JPH04321688A - 2-(substituted pyrrolidinylthio)carbapenem derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound having strong antibacterial activity against sensitive and resistant Gram-positive bacteria and Gram-negative bacteria and excellent stability to beta-lactamase and DHP-I and useful as an antibacterial agent. CONSTITUTION:The compound of formula I [R is H or methyl; R<1> is H or negative charge; R<2> and R<3> are H, alkyl, formimidoyl, COOR<4>, NR<5>R<6> (R<4> is H or alkyl; R<5> and R<6> are H, alkyl or together with adjacent N form a heterocyclic group), etc.; p is 0-3; q and r are 0-5; A is CON(R<7>), (CON(R<7>)CO, CON(R<7>)N (R<8>), etc., when q=r and A is NR<7>, group of formula II (R<7> and R<8> are H, alkyl, acetamidoyl, etc.), etc., when qnot equal to r], e.g. (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2 S,4S)-2-(2-pyrrolidon-4-yl)]-pyrrolidin-4-ylthio]-1-carbapen-2-em-3-ca rboxylic acid. The compound can be produced by reacting a compound of formula III with a compound of formula IV and optionally deprotecting the reaction product.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention provides a novel carbapenem (
7-oxo-1-azabicyclo[3.2.0]hepta-
The present invention relates to a compound (2-ene-2-carboxylic acid), an antibacterial agent containing the compound as an active ingredient, and a method for producing the compound.

0002

BACKGROUND OF THE INVENTION In recent years, novel β-lactam antibiotics having the same β-lactam ring as penicillins and cephalosporins but having a different basic skeleton have been discovered one after another from nature.

For example, Streptomyces Cattleya (
Thienamycin isolated from the fermentation of Streptomyces cattleya
) [Journal of the American Chemical Society (J.Am.Chem.Soc.)
, Vol. 100, p. 6491 (1978)]. Thienamycin has a wide range of excellent antibacterial spectrum and strong antibacterial activity against Gram-positive and Gram-negative bacteria, and was expected to be developed as a highly useful β-lactam agent. However, thienamycin itself is chemically unstable and is degraded by certain in vivo enzymes, such as renal dehydropeptidase I (hereinafter abbreviated as DHP-I), reducing the efficacy of its antibacterial activity and causing urine to be released. It has been reported that the recovery rate is low [Antimicrobial Agents and Chemotherapy (Antimic
rob. Agents Chemother. ), vol. 22, p. 62 (1982); vol. 23, 300
Page (1983)].

[0004] Merck has synthesized a number of thienamycin analogs in order to maintain the excellent antibacterial activity of thienamycin and to ensure its chemical stability. As a result, imipenem [Imipenem: (5
R,6S,8R)-3-[[2-(formimidoylamino)ethyl]thio]-6-(1-hydroxyethyl)
-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate; Journal
of Medicinal Chemistry (J.Med
．． Chem. ), vol. 22, p. 1435 (1979)
] has been put into practical use as a medicine.

Imipenem maintains antibacterial activity and β-lactamase resistance comparable to or higher than thienamycin against various bacterial species, and in particular, its antibacterial action against Pseudomonas aeruginosa is 2 to 4 times better. There is. Also, the stability of imipenem as an aqueous solution and as a solid was significantly improved compared to thienamycin.

However, like thienamycin, imipenem is degraded by DHP-I in the human kidney;
Not only can it not be used for urinary tract infections, but its degradation products are nephrotoxic. Therefore, imipenem cannot be administered alone, and cilastatin (cilastatin)
) must be used in combination with DHP-I inhibitors such as [Antimicrobial Agents and Chemotherapy].
Chemother. ), Volume 12 (Suppl D
), p. 1 (1983)]. In addition, in recent years, imipenem has been frequently used for the treatment and prevention of infectious diseases, and highly methicillin-resistant Staphylococcus aureus and imipenem-resistant Pseudomonas aeruginosa, which are resistant to imipenem, are increasing in clinical settings, and imipenem is effective against these resistant bacteria. It has not shown sufficient therapeutic effect.

The prior art most similar to the present invention is:
Japanese Patent Publication No. 63-55514 is mentioned. In this publication, meropenem [meropenem; SM-7338
:(4R, 5S, 6S, 8R, 2'S, 4'S) -6-
(1-hydroxyethyl)-4-methyl-3-[2-(
N,N-dimethylaminocarbonyl)pyrrolidine-4-
ylthio]-7-oxo-1-azabicyclo[3.2.
0]hept-2-ene-2-carboxylic acid], the 2-(aminocarbonyl or N-mono- or N,N-dilower alkylaminocarbonyl)pyrrolidine-4- Carbapenem compounds with an ylthio group have been described.

[0008]

[Problems to be Solved by the Invention] β-lactam antibiotics are selectively toxic only to bacteria and have no effect on animal cells, so they are useful in the treatment of bacterial infections as antibiotics with few side effects. It is a widely used and highly useful drug.

However, in recent years, highly methicillin-resistant Staphylococcus aureus and resistant Pseudomonas aeruginosa are frequently isolated from immunocompromised patients as causative agents of refractory infections, and are becoming a major clinical problem. Therefore, the development of antibacterial agents with improved antibacterial activity against these resistant bacteria, especially for carbapenem compounds, is strongly desired to improve antibacterial activity, improve stability against DHP-I, and reduce side effects on the central nervous system. It is rare.

Furthermore, the stability of the compounds described in Japanese Patent Publication No. 63-55514, especially meropenem, against DHP-I has been greatly improved. However, the antibacterial activity against the highly methicillin-resistant Staphylococcus aureus is not sufficient, and carbapenem compounds having better antibacterial activity are being sought.

[0011]

[Means for Solving the Problems] The present inventors have conducted extensive research with the aim of providing a new carbapenem compound that has excellent antibacterial activity and is resistant to DHP-I. As a result, the general formula

0012
]

[Formula, R2 and R3 are the same or different and are a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a formimidoyl group, an acetimidoyl group, -COOR4,
-CON(R5)R6, -N(R5)R6, -CH2C
OOR4, -CH2N(R5)R6 or -CH2CO
N(R5)R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and the hydrogen atom, lower alkyl group, or the lower alkyl group is bonded to each other and together with the adjacent nitrogen atom, aziridinyl forming a heterocyclic group selected from the group consisting of azetidinyl group, pyrrolidinyl group and piperidyl group), A is =NR7,

[0013]

[Chemical 25] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)CO(CH
2) sN(R8)-, -N(R7)CO(CH2)sC
ON(R8)-, -CON(R7)N(R8)- or -N(R7)(CH2)sN(R8)-{Here, R7 and R8 are the same or different and represent a hydrogen atom, a lower alkyl group, Hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CO
N(R5)R6, -N(R5)R6, -CH2COOR
4, -CH2N(R5)R6 or -CH2CON(R
5) R6 (here, R4, R5 and R6 have the above meanings), s represents an integer from 1 to 3}, p
is an integer from 0 to 3, and q and r are the same or different integers from 0 to 5 (except when q and r are both 0, and the sum of q and r is 6 or less)]. The carbapenem compound of the present invention having the group represented is a novel compound that has not been described in any literature, and has strong antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus and Gram-negative bacteria including Pseudomonas aeruginosa. Furthermore, the present invention was completed based on the discovery that it exhibits excellent stability against DHP-I.

The present invention is based on the general formula

[0015]

[Formula, R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a negative charge, R2 and R3 are the same or different,
Hydrogen atom, lower alkyl group, hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COO
R4, -CON(R5)R6, -N(R5)R6, -C
H2COOR4, -CH2N(R5)R6 or -CH
2CON(R5)R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and the hydrogen atom, lower alkyl group, or the lower alkyl group is bonded to each other and together with the adjacent nitrogen atom, aziridinyl forming a heterocyclic group selected from the group consisting of azetidinyl group, azetidinyl group, pyrrolidinyl group and piperidyl group)
, A is =NR7,

[0016]

[Chemical 27] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)CO(CH
2) sN(R8)-, -N(R7)CO(CH2)sC
ON(R8)-, -CON(R7)N(R8)- or -N(R7)(CH2)sN(R8)-{Here, R7 and R8 are the same or different and represent a hydrogen atom, a lower alkyl group, Hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CO
N(R5)R6, -N(R5)R6, -CH2COOR
4, -CH2N(R5)R6 or -CH2CON(R
5) R6 (here, R4, R5 and R6 have the above meanings), s represents an integer from 1 to 3}, p
is an integer from 0 to 3, and q and r are the same or different integers from 0 to 5 (except when q and r are both 0, and the sum of q and r is 6 or less)]. It relates to the represented compounds or their pharmaceutically acceptable salts or esters, to processes for their preparation and to their use as antibacterial agents.

[0017] The symbols and terms described in this specification will be explained.

The basic structure of the compound of the present invention is

[0019]

[3.
2.0] hept-2-ene-2-carboxylic acid. In this specification, for the sake of simplicity, numbers are assigned based on the commonly used carbapenem, and the basic structure thereof is described as 1-carbapen-2-em-3-carboxylic acid.

[0020]

embedded image The present invention includes optical isomers and stereoisomers based on the asymmetric carbon atoms at the 1st, 5th, 6th, and 8th positions of the carbapenem skeleton, and preferred compounds among these isomers are: 5R,6S configuration with thienamycin-like configuration (
(5,6-trans), and the carbon atom at the 8th position is a compound with the R configuration (5R,6S,8R), or when it has a methyl group at the 1st position, it is (1R,5S,6S,
8R) configuration can be mentioned.

The present invention provides 2-(alicyclic heterocycle substituted or alicyclic heterocycle lower alkyl) pyrrolidine-4 at the 2-position side chain.
-ylthio group also includes isomers based on the 2-position, 4-position and asymmetric carbon of the 2-position side chain of the pyrrolidine nucleus,
Preferred compounds among these isomers are, when p is 0, (
Compounds having the 2'S, 4'S) configuration and (2'R, 4'R) configuration can be mentioned, and when p is an integer from 1 to 3, the (2'R, 4'S) configuration can be mentioned. and (2'S,4'
Compounds having the R) configuration can be mentioned.

Furthermore, there are isomers based on asymmetric carbon atoms regarding the alicyclic heterocyclic group at the 2-position of the pyrrolidine nucleus.
The present invention includes both isomers.

The lower alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert -butyl group, pentyl group, hexyl group, etc., methyl group, ethyl group, t
An ert-butyl group is preferred.

The hydroxy lower alkyl group refers to a hydroxy alkyl group in which the above-mentioned lower alkyl group is substituted with a hydroxy group, such as hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group, etc. and hydroxyethyl group are suitable.

The lower alkylcarbamoyl group refers to a carbamoyl group substituted with the above-mentioned lower alkyl group, such as N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, etc. and the like are preferred.

The di-lower alkylcarbamoyl group refers to a carbamoyl group in which the above-mentioned lower alkyl group is di-substituted,
Examples include N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, and N,N-dimethylcarbamoyl group is preferred.

Examples of protective groups for carboxyl groups include methyl group, ethyl group, propyl group, isopropyl group, t
Lower alkyl groups such as ert-butyl; e.g. 2,2,
Halo-substituted lower alkyl groups such as 2-trichloroethyl group and 2,2,2-trifluoroethyl group; for example, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-propionyl group Lower alkanoyloxyalkyl groups such as oxyethyl groups; for example, 1-(methoxycarbonyloxy)ethyl groups, 1-(ethoxycarbonyloxy)ethyl groups, 1-
Lower alkoxycarbonyloxyalkyl groups such as (isopropoxycarbonyloxy)ethyl; for example, 2-propenyl, 2-chloro-2-propenyl, 3-methoxycarbonyl-2-propenyl, 2-methyl-2-
Lower alkenyl groups such as propenyl group, 2-butenyl group, cinnamyl group; for example, benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, bis Aralkyl groups such as (p-methoxyphenyl)methyl; (5-substituted-2-oxo-1,3- such as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) dioxol-4-yl) methyl group; for example, lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; indanyl group, phthalidyl group, methoxymethyl group, etc., especially 2-propenyl group, p-nitrobenzyl group; A p-methoxybenzyl group, a benzhydryl group, a tert-butyldimethylsilyl group, and the like are preferred.

Examples of protecting groups for hydroxyl groups include lower alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl; lower alkoxymethyl groups such as methoxymethyl and 2-methoxyethoxymethyl;
For example, a tetrahydropyranyl group; for example, a benzyl group, p
- Aralkyl groups such as methoxybenzyl group, 2,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group; For example, acyl groups such as formyl group and acetyl group; For example, tert-butoxycarbonyl group, Lower alkoxycarbonyl groups such as 2-iodoethoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group,
2-chloro-2-propenyloxycarbonyl group, 3-
methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group,
Alkenyloxycarbonyl groups such as 2-butenyloxycarbonyl group and cinnamyloxycarbonyl group; for example, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc. Examples include aralkyloxycarbonyl groups such as 2-propenyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, and tert-butyldimethylsilyl group.

Examples of protecting groups for amino or imino groups include benzylidene group, p-chlorobenzylidene group,
Aralkylidene groups such as p-nitrobenzylidene group, salicylidene group, α-naphthylidene group, β-naphthylidene group; for example, benzyl group, p-methoxybenzyl group, 3,4
-dimethoxybenzyl group, o-nitrobenzyl group, p-
Aralkyl groups such as nitrobenzyl group, benzhydryl group, bis(p-methoxyphenyl)methyl group, trityl group; lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group, pivaloyl group For example, halo-substituted lower alkanoyl groups such as chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group; For example, arylalkanoyl groups such as phenylacetyl group and phenoxyacetyl group; For example, methoxycarbonyl group, ethoxycarbonyl group, propoxy carbonyl group, tert
Lower alkoxycarbonyl groups such as -butoxycarbonyl groups; e.g. 2-iodoethoxycarbonyl groups, 2,2,
Halo-substituted lower alkoxycarbonyl group such as 2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl- Alkenyloxycarbonyl groups such as 2-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, cinnamyloxycarbonyl group; For example, benzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, phenethyl group Aralkyloxycarbonyl groups such as oxycarbonyl group; examples include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; in particular, 2-propenyloxycarbonyl group, tert-butoxycarbonyl group, p
-Nitrobenzyloxycarbonyl group and the like are preferred.

The alicyclic heterocyclic group on the pyrrolidin-4-ylthio group, which is the 2-position side chain of the carbapenem skeleton, is substituted at the 2-position of the pyrrolidine nucleus, and has the formula

[0031]

embedded image [wherein R2 and R3 are the same or different, hydrogen atom, lower alkyl group, hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4,
-CON(R5)R6, -N(R5)R6, -CH2C
OOR4, -CH2N(R5)R6 or -CH2CO
N(R5)R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and the hydrogen atom, lower alkyl group, or the lower alkyl group is bonded to each other and together with the adjacent nitrogen atom, aziridinyl forming a heterocyclic group selected from the group consisting of azetidinyl group, pyrrolidinyl group and piperidyl group), A is =NR7,

[0032]

[Chemical 31] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)CO(CH
2) sN(R8)-, -N(R7)CO(CH2)sC
ON(R8)-, -CON(R7)N(R8)- or -N(R7)(CH2)sN(R8)-{Here, R7 and R8 are the same or different and represent a hydrogen atom, a lower alkyl group, Hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CO
N(R5)R6, -N(R5)R6, -CH2COOR
4, -CH2N(R5)R6 or -CH2CON(R
5) R6 (here, R4, R5 and R6 have the above meanings), s represents an integer from 1 to 3}, p
is an integer from 0 to 3, and q and r are the same or different integers from 0 to 5 (except when q and r are both 0, and the sum of q and r is 6 or less)]. has the structure represented.

R2 and R3 (R20 and R30) may be the same or different, and can be substituted at any substitutable position on the carbon forming the alicyclic heterocycle.

R2 and R3 are hydrogen atoms, lower alkyl groups, hydroxy lower alkyl groups, -CON(R
5) R6, -N(R5)R6 [herein, R5 and R6 have the above-mentioned meaning], etc. are preferred, and among them, a hydrogen atom, a carbamoyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, an amino and the like are preferred.

A represents a partial structure of the alicyclic heterocyclic group. For A, =NR7,

[0036]

[Chemical 32] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)COCH2
N(R8)-,-CON(R7)N(R8)-,-N(
R7) (CH2)2N(R8) - [Here, R7
and R8 have the above meanings], among others, =NR7,

[0037]

embedded image -CON(R7)- [wherein R7 and R8 have the above meanings] is preferred, especially =NH,
=NMe, =N-CH2CONH2,

[0038]

[C34] -CONH- etc. are preferred.

p represents an integer from 0 to 3, 0 or 1
The case of 0 is preferable, and the case of 0 is particularly preferable.

Specific examples of the alicyclic heterocyclic group include, when p is 0, aziridinyl group, azetidinyl group, 2
-Carbamoylazetidinyl group, 2-oxoazetidinyl group, N-methyl-2-oxoazetidinyl group, pyrrolidinyl group, N-methylpyrrolidinyl group, N-(carbamoylmethyl)pyrrolidinyl group, N,N -dimethylpyrrolidinio group, 2-oxopyrrolidinyl group, 2,5-dioxopyrrolidinyl group, N-(2-hydroxyethyl)pyrrolidinyl group, 2,5-dioxo-N-methylpyrrolidinyl group , 2-carbamoylpyrrolidinyl group, 2-(N-methylcarbamoyl)pyrrolidinyl group, 2-(N,N-dimethylcarbamoyl)pyrrolidinyl group, 3-amino-2
-oxopyrrolidinyl group, pyrazolidinyl group, 3-oxopyrazolidinyl group, imidazolidinyl group, 2,4-dioxoimidazolidinyl group, piperazinyl group, 2-oxopiperazinyl group, piperidyl group, N-methyl piperidyl group, N,N-dimethylpiperidinio group, 2-oxopiperidyl group, 2,6-dioxopiperidyl group, 2-carbamoylpiperidyl group, hexahydroazepinyl group, N
-Methylhexahydroazepinyl group, N,N-dimethylhexahydroazepinio group, hexahydro-2-oxoazepinyl group, 2,7-dioxohexohexahydroazepinyl group, 2-carbamoylhexahydroazepinyl group , hexahydro-1H-1,4-diazepinyl group, hexahydro-2-oxo-1H-1,4-diazepinyl group, octahydroazocinyl group, N-methyloctahydroazocinyl group and N,N-dimethyloctahydroazo Cinio group, among others, 2-oxoazetidinyl group, pyrrolidinyl group, N,N-dimethylpyrrolidinio group,
2-carbamoylpyrrolidinyl group, 3-amino-2-oxopyrrolidinyl group, 2-oxopyrrolidinyl group, piperidyl group, 2-oxopiperidyl group, and the like are preferred.

When p is 1, aziridinylmethyl group, azetidinylmethyl group, 2-carbamoylazetidinylmethyl group, 2-oxoazetidinylmethyl group, N-methyl-2-oxoazetidinylmethyl group group, pyrrolidinylmethyl group, N-methylpyrrolidinylmethyl group, N-(carbamoylmethyl)pyrrolidinylmethyl group, N,N-dimethylpyrrolidiniomethyl group, 2-oxopyrrolidinylmethyl group, 2 , 5-dioxopyrrolidinylmethyl group, N-(
2-hydroxyethyl)pyrrolidinylmethyl group, 2,5
-dioxo-N-methylpyrrolidinylmethyl group, 2-carbamoylpyrrolidinylmethyl group, 2-(N-methylcarbamoyl)pyrrolidinylmethyl group, 2-(N,N-dimethylcarbamoyl)pyrrolidinylmethyl group , 3-amino-2-oxopyrrolidinylmethyl group, pyrazolidinylmethyl group, 3-oxopyrazolidinylmethyl group, imidazolidinylmethyl group, 2,4-dioxoimidazolidinylmethyl group, pipette Radinylmethyl group, 2-oxopiperazinylmethyl group, piperidylmethyl group, N-methylpiperidylmethyl group, N,N-dimethylpiperidiniomethyl group, 2-oxopiperidylmethyl group, 2,6-dioxopiperidyl Methyl group, 2-carbamoylpiperidylmethyl group, hexahydroazepinylmethyl group, N-methylhexahydroazepinylmethyl group, N,N-dimethylhexahydroazepiniomethyl group, hexahydro-2-oxoazepinyl group Methyl group, 2,7-dioxohexahydroazepinylmethyl group, 2-carbamoylhexahydroazepinylmethyl group, hexahydro-1H-1,4-diazepinylmethyl group, hexahydro-2-oxo-1H-
Examples include 1,4-diazepinylmethyl group, octahydroazosinylmethyl group, N-methyloctahydroazosinylmethyl group, and N,N-dimethyloctahydroazosiniomethyl group, among which 2-oxoazetidine methyl group, pyrrolidinylmethyl group, N,N-dimethylpyrrolidiniomethyl group, 2-carbamoylpyrrolidinylmethyl group, 3-amino-2-oxopyrrolidinylmethyl group,
2-oxopyrrolidinylmethyl group, piperidylmethyl group, 2-oxopiperidylmethyl group, and the like are preferred.

R1 represents a hydrogen atom or a negative charge. When the alicyclic heterocyclic group substituted at the 2-position of the pyrrolidine nucleus has a quaternary ammonium structure, R1 exhibits a negative charge, and by forming a pair with the ammonium ion, the compound of general formula [I] Forms salt.

[0043] The salt of general formula [I] means a conventional pharmaceutically acceptable salt, and includes a carboxyl group at the 3-position of the carbapenem skeleton, a pyrrolidine base at the side chain at the 2-position, or an alicyclic heterocyclic group. Mention may be made of salts in bases.

Examples of basic addition salts for the carboxyl group include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; for example ammonium salts; for example trimethylamine salts and triethylamine salts. Aliphatic amine salts such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt; Aralkylamine salt such as N,N'-dibenzylethylenediamine; For example, pyridine salt, picoline salt, quinoline salt , heterocyclic aromatic amine salts such as isoquinoline salts; for example, tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, tetrabutylammonium salts, etc. Quaternary ammonium salts include basic amino acid salts such as arginine salts and lysine salts.

Examples of acid addition salts of pyrrolidine bases or bases of alicyclic heterocyclic groups include hydrochlorides, sulfates,
Inorganic acid salts such as nitrates, phosphates, carbonates, bicarbonates, perchlorates; for example acetates, propionates, lactates,
maleate, fumarate, tartrate, malate,
Organic acid salts such as citrate and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate; acids such as aspartate and glutamate; Examples include amino acid salts.

As the non-toxic ester of general formula [I],
It means a conventional pharmaceutically acceptable carboxyl group at the 3-position of the carbapenem skeleton. For example, esters with alkanoyloxymethyl groups such as acetoxymethyl group and pivaloyloxymethyl group, esters with alkoxycarbonyloxyalkyl groups such as 1-(ethoxycarbonyloxy)ethyl group, esters with phthalidyl group,
(5-methyl-2-oxo-1,3-dioxole-4
-yl)methyl group, etc. (5-substituted-2-oxo-1,3
-dioxol-4-yl) methyl group, and the like.

General formula

[0048]

[Formula, R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a negative charge, R2 and R3 are the same or different,
Hydrogen atom, lower alkyl group, hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COO
R4, -CON(R5)R6, -N(R5)R6, -C
H2COOR4, -CH2N(R5)R6 or -CH
2CON(R5)R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and the hydrogen atom, lower alkyl group, or the lower alkyl group is bonded to each other and together with the adjacent nitrogen atom, aziridinyl forming a heterocyclic group selected from the group consisting of azetidinyl group, azetidinyl group, pyrrolidinyl group and piperidyl group)
, A is =NR7,

[0049]

[Chemical 36] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)CO(CH
2) sN(R8)-, -N(R7)CO(CH2)sC
ON(R8)-, -CON(R7)N(R8)- or -N(R7)(CH2)sN(R8)-{Here, R7 and R8 are the same or different and are a hydrogen atom, a lower alkyl group, Hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CO
N(R5)R6, -N(R5)R6, -CH2COOR
4, -CH2N(R5)R6 or -CH2CON(R
5) R6 (here, R4, R5 and R6 have the above meanings), s represents an integer from 1 to 3}, m
, n and p are the same or different and represent an integer of 0 to 3 (excluding cases where m and n are both 0), a compound represented by the general formula

[0050]

[Formula, R is a hydrogen atom or a methyl group, A1 is =N
-R9, -CON(R10)- or -CON(R
10) CO- (here, R9 represents a hydrogen atom, a lower alkyl group, a formimidoyl group, or an acetimidoyl group, and R10 represents a hydrogen atom or a lower alkyl group),
m and n are the same or different and represent an integer of 0 to 3 (however, the case where m and n are both 0 is excluded), a compound represented by the general formula

[0051]

[Formula, R is a hydrogen atom or a methyl group, A is =N-
R9, -CON(R10)- or -CON(R1
0) CO- (here, R9 represents a hydrogen atom, a lower alkyl group, a formimidoyl group, or an acetimidoyl group, and R10 represents a hydrogen atom or a lower alkyl group), m
, n and p are the same or different and represent an integer of 0 to 3 (excluding cases where m and n are both 0) and the general formula

[0052]

[Formula, R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a negative charge, A2 is =N-R9,

[0053]

[Chemical formula 40] -CON(R10)- or -CON(R10
)CO-(wherein, R9 is a hydrogen atom, a lower alkyl group, a formimidoyl group or an acetimidoyl group,
R10 is a hydrogen atom or a lower alkyl group, R11 and R12 are the same or different and represent a lower alkyl group),
The compound represented by m, n and p are the same or different and represent an integer of 0 to 3 (however, the case where m and n are both 0 is excluded) is included in the compound group represented by the general formula [I]. included.

Compounds of general formula [I-b] and compounds of general formula [I-b]
I-c], A1 is -CON(R10)-
In addition to compounds where =N--R9 are preferred.

In the compound of general formula [I-d], A2 is =NR9,

[0056]

embedded image Or -CON(R10)- Compounds are preferred.

Specific examples of compounds of general formula [I] include:
Examples include the following compounds.

[0058]

[Table 1]

[0059]

[Table 2]

[0060]

[Table 3]

[0061]

[Table 4]

[0062]

[Table 5]

[0063]

[Table 6]

[0064]

[Table 7]

[0065]

[Table 8]

[0066]

[Table 9]

[0067]

[Table 10]

[0068]

[Table 11]

[0069]

[Table 12]

[0070]

[Table 13]

[0071]

[Table 14]

[0072]

[Table 15]

[0073]

[Table 16]

[0074]

[Table 17]

[0075]

[Table 18]

[0076]

[Table 19]

[0077]

[Table 20]

[0078]

[Table 21]

[0079]

[Table 22]

[0080]

[Table 23]

[0081]

[Table 24]

[0082]

[Table 25]

[0083]

[Table 26]

[0084]

[Table 27]

[0085]

[Table 28]

[0086]

[Table 29]

[0087]

[Table 30]

[0088]

[Table 31]

[0089]

[Table 32]

[0090]

[Table 33]

[0091]

[Table 34]

[0092]

[Table 35]

[0093]

[Table 36]

[0094]

[Table 37]

[0095]

[Table 38]

[0096]

[Table 39]

[0097]

[Table 40]

[0098]

[Table 41]

0099

[Table 42]

[0100]

[Table 43]

[0101]

[Table 44]

[0102]

[Table 45]

[0103]

[Table 46]

[0104]

[Table 47]

[0105]

[Table 48] Among the above compounds, preferred compounds are (5), (7), and (9).
, (13), (14), (20), (23), (24)
, (26), (27), (28), (32), (34)
, (44), (45), (54), (63), (79)
, (85), (89), (90), (95), (96)
, (99), (100), (104), (114), (
115), (117), (119), (121), (1
22), (124), (125), (127), (12
8), (130), (132), (134), (136
), (138), (140), (142), (143)
, (144), (149), (152), (153),
(155), (156), (157), (159), (
161), (163), (167), (171), (1
73), (174), (180), (183), (19
2), (201), (205), (208), (214
), (218), (219), (224), (225)
, (227), (228), (229), (233),
(237), (239), (240), (242), (
243), (244), (245), (246), (2
47), (248), (249), (250), (25
1), (252), (253), (254), (255
), (256), (257), (258), (263)
, (265), (267), (271), (273),
(278), (281), (282), (284), (
286), (290), (292), (302), (3
12), (313), (314), (343), (35
3), (354), (357), (372), (373
), (375), (377), (379), (380)
, (382), (383), (385), (386),
(388), (389), (390), (392), (
393), (394), (396), (398), (4
00), (401), (402), (407), (41
0), (411), (413), (415), (417
), (419), (421), (431), (438)
, (441), (442), (443), (450),
(459), (463), (466), (472), (
476), (482), (483), (485), (4
86), (495), (497), (498), (50
0), (501), (502), (503), (504
), (505), (506), (507), (508)
, (509), (510), (511), (512),
(513), (514), (515) and (516)
Among them, (9)(5R,6S)-6-
[(R)-1-hydroxyethyl]-2-[(2S,4
S)-2-(pyrrolidin-2-yl)pyrrolidine-4-
ylthio]-1-carbapen-2-em-3-carboxylic acid, (13)(5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-( pyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (14)(
5R,6S)-6-[(R)-1-hydroxyethyl]
-2-[(2S,4S)-2-(N-methylpyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (23)(5R,6
S)-6-[(R)-1-hydroxyethyl]-2-[
(2S,4S)-2-(piperidin-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3
-carboxylic acid, (26)(5R,6S)-2-[(2S
,4S)-2-(2-azetidinon-4-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbepen-2-em-3-carboxylic acid, (27 )(5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(N-methyl-2-azetidinon-4-yl)pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid, (32)(5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(2- pyrrolidon-3-yl)pyrrolidin-4-ylthio]-1-
Carbapen-2-em-3-carboxylic acid, (34) (5
R,6S)-6-[(R)-1-hydroxyethyl]-
2-[(2S,4S)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2
-M-3-carboxylic acid, (44)(5R,6S)-2
-[(2S,4S)-2-(2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-6-[(
R)-1-hydroxyethyl]-1-carbapen-2-
Em-3-carboxylic acid, (45)(5R,6S)-6-
[(R)-1-hydroxyethyl]-2-[(2S,4
S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (54) (5R,6
S)-2-[(2S,4S)-2-(2-carbamoylpyrrolidin-4-yl)pyrrolidin-4-ylthio]-
6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid, (63)(5R,6S
)-2-[(2S,4S)-2-(N,N-dimethyl-
3-pyrrolidinio)pyrrolidin-4-ylthio]-6-
[(R)-1-hydroxyethyl]-1-carbapene-
2-M-3-carboxylate, (79)(5R,6
S)-2-[(2S,4S)-2-(3-amino-2-
pyrrolidon-4-yl)pyrrolidin-4-ylthio]-
6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid, (89)(5R,6S
)-2-[(2S,4S)-2-(5-oxopiperazin-3-yl)pyrrolidin-4-ylthio]-6-[(
R)-1-hydroxyethyl]-1-carbapen-2-
Em-3-carboxylic acid, (90)(5R,6S)-2-
[(2S,4S)-2-(2-oxopiperazine-5-
yl)pyrrolidin-4-ylthio]-6-[(R)-1
-hydroxyethyl]-1-carbapen-2-em-3
-carboxylic acid, (99)(5R,6S)-2-[(2S
,4S)-2-(2,4-dioxoimidazolidine-5
-yl)pyrrolidin-4-ylthio]-6-[(R)-
1-Hydroxyethyl]-1-carbapen-2-m-
3-carboxylic acid, (100)(5R,6S)-6-[(
R)-1-hydroxyethyl]-2-[(2S,4S)
-2-(3-pyrazolidinon-5-yl)pyrrolidine-
4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (104)(5R,6S)-2-[(2S,4
S)-2-[N-(carbamoylmethyl)pyrrolidine-
3-yl]pyrrolidin-4-ylthio]-6-[(R)
-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid, (134)(1R,5S,6S)-
2-[(2S,4S)-2-(azetidin-3-yl)
pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (136) (1R,5S,6S)
-2-[(2S,4S)-2-(N-formimidoylazetidin-3-yl)pyrrolidin-4-ylthio]-
6-[(R)-1-hydroxyethyl]-1-methyl-
1-carbapen-2-em-3-carboxylic acid, (138
)(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-
(pyrrolidin-2-yl)pyrrolidin-4-ylthio]
-1-carbapen-2-em-3-carboxylic acid, (14
2) (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2
-(pyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (1
43) (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-
2-(N-methylpyrrolidin-3-yl)pyrrolidine-
4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (144)(1R,5S,6S)-2-[(2
S,4S)-2-(N-formimidoylpyrrolidine-
3-yl)pyrrolidin-4-ylthio]-6-[(R)
-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (149) (1R,5
S,6S)-6-[(R)-1-hydroxyethyl]-
1-Methyl-2-[(2S,4S)-2-(piperidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (152) (1R,
5S,6S)-6-[(R)-1-hydroxyethyl]
-1-Methyl-2-[(2S,4S)-2-(piperidin-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (153) (1R
,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(N-methylpiperidin-4-yl)pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid, (1
55) (1R,5S,6S)-2-[(2S,4S)-
2-(2-azetidinon-4-yl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-Methyl-1-carbapen-2-em-3-carboxylic acid, (156)(1R,5S,6S)-6-[(R)-
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-(N-methyl-2-azetidinon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2
-M-3-carboxylic acid, (157)(1R,5S,6
S)-2-[(2S,4S)-2-(2-azetidinon-3-yl)pyrrolidin-4-ylthio]-6-[(R
)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (159) (1R,
5S,6S)-6-[(R)-1-hydroxyethyl]
-1-Methyl-2-[(2S,4S)-2-(2-pyrrolidon-5-yl)pyrrolidin-4-ylthio]-1-
Carbapen-2-em-3-carboxylic acid, (161) (
1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(2
-pyrrolidon-3-yl)pyrrolidin-4-ylthio]
-1-carbapen-2-em-3-carboxylic acid, (16
3) (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2
-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid,
(173)(1R,5S,6S)-2-[(2S,4S
)-2-(2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3 -Carboxylic acid, (174)(1R,5S,6S)-
6-[(R)-1-hydroxyethyl]-1-methyl-
2-[(2S,4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (
183) (1R,5S,6S)-2-[(2S,4S)
-2-(2-carbamoylpyrrolidin-4-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-
3-carboxylic acid, (192)(1R,5S,6S)-2
-[(2S,4S)-2-(N,N-dimethyl-3-pyrrolidinio)pyrrolidin-4-ylthio]-6-[(R
)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate, (208)(
1R,5S,6S)-2-[(2S,4S)-2-(3
-amino-2-pyrrolidon-4-yl)pyrrolidine-4
-ylthio]-6-[(R)-1-hydroxyethyl]
-1-Methyl-1-carbapen-2-em-3-carboxylic acid, (214)(1R,5S,6S)-6-[(R)
-1-hydroxyethyl]-1-methyl-2-[(2S
,4S)-2-(piperazin-2-yl)pyrrolidine-
4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (218)(1R,5S,6S)-2-[(2
S,4S)-2-(5-oxopiperazin-3-yl)
pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (219) (1R,5S,6S)
-2-[(2S,4S)-2-(2-oxopiperazin-5-yl)pyrrolidin-4-ylthio]-6-[(R
)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (224) (1R,
5S,6S)-2-[(2S,4S)-2-(hexahydro-1H-1,4-diazepin-6-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-
Carboxylic acid, (225)(1R,5S,6S)-2-[
(2S,4S)-2-(hexahydro-2-oxo-1
H-1,4-diazepin-6-yl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-Methyl-1-carbapen-2-em-3-carboxylic acid, (228)(1R,5S,6S)-2-[(2S,
4S)-2-(2,4-dioxoimidazolidine-5-
yl)pyrrolidin-4-ylthio]-6-[(R)-1
-hydroxyethyl]-1-methyl-1-carbapene-
2-M-3-carboxylic acid, (229)(1R,5S,
6S)-6-[(R)-1-hydroxyethyl]-1-
Methyl-2-[(2S,4S)-2-(3-pyrazolidinon-5-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (233)(1
R,5S,6S)-2-[(2S,4S)-2-[N-
(carbamoylmethyl)pyrrolidin-3-yl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3
-carboxylic acid, (240)(1R,5S,6S)-6-
[(R)-1-hydroxyethyl]-2-[(2S,4
S)-2-[N-(2-hydroxyethyl)pyrrolidin-3-yl]pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (24
3) (1R,5S,6S)-2-[(2S,4S)-2
-(N,N-dimethyl-4-piperidinio)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate, ( 244) (1R, 5S, 6S)-2
-[(2S,4S)-2-(hexahydroazepine-4
-yl)pyrrolidin-4-ylthio]-6-[(R)-
1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (246) (1R,5S
,6S)-6-[(R)-1-hydroxyethyl]-1
-methyl-2-[(2S,4S)-2-(N-methylhexahydroazepin-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid,
(248)(1R,5S,6S)-2-[(2S,4S
)-2-(N,N-dimethylhexahydro-4-azepinio)pyrrolidin-4-ylthio]-6-[(R)-1
-hydroxyethyl]-1-methyl-1-carbapene-
2-M-3-carboxylate, (250) (1R,
5S,6S)-6-[(R)-1-hydroxyethyl]
-1-Methyl-2-[(2S,4S)-2-(octahydroazocin-5-yl)pyrrolidin-4-ylthio]
-1-carbapen-2-em-3-carboxylic acid, (25
1) (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2
-(octahydroazosin-4-yl)pyrrolidine-4
-ylthio]-1-carbapen-2-em-3-carboxylic acid, (253)(1R,5S,6S)-6-[(R)
-1-hydroxyethyl]-1-methyl-2-[(2S
,4S)-2-(N-methyloctahydroazocine-5
-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (254)(1R,5S
,6S)-6-[(R)-1-hydroxyethyl]-1
-methyl-2-[(2S,4S)-2-(N-methyloctahydroazocin-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid,
(256)(1R,5S,6S)-2-[(2S,4S
)-2-(N,N-dimethyloctahydro-5-azocinio)pyrrolidin-4-ylthio]-6-[(R)-1
-hydroxyethyl]-1-methyl-1-carbapene-
2-M-3-carboxylate, (257) (1R,
5S,6S)-2-[(2S,4S)-2-(N,N-
Dimethyloctahydro-4-azocinio)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate, (271)(5R,6S)-6-[(R
)-1-hydroxyethyl]-2-[(2R,4S)-
2-(pyrrolidin-3-ylmethyl)pyrrolidine-4-
ylthio]-1-carbapen-2-em-3-carboxylic acid, (286)(5R,6S)-2-[(2R,4S)
-2-(2-azetidinon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid,
(290)(5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2R,4S)-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]
-1-carbapen-2-em-3-carboxylic acid, (30
2) (5R,6S)-2-[(2R,4S)-2-(2
,5-dioxopyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid,
(312)(5R,6S)-2-[(2R,4S)-2
-[(2S)-2-carbamoylpyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-
1-Hydroxyethyl]-1-carbapen-2-m-
3-carboxylic acid, (313)(5R,6S)-6-[(
R)-1-hydroxyethyl]-2-[(2R,4S)
-2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (3
14) (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2R,4S)-2-[(2S)-2
-(N,N-dimethylcarbamoyl)pyrrolidine-4-
ylmethyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (357) (5R,
6S)-2-[(2R,4S)-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-carbapen-2-em-3-carboxylic acid, (392
)(1R,5S,6S)-2-[(2R,4S)-2-
(azetidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-
methyl-1-carbapen-2-em-3-carboxylic acid,
(394)(1R,5S,6S)-2-[(2R,4S
)-2-(N-formimidoylazetidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-
1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (400) (1R,5S
,6S)-6-[(R)-1-hydroxyethyl]-1
-Methyl-2-[(2R,4S)-2-(pyrrolidine-
3-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (401)(1
R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R,4S)-2-(N-
Methylpyrrolidin-3-ylmethyl)pyrrolidine-4-
ylthio]-1-carbapen-2-em-3-carboxylic acid, (402)(1R,5S,6S)-2-[(2R,
4S)-2-(N-formimidoylpyrrolidine-3-
ylmethyl)pyrrolidin-4-ylthio]-6-[(R
)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (413) (1R,
5S,6S)-2-[(2R,4S)-2-(2-azetidinon-4-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1 -carbapen-2-em-3-carboxylic acid, (4
15) (1R,5S,6S)-2-[(2R,4S)-
2-(2-azetidinon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (417 )(1R,5S,6S)-6-[(
R)-1-hydroxyethyl]-1-methyl-2-[(
2R,4S)-2-(2-pyrrolidon-5-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2-
Em-3-carboxylic acid, (419) (1R,5S,6S
)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R,4S)-2-(2-pyrrolidone-3
-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (421) (1R
,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R,4S)-2-(2-pyrrolidon-4-ylmethyl)pyrrolidin-4-ylthio]- 1-carbapen-2-em-3-carboxylic acid, (4
31) (1R,5S,6S)-2-[(2R,4S)-
2-(2,5-dioxopyrrolidin-3-ylmethyl)
pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (441) (1R,5S,6S)
-2-[(2R,4S)-2-(2-carbamoylpyrrolidin-4-ylmethyl)pyrrolidin-4-ylthio]
-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (44
2) (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R,4S)-2
-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-
1-carbapen-2-em-3-carboxylic acid, (443
)(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R,4S)-2-
[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (4
50) (1R,5S,6S)-2-[(2R,4S)-
2-(N,N-dimethyl-3-pyrrolidiniomethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate, (466)(1R,5S,6
S)-2-[(2R,4S)-2-(3-amino-2-
pyrrolidon-4-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (
476) (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R,4S)
-2-(3-oxopiperazin-5-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-
3-carboxylic acid, (486)(1R,5S,6S)-2
-[(2R,4S)-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]
-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid and (
498) (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-2-[(2R,4S)-2-[N-
(2-hydroxyethyl)pyrrolidin-3-ylmethyl]pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylic acid, especially (14
2) (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2
-(pyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid and (152)(1R,5S,6S)-6-[(R)-1-
hydroxyethyl]-1-methyl-2-[(2S,4S
)-2-(piperidin-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid is preferred.

Next, the method for producing the compound of the present invention will be explained. general formula

[0107]

embedded image In the formula, R is a hydrogen atom or a methyl group, R13 is a hydrogen atom or a hydroxyl group-protecting group, and R14 is a hydrogen atom or a carboxyl group-protecting group], an inert organic solvent is added to the compound represented by the following formula: By reacting the activating reagent in the presence of a base, the general formula

[0108]

embedded image [wherein R, R13 and R14 have the above meanings,
Y represents a leaving group] [II']
lead to.

Examples of the inert organic solvent used in the above reaction include diethyl ether, tetrahydrofuran,
Mention may be made of dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide, hexamethylphosphoric triamide or mixtures of the abovementioned solvents, especially acetonitrile. , benzene is preferred.

Examples of the base used in the reaction include trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8- Tertiary aliphatic amines such as diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); e.g. pyridine, 4 Aromatic amines such as -dimethylaminopyridine, picoline, lutidine, quinoline, and isoquinoline are mentioned, and N,N-diisopropylethylamine and triethylamine are particularly preferred.

[0111] As the activating reagent used in the reaction, acid anhydrides such as trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-toluenesulfonic anhydride; for example, methanesulfonyl Examples include acid chlorides such as chloride, p-toluenesulfonyl chloride, and diphenylchlorophosphate, with diphenylchlorophosphate being particularly preferred.

The group Y in the general formula [II'] means a leaving group, such as trifluoroacetoxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p
Examples include -toluenesulfonyloxy group, diphenoxyphosphoryloxy group, and diphenoxyphosphoryloxy group is particularly preferred.

In the reaction, 1 to 3 mol, preferably 1 to 1.5 mol of the base and 1 to 1.2 mol of the activating reagent are used per 1 mol of the compound of general formula [II].

[0114] The reaction is carried out at -40 to 50°C, preferably -20°C.
It is carried out at a temperature range of ~20°C, and is generally completed quantitatively in 0.5 to 3 hours.

After completion of the reaction, the reaction derivative [II'] of the general formula [II] is quantitatively obtained by treatment according to a conventional method.

Reactive derivative [II'] and general formula

011
7]

[In the formula, R15 is a hydrogen atom or a protecting group for an imino group, R
20 and R30 are the same or different and are a hydrogen atom, a lower alkyl group, an optionally protected hydroxy lower alkyl group, a formimidoyl group or an acetimidoyl group, -COOR40, -CON(R50)R60,
-N(R50)R60, -CH2COOR40, -CH
2N(R50)R60 or -CH2CON(R50)
R60 (here, R40 is a hydrogen atom, a lower alkyl group or a carboxyl group protecting group, R50 and R6
0 are the same or different, hydrogen atom, lower alkyl group,
Protecting groups for amino or imino groups or the lower alkyl groups bond with each other to form, together with adjacent nitrogen atoms, a heterocyclic group selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidyl groups)
, B is =NR70,

[0118]

[Chemical 45] -CON(R70)-, -CON(R70)CO-,-
CON(R70)CON(R80)-,-N(R70)
CO(CH2)sN(R80)-,-N(R70)CO
(CH2) sCON (R80) -, -CON (R70)
N(R80)-or-N(R70)(CH2)sN(
R80) - {Here, R70 and R80 are the same or different and are a hydrogen atom, a lower alkyl group, an optionally protected hydroxy lower alkyl group, a formimidoyl group or an acetimidoyl group, a protecting group for an imino group , -COOR40, -CON(R50)R60, -N
(R50)R60, -CH2COOR40, -CH2N
(R50)R60 or -CH2CON(R50)R6
0 (here, R40, R50 and R60 have the above meanings), s represents an integer from 1 to 3}, p
is an integer from 0 to 3, and q and r are the same or different integers from 0 to 5 (except when q and r are both 0, and the sum of q and r is 6 or less)]. The reaction with the compound represented is carried out using an inert organic solvent and a base as described above, and the general formula

[0119]

embedded image [wherein R, R13, R14, R15, R20, R30
, B, p, q and r have the above meanings].

The reaction is carried out using 1 to 2 mol, preferably 1 to 1.5 mol, of base per 1 mol of reactive derivative [II'].
1 to 1.2 mol of the compound of general formula [III] is used,
It is carried out at a temperature range of -40 to 50°C, preferably -20 to 20°C, and is usually completed in 0.5 to 3 hours.

The compound of general formula [IV] can also be produced in one step from the compound of general formula [II]. That is, the compound of general formula [IV] is produced by reacting the compound of general formula [III] in the same reaction system without isolating the reactive derivative [II'] derived from the compound of general formula [II]. It can be manufactured efficiently. When carried out in one step, 2 to 4 mol, preferably 2.5 to 3.5 mol of the base is used per 1 mol of the compound of general formula [II].

After the reaction is completed, usual treatment is carried out to obtain the general formula [
A crude product of the compound represented by IV] can be obtained and subjected to a deprotection reaction without purification, but the crude product cannot be purified by crystallization or column chromatography using silica gel or the like. preferable.

From the compound of the general formula [IV] thus obtained, if necessary, by carrying out a reaction for removing the protective groups of the hydroxyl group, imino group and carboxyl group in an appropriate combination, the compound of the general formula [I] Compounds of can be produced.

[0124] Removal of the protecting group varies depending on the type, but
This is carried out according to customary methods, for example by solvolysis, chemical reduction or hydrogenation.

In the general formula [IV], the protecting group for the hydroxyl group and/or amino group or imino group is, for example, an aralkyloxycarbonyl group such as benzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group, and the protecting group for the carboxyl group is The protecting group is, for example, a benzyl group,
When it is an aralkyl group such as p-nitrobenzyl group or benzhydryl group, platinum catalyst such as platinum oxide, platinum wire, platinum black; for example, palladium black, palladium oxide,
The protecting group can be removed by catalytic hydrogenation using a palladium catalyst such as palladium-carbon, palladium hydroxide-carbon, etc.

Examples of the solvent used in the catalytic hydrogenation reaction include methanol, ethanol, tetrahydrofuran, dioxane, acetic acid, etc., or a mixed solvent of these organic solvents with water or a buffer such as a phosphate.

The reaction was carried out under a hydrogen gas flow of 1 to 4 atm.
It is completed in 0.5 to 4 hours at a temperature range of ~50°C.

In the general formula [IV], when the protecting group for the hydroxyl group and/or amino group or imino group is, for example, an allyloxycarbonyl group, and the protecting group for the carboxyl group is, for example, an allyl group, allyl The protecting group can be removed by reaction with an organic soluble palladium complex catalyst in an inert organic solvent containing a group scavenger [W. The method of McCombie et al.
The Journal of Organic Chemistry (J.Org.Chem.), Volume 47, 587-5
90 (1982) and F. Guib▲e
▼) etc. method, same literature, vol. 52, 4984-499
3 (1987)].

Examples of the solvent used in the reaction include water, acetone, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, methylene chloride,
Examples include chloroform and a mixed solvent thereof.

Suitable palladium compound complexes used in this reaction include, for example, palladium-carbon, palladium hydroxide-carbon, palladium(II) chloride, palladium(II) acetate, and tetrakis(triphenylphosphine).
Palladium(0), Tetrakis(triphenoxyphosphine)palladium(0), Tetrakis(triethoxyphosphine)palladium(0), Bis[ethylenebis(diphenylphosphine)]palladium(0), Tetrakis[tri(2-furyl)phosphine ] Palladium (0),
Bis(triphenylphosphine)palladium(II)
Examples include chloride, bis(triphenylphosphine)palladium(II) acetate, and the like.

Examples of allyl group scavengers include dimedone, formic acid, acetic acid, ammonium formate, sodium formate,
Examples include sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, pyrrolidine, piperidine, and tributyltin hydride.

The reaction is carried out using 0.01 to 0.5 mol of catalyst and 1 to 6 mol of nucleophile per 1 mol of the compound of general formula [IV], preferably at a temperature of -10 to 50°C. is 0~
It is carried out at a temperature range of 30°C and is usually completed in 0.5 to 3 hours.

In addition, in the general formula [IV], when the protecting group for the hydroxyl group and/or amino group or imino group is an o-nitrobenzyloxycarbonyl group, and the protecting group for the carboxyl group is an o-nitrobenzyl group, teeth,
Protecting groups can be removed by photoreaction [method of Amit et al., The Journal of Organic Chemistry (J. Org. Chem.
), Vol. 39, 192-196 (1974)].

After the protective group removal reaction is completed, the compound of general formula [I] is removed by a conventional treatment method, for example, by column chromatography using silica gel or adsorption resin, or by freeze-drying or crystallization. The compound can be isolated.

The protecting group for the carboxyl group at position 3 of the compound of general formula [IV] is, for example, a lower alkanoyloxyalkyl group such as an acetoxymethyl group or a pivaloyloxymethyl group; for example, a methoxymethyl group, an indanyl group, In the case of phthalidyl groups, such esters are physiologically hydrolyzed in vivo, and therefore can be directly administered to humans or animals without removing the protective group.

The compound of general formula [I] can be converted into a pharmaceutically acceptable salt or ester by a conventional method.

[0137] The starting material represented by the general formula [II], for example, when R1 is a hydrogen atom, is
mann) et al. [Journal of the American Chemical Society (J.Am.Chem.
．． Soc. ), Vol. 102, pp. 6161-6163 (1
981)]; When R1 is a methyl group, C(
Shih et al.'s method [Heterocycles
21, pp. 29-40 (1984)] or a method analogous thereto.

The starting material represented by the general formula [III] is
It can be synthesized by the following method.

After activating the hydroxyl group of Compound 1 by a conventional method, acetylthio derivative 3 is obtained by reacting with a thioacetate such as potassium thioacetate, and then acetylthio derivative 3 is obtained by alkaline hydrolysis or acid hydrolysis. thiol derivatives can be obtained.

[0140]

[Formula, R16 is a hydrogen atom or a hydroxyl group protecting group, X is a chlorine atom, bromine atom, iodine atom, trifluoroacetoxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyl a leaving group selected from the group consisting of oxy groups, Ac represents an acetyl group, R15, R20, R30, B, p, q and r have the above-mentioned meanings] A group of compounds having the structural formula of Compound 1 are: Each can be manufactured according to the manufacturing method shown in the reference example.

The compounds of the present invention exhibit strong antibacterial activity against various Gram-positive and Gram-negative bacteria.

In order to specifically demonstrate the usefulness of the compounds of the present invention, in vitro antibacterial activity against bacteria was measured by the agar plate dilution method described below [Japanese Society of Chemotherapy Standard Method: Chemotherapy, Vol. 29 ,7
6-79 (1981)]. Mueller Hinton Bros.
Mueller Hinton agar (MH agar) was inoculated with one loopful of each test strain (inoculum amount: 106 CFU/ml) that had been cultured overnight in MH agar. This medium contains antibacterial agents at various concentrations, and after culturing at 37°C for 16 hours, the minimum inhibitory concentration (MIC: μg/ml)
was measured. The results are shown in Table 1.

[0143]

[Table 49] In addition, the antibacterial activity of the compounds of the present invention exemplified in Examples as representative examples of the compounds of the present invention was determined using the Bauer method.
[The American Journal of Clinical Pathology (Amer. J. Cl.
in. Pathol. ), Volume 45, Page 493 (1
The measurement was carried out by the disk diffusion test according to [1996]. Thienamycin or imipenem were used as internal standards.

The MIC of a test compound is determined from the diameter of the inhibition circle produced by the disk containing the test compound, as determined by Humphrey and Light.
[The Journal of General Microbiology (J
．． Gen. Microbiol. ), Volume 7,
129 (1952)]. The geometric mean of MIC was determined for each bacterial species and the activity ratio with thienamycin was calculated.

[0145] Antibacterial efficacy is thienamycin (=1.0)
The higher the number, the stronger the activity.

DHP-I sensitivity was determined by Krop (Krop).
p) and other methods [Antimicrobial agents and chemotherapy (Antimicrob.Ag.
entsChemother. ), Volume 22, 62-7
(1982)], and imipenem (=
1.0), and the smaller the number, the higher the stability.

The antibacterial activity and DHP-I susceptibility of the compounds of the present invention were evaluated using imipenem as a comparative compound.
m) and meropenem. The results are shown in Table 2.

[0148]

Table 50 The compounds of the present invention have excellent antibacterial activity against various Gram-positive and Gram-negative bacteria, and are useful for the treatment and prevention of human bacterial infections caused by these pathogenic bacteria. It is a compound useful as an antibacterial agent. Typical pathogens susceptible to the antibacterial agent of the present invention include, for example, the genus Staphylococcus, the genus Enterococcus, the genus Escherichia, the genus Enterobacter, and the genus Klebsiella.
ebsiella) genus, Serratia
Examples include bacterial species such as the genus Proteus, the genus Pseudomonas, and in particular Staphylococcus aureus resistant to methicillin.
t Staphylococcus aureus
) and thienamycin resistant Pseudomonas aeruginosa
nt Pseudomonas aerugino
It showed excellent antibacterial activity against sa).

The compounds of the present invention are extremely stable against DHP-I, and have excellent physicochemical stability and solubility in water, although this varies depending on each compound.

The compounds of this invention can be mixed with solid or liquid excipient carriers well known in the art and used in the form of pharmaceutical preparations suitable for parenteral, oral or external administration. The main ones are parenteral (intravenous or intramuscular) administration, either locally or by injection. Examples of pharmaceutical preparations include liquid preparations such as injections, syrups, and emulsions; solid preparations such as tablets, capsules, and granules; and external preparations such as ointments and suppositories. These preparations may contain commonly used additives such as bases, auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants, etc., as required.

Examples of additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.

[0152] The dosage varies depending on the patient's symptoms, body weight, age, sex, dosage form, number of administrations, etc., but the preferred daily dosage for adults is usually about 5 to 50 mg/k of the active ingredient.
g, the preferred daily dose for children is about 5-25 mg/k
It is preferably administered once or in divided doses per day.

[0153] The compound of the present invention may optionally contain cilastatin [(Z)-7-(L-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid. D such as sodium]
HP-I inhibitors [JP-A-56-81518, European Patent Application No. 28,778, Journal of Medicinal Chemistry (J. Med. Chem.
), Vol. 30, p. 1074 (1987)].

[0154]

[Examples] The present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited by these in any way.

[0155] The thin layer chromatographs of Examples and Reference Examples used Silicagel 60F24 as a plate.
5 (Merck) using a UV detector as the detection method. WakogelTM is a silica gel for columns.
C-300 (Wako Pure Chemical Industries, Ltd.) and LC-SORBTM SP-B-ODS (
Chemco) or YMC・GELTM ODS-
AQ 120-S50 (Yamamura Chemical Research Institute) was used. JASCO 80 is a high-performance liquid chromatograph.
0 series (JASCO) was used. NMR spectra are determined by using tetramethylsilane (TMS) as an internal standard when measuring with deuterated dimethyl sulfoxide or deuterated chloroform solution, and with 2,2-dimethyl-2- as an internal standard when measuring with deuterated water solution. Silapentane-5-
Using sulfonate (DSS), XL-200 (200
It was measured using a MHz (Varian) type spectrometer, and all δ values were expressed in ppm.

[0156] The meanings of the abbreviations in NMR measurement are shown below. s: Singlet d: Doublet t: Triplet q: Quartet ABq: AB type quartet dd: Double doublet m: Multiplet br: Broad J: Coupling constant Hz: Hertz DMSO-d6: Heavy dimethyl sulfoxide CDCl3:
Deuterated chloroform CD3OD: heavy methanol D2O: heavy water The meanings of the abbreviations in the reaction formula are shown below. Ac: Acetyl group All: Allyl group Alloc: Allyloxycarbonyl group Boc: ter
t-Butoxycarbonyl group Bzl: benzyl group Et: ethyl group Me: methyl group Ms: methanesulfonyl group PNB: p-nitrobenzyl group PNZ: p-nitrobenzyloxycarbonyl group TBD
MS: tert-butyldimethylsilyl group THP: Tetrahydropyranyl group Tr: Trityl group Ts: p-toluenesulfonyl group Example 1 Sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2- [(2S,4S)-2-(2-
pyrrolidon-4-yl)pyrrolidin-4-ylthio]-
1-Carbapen-2-M-3-carboxylate 1)

[0157]

[Chemical Formula 48] p-Nitrobenzyl (5R,
6S)-2-diphenoxyphosphoryloxy-6-[(
R)-1-hydroxyethyl]-1-carbapen-2-
Em-3-carboxylate (300mg, 0.55m
mol) in acetonitrile solution (15 ml) (2S,
4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)
Pyrrolidine [205mg, 0.56mmol, Reference Example 1
-9) compound] in acetonitrile (6 ml), and then N,N-diisopropylethylamine (0.10 ml).
1, 0.57 mmol) was added dropwise. After stirring at 0° C. for 7 hours, ethyl acetate (70 ml) was added to the reaction solution, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM C-30
0, ethyl acetate) and p-nitrobenzyl (5
R,6S)-6-[(R)-1-hydroxyethyl]-
2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (313 mg, yield: 86.2
%) was obtained.

IR(KBr)cm-1:1780,17
00,1520,1350 NMR (CDCl3) δ: 1.37 (3H, d, J=6
Hz), 5.24 (3H, m), 5.52 (1H, d,
J = 14Hz), 7.33 (2H, d, J = 9Hz),
7.46 (2H, d, J = 9Hz), 8.24 (2H,
d, J=9Hz), 8.26 (2H, d, J=9Hz)
2)

[0159]

embedded image The compound obtained in the above reaction (300 mg, 0.45 mm
ol) of tetrahydrofuran (10 ml) and 0.1
M 10% palladium-carbon catalyst [150 mg, 0.1 M in a hydrogen stream in advance was added to a mixture of sodium 3-morpholinopropanesulfonate buffer (10 ml).
Activated by stirring for 1 hour with sodium 3-morpholinopropanesulfonate buffer] was added and the mixture was stirred at room temperature for 2 hours under a stream of hydrogen. The catalyst was filtered off from the reaction mixture, the filtrate was washed with ethyl acetate (20 ml), and the insoluble matter in the aqueous layer was filtered off. The obtained filtrate was concentrated to about 15 ml. The residue was subjected to reverse phase column chromatography (LC-
SORBTM SP-B-ODS, 10% methanol aqueous solution), and the target fraction was concentrated and lyophilized to obtain the title compound (70 mg, yield: 38.4%).

IR(KBr)cm-1:1760,16
80,1590,1390 NMR (D2O) δ: 1.26 (3H, d, J = 7Hz
), 1.54 (1H, m), 2.28 (1H, m), 3
．． 86 (1H, m), 4.21 (2H, m) HPLC; Column: YMCTM-Pack ODS-AQ, 5μ
, 4.6φ x 150mm, mobile phase: 0.01M phosphate buffer (pH 6.5)-methanol (80:20),
Flow rate: 1.0ml/min, temperature: 40°C, detection: 29
0 nm, retention time: 2.23 min Example 2 Sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2R,4S)-2-(2-
pyrrolidon-4-yl)pyrrolidin-4-ylthio]-
1-Carbapen-2-M-3-carboxylate 1)

[0161]

embedded image p-Nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (300 mg, 0 .55 mmol) and (2R
,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine (200 mg, 0.55 mmol, compound of Reference Example 2) A reaction similar to 1-1) was carried out to produce p-nitrobenzyl (5R,6S)-6-[
(R)-1-hydroxyethyl]-2-[(2R,4S
)-N-(p-nitrobenzyloxycarbonyl)-2
-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (127 mg, yield: 35%) was obtained.

IR(KBr)cm-1:1790,17
10,1520,1350 NMR (CDCl3) δ: 1.36 (3H, d, J=6
Hz), 5.25 (3H, m), 5.52 (1H, d,
J = 14Hz), 7.54 (2H, d, J = 9Hz),
7.66 (2H, d, J = 9Hz), 8.23 (2H,
d, J=9Hz), 8.26 (2H, d, J=9Hz)
2)

[0163]

embedded image The compound obtained in the above reaction (127 mg, 0.19 mm
ol) of tetrahydrofuran (10 ml) and 0.1
A 10% palladium-carbon catalyst (60 mg) was added to a mixture of M 3-morpholinopropanesulfonate sodium buffer (10 ml), and the mixture was stirred at room temperature for 1.5 hours in a hydrogen stream of 2.9 atm. The catalyst was filtered off from the reaction mixture, the filtrate was washed with ethyl acetate (20 ml),
Insoluble matter in the aqueous layer was filtered off. The obtained filtrate was subjected to reverse phase column chromatography (LC-SORBTM SP-B-
The title compound (5.5 mg, yield:
7.1%).

IR(KBr)cm-1:1780,16
00,1270 NMR (D2O) δ: 1.28 (3H, d, J = 8Hz
), 2.54 (3H, m) HPLC (conditions are the same as Example 1) Retention time: 5.54 min Example 3 Sodium (1R,5S,6S)-6-[(R)-
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate 1)

[0165]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (230mg, 0.41mm
ol) and (2S,4S)-4-mercapto-N-(
p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine [140 mg, 0.3
8 mmol, the compound of Reference Example 1-9)], the same reaction as in Example 1-1) was carried out, and p-nitrobenzyl
(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-
(p-nitrobenzyloxycarbonyl)-2-(2-
pyrrolidon-4-yl)pyrrolidin-4-ylthio]-
1-carbapen-2-em-3-carboxylate (2
23 mg, yield: 80.6%) was obtained.

IR(KBr)cm-1:1770,17
00,1520,1340 NMR (CDCl3) δ: 1.28 (3H, d, J=8
Hz), 1.33 (3H, d, J=7Hz), 5.24
(2H, m), 5.31 and 5.52 (2H, ABq
, J=14Hz), 7.53 (2H, d, J=8Hz)
, 7.66 (2H, d, J = 8Hz), 8.20 (2H
, d, J=8Hz), 8.22(2H, d, J=8Hz
) 2)

[0167]

embedded image The compound obtained in the above reaction (223 mg, 0.33 mm
A reaction similar to Example 1-2) was carried out using
The title compound (73 mg, yield: 53.2%, diastereomers A and B 44:56) was obtained.

IR(KBr)cm-1:1760,16
80,1590,1390 NMR (D2O) δ: 1.23 (3H, d, J = 8Hz
), 1.30 (3H, d, J = 7Hz), 1.77 (1
H, m), 2.27-2.42 (1H, m), 4.06
(1H, m), 4.26 (2H, m) HPLC; Column: INERTSILTM ODS-2, 5μ,
4.6φ×250mm, mobile phase: 0.01M phosphate buffer (pH 7.0)-methanol (90:10), flow rate: 1.0ml/min, temperature: 40°C, detection: 254
nm, retention time: 13.2 min, 14.6 min (4
4:56) Example 4 Sodium (1R,5S,6S)-6-[(R)-
1-hydroxyethyl]-1-methyl-2-[(2R,
4S)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate 1)

[0169]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (230mg, 0.41mm
ol) and (2R,4S)-4-mercapto-N-(
p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine [140 mg, 0.3
8 mmol, the compound of Reference Example 2], Example 1-
A reaction similar to 1) was carried out to produce p-nitrobenzyl (1
R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R,4S)-N-(p-
Nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (174m
g, yield: 62.9%).

IR(KBr)cm-1:1780,17
00,1520,1340 NMR (CDCl3) δ: 1.27 (3H, d, J=8
Hz), 1.36 (3H, d, J=6Hz), 5.25
(3H, m), 5.53 (1H, d, J=14Hz),
7.54 (2H, d, J=9Hz), 7.67 (2H,
d, J=9Hz), 8.24 (2H, d, J=9Hz)
, 8.26 (2H, d, J = 9Hz) 2)

[0171]

embedded image The compound obtained in the above reaction (174 mg, 0.26 mm
A reaction similar to Example 1-2) was carried out using
The title compound (22 mg, yield: 20.6%) was obtained.

IR(KBr)cm-1:1780,16
00,1380,1300 NMR (D2O) δ: 1.24 (3H, d, J = 8Hz
), 1.31 (3H, d, J=7Hz), 1.98~2
．． 98 (3H, m), 3.44 (3H, m), 3.74
(3H, m) HPLC (conditions are the same as Example 1) Retention time: 7.46 min Example 5 Sodium (1R,5S,6S)-2-[(2S,
4S)-2-azetidinon-4-yl)pyrrolidine-4
-ylthio)-6-[(R)-1-hydroxyethyl]
-1-Methyl-1-carbapen-2-em-3-carboxylate diastereomer B 1)

[0173]

embedded image p-nitrobenzyl (1R
,5S,6S)-2-diphenoxyphosphoryloxy-
6-[(R)-1-hydroxyethyl]-1-methyl-
1-carbapen-2-em-3-carboxylate (1
(2S,4S)-2-(2-azetidinon-4-yl)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer was added to an acetonitrile solution (5 ml) of 10 mg, 0.195 mmol). An acetonitrile solution (5 ml) of B (67 mg, 0.191 mmol, compound of Reference Example 3) was added, and then N,N-diisopropylamine (34 μl, 0.21 mmol) was added.
mol) was added dropwise. After stirring overnight at 4°C, ethyl acetate (50 ml) was added to the reaction solution, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM C-3
p-nitrobenzyl (1R,5S,6S)-2-[(2S
,4S)-2-(2-azetidinon-4-yl)-N-
(p-nitrobenzyloxycarbonyl)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer B (88.5 mg,
Yield: 68.2%) was obtained.

IR(KBr)cm-1:1760,17
00,1520,1340 NMR (CDCl3) δ: 1.28 (3H, d, J=7
Hz), 1.35 (3H, d, J=6Hz), 1.67
(1H, m), 2.50-2.74 (3H, m), 3.
08 (1H, dd, J=15,5Hz), 3.24~3
．． 45 (3H, m), 3.70 (2H, m), 3.96
~4.33 (4H, m), 5.23 (3H, m), 5.
52 (1H, d, J = 13Hz), 7.52 (2H, d
, J=8Hz), 7.65 (2H, d, J=8Hz),
8.22 (2H, d, J = 8Hz), 8.24 (2H,
d, J=8Hz) 2)

[0175]

embedded image The compound obtained in the above reaction (88 mg, 0.13 mmo
The same reaction as in Example 1-2) was carried out using 1) to obtain the title compound (18 mg, yield: 33.7%).

IR(KBr)cm-1:1750,15
90,1390 NMR (D2O) δ: 1.26 (3H, d, J = 7Hz
), 1.31 (3H, d, J = 6Hz), 1.65 (1
H, m), 2.69 (1H, dd, J=16,8Hz)
, 2.73 (1H, br d, J=16Hz), 3.
20-3.53 (4H, m), 3.61 (1H, dd,
J=12,6Hz), 3.75(1H,q,J=8Hz
), 3.85-4.40 (4H, m) HPLC (conditions are the same as Example 1) Retention time: 3.8 min Example 6 Sodium (1R,5S,6S)-2-[(2S,
4S)-2-(2-azetidinon-4-yl)pyrrolidin-4-ylthio)-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-
Carboxylate diastereomer A 1)

[0177]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (153mg, 0.27mm
ol) and (2S,4S)-2-(2-azetidinon-4-yl)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (90 mg, 0.26 mmol, Reference Example 4 The same reaction as in Example 1-1) was carried out using the compound p-
Nitrobenzyl (1R,5S,6S)-2-[(2
S,4S)-2-(2-azetidinon-4-yl)-N
-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer A ( 128mg,
Yield: 70.9%) was obtained.

IR(KBr)cm-1:1760,17
00,1520,1340 NMR (CDCl3) δ: 1.28 (3H, d, J=7
Hz), 1.34 (3H, d, J=6Hz), 1.91
(2H, m), 2.44-3.10 (3H, m), 3.
17-3.46 (2H, m), 3.66 (1H, m),
4.00-4.36 (5H, m), 5.24 (3H, m
), 5.50 (1H, d, J = 14Hz), 7.52 (
2H, d, J = 8 Hz), 7.65 (2H, d, J = 8
Hz), 8.21 (2H, d, J=8Hz), 8.23
(2H, d, J=8Hz) 2)

[0179]

embedded image The compound obtained in the above reaction (128 mg, 0.19 mm
A reaction similar to Example 1-2) was carried out using
The title compound (28.5 mg, yield: 36.7%) was obtained.

IR(KBr)cm-1:1750,15
90,1390 NMR (D2O) δ: 1.25 (3H, d, J = 7Hz
), 1.32 (3H, d, J = 6Hz), 1.83 (1
H, m), 2.75 (1H, dd, J=15,8Hz)
, 2.88 (1H, dd, J=15, 2Hz), 3.1
8-3.55 (4H, m), 3.68 (1H, dd, J
= 12,6Hz), 3.86-4.40 (5H, m) HPLC (conditions are the same as Example 1) Retention time: 3.46min Example 7 (5R,6S)-6-[(R)- 1-hydroxyethyl]-2-[(2R,4S)-2-(2-pyrrolidone-3
-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid 1)

[0181]

embedded image Allyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1
-carbapen-2-m-3-carboxylate (36
9mg, 0.76mmol) and (2R,4S)-N
-allyloxycarbonyl-4-mercapto-2-(2
-pyrrolidon-3-ylmethyl)pyrrolidine (216m
g, 0.76 mmol) of acetonitrile (5.6 ml
) N,N-diisopropylethylamine (0.13 ml, 0.76 mmol) was added dropwise to the solution under ice cooling. The reaction mixture solution was stirred at the same temperature for 1 hour, and further stirred at 5°C for 16 hours. Ethyl acetate (60 ml) was added to the reaction solution, and the mixed solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel flash column chromatography [WakogelTM C-300, 40ml
, acetone-ethyl acetate (2:3)] and concentrate the fraction containing the target product to obtain a foamy allyl.
(5R,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1
-hydroxyethyl]-1-carbapen-2-em-3
-carboxylate (303 mg, yield: 76.7%)
I got it.

NMR (CDCl3) δ: 1.35 (3H
, d, J=6Hz), 1.7-2.2 (4H, m), 2
．． 34 (2H, m), 2.61 (1H, m), 3.1~
3.4 (6H, m), 3.55 (1H, m), 4.0~
4.3 (4H, m), 4.6-4.9 (4H, m), 5
．． 2-5.5 (4H, m), 5.78 (1H, brs)
,6.0(2H,m) 2)

[0183]

embedded image Compound obtained in the above reaction (300 mg, 0.58 mm
ol) in methylene chloride (6 ml) and water (52 μl).
was added and the mixture was degassed. Add bis(triphenylphosphine)palladium(II) to this mixed solution under ice cooling.
Chloride (8 mg, 0.011 mmol) and tributyltin hydride (0.466 ml, 1.73 mmol)
was added, and the mixed solution was heated at the same temperature for 5 minutes, and then at room temperature for 3 minutes.
Stirred for 0 minutes. After adding 40 ml of water to the reaction solution and washing the aqueous layer with chloroform (20 ml, twice), under reduced pressure,
The remaining organic solvent was removed. Activated charcoal (50 mg) was added and the mixture was stirred for 30 minutes and filtered. 7 of the filtrate
Concentrate to 00 mg and add ethanol (1.4 ml) at room temperature.
was added, and the mixed solution was allowed to stand at the same temperature for 30 minutes, producing a precipitate. This suspension was mixed with ethanol (1.4
ml) was added dropwise over 1 hour, and the suspension was stirred at room temperature for 30 minutes and then at 5°C for 16 hours. Collect the precipitate by filtration and add water.
Washed sequentially with ethanol (1:4) mixture (1.3 ml, twice) and acetone (2 ml), dried under reduced pressure for 2 hours,
The title compound (159 mg, yield: 69.6%) was obtained.

IR(KBr)cm-1:1740,16
90,1600,1380 NMR (D2O) δ: 1.26 (3H, d, J = 8Hz
), 1.7-2.0 (3H, m), 1.18 (1H, m
), 1.38 (1H, m), 2.6-2.8 (2H, m
), 3.2 (2H, d, J=9Hz), 3.3-3.4
(4H, m), 3.7-3.9 (2H, m), 4.0 (
1H,m), 4.1-4.3(2H,m) Example 8 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R ,4S)-2-(
2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid 1)

[0185]

embedded image Allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate ( 759 mg, 1.52 mmol) and (2R,4S)-N-allyloxycarbonyl-4-mercapto-2-(2-pyrrolidon-3-ylmethyl)pyrrolidine (432 mg, 1.52 mmol) in acetonitrile (11 ml), N,N-diisopropylethylamine (0.26 ml, 1.52 mmo
l) was added dropwise. The reaction mixture solution was stirred at the same temperature for 3 hours and further at 5°C for 16 hours. Add ethyl acetate (60m
1) was added thereto, and the mixed solution was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel flash column chromatography [WakogelTM C-30
0.40 ml, acetone-ethyl acetate (2:3)], and the fraction containing the target product was concentrated to obtain a foamy allyl (1R,5S,6S)-2-[(2R,
4S)-N-allyloxycarbonyl-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]
-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (
420 mg, yield: 51.8%) was obtained.

NMR (CDCl3) δ: 1.26 (3H
, d, J=8Hz), 1.35(3H, d, J=6Hz
), 1.7 (1H, m), 1.9-2.4 (5H, m)
, 2.60 (1H, m), 3.2-3.4 (5H, m)
, 3.58 (1H, m), 3.9-4.3 (4H, m)
, 4.5-4.9 (4H, m), 5.2-5.5 (4H
, m), 5.8-6.1 (3H, m)2)

[0187]

embedded image Compound obtained in the above reaction (420 mg, 0.79 mm
ol) in methylene chloride (8.4 ml) was added water (71μ
1) was added and the solution was degassed. Add bis(triphenylphosphine)palladium(II) to this mixed solution under ice cooling.
) chloride (11 mg, 0.016 mmol) and tributyltin hydride (0.635 ml, 2.36 mmol)
1) was added, and the mixed solution was stirred at the same temperature for 3 minutes and then at room temperature for 30 minutes. Add water (40ml) to the reaction solution,
After washing the aqueous layer with chloroform (20 ml, twice),
The remaining organic solvent was removed under reduced pressure. Activated carbon (50m
g) was added and the mixture was stirred for 30 minutes and filtered. The filtrate was concentrated to 500 mg and added with ethanol (1 m
1) was added, and the mixed solution was allowed to stand at the same temperature for 1 hour, resulting in precipitation. This suspension was added with ethanol (3.
5 ml) was added dropwise over 1 hour, and this suspension was stirred at room temperature for 3 ml.
The mixture was further stirred at 5° C. for 16 hours. The precipitate was collected by filtration, washed successively with a water-ethanol (1:9) mixture (1 ml, 3 times) and acetone (3 ml), and dried under reduced pressure for 2 hours to give the title compound (232 mg, yield: 72. 0%) was obtained.

IR(KBr)cm-1:1760,17
00,1640,1590,1390 NMR (D2O) δ: 1.21 (3H, d, J = 8Hz
), 1.28 (3H, d, J=6Hz), 1.7-2.
0 (3H, m), 2.20 (1H, m), 2.40 (1
H, m), 2.6-2.9 (2H, m), 3.3-3.
5 (5H, m), 3.70 (1H, m), 3.86 (1
H, m), 4.0 (1H, m), 4.24 (2H, m) Example 9 (1R,5S,6S)-2-[(2R,4S)-2-(
2-azetidinone-3-ylmethyl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-Methyl-1-carbapen-2-em-3-carboxylic acid 1)

[0189]

embedded image Allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate ( 331mg, 0.66mmol), (2
R,4S)-N-allyloxycarbonyl-2-(2-
azetidinon-3-ylmethyl)-4-mercaptopyrrolidine (180 mg, 0.66 mmol) and N,N
-diisopropylethylamine (0.12 ml, 0.6
The same reaction as in Example 8-1) was carried out using 6 mmol) of foam-like allyl (1R,5S,6S)-2.
-[(2R,4S)-N-allyloxycarbonyl-2
-(2-azetidinone-3-ylmethyl)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (125 mg, yield: 36.3%) was obtained.

NMR (CDCl3) δ: 1.29 (3H
, d, J=7Hz), 1.36(3H, d, J=6Hz
), 1.8 (1H, m), 2.0 (1H, m), 2.6
5 (2H, m), 3.1 (1H, m), 3.3 (3H,
m), 3.48 (1H, t, J = 6Hz), 3.6 (1
H, m), 4.0 (2H, m), 4.25 (2H, m)
, 4.62 (2H, br d, J=6Hz), 4.8
(2H, m), 5.2-5.5 (4H, m), 5.66
(1H, br s), 5.98 (2H, m)2)

[0191]

embedded image The compound obtained in the above reaction (125 mg, 0.24 mm
ol), bis(triphenylphosphine)palladium (
II) Chloride (3.4 mg, 0.0048 mmol)
, tributyltin hydride (0.194ml, 0.722
Example 8-2 using mmol) and water (22 μl)
), and the resulting aqueous layer was subjected to reverse phase column chromatography [YMC/GELT
MODS-AQ 120-S50, 50 ml, methanol-water (15:85)], and the fraction containing the target compound was concentrated and lyophilized to obtain the title compound (20 mg, yield: 21.0%). Obtained.

IR(KBr)cm-1:1740,16
00,1390 NMR (D2O) δ: 1.18 (3H, d, J = 7Hz
), 1.26 (3H, d, J = 6Hz), 1.3 (1H
, m), 2.2 (3H, m), 2.7 (1H, m), 3
．． 1-3.7 (7H, m), 3.92 (1H, m), 4
．． 1 to 4.3 (2H, m) Example 10 Potassium (1R,5S,6S)-6-[(R)-1
-hydroxyethyl]-1-methyl-2-[(2S,4
S)-2-(2-pyrrolidon-4-yl)pyrrolidine-
4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomers A and B

019
3]

embedded image The compound of Example 3 (100 mg) was added to Waters (Wat
ers) 600E [Column: YMCTM-Pack
SH-365-5 S-5 120A ODS,
Elution: 0.01M potassium phosphate buffer (pH 7.
0)-methanol 85:15, flow rate: 14ml/min
, detection: 290 nm, temperature: 26° C.], and fractions of diastereomer A (retention time: 25.5 min) and diastereomer B (retention time: 30.2 min) were separated, respectively. Approximately 1 fraction containing diastereomer A
Concentrate to 5 ml, and apply the concentrated solution to reverse phase column chromatography (YMC/GELTM ODS-AQ
120-S50, after desalting by flowing distilled water, the target product was eluted with a 20% methanol aqueous solution). The target fraction was concentrated and lyophilized to obtain diastereomer A of the title compound (
16 mg) was obtained. Diastereomer B (14.8 mg) was obtained in the same manner as above. Diastereomer A IR (KBr) cm-1: 1760, 1680, 159
0,1390NMR(D2O)δ:1.22(3H,d
, J=8Hz), 1.30 (3H, d, J=7Hz),
1.67 (1H, m), 2.35 (1H, dd, J=8
, 17Hz), 4.02 (1H, m), 4.25 (2H
, m) Diastereomer B IR (KBr) cm-1: 1760, 1680, 159
0,1390 NMR (D2O) δ: 1.22 (3H, d, J = 8Hz
), 1.30 (3H, d, J = 7Hz), 1.72 (1
H, m), 2.28 (1H, dd, J=8,17Hz)
, 4.02 (1H, m), 4.26 (2H, m) Example 11 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[( 2S,4S)-2-(
pyrrolidin-3-yl)pyrrolidin-4-ylthio]-
1-Carbapen-2-em-3-carboxylic acid diastereomers A and B 1)

[0194]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (1.39g, 2.34mm
ol) and (2S,4S)-4-mercapto-N-(
p-nitrobenzyloxycarbonyl)-2-[N-(
p-nitrobenzyloxycarbonyl)pyrrolidine-3
-yl]pyrrolidine [1.24g, 2.34mmol,
The same reaction as in Example 1-1) was carried out using the compound of Reference Example 5-6), and p-nitrobenzyl (1R,5
S,6S)-6-[(R)-1-hydroxyethyl]-
1-Methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidin-4-ylthio]- 1-carbapen-2-em-3-carboxylate (1.59 g, yield: 77.7
%) was obtained.

IR(KBr)cm-1:1770,17
00,1610,1520,1400,1350NMR
(CDCl3)δ: 1.28 (3H, d, J=7Hz)
, 1.34 (3H, d, J=6Hz), 5.14-5.
58 (6H, m), 7.52 (4H, br d, J=
8Hz), 7.65 (2H, d, J=8Hz), 8.2
0(6H,br d,J=8Hz)2)

[0196]

embedded image The compound obtained in the above reaction (1.52 g, 1.74 mm
ol) in tetrahydrofuran (40 ml), ethanol (2 ml) and 0.25 M sodium 3-morpholinopropanesulfonate buffer (pH 7.0, 18 ml).
) and 10% palladium-carbon catalyst (7
50 mg), and the mixture was heated in a hydrogen stream at 3 atm.
Stirred at room temperature for 2 hours. filtering the catalyst from the reaction mixture;
After washing the filtrate with ethyl acetate (50 ml), the insoluble matter in the aqueous layer was filtered off. The resulting aqueous layer was subjected to reverse phase column chromatography (LC-SORBTM SP-B-ODS, 15
% methanol aqueous solution → 20% methanol aqueous solution), concentrated and lyophilized to obtain diastereomer A (97 mg, yield: 14.6%) and diastereomer B (110 mg, yield: 16%) of the title compound. .6%) were obtained, respectively. Diastereomer A IR (KBr) cm-1: 1760, 1580, 154
0,1380 NMR (D2O) δ: 1.16 (3H, d, J = 8Hz
), 1.24 (3H, d, J = 7Hz), 1.74 (1
H, m), 2.20 (1H, m), 2.44 (2H, m
), 3.73 (1H, m), 4.17 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 2.6 min Diastereomer B IR (KBr) cm-1: 1750, 1590 ,139
0NMR (D2O) δ: 1.23 (3H, d, J = 8H
z), 1.30 (3H, d, J = 7Hz), 1.74 (
1H, m), 2.23 (1H, m), 2.50 (2H,
m), 3.78 (1H, m), 4.24 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 3.6 min Example 12 (1R, 5S, 6S)-6-[ (R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(
N-methylpyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid diastereomers A and B 1)

[0197]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (680mg, 1.14mm
ol) and (2S,4S)-4-mercapto-2-(
N-methylpyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate [650mg, 1.26mmol
, Reference Example 6-9)], Example 1-1)
By carrying out the reaction in the same manner, p-nitrobenzyl
(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-
(p-nitrobenzyloxycarbonyl)-2-(N-
Methylpyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (603 mg, yield: 74.3%) was obtained.

IR(KBr)cm-1:1770,17
00,1610,1520 NMR (CDCl3) δ: 1.37 (3H, d, J=6
Hz), 1.42 (3H, d, J=7Hz), 5.24
(4H, m), 7.54 (2H, d, J=8Hz), 7
．． 68 (2H, d, J = 8Hz), 8.25 (2H, d
, J=8Hz), 8.27 (2H, d, J=8Hz)2
)

[0199]

embedded image The compound obtained in the above reaction (290 mg, 0.41 mm
Diastereomer A of the title compound (27 mg
, yield: 16.7%) and diastereomer B (27
mg, yield: 16.7%) were obtained. Diastereomer A IR (KBr) cm-1: 1760, 1590, 138
0NMR (D2O) δ: 1.21 (3H, d, J = 8H
z), 1.30 (3H, d, J = 7Hz), 1.53 (
1H, m), 1.92 (1H, m), 2.94 (3H,
s), 3.91 (1H, m), 4.23 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 3.5 min Diastereomer B IR (KBr) cm-1: 1750, 1590,138
0NMR (D2O) δ: 1.18 (3H, d, J = 8H
z), 1.27 (3H, d, J = 7Hz), 1.80 (
1H, m), 2.24 (1H, m), 2.88 (3H,
s), 3.52 (1H, m), 3.74 (1H, m),
4.20 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 4.3 min Example 13 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1- Methyl-2-[(2S,4S)-2-(
N,N-dimethyl-3-pyrrolidinio)pyrrolidine-4
-ylthio]-1-carbapen-2-em-3-carboxylate diastereomers A and B

0200
]

embedded image The compound obtained in Example 12-1) (300 mg, 0.
Methyl iodide (0.13 ml, 2.09 mmol) was added to a solution of 42 mmol) in acetone (5 ml), and the mixture was stirred at room temperature overnight. Diastereomer A (17 mg,
Yield: 9.8%) and diastereomer B (29 mg
, yield: 16.7%) were obtained. Diastereomer A IR (KBr) cm-1: 1750, 1590, 138
0NMR (D2O) δ: 1.20 (3H, d, J = 8H
z), 1.29 (3H, d, J = 7Hz), 2.12 (
1H, m), 2.44 (2H, m), 3.17 (3H,
s), 3.24 (3H, s), 3.77 (2H, m),
4.22 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 2.7 min Diastereomer B IR (KBr) cm-1: 1750, 1590, 138
0NMR (D2O) δ: 1.22 (3H, d, J = 8H
z), 1.30 (3H, d, J=7Hz), 2.02(
1H, m), 2.52 (2H, m), 3.17 (3H,
s), 3.25 (3H, s), 3.78 (2H, m),
4.22 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 3.5 min Example 14 Sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[ (2S,4S)-2-(N-
Methyl-2-azetidinon-4-yl)pyrrolidine-4
-ylthio]-1-carbapen-2-em-3-carboxylate 1)

[0201]

embedded image p-Nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (235 mg, 0 .40mmol) and (2S
,4S)-4-mercapto-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (149 mg, 0.41 m
mol, using the compound of Reference Example 7), Example 1-1)
The same reaction as p-nitrobenzyl (5R,
6S)-6-[(R)-1-hydroxyethyl]-2-
[(2S,4S)-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3- Carboxylate (265 mg, yield: 94.5%) was obtained.

IR(KBr)cm-1:1780,17
40,1700,1520,1340 NMR (CDCl3) δ: 1.36 (3H, d, J=6
Hz), 2.78 (3H, s), 5.26 (3H, m)
, 5.52 (1H, d, J = 14Hz), 7.54 (2
H, d, J = 8Hz), 7.66 (2H, d, J = 8H
z), 8.22 (2H, d, J = 8Hz), 8.24 (
2H, d, J=8Hz) 2)

[0203]

embedded image Compound obtained in the above reaction (265 mg, 0.37 mm
Diastereomer A (4 mg, yield: 2.7%) and diastereomer B (25 mg, yield: 16) of the title compound were carried out using the same reaction as in Example 1-2). .7%) and a mixture of diastereomers A and B (25 mg, yield: 16.7%). Diastereomer A IR (KBr) cm-1: 1750, 1590, 139
0NMR (D2O) δ: 1.27 (3H, d, J = 6H
z), 1.66 (1H, m), 2.74 (2H, m),
2.90 (3H, s), 3.10-3.47 (5H, m
), 3.67 (2H, m), 4.22 (2H, m) HP
LC (conditions are the same as Example 1) Retention time: 2.68 min Diastereomer B IR (KBr) cm-1: 1750, 1590, 139
0NMR (D2O) δ: 1.28 (3H, d, J = 6H
z), 1.89 (1H, m), 2.88 (3H, s),
2.92 (2H, m), 3.16-3.48 (5H, m
), 3.75 (1H, dd, J=12,6Hz), 4.
24 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 2.85 min Example 15 Sodium (1R,5S,6S)-6-[(R)-
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-(N-methyl-2-azetidinon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2
-M-3-carboxylate 1)

[0204]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (240mg, 0.40mm
ol) and (2S,4S)-4-mercapto-2-(
N-methyl-2-azetidinon-4-yl)-N-(p
-nitrobenzyloxycarbonyl)pyrrolidine (14
Example 1-1)
By performing the same reaction as p-nitrobenzyl
(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-
(N-methyl-2-azetidinon-4-yl)-N-(
p-nitrobenzyloxycarbonyl)pyrrolidine-4
-ylthio]-1-carbapen-2-em-3-carboxylate (236 mg, yield: 82.7%) was obtained.

IR(KBr)cm-1:1750,17
00,1520,1350 NMR (CDCl3) δ: 1.28 (3H, d, J=7
Hz), 1.36 (3H, d, J=6Hz), 2.78
(3H, s), 5.26 (3H, m), 5.50 (1H
, d, J=14Hz), 7.54(2H, d, J=8H
z), 7.67 (2H, d, J = 8Hz), 8.22 (
2H, d, J = 8 Hz), 8.24 (2H, d, J = 8
Hz) 2)

[0206]

embedded image The compound obtained in the above reaction (236 mg, 0.33 mm
Diastereomer A of the title compound (25 mg
, yield: 18.1%) and diastereomer B (39
mg, yield: 28.2%) was obtained. Diastereomer A IR (KBr) cm-1: 1750, 1600, 139
0NMR (D2O) δ: 1.22 (3H, d, J = 7H
z), 1.30 (3H, d, J = 6Hz), 1.78 (
1H, m), 2.81 (2H, m), 2.94 (3H,
s), 3.20-3.55 (5H, m), 3.74 (1
H, dd, J = 12,6 Hz), 4.26 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 4.86 min Diastereomer B IR (KBr) cm-1: 1750, 1600 ,139
0NMR (D2O) δ: 1.24 (3H, d, J = 7H
z), 1.30 (3H, d, J = 6Hz), 1.88 (
1H, m), 2.90 (3H, s), 2.95 (2H,
m), 3.18-3.34 (5H, m), 3.70 (1
H, dd, J = 12,6 Hz), 4.26 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 5.43 min Example 16 Sodium (1R, 5S, 6S)-6-[ (R)-
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer A 1)

[0207]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (500mg, 0.84mm
ol) and (2S,4S)-4-mercapto-2-(
N-methyl-2,5-dioxopyrrolidin-3-yl)
-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (330mg, 0.84m
Example 1-1 using mol, compound of Reference Example 8)
), p-nitrobenzyl (1R
,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl )-N-
(p-nitrobenzyloxycarbonyl)pyrrolidine-
4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer A (311 mg, yield: 50.1%) was obtained.

IR(KBr)cm-1:1770,17
00,1520,1350 NMR (CDCl3) δ: 1.28 (3H, d, J=8
Hz), 1.34 (3H, d, J=7Hz), 2.95
(3H, br s), 3.68 (1H, m), 4.5
7 (1H, m), 5.20 (3H, m), 5.52 (1
H, d, J = 14Hz), 7.48 (2H, d, J = 8
Hz), 7.66 (2H, d, J=8Hz), 8.22
(4H, d, J=8Hz) 2)

[0209]

embedded image Compound obtained in the above reaction (311 mg, 0.42 mm
A reaction similar to Example 1-2) was carried out using
The title compound (76.8 mg, yield: 40.9%) was obtained.

IR(KBr)cm-1:1750,17
00,1610,1590 NMR (D2O) δ: 1.20 (3H, d, J = 7Hz
), 1.26 (3H, d, J = 6Hz), 1.95 (1
H, m), 2.96 (3H, s), 3.25-3.74
(5H, m), 4.00 (2H, m), 4.20 (2H
, m) HPLC (conditions are the same as Example 1) Retention time: 4.60 min Example 17 Sodium (1R,5S,6S)-6-[(R)-
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer B 1)

[0211]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (220mg, 0.37mm
ol) and (2S,4S)-4-mercapto-2-(
N-methyl-2,5-dioxopyrrolidin-3-yl)
-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer B (140mg, 0.36m
A reaction similar to Example 1-1) was carried out using p-nitrobenzyl (1R,5S,6S)-6-
[(R)-1-hydroxyethyl]-1-methyl-2-
[(2S,4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-
Carbapen-2-em-3-carboxylate diastereomer B (244 mg, yield: 89.4%) was obtained.

IR(KBr)cm-1:1780,17
00,1520,1350 NMR (CDCl3) δ: 1.28 (3H, d, J=7
Hz), 1.34 (3H, d, J=6Hz), 1.62
(1H, m), 2.96 (3H, s), 5.26 (3H
, m), 5.50 (1H, d, J=14Hz), 7.5
4 (2H, d, J = 8Hz), 7.67 (2H, d, J
=8Hz), 8.22 (4H, d, J=8Hz)2)

[0213]

embedded image The compound obtained in the above reaction (244 mg, 0.322 m
mol), the same reaction as in Example 1-2) was carried out to obtain the title compound (35 mg, yield: 23.7%).

IR(KBr)cm-1:1750,17
00,1610,1590 NMR (D2O) δ: 1.22 (3H, d, J = 7Hz
), 1.30 (3H, d, J = 6Hz), 1.84 (1
H, m), 2.66 (1H, dd, J=18,6Hz)
, 2.84 (1H, m), 2.98 (3H, s), 3.
12 (1H, dd, J=18,9Hz), 3.30~3
．． 58 (4H, m), 3.72 (1H, dd, J=12
, 6Hz), 3.97 (2H, m), 4.25 (2H,
m) HPLC (conditions are the same as Example 1) Retention time: 6.99 min Example 18 (1R,5S,6S)-2-[(2S,4S)-2-(
2,5-dioxopyrrolidin-3-yl)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid 1)

[0215]

embedded image Allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate ( 230 mg, 0.46 mmol) and (2S,4S)-N-allyloxycarbonyl-2-(
Using 2,5-dioxopyrrolidin-3-yl)-4-mercaptopyrrolidine (130 mg, 0.46 mmol, compound of Reference Example 9), the same reaction as in Example 8-1) was carried out, and allyl (1R ,5S,6S)-2-[(2
S,4S)-N-allyloxycarbonyl-2-(2,
5-dioxopyrrolidin-3-yl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-Methyl-1-carbapen-2-em-3-carboxylate (125 mg, yield: 50.9%) was obtained.

IR(KBr)cm-1:1780,17
20,1410,1330 NMR (CDCl3) δ: 1.24 (3H, d, J=7
Hz), 1.33 (3H, d, J=6Hz), 1.63
(1H, m), 5.13-5.54 (4H, m), 5.
78~6.08 (2H, m) 2)

[0217]

embedded image The compound obtained in the above reaction (120 mg, 0.23 mm
The title compound (28.5 mg, yield: 30.9%) was obtained by carrying out the same reaction as in Example 8-2) using
) was obtained.

IR(KBr)cm-1:1760,17
20,1600,1380 NMR (D2O) δ: 1.18 (3H, d, J = 7Hz
), 1.25 (3H, d, J = 6Hz), 1.70 (1
H, m), 2.53-2.80 (2H, m), 3.03
(1H, m), 3.25-3.50 (4H, m), 3.
60 (1H, m), 3.80-4.00 (2H, m),
4.20 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 2.46 min Example 19 (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[( 2S,4S)-2-(3-pyrazolidinon-5-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid 1)

[0219]

embedded image Allyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1
-carbapen-2-m-3-carboxylate (19
5mg, 0.40mmol) and (2S,4S)-N
The same reaction as in Example 8-1) was carried out using -allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)-4-mercaptopyrrolidine (162 mg, 0.40 mmol). , allyl
(5R,6S)-2-[(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)pyrrolidin-4-ylthio]-6-[(R )-1-hydroxyethyl]-1
-carbapen-2-m-3-carboxylate (15
5 mg, yield: 65.4%) was obtained.

IR(KBr)cm-1:1780,17
00,1550,1410,1330 NMR (CDCl3) δ: 1.32 (3H, d, J=6
Hz), 4.52-4.90 (6H, m), 5.18-
5.56 (6H, m), 5.78-6.10 (3H, m
) 2)

[0221]

embedded image Compound obtained in the above reaction (155 mg, 0.26 mm
A reaction similar to Example 8-2) was carried out using
The title compound (39 mg, yield: 38.8%) was obtained.

IR(KBr)cm-1:1760,16
80,1590,1390 NMR (CDCl3) δ: 1.26 (3H, d, J=6
Hz), 1.88 (1H, m), 2.35 (1H, m)
, 2.70 (1H, m), 3.06-3.27 (2H,
m), 3.42 (2H, m), 3.70-3.90 (2
H, m) HPLC (conditions are the same as Example 1) Retention time: 1.53 min Example 20 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2- [(2S,4S)-2-(
3-pyrazolidinone-5-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid 1
)

[0223]

embedded image Allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate ( 330 mg, 0.66 mmol) and (2S,4S)-N-allyloxycarbonyl-2-(
1-allyloxycarbonyl-3-pyrazolidinone-5
-yl)-4-mercaptopyrrolidine (234 mg, 0
．． By carrying out the same reaction as in Example 8-1) using 66 mmol), allyl (1R,5S,6S)
-2-[(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)pyrrolidin-4-ylthio]-6-[
(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (172 m
g, yield: 43.1%).

IR(KBr)cm-1:1770,17
00,1410,1320 NMR (CDCl3) δ: 1.24 (3H, d, J=7
Hz), 1.35 (3H, d, J=6Hz), 4.50
~4.90 (6H, m), 5.20 ~ 5.56 (6H,
m), 5.80-6.10 (3H, m)2)

[0225]

embedded image The compound obtained in the above reaction (172 mg, 0.285 m
The title compound (42 mg, yield: 37.2%) was obtained by carrying out the same reaction as in Example 8-2) using
) was obtained.

IR(KBr)cm-1:1760,16
80,1590,1390 NMR (D2O) δ: 1.20 (3H, d, J = 7Hz
), 1.26 (3H, d, J = 6Hz), 1.85 (1
H, m), 2.35 (1H, br d, J=18Hz
), 2.70 (1H, m), 3.10 (1H, dd, J
= 18.9Hz), 3.15-3.52 (3H, m),
3.62-3.90 (2H, m), 3.93-4.32
(4H, m) HPLC (conditions are the same as Example 1) Retention time: 2.23 min Example 21 Sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S, 4S)-2-(2-
pyrrolidon-3-yl)pyrrolidin-4-ylthio]-
1-Carbapen-2-M-3-carboxylate 1)

[0227]

embedded image p-Nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (180 mg, 0 .31 mmol) and (2S
,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidine (110 mg, 0.30 mmol, compound of Reference Example 11) By carrying out the same reaction as in 1-1), p-nitrobenzyl (5R,6
S)-6-[(R)-1-hydroxyethyl]-2-[
(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-
Carboxylate (151 mg, yield: 70%) was obtained.

IR(KBr)cm-1:1780,17
00,1520,1350 NMR (CDCl3) δ: 1.38 (3H, d, J=6
Hz), 5.30 (3H, m), 5.56 (1H, d,
J = 14Hz), 7.57 (2H, d, J = 8Hz),
7.70 (2H, d, J=8Hz), 8.25 (2H,
d, J=8Hz), 8.28 (2H, d, J=8Hz)
2)

[0229]

embedded image Compound obtained in the above reaction (150 mg, 0.22 mm
The title compound (35 mg, yield: 38.1%) was obtained by carrying out the same reaction as in Example 1-2) using
I got it.

IR(KBr)cm-1:1760,16
90,1590,1380 NMR (D2O) δ: 1.29 (3H, d, J = 6Hz
), 1.72-2.07 (3H, m), 2.39 (1H
, m), 2.80 (1H, m), 3.00 (1H, m)
, 3.20 (2H, m), 3.44 (3H, m), 3.
78 (2H, m), 3.99 (1H, m), 4.24 (
2H, m) HPLC (conditions are the same as Example 1) Retention time: 1.93 min Example 22 Sodium (1R,5S,6S)-6-[(R)-
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-(2-pyrrolidon-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate 1)

[0231]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (180mg, 0.30mm
ol) and (2S,4S)-4-mercapto-N-(
p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidine (110 mg, 0.3
The same reaction as in Example 1-1) was carried out using p-nitrobenzyl (1R,5S,6S)-
6-[(R)-1-hydroxyethyl]-1-methyl-
2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (161 mg, yield: 74.9
%) was obtained.

IR(KBr)cm-1:1780,17
00,1520,1350 NMR (CDCl3) δ: 1.32 (3H, d, J=7
Hz), 1.40 (3H, d, J=6Hz), 5.32
(3H, m), 5.56 (1H, d, J=14Hz),
7.58 (2H, d, J=8Hz), 7.70 (2H,
d, J=8Hz), 8.27 (2H, d, J=8Hz)
, 8.29 (2H, d, J = 8Hz) 2)

[0233]

embedded image The compound obtained in the above reaction (160 mg, 0.23 mm
A reaction similar to Example 1-2) was carried out using
The title compound (37 mg, yield: 37.5%) was obtained.

IR(KBr)cm-1:1760,16
90,1600,1380 NMR (D2O) δ: 1.18 (3H, d, J = 7Hz
), 1.25 (3H, d, J=6Hz), 1.63~2
．． 07 (3H, m), 2.36 (1H, m), 2.74
(1H, m), 2.98 (1H, m), 3.30-3.
50 (4H, m), 3.72 (2H, m), 3.95 (
1H, m), 4.22 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 3.23 min Example 23 (1R, 5S, 6S)-2-[(2S, 4S)-2 −(
2-Carbamoylpyrrolidin-4-yl)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid diastereomer I 1)

[0235]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (174 mg, 0.29 mm
ol) and (2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereo Mer I (160 mg, 0.28 mmol, Reference Example 13
The same reaction as in Example 1-1) was carried out using p-nitrobenzyl (1R,5S,6S)-2
-[(2S,4S)-2-[2-carbamoyl-N-(
p-nitrobenzyloxycarbonyl)pyrrolidine-4
-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-
Em-3-carboxylate diastereomer I (
223 mg, yield: 82.9%) was obtained.

IR(KBr)cm-1:1770,17
00,1520,1400,1350 NMR (CDCl3) δ: 1.28 (3H, d, J=7
Hz), 1.37 (3H, d, J=6Hz), 5.25
(5H, m), 5.52 (1H, d, J=14Hz),
7.53 (4H, d, J = 8Hz), 7.67 (2H,
d, J=8Hz), 8.23 (6H, d, J=8Hz)
2)

[0237]

embedded image The compound obtained in the above reaction (223 mg, 0.24 mm
The title compound (50.7 mg, yield: 49.8
%) was obtained.

IR(KBr)cm-1:1750,17
00,1390 NMR (D2O) δ: 1.19 (3H, d, J = 7Hz
), 1.27 (3H, d, J = 6Hz), 1.58 (2
H, m), 2.00-2.32 (2H, m), 2.42
~2.74 (2H, m), 2.82 (1H, dd, J=
12,8Hz), 3.22 (1H, dd, J=12,4
Hz), 3.30-3.54 (4H, m), 3.92 (
1H, m), 4.10 (1H, dd, J=9,4Hz)
,4.20(2H,m) Example 24 (1R,5S,6S)-2-[(2S,4S)-2-(
2-Carbamoylpyrrolidin-4-yl)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid diastereomer II 1)

[0239]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (290mg, 0.49mm
ol) and (2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereo Using Mer II (280 mg, 0.49 mmol, compound of Reference Example 14), the same reaction as in Example 1-1) was carried out, and p-nitrobenzyl (1R,5S,6S
)-2-[(2S,4S)-2-[2-carbamoyl-
N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-
1-Hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer II (419 mg, yield: 93.4%) was obtained.

IR(KBr)cm-1:1770,17
00,1520,1350 NMR (CDCl3) δ: 1.28 (3H, d, J=7
Hz), 1.37 (3H, d, J=6Hz), 5.26
(5H, m), 5.52 (1H, d, J=14Hz),
7.53 (4H, d, J=8Hz), 7.68 (2H,
d, J=8Hz), 8.24 (6H, d, J=8Hz)
2)

[0241]

embedded image Compound obtained in the above reaction (419 mg, 0.46 mm
The title compound (93 mg, yield: 48%) was obtained by performing the same reaction as in Example 1-2) using ol).

IR(KBr)cm-1:1760,17
00,1390 NMR (D2O) δ: 1.20 (3H, d, J = 7Hz
), 1.28 (3H, d, J = 6Hz), 1.62 (2
H, m), 2.44-2.75 (3H, m), 2.83
(1H, dd, J=10,8Hz), 3.16~3.5
7 (6H, m), 3.94 (1H, m), 4.08 (1
H, m), 4.23 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 2.84 min Example 25 (5R,6S)-6-[(R)-1-hydroxyethyl] -2-[(2S,4S)-2-(pyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2
-M-3-carboxylic acid diastereomer A1)

[0243]

embedded image p-Nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (255 mg, 0 .45 mmol) and (2S
,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine (240 mg, 0.45 mmol, Reference Example 5) Compound)
The same reaction as in Example 1-1) was carried out using p-nitrobenzyl (5R,6S)-6-[(R)-1-
hydroxyethyl]-2-[(2S,4S)-N-(p
-nitrobenzyloxycarbonyl)-2-[N-(p
-nitrobenzyloxycarbonyl)pyrrolidine-3-
yl]pyrrolidin-4-ylthio]-1-carbapene-
2-M-3-carboxylate (297 mg, yield:
78.6%).

IR(KBr)cm-1:1780,17
00,1520,1350 NMR (CDCl3) δ: 1.25 (3H, d, J=6
Hz), 4.00~4.40 (4H, m), 5.16~
5.35 (5H, m), 5.52 (1H, d, J = 14
Hz), 7.52 (4H, d, J=8Hz), 7.65
(2H, d, J=8Hz), 8.21 (6H, m)2)

[0245]

embedded image The compound obtained in the above reaction (297 mg, 0.345 m
The same reaction as in Example 1-2) was carried out using mol) to obtain diastereomer A (13.6 mg, yield: 10.7%) of the title compound.

IR(KBr)cm-1:1760,16
90,1390 NMR (D2O) δ: 1.27 (3H, d, J = 6Hz
), 1.46 (1H, m), 1.68-2.10 (2H
, m), 2.14-2.80 (3H, m), 3.80 (
2H, m), 4.22 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 2.03 min Example 26 (1R,5S,6S)-6-[(R)-1-hydroxy ethyl]-1-methyl-2-[(2S,4S)-2-(
pyrrolidin-3-yl)pyrrolidin-4-ylthio]-
1-Carbapen-2-em-3-carboxylic acid diastereomer A 1)

[0247]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (1.75g, 2.94mm
ol) and (2S,4S)-4-mercapto-N-(
p-nitrobenzyloxycarbonyl)-2-[N-(
p-nitrobenzyloxycarbonyl)pyrrolidine-3
-yl]pyrrolidine diastereomer A[1.56
p-nitrobenzyl (1R,5S,6S)-6-[(R) −
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-N-(p-nitrobenzyloxycarbonyl)
-2-[N-(p-nitrobenzyloxycarbonyl)
pyrrolidin-3-yl]pyrrolidin-4-ylthio]-
1-Carbapen-2-em-3-carboxylate diastereomer A (2.37 g, yield: 92%) was obtained.

IR(KBr)cm-1:1780,17
00,1520,1350 NMR (CDCl3) δ: 1.28 (3H, t, J=7
Hz), 1.37 (3H, d, J=6Hz), 1.60
~2.15 (4H, m), 2.55 (1H, m), 2.
78 (1H, m), 4.04-4.35 (3H, m),
5.24 (5H, m), 5.53 (1H, br d,
J=14Hz), 7.54(4H,brd,J=8Hz
), 7.67 (2H, d, J = 8Hz), 8.24 (6
H,brd,J=8Hz) 2)

[0249]

embedded image The compound obtained in the above reaction (2.37 g, 2.71 mm
The same reaction as in Example 11-2) was carried out using ol) to obtain the title compound (298 mg, yield: 28.8%). Various spectral data of this compound matched with diastereomer A obtained in Example 11-2). Example 27 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(
pyrrolidin-3-yl)pyrrolidin-4-ylthio]-
1-Carbapen-2-em-3-carboxylic acid diastereomer B 1)

0250]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (1.27g, 2.14mm
ol) and (2S,4S)-4-mercapto-N-(
p-nitrobenzyloxycarbonyl)-2-[N-(
p-nitrobenzyloxycarbonyl)pyrrolidine-3
-yl]pyrrolidine diastereomer B (1.14
g, 2.15 mmol, the compound of Reference Example 16), the same reaction as in Example 1-1) was carried out, and p-nitrobenzyl (1R,5S,6S)-6-[(R)-1- hydroxyethyl]-1-methyl-2-[(2S,4S)-N
-(p-nitrobenzyloxycarbonyl)-2-[N
-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer B (1.65g, yield: 88.3% ) was obtained.

IR(KBr)cm-1:1780,17
00,1520,1350 NMR (CDCl3) δ: 1.28 (3H, t, J=7
Hz), 1.37 (3H, t, J=6Hz), 1.50
~2.08 (4H, m), 2.42 ~ 2.70 (2H,
m), 3.48-3.70 (3H, m), 4.01-4
．． 76 (3H, m), 5.24 (5H, m), 5.54
(1H, d, J=14Hz), 7.54 (4H, br
d, J = 8Hz), 7.67 (2H, d, J = 8Hz
), 8.24 (6H, br d, J=8Hz)2)

0252]

embedded image The compound obtained in the above reaction (1.65 g, 1.89 mm
A reaction similar to Example 1-2) was carried out using
Only the title compound (220 mg, yield: 30.6%) was obtained. Various spectral data of this compound matched with diastereomer B obtained in Example 11-2). Example 28 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(
2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid diastereomer A 1)

0253]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (6.67g, 11.2mm
ol) and (2S,4S)-4-mercapto-N-(
Example 1- The same reaction as in 1) was carried out to produce p-nitrobenzyl (1R,5S,6S)-6-
[(R)-1-hydroxyethyl]-1-methyl-2-
[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3
-carboxylate diastereomer A (6.01
g, yield: 77.1%).

IR(KBr)cm-1:1770,17
00,1520,1340,1250 NMR (CDCl3) δ: 1.28 (3H, d, J=8
Hz), 1.33 (3H, d, J=7Hz), 1.72
(2H, m), 2.06-2.68 (3H, m), 2.
96-3.7 (5H, m), 4.04-4.36 (2H
, m), 5.24 (2H, m), 5.31 and 5.5
2 (2H, ABq, J=14Hz), 5.8 (1H, b
r), 7.53 (2H, d, J = 8Hz), 7.64 (
2H, d, J = 8Hz), 8.20 (2H, d, J = 8
Hz), 8.22 (2H, d, J=8Hz)2)

0255]

embedded image Compound obtained in the above reaction (6 g, 8.62 mmol)
The same reaction as in Example 1-2) was carried out using the following to obtain the title compound (1.68 g, yield: 49.4%).

IR(KBr)cm-1:1755,16
80,1595,1385,1280 NMR (D2O) δ: 1.15 (3H, d, J = 8Hz
), 1.23 (3H, d, J = 7Hz), 1.7 (1H
, m), 2.3 (1H, m), 2.54-3.1 (3H
, m), 3.1-3.5 (3H, m), 3.55-3.
94 (3H, m), 4.0 (1H, m), 4.19 (2
H, m) HPLC; Column: YMC AQ-304, mobile phase: 0.01M
Phosphate buffer (pH 7.0)-acetonitrile (96:
4), Flow rate: 1.0 ml/min, temperature 40°C, detection: 254 nm, retention time: 14.83 min Example 2
9 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(
2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid diastereomer B 1)

0257]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (10.61g, 17mmo
l) and (2S,4S)-4-mercapto-N-(p
-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B
Using [5.92 g, 16.2 mmol, compound of Reference Example 19-4)], the same reaction as in Example 1-1) was carried out to give p-nitrobenzyl (1R,5S,6S)-6-
[(R)-1-hydroxyethyl]-1-methyl-2-
[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3
-Carboxylate diastereomer B (9.9g
, yield: 83.7%).

IR(KBr)cm-1:1770,17
05,1695,1605,1345,1205NMR
(D2O)δ: 1.27 (3H, d, J=8Hz), 1
．． 36 (3H, d, J=7Hz), 1.72-2.06
(2H, m), 2.1-2.68 (3H, m), 3.0
2-3.7 (5H, m), 4.06-4.16 (2H,
m), 5.31 and 5.52 (2H, ABq, J=1
4Hz), 6.04 (1H, br), 7.53 (2H,
d, J=8Hz), 7.66 (2H, d, J=8Hz)
, 8.20 (2H, d, J = 8Hz), 8.22 (2H
, d, J=8Hz) 2)

0259]

embedded image The compound obtained in the above reaction (9.8 g, 14.1 mmo
The same reaction as in Example 1-2) was carried out using 1) to obtain the title compound (1.42 g, yield: 25.5%).

IR(KBr)cm-1:1755,16
80,1590,1390,1280 NMR (D2O) δ: 1.19 (3H, d, J = 8Hz
), 1.26 (3H, d, J = 7Hz), 1.72 (1
H, m), 2.28 (1H, m), 2.52-3.10
(3H, m), 3.26-3.50 (3H, m), 3.
60-3.90 (3H, m), 4.02 (1H, m),
4.22 (2H, m) HPLC; Column: YMC AQ-304, mobile phase: 0.01M
Phosphate buffer (pH 7.0)-acetonitrile (96:
4), flow rate: 1.0 ml/min, temperature 40°C, detection: 254 nm, retention time: 15.18 min Example 3
0 (1R,5S,6S)-2-[(2S,4S)-2-(
3-amino-2-pyrrolidon-4-yl)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid 1)

[0261]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (155.4 mg, 0.26
mmol) and (2S,4S)-4-mercapto-N
-(p-nitrobenzyloxycarbonyl)-2-[3
-[(p-nitrobenzyloxycarbonyl)amino]
-2-pyrrolidon-4-yl]pyrrolidine [110mg
.
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-N-(p-nitrobenzyloxycarbonyl)
-2-[3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidine-
4-ylthio]-1-carbapen-2-em-3-carboxylate (87 mg, yield: 48.9%) was obtained.

IR(KBr)cm-1:1775,17
10,1605,1525,1350,735NMR(
CDCl3) δ: 1.27 (3H, d, J = 8Hz),
1.35 (3H, d, J = 8Hz), 1.6-1.8 (
2H, m), 2.78 (1H, m), 3.1 to 3.5 (
6H, m), 3.65 (1H, m), 4.0 to 4.4 (
5H, m), 5.2 (4H, s), 5.28 (1H, d
, J=16Hz), 5.5 (1H, d, J=16Hz)
, 6.32 (1H, br), 7.52 (4H, d, J=
9Hz), 7.65 (2H, d, J=8Hz), 8.2
(6H, m) 2)

0263

embedded image The compound obtained in the above reaction (87 mg, 0.096 mm
A reaction similar to Example 1-2) was carried out using
The resulting reaction solution was subjected to column chromatography (HP-2
The title compound (25.
72 mg, yield: 65.1%) was obtained.

IR(KBr)cm-1:1755,17
00,1605,1595,1385 NMR (D2O) δ: 1.17 (3H, d, J = 8Hz
), 1.24 (3H, d, J=8Hz), 2.5-2.
8 (2H, m), 2.6-2.8 (2H, m), 3.1
~3.6 (5H, m), 3.9 ~ 4.4 (5H, m) Example 31 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl- 2-[(2R,4S)-2-(
pyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid 1)

0265]

embedded image Allyl (1R,5S,6S)-6-[(R)-1-
hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (790 mg, 1.6 mmol), (2R
,4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-3-ylmethyl)-
4-Mercaptopyrrolidine (560 mg, 1.6 mmo
l), N,N-diisopropylethylamine (0.28
ml, 1.6 mmol) in the same manner as in Example 8-1), and allyl (1R,5S,6S)-2-[(
2R,4S)-N-allyloxycarbonyl-2-(N
-allyloxycarbonylpyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-
Em-3-carboxylate (480 mg, yield: 50
%) was obtained.

[0266] NMR (CDCl3) δ: 1.28 (3H
, d, J=6Hz), 1.36(3H, d, J=6Hz
), 1.5-1.8 (3H, m), 1.9-2.2 (4
H, m), 2.62 (1H, m), 3.02 (1H, m
), 3.2-3.4 (4H, m), 3.5-3.7 (3
H, m), 4.0-4.3 (3H, m), 4.6-4.
9 (6H, m), 5.2-5.56 (6H, m), 5.
9-6.1 (3H, m) 2)

0267]

embedded image The compound obtained in the above reaction (480 mg, 0.8 mmo
l), bis(triphenylphosphine)palladium(I
I) Chloride (11 mg, 0.016 mmol), tributyltin hydride (1.28 ml, 4.77 mmol)
and water (107 μl, 5.96 mmol) in the same manner as in Example 8-2), and the resulting aqueous layer was subjected to reverse phase column chromatography [YMC・GELTM ODS-A
Q120-S50, 50ml, methanol-water (1:4
) and lyophilized to obtain the title compound (128
mg, yield: 41%) was obtained.

IR(KBr)cm-1:1760,16
00,1390 NMR (D2O) δ: 1.2 (3H, d, J = 6Hz)
, 1.28 (3H, d, J=7Hz), 1.6-1.9
(3H, m), 2.2~2.7 (3H, m), 2.9~
3.6 (10H, m), 3.8 (1H, m), 4.2~
4.4(2H,m) Example 32 (1R,5S,6S)-2-[(2R,4S)-2-[
(2S)-2-carbamoylpyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-
hydroxyethyl]-1-methyl-1-carbapene-2
-M-3-carboxylic acid 1)

0269]

embedded image Allyl (1R,5S,6S)-6-[(R)-1-
hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (264 mg, 0.49 mmol), (2
R,4S)-N-allyloxycarbonyl-2-[(2
S) -N-allyloxycarbonyl-2-carbamoylpyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (210 mg, 0.49 mmol), N,N-diisopropylethylamine (92 μl, 0.49 mmol)
) in the same manner as in Example 8-1), and allyl
(1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-carbamoylpyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio ]-6-[(R)
-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (250 mg, yield: 73%) was obtained.

[0270] NMR (CDCl3) δ: 1.25 (3H
, d, J=6Hz), 1.34(3H, d, J=7Hz
), 1.5-1.8 (3H, m), 1.8-2.7 (4
H, m), 3.0-3.4 (4H, m), 3.5-4.
4 (7H, m), 4.5-4.9 (6H, m), 5.2
~5.5 (7H, m), 5.8 ~ 6.1 (3H, m),
6.9 (0.5H, br s), 7.3 (0.5H,
brs) 2)

0271]

embedded image The compound obtained in the above reaction (250 mg, 0.387 m
mol), bis(triphenylphosphine)palladium(II) chloride (5.4 mg, 0.008 mmol)
, tributyltin hydride (0.62ml, 2.3mmo
1) and water (52 μl, 2.9 mmol) in the same manner as in Example 8-2), and the resulting aqueous layer was subjected to reverse phase column chromatography [LC-SORBTM SP-B-
ODS, 14 ml, eluted with methanol-water (3:7)]
The residue was purified and freeze-dried to obtain the title compound (107 mg, yield: 63%).

IR(KBr)cm-1:1750,16
80,1590,1390 NMR (D2O) δ: 1.22 (3H, d, J=7
Hz), 1.28 (3H, d, J=6Hz), 1.58
(1H, m), 1.8~2.4 (5H, m), 2.6~
2.84 (2H, m), 3.2-3.7 (6H, m),
3.95 (1H, m), 4.1 (1H, dd, J=10
,4Hz),4.2-4.3(2H,m)Example 33 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R, 4S)-2-[
(2S)-2-(methylcarbamoyl)pyrrolidine-4
-ylmethyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid 1)

0273

embedded image Allyl (1R,5S,6S)-6-[(R)-1-
hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (204 mg, 0.41 mmol), (2
R,4S)-N-allyloxycarbonyl-2-[(2
S) -N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (168 mg, 0.41 mmol), N
, N-diisopropylethylamine (71 μl, 0.4
1 mmol) in the same manner as in Example 8-1),
Allyl(1R,5S,6S)-2-[(2R,4S)-
N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl] -1-Methyl-1-carbapen-2-em-3-carboxylate (180 mg, yield: 67%) was obtained.

[0274] NMR (CDCl3) δ: 1.26 (3H
, d, J=6Hz), 1.36(3H, d, J=6Hz
), 1.5-1.8 (3H, m), 1.8-2.6 (4
H, m), 2.8 (3H, d, J = 4Hz), 3.0 (
1H, m), 3.1-3.4 (3H, m), 3.8 (2
H, m), 3.9-4.4 (5H, m), 4.5-4.
9 (6H, m), 5.1-5.5 (6H, m), 5.8
~6.0 (3H, m), 6.9 (0.5H, br s
), 7.3 (0.5H, brs) 2)

0275]

embedded image The compound obtained in the above reaction (180 mg, 0.27 mm
ol), bis(triphenylphosphine)palladium (
II) Chloride (4 mg, 0.005 mmol), tributyltin hydride (0.44 ml, 1.6 mmol),
Example 8-2) using water (37 μl, 2 mmol)
The resulting aqueous layer was subjected to reverse phase column chromatography [LC-SORBTM SP-B-ODS, 1
4 ml, eluted with methanol-water (3:7)].
Freeze-drying gave the title compound (60 mg, yield: 49%).

IR(KBr)cm-1:1750,16
00,1390 NMR (D2O) δ: 1.2 (3H, d, J = 6Hz)
, 1.28 (3H, d, J=7Hz), 1.56 (1H
, m), 1.8-2.3 (5H, m), 2.6-2.8
(2H, m), 2.76 (3H, s), 3.2-3.7
(6H, m), 3.95 (1H, m), 4.04 (1H
, dd, J=10,4Hz), 4.2~4.3(2H,
m) Example 34 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2R,4S)-2-[
(2S)-2-(dimethylcarbamoyl)pyrrolidine-
4-ylmethyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid 1)

0277]

embedded image Allyl (1R,5S,6S)-6-[(R)-1-
hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (129 mg, 0.26 mmol), (2
R,4S)-N-allyloxycarbonyl-2-[(2
S) -N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (110 mg, 0.26 mmol),
N,N-diisopropylethylamine (45 μl, 0.
Allyl (1R,5S,6S)-2-[(2R,4
S)-N-allyloxycarbonyl-2-[(2S)-
N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-Methyl-1-carbapen-2-em-3-carboxylate (78 mg, yield: 45%) was obtained.

[0278] NMR (CDCl3) δ: 1.26 (3H
, d, J=6Hz), 1.37(3H, d, J=6Hz
), 1.4-2.6 (7H, m), 2.9-3.3 (4
H, m), 2.98 (3H, s), 3.12 (3H, s
), 3.5-4.3 (7H, m), 4.5-4.9 (6
H, m), 5.1-5.5 (6H, m), 5.9 (3H
, m) 2)

0279]

embedded image The compound obtained in the above reaction (78 mg, 0.12 mmo
l), bis(triphenylphosphine)palladium(I
I) Chloride (2 mg, 0.002 mmol), tributyltin hydride (0.186 ml, 0.69 mmol)
and water (16 μl, 0.87 mmol) in the same manner as in Example 8-2), and the resulting aqueous layer was subjected to reverse phase column chromatography [LC-SORBTM SP-B-O
DS, 14 ml, eluted with methanol-water (2:3)] and lyophilized to give the title compound (11 mg, yield: 2
0%) was obtained.

IR(KBr)cm-1:1750,16
40,1600,1390 NMR (D2O) δ: 1.2 (3H, d, J = 6Hz)
, 1.28 (3H, d, J=7Hz), 1.5 (1H,
m), 1.8-2.4 (5H, m), 2.6-2.9 (
2H, m), 2.96 (3H, s), 3.06 (3H,
s), 3.1-3.6 (6H, m), 3.8-4.0 (
2H, m), 4.1 to 4.3 (2H, m) Example 35 (1R,5S,6S)-2-[(2S,4S)-2-(
2,4-Dioxoimidazolidin-5-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-
Carboxylic acid 1)

0281]

embedded image (2S,4S)-2-(2,4-dioxoimidazolidin-5-yl)-4-(p-methoxybenzylthio)-
N-(p-nitrobenzyloxycarbonyl)pyrrolidine (250 mg, 0.499 mmol, compound of Reference Example 28) and anisole (0.27 ml, 2.48 mm
ol) in trifluoroacetic acid (5 ml) and cooled on ice under a nitrogen stream. Trifluoromethanesulfonic acid (0.0
7 ml, 0.791 mmol) was added dropwise and cooled on ice for 50
Stir for a minute. The solvent was evaporated and the residue was washed with ether.
Crude thiol was obtained.

p-Nitrobenzyl (1R,5S,6
S)-2-diphenoxyphosphoryloxy-6-[(R
)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (300 mg,
0.505 mmol) and the thiol obtained in the above reaction, the same reaction as in Example 1-1) was carried out, and p-
Nitrobenzyl (1R,5S,6S)-2-[(2
S,4S)-2-(2,4-dioxoimidazolidine-
5-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-
hydroxyethyl]-1-methyl-1-carbapene-2
-M-3-carboxylate (100 mg, yield: 2
8%).

IR(KBr)cm-1:3430,17
75, 1725, 1610, 1520, 1350, 12
85,1250 NMR (CDCl3) δ: 1.27 (3H, d, J=6
Hz), 1.33 (3H, d, J = 6Hz), 4.4 (
1H, m), 4.7 and 5.05 (1H, s), 5.
25 (2H, s), 5.3 and 5.5 (2H, ABq
, J=14Hz), 7.58 (2H, d, J=8Hz)
, 7.69 (2H, d, J=8Hz), 8.2-8.3
(4H, m) 2)

0284

embedded image The compound obtained in the above reaction (100 mg, 0.138 m
The same reaction as in Example 1-2) was carried out using mol) to obtain the title compound (23 mg, yield: 41%).

IR(KBr)cm-1:3440,17
60,1730,1600,1400 NMR (D2O) δ: 1.20 (3H, d, J = 7Hz
), 1.27 (3H, d, J = 7Hz), 1.75 (1
H, m), 2.6 (1H, m), 3.0-3.6 (4H
, m), 3.7-4.0 (2H, m), 4.1-4.3
(2H, m), 4.57 (1H, d, J=8Hz) UV
λmax (0.1M 3-morpholinopropanesulfonic acid buffer, pH 7.0): 300 nm (ε=9400
) Example 36 (5R,6S)-2-[(2S,4S)-2-(2,4
-dioxoimidazolidin-5-yl)pyrrolidine-4
-ylthio]-6-[(R)-1-hydroxyethyl]
-1-carbapen-2-em-3-carboxylic acid 1)

0286]

embedded image p-Nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (150 mg, 0 .258 mmol) and (2
S,4S)-2-(2,4-dioxoimidazolidine-
5-yl)-4-(p-methoxybenzylthio)-N-
(p-nitrobenzyloxycarbonyl)pyrrolidine (
Using 120 mg, 0.240 mmol, the compound of Reference Example 28), the same reaction as in Example 1-1) was carried out, and p-
Nitrobenzyl (5R,6S)-2-[(2S,4
S)-2-(2,4-dioxoimidazolidin-5-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]- 1-carbapen-2-em-3-carboxylate (30 mg, yield: 18%) was obtained.

IR(KBr)cm-1:3400,17
80, 1730, 1610, 1520, 1350NMR
(CDCl3+CD3OD)δ:1.32(3H,d,
J=6Hz), 1.78 (1H, m), 2.40 (1H
, m), 3.0 to 3.5 (4H, m), 4.0 to 4.5
(4H, m), 4.73 and 5.04 (1H, s),
5.28 (2H, s), 5.28 and 5.49 (2H
,ABq,J=13Hz),7.57(2H,d,J=
9Hz), 7.67 (2H, d, J=9Hz), 8.1
~8.3 (4H, m) 2)

0288

embedded image The compound obtained in the above reaction (30 mg, 0.042 mm
A reaction similar to Example 1-2) was carried out using
The title compound (11 mg, yield: 66%) was obtained.

IR(KBr)cm-1:3430,17
60,1720,1600,1400 NMR (D2O) δ: 1.26 (3H, d, J = 7Hz
), 1.55 (1H, m), 2.5 (1H, m), 3.
1-3.6 (4H, m), 4.1-4.3 (2H, m)
,4.38(1H,d,J=5Hz)UVλmax(0
．． 1M 3-morpholinopropanesulfonic acid buffer,
pH7.0): 301 nm (ε=4600) Example 37 (1R,5S,6S)-2-[(2R,4S)-2-(
2,4-Dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid dia stereomer A1)

0290]

Allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate ( 220 mg, 0.440 mmol) and (2R,4S)-N-allyloxycarbonyl-2-
(2,4-dioxoimidazolidin-5-ylmethyl)
-4-Tritylthiopyrrolidine diastereomer A
(270 mg, 0.498 mmol, the compound of Reference Example 29), the same reaction as in Example 8-1) was carried out, and allyl (1R,5S,6S)-2-[(2R,4S)
-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-Methyl-1-carbapen-2-em-3-carboxylate diastereomer A (70 mg, yield: 2
6%).

IR(KBr)cm-1:3550,34
80, 3420, 3200, 1780, 1730, 15
50,1420 NMR (CDCl3) δ: 1.26 (3H, d, J=7
Hz), 1.36 (3H, d, J=7Hz), 1.5~
2.5 (4H, m), 2.7 (2H, m), 3.1-3
．． 6 (3H, m), 3.7 (1H, m), 3.8-4.
4 (4H, m), 4.4-4.9 (4H, m), 5.0
~5.5 (4H, m), 5.6 ~ 6.05 (2H, m)
, 6.89 (1H, s), 8.78 (1H, s) 2)

0292

embedded image The compound obtained in the above reaction (70 mg, 0.128 mm
A reaction similar to Example 8-2) was carried out using
The title compound (19 mg, yield: 35%) was obtained.

0293 IR(KBr)cm-1:3400,32
50, 1760, 1720, 1590, 1390NMR
(D2O)δ: 1.15 (3H, d, J=6Hz), 1
．． 22 (3H, d, J=7Hz), 1.7 (1H, m)
, 2.3 (2H, m), 2.75 (1H, m), 3.2
~3.5 (3H, m), 3.5 ~ 3.9 (2H, m),
3.95 (1H, m), 4.2 (2H, m), 4.34
(1H, t, J=6Hz) UVλmax (0.1M
3-morpholinopropanesulfonic acid buffer, pH 7.0
): 298 nm (ε=9300) Example 38 (1R,5S,6S)-2-[(2R,4S)-2-(
2,4-Dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid dia stereomer B1)

0294

embedded image Allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate ( 220 mg, 0.440 mmol) and (2R,4S)-N-allyloxycarbonyl-2-
(2,4-dioxoimidazolidin-5-ylmethyl)
-4-Tritylthiopyrrolidine diastereomer B
Allyl (1R,5S,6S)-2-[(2R,4S)
-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-Methyl-1-carbapen-2-em-3-carboxylate diastereomer B (70 mg, yield: 3
1%).

IR(KBr)cm-1:3420,32
70, 1775, 1730, 1550, 1415 NMR
(CDCl3)δ: 1.27 (3H, d, J=7Hz)
, 1.36 (3H, d, J=7Hz), 1.5-2.1
(4H, m), 2.3 (1H, m), 2.7 (1H, m
), 3.1-3.45 (3H, m), 3.65 (1H,
m), 3.9-4.4 (4H, m), 4.4-4.9 (
4H, m), 5.1-5.6 (4H, m), 5.7-6
．． 1 (2H, m), 6.73 (1H, s), 8.34 (
1H,s) 2)

0296

embedded image The compound obtained in the above reaction (70 mg, 0.128 mm
A reaction similar to Example 8-2) was carried out using
The title compound (18 mg, yield: 33%) was obtained.

IR(KBr)cm-1:3420,32
30, 1760, 1720, 1590, 1395NMR
(D2O)δ: 1.12 (3H, d, J=7Hz), 1
．． 19 (3H, d, J = 7Hz), 1.65 (1H, m
), 2.3 (2H, m), 2.73 (1H, m), 3.
2-3.5 (3H, m), 3.61 (1H, m), 3.
8 (1H, m), 3.94 (1H, m), 4.15 (2
H, m), 4.34 (1H, t, J = 6Hz) UVλm
ax (0.1M 3-morpholinopropanesulfonic acid buffer, pH 7.0): 298 nm (ε=9400) Example 39 Sodium (1R,5S,6S)-2-[(2R,
4S)-2-(2,5-dioxopyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-
1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate 1)

0298

embedded image (2R,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-(2,5-dioxopyrrolidin-3-ylmethyl)pyrrolidine (250 mg
, 0.57 mmol, the compound of Reference Example 30) in methanol (5.0 ml) was added a 2N aqueous sodium hydroxide solution (0.34 ml, 0.68 mmol) under ice cooling, and the mixture was stirred for 30 minutes. 6N hydrochloric acid (0.11 ml, 0.
66 mmol) was added, extracted with methylene chloride, dried (MgSO4), and concentrated to give (2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl).
-2-(2,5-dioxopyrrolidin-3-ylmethyl)pyrrolidine was obtained.

Thiol and p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapene obtained in the above reaction Using 2-m-3-carboxylate (273 mg, 0.46 mmol), the same reaction as in Example 1-1) was carried out to give p-nitrobenzyl (1R,5S,6S)-2-[(2R, 4
S)-2-(2,5-dioxopyrrolidin-3-ylmethyl)-N-(p-nitrobenzyloxycarbonyl)
pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (229 mg, yield: 67%
) was obtained.

[0300] NMR (CDCl3) δ: 1.28 (3H
, d, J=8Hz), 1.38(3H, d, J=8Hz
), 5.24 (4H, br s), 7.54 (4H,
d, J=8Hz), 8.25 (4H, d, J=8Hz)
2)

0301]

embedded image The compound obtained in the above reaction (210 mg, 0.28 mm
A reaction similar to Example 1-2) was carried out using
The title compound (26 mg, yield: 21%) was obtained.

0302 IR(KBr)cm-1:3400,29
50, 1760, 1720, 1600, 1380, 11
80 NMR (D2O) δ: 1.10 (3H, d, J = 6Hz
), 1.16 (3H, d, J = 6Hz), 1.58 (1
H, m), 2.00 (1H, m), 2.46 (1H, m
), 2.66 (1H, m), 2.94 (2H, m), 3
．． 28 (2H, m), 3.54 (1H, m), 3.74
(1H, m), 4.12 (2H, m) HPLC; Mobile phase: 0.01M phosphate buffer (pH 6.5) -
Methanol (85:15), flow rate: 0.8ml/min
, other conditions are the same as in Example 1, retention time: 4.28
min Example 40 (1R,5S,6S)-2-[(2S,4S)-2-(
5-oxopiperazin-2-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1
-Methyl-1-carbapen-2-em-3-carboxylic acid diastereomer A 1)

0303]

embedded image (2S,4S)-N-allyloxycarbonyl-4-acetylthio-2-(1-allyloxycarbonyl-5-
Oxopiperazin-2-yl)pyrrolidine diastereomer A (250 mg, 0.60 mmol, Reference Example 3
Using compound No. 1), (2S,4S)-N-allyloxycarbonyl-2-
(1-allyloxycarbonyl-5-oxopiperazin-2-yl)-4-mercaptopyrrolidine diastereomer A was obtained.

Thiol and allyl obtained in the above reaction
(1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (242 mg, 0.48 mmol ), allyl (1R,5S,6S
)-2-[(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5-oxopiperazin-2-yl)pyrrolidin-4-ylthio]-6
-[(R)-1-hydroxyethyl]-1-methyl-1
-Carbapen-2-em-3-carboxylate diastereomer A (222 mg, yield: 74%) was obtained.

[0305] NMR (CDCl3) δ: 1.26 (3H
, d, J=6Hz), 1.38(3H, d, J=6Hz
), 1.80 (1H, m), 2.50 (1H, m), 3
．． 0-5.0 (19H, m), 5.20-5.60
(6H, m), 5.96 (3H, m) 2)

0306]

embedded image The compound obtained in the above reaction (diastereomer A, 22
Example 9-2)
The title compound (diastereomer A, 88
mg, yield: 60%).

0307 IR(KBr)cm-1:3400,29
50, 1760, 1660, 1600, 1380NMR
(D2O)δ: 1.20 (3H, d, J=6Hz), 1
．． 26 (3H, d, J = 6Hz), 1.78 (1H, m
), 2.64 (1H, m), 3.10-3.80 (10
H, m), 4.00 (1H, m), 4.22 (2H, m
) HPLC; Flow rate: 0.8 ml/min, other conditions are the same as Example 1, retention time: 3.02 min Example 41 (1R,5S,6S)-2-[(2S,4S)-2-(
5-oxopiperazin-2-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1
-Methyl-1-carbapen-2-em-3-carboxylic acid diastereomer B 1)

0308

embedded image (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5-
Oxopiperazin-2-yl)pyrrolidine diastereomer B (200 mg, 0.48 mmol, Reference Example 3
(2S,4S)-N-allyloxycarbonyl-2-
(1-allyloxycarbonyl-5-oxopiperazin-2-yl)-4-mercaptopyrrolidine diastereomer B was obtained.

Thiol and allyl obtained in the above reaction
(1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (243 mg, 0.48 mmol ), allyl (1R,5S,6S
)-2-[(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5-oxopiperazin-2-yl)pyrrolidin-4-ylthio]-6
-[(R)-1-hydroxyethyl]-1-methyl-1
-Carbapen-2-em-3-carboxylate diastereomer B (246 mg, yield: 65%) was obtained.

[0310] NMR (CDCl3) δ: 1.24 (3H
, d, J=6Hz), 1.38(3H, d, J=6Hz
), 1.80 (1H, m), 2.60 (1H, m), 3
．． 10-3.80 (10H, m), 4.0-5.0 (9
H, m), 5.20-5.60 (6H, m), 5.96
(3H, m) 2)

0311]

embedded image The compound obtained in the above reaction (diastereomer B, 24
Example 9-2)
The title compound (diastereomer B, 53
mg, yield: 33%).

IR(KBr)cm-1:3400,17
60,1660,1600,1380 NMR (D2O) δ: 1.18 (3H, d, J = 6Hz
), 1.20 (3H, d, J = 6Hz), 1.76 (1
H, m), 2.64 (1H, m), 3.10 to 3.80
(10H, m), 3.94 (1H, m), 4.18 (2
H, m) HPLC; Mobile phase: 0.1M phosphate buffer (pH 6.5)-methanol (85:15), flow rate: 0.8ml/min,
Other conditions are the same as Example 1, holding time: 3.92 min
Example 42 (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(piperidin-4-yl)pyrrolidin-4-ylthio]-1-carbapene -2
-M-3-carboxylic acid 1)

0313]

embedded image p-Nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (270 mg, 0 .46 mmol) and (2S
,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidine (216 mg, 0.40 mmol, Reference Example 32) The same reaction as in Example 1-1) was carried out using p-
Nitrobenzyl (5R,6S)-6-[(R)-1
-hydroxyethyl]-2-[(2S,4S)-N-(
p-nitrobenzyloxycarbonyl)-2-[N-(
p-nitrobenzyloxycarbonyl)piperidine-4
-yl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (267 mg, yield: 65.6%) was obtained.

IR(KBr)cm-1:1780,17
00,1520,1340 NMR (CDCl3) δ: 1.35 (3H, d, J=6
Hz), 2.76 (2H, m), 3.54 (1H, m)
, 4.00 (1H, m), 5.24 (5H, m), 5.
52 (1H, d, J = 14Hz), 7.52 (4H, d
, J=8Hz), 7.66 (2H, d, J=8Hz),
8.22 (6H, m) 2)

0315]

embedded image The compound obtained in the above reaction (265 mg, 0.30 mm
A reaction similar to Example 1-2) was carried out using
The title compound (33 mg, yield: 28.5%) was obtained.

IR(KBr)cm-1:1760,15
90,1390 NMR (D2O) δ: 1.26 (3H, d, J = 6Hz
), 1.31-1.56 (3H, m), 1.69 (1H
, m), 1.85-2.14 (2H, m), 2.50 (
1H, m), 2.81-3.06 (4H, m), 3.1
0 (3H, m), 3.40 (3H, m), 3.74 (1
H, m), 4.20 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 3.06 min Example 43 (1R,5S,6S)-6-[(R)-1-hydroxy ethyl]-1-methyl-2-[(2S,4S)-2-(
piperidin-4-yl)pyrrolidin-4-ylthio]-
1-carbapen-2-em-3-carboxylic acid 1)

0317]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (245 mg, 0.41 mm
ol) and (2S,4S)-4-mercapto-N-(
p-nitrobenzyloxycarbonyl)-2-[N-(
p-nitrobenzyloxycarbonyl)piperidine-4
-yl]pyrrolidine (216 mg, 0.40 mmol,
Using the compound of Reference Example 32), the same reaction as in Example 1-1) was carried out to produce p-nitrobenzyl (1R,5S,
6S)-6-[(R)-1-hydroxyethyl]-1-
Methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidin-4-ylthio]-1- Carbapen-2-M-3
-Carboxylate (279 mg, yield: 76.2%)
I got it.

IR(KBr)cm-1:1770,17
00,1520,1340 NMR (CDCl3) δ: 1.28 (3H, t, J=7
Hz), 1.36 (3H, t, J=6Hz), 1.44
~1.84 (3H, m), 5.15 (5H, m), 5.
53 (1H, d, J = 14Hz), 7.56 (4H, d
, J=8Hz), 7.68 (2H, d, J=8Hz),
8.24 (6H, m) 2)

0319]

embedded image The compound obtained in the above reaction (275 mg, 0.31 mm
A reaction similar to Example 1-2) was carried out using
The title compound (57 mg, yield: 46.6%) was obtained.

IR(KBr)cm-1:1750,15
90,1390 NMR (D2O) δ: 1.19 (3H, d, J = 7Hz
), 1.27 (3H, d, J=6Hz), 1.28~1
．． 58 (3H, m), 1.70 (1H, m), 1.85
~2.15 (2H, m), 2.46 (1H, m), 2.
78-3.18 (5H, m), 3.40 (4H, m),
3.76 (1H, m), 4.22 (2H, m) HPLC
(Conditions are the same as Example 1) Retention time: 3.28 min Example 44 (1R, 5S, 6S)-2-[(2S,4S)-2-(
2-Carbamoylpyrrolidin-4-yl)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid diastereomer III 1)

0321]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (185mg, 0.31mm
ol) and (2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereo Using Mer III (175 mg, 0.31 mmol, compound of Reference Example 33), the same reaction as in Example 1-1) was carried out, and p-nitrobenzyl (1R,5S,6S)
-2-[(2S,4S)-2-[2-carbamoyl-N
-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1
-hydroxyethyl]-1-methyl-1-carbapene-
2-m-3-carboxylate (218 mg, yield:
76.3%).

IR(KBr)cm-1:1770,17
00,1600,1520,1340 NMR (CDCl3) δ: 1.27 (3H, d, J=7
Hz), 1.36 (3H, d, J=6Hz), 4.02
~4.40 (5H, m), 5.22 (5H, m), 5.
52 (1H, d, J = 14Hz), 7.50 (4H, d
, J=8Hz), 7.66 (2H, d, J=8Hz),
8.22 (6H, m) 2)

0323]

embedded image The compound obtained in the above reaction (218 mg, 0.24 mm
A reaction similar to Example 1-2) was carried out using
The title compound (46 mg, yield: 45.6%) was obtained.

IR(KBr)cm-1:1760,16
80,1600,1390 NMR (D2O) δ: 1.19 (3H, d, J = 7Hz
), 1.27 (3H, d, J=6Hz), 1.40~1
．． 68 (2H, m), 2.45 (2H, m), 2.60
(1H, m), 2.82 (1H, m), 3.04-3.
47 (6H, m), 3.85 (1H, m), 3.98 (
1H, t, J = 8Hz), 4.21 (2H, m) HPL
C (conditions are the same as Example 1) Retention time: 2.15 min Example 45 (1R, 5S, 6S)-2-[(2S, 4S)-2-[
N-(carbamoylmethyl)pyrrolidin-3-yl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid diastereo Mar A and B1)

0325]

embedded image p-Nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate (570mg, 0.96mm
ol) and (2S,4S)-2-[N-(carbamoylmethyl)pyrrolidin-3-yl]-4-mercapto-
N-(p-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate (540mg,
The same reaction as in Example 1-1) was carried out using p-nitrobenzyl (1R,5S,6
S)-2-[(2S,4S)-2-[N-(carbamoylmethyl)pyrrolidin-3-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio-6-[(R) -1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (
197 mg, yield: 27.3%) was obtained.

IR(KBr)cm-1:1770,17
00,1520,1350 NMR (CDCl3) δ: 1.28 (3H, t, J=7
Hz), 1.35 (3H, t, J=6Hz), 3.61
(1H, m), 4.04-4.35 (4H, m), 5.
10-5.34 (3H, m), 5.53 (1H, d, J
= 14Hz), 7.52 (2H, d, J = 8Hz), 7
．． 66 (2H, d, J = 8Hz), 8.22 (4H, m
) 2)

0327]

embedded image The compound obtained in the above reaction (195 mg, 0.26 mm
A reaction similar to Example 1-2) was carried out using
Diastereomer A of the title compound (27 mg, yield: 2
3.8%) and diasteomer B (27 mg, yield:
23.8%) were obtained. Diastereomer A IR (KBr) cm-1: 1760, 1670, 159
0,1390 NMR (D2O) δ: 1.20 (3H, t, J = 7Hz
), 1.29 (3H, t, J=6Hz), 1.45~1
．． 78 (2H, m), 2.15 (1H, m), 2.43
~2.64 (3H, m), 2.84 (2H, m), 3.
02 (1H, m), 3.20 (1H, dd, J=12,
4Hz), 3.30-3.54 (6H, m), 3.92
(1H, m), 4.23 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 3.28 min Diastereomer B IR (KBr) cm-1: 1760, 1670, 159
0,1390 NMR (D2O) δ: 1.22 (3H, t, J = 7Hz
), 1.30 (3H, t, J = 6Hz), 1.66 (2
H, m), 2.17 (1H, m), 2.52-2.80
(3H, m), 2.87 (2H, t, J=7Hz), 3
．． 03 (1H, m), 3.22-3.64 (7H, m)
, 3.94 (1H, m), 4.24 (2H, m) HPLC (conditions are the same as Example 1) Retention time: 6.16 min Example 46 (1R,5S,6S)-6-[(R )-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(
pyrrolidin-2-yl)pyrrolidin-4-ylthio]-
1-Carbapen-2-em-3-carboxylic acid diastereomer A 1)

0328

embedded image (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)pyrrolidine diastereomer A (
(2S,
4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)-4-mercaptopyrrolidine diastereomer A was obtained.

Thiol and allyl obtained in the above reaction
(1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (243mg, 0.487mmol ), allyl (1R,5S,6
S)-2-[(2S,4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidine-
2-yl)pyrrolidin-4-ylthio]-6-[(R)
-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer A (160 mg, yield: 55.7%) was obtained.

IR(KBr)cm-1:1780,17
00,1550,1410 NMR (CDCl3) δ: 1.25 (3H, d, J=7
Hz), 1.34 (3H, d, J=6Hz), 1.5~
2.1 (5H, m), 2.3-2.9 (2H, m), 3
．． 07 (1H, t, J = 11Hz), 3.2-3.8 (
6H, m), 4.1-4.4 (4H, m), 4.5-5
．． 0 (6H, m), 5.2-5.6 (6H, m), 5.
8-6.2 (3H, m) 2)

0331]

embedded image The compound obtained in the above reaction (diastereomer A; 15
Example 9-2
), the title compound (diastereomer A; 2
8.5 mg, yield: 28%) was obtained.

IR(KBr)cm-1:1750,15
90,1390 NMR (D2O) δ: 1.16 (3H, d, J = 7Hz
), 1.24 (3H, d, J = 6Hz), 1.42 (1
H, m), 1.74 (1H, m), 2.00 (2H, m
), 2.24 (1H, m), 2.53 (1H, m), 2
．． 87 (1H, dd, J=12,4Hz), 3.1~3
．． 6 (7H, m), 3.78 (1H, m), 4.1-4
．． 3(2H,m) HPLC (conditions are the same as Example 1) Retention time: 2.8 min Example 47 (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl- 2-[(2S,4S)-2-(
pyrrolidin-2-yl)pyrrolidin-4-ylthio]-
1-Carbapen-2-em-3-carboxylic acid diastereomer B 1)

0333]

embedded image (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)pyrrolidine diastereomer B (
(2S,
4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)-4-mercaptopyrrolidine diastereomer B was obtained.

Thiol and allyl obtained in the above reaction
(1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (174 mg, 0.348 mmol ), allyl (1R,5S,6
S)-2-[(2S,4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidine-
2-yl)pyrrolidin-4-ylthio]-6-[(R)
-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer B (109 mg, yield: 53.1%) was obtained.

IR(KBr)cm-1:1780,17
00,1550,1410 NMR (CDCl3) δ: 1.26 (3H, d, J=7
Hz), 1.35 (3H, d, J=6Hz), 1.65
(2H, m), 1.93 (3H, m), 2.3-2.7
(2H, m), 3.1~3.8 (6H, m), 4.0~
4.5 (4H, m), 4.5-5.0 (6H, m), 5
．． 1-5.6 (6H, m), 5.8-6.1 (3H, m
) 2)

0336]

embedded image The compound obtained in the above reaction (diastereomer B; 10
Example 9-2
), the title compound (diastereomer B; 1
0.0 mg, yield: 15%) was obtained.

IR(KBr)cm-1:1750,15
90,1390 HPLC (conditions are the same as Example 1) Retention time: 3.4 min Example 48 (1R,5S,6S)-2-[(2S,4S)-2-(
5-oxopiperazin-3-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1
-Methyl-1-carbapen-2-em-3-carboxylic acid 1)

0338]

embedded image (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5-
Oxopiperazin-3-yl)pyrrolidine (168mg
(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5-oxopiperazin-3-yl)- in the same manner as in Example 39-1). 4-Mercaptopyrrolidine was obtained.

Thiol and allyl obtained in the above reaction
(1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (200mg, 0.40mmol ), allyl (1R,5S,6S
)-2-[(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5-oxopiperazin-3-yl)pyrrolidin-4-ylthio]-6
-[(R)-1-hydroxyethyl]-1-methyl-1
-carbapen-2-m-3-carboxylate (15
6 mg, yield: 58%) was obtained.

[0340] NMR (CDCl3) δ: 1.28 (3H
, d, J=8Hz), 1.34(3H, d, J=8Hz
), 1.80 (1H, m), 2.60 (1H, m), 2
．． 90-5.00 (19H, m), 5.20-5.60
(6H, m), 5.96 (3H, m)2)

0341]

embedded image The compound obtained in the above reaction (156 mg, 0.25 mmol
) and in the same manner as in Example 9-2) to prepare the title compound (
50 mg, yield: 48%) was obtained.

[0342] NMR (D2O) δ: 1.24 (3H, d
, J=8Hz), 1.30 (3H, d, J=8Hz),
1.76 (1H, m), 2.70 (1H, m), 3.0
0 (1H, m), 3.10 to 4.10 (10H, m),
4.26 (2H, m) HPLC; Mobile phase: 0.01M phosphate buffer (pH 6.5):
Methanol (85/15), flow rate 0.8 ml/min,
Other conditions are the same as Example 1, holding time: 4.91 min
Reference Example 1 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidone-4
-yl)pyrrolidine 1)

0343]

embedded image L-hydroxyproline methyl ester hydrochloride (8
．． 2 g, 45.2 mmol) in an aqueous solution (40 ml),
triethylamine (7.54 ml, 54.2 mm) at room temperature.
ol) and then 2-(tert-butoxycarbonylthio)-4,6-dimethylpyrimidine (10.8 g
, 45 mmol) in dioxane (80 ml) was added. After stirring the reaction solution at room temperature for 1.5 hours, dioxane was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (250 ml). The organic layer was washed successively with 0.1N aqueous sodium hydroxide solution, dilute hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM
C-300, 5% methanol-methylene chloride),
N-tert-butoxycarbonyl-L-hydroxyproline methyl ester (9.3 g, yield: 84%)
I got it.

NMR (CDCl3) δ: 1.38-1.
48 (9H, m), 1.98-2.38 (2H, m),
3.40-3.72 (2H, m), 3.86 (3H, s
), 4.35-4.58 (2H, m)2)

0345]

embedded image Compound obtained in the above reaction (14.0 g, 57.1 mm
ol) in N,N-dimethylformamide (150 m
l) at room temperature in a nitrogen stream, imidazole (4.95 g
, 72.7 mmol) and tert-butyldimethylsilyl chloride (10.7 g, 71.0 mmol) were added and the solution was stirred at room temperature overnight. Ethyl acetate (500 ml) was added to the reaction solution, and the organic layer was washed twice with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (2S,4R)-N-tert-
Butoxycarbonyl-4-tert-butyldimethylsiloxy-L-proline methyl ester (19 g, yield: 92.6%) was obtained. 3)

0346]

embedded image The compound obtained in the above reaction (19.0 g, 52.9 mm
In a nitrogen stream, lithium chloride (4.49 g, 106 mmol) was added to a tetrahydrofuran solution (180 ml) of
), then sodium borohydride (4.0 g, 106
mmol) was added. Add ethanol (180
ml) was added dropwise and the reaction solution was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution (100 ml) was added to the reaction mixture to decompose excess reducing agent, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (500 ml), and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM
C-300, hexane-ethyl acetate (5:1)] to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-hydroxymethylpyrrolidine (14.88 g, yield Rate: 84.9
%) was obtained. 4)

0347]

embedded image Oxalyl chloride (2.89 ml) at -78°C in a nitrogen stream
, 33.9 mmol) in methylene chloride solution (100 ml
) to dimethyl sulfoxide (3.6 ml, 50.7 mm
A methylene chloride solution (15 ml) of ol) was added dropwise, and the reaction solution was stirred at the same temperature for 30 minutes. -78℃ to this mixture
(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-hydroxymethylpyrrolidine (8.0 g, 24.2 mmol)
A methylene chloride solution (50 ml) of
ml, 79.8 mmol) and further stirred for 30 minutes. The reaction mixture was poured into methylene chloride (200ml),
The organic layer was washed sequentially with dilute hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain (2S, 4R
)-N-tert-butoxycarbonyl-4-tert
An oily residue of -butyldimethylsiloxy-2-formylpyrrolidine was obtained.

Ethyl diethoxyphosphorylacetate (6.0 g, 26.8 mmol) was added to a suspension of 60% sodium hydride (1.0 g, 25.0 mmol) in tetrahydrofuran (100 ml) under ice cooling in a nitrogen stream. was added, and the solution was stirred at the same temperature for 30 minutes. The (2S,4R)-N-ter obtained in the reaction was added to this reaction solution.
A tetrahydrofuran solution (20 ml) of t-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-formylpyrrolidine was added dropwise, and the mixture was further stirred at the same temperature for 30 minutes. The reaction solution was extracted with ethyl acetate (150 ml), and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM
C-300, hexane-ethyl acetate (10:1)] to give (E)-3-[(2S,4R)-N-tert-
Butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]acrylic acid ethyl ester (9.4 g, yield: 97.5%) was obtained.

[0349] NMR (CDCl3) δ: 0.06 (6H
, s), 0.88 (9H, s), 1.30 (3H, d,
J=7Hz), 1.44 (9H, br s), 1.8
4 (1H, m), 2.10 (1H, m), 3.48 (2
H, m), 4.12 (2H, q, J=7Hz), 4.3
5 (1H, m), 5.88 (1H, br d, J=1
6Hz), 6.86 (1H, m) 5)

0350]

embedded image In a nitrogen stream, the compound obtained in the above reaction (9.0 g, 2
2.6 mmol) in nitromethane (33 ml),
1,1,3,3-tetramethylguanidine (5.
8 ml, 46.2 mmol) was added dropwise, and the mixture was stirred at the same temperature overnight. Add ethyl acetate (200ml) to the reaction solution.
was added, and the organic layer was sequentially washed with dilute hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wa
kogelTM C-300, hexane-ethyl acetate (10:1)] to give 3-[(2S,4R)-Nt
ert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-4-nitrobutyric acid ethyl ester (10.1 g, yield: 97.3%
) was obtained.

[0351] NMR (CDCl3) δ: 0.06 (6H
, s), 0.86 (9H, s), 1.27 (3H, d,
J=7Hz), 1.48 (9H, br s), 1.7
3 (1H, m), 2.00 (1H, m), 2.44 (2
H, m), 3.16 (1H, m), 4.16 (4H, m
), 4.33 (1H, m), 4.53 (1H, m) 6)

0352]

embedded image The compound obtained in the above reaction (3.6 g, 7.8 mmol
) to an ethanol solution (50 ml) of Raney nickel (
W-2 type, 3.0 ml) was added, and the mixture was heated in a hydrogen stream.
Stir overnight at room temperature. The catalyst was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure. The residue was dissolved in benzene (50ml) and refluxed overnight. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakoge column chromatography).
(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2
-(2-pyrrolidon-4-yl)pyrrolidine (1.87
g, yield: 62.2%).

[0353] NMR (CDCl3) δ: 0.06 (6H
, s), 0.86 (9H, s), 1.47 (9H, s)
, 1.72 (1H, m), 1.88-2.48 (3H,
m), 2.95-3.75 (5H, m), 4.13 (1
H, m), 4.30 (1H, m) 7)

0354]

embedded image The compound obtained in the above reaction (1.87 g, 4.87 mm
ol) was dissolved in 80% trifluoroacetic acid aqueous solution (20 ml) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dioxane (10 ml) and water (10 ml).
1) was dissolved in the mixture of 1). After adjusting the pH to 8 with 1N aqueous sodium hydroxide solution, 4,6-dimethyl-2-(
p-Nitrobenzyloxycarbonylthio)pyrimidine (1.55 g, 4.86 mmol) was added and the solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM C-300, 3%
(2S,4R)-
4-hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine (769 mg, yield: 45.2%) was obtained.

NMR (CDCl3) δ: 1.72-2.
52 (5H, m), 2.98-3.58 (3H, m),
3.78 (1H, m), 4.24 (1H, m), 4.4
8 (1H, m), 5.25 (2H, br s), 7.
54 (2H, d, J=9Hz), 8.24 (2H, d,
J=9Hz) 8)

0356]

embedded image Under a nitrogen stream, the compound obtained in the above reaction (302 mg,
0.87 mmol) in tetrahydrofuran solution (10 m
triphenylphosphine (567 mg, 2.16
mmol), and then, under ice-cooling, add diethyl azodicarboxylate (0.341 ml, 2.17 mmol).
) was added dropwise. After stirring the reaction solution for 30 minutes under ice cooling, thioacetic acid (0.155 ml, 2.17 mmol) was added dropwise. After stirring at room temperature for 2 hours, the reaction solution was extracted with ethyl acetate (100 ml), and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (W
akogelTM C-300) and hexane-
By elution with ethyl acetate (1:1), (2S,4S)-4
(2R,4S )-4-
Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine (166 mg, yield: 47.1%) was obtained. (2S,4S) isomer IR (KBr) cm-1: 1700, 1520, 134
0,1110 NMR (CDCl3) δ: 1.70 (1H, m), 1.
98-2.62 (4H, m), 2.37 (3H, s),
3.17 (2H, m), 3.42 (1H, m), 3.8
7 (1H, m), 4.05-4.35 (2H, m), 5
．． 24 (2H, br s), 7.55 (2H, d, J
= 9Hz), 8.26 (2H, d, J = 9Hz) (2R
, 4S) isomer IR (KBr) cm-1: 1700, 1520, 135
0,1120 NMR (CDCl3) δ: 1.68 (1H, m), 2.
30-2.95 (4H, m), 2.38 (3H, s),
3.20 (1H, m), 3.55 (1H, m), 3.8
8 (2H, m), 4.06-4.30 (2H, m), 5
．． 26 (2H, br s), 7.56 (2H, d, J
=9Hz), 8.26 (2H, d, J = 9Hz)9)

0357]

embedded image In a nitrogen stream and under ice cooling, the (2S, 4S) obtained in the above reaction
) 1N aqueous sodium hydroxide solution (0.42 ml) was added dropwise to a methanol solution (10 ml) of the isomer (166 mg, 0.41 mmol), and the solution was stirred at the same temperature for 15 min.
Stir for a minute. Add 1N hydrochloric acid (0.45m
After dropping 1), the reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (70 ml). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-
2-(2-pyrrolidon-4-yl)pyrrolidine (140
mg, yield: 94%). Reference Example 2 (2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidone-4
-yl)pyrrolidine

0358]

embedded image (2R,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidone-
4-yl)pyrrolidine [166 mg, 0.41 mmol
, Reference Example 1-9) using the compound of Reference Example 1-8)]
A similar reaction was carried out to obtain the title compound (140 mg, yield:
94%). Reference example 3 (2S,4S)-2-(2-azetidinon-4-yl)
-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer B1)

0359]

embedded image [(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine-
2-yl]acrylic acid ethyl ester [2.18g
, 5.46 mmol, Compound of Reference Example 1-4)] was added benzylamine (1.2 ml, 11 mmol). After stirring at room temperature for 5 days, the mixture was subjected to silica gel column chromatography [WakogelTM C-30
0, hexane-ethyl acetate (3:1)] to give 3-benzylamino-3-[(2S,4R)-N-tert-
Butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]propionic acid ethyl ester (1.95 g, yield: 70.5%) was obtained.

[0360] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.24 (3H, t,
J=8Hz), 1.44 (9H, s), 1.90 (1H
, m), 2.35 (2H, m), 3.26 (1H, m)
, 3.89 and 3.96 (2H, ABq, J=8Hz
), 4.14 (2H, q, J = 8Hz), 4.39 (1
H, m), 7.31 (5H, m)2)

0361]

embedded image The compound obtained in the above reaction (1.98 g, 3.9 mmo
l) in ethanol solution (30 ml) at room temperature.
Aqueous sodium hydroxide solution (4.3 ml) was added dropwise, and the solution was stirred at the same temperature overnight. 1N hydrochloric acid (4.3 ml) was added to the reaction solution, and the solution was concentrated under reduced pressure. Tetrahydrofuran (50 ml) was added to the residue, and insoluble materials were filtered off. The organic layer was dried with anhydrous magnesium sulfate,
Concentrated under reduced pressure. The obtained oil (1.83 g) was dissolved in acetonitrile (380 ml), and triphenylphosphine (1.2 g, 4.58 mmol) was dissolved in a nitrogen stream.
and 2,2'-dipyridyl disulfide (1.01 g
, 4.58 mmol) and the solution was heated at 80°C for 4.58 mmol).
Stirred for 5 hours. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (150 ml). The organic layer was washed with a 0.1N aqueous sodium hydroxide solution, water, and saturated saline in this order.
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakog
elTM C-300, hexane-ethyl acetate (10
:1→3:1)], (2S,4R)-2-(N-
benzyl-2-azetidinon-4-yl)-N-ter
t-Butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine diastereomer B (1.0
7 g, yield: 60.7%, a highly polar compound) and diastereomer A (0.47 g, yield: 26.8%) were obtained. Diastereomer B IR (KBr) cm-1: 1730, 1690, 139
0,1170NMR(CDCl3)δ:0.06(6H
, s), 0.88 (9H, s), 1.50 (9H, br
s), 2.54 (1H,br d,J=14Hz
), 2.93 (1H, dd, J=14,4Hz), 3.
16 (1H, dd, J = 12,4Hz), 7.35 (5
H, m) Diastereomer A IR (KBr) cm-1: 1760, 1700, 140
0,1260 NMR (CDCl3) δ: 0.04 (6H, s), 0.
85 (9H, s), 1.45 (9H, br s), 1
．． 84 (2H, m), 2.58 (1H, br d, J
= 16Hz), 2.92 (2H, m), 3.44 (1H
, m), 3.95-4.30 (4H, m), 4.60 (
1H, m), 7.30 (5H, m) 3)

0362]

embedded image Diastereomer B (470 mg,
0.98 mmol) of tetrahydrofuran (10 ml)
and tert-butyl alcohol (1 ml) at -78°C was added liquid ammonia (approximately 30 ml). Metallic sodium (100 mg, 4.0 mg) was added to the reaction solution at the same temperature.
35 mmol) was added. After stirring for 15 minutes, ammonium chloride (465 mg, 8.69 mmol) was added, the reaction mixture was returned to room temperature, and ammonia was distilled off. The residue was extracted with ethyl acetate (100 ml), and the organic layer was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate,
Concentrate under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, hexane-ethyl acetate (1:1)] to give (2S,4R)-
2-(2-azetidinon-4-yl)-N-tert-
Butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine diastereomer B (340 mg
, yield: 89.1%).

IR(KBr)cm-1:1750,17
00,1380,1260 NMR (CDCl3) δ: 0.06 (6H, s), 0.
87 (9H, s), 1.47 (9H, s), 1.61 (
1H, m), 2.02 (1H, m), 2.62 (1H,
br d, J=16Hz), 3.02 (1H, dd,
J=16,6Hz), 3.33 (1H, m), 3.50
(2H, m), 4.05 (1H, m), 4.30 (1H
, m) 4)

0364

embedded image The compound obtained in the above reaction (340 mg, 0.88 mm
ol) in methylene chloride solution (3 ml) in a nitrogen stream,
Under ice cooling, anisole (1 drop) and trifluoroacetic acid (
3 ml) was added dropwise. The reaction solution was stirred for 1 hour under ice cooling and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 m
1) and add triethylamine (1.2 ml) under ice cooling.
, 8.6 mmol) and 4,5-dimethyl-2-(p
-nitrobenzyloxycarbonylthio)pyrimidine (
280 mg, 0.88 mmol) and 1.5 mg at room temperature.
Stir for hours. The reaction solution was extracted with ethyl acetate (70 ml), and the organic layer was extracted with 0.1N aqueous sodium hydroxide solution,
The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (5
ml) and dissolved in 46% hydrofluoric acid (0.5 ml) at room temperature.
l) was added dropwise. After stirring at room temperature for 1.5 hours, the reaction solution was extracted with ethyl acetate (70 ml), and the organic layer was washed successively with 5% aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Concentrated. The residue was subjected to silica gel column chromatography (WakogelTM C-
300,3% methanol-chloroform), (2
S,4R)-2-(2-azetidinon-4-yl)-4
-Hydroxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer B (177mg
, yield: 60.3%).

IR(KBr)cm-1:1750,17
00,1520,1340 NMR (CDCl3) δ: 1.72 (1H, m), 2.
14 (1H, m), 2.64 (1H, d, J = 14Hz
), 3.06 (2H, m), 3.57 (1H, m), 3
．． 74 (1H, m), 4.12 (1H, m), 4.44
(1H, m), 5.22 (2H, br s), 7.5
2 (2H, d, J = 8Hz), 8.22 (2H, d, J
=8Hz) 5)

0366]

embedded image In a nitrogen stream and under ice-cooling, the compound (17
Triphenylphosphine (347 mg, 0.53 mmol) in tetrahydrofuran solution (10 ml)
1.32 mmol) and then diethyl azodicarboxylate (0.208 ml, 0.132 mmol).
l) was added dropwise. After stirring the reaction solution for 30 minutes under ice-cooling, thioacetic acid (95 μl, 0.132 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 3 hours. The reaction solution was extracted with ethyl acetate (50 ml), and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM C-300, ethyl acetate) to obtain (2S,4S)-4-acetylthio-
2-(2-Azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer B (77 mg, yield: 37.1%) was obtained.

NMR (CDCl3) δ: 1.65 (1H
, m), 2.38 (3H, s), 3.08 (1H, dd
, J=16,4Hz), 3.30(1H,t, J=9H
z), 3.64-4.28 (4H, m), 5.25 (2
H, brs), 7.55 (2H, d, J=8Hz), 8
．． 26 (2H, d, J=8Hz)6)

0368

embedded image In a nitrogen stream and under ice cooling, the compound (77
mg, 0.22 mmol) in methanol solution (10 ml
), 0.1N sodium hydroxide aqueous solution (0.19
6 ml) was added dropwise. After stirring the reaction solution for 15 minutes under ice-cooling, 1N hydrochloric acid (0.21 ml) was added, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50
(2S,4S)-2-(2-azetidinone-
4-yl)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer B (67 mg, yield: 97%) was obtained. Reference example 4 (2S,4S)-2-(2-azetidinon-4-yl)
-4-Mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A1)

0369]

embedded image (2S,4R)-2-(N-benzyl-2-azetidinon-4-yl)-N-tert-butoxycarbonyl-
4-tert-butyldimethylsiloxypyrrolidine
Diastereomer A (500mg, 1.05mmol)
and metallic sodium (75 mg, 3.26 mmol)
The same reaction as in Reference Example 3-3) was carried out using (2S
,4R)-2-(2-azetidinon-4-yl)-N-
tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine diastereomer A (
360 mg, yield: 88.4%) was obtained.

0370 IR(KBr)cm-1:1760,17
40,1690,1390,1260 NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.47 (9H, s), 1.93 (
2H, m), 2.66 (1H, d, J=16Hz), 2
．． 97 (1H, ddd, J=16,5,2Hz), 3.
26 (1H, dd, J = 12,5Hz), 3.55 (1
H, m), 4.00-4.44 (3H, m)2)

0371]

embedded image The compound obtained in the above reaction (350 mg, 0.90 mm
The same reaction as in Reference Example 3-4) was carried out using
(2S,4R)-2-(2-azetidinon-4-yl)
-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (185
mg, yield: 61%).

IR(KBr)cm-1:1740,16
70,1520,1440,1340 NMR (CDCl3) δ: 2.06 (2H, m), 2.
70 (1H, d, J = 16Hz), 3.02 (1H, b
r d, J=16Hz), 3.47 (1H, m), 3
．． 76 (1H, m), 4.16 (1H, m), 4.34
(1H, m), 4.50 (1H, m), 5.26 (2H
, br s), 7.54 (2H, d, J=8Hz),
8.24 (2H, d, J=8Hz) 3)

0373]

embedded image The compound obtained in the above reaction (185 mg, 0.55 mm
ol), diethyl azodicarboxylate (0.2
The same reaction as in Reference Example 3-5) was carried out using 18 ml, 0.138 mmol), triphenylphosphine (365 mg, 0.138 mmol) and thioacetic acid (99 μl, 0.138 mmol), and (2S,4S)- 4-acetylthio-2-(2-azetidinon-4-yl)-N
-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (107 mg, yield: 49.3
%) was obtained.

[0374] NMR (CDCl3) δ: 1.87 (1H
, m), 2.36 (3H, s), 2.52 (1H, m)
, 2.78 (1H, m), 3.04 (1H, br d
, J=12Hz), 3.18(1H, t, J=10Hz
), 3.80-4.32 (4H, m), 5.24 (2H
, br s), 7.54 (2H, d, J=8Hz),
8.23 (2H, d, J=8Hz) 4)

0375]

embedded image The compound obtained in the above reaction (107 mg, 0.27 mm
ol) and 1N aqueous sodium hydroxide solution (0.2
7 ml), the same reaction as in Reference Example 3-6) was carried out, and (2S,4S)-2-(2-azetidinon-4-yl)-4-mercapto-N-(p-nitrobenzyloxycarbonyl ) Pyrrolidine diastereomer A (90
．． 8 mg, yield: 95%) was obtained. Reference Example 5 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine 1)

0376]

embedded image Compound obtained in Reference Example 1-6) (1.46 g, 3.8
Triethylamine (0.53 ml, 3.0 mmol) was added to a methylene chloride solution (15 ml) at room temperature in a nitrogen stream.
81 mmol), 4-dimethylaminopyridine (465
mg, 3.81 mmol) and di-tert-butyl dicarbonate (1.66 g, 760 mmol),
The mixture was stirred at the same temperature for 4.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 ml). The organic layer was washed with dilute hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-
300, hexane-ethyl acetate (5:1)], (
2S,4R)-N-tert-butoxycarbonyl-4
-tert-butyldimethylsiloxy-2-(N-te
rt-Butoxycarbonyl-2-pyrrolidon-4-yl)pyrrolidine (1.76 g, yield: 96%) was obtained.

[0377] NMR (CDCl3) δ: 0.06 (6H
, s), 0.86 (9H, s), 1.48 (9H, s)
, 1.54 (9H, s), 1.68 (1H, m), 2.
00 (1H, m), 3.25 (1H, m), 4.10 (
1H, m), 4.34 (1H, m)2)

0378]

embedded image The compound obtained in the above reaction (1.76 g, 3.64 mm
Borane-dimethylsulfide complex (1.ol) was added to a tetrahydrofuran solution (18ml) of borane-dimethylsulfide complex (1.
After dropping 09 ml, 10.9 mmol), the mixture was refluxed for 1.5 hours. Methanol (5 ml) was added to the reaction solution under ice cooling, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, hexane-ethyl acetate (10:1)] to obtain (2S,4R
)-N-tert-butoxycarbonyl-4-tert
-butyldimethylsiloxy-2-(N-tert-butoxycarbonylpyrrolidin-3-yl)pyrrolidine (1
．． 62 g, yield: 94.8%) was obtained.

[0379] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.46 (18H, s
), 1.60-2.04 (4H, m), 4.07 (1H
, m), 4.34 (1H, m) 3)

0380]

embedded image The compound obtained in the above reaction (1.60 g, 3.40 mm
A methanol solution of 1.6N hydrogen chloride (15m
1) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dioxane (20 ml) and water (1
0 ml) and pH 8 with triethylamine.
．． 5, 4,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (2.17 g
, 6.80 mmol), and the reaction solution was diluted with 1
．． Stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 ml). Organic layer 1N
The mixture was washed with an aqueous sodium hydroxide solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakoge
(2S,4R)-4-hydroxy-N-(p
-nitrobenzyloxycarbonyl)-2-[N-(p
-nitrobenzyloxycarbonyl)pyrrolidine-3-
yl]pyrrolidine (1.55 g, yield: 88.6%) was obtained.

NMR (CDCl3) δ: 1.52-2.
20 (4H, m), 3.76 (1H, m), 4.23 (
1H, m), 4.48 (1H, m), 5.22 (4H,
s), 7.52 (4H, d, J = 8Hz), 8.20 (
4H, d, J=8Hz) 4)

0382

embedded image The compound obtained in the above reaction (1.55 g, 3.02 mm
To a tetrahydrofuran solution (15 ml) of 3.ol) was added triethylamine (0.52 ml, 3.
74 mmol) and methanesulfonyl chloride (0.28
ml, 3.62 mmol) and stirred at the same temperature for 30 minutes. The reaction solution was extracted with ethyl acetate (50ml),
The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM C
-300, ethyl acetate), (2S,4R)-4-
Methanesulfonyloxy-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine (
1.76 g, yield: 98.6%) was obtained.

[0383] NMR (CDCl3) δ: 3.04 (3H
, s), 4.18 (2H, m), 5.24 (4H, br
s), 7.53 (4H, d, J=8Hz), 8.2
4 (4H, d, J=8Hz) 5)

0384

embedded image In a nitrogen stream, anhydrous potassium carbonate (616 mg, 4.46
mmol) in N,N-dimethylformamide (30
ml) and thioacetic acid (0.31 ml, 4.50 ml) at 0°C.
mol) was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. The compound obtained in the above reaction (1.76 g,
2.97 mmol) in N,N-dimethylformamide (5 ml) and sodium iodide (450 mg, 3
0 mmol) was added and the reaction mixture was stirred at 60-70°C overnight. The reaction mixture was diluted with ethyl acetate (100ml).
The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel
TM C-300, hexane-ethyl acetate (1:1)
] and (2S,4S)-4-acetylthio-N-(
p-nitrobenzyloxycarbonyl)-2-[N-(
p-nitrobenzyloxycarbonyl)pyrrolidine-3
-yl]pyrrolidine (1.34g, yield: 78.8%)
I got it.

NMR (CDCl3) δ: 1.54-2.
10 (4H, m), 2.36 (3H, s), 3.90 (
1H, m), 4.12 (1H, m), 4.26 (1H,
m), 5.24 (4H, s), 7.52 (4H, d, J
= 8Hz), 8.24 (4H, d, J = 8Hz) 6)

0386]

embedded image The compound obtained in the above reaction (1.34 g, 2.34 mm
ol) in a mixture of methanol (25 ml) and tetrahydrofuran (10 ml) and diluted with 1N aqueous sodium hydroxide solution (2.46 ml) under ice cooling in a nitrogen stream.
was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. 1N to the reaction solution
After adding hydrochloric acid (2.53 ml) dropwise, the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (50 ml), the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.
24 g, yield: 100%) was obtained. Reference Example 6 (2S,4S)-4-mercapto-2-(N-methylpyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate 1)

0387]

embedded image Compound obtained in Reference Example 1-6) (1.72 g, 4.4
2,6-lutidine (1.04 ml, 8 mmol) was added to a methylene chloride solution (17 ml) in a nitrogen stream at room temperature.
93 mmol) and trimethylsilyl trifluoromethanesulfonate (1.34 ml, 6.70 mmol)
1) was added and stirred at the same temperature for 30 minutes. After adding methanol (5 ml) dropwise to the reaction solution, it was concentrated under reduced pressure, and dioxane (15 ml) was added to the residue. Triethylamine (0.94 ml, 6.72 mmol) and 4,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (1.43 g, 4.48 mmol) were added to this reaction solution.
mol) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 ml). The organic layer was washed with dilute hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelT
M C-300, ethyl acetate), (2S, 4R
)-4-tert-butyldimethylsiloxy-N-(p
-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine (813 mg, yield: 3
9.2%).

[0388] NMR (CDCl3) δ: 0.03 (3H
, s), 0.06 (3H, s), 0.84 (9H, s)
, 1.78 (1H, m), 1.92-2.50 (3H,
m), 2.93-3.54 (4H, m), 3.66 (1
H, m), 4.10 (1H, m), 4.38 (1H, m
), 5.23 (2H, ABq, J=14Hz), 7.5
2 (2H, d, J = 8Hz), 8.23 (2H, d, J
=8Hz) 2)

0389]

embedded image The compound obtained in the above reaction (813 mg, 1.76 mm
ol) and di-tert-butyl dicarbonate (76
Reference Example 5-1)
By carrying out the reaction in the same manner as (2S,4R)-4-
tert-butyldimethylsiloxy-2-(N-tert
t-butoxycarbonyl-2-pyrrolidon-4-yl)
-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (944 mg, yield: 95.5%) was obtained.

[0390] NMR (CDCl3) δ: 0.04 (3H
, s), 0.06 (3H, s), 0.84 (9H, s)
, 1.52 (9H, s), 1.74 (1H, m), 2.
00 (1H, m), 2.20-2.96 (3H, m),
4.19 (1H, m), 4.39 (1H, br s)
, 5.24 (2H, ABq, J=14Hz), 7.53
(2H, d, J=8Hz), 8.24 (2H, d, J=
8Hz) 3)

0391

embedded image The compound obtained in the above reaction (944 mg, 1.68 mm
ol) and borane-dimethylsulfide complex (0.5
By carrying out the reaction in the same manner as in Reference Example 5-2) using (2S,4R)-4-t
ert-butyldimethylsiloxy-2-(N-tert
-butoxycarbonylpyrrolidin-3-yl)-N-(
p-nitrobenzyloxycarbonyl)pyrrolidine (7
30 mg, yield: 79.3%) was obtained.

[0392] NMR (CDCl3) δ: 0.05 (3H
, s), 0.07 (3H, s), 0.85 (9H, s)
, 1.45 (9H, s), 1.52-2.08 (4H,
m), 2.82 (1H, m), 2.90-3.80 (6
H, m), 4.15 (1H, m), 4.40 (1H, b
r s), 5.24 (2H, m), 7.54 (2H,
d, J=8Hz), 8.23 (2H, d, J=8Hz) 4)

0393

embedded image The compound obtained in the above reaction (6.98 g, 12.7 mm
A tetrahydrofuran solution (13.7 ml) of 1M tetrabutylammonium fluoride was added to a tetrahydrofuran solution (100 ml) of 1M tetrabutylammonium fluoride under ice cooling in a nitrogen stream, and the mixture was stirred at the same temperature for 40 minutes. A saturated aqueous ammonium chloride solution (20 ml) was added to the reaction solution, followed by extraction with ethyl acetate (150 ml). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 ml), and triethylamine (1.77 ml, 1
2.7 mmol) and methanesulfonyl chloride (0.9
9 ml, 12.8 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was extracted with ethyl acetate (150 ml), and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM
C-300, hexane-ethyl acetate (1:1)] to give (2S,4R)-2-(N-tert-butoxycarbonylpyrrolidin-3-yl)-4-methanesulfonyloxy-N-(p -nitrobenzyloxycarbonyl)
Pyrrolidine (6.64 g, yield: 100%) was obtained.

[0394] NMR (CDCl3) δ: 1.36 (9H
, s), 2.96 (3H, s), 3.98-4.24 (
2H, m), 5.18 (2H, m), 7.46 (2H,
d, J=8Hz), 8.16 (2H, d, J=8Hz) 5)

0395]

embedded image The compound obtained in the above reaction (6.6 g, 12.9 mmo
l) and thioacetic acid (1.33 ml, 19.3 mmol
) and the same reaction as in Reference Example 5-5), (2S,4S)-4-acetylthio-2-(N-
tert-butoxycarbonylpyrrolidin-3-yl)
-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.57 g, yield: 72.1%) was obtained.

NMR (CDCl3) δ: 1.44 (9H
, s), 2.35 (3H, s), 3.86 (1H, m)
, 4.08 (1H, m), 4.24 (1H, m), 5.
23 (2H, br s), 7.53 (2H, d, J=
8Hz), 8.24 (2H, d, J=8Hz)6)

0397]

embedded image The compound obtained in the above reaction (4.56 g, 9.25 mm
A 1N aqueous sodium hydroxide solution (9.7ml) was added to a methanol solution (100ml) of
1) was added and stirred at the same temperature for 15 minutes. Add triethylamine (2.0 ml, 14.4 mmol) to this reaction solution.
and p-methoxybenzyl chloride (1.82 ml,
13.4 mmol) was added thereto, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (300
ml). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wak
ogelTM C-300, hexane-ethyl acetate (
3:1)] and (2S,4S)-2-(N-ter
t-butoxycarbonylpyrrolidin-3-yl)-4-
(p-methoxybenzylthio)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.97 g, yield: 94.1%) was obtained.

NMR (CDCl3) δ: 1.44 (9H
, s), 1.50-1.98 (3H, m), 2.33 (
1H, m), 2.70 (1H, m), 3.74 (2H,
s), 3.80 (3H, s), 3.96 (1H, m),
5.20 (2H, br s), 6.86 (2H, d,
J=8Hz), 7.24 (2H, d, J=8Hz), 7
．． 50 (2H, d, J = 8Hz), 8.24 (2H, d
, J=8Hz) 7)

0399]

embedded image The compound obtained in the above reaction (4.97 g, 8.70 mm
To a methylene chloride solution (50 ml) of ol) was added trifluoroacetic acid (6.7 ml, 10.0 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (150 ml). The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (2S,4S)-4-(p-methoxybenzylthio)-N-( p-nitrobenzyloxycarbonyl)-2-(3-pyrrolidinyl)pyrrolidine (4.0
g, yield: 97.6%).

[0400] NMR (CDCl3) δ: 1.62 (1H
, m), 1.75-2.18 (2H, m), 2.42 (
1H, m), 2.82 (1H, m), 3.75 (2H,
s), 3.82 (3H, s), 4.09 (1H, m),
5.20 (2H, br s), 6.86 (2H, d,
J=8Hz), 7.24 (2H, d, J=8Hz), 7
．． 50 (2H, d, J = 8Hz), 8.27 (2H, d
, J=8Hz) 8)

0401]

embedded image The compound obtained in the above reaction (1.4 g, 2.97 mmo
l) in acetonitrile solution (15 ml) at room temperature.
% formalin aqueous solution (0.6 ml, 7.5 mmol) and sodium cyanoborohydride (300 mg,
4.77 mmol) was added thereto, and the mixture was stirred at the same temperature for 15 minutes. After neutralizing the reaction mixture with acetic acid, the reaction mixture was further heated to room temperature for 1
Stir for hours. The reaction mixture was extracted with ethyl acetate (50 ml), and the organic layer was washed with a 1N aqueous sodium hydroxide solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300,
Ethyl acetate-methanol (1:1)] to give (2S,
4S)-4-(p-methoxybenzylthio)-2-(N
-Methylpyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (617 mg, yield: 42.8%) was obtained.

NMR (CDCl3) δ: 1.42-2.
04 (3H, m), 3.74 (2H, s), 3.82 (
3H, s), 3.98 (1H, m), 5.20 (2H,
brs), 6.86 (2H, d, J=8Hz), 7.2
4 (2H, d, J = 8Hz), 7.47 (2H, br
d, J=8Hz), 8.25(2H, d, J=8Hz
) 9)

0403]

embedded image The compound obtained in the above reaction (617 mg, 1.27 mm
ol) in a trifluoroacetic acid solution (2.26 ml),
Anisole (0.34 ml, 3.13 mmol) and trifluoromethanesulfonic acid (0.27 ml, 3
．． 05 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was repeatedly decanted with dry diethyl ether to obtain the title compound (
650 mg, yield: 99%) was obtained. Reference Example 7 (2S,4S)-4-mercapto-2-(N-methyl-
2-Azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine 1)

0404]

embedded image 3-[(2S,4R)-4-tert-butyldimethylsiloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]acrylic acid ethyl ester [
2.94g, 6.15mmol; Patent Application Hei 1-34294
8, Compound of Reference Example 1-6)] was added with a 5.3 M methylamine-ethanol solution (5 ml, 26.6 mmol) at room temperature.
was added and left at the same temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (W
akogelTM C-300, ethyl acetate) to give 3-methylamino-3-[(2S,4R)-4-te
rt-Butyldimethylsiloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]propionic acid ethyl ester (1.67g, yield: 53.3%
) was obtained.

[0405] NMR (CDCl3) δ: 0.04 (3H
, s), 0.06 (3H, s), 0.84 (9H, s)
, 1.26 (3H, t, J=7Hz), 1.80-2.
16 (2H, m), 2.24-2.50 (6H, m),
3.40 (2H, m), 3.65 (1H, m), 4.1
6 (2H, m), 4.40 (1H, m), 5.30 (2
H, m), 7.56 (2H, m), 8.24 (2H, d
, J=8Hz) 2)

0406]

embedded image The compound obtained in the above reaction (1.67 g, 3.28 mm
(2S,4R)-4-tert-butyldimethylsiloxy-2-(N-methyl-2-azetidinone-
4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (700 mg, yield: 46.1%) was obtained.

[0407] NMR (CDCl3) δ: 0.04 (3H
, s), 0.06 (3H, s), 0.84 (9H, s)
, 1.72-2.00 (2H, m), 2.55 (1H,
m), 2.80 (3H, s), 2.94 (1H, m),
3.36 (1H, m), 3.70 (1H, m), 4.1
0 (1H, m), 4.40 (2H, m), 5.16-5
．． 22 (2H, m), 7.67 (2H, d, J = 8Hz
), 8.24 (2H, d, J = 8Hz) 3)

0408]

embedded image The compound obtained in the above reaction (700 mg, 1.51 mm
ol) in acetonitrile solution (10 ml) at room temperature.
After adding 6% hydrofluoric acid (1 ml) and stirring at the same temperature for 1 hour, the reaction solution was extracted with ethyl acetate (70 ml). The organic layer was washed successively with 5% aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakoge
(2S,4R)-4-hydroxy-2-(N
-Methyl-2-azetidinon-4-yl)-N-(p-
nitrobenzyloxycarbonyl)pyrrolidine (316
mg, yield: 59.9%).

NMR (CDCl3) δ: 1.70-2.
18 (2H, m), 2.52 (1H, m), 2.74 (
3H, s), 2.88 (1H, m), 3.60-3.8
8 (2H, m), 4.08 (1H, m), 4.40 (2
H, m), 5.22 (2H, br s), 7.50 (
2H, d, J = 8 Hz), 8.16 (2H, d, J = 8
Hz) 4)

0410]

embedded image The compound obtained in the above reaction (315 mg, 0.90 mm
(2S,4S)-4-acetylthio-2-(
N-methyl-2-azetidinon-4-yl)-N-(p
-nitrobenzyloxycarbonyl)pyrrolidine (34
8 mg, yield: 94.7%) was obtained.

0411 IR(KBr)cm-1:1760,17
00,1520,1340 NMR (CDCl3) δ: 1.75 (1H, m), 2.
37 (3H, s), 2.79 (3H, s), 3.88 (
1H, m), 3.98-4.20 (3H, m), 5.2
8 (2H, br s), 7.55 (2H, d, J=8
Hz), 8.25 (2H, d, J=8Hz)5)

0412]

embedded image The compound obtained in the above reaction (348 mg, 0.86 mm
The title compound (298 mg, yield: 95.5%) was obtained by carrying out the same reaction as in Reference Example 1-9) using
) was obtained. Reference Example 8 (2S,4S)-4-mercapto-2-(N-methyl-
2,5-dioxopyrrolidin-3-yl)-N-(p-
Nitrobenzyloxycarbonyl)pyrrolidine diastereomers A and B 1)

0413]

embedded image 3-[(2S,4R)-4-tert-butyldimethylsiloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]acrylic acid ethyl ester [
3.8g, 7.95mmol; Patent Application Hei 1-342948
, Compound of Reference Example 1-6)], Reference Example 1-5)
By performing the same reaction as 3-[(2S,4R)
-4-tert-butyldimethylsiloxy-N-(p-
Nitrobenzyloxycarbonyl)pyrrolidin-2-yl]-4-nitrobutyric acid ethyl ester (4.0 g, yield: 93.3%) was obtained.

[0414] NMR (CDCl3) δ: 0.04 (3H
, s), 0.06 (3H, s), 0.82 (9H, s)
, 1.26 (3H, m), 1.80 (1H, m), 2.
03 (1H, m), 2.22-2.54 (3H, m),
3.27 (2H, m), 4.15 (3H, m), 4.3
2-4.70 (2H, m), 5.24 (2H, brs)
, 7.54 (2H, m), 8.25 (2H, d, J=8
Hz) 2)

0415]

embedded image The compound obtained in the above reaction (4.0 g, 7.42 mmo
Sodium nitrite (2.56 g, 37.1 g) was added to a dimethyl sulfoxide solution (40 ml) of 1) at room temperature in a nitrogen stream.
Butyl nitrite (1.74 ml) was added.
, 14.9 mmol) was added dropwise, and the mixture was stirred overnight at the same temperature. The reaction solution was extracted with ethyl acetate (150 ml), and the organic layer was washed three times with water and once with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml) and heated at -20°C in a nitrogen stream.
and triethylamine (0.97 ml, 6.95 mmol
) and isobutyl chloroformate (0.90 ml,
6.94 mmol) was added dropwise, and after stirring at the same temperature for 30 minutes,
40% methylamine (1 ml) was added. The reaction mixture was stirred for 30 minutes under ice cooling, and then extracted with ethyl acetate (100 ml). The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel
TMC-300, ethyl acetate) (2S,4R)-
4-tert-butyldimethylsiloxy-2-(2-ethoxycarbonyl-1-methylcarbamoylethyl)-
N-(p-nitrobenzyloxycarbonyl)pyrrolidine (1.8 g, yield: 45.6%) was obtained.

[0416] NMR (CDCl3) δ: 0.04 (3H
, s), 0.05 (3H, s), 0.83 (9H, s)
, 1.24 (3H, t, J=7Hz), 3.34 (1H
, m), 3.56 (1H, m), 4.12 (2H, m)
, 4.32 (1H, m), 5.28 (2H, m), 7.
52 (2H, m), 8.25 (2H, m) 3)

0417]

embedded image The compound obtained in the above reaction (1.8 g, 3.35 mmo
l) in ethanol solution (30 ml) at room temperature.
An aqueous solution of sodium hydroxide (3.7 ml) was added dropwise, and the mixture was stirred at the same temperature overnight. Add 1N hydrochloric acid (3.7ml) to the reaction solution.
) and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (70 m
l). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in acetic anhydride (15 ml) and sodium acetate (1
．． 38g, 16.8mmol) was added and heated at 100°C for 1.
Stirred for 5 hours. After concentrating the reaction mixture under reduced pressure, the residue was extracted with ethyl acetate (70 ml). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, hexane-
ethyl acetate (3:1)] to give (2S,4R)-4-
tert-butyldimethylsiloxy-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)-N-(p
-nitrobenzyloxycarbonyl)pyrrolidine (1.
28g, yield: 77.8%) was obtained.

[0418] NMR (CDCl3) δ: 0.04 (3H
, s), 0.06 (3H, s), 0.84 (9H, s)
, 1.71 (1H, m), 2.96 (3H, s), 3.
16-3.87 (3H, m), 4.37 (1H, m),
4.54 (1H, m), 5.22 (2H, m), 7.5
0 (2H, m), 8.20 (2H, m) 4)

0419]

embedded image The compound obtained in the above reaction (1.28 g, 2.61 mm
(2S,4S)-4-acetylthio-2-
(N-Methyl-2,5-dioxopyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (406 mg, yield: 3
(5.8%) and diastereomer B (170 mg, yield: 15%), respectively. Diastereomer A NMR (CDCl3) δ: 1.60 (1H, m), 2.
34 (3H, s), 2.97 (3H, s), 3.60~
3.98 (2H, m), 4.22 (1H, m), 4.4
7 (1H, m), 5.24 (2H, br s), 7.
56 (2H, d, J=8Hz), 8.24 (2H, d,
J=8Hz) Diastereomer B IR (KBr) cm-1: 1700, 1520, 144
0,1350NMR(CDCl3)δ:1.72(1H
, m), 2.36 (3H, s), 2.97 (3H, br
s), 3.25 (2H, m), 3.88 (1H, m
), 4.18 (1H, m), 4.42 (1H, m), 5
．． 07-5.30 (2H, m), 7.51 (2H, d,
J=8Hz), 8.24 (2H, d, J=8Hz)5)

0420]

embedded image The compound of diastereomer A obtained in the above reaction (40
Reference Example 1-9)
A similar reaction was carried out to obtain diastereomer A of the title compound.
(330 mg, yield: 90%) was obtained. 6)

0421]

embedded image Using the diastereomer B compound (170 mg, 0.39 mmol) obtained in Reference Example 8-4), Reference Example 1
The same reaction as in -9) was carried out to obtain diastereomer B (145 mg, yield: 94.6%) of the title compound. Reference Example 9 (2S,4S)-N-allyloxycarbonyl-2-(
2,5-dioxopyrrolidin-3-yl)-4-mercaptopyrrolidine 1)

0422]

embedded image 3-[(2S,4S)-N-allyloxycarbonyl- obtained by carrying out the same reaction as in Reference Example 1-4)
By carrying out the same reaction as in Reference Example 1-5) using 4-tritylthiopyrrolidin-2-yl]acrylic acid ethyl ester (5.23 g, 9.9 mmol), 3-
[(2S,4S)-N-allyloxycarbonyl-4-
Tritylthiopyrrolidin-2-yl]-4-nitrobutyric acid ethyl ester (4.74 g, yield: 81.2%) was obtained.

[0423] NMR (CDCl3) δ: 1.24 (3H
, t, J=8Hz), 3.92 (1H, m), 4.12
(2H, q, J=8Hz), 4.47 (3H, m), 5
．． 26 (2H, m), 5.86 (1H, m), 7.16
~7.74 (15H, m) 2)

0424]

embedded image The compound obtained in the above reaction (4.7 g, 8.0 mmol
) to a dimethyl sulfoxide solution (35 ml) of sodium nitrite (2.76 g, 40 mm
After adding butyl nitrite (1.87 ml, 16
mmol) was added dropwise and stirred overnight at the same temperature. The reaction solution was extracted with ethyl acetate (150 ml), and the organic layer was extracted with water three times.
After washing with saturated saline and drying with anhydrous magnesium sulfate,
Concentrate under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM C-300, 1% methanol-chloroform) to obtain (2S,4S)-N
-allyloxycarbonyl-2-(1-carboxy-2
-ethoxycarbonylethyl)-4-tritylthiopyrrolidine (1.9 g, yield: 41.5%) was obtained.

[0425] NMR (CDCl3) δ: 1.23 (3H
, m), 3.90-4.24 (3H, m), 4.48 (
2H, m), 5.18-5.32 (2H, m), 5.8
6 (1H, m), 7.16-7.60 (15H, m)3
)

0426]

embedded image The compound obtained in the above reaction (1.9 g, 3.3 mmol
) to a tetrahydrofuran solution (30 ml) in a nitrogen stream at -20°C, triethylamine (0.56 ml, 4.
0 mmol) and isobutyl chloroformate (0.
After stirring at the same temperature for 30 minutes, concentrated ammonia water (0.7 ml, 10.5 mmol) was added dropwise and stirred at the same temperature for 30 minutes.
1) was added thereto, and the mixture was further stirred for 30 minutes under ice cooling. The reaction solution was extracted with ethyl acetate (100 ml), and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, hexane-ethyl acetate (5:1)] to obtain (2S, 4S)
-N-allyloxycarbonyl-2-(1-carbamoyl-2-ethoxycarbonylethyl)-4-tritylthiopyrrolidine polar compound (744 mg, yield: 39.
2%) and a low polar compound (711 mg, yield: 37.
5%).

Polar compound NMR (CDCl3) δ: 1.23 (3H, t, J=7
Hz), 1.98 (2H, m), 3.85 (1H, m)
, 4.15 (2H, q, J = 7Hz), 4.50 (2H
, m), 5.24 (2H, m), 5.85 (1H, m)
, 7.15-7.60 (15H, m) Low polar compound NMR (CDCl3) δ: 1.23 (3H, t, J = 7
Hz), 1.95 (2H, m), 2.26 (1H, m)
, 3.76 (1H, m), 4.12 (2H, q, J=7
Hz), 4.50 (2H, m), 5.24 (2H, m)
, 5.84 (1H, m), 7.14-7.57 (15H
, m) 4)

0428]

embedded image The polar compound obtained in the above reaction (744 mg, 1.3 m
mol) in tetrahydrofuran solution (37 ml) under ice cooling, sodium hydride (57 mg, 1.43 mmol)
was added and stirred at the same temperature for 15 minutes. Add water (1 m
After adding 1N hydrochloric acid (1.43 ml), the mixture was extracted with ethyl acetate (70 ml). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, hexane-ethyl acetate (3:1)] to give (2S,4S)-N-allyloxycarbonyl-2-(2,5-dioxopyrrolidine-3 -yl)-4-tritylthiopyrrolidine (630
mg, yield: 92.1%).

[0429] NMR (CDCl3) δ: 1.40 (1H
, m), 2.14 (1H, m), 2.15-2.95 (
4H, m), 3.88 (1H, m), 4.10 (1H,
m), 4.47 (2H, m), 5.13-5.36 (2
H, m), 5.84 (1H, m), 7.10-7.60
(15H, m) 5)

0430]

embedded image The compound obtained in the above reaction (630 mg, 1.2 mmo
The title compound (219 mg, yield: 64.4%) was obtained by carrying out the same reaction as in Reference Example 22-2) using
) was obtained.

[0431] NMR (CDCl3-CD3OD) δ:2
．． 38-2.78 (4H, m), 2.95-3.26 (
2H, m), 3.80-4.22 (1H, m), 4.3
4 (1H, m), 4.56 (2H, m), 5.16-5
．． 38 (2H, m), 5.90 (1H, m) Reference Example 10 (2S,4S)-N-allyloxycarbonyl-4-mercapto-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl ) Pyrrolidine 1)

0432]

embedded image 3-[(2S,4S)-N-allyloxycarbonyl-
To an ethanol solution (7.5 ml) of 4-tritylthiopyrrolidin-2-yl]acrylic acid ethyl ester (1.53 g, 2.9 mmol) was added hydrazine monohydrate (0.61 ml, 12.5 ml) under ice cooling. 6 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure,
The residue was subjected to silica gel column chromatography (Wako
gelTMC-300, 2% methanol-chloroform) to give (2S,4S)-N-allyloxycarbonyl-2-(3-pyrazolidinon-5-yl)-4-tritylthiopyrrolidine (830 mg, yield: 51 .1%)
I got it. This compound was immediately dissolved in methylene chloride (10 m
1), and added triethylamine (0.24 ml) under ice-cooling.
, 1.7 mmol) and allyl chloroformate (0
．． 18 ml, 1.7 mmol) was added dropwise and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 ml). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (W
akogelTM C-300, 1% methanol-chloroform) to give (2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3
-pyrazolidinone-5-yl)-4-tritylthiopyrrolidine (592 mg, yield: 62%) was obtained.

NMR (CDCl3) δ: 1.46-1.
88 (2H, m), 1.94-2.24 (2H, m),
2.56-3.00 (4H, m), 3.70 (1H, m
), 4.34-4.50 (4H, m), 5.12-5.
40 (4H, m), 5.75-6.00 (2H, m),
7.15-8.60 (15H, m)2)

0434]

embedded image The compound obtained in the above reaction (592 mg, 0.92 mm
(2S,4S)-N-allyloxycarbonyl-4-mercapto-2-(1-allyloxycarbonyl-3-pyrazolidinone- 5-yl)pyrrolidine(3
24 mg, yield: 87.8%) was obtained.

NMR (CDCl3) δ: 1.60-1.
95 (2H, m), 2.30 (1H, dd, J=17,
3Hz), 2.56 (1H, m), 2.88-3.30
(3H, m), 3.88-4.24 (2H, m), 4.
52-4.98 (4H, m), 5.00-5.45 (4
H, m), 5.82 to 6.08 (2H, m) Reference Example 11 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidone-3
-yl)pyrrolidine 1)

0436]

embedded image 3-[(2S,4R)-N- obtained in Reference Example 1-5)
Using tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-4-nitrobutyric acid ethyl ester (5.9 g, 12.8 mmol), carry out the same reaction as in Reference Example 9-2). By this, (2S,4R)-2-(2-ethoxycarbonyl-1
-Carboxyethyl)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylpyrrolidine (3.57 g, yield: 62.5%) was obtained.

[0437] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.26 (3H, t,
J = 8Hz), 1.48 (9H, s), 2.01 (1H
, m), 2.34 (1H, m), 2.38 (1H, m)
, 3.25 (1H, dd, J=12,4Hz), 3.3
8-3.90 (3H, m), 4.16 (2H, q, J=
8Hz), 4.25-4.55 (2H, m) 2)

0438]

embedded image The compound obtained in the above reaction (3.57 g, 8.0 mmo
l) and benzylamine (1.55 ml, 14.2 m
(2S,4R)-2-(1-benzylcarbamoyl-2-ethoxycarbonylethyl)-4-te
rt-Butyldimethylsiloxy-N-tert-butoxycarbonylpyrrolidine (3.7g, yield: 86.3%
) was obtained.

[0439] NMR (CDCl3) δ: 0.04 (6H
, s), 0.85 (9H, s), 1.24 (3H, t,
J=8Hz), 1.33 to 1.55 (9H, m), 1.
90 (1H, m), 2.30 (1H, m), 2.82 (
1H, m), 3.22 (1H, m), 3.35-3.8
2 (2H, m), 4.00-4.65 (5H, m), 7
．． 30 (5H, m) 3)

0440]

embedded image The compound obtained in the above reaction (1.89 g, 3.5 mmo
l) in ethanol solution (30 ml) at room temperature.
Aqueous sodium hydroxide solution (3.9 ml) was added, and the mixture was stirred at the same temperature overnight. Add 1N hydrochloric acid (3.9ml) to the reaction solution.
By adding and concentrating under reduced pressure, (2S,4R)
-2-(1-benzylcarbamoyl-2-carboxyethyl)-N-tert-butoxycarbonyl-4-te
rt-butyldimethylsiloxypyrrolidine (1.79g
, yield: 100%). Borane dimethyl sulfide complex (0.72 ml, 7.2 mm) was added to a tetrahydrofuran solution (35 ml) of this compound at room temperature in a nitrogen stream.
ol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After adding methanol (5 ml) to the reaction solution, it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakog
elTM C-300, hexane-ethyl acetate (1:
1)] to give 3-benzylcarbamoyl-3-[(2
S,4R)-N-tert-butoxycarbonyl-4-
tert-butyldimethylsiloxypyrrolidin-2-yl]-1-propanol (1.27 g, yield: 72.9
%) was obtained.

[0441] NMR (CDCl3) δ: 0.04 (6H
, s), 0.86 (9H, s), 1.24-1.60 (
11H, m), 1.73-2.32 (2H, m), 3.
32-3.73 (3H, m), 4.12-4.34 (2
H, m), 4.40 (1H, m), 7.30 (5H, m
) 4)

0442]

embedded image The compound obtained in the above reaction (1.27 g, 2.6 mmo
l) in hexamethylphosphoric triamide solution (17
ml) was added dropwise to a tetrahydrofuran solution (17 ml) of potassium tert-butoxide (640 mg, 5.7 mmol) at 0°C in a nitrogen stream, and the mixture was stirred at the same temperature for 1 hour. Add p-toluenesulfonyl chloride (520
mg, 2.7 mmol) in tetrahydrofuran solution (3
ml) was added dropwise, and the mixture was stirred at 0°C for 1 hour and at 50°C for 2 hours. After cooling the reaction mixture on ice, a saturated aqueous ammonium chloride solution (5 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed three times with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM
C-300, hexane-ethyl acetate (10:1)] to give (2S,4R)-2-(N-benzyl-2-pyrrolidon-3-yl)-N-tert-butoxycarbonyl-4-tert. -butyldimethylsiloxypyrrolidine (
343 mg, yield: 39.8%) was obtained.

[0443] NMR (CDCl3) δ: 0.06 (6H
, s), 0.87 (9H, s), 1.46 (9H, s)
, 1.90-2.30 (3H, m), 3.00-3.6
0 (5H, m), 4.18-4.64 (5H, m), 7
．． 18-7.42 (5H, m) 5)

0444]

embedded image The compound obtained in the above reaction (760 mg, 1.6 mmo
(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-
(2-pyrrolidon-3-yl)pyrrolidine (476 mg
, yield: 77.2%).

[0445] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.46 (9H, s)
, 1.82 (1H, m), 2.04 (2H, m), 3.
20-3.70 (5H, m), 4.32 (1H, m),
4.42 (1H, m) 6)

0446]

embedded image The compound obtained in the above reaction (476 mg, 1.24 mm
(2S,4R)-4-hydroxy-N-(p
-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidine (342 mg, yield: 7
9.1%).

0447 IR(KBr)cm-1:1700,15
20,1350 NMR (CDCl3) δ: 1.70-2.28 (4H,
m), 3.18-3.50 (3H, m), 3.52-3
．． 88 (2H, m), 4.28-4.68 (2H, m)
, 5.22 (2H, m), 7.53 (2H, d, J=8
Hz), 8.20 (2H, d, J=8Hz)7)

0448]

embedded image The compound obtained in the above reaction (342 mg, 0.98 mm
(2S,4S)-4-acetylthio-N-(
p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidine (271 mg, yield:
68.2%).

0449 IR(KBr)cm-1:1700,15
30,1520 NMR (CDCl3) δ: 1.62-2.18 (3H,
m), 2.35 (3H, s), 3.02-3.70 (5
H, m), 3.83 (1H, m), 4.25 (1H, m
), 4.44 (1H, m), 5.28 (2H, br
s), 7.56 (2H, d, J = 8Hz), 8.25 (
2H, d, J=8Hz) 8)

0450]

embedded image The compound obtained in the above reaction (271 mg, 0.67 mm
The title compound (220 mg, yield: 90.5%) was obtained by carrying out the same reaction as in Reference Example 1-9) using
) was obtained. Reference Example 12 (2S,4R)-N-tert-butoxycarbonyl-
4-tert-butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomers A and B

0451]

embedded image Compound of Reference Example 1-6) (10.82g, 22.32m
n-hexane (75 ml) was added to the mixture (mol), and the mixed solution was dissolved at 40°C and filtered. The filtrate was left at room temperature overnight. The precipitate was collected by filtration and dried to obtain the polar compound of the title compound (diastereomer A; 3.74 g, yield: 34.
6%). This filtrate was concentrated, n-hexane (70 ml) was added to the residue, and the same operation as above was performed to obtain a low polar compound of the title compound (diastereomer B;
1.87 g, yield: 17.3%) was obtained. Diastereomer A (polar compound) mp: 92-95°C [α]D: -50.8° (20°C, C = 1.031, M
eOH) IR (KBr) cm-1: 1685, 1395, 125
0,1175 NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.46 (9H, s), 1.72 ~
1.97 (2H, m), 2.2 (1H, dd, J=18
, 8Hz), 2.41 (1H, dd, J=18,8Hz
), 2.9-3.8 (5H, m), 4.15 (1H, b
r), 4.32 (1H, br), 6.06 (1H, br
) Diastereomer B (low polar compound) mp: 97-1
00°C [α]D: -53.9° (20°C, C=0.978, M
eOH) IR (KBr) cm-1: 1685, 1665, 138
5,1255,1160 NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.46 (9H, s), 1.7-1
．． 95 (2H, m), 2.04 (1H, dd, J=16
, 8Hz), 2.32 (1H, dd, J=16,8Hz
), 2.9-3.6 (5H, m), 4.1 (1H, br
), 4.32 (1H, br), 6.0 (1H, br)H
PLC; Column: Daicel CHIRALCEL OD
, Mobile phase: hexane:isopropanol (9:1), flow rate: 0.5 ml/min, temperature: 38°C, detection: 210
nm, retention time: diastereomer A: 19.8 min
, Diastereomer B: 16.3min Reference Example 13 (2S,4S)-2-[2-carbamoyl-N-(p-
nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer I1)

0452]

embedded image (2S,4R)-N-tert- obtained in Reference Example 12
Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer A (polar compound; 8.0 g, 20
．． (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-
(N-tert-butoxycarbonyl-2-pyrrolidon-4-yl)pyrrolidine diastereomer A (9.
5 g, yield: 94.2%) was obtained.

[0453] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.46 (9H, s)
, 1.53 (9H, s), 1.70 (1H, m), 1.
97 (1H, m), 2.16-2.90 (3H, m),
3.24 (1H, dd, J=12,4Hz), 3.36
~3.70 (2H, m), 3.76 (1H, dd, J=
10.8Hz), 4.12 (1H, m), 4.33 (1
H, m) 2)

0454]

embedded image The compound obtained in the above reaction (9.3 g, 19.2 mmo
A 1M vinylmagnesium bromide-tetrahydrofuran solution (23 ml) was added dropwise to the tetrahydrofuran solution (120 ml) of 1) at -40°C in a nitrogen stream, and the mixture was stirred at the same temperature for 2 hours. A 50% acetic acid-methanol solution (10 ml) was added dropwise to the reaction solution, and ethyl acetate (200 ml) was added dropwise to the reaction solution.
) was extracted. The organic layer was washed successively with saturated sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, hexane-ethyl acetate (10:1)] to obtain 5-[(2S,4R)-
N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-6-t
ert-butoxycarbonylamino-1-hexene-3
-one diastereomer A (4.1 g, yield: 41
．． 7%).

[0455] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.42 (9H, s)
, 1.46 (9H, s), 4.04 (1H, m), 4.
24 (1H, m), 5.80 (1H, br d, J=
10Hz), 6.22 (1H, d, J=17Hz), 6
．． 38 (1H, dd, J = 17, 10Hz) 3)

0456]

embedded image The compound obtained in the above reaction (4.1 g, 8.0 mmol
), cerium chloride hexahydrate (2.84g, 8.0m
Add a methanol solution (30 ml) of -15 mol)
Sodium borohydride (310 mg, 8.2 mm
ol) was added and stirred at the same temperature for 15 minutes. Water (10 ml) was added to the reaction mixture and concentrated under reduced pressure. The residue was extracted with ethyl acetate (100 ml), and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, hexane-
ethyl acetate (8:1)] to give 5-[(2S,4R)
-N-tert-butoxycarbonyl-4-tert-
butyldimethylsiloxypyrrolidin-2-yl]-6-
tert-butoxycarbonylamino-1-hexene-
3-ol (3.53 g, yield: 85.8%) was obtained.

[0457] NMR (CDCl3) δ: 0.04 (6H
, s), 0.86 (9H, s), 1.43 (9H, s)
, 1.46 (9H, s), 4.30 (2H, m), 5.
12 (1H, br d, J = 10Hz), 5.28 (
1H,brd,J=16Hz),5.90(1H,m) 4)

0458]

embedded image The compound obtained in the above reaction (3.53 g, 6.9 mmo
Potassium tert-butoxide (15 ml) was added to potassium tert-butoxide (15 ml) at -10°C in a nitrogen stream.
．． 7 g, 15.1 mmol) in tetrahydrofuran solution (50 ml) and stirred at the same temperature for 30 minutes.
-Toluenesulfonyl (1.44g, 7.5mmol)
A tetrahydrofuran solution (10 ml) was added dropwise. After stirring the reaction solution at the same temperature for 1 hour, saturated ammonium chloride aqueous solution (10 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM
C-300, hexane-ethyl acetate (10:1)]
(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-
(N-tert-butoxycarbonyl-2-vinylpyrrolidin-4-yl)pyrrolidine (2.09g, yield: 6
1.5%).

[0459] NMR (CDCl3) δ: 0.04 (6H
, s), 0.86 (9H, s), 1.42 (9H, s)
, 1.45 (9H, s), 2.98 (1H, m), 3.
14 (1H, dd, J=12,4Hz), 3.32~3
．． 72 (2H, m), 3.92-4.20 (2H, m)
, 4.34 (1H, m), 4.96-5.20 (2H,
m), 5.74 (1H, m) 5)

0460]

embedded image The compound obtained in the above reaction (2.09 g, 4.2 mmo
l) of carbon tetrachloride (10 ml) and acetonitrile (
10 ml), add water (13 ml) and sodium periodate (3.70 g, 17.3 mmol),
Stir vigorously. Ruthenium chloride hydrate (20 mg, 0.096 mmol) was added to the reaction mixture, and the mixture was vigorously stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure;
The residue was extracted with ethyl acetate (100ml). The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM C-300
, 1% methanol-chloroform) and (2S,4
R)-N-tert-butoxycarbonyl-4-ter
t-Butyldimethylsiloxy-2-(N-tert-butoxycarbonyl-2-carboxypyrrolidin-4-yl)pyrrolidine (1.07 g, yield: 50.7%) was obtained.

[0461] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.46 (18H, b
r s), 3.10 (1H, m), 3.24 (1H,
m), 3.40-3.74 (2H, m), 3.96-4
．． 40 (3H, m) 6)

0462]

embedded image The compound obtained in the above reaction (1.07 g, 2.1 mmo
l), the same reaction as in Reference Example 9-3) was carried out, and (
2S,4R)-N-tert-butoxycarbonyl-4
-tert-butyldimethylsiloxy-2-(N-te
rt-Butoxycarbonyl-2-carbamoylpyrrolidin-4-yl)pyrrolidine (867 mg, yield: 81.
2%). NMR (CDCl3) δ: 0.05 (6H, s), 0.
86 (9H, s), 1.46 (18H, s), 3.06
(1H,br t,J=12Hz),3.23(1H
, dd, J=12,4Hz), 3.36~3.82 (2
H, m), 3.98-4.40 (3H, m)7)

0463]

embedded image The compound obtained in the above reaction (861 mg, 1.68 mm
A reaction similar to Reference Example 5-3) was carried out using
(2S,4R)-2-[2-carbamoyl-N-(p-
Diastereomer I (polar compound, 621 mg, yield: 66.4%) and diastereomer of nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine II (low polar compound, 216 mg, yield: 2
3.1%). Polar compound NMR (CDCl3) δ: 3.78 (2H, m), 4.
26 (2H, m), 4.50 (1H, m), 5.26 (
4H, br s), 7.54 (4H, d, J=8Hz
), 8.25 (4H, d, J=8Hz) Low polar compound NMR (CDCl3) δ: 3.70 (2H, m), 4.
00-4.53 (3H, m), 5.24 (4H, br
s), 7.51 (4H, d, J=8Hz), 8.20
(4H, d, J=8Hz) 8)

0464

embedded image The polar compound obtained in the above reaction (621 mg, 1.1 m
The same reaction as in Reference Example 5-4) was carried out using (2S,4R)-2-[2-carbamoyl-N-(p
-nitrobenzyloxycarbonyl)pyrrolidine-4-
yl]-4-methanesulfonyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer I (670 mg, yield: 94.6%).

[0465] NMR (DMSO-d6) δ: 3.25 (
3H, s), 3.48-3.70 (2H, m), 3.9
2-4.22 (3H, m), 5.04-5.34 (5H
, m), 7.64 (4H, d, J=8Hz), 8.24
(4H, m) 9)

0466]

embedded image The compound obtained in the above reaction (670 mg, 1.06 mm
ol) in N,N-dimethylformamide (10 ml
), sodium iodide (174 mg, 1
．． 16 mmol) and potassium thioacetate (240 mg
, 2.1 mmol) and stirred at 60-70°C overnight. The reaction solution was extracted with ethyl acetate (70 ml), and the organic layer was washed three times with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM C-3
00,1% methanol-chloroform) and (2S
,4S)-4-acetylthio-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer I (479
mg, yield: 73.8%).

[0467] NMR (CDCl3) δ: 1.74 (1H
, m), 2.00 (1H, m), 2.35 (3H, s)
, 2.40-2.90 (3H, m), 5.24 (4H,
brs), 7.54 (4H, br d, J=8Hz)
, 8.22 (4H, br d, J=8Hz) 10)

0468]

embedded image The compound obtained in the above reaction (479 mg, 0.78 mm
The same reaction as in Reference Example 1-9) was carried out using
(2S,4S)-2-[2-carbamoyl-N-(p-
nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer I (2
80 mg, yield: 62.7%) was obtained. Reference Example 14 (2S,4S)-2-[2-carbamoyl-N-(p-
nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer II1
)

0469]

embedded image (2S,4R)-2-[2 obtained in Reference Example 13-7)
-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-hydroxy-N
Using -(p-nitrobenzyloxycarbonyl)pyrrolidine (low polar compound; 216 mg, 0.39 mmol), the same reaction as in Reference Example 5-4) was carried out, and (2S,4
R)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-
Methanesulfonyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer II
(221 mg, yield: 89.7%) was obtained.

[0470] NMR (CDCl3) δ: 3.04 (3H
, s), 3.58 (2H, m), 4.08-4.32 (
2H, m), 4.42 (1H, m), 5.10-5.3
8 (5H, m), 5.50-5.68 (1H, m) 2)

0471]

embedded image The compound obtained in the above reaction (221 mg, 0.35 mm
(2S,4S)-4-acetylthio-2-
[2-Carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer II (180 mg, yield: 84.0%) was obtained. Ta.

[0472] NMR (CDCl3) δ: 1.66 (1H
, m), 1.88-2.28 (2H, m), 2.36 (
3H, s), 2.54 (1H, m), 2.82 (1H,
m), 3.06-3.35 (2H, m), 3.63 (1
H, m), 3.86 (1H, m), 4.08 (1H, m
), 4.27 (1H, m), 4.47 (1H, m), 5
．． 62 (4H, m), 7.54 (4H, d, J=8Hz
), 8.24 (4H, d, J = 8Hz) 3)

0473]

embedded image The compound obtained in the above reaction (180 mg, 0.29 mm
(2S,4S)-2-[2-carbamoyl-
N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer II (160 mg, yield: 95%) was obtained. Reference Example 15 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]pyrrolidine diastereomer A 1)

0474]

embedded image (2S,4R)-4-tert- obtained in Reference Example 12
Butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer A (4.8g, 12.0mmol
), the same reaction as in Reference Example 5-1) was carried out to obtain crude (2S,4R)-4-tert-butyldimethylsiloxycarbonyl-2-(N-tert-butoxycarbonyl-2-pyrrolidone-4). -yl)pyrrolidine diastereomer A (6.8 g) was obtained.

[0475] NMR (CDCl3) δ: 0.06 (6H
, s), 0.86 (9H, s), 1.48 (9H, s)
, 1.52 (9H, s), 1.60 (1H, m), 1.
90 (1H, m), 2.10-2.58 (2H, m),
3.22 (1H, m), 3.42-3.88 (3H, m
), 4.08 (1H, m), 4.30 (1H, m) 2)

0476]

embedded image Using the compound (6.8 g) obtained in the above reaction, the same reaction as in Reference Example 5-2) was carried out to obtain (2S,4R)-4-
A yellow oil (5.7 g) of tert-butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(N-tert-butoxycarbonylpyrrolidin-4-yl)pyrrolidine diastereomer A was obtained and was purified as follows without purification. It was used in the reaction.

[0477] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.44 (18H, s
), 1.56-2.04 (4H, m), 3.02-3.
70 (6H, m), 4.00 (1H, m), 4.34 (
1H, m) 3)

0478]

embedded image The compound (5.7 g) obtained in the above reaction was added to an approximately 3N hydrogen chloride-methanol solution, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain crystals of (2S,4R)-4-hydroxy-2-(3-pyrrolidinyl)pyrrolidine diastereomer A2 hydrochloride (2.4 g).

0479 IR(KBr)cm-1:3300,29
00,2700,1430,1410,1060NMR
(D2O)δ: 1.92 (2H, m), 2.16-2.
46 (2H, m), 2.68 (1H, m), 3.06 (
1H, dd, J = 12, 10Hz), 3.34 (2H,
br d, J=12Hz), 3.42~3.66(3
H, m), 3.82 (1H, m), 4.67 (1H, m
) 4)

0480]

embedded image Using the compound (1.1 g) obtained in the above reaction, the same reaction as in Reference Example 5-3) was carried out to obtain (2S,4R)-4-
Hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]pyrrolidine diastereomer A oil (2.2 g, yield: 88%) ) was obtained. 5)

0481]

embedded image Using the compound (2.2 g) obtained in the above reaction, the same reaction as in Reference Example 5-4) was carried out to obtain (2S,4R)-4-
Methanesulfonyloxy-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]pyrrolidine
A foam of diastereomer A (2.6 g) was obtained.

[0482] NMR (CDCl3) δ: 2.02 (2H
, m), 2.50 (2H, m), 3.04 (3H, s)
, 3.14-3.82 (6H, m), 4.20 (2H,
m), 5.24 (4H, br s), 7.53 (4H
, d, J=8Hz), 8.24(4H, d, J=8Hz
)6)

0483]

embedded image Using the compound (2.6 g) obtained in the above reaction, the same reaction as in Reference Example 5-5) was carried out to obtain (2S,4S)-4-
Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]pyrrolidine (1.7 g,
Yield from the first step: 73%) was obtained.

NMR (CDCl3) δ: 1.54-2.
10 (4H, m), 2.36 (3H, s), 2.40~
2.82 (2H, m), 3.02-3.70 (6H, m
), 3.88 (1H, m), 4.00-4.32 (2H
, m), 5.24 (4H, br s), 7.52 (4
H, d, J = 8Hz), 8.24 (4H, d, J = 8H
z)7)

0485]

embedded image Using the compound (1.7 g) obtained in the above reaction, the same reaction as in Reference Example 1-9) was carried out to obtain the title compound (1.59 g).
g) was obtained. Reference Example 16 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]pyrrolidine diastereomer B 1)

0486]

embedded image (2S,4R)-4-tert- obtained in Reference Example 12
Butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (5.1 g, 13.3 mmol
), the same reaction as in Reference Example 5-1) was carried out to obtain crude (2S,4R)-4-tert-butyldimethylsiloxycarbonyl-2-(N-tert-butoxycarbonyl-2-pyrrolidone-4). -yl)pyrrolidine diastereomer B (7.5 g) was obtained. 2)

0487]

embedded image Using the compound (7.5 g) obtained in the above reaction, the same reaction as in Reference Example 5-2) was carried out to obtain (2S,4R)-4-
tert-Butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(N-tert-butoxycarbonylpyrrolidin-4-yl)pyrrolidine Diastereomer B was obtained as a yellow oil (6.9 g) and was purified as follows without purification. It was used in the reaction. 3)

0488]

embedded image The compound (6.9 g) obtained in the above reaction was added to an approximately 3N hydrogen chloride-methanol solution, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain crystals of (2S,4R)-4-hydroxy-2-(3-pyrrolidinyl)pyrrolidine diastereomer B2 hydrochloride (3.0 g). 4)

0489]

embedded image Using the compound (3.0 g) obtained in the above reaction, the same reaction as in Reference Example 5-3) was carried out to obtain (2S,4R)-4-
Hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]pyrrolidine diastereomer B oil (6.8 g, yield: 99%) ) was obtained. 5)

0490]

embedded image Using the compound (6.8 g) obtained in the above reaction, the same reaction as in Reference Example 5-4) was carried out to obtain (2S,4R)-4-
Methanesulfonyloxy-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]pyrrolidine
A foam of diastereomer B (7.8 g) was obtained. 6)

0491

embedded image The compound obtained in the above reaction (3.6 g, 5.8 mmol
), the same reaction as in Reference Example 5-5) was carried out, and (2
S,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]pyrrolidine diastereomer B (1.3 g, yield Rate: 39%
) was obtained.

NMR (CDCl3) δ: 1.54-2.
10 (4H, m), 2.36 (3H, s), 2.40~
2.82 (2H, m), 3.02-3.70 (6H, m
), 3.88 (1H, m), 4.00-4.32 (2H
, m), 5.24 (4H, br s), 7.52 (4
H, d, J = 8Hz), 8.24 (4H, d, J = 8H
z) 7)

0493

embedded image Using the compound (1.7 g) obtained in the above reaction, the same reaction as in Reference Example 1-9) was carried out to obtain the title compound (1.6 g).
) was obtained. Reference Example 17 (2S,4R)-4-hydroxy-2-(3-pyrrolidinyl)pyrrolidine dihydrochloride

0494

embedded image (2S,4R)-N-tert-butoxycarbonyl-
4-tert-butyldimethylsiloxy-2-(N-t
ert-butoxycarbonylpyrrolidin-3-yl)pyrrolidine [308g, 0.654mol; Reference Example 5-2
) was used to carry out the same reaction as in Reference Example 15-3) to obtain the title compound (133 g, yield: 88%).

0495 IR(KBr)cm-1:3390,30
00～2400,1600,1420,1270,10
65,980 NMR (D2O) δ: 1.76-2.18 (2H, m)
, 2.20-2.48 (2H, m), 2.58-2.9
8 (2H, m), 3.10-3.28 (1H, m), 3
．． 30-3.50 (2H, m), 3.50-3.82 (
3H, m), 3.82-4.04 (1H, m), 4.7
0(1H,m) Reference Example 18 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidone-4
-yl)pyrrolidine diastereomer A1)

0496]

embedded image (2S,4R)-N-tert-butoxycarbonyl-
Using 4-tert-butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer A (61.38 g, 160 mmol, compound of Reference Example 12), the same procedure as in Reference Example 1-7) was carried out. Perform the reaction (
2S,4R)-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidone-4-
yl)pyrrolidine diastereomer A (41.68
g, yield: 74.6%).

0497 IR(KBr)cm-1:1695,16
05,1520,1430,1345,1110NMR
(CDCl3)δ: 1.6-2.0 (2H, m), 2.
0-2.54 (2H, m), 3.0-3.56 (4H,
m), 3.8 (1H, m), 4.26 (1H, m), 4
．． 5 (1H, m), 5.25 (2H, s), 5.83 (
1H, br), 7.54 (2H, d, J=9Hz), 8
．． 22 (2H, d, J = 9Hz) 2)

0498

embedded image The compound obtained in the above reaction (41.6 g, 120 mmo
Using 1), the same reaction as in Reference Example 5-4) was carried out, and (
2S,4R)-4-methanesulfonyloxy-N-(p
-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer A
(47.28 g, yield: 92.3%) was obtained.

0499 IR(KBr)cm-1:1710,16
95, 1605, 1525, 1345, 1170NMR
(CDCl3)δ: 1.5-2.1 (4H, m), 2.
4-2.8 (2H, m), 3.04 (3H, s), 3.
1-3.64 (3H, m), 4.0-4.5 (2H, m
), 5.2 (2H, s), 6.32 (1H, br), 7
．． 52 (2H, d, J = 9Hz), 8.22 (2H, d
, J=9Hz) 3)

0500]

embedded image Using the compound (13 g, 30 mmol) obtained in the above reaction, the same reaction as in Reference Example 5-5) was carried out to obtain (2S,
4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer A (4.61 g, yield:
37.7%).

0501 IR(KBr)cm-1:1705,16
95, 1515, 1405, 1345, 1110NMR
(CDCl3)δ: 1.68 (2H, m), 2.04~
2.64 (4H, m), 2.35 (3H, s), 3.1
8 (2H, m), 3.42 (1H, m), 3.84 (1
H, m), 4.04-4.34 (2H, m), 5.23
(2H, s), 5.97 (1H, br), 7.53 (2
H, d, J = 9Hz), 8.25 (2H, d, J = 9H
z) 4)

0502]

embedded image The compound obtained in the above reaction (4.61 g, 11 mmol
) was used to carry out the same reaction as in Reference Example 5-6) to obtain the title compound (3.92 g, yield: 97.5%).

0503 IR(KBr)cm-1:1695,15
25,1400,1345,1110NMR(CDCl
3) δ: 1.42 to 1.8 (2H, m), 1.73 (1
H, d, J=8Hz), 2.04-2.6 (3H, m)
, 2.98-3.48 (5H, m), 4.10 (2H,
m), 5.24 (2H, s), 6.0 (1H, br),
7.52 (2H, d, J = 9Hz), 8.24 (2H,
d, J=9Hz) Reference Example 19 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidone-4
-yl)pyrrolidine diastereomer B1)

0504]

embedded image (2S,4R)-N-tert-butoxycarbonyl-
4-tert-Butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (62.48 g, 163 mmol, compound of Reference Example 12) was dissolved in methanol (600 ml) and cooled to 0°C. After that, 2.5N HCl/MeOH (230 ml, 57
0 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration, dried, and (2S,4R)-4-hydroxy-
A white powder (30.01 g, yield: 89.1%) of 2-(2-pyrrolidon-4-yl)pyrrolidine hydrochloride was obtained. This white powder (10.53 g, 50 mmol) was dissolved in a mixed solvent of dioxane (50 ml) and water (50 ml), and the pH was adjusted to 8 with triethylamine. Add thio)pyrimidine (17.55g, 55mmol),
The reaction was carried out for 6 hours while maintaining the pH at 8. After concentrating the reaction solution, tetrahydrofuran (100 ml) was added, insoluble materials were removed by filtration, and the filtrate was concentrated. The residue was subjected to column chromatography [WakogelTM C-300, chloroform-methanol (40:1)], and (2S, 4R
)-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (17.48 g, yield:
98.2%).

0505 IR(KBr)cm-1:1690,16
80, 1525, 1345, 1110, 1095NMR
(CDCl3)δ: 1.5-1.96 (2H, m), 1
．． 98-2.46 (2H, m), 3.0-3.56 (4
H, m), 3.7-3.9 (1H, m), 4.25 (1
H, m), 4.5 (1H, br), 5.26 (2H, s
), 6.02 (1H, br), 7.54 (2H, d, J
= 9Hz), 8.25 (2H, d, J = 9Hz) 2)

0506]

embedded image The compound obtained in the above reaction (17.46 g, 50 mmo
Using 1), the same reaction as in Reference Example 5-4) was carried out, and (
2S,4R)-4-methanesulfonyloxy-N-(p
-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B
(17.46 g, yield: 81.8%) was obtained.

0507 IR(KBr)cm-1:1705,16
90,1520,1345,1170,905NMR(
CDCl3) δ: 1.74 (2H, br), 1.9-2
．． 6 (4H, m), 3.04 (3H, s), 3.2-3
．． 64 (3H, m), 4.1-4.36 (2H, m),
5.28 (2H, s), 5.92 (1H, br), 7.
54 (2H, d, J=9Hz), 8.24 (2H, d,
J=9Hz) 3)

0508]

embedded image The compound obtained in the above reaction (17.4 g, 41 mmol
), the same reaction as in Reference Example 5-5) was carried out, and (2
S,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidone-4-
yl) pyrrolidine diastereomer B (14.29g,
Yield: 85.6%).

0509 IR(KBr)cm-1:1705,16
95, 1520, 1400, 1345, 1110NMR
(CDCl3)δ: 1.74 (2H, m), 2.0~2
．． 60 (4H, m), 2.34 (3H, s), 3.0~
3.5 (3H, m), 3.84 (1H, m), 4.0~
4.3 (2H, m), 5.22 (2H, s), 6.02
(1H, br), 7.52 (2H, d, J=9Hz),
8.24 (2H, d, J = 9Hz) 4)

0510]

embedded image Using the compound (7 g, 17 mmol) obtained in the above reaction, the same reaction as in Reference Example 5-6) was carried out to obtain the title compound (5.94 g, yield: 95.6%). Ta.

0511 IR(KBr)cm-1:1695,15
20,1400,1345,1105NMR(CDCl
3) δ: 1.5 to 1.88 (2H, m), 1.75 (1
H, d, J = 8Hz), 2.12 (1H, dd, J = 1
8,8Hz), 2.37 (1H, dd, J=18,8H
z), 2.44 (1H, m), 3.0 to 3.56 (5H
, m), 4.0 to 4.22 (2H, m), 5.22 (2
H, s), 6.14 (1H, br), 7.52 (2H,
d, J=9Hz), 8.23 (2H, d, J=9Hz) Reference Example 20 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[3-[( p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidine 1)

0512]

embedded image Diisopropylamine (0.64ml, 4.6mmol
) into a solution of 1.6 M n-butyllithium (
2.5 ml, 4 mmol) was added dropwise, and the reaction solution was stirred for 45 minutes. Add (2S,4R)-N-tert to this solution.
-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-tert-butoxycarbonyl-
2-pyrrolidon-4-yl)pyrrolidine [986 mg,
A solution of 2 mmol, Compound of Reference Example 5-1) in tetrahydrofuran (10 ml) was added dropwise, and after stirring at the same temperature for 2 hours, p-toluenesulfonyl azide (945 mg
, 4.8 mmol) and further stirred for 1 hour. Next, trimethylsilyl chloride (1.
29 ml, 10 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with methylene chloride (50 ml). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (WakogelTM
C-300, chloroform), (2S,4R)
-2-(3-azido-N-tert-butoxycarbonyl-2-pyrrolidon-4-yl)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsiloxy)pyrrolidine (720 mg, yield: 68.5 %) was obtained.

0513 IR(KBr)cm-1:2110,17
90, 1760, 1695, 1315, 1155NMR
(CDCl3)δ:0.06(6H,s),0.86(
9H, s), 1.48 (9H, s), 1.6-2.2 (
2H, m), 3.1-3.85 (5H, m), 4.10
(1H, br), 4.26 (1H, br), 4.5 (1
H, br) 2)

0514]

embedded image The compound obtained in the above reaction (720 mg, 1.37 mm
ol) in methanol (50 ml), 10% palladium-carbon catalyst (200 mg) was added, and under a hydrogen stream,
Stir vigorously for 2 hours. After filtration, the resulting filtrate was concentrated to obtain a crude oil (730 mg). This oil was dissolved in a mixed solution of dioxane (20 ml) and water (20 ml). After adjusting the pH to 8 with triethylamine,
,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (504mg, 1.6mmol
) was added, and the solution was stirred for 6 hours while maintaining the pH at 8. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50%
ml) and washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-3
00, chloroform-methanol (100:1)] to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[N
-tert-butoxycarbonyl-3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidine (840 mg, yield: 90.6
%) was obtained.

0515 IR(KBr)cm-1:1795,16
95, 1525, 1350, 1255, 1155NMR
(CDCl3)δ:0.06(6H,s),0.86(
9H, s), 1.48 (9H, s), 1.54 (9H,
s), 1.72-2.1 (2H, m), 3.08-3.
78 (5H, m), 4.1-4.3 (3H, m), 5.
2 (2H, br), 7.5 (2H, d, J=9Hz),
8.24 (2H, d, J = 9Hz) 3)

0516]

embedded image The compound obtained in the above reaction (840 mg, 1.2 mmo
1) was dissolved in dry methylene chloride (20 ml), and after cooling to 0°C, trifluoroacetic acid (1 ml, 13 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction solution and removing trifluoroacetic acid, the residue was dissolved in methanol (30%
ml) and 2.5N HCl-MeOH (0.ml).
63 ml, 1.6 mmol) was added thereto, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction solution, the resulting residue was mixed with dioxane (
20ml) and water (20ml),
While adjusting the pH to 8 with triethylamine, 4,6-
Dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (850 mg, 2.6 mmol) was added and stirred at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure,
The residue was extracted with ethyl acetate (100 ml) and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, chloroform-methanol (50:1)], and (2S
,4R)-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-[3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidone-4-
yl]pyrrolidine (450 mg, yield: 69%) was obtained.

0517 IR(KBr)cm-1:1700,15
20,1345 NMR (CDCl3+CD3OD) δ: 1.96-2.
24 (2H, m), 3.06-3.84 (5H, m),
4.08-4.5 (3H, m), 5.22 (2H, s)
, 5.24 (2H, s), 7.54 (4H, d, J=9
Hz), 8.22 (4H, d, J = 9Hz) 4)

0518]

embedded image The compound obtained in the above reaction (450 mg, 0.83 mm
The same reaction as in Reference Example 5-4) was carried out using
Crude (2S,4R)-4-methanesulfonyloxy-N-(p-nitrobenzyloxycarbonyl)-2-
[3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidine (620
mg) was obtained.

0519 IR(KBr)cm-1:1710,16
10,1525,1350,11755)

0520]

embedded image Using the compound (620 mg) obtained in the above reaction, the same reaction as in Reference Example 5-5) was carried out to obtain (2S,4S)-4
-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-[3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidine (130 mg, yield: 26%) Obtained.

0521 IR(KBr)cm-1:1710,17
00,1610,1525,1350,1110NMR
(CDCl3)δ: 1.86-1.96 (2H, m),
2.34 (3H, s), 2.68 (1H, br), 3.
0-3.4 (4H, m), 4.84 (1H, m), 4.
1-4.4 (2H, m), 5.2 (4H, br), 5.
92 (1H, br), 6.84 (1H, br), 7.5
4 (4H, d, J = 9Hz), 8.22 (4H, d, J
=9Hz) 6)

0522]

embedded image The compound obtained in the above reaction (130 mg, 0.21 mm
The same reaction as in Reference Example 5-6) was carried out using
(2S,4S)-4-mercapto-N-( of the title compound
p-nitrobenzyloxycarbonyl)-2-[3-[
(p-nitrobenzyloxycarbonyl)amino]-2
-pyrrolidon-4-yl]pyrrolidine (110 mg, yield: 91%) was obtained.

0523 IR(KBr)cm-1:1710,16
10,1515,1350NMR(CDCl3)δ:1
．． 6-1.9 (2H, br), 1.77 (1H, d, J
=8Hz), 2.77 (1H, br), 3.95-4.
42 (4H, m), 4.05-4.2 (3H, br),
5.19 (2H, s), 5.21 (2H, s), 5.9
(1H, br), 6.92 (1H, br), 7.54 (
4H, d, J = 9Hz), 8.2 (4H, d, J = 9H
z) Reference Example 21 (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine 1)

0524]

embedded image (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine [119
g, 259 mmol; Compound of Japanese Patent Application No. 2-192093, Reference Example 3-1)], triethylamine (40.3 ml)
, 289 mmol) in a solution of methylene chloride (1 L),
Methanesulfonyl chloride (20.5 ml, 265 m
mol), a solution of methylene chloride (20 ml) was added dropwise,
The mixture was stirred at the same temperature for 30 minutes. Add the reaction solution to water (500ml)
, saturated sodium bicarbonate water (250 ml), and saturated brine (250 ml), then dehydrated and concentrated over anhydrous sodium sulfate. Ethyl acetate (30 ml) and diisopropyl ether (270 ml) were added to the residue, and the precipitated crystals were collected by filtration to give (2S,4S)-N-allyloxycarbonyl-2-methanesulfonyloxymethyl-4
-Tritylthiopyrrolidine (130.8g, yield: 94
%) was obtained.

[0525] NMR (CDCl3) δ: 1.8 (1H,
m), 2.1 (1H, m), 1.7-2.4 (3H, m
), 3.0 (3H, s), 3.9 (1H, m), 4.1
~4.6 (4H, m), 5.2 ~ 5.4 (2H, m),
5.9 (1H, m), 7.2-7.6 (15H, m) 2)

0526]

embedded image The compound obtained in the above reaction (130.8 g, 243 mm
ol), sodium iodide (180g, 1.2mol)
, 2-butanone (1.3 L) was heated and stirred for 3 hours. The reaction solution was washed successively with water (300 ml), 10% sodium thiosulfate water (200 ml), and saturated brine (500 ml), then dehydrated and concentrated over anhydrous sodium sulfate. Diisopropyl ether (120 ml) and n
-Hexane (300 ml) was added, and the precipitated crystals were collected by filtration to obtain the title compound (123.7 g, yield: 89%). NMR (CDCl3) δ: 1.6 (1H, m), 2.
1 (1H, m), 2.7-3.1 (3H, m), 3.3
~3.6 (3H, m), 4.5 (2H, br s),
5.25 (2H, m), 5.9 (1H, m), 7.2~
7.6 (15H, m) Reference Example 22 (2R,4S)-N-allyloxycarbonyl-4-mercapto-2-(2-oxopyrrolidin-3-ylmethyl)pyrrolidine 1)

0527]

embedded image Lithium diisopropylamide (2.1M tetrahydrofuran solution, 6. 45 ml, 13.5 mmol) was added dropwise,
After stirring at the same temperature for 15 minutes, a solution of (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (2.57 g, 4.5 mmol) and tetrahydrofuran (18 ml) was added dropwise. The mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate (150 ml).
) and 10% aqueous ammonium chloride (50 ml) to separate the layers. The organic layer was washed successively with 10% aqueous sodium dihydrogen phosphate (100 ml) and saturated brine (100 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (12 ml) and methanol (3 ml).
1), add 6N hydrochloric acid (3 ml) under ice-cooling, and add 1
Stir for hours. Ethyl acetate (50 ml) was added to the reaction mixture, which was washed successively with saturated sodium hydrogen carbonate water (30 ml) and saturated brine (30 ml), then dehydrated and concentrated over anhydrous sodium sulfate. The residue was subjected to silica gel flash column chromatography [WakogelTM C-300
, 40ml, eluted with ethyl acetate-n-hexane (3:1)] to give (2R,4S)-N-allyloxycarbonyl-2-(2-oxopyrrolidin-3-ylmethyl)-4-trityl. Thiopyrrolidine (880 mg, yield: 37%) was obtained.

[0528] NMR (CDCl3) δ: 1.5 (1H,
m), 1.7-2.3 (6H, m), 2.6-3.0 (
3H, m), 3.34 (2H, m), 3.66 (1H,
m), 4.5 (2H, br s), 5.3 (2H, m
), 5.9 (2H, m), 7.2-7.6 (15H, m
) 2)

0529]

embedded image The compound obtained in the above reaction (1.32 g, 2.51 mm
To a solution of methylene chloride (1.3 ml) were added trifluoroacetic acid (1.3 ml) and triethylsilane (0.42 ml, 2.63 mmol) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After removing the organic solvent under reduced pressure, ethyl acetate (50 ml) was added and 1M phosphate buffer (
pH 5.5, 30ml x 2), saturated saline (30ml)
The mixture was washed successively with water, dehydrated with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel flash column chromatography [Wakogel™ C-300, 40 ml, eluted with acetone-ethyl acetate (3:7)] to obtain the title compound (650 mg, yield: 91%).

[0530] NMR (CDCl3) δ: 1.5-1.7
(2H, m), 1.9-2.4 (5H, m), 2.65
(1H, m), 3.1-3.4 (4H, m), 3.92
(1H, m), 4.1 (1H, m), 4.6 (2H, b
r d, J=6Hz), 5.2 to 5.4 (2H, m)
, 5.95 (2H, m) Reference Example 23 (2R,4S)-N-allyloxycarbonyl-4-mercapto-2-(2-oxoazetidin-3-ylmethyl)pyrrolidine 1)

0531]

embedded image N-tert-butyldimethylsilyl-2-oxoazetidine (650 mg, 3.5 mmol), lithium diisopropylamide (2.1 M tetrahydrofuran solution, 3.34 ml, 7.0 mmol), (2S, 4S)
-N-allyloxycarbonyl-2-iodomethyl-4
-Tritylthiopyrrolidine (1g, 1.75mmol)
was carried out in the same manner as in Reference Example 22-1) using (2R,4
S)-N-allyloxycarbonyl-2-(2-oxoazetidin-3-ylmethyl)-4-tritylthiopyrrolidine (220 mg, yield: 24%) was obtained.

[0532] NMR (CDCl3) δ: 1.5 (1H,
m), 1.9-2.3 (2H, m), 2.7-3.1 (
4H, m), 3.2 (1H, m), 3.4 (1H, t,
J = 5Hz), 3.7 (1H, m), 4.5 (2H, b
r s), 5.3 (2H, m), 5.62 (1H, b
r s), 5.9 (1H, m), 7.2-7.6 (1
5H, m) 2)

0533]

embedded image The compound obtained in the above reaction (510 mg, 0.99 mm
ol), triethylsilane (0.17ml, 1.05m
mol) in the same manner as in Reference Example 22-2) to obtain the title compound, which was used in the next reaction without purification. Reference Example 24 (2R,4S)-N-allyloxycarbonyl-2-(
N-allyloxycarbonylpyrrolidin-3-ylmethyl)-4-mercaptopyrrolidine 1)

0534]

embedded image (2S,4S)-N-allyloxycarbonyl-2-[
(Z)-2-oxopyrrolidin-3-ylidenemethyl]
-4-tritylthiopyrrolidine [3g, 5.7mmol
;Patent Application No. 2-192093, Compound of Reference Example 7-1)]
, triethylamine (0.8 ml, 5.7 mmol),
4-(dimethylamino)pyridine (699mg, 5.7
di-tert-butyl dicarbonate (1.97 ml,
After stirring at room temperature for 5 hours, the solvent was removed under reduced pressure. Add ethyl acetate (50ml) to the residue.
and 10% sodium dihydrogen phosphate water (20ml)
, and saturated brine (20 ml), then dehydrated and concentrated over anhydrous sodium sulfate. The residue was subjected to silica gel flash column chromatography [WakogelTM
C-300, 40ml, ethyl acetate-n-hexane (
(2S,4S)-N-allyloxycarbonyl-2-[(Z)-N-tert-
Butoxycarbonyl-2-oxopyrrolidin-3-ylidenemethyl]-4-tritylthiopyrrolidine (3.24
g, yield: 91%) was obtained.

[0535] NMR (CDCl3) δ: 1.5 (1H,
m), 1.56 (9H, s), 2.4-3.2 (6H,
m), 3.7 (2H, m), 4.3 to 4.6 (2H, m
), 5.1-5.5 (3H, m), 5.7-6.0 (2
H, m), 7.2-7.6 (15H, m)2)

0536]

embedded image The compound obtained in the above reaction (500 mg, 0.8 mmo
Lithium chloride (68 mg, 1.6 mmol), sodium borohydride (61 mg, 1.6 mmol), and ethanol (5 ml) were sequentially added to a solution of 1) and tetrahydrofuran (2.5 ml), and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (30 ml) was added to the reaction solution, and water (15 ml x 2) was added.
, and saturated brine (15 ml), then dehydrated and concentrated over anhydrous sodium sulfate. The residue was subjected to silica gel flash column chromatography [WakogelTM
C-300, 40ml, ethyl acetate-n-hexane (
(2R,4S)-N-allyloxycarbonyl-2-[4-tert-butoxycarbonylamino-2-(hydroxymethyl)butyl]
-4-tritylthiopyrrolidine (270 mg, yield: 5
4%).

[0537] NMR (CDCl3) δ: 1.2-1.5
(4H, m), 1.44 (9H, s), 1.7-2.1
(2H, m), 2.22 (1H, m), 2.6-3.0
(3H, m), 3.16 (2H, m), 3.4-3.8
(3H, m), 4.5 (2H, br s), 4.7 (
0.5H,br s), 4.9(0.5H,br
s), 5.2-5.4 (2H, m), 5.9 (1H, m
), 7.2-7.6 (15H, m) 3)

0538]

embedded image The compound obtained in the above reaction (270 mg, 0.43 mm
ol), triethylamine (66 μl, 0.47 mmo
l), methanesulfonyl chloride (35 μl, 0.45 mmol) was added dropwise to a solution of methylene chloride (3 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Methylene chloride (30 ml) was added to the reaction mixture, and the mixture was washed successively with water (15 ml), saturated aqueous sodium bicarbonate (15 ml), and saturated brine (15 ml), and then dehydrated and concentrated over anhydrous sodium sulfate. The residue was purified by silica gel flash column chromatography [WakogelTM C-300, 40 ml, eluted with ethyl acetate-n-hexane (1:1)],
(2R,4S)-N-allyloxycarbonyl-2-[
4-tert-butoxycarbonylamino-2-(methanesulfonyloxymethyl)butyl]-4-tritylthiopyrrolidine (270 mg, yield: 89%) was obtained.

[0539] NMR (CDCl3) δ: 1.3-2.0
(6H, m), 1.44 (9H, s), 2.2 (1H,
m), 2.6-3.3 (5H, m), 3.0 (1.5H
, s), 3.02 (1.5H, s), 3.8 (1H, m
), 4.14 (2H, m), 4.4-4.7 (2.5H
, m), 5.02 (0.5H, br s), 5.2~
5.4 (2H, m), 5.9 (1H, m), 7.2-7
．． 6 (15H, m) 4)

0540]

embedded image The compound obtained in the above reaction (260mg.0.367m
mol) was added to a 1.55N hydrogen chloride-methanol solution (0.
7 ml) and stirred at room temperature for 4 hours. After removing the solvent under reduced pressure, tetrahydrofuran (5 ml) and triethylamine (0.11 ml, 0.81 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After adding triethylamine (0.11 ml, 0.81 mmol) to the reaction solution, allyl chloroformate (43 μl, 0.4 mmol) was added under ice cooling.
) was added dropwise and stirred at the same temperature for 30 minutes. Ethyl acetate (30 ml) was added to the reaction solution, followed by water (15 ml), saturated aqueous sodium bicarbonate (15 ml), and saturated brine (15 ml).
After sequentially washing with water, the mixture was dehydrated with anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel flash column chromatography [WakogelTM C-300, 40ml,
(2R,4S)-N-allyloxycarbonyl-2
-(N-allyloxycarbonylpyrrolidin-3-ylmethyl)-4-tritylthiopyrrolidine (180mg,
Yield: 82%) was obtained.

[0541] NMR (CDCl3) δ: 1.3-1.5
(3H, m), 1.8~2.2 (4H, m), 2.6~
3.0 (4H, m), 3.3 (1H, m), 3.4~3
．． 7 (3H, m), 4.5 (2H, br s), 4.
6 (2H, br d, J=5Hz), 5.2-5.4
(4H, m), 5.8~6.1 (2H, m), 7.2~
7.6 (15H, m) 5)

0542]

embedded image The compound obtained in the above reaction (1.03 g, 1.73 mm
ol), triethylsilane (0.29ml, 1.81m
mol) in the same manner as in Reference Example 22-2) to obtain the title compound (560 mg, yield: 92%).

[0543] NMR (CDCl3) δ: 1.5-1.8
(4H, m), 1.9-2.3 (4H, m), 2.62
(1H, m), 2.9-4.2 (7H, m), 4.6 (
4H, m), 5.2-5.4 (4H, m), 5.9-6
．． 1(2H,m) Reference Example 25 (2R,4S)-N-allyloxycarbonyl-2-[
(2S)-N-allyloxycarbonyl-2-carbamoylpyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine 1)

0544]

embedded image (S)-N-tert-butyldimethylsilyl-5-t
ert-butyldimethylsiloxymethyl-2-oxopyrrolidine (10.67g, 31.6mmol), lithium diisopropylamide (2.1M tetrahydrofuran solution, 15.1ml, 31.6mmol), (2S
,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (10g, 17.6
mmol) in the same manner as in Reference Example 22-1),
(2R,4S)-N-allyloxycarbonyl-2-[
(5S)-5-hydroxymethyl-2-oxopyrrolidin-3-ylmethyl]-4-tritylthiopyrrolidine (
2g, yield: 21%) was obtained.

[0545] NMR (CDCl3) δ: 1.3-2.4
(8H, m), 2.7-3.0 (2H, m), 3.5 (
1H, m), 3.6-3.8 (3H, m), 4.5 (2
H, br s), 5.2-5.4 (2H, m), 5.
9 (1H, m), 6.3 (1H, br s), 7.2
~7.6 (15H, m) 2)

0546]

embedded image Compound obtained in the above reaction (4 g, 7.18 mmol)
, tert-butyldimethylsilyl chloride (1.19
g, 7.9 mmol) and N,N-dimethylformamide (20 ml), 4-(dimethylamino)pyridine (88 mg, 0.72 mmol) and triethylamine (1.2 ml, 8.6 mmol) were added under ice cooling. Add sequentially,
Stirred at room temperature for 3 hours. Ethyl acetate (80ml) was added to the reaction solution.
) was added thereto, and the mixture was washed successively with water (40 ml x 2), saturated aqueous sodium bicarbonate (40 ml), and saturated brine (40 ml), then dehydrated and concentrated over anhydrous sodium sulfate. The residue was subjected to silica gel flash column chromatography [Wa
kogelTM C-300, 40ml, eluted with ethyl acetate-n-hexane (2:1)] and purified with (2R
,4S)-N-allyloxycarbonyl-2-[(5S
)-5-tert-butyldimethylsiloxymethyl-2
-Oxopyrrolidin-3-ylmethyl]-4-tritylthiopyrrolidine (4.1 g, yield: 85%) was obtained.

[0547] NMR (CDCl3) δ: 0.05 (6H
, s), 0.9 (9H, s), 1.3-2.4 (8H,
m), 2.8-3.0 (2H, m), 3.3-3.7 (
4H, m), 4.5 (2H, br s), 5.2-5
．． 4 (2H, m), 5.9 (2H, m), 7.2-7.
6 (15H, m) 3)

0548]

embedded image The compound obtained in the above reaction (4.1 g, 6.1 mmol
), di-tert-butyl dicarbonate (2.53 m
l, 11 mmol), 4-(dimethylamino)pyridine (746 mg, 6.1 mmol), triethylamine (
Reference Example 24
-1), and (2R,4S)-N-allyloxycarbonyl-2-[(5S)-N-tert-butoxycarbonyl-5-tert-butyldimethylsiloxymethyl-2-oxopyrrolidine-3- ylmethyl]-4
-Tritylthiopyrrolidine (4.7g, yield: 100%
) was obtained.

[0549] NMR (CDCl3) δ: 0.04 (3H
, s), 0.06 (3H, s), 0.9 (9H, s),
1.5 (2H, m), 1.52 (9H, s), 1.9 (
2H, m), 2.15 (2H, m), 2.8-3.0 (
4H, m), 3.62 (1H, m), 3.7 (1H, d
d, J=10,2Hz), 3.9(1H, dd, J=1
0.4Hz), 4.1 (1H, m), 4.5 (2H, b
rs), 5.1-5.3 (2H, m), 5.9 (1H,
m), 7.2-7.6 (15H, m)4)

0550]

embedded image The compound obtained in the above reaction (4.7 g, 6.1 mmol
), lithium chloride (518 mg, 12.2 mmol),
Sodium borohydride (463 mg, 12.2 mmo
l) in the same manner as in Reference Example 24-2), and (2R
,4S)-N-allyloxycarbonyl-2-[(4S
)-4-tert-butoxycarbonylamino-5-t
ert-butyldimethylsiloxy-2-hydroxymethylpentyl]-4-tritylthiopyrrolidine (2.18
g, yield: 46%).

[0551] NMR (CDCl3) δ: 0.04 (6H
, s), 0.9 (9H, s), 1.4-1.8 (6H,
m), 1.48 (9H, s), 2.2 (1H, m), 2
．． 6-3.0 (3H, m), 3.5-3.9 (6H, m
), 4.5 (2H, br s), 4.7 (1H, br
s), 5.2-5.4 (2H, m), 5.9 (1H
, m), 7.2-7.6 (15H, m) 5)

0552]

embedded image The compound obtained in the above reaction (2.18 g, 2.8 mmo
l), methanesulfonyl chloride (0.24 ml, 3 mmo
l), triethylamine (0.47ml, 3.4mmo
l) in the same manner as in Reference Example 24-3), and (2R
,4S)-N-allyloxycarbonyl-2-[(4S
)-4-tert-butoxycarbonylamino-5-t
Ert-butyldimethylsiloxy-2-methanesulfonyloxymethylpentyl]-4-tritylthiopyrrolidine (2.15 g, yield: 90%) was obtained.

[0553] NMR (CDCl3) δ: 0.04 (6H
, s), 0.9 (9H, s), 1.3 to 1.9 (6H,
m), 1.45 (9H, s), 2.2 (1H, m), 2
．． 6-3.0 (3H, m), 3.0 (3H, s), 3.
4-3.8 (4H, m), 4.1-4.7 (5H, m)
, 5.1-5.3 (2H, m), 5.9 (1H, m),
7.2-7.6 (15H, m)6)

0554]

embedded image The compound obtained in the above reaction (2.15 g, 2.52 mm
ol), 1N hydrogen chloride-methanol solution (25ml
), allyl chloroformate (0.35 ml, 3.28
mmol), triethylamine (1.76 ml, 12.
6 ml) was carried out in the same manner as in Reference Example 24-4), and (
2R,4S)-N-allyloxycarbonyl-2-[(
2S)-N-allyloxycarbonyl-2-hydroxymethylpyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (1.21 g, yield: 77%) was obtained.

[0555] NMR (CDCl3) δ: 1.3-2.2
(7H, m), 2.6-3.05 (4H, m), 3.5
~3.7 (4H, m), 4.05 (1H, m), 4.4
5 (2H, br d, J=4Hz), 4.6 (2H,
m), 5.1-5.3 (4H, m), 5.8-6.0 (
2H, m), 7.2-7.6 (15H, m) 7)

0556]

embedded image The compound obtained in the above reaction (1.21 g, 1.93 mm
ol), pyridinium dichromate (3.63 g, 9.
65 mmol), N,N-dimethylformamide (7.
2 ml) solution was stirred at room temperature for 16 hours. After adding ethyl acetate (50 ml) to the reaction solution, water (20 ml x 2) was added.
Washed with. Potassium carbonate (270 mg, 1.
Water (30 ml) containing 93 mmol) was added, and the layers were separated. After acidifying the aqueous layer with 6N hydrochloric acid, ethyl acetate (5
0 ml) was added, the layers were separated, and the organic layer was diluted with saturated brine (20 ml).
1), dehydrated with anhydrous sodium sulfate, and concentrated to give (2R,4S)-N-allyloxycarbonyl-
2-[(2S)-N-allyloxycarbonyl-2-carboxypyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (1 g, yield: 81%) was obtained.

[0557] NMR (CDCl3) δ: 1.3-1.5
(2H, m), 1.8~2.4 (5H, m), 2.7~
3.1 (4H, m), 3.5-3.9 (2H, m), 4
．． 3-4.8 (5H, m), 5.1-5.5 (4H, m
), 5.8-6.0 (2H, m), 7.2-7.6 (1
5H, m) 8)

0558]

embedded image The compound obtained in the above reaction (400 mg, 0.62 mm
ol), triethylamine (96 μl, 0.69 mmo
l), -15 in a solution of tetrahydrofuran (6 ml)
isobutyl chloroformate (90 μl, 0.69
After stirring at the same temperature for 20 minutes, concentrated aqueous ammonia (0.18 ml) was added, and the mixture was stirred at 0°C for 1 hour. Ethyl acetate (30 ml) was added to the reaction solution, and saturated sodium bicarbonate water (15 ml) and saturated brine (15 ml) were added.
ml), dehydrated with anhydrous sodium sulfate, and concentrated to give (2R,4S)-N-allyloxycarbonyl-
2-[(2S)-N-allyloxycarbonyl-2-carbamoylpyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (310 mg, yield: 78%) was obtained.

[0559] NMR (CDCl3) δ: 1.3-2.5
(7H, m), 2.7-3.1 (4H, m), 3.72
(2H, m), 4.3~4.7 (5H, m), 5.1~
5.5 (5H, m), 5.9-6.1 (2.5H, m)
, 6.8 (0.5H, brs), 7.2~7.6 (15
H, m) 9)

0560]

embedded image The compound obtained in the above reaction (310 mg, 0.48 mm
ol), triethylsilane (81 μl, 0.51 mmo
1) in the same manner as in Reference Example 22-2) to obtain the title compound (190 mg, yield: 100%).

0561 NMR (CDCl3) δ: 1.5-2.7
(8H, m), 3.0-3.3 (3H, m), 3.7 (
1H, m), 3.86 (1H, m), 4.06 (1H,
m), 4.4 (1H, d, J = 8Hz), 4.6 (4H
, m), 5.2-5.5 (5H, m), 5.8-6.0
(2.5H, m), 6.8 (0.5H, br s) Reference Example 26 (2R,4S)-N-allyloxycarbonyl-2-[
(2S)-N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine 1)

0562]

embedded image (2R,4S)-N-allyloxycarbonyl-2-[
(2S)-N-allyloxycarbonyl-2-carboxypyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (300 mg, 0.47 mmol), isobutyl chloroformate (74 μl, 0.56 mmol),
Triethylamine (78 μl, 0.56 mmol), 4
Using 0% methylamine aqueous solution (0.19 ml), the same procedure as in Reference Example 25-8) was carried out to obtain (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl- 2-(Methylcarbamoyl)pyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (
300 mg, yield: 98%) was obtained.

[0563] NMR (CDCl3) δ: 1.3-2.5
(7H, m), 2.6-3.0 (3H, m), 2.8 (
3H, d, J=5Hz), 3.6 (2H, m), 4.3
(1H, d, J=8Hz), 4.4-4.6 (4H, m
), 5.1-5.4 (4H, m), 5.8-6.0 (2
．． 5H, m), 6.7 (0.5H, br s), 7.
2-7.6 (15H, m) 2)

0564]

embedded image The compound obtained in the above reaction (300 mg, 0.46 mm
ol), triethylsilane (83 μl, 0.5 mmol
) to obtain the title compound (168 mg, yield: 89%) in the same manner as in Reference Example 22-2).

[0565] NMR (CDCl3) δ: 1.5-2.7
(8H, m), 2.82 (3H, d, J=5Hz), 3
．． 0-3.3 (3H, m), 3.7 (1H, m), 3.
9 (1H, m), 4.1 (1H, m), 4.4 (1H,
d, J=8Hz), 4.6 (4H, m), 5.2-5.
4 (4H, m), 5.8-6.1 (2.5H, m), 6
．． 9(0.5H, br s) Reference Example 27 (2R,4S)-N-allyloxycarbonyl-2-[
(2S)-N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]-4-
Mercaptopyrrolidine 1)

0566]

embedded image (2R,4S)-N-allyloxycarbonyl-2-[
(2S)-N-allyloxycarbonyl-2-carboxypyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (300 mg, 0.47 mmol), isobutyl chloroformate (74 μl, 0.56 mmol),
Triethylamine (78 μl, 0.56 mmol), 5
Using 0% dimethylamine aqueous solution (0.27 ml),
In the same manner as in Reference Example 25-8), (2R,4S)-N-
Allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (290 mg, yield: 93%) was obtained.

[0567] NMR (CDCl3) δ: 1.3-2.3
(7H, m), 2.6-3.0 (4H, m), 2.9 (
6H, s), 3.5 (2H, m), 4.1 to 4.7 (5
H, m), 5.1-5.3 (4H, m), 5.7-5.
9 (2H, m), 7.2-7.6 (15H, m) 2)

0568]

embedded image The compound obtained in the above reaction (290 mg, 0.43 mm
ol), triethylsilane (76 μl, 0.48 mmo
1) in the same manner as in Reference Example 22-2) to obtain the title compound (110 mg, yield: 60%).

[0569] NMR (CDCl3) δ: 1.5-2.7
(8H, m), 2.9-3.3 (3H, m), 2.98
(3H,s), 3.1(3H,s), 3.7~4.2(
3H, m), 4.4-4.8 (5H, m), 5.2-5
．． 4(4H,m), 5.9(2H,m) Reference Example 28 (2S,4S)-2-(2,4-dioxoimidazolidin-5-yl)-4-(p-methoxybenzylthio) −
N-(p-nitrobenzyloxycarbonyl)pyrrolidine 1)

0570]

embedded image Dimethyl sulfoxide (2.2
ml, 3.10 mmol) in methylene chloride solution (30 m
l) to oxalyl chloride (1.3 ml, 14.9 mmol
) was added dropwise, and the reaction solution was stirred at the same temperature for 30 minutes. To this mixture was added (2S,4S)-2-hydroxymethyl-4-(p-methoxybenzylthio)-N
A methylene chloride solution (20 ml) of -(p-nitrobenzyloxycarbonyl)pyrrolidine (4.32 g, 9.99 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes, followed by triethylamine (7.0 ml, 50.2 mmol).
l) was added dropwise. After stirring this mixture at the same temperature for 10 minutes and further at room temperature for 1 hour, methylene chloride (400 ml) was added and the mixture was washed with a 1N aqueous potassium hydrogen sulfate solution and water. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off to obtain a crude aldehyde.

[0571] The crude aldehyde obtained in the above reaction was dissolved in a mixed solvent of ethanol (15 ml), water (15 ml) and N,N-dimethylformamide (6 ml), and ammonium carbonate (4.50 g, 46.8 mmol), Then sodium cyanide (0.98g, 20.0mmol
) and stirred at 60°C for 6 hours. After cooling to room temperature, the organic solvent was distilled off, and water (100 ml) and chloroform (100 ml) were added to the residue. After separating the organic layer, the aqueous layer was extracted with chloroform (100ml x 2).
The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure,
The residue was subjected to silica gel column chromatography (Wako
gelTM C-300, methanol-chloroform) to obtain the title compound (1.82 g, yield: 36%).

0572 IR(KBr)cm-1:3250,17
70, 1730, 1710, 1610, 1510, 13
50 NMR (CDCl3+CD3OD) δ: 1.9-2.3
(2H, m), 3.7-4.1 (1H, m), 4.26
(1H, m), 4.72 and 5.04 (1H, s),
5.22 (2H, s), 6.86 (2H, d, J=8H
z), 7.24 (2H, d, J = 8Hz), 7.51 (
2H, d, J = 8 Hz), 8.26 (2H, d, J = 8
Hz) Reference Example 29 (2R,4S)-N-allyloxycarbonyl-2-(
2,4-dioxoimidazolidin-5-ylmethyl)-
4-Tritylthiopyrrolidine diastereomers A and B 1)

0573]

embedded image Diisopropylamine (1 ml) was added at -78°C under a nitrogen stream.
, 7.14 mmol) in tetrahydrofuran solution (5 m
A 1.6M n-butyllithium-hexane solution (4.1 ml, 6.56 mmol) was added dropwise to the solution (1), and the reaction solution was stirred at the same temperature for 10 minutes and then under ice cooling for 30 minutes. N,N'-bis(tert-butyldimethylsilyl)hydantoin (1.65 g, 5.02 m
mol) of tetrahydrofuran (2 ml) was added dropwise, and this solution was stirred at the same temperature for 1 hour. Hexamethylphosphoric triamide (1.75 ml, 10 m
After stirring for 10 minutes, (2S,4S)
-N-allyloxycarbonyl-2-iodomethyl-4
-Tritylthiopyrrolidine [2.28g, 4.00mm
A tetrahydrofuran solution (3 ml) of the compound of Reference Example 21-2) was added dropwise, and the reaction solution was stirred at the same temperature for 2 hours. A saturated ammonium chloride aqueous solution (10 m
l) and ethyl acetate (300 ml) were added. 1 organic layer
The mixture was washed successively with an aqueous N potassium hydrogen sulfate solution, water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (W
akogelTM C-300, hexane-ethyl acetate) to give (2R,4S)-N-allyloxycarbonyl-2-(1-tert-butyldimethylsilyl-2
,4-dioxoimidazolidin-5-ylmethyl)-4
-Tritylthiopyrrolidine (1.19g, yield: 45%
) was obtained.

0574 IR(KBr)cm-1:3420,32
50, 1765, 1700, 1400, 1200NMR
(CDCl3)δ: 0.27 and 0.35 (6H,s
), 0.94 and 0.97 (9H,s), 1.5 (1
H, m), 1.7 (1H, m), 2.25 (1H, m)
, 2.6-3.0 (3H, m), 4.2 (1H, m),
4.3-4.6 (3H, m), 5.25 (2H, m),
6.85 (1H, m), 7.1-7.7 (15H, m)
, 8.06 and 8.11 (1H,s)2)

0575]

embedded image The compound obtained in the above reaction (1.10 g, 1.68 mm
49% hydrofluoric acid (1.5 ml)-acetonitrile (13.5 ml) was added to an acetonitrile solution (15 ml) of
ml) mixture was added and the solution was stirred at room temperature overnight. Ethyl acetate (300 ml) was added to the reaction solution, and this solution was washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakoge column chromatography).
lTM C-300, methanol-chloroform) to give the title compound diastereomer A (550mg
, yield: 61%; polar compound) and diastereomer B (220 mg, yield: 24%; low polar compound). Diastereomer A IR (KBr) cm-1: 3550, 3480, 342
0,1770,1730,1680,1445,141
0NMR (CDCl3) δ: 1.2-2.4 (4H, m
), 2.75 (2H, m), 3.05 (1H, m), 3
．． 8 (1H, m), 4.10 (1H, d, J=8Hz)
, 4.49 (2H, d, J = 6Hz), 5.26 (2H
, m), 5.9 (1H, m), 6.54 (1H, s),
7.0-7.7 (15H, m), 8.41 (1H, s) Diastereomer B IR (KBr) cm-1: 3420, 3230, 177
5,1730,1700,1445,1410NMR(
CDCl3) δ: 1.2-1.9 (2H, m), 1.9
5-2.45 (2H, m), 2.7 (2H, m), 3.
05 (1H, m), 3.8-4.05 (2H, m), 4
．． 46 (2H, d, J = 5Hz), 5.26 (2H, m
), 5.85 (1H, m), 6.59 (1H, s), 7
．． 1 to 7.6 (15H, m), 8.12 (1H, s) Reference Example 30 (2R,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-(2,5- Dioxopyrrolidin-3-ylmethyl)pyrrolidine 1)

0576]

embedded image Ethyl 3-[(2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylpyrrolidin-2-yl]acrylate (10 g, 26
．． 8 mmol) in ethanol (200 ml) at 10%
3 using palladium on carbon (500 mg) at 60°C.
Catalytic hydrogenation was carried out for an hour. After cooling, the catalyst was filtered off, concentrated under reduced pressure, and subjected to silica gel column chromatography [Wa
kogelTM C-300, 300ml, ethyl acetate-hexane (1:10)] to give ethyl 3-[
(2R,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylpyrrolidine-2
-yl] propionate (9.91 g, yield: 98%)
I got it.

[0577] NMR (CDCl3) δ: 0.04 (6H
, s), 0.90 (9H, s), 1.28 (3H, t,
J = 8Hz), 1.48 (9H, s), 1.78 (2H
, m), 2.00 (2H, m), 2.30 (2H, m)
, 3.38 (2H, m), 3.96 (1H, m), 4.
14 (2H, q, J = 8Hz), 4.32 (1H, m) 2)

0578]

embedded image Compound obtained in the above reaction (5.0 g, 13.3 mmol)
2.1 M lithium diisopropylamide (7.6 ml, 16.0 mmol) was added dropwise to a tetrahydrofuran solution (250 ml) at -78°C in a nitrogen stream, and 1
Stirred for 0 minutes. Next, allyl bromide (3.46 ml,
40 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. After removing the refrigerant and stirring for an additional 30 minutes, a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was dried (MgSO4), concentrated, and subjected to silica gel column chromatography [WakogelTM C-300, ethyl acetate-hexane (1:6)] to give 2-ethoxycarbonyl-1-[(2R,4R)-4 -tert-butyldimethylsiloxy-N-tert-butoxycarbonylpyrrolidin-2-yl]-4-pentene (6.09 g,
Yield: 110%) was obtained.

[0579] NMR (CDCl3) δ: 0.08 (6H
, s), 0.86 (9H, s), 1.26 (3H, t,
J=8Hz), 1.48 (9H, s), 1.50-2.
20 (3H, m), 2.16-2.74 (2H, m),
3.34 (2H, m), 3.90 (1H, m), 4.1
4 (2H, m), 4.32 (1H, m), 5.04 (2
H, m), 5.70 (1H, m)3)

0580]

embedded image The compound obtained in the above reaction (507 mg, 1.22 mmol
), carbon tetrachloride (2.5 ml), acetonitrile (2.
5 ml), sodium periodate (1.1 g, 5.14
Ruthenium trichloride (6.25 mg, 30 μmol) was added to a mixture of Mmol) and water (3.75 ml) at room temperature. After stirring the reaction solution for 2 hours, it was extracted with methylene chloride. The organic layer was dried (MgSO4), concentrated, and subjected to silica gel column chromatography [WakogelTM
C-300, ethyl acetate-hexane (1:1)] to give 3-ethoxycarbonyl-4-[(2R,4R)-4
-tert-butyldimethylsiloxy-N-tert-
Butoxycarbonylpyrrolidin-2-yl]butyric acid (48
0 mg, yield: 90%).

[0581] NMR (CDCl3) δ: 0.08 (6H
, s), 0.88 (9H, s), 1.28 (3H, t,
J = 8Hz), 1.48 (9H, s), 1.78 (2H
, m), 2.04 (2H, m), 2.80 (3H, m)
, 3.38 (2H, m), 3.90 (1H, m), 4.
20 (2H, m), 4.36 (1H, m) 4)

0582]

embedded image The compound obtained in the above reaction (847 mg, 1.95 mmol
) in tetrahydrofuran solution (17 ml) at room temperature was carbonyldiimidazole (475 mg, 2.93 mmo
1) was added, the reaction mixture was stirred for 1 hour, and then concentrated aqueous ammonia (3.4 ml) was added. After stirring the reaction solution for 30 minutes, it was diluted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried (MgSO4), and concentrated. The residue was dissolved in tetrahydrofuran (15 ml), and 60% sodium hydride (94 mg, 2.3 mmol) was added under ice cooling.
1) was added and the reaction solution was stirred for 20 minutes. The liquid was separated in the same manner as before, and the organic layer was dried and concentrated. The residue was subjected to silica gel column chromatography [WakogelTM C
-300, ethyl acetate-hexane (1:1)],
(2R,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(2,5
-dioxopyrrolidin-3-ylmethyl)pyrrolidine (
576 mg, yield: 76%) was obtained.

[0583] NMR (CDCl3) δ: 0.08 (6H
, s), 0.90 (9H, s), 1.48 (6H, s)
, 1.70 (2H, m), 2.00 (2H, m), 2.
58 (1H, m), 2.90 (3H, m), 3.38 (
2H, m), 4.12 (1H, m), 4.40 (1H,
m) 5)

0584]

embedded image Compound obtained in the above reaction (570 mg, 1.47 mmol
), methanol (11 ml) and thionyl chloride (0.3
2 ml, 4.4 mmol) under ice-cooling. The reaction solution was returned to room temperature, stirred for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in chloroform (10 ml) and diluted with triethylamine (0.61 ml, 5.86 mmol).
,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (470mg, 1.47mmo
1) was added and stirred overnight. The reaction solution was washed with 1N hydrochloric acid, dried (MgSO4), and concentrated. The residue was dissolved in methylene chloride (10 ml) and methanesulfonyl chloride (0
．． 14 ml, 1.77 mmol) and triethylamine (
0.31 ml, 2.2 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, extracted with methylene chloride, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography (WakogelTM
C-300, ethyl acetate), (2R, 4R)
-4-methanesulfonyloxy-N-(p-nitrobenzyloxycarbonyl)-2-(2,5-dioxopyrrolidin-3-ylmethyl)pyrrolidine (420 mg, yield: 62%) was obtained.

[0585] NMR (CDCl3) δ: 1.80-2.
40 (4H, m), 2.45-3.30 (5H, m),
3.06 (3H, s), 4.00-4.40 (2H, m
), 5.26 (2H, m), 7.54 (2H, d, J=
8Hz), 8.28 (2H, d, J=8Hz)6)

0586]

embedded image The compound obtained in the above reaction (410 mg, 0.90 mmol
) and N,N-dimethylformamide (4.1 ml),
A mixture of potassium thioacetate (308 mg, 2.70 mmol) was stirred at 70° C. for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, dried, and concentrated. The residue was subjected to silica gel column chromatography [WakogelTM
C-300, ethyl acetate-hexane (1:1)] to give (2R,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-(2,5-dioxopyrrolidine- 3-ylmethyl)pyrrolidine (251
mg, yield: 64%).

[0587] NMR (CDCl3) δ: 1.70 (2H
, m), 2.16 (2H, m), 2.38 (3H, s)
, 2.40-3.40 (5H, m), 3.80-4.3
0 (2H, m), 5.22 (2H, m), 7.56 (2
H, d, J = 8Hz), 8.24 (2H, d, J = 8H
z) Reference Example 31 (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5-
Oxopiperazin-2-yl)pyrrolidine 1)

0588]

embedded image (2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylprolinal (
19.1 g, 57.87 mmol) of nitromethane (9
5 ml) solution, add triethylamine (1.
27 ml, 9.55 mmol) was added and the solution was left at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [WakogelT
MC-300, 350g, hexane-ethyl acetate (
9:1)] to form an oily (2S,4R)-4-ter
t-Butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(1-hydroxy-2-nitroethyl)pyrrolidine (14.81 g, yield: 65.5%) was obtained.

0589 IR(KBr)cm-1:3420,16
75-1700, 1560, 1415, 1255, 11
65,840,780NMR (CDCl3) δ: 0.0
7 (6H, s), 0.87 (9H, s), 1.49 (9
H, s), 1.7-2.1 (2H, m), 3.2-3.
6 (2H, m), 4.12-4.56 (5H, m) 2)

0590]

embedded image The compound obtained in the above reaction (14.8g, 37.89m
-50 mol) of methylene chloride solution (150 ml)
Thionyl chloride (3.58 ml, 49.33 mmol
) was added dropwise. After stirring the reaction solution at -50°C for 5 minutes, triethylamine (16.5ml, 118.39mm
ol) was added dropwise. The cold bath was removed and the reaction solution was stirred at room temperature for 3 hours, then poured into ice water (100ml) and extracted with methylene chloride. The organic layer was washed with water and 10% aqueous sodium bicarbonate, dried (Na2SO4), and concentrated. The residue was subjected to silica gel column chromatography [WakogelTM C-
300, hexane-ethyl acetate (95:5)],
(2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(2-nitrovinyl)pyrrolidine (11.48 g, yield: 81.
3%) of solids was obtained.

0591 IR(KBr)cm-1:1685,15
20,1400,1350,1250,1160,83
5,770 NMR (CDCl3) δ: 0.09 (6H, s), 0.
80 (9H, s), 1.46 (9H, br s), 1
．． 80-2.28 (2H, m), 3.40-3.71 (
2H, m), 4.36-4.76 (2H, m), 7.0
2-7.24 (2H, m) 3)

0592]

embedded image Compound obtained in the above reaction (2.0 g, 5.37 mmol)
, methylene chloride (40 ml), tetrahydrofuran (1
0ml), glycine ethyl ester hydrochloride (750mg)
, 5.37 mmol), triethylamine (
0.74 ml, 5.58 mmol) was added at room temperature, and 30
The mixture was stirred for a minute, poured into saturated aqueous sodium bicarbonate solution, and extracted with methylene chloride. The organic layer was dried (MgSO4), concentrated, and then subjected to silica gel column chromatography [WakogelTM C
-300, ethyl acetate-hexane (1:3)],
(2S,4R)-N-tert-butoxycarbonyl-
4-tert-butyldimethylsiloxy-2-[1-(
Ethoxycarbonylmethyl)amino-2-nitroethyl]pyrrolidine (2.32 g, yield: 91%) was obtained.

0593 NMR (CDCl3) δ: 0.08 (6H
, s), 0.88 (9H, s), 1.28 (3H, t,
J=6Hz), 1.50 (9H, br s), 1.9
8 (2H, m), 3.24 (1H, m), 3.50 (2
H, m), 3.80 (1H, m), 4.08 (1H, m
), 4.18 (1H, m), 4.20 (2H, q, J=
6Hz), 4.40 (3H, m)4)

0594

embedded image The compound obtained in the above reaction (1.26 g, 2.65 mmol
), ammonium formate (1.67g, 26.6m
A mixture of 10% palladium on carbon catalyst (300 mg) and methanol (25 ml) was stirred at room temperature for 1 hour and then at 60° C. for 1 hour. Filter the catalyst from the reaction solution,
It was concentrated, redissolved in methylene chloride, and washed with water. The organic layer was dried (MgSO4), concentrated and (2S,4R)-N
-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(5-oxopiperazine-2
An oil containing pyrrolidine was obtained.

0595 NMR (CDCl3) δ: 0.06 (6H
, s), 0.86 (9H, s), 1.48 (9H, br
s), 1.96 (2H, m), 3.22 (3H, m
), 3.52 (3H, m), 4.10 (1H, m), 4
．． 32 (1H, m), 4.38 (1H, m) 5)

0596]

[Chemical formula 283] Methylene chloride solution (25 ml) of the compound obtained in the above reaction
to allyl chlorocarbonate (0.33 ml, 3.1
8 mmol) and triethylamine (0.55 ml, 3.
98 mmol) was added under ice-cooling, and the mixture was stirred for 1 hour. The reaction solution was poured into saturated sodium bicarbonate solution, extracted with methylene chloride, and dried (M
gSO4), concentrated, and subjected to silica gel column chromatography [WakogelTM C-300, ethyl acetate-hexane (3:1)] to obtain (2S,4R)-N-
tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(1-allyloxycarbonyl-5-oxopiperazin-2-yl)pyrrolidine diastereomer A (low polar compound; 710 mg, two-step yield: 59 %) and diastereomer B (highly polar compound; 290 mg, two-step yield: 24%). Diastereomer A NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.46 (9H, br s), 1
．． 86 (2H, m), 3.20-3.90 (5H, m)
, 4.10 (1H, m), 4.38 (1H, m), 4.
48 (2H, m), 4.64 (2H, m), 5.30 (
2H, m), 5.90 (1H, m) Diastereomer B NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.44 (9H, br s), 1
．． 82 (1H, m), 2.00 (1H, m), 3.10
~3.80 (4H, m), 4.00 ~ 4.50 (5H,
m), 4.60 (2H, m), 5.30 (2H, m),
5.90 (1H, m) 6)

0597]

embedded image The compound obtained in the above reaction (diastereomer A, 993m
g, 2.05 mmol), methylene chloride (4.5 ml
) and trifluoroacetic acid (4.5 ml) were added under ice cooling, the mixture was returned to room temperature, stirred for 10 minutes, and concentrated under reduced pressure. Next, methylene chloride (18 ml), triethylamine (1.51 ml)
1, 10.3 mmol), and a methylene chloride solution (2.8 ml) of allyl chlorocarbonate (0.69 ml, 6.16 mmol) was added dropwise under ice cooling. The mixture was stirred for 1 hour, poured into saturated sodium bicarbonate solution, and extracted with methylene chloride. Drying (M
gSO4), concentrated, and subjected to silica gel column chromatography [WakogelTM C-300, ethyl acetate] to obtain (2S,4R)-N-allyloxycarbonyl-4-tert-butyldimethylsiloxy-2-(1
-allyloxycarbonyl-5-oxopiperazine-2
-yl)pyrrolidine diastereo A (698 mg
, yield: 73%).

Diastereomer B (72
Similarly, (2
S,4R)-N-allyloxycarbonyl-4-ter
t-Butyldimethylsiloxy-2-(1-allyloxycarbonyl-5-oxopiperazin-2-yl)pyrrolidine diastereomer B (451 mg, yield: 64
%) was obtained. Diastereomer A NMR (CDCl3) δ: 0.04 (6H, s), 0.
86 (9H, s), 1.86 (2H, m), 3.50 (
4H, m), 3.80 (1H, m), 4.16 (1H,
m), 4.44 (3H, m), 4.58 (2H, m),
4.66 (2H, m), 5.32 (4H, m), 5.9
6 (2H, m) Diastereomer B NMR (CDCl3) δ: 0.04 (6H, s), 0.
86 (9H, s), 1.86 (1H, m), 2.02 (
1H, m), 3.20-3.80 (4H, m), 4.2
0 (3H, m), 4.44 (2H, m), 4.60 (4
H, m), 5.30 (4H, m), 5.92 (2H, m
) 7)

0599]

embedded image The compound obtained in the above reaction (diastereomer A, 698m
g, 1.49 mmol) in tetrahydrofuran solution (7
．． 0 ml), 1M tetrabutylammonium fluoride solution (2.28 ml, 2.28 mmol) under ice-cooling.
) and stirred for 2 hours at room temperature. The reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, and dried (MgSO4
), concentrated. Next, it was dissolved in methylene chloride (14 ml), and triethylamine (0.88 ml, 5.9
8 mmol) and methanesulfonyl chloride (0.24 ml,
2.99 mmol) was added and stirred for 40 minutes. The reaction solution was poured into aqueous sodium bicarbonate, extracted with methylene chloride, and dried (MgSO4
), after concentration, silica gel column chromatography [W
akogelTM C-300, ethyl acetate] to give (2S,4R)-N-allyloxycarbonyl-4-
Methanesulfonyloxy-2-(1-allyloxycarbonyl-5-oxopiperazin-2-yl)pyrrolidine diastereomer A (487 mg, yield: 75%)
I got it.

Diastereomer B (45) obtained in the above reaction
Using (2 mg, 0.96 mmol) in the same manner, (2
S,4R)-N-allyloxycarbonyl-4-methanesulfonyloxy-2-(1-allyloxycarbonyl-5-oxopiperazin-2-yl)pyrrolidine diastereomer B (285 mg, yield: 68%) Obtained. Diastereomer A NMR (CDCl3) δ: 2.24 (2H, m), 3.
08 (3H, s), 3.56 (2H, m), 3.58 (
1H, m), 3.72 (2H, m), 4.18 (2H,
m), 4.50 (2H, m), 4.64 (4H, m),
5.36 (4H, m), 5.86 (2H, m) Diastereomer B NMR (CDCl3) δ: 2.18 (1H, m), 2.
48 (1H, m), 3.04 (3H, s), 3.20~
3.80 (4H, m), 3.90-4.30 (4H, m
), 4.62 (5H, m), 5.30 (4H, m), 5
．． 92 (2H, m) 8)

0601]

embedded image The compound obtained in the above reaction (diastereomer A, 487m
g, 1.12 mmol), potassium thioacetate (386 m
A mixture of N,N-dimethylformamide (9.7 ml) was stirred at 70°C for 1.5 hours. After cooling, it was diluted with ethyl acetate, washed with saturated brine, dried (MgSO4), concentrated, and subjected to silica gel column chromatography [WakogelTM C-300].
, ethyl acetate] to give (2S,4S)-N-allyloxycarbonyl-4-acetylthio-2-(1-allyloxycarbonyl-5-oxopiperazin-2-yl)
Pyrrolidine diastereomer A (508 mg, yield: 109%) was obtained.

Using the compound obtained in the above reaction (diastereomer B), (2S,4S)-N-allyloxycarbonyl-4-acetylthio-2-(1-allyloxycarbonyl-5-oxo piperazin-2-yl)
Pyrrolidine diastereomer B (200 mg, yield: 73%) was obtained. Diastereomer A NMR (CDCl3) δ: 1.78 (1H, m), 2.
36 (3H, s), 2.44 (1H, m), 3.10 (
1H, m), 3.52 (2H, m), 3.82 (2H,
m), 4.36 (4H, m), 4.66 (4H, m),
5.34 (4H, m), 5.98 (2H, m) Diastereomer B NMR (CDCl3) δ: 1.80 (1H, m), 2.
64 (1H, m), 2.38 (3H, s), 3.30 (
1H, m), 3.68 (2H, m), 3.96 (1H,
m), 4.10 to 4.60 (5H, m), 4.62 (4
H, m), 5.28 (4H, m), 5.98 (2H, m
) Reference Example 32 (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidine 1)

0603]

embedded image To a tetrahydrofuran solution (100 ml) of a mixture of copper(I) iodide (50 mg, 0.26 mmol) and a 1M vinylmagnesium bromide tetrahydrofuran solution (15 ml) was added trimethylsilyl chloride (3. 18ml, 25.0mm
ol) and (E)-3-[(2S,4R)-N-te
A tetrahydrofuran solution (30 ml) of a mixture of rt-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]acrylic acid ethyl ester (2.0 g, 5.0 mmol) was added dropwise over 30 minutes. The reaction solution was stirred at the same temperature for 2 hours, saturated ammonium chloride aqueous solution (15 ml) was added, and ethyl acetate (100 ml) was added.
l). The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wak
ogelTM C-300, hexane-ethyl acetate (
15:1)] and 3-[(2S,4R)-N-te
rt-Butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-4-pentenoic acid ethyl ester (1.7 g, yield: 79.4%) was obtained.

[0604] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.24 (3H, t,
J=8Hz), 1.48 (9H, s), 1.66-1.
97 (2H, m), 2.12-2.59 (2H, m),
3.10-3.30 (2H, m), 3.33-3.70
(1H, m), 3.93-4.24 (3H, m), 4.
30 (1H, m), 5.08 (1H, d, J = 10Hz
), 5.11 (1H, d, J = 18Hz), 5.64 (
1H, m) 2)

0605]

embedded image The compound obtained in the above reaction (1.7 g, 3.98 m
A tetrahydrofuran solution (10 ml) of mol) was added to lithium aluminum hydride (113 mg, 2.98 mm
The mixture was added to a tetrahydrofuran solution (30 ml) of ol) at 0°C under a nitrogen stream, and the reaction solution was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution (5 ml) was added to this solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed successively with a 1N aqueous sodium hydroxide solution, water, and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [
WakogelTM C-300, hexane-ethyl acetate (5:1)] to give 3-[(2S,4R)-N-
tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]pent-4-
En-1-ol (1.09 g, yield: 59.9%) was obtained.

[0606] NMR (CDCl3) δ: 0.04 (6H
, s), 0.86 (3H, s), 1.46 (9H, s)
, 1.50-1.95 (4H, m), 2.73 (1H,
m), 3.12 (1H, dd, J=12,4Hz), 3
．． 32-3.77 (3H, m), 3.88-4.20 (
1H, m), 4.32 (1H, m), 5.12 (2H,
m), 5.64 (1H, m)3)

0607]

embedded image The compound obtained in the above reaction (1.09 g, 2.83 mm
Triphenylphosphine (1.0 g,
3.81 mmol) and phthalimide (0.63 g,
Add 4.28 mmol) and add diethyl under ice cooling.
Azodicarboxylate (0.58ml, 3.68m
mol) was added. The reaction solution was stirred at the same temperature for 2 hours and extracted with ethyl acetate (70 ml). The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate,
Concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM C-300, hexane-ethyl acetate (6:1)] to obtain 3-[(2S,4
R)-N-tert-butoxycarbonyl-4-ter
t-butyldimethylsiloxypyrrolidin-2-yl]-
5-phthalimido-1-pentene (1.31 g, yield:
90.0%).

[0608] NMR (CDCl3) δ: 0.03 (6H
, s), 0.84 (9H, s), 1.42 (9H, s)
, 1.50-1.93 (4H, m), 2.73 (1H,
m), 3.20 (1H, dd, J=12,4Hz), 3
．． 28-3.80 (3H, m), 3.84-4.17 (
1H, m), 4.28 (1H, m), 5.04-5.3
0 (2H, m), 5.62 (1H, m), 7.71 (2
H, m), 7.84 (2H, m) 4)

0609]

embedded image The compound obtained in the above reaction (1.31 g, 2.55 mm
ol) in ethanol solution (15 ml) of hydrazine.
Monohydrate (0.37ml, 7.63mmol) was added at room temperature. The reaction solution was stirred at the same temperature overnight and concentrated under reduced pressure. The residue was taken up in water and ethyl acetate and the organic layer was diluted with 2N
The mixture was washed with an aqueous ammonium hydroxide solution, water, and saturated brine in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml) and di-tert-butyl dicarbonate (6
40 mg, 2.93 mmol) was added. After stirring the reaction solution for 1 hour, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [WakogelTM C-3
00, hexane-ethyl acetate (5:1)] to give 3-
[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine-
2-yl]-5-tert-butoxycarbonylamino-1-pentene (983 mg, yield: 79.3%) was obtained.

[0610] NMR (CDCl3) δ: 0.04 (6H
, s), 0.86 (9H, s), 1.42 (9H, s)
, 1.46 (9H, s), 1.82 (2H, m), 2.
48-2.82 (1H, m), 3.00 (1H, m),
3.22 (2H, m), 3.37-3.73 (1H, m
), 4.01 (1H, m), 4.30 (1H, m), 4
．． 42-4.75 (1H, m), 5.02-5.22 (
2H, m), 5.58 (1H, m) 5)

0611]

embedded image The compound obtained in the above reaction (980 mg, 2.02 mm
A tetrahydrofuran solution (5 ml) of 9-borabicyclo[3.3.1]nonane (545 mg, 2.2
3 mmol) of tetrahydrofuran (10 ml) under a nitrogen stream at room temperature, and the reaction solution was stirred at the same temperature for 2.5 hours. Water (6 ml) and sodium perborate tetrahydrate (1.23 g, 7.99 mmol) were added to this solution, and after stirring vigorously at room temperature overnight, ethyl acetate (50 ml) was added.
l). The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wak
ogelTM C-300, hexane-ethyl acetate (
2:1)] and 3-[(2S,4R)-N-ter
t-Butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-5-tert-butoxycarbonylamino-1-propanol (753 m
g, yield: 71.5%).

[0612] NMR (CDCl3) δ: 0.06 (6H
, s), 0.87 (9H, s), 1.44 (9H, s)
, 1.48 (9H, s), 2.30 (1H, m), 3.
00-3.40 (4H, m), 3.54 (1H, m),
3.74 (2H, m), 4.08 (1H, m), 4.3
0 (1H, m) 6)

0613]

embedded image The compound obtained in the above reaction (753 mg, 1.50 mm
ol), potassium tert-butoxide (370m
The same reaction as in Reference Example 13-4) was carried out using (2S,4R)-N
-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-tert-butoxycarbonylpiperidin-4-yl)pyrrolidine (494m
g, yield: 68.0%).

[0614] NMR (CDCl3) δ: 0.05 (6H
, s), 0.87 (9H, s), 1.00-1.28 (
2H, m), 1.45 (18H, s), 1.78 (2H
, m), 2.64 (2H, m), 3.22 (1H, dd
, J=12,4Hz), 3.38-3.66 (1H, m
), 3.96 (1H, m), 4.14 (2H, m), 4
．． 29 (1H, m) 7)

0615]

embedded image The compound obtained in the above reaction (494 mg, 1.02 mm
ol) and 4,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (684 mg,
The same reaction as in Reference Example 5-3) was carried out using (2.14 mmol) to produce (2S,4R)-4-hydroxy-N-(
p-nitrobenzyloxycarbonyl)-2-[N-(
p-nitrobenzyloxycarbonyl)piperidine-4
-yl]pyrrolidine (485 mg, yield: 89.8%)
I got it.

NMR (CDCl3) δ: 1.05-1.
34 (2H, m), 1.42 to 1.70 (2H, m),
1.94 (2H, m), 2.13-2.46 (2H, m
), 2.58-2.94 (2H, m), 3.38 (1H
, m), 3.76 (1H, m), 4.03-4.36 (
3H, m), 4.45 (1H, m), 5.12-5.3
7 (4H, m), 7.54 (4H, d, J=8Hz),
8.23 (2H, d, J = 8Hz), 8.24 (2H,
d, J=8Hz) 8)

0617]

embedded image The compound obtained in the above reaction (485 mg, 0.92 mm
ol) and methanesulfonyl chloride (82 μl, 1.0
The same reaction as in Reference Example 5-4) was carried out using (2S,4R)-4-methanesulfonyloxy-
N-(p-nitrobenzyloxycarbonyl)-2-[
N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidine (556 mg, yield: 99.
9%).

NMR (CDCl3) δ: 1.04-1.
32 (2H, m), 1.44-1.75 (2H, m),
1.93-2.38 (3H, m), 2.78 (2H, m
), 3.05 (3H, s), 3.48 (1H, m), 4
．． 04-4.35 (4H, m), 5.12-5.38 (
5H, m), 7.53 (2H, d, J=8Hz), 7.
55 (2H, d, J = 8Hz), 8.25 (2H, d,
J=8Hz), 8.26 (2H, d, J=8Hz)9)

0619]

embedded image The compound obtained in the above reaction (556 mg, 0.92 mm
ol), potassium thioacetate (210 mg, 1.84 mm
ol) and sodium iodide (155 mg, 1.03
The same reaction as in Reference Example 13-9) was carried out using (2S,4S)-4-acetylthio-N-(p-
nitrobenzyloxycarbonyl)-2-[N-(p-
Nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidine (476 mg, yield: 88.5%) was obtained.

NMR (CDCl3) δ: 1.07-1.
35 (2H, m), 1.45-1.84 (3H, m),
2.10-2.46 (5H, m), 2.76 (2H, m
), 3.00 (1H, t, J = 10Hz), 3.80 (
1H, m), 3.98 (1H, m), 4.26 (3H,
m), 5.23 (4H, s), 7.52 (2H, d, J
=8Hz), 7.54 (2H, d, J=8Hz), 8.
23 (2H, d, J = 8Hz), 8.24 (2H, d,
J=8Hz) 10)

0621]

embedded image Using the compound obtained in the above reaction, the same reaction as in Reference Example 1-9) was carried out to obtain the title compound (433 mg, yield: 9).
8%). Reference Example 33 (2S,4S)-2-[2-carbamoyl-N-(p-
nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer III
1)

0622]

embedded image (2S,4R)-N-tert-butoxycarbonyl-
Using 4-tert-butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (10.0 g, 26.0 mmol, compound of Reference Example 12), Reference Example 6-2) and Perform a similar reaction and (
2S,4R)-N-tert-butoxycarbonyl-4
-tert-butyldimethylsiloxy-2-(N-te
rt-Butoxycarbonyl-2-pyrrolidon-4-yl)pyrrolidine diastereomer B (12.37g,
Yield: 98.1%) was obtained.

[0623] NMR (CDCl3) δ: 0.06 (6H
, s), 0.86 (9H, s), 1.46 (9H, s)
, 1.52 (9H, s), 1.66 (1H, m), 1.
96 (1H, m), 2.27 (1H, dd, J=18,
10Hz), 2.50 (1H, dd, J=18,8Hz
), 3.24 (1H, dd, J=13,4Hz), 3.
62 (1H, dd, J = 13,8Hz), 3.82 (1
H, dd, J=10,8Hz), 4.09 (1H, m)
,4.32(1H,m) 2)

0624]

embedded image The compound obtained in the above reaction (12.3 g, 25.4 mm
The same reaction as in Reference Example 13-2) was carried out using 5-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-6 -tert-Butoxycarbonylamino-1-hexen-3-one diastereomer B (10.39 g, yield: 79.8%) was obtained.

[0625] NMR (CDCl3) δ: 0.04 (6H
, s), 0.85 (9H, s), 1.42 (9H, s)
, 1.47 (9H, s), 1.68 (1H, m), 1.
92 (1H, m), 2.24-2.57 (2H, m),
3.16 (1H, dd, J=12,4Hz), 3.23
~3.68 (2H, m), 4.03 (1H, m), 4.
33 (1H, m), 5.82 (1H, br d, J=
10Hz), 6.20 (1H, br d, J=18H
z), 6.38 (1H, dd, J=18,10Hz) 3)

0626]

embedded image The compound obtained in the above reaction (10.3 g, 20.1 mm
The same reaction as in Reference Example 13-3) was carried out using 5-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-6 -tert-butoxycarbonylamino-1-hexen-3-ol (2.84g,
Yield: 27.5%) was obtained.

[0627] NMR (CDCl3) δ: 0.04 (6H
, s), 0.86 (9H, s), 1.44 (9H, s)
, 1.46 (9H, s), 1.73 (1H, m), 1.
95 (1H, m), 2.95 (1H, m), 3.18 (
1H, dd, J=12,4Hz), 3.56(2H, m
), 3.94 (1H, m), 4.30 (1H, m), 5
．． 10 (1H, d, J = 10Hz), 5.30 (1H,
d, J=18Hz), 5.86 (1H, m)4)

0628]

embedded image The compound obtained in the above reaction (2.84 g, 5.52 mm
The same reaction as in Reference Example 13-4) was carried out using (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-
tert-Butoxycarbonyl-2-vinylpyrrolidin-4-yl)pyrrolidine (1.04g, yield: 37.9
%) was obtained.

[0629] NMR (CDCl3) δ: 0.05 (6H
, s), 0.86 (9H, s), 1.42 (9H, s)
, 1.46 (9H, s), 1.66-2.34 (4H,
m), 3.02-3.34 (2H, m), 3.30-3
．． 84 (2H, m), 3.86-4.28 (2H, m)
, 4.34 (1H, m), 5.08 (2H, m), 5.
76 (1H, m) 5)

0630]

embedded image The compound obtained in the above reaction (1.04 g, 2.1 mmo
l), perform the same reaction as in Reference Example 13-5),
(2S,4R)-N-tert-butoxycarbonyl-
4-tert-butyldimethylsiloxy-2-(N-t
ert-butoxycarbonyl-2-carboxypyrrolidin-4-yl)pyrrolidine (500 mg, yield: 46.
4%).

[0631] NMR (CDCl3) δ: 0.06 (6H
, s), 0.86 (9H, s), 1.46 (18H, s
), 1.68-2.50 (5H, m), 3.26 (2H
, m), 3.38~3.80 (2H, m), 3.90~
4.40 (3H, m) 6)

0632]

embedded image The compound obtained in the above reaction (500 mg, 0.97 mm
The same reaction as in Reference Example 9-3) was carried out using
(2S,4R)-N-tert-butoxycarbonyl-
4-tert-butyldimethylsiloxy-2-(N-t
ert-butoxycarbonyl-2-carbamoylpyrrolidin-4-yl)pyrrolidine (388 mg, yield: 77
．． 7%).

[0633] NMR (CDCl3) δ: 0.02 (6H
, s), 0.84 (9H, s), 1.42 (18H, s
), 1.64-2.42 (5H, m), 3.25 (2H
, m), 3.36~3.80 (2H, m), 3.88~
4.35 (3H, m) 7)

0634]

embedded image Compound obtained in the above reaction (388 mg, 0.76 mm
The same reaction as in Reference Example 5-3) was carried out using
(2S,4R)-2-[2-carbamoyl-N-(p-
nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (360 mg, yield: 85.
4%).

NMR (CDCl3) δ: 1.72-2.
50 (5H, m), 3.22-3.55 (2H, m),
3.62-3.92 (2H, m), 4.04-4.35
(2H, m), 4.46 (1H, m), 5.24 (4H
, m), 7.52 (4H, m), 8.20 (4H, m) 8)

0636]

embedded image The compound obtained in the above reaction (360 mg, 0.65 mm
The same reaction as in Reference Example 5-4) was carried out using
(2S,4R)-2-[2-carbamoyl-N-(p-
nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-methanesulfonyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (229 mg,
Yield: 55.8%) was obtained.

NMR (CDCl3) δ: 1.72-2.
64 (5H, m), 3.07 (3H, s), 3.26~
3.65 (2H, m), 3.84 (1H, m), 4.0
8-4.36 (3H, m), 5.26 (5H, m), 7
．． 52 (4H, m), 8.18 (4H, m) 9)

0638]

embedded image The compound obtained in the above reaction (229 mg, 0.36 mm
The same reaction as in Reference Example 13-9) was carried out using (2S,4S)-4-acetylthio-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidine-4- yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (191 mg, yield: 8
6.5%).

[0639] NMR (CDCl3-CD3OD) δ:1
．． 58-1.88 (2H, m), 2.28 (3H, s)
, 2.48 (3H, m), 3.10 (1H, m), 3.
38 (1H, m), 3.78 (2H, m), 4.00 (
1H, m), 4.09 (2H, m), 5.15 (4H,
br s), 7.46 (4H, m), 8.10 (4H
,br d,J=8Hz) 10)

0640]

embedded image The compound obtained in the above reaction (191 mg, 0.31 mm
The same reaction as in Reference Example 1-9) was carried out using
The title compound (175 mg, yield: 98.3%) was obtained. Reference Example 34 (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)pyrrolidine diastereomer A1
)

0641]

embedded image In a tetrahydrofuran solution (165 ml) of propargyl 2-tetrahydropyranyl ether (15.2 g, 109 mmol), 1.6
N Hexane solution of n-butyllithium (68.1m
1, 109 mmol) was added thereto, and the mixture was stirred for 1 hour under ice-cooling. After cooling this mixture to -78°C, Reference Example 1-3
), (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-formylpyrrolidine (31.7 g, 90.3 mm
ol) in tetrahydrofuran (150 ml) in a nitrogen stream at -78°C, and the mixture was stirred at the same temperature for 1 hour. This mixture was slowly heated to -20°C and stirred at the same temperature for 1.5 hours, followed by a saturated aqueous ammonium chloride solution (
150 ml) was added and stirred. After adding ethyl acetate to this, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [WakogelTM
C-300, hexane-ethyl acetate (1:1)] to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[1
-Hydroxy-4-(2-tetrahydropyranyloxy)-2-butynyl]pyrrolidine (38.2 g, yield: 9
0%) was obtained.

0642 IR(KBr)cm-1:3400,29
50,1700,1680,1400 NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.46 (9H, s), 1.1-2
．． 2 (8H, m), 3.34 (1H, m), 3.43~
3.63 (2H, m), 3.83 (1H, m), 4.0
4-4.54 (5H, m), 4.80 (1H, br, s
) 2)

0643]

embedded image The compound obtained in the above reaction (17.5 g, 37.2 mm
A 10% palladium-carbon catalyst (7 g) was added to a methanol solution (300 ml) of ol), and the mixture was stirred at room temperature for 3 hours in a hydrogen stream. Furthermore, 10% palladium-carbon catalyst (7
After adding g) and stirring at room temperature in a hydrogen stream for 4 hours,
The catalyst was filtered off, the filtrate was concentrated under reduced pressure, (2S,4R)
-N-tert-butoxycarbonyl-4-tert-
Butyldimethylsiloxy-2-[1-hydroxy-4-
(2-Tetrahydropyranyloxy)butyl]pyrrolidine (14.8 g, yield: 84%) was obtained. 3)

0644]

embedded image The compound obtained in the above reaction (19.0 g, 40.1 mm
Pyridinium para-toluenesulfonate (1.27 g, 4.75 mm
ol) was added and stirred at 55°C for 1.5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue, which was washed successively with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(1,
4-dihydroxybutyl)pyrrolidine (15.4 g, yield: 99%) was obtained.

0645 IR(KBr)cm-1:3400,29
50,1670,1400 NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.46 (9H, s), 1.3-2
．． 1 (6H, m), 2.64 (2H, br s), 3
．． 26 (1H, m), 3.4-3.8 (4H, m), 3
．． 8-4.2 (1H, m), 4.32 (1H, m) 4)

0646]

embedded image The compound obtained in the above reaction (2.42 g, 6.21 mm
ol) and p-toluenesulfonyl chloride (1.20 g, 6
．． 29 mmol) was dissolved in pyridine (6 ml) and stirred at room temperature for 1 hour. Add diethyl ether to the reaction solution,
After separating the precipitate by filtration, the filtrate was washed successively with water, 10% citric acid, a saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [
WakogelTM C-300, heptane-ethyl acetate (1:1)] to give (2S,4R)-N-ter
t-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(1-hydroxy-4-p-toluenesulfonyloxybutyl)pyrrolidine (2.08 g, yield: 62%) was obtained. 5)

0647]

embedded image The compound obtained in the above reaction (2.08 g, 3.82 mm
Sodium azide (0.90 g, 14 mmol) was added to a dimethyl sulfoxide solution (63 ml) of
The mixture was stirred at 70°C for 3 hours. Add ethyl acetate to the mixture;
Washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and (2S,4R)-2-(4-azido-1-hydroxybutyl)-N-tert-butoxycarbonyl-4-tert-butyl Dimethylsiloxypyrrolidine (
1.42 g, yield: 90%) was obtained.

0648 IR(KBr)cm-1:3450,21
00,1700,1680,1410 NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.46 (9H, s), 1.5-2
．． 1 (7H, m), 3.2-4.4 (7H, m) 6)

0649]

embedded image Dimethyl sulfoxide (0.7
24 ml, 10.5 mmol) of methylene chloride solution (1
3 ml), oxalyl chloride (0.472 ml, 5.4
1 mmol) was added dropwise, and the reaction solution was stirred at the same temperature for 45 minutes. A methylene chloride solution (4 ml) of the azide compound (1.21 g, 2.92 mmol) obtained in the above reaction was added dropwise to this mixture at -78°C. After stirring this mixture at the same temperature for 30 minutes, triethylamine (2.44
ml, 17.5 mmol) and stirred at room temperature for 20 minutes. The mixture was washed successively with water, dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel TMC-300,
heptane-ethyl acetate (2:1)], (2S,4
R)-2-(4-azidobutyryl)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine (1.02 g, yield: 85%) was obtained.

0650 IR(KBr)cm-1:2100,17
00,1400 NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.46 (9H, s), 1.7-2
．． 2 (4H, m), 2.62 (2H, m), 3.34 (
2H, m), 3.56 (2H, m), 4.3-4.6 (
2H, m) 7)

0651]

embedded image The compound obtained in the above reaction (2.34 g, 5.67 mm
A 10% palladium-carbon catalyst (236 mg) was added to a methanol solution (60 ml) of ol), and the mixture was stirred at room temperature for 1 hour in a hydrogen stream. 10% palladium-carbon catalyst (2
36 mg) was added for 1 hour, and then 10% palladium-
Additional carbon was added and hydrogenation was carried out for 2 hours at room temperature. The catalyst was filtered off, and the filtrate was added with acetic acid (0.67 ml, 11
．． 7 mmol) and sodium boron cyanide (73
6 mg, 11.7 mmol) was added thereto, and the mixture was stirred at the same temperature for 30 minutes. After concentrating under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel
TM C-300, chloroform-methanol (97
:3)] to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(pyrrolidin-2-yl)pyrrolidine (883
mg, yield: 42%).

[0652] NMR (CDCl3) δ: 0.08 (6H
, s), 0.86 (9H, s), 1.47 & 1.48 (
total 9H, both s), 1.5-1.
8 (2H, m), 1.9-2.4 (4H, m), 3.1
~4.2 (6H, m), 4.32 (1H, br s)
8)

0653]

embedded image The compound obtained in the above reaction (883 mg, 2.38 mm
A methylene chloride solution (2.2 ml) of allyl chlorocarbonate (0.47 ml, 4.43 mmol) was added to a pyridine solution (4.5 ml) of ol) under ice cooling, and the mixture was stirred overnight at the same temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, 10% citric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wa
kogelTM C-300, heptane-ethyl acetate (2:1)] to give (2S,4R)-2-(N-allyloxycarbonylpyrrolidin-2-yl)-N-te.
rt-Butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine (718 mg, yield: 66%)
I got it. 9)

0654]

embedded image The compound obtained in the above reaction (912 mg, 2.00 mm
ol) and 2,6-lutidine (0.47 ml, 4.1
mmol) of methylene chloride solution (16 ml) under ice cooling, trimethylsilyltrifluoromethanesulfonate (
0.60 ml, 3.0 mmol) was added dropwise, and 1.
Stirred for 5 hours. Methanol (2.4 ml) was added to the reaction mixture.
) and stirred at room temperature for 45 minutes, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (16 ml),
Add triethylamine (0.61ml, 4.38mm) to this.
ol), then allyl chlorocarbonate (0.426 ml, 4.
02 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, then warmed to room temperature and stirred for 30 minutes. The reaction solution was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel
TM C-300, hexane-ethyl acetate (2:1)
], (2S,4R)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidine-2
-yl)-4-tert-butyldimethylsiloxypyrrolidine diastereomer A (low polar compound; 330
mg, yield: 38%) and diastereomer B (highly polar compound; 242 mg, yield: 28%). Diastereomer A NMR (CDCl3) δ: 0.05 (6H, s), 0.
85 (9H, s), 1.88 (6H, m), 3.2-3
．． 8 (5H, m), 4.13 (1H, m), 4.42 (
1H, m), 4.59 (4H, m), 5.1 to 5.4 (
4H, m), 5.8-6.1 (2H, m) Diastereomer B NMR (CDCl3) δ: 0.06 (6H, s), 0.
86 (9H, s), 1.90 (6H, m), 3.2-3
．． 7 (5H, m), 4.0-4.7 (2H, m), 4.
58 (4H, m), 5.1-5.5 (4H, m), 5.
8-6.1 (2H, m) 10)

0655]

embedded image Diastereomer A obtained in the above reaction (330 mg, 0.
752 mmol) in tetrahydrofuran solution (4 ml)
Then, a solution of 1M tri-n-butylammonium fluoride in tetrahydrofuran (0.83 ml, 0.83 mmol
) was added under ice-cooling, and stirred at the same temperature for 45 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in methylene chloride (7 ml).
) and add triethylamine (0.44 ml) under ice cooling.
, 3.0 mmol), then methanesulfonyl chloride (0
．． 12 ml, 1.5 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wak
ogelTM C-300, hexane-ethyl acetate (
2:1)] to give (2S,4R)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)-4-methanesulfonyloxypyrrolidine diastereomer A (249 mg, yield Rate: 82
%) was obtained.

[0656] NMR (CDCl3) δ: 1.89 (4H
, m), 2.24 (2H, m), 3.04 (3H, s)
, 3.36 (1H, m), 3.54 (2H, m), 3.
9-4.4 (3H, m), 4.62 (4H, m), 5.
2-5.5 (5H, m), 5.8-6.1 (2H, m) 11)

0657]

embedded image Diastereomer A (249 mg,
0.619 mmol) in N,N-dimethylformamide (2.7 ml), potassium thioacetate (141 mg
, 1.24 mmol) and sodium iodide (92.
9 mg, 0.619 mmol) was added thereto, and the mixture was stirred at 70°C for 4 hours. After the reaction solution was allowed to cool, ethyl acetate was added thereto, washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel TMC-300, hexane-ethyl acetate (2:1)] to obtain (2S,4S)-
4-acetylthio-N-allyloxycarbonyl-2-
(N-allyloxycarbonylpyrrolidin-2-yl)
Pyrrolidine diastereomer A (186 mg, yield: 79%) was obtained.

[0658] NMR (CDCl3) δ: 1.84 (5H
, m), 2.34 (3H, s), 2.46 (1H, m)
, 3.01 (1H, t, J = 10Hz), 3.36 (1
H, m), 3.58 (1H, m), 3.79 (1H, m
), 4.23 (3H, m), 4.61 (4H, d, J=
6Hz), 5.1-5.5 (4H, m), 5.8-6.
1(2H,m) Reference Example 35 (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)pyrrolidine Diastereomer B1
)

0659]

embedded image (2S,4R)-N-allyloxycarbonyl-2-(
N-allyloxycarbonylpyrrolidin-2-yl)-
4-tert-butyldimethylsiloxypyrrolidine
Diastereomer B [242 mg, 0.552 mmol
; Compound of Reference Example 34-9)] was used to prepare Reference Example 34-
10) was carried out to give (2S,4R)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)-4-methanesulfonyloxypyrrolidine diastereomer B (172 mg, yield). rate: 78%).

[0660] NMR (CDCl3) δ: 1.5-2.5
(6H, m), 3.04 (3H, s), 3.2-4.6
(6H, m), 4.60 (4H, br s), 5.1
~5.5 (5H, m), 5.8 ~ 6.1 (2H, m)2
)

0661]

embedded image The compound obtained in the above reaction (172 mg, 0.428 m
The same reaction as in Reference Example 34-11) was carried out using (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-2-yl)pyrrolidine. Diastereomer B (133 mg, yield: 81%) was obtained.

[0662] NMR (CDCl3) δ: 1.64 (2H
, m), 1.93 (3H, m), 2.34 (3H, s)
, 2.47 (1H, m), 3.0-3.8 (3H, m)
, 3.86 (1H, m), 4.0-4.5 (3H, m)
, 4.60 (4H, br s), 5.1~5.5 (4
H, m), 5.8-6.1 (2H, m) Reference Example 36 (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5-
Oxopiperazin-3-yl)pyrrolidine 1)

0663]

embedded image (2S,4R)-N-tert-butoxycarbonyl-
4-tert-butyldimethylsiloxy-2-vinylpyrrolidine (4.0 g, 13.2 mmol), acetone (
40 ml), water (40 ml), and N-methylmorpholine-N-oxide (2.5 g, 20 mmol) was added with a 4% aqueous osmium tetroxide solution (2.0 ml), and the mixture was stirred at room temperature overnight. After distilling off acetone under reduced pressure, the reaction solution was adjusted to pH 2.0 with 6N sulfuric acid and extracted with ethyl acetate. The organic layer was dried and concentrated, and (2S,4R)-
Oil containing N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(1,2-dihydroxyethyl)pyrrolidine (4.35 g, yield: 9
8%).

[0664] NMR (CDCl3) δ: 0.06 (6H
, s), 0.82 (9H, s), 1.40 (9H, s)
, 2.00 (2H, m), 3.28 (2H, m), 3.
52 (2H, m), 3.98 (1H, m), 4.30 (
2H, m) 2)

0665]

embedded image Compound obtained in the above reaction (8.7 g, 26.0 mmol)
Methanesulfonyl chloride (6.0 ml, 78 mmol) and triethylamine (16.2 ml, 116 mmol) were added to a methylene chloride solution (174 ml) under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was washed with saturated aqueous sodium bicarbonate, dried (MgSO4), concentrated, and subjected to silica gel column chromatography [WakogelTM C-300, ethyl acetate-hexane (1:1)].
)-N-tert-butoxycarbonyl-4-tert
-butyldimethylsiloxy-2-[1,2-di(methanesulfonyloxy)ethyl]pyrrolidine (9.50
g, yield: 74.5%).

[0666] NMR (CDCl3) δ: 0.06 (6H
, s), 0.84 (9H, s), 1.46 (9H, br
s), 2.00 (2H, m), 3.04 (3H, s
), 3.08 (3H, s), 3.36 (2H, m), 4
．． 10 (1H, m), 4.30 (1H, m), 4.36
(2H, m), 5.40 (1H, m)3)

0667]

embedded image The compound obtained in the above reaction (9.50 g, 19.3 mmol
), sodium azide (8.72g, 134mmol)
and dimethyl sulfoxide (95 ml),
The mixture was stirred at 100°C for 1.5 hours. After cooling the reaction solution, it was diluted with ethyl acetate, washed with water and then with saturated brine, dried (MgSO4), concentrated, and subjected to silica gel column chromatography [WakogelTM C-300, ethyl acetate-hexane (1:5 )], (2S, 4R)
-N-tert-butoxycarbonyl-4-tert-
Butyldimethylsiloxy-2-(1,2-diazidoethyl)pyrrolidine (4.54 g, yield: 61%) was obtained.

[0668] NMR (CDCl3) δ: 0.06 (6H
, s), 0.88 (9H, s), 1.48 (9H, br
s), 2.00 (2H, m), 3.10-3.90
(5H, m), 4.26 (1H, m), 4.40 (1H
, m) 4)

0669]

embedded image Compound obtained in the above reaction (720 mg, 1.87 mmol
) was stirred in methanol (14 ml) using a 10% palladium on carbon catalyst (140 mg) for 2 hours under a stream of hydrogen. The catalyst was filtered from the reaction solution, concentrated, dissolved in methylene chloride (14 ml), and dissolved in 4,6-dimethyl-
2-(Benzyloxycarbonylthio)pyrimidine (4
10 mg, 1.49 mmol) and stirred for 30 minutes. Next, acetoxyacetyl chloride (0.32 ml,
2.99 mmol) and triethylamine (0.52
ml, 3.74 mmol) and stirred for 1 hour. The reaction solution was washed with saturated sodium bicarbonate solution, dried (MgSO4), concentrated, and subjected to silica gel column chromatography [Wakog
elTM C-300, ethyl acetate-hexane (1:
2)] and (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[1-(α-acetoxyacetamide)-2-(
Benzyloxycarbonylamino)ethyl]pyrrolidine (1.02 g, yield: 96%) was obtained.

[0670] NMR (CDCl3) δ: 0.06 (6H
, s), 0.88 (9H, s), 1.86 (1H, m)
, 2.06 (1H, m), 2.20 (3H, s), 3.
10-3.70 (4H, m), 3.80 (1H, m),
4.16 (1H, m), 4.34 (1H, m), 4.4
6 and 4.58 (2H, ABq, J=16Hz), 5
．． 14 (2H, br s), 7.38 (5H, m) 5)

0671]

embedded image The compound obtained in the above reaction (1.41 g, 2.49 mmol
), 10% palladium on carbon catalyst (280 mg), and methanol (28 ml) were stirred at room temperature in a hydrogen stream for 6 hours. The catalyst was filtered from the mixture, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in p-toluenesulfonyl chloride (0.47 g, 2.46 mmol) in pyridine at room temperature.
l). After 4 hours, pyridine was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), concentrated, and subjected to silica gel column chromatography [WakogelTM C-300, ethyl acetate-hexane]. (3:1)], (2S, 4R)
-N-tert-butoxycarbonyl-4-tert-
Butyldimethylsiloxy-2-[1-(α-acetoxyacetamido)-2-(p-toluenesulfonylamino)ethyl]pyrrolidine (984 mg, yield: 67%) was obtained.

[0672] NMR (CDCl3) δ: 0.08 (6H
, s), 0.88 (9H, s), 1.46 (9H, s)
, 1.76 (1H, m), 2.10 (1H, m), 2.
26 (3H, s), 2.44 (3H, s), 2.80~
4.60 (9H, m), 5.70 (1H, br t,
J=4Hz), 7.32 (2H, d, J=8Hz), 7
．． 76 (2H, d, J=8Hz)6)

0673]

embedded image The compound obtained in the above reaction (1.16 g, 1.97 mmol
) methanol solution (22 ml) was added with a 2N aqueous sodium hydroxide solution (1.48 ml, 2.96 mmol) under ice-cooling.
) for 15 minutes. The reaction solution was poured into brine, extracted with methylene chloride, dried (MgSO4), and concentrated. A methylene chloride solution (20 ml) of the resulting residue was added with triethylamine (0.33 ml, 2.36 mmol) under ice cooling.
l) and methanesulfonyl chloride (0.18 ml, 2.
36 mmol) for 30 minutes. The reaction solution was poured into sodium bicarbonate solution, extracted with methylene chloride, dried (MgSO4),
Concentrated. A methylene chloride solution (20 ml) of the resulting residue
), DBU (1,8-Diazabicyc
lo[5.4.0] undec-7-ene) (0.3
5 ml, 2.36 mmol) was added, the mixture was brought to room temperature, and stirred for 1 hour. The reaction solution was washed with aqueous sodium bicarbonate and dried (MgSO
4) After concentration, silica gel column chromatography [
WakogelTM C-300, ethyl acetate-hexane (2:1)], (2S,4R)-N-ter
t-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[1-(p-toluenesulfonyl)-
5-oxopiperazin-3-yl]pyrrolidine (855
mg, yield: 82%).

[0674] NMR (CDCl3) δ: 0.08 (6H
, s), 0.86 (9H, s), 1.46 (9H, s)
, 1.92 (1H, m), 2.48 (3H, s), 2.
72-4.40 (9H, m), 7.40 (2H, d, J
=8Hz), 7.70 (2H, d, J=8Hz)7)

0675]

embedded image Compound obtained in the above reaction (850 mg, 1.61 mmol
) was treated with metallic sodium in liquid ammonia at -78°C. Metallic sodium was added until the blue color of the reaction solution did not disappear, and the mixture was further stirred for 1 hour. Solid ammonium chloride was added to the reaction mixture to neutralize excess sodium, and the mixture was returned to room temperature while bubbling with nitrogen to remove ammonia. Water was added to the residue, extracted with ethyl acetate, and dried (MgSO
4), concentrated. The obtained residue was diluted with methylene chloride (15
ml) and diluted with triethylamine (0.34 ml) under ice-cooling.
ml, 2.41 mmol) and allyl chloroformate (0.20 ml, 1.93 mmol) for 1 hour. The reaction solution was washed with aqueous sodium bicarbonate, dried (MgSO4), concentrated, and subjected to silica gel column chromatography [Wako
gelTM C-300, ethyl acetate-hexane (1
:3)] to reduce (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(1-allyloxycarbonyl-5-oxopiperazin-3-yl)pyrrolidine. Polar compounds (13
3 mg, yield: 18%) and highly polar compound (410 m
g, yield: 55%) were obtained. Low polar compound NMR (CDCl3) δ: 0.08 (6H, s), 0.
86 (9H, s), 1.48 (9H, s), 1.80 (
2H, m), 3.10-4.50 (9H, m), 4.6
4 (2H, m), 5.20-5.40 (2H, m), 5
．． 80-6.04 (1H, m) Highly polar compound NMR (CDCl3) δ: 0.08 (6H, S), 0.
86 (9H, s,) 2.00 (2H, m), 3.00~
4.50 (9H, m), 4.64 (2H, m), 5.2
0-5.40 (2H, m), 5.80-6.04 (1H
, m) 8)

0676]

embedded image The highly polar compound obtained in the above reaction (410 mg, 0.90 m
Methylene chloride (4.0 ml) and trifluoroacetic acid (4.0 ml) were added to the mixture, and the mixture was stirred at room temperature for 30 minutes. After concentrating under reduced pressure, it was dissolved in methylene chloride (8.0 ml), and triethylamine (0.38 ml, 2.
73 mmol) and allyl chlorocarbonate (0.
11 ml, 1.1 mmol) was added and stirred for 1 hour. The reaction solution was washed with saturated sodium bicarbonate solution, dried (MgSO4), and concentrated to give (2S,4R)-N-allyloxycarbonyl-4-tert-butyldimethylsiloxy-2-(1-
Allyloxycarbonyl-5-oxopiperazine-3-
Oil containing pyrrolidine (417 mg, yield: 1
05%) was obtained.

[0677] NMR (CDCl3) δ: 0.06 (6H
, s), 0.86 (9H, s), 1.80 (1H, m)
, 2.04 (1H, m), 3.10-4.40 (9H,
m), 4.64 (4H, m), 5.20-5.40 (2
H, m), 5.84-6.02 (2H, m)9)

0678]

embedded image Compound obtained in the above reaction (417 mg, 0.94 mmol
) in tetrahydrofuran solution (8.0 ml), 1N tetrabutylammonium fluoride (0.94 ml, 0
．． After stirring at room temperature for 3 hours, diluted with ethyl acetate, washed with saturated brine, and dried (MgSO4
), concentrated. Next, it was dissolved in methylene chloride (8.0 ml), and methanesulfonyl chloride (0.15 ml, 1
．． 89 mmol) and triethylamine (0.39 mmol)
1, 2.83 mmol) and stirred for 1 hour. The reaction solution was washed with saturated sodium bicarbonate solution, dried (MgSO4), concentrated, and subjected to silica gel column chromatography (Wakoge
lTM C-300, 5% methanol-ethyl acetate)
(2S,4R)-N-allyloxycarbonyl-4-methanesulfonyloxy-2-(1-allyloxycarbonyl-5-oxopiperazin-3-yl)pyrrolidine (234 mg, yield: 61%) I got it.

[0679] NMR (CDCl3) δ: 1.78 (1H
, m), 2.08 (1H, m), 2.52 (1H, m)
, 3.06 (3H, s), 3.20-4.20 (7H,
m), 4.66 (4H, m), 5.20-5.34 (5
H, m), 5.80-6.04 (2H, m) 10)

0680]

embedded image The compound obtained in the above reaction (234 mg, 0.58 mmol
), potassium thioacetate (197 ml, 1.73 mmol
) and N,N-dimethylformamide (5.0ml)
The mixture was stirred at 70°C for 1 hour. After cooling the reaction solution, it was diluted with ethyl acetate, washed with saturated brine, and dried (M
gSO4), concentrated, and subjected to silica gel column chromatography (WakogelTM C-300, ethyl acetate) to obtain (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-5- oxopiperazin-3-yl)pyrrolidine (
168 mg, yield: 75%) was obtained.

[0681] NMR (CDCl3) δ: 1.78 (1H
, m), 2.28 (3H, s), 2.58 (1H, m)
, 3.28 (1H, m), 3.50-4.40 (8H,
m), 4.64 (4H, m), 5.22-5.40 (4
H, m), 5.92 (2H, m)

0682]

Effects of the Invention The compound of the present invention is a new compound that has not been described in any literature, and has strong antibacterial activity against sensitive and resistant Gram-positive bacteria and Gram-negative bacteria,
It has excellent stability against HP-I and is therefore useful as an antibacterial agent.

Claims (21)

[Claims] Claim 1: General formula [Formula 1] [wherein R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a negative charge, R2 and R3 are the same or different,
Hydrogen atom, lower alkyl group, hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COO
R4, -CON(R5)R6, -N(R5)R6, -C
H2COOR4, -CH2N(R5)R6 or -CH
2CON(R5)R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and the hydrogen atom, lower alkyl group, or the lower alkyl group is bonded to each other and together with the adjacent nitrogen atom, aziridinyl forming a heterocyclic group selected from the group consisting of azetidinyl group, azetidinyl group, pyrrolidinyl group and piperidyl group)
, A is =NR7, [Chemical formula 2] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)CO(CH
2) sN(R8)-, -N(R7)CO(CH2)sC
ON(R8)-, -CON(R7)N(R8)- or -N(R7)(CH2)sN(R8)-{Here, R7 and R8 are the same or different and represent a hydrogen atom, a lower alkyl group, Hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CO
N(R5)R6, -N(R5)R6, -CH2COOR
4, -CH2N(R5)R6 or -CH2CON(R
5) R6 (here, R4, R5 and R6 have the above meanings), s represents an integer from 1 to 3}, p
is an integer from 0 to 3, and q and r are the same or different integers from 0 to 5 (except when q and r are both 0, and the sum of q and r is 6 or less)]. A represented compound or a pharmaceutically acceptable salt or ester thereof. [Claim 2] General formula [Formula 3] [wherein R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a negative charge, R2 and R3 are the same or different,
Hydrogen atom, lower alkyl group, hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COO
R4, -CON(R5)R6, -N(R5)R6, -C
H2COOR4, -CH2N(R5)R6 or -CH
2CON(R5)R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and the hydrogen atom, lower alkyl group, or the lower alkyl group is bonded to each other and together with the adjacent nitrogen atom, aziridinyl forming a heterocyclic group selected from the group consisting of azetidinyl group, azetidinyl group, pyrrolidinyl group and piperidyl group)
, A is =NR7, [Chemical formula 4] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)CO(CH
2) sN(R8)-, -N(R7)CO(CH2)sC
ON(R8)-, -CON(R7)N(R8)- or -N(R7)(CH2)sN(R8)-{Here, R7 and R8 are the same or different and are a hydrogen atom, a lower alkyl group, Hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CO
N(R5)R6, -N(R5)R6, -CH2COOR
4, -CH2N(R5)R6 or -CH2CON(R
5) R6 (here, R4, R5 and R6 have the above meanings), s represents an integer from 1 to 3}, m
, n and p are the same or different and represent an integer of 0 to 3 (excluding cases where m and n are both 0). [Claim 3] General formula [Formula 5] [In the formula, R is a hydrogen atom or a methyl group, and A1 is =N
-R9, -CON(R10)- or -CON(R
10) CO- (here, R9 represents a hydrogen atom, a lower alkyl group, a formimidoyl group, or an acetimidoyl group, and R10 represents a hydrogen atom or a lower alkyl group),
2. The compound according to claim 1, wherein m and n are the same or different and represent an integer of 0 to 3 (excluding cases where m and n are both 0). [Claim 4] General formula [Formula 6] [In the formula, R is a hydrogen atom or a methyl group, and A is =N-
R9, -CON(R10)- or -CON(R1
0) CO- (here, R9 represents a hydrogen atom, a lower alkyl group, a formimidoyl group, or an acetimidoyl group, and R10 represents a hydrogen atom or a lower alkyl group), m
, n and p are the same or different and represent an integer of 0 to 3 (excluding cases where m and n are both 0). [Claim 5] General formula [Formula 7] [In the formula, R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a negative charge, A2 is =N-R9, [Formula 8] -CON(R10)- or - CON(R10
)CO-(wherein, R9 is a hydrogen atom, a lower alkyl group, a formimidoyl group or an acetimidoyl group,
R10 is a hydrogen atom or a lower alkyl group, R11 and R12 are the same or different and represent a lower alkyl group),
2. The compound according to claim 1, wherein m, n and p are the same or different and represent an integer of 0 to 3 (excluding cases where m and n are both 0). [Claim 6] A is =NR7, [Claim 9] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)COCH2
N(R8)-, -CON(R7)N(R8)-or-
N(R7)(CH2)2N(R8)—[Here,
R7 and R8 are the same or different and are a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a formimidoyl group, an acetimidoyl group, -COOR4, -CON
(R5)R6, -N(R5)R6, -CH2COOR4
, -CH2N(R5)R6 or -CH2CON(R5
) R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and the lower alkyl groups are bonded to each other and together with the adjacent nitrogen atom, an aziridinyl group, azetidinyl 2. The compound according to claim 1, which forms a heterocyclic group selected from the group consisting of a pyrrolidinyl group and a piperidyl group. 7. A is =NR7, [Formula 10] or -CON(R7)- [wherein R7 and R8 are the same or different and are a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a formimidoyl group; , acetimidoyl group, -COOR4, -CON(R5)R
6, -N(R5)R6, -CH2COOR4, -CH2
N(R5)R6 or -CH2CON(R5)R6 (where R4 is a hydrogen atom or lower alkyl group, R
5 and R6 are the same or different, and together with a hydrogen atom, a lower alkyl group, or an adjacent nitrogen atom in which the lower alkyl groups are bonded to each other, a heterocyclic ring selected from the group consisting of an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, and a piperidyl group. 2. The compound according to claim 1, which is a group forming a group. Claim 8: A1 is =N-R9 or -CON(R
10) - [Here, R9 is a hydrogen atom, a lower alkyl group, a formimidoyl group, or an acetimidoyl group,
5. The compound according to claim 3 or 4, wherein R10 represents a hydrogen atom or a lower alkyl group. [Claim 9] A2 is =N-R9, [Formula 11] -CON(R10)- [wherein R9 is a hydrogen atom, a lower alkyl group, a formimidoyl group or an acetimidoyl group, and R10 is a hydrogen atom or lower alkyl group,
6. The compound according to claim 5, wherein R11 and R12 are the same or different and represent a lower alkyl group. Claim 10: R2 and R3 are the same or different;
2. The compound according to claim 1, which is a hydrogen atom, a carbamoyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, or an amino group. 11. The compound according to claim 1, wherein p is 0. 12. The compound according to claim 1, wherein p is 1 or 2. [Claim 13] The formula [Image Omitted] represents an aziridinyl group, an azetidinyl group, a 2-carbamoylazetidinyl group, a 2-oxoazetidinyl group, an N-methyl-2-oxoazetidinyl group, a pyrrolidinyl group,
-methylpyrrolidinyl group, N-(carbamoylmethyl)
pyrrolidinyl group, N,N-dimethylpyrrolidinio group, 2
-oxopyrrolidinyl group, 2,5-dioxopyrrolidinyl group, N-(2-hydroxyethyl)pyrrolidinyl group,
2,5-dioxo-N-methylpyrrolidinyl group, 2-carbamoylpyrrolidinyl group, 2-(N-methylcarbamoyl)pyrrolidinyl group, 2-(N,N-dimethylcarbamoyl)pyrrolidinyl group, 3-amino- 2-oxopyrrolidinyl group, pyrazolidinyl group, 3-oxopyrazolidinyl group, imidazolidinyl group, 2,4-dioxoimidazolidinyl group, piperazinyl group, 2-oxopiperazinyl group, piperidyl group, N- Methylpiperidyl group, N,N
-dimethylpiperidinio group, 2-oxopiperidyl group,
2,6-dioxopiperidyl group, 2-carbamoylpiperidyl group, hexahydroazepinyl group, N-methylhexahydroazepinyl group, N,N-dimethylhexahydroazepinio group, hexahydro-2-oxoazepinyl group , 2,7-dioxohexahydroazepinyl group, 2-carbamoylhexahydroazepinyl group, hexahydro-
From 1H-1,4-diazepinyl group, hexahydro-2-oxo-1H-1,4-diazepinyl group, octahydroazocinyl group, N-methyloctahydroazocinyl group and N,N-dimethyloctahydroazocinio group The compound according to claim 1, which is a substituent selected from the group consisting of: [Claim 14] The formula [Chemical formula 13] represents a 2-oxoazetidinyl group, a pyrrolidinyl group, N,
N-dimethylpyrrolidinio group, 2-carbamoylpyrrolidinyl group, 3-amino-2-oxopyrrolidinyl group, 2
14. The compound according to claim 13, which is a substituent selected from the group consisting of -oxopyrrolidinyl group, piperidyl group, and 2-oxopiperidyl group. [Claim 15] The formula [Image Omitted] represents an aziridinylmethyl group, an azetidinylmethyl group, 2
-carbamoylazetidinylmethyl group, 2-oxoazetidinylmethyl group, N-methyl-2-oxoazetidinylmethyl group, pyrrolidinylmethyl group, N-methylpyrrolidinylmethyl group, N-(carbamoylmethyl ) pyrrolidinylmethyl group, N,N-dimethylpyrrolidiniomethyl group, 2-oxopyrrolidinylmethyl group, 2,5-dioxopyrrolidinylmethyl group, N-(2-hydroxyethyl)
pyrrolidinylmethyl group, 2,5-dioxo-N-methylpyrrolidinylmethyl group, 2-carbamoylpyrrolidinylmethyl group, 2-(N-methylcarbamoyl)pyrrolidinylmethyl group, 2-(N,N -dimethylcarbamoyl)pyrrolidinylmethyl group, 3-amino-2-oxopyrrolidinylmethyl group, pyrazolidinylmethyl group, 3-oxopyrazolidinylmethyl group, imidazolidinylmethyl group, 2
, 4-dioxoimidazolidinylmethyl group, piperazinylmethyl group, 2-oxopiperazinylmethyl group, piperidylmethyl group, N-methylpiperidylmethyl group, N,N
-dimethylpiperidiniomethyl group, 2-oxopiperidylmethyl group, 2,6-dioxopiperidylmethyl group, 2
-carbamoylpiperidylmethyl group, hexahydroazepinylmethyl group, N-methylhexahydroazepinylmethyl group, N,N-dimethylhexahydroazepiniomethyl group, hexahydro-2-oxoazepinylmethyl group,
2,7-dioxohexahhydroazepinylmethyl group, 2
-carbamoylhexahydroazepinylmethyl group, hexahydro-1H-1,4-diazepinylmethyl group, hexahydro-2-oxo-1H-1,4-diazepinylmethyl group, octahydroazosinylmethyl group, N 2. The compound according to claim 1, which is a substituent selected from the group consisting of -methyloctahydroazosinylmethyl group and N,N-dimethyloctahydroazosiniomethyl group. [Claim 16] The formula [Chemical formula 15] represents a 2-oxoazetidinylmethyl group, a pyrrolidinylmethyl group, an N,N-dimethylpyrrolidiniomethyl group, a 2-
Carbamoylpyrrolidinylmethyl group, 3-amino-2-
16. The compound according to claim 15, which is a substituent selected from the group consisting of oxopyrrolidinylmethyl group, 2-oxopyrrolidinylmethyl group, piperidylmethyl group, and 2-oxopiperidylmethyl group. Claim 17: (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(2-
pyrrolidon-4-yl)pyrrolidin-4-ylthio]-
1-carbepen-2-em-3-carboxylic acid, (1R,
5S,6S)-6-[(R)-1-hydroxyethyl]
-1-Methyl-2-[(2S,4S)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-
Carbapen-2-em-3-carboxylic acid, (5R,6S
)-6-[(R)-1-hydroxyethyl]-2-[(
2R,4S)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-
3-carboxylic acid, (1R,5S,6S)-6-[(R)
-1-hydroxyethyl]-1-methyl-2-[(2R
,4S)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-
Carboxylic acid, (5R,6S)-2-[(2S,4S)-
2-(2-azetidinon-4-yl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-carbapen-2-em-3-carboxylic acid, (1R,
5S,6S)-2-[(2S,4S)-2-(2-azetidinon-4-yl)pyrrolidin-4-ylthio]-6
-[(R)-1-hydroxyethyl]-1-methyl-1
-carbapen-2-em-3-carboxylic acid, (5R,6
S)-6-[(R)-1-hydroxyethyl]-2-[
(2R,4S)-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2
-Em-3-carboxylic acid, (1R,5S,6S)-6-
[(R)-1-hydroxyethyl]-1-methyl-2-
[(2R,4S)-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-
2-M-3-carboxylic acid, (5R,6S)-2-[(
2R,4S)-2-(2-azetidinon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-
hydroxyethyl]-1-carbapen-2-em-3-
Carboxylic acid, (1R,5S,6S)-2-[(2R,4
S)-2-(2-azetidinon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-
3-carboxylic acid, (5R,6S)-6-[(R)-1-
hydroxyethyl]-2-[(2S,4S)-2-(pyrrolidin-3-yl)pyrrolidin-4-ylthio]-1
-carbapen-2-em-3-carboxylic acid, (1R,5
S,6S)-6-[(R)-1-hydroxyethyl]-
1-Methyl-2-[(2S,4S)-2-(pyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-6
-[(R)-1-hydroxyethyl]-2-[(2S,
4S)-2-(N-methylpyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-
3-carboxylic acid, (1R,5S,6S)-6-[(R)
-1-hydroxyethyl]-1-methyl-2-[(2S
,4S)-2-(N-methylpyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-2-[(2S,4
S)-2-(N,N-dimethyl-3-pyrrolidinio)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate, ( 1R,5S,6S)-2-[(2S,4
S)-2-(N,N-dimethyl-3-pyrrolidinio)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3- Carboxylate, (5R,6S)-6-[(R
)-1-hydroxyethyl]-2-[(2S,4S)-
2-(N-methyl-2-azetidinon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-
3-carboxylic acid, (1R,5S,6S)-6-[(R)
-1-hydroxyethyl]-1-methyl-2-[(2S
,4S)-2-(N-methyl-2-azetidinone-4-
yl)pyrrolidin-4-ylthio]-1-carbapene-
2-M-3-carboxylic acid, (5R,6S)-6-[(
R)-1-hydroxyethyl]-2-[(2S,4S)
-2-(N-methyl-2,5-dioxopyrrolidine-3
-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (1R,5S,6S)-
6-[(R)-1-hydroxyethyl]-1-methyl-
2-[(2S,4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (
5R,6S)-2-[(2S,4S)-2-(2,5-
dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-
Carbapen-2-em-3-carboxylic acid, (1R,5S
,6S)-2-[(2S,4S)-2-(2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1- Methyl-1-carbapen-2-em-3-carboxylic acid, (5
R,6S)-6-[(R)-1-hydroxyethyl]-
2-[(2S,4S)-2-(3-pyrazolidinone-5
-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (1R,5S,6S)-
6-[(R)-1-hydroxyethyl]-1-methyl-
2-[(2S,4S)-2-(3-pyrazolidinone-5
-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-6-[
(R)-1-hydroxyethyl]-2-[(2S,4S
)-2-(2-pyrrolidon-3-yl)pyrrolidine-4
-ylthio]-1-carbapen-2-em-3-carboxylic acid, (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S) −
2-(2-pyrrolidon-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-2-[(2S,4S)-2-(2 −
Carbamoylpyrrolidin-4-yl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-carbapen-2-em-3-carboxylic acid, (1R,
5S,6S)-2-[(2S,4S)-2-(2-carbamoylpyrrolidin-4-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-
methyl-1-carbapen-2-em-3-carboxylic acid,
(5R,6S)-2-[(2S,4S)-2-(3-amino-2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]- 1
-carbapen-2-em-3-carboxylic acid, (1R,5
S,6S)-2-[(2S,4S)-2-(3-amino-2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1 -Methyl-1-carbapen-2-em-3-carboxylic acid, (
5R,6S)-6-[(R)-1-hydroxyethyl]
-2-[(2R,4S)-2-(pyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (1R,5S,6S)-
6-[(R)-1-hydroxyethyl]-1-methyl-
2-[(2R,4S)-2-(pyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-1-carbapen-
2-M-3-carboxylic acid, (5R,6S)-2-[(
2R,4S)-2-[(2S)-2-carbamoylpyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]
-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid, (1R,5S,6S
)-2-[(2R,4S)-2-[(2S)-2-carbamoylpyrrolidin-4-ylmethyl]pyrrolidine-4
-ylthio]-6-[(R)-1-hydroxyethyl]
-1-Methyl-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2R,4S)-2-[( 2S)-2
-(N-methylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-1-carbapene-
2-M-3-carboxylic acid, (1R,5S,6S)-6
-[(R)-1-hydroxyethyl]-1-methyl-2
-[(2R,4S)-2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3
-carboxylic acid, (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2R,4S)-2-[(2
S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-1
-carbapen-2-em-3-carboxylic acid, (1R,5
S,6S)-6-[(R)-1-hydroxyethyl]-
1-Methyl-2-[(2R,4S)-2-[(2S)-
2-(N,N-dimethylcarbamoyl)pyrrolidine-4
-ylmethyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-
2-[(2S,4S)-2-(2,4-dioxoimidazolidin-5-yl)pyrrolidin-4-ylthio]-6
-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid, (1R,5S,6S)-
2-[(2S,4S)-2-(2,4-dioxoimidazolidin-5-yl)pyrrolidin-4-ylthio]-6
-[(R)-1-hydroxyethyl]-1-methyl-1
-carbapen-2-em-3-carboxylic acid, (5R,6
S)-2-[(2R,4S)-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1
-carbapen-2-em-3-carboxylic acid, (1R,5
S,6S)-2-[(2R,4S)-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidine-
4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-2-[(2R,4S)- 2-
(2,5-dioxopyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid, (1R,5S ,6S)-2-[(2R,4S)-2
-(2,5-dioxopyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid , (5R,6S)-2-[(2S,4
S)-2-(2-oxopiperazin-5-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid, (1R ,5S,6S)-2-[(2S,4S)-2-
(2-oxopiperazin-5-yl)pyrrolidine-4-
ylthio]-6-[(R)-1-hydroxyethyl]-
1-Methyl-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(piperidine- 4
-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (1R,5S,6S)-
6-[(R)-1-hydroxyethyl]-1-methyl-
2-[(2S,4S)-2-(piperidin-4-yl)
pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-2-[(2S,
4S)-2-[N-(carbamoylmethyl)pyrrolidin-3-yl]pyrrolidin-4-ylthio]-6-[(R
)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylic acid, (1R,5S,6S)-2-[(
2S,4S)-2-[N-(carbamoylmethyl)pyrrolidin-3-yl]pyrrolidin-4-ylthio]-6-
[(R)-1-hydroxyethyl]-1-methyl-1-
Carbapen-2-em-3-carboxylic acid, (5R,6S
)-6-[(R)-1-hydroxyethyl]-2-[(
2S,4S)-2-(pyrrolidin-2-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-
Carboxylic acid, (1R,5S,6S)-6-[(R)-1
-hydroxyethyl]-1-methyl-2-[(2S,4
S)-2-(pyrrolidin-2-yl)pyrrolidine-4-
ylthio]-1-carbapen-2-em-3-carboxylic acid, (5R,6S)-2-[(2S,4S)-2-(5
-oxopiperazin-3-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-
Carbapen-2-em-3-carboxylic acid and (1R,
5S,6S)-2-[(2S,4S)-2-(5-oxopiperazin-3-yl)pyrrolidin-4-ylthio]
2. The compound according to claim 1, which is -6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid. Claim 18: (1R, 5S, 6S)-6-[(R)-
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-(pyrrolidin-3-yl)pyrrolidine-4
-ylthio]-1-carbapen-2-em-3-carboxylic acid. Claim 19: (1R, 5S, 6S)-6-[(R)-
1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-(piperidin-4-yl)pyrrolidine-4
-ylthio]-1-carbapen-2-em-3-carboxylic acid. [Claim 20] Represented by the general formula [Formula 16] [wherein R is a hydrogen atom or a methyl group, R13 is a hydrogen atom or a hydroxyl group-protecting group, and R14 is a hydrogen atom or a carboxyl group-protecting group] A compound or a reactive derivative thereof and the general formula [Formula, R15 is a hydrogen atom or an imino group protecting group, R
20 and R30 are the same or different and are a hydrogen atom, a lower alkyl group, an optionally protected hydroxy lower alkyl group, a formimidoyl group or an acetimidoyl group, -COOR40, -CON(R50)R60,
-N(R50)R60, -CH2COOR40, -CH
2N(R50)R60 or -CH2CON(R50)
R60 (here, R40 is a hydrogen atom, a lower alkyl group or a carboxyl group protecting group, R50 and R6
0 is the same or different and is a hydrogen atom, a lower alkyl group,
Protecting groups for amino or imino groups or the lower alkyl groups bond with each other to form a heterocyclic group selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidyl groups, together with adjacent nitrogen atoms)
, B is =NR70, [Chemical formula 18] -CON(R70)-, -CON(R70)CO-, -
CON(R70)CON(R80)-,-N(R70)
CO(CH2)sN(R80)-,-N(R70)CO
(CH2) sCON (R80) -, -CON (R70)
N(R80)-or-N(R70)(CH2)sN(
R80) - {Here, R70 and R80 are the same or different and are a hydrogen atom, a lower alkyl group, an optionally protected hydroxy lower alkyl group, a formimidoyl group or an acetimidoyl group, a protecting group for an imino group , -COOR40, -CON(R50)R60, -N
(R50)R60, -CH2COOR40, -CH2N
(R50)R60 or -CH2CON(R50)R6
0 (here, R40, R50 and R60 have the above meanings), s represents an integer from 1 to 3}, p
is an integer from 0 to 3, and q and r are the same or different integers from 0 to 5 (except when q and r are both 0, and the sum of q and r is 6 or less)]. By reacting with the compound represented by the general formula:
, B, p, q and r have the above-mentioned meanings], and if necessary, the protecting group of the compound of general formula [IV] is removed, ] [In the formula, R1 is a hydrogen atom or a negative charge, R2 and R3
are the same or different, hydrogen atom, lower alkyl group, hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CON(R5)R6,
-N(R5)R6, -CH2COOR4, -CH2N(
R5) R6 or -CH2CON(R5)R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and hydrogen atoms, lower alkyl groups, or the lower alkyl groups are bonded to each other and adjacent Together with the nitrogen atom, it forms a heterocyclic group selected from the group consisting of aziridinyl group, azetidinyl group, pyrrolidinyl group and piperidyl group), A is =NR7, [Image Omitted] -CON(R7)-, -CON(R7) CO-, -CO
N(R7)CON(R8)-,-N(R7)CO(CH
2) sN(R8)-, -N(R7)CO(CH2)sC
ON(R8)-, -CON(R7)N(R8)- or -N(R7)(CH2)sN(R8)-{Here, R7 and R8 are the same or different and represent a hydrogen atom, a lower alkyl group, Hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CO
N(R5)R6, -N(R5)R6, -CH2COOR
4, -CH2N(R5)R6 or -CH2CON(R
5) R6 (wherein R4, R5 and R6 have the above meanings), s represents an integer from 1 to 3}, and R, p, q and r have the above meanings] A method for producing a compound or a pharmaceutically acceptable salt or ester thereof. [Claim 21] General formula: [In the formula, R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a negative charge, R2 and R3 are the same or different,
Hydrogen atom, lower alkyl group, hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COO
R4, -CON(R5)R6, -N(R5)R6, -C
H2COOR4, -CH2N(R5)R6 or -CH
2CON(R5)R6 (wherein, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different, and the hydrogen atom, lower alkyl group, or the lower alkyl group is bonded to each other and together with the adjacent nitrogen atom, aziridinyl forming a heterocyclic group selected from the group consisting of azetidinyl group, azetidinyl group, pyrrolidinyl group and piperidyl group)
, A is =NR7, [Chemical formula 23] -CON(R7)-, -CON(R7)CO-, -CO
N(R7)CON(R8)-,-N(R7)CO(CH
2) sN(R8)-, -N(R7)CO(CH2)sC
ON(R8)-, -CON(R7)N(R8)- or -N(R7)(CH2)sN(R8)-{Here, R7 and R8 are the same or different and represent a hydrogen atom, a lower alkyl group, Hydroxy lower alkyl group, formimidoyl group, acetimidoyl group, -COOR4, -CO
N(R5)R6, -N(R5)R6, -CH2COOR
4, -CH2N(R5)R6 or -CH2CON(R
5) R6 (here, R4, R5 and R6 have the above meanings), s represents an integer from 1 to 3}, p
is an integer from 0 to 3, and q and r are the same or different integers from 0 to 5 (except when q and r are both 0, and the sum of q and r is 6 or less)]. An antibacterial agent containing the represented compound or its pharmaceutically acceptable salt or ester as an active ingredient.