 10 (1R, 5S.6S) -2-[(2S, 4S) -2-
[3- (1-Imidazolyl) azetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R)
-1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0097]

[Chemical formula 26]

(1) (1R, 5R.6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-
A solution of em-3-carboxylic acid 4-nitrobenzyl ester (4.27 g) in dry acetonitrile (55 ml) was cooled with ice (2S, 4S) -2- [3- (1-imidazolyl).
Azetidin-1-ylcarbonyl] -4-mercapto-
1- (4-Nitrobenzyloxycarbonyl) pyrrolidine (3.10 g) in dry acetonitrile (25 ml) and diisopropylethylamine (1.25 ml) were added dropwise at the same time, and the mixture was left at the same temperature for 1 hour and then left in the refrigerator overnight. The reaction solution was concentrated, diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure,
The residue was subjected to column chromatography using silica gel, methylene chloride / ethyl acetate / methanol = 7/7.
The fractions eluted at / 6 are combined and concentrated to give a powder (1R,
5S, 6S) -2-[(2S, 4S) -2- [3- (1
-Imidaryl) azetidin-1-ylcarbonyl] -1
-(4-Nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-
Carboxylic acid 4-nitrobenzyl ester (2.94 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ^-1 :
1772,1708,1667,1607,1522,1449,1403,1346,1209. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm
: 1.27 (3H, d, J = 7.19Hz), 1.
36 (3H, d, J = 6.14 Hz), 2.15-5.
55 (19H, m), 7.10-8.28 (11H,
m) The compound (0.25 g) obtained in (2) (1) was dissolved in a mixed solvent of tetrahydrofuran (7.5 ml) and water (7.5 ml), 10% palladium carbon catalyst (0.25 g) was added,
Hydrogenation was carried out at room temperature for 1.5 hours. The catalyst was removed by filtration, the filtrate was washed with ether, the aqueous layer was concentrated under reduced pressure, and the residue was subjected to reverse phase column chromatography (Nacalai Tesque, Cosmo Seal 75C ₁₈ -PREP 30 g).
The fraction containing the desired compound was concentrated and lyophilized from the fraction eluted with 7% aqueous acetonitrile to give the target compound (70 mg) in the form of powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 297. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1757,1660,1
598,1466,1383,1285,1255,1181,1149. Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3
H, d, J = 7.12Hz), 1.30 (3H, d, J = 6.27Hz), 1.90-2.02 (1H, m),
2.84-2.95 (1H, m), 3.29-3.50 (3H, m), 3.56-3.65 (1H, m), 3.
91-4.03 (1H, m), 4.20-4.43 (4H, m), 4.50-5.45 (4H, m), 7.2
2,7.23 (1H, s × 2), 7.54 (1H, s), 8.12 (1H, s). Example 11 (1R, 5S.6S) -2-[(2S, 4S) -2-
(3-Aminoazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-
3-carboxylic acid

[0101]

[Chemical 27]

Compound obtained in Example 1- (1) (3630 mg)
Was dissolved in tetrahydrofuran-water (3: 2,190 ml), 10% palladium carbon catalyst (5500 mg) was added, and the mixture was added to 30
Hydrogenation was carried out at 1.5 ° C. for 1.5 hours. The catalyst was filtered off, the filtrate was washed with ether and the water bath was concentrated under reduced pressure to 10 ml. The solution reversed phase silica gel chromatography (Nacalai Tesque, Cosmosil 75C ₁₈ -pre
P. 250 ml), and acetonitrile-water (0:10)
0, 2:98, 4:96, 6:94).
The target fractions were collected, concentrated, and lyophilized to give the title compound (901 mg) as a powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 298.5. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1755,1642,1
594,1464,1387. Nuclear magnetic resonance spectrum (270MHz, D ₂ O, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3H,
d, J = 7.2Hz), 1.29 (3H, d, J = 5.3Hz), 1.75-1.85 (1H, m), 2.70
-2.83 (1H, m), 3.14-3.21 (1H, m), 3.35-3.47 (3H, m), 3.82-
3.92 (1H, m), 3.96-4.03 (1H, m), 4.05-4.18 (2H, m), 4.19-4.
28 (3H, m), 4.34-4.43 (1H, m), 4.56-4.65 (1H, m). Example 12 (1R, 5S.6S) -2-[(2S, 4S) -2-
(3-Methylaminoazetidin-1-ylcarbonyl)
Pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-
M-3-carboxylic acid

[0104]

[Chemical 28]

(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (5
58 mg) in a solution of dry acetonilotril (12 ml) under ice-cooling (2S, 4S) -4-mercapto-2- [3-
[N-methyl-N (4-nitrobenzyloxycarbonyl) amino] azetidin-1-ylcarbonyl] -1-
A solution of (4-nitrobenzyloxycarbonyl) pyrrolidine (538 mg) in dry acetonitrile (6 ml) and diisopropylethylamine (172 μl) were simultaneously added dropwise, and the mixture was allowed to stand at the same temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with water and brine in this order. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Merck silica gel 60, 9385, 70 ml), and methylene chloride: ethyl acetate: methanol (50:50:50).
Amorphous (1R, 5
S, 6S) -2-[(2S, 4S) -2- [3- [N-
Methyl-N (4-nitrobenzyloxycarbonyl) amino] azetidin-1-ylcarbonyl] -1- (4-
Nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-Methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (725 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ^-1 :
1773,1708,1666,1607,1522,1449,1404,1346. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.27 (3
H, d, J = 7.27Hz), 1.37 (3H, d, J = 6.37Hz), 2.01-2.20 (1H, m),
2.52-2.72 (1H, m), 2.79,2.90,3.03,3.05 (3H, s × 4), 3.25-
3.74 (4H, m), 3.96-5.40 (9H, m), 5.15-5.54 (6H, m), 7.47-7.
56 (4H, m), 7.65 (2H, d, J = 8.64Hz), 8.20-8.26 (6H, m). (2) The compound (0.70 g) obtained in (1) was converted into tetrahydrofuran: water (1: 1,26 ml), 10% palladium-carbon catalyst (0.80 g) was added, and hydrogenation was carried out at room temperature for 2 hours. The catalyst was removed by filtration, the filtrate was washed with ether, the aqueous layer was concentrated under reduced pressure, and the residue was subjected to reverse-phase column chromatography (Nacalai Tesque Cosmo Seal 7
5C ₁₈ -PREP (70 ml) and eluted with an 8% aqueous acetonitrile solution, the fraction containing the desired compound was concentrated and freeze-dried to give the title compound (0.18 g) as a powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 299. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1754,1648,1
596,1464,1387,1287,1259,1181,1149. Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3
H, d, J = 7.22Hz), 1.30 (3H, d, J = 6.43Hz), 1.72-1.81 (1H, m),
2.57,2.58 (3H, s × 2), 2.67-2.79 (1H, m), 3.06-3.17 (1H,
m), 3.31-3.48 (3H, m), 3.80-3.89 (1H, m), 3.95-4.08 (3H,
m), 4.20-4.43 (4H, m), 4.55-4.66 (1H, m) Example 13 (1R, 5S.6S) -2-[(2S, 4S) -2-
(3-Aminomethyl-3-methylazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0108]

[Chemical 29]

(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (0.
42 g), diisopropylethylamine (0.12 ml) and (2S, 4S) -4-mercapto-2- [3-methyl-
3- (4-Nitrobenzyloxycarbonylaminomethyl) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (0.42 g)
The reaction, treatment and purification were carried out in the same manner as in Example 4- (1) to give amorphous (1R, 5S, 6S) -2.
-[(2S, 4S) -2- [3-Methyl-3- (4-nitrobenzyloxycarbonylaminomethyl) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio ] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.53 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ^-1 :
1773,1713,1656,1608,1522,1451,1346. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.09-
1.33 (6H, m), 1.37 (3H, d, J = 6.33Hz), 1.88-2.23 (2H, m), 2.5
0-2.66 (1H, m), 3.20-4.44 (15H, m), 4.91-5.51 (6H, m), 7.33
-7.66 (6H, m), 8.11-8.24 (6H, m). (2) Using the compound (0.53 g) obtained in (1) and 10% palladium carbon catalyst (0.53 g), Example 4-
Hydrogenation, treatment and purification were carried out in the same manner as in (2) to give the title compound (0.14 g) as a powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 301. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1755,1638,1
591,1471,1455,1387. Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3
H, d, J = 7.22Hz), 1.30 (3H, d, J = 6.26Hz), 1.43 (3H, s), 1.64-
1.72 (1H, m), 2.62-2.70 (1H, m), 3.02-3.07 (1H, m), 3.19-3.
45 (5H, m), 3.76-3.97 (4H, m), 4.03-4.15 (2H, m), 4.19-4.29
(2H, m) Example 14 (1R, 5S.6S) -2-[(2S, 4S) -2-
(3-formimidoylaminomethylazetidine-1-
Ylcarbonyl) pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid

[0112]

[Chemical 30]

(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (1.
97 g) in a solution of dry acetonitrile (30 ml) under ice-cooling (2S, 4S) -4-mercapto-2- [3- (N
-4-Nitrobenzyloxycarbonylformimidoylaminomethyl) azetidin-1-ylcarbonyl]-
A solution of 1- (4-nitrobenzyloxycarbonyl) pyrrolidine trifluoromethanesulfonate (2.74 g) in dry acetonitrile (30 ml) and diisopropylethylamine (1.27 ml) were simultaneously added dropwise, and the mixture was allowed to stand at the same temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with water and brine in this order. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Merck silica gel 60, 9).
385, 240 ml) and distilled from methylene chloride: ethyl acetate: methanol (9: 9: 2) to obtain amorphous (1R, 5S, 6S) -2-[(2S,
4S) -2- [3- (N-4-nitrobenzyloxycarbonylformimidoylaminomethyl) azetidine-
1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (1.76 g) was obtained.

Infrared absorption spectrum (KBr) ν _max c
m- ¹ : 1773, 1708, 1659, 160
6,1521,1446,1404,1375,134
6. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.27 (3H, d, J = 7.32Hz), 1.37 (3H, d, J = 6.19Hz), 1.50
-4.45 (20H, m), 5.15-5.54 (6H, m), 7.46-7.70 (6H, m), 8.15-
8.29 (6H, m) (2) The compound (180 mg) obtained in (1) was dissolved in tetrahydrofuran: water (1: 1,10 ml), 10% palladium carbon catalyst (0.40 g) was added, and the mixture was stirred at room temperature. Hydrogenation was carried out for 2 hours. The catalyst was removed by filtration, the filtrate was washed with ether, and the aqueous layer was concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography (Cosmo Nacalai Tesque seal 75C ₁₈ -PREP.20ml), from the fraction eluted with 7% acetonitrile aqueous solution, enriched fractions containing the desired compound, by lyophilization A powdery title compound (31 mg) was obtained.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 301. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1754,1717,1
638,1591,1472,1389,1289,1263,1182.Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3
H, d, J = 7.24Hz), 1.30 (3H, d, J = 6.19Hz), 1.60-1.73 (1H, m),
2.58-2.71 (1H, m), 2.98-3.24 (3H, m), 3.30-3.48 (2H, m), 3.
60-3.88 (5H, m), 3.98-4.52 (5H, m), 7.85,7.91,7.92 (1H, s
X3) Example 15 (1R, 5S.6S) -2-[(2S, 4S) -2-
(3-Aminomethylazetidin-1-ylcarbonyl)
Pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-
M-3-carboxylic acid

[0116]

[Chemical 31]

(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (0.
60 g), diisopropylethylamine (0.18 ml) and (2S, 4S) -4-mercapto-2- [3- (4-nitrobenzyloxycarbonylaminomethyl) azetidin-1-ylcarbonyl] -1- (4-nitro Using benzyloxycarbonyl) pyrrolidine (0.58 g), the reaction, treatment and purification were carried out in the same manner as in Example 4- (1).
Amorphous (1R, 5S, 6S) -2-[(2
S, 4S) -2- [3- (4-Nitrobenzyloxycarbonylaminomethyl) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio] -6-[(1R ) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.
56 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ^-1 :
1773,1712,1655,1607,1522,1449,1404,1346. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.27 (3
H, d, J = 7.23Hz), 1.37 (3H.d, J = 6.28Hz), 1.66 (1H, s), 2.03-
2.21 (1H, m), 2.51-2.88 (2H, m), 3.27-4.56 (13H, m), 5.02-
5.51 (7H, m), 5.73-5.76 (1H, m), 7.39-7.67 (6H, m), 8.14-8.
23 (6H, m) (2) Using the compound (0.56 g) obtained in (1) and 10% palladium carbon catalyst (0.6 g), Example 4- (2)
Hydrogenation, treatment and purification were carried out in the same manner as in to give the title compound (0.12 g) as a powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 301. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1754,1637,1
588,1475,1391,1289,1263. Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3
H, d, J = 7.16Hz), 1.30 (3H, d, J = 6.23Hz), 1.63-1.70 (1H, m),
2.59-2.69 (1H, m), 3.01-3.13 (2H, m), 3.18-3.22 (1H, m), 3.
23-3.45 (3H, m), 3.44 (1H, dd, J = 6.28,2.56Hz), 3.76-3.8
9 (3H, m), 4.04-4.14 (1H, m), 4.20-4.29 (3H, m), 4.43-4.52
(1H, m) Example 16 (1R, 5S.6S) -2-[(2S, 4S) -2-
(3-Amino-3-methylazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R)-
1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0120]

[Chemical 32]

(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (1.
06 g), diisopropylethylamine (0.31 ml), and (2S, 4S) -4-mercapto-2- [3-methyl-
3- (4-Nitrobenzyloxycarbonylamino) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1.12 g) was used in the same manner as in Example 4- (1). , (1R, 5S, 6S) -2-
[(2S, 4S) -2- [3-Methyl-3- (4-nitrobenzyloxycarbonylamino) azetidine-1-
Ilcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (1.13 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ^-1 :
1774,1713,1656,1608,1522,1445,1347 Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.27 (3H,
d, J = 7.14Hz), 1.37 (3H.dJ = 6.28Hz), 1.51-1.62 (3H, m), 2.
05-2.14 (1H, m), 2.56-2.70 (1H, m), 3.27-4.57 (13H, m), 5.0
5-5.51 (7H, m), 7.46-7.66 (6H, m), 8.22,8.23 (6H, d × 2, J =
8.62 Hz) (2) Using the compound (1.12 g) obtained in (1) and 10% palladium carbon catalyst (1.10 g), Example 4-
Hydrogenation, treatment and purification were carried out in the same manner as in (2) to obtain the title compound (0.144 g) as a powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 299. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1755,1642,1
591,1459,1389,1287,1261. Nuclear magnetic resonance spectrum (270MHz, D ₂ O _, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.22 (3
H, d, J = 7.26Hz), 1.30 (3H, d, J = 6.47Hz), 1.59 (3H, s), 1.76-
1.83 (1H, m), 2.70-2.80 (1H, m), 3.12-3.19 (1H, m), 3.35-3.
46 (2H, m), 3.45 (1Hd, d, J = 6.16,2.56Hz), 3.85-3.88 (1H,
m), 4.04-4.12 (3H, m), 4.21-4.37 (4H, m) Example 17 (1R, 5S.6S) -2-[(2S, 4S) -2-
(3-acetimidoylmethylaminoazetidine-1-
Ylcarbonyl) pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid

[0124]

[Chemical 33]

(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (0.
91 g) and (2S, 4S) -4-mercapto-2- [3-
(N-4-Nitrobenzyloxycarbonylacetimidoylaminomethyl) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine trifluoromethanesulfonate (1.29 g)
From the above, the reaction, treatment and purification were carried out in the same manner as in Example 14- (1) to give amorphous (1R, 5S, 6S)-
2-[(2S, 4S) -2- [3- (N-4-nitrobenzyloxycarbonylacetimidoylaminomethyl) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine-4 -Ilthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.81 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ^-1 :
1773,1709,1660,1607,1557,1521,1445,1403,1373,134
6. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm: 1.
27 (3H, d, J = 7.25Hz), 1.37 (3H, d, J = 6.15Hz), 1.50-4.35 (20
H, m), 5.16-5.54 (6H, m), 7.45-7.70 (6H, m), 8.16-8.30 (6H,
m) (2) The compound (0.78 g) obtained in (1) and 10% palladium-carbon catalyst (0.85 g) were reacted, treated and purified in the same manner as in Example 14- (2) to give a powder. The title compound (0.25 g) was obtained.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 300. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1755,1681,1
. 640,1593,1455,1386,1287,1262,1181 Nuclear magnetic resonance spectrum _(270MHz, D ₂ O, internal standard trimethylsilyl propionic acid sodium _{-d 4) δppm: 1.22 (3H} ,
d, J = 7.25Hz), 1.30 (3H, d, J = 6.33Hz), 1.61-1.71 (1H, m), 2.
24 (3H, s), 2.59-2.70 (1H, m), 2.29-3.23 (3H, m), 3.36-3.48
(2H, m), 3.56 (2H, d, J = 7.44Hz), 3.74-3.86 (3H, m), 3.96-4.
08 (1H, m), 4.17-4.51 (4H, m) Reference Example 1 (2S, 4S) -4-Mercapto-2- [3- (4-nitrobenzyloxycarbonylamino) azetidine-1
-Ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl)-
2-Pyrrolidinecarboxylic acid (2.05 g) was dissolved in dry acetonitrile (20 ml), N, N'-carbonyldiimidazole (0.78 g) was added, and the mixture was stirred at 40 ° C for 1 hr.
This was added dropwise to a solution of 3-aminoazetidine dihydrochloride (1.00 g) and diisopropylethylamine (2.40 ml) in methanol (10 ml) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed successively with water and brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (manufactured by Merck, silica gel 60 9385 100).
g) and eluted with ethyl acetate: methanol (65:35) to give amorphous (2S, 4S)-
2- (3-aminoazetidin-1-ylcarbonyl)-
4- (4-Methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (2.56 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1708, 1660, 1609, 1513, 1442,
1404, 1346, 1248 Nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 1.88-2.04 (1H, m), 2.38-3.20 (4H, m), 3.25
-3.34 (1H, m), 3.67-4.62 (6H, m), 3.72 (2H, s), 3.78,3.79 (3
H, s × 2), 5.09-5.37 (2H, m), 6.84 (2H, d, J = 8.78Hz), 7.22
(2H, d, J = 8.78), 7.45 (2H, d, J = 8.78Hz), 8.21 (2H, d, J = 8.78)
Hz) (2) To a solution of the compound (0.81 g) obtained in (1) in methylene chloride (20 ml), diisopropylethylamine (0.32 g) and p-nitrobenzyl chloroformate (0.
40 g) was added and the mixture was stirred at the same temperature for 40 minutes. The reaction solution was diluted with ethyl acetate, washed successively with water and brine, the ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (40 g of silica gel 609385 manufactured by Merck & Co., Inc.), and amorphous (2S, 4S) -4- (4-) was obtained from the fraction eluted with ethyl acetate: methanol (99: 1). Methoxybenzylthio) -2- [3- (4-nitrobenzyloxycarbonylamino) azetidin-1-ylcarbonyl]
-1- (4-Nitrobenzyloxycarbonyl) pyrrolidine (0.64 g) was obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _max c
m ^-1 : 1725,1662,1608,1521,1440,1347,1250 Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.94-2.0
4 (1H, m), 2.31-2.48 (1H, m), 3.04-3.12 (1H, m), 3.26-3.34
(1H, m), 3.72 (2H, s), 3.79 (3H, s), 3.81-3.99 (1H, m), 4.08-
4.87 (6H, m), 5.09-5.72 (5H, m), 6.82-6.87 (2H, m), 7.23 (2
H, d, J = 8.30), 7.45,7.50 (4H, d × 2, J = 8.79Hz), 8.22,8.23
(4H, d × 2, J = 8.79Hz) (3) The compound (0.59g) obtained in (2) was suspended in anisole (0.94ml), and trifluoroacetic acid (3.
32 ml) and trifluoromethanesulfonic acid (0.15 ml) were added dropwise, and the mixture was stirred at the same temperature for 1 hour. 1,2-Dichloroethane was added to the reaction solution, the solvent was distilled off, and the residue was washed by repeating tecantation with hexane and ether in this order.

The residue was diluted with ethyl acetate, made alkaline with sodium bicarbonate water, the ethyl acetate layer was washed with water and brine in this order, dehydrated with magnesium sulfate, and concentrated under reduced pressure to give the amorphous title compound. A compound (0.44 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1709,1656,1521,1440,1405,1347,1257 Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ ) δppm: 1.62
-1.85 (1H, m), 2.56-2.69 (1H, m), 3.05-3.25 (2H, m), 3.70-
4.55 (8H, m), 5.08-5.28 (4H, m), 7.55-7.65 (4H, m), 8.11-8.
25 (5H, m) Reference Example 2 (2S, 4S) -4-Mercapto-2- [3- (N-4
-Nitrobenzyloxycarbonylacetimidoylamino) azetidin-1-ylcarbonyl] -1- (4-
Nitrobenzyloxycarbonyl) pyrrolidine (1) The compound (0.78 g) obtained in Reference Example 1- (1) was dissolved in ethyl acetate (15 ml), and 4N hydrogen chloride-ethyl acetate solution (0.78 ml) was added under ice cooling. , Ether was added to the reaction solution, the powder was filtered off and dried, and (2S, 4S) -2- (3-
Aminoazetidin-1-ylcarbonyl) -4- (4-
Methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidine hydrochloride (0.79 g) was obtained.

The above compound (0.78 g) was suspended in dry acetonitrile (20 ml), N- (4-nitrobenzyloxycarbonyl) acetamidine (0.51 g) was added, and 50
Stir at 80 ° C. for 80 minutes. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck silica gel 6
0 9385 150 ml) and eluted with ethyl acetate: methanol (95: 5) to obtain amorphous (2S, 4S) -4- (4-methoxybenzylthio).
2- [3- (N-4-nitrobenzyloxycarbonylacetimidoylamino) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (0.99 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1707, 1667, 1608, 1551, 1520,
1442, 1346, 1238 Nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 1.29-2.59 (7H, m), 3.05-3.14 (1H, m), 3.26
-3.34 (1H, m), 3.67-4.86 (6H, m), 3.73 (2H, s), 3.79 (3H, s),
5.09-5.33 (4H, m), 6.85 (2H, d, J = 8.79Hz), 7.23 (2H, d, J = 8.
79Hz), 7.44-7.65 (4H, m), 8.19-8.25 (4H, m) (2) The compound (0.99g) obtained in (1) was converted to anisole (1.
49 ml), and under ice cooling, trifluoroacetic acid (10 ml)
And trifluoromethanesulfonic acid (0.24 ml) were added dropwise, and the mixture was stirred at the same temperature for 40 minutes and then at room temperature for 50 minutes, 1,2-dichloroethane was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was washed by repeating decantation in the order of hexane and ether, diluted with ethyl acetate, made alkaline with sodium bicarbonate water, and the ethyl acetate layer was washed with water and brine in this order, and then with sulfuric acid. By dehydrating with magnesium and concentrating under reduced pressure, an amorphous title compound (0.82 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1706,1664,1607,1551,1521,1442,1346,1228 Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.73-
2.65 (4H, m), 2.23 (3H, s), 3.23-3.54 (2H, m), 3.78-4.94 (7
H, m), 5.11-5.37 (4H, m), 7.48-7.59 (4H, m), 8.22,8.23 (4H,
d × 2, J = 8.79 Hz) Reference Example 3 (2S, 4S) -4-Mercapto-2- [3- (N-4
-Nitrobenzyloxycarbonylformimidoylamino) azetidin-1-ylcarbonyl] -1- (4-
Nitrobenzyloxycarbonyl) pyrrolidine (2S, 4S) -2- (3-aminoazetidin-1-ylcarbonyl) -4- (4-methoxybenzylthio)-
1- (4-Nitrobenzyloxycarbonyl) pyrrolidine Hydrochloride and N- (4-nitrobenzyloxycarbonyl) formamidine were obtained in the same manner as in Reference Example 2 to obtain the title compound.

Reference Example 4 (2S, 4S) -4-Mercapto-1-methyl-2-
[3- (4-nitrobenzyloxycarbonylamino)
Azetidin-1-ylcarbonyl] pyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio) -1-methyl-2-pyrrolidinecarboxylic acid (1.62
g) was suspended in dry acetonitrile (20 ml),
N, N'-Carbonyldiimidazole (1.02 g) was added, and the mixture was stirred at 40 ° C for 45 minutes. To this, a solution of 3-aminoazetidine dihydrochloride (1.00 g) and diisopropylethylamine (2.40 ml) in methanol (10 ml) was added dropwise under ice cooling, and after stirring at the same temperature for 90 minutes,
The reaction solution was concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography (Nacalai Tesque Cosmo Seal 75C ₁₈ -P
REP145 g) and eluted with 30% acetonitrile-water to give a colorless oily (2S, 4S) -2-
(3-Aminoazetidin-1-ylcarbonyl) -4-
(4-Methoxybenzylthio) -1-methylpyrrolidine (1.21 g) was obtained.

Infrared absorption spectrum (CDCl ₃ ) ν _max c
m ^-1 : 1618,1510,1465,1246,1176 Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.77-
2.00 (3H, m), 2.30 (3H, s), 2.45-2.56 (2H, m), 2.88-2.95 (1
H, m), 3.00-3.16 (2H, m), 3.70 (2H, m), 3.80 (3H, m), 3.65-4.
06 (3H, m), 4.23-4.33 (1H, m), 4.50-4.68 (1H, m), 6.81-6.87
(2H, m), 7.18-7.24 (2H, m) (2) To a solution of the compound (0.60g) obtained in (1) in methylene chloride (18ml), diisopropylethylamine (0.38ml) and chloroform were added under ice cooling. Acid p-nitrobenzyl (0.
46 g) was added and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed successively with water and brine, the ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (40 g of silica gel 609385 manufactured by Merck & Co., Inc.), and from the fraction eluted with ethyl acetate: methanol (95: 5), amorphous (2S, 4S) -4- (4- Methoxybenzylthio) -1-methyl-2- [3- (4-nitrobenzyloxycarbonylamino) azetidin-1-ylcarbonyl] pyrrolidine (0.85 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1725,1637,1610,1512,1463,1346,1251 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.77
-1.95 (1H, m), 2.32, 2.36 (3H,
s × 2), 2.49-2.66 (2H, m), 2.98
-3.14 (3H, m), 3.69 (2H, s), 3.
80 (3H, s), 3.73-3.94 (1H, m),
4.11-4.83 (4H, m), 5.20 (2H,
m), 5.40-5.51 (1H, m), 6.81-
6.87 (2H, m), 7.18-7.22 (2H,
m), 7.51 (2H, d, J = 8.79Hz), 8.
22 (2H, d, J = 8.79Hz) (3) The compound (0.73g) obtained in (2) was dissolved in anisole (1.53ml), and trifluoroacetic acid (7.25g) under ice cooling.
ml) and trifluoromethanesulfonic acid (0.25 ml) were added dropwise, and the mixture was stirred at room temperature for 90 minutes, 1,2-dichloroethane was added to the reaction solution, and the solvent was evaporated. The residue was washed with hexane and ether in this order by repeating decantation. The residue was diluted with ethyl acetate, made alkaline with sodium bicarbonate water, the ethyl acetate layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the amorphous title compound (420 mg). Obtained.

Infrared absorption spectrum (film) ν _max cm ⁻¹ :
1721,1638,1609,1522,1460,1347,1258 Nuclear magnetic resonance spectrum (270MHz, CDClO ₃ ) δppm: 1.85-
2.12 (2H, m), 2.35,2.37 (3H, s × 2), 2.63-2.82 (2H, m), 3.00
-3.10 (2H, m), 3.30 (1H, br.s), 3.86-3.96 (1H, m), 4.08-4.7
9 (4H, m), 5.21 (2H, s), 5.40-5.62 (1H, m), 7.51 (2H, d, J = 8.7
9Hz), 8.22 (2H, d, J = 8.79Hz) Reference Example 5 (2S, 4S) -4-Mercapto-1-methyl-2-
[3- (N-4-nitrobenzyloxycarbonylacetimidoylamino) azetidin-1-ylcarbonyl] pyrrolidine (1) The compound (540 mg) obtained in Reference Example 4- (1) was chlorinated with ethyl acetate (15 ml). Dissolve in methylene (5 ml),
A 4N hydrogen chloride-ethyl acetate solution (1.61 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. After diluting with ether,
The powder was filtered off and dried to give the hydrochloride salt (650 mg).

Then, the hydrochloride (650 mg) and N- (4-nitrobenzyloxycarbonyl) acetamidine (41
5 mg) and diisopropylethylamine (277 μl) were suspended in dry acetonitrile (10 ml) at 55 ° C., 1
Stir for hours. The insoluble material was filtered off from the reaction solution, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, methylene chloride: ethyl acetate: methanol = 45: 4.
Powdered (2S, 4S) -4 from the fraction eluted at 5: 5
-(4-Methoxybenzylthio) -1-methyl-2-
[3- (N-4-nitrobenzyloxycarbonylacetimidoylamino) azetidin-1-ylcarbonyl] pyrrolidine (622 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1682,1638,1609,1553,1512,1454,1346,1225,1190,1080 Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm: 1.
60-2.38 (7H, m), 2.43-2.68 (2H, m), 2.83-3.20 (3H, m), 3.69
(2H, s), 3.79 (3H, s), 3.84-5.02 (5H, m), 5.22 (2H, s), 6.84
(2H, d, J = 8.79Hz), 7.20 (2H, d, J = 8.79Hz), 7.51-7.62 (2H,
m), 8.15-8.28 (2H, m) (2) The compound (610 mg) obtained in (1) was dissolved in anisole (1.19 ml), and trifluoroacetic acid (4.23
ml) and trifluoromethanesulfonic acid (193 μl) were added, and the mixture was stirred under the same conditions for 1 hour and further at room temperature for 1 hour. The solvent was evaporated, the residue was washed with hexane and diethyl ether, and dried under reduced pressure to give a powdery trifluoromethanesulfonate salt. In this compound,
Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to make the mixture alkaline, the ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (448 mg) as a powder.

Infrared absorption spectrum (film) ν _max cm ⁻¹ :
1642,1608,1554,1522,1465,1347,1237,1193 Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm: 1.
81-1.98 (1H, m), 2.07-3.50 (11H, m), 3.83-5.02 (5H, m), 5.2
2,5.28 (2H, s × 2), 7.50-7.62 (2H, m), 8.15-8.28 (2H, m) Reference Example 6 (2S, 4S) -4-Mercapto-1-methyl-2-
[3- (N-4-nitrobenzyloxycarbonylformimidoylamino) azetidin-1-ylcarbonyl] pyrrolidine (2S, 4S) -2- (3-aminoazetidin-1-ylcarbonyl) -4- (4 -Methoxybenzylthio)-
The title compound was obtained from 1-methylpyrrolidine hydrochloride and N- (4-nitrobenzyloxycarbonyl) formamidine in the same manner as in Reference Example 5.

Reference Example 7 (1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (1R, 5R, 6S) -2-oxo-6-[(1R)-
1-Hydroxyethyl] -1-methyl-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (3.
63 g) was dissolved in dry acetonitrile (72 ml), and diphenylphosphoryl chloride (2.28 ml) and diisopropylethylamine (1.92 ml) were added dropwise under ice-cooling stirring. After stirring for 1 hour under the same conditions, the reaction solution was concentrated. The residue was dissolved in ethyl acetate and washed with water (twice) and brine successively,
It was dried over sodium sulfate and concentrated. The residue was dissolved in ethyl acetate (10 ml) and allowed to stand, to precipitate crystals. After diluting with isopropyl ether (500 ml), the crystals formed were collected by filtration and dried. Colorless needle crystals (5.34 g) were obtained.

Melting point 123-125 ° C. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.22 (3
H, d, J = 7.2Hz), 1.33 (3H, d, J = 6.6Hz), 3.32 (1H, dd, J = 6.6,
2.6Hz), 3.42-3.56 (1H, m), 4.20-4.31 (2H, m), 5.22 (1H, d, J
= 13.8Hz), 5.35 (1H, d, J = 13.8Hz), 7.13-7.40 (10H, m), 7.55
(1H, d, J = 8.6Hz), 8.13 (2H, d, J = 8.6Hz) Reference Example 8 (2S, 4S) -4-mercapto-2- [1- (4-nitrobenzyloxycarbonyl) azetidine- 3-ylaminocarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine Infrared absorption spectrum (Liquid film) ν _max cm ⁻¹ : 170
9,1662,1609,1523,1435,1406,1348,1287. Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ + D ₂ O) δppm:
1.86-2.04 (1H, m), 2.65-2.80 (1H, m), 2.98-3.61 (5H, m), 3.
87-4.53 (4H, m), 5.08-5.27 (4H, m), 7.51-7.67 (4H, m), 8.14
-8.26 (4H, m) Reference Example 9 (2S, 4S) -2- (3-Dimethylaminoazetidin-1-ylcarbonyl) -4-mercapto-1- (4-
Nitrobenzyloxycarbonyl) pyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl)-
2-Pyrrolidinecarboxylic acid (2.05 g) was dissolved in dry acetonitrile (20 ml), N, N′-carbonyldiimidazole (0.78 g) was added, and the mixture was stirred at 40 ° C. for 1 hr. This was mixed with 3-aminoazetidine dihydrochloride (1.00 g) and diisopropylethylamine (2.40 ml) in methanol (10 ml).
The mixture was added dropwise to the solution under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed successively with water and brine.
The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (manufactured by Merck & Co., Inc., silica gel 60 9385 100 g), and from a fraction eluted with ethyl acetate: methanol (65:35), amorphous (2S, 4S) -2- (3) was obtained.
-Aminoazetidin-1-ylcarbonyl) -4- (4
-Methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (2.56g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1708,1660,1609,1513,1442,1404,1346,1248. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.88-2.0
4 (1H, m), 2.38-3.20 (4H, m), 3.25-3.34 (1H, m), 3.67-4.62
(6H, m), 3.72 (2H, s), 3.78-3.79 (3H, s × 2), 5.09-5.37 (2
H, m), 6.84 (2H, d, J = 8.78Hz), 7.22 (2H, d, J = 8.78Hz), 7.45
(2H, d, J = 8.78Hz), 8.21 (2H, d, J = 8.78Hz) (2) (2S, 4S) -2- (3-aminoazetidine-
1-ylcarbonyl) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1.75 g) under ice cooling with formic acid (644 mg) and 35%
Formaldehyde solution (750 mg) was added, and the mixture was stirred at 50 ° C. for 5 hours. After diluting with ethyl acetate, the solution was washed with aqueous sodium hydrogen carbonate solution, water, and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was subjected to column chromatography using silica gel, and the fraction eluted with methylene chloride / ethyl acetate / methanol = 45/45/10 gave colorless powder (2S, 4S) -2-
(3-Dimethylaminoazetidin-1-ylcarbonyl) -4- (4-methoxybenzylthio) -1- (4-
Nitrobenzyloxycarbonyl) pyrrolidine (1.45g)
Got

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1710,1664,1609,1513,1442,1403,1345,1248,1172. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm ： 1.86-2.0
5 (1H, m), 2.11,2.13,2.27 (6H, s × 3), 2.34-2.52 (1H, m),
2.83-3.36 (3H, m), 3.73 (2H, s), 3.79,3.80 (3H, s × 2), 3.68
-4.51 (6H, m), 5.05-5.36 (2H, m), 6.85 (2H, d, J = 8.52Hz), 7.
23 (2H, d, J = 8.52Hz), 7.46,7.50 (2H, d × 2, J = 8.57Hz), 8.2
3 (2H, d, J = 8.57Hz) (3) The compound (1.47g) obtained in (2) was anisole.
(3.02 ml), and under ice cooling, trifluoroacetic acid (10.71
ml) and trifluoromethanesulfonic acid (0.488 ml) were added, and the mixture was stirred at the same temperature for 1 hr. The solvent is distilled off and the residue is
-Washing by repeating decantation in the order of hexane and ether. The residue was made alkaline by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give the title compound in powder form (2S, 4S). ) -2- (3-Dimethylaminoazetidin-1-ylcarbonyl) -4-mercapto-1- (4-
Nitrobenzyloxycarbonyl) pyrrolidine (1.01g)
Got

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1710,1645,1607,1517,1459,1432,1403,1343,1169. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.87-2.0
5 (2H, m), 2.11,2.13,2.25 (6H, s × 3), 2.58-2.73 (1H, m),
2.82-3.46 (3H, m), 3.75-4.54 (6H, m), 5.05-5.37 (2H, m), 7.
50 (2H, d, J = 8.57Hz), 8.22 (2H, d, J = 8.57Hz) Reference Example 10 (2S, 4S) -2- [3- (1-Imidazolyl) azetidin-1-ylcarbonyl]- 4-mercapto-1-
(4-Nitrobenzyloxycarbonyl) pyrrolidine (1) To a suspension of sodium hydride (55% content, 2.10 g) in dimethylformamide (25 ml) was added a solution of imidazole (3.20 g) in dimethylformamide (25 ml) under ice cooling. It was After stirring at room temperature for 1 hour, 1-benzhydryl-3-
A solution of methanesulfonyloxyazetidine (5.00 g) in dimethylformamide (50 ml) was added, and the mixture was stirred at 70 ° C for 17 hours. The reaction solution was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography. The fraction eluted with ethyl acetate / methanol = 95/5 was used to give powdery 1-benzhydryl-3- (1-imidazolyl). Azetidine (2.88 g) was caught.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1490,1452,1311,1236,1074,905,755,707.Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 3.23-3.3
5 (2H, m), 3.60-3.69 (2H, m), 4.43 (1H, s), 4.67-4.79 (1H,
m), 7.08-7.69 (13H, m) (2) To the solution of the compound (3.20 g) obtained in (1) in methanol (30 ml) was added 10% hydrogen chloride methanol solution (8.90 ml) under ice cooling. It was Then, 20% palladium hydroxide-carbon catalyst (1.60 g) was added, and hydrogenation was carried out at 50 ° C. for 40 minutes. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was washed with diethyl ether, and dried under reduced pressure to give powdery 3- (1-imidazolyl) azetidine dihydrochloride.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1581,1554,1509,1435,1303,1092,839,637,623 Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ ) δppm: 4.27-
4.35 (2H, m), 4.39-4.46 (2H, m), 5.40-5.50 (1H, m), 7.48 (1
H, s), 8.03 (1H, s), 8.85 (1H, s) (3) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidinecarboxylic acid (3.80 g) to dry acetonitrile (4
0 ml), N, N'-carbonyldiimidazole (1.65 g) was added, and the mixture was stirred at 40 ° C for 1 hr. Into this reaction solution, the compound (2.00 g) obtained in (2) and diisopropylethylamine (2.90 g) were dried in acetonitrile (30 g).
ml) and methanol (5 ml) solution were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with ethyl acetate / methanol = 85/15 was converted into powder (2
S, 4S) -2- [3- (1-Imidazolyl) azetidin-1-ylcarbonyl] -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (4.00 g) was obtained. It was

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1706,1667,1609,1512,1442,1403,1346,1245. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 2.05-3.3
8 (4H, m), 3.75 (2H, s), 3.79 (3H, s), 4.12-5.45 (9H, m), 6.84
-8.29 (11H, m) (4) The compound (4.00 g) obtained in (3) was dissolved in anisole (7.88 ml), and trifluoroacetic acid (27.9
ml) trifluoromethanesulfonic acid (1.27 ml),
It stirred under the same conditions for 1 hour. The solvent is distilled off and the residue is n-
It was washed with hexane and diethyl ether, and dried under reduced pressure to give a powdery trifluoromethanesulfonate. To this compound, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to make it alkaline, the ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound in powder form (3.10 g). It was

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
2606,1746,1722,1623,1569,1468,1419,1378,1344,125
0. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm:
2.01-3.50 (4H, m), 4.00-5.35 (9H, m), 7.10-8.30 (7H, m) Reference Example 11 (2S, 4S) -4-Mercapto-2- [3- [N-methyl-N] (4-Nitrobenzyloxycarbonyl) amino] azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1) trans-4-hydroxy-1- (4-nitrobenzyloxycarbonyl) -L -Proline (628 mg)
Solution of triethylamine (280 μl) and pivaloyl chloride (2 ml) in a dry tetrahydrofuran (6 ml) solution of
49 μl) was added and the mixture was stirred at the same temperature for 20 minutes. Then
3- (N-methyl-N-4-nitrobenzyloxycarbonylamino) azetidine trifluoroacetate (76
To a suspension of 8 mg) in dry tetrahydrofuran (6 ml) was added dropwise a mixture of diisopropylethylamine (353 μl), and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with water and brine in this order. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel, methylene chloride: ethyl acetate:
Fractions eluted with methanol (10: 10: 1) were combined and concentrated to give powdery (2S, 4S) -4-hydroxy-2.
-[3- (N-Methyl-N-4-nitrobenzyloxycarbonyl) aminoazetidin-1-ylcarbonyl]
-1- (4-Nitrobenzyloxycarbonyl) pyrrolidine (815 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
3416,1706,1651,1608,1522,1445,1406,1346,1322. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.64 (1
H, s), 2.09-2.30 (2H, m), 2.71,2.94,3.04,3.06 (3H, s × 4),
3.55-3.80 (2H, m), 3.96-4.31 (3H, m), 4.33-4.48 (2H, m), 4.
50-5.10 (2H, m), 5.13-5.44 (4H, m), 7.45-7.54 (4H, m), 8.19
-8.26 (4H, m) (2) To a solution of the compound (980 mg) obtained in (1) in dry tetrahydrofuran (10 ml) was added triphenylphosphine (922 mg) and diethyl azodicarboxylate (542 μl) under ice cooling. The mixture was stirred at the same temperature for 30 minutes.
Then, thioacetic acid (250 μl) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with water and brine in this order. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, methylene chloride:
From the fraction eluted with ethyl acetate: methanol (100: 100: 3), amorphous (2S, 4S) -4-
Acetylthio-2- [3- (N-methyl-N-4-nitrobenzyloxycarbonyl) aminoazetidine-1-
Ilcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (925 mg) was obtained. Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1706,1666,1
. 607,1522,1444,1404,1346,1322,1169,1112 Nuclear magnetic resonance spectrum _{(270MHz, CDCl 3) δppm:} 1.94-2.
10 (1H, m), 2.34 (3H, s), 2.49-2.65 (1H, m), 2.76,2.93,3.0
3,3.06 (3H, s × 4), 3.77-3.45 (1H, m), 3.87-5.05 (8H, m), 5.
07-5.44 (4H, m), 7.44-7.58 (4H, m), 8.20-8.26 (4H, m) (3) 10% hydrogen chloride methanol solution of compound (878mg) obtained in (2) (5ml) Was stirred at 40 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed successively with aqueous sodium hydrogen carbonate and brine.
The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel, and methylene chloride: ethyl acetate: methanol (4
The fractions eluted at 8: 48: 3) were combined and concentrated to obtain the amorphous title compound (565 mg).

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1706,1664,1607,1521,1443,1404,1346,1322,1169. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.94 (1
H, d, J = 8.81Hz), 1.95-2.09 (1H, m), 2.56-2.72 (1H, m), 2.7
7,2.93,3.04,3.06 (3H, s × 4), 3.20-3.47 (2H, m), 4.00-4.
43 (5H, m), 4.53-5.15 (2H, m), 5.15-5.40 (4H, m), 7.45-7.58
(4H, m), 8.20-8.28 (4H, m) Reference Example 12 (2S, 4S) -4-mercapto-2- [3-methyl-
3- (4-Nitrobenzyloxycarbonylaminomethyl) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio)- 1- (4-nitrobenzyloxycarbonyl)-
2-Pyrrolidinecarboxylic acid (1.0 g) was dissolved in dry acetonitrile (10 ml), N, N'-carbonyldiimidazole (0.44 g) was added, and the mixture was stirred at room temperature for 30 minutes. To this, a mixed solution of 3-tert-butyloxycarbonylaminomethyl-3-methylazetidine hydrochloride (0.64 g) and diisopropylethylamine (0.39 g) in dry acetonitrile (10 ml) was added dropwise at room temperature. Stir at temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water and brine in this order, and then the ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, silica gel 60 9385 100 ml), and from a fraction eluted with cyclohexane: ethyl acetate (9: 1), amorphous (2S, 4S) -2- (3-tert.
-Butyloxycarbonylaminomethyl-3-methylazetidin-1-ylcarbonyl) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1.23 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1709,1657,1609,1522,1514,1449,1443,1404,1347. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.06-1.
28 (3H, m), 1.42-1.45 (9H, m), 1.65 (1H, s), 1.90-2.10 (1H,
m), 2.30-2.47 (1H, m), 2.99-3.39 (4H, m), 3.51-4.33 (6H,
m), 3.73 (2H, s), 3.79,3.80 (3H, s × 2), 5.08-5.38 (2H, m),
6.85 (2H, d, J = 8.57Hz), 7.22-7.26 (2H, m), 7.45-7.53 (2H,
m), 8.22-8.30 (2H, m) (2) Ethyl acetate (6) of the compound (1.20 g) obtained in (1)
4N hydrogen chloride-ethyl acetate solution (4.8 ml)
Was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. Ether was added to the reaction solution, washed by decantation, the residue was diluted with ethyl acetate, made alkaline with sodium bicarbonate water, the ethyl acetate layer was washed with water and brine in this order, and dehydrated with magnesium sulfate, It was concentrated under reduced pressure. This residue was dissolved in dry acetonitrile (10 ml), and diisopropylethylamine (0.30
g) and p-nitrobenzyl chloroformate (0.49 g) in dry acetonitrile (6 ml) were added dropwise and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed successively with water and brine, the ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck,
Silica gel 60 9385 100 ml), and the fraction eluted with ethyl acetate gave an amorphous (2S,
4S) -4- (4-methoxybenzylthio) -2- [3
-Methyl-3- (4-nitrobenzyloxycarbonylaminomethyl) azetidin-1-ylcarbonyl] -1
-(4-Nitrobenzyloxycarbonyl) pyrrolidine (0.56 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1713,1659,1608,1520,1441,1403,1346,1242. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.09-1.
34 (3H, m), 1.93-2.12 (1H, m), 2.32-2.48 (1H, m), 3.04-4.42
(10H, m), 3.73 (2H, s), 3.79,3.80 (3H, s × 2), 4.85-5.37 (4
H, m), 6.84-6.92 (2H, m), 7.23-7.50 (7H, m), 8.11-8.23 (4H,
m) (3) Using anisole (0.83 ml), trifluoroacetic acid (5.4 ml) and trifluoromethanesulfonic acid (0.14 ml) to the compound (0.54 g) obtained in (2), Reference Example 1-
By performing reaction and treatment in the same manner as in (3), the title compound (0.42 g) in an amorphous form was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1710,1656,1608,1521,1441,1404,1347,1243.Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.07-1.
32 (3H, m), 1.90-2.13 (2H, m), 2.55-2.67 (1H, m), 3.14-3.39
(7H, m), 3.42-4.47 (4H, m), 4.89-5.40 (4H, m), 7.28-7.53 (4
H, m), 8.13-8.24 (4H, m) Reference Example 13 (2S, 4S) -4-Mercapto-2- [3- (N-4
-Nitrobenzyloxycarbonylformimidoylaminomethyl) azetidin-1-ylcarbonyl] -1-
(4-Nitrobenzyloxycarbonyl) pyrrolidine
Trifluoromethanesulfonate (1) Compound obtained in Reference Example 12- (1) (3.82)
g) was dissolved in trifluoroacetic acid (15 ml) under ice cooling,
The mixture was stirred at the same temperature for 1 hour. After diluting with 1,2-dichloroethane and concentrating, the residue is washed by repeating decantation in the order of hexane and ether, and dried under reduced pressure to give (2S, 4S) -2- (3-aminomethylazetidine- 1-ylcarbonyl) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidine trifluoroacetate (3.95 g) was obtained.

The above compound (3.95 g) and N- (4-nitrobenzyloxycarbonyl) formamidine (2.08 g)
Was used in the same manner as in Reference Example 2- (1) to carry out a reaction, treatment and purification to obtain amorphous (2S, 4S) -4-.
(4-Methoxybenzylthio) -2- [3- (N-4-
Nitrobenzyloxycarbonylformimidoylaminomethyl) azetidin-1-ylcarbonyl] -1-
(4-Nitrobenzyloxycarbonyl) pyrrolidine (2.70 g) was obtained. Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1750,1706,1
655,1608,1520,1442,1404,1346. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm:
1.85-3.14 (4H, m), 3.25-4.37 (9H, m), 3.72,3.73 (2H, s ×
2), 3.79,3.84 (3H, s × 2), 5.12-5.43 (4H, m), 6.81-6.90 (2
H, m), 7.16-7.34 (2H, m), 7.42-7.63 (4H, m), 8.13-8.31 (4H,
m), 8.49,8.97 (1H, s × 2) (2) Using the compound (388 mg) obtained in (1), the reaction, treatment and purification were carried out in the same manner as in Reference Example 2- (2) to give a powder. The title compound (420 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1785,1698,1609,1524,1498,1447,1407,1349. Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ + D ₂ O) δppm:
1.66-1.80 (1H, m), 2.56-2.89 (2H, m), 3.00-4.40 (10H, m),
5.06-5.34 (2H, m), 5.36 (2H, s), 7.55-7.72 (4H, m) 8.20-8.2
8 (4H, m), 8.89 (1H, s) Reference Example 14 (2S, 4S) -4-Mercapto-2- [3- (4-nitrobenzyloxycarbonylaminomethyl) azetidin-1-ylcarbonyl] -1 -(4-Nitrobenzyloxycarbonyl) pyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl)-
2-Pyrrolidinecarboxylic acid (1.50 g), N, N'-carbonyldiimidazole (0.60 g), 3-tert-butyloxycarbonylaminomethylazetidine hydrochloride (0.90
g) and diisopropylethylamine (0.70 ml) were used to carry out the reaction, treatment and purification in the same manner as in Reference Example 12- (1) to give amorphous (2S, 4S) -2- (3-).
tert-Butyloxycarbonylaminomethylazetidin-1-ylcarbonyl) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl)
Pyrrolidine (1.82 g) was obtained. Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1709,1660,1
609,1513,1441,1346,1249,1170. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.44 (9
H, s), 1.91-2.07 (1H, m), 2.34-2.48 (1H, m), 2.58-2.80 (1H, m
m), 3.05-3.34 (4H, m), 3.61-4.24 (6H, m), 3.72,3.73 (2H, s
× 2), 3.79, 3.80 (3H, s × 2), 4.45-4.67 (1H, m), 5.07-5.37
(2H, m), 6.85 (2H, d, J = 8.38Hz), 7.24 (2H, d, J = 8.38Hz), 7.4
5-7.52 (2H, m), 8.23 (2H, d, J = 8.44Hz) (2) To the compound (1.81 g) obtained in (1) under ice cooling,
Trifluoroacetic acid (7.0 ml) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes. The reaction mixture was diluted with 1,2-dichloroethane, concentrated under reduced pressure, and the residue was mixed with hexane and
It was washed by decantation in the order of ether and then dried under reduced pressure.

This residue was dried methylene chloride (18 ml).
Dissolve in diisopropylethylamine (1.1
ml) and p-nitrobenzyl chloroformate (0.64 g) in dry methylene chloride (7 ml) were used, and Reference Example 13-
Reaction (2S, 4S) -4- (4-methoxybenzylthio) -2- [3- (4-nitrobenzyloxycarbonylaminomethyl) azetidine in the form of amorphous was subjected to reaction, treatment and purification in the same manner as (2). -1-ylcarbonyl]
-1- (4-Nitrobenzyloxycarbonyl) pyrrolidine (1.84 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1710,1659,1608,1520,1441,1404,1346,1246. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.88-2.
09 (1H, m), 2.21-2.84 (2H, m), 3.06-3.13 (1H, m), 3.28-4.57
(9H, m), 3.73 (2H, s), 3.79,3.80 (3H, s × 2), 4.89-5.37 (4H,
m), 5.76 (1H, s), 6.85 (2H, d, J = 8.39Hz), 7.23 (2H, d, J = 8.38
Hz), 7.31-7.49 (4H, m), 8.15-8.23 (4H, m) (3) Compound (1.18 g) obtained in (2), anisole (1.85 ml), trifluoroacetic acid (6.55 ml) And trifluoromethanesulfonic acid (0.30 ml) were used, and Reference Example 1-
After the reaction and treatment were performed in the same manner as in (3), the residue was subjected to silica gel column chromatography (Merck & Co., Inc., silica gel 60 9385 10 g), and ethyl acetate:
The amorphous title compound (0.59 g) was obtained from the fraction eluted with methanol (95: 5).

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1710,1655,1607,1521,1439,1404,1347,1246. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.88-2.
21 (2H, m), 2.55-2.91 (2H, m), 3.11-3.70 (4H, m), 3.78-4.65
(6H, m), 4.84-5.40 (4H, m), 5.77-5.80 (1H, m), 7.39-7.59 (4
H, m), 8.16-8.23 (4H, m) Reference Example 15 (2S, 4S) -4-Mercapto-2- [3-methyl-
3- (4-Nitrobenzyloxycarbonylamino) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio) -1 -(4-Nitrobenzyloxycarbonyl)-
2-Pyrrolidinecarboxylic acid (1.06 g), N, N'-carbonyldiimidazole (0.42 g), 3-methyl-3-
(4-Nitrobenzyloxycarbonylamino) azetidine Using trifluoroacetic acid salt (1.04 g) and diisopropylethylamine (0.53 ml), Reference Example 12-
The reaction, treatment and purification were carried out in the same manner as in (1) to give amorphous (2S, 4S) -4- (4-methoxybenzylthio) -2-[(3-methyl-3- (4-nitrobenzyloxycarbonyl). Amino) azetidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl)
Pyrrolidine (1.40 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1713,1656,1609,1520,1443,1403,1346,1250. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.37-1.
63 (3H, m), 1.93-2.05 (1H, m), 2.37-2.49 (1H, m), 3.03-3.09
(1H, m), 3.31 (1H, t, J = 10.25Hz), 3.65-4.57 (6H, m), 3.73 (2
H, s), 3.79,3.80 (3H, s × 2), 4.95-5.34 (5H, m), 6.85 (2H,
d, J = 8.56Hz), 7.23 (2H, d, J = 8.56Hz), 7.44-7.52 (4H, m), 8.
23 (4H, d, J = 8.43Hz) (2) Compound (1.40 g) obtained in (1), anisole (2.19 ml), trifluoroacetic acid (7.77 ml) and trifluoromethanesulfonic acid (0.35 ml) Reference Example 1
By subjecting to the reaction and treatment in the same manner as in (3), the amorphous title compound (1.12 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1713,1656,1607,1521,1443,1404,1346,1249. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 1.36-1.
63 (3H, m), 1.92-2.17 (1H, m), 2.60-2.74 (1H, m), 3.25-3.45
(2H, m), 3.78-4.57 (7H, m), 4.96-5.36 (5H, m), 7.49-7.52 (4
H, m), 8.22 (4H, d, J = 8.53Hz) Reference Example 16 (2S, 4S) -4-Mercapto-2- [3- (N-4
-Nitrobenzyloxycarbonylacetamidoylaminomethyl) azetidin-1-ylcarbonyl] -1-
(4-Nitrobenzyloxycarbonyl) pyrrolidine
Trifluoromethanesulfonate (1) Reference Example Using the trifluoroacetate (1.48 g) obtained in 13- (1) and N- (4-nitrobenzyloxycarbonyl) acetamidine (0.67 g), Reference Example 2-
The reaction, treatment and purification were carried out in the same manner as in (1) to give amorphous (2S, 4S) -4- (4-methoxybenzylthio) -2- [3- (N-4-nitrobenzyloxycarbonylacetimidoyl). Aminomethyl) azetidine-
1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1.24 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1708,1665,1608,1563,1520,1431,1346,1216,1174. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm:
1.85-3.15 (4H, m), 2.26,2.27 (3H, s × 2), 3.22-4.70 (9H,
m), 3.73 (2H, s), 3.79,3.80 (3H, s × 2), 5.03-5.40 (4H, m),
6.85 (2H, d, J = 8.62Hz), 7.23 (2H, d, J = 8.62Hz), 7.40-7.61
(4H, m), 8.17-8.28 (4H, m) (2) Using the compound (1.24 g) obtained in (1), the same reaction, treatment and purification as in Reference Example 2- (2) were performed. ,
A powdery title compound (1.30 g) was obtained. Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1787,1702,1
664,1609,1523,1443,1407,1349,1286,1248,1227. Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ + D ₂ O) δppm:
1.65-1.80 (1H, m), 2.35-4.4
3 (15H, m), 5.08-5.51 (4H, m),
7.54-7.78 (4H, m), 8.21-8.34
(4H, m)

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Katsuhiko Watanabe 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Katsuya Ishikawa 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Hiro Yasuda 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Satoshi Oya 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock Inside the ceremony company (72) Inventor Yukio Utsui 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. Inside the ceremony company

Claims (1)

[Claims] 1. The formula: A carbapenem derivative having the following formula and a pharmaceutically acceptable salt thereof. In the formula, R ¹ represents a hydrogen atom or a methyl group, and R ^1
2 is a hydrogen atom, a lower alkyl group with or without a substituent, a lower alkenyl group, a lower alkynyl group or a -C (= NH) R ⁰ group (in the formula, R ⁰ represents a hydrogen atom or a lower alkyl group) And R ¹⁰ represents a hydrogen atom or an ester residue that undergoes hydrolysis in vivo. A represents any group represented by the following general formulas and. Formula [2] In the formula, l represents 0 or 1, and R ³ is a hydrogen atom, a lower alkyl group having a substituent or not, a lower alkenyl group, a lower alkynyl group or a —C (═NH) R ⁶ group (wherein R 3 ⁶ represents a hydrogen atom, a lower alkyl group with or without a substituent, a cycloalkyl group or a cycloalkyl lower alkyl group, and R ⁴ is a hydrogen atom, a lower alkyl group with or without a substituent, a lower group An alkenyl group or a lower alkynyl group, R ⁵ represents a substituent on the ring, independently of each other a hydrogen atom, a halogen atom,
A lower alkyl group with or without a substituent, a hydroxy group, a carboxy group, a carbamoyl group, an amino group, a cyano group or a carbamoyloxy group is shown. Formula [3] (In the formula, m represents 0 or 1, R ⁵ has the same meaning as described above, R ⁷ represents a hydrogen atom or a lower alkyl group, and R ⁸ represents a hydrogen atom, a substituent or not. a lower alkyl group, a lower alkenyl group, lower alkynyl group, or -C (= NH) R ⁶ group (wherein, R ⁶ have the same meanings as defined above.)