JPH1036370A - 1-methylcarbapenem derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a 1-methylcarbapenem derivative having excellent antimicrobial activity, being stable to dehydropeptidase I, having high recovery in urine, excellent in pharmacokinetics such as half-life in blood, having low nephrotoxic property and useful as a medicine for treating and preventing bacterial infectious diseases. SOLUTION: This 1-methylcarbapenem derivative is represented by the formula R<1> and R<2> are each H or an alkyl; R<3> is H, a cycloalkyl, etc.}, e.g. (1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[-(2S, 4S)-2-[(3R)-3- methylaminomethylpyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbap en-2-em-3- carboxylic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 1-methylcarbapenem compound (I) which is an excellent antibacterial agent.

[0002]

BACKGROUND ART Thienamycin derivatives, which are carbapenem antibiotics, have excellent antibacterial activity, but have low chemical stability, and are decomposed by dehydropeptidase-I, an enzyme present in the human body. Easy to lose activity,
In addition, urine collection rate is low (H. Kropp et a
l. , Antimicrob. Agents Chem
other. , 2262, (1982); R. N
orrby et al. , Ibid. , 23,300
(1983)). Furthermore, some experimental animal species may be toxic to the kidneys. Therefore, thipenamicin derivative imipenem was developed as a combination with dehydropeptidase-I inhibitor cilastatin, and panipenem was developed with betamipron, an organic anion transport inhibitor. Thereafter, it was found that the chemical stability and stability against dehydropeptidase-I were improved by introducing a methyl group at the 1-position of the carbapenem skeleton, and meropenem (USP-5122).
No. 604), a carbapenem derivative that can be used as a single agent has also been developed. However, 1-like Meropenem
As methylcarbapenem derivatives have also been used in clinical settings, resistant strains have begun to appear in Pseudomonas aeruginosa and the like.

[0003] Therefore, the development of derivatives that have a more potent and balanced antibacterial activity against a wide range of bacteria, including Pseudomonas aeruginosa and the like that are resistant to meropenem, and that are not toxic to the kidneys has been developed. Is desired. JP-A-5-31074
0, JP-A-5-339269, JP-A-6-1723
No. 56, JP-A-6-199860 and the like disclose 1-methylcarbapenem derivatives synthesized for this purpose.

[0004]

SUMMARY OF THE INVENTION The present inventors have made these 1
As a result of various studies to solve the drawbacks of the -methylcarbapenem derivative, the compound (I) of the present invention has a stronger antibacterial activity than the conventional 1-methylcarbapenem derivative, is stable against dehydropeptidase-I, and The medium recovery rate was high, and it was found to be excellent in pharmacokinetics such as blood half-life. Furthermore, the compound (I) of the present invention has low renal toxicity and has been found to be effective as an antibacterial agent for treating or preventing (especially treating) bacterial infections, thereby completing the present invention.

[0005] JP-A-5-310740, JP-A-5-339269 and JP-A-6-172356 disclose a compound having a 3- (aminomethyl) pyrrolidine group [in the general formula (I), R ¹ , R ^{And the like, wherein 2} and R ³ are all hydrogen atoms, etc.], and specifically produce and disclose a compound belonging to the present invention in which a substituent is disposed on the amino portion of the 3- (aminomethyl) pyrrolidine group. No example was found.

[0006]

The 1-methylcarbapenem derivative of the present invention has the general formula

[0007]

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[0008]

[0009] In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group, R ³
Is a hydrogen atom, a lower alkyl group, a lower alkyl group having 1 to 3 substituents (the substituent is a hydroxyl group, a halogen atom,
A carbamoyl group, a carbamoyl group substituted with 1 to 2 lower alkyl groups, a carbamoyloxy group, a carbamoyloxy group substituted with 1 to 2 lower alkyl groups, a lower alkoxy group, an amino group or 1 to 2 Indicates an amino group substituted with a lower alkyl group. ), A cycloalkyl group or a group represented by the formula —C (＝ NH) R ⁴ (wherein R
⁴ represents a hydrogen atom, a lower alkyl group or an amino group. Or R ² and R ³ are a group bonded to each other, and may be an alkylene group which may be mediated by one oxygen atom, nitrogen atom or sulfur atom (the nitrogen atom is substituted by a lower alkyl group). May be shown).

However, compounds in which R ¹ , R ² and R ³ are all hydrogen atoms are excluded from the compound (I) of the present invention.

In the above, R ¹ , R ² , R ³ and R
The “lower alkyl group” in the definition of ⁴ includes 1 to 4 carbon atoms.
Linear or branched alkyl groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl group, preferably methyl or ethyl group, More preferably, it is a methyl group.

A “halogen atom” in the definition of R ³ is
For example, a fluorine, chlorine or bromine atom can be mentioned, and a fluorine atom is preferable.

The "carbamoyl group substituted by one or two lower alkyl groups" in the definition of R ³ includes, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl, and preferably methylcarbamoyl. Or a dimethylcarbamoyl group.

The "carbamoyloxy group substituted by one or two lower alkyl groups" in the definition of R ³ includes, for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy and diethylcarbamoyloxy groups. Preferably, it is a methylcarbamoyloxy or dimethylcarbamoyloxy group.

The "amino group substituted by one or two lower alkyl groups" in the definition of R ³ includes, for example, methylamino, ethylamino, dimethylamino and diethylamino groups. It is a dimethylamino group.

"Lower alkoxy group" in the definition of R ³
Is an alkoxy group having 1 to 4 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy and butoxy groups, and preferably a methoxy group.

The "substituent" of the "lower alkyl group having 1 to 3 substituents" in the definition of R ³ is preferably a hydroxyl group, a fluorine atom, carbamoyl, methylcarbamoyl,
A dimethylcarbamoyl, carbamoyloxy, methoxy, amino, methylamino or dimethylamino group;

The above "lower alkyl group having 1 to 3 substituents" includes, for example, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, fluoromethyl, difluoromethyl, Trifluoromethyl, 2-fluoroethyl, 2,
2,2-trifluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, carbamoylmethyl, N-methylcarbamoylmethyl, N, N
-Dimethylcarbamoylmethyl, 2-carbamoylethyl, 2- (N-methylcarbamoyl) ethyl, 2-
(N, N-dimethylcarbamoyloxy) ethyl, 2-carbamoyloxyethyl, 2- (N, N-dimethylcarbamoyloxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-aminoethyl, 3-aminopropyl,
-Aminopropyl, 2- (methylamino) ethyl, 3-
(Methylamino) propyl, 2- (dimethylamino) ethyl, 3- (dimethylamino) propyl and the like, preferably 2-hydroxyethyl, 2-fluoroethyl, 2,2,2-trifluoro Ethyl, carbamoylmethyl, 2-carbamoylethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-methoxyethyl, 2-carbamoyloxyethyl, 2-aminoethyl, 2- (methylamino) ethyl or 2- (Dimethylamino) ethyl group, more preferably 2-hydroxyethyl, carbamoylmethyl, 2-
An aminoethyl or 2- (methylamino) ethyl group.

"Cycloalkyl group" in the definition of R ³
Is a cycloalkyl group having 3 to 6 carbon atoms, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably a cyclopropyl or cyclobutyl group, more preferably a cyclopropyl group It is.

In the definition of R ³ , “formula —C (＝ NH) R
^The "group represented by ⁴ " includes, for example, formimidoyl, acetimidoyl, propioimidoyl or amidino group, and is preferably formimidoyl, acetimidoyl or amidino group.

In the definition of the group in which R ² and R ³ are bonded to each other, “alkylene group” of “alkylene group optionally having one oxygen atom, nitrogen atom or sulfur atom interposed” is
A linear or branched alkylene group having 2 to 6 carbon atoms, for example, ethylene, propylene, trimethylene, 1-
Examples include methyltrimethylene, 2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, pentamethylene, and the like.

The alkylene group may be linked via one oxygen atom, nitrogen atom or sulfur atom. Examples of such an alkylene group include ethyleneoxyethyl (CH ₂ C
H ₂ OCH ₂ CH ₂ ), ethyleneaminoethyl (CH ₂ CH ₂ NHCH ₂ C
H ₂ ), ethyleneaminopropyl (CH ₂ CH ₂ NHCH ₂ CH ₂ CH
₂ ), ethylenethioethyl (CH ₂ CH ₂ SCH ₂ CH ₂ ) group and the like.

The nitrogen atom which may be interposed in the alkylene group may be substituted with a lower alkyl group. The lower alkyl group is an alkyl group having 1 to 4 carbon atoms, and a methyl group is preferable. .

The above-mentioned "alkylene group optionally having one oxygen atom, nitrogen atom or sulfur atom via" is, for example, ethylene, trimethylene, tetramethylene, pentamethylene, ethyleneoxyethyl, ethylenethioethyl, ethyleneaminoethyl, Ethyleneaminopropyl, ethylene (methylamino) ethyl, ethylene (ethylamino) ethyl, ethylene (methylamino) propyl and the like, preferably trimethylene, tetramethylene,
Pentamethylene, ethyleneoxyethyl, ethylenethioethyl, ethyleneaminoethyl, ethylene (methylamino) ethyl or ethyleneaminopropyl, more preferably a tetramethylene group.

R ¹ is preferably a hydrogen atom or a group having 1 carbon atom.
４4 alkyl groups, more preferably a hydrogen atom, a methyl group or an ethyl group, particularly preferably a hydrogen atom or a methyl group.

R ² is preferably a hydrogen atom or a carbon atom.
４4 alkyl groups, more preferably a hydrogen atom, a methyl group or an ethyl group, particularly preferably a hydrogen atom or a methyl group.

R ³ is preferably a hydrogen atom, having 1 to 4 carbon atoms.
Alkyl groups, 1 to 1 carbon atoms having 1 to 3 substituents
4 alkyl groups (the substituents are a hydroxyl group, a halogen atom,
A carbamoyl group, a carbamoyl group substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms, a carbamoyloxy group, a carbamoyloxy group substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms, It represents an alkoxy group having 1 to 4 carbon atoms, an amino group or an amino group substituted with 1 to 2 alkyl groups having 1 to 2 carbon atoms. ), Group (wherein, represented by the number 3-6 cycloalkyl group or the formula -C (= NH) R ⁴ carbons, R ⁴ is a hydrogen atom, a 1-4 alkyl group or an amino group having a carbon number And more preferably a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyethyl group, a 2-fluoroethyl group, a 2,2,2-trifluoroethyl group, a carbamoylmethyl group, or a 2-carbamoylethyl. Group, N-methylcarbamoylmethyl group, N, N-dimethylcarbamoylmethyl group, 2-methoxyethyl group,
2-carbamoyloxyethyl group, 2-aminoethyl group, 2- (methylamino) ethyl group, 2- (dimethylamino) ethyl group, cyclopropyl group, formimidoyl group, acetimidoyl group or amidino group, Still more preferably, a hydrogen atom, a methyl group, a 2-hydroxyethyl group, a carbamoylmethyl group, a 2-aminoethyl group,
-(Methylamino) ethyl, cyclopropyl, formimidoyl, acetimidoyl or amidino, particularly preferably hydrogen, methyl, formimidoyl, acetimidoyl or amidino. is there.

The group in which R ² and R ³ are bonded to each other is preferably an alkylene group having 2 to 6 carbon atoms which may be via one oxygen atom, nitrogen atom or sulfur atom (the nitrogen atom May be substituted with an alkyl group having 1 to 4 carbon atoms.), More preferably, a trimethylene group, a tetramethylene group, a pentamethylene group, an ethyleneoxyethyl group, an ethylenethioethyl group, an ethyleneaminoethyl group. Group,
An ethylene (methylamino) ethyl group or an ethyleneaminopropyl group, particularly preferably a tetramethylene group.

The compound (I) of the present invention can be converted into a "pharmaceutically acceptable salt or derivative", if necessary.

"Pharmacologically acceptable salts" include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate,
Minerates such as nitrates; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate , Succinate, acetate,
Acid addition salts such as organic acid salts such as benzoate, mandelate, ascorbate, lactate, gluconate, malate, glycine, lysine, arginine, ornithine, ornithine, glutamate, asparagine Amino acid salts such as acid salts, or inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts or salts with organic bases such as ammonium salts, triethylamine salts, diisopropylamine salts, and cyclohexylamine salts. And hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-
Toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, glutamate, aspartate, sodium, potassium, ammonium or triethylamine salts, more preferably the hydrochloride salt, Sulfate, methanesulfonate, citrate, acetate or lactate, particularly preferably hydrochloride or sulfate.

The compound (I) of the present invention absorbs water by leaving it in the air, freeze-drying from an aqueous solution, or recrystallizing to form adsorbed water,
It may be a hydrate, and such salts are also included in the present invention.

A “pharmacologically acceptable derivative” is a group that forms a compound (I) or a salt thereof when cleaved in a human body by a chemical or biological method such as hydrolysis (forming a so-called prodrug). A derivative in which the carboxyl group, hydroxyl group, amino group and the like of compound (I) are protected by a compound having the above formula (I). Whether such a derivative is administered orally or intravenously to experimental animals such as rats and mice Then, the body fluid of the animal is examined, and the determination can be made by detecting the original compound or a pharmacologically acceptable salt thereof. Examples of such a protecting group such as a carboxyl group, a hydroxyl group and an amino group may include an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a phthalidyl group, an alkyl group at the 5-position, and an aryl group (2 -Oxo-1,3-dioxolen-4-yl) alkyl group, acyl group, alkoxycarbonyl group, aminoacyl group and the like.

Examples of the acyloxyalkyl group include pivaloyloxymethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, acetoxymethyl, 1- (acetoxy) ethyl, 1-methylcyclohexylcarbonyloxymethyl And 1-methylcyclopentylcarbonyloxymethyl, 2-ethylbutyryloxymethyl, hexanoyloxymethyl and the like, and preferably pivaloyloxymethyl, acetoxymethyl or 1-methylcyclohexylcarbonyloxymethyl. is there.

Examples of the alkoxycarbonyloxyalkyl group include t-butoxycarbonyloxymethyl,
1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (cyclohexylcarbonyloxy) ethyl, 1- (cyclohexylcarbonyloxy) ethyl Examples thereof include a (cyclopentylcarbonyloxy) ethyl group and the like, preferably a 1- (isopropoxycarbonyloxy) ethyl or 1- (cyclohexylcarbonyloxy) ethyl group.

Examples of the 1- (2-oxo-1,3-dioxolen-4-yl) alkyl group which may have an alkyl group or an allyl group at the 5-position include, for example, 2-oxo-1,3
-Dioxolen-4-ylmethyl, 1- (2-oxo-
1,3-dioxolen-4-yl) ethyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 1- (5-methyl-2-oxo-1,3-dioxolen-4-yl ) Ethyl, 5-ethyl-2-oxo-
Examples include 1,3-dioxolen-4-ylmethyl, 5-propyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl group, and the like. And preferably 5
-Methyl-2-oxo-1,3-dioxolen-4-ylmethyl group.

Among the above, more preferred protecting groups include 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, acetoxymethyl, pivaloyloxymethyl, 1-
Methylcyclohexylcarbonyloxymethyl, 1-
(Isopropoxycarbonyloxy) ethyl or 1-
(Cyclohexyloxycarbonyloxy) ethyl groups, which are preferably used as protecting groups for carboxy groups to form ester derivatives.

The compound (I) of the present invention represents one or a mixture of isomers. Preferred among these isomers are the R-configuration at the 1-position of the carbapenem skeleton, the 5-position and the 6-position.
The position is a (5S, 6S) configuration which is the same configuration as that of thienamycin, and examples thereof include compounds in which the configuration of the α-carbon having a hydroxyl group at the 6-position substituent is the R configuration.

Further, the 2-position of the 2-position substituent of the carbapenem skeleton
The 2- and 4-positions of the -substituted pyrrolidin-4-ylthio group are preferably of the (2S, 4S) configuration.

The 3-position of the 3- (substituted aminomethyl) pyrrolidin-1-yl group is not particularly limited.

In the compound having the general formula (I), R ¹ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ² is preferably a hydrogen atom or 1 to 4 carbon atoms.
R ³ is a hydrogen atom, having 1 to 4 carbon atoms.
Alkyl groups, 1 to 1 carbon atoms having 1 to 3 substituents
4 alkyl groups (the substituents are a hydroxyl group, a halogen atom,
A carbamoyl group, a carbamoyl group substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms, a carbamoyloxy group, a carbamoyloxy group substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms, It represents an alkoxy group having 1 to 4 carbon atoms, an amino group or an amino group substituted with 1 to 2 alkyl groups having 1 to 2 carbon atoms. ), Group (wherein, represented by the number 3-6 cycloalkyl group or the formula -C (= NH) R ⁴ carbons, R ⁴ is a hydrogen atom, a 1-4 alkyl group or an amino group having a carbon number Or R ² and R
³ is a group bonded to each other, one oxygen atom,
2 to 6 carbon atoms which may be via a nitrogen atom or a sulfur atom
And the alkylene group (the nitrogen atom may be substituted with an alkyl group having 1 to 4 carbon atoms).

More preferably, R ¹ is a hydrogen atom, a methyl or ethyl group, R ² is a hydrogen atom, a methyl or ethyl group, R ³ is a hydrogen atom, methyl, ethyl, 2-hydroxyethyl, 2-fluoro Ethyl, 2,2,2-trifluoroethyl, carbamoylmethyl, 2-carbamoylethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-methoxyethyl, 2-carbamoyloxyethyl, 2-aminoethyl, 2- (methylamino) ethyl, 2- (dimethylamino) ethyl,
A cyclopropyl, formimidoyl, acetimidoyl or amidino group, or R ² and R ³ are bonded to each other, and trimethylene, tetramethylene, pentamethylene,
Compounds that are ethyleneoxyethyl, ethylenethioethyl, ethyleneaminoethyl, ethylene (methylamino) ethyl or ethyleneaminopropyl groups can be mentioned.

More preferably, R ¹ is a hydrogen atom or a methyl group, and R ² is a hydrogen atom or a methyl group, R ³
Is methyl, 2-hydroxyethyl, carbamoylmethyl, 2-aminoethyl, 2- (methylamino) ethyl,
Examples thereof include a cyclopropyl, formimidoyl, acetimidoyl or amidino group, or a compound in which R ² and R ³ are bonded to each other to form a tetramethylene group.

Particularly preferably, R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a methyl group,
Compounds in which ³ is a hydrogen atom, methyl, formimidoyl, acetimidoyl or amidino group can be mentioned.

In the above preferred, even more preferred, even more preferred or particularly preferred compounds (I),

[0045]

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Or the general formula

[0047]

Embedded image

The stereoisomer represented by is a more preferred compound.

Preferred compounds in the general formula (I) are shown in Table 1.
Can be specifically exemplified.

[0050]

[Table 1]

[0051]

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{Exemplary Compound Number R ¹ R ² R ³ } ────────────────────────────── 1 HH Me 2 HH Et 3 HH CH ₂ CH ₂ OH 4 HH CH ₂ CH ₂ F 5 HH CH ₂ CF ₃ 6 HH CH ₂ CONH ₂ 7 HH CH ₂ CH ₂ CONH ₂ 8 HH CH ₂ CONHMe 9 HH CH ₂ CONMe ₂ 10 HH CH ₂ CH ₂ OMe 11 HH CH ₂ CH ₂ OCONH ₂ 12 HH CH ₂ CH ₂ NH ₂ 13 HH CH ₂ CH ₂ NHMe 14 HH CH ₂ CH ₂ NMe ₂ 15 HH cPr 16 HHC (= NH) H 17 HHC (= NH) Me 18 HHC (= NH) NH ₂ 19 H Me Me 20 H Me Et 21 H Me CH ₂ CH ₂ OH 22 H Me CH ₂ CH ₂ F 23 H Me CH ₂ CF ₃ 24 H Me CH ₂ CONH ₂ 25 H Me CH ₂ CH ₂ CONH ₂ 26 H Me CH ₂ CONHMe 27 H Me _{CH 2 CONMe 2 28 H Me CH} 2 CH 2 OMe 29 H Me CH 2 CH 2 OCONH 2 30 H Me CH 2 CH 2 NH 2 31 H Me CH 2 CH 2 NHMe 32 H Me CH 2 CH 2 NMe 2 33 H Me cPr 34 H Me C (= NH) H 35 H Me C (= NH) Me 36 H Me C (= NH) NH ₂ 37 H Et Et 38 H Et CH ₂ CH ₂ OH 39 H Et CH ₂ CH ₂ F 40 H Et CH ₂ CF ₃ 41 H Et CH ₂ CO NH ₂ 42 H Et CH ₂ CH ₂ CONH ₂ 43 H Et CH ₂ CONHMe 44 H Et CH ₂ CONMe ₂ 45 H Et CH ₂ CH ₂ OMe 46 H Et CH ₂ CH ₂ OCONH ₂ 47 H Et CH ₂ CH ₂ NH ₂ 48 H Et CH ₂ CH ₂ NHMe 49 H Et CH ₂ CH ₂ NMe ₂ 50 H Et cPr 51 H Et C (= NH) H 52 H Et C (= NH) Me 53 H Et C (= NH) NH ₂ 54 _{H -CH 2 CH 2 CH 2 CH} 2 - 55 H -CH 2 CH 2 CH 2 CH 2 CH 2 - 56 H -CH 2 CH 2 OCH 2 CH 2 - 57 H -CH 2 CH 2 SCH 2 CH 2 - 58 _{H -CH 2 CH 2 NHCH 2 CH} 2 - 59 H -CH 2 CH 2 NHCH 2 CH 2 CH 2 - 60 H -CH 2 CH 2 NMeCH 2 CH 2 - 61 Me HH 62 Me H Me 63 Me H Et 64 Me H CH ₂ CH ₂ OH 65 Me H CH ₂ CH ₂ F 66 Me H CH ₂ CF ₃ 67 Me H CH ₂ CONH ₂ 68 Me H CH ₂ CH ₂ CONH ₂ 69 Me H CH ₂ CONHMe 70 Me H CH ₂ CONMe ₂ 71 Me H CH ₂ CH ₂ OMe 72 Me H CH ₂ CH ₂ OCONH ₂ 73 Me H CH ₂ CH ₂ NH ₂ 74 Me H CH ₂ CH ₂ NHMe 75 Me H CH ₂ CH ₂ NMe ₂ 76 Me H cPr 77 Me HC (= NH) H 78 Me HC (= NH) Me 79 Me HC (= NH) NH ₂ 80 Me Me Me 81 Me Me Et 82 Me Me CH ₂ CH ₂ OH 83 Me Me CH ₂ CH ₂ F 84 Me Me CH ₂ CF ₃ 85 Me Me CH ₂ CONH ₂ 86 Me Me CH ₂ CH ₂ CONH ₂ 87 Me Me CH ₂ CONHMe 88 Me Me CH ₂ CONMe ₂ 8 8 Me Me CH ₂ CH ₂ OMe 89 Me Me CH ₂ CH ₂ OCONH ₂ 90 Me Me CH ₂ CH ₂ NH ₂ 91 Me Me CH ₂ CH ₂ NHMe 92 Me Me CH ₂ CH ₂ NMe ₂ 93 Me Me cPr 94 Me Me C (= NH) H 95 Me Me C (= NH) Me 96 Me Me C (= NH) NH ₂ 97 Me Et Et 98 Me Et CH ₂ CH ₂ OH 99 Me Et CH ₂ CH ₂ F 100 Me Et CH ₂ CF ₃ 101 Me Et CH ₂ CONH ₂ 102 Me Et CH ₂ CH ₂ CONH ₂ 103 Me Et CH ₂ CONHMe 104 Me Et CH ₂ CONMe ₂ 105 Me Et CH ₂ CH ₂ OMe 106 Me Et CH ₂ CH ₂ OCONH ₂ 107 Me Et CH ₂ CH ₂ NH ₂ 108 Me Et CH ₂ CH ₂ NHMe 109 Me Et CH ₂ CH ₂ NMe ₂ 110 Me Et c Pr 111 Me Et C (= NH) H 112 Me Et C (= NH) Me 113 Me Et C _{(= NH) NH 2 114 Me} -CH 2 CH 2 CH 2 CH 2 - 115 Me -CH 2 CH 2 CH 2 CH 2 CH 2 - 116 Me -CH 2 CH 2 OCH 2 CH 2 - 117 Me -CH 2 CH _{2 SCH 2 CH 2 - 118 Me} -CH 2 CH 2 NHCH 2 CH 2 - 119 Me -CH 2 CH 2 NHCH 2 CH 2 CH 2 - 120 Me -CH 2 CH 2 NMeCH 2 CH 2 - 121 Et HH 122 Et H Me 123 Et H Et 124 Et H CH ₂ CH ₂ OH 125 Et H CH ₂ CH ₂ F 126 Et H CH ₂ CF ₃ 127 Et H CH ₂ CONH ₂ 128 Et H CH ₂ CH ₂ CONH ₂ 129 Et H CH ₂ CONHMe 130 Et H CH ₂ CONMe ₂ 131 Et H CH ₂ CH ₂ OMe 132 Et H CH ₂ CH ₂ OCONH ₂ 133 Et H CH ₂ CH ₂ NH ₂ 134 Et H CH ₂ CH ₂ NHMe 135 Et H CH ₂ CH ₂ NMe ₂ 136 Et H cPr 137 Et HC (= NH) H 138 Et HC ( = NH) Me 139 Et HC (= NH) NH ₂ 140 Et Me Me 141 Et Me Et 142 Et Me CH ₂ CH ₂ OH 143 Et Me CH ₂ CH ₂ F 144 Et Me CH ₂ CF ₃ 145 Et Me CH ₂ CONH ₂ 146 Et Me CH ₂ CH ₂ CONH ₂ 147 Et Me CH ₂ CONHMe 148 Et Me CH ₂ CONMe ₂ 149 Et Me CH ₂ CH ₂ OMe 150 Et Me CH ₂ CH ₂ OCONH ₂ 151 Et Me CH ₂ CH ₂ NH ₂ 152 Et Me CH ₂ CH ₂ NHMe 153 Et Me CH ₂ CH ₂ NMe ₂ 154 Et Me cPr 155 Et Me C (= NH) H 156 Et Me C (= NH) Me 157 Et Me C (= NH) NH ₂ 158 Et Et Et 159 Et Et CH ₂ CH ₂ OH 160 Et Et CH ₂ CH ₂ F 161 Et Et CH ₂ CF ₃ 162 Et Et CH ₂ CONH ₂ 163 Et Et CH ₂ CH ₂ CONH ₂ 164 Et Et CH ₂ CONHMe 165 Et Et CH ₂ CONMe ₂ 166 Et Et CH ₂ CH ₂ OMe 167 Et Et CH ₂ CH ₂ OCONH ₂ 168 Et Et CH ₂ CH ₂ NH ₂ 169 Et Et CH ₂ CH ₂ NHMe 170 Et Et CH ₂ CH ₂ NMe ₂ 171 Et Et cPr 172 Et Et C (= NH ) H 173 Et Et C (= NH) Me 174 Et Et C (= NH) NH 2 175 Et -CH 2 CH 2 CH 2 CH 2 - 176 Et -CH 2 CH 2 CH 2 _{CH 2 CH 2 - 177 Et -CH} 2 CH _{2 OCH 2 CH 2 - 178 Et} -CH 2 CH 2 SCH 2 CH 2 - 179 Et -CH 2 CH 2 NHCH 2 CH 2 - 180 Et -CH 2 CH 2 NHCH 2 CH 2 CH 2 - 181 Et -CH 2 CH ₂ NMeCH ₂ CH ₂ -────────────────────────────────── In the above table, Me is a methyl group , Et represents an ethyl group, and cPr represents a cyclopropyl group.

Of the above exemplified compounds, more preferably, exemplified compound numbers 1, 3, 6, 12, 13, 16, 17, 18, 34, 3
5, 36, 61, 62, 77, 78, 79, 94, 9
5,96 compounds.

Among the above-mentioned compounds, the compounds specified by the following chemical names are particularly preferred.

Stereoisomer of Exemplified Compound 1 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3R) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid (compound of Example 3) (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl]- 1-methyl-2-[(2S, 4S) -2-
[(3S) -3-methylaminomethylpyrrolidine-1-
Ilcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid (compound of Example 5) Stereoisomer of Exemplified Compound 3 (1R, 5S, 6S) -6-[(1R) -1-Hydroxyethyl] -2-[(2S, 4S) -2-[(3R)-
3- (2-hydroxyethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -6-[(1R) -1 -Hydroxyethyl] -2-[(2S, 4S) -2-[(3S)-
3- (2-hydroxyethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (compound of Example 13) Stereoisomer of Exemplified Compound 6 (1R , 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (carbamoylmethylaminomethyl)
Pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapene-2-em-3-carboxylic acid (compound of Example 14) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (carbamoylmethylaminomethyl)
Pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapene-2-em-3-carboxylic acid Stereoisomer of Exemplified Compound 12 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (2-aminoethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [ (2S, 4S) -2-
[(3S) -3- (2-aminoethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid Stereoisomers of Exemplified Compound 13 (1R, 5S , 6S) -2-[(2S, 4S) -2-
[(3R) -3- (2- (N-methylamino) ethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2- (N-methylamino) ethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid Stereoisomer of Exemplified Compound 16 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid (compound of Example 23) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid Stereoisomer of Exemplified Compound 17 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid (compound of Example 8) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (compound of Example 10) Stereoisomer of Exemplified Compound 18 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid (compound of Example 7) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid (Example 11
Compound of the formula (3) Stereoisomer of Exemplified Compound 34 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-N-methyl-N-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-M-3
-Carboxylic acid (compound of Example 21) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-N-methyl-N-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-M-3
-Carboxylic acid Stereoisomer of Exemplified Compound 35 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-N-methyl-N-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-M-3
-Carboxylic acid (compound of Example 20) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-N-methyl-N-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-M-3
-Carboxylic acid Stereoisomer of Exemplified Compound 36 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (1-Methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid (compound of Example 19) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (1-methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid Stereoisomer of Exemplified Compound 61 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-Aminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (compound of Example 1) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-Aminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (compound of Example 2) Stereoisomer of Exemplified Compound 62 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3R) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carbapene-2-em-3-carboxylic acid (compound of Example 4) (1R, 5S, 6S) -6-[(1R) -1- Hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3S) -3-methylaminomethylpyrrolidine-1-
Ilcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid (compound of Example 6) Stereoisomer of Exemplified Compound 77 (1R, 5S, 6S) -2- [(2S, 4S) -2-
[(3R) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (compound of Example 26) (1R, 5S, 6S) -2 − [(2S, 4S) -2-
[(3S) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid Stereoisomers of Exemplified Compound 78 (1R, 5S, 6S) -2 − [(2S, 4S) -2-
[(3R) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (compound of Example 25) (1R, 5S, 6S) -2 − [(2S, 4S) -2-
[(3S) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid Stereoisomer of Exemplified Compound 79 (1R, 5S, 6S) -2 − [(2S, 4S) -2-
[(3R) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (compound of Example 24) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid Stereoisomer of Exemplified Compound 94 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-N-methyl-N-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid (compound of Example 29) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-N-methyl-N-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid Stereoisomer of Exemplified Compound 95 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-N-methyl-N-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid (compound of Example 28) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-N-methyl-N-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid Stereoisomer of Exemplified Compound 96 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (1-Methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-m-3-
Carboxylic acid (compound of Example 27) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (1-Methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-m-3-
carboxylic acid

[0056]

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, a compound having the general formula (I)
The methylcarbapenem derivative has the general formula

[0057]

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(Wherein R ^L represents a leaving group and R ⁵ represents a carboxyl-protecting group) and a carbapenem compound represented by the general formula:

[0059]

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(Wherein, R ¹ p is the same as the amino-protecting group or R ¹ described above, and R ² p is the amino-protecting group or the amino group, hydroxyl group and imino group contained in R ² described above.) R ³ p is the same as defined for R ^2, which may be protected, and R ³ p may be a group for protecting an amino group, or an amino group, a hydroxyl group and an imino group included in R ³ may be protected. ^Three
Is equivalent to )) And reacting the resulting product with a mercaptopyrrolidine derivative represented by the formula (1) to remove a protecting group, if necessary. In addition, it can be converted to a pharmacologically acceptable salt or derivative, if necessary.

In detail, the compound (I) of the present invention can be produced by the method shown below (Method A or Method B).

[0062]

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[0063]

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In the above formula, R ¹ , R ² , R ³ , R ¹ p and R ² p
And R ³ p have the same meanings as described above, and R ⁵ represents a carboxyl-protecting group.

The protecting groups for the hydroxyl group, amino group and imino group contained in R ¹ p, R ² p and R ³ p may be any of those commonly used in the field of synthetic organic chemistry (Greene & Wut).
s, Protective Groups in Or
ganic Synthesis, 2nd Editi
on, 1991, John Wiley & Son
s, Inc. ), Preferably a benzyl group which may have a substituent such as benzyl or 4-nitrobenzyl, or a benzyloxy which may have a substituent such as benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl. A carbonyl group or an allyloxycarbonyl group which may be substituted at the 2-position such as allyloxycarbonyl, 2-chloroallyloxycarbonyl, or 2-methylallyloxycarbonyl; more preferably, 4-nitrobenzyl or 4-nitrobenzyl; It is a nitrobenzyloxycarbonyl group.

The “protecting group for carboxy group” of R ⁵ is a protecting group (Greene) commonly used in the field of synthetic organic chemistry.
& Wuts, Protective Groups
in Organic Synthesis, 2nd
Edition, 1991, John Wiley
& Sons, Inc. ), And, for example, methyl, C ₁ -C ₄ alkyl groups such as ethyl or t- butyl;
A benzyl group which may have a substituent such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl or 2-nitrobenzyl; a benzhydryl group; a substituent at the 2-position such as allyl, 2-chloroallyl or 2-methylallyl An allyl group which may have a halogenoethyl group such as 2,2,2-trichloroethyl, 2,2-dibromoethyl or 2,2,2-tribromoethyl or a 2-trimethylsilylethyl group. And preferably a 4-nitrobenzyl or benzyl group.

R ⁶ is a C ₁ -C ₄ alkanesulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl; phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl C ₆ -C ₁₀ arylsulfonyl group; dimethylphosphoryl, diethylphosphoryl, dipropyl phosphoryl, diisopropylphosphoryl, dibutyl phosphoryl, dipentyl phosphoryl or dihexyl phosphoryl di -C ₁ -C ₆ alkyl phosphoryl group or diphenylphosphoryl or ditolyl phosphoryl, such as Le It indicates di -C ₆ -C ₁₀ aryl phosphoryl groups such as, preferably a diphenylphosphoryl group.

R ⁷ is a C ₁ -C ₄ alkyl group such as methyl, ethyl, propyl or isopropyl; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoroethyl C ₆ -C such as phenyl or naphthyl which may have a substituent; 2-acetylamino-ethyl group; 2-acetylamino-vinyl methyl or halogeno -C ₁ -C ₄ alkyl groups such as trifluoroethyl ₁₀ aryl groups (the aryl groups may have 1 to 3 identical or different substituents as shown below; the substituents may be halogen atoms such as fluorine, chlorine, bromine; methyl, ethyl, propyl, C ₁ -C ₄ alkyl groups such as isopropyl; methoxy, ethoxy, propoxy, iso C ₁ -C ₄ alkoxy groups such as carboxymethyl; methoxycarbonyl, ethoxycarbonyl, t-
(C ₁ -C ₄ alkoxy) such as butoxycarbonyl
Carbonyl group; carbamoyl, mono- or di- (C
₁ -C ₄ alkyl) carbamoyl group; a nitro group; a hydroxyl group or a cyano group. ) Or a heteroaryl group optionally having 1 to 2 nitrogen atoms such as pyridyl or pyrimidinyl which may have a substituent (the heteroaryl group is the same or different from one to three substituents shown below) The substituent may be a halogen atom or a C ₁ -C ₄ alkyl group of the substituent of the aryl group.).

The “leaving group” of R ^L is, for example, a group represented by the formula —O
It is a group having R ⁶ or —S (O) R ⁷ .

In the method A, the compound having the formula (IV) is reacted with a sulfonylating agent or a phosphorylating agent in the presence of a base to produce a compound having the formula (V) (Step A1). V) in the presence of a base with the formula (II)
This is a method for producing a compound having formula (VI) by reacting with a compound having I) (Step A2) and finally subjecting the compound to a reaction for removing a protecting group to produce compound (I). Hereinafter, each step will be described.

(Step A1) The step A1 is based on the formula (IV)
Is a step of producing a compound having the general formula (V) by reacting a compound having the general formula (V) with a sulfonylating agent or a phosphorylating agent in the presence of a base in an inert solvent.

The sulfonylating agent may be, for example, a C ₁ -C ₄ alkanesulfonic anhydride such as methanesulfonic anhydride, trifluoromethanesulfonic anhydride or ethanesulfonic anhydride, or benzenesulfonic anhydride or p-toluenesulfonic anhydride. And anhydrous C ₆ -C ₁₀ arylsulfonic acid, and preferably p-toluenesulfonic anhydride.

The phosphorylating agent is, for example, a di-C ₁ -C ₄ alkyl phosphoryl halide such as dimethyl phosphoryl chloride or diethyl phosphoryl chloride or a di-C ₆ -C ₁₀ aryl phosphoryl halide such as diphenyl phosphoryl chloride or diphenyl phosphoryl bromide. And diphenylphosphoryl chloride is preferred.

The solvent used is not particularly limited as long as it does not participate in the reaction. For example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, nitriles such as acetonitrile, or N, N −
Examples thereof include amides such as dimethylformamide and N, N-dimethylacetamide, esters such as ethyl acetate and methyl acetate, and ethers such as diethyl ether, tetrahydrofuran and dioxane. Preferably, acetonitrile, N , N-dimethylformamide or tetrahydrofuran, particularly preferably acetonitrile.

The base to be used is not particularly limited as long as it does not affect the other parts of the compound, particularly the β-lactam ring, but preferably triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine And particularly preferably diisopropylethylamine.

The reaction temperature is not particularly limited, but it is preferable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, and it is usually carried out at -20 ° C to 40 ° C (preferably -10 ° C to 20 ° C). Will be The reaction time varies mainly depending on the reaction temperature and the type of the reaction reagent, but is 10 minutes to 5 hours (preferably 15 minutes to 1 hour).

After completion of the reaction, the target compound (V) in this step 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 a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. If desired, the target compound (V) can be subjected to the next step without isolation.

(Step A2) The step A2 is performed according to the general formula (V
In the step of producing a compound having I), in an inert solvent,
It is achieved by reacting compound (V) with a mercaptopyrrolidine derivative having the general formula (III) in the presence of a base.

The solvent used is not particularly limited as long as it does not participate in the reaction. For example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, nitriles such as acetonitrile, N, N Amides such as -dimethylformamide and N, N-dimethylacetamide, esters such as ethyl acetate and methyl acetate, and ethers such as diethyl ether, tetrahydrofuran and dioxane. Preferably, acetonitrile, N, N-dimethylformamide or tetrahydrofuran, particularly preferably acetonitrile.

The base used in this step is not particularly limited, but preferably includes organic amines such as triethylamine and diisopropylethylamine and inorganic bases such as potassium carbonate and sodium carbonate. Diisopropylethylamine.

The reaction temperature is not particularly limited, but is usually -2.
It is carried out at 0 ° C to 40 ° C (preferably -10 ° C to 20 ° C). The reaction time is 30 minutes to 108 hours (preferably 1 hour to 18 hours).

After completion of the reaction, the desired compound (VI) of this step is obtained.
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 a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. In addition, if desired, the target compound (VI) can be subjected to the next step without isolation.

(Step A3) In step A3, compound (V)
This is a step of converting I) to compound (I), which is achieved by removing the protecting group of the compound.

The removal of the protecting group depends on its type, but is generally performed by a method used in the field of synthetic organic chemistry (Greene & Wuts, P.S.
protective Groups in Organ
ic Synthesis, 2nd Edition,
1991, John Wiley & Sons, In
c. ).

(1) When the protecting group R ⁵ is a benzyl group or a benzhydryl group which may have a substituent such as benzyl or 4-nitrobenzyl, and R ¹ p, R
Hydroxyl group contained in ² p and R ³ p, benzyl protecting group of the amino group and imino group, 4-nitro good benzyl group or benzyloxycarbonyl which may have a substituent such as benzyl, 4-nitrobenzyl oxycarbonyl In the case of a benzyloxycarbonyl group which may have a substituent as described above, the protecting group can be removed by reacting with hydrogen and a reducing agent using a catalytic reduction catalyst or an alkali metal sulfide.

The reducing agent is, for example, hydrogen and palladium-
Mention may be made of a catalytic reduction catalyst such as carbon or an alkali metal sulfide such as sodium sulfide or potassium sulfide, preferably hydrogen and a palladium-carbon catalyst.

The solvent to be used is not particularly limited as long as it does not participate in the present reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran,
Ethers such as dioxane and mixed solvents of these organic solvents and water.

The reaction temperature is usually from 0 ° C. to 50 ° C. (preferably from 10 ° C. to 40 ° C.), and the reaction time varies depending on the type of the starting compound and the reducing agent.
2 hours (preferably 30 minutes to 4 hours).

After completion of the reaction, the desired compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles from the reaction mixture and then distilling off the solvent.

(2) When the protecting group R ⁵ is an allyl group which may be substituted at the 2-position such as allyl, 2-chloroallyl and 2-methylallyl, and R ¹ p, R ² p and R ³ The protecting group for the hydroxyl group, amino group and imino group contained in p is an allyloxycarbonyl group which may be substituted at the 2-position such as allyloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylallyloxycarbonyl. In the case, palladium-trialkyltin hydrides such as bis (triphenylphosphine) palladium chloride-tributyltin hydride, tetrakis (triphenylphosphine) palladium-tributyltin hydride or tetrakis (triphenylphosphine) palladium-2-ethylhexane Potassium acid or 2-ethyl Palladium compounds such as sodium hexanoate - can be removed protecting group by reaction with a deprotecting agent such as an organic carboxylic acid alkali metal salts.

The deprotecting agent is preferably bis (triphenylphosphine) palladium chloride-tributyltin hydride or tetrakis (triphenylphosphine)
Potassium palladium-2-ethylhexanoate.

The solvent to be used is not particularly limited as long as it does not participate in the reaction, but halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, and esters such as ethyl acetate. Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol, water or a mixed solvent thereof. , Ethyl acetate or a mixed solvent thereof.

The reaction temperature is not particularly limited, but is usually -20 ° C.
To 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the deprotected compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles precipitated from the reaction mixture and then distilling off the solvent.

(3) When the protecting group R ⁵ is a halogenoethyl group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl, a metal such as zinc and a metal such as acetic acid or hydrochloric acid are used. The protective group can be removed by reacting with a reducing agent using an acid.

As the reducing agent, zinc and acetic acid are preferred.

The solvent to be used is not particularly limited as long as it does not participate in the present reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran,
They are ethers such as dioxane, fatty acids such as acetic acid, and mixed solvents of these organic solvents and water.

The reaction temperature is usually 0 ° C. to 40 ° C. (preferably 10 ° C. to 30 ° C.), and the reaction time varies depending on the type of the starting compound and the reducing agent, but is usually 5 minutes to 12 hours (preferably Is 30 minutes to 4 hours).

After completion of the reaction, the desired compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles from the reaction mixture and then distilling off the solvent.

The target compound (I) thus obtained
Can be purified, if necessary, by a conventional method such as a recrystallization method, thin-layer chromatography for preparative use, or column chromatography.

On the other hand, the method B is a method for separately producing the compound (I). That is, a compound having the formula (VII) is reacted with a compound having the formula (III) in the presence of a base to produce a compound having the formula (VI) (Step B1). To produce compound (I) (Step B2). The starting compound having the formula (VII) in the present synthesis method is disclosed in
Manufactured according to the method disclosed in US Pat. Hereinafter, each step will be described.

(Step B1) The step B1 is based on the formula (VI)
Is a method for producing a compound having, in an inert solvent,
It is achieved by reacting compound (VII) with mercaptopyrrolidine derivative (III) in the presence of a base.

The solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, water and a mixed solvent thereof, and acetonitrile is preferred.

The base to be used is not particularly limited as long as it does not affect the other parts of the compound, especially the β-lactam ring, and examples thereof include diisopropylethylamine, triethylamine, N-methylpiperidine, and 4-dimethylamino. Organic bases such as pyridine or inorganic bases such as potassium carbonate and sodium bicarbonate;
Preferably it is diisopropylethylamine.

The reaction temperature is not particularly limited, but it is preferable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at a temperature of -20 ° C to 40 ° C (preferably -10 ° C to 20 ° C). Will be

The reaction time depends mainly on the reaction temperature and the type of the reaction reagent, but is usually from 15 minutes to 75 hours (preferably from 30 minutes to 18 hours).

After completion of the reaction, the desired compound (VI) of this step is obtained.
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 a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. In addition, if desired, the target compound (VI) can be subjected to the next step without isolation.

(Step B2) The step B2 is based on the formula (VI)
This is a step of producing a compound (I) by removing a protecting group from a compound having the formula (I).

This step can be achieved according to the method described in Step A3 of Method A.

The 1-methylcarbapenem compound having the general formula (I) thus obtained by Method A or Method B is pharmacologically prepared by methods and techniques well known in the field of β-lactam antibiotics. It can be converted to an acceptable salt or derivative (preferably an ester derivative).

The raw material mercaptopyrrolidine compound (IV) used in Method A and Method B can be prepared by a known method,
For example, I. Kawamoto et al. , Synl
ett., 1995, 575; JP-A-2-28180;
It can be produced according to the method described in JP-A-2-3687; JP-A-4-211083 or JP-A-5-339269.

The compound of the present invention having the above general formula (I) or a pharmaceutically acceptable salt or derivative thereof has a strong antibacterial activity against a wide range of pathogenic bacteria, and is therefore a therapeutic or prophylactic agent for bacterial infections. (Preferably, a therapeutic agent).

When compound (I) or a pharmaceutically acceptable salt thereof is used as an antibacterial agent, the compound is mixed with the compound itself or an appropriate pharmaceutically acceptable excipient, diluent, etc. , Capsules, granules, powders or syrups or parenterally by injection or the like.

These preparations may contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbite; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate; Silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; Agent Gelatin; polyvinylpyrrolidone;
Maglogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl starch)
Disodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica) Luxes such as bee gum and gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfate salts such as sodium sulfate; Lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (such as methylparaben and propylparaben) Paraoxybenzoic acid esters; chlorobutanol, Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.), suspending agents (for example, polysorbate 80, sodium carboxymethyl cellulose), diluents, solvents for preparations (for example, Water, ethanol, glycerin and the like) are used and manufactured by a known method.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 10 mg).
In the case of intravenous administration, the lower limit is 10 mg (preferably 100 mg) and the upper limit is 3000 mg per dose.
(Preferably 2000 mg) is desirably administered to an adult 1 to 6 times a day depending on the symptoms.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Formulation Examples, but the scope of the present invention is not limited thereto. Incidentally, trimethylsilyl propionic acid sodium -d ₄ unless otherwise specified for the measurement of heavy water for nuclear magnetic resonance spectra in the Examples and Reference Examples using the internal standard tetramethylsilane as the internal standard in the other solvents It measured using.

[0117]

【Example】

Example 1 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-Aminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 61)

[0118]

Embedded image

(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.72 g) solution in dry acetonitrile (7 ml) While stirring under ice-cooling, N, N-diisopropylethylamine (0.21 ml) and (2S, 4S) -4-mercapto-1-methyl-2-[(3R) -3- (4-nitrobenzyloxycarbonyl) Aminomethyl) pyrrolidine-
A solution of 1-ylcarbonyl] pyrrolidine (0.54 g) in dry acetonitrile (10 ml) was added, and the mixture was stirred at 0 ° C overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 7/3),
R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -1-methyl-2-[(3R) -3- (4-nitro Benzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-
2-M-3-carboxylic acid 4-nitrobenzyl ester (0.74 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1771,1721,1637,1608,1522,1490,1274,1245,
1210,1181,1137,1107,1074,1046,1026,1014. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.27 (3H, d, J = 7.3Hz), 1.36 (3H, d, J = 6.6Hz), 1.45-
2.80 (5H, m), 2.31,2.31 (3H, s × 2), 2.98-3.90 (13H, m), 4.1
8-4.30 (2H, m), 5.10-5.50 (4H, m), 7.48 (2H, d, J = 8.6Hz), 7.
63 (2H, d, J = 8.6 Hz), 8.20 (4H, d, J = 8.6 Hz). (2) Compound (0.73 g) obtained in (1) in tetrahydrofuran (40 ml), water (28 ml) Into the solution
A 10% palladium-carbon catalyst (1.46 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was separated by reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 6/94 → 1/9 (eluting while gradually increasing the acetonitrile concentration from 6% to 10%)]. Thereafter, the mixture was concentrated under reduced pressure and freeze-dried to obtain a powdery compound (246 mg).

Further, 230 mg of this was eluted with an HPLC preparative column [Cosmo Seal 5C18-AR (Nacalai Tesque), acetonitrile / water = 6/94 → 1/9 (eluting while gradually increasing the acetonitrile concentration from 6% to 10%). )], Concentrated under reduced pressure, and freeze-dried to obtain a powdery target compound (156 mg).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1758,1633,1594,1488,1455,1385,1340,1313,
1253,1225,1210,1181,1149,1095. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.21 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.63-1.8
6 (2H, m), 2.14-2.93 (4H, m), 2.32 (3H, s), 3.03-4.01 (13H, m
m), 4.17-4.30 (2H, m). Example 2 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-Aminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 61)

[0123]

Embedded image

(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.73 g) in dry acetonitrile (7 ml) While stirring under ice-cooling, N, N-diisopropylethylamine (0.22 ml) and (2S, 4S) -4-mercapto-1-methyl-2-[(3S) -3- (4-nitrobenzyloxycarbonyl) Aminomethyl) pyrrolidine-
A solution of 1-ylcarbonyl] pyrrolidine (0.57 g) in dry acetonitrile (10 ml) was added, and the mixture was stirred at 0 ° C overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 7/3),
R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -1-methyl-2-[(3S) -3- (4-nitro Benzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-
2-M-3-carboxylic acid 4-nitrobenzyl ester (0.78 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1771,1721,1638,1608,1522,1490,1453,1375,
1347,1324,1274,1246,1210,1181,1137. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.25 (3H, d, J = 7.3Hz), 1.36 (3H, d, J = 6.6Hz), 1.46-
2.80 (5H, m), 2.31 (3H, s), 2.98-4.00 (13H, m), 4.18-4.31 (2
H, m), 5.11-5.50 (4H, m), 7.42-7.67 (4H, m), 8.13-8.25 (4H, m
m). (2) A solution of the compound (0.76 g) obtained in (1) in tetrahydrofuran (40 ml) and water (28 ml) was added.
A 10% palladium-carbon catalyst (1.55 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was separated by reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 6/94 → 1/9], concentrated under reduced pressure, and lyophilized to give a powdery compound (248 mg). I got Furthermore, 189 mg of this is H
PLC preparative column [Cosmo Seal 5C18-AR (Nacalai Tesque), acetonitrile / water = 6/94 → 1 /
9] to obtain a powdery target compound (125 mg).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1759,1633,1595,1488,1455,1384,1253,1211,
1180, 1148, 1095. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.21 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.63-1.8
7 (1H, m), 2.13-2.40 (1H, m), 2.31,2.30 (3H, s × 2), 2.53-2.
Example 3 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1 93 (3H, m), 3.08-3.90 (11H, m), 4.18-4.29 (2H, m). -Methyl-2-[(2S, 4S) -2-
[(3R) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 1)

[0127]

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(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (1.76 g) in dry acetonitrile (20 ml) And N, N-diisopropylethylamine (0.51 ml) and (2S, 4S) -4-mercapto-2-[(3S) -3- (N-methyl-N-4-nitrobenzyl) while stirring under ice cooling. A solution of (oxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1.92 g) in dry acetonitrile (20 ml) was added and reacted at 0 ° C. overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 95/5 → 9/1) to give (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl -2-[(2S, 4S)-
2-[(3S) -3- (N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl) -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]- 1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (2.52 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1774,1707,1652,1607,1522,1441,1404,1346,
1295,1210,1143,1110. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δp
pm: 1.29 (3H, d, J = 7.2 Hz), 1.37 (3H, d, J = 6.1 Hz), 1.55-
2.73 (5H, m), 2.93-4.58 (18H, m), 5.02-5.52 (6H, m), 7.40-
7.70 (6H, m), 8.15-8.30 (6H, m). (2) 10% palladium-carbon was added to a solution of the compound (2.52 g) obtained in (1) in tetrahydrofuran (120 ml) and water (84 ml). A catalyst (5.07 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C. The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 6/94 → 8 /
92], concentrated under reduced pressure, and freeze-dried to obtain a powdery target compound (406 mg).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1757,1634,1598,1456,1386,1311,1284,1257,
1225,1180,1148,1099. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.22 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.58-1.8
7 (2H, m), 2.16-2.31 (1H, m), 2.58-2.80 (2H, m), 2.76 (3H, m
s), 3.03-4.07 (12H, m), 4.18-4.29 (2H, m). Example 4 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2 − [(2S, 4S) -2-
[(3R) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 62)

[0131]

Embedded image

(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.72 g) in dry acetonitrile (5 ml) Then, N, N-diisopropylethylamine (0.21 ml) and (2S, 4S) -4-mercapto-1-methyl-2-[(3S) -3- (N-methyl-N- A solution of 4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (0.54 g) in dry acetonitrile (5 ml) was added, and the mixture was reacted at 0 ° C overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / methanol = 6/4).
And (1R, 5S, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-[(2S,
4S) -1-methyl-2-[(3S) -3- (N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-
4-ylthio] -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.46 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1770,1705,1640,1607,1522,1489,1452,1403,
1376,1346,1278,1210,1143,1106. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δp
pm: 1.27 (3H, d, J = 7.3Hz), 1.37 (3H, d, J = 6.2Hz), 1.49-
2.83 (5H, m), 2.31,2.35 (3H, s × 2), 2.95-3.80 (13H, m), 4.2
0-4.30 (2H, m), 5.16-5.53 (4H, m), 7.52 (2H, d, J = 8.8Hz), 7.
64,7.65 (2H, d × 2, J = 8.8Hz), 8.22,8.23 (4H, d × 2, J = 8.8
(2) A solution of the compound (0.46 g) obtained in (1) in tetrahydrofuran (22 ml) and water (15 ml) was added to the solution.
A 10% palladium-carbon catalyst (0.93 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 4/96 → 8/92]
, And concentrated under reduced pressure and freeze-dried to obtain a powdery compound (150 mg).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1760,1634,1598,1486,1454,1383,1314,1279,
1253,1221,1180,1148,1095. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.21 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.2Hz), 1.65-1.8
6 (2H, m), 2.15-2.30 (1H, m), 2.38 (3H, s), 2.57-3.00 (2H, m
m), 3.10-3.99 (12H, m), 4.18-4.29 (2H, m). Example 5 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2 − [(2S, 4S) -2-
[(3S) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 1)

[0135]

Embedded image

(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.85 g) in dry acetonitrile (5 ml) While stirring under ice-cooling, N, N-diisopropylethylamine (0.25 ml) and (2S, 4S) -4-mercapto-2-[(3R) -3- (N-methyl-N-4-nitrobenzyl) A solution of (oxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (0.90 g) in dry acetonitrile (10 ml) was added, and the mixture was reacted at 0 ° C. overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 95/5 → 9/1) to give (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl -2-[(2S, 4S)-
2-[(3R) -3- (N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl) -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]- 1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (1.07 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1773,1707,1654,1607,1522,1441,1404,1373,
1346,1295,1210,1180,1143,1110,1047,1015. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δp
pm: 1.27 (3H, d, J = 7.3 Hz), 1.37 (3H, d, J = 6.3 Hz), 1.50-
2.72 (5H, m), 2.90-4.31 (14H, m), 4.40-4.55 (1H, m), 5.01-
5.52 (6H, m), 7.41-7.67 (6H, m), 8.13-8.27 (6H, m). (2) The compound (1.05 g) obtained in (1) in tetrahydrofuran (50 ml) and water (35 ml) ) Solution
A 10% palladium-carbon catalyst (2.10 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was separated by reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 6/94 → 1/9], concentrated under reduced pressure, and lyophilized to obtain a powdered target compound (127 mg). ) Got.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1756,1633,1598,1457,1387,1311,1285,1258,
1226,1181,1149,1096,1074. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.22 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.59-1.8
7 (2H, m), 2.16-2.32 (1H, m), 2.58-2.81 (2H, m), 2.77 (3H, m
s), 3.05-3.86 (12H, m), 3.94-4.03 (1H, m), 4.18-4.28 (2H, m
m). Example 6 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3S) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 62)

[0139]

Embedded image

(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.66 g) in dry acetonitrile (5 ml) And N, N-diisopropylethylamine (0.19 ml) and (2S, 4S) -4-mercapto-1-methyl-2-[(3R) -3- (N-methyl-N- A solution of 4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (0.53 g) in dry acetonitrile (5 ml) was added, and the mixture was reacted at 0 ° C. overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / methanol = 6/4).
And (1R, 5S, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-[(2S,
4S) -1-Methyl-2-[(3R) -3- (N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-
4-ylthio] -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.43 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1771,1734,1705,1639,1608,1522,1489,1452,
1403,1375,1346,1278,1246,1210,1142. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δp
pm: 1.27 (3H, d, J = 7.2Hz), 1.37 (3H, d, J = 6.2Hz), 1.52-
2.78 (8H, m), 2.94-3.82 (13H, m), 4.19-4.30 (2H, m), 5.12-
5.50 (4H, m), 7.50-7.68 (4H, m), 8.21-8.23 (4H, m). (2) Tetrahydrofuran (20 ml) of the compound (0.42 g) obtained in (1), water (15 ml) ) Solution
A 10% palladium-carbon catalyst (0.83 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 6/94 → 8/92]
, And concentrated under reduced pressure, followed by lyophilization to obtain a powdery target compound (28 mg).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1757,1642,1597,1489,1457,1384,1251,1210,
1158,1095,1028. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.21 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.67-1.1.8
8 (2H, m), 2.17-2.32 (1H, m), 2.51 (3H, br.s), 2.57-2.75 (1
H, m), 2.76 (3H, s), 2.87-3.01 (1H, m), 3.05-3.87 (11H, m),
3.90-4.00 (1H, m), 4.18-4.29 (2H, m). Example 7 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 18)

[0143]

Embedded image

(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.70 g) in dry acetonitrile (10 ml) Then, while stirring under ice-cooling, N, N-diisopropylethylamine (0.21 ml) and (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl)-
A solution of 2-[(3R) -3- (4-nitrobenzyloxycarbonylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (1.28 g) in dry acetonitrile (10 ml) was added, and the mixture was reacted overnight at 0 ° C. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 95/5 → 9/1 → 6/4).
(1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -1-
(4-nitrobenzyloxycarbonyl) -2-[(3
R) -3- (4-Nitrobenzyloxycarbonylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-
3-carboxylic acid 4-nitrobenzyl ester (0.9
7 g) were obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1772,1709,1647,1608,1522,1491,1440,1404,
1378,1346,1322,1287,1210,1178,1133,1109. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.28 (3H, d, J = 7.4Hz), 1.37 (3H, d, J = 6.3Hz), 1.50-
2.77 (8H, m), 2.94-4.05 (12H, m), 4.18-4.28 (2H, m), 4.40-
4.55 (1H, m), 5.10-5.51 (6H, m), 7.37-7.68 (6H, m), 8.10-8.
27 (6H, m). (2) A solution of the compound obtained in (1) (0.95 g) in tetrahydrofuran (50 ml) and water (35 ml) was added to the solution.
A 10% palladium-carbon catalyst (1.90 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 8/92 → 12/8]
8], concentrated under reduced pressure and freeze-dried to obtain a powdery compound (224 mg).

Further, this was separated and purified with an HPLC preparative column [Cosmo Seal 5C18-AR (Nacalai Tesque), acetonitrile / water = 8/92 → 12/88], concentrated under reduced pressure, and lyophilized to obtain a powdery product. Compound (166m
g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1757,1630,1455,1386,1313,1283,1260,1224,
1182,1147,1102,1074. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.22 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.55-1.8
4 (2H, m), 2.18-2.23 (1H, m), 2.52-2.78 (2H, m), 3.06 (1H, d
d, J = 12.3,3.6Hz), 3.13-3.85 (10H, m), 3.96-4.03 (1H, m),
4.18-4.29 (2H, m). Example 8 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 17)

[0148]

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(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.81 g) in dry acetonitrile (10 ml) Then, while stirring under ice-cooling, N, N-diisopropylethylamine (0.44 ml) and (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl)-
2-[(3R) -3- (4-nitrobenzyloxycarbonylacetimidoylaminomethyl) pyrrolidine-1
[-Ylcarbonyl] pyrrolidine (1.35 g) in dry acetonitrile (15 ml) was added and reacted at 0 ° C overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 95/5 → 9/1 → 8/2) to give (1R, 5S, 6S) -6-[(1R) -1
-Hydroxyethyl] -1-methyl-2-[(2S, 4
S) -1- (4-Nitrobenzyloxycarbonyl)-
2-[(3R) -3- (4-nitrobenzyloxycarbonylacetimidoaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid 4-nitro The benzyl ester (1.15 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1773, 1709, 1650, 1607,
1556, 1522, 1494, 1441, 1404
1373, 1246, 1278, 1237, 1212
1126, 1110. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ )
δ ppm: 1.29 (3H, d, J = 7.1 Hz), 1.37 (3H, d, J = 6.1 Hz), 1.
50-2.72 (9H, m), 2.98-4.06 (12H, m), 4.22-4.30 (2H, m), 4.4
6-4.57 (1H, m), 5.16-5.52 (6H, m), 7.43-7.67 (6H, m), 8.17-
8.27 (6H, m). (2) A solution of the compound (1.13 g) obtained in (1) in tetrahydrofuran (60 ml) and water (42 ml) was added to the solution.
A 10% palladium-carbon catalyst (2.28 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 8/92 → 12/8]
8], concentrated under reduced pressure, and freeze-dried to obtain a powdery compound (337 mg).

Further, this was separated and purified on an HPLC preparative column [Cosmo Seal 5C18-AR (Nacalai Tesque), acetonitrile / water = 8/92 → 12/88], concentrated under reduced pressure, and lyophilized to obtain a powdery product. Compound (254m
g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1756,1684,1633,1593,1455,1386,1312,1284,
1261,1226,1182,1284,1261,1226,1182,1148. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.22 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.56-1.6
7 (1H, m), 1.69-1.87 (1H, m), 2.12-2.26 (1H, m), 2.25 (3H,
s), 2.58-2.78 (2H, m), 3.06 (1H, dd, J = 12.3,3.5Hz), 3.14-
3.85 (10H, m), 3.96-4.04 (1H, m), 4.18-4.28 (2H, m). Example 9 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-cyclopropylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]
-6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 15)

[0153]

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(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.66 g) in dry acetonitrile (7 ml) Then, while stirring under ice-cooling, N, N-diisopropylethylamine (0.19 ml) and (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl)-
2-[(3S) -3- (N-cyclopropyl-N-4-
Nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (0.14 g)
Was added to a dry acetonitrile (8 ml) solution and reacted at 0 ° C. overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 95/5).
(1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -1-
(4-nitrobenzyloxycarbonyl) -2-[(3
S) -3- (N-Cyclopropyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine-1-
[Ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.80 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1774,1708,1652,1607,1522,1496,1444,1404,
1346,1287,1210,1181,1138,1110. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δp
pm: 0.60-0.92 (4H, m), 1.29 (3H, d, J = 7.4Hz), 1.37,1.38
(3H, d × 2, J = 6.3Hz), 1.48-2.74 (6H, m), 3.00-4.05 (11H,
m), 4.22-4.30 (2H, m), 4.36-4.56 (1H, m), 5.16-5.52 (6H,
m), 7.43-7.68 (6H, m), 8.17-8.26 (6H, m). (2) A solution of the compound (0.78 g) obtained in (1) in tetrahydrofuran (40 ml) and water (28 ml) was prepared.
A 10% palladium-carbon catalyst (1.57 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was separated by reversed-phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 6/94 → 1/9], concentrated under reduced pressure, and lyophilized to obtain a powdered target compound (106 mg). ) Got.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1759,1637,1599,1455,1386,1312,1283,1259,
1224,1180,1147,1103. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 0.73-0.88 (4H, m), 1.22 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J
= 6.4Hz), 1.63-1.86 (2H, m), 2.14-2.30 (1H, m), 2.58-2.83
(3H, m), 3.08-3.92 (11H, m), 4.06-4.14 (1H, m), 4.19-4.30
Example 10 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 17)

[0157]

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(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (0.58 g) in dry acetonitrile (10 ml) Then, while stirring under ice cooling, N, N-diisopropylethylamine (0.17 ml) and (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl)-
2-[(3S) -3- (4-nitrobenzyloxycarbonylacetimidoylaminomethyl) pyrrolidine-1
A solution of [-ylcarbonyl] pyrrolidine (0.93 g) in dry acetonitrile (10 ml) was added and reacted at 0 ° C overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 9/1) to give (1R,
5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -1- (4-
Nitrobenzyloxycarbonyl) -2-[(3S)-
3- (4-nitrobenzyloxycarbonylacetimidoylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-2
-M-3-carboxylic acid 4-nitrobenzyl ester (0.61 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1774,1709,1651,1607,1558,1522,1496,1441,
1404,1373,1346,1278,1238,1212,1126,1110,1074,1015. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δp
pm: 1.29 (3H, d, J = 7.1Hz), 1.37 (3H, d, J = 6.2Hz), 1.55-
2.75 (9H, m), 3.05-4.06 (11H, m), 4.22-4.27 (2H, m), 4.44-
4.60 (1H, m), 5.17-5.53 (6H, m), 7.42-7.68 (6H, m), 8.15-8.
26 (6H, m). (2) A solution of the compound obtained in (1) (0.58 g) in tetrahydrofuran (30 ml) and water (20 ml) was added.
A 10% palladium-carbon catalyst (1.15 g) was added, and hydrogen was absorbed for 1.5 hours while stirring at an external temperature of 30 ° C.
The catalyst was filtered off, and the filtrate was washed with ether and ethyl acetate, and then concentrated under reduced pressure. The residue was separated by reverse-phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 6/94 → 1/9], concentrated under reduced pressure, and lyophilized to obtain a powdered target compound (156 mg). ) Got.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1756,1687,1633,1592,1454,1386,1313,1284,
1261,1226,1182. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.22 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.57-1.6
7 (1H, m), 1.70-1.85 (1H, m), 2.12-2.27 (1H, m), 2.25 (3H,
s), 2.58-2.79 (2H, m), 3.03-3.85 (11H, m), 3.92-4.01 (1H,
m), 4.18-4.29 (2H, m). Example 11 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 18)

[0161]

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(1) (1R, 5R, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2- (diphenylphosphoryloxy) -1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (8
N, N-diisopropylethylamine (0.256 ml) and (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) 2 were added to a solution of 74 mg) in dry acetonitrile (9 ml) while stirring under ice cooling. −
A solution of [(3S) -3- (4-nitrobenzyloxycarbonylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (926 mg) in dry acetonitrile (1.0 ml) was added, and the mixture was reacted at 0 ° C overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 7/1).
(1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -1-
(4-nitrobenzyloxycarbonyl) -2-[(3
S) -3- (4-Nitrobenzyloxycarbonylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-
3-carboxylic acid 4-nitrobenzyl ester (1.2
3 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1773,1710,1656,1607,1521,1438,1404,1385,
1346,1285,1208,1177,1135,1109,1030. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δp
pm: 1.28 (3H, d, J = 7.2Hz), 1.34 (3H, d, J = 6.3Hz), 1.65-
1.85 (1H, m), 1.90-2.10 (2H, m), 2.15-2.80 (5H, m), 3.05-3.
70 (11H, m), 4.00-4.10 (1H, m), 4.10-4.30 (2H, m), 4.45-4.6
0 (1H, m), 5.00-5.55 (6H, m), 7.40-7.70 (6H, m), 8.15-8.30
(6H, m). (2) A solution of the compound (1.14 g) obtained in (1) in tetrahydrofuran (38 ml) and water (19 ml) was added.
A 10% palladium-carbon catalyst (2.3 g) was added, and hydrogen was absorbed for 1.2 hours while stirring at an external temperature of 30 ° C. The catalyst was separated by filtration, and the filtrate was washed with ether and concentrated under reduced pressure. The residue was separated by reverse phase column chromatography [Cosmo Seal 75C18-PREP (Nacalai Tesque), acetonitrile / water = 8/92], concentrated under reduced pressure, and lyophilized to obtain the desired compound (187 mg) in powder form. .

Nuclear magnetic resonance spectrum (270 MHz, D ₂
O, internal standard trimethylsilyl propionic acid sodium _{-d 4) δppm: 1.25 (3H} , d, J = 7.0Hz), 1.33 (3H, d, J =
6.3Hz), 1.55-1.90 (2H, m), 2.10-2.30 (1H, m), 2.50-2.90 (2H, m)
H, m), 3.05-3.35 (4H, m), 3.35-3.50 (3H, m), 3.60-3.75 (2H,
m), 3.78-3.90 (1H, m), 3.90-4.10 (1H, m), 4.20-4.35 (2H,
m). Example 12 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3R) -3- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 54)

[0166]

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(1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-emu-3-carboxylic acid 4-nitrobenzyl ester ( 255 mg) of dry dimethylformamide (3 ml)
(2S, 4S) -4-mercapto-1 in ice-cooled solution
-(4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (198 m
A solution of g) in dry dimethylformamide (1 ml) and diisopropylethylamine (97 μl) were added, and the mixture was stirred at the same temperature for 20 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate / methanol = 4/1, a powdery (1R, 5
S, 6S) -6-[(1R) -1-hydroxyethyl]
-1-Methyl-2-[(2S, 4S) -1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-2-emu 3-Carboxylic acid 4-nitrobenzyl ester (235 mg) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3351, 2970, 1773, 1709, 1697, 1525, 1447,
1246. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.20-1.30 (3H, m), 1.34 (3H, d, J = 6.1Hz), 1.
40-2.10 (6H, m), 2.00-3.00 (8H, m), 3.10-3.80 (6H, m),
3.80-4.40 (4H, m), 4.50-4.70 (1H, m), 5.00-5.40 (3H,
m), 5.40-5.55 (1H, m), 7.40-7.55 (2H, m), 7.60-7.70
(2h, m), 8.15-8.25 (4H, m). (2) The compound (161 mg) obtained in (1) was dissolved in tetrahydrofuran (3 ml) -water (1.5 ml), and the mixture was dissolved in 10% palladium on carbon catalyst. (320 mg)
Hydrogenation was performed at room temperature for 90 minutes. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure to remove tetrahydrofuran, washed with ether, and the aqueous layer was concentrated under reduced pressure. The residue is subjected to reverse phase column chromatography (Nakarai Tesque, Cosmo Seal 7).
5C18-PREP) and acetonitrile / water = 2
The fraction eluted at / 98 → 1/9 was freeze-dried to obtain a powdery target compound (51 mg).

Infrared absorption spectrum (KBr) νmax
^{cm -1: 3378, 1763, 1655} , 1593, 1489, 1376. Nuclear Magnetic Resonance Spectrum (400MHz, D ₂ 0) δpp
m: 1.20 (3H, d, J = 7.2Hz), 1.28 (3H, d, J = 6.4Hz), 1.
65-1.90 (2H, m), 1.95-2.40 (9H, m), 2.65-2.80 (1H, m
m), 3.00-3.25 (3H, m), 3.30-3.40 (2H, m), 3.40-3.55
(2H, m), 3.60-4.00 (4H, m), 4.00-4.10 (1H, m), 4.20-
4.30 (2H, m), 4.65-4.75 (1H, m). Example 13 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -2-[(2S, 4S) -2 -[(3S)-
3- (2-hydroxyethylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]-
1-methyl-1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 3)

[0170]

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(2S, 4S) -2-[(3R) -3-
(N-2-hydroxyethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -pyrrolidine (214 mg) Example 12 A powdery target compound (85.1 mg) was obtained in the same manner as in (1) and (2).

Infrared absorption spectrum (KBr) νmax
^{cm -1: 3409, 1747, 1644} , 1601, 1455, 1386. Nuclear Magnetic Resonance Spectrum (400MHz, D ₂ 0) δpp
m: 1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.
70-1.95 (2H, m), 2.15-2.35 (2H, m), 2.60-2.85 (2H, m
m), 2.85-2.95 (1H, m), 3.15-3.30 (3H, m), 3.30-3.50
(5H, m), 3.55-3.90 (2H, m), 3.90-4.00 (1H, m), 4.20-
Example 14 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (carbamoylmethylaminomethyl)
Pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 6)

[0173]

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(2S, 4S) -2-[(3S) -3-
Example 12 using (N-carbamoylmethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -pyrrolidine (368 mg). -A powdery target compound (158 mg) was obtained in the same manner as in (1) and (2).

Infrared absorption spectrum (KBr) νmax
^{cm -1: 3401, 1754, 1695} , 1645, 1597, 1455. Nuclear Magnetic Resonance Spectrum (400MHz, D ₂ 0) δpp
m: 1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.
70-1.90 (1H, m), 1.90-2.05 (1H, m), 2.20-2.35 (1H,
m), 2.65-2.80 (1H, m), 2.95-3.10 (1H, m), 3.10-3.22
(2H, m), 3.22-3.30 (1H, m), 3.35-3.60 (4H, m), 3.60-
3.95 (5H, m), 4.00-4.08 (1H, m), 4.22-4.30 (2H, m),
4.60-4.70 (1H, m). Example 15 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (2-aminoethylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 12)

[0176]

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(2S, 4S) -4-mercapto-1-
(4-nitrobenzyloxycarbonyl) -2-[(3
Example 12 using S) -3- [N-2- (4-nitrobenzyloxycarbonylamino) ethyl-N-4-nitrobenzyloxycarbonylaminomethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (248 mg). A powdery target compound (48.5 mg) was obtained in the same manner as in (1) and (2).

Infrared absorption spectrum (KBr) νmax
^{cm -1: 3370, 1758, 1648} , 1603, 1455, 1386. Nuclear Magnetic Resonance Spectrum (400MHz, D ₂ 0) δpp
m: 1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.
70-1.90 (1H, m), 1.90-2.05 (1H, m), 2.15-2.33 (1H, m
m), 2.55-2.70 (1H, m), 2.97-3.13 (4H, m), 3.15-3.33
(5H, m), 3.34-3.52 (3H, m), 3.57-3.67 (1H, m), 3.68-
3.90 (3H, m), 4.21-4.30 (2H, m), 4.60-4.67 (1H, m). Example 16 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (2-dimethylaminoethylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 14)

[0179]

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(2S, 4S) -2-[(3S) -3-
(N-2-dimethylaminoethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine-1-
Ylcarbonyl] -4-mercapto-1- (4-nitrobenzyloxycarbonyl) pyrrolidine (428 mg)
Was used to obtain a powdery target compound (109 mg) in the same manner as in Example 12- (1) and (2).

The nuclear magnetic resonance spectrum (270 MHz, D
₂₀ ) δppm: 1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d,
J = 6.3Hz), 1.60-1.90 (2H, m), 2.10-2.25 (1H, m), 2.45
-2.60 (1H, m), 2.77 (3H, s), 2.79 (3H, s), 2.70-3.00
(2H, m), 3.00-3.10 (1H, m), 3.31-3.53 (5H, m), 3.55-
3.87 (3H, m), 3.88-4.00 (1H, m), 4.20-4.30 (2H, m),
4.17-4.40 (1H, m). Example 17 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3R) -3- (N-methyl-N-2-methylaminoethylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-2
-M-3-carboxylate hydrochloride (stereoisomeric hydrochloride of Exemplified Compound 31)

[0182]

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(1) (2S, 4S) -4-mercapto-2-[(3R) -3- [N-2- (N-methyl-N-
4-nitrobenzyloxycarbonylamino) ethyl-
N-methylaminomethyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl)
Example 12- (1) using pyrrolidine (617 mg)
In the same manner, powdery (1R, 5S, 6S) -6-
[(1R) -1-hydroxyethyl] -1-methyl-2
-[(2S, 4S) -1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- [N-2- (N-
Methyl-N-4-nitrobenzyloxycarbonylamino) ethyl-N-methylaminomethyl] pyrrolidine-1
-Ylcarbonyl] pyrrolidin-4-ylthio] -1-
Carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (527 mg) was obtained.

(2) Compound (202) obtained in (1)
mg) in water (1.5 ml), 1N hydrochloric acid (0.201 m
l) and tetrahydrofuran (3 ml).
% Palladium on carbon catalyst (400 mg)
Hydrogenation was performed for 5 minutes. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure to remove tetrahydrofuran, washed with ether, and the aqueous layer was concentrated under reduced pressure. The residue is subjected to reverse phase column chromatography (Nakarai Tesque, Cosmo Seal 75C18).
-PREP), and the fraction eluted with water was freeze-dried to obtain a powdery target compound (61 mg).

Nuclear magnetic resonance spectrum (400 MHz, D
₂₀ ) δppm: 1.21 (3H, d, J = 7.2Hz), 1.29 (3H, d,
J = 6.3Hz), 1.70-1.87 (1H, m), 1.96-2.05 (1H, m), 2.22
-2.34 (1H, m), 2.60-2.69 (1H, m), 2.75 (3H, s), 2.90
(3H, s), 3.00-3.10 (1H, m), 3.10-3.35 (7H, m), 3.35-
3.44 (1H, m), 3.45-3.60 (3H, m), 3.62-3.92 (3H, m),
4.01-4.08 (1H, m), 4.20-4.27 (2H, m), 4.65-4.79 (1H, m
m). Example 18 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (2-fluoroethylaminomethyl)
Pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 4)

[0186]

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(2S, 4S) -2-[(3S) -3-
Example 12- (N-2-fluoroethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] -4-mercapto-1- (4-nitrobenzyloxycarbonyl) pyrrolidine The target compound can be synthesized in the same manner as described in 1) and 2). Example 19 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (1-Methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 36)

[0188]

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(2S, 4S) -4-mercapto-2-
[(3R) -3- [1-Methyl-2,3-bis (4-nitrobenzyloxycarbonyl) guanidinomethyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (996 mg) In the same manner as described in Example 12- (1) and (2) to obtain the desired compound (149 mg).

Nuclear magnetic resonance spectrum (400 MHz, D
₂₀ ) δppm: 1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d,
J = 6.4Hz), 1.55-1.70 (1H, m), 1.70-1.85 (1H, m), 2.10
-2.25 (1H, m), 2.65-2.80 (2H, m), 3.09 (3H, s), 3.15-
3.30 (2H, m), 3.35-3.55 (6H, m), 3.70-3.85 (2H, m),
3.95-4.05 (1H, m), 4.20-4.30 (2H, m). Example 20 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (N-acetimidoyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl -1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 35)

[0191]

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(2S, 4S) -4-mercapto-1-
(4-nitrobenzyloxycarbonyl) -2-[(3
Example 1 using R) -3- (N-4-nitrobenzyloxycarbonylacetimidoyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine.
2-The target compound can be synthesized in the same manner as described in (1) and (2).

Example 21 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (N-formimidoyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl -1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 34)

[0194]

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(2S, 4S) -4-mercapto-1-
(4-nitrobenzyloxycarbonyl) -2-[(3
Example 1 using R) -3- (N-4-nitrobenzyloxycarbonylformimidyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine.
2-The target compound can be synthesized in the same manner as described in (1) and (2).

Example 22 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3R) -3- (2,2,2-trifluoroethylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3
-Carboxylic acid (stereoisomer of Exemplified Compound 5)

[0197]

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(2S, 4S) -4-mercapto-1-
(4-nitrobenzyloxycarbonyl) -2-[(3
S) -3- (N-4-Nitrobenzyloxycarbonyl-N-2,2,2-trifluoroethylaminomethyl]
Using pyrrolidin-1-ylcarbonyl] pyrrolidine, the target compound can be synthesized in the same manner as described in Example 12- (1) and (2).

Example 23 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 16)

[0200]

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(2S, 4S) -4-mercapto-1-
(4-nitrobenzyloxycarbonyl) -2-[(3
R) -3- (4-Nitrobenzyloxycarbonylformimidylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine in the same manner as described in Example 12- (1) and (2) to obtain the desired compound Can be synthesized.

Example 24 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 79)

[0203]

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(2S, 4S) -2-[(3R) -3-
Example 4- (1) using [2,3-bis (4-nitrobenzyloxycarbonyl) guanidinomethyl] pyrrolidin-1-ylcarbonyl] -4-mercapto-1- (4-nitrobenzyloxycarbonyl) pyrrolidine The target compound can be synthesized in the same manner as in the method described in (2).

Example 25 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 78)

[0206]

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(2S, 4S) -4-Mercapto-1-methyl-2-[(3R) -3- (N-4-nitrobenzyloxycarbonylacetimidoyl-N-methylaminomethyl) pyrrolidin-1-yl Using carbonyl] pyrrolidine, the target compound can be synthesized in the same manner as described in Examples 4- (1) and (2).

Example 26 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 77)

[0209]

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(2S, 4S) -4-mercapto-1-methyl-2-[(3R) -3- (4-nitrobenzyloxycarbonylformimidoylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine Example 4
The target compound can be synthesized in the same manner as described in (1) and (2).

Example 27 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (1-Methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-m-3-
Carboxylic acid (stereoisomer of Exemplified Compound 96)

[0212]

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(2S, 4S) -2-[(3R) -3-
[2,3-bis (4-nitrobenzyloxycarbonyl) -1-methylguanidinomethyl] pyrrolidine-1-
The desired compound can be synthesized in the same manner as described in Examples 4- (1) and (2) using [ylcarbonyl] -4-mercapto-1-methylpyrrolidine.

Example 28 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (N-acetimidoyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] -1
-Methylpyrrolidin-4-ylthio] -6-[(1R)
-1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 95)

[0215]

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(2S, 4S) -4-mercapto-1-methyl-2-[(3R) -3- (N-4-nitrobenzyloxycarbonylacetimidoyl-N-methylaminomethyl) pyrrolidin-1-yl Using carbonyl] pyrrolidine, the target compound can be synthesized in the same manner as described in Examples 4- (1) and (2).

Example 29 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (N-formimidoyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] -1
-Methylpyrrolidin-4-ylthio] -6-[(1R)
-1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (stereoisomer of Exemplified Compound 94)

[0218]

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(2S, 4S) -4-Mercapto-1-methyl-2-[(3R) -3- (N-4-nitrobenzyloxycarbonylformimidoyl-N-methylaminomethyl) pyrrolidin-1-yl Using carbonyl] pyrrolidine, the target compound can be synthesized in the same manner as described in Examples 4- (1) and (2).

Example 30 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3R) -3-methylaminomethylpyrrolidine-1-
Ilcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-2-em-3-carboxylate hydrochloride (stereoisomer of Exemplified Compound 1 hydrochloride)

[0221]

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Compound of Example 3 (1R, 5S, 6S)-
6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-[(3R) -3-methylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio ] -1-carbapene-2-M-3
1 in an aqueous solution (2 ml) of carboxylic acid (59.7 mg)
Normal aqueous hydrochloric acid (0.122 ml) was added, and the aqueous solution was subjected to reverse phase column chromatography (manufactured by Nacalai Tesque, Cosmoseal 75C18PREP) to obtain a powdery target compound (46 mg) from the fraction eluted with water.

Infrared absorption spectrum (KBr) νmax
^{cm -1: 3409, 1757, 1634} , 1598, 1456, 1386. Nuclear Magnetic Resonance Spectrum (400MHz, D ₂ 0) δpp
m: 1.21 (3H, d, J = 7.2Hz), 1.29 (3H, d, J = 6.3Hz), 1.
70-1.87 (1H, m), 1.96-2.05 (1H, m), 2.20-2.32 (1H,
m), 2.60-2.70 (1H, m), 2.75 (3H, s), 3.00-3.10 (1H,
m), 3.10-3.35 (3H, m), 3.35-3.45 (1H, m), 3.45-3.50
(3H, m), 3.60-3.90 (3H, m), 4.02-4.09 (1H, m), 4.21-
4.28 (2H, m), 4.66-4.78 (1H, m). Reference Example 1 (2S, 4S) -4-mercapto-1-methyl-2-
[(3R) -3- (4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (1) (3S) -3-hydroxymethyl-1-[(1
R) -1-Phenylethyl] pyrrolidine (11.5 g)
Palladium hydroxide in ethanol solution (240 ml)
A carbon catalyst (11.6 g) was added, and hydrogen was absorbed for 3 hours while stirring at an external temperature of 40 ° C. The catalyst was filtered off and concentrated under reduced pressure. Acetonitrile (60 m) was added to the residue (6.01 g).
1) was poured, and di-tert-butyl carbonate (14 ml) was added under ice cooling. After returning the reaction solution to room temperature and stirring for 1 hour, the reaction was stopped by pouring a saturated saline solution, and the mixture was extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give (3S) -1-tert-butoxycarbonyl-
3-hydroxymethylpyrrolidine (8.66 g) was obtained.

Light intensity: [α] _D ²⁵ = 16.5 ° (C =
1.0, CHCl ₃ ).

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 3432,1698,1675,1479,1454,1418,1367. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.46 (9H, s), 1.61-1.80 (1H, m), 1.92-2.30 (2H, m),
2.37-2.47 (1H, m), 3.07-3.17 (1H, m), 3.30-3.69 (5H, m). (2) Compound obtained in Reference Example 1- (1) (1.30
To a solution of g) in tetrahydrofuran (13 ml), triethylamine (0.99 ml) and methanesulfonyl chloride (0.55 ml) were sequentially added under ice-cooling, followed by stirring for 1 hour. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residue (1.8
N, N-dimethylformamide (20 ml) was poured into 3 g), and sodium azide (1.26 g) was added thereto.
Stirred at 1.5 ° C. for 1.5 hours. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with diethyl ether. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7/3) to give (3S) -3-azidomethyl-1-tert.
-Butoxycarbonylpyrrolidine (1.39 g) was obtained.

(3) To a solution of the compound (1.23 g) obtained in Reference Example 1- (2) in acetonitrile (13 ml) was added:
Triphenylphosphine (1.50 g) was added, and the mixture was refluxed for 1 hour. 4-Nitrobenzyl chloroformate (1.52 g) was added to the reaction mixture under ice-cooling, and a 1N aqueous sodium hydroxide solution (7 m
1) was added in sequence, and the mixture was returned to room temperature and stirred for 30 minutes. The reaction was diluted with water and extracted three times with methylene chloride. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/6) to give (3R) -1-tert-butoxycarbonyl-3- (4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine (1. 97 g) were obtained.

Light intensity: [α] _D ²⁵ = 14.3 ° (C =
1.0, CHCl ₃ ).

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 3326,1727,1683,1524,1413,1348,1250. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.45 (9H, s), 1.55-1.66 (1H, m), 1.92-2.03 (1H, m),
2.35-2.45 (1H, m), 2.95-3.55 (6H, m), 5.18 (1H, brs), 5.20
(2H, s), 7.51 (2H, d, J = 8.6 Hz), 8.22 (2H, d, J = 8.6 Hz). (4) Compound (1.90) obtained in Reference Example 1- (3)
To a solution of g) in methylene chloride (20 ml) was added trifluoroacetic acid (3.9 ml) under ice-cooling, and the reaction solution was returned to room temperature and stirred for 2 hours. The reaction mixture was diluted with methylene chloride and extracted three times with water. The mixture was alkalified by pouring a 1N aqueous sodium hydroxide solution (60 ml), and then extracted three times with methylene chloride. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (3S) -3- (4-Nitrobenzyloxycarbonylaminomethyl) pyrrolidine (1.38 g) was obtained as a crude product.

(5) A solution of (2S, 4S) -4- (4-methoxybenzylthio) -1-methyl-2-pyrrolidinecarboxylic acid (0.69 g) in tetrahydrofuran (7 ml) was added with N, N under ice cooling. -Diisopropylethylamine (0.43 ml) and pivaloyl chloride (0.30 ml)
Was added and stirred at 0 ° C. for 10 minutes. The compound (0.68 g) obtained in Reference Example 1- (4) and N, N
A solution of a mixture of diisopropylethylamine (0.43 ml) in acetonitrile (8 ml) was added and
Stirred for minutes. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 7/3) to give (2S,
4S) -4- (4-Methoxybenzylthio) -1-methyl-2-[(3R) -3- (4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (0.73 g) Obtained.

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 1722,1639,1610,1585,1513,1445,1373,1
347,1322,1302,1247,1177,1144,1109. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.50-2.62 (5H, m), 2.29,2.31 (3H, s × 2), 3.02-3.83
(10H, m), 3.69,3.70 (2H, s × 2), 3.79 (3H, s), 4.98-5.18 (1
H, m), 5.19 (2H, s), 6.83 (2H, d, J = 6.6Hz), 7.21 (2H, d, J = 6.6
Hz), 7.50 (2H, d, J = 8.6 Hz), 8.22 (2H, d, J = 8.6 Hz). (6) Compound (0.65) obtained in Reference Example 1- (5)
To a mixed solution of g) of anisole (0.65 ml) and trifluoroacetic acid (6.5 ml), trifluoromethanesulfonic acid (0.27 ml) was added with stirring under ice cooling. The reaction solution was returned to room temperature and stirred for 1 hour. Trifluoroacetic acid was distilled off under reduced pressure, and the residue was washed with n-hexane and diethyl ether to remove anisole. Then, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated saline. Drying over anhydrous sodium sulfate and concentration under reduced pressure gave the title compound (0.54 g).

[Separate synthesis method of title compound] (7) (3R) -1-tert-butoxycarbonyl-
3-Pyrrolidinol (10.0 g) was added to dry pyridine (1
00 ml), and dimethylaminopyridine (652 mg) and p-toluenesulfonyl chloride (15.
3g) was added and the mixture was stirred for 48 hours in an ice bath. The solvent was removed under reduced pressure, and the obtained residue was dissolved in methylene chloride (200 ml) and washed with water. After the aqueous layer was extracted twice with methylene chloride, all the organic layers were washed with saturated saline. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 24.2 g of a crude product. The obtained crude product was purified by silica gel column chromatography (eluent methylene chloride / acetonitrile = 40/1) to give (3R) -1-tert-butoxycarbonyl-3
-P-toluenesulfonyloxypyrrolidine (16.8)
g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δ ppm: 1.43 (9H, s), 2.25-1.90 (2H, m), 2.46
(3H, s), 3.60-3.30 (4H, m), 5.05 (1H, m), 7.35 (2H, d, J = 7.9H
z), 7.79 (2H, d, J = 7.9 Hz). (8) The compound (12.2 g) obtained in (7) was dissolved in dry acetonitrile (122 ml), and 1,8-diazabicyclo [5,4 , 0] -7-undecene (8.02 m
l), acetone cyanohydrin (6.53 ml) was added, and the mixture was heated under reflux for 10 hours. The reaction solution was treated with ethyl acetate (1
Liter) and washed five times with water (200 ml) and once with a saturated aqueous ammonium chloride solution (200 ml).
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product (9.10 g). The obtained crude product was purified by column chromatography (eluent: benzene / ethyl acetate = 17/1) to give (3R) -1-tert-butoxycarbonyl-3-cyanopyrrolidine (4.41 g).
I got

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δ ppm: 1.47 (9H, s), 2.35-2.15 (2H, m), 3.15
3.00 (1H, m), 3.75-3.35 (4H, m). (9) The compound (2.10 g) obtained in (8) was dissolved in dry tetrahydrofuran (21 ml), and lithium aluminum hydride was placed in an ice bath. (2.03 g), and the mixture was stirred in an ice bath for 20 minutes and at room temperature for 50 minutes. Tetrahydrofuran (40 ml) and water (4.6 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure, and methylene chloride (250 ml) and anhydrous sodium sulfate (24 g) were added to the obtained residue, followed by stirring at room temperature for 1 hour. After filtration, the solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate / methanol =
1: 1) to give (3R) -3-aminomethyl-1-
tert-butoxycarbonylpyrrolidine (703 m
g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δ ppm: 1.30-1.50 (2H, brs), 1.46 (9H, s), 1.5
0-1.65 (1H, m), 1.90-2.10 (1H, m), 2.15-2.30 (1H, m), 2.65-
2.80 (2H, m), 2.90-3.10 (1H, m), 3.20-3.60 (3H, m). (10) The compound (550 mg) obtained in (9) was dissolved in dry acetonitrile (5.5 ml). Under ice-cooling, diisopropylethylamine (0.575 ml) and p-nitrobenzyl chloroformate (711 mg) were added, and the mixture was stirred under ice-cooling for 5 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride (50 ml) and washed with water. The aqueous layer was extracted twice with methylene chloride, all the organic layers were washed with saturated saline, and the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: benzene / acetonitrile = 8/1) to give (3R) -1-tert-butoxycarbonyl-3- (4-nitrobenzyloxy). Carbonylaminomethyl) pyrrolidine (599 mg) was obtained. This was completely in agreement with that obtained in (3) in the degree of light irradiation, infrared absorption spectrum and nuclear magnetic resonance spectrum.

Reference Example 2 (2S, 4S) -4-mercapto-1-methyl-2-
[(3S) -3- (4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (1) (3R) -3-hydroxymethyl-1-[(1
R) -1-Phenylethyl] pyrrolidine (12.6 g)
Palladium hydroxide in ethanol solution (250 ml)
A carbon catalyst (12.5 g) was added, and hydrogen was absorbed for 5 hours while stirring at an external temperature of 40 ° C. The catalyst was filtered off and concentrated under reduced pressure. Acetonitrile (70 m) was added to the residue (7.08 g).
1) was poured, and di-tert-butyl carbonate (16 ml) was added under ice cooling. After the reaction solution was returned to room temperature and stirred for 1 hour, it was treated in the same manner as in Reference Example 1- (1) to give (3R)
-1-tert-Butoxycarbonyl-3-hydroxymethylpyrrolidine (10.6 g) was obtained.

Light intensity: [α] _D ²⁵ = + 16.7 ° (C =
1.0, CHCl ₃ ).

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 3434,1698,1675,1479,1454,1418,1367. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.46 (9H, s), 1.61-1.80 (2
H, m), 1.92-2.30 (1H, m), 2.37
-2.47 (1H, m), 3.07-3.17 (1H,
m), 3.30-3.69 (5H, m). (2) Compound (1.55) obtained in Reference Example 2- (1)
To a solution of g) in tetrahydrofuran (16 ml), triethylamine (1.18 ml) and methanesulfonyl chloride (0.66 ml) were sequentially added under ice-cooling, followed by stirring for 1 hour. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residue (2.1
N, N-dimethylformamide (20 ml) was poured into 9 g), and sodium azide (1.50 g) was added thereto.
Stirred at 1.5 ° C. for 1.5 hours. By treating in the same manner as in Reference Example 1- (2), (3R) -3-azidomethyl-1-tert-
Butoxycarbonylpyrrolidine (1.43 g) was obtained.

(3) To a solution of the compound (1.00 g) obtained in Reference Example 2- (2) in acetonitrile (10 ml) was added:
Triphenylphosphine (1.22 g) was added, and the mixture was refluxed for 1 hour. The reaction solution was added with 4-nitrobenzyl chloroformate (1.24 g) and a 1N aqueous sodium hydroxide solution (6
ml) were sequentially added, and the mixture was returned to room temperature and stirred for 30 minutes. The same processing as in Reference Example 1- (3) was performed to obtain (3S) -1-te.
rt-butoxycarbonyl-3- (4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine (1.51
g) was obtained.

Light intensity: [α] _D ²⁵ + 14.5 °
(C = 1.0, CHCl ₃ ).

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 3325,1726,1682,1524,1414,1348,1249. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.45 (9H, s), 1.55-1.66 (1H, m), 1.92-2.03 (1H, m),
2.35-2.45 (1H, m), 2.95-3.55 (6H, m), 5.06 (1H, brs), 5.19
(2H, s), 7.51 (2H, d, J = 8.6 Hz), 8.22 (2H, d, J = 8.6 Hz). (4) Compound (1.51) obtained in Reference Example 2- (3)
To a methylene chloride solution (17 ml) of g), trifluoroacetic acid (3.1 ml) was added under ice-cooling, and the reaction solution was returned to room temperature and stirred for 2 hours. The same treatment as in Reference Example 1- (4) was carried out, and as a crude product, (3R) -3- (4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine (1.1
6 g) were obtained.

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δppm: 1.42-1.60 (1H, m), 1.90-2.07 (1H, m),
2.27-2.50 (1H, m), 2.52-3.28 (7H, m), 5.13-5.31 (1H, m), 5.
19 (2H, s), 7.51 (2H, d, J = 8.6Hz), 8.22 (2H, d, J = 8.6Hz). (5) (2S, 4S) -4- (4-methoxybenzylthio)- 1-methyl-2-pyrrolidinecarboxylic acid (0.7
0g) in a solution of tetrahydrofuran (7 ml) under ice cooling with N, N-diisopropylethylamine (0.43 ml).
And pivaloyl chloride (0.31 ml) at 0 ° C.
Stirred for 0 minutes. A solution of a mixture of the compound (0.70 g) obtained in Reference Example 2- (4) and N, N-diisopropylethylamine (0.43 ml) in acetonitrile (8 ml) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. did. Processing is performed in the same manner as in Reference Example 1- (5), and (2S, 4S) -4
-(4-methoxybenzylthio) -1-methyl-2-
[(3S) -3- (4-Nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (0.75 g) was obtained.

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 1722,1639,1610,1585,1513,1445,1347,1
302,1248,1176,1144,1120,1109. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.52-2.61 (5H, m), 2.30 (3H, s), 3.03-3.78 (10H, m),
3.70 (2H, s), 3.79,3.80 (3H, s × 2), 5.04-5.05 (1H, m), 5.1
9 (2H, s), 6.83,6.84 (2H, d × 2, J = 8.6Hz), 7.20,7.22 (2H, d
× 2, J = 8.6Hz), 7.51 (2H, d, J = 8.6Hz), 8.22 (2H, d, J = 8.6H
z). (6) Compound (0.67) obtained in Reference Example 2- (5)
To a mixed solution of g) of anisole (0.67 ml) and trifluoroacetic acid (6.7 ml), trifluoromethanesulfonic acid (0.27 ml) was added with stirring under ice cooling. The reaction solution was returned to room temperature and stirred for 1 hour. Reference Example 1-
The same treatment as in (6) was carried out to give the title compound (0.57 g)
I got

Reference Example 3 (2S, 4S) -4-mercapto-2-[(3S) -3
-(N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl) pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1) Obtained in Reference Example 1- (1). Compound (0.82
To a solution of g) in tetrahydrofuran (8 ml), triethylamine (0.62 ml) and methanesulfonyl chloride (0.35 ml) were sequentially added under ice cooling, followed by stirring for 1 hour. The reaction was quenched by pouring a saturated saline solution into the reaction mixture, and the reaction mixture was diluted with ethyl acetate.
Extracted times. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

A 40% methylamine-methanol solution (18 ml) was added to the residue (1.16 g), and the mixture was heated at 100 ° C. for 4 hours in bomben roll. After returning the reaction solution to room temperature, it was concentrated under reduced pressure. N, N-Diisopropylethylamine (1.4 ml) and 4-nitrobenzyl chloroformate (1.73 g) were added to an acetonitrile solution (15 ml) of the residue (1.32 g) under ice cooling, and the mixture was stirred at 0 ° C. for 2 hours. did. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/6 → 3/7) to give (3
R) -1-tert-butoxycarbonyl-3- [N-
Methyl-N- (4-nitrobenzyloxycarbonyl)
[Aminomethyl] pyrrolidine (1.42 g) was obtained.

Light intensity: [α] _D ²⁵ = −6.9 ° (C =
1.0, CHCl ₃ ).

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 1696,1608,1524,1480,1455,1404,1366,1
347,1293,1255,1211,1191,1170,1152,1125. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.45 (9H, s), 1.56-1.68 (1H, m), 1.89-2.01 (1H, m),
2.45-2.55 (1H, m), 2.98 (3H, s), 2.98-3.10 (1H, m), 3.27-3.
57 (5H, m), 5.23 (2H, s), 7.51 (2H, d, J = 8.6Hz), 8.23 (2H, d, J
= 8.6 Hz). (2) Compound (1.96) obtained in Reference Example 3- (1)
To a solution of g) in methylene chloride (25 ml) was added trifluoroacetic acid (3.8 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Processing is performed in the same manner as in Reference Example 1- (4), and (3S) -3
-[N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl] pyrrolidine (1.55 g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δ ppm: 1.30-1.51 (1H, m), 1.81-1.97 (1H, m),
2.20-2.69 (3H, m), 2.85-3.06 (6H, m), 3.20-3.35 (2H, m), 5.
22 (2H, s), 7.51 (2H, d, J = 8.6Hz), 8.22 (2H, d, J = 8.6Hz). (3) (2S, 4S) -4- (4-methoxybenzylthio)- 1- (4-nitrobenzyloxycarbonyl)-
N, N-Diisopropylethylamine (0.59 ml) and pivaloyl chloride (0.42 ml) were added to a solution of 2-pyrrolidinecarboxylic acid (1.52 g) in tetrahydrofuran (15 ml) under ice cooling, and the mixture was stirred at 0 ° C. for 10 minutes. .
The reaction solution was added to the compound obtained in Reference Example 3- (2) (1.
00g) and N, N-diisopropylethylamine (0.59 ml) in a mixture of acetonitrile (15 m
l) The solution was added and stirred at 0 ° C. for 30 minutes. Reference Example 1-
The same processing as in (5) is performed to obtain (2S, 4S) -4- (4-
Methoxybenzylthio) -2-[(3S) -3- (N-
Methyl-N- (4-nitrobenzyloxycarbonyl)
Aminomethyl) pyrrolidin-1-ylcarbonyl] -1
-(4-Nitrobenzyloxycarbonyl) pyrrolidine (2.08 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1706,1654,1608,1585,1520,1439,1403,1346,
1299,1249,1210,1194,1175,1149,1110. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.50-2.70 (5H, m), 2.92-4.08 (12H, m), 3.74 (2H, s),
3.80,3.81 (3H, s × 2), 4.22-4.45 (1H,
m), 4.98-5.33 (4H, m), 6.87 (2
H, d, J = 8.6 Hz), 7.22 to 7.56 (6
H, m), 8.20-8.30 (4H, m). (4) Compound (2.03) obtained in Reference Example 3- (3)
To a mixed solution of g) of anisole (2.0 ml) and trifluoroacetic acid (20 ml) was added trifluoromethanesulfonic acid (0.62 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Processed in the same manner as in Reference Example 1- (6),
The title compound (1.92 g) was obtained.

[Separate synthesis method of title compound] (5) (2S, 4R) -4-hydroxy-1- (4-nitrobenzyloxycarbonyl) proline (4.65)
g) in a solution of dried dimethylformamide (60 ml) was added to (3S) -3- [N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl] pyrrolidine hydrochloride (4.95 g), diisopropylethylamine ( 5.23 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.03 g) and 1-hydroxybenzotriazole (2.23 g)
Was added and stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate / methanol = 9/1, powdery (2S, 4R) -4-hydroxy-2-[(3S) -3 was obtained.
-[N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (8.70 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3402, 1706, 1654, 1607, 1522, 1436, 13
46. Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δp
pm: 1.30-2.20 (3H, m), 2.30-2.60 (1H, m), 2.80-3.0
0 (3H, m), 3.00-3.80 (10H, m), 4.20-4.40 (1H, m), 4.40
-4.60 (1H, m), 5.00-5.30 (4H, m), 7.50-7.70 (4H, m),
8.10-8.30 (4H, m). (6) The compound (8.70 g) obtained in (5) was dissolved in dry acetonitrile (87 ml), and triethylamine (2.72 ml) and methanesulfonyl chloride (1 .34 ml) and stirred at the same temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate / methanol = 18/1 → 14/1, powdery (2S, 4R) -4-methanesulfonyloxy-2-[(3S) -3 was obtained. -[N-methyl-
N- (4-nitrobenzyloxycarbonyl) aminomethyl] pyrrolidin-1-ylcarbonyl] -1- (4-
Nitrobenzyloxycarbonyl) pyrrolidine (9.3
3 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1706, 1652, 1607, 1522, 1441, 1405, 1347. Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ ) δp
pm: 1.50-2.20 (3H, m), 2.30-2.80 (3H, m), 2.90-3.0
5 (3H, m), 3.08 (3H, s), 3.10-3.70 (6H, m), 3.80-4.10
(2H, m), 4.50-4.70 (1H, m), 5.20-5.40 (4H, m), 7.40-
7.55 (4H, m), 8.15-8.25 (4H, m). (7) The compound (2.00 g) obtained in (6) was dissolved in dry dimethylformamide (25 ml), and potassium thioacetate (520 mg) was added. In addition, the mixture was stirred at 75 ° C. for 1.5 hours. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate,
The extract was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate / methanol = 100/1, powdery (2S, 4S) -4-acetylthio-2-[(3S) -3- [N-methyl- N- (4-Nitrobenzyloxycarbonyl) aminomethyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1.60 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1705, 1654, 1607, 1522, 1437, 1404, 1346. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δpp
m: 1.70-2.10 (3H, m), 2.34 (3H, s), 2.40-2.70 (2H,
m), 2.90-3.10 (3H, m), 3.10-3.70 (6H, m), 3.80-4.10
(2H, m), 4.11 (1H, t, J = 9.1Hz), 4.40-4.60 (1H, m),
5.00-5.40 (4H, m), 7.40-7.60 (4H, m), 8.15-8.30 (4H, m
m). (8) The compound (1.48 g) obtained in (7) was dissolved in methanol (30 ml) and methylene chloride (4.4 ml), and a 1N methanol solution of sodium methoxide (30 ml) was added under ice cooling. 2.3 ml) and stirred at the same temperature for 10 minutes. 1N hydrochloric acid (2.4 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (1.
34 g) was obtained. This was in agreement with that obtained in (4) in the infrared absorption spectrum and the nuclear magnetic resonance spectrum.

Reference Example 4 (2S, 4S) -4-Mercapto-1-methyl-2-
[(3S) -3- (N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl) pyrrolidine-1
-Ylcarbonyl] pyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio) -1-methyl-2-pyrrolidinecarboxylic acid (0.4
N, N-diisopropylethylamine (0.30 ml) was added to a solution of 9 g) in tetrahydrofuran (5 ml) under ice-cooling.
And pivaloyl chloride (0.21 ml) at 0 ° C.
Stirred for 0 minutes. A solution of a mixture of the compound (0.46 g) obtained in Reference Example 3- (2) and N, N-diisopropylethylamine (0.30 ml) in acetonitrile (10 ml) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. did.
The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 6/4) to give (2S, 4S) -4-
(4-methoxybenzylthio) -1-methyl-2-
[(3S) -3- (N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl) pyrrolidine-1
-Ylcarbonyl] pyrrolidine (0.76 g) was obtained.

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 1734,1705,1646,1609,1585,1513,1440,1
403,1373,1346,1301,1248,1212,1191,1149,1107. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.55-2.18 (2H, m), 2.35,2.37 (3H, s × 2), 2.41-2.70
(3H, m), 3.04,3.06 (3H, s × 2), 3.10-3.88 (10H, m), 3.75 (2
H, s), 3.85 (3H, s), 5.27 (2H, s), 6.89 (2H, d, J = 8.6Hz), 7.27
(2H, d, J = 7.9Hz), 7.57 (2H, d, J = 8.6Hz), 8.28 (2H, d, J = 7.9H
z). (2) Compound (0.64) obtained in Reference Example 4- (1)
To a mixed solution of g) of anisole (0.65 ml) and trifluoroacetic acid (6.5 ml), trifluoromethanesulfonic acid (0.26 ml) was added with stirring under ice-cooling, followed by stirring at room temperature for 1 hour. This was treated in the same manner as in Reference Example 1- (6) to obtain the title compound (0.54 g).

Reference Example 5 (2S, 4S) -4-mercapto-2-[(3R) -3
-(N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl) pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1) Obtained in Reference Example 2- (1). Compound (1.17)
To a solution of g) in tetrahydrofuran (12 ml), triethylamine (0.89 ml) and methanesulfonyl chloride (0.50 ml) were sequentially added under ice cooling, followed by stirring for 1 hour. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

A 40% methylamine-methanol solution (25 ml) was added to the residue (1.66 g), and the mixture was heated at 100 ° C. for 4 hours in bomben roll. After returning the reaction solution to room temperature, it was concentrated under reduced pressure. To a solution of the residue (1.89 g) in acetonitrile (20 ml) were added N, N-diisopropylethylamine (1.84 ml) and chloroformate 4- under ice-cooling.
Nitrobenzyl (2.28 g) was added, and the mixture was stirred at 0 ° C. for 2 hours. Processing is performed in the same manner as in Reference Example 3- (1), and (3S)
-1-tert-Butoxycarbonyl-3- [N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl] pyrrolidine (1.92 g) was obtained.

Light intensity: [α] _D ²⁵ = + 7.2 ° (C =
1.0, CHCl ₃ ).

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 1696,1608,1524,1480,1455,1404,1366,1
347,1293,1255,1211,1191,1170,1152,1125. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.45 (9H, s), 1.56-1.68 (1H, m), 1.89-2.01 (1H, m),
2.45-2.55 (1H, m), 2.98 (3H, s), 2.98-3.10 (1H, m), 3.27-3.
57 (5H, m), 5.22 (2H, s), 7.51 (2H, d, J = 8.6Hz), 8.23 (2H, d, J
(8.6 Hz). (2) Compound (0.84) obtained in Reference Example 5- (1)
To a solution of g) in methylene chloride (8 ml) was added trifluoroacetic acid (1.6 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The same treatment as in Reference Example 1- (4) was performed to obtain (3R) -3
-[N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl] pyrrolidine (0.58 g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δ ppm: 1.30-1.51 (1H, m), 1.81-1.97 (1H, m),
2.20-2.69 (3H, m), 2.85-3.06 (6H, m), 3.20-3.35 (2H, m), 5.
22 (2H, s), 7.51 (2H, d, J = 8.6Hz), 8.22 (2H, d, J = 8.6Hz). (3) (2S, 4S) -4- (4-methoxybenzylthio)- 1- (4-nitrobenzyloxycarbonyl)-
N, N-diisopropylethylamine (0.36 ml) and pivaloyl chloride (0.25 ml) were added to a solution of 2-pyrrolidinecarboxylic acid (0.92 g) in tetrahydrofuran (10 ml) under ice cooling, and the mixture was stirred at 0 ° C. for 10 minutes. .
This reaction solution was added with the compound (0. 0) obtained in Reference Example 5- (2).
55 g) and N, N-diisopropylethylamine (0.36 ml) in a mixture of acetonitrile (10 m
l) The solution was added and stirred at 0 ° C. for 30 minutes. Reference Example 1-
The same processing as in (5) is performed to obtain (2S, 4S) -4- (4-
Methoxybenzylthio) -2-[(3R) -3- (N-
Methyl-N- (4-nitrobenzyloxycarbonyl)
Aminomethyl) pyrrolidin-1-ylcarbonyl] -1
-(4-Nitrobenzyloxycarbonyl) pyrrolidine (1.00 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1706,1654,1608,1585,1520,1438,1403,1346,
1299,1249,1210,1194,1175,1148,1109. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.50-2.68 (5H, m), 2.92-4.08 (9H, m), 2.97 (3H, s),
3.73 (2H, s), 3.79,3.80 (3H, s × 2), 4.30-4.46 (1H, m), 4.97
-5.35 (4H, m), 6.85 (2H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6Hz),
7.46 (2H, d, J = 8.6Hz), 7.51 (2H, d, J = 8.6Hz), 8.23 (4H, d, J =
(4) Compound (0.99) obtained in Reference Example 5- (3).
To a mixed solution of g) of anisole (1.0 ml) and trifluoroacetic acid (10 ml) was added trifluoromethanesulfonic acid (0.30 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. This was treated in the same manner as in Reference Example 1- (6) to obtain the title compound (0.90 g).

Reference Example 6 (2S, 4S) -4-mercapto-1-methyl-2-
[(3R) -3- (N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl) pyrrolidine-1
-Ylcarbonyl] pyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio) -1-methyl-2-pyrrolidinecarboxylic acid (0.5
0g) in a solution of tetrahydrofuran (5 ml) under ice cooling with N, N-diisopropylethylamine (0.31 ml).
And pivaloyl chloride (0.22 ml) at 0 ° C.
Stirred for 0 minutes. A solution of a mixture of the compound (0.47 g) obtained in Reference Example 5- (2) and N, N-diisopropylethylamine (0.31 ml) in acetonitrile (10 ml) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. did.
Processing is performed in the same manner as in Reference Example 4- (1), and (2S, 4S)-
4- (4-methoxybenzylthio) -1-methyl-2-
[(3R) -3- (N-methyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl) pyrrolidine-1
-Ylcarbonyl] pyrrolidine (0.67 g) was obtained.

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 1705,1647,1609,1585,1512,1440,1403,1
346,1301,1248,1212,1191,1149,1107. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.50-2.12 (2H, m), 2.29,2.32 (3H, s × 2), 2.37-2.66
(3H, m), 3.00,3.02 (3H, s × 2), 3.00-3.88 (10H, m), 3.72 (2
H, s), 3.81 (3H, s), 5.23 (2H, s), 6.85 (2H, d, J = 8.6Hz), 7.23
(2H, d, J = 8.6Hz), 7.53 (2H, d, J = 8.6Hz), 8.24 (2H, d, J = 8.6H
z). (2) Compound (0.59) obtained in Reference Example 6- (1)
To a mixed solution of g) of anisole (0.6 ml) and trifluoroacetic acid (6.0 ml) was added trifluoromethanesulfonic acid (0.24 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The same treatment as in Reference Example 1- (6) was performed to obtain the title compound (0.53 g).

Reference Example 7 (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (4
-Nitrobenzyloxycarbonylguanidinomethyl)
Pyrrolidin-1-ylcarbonyl] pyrrolidine (1) Compound (1.50) obtained in Reference Example 1- (2)
To a solution of g) in acetonitrile (15 ml) was added triphenylphosphine (1.83 g), and the mixture was refluxed for 1 hour.
Sodium sulfate hydrate (2.24 g) was added to the reaction solution,
After refluxing for an additional hour, the temperature was returned to room temperature, and the insoluble material was separated by filtration.
The filtrate was concentrated under reduced pressure. Diethyl ether was poured into the residue, the precipitated insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure.

The residue (1.90 g) in ethanol (20
ml) solution was added with 1H-pyrazole-1-carboxamidine hydrochloride (1.02 g) and refluxed for 3 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure, and the obtained residue was washed with diethyl ether.

To a mixed solution of the residue (2.86 g) in tetrahydrofuran (25 ml) -water (25 ml), 4-nitrobenzyl chloroformate (3.57 g) and a 1N aqueous solution of sodium hydroxide (33 ml) were sequentially added under ice-cooling. And stirred at 0 ° C. for 30 minutes. The reaction was diluted with water and extracted three times with methylene chloride. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate / methanol = 9/1) to give (3R)-
1-tert-butoxycarbonyl-3- (4-nitrobenzyloxycarbonylguanidinomethyl) pyrrolidine (1.29 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3393,3327,1693,1652,1641,1604,1523,1408,
1347,1289. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.44 (9H, s), 1.68-1.52 (1H, m), 1.95-2.04 (1H, m),
2.36-2.48 (1H, m), 3.03 (1H, dd, J = 11.2,7.2Hz), 3.15-3.54
(5H, m), 5.19 (2H, s), 6.72 (2H, brs), 7.54 (2H, d, J = 8.6Hz),
8.20 (2H, d, J = 8.6 Hz). (2) Compound (1.23) obtained in Reference Example 7- (1)
To a solution of g) in methylene chloride (13 ml) was added trifluoroacetic acid (2.2 ml) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Processing is performed in the same manner as in Reference Example 1- (4), and (3S) -3
-(4-Nitrobenzyloxycarbonylguanidinomethyl) pyrrolidine (0.72 g) was obtained.

(3) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-pyrrolidinecarboxylic acid (1.05 g)
In a tetrahydrofuran (10 ml) solution under ice-cooling.
N-Diisopropylethylamine (0.41 ml) and pivaloyl chloride (0.29 ml) were added, and the mixture was stirred at 0 ° C for 10 minutes. A solution of a mixture of the compound (0.72 g) obtained in Reference Example 7- (2) and N, N-diisopropylethylamine (0.41 ml) in acetonitrile (10 ml) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. did. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 9/1) to give (2S, 4S) -4- (4
-Methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (4-nitrobenzyloxycarbonylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (0.93 g)
I got

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1707,1651,1609,1521,1432,1405,1346,1319,
1287,1251,1207,1174,1110. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.55-2.71 (5H, m), 2.96-4.40 (10H, m), 3.72,3.74 (2
H, s × 2), 3.79 (3H, s), 4.97-5.38 (4H, m), 6.81-6.88 (2H,
m), 7.20-7.25 (2H, m), 7.39-7.56 (4H, m), 7.99-8.25 (4H,
m). (4) Compound (0.88) obtained in Reference Example 7- (3)
To a mixed solution of g) of anisole (1.4 ml) and trifluoroacetic acid (14 ml), trifluoromethanesulfonic acid (0.31 ml) was added while stirring under ice cooling, and the mixture was stirred at room temperature for 1 hour. Processed in the same manner as in Reference Example 1- (6),
The title compound (1.28 g) was obtained.

Reference Example 8 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (4
-Nitrobenzyloxycarbonylacetimidoylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (1) Compound (1.00) obtained in Reference Example 1- (2)
To a solution of g) in acetonitrile (10 ml) was added triphenylphosphine (1.22 g), and the mixture was refluxed for 1 hour.
Sodium sulfate + hydrate (1.50 g) was added to the reaction solution, and the mixture was further refluxed for 1 hour, returned to room temperature, filtered to remove insolubles, and concentrated under reduced pressure. Diethyl ether was poured into the residue, the precipitated insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure.

To a solution of the residue (1.27 g) in acetonitrile (25 ml) was added a 4N solution of hydrogen chloride-ethyl acetate (1.1 ml) under ice-cooling, followed by stirring at 0 ° C. for 15 minutes. N- (4-Nitrobenzyloxycarbonyl) acetamidine (1.15 g) was added to the reaction mixture under ice-cooling.
Stirred at 1.5 ° C. for 1.5 hours. The reaction solution was returned to room temperature, diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give (3R) -1-tert-butoxycarbonyl-3- [N- (4-nitrobenzyloxycarbonyl) acetimidoylaminomethyl) pyrrolidine (1.
66 g) were obtained.

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 3313,3112,1687,1564,1523,1411,1346,1
220. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.46 (9H, s), 1.58-1.72 (1H, m), 1.95-2.12 (1H, m),
2.16,2.25 (3H, s × 2), 2.39-2.53 (1H, m), 3.00-3.11 (1H,
m), 3.28-3.62 (5H, m), 5.20,5.23 (2H, s × 2), 7.57 (2H, d, J
= 8.6 Hz), 8.21 (2H, d, J = 8.6 Hz). (2) Compound (1.66) obtained in Reference Example 8- (1)
To a solution of g) in methylene chloride (17 ml) was added trifluoroacetic acid (2.9 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Processing is performed in the same manner as in Reference Example 1- (4), and (3S) -3
-[N- (4-nitrobenzyloxycarbonyl) acetimidoylaminomethyl] pyrrolidine (0.81 g)
I got

(3) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-pyrrolidinecarboxylic acid (1.18 g)
To a tetrahydrofuran (12 ml) solution under ice cooling.
N-Diisopropylethylamine (0.46 ml) and pivaloyl chloride (0.33 ml) were added, and the mixture was stirred at 0 ° C for 10 minutes. A solution of a mixture of the compound (0.81 g) obtained in Reference Example 8- (2) and N, N-diisopropylethylamine (0.46 ml) in acetonitrile (10 ml) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. did. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 95/5 → 9/1) to give (2S, 4S)
-4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3-
(N- (4-Nitrobenzyloxycarbonyl) acetimidoylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (1.05 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3300,3113,3080,1709,1651,1608,1585,1564,
1520,1439,1404,1346,1301,1241,1213,1176,1110. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.49-2.77 (8H, m), 3.03-4.12 (10H, m), 3.79 (2H, s),
3.84 (3H, s), 4.30-4.50 (1H, m), 5.04-5.40 (4H, m), 6.90 (2
(H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.6Hz), 7.43-7.65 (4H, m), 8.
16-8.32 (4H, m). (4) Compound (1.02) obtained in Reference Example 8- (3)
To a mixed solution of g) of anisole (1.5 ml) and trifluoroacetic acid (15 ml) was added trifluoromethanesulfonic acid (0.36 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Processed in the same manner as in Reference Example 1- (6),
The title compound (1.35 g) was obtained.

Reference Example 9 (2S, 4S) -2-[(3S) -3- (N-cyclopropyl-N- (4-nitrobenzyloxycarbonyl)]
Aminomethyl) pyrrolidin-1-ylcarbonyl] -4
-Mercapto-1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1) Compound (1.00) obtained in Reference Example 1- (1)
To a solution of g) in tetrahydrofuran (10 ml), triethylamine (0.83 ml) and methanesulfonyl chloride (0.46 ml) were sequentially added under ice cooling, followed by stirring for 1 hour.
The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The residue (1.53 g) in methanol (10
ml) solution was added cyclopropylamine (10 ml) and heated in bomben roll at 100 ° C. for 4 hours. After returning the reaction solution to room temperature, it was concentrated under reduced pressure. Residue (1.93
g) in acetonitrile (20 ml) solution under ice cooling.
N-Diisopropylethylamine (0.95 ml) and 4-nitrobenzyl chloroformate (1.18 g) were added,
Stirred at room temperature for 2 hours. The reaction was quenched by pouring saturated saline into the reaction mixture, and extracted three times with ethyl acetate. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/6) to give (3S) -1-tert-butoxycarbonyl-3.
-[N-cyclopropyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl] pyrrolidine (0.95
g) was obtained.

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 1697,1607,1524,1494,1479,1453,1405,1
366,1346,1288,1258,1210,1171,1141,1111. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 0.63-0.71 (2H, m), 0.78-0.87 (2H, m), 1.45 (9H, s),
1.55-1.68 (1H, m), 1.90-2.00 (1H, m), 2.50-2.67 (2H, m), 2.
96-3.09 (1H, m), 3.18-3.59 (5H, m), 5.23 (2H, s), 7.53 (2H,
d, J = 8.6 Hz), 8.23 (2H, d, J = 8.6 Hz). (2) The compound (0.77) obtained in Reference Example 9- (1)
To methylene chloride (12 ml) of g), trifluoroacetic acid (1.4 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours.
The same processing as in Reference Example 1- (4) was performed to obtain (3S) -3-
[N-cyclopropyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl] pyrrolidine (0.72
g) was obtained.

(3) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-pyrrolidinecarboxylic acid (1.00 g)
In a tetrahydrofuran (10 ml) solution under ice-cooling.
N-Diisopropylethylamine (0.39 ml) and pivaloyl chloride (0.28 ml) were added, and the mixture was stirred at 0 ° C for 10 minutes. A solution of a mixture of the compound (0.72 g) obtained in Reference Example 9- (2) and N, N-diisopropylethylamine (0.39 ml) in acetonitrile (10 ml) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. did. The reaction was quenched by pouring a saturated saline solution into the reaction solution,
Extracted times. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give (2S, 4S) -2-[(3S) -3- (N-cyclopropyl-N- (4-nitrobenzyloxycarbonyl) aminomethyl) Pyrrolidin-1-ylcarbonyl]
-4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (0.93
g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1707,1655,1609,1585,1521,1440,1404,1346,
1289,1250,1210,1176,1139,1110. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 0.50-0.75 (2H, m), 0.75-0.95 (2H, m), 1.47-2.02 (3
H, m), 2.32-2.74 (3H, m), 2.92-4.08 (9H, m), 3.73 (2H, s), 3.
79,3.80 (3H, s × 2), 4.26-4.45 (1H, m), 4.97-5.34 (4H, m),
6.85 (2H, d, J = 8.6Hz), 7.23,7.25 (2H, d × 2, J = 8.6Hz), 7.4
6,7.53 (4H, d × 2, J = 8.6Hz), 8.23 (4H, d, J = 8.6Hz). (4) The compound obtained in Reference Example 9- (3) (0.82
g) was added to a mixed solution of anisole (0.8 ml) and trifluoroacetic acid (8 ml) while stirring under ice-cooling, and trifluoromethanesulfonic acid (0.24 ml) was added.
Stirred for hours. This was treated in the same manner as in Reference Example 1- (6) to obtain the title compound (0.77 g).

Reference Example 10 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- (4
-Nitrobenzyloxycarbonylacetimidoylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (1) Compound (1.00) obtained in Reference Example 2- (2)
To a solution of g) in acetonitrile (10 ml) was added triphenylphosphine (1.22 g), and the mixture was refluxed for 1 hour.
Sodium sulfate + hydrate (1.50 g) was added to the reaction solution, and the mixture was further refluxed for 1 hour, returned to room temperature, filtered to remove insolubles, and concentrated under reduced pressure. Diethyl ether was poured into the residue, the precipitated insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure.

To a solution of the residue (1.33 g) in acetonitrile (25 ml) was added a 4N solution of hydrogen chloride-ethyl acetate (1.1 ml) under ice-cooling, followed by stirring at 0 ° C. for 15 minutes.
N- (4-Nitrobenzyloxycarbonyl) acetamidine (1.15 g) was added to the reaction mixture under ice-cooling.
Stirred at 1.5 ° C. for 1.5 hours. The same treatment as in Reference Example 8- (1) was carried out to give (3S) -1-tert-butoxycarbonyl-3- [N- (4-nitrobenzyloxycarbonyl).
Acetimidylaminomethyl] pyrrolidine (1.58
g) was obtained.

Infrared absorption spectrum (Liquid film) νm
ax cm ^-1 : 3314,3112,1690,1565,1523,1409,1346,1
221. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.46 (9H, s), 1.58-1.72 (1H, m), 1.95-2.12 (1H, m),
2.16,2.25 (3H, s × 2), 2.39-2.53 (1H, m), 3.00-3.11 (1H,
m), 3.28 (5H, m), 5.20,5.23 (2H, s × 2), 7.57 (2H, d, J = 8.6H
z), 8.21 (2H, d, J = 8.6 Hz). (2) The compound (1.58) obtained in Reference Example 10- (1)
To a solution of g) in methylene chloride (15 ml) was added trifluoroacetic acid (2.9 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The same treatment as in Reference Example 1- (4) was performed to obtain (3R) -3
-[N- (4-nitrobenzyloxycarbonyl) acetimidoylaminomethyl] pyrrolidine (0.97 g)
I got

(3) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-pyrrolidinecarboxylic acid (1.06 g)
In a tetrahydrofuran (10 ml) solution under ice-cooling.
N-Diisopropylethylamine (0.41 ml) and pivaloyl chloride (0.29 ml) were added, and the mixture was stirred at 0 ° C for 10 minutes. A solution of a mixture of the compound (0.76 g) obtained in Reference Example 10- (2) and N, N-diisopropylethylamine (0.41 ml) in acetonitrile (10 ml) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. did. Processing is performed in the same manner as in Reference Example 8- (3), and (2S, 4S) -4
-(4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- (N
-(4-Nitrobenzyloxycarbonyl) acetimidoylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (1.00 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3296,3113,3080,1708,1680,1652,1608,1584,
1564,1521,1432,1405,1346,1301,1239,1216,1176,1110. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δp
pm: 1.60-1.80 (8H, m), 3.02-4.10 (9H, m), 3.78 (2H, s),
3.83 (3H, s), 4.32-4.52 (1H, m), 5.02-5.38 (4H, m), 6.90 (2
(H, d, J = 8.6Hz), 7.28 (2H, d, J = 8.6Hz), 7.45-7.69 (4H, m), 8.
20-8.34 (4H, m). (4) Compound (1.00) obtained in Reference Example 10- (3)
g) anisole (1 ml), trifluoroacetic acid (10
trifluoromethanesulfonic acid (0.20 ml) was added to the mixed solution while stirring under ice cooling, and the mixture was stirred at room temperature for 2 hours. This was treated in the same manner as in Reference Example 1- (6) to obtain the title compound (0.93 g).

Reference Example 11 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- (4
-Nitrobenzyloxycarbonylguanidinomethyl)
Pyrrolidin-1-ylcarbonyl] pyrrolidine (1) Compound (1.01) obtained in Reference Example 2- (2)
To a solution of g) in dry acetonitrile (10 ml) was added triphenylphosphine (1.23 g), and the mixture was refluxed for 1 hour. After adding 1.51 g of sodium sulfate decahydrate to the reaction solution and refluxing for 1 hour, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 1/1) to give (3S) -3-aminomethyl-1-tert-.
Butoxycarbonylpyrrolidine (840 mg) was obtained.
This was obtained by combining the compound obtained in Reference Example 1- (9) with HPL
C and NMR data were completely consistent.

(2) Compound (840m) obtained in (1)
1H-Pyrazole-1-carboxamidine hydrochloride (686 mg) was added to a solution of g) in ethanol (14 ml), and the mixture was refluxed for 3 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure.
The obtained residue was washed with diisopropyl ether.

To a mixed solution of the residue (1.50 g) in tetrahydrofuran (20 ml) -water (20 ml) were successively added 4-nitrobenzyl chloroformate (2.41 g) and a 1N aqueous sodium hydroxide solution (22 ml) under ice-cooling. In addition, 0 ° C
For 30 minutes. The reaction was diluted with water and extracted three times with methylene chloride. The mixed organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 25/1) to give (3S) -1-te.
rt-butoxycarbonyl-3- (4-nitrobenzyloxycarbonylguanidinomethyl) pyrrolidine (74
6 mg).

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δ ppm: 1.44 (9H, s), 1.68-1.52 (1H, m), 1.95
2.04 (1H, m), 2.36-2.48 (1H, m), 3.03 (1H, dd, J = 11.1,7.1H
z), 3.15-3.54 (5H, m), 5.19 (2H, s), 6.70 (1H, brs), 7.54 (2
H, d, J = 8.6Hz), 8.20 (2H, d, J = 8.6Hz). (3) A 4N solution of hydrochloric acid in ethyl acetate (7 ml) of the compound (701 mg) obtained in (2) (3.
3 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was washed with ethyl ether (3S) -3-.
(4-Nitrobenzyloxycarbonylguanidinomethyl) pyrrolidine hydrochloride (647 mg) was obtained.

(4) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-pyrrolidinecarboxylic acid (947 mg)
In N, N-dimethylformamide (10 ml) solution,
N, N-diisopropylethylamine (0.369m
l), the compound (647 mg) obtained in (3), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (406 mg), and 1-hydroxybenzotriazole (286 mg) were added, and the mixture was added at room temperature overnight. Stirred. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / methanol = 12/1) to give (2
S, 4S) -4- (4-Methoxybenzylthio) -1-
(4-nitrobenzyloxycarbonyl) -2-[(3
S) -3- (4-Nitrobenzyloxycarbonylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (1.13 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1:. 1708,1520,1251,1032,739 Nuclear magnetic resonance spectrum _{(400 MHz, DMSO-d 6} )
δppm: 1.5-2.7 (5H, m), 2.9-3.6 (10H, m), 3.71,3.73 (2
H, s × 2), 3.77 (3H, s), 3.80-3.90 (1H, m), 4.95-5.25 (4H,
m), 6.87 (2H, d, J = 8.45Hz), 7.25-7.28 (2H, m), 7.45-7.65 (4
H, m), 8.15-8.3 (4H, m). (5) Anilyl (1.65 ml) of the compound (1.10 g) obtained in (4) and trifluoroacetic acid (8.0 m).
Trifluoromethanesulfonic acid (0.26 ml) was added to the mixed solution of 1) with stirring under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. This was treated in the same manner as in Reference Example 1- (6) to obtain the title compound (926 mg).

Reference Example 12 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylcarbonyl] Pyrrolidine (1) (3R) -1-tert-butoxycarbonyl-
(3S) synthesized from 3-hydroxymethylpyrrolidine
-3- (Pyrrolidin-1-ylmethyl) pyrrolidine hydrochloride (367 mg) in dry dimethylformamide (10 m
1) Add (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-pyrrolidinecarboxylic acid (804 mg), diisopropylethylamine (1.16 ml), 1- Hydroxybenzotriazole (243 mg), 1-ethyl-
3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (483 mg) was added, and the mixture was stirred at room temperature for 10 hours.
The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 5/1 → 1/1) to give powdery (2S, 4S) -4- (4-methoxybenzylthio).
-2-[(3R) -3- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (362 m
g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.00-2.00 (3H, m), 2.00-3.00 (2
H, m), 3.00-4.20 (17H, m), 3.73 (2H, s), 3.79 (3H,
s), 4.32-4.46 (1H, m), 4.90-5.40 (2H, m), 6.85 (2H,
d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J
= 8.6 Hz), 8.23 (2H, d, J = 8.6 Hz). (2) Anisole (0.68 ml) of the compound (362 mg) obtained in (1), trifluoroacetic acid (3.4 m)
trifluoromethanesulfonic acid (0.14 ml) was added to the mixed solution of 1) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes.
Stir for a minute. The trifluoroacetic acid was concentrated under reduced pressure, the residue was washed with hexane and ether, dried under reduced pressure, saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and washed with saturated saline.

The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (287 mg) as a powder.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1697, 1525, 1246. Reference Example 13 (2S, 4S) -2-[(3R) -3- (N-2-hydroxyethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine-1 -Ylcarbonyl]-
4-mercapto-1- (4-nitrobenzyloxycarbonyl) -pyrrolidine (3S) -3- (N-2-hydroxyethyl-N-4-
Reference Example 12- using nitrobenzyloxycarbonylaminomethyl) pyrrolidine hydrochloride (197 mg).
In the same manner as in (1) and (2), the title compound (2
14 mg).

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.50-2.20 (2H, m), 2.50-2.90 (2
H, m), 2.90-4.10 (12H, m), 4.15-4.30 (2H, m), 4.40-4.
55 (1H, m), 5.20-5.30 (4H, m), 7.50-7.60 (4H, m), 8.1
9-8.28 (4H, m). Reference Example 14 (2S, 4S) -2-[(3S) -3- (N-carbamoylmethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidin-1-ylcarbonyl ] -4
Reference Example 12 using -mercapto-1- (4-nitrobenzyloxycarbonyl) -pyrrolidine (3S) -3- (N-carbamoylmethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine hydrochloride (261 mg). -(1),
In the same manner as in (2), the title compound (368m
g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3371, 2948, 2879, 1706, 1645, 1608, 1522,
1347, 1259. Nuclear magnetic resonance spectrum (400 MHz, DMSO-d
₆ ) δppm: 1.40-2.05 (2H, m), 2.30-2.75 (3H, m),
2.90-3.60 (5H, m), 3.60-4.95 (4H, m), 4.30-4.60 (1H,
m), 5.00-5.30 (4H, m), 7.40-7.70 (4H, m), 8.10-8.30
Reference Example 15 (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- [N
-2- (4-nitrobenzyloxycarbonylamino)
Ethyl-N-4-nitrobenzyloxycarbonylaminomethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (3S) -3- [N-2- (4-nitrobenzyloxycarbonylamino) ethyl) -N-4-nitrobenzyl Oxycarbonylaminomethyl] pyrrolidine hydrochloride (1
95 mg) to give the title compound (248 mg) in the form of a powder in the same manner as in Reference Examples 12- (1) and (2).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1705, 1648, 1607, 1521, 1437, 1347. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ + CD
₃ OD) δ ppm: 1.50-2.10 (3H, m), 2.60-2.80 (2H,
m), 3.00-3.70 (11H, m), 3.80-4.00 (1H, m), 4.00-4.20
(1H, m), 4.40-4.60 (1H, m), 5.15-5.30 (6H, m), 7.45-
7.60 (6H, m), 8.10-8.30 (6H, m). Reference Example 16 (2S, 4S) -2-[(3S) -3- (N-2-dimethylaminoethyl-N-4-nitrobenzyloxy) Carbonylaminomethyl) pyrrolidin-1-ylcarbonyl] -4-mercapto-1- (4-nitrobenzyloxycarbonyl) pyrrolidine (3S) -3- (N-2-dimethylaminoethyl-N-
Reference Example 12- using 4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine dihydrochloride (302 mg).
In the same manner as in (1) and (2), the title compound (4
61 mg).

Reference Example 17 (2S, 4S) -4-mercapto-2-[(3R) -3
-[N-2- (N-methyl-N-4-nitrobenzyloxycarbonylamino) ethyl-N-methylaminomethyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (3S Reference Example 12- (1) using) -3- [N-2- (N-methyl-N-4-nitrobenzyloxycarbonylamino) ethyl-N-methylaminomethyl] pyrrolidine dihydrochloride (580 mg), The title compound (628 mg) was obtained in the form of a powder in the same manner as in (2).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1699, 1645, 1523, 1442, 1347. Nuclear magnetic resonance spectrum (270 MHz, DMSO-d
₆ ) δppm: 1.40-2.00 (3H, m), 2.00-4.10 (21H, m),
4.30-4.60 (1H, m), 5.00-5.30 (4H, m), 7.51-7.65 (4H, m
m), 8.21-8.28 (4H, m). Reference Example 18 (2S, 4S) -2-[(3S) -3- (N-2-fluoroethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine -1-ylcarbonyl] -4
-Mercapto-1- (4-nitrobenzyloxycarbonyl) pyrrolidine Reference Example 12- (3S) -3- (N-2-fluoroethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine hydrochloride The title compound can be obtained in the same manner as in 1) and (2).

Reference Example 19 (2S, 4S) -4-mercapto-2-[(3R) -3
-[1-Methyl-2,3-bis (4-nitrobenzyloxycarbonyl) guanidinomethyl] pyrrolidine-1-
Ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (3S) -3- [1-methyl-2,3-bis (4-nitrobenzyloxycarbonyl) guanidinomethyl] pyrrolidine hydrochloride (1.20 g) Reference Example 12-
In the same manner as in (1) and (2), the title compound (996m
g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1754, 1709, 1645, 1608, 1521, 1441, 1405,
1347. Nuclear magnetic resonance spectrum (270MHz, DMSO-d
₆ ) δppm: 1.50-2.00 (2H, m), 2.60-2.80 (1H, m),
2.90-3.05 (4H, m), 3.10-3.60 (7H, m), 3.65-3.80 (2H,
m), 3.80-4.05 (1H, m), 4.30-4.60 (1H, m), 5.00-5.30
(6H, m), 7.45-7.70 (6H, m), 8.05-8.30 (6H, m). Reference Example 20 (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [(3R) -3- (N
-4-nitrobenzyloxycarbonylacetimidoyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (3S) -3- (N-4-nitrobenzyloxycarbonylacetimidoyl-N-methylaminomethyl) The title compound can be obtained in the same manner as in Reference Examples 12- (1) and (2) using pyrrolidine hydrochloride.

Reference Example 21 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (N
-4-nitrobenzyloxycarbonylformimidoyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (3S) -3- (N-4-nitrobenzyloxycarbonylformimidyl-N-methylaminomethyl) The title compound can be obtained in the same manner as in Reference Examples 12- (1) and (2) using pyrrolidine hydrochloride.

Reference Example 22 (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- (N
-2,2,2-trifluoroethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine-1
-Ylcarbonyl] pyrrolidine Reference Example 12- (1) using (3S) -3- (N-2,2,2-trifluoroethyl-N-4-nitrobenzyloxycarbonylaminomethyl) pyrrolidine hydrochloride,
The title compound can be obtained in the same manner as in (2).

Reference Example 23 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (4
-Nitrobenzyloxycarbonylformimidoylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine Reference Example 12- (3S) -3- (4-nitrobenzyloxycarbonylformimidylmethylaminomethyl) pyrrolidine hydrochloride The title compound can be obtained in the same manner as in 1) and (2).

Reference Example 24 (2S, 4S) -2-[(3S) -3- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidinomethyl] pyrrolidin-1-ylcarbonyl] -4-mercapto- 1-Methylpyrrolidine Using (3S) -3- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidinomethyl] pyrrolidine, the title compound was prepared in the same manner as in Reference Examples 4- (1) and (2). Obtainable.

Reference Example 25 (2S, 4S) -4-Mercapto-1-methyl-2-
[(3S) -3- (4-nitrobenzyloxycarbonylacetimidoylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine Using (3S) -3- (4-nitrobenzyloxycarbonylacetimidoylaminomethyl) pyrrolidine The title compound can be obtained in the same manner as in Reference Examples 4- (1) and (2).

Reference Example 26 (2S, 4S) -4-Mercapto-1-methyl-2-
[(3R) -3- (4-nitrobenzyloxycarbonylformimidylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine Using (3S) -3- (4-nitrobenzyloxycarbonylformimidylaminomethyl) pyrrolidine The title compound can be obtained in the same manner as in Reference Examples 4- (1) and (2).

Reference Example 27 (2S, 4S) -2-[(3R) -3- [1-methyl-
2,3-bis (4-nitrobenzyloxycarbonyl)
Guanidinomethyl] -4-mercapto-1-methyl-pyrrolidin-1-ylcarbonyl] pyrrolidine Using (3S) -3- [1-methyl-2,3-bis (4-nitrobenzyloxycarbonyl) guanidinomethyl] pyrrolidine The title compound can be obtained in the same manner as in Reference Example 12- (1), (2).

Reference Example 28 (2S, 4S) -4-Mercapto-1-methyl-2-
[(3S) -3- (N-4-nitrobenzyloxycarbonylacetimidoyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (3S) -3- (N-4-nitrobenzyloxycarbonylacetate The title compound can be obtained in the same manner as in Reference Examples 4- (1) and (2) using imidoyl-N-methylaminomethyl) pyrrolidine.

Reference Example 29 (2S, 4S) -4-Mercapto-1-methyl-2-
[(3R) -3- (N-4-nitrobenzyloxycarbonylformimidyl-N-methylaminomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (3S) -3- (N-4-nitrobenzyloxycarbonylform) The title compound can be obtained in the same manner as in Reference Examples 4- (1) and (2) using imidoyl-N-methylaminomethyl) pyrrolidine.

Formulation Example 1 Injection 500 mg of the compound of Example 3 was dissolved in 5 ml of distilled water for injection, passed through a filter for sterilization, and then lyophilized to give a lyophilized preparation for injection.

Formulation Example 2 Tablets 50 mg of the compound of Example 3 Lactose 126 mg Corn starch 23 mg Magnesium stearate 1 mg 200 mg The powder of the above formulation was mixed, wet-granulated using corn starch paste, dried, and compressed with a tablet machine. Lock it, 1
Tablets 200 mg tablets. The tablets can be sugar-coated as needed.

Test Example 1 In Vitro Antibacterial Test The antibacterial activity was measured by an agar plate dilution method, and the minimum inhibitory concentration (MIC: μg / ml) against various pathogenic bacteria was determined. The compounds of Example 3 and Example 7 of the present invention, Staphylococcus aureus 209P strain, Escherichia coli NIHJ strain and P. aeruginosa No. Table 2 shows the test results for the seven strains.

Compound A and Compound B used for comparison
Shows the compound of Example 3 of JP-A-5-310740 [compound in which R ¹ , R ² and R ³ are all hydrogen atoms in the general formula (I) of the present invention].

Compound A: an isomer in which the configuration at the bonding position of the aminomethyl group is R Compound B: an isomer having the configuration at the bonding position of the aminomethyl group is S

[0315]

[Table 2] Minimum growth inhibitory concentration (MIC: μg / ml)比 Specific test strain Staphylococcus aureus E. coli Pseudomonas aeruginosa 209P strain NIHJ strain No. 7 strains 化合物 Compound of Example 3 0.02 0.020 0.05 Compound of Example 7 0.02 0.02 0.05 Compound A 0.02 0.02 0.1 Compound B 0.02 0.02 0.1 ──────────────────────── The measurement medium is Mueller-Hinton IIa
gar (MHA, Becton Dickinson M
microbiology Systems).

Test Example 2 In Vitro Antibacterial Test The test results of the compounds of Examples 3 and 7 of the present invention and meropenem against Staphylococcus aureus 209P strain, Escherichia coli NIHJ strain and Pseudomonas aeruginosa 3719 strain (Meropenem-resistant strain) are shown in the following Table. 3 is shown.

[0317]

[Table 3] Minimum growth inhibitory concentration (MIC: μg / ml) ─ Specific bacterial strain S. aureus E. coli Pseudomonas aeruginosa 209P strain NIHJ strain 3719 strain ─────────────────────────────────化合物 Compound of Example 3 ≦ 0.01 ≦ 0.01 0.2 Compound of Example 7 ≦ 0.01 ≦ 0.01 0.1 Meropenem 0.02 ≦ 0.01 6.2 ──── ──────────────────────────────── Measurement medium is Neutrient Agar Eike
n (Eiken Chemicals Co., Ltd.
d. )It was used.

Test Example 3 In Vivo Antibacterial Test (Effect of Treatment of Infection) A bacterial solution of a comparative strain was applied to 7 mice (SPF, DDY)
, Male)), the drug solution was subcutaneously administered twice immediately after the inoculation and 4 hours after the inoculation.
The 50% effective dose (ED ₅₀ : mg / kg) was determined by the robit method, and the dose of the drug per administration was shown.

The compound of Example 3 of the present invention comprising Pseudomonas aeruginosa 100
Table 4 shows the test results for the eight strains. Compound A is as described above.

[0320]

[Table 4] infection therapeutic effect _{(ED 50: mg / kg)} ─────────────────────────────────── ─ Comparative strain Pseudomonas aeruginosa 1008 strain 化合物 Compound of Example 3 0.22 Compound A 0.44 Meropenem 0.72% or more The test results indicate that the compound of the present invention is in vitro
It has strong antibacterial activity in the test and
The vo test also shows that it has an excellent infection therapeutic effect. That is, the compound of the present invention (for example,
The compound of Example 3 is an unsubstituted aminomethyl compound disclosed in JP-A-5-310740 [compound in which R ¹ , R ² and R ³ are all hydrogen atoms in the general formula (I) of the present invention]. ] (Compound A and compound B). The compounds of the present invention also showed excellent antibacterial activity against P. aeruginosa 3719 strain resistant to meropenem.

Further, the compounds of the present invention (for example, Example 3
Has excellent properties in pharmacokinetics such as blood half-life. Furthermore, when the compound of the present invention was administered to rabbits, the uptake into the renal cortex was low, and the compound 2 of Example 3
A single intravenous dose of 00 mg / kg to rabbits showed no nephrotoxicity.

[0322]

The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof includes, for example, Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis, Escherichia coli, Shigella,
Shows strong and balanced antibacterial activity against a wide range of pathogens, including gram-negative bacteria such as Klebsiella pneumoniae, deformants, Serratia, Enterobacter, and Pseudomonas aeruginosa, and anaerobic bacteria such as Bacteroides fragilis, and is resistant to meropenem Also exhibited excellent antibacterial activity against Pseudomonas aeruginosa. In addition, the compound (I) of the present invention has high stability against β-lactamase, is stable against dehydropeptidase-I, and has a high urinary recovery rate. Furthermore, the compound (I) of the present invention is an excellent antibacterial agent because it has excellent pharmacokinetics such as half-life in blood and low toxicity to the kidney.

Incidentally, unsubstituted aminomethyl compounds disclosed in JP-A-5-310740 [General formula (I) of the present invention]
Wherein R ¹ , R ² and R ³ are all hydrogen atoms] (compound A and compound B), the compound (I) of the present invention having a substituent on the amino group is an excellent anti-green It showed Pseudomonas aeruginosa activity, excellent pharmacokinetics, and low nephrotoxicity.

Therefore, the compound (I) of the present invention or a pharmaceutically acceptable salt or derivative thereof is an excellent antibacterial agent for treating or preventing (preferably treating) bacterial infections caused by various pathogenic bacteria.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Katsuhiko Kojima, Inventor, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Yasuo Shimo 1-2-58, Hiromachi, Shinagawa-ku, Tokyo (72) Inventor Tetsu Oya 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (8)

[Claims] 1. A compound of the general formula [Wherein, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom, a lower alkyl group, or a lower alkyl group having 1 to 3 substituents (the The substituent is a hydroxyl group, a halogen atom, a carbamoyl group, a carbamoyl group substituted with one or two lower alkyl groups, a carbamoyloxy group,
A carbamoyloxy group, a lower alkoxy group, an amino group or an amino group substituted with one or two lower alkyl groups. ), Group (wherein represented by a cycloalkyl group, or the formula ^{-C (= NH) R 4,} R 4 represents a hydrogen atom, a lower alkyl group or an amino group.), Or, R ² and R ³ are each A bonding group, which represents an alkylene group which may be interposed through one oxygen atom, nitrogen atom or sulfur atom (the nitrogen atom may be substituted by a lower alkyl group); (Excluding compounds in which all of R ¹ , R ² and R ³ are hydrogen atoms) or a pharmacologically acceptable salt or derivative thereof. 2. The compound (I) according to claim 1, wherein R ¹ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ² is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R ³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, 1 to 3
Alkyl groups having 1 to 4 carbon atoms having 1 substituent (the substituents are a hydroxyl group, a halogen atom, a carbamoyl group,
Carbamoyl group substituted with an alkyl group having 1 to 4 carbon atoms, carbamoyloxy group, 1 to 2 carbon atoms having 1 to 2 carbon atoms
A carbamoyloxy group substituted with four alkyl groups,
An alkoxy group having 1 to 4 carbon atoms, an amino group or 1 to 2
Represents an amino group substituted with an alkyl group having 1 to 4 carbon atoms. ), Group (wherein, represented by the number 3-6 cycloalkyl group or the formula -C (= NH) R ⁴ carbons, R ⁴ is a hydrogen atom, a 1-4 alkyl group or an amino group having a carbon number Or a group in which R ² and R ³ are bonded to each other, and may be an alkylene group having 2 to 6 carbon atoms which may be via one oxygen atom, nitrogen atom or sulfur atom. Atom has 1 to 4 carbon atoms
May be substituted with an alkyl group. Or a pharmacologically acceptable salt or derivative thereof. 3. The compound (I) according to claim 1, wherein R ¹ is a hydrogen atom, a methyl or ethyl group, R ² is a hydrogen atom, a methyl or ethyl group, R ³ is a hydrogen atom, methyl, ethyl, 2-hydroxyethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, carbamoylmethyl, 2-carbamoylethyl,
N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-methoxyethyl, 2-carbamoyloxyethyl, 2-aminoethyl, 2- (methylamino) ethyl, 2- (dimethylamino) ethyl, cyclopropyl, form Imidoyl, acetimidoyl or amidino group, or R ² and R ³ are bonded to each other, and trimethylene, tetramethylene, pentamethylene, ethyleneoxyethyl, ethylenethioethyl, ethyleneaminoethyl, ethylene (methylamino) ethyl or ethylene A compound which is an aminopropyl group, or a pharmacologically acceptable salt or derivative thereof. 4. The compound (I) according to claim 1, wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, methyl, 2-hydroxyethyl. A compound in which R ² and R ³ are bonded to each other to form a tetramethylene group A pharmacologically acceptable salt or derivative thereof. 5. The compound (I) according to claim 1, wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom, methyl, formimide A compound which is an yl, acetimidoyl or amidino group, or a pharmacologically acceptable salt or derivative thereof. 6. The compound (I) according to any one of claims 1 to 5, wherein Or the general formula: Or a pharmacologically acceptable salt or derivative thereof. 7. The compound (I) according to claim 1, wherein the compound is selected from the group consisting of: and a pharmaceutically acceptable salt or derivative thereof. (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3R) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2- [ (2S, 4S) -2-
[(3S) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -2-[(2S, 4S ) -2-[(3R)-
3- (2-hydroxyethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -6-[(1R) -1 -Hydroxyethyl] -2-[(2S, 4S) -2-[(3S)-
3- (2-hydroxyethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-carbamoylmethylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-carbamoylmethylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (2-aminoethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [ (2S, 4S) -2-
[(3S) -3- (2-aminoethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [ (2S, 4S) -2-
[(3R) -3- (2- (N-methylamino) ethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2- (N-methylamino) ethylaminomethyl) pyrrolidin-1-ylcarbonyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-N-methyl-N-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-M-3
-Carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-N-methyl-N-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-M-3
-Carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-N-methyl-N-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-M-3
-Carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-N-methyl-N-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-M-3
-Carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (1-Methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (1-methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-Aminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-Aminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl]- 1-methyl-2-[(2S, 4S) -2-
[(3R) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl -2-[(2S, 4S) -2-
[(3S) -3-methylaminomethylpyrrolidine-1-
Ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-
4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-guanidinomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-N-methyl-N-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-N-methyl-N-formimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-N-methyl-N-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-N-methyl-N-acetimidoylaminomethylpyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methyl-1-carbapene-
2-M-3-carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3- (1-Methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-m-3-
Carboxylic acid (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (1-Methylguanidinomethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1 -Carbapene-2-m-3-
carboxylic acid 8. An antibacterial agent comprising the compound (I) according to claim 1 or a pharmaceutically acceptable salt or derivative thereof as an active ingredient.