JPWO2006109823A1 - 2-position thioethenyl carbapenem derivatives - Google Patents

Abstract

According to the present invention, there is provided a 2-ethenylthio carbapenem derivative of the formula (I) or a pharmaceutically acceptable salt thereof. The compound according to the present invention has a strong antibacterial activity and a broad antibacterial spectrum against pneumococci including penicillin-resistant pneumococci (PRSP), β-lactamase non-producing ampicillin-resistant Haemophilus influenzae (BLNAR), Have [Chemical 1]

Description

Reference to related applications

  The present application is Japanese Patent Application No. 2005-114690 (application date: April 12, 2005) and Japanese Patent Application No. 2005-235590 (application date: August 16, 2005), which are prior Japanese patent applications, and Based on the prior U.S. Provisional Patent Application Nos. 60/673892 (filing date: April 22, 2005) and 60/710157 (filing date: August 23, 2005), All of which are hereby incorporated by reference in their entirety.

Background of the Invention

The present invention relates to carbapenem compounds having excellent antibacterial activity and a broad antibacterial spectrum. Specifically, the present invention relates to a novel carbapenem derivative having a thioethenylthiazole group at the 2-position on the carbapenem ring.

Background Art Since carbapenem derivatives exhibit strong antibacterial activity and a wide range of excellent antibacterial spectrum, they have been actively studied as highly useful β-lactam agents. It is used in the field.

A group of compounds using various bonding modes at the 2-position of the carbapenem ring has been studied (Expert Opinion Therapeutic Patents, (UK), 2001, 11 (8), p1267-1276), and in particular, at the 2-position of the carbapenem ring Studies have been made on compounds having a heterocyclic ring via a sulfur atom.
For example, JP-A-57-40487 discloses a compound having a hydrogen atom at the 1-position on the carbapenem ring and a thioethenyltetrazole at the 2-position. In JP-A-08-12675 and JP-A-08-12676, the 1-position on the carbapenem ring is a methyl group (sometimes referred to as “1β-methyl group”) and the 2-position is a thioalkenylene halophenyl group. Or compounds having a thioalkenylene pyridyl group are disclosed. JP-A-01-279888 discloses a compound having a methyl group at the 5-position on the carbapenem ring and a side chain via a sulfur atom at the 2-position.

  However, in any case, there is no disclosure or suggestion of a compound having a thioethenylthiazole group at the 2-position on the carbapenem ring.

  JP-A-2002-332288 discloses a cephalosporin-based compound having thioethenylthiazole. However, these include pneumococci, including penicillin-resistant pneumococci (hereinafter sometimes abbreviated as “PRSP”) and β-lactamase non-producing ampicillin-resistant Haemophilus influenzae (hereinafter referred to as “BLNAR”). There is no disclosure or suggestion of antibacterial activity against Haemophilus influenzae, Catalcoccus, resistant Pseudomonas aeruginosa, etc.

  Japanese Patent Application Laid-Open No. 2002-332288 describes 4-tritylthioethenylthiazole having a methyl group at the 4-position of the thiazole ring. However, there is no disclosure of thiazole having other substituents, and the production method thereof is different from that in the present invention. Further, the publication discloses 5-ethynyl-4-methylthiazole, but does not disclose any other thiazole having a substituent.

  Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, penicillin-resistant pneumococci (PRSP), β-lactamase non-producing ampicillin-resistant Haemophilus influenzae (BLNAR), resistant Pseudomonas aeruginosa On the other hand, it is not always sufficient antibacterial activity, and no satisfactory drug has been found.

  The carbapenem derivatives and cephalosporin derivatives disclosed in the above-mentioned prior art documents, including various resistant bacteria, are not always satisfactory from the viewpoint of antibacterial activity. Therefore, development of compounds having satisfactory activity against various resistant bacteria and infectious disease-causing bacteria is still desired.

Summary of the Invention

  The present inventors have now found that the novel carbapenem derivative represented by the formula (I) has a wide and strong antibacterial activity against gram positive bacteria and gram negative bacteria. This derivative exhibited a strong antibacterial activity against Haemophilus influenzae, catalcoccus and β-lactamase producing bacteria. In addition, by using the compound of formula (III) and the compound of formula (IV) as important synthesis intermediates, the compound of formula (I) could be efficiently obtained. The present invention is based on these findings.

  The present invention provides a carbapenem derivative having excellent antibacterial activity and a broad antibacterial spectrum, more specifically, among infection-causing bacteria, among others, Streptococcus pneumoniae including PRSP, Haemophilus influenzae including BLNAR, An object of the present invention is to provide a carbapenem derivative having a strong antibacterial activity and a broad antibacterial spectrum against β-lactamase producing bacteria.

［式中、
Ｒ^１は、水素原子またはメチル基を表し、
Ｒ^２およびＲ^３は、同一でも異なっていてもよく、それぞれ、
水素原子、
ハロゲン原子、
アミノ基、
置換されたアミノ基、
低級アルキル基、
置換された低級アルキル基、
カルバモイル基、
置換されたアミノカルボニル基、
低級アルコキシカルボニル基、
置換された低級アルコキシカルボニル基、
複素環カルボニル基、または、
置換された複素環カルボニル基
を表し、
Ｒ^４は、水素原子、または生体内で加水分解されうる基
を表す］。The compound according to the present invention is represented by the following formula (I), and according to the present invention, a pharmaceutically acceptable salt thereof is also provided:

[Where:
R ¹ represents a hydrogen atom or a methyl group,
R ² and R ³ may be the same or different,
Hydrogen atom,
Halogen atoms,
An amino group,
A substituted amino group,
A lower alkyl group,
A substituted lower alkyl group,
A carbamoyl group,
A substituted aminocarbonyl group,
A lower alkoxycarbonyl group,
A substituted lower alkoxycarbonyl group,
A heterocyclic carbonyl group, or
Represents a substituted heterocyclic carbonyl group,
R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo].

［式中、
Ｒ^１は、水素原子またはメチル基を表し、
Ａ環は、
４−ヒドロキシメチルチアゾール、
５−ヒドロキシメチルチアゾール、
４−（２−ヒドロキシエトキシ）メチルチアゾール、
４−Ｎ，Ｎ−ジメチルカルバモイルチアゾール、
２−Ｎ，Ｎ−ジメチルカルバモイルチアゾール、
４−メチルチアゾール、
４−カルバモイルチアゾール、
２−カルバモイルチアゾール、
４−Ｎ−メチルカルバモイルチアゾール、
４−Ｎ−シアノメチル−Ｎ−メチルカルバモイルチアゾール、
４−Ｎ−シアノメチルカルバモイルチアゾール、
４−Ｎ−（２−シアノエチル）カルバモイルチアゾール、
４−シアノメチルチアゾール、
４−（２−メトキシエトキシ）メチルチアゾール、
４−（３−シアノアゼチジン−１−イル）カルボニルチアゾール、
４−Ｎ−（２−ヒドロキシエチル）カルバモイルチアゾール、
４−Ｎ−（３−ヒドロキシプロパン−１−イル）カルバモイルチアゾール、
４−Ｎ−（２−ヒドロキシエチル）−Ｎ−メチルカルバモイルチアゾール、
４−（アゼチジン−１−イル）カルボニルチアゾール、
４−（３−ヒドロキシアゼチジン−１−イル）カルボニルチアゾール、
４−（３−ヒドロキシプロパン−１−イルオキシ）メチルチアゾール、
２−アミノ−４−カルバモイルチアゾール、
２−アミノチアゾール、
４，５−ジカルバモイルチアゾール、
４−アセトキシメチルチアゾール、
４−（２−アセトキシエトキシ）メチルチアゾール、
４−（Ｌ−バリルオキシメチル）チアゾール、
４−メトキシカルボニルチアゾール、
４−エトキシカルボニルチアゾール、
２−アミノ−４−メトキシカルボニルチアゾール、または、
２−アミノ−４−エトキシカルボニルチアゾール、
を表し、
Ｒ^４は、水素原子、または生体内で加水分解されうる基を表す］。According to a preferred embodiment of the invention, the compound of formula (I) is a compound of formula (II)

[Where:
R ¹ represents a hydrogen atom or a methyl group,
Ring A is
4-hydroxymethylthiazole,
5-hydroxymethylthiazole,
4- (2-hydroxyethoxy) methylthiazole,
4-N, N-dimethylcarbamoylthiazole,
2-N, N-dimethylcarbamoylthiazole,
4-methylthiazole,
4-carbamoylthiazole,
2-carbamoylthiazole,
4-N-methylcarbamoylthiazole,
4-N-cyanomethyl-N-methylcarbamoylthiazole,
4-N-cyanomethylcarbamoylthiazole,
4-N- (2-cyanoethyl) carbamoylthiazole,
4-cyanomethylthiazole,
4- (2-methoxyethoxy) methylthiazole,
4- (3-cyanoazetidin-1-yl) carbonylthiazole,
4-N- (2-hydroxyethyl) carbamoylthiazole,
4-N- (3-hydroxypropan-1-yl) carbamoylthiazole,
4-N- (2-hydroxyethyl) -N-methylcarbamoylthiazole,
4- (azetidin-1-yl) carbonylthiazole,
4- (3-hydroxyazetidin-1-yl) carbonylthiazole,
4- (3-hydroxypropan-1-yloxy) methylthiazole,
2-amino-4-carbamoylthiazole,
2-aminothiazole,
4,5-dicarbamoylthiazole,
4-acetoxymethylthiazole,
4- (2-acetoxyethoxy) methylthiazole,
4- (L-valyloxymethyl) thiazole,
4-methoxycarbonylthiazole,
4-ethoxycarbonylthiazole,
2-amino-4-methoxycarbonylthiazole, or
2-amino-4-ethoxycarbonylthiazole,
Represents
R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo].

［式中、
Ｒ^２’およびＲ^３’の一方は、
ヒドロキシ低級アルキル基、
水酸基の保護基で保護されたヒドロキシ低級アルキル基、
低級アルコキシ低級アルキル基、または、
低級アルコキシカルボニル基
を表し、かつ、もう一方は水素原子であり、
Ｒ^５は、水素原子、またはアルキニル基の保護基を表す］。According to another aspect of the present invention, there is provided a compound of formula (III):

[Where:
One of R ² ′ and R ^{3 ′} is
A hydroxy lower alkyl group,
A hydroxy lower alkyl group protected with a hydroxyl protecting group,
A lower alkoxy lower alkyl group, or
Represents a lower alkoxycarbonyl group, and the other is a hydrogen atom,
R ⁵ represents a hydrogen atom or an alkynyl protecting group.

［式中、
Ｒ^２’およびＲ^３’は、同一でも異なっていてもよく、それぞれ、
水素原子、
ハロゲン原子、
アミノ基、
置換されたアミノ基、
ヒドロキシ低級アルキル基、
シアノ低級アルキル基、
低級アルコキシ低級アルキル基、
置換された低級アルコキシ低級アルキル基、
低級アルコキシ低級アルコキシ低級アルキル基、
置換された低級アルコキシ低級アルコキシ低級アルキル基、
アシルオキシ低級アルキル基、
置換されたアシルオキシ低級アルキル基、
カルバモイル基、
モノ低級アルキルカルバモイル基、
置換されたモノ低級アルキルカルバモイル基、
ジ低級アルキルカルバモイル基、
置換されたジ低級アルキルカルバモイル基、
低級アルコキシカルボニル基、
アゼチジニルカルボニル基、または、
置換されたアゼチジニルカルボニル基
を表し、
Ｒ^６は、
Ｒ^７−Ｓ−Ｃ＝Ｃ―
を表し、ここでＲ^７は、水素原子、金属イオン、またはチオールの保護基を表す］。According to yet another aspect of the present invention, there is provided a compound of formula (IV):

[Where:
R ^{2 ′} and R ^{3 ′} may be the same or different,
Hydrogen atom,
Halogen atoms,
An amino group,
A substituted amino group,
A hydroxy lower alkyl group,
A cyano lower alkyl group,
A lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkyl group,
Lower alkoxy lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkoxy lower alkyl group,
An acyloxy lower alkyl group,
A substituted acyloxy lower alkyl group,
A carbamoyl group,
A mono-lower alkylcarbamoyl group,
A substituted mono-lower alkylcarbamoyl group,
Di-lower alkylcarbamoyl group,
A substituted di-lower alkylcarbamoyl group,
A lower alkoxycarbonyl group,
An azetidinylcarbonyl group, or
Represents a substituted azetidinylcarbonyl group,
R ⁶ is
R ⁷ —S—C═C—
Wherein R ⁷ represents a hydrogen atom, a metal ion, or a protecting group for a thiol].

［式中、
Ｒ^１は、水素原子、またはメチル基を表し、
Ｒ^８は、水素原子、または水酸基の保護基を表し、
Ｒ^９は、カルボキシル基の保護基を表し、および、
Ｌは、脱離基を表す］；

［式中、
Ｒ^７ｃは、金属イオンを表し、
Ｒ^２’およびＲ^３’は、同一でも異なっていてもよく、それぞれ、
水素原子、
ハロゲン原子、
アミノ基、
置換されたアミノ基、
ヒドロキシ低級アルキル基、
シアノ低級アルキル基、
低級アルコキシ低級アルキル基、
置換された低級アルコキシ低級アルキル基、
低級アルコキシ低級アルコキシ低級アルキル基、
置換された低級アルコキシ低級アルコキシ低級アルキル基、
アシルオキシ低級アルキル基、
置換されたアシルオキシ低級アルキル基、
カルバモイル基、
モノ低級アルキルカルバモイル基、
置換されたモノ低級アルキルカルバモイル基、
ジ低級アルキルカルバモイル基、
置換されたジ低級アルキルカルバモイル基、
低級アルコキシカルボニル基、
アゼチジニルカルボニル基、または、
置換されたアゼチジニルカルボニル基
を表す］。The present invention also provides a process for producing the compound of formula (I). This method is characterized by reacting a compound of the following formula (V) with a compound of the following formula (IVc):

[Where:
R ¹ represents a hydrogen atom or a methyl group,
R ⁸ represents a hydrogen atom or a hydroxyl-protecting group,
R ⁹ represents a protecting group for a carboxyl group, and
L represents a leaving group];

[Where:
R ^7c represents a metal ion,
R ^{2 ′} and R ^{3 ′} may be the same or different,
Hydrogen atom,
Halogen atoms,
An amino group,
A substituted amino group,
A hydroxy lower alkyl group,
A cyano lower alkyl group,
A lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkyl group,
Lower alkoxy lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkoxy lower alkyl group,
An acyloxy lower alkyl group,
A substituted acyloxy lower alkyl group,
A carbamoyl group,
A mono-lower alkylcarbamoyl group,
A substituted mono-lower alkylcarbamoyl group,
Di-lower alkylcarbamoyl group,
A substituted di-lower alkylcarbamoyl group,
A lower alkoxycarbonyl group,
An azetidinylcarbonyl group, or
Represents a substituted azetidinylcarbonyl group].

［式中、
Ｒ^２’およびＲ^３’の一方は、
ヒドロキシ低級アルキル基、
水酸基の保護基で保護されたヒドロキシ低級アルキル基、
低級アルコキシ低級アルキル基、または、
低級アルコキシカルボニル基
を表し、かつ、もう一方は水素原子であり、
Ｒ^５は、水素原子、またはアルキニル基の保護基を表す］、および
ここで、前記対応するチオール中のＲ^７ｂは、トリフェニルメチル基、ジフェニルメチル基、アシル系の保護基、置換されても良いベンジル基、および、シリル系の保護基からなる群より選択される基である。According to a preferred embodiment of the present invention, the method for producing the compound of the formula (I) comprises a compound of the formula (IVc), a compound of the following formula (III), and a corresponding thiol represented by the formula R ^7b SH. Further comprising obtaining by reacting:

[Where:
One of R ² ′ and R ^{3 ′} is
A hydroxy lower alkyl group,
A hydroxy lower alkyl group protected with a hydroxyl protecting group,
A lower alkoxy lower alkyl group, or
Represents a lower alkoxycarbonyl group, and the other is a hydrogen atom,
R ⁵ represents a hydrogen atom or a protecting group for an alkynyl group], and R ^7b in the corresponding thiol may be a triphenylmethyl group, a diphenylmethyl group, an acyl-based protecting group, or a substituted group. It is a group selected from the group consisting of a good benzyl group and a silyl protecting group.

  A pharmaceutical composition according to the present invention comprises a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutical composition comprises a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. More preferably, this pharmaceutical composition is used as an antibacterial agent.

  According to another aspect of the present invention, a bacterial infection comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention. Or a method of treating or preventing a symptom associated therewith is provided. Here, preferably, the bacterium is selected from the group consisting of pneumococci, Haemophilus influenzae, catalucoccus, and β-lactamase producing bacteria.

  According to yet another aspect of the present invention, use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention for the manufacture of a medicament for the treatment or prevention of bacterial infections or symptoms associated therewith. Is provided.

The carbapenem derivative of the formula (I) according to the present invention has a wide and strong antibacterial activity against gram positive bacteria and gram negative bacteria. In particular, it has a strong antibacterial activity against pneumococci including PRSP, Haemophilus influenzae including BLNAR, catalucocci, and various pathogens including β-lactamase producing bacteria. Of the compounds of formula (I) according to the present invention, the carbapenem derivative of (I), wherein R ⁴ is a group that is hydrolyzed in vivo, exhibits oral absorption and is metabolically deesterified in vivo. To produce a drug substance (compound of formula (I ′)) having antibacterial activity. Therefore, the compound of the formula (I) of the present invention is useful not only as an injection but also as an ester. Furthermore, the carbapenem derivative according to the present invention has low toxicity and high safety.

DETAILED DESCRIPTION OF THE INVENTION

Definitions In this specification, the term “lower alkyl group” or “lower alkoxy group” as a group or part of a group means that the group is linear or branched, having 1 to 6, preferably 1 to 4 carbon atoms. It means an alkyl group or an alkoxy group, respectively.

  Examples of “lower alkyl” as a group or part of a group include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, i -Pentyl, t-pentyl, n-hexyl, i-hexyl and the like.

  Examples of “lower alkoxy” as a group or part of a group include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyloxy, neopentyl Examples include oxy, i-pentyloxy, t-pentyloxy, n-hexyloxy, i-hexyloxy and the like.

  In the present specification, the “lower cycloalkyl group” as a group or a part of the group means a monocyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. .

  Examples of the “acyl group” as a group or a part of the group include formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, isobutyryl group, valeryl group, benzoyl group, phthaloyl group, arylcarbonyl group, Heterocyclic carbonyl group etc. are mentioned.

  In the present specification, the “halogen atom” represents an atom such as fluorine, chlorine, bromine or iodine. Preferably, the halogen atom is a chlorine atom or a bromine atom.

  In this specification, the term “aryl group” as a group or part of a group means a phenyl group, a naphthyl group, or the like.

  In the present specification, the term “heterocycle” as a group or a part of the group is the same or different and has 4 to 7 having one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. It means a heterocyclic ring having a member ring (preferably a 5-6 member ring). Preferably, the heterocyclic ring includes furan, pyrrole, imidazole, pyrazole, thiazole, triazole, thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine, isoxazole, thiophene, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazoline, and the like. And more preferably, furan, thiophene, imidazole, thiazole, pyridine, pyrimidine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiazoline and the like.

Compound R ¹ represents a hydrogen atom or a methyl group. According to one preferred embodiment of the invention, R ¹ is a methyl group.

R ² and R ³ , and R ^{2 ′} and R ^{3 ′} may be the same or different, and are a hydrogen atom, a halogen atom, an amino group, a substituted amino group, a lower alkyl group, a substituted lower alkyl group, It represents a carbamoyl group, a substituted aminocarbonyl group, a lower alkoxycarbonyl group, a substituted lower alkoxycarbonyl group, a heterocyclic carbonyl group, or a substituted heterocyclic carbonyl group.

  Here, the substituent of the amino group in the “substituted amino group” and the “substituted aminocarbonyl group” includes a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a lower alkylcarbonyl group. A lower alkoxycarbonyl group, a formyl group, an aminocarbonyl group, an aminosulfonyl group, a lower alkylcarbamoyl group, a hydroxy lower alkyl group, an amino lower alkyl group, an aryl group, or a heteroaryl group.

  “Substituted lower alkyl group”, “Substituted lower alkoxycarbonyl group”, “Substituted lower alkoxycarbonyl group”, “Substituted lower alkoxy lower alkyl group”, “Substituted lower alkoxy lower alkoxy lower alkyl” As the substituents of “lower alkyl group” in “group”, “substituted mono-lower alkylcarbamoyl group”, and “substituted di-lower alkylcarbamoyl group”, and “lower alkyl group” of a part of the group, Hydroxyl group, lower alkoxy group, lower alkylthio group, amino group, aryl group, heterocyclic group, carbamoyl group, lower alkylaminocarbonyl group, formylamino group, lower alkylcarbonylamino group, aminosulfonylamino group, aminocarbonylamino group, etc. Is mentioned.

  Examples of the substituent of the heterocyclic ring in the “substituted heterocyclic carbonyl group” include a hydroxyl group, an amino group, a lower alkyl group, or a lower alkoxy group.

Preferred groups for R ² and R ³ , and R ^{2 ′} and R ^{3 ′} include a hydrogen atom, a halogen atom, an amino group, a substituted amino group, a lower alkyl group, a hydroxy lower alkyl group, and a protective group for a hydroxyl group. Hydroxy lower alkyl group, cyano lower alkyl group, lower alkoxy lower alkyl group, substituted lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, substituted lower alkoxy lower alkoxy lower alkyl group, acyloxy lower alkyl group Substituted acyloxy lower alkyl group, carbamoyl group, mono lower alkyl carbamoyl group, substituted mono lower alkyl carbamoyl group, di lower alkyl carbamoyl group, substituted di lower alkyl carbamoyl group, lower alkoxycarbonyl group, azetidinyl group Examples include a rubonyl group and a substituted azetidinylcarbonyl group.

  In this specification, examples of the hydroxyl-protecting group include a silyl-based protecting group, a methyl group, a methoxymethyl group, an allyl group, a benzyl group, an allyloxycarbonyl group, a t-butoxycarbonyl group, and an optionally substituted benzyloxycarbonyl group. Group, acyl group, etc., preferably trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, allyloxycarbonyl group, t-butoxycarbonyl group, 4-nitrobenzyloxycarbonyl group, and 4-methoxybenzyl An oxycarbonyl group etc. are mentioned.

More preferably, R ² and R ³ , and R ^{2 ′} and R ^{3 ′} include a hydrogen atom, a halogen atom, an amino group, a methyl group, an ethyl group, a propyl group, a cyanomethyl group, a hydroxymethyl group, a hydroxyethyl group, Acetoxymethyl group, (2-hydroxyethoxy) methyl group, (3-hydroxypropyloxy) methyl group, (2-methoxyethoxy) methyl group, (2-acetoxyethoxy) methyl group, L-valyloxymethyl group, carbamoyl group N-methylcarbamoyl group, N-cyanomethylcarbamoyl group, N- (2-cyanoethyl) carbamoyl group, N- (2-hydroxyethyl) carbamoyl group, N- (3-hydroxypropyl) carbamoyl group, N, N- Dimethylcarbamoyl group, N- (2-hydroxyethyl) -N-methylcarba Moyl group, N-cyanomethyl-N-methylcarbamoyl group, methoxycarbonyl group, ethoxycarbonyl group, (azetidin-1-yl) carbonyl group, (3-cyanoazetidin-1-yl) carbonyl group, (3-hydroxyazetidine- 1-yl) carbonyl group and the like.

  According to a further preferred embodiment of the present invention, the ring A in formula (II) is 2-hydroxymethylthiazole, 4-hydroxymethylthiazole, 5-hydroxymethylthiazole, 4- (2-hydroxyethoxy) methylthiazole, 2- N, N-dimethylcarbamoylthiazole, 4-N, N-dimethylcarbamoylthiazole, 5-N, N-dimethylcarbamoylthiazole, 4-methylthiazole, 2-carbamoylthiazole, 4-carbamoylthiazole, 5-carbamoylthiazole, 4- N-methylcarbamoylthiazole, 4-N-cyanomethyl-N-methylcarbamoylthiazole, 4-N-cyanomethylcarbamoylthiazole, 4-N- (2-cyanoethyl) carbamoylthiazole, 4-cyanomethylthiazole, 4- ( -Methoxyethoxy) methylthiazole, 4- (3-cyanoazetidin-1-yl) carbonylthiazole, 4-N- (2-hydroxyethyl) carbamoylthiazole, 4-N- (3-hydroxypropan-1-yl) carbamoylthiazole 4-N- (2-hydroxyethyl) -N-methylcarbamoylthiazole, 4- (azetidin-1-yl) carbonylthiazole, 4- (3-hydroxyazetidin-1-yl) carbonylthiazole, 4- (3 -Hydroxypropan-1-yloxy) methylthiazole, 2-amino-4-carbamoylthiazole, 2-aminothiazole, 4,5-dicarbamoylthiazole, 4-acetoxymethylthiazole, 4- (2-acetoxyethoxy) methylthiazole, 4- (L-valyloxy Methyl) thiazole, 4-methoxycarbonylthiazole, 4-ethoxycarbonylthiazole, 2-amino-4-methoxycarbonylthiazole, 2-amino-4-ethoxycarbonylthiazole and the like.

R ⁴ is a hydrogen atom or a group that is hydrolyzed in vivo. R ^{4 ′} has the same meaning as the group of R ⁴ that is hydrolyzed in vivo.

When R ⁴ is a group that is hydrolyzed in vivo, the group is preferably an ester residue, examples of which include lower alkyl groups, lower alkenyl groups, lower alkylcarbonyloxy lower alkyl groups, lower cycloalkyl groups. Carbonyloxy lower alkyl group, lower cycloalkylmethylcarbonyloxy lower alkyl group, lower alkenylcarbonyloxy lower alkyl group, arylcarbonyloxy lower alkyl group, tetrahydrofuranylcarbonyloxymethyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl Group, arylmethyloxy lower alkyl group, arylmethyloxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxycarbonyloxy lower alkoxy group, Lower cycloalkoxycarbonyloxy lower alkyl group, lower cycloalkylmethoxycarbonyloxy lower alkyl group, aryloxycarbonyloxy lower alkyl group, 3-phthalidyl group which may have a substituent on the aromatic ring, substituent on the aromatic ring 2- (3-phthalidylidene) ethyl group, 2-oxotetrahydrofuran-5-yl group, mono-lower alkylaminocarbonyloxymethyl group, di-lower alkylaminocarbonyloxymethyl group, 2-oxo-5- Commonly used ones such as a lower alkyl-1,3-dioxolen-4-ylmethyl group, an optionally substituted piperidinylcarbonyloxy lower alkyl group, or a lower alkyl lower cycloalkylaminocarbonyloxy lower alkyl group Can be mentioned.

Preferably, R ⁴ is a methyl group, ethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, acetoxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, pi Valoyloxymethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (isobutyloxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl group, isobutyloxycarbonyloxymethyl group, Isopropyloxycarbonyloxymethyl group, isobutyryloxymethyl group, (pentan-1-yl) oxycarbonyloxymethyl group, (butan-1-yl) oxycarbonyloxymethyl group, (1-ethylpropan-1-yl) Oxy Carbonyloxymethyl group, isopentyloxycarbonyloxymethyl group, (propan-1-yl) oxymethyl group, ethoxycarbonyloxymethyl group, neopentyloxycarbonyloxymethyl group, methoxycarbonyloxymethyl group, cyclopentyloxycarbonyloxymethyl group , T-butoxycarbonyloxymethyl group, phthalidyl group, 1- (methoxycarbonyloxy) ethyl group, 1- (cyclopentyloxycarbonyloxy) ethyl group, (tetrahydropyran-4-yl) oxycarbonyloxymethyl group, 1- ( Neopentyloxycarbonyloxy) ethyl group, (piperidin-1-yl) carbonyloxymethyl group, allyl group, 1- (t-butoxycarbonyloxy) ethyl group, (N, N-di-n-propylamino) ) Carbonyloxymethyl group, phenyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, (cis-2,6-dimethylpiperidin-1-yl) carbonyl Oxymethyl group, N, N-di- (butan-1-yl) aminocarbonyloxymethyl group, hexane-1-yl group, N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl group, N , N-diisobutylaminocarbonyloxymethyl group, N, N-diisopropylaminocarbonyloxymethyl group, N-cyclohexyl-N-methylaminocarbonyloxymethyl group, N-pentan-1-ylaminocarbonyloxymethyl group, N-cyclohexyl -N-ethylaminocarbonyloxymethyl group, N-isobutyl N-isopropylaminocarbonyloxymethyl group, Nt-butyl-N-ethylaminocarbonyloxymethyl group, 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl group, 1- ( N, N-diisopropylaminocarbonyloxy) ethyl group or N-ethyl-N-isoamylaminocarbonyloxymethyl group.

R ⁵ represents a hydrogen atom or an alkynyl protecting group.
R ⁶ represents R ⁷ —S—C═C—, wherein R ⁷ represents a hydrogen atom, a metal ion, or a thiol protecting group.

Examples of the protecting group for the alkynyl group of R ⁵ include a silyl-based protecting group and a 2- (2-hydroxypropyl) group, preferably a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, and the like.

Examples of the metal ion of R ⁷ include alkali metal ions, alkaline earth metal ions, mercury ions, copper ions, silver ions, iron ions, etc., preferably lithium ions, sodium ions, potassium ions, silver ions, mercury ions. Etc. ^Further, the ^{R 7c,} is that the metal ion of ^{R 7,} the same meaning.

The protective group for the thiol of R ⁷ is a triphenylmethyl group, a diphenylmethyl group, an acyl-based protective group (for example, acetyl group, benzoyl group, trifluoroacetyl group), an optionally substituted benzyl group, a silyl-based group Examples include a protecting group, and a triphenylmethyl group, an acetyl group, a benzoyl group, a 4-methoxybenzyl group, and the like are preferable. ^Further, the ^{R 7b,} and that the protecting group of a thiol of ^{R 7,} the same meaning.

The hydroxyl protecting group for R ⁸ is a silyl protecting group, methyl group, methoxymethyl group, allyl group, benzyl group, allyloxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group which may be substituted, acyl Groups such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, allyloxycarbonyl group, t-butoxycarbonyl group, 4-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, etc. is there.

Examples of the protecting group for the carboxyl group of R ⁹ include a lower alkyl group, an optionally substituted benzyl group, a silyl-based protecting group, an allyl group, a triphenylmethyl group, a diphenylmethyl group, preferably a methyl group, t-butyl group, benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, allyl group and the like.

  L is a leaving group, for example, a halogen atom, a lower alkylsulfonyloxy group, an optionally substituted arylsulfonyloxy group, a perfluoroalkanesulfonyloxy group, a fluorosulfonyloxy group, a lower alkylsulfenyl group, And arylsulfenyl group, heterocyclic sulfenyl group, diphenylphosphoryloxy group and the like, preferably methanesulfonyloxy group, toluenesulfonyloxy group, trifluoromethanesulfonyloxy group, diphenylphosphoryloxy group and the like.

R ¹⁰ represents a hydrogen atom or a metal ion, and is preferably a hydrogen atom, a sodium ion, or a potassium ion.

The salts of the general formula (I) are pharmaceutically acceptable salts, for example inorganic salts such as lithium, sodium, potassium, calcium, magnesium, or organic bases such as ammonium salts, triethylamine, diisopropylethylamine. Or salts with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or salts with organic acids such as acetic acid, carbonic acid, citric acid, malic acid, oxalic acid, methanesulfonic acid. Can be mentioned. Preferably, the salt is a sodium salt, potassium salt or hydrochloride.
Furthermore, the compounds according to the invention may be solvates. Examples of such solvates include hydrates, alcohol solvates (eg, methanol solvate, ethanol solvate), and ether solvates (eg, diethyl ether solvate).

According to one preferred embodiment of the present invention,
In the formula (III), one of R ^{2 ′} and R ^{3 ′} is
A hydroxymethyl group,
An acetoxymethyl group,
A methoxycarbonyl group,
An ethoxycarbonyl group,
And the other is a hydrogen atom.

According to one preferred embodiment of the present invention,
In formula (IV), one of R ^{2 ′ and} R ^{3 ′} is
A hydroxy lower alkyl group,
A hydroxy lower alkyl group protected with a hydroxyl protecting group,
A lower alkoxy lower alkyl group, or
Represents a lower alkoxycarbonyl group, and the other represents a hydrogen atom.

According to one more preferred aspect of the present invention,
In formula (IV), one of R ^{2 ′} and R ^{3 ′} is
A hydroxymethyl group,
An acetoxymethyl group,
A methoxycarbonyl group, or
An ethoxycarbonyl group,
And the other represents a hydrogen atom.

According to one preferred embodiment of the invention, R ⁶ is in the 5-position on the thiazole ring of formula (IV).

Next, although the specific example of the carbapenem derivative of general formula (I) by this invention and its intermediate body is illustrated, this invention is not limited to this. In the following, the numbers described before the compound names mean the compound numbers.
1. 4-hydroxymethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 2. 4- (2-hydroxyethoxy) methyl-5-((Z) -2-tritylthioethene- 1-yl) thiazole 3. 4-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 4. 4-hydroxymethyl-2-((Z) -2- Tritylthioethen-1-yl) thiazole 5. 4-Methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 6. 4-carbamoyl-5-((Z) -2-tritylthio Ethen-1-yl) thiazole 7. 4-N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 8. 4-N-cyanomethyl-N-methylcarbamoyl-5- ( (Z) -2-Tritylthioethen-1-yl) thiazole 9. 4-N-cyanomethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 10.4-N- ( 2-Cyanoethyl) carbamoyl-5-((Z) -2-tritylthioethene-1- L) thiazole 11. 4-cyanomethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 12. 4- (2-methoxyethoxy) methyl-5-((Z) -2-tritylthio Ethen-1-yl) thiazole 13.4- (3-Cyanoazetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 14.4-N- (2-hydroxy Ethyl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 15.4-N- (3-hydroxypropan-1-yl) carbamoyl-5-((Z) -2-trityl Thioethen-1-yl) thiazole 16. 4-N- (2-hydroxyethyl) -N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 17.4- (azetidine -1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 18. 4- (3-hydroxyazetidin-1-yl) carbonyl-5-((Z) -2 -Tritylthioethen-1-yl) thiazole 19.4- (3 -Hydroxypropan-1-yloxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 20. 2-Amino-4-carbamoyl-5-((Z) -2-tritylthioethene -1-yl) thiazole

21. 4-Hydroxymethyl-5-((E) -2-tritylthioethen-1-yl) thiazole 22. Carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 23 2-Amino-5-((Z) -2-tritylthioethen-1-yl) thiazole 24. 2-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl ) Thiazole 25.4-carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 26.4-N- (2-hydroxyethyl) carbamoyl-2-((Z) -2-trityl) Thioethen-1-yl) thiazole 27. 4-N, N-dimethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 28. 4-N-methylcarbamoyl-2-(( Z) -2-Tritylthioethen-1-yl) thiazole 29. 4-N-cyanomethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 30. 4-N-cyanomethyl- N-methylcarbamoyl-2-((Z) -2-tritium Thioethen-1-yl) thiazole 31. 4-Cyanomethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 32. 4- (3-hydroxyazetidin-1-yl) carbonyl-2- ((Z) -2-tritylthioethen-1-yl) thiazole 33. 4- (3-cyanoazetidin-1-yl) carbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 34 5-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 35.4,5-dicarbamoyl-2-((Z) -2-tritylthioethen-1-yl) Thiazole 36.4-((Z) -2-tritylthioethen-1-yl) thiazole 37. 2-carbamoyl-4-((Z) -2-tritylthioethen-1-yl) thiazole 38.5-hydroxy Methyl-4-((Z) -2-tritylthioethen-1-yl) thiazole 39.4-Ethoxycarbonyl-5- (2-trimethylsilylethynyl) thiazole 40. 4-Ethoxycarbonyl-5-ethynyl Azole

41. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Sodium -1-methyl-1-carbapene-2-em-3-carboxylate 42. (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6-((1R)- 1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 50-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-2-yl) ethen-1-yl] thio] Sodium -1-methyl-1-carbapene-2-em-3-carboxylate 45. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-methylthiazol-5-yl) ethen-1-yl ] Sodium] thio] -1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl)- Sodium 1-methyl-1-carbapene-2-em-3-carboxylate 47. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-N-methylcarbamoylthiazol-5-yl) ethene- 1-yl] thio] -1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N-Cyanomethyl-N-methylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) 1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N-Cyanomethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- 50. Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- [4-N- (2-cyanoethyl) carbamoylthiazol-5-yl] ethen-1-yl] thio] -6-((1R) 1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 51. (1R, 5S, 6S) -2-[[(Z) -2- (4-Cyanomethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) Sodium -1-methyl-1-carbapene-2-em-3-carboxylate 52. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4- (2-methoxyethoxy) methylthiazol-5-yl] ethene-1 -Il] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (3-Cyanoazetidin-1-yl) carbonylthiazol-5-yl] ethen-1-yl] thio] -6-(( 1R) -1-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 54. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthiazol-5-yl] ethene 1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (3-hydroxypropan-1-yl) carbamoylthiazole-5 -Yl] ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) -N-methylcarbamoylthiazole-5 -Yl] ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 57. (1R, 5S, 6S) -2-[[(Z) -2- [4- (azetidin-1-yl) carbonylthiazol-5-yl] ethen-1-yl] thio] -6-((1R) 1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-Hydroxyazetidin-1-yl) carbonylthiazol-5-yl) ethen-1-yl] thio] -6- ((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4- (3-hydroxypropan-1-yloxy) methylthiazol-5-yl ] Ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-Amino-4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium

61. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(E) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Sodium -1-methyl-1-carbapene-2-em-3-carboxylate 62. (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl)- Sodium 1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -2-[[(Z) -2- (2-Aminothiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl)- Sodium 1-methyl-1-carbapene-2-em-3-carboxylate 64. (1R, 5S, 6S) -2-[[(Z) -2- (2-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 65-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-Carbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl)- Sodium 1-methyl-1-carbapene-2-em-3-carboxylate 66. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthiazol-2-yl] ethene 1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1 67-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-N-methylcarbamoylthiazol-2-yl) ethene- 1-yl] thio] -1-carbapene-2-em-3-carboxylate 69. (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1- Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 70. (1R, 5S, 6S) -2-[[(Z) -2- (4-N-Cyanomethyl-N-methylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) 1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 71. (1R, 5S, 6S) -2-[[(Z) -2- (4-Cyanomethylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) Sodium -1-methyl-1-carbapene-2-em-3-carboxylate 72. (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-Hydroxyazetidin-1-yl) carbonylthiazol-2-yl) ethen-1-yl] thio] -6- ((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 73. (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-Cyanoazetidin-1-yl) carbonylthiazol-2-yl) ethen-1-yl] thio] -6-(( 1R) -1-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 74. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (5-hydroxymethylthiazol-2-yl) ethen-1-yl] thio] Sodium -1-methyl-1-carbapene-2-em-3-carboxylate 75. (1R, 5S, 6S) -2-[[(Z) -2- (4,5-Dicarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxy Ethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 76. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (thiazol-4-yl) ethen-1-yl] thio] Sodium -1-carbapene-2-em-3-carboxylate 77. (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-4-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl)- Sodium 1-methyl-1-carbapene-2-em-3-carboxylate 78. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (5-hydroxymethylthiazol-4-yl) ethen-1-yl] thio] Sodium 1-methyl-1-carbapene-2-em-3-carboxylate 79. (1R, 5S, 6S) -2-[[(Z) -2- (4-Acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) Sodium 1-methyl-1-carbapene-2-em-3-carboxylate 80. (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6-((1R)- 1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate

81. (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6-((1R)- 1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
82. (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 -Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
83. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-2-yl) ethen-1-yl] thio] 1- (Cyclohexyloxycarbonyloxy) ethyl 1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
84. (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl)- 1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
85. (1R, 5S, 6S) -2-[[(Z) -2- (4-N-Cyanomethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- 1- (Cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers) -1-hydroxy-1-carb-1-ene-2-em-3-carboxylic acid
86. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthiazol-5-yl] ethene -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
87. (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl)- Pivaloyloxymethyl 1-methyl-1-carbapene-2-em-3-carboxylate 88. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthiazol-2-yl] ethene -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
89. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (Cyclohexyloxycarbonyloxy) ethyl 1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
90. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 91-acetoxymethyl 1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (Isopropyloxycarbonyloxy) ethyl-1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
92. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (Ethoxycarbonyloxy) ethyl 1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
93. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -Pivaloyloxymethyl 1-methyl-1-carbapene-2-em-3-carboxylate 94. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Cyclohexyloxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate 95. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (Isobutyloxycarbonyloxy) ethyl-1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
96. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (Cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl (diastereomeric mixture)
97. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Isobutyloxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate 98. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 99. Isopropyloxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 100-Isobutyryloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-Methyl-1-carbapen-2-em-3-carboxylic acid (pentan-1-yl) oxycarbonyloxymethyl

101. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 101. 1-Methyl-1-carbapene-2-em-3-carboxylic acid (butan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 103. 1-Methyl-1-carbapen-2-em-3-carboxylic acid (1-ethylpropan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Isopentyloxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate 104. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 105.-1-Methyl-1-carbapen-2-em-3-carboxylic acid (propan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-Acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) 1- (Cyclohexyloxycarbonyloxy) ethyl 1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
106. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 107. Ethoxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Neopentyloxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate 108. (1R, 5S, 6S) -6-((1R) -1-Hydroxyethyl) -2-[[(Z) -2- (4-Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Methoxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate 109. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 110. Cyclopentyloxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 111. t-Butoxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Phthalidyl-1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
112. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (Methoxycarbonyloxy) ethyl-1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
113. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (Cyclopentyloxycarbonyloxy) ethyl 1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
114. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 115.-1-Methyl-1-carbapen-2-em-3-carboxylic acid (tetrahydropyran-4-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (Neopentyloxycarbonyloxy) ethyl-1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
116. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid (piperidin-1-yl) carbonyloxymethyl; (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 118-Allyl 1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-Hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (L-valinyloxymethyl) thiazole-5- Yl) ethen-1-yl] thio] -1-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (t-butoxycarbonyloxy) ethyl-1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)
120. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (t-butoxycarbonyloxy) ethyl-1-methyl-1-carbapene-2-em-3-carboxylate (mixture of diastereomers)

121. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 122. ethyl 1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 123. 1-methyl-1-carbapen-2-em-3-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 124. phenyloxycarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 125, -1-Methyl-1-carbapen-2-em-3-carboxylic acid N, N-di (propan-1-yl) aminocarbonyloxymethyl; (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 126. -1-methyl-1-carbapen-2-em-3-carboxylic acid (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] N, N-di- (butan-1-yl) aminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylic acid 127. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 128-Hexane-1-yl-1-methyl-1-carbapen-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 129. N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] N, N-diisobutylaminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylic acid130. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] N, N-diisopropylaminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylic acid 131. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 132. N-cyclohexyl-N-methylaminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-pentan-1-ylaminocarbonyloxymethyl 133. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 134. N-cyclohexyl-N-ethylaminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 135. N-isobutyl-N-isopropylaminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 136. Nt-butyl-N-ethylaminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1- (N, N-diisopropylaminocarbonyloxy) ethyl 1-methyl-1-carbapene-2-em-3-carboxylic acid (mixture of diastereomers)
137. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl-1-methyl-1-carbapene-2-em-3-carboxylic acid (diastereomeric mixture)
138. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 138. N-ethyl-N-isoamylaminocarbonyloxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate (5-bromothiazol-4-yl) methanol [5- [2- (Trimethylsilyl) ethynyl] thiazol-4-yl] methanol

141.5-Ethynyl-4-hydroxymethylthiazole 142. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N, N-diisopropylaminocarbonyloxymethyl143. (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1 Sodium carbapen-2-em-3-carboxylate 144. (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1 N-N-diisopropylaminocarbonyloxymethyl-carbapent-2-em-3-carboxylic acid 145. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 146. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-Methyl-1-carbapene-2-em-3-carboxylate potassium 147. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(E) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N, N-diisopropylaminocarbonyloxymethyl.

Compound Production Method The compound according to the present invention can be produced, for example, according to the following scheme. The starting materials necessary for the synthesis of the compounds according to the invention are either commercially available or can be readily prepared by conventional methods.

Among the compounds of the formula (I) according to the present invention, the compound of the formula (I ′) in which R ⁴ is a hydrogen atom or a salt thereof can be preferably prepared according to the following scheme.

［上記スキーム中で、Ｒ^１，Ｒ^２，およびＲ^３は前記式（Ｉ）で定義したものと同じ意味を表し、Ｒ^７ｂは前記Ｒ^７で定義したチオールの保護基（例えば、トリフェニルメチル基、アセチル基、ベンゾイル基、４−メトキシベンジル基等）と同義であり、Ｒ^７ｃは前記Ｒ^７で定義した金属イオン（例えば、リチウムイオン、ナトリウムイオン、カリウムイオン、銀イオン、水銀イオン等）と同義であり、Ｒ^８は、水素原子またはヒドロキシル保護基（例えば、ｔ−ブチルジメチルシリル基、トリメチルシリル基、トリエチルシリル基、４−ニトロベンジルオキシカルボニル基、４−メトキシベンジルオキシカルボニル基、アリルオキシカルボニル基等）を表し、Ｒ^９は、カルボキシル保護基（例えば、４−ニトロベンジル基、４−メトキシベンジル基、ジフェニルメチル基、ｔ−ブチルジメチルシリル基、アリル基等）を表し、Ｒ^１０は水素原子、またはカリウム、ナトリウムなどの金属イオンを表す。また、Ｘはハロゲン原子を表す。］

[In the above scheme, R ¹ , R ² , and R ³ represent the same meaning as defined in the formula (I), and R ^7b represents a thiol protecting group defined in the R ⁷ (for example, triphenylmethyl Group, acetyl group, benzoyl group, 4-methoxybenzyl group, and the like, and R ^7c is a metal ion defined by R ⁷ (for example, lithium ion, sodium ion, potassium ion, silver ion, mercury ion, etc.) R ⁸ is a hydrogen atom or a hydroxyl protecting group (for example, t-butyldimethylsilyl group, trimethylsilyl group, triethylsilyl group, 4-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, allyloxy group) represents a carbonyl group, etc.), ^{R 9} is a carboxyl protecting group (e.g., 4-nitrobenzyl group, 4-main Kishibenjiru group, diphenylmethyl group, t- butyl dimethyl silyl group, an allyl group, etc.), R ¹⁰ represents a metal ion, such as hydrogen atom or a potassium, sodium,. X represents a halogen atom. ]

［上記スキーム中、Ａｋはメチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、ｉ−ブチル、ｓ−ブチル、ｔ−ブチル、ｎ−ペンチル、ネオペンチル、ｉ−ペンチル、ｔ−ペンチル、ｎ−ヘキシル、ｉ−ヘキシル基等の低級アルキル基を表す。］The compound of formula (IIIa) is a Sonogashira reaction and detrimethylsilylation of a thiazole compound of formula (A) having a leaving group such as a halogen atom with trimethylsilylacetylene, or a thiazole compound of formula (A) and tributylethynyl tin It can be obtained by the Stille coupling reaction. Hereinafter, the case where one of R ² or R ³ is a hydroxymethyl group and the other is a hydrogen atom (compound of formula (d)) will be described as an example.

[In the above scheme, Ak is methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, i-pentyl, t-pentyl, n-hexyl. , Represents a lower alkyl group such as an i-hexyl group. ]

  The compound of the formula (b) is synthesized in a suitable solvent (for example, acetonitrile, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, toluene, benzene, methanol, ethanol, water, or a mixed solvent thereof). The compound (a) is reacted with a reducing agent such as sodium borohydride, diisobutylaluminum, lithium aluminum hydride and the like in the presence or absence of lithium chloride, calcium chloride, cerium chloride, etc. for 10 minutes to 72 hours. Can be obtained.

  Subsequently, the compound of the formula (c) is prepared by reacting the compound of the formula (b) with a suitable solvent (for example, acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, Hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, triethylamine, hexamethylphosphoric triamide, or a mixed solvent thereof) or an equivalent amount of a base (as an organic base) Examples of inorganic bases such as triethylamine, diisopropylamine, diisopropylethylamine, pyridine and the like include, for example, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate In the presence of cesium carbonate, etc., various palladium complexes (for example, dichlorobis (triphenylphosphine) palladium, bis (benzonitrile) palladium dichloride) and copper iodide, and trivalent phosphines such as triphenylphosphine, tributylphosphine, and trifurylphosphine Phosphorus reagent) and 1 equivalent or an excess amount of trimethylacetylene at -30 ° C to 100 ° C for 10 minutes to 72 hours.

  Finally, the compound of formula (d) is obtained by adding 10 equivalents of the compound of formula (c) in an appropriate solvent (eg, acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, etc.). Add the following acetic acid and tetra n-butylammonium fluoride or 10 equivalents or less of base (for example, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.) The reaction is carried out at −80 ° C. to 50 ° C. for 5 minutes to 24 hours. After the reaction, compound (d) can be obtained by ordinary post-treatment.

  The compound of formula (d) can also be obtained by a method via the compounds of formula (e) and formula (f). The compound of the formula (e) can be obtained from the compound of the formula (a) from the compound of the formula (b) described above in the same manner as in the step of the compound of the formula (c). The compound of formula (f) can be obtained from the compound of formula (e) from the compound of formula (c) described above in the same manner as in the step of the compound of formula (d). Finally, the step of the compound of the formula (f) to the compound of the formula (d) can be obtained by the same method as the above-described step of the compound of the formula (a) to the compound of the formula (b). .

Conversion from the compound of formula (IIIa) to the compound of formula (IVb) can be carried out by the following method. That is, the compound of formula (IVb) can be obtained by allowing the corresponding thiol to act on ethynylthiazole of formula (IIIa).
Here, the corresponding thiol is represented by the formula R ^7b SH. This R ^7b has the same meaning as described above, and examples thereof include triphenylmethanethiol, thioacetic acid, thiobenzoic acid, 4-methoxy-α-toluenethiol and the like.

Here, the case where R ^7b is a triphenylmethyl group will be described as an example.
For the compound of formula (IIIa), acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dioxane, methanol, ethanol, dichloromethane, toluene, hexamethylphosphoric triamide, water, etc. Or, in these mixed solvents, 1 equivalent or excess of triphenylmethanethiol and a catalytic amount or more of a base (as organic bases, for example, diisopropylethylamine, triethylamine, 2,6-lutidine, pyridine, etc. For example, sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. The compound of formula (IVb) can be obtained by ordinary post-treatment after reacting at −80 ° C. to + 100 ° C. for 5 minutes to 24 hours.

Next, the conversion from the compound of formula (IVb) to the compound of formula (IVc) can be carried out by the following method. Here, the case of silver ions will be described as an example.
That is, 1 equivalent or an excess amount of pyridine and silver nitrate is added to the compound of formula (IVb), and in a solvent such as THF, acetone, methanol, dichloromethane, chloroform, water or a mixed solvent thereof at 0 ° C. to + 50 ° C. After reacting for 5 minutes to 8 hours, the compound of formula (IVc) can be obtained by filtration.

In the next step, the compound of formula (IVc) can be converted to the compound of formula (VI). This conversion can be performed by the following method.
That is, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dioxane, methanol, ethanol, dichloromethane, toluene, hexamethyl for the compound of formula (IVc) and the compound of formula (V) In phosphoric triamide or the like and a mixed solvent thereof, at −20 ° C. to 100 ° C., 1 equivalent or an excess amount of sodium iodide is added to the compound of formula (IVc) as necessary, and the reaction is carried out for 10 minutes to 3 days. Then, the compound of the formula (VI) can be obtained by subjecting to usual post-treatment.
In addition, as a compound of the above-mentioned formula (V), a commercial item can be used, for example.

Finally, the protecting group of the compound of formula (VI) can be removed by a deprotection reaction according to the type of protecting group in one step or multiple steps to obtain the compound of formula (I ′) of the present invention. it can.
In this case, the deprotection reaction for removing the protecting group varies depending on the kind of the protecting group used, but can be generally performed according to a conventional method known in the art of this field. If any or all of them can be deprotected under acidic conditions, use mineral acids such as hydrochloric acid, organic acids such as formic acid, acetic acid and citric acid, or Lewis acids such as aluminum chloride. In the case of removal by, catalytic reduction with various catalysts or metal reducing agents such as zinc and iron can be used. In addition, when R ⁸ is a silyl protecting group (eg, t-butyldimethylsilyl group, trimethylsilyl group, triethylsilyl group, etc.), by using a fluorine ion reagent (eg, tetrabutylammonium fluoride). Furthermore, when R ⁸ is an allyloxycarbonyl group and R ⁹ is an allyl group, it can be easily removed by using various palladium complexes (eg, tetrakis (triphenylphosphine) palladium (0)). Can do.

  The compound of the formula (I ′) thus obtained can be obtained by using chromatography such as nonionic macrohypoporous resin, gel filtration using Sephadex, etc., reverse phase silica gel column chromatography, etc. Can be released and purified.

［上記スキーム中で、Ｒ^１，Ｒ^２，およびＲ^３は前記式（Ｉ）で定義したものと同じ意味を表す。Ｒ^１０は水素原子、またはカリウム、ナトリウムなどの金属イオンを表し、Ｒ^４’は生体内で加水分解される基（前記「化合物」の項にて「Ｒ^４が生体内で加水分解される基である場合」で定義したものと同じ意味を表す）を表し、Ｘは塩素、臭素、ヨウ素、−ＯＳＯ_２ＣＦ_３、−ＯＳＯ_２ＣＨ_３、−ＯＳＯ_２ＰｈＣＨ_３等の脱離基を表す。］Of the compounds of the general formula (I) according to the present invention, the compound of the formula (I ″) in which R ⁴ is a group that is hydrolyzed in vivo can be preferably produced according to the following scheme.

[In the above scheme, R ¹ , R ² , and R ³ represent the same meaning as defined in Formula (I) above. R ¹⁰ represents a hydrogen atom or a metal ion such as potassium or sodium, and R ^{4 ′} represents a group that is hydrolyzed in vivo (in the above-mentioned “Compound” section, “R ⁴ is a group that is hydrolyzed in vivo”). X represents a leaving group such as chlorine, bromine, iodine, —OSO ₂ CF ₃ , —OSO ₂ CH ₃ , —OSO ₂ PhCH _{3, and the} like. ]

1 equivalent or an excess of a base (as an organic base, such as diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2,6-lutidine, etc.) as necessary with respect to the compound of formula (I ′) Is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.) or / and a quaternary ammonium salt (eg, triethylbenzylammonium chloride, tetraethylammonium chloride, In the presence of tetrabutylammonium chloride, tetrabutylammonium bromide, etc., one equivalent or an excess of alkyl halide (R ^{4 ′} -X: X represents a halogen atom, preferably iodine, bromine or chlorine. For example, ethyl iodide, 1- ( Cyclohexyloxycarbonyloxy) ethyl iodide, bromomethyl acetate 1- (isopropyloxycarbonyloxy) ethyl iodide, 1- (ethoxycarbonyloxy) ethyl iodide, iodomethyl pivalate, cyclohexyloxycarbonyloxymethyl iodide, 1- ( Isobutyloxycarbonyloxy) ethyl iodide, 1- (cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl iodide, isobutyloxycarbonyloxymethyl iodide, isopropyloxycarbonyloxymethyl iodide, isobutyryloxymethyl iodide , (Pentan-1-yl) oxycarbonyloxymethyl iodide, (butan-1-yl) oxycarbonyloxymethyl iodide, ( -Ethylpropan-1-yl) oxycarbonyloxymethyl iodide, isopentyloxycarbonyloxymethyl iodide, (propan-1-yl) oxymethyl iodide, ethoxycarbonyloxymethyl iodide, neopentyloxycarbonyloxymethyl iodide Id, methoxycarbonyloxymethyl iodide, cyclopentyloxycarbonyloxymethyl iodide, t-butoxycarbonyloxymethyl iodide, 3-bromophthalide, 1- (methoxycarbonyloxy) ethyl iodide, 1- (cyclopentyloxycarbonyloxy) ) Ethyl iodide, (tetrahydropyran-4-yl) oxycarbonyloxymethyl iodide, 1- (neopentyloxycarbonyloxy) ethyl iodide (Piperidin-1-yl) carbonyloxymethyl iodide, allyl iodide, 1- (t-butoxycarbonyloxy) ethyl iodide, N, N-di (propan-1-yl) aminocarbonyloxymethyl iodide, Phenyloxycarbonyloxymethyl iodide, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl bromide, (Z) -2- (3-phthalidylidene) ethyl bromide, (cis-2,6) -Dimethylpiperidin-1-yl) carbonyloxymethyl chloride, chloromethyl N, N-di-n-butylcarbamate, 1-iodohexane, Nn-hexyl-N-methylcarbamate chloromethyl, N, N-diisobutyl Chloromethyl carbamate, N, N-diisopropylcarbamate Chloromethyl, chloromethyl N-cyclohexyl-N-methylcarbamate, chloromethyl N-pentan-1-ylcarbamate, chloromethyl N-cyclohexyl-N-ethylcarbamate, chloromethyl N-isobutyl-N-isopropylcarbamate, N -Chloromethyl t-butyl-N-ethylcarbamate, 1-chloroethyl N, N-diisopropylcarbamate, 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl chloride, N- Ethyl-N-isoamylcarbamate chloromethyl, etc.) alone or in combination with an inert solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylformamide, N, N-diethylacetamide) N-methylpyrrolidinone, N N-dimethylimidazolidinone, dimethyl sulfoxide, sulfolane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, diethyl ether, anisole, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, hexamethylphosphoric The compound of the formula (I ″) can be obtained by reacting at −70 to + 50 ° C. (preferably −30 ° C. to + 30 ° C.) for 10 minutes to 24 hours in triamide, methanol, ethanol or the like.

  The ester obtained as described above can be isolated and purified by precipitation, gel filtration using Sephadex, etc., silica gel column chromatography, reverse phase column chromatography or the like.

Use of Compound / Pharmaceutical Composition The compound according to the present invention inhibits the growth of pathogenic bacteria in vitro and exhibits antibacterial activity (see Test Example 1). In addition, it has been confirmed that the compound according to the present invention inhibits the growth of pathogenic bacteria and exhibits antibacterial activity in in vivo tests. That is, the carbapenem derivative of the formula (I) according to the present invention exhibits a strong antibacterial activity against various pathogenic bacteria including pneumococci including PRSP, Haemophilus influenzae including BLNAR, catalucocci, and β-lactamase producing bacteria. Therefore, it can be said that the compound according to the present invention is extremely effective in preventing or treating infections caused by these bacteria or symptoms associated therewith.

  The compounds according to the invention can therefore be used for the prevention or treatment of bacterial infections and associated symptoms. Examples of the bacteria that cause such bacterial infection include those selected from the group consisting of pneumococci, Haemophilus influenzae, catalucoccus, and β-lactamase producing bacteria.

  According to the present invention there is provided a pharmaceutical composition comprising a compound according to the present invention or a pharmacologically acceptable salt thereof. Preferably, the pharmaceutical composition can further comprise a pharmaceutically acceptable carrier. The pharmaceutical composition according to the present invention can be used for the prevention or treatment of bacterial infections. That is, it can be used as an antibacterial agent.

  According to another aspect of the present invention, as described above, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof. A method of treating or preventing a bacterial infection or a symptom associated therewith is provided.

  As used herein, “effective amount” means the amount of an active ingredient that is at least required to exert its effect in order to treat, prevent, suppress progression, or ameliorate a disease or symptom or condition. “Patient” refers to a human or a mammal other than a human (eg, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.) to which the compound or composition of the present invention is to be administered. means. “Administration” means that a target substance is taken into a living body orally or parenterally to a subject patient.

  The present invention also provides an antibacterial agent comprising the compound according to the present invention or a pharmacologically acceptable salt thereof as an active ingredient.

  The compound according to the present invention or a pharmacologically acceptable salt thereof can be administered to human and parenteral (eg, intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, transdermal administration) It can be administered to animals other than humans.

Accordingly, a pharmaceutical composition comprising a compound according to the present invention is formulated into a suitable dosage form depending on the route of administration. Specifically, examples of oral preparations include tablets, capsules, powders, granules, pills, fine granules, troches, syrups, and parenterals such as intravenous injection or intramuscular injection. Injections, suppositories, tapes, ointments and the like can be mentioned.
These various preparations are commonly used excipients, extenders, disintegrants, binders, lubricants, colorants, diluents, wetting agents, surfactants, dispersants, buffers, storage. Can be produced by a conventional method using additives (carriers) such as an agent, a solubilizer, a preservative, a flavoring agent, a soothing agent, and a stabilizer.

Examples of excipients include lactose, fructose, glucose, corn starch, sorbite, and crystalline cellulose. Examples of disintegrants include starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, and dextrin. Examples of the agent include dimethyl cellulose or a salt thereof, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, and polyvinyl pyrrolidone. Examples of the lubricant include talc, magnesium stearate, and polyethylene glycol. And hydrogenated vegetable oils. Other non-toxic additives that can be used include, for example, syrup, petrolatum, lanolin, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, β-cyclodextrin, hydroxypropyl- β-cyclodextrin, Tween 80 and the like can be mentioned.
Moreover, the said injection can be manufactured by adding a buffer, a pH adjuster, a stabilizer, an isotonic agent, a preservative, etc. as needed.

In the pharmaceutical composition according to the present invention, the content of the compound according to the present invention varies depending on the dosage form, but is usually 0.01 to 100% by weight, preferably 0.1 to 90% by weight, based on the total composition. Preferably it is 0.5 to 50 weight%. The dose is appropriately determined according to the individual case in consideration of the patient's age, weight, sex, disease difference, symptom level, etc. Usually, the dose is about 1 to 2000 mg, preferably 10 to 1000 mg per adult per day, which can be administered once to 6 times a day depending on the symptoms.
The compound according to the present invention may be mixed or administered in combination with, for example, a DHP-1 inhibitor (Dehydrogenase-1 inhibitor) such as cilastatin, an organic ion transport inhibitor such as betamipron, and the like.

  EXAMPLES Hereinafter, although an Example and an example demonstrate this invention, this invention is not limited to these.

Example 1 4-Hydroxymethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
a) 2-Amino-4-ethoxycarbonyl-5-iodothiazole
A solution of 14.53 g of 2-amino-4-ethoxycarbonylthiazole in 200 ml of THF was ice-cooled under an argon atmosphere, 20.0 g of N-iodosuccinimide was added, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction solution was added brine and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 2) to give 2-amino-4 21.12 g of -ethoxycarbonyl-5-iodothiazole were obtained.
NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.2 Hz), 4.39 (2H, q, J = 7.2 Hz), 5.4 (2H, br s)

b) 4-Ethoxycarbonyl-5-iodothiazole
A solution of 10.68 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole in 140 ml of DMF was ice-cooled under an argon atmosphere, 6.15 ml of t-butyl nitrite was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into brine, extracted 3 times with ethyl acetate, and the organic layers were combined and washed 3 times with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-3: 1) to give 4-ethoxycarbonyl- 5.08 g of 5-iodothiazole was obtained.
NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.2 Hz), 4.46 (2H, q, J = 7.2 Hz), 8.94 (1H, s)

c) 5-ethynyl-4-methoxycarbonylthiazole
Dissolve 71.47 g of 4-ethoxycarbonyl-5-iodothiazole in 250 ml of DMF, and then add 70 ml of triethylamine, 53.4 ml of ethynyltrimethylsilane, 960 mg of copper (I) iodide, and 3.54 g of bis (triphenylphosphine) palladium (II) dichloride sequentially. The mixture was stirred at 60 ° C. for 1.5 hours under an argon atmosphere. The reaction solution was added to 1000 ml of ethyl acetate and 500 ml of brine and adjusted to pH 3 with 1N aqueous hydrochloric acid. The organic layer was separated and washed successively with 500 ml of sodium bicarbonate water and 500 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 1) to give 5- (2- 53.66 g of trimethylsilylethynyl) -4-ethoxycarbonylthiazole were obtained. This was dissolved in 250 ml of methanol, added with 3.1 g of potassium carbonate under ice cooling, and stirred at the same temperature for 45 minutes. The reaction solution was added to 500 ml of ethyl acetate and 250 ml of brine, and the organic layer was separated and washed twice with 500 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to give 5-ethynyl-4 29.91 g of methoxycarbonylthiazole were obtained.
NMR (CDCl ₃ ) δ: 3.86 (1H, s), 4.00 (3H, s), 8.72 (1H, s)

d) 5-ethynyl-4-hydroxymethylthiazole
To a solution of 25.05 g of 5-ethynyl-4-methoxycarbonylthiazole in 450 ml of toluene was added dropwise 165 ml of a 1.0 M diisobutylaluminum hydride / toluene solution at −40 ° C. in an argon atmosphere. After stirring at the same temperature for 1 hour, the reaction solution was poured into brine and 200 ml of 1N hydrochloric acid was added. Insoluble material was removed by filtration through Celite, and the filtrate was extracted 4 times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in 300 ml of ethanol and 150 ml of THF, and 2.2 g of sodium borohydride was added under an argon atmosphere under ice cooling, followed by stirring at room temperature for 1 hour. Brine was added to the reaction solution, and 1N hydrochloric acid was added to adjust the pH to 3. Then, the organic solvent was distilled off under reduced pressure. The remaining aqueous solution was extracted with ethyl acetate three times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1 to 1: 1). As a result, 19.25 g of 5-ethynyl-4-hydroxymethylthiazole was obtained.
NMR (CDCl ₃ ) δ: 2.75 (1H, br s), 3.60 (1H, s), 4.86 (2H, s), 8.68 (1H, s)

e) 4-Hydroxymethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
A 65 ml THF solution of 2.73 g of 5-ethynyl-4-hydroxymethylthiazole was ice-cooled under an argon atmosphere, and 6.5 g of triphenylmethanethiol and 440 mg of potassium tert-butoxide were added. After stirring at room temperature for 2 hours, brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. To the resulting residue were added 10 ml of ethyl acetate and 10 ml of hexane, and the precipitate was collected by filtration to give the title compound 7.26. g was obtained.
NMR (DMSO-d ₆ ) δ: 4.58 (2H, d, J = 4.8 Hz), 5.17 (3H, t, J = 4.8 Hz), 5.88 (1H, d, J = 10.8 Hz), 6.94 (1H, d , J = 10.8 Hz), 7.2-7.4 (15H, m), 8.99 (1H, s)

Example 2 4- (2-hydroxyethoxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4-Chloromethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 4-hydroxymethyl-5-((Z) -2-tritylthio obtained in Example 1-e) Ethene-1-yl) thiazole (816 mg) in THF (25 ml) was ice-cooled, and triethylamine (0.301 ml) and thionyl chloride (0.157 ml) were added under an argon atmosphere. After stirring at the same temperature for 20 minutes, brine was added to the reaction mixture, and the pH was adjusted to 8 with aqueous sodium bicarbonate. Extraction was performed twice with ethyl acetate, and the organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 1: 1) to give 4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl ) 512 mg of thiazole was obtained.
NMR (CDCl ₃ ) δ: 4.77 (2H, s), 6.11 (1H, d, J = 10.5 Hz), 6.64 (1H, d, J = 10.5 Hz), 7.2-7.4 (15H, m), 8.71 (1H , s)

b) 4- (2-hydroxyethoxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole (5.57 g) was suspended in THF (100 ml) and ethylene glycol (30 ml), sodium hydride (1.5 g) was added, and the mixture was stirred at 50 ° C. for 37 hours. . Brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give 4.87 g of the title compound.
NMR (CDCl ₃ ) δ: 3.6-3.7 (2H, m), 3.7-3.8 (2H, m), 4.73 (2H, s), 6.03 (1H, d, J = 10.8 Hz), 6.68 (1H, d, J = 10.8 Hz), 7.2-7.4 (15H, m), 8.72 (1H, s)

Example 3 4-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4-Methoxycarbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole and 4-methoxycarbonyl-5-((E) -2-tritylthioethen-1-yl) thiazole Example In the same manner as in 1-e), 7.67 g of 4-methoxycarbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole was obtained from 3.96 g of 5-ethynyl-4-methoxycarbonylthiazole.
NMR (CDCl ₃ ) δ: 3.93 (3H, s), 6.31 (1H, d, J = 11.2 Hz), 7.26-7.34 (15H, m), 7.67 (1H, d, J = 11.2 Hz), 8.69 (1H , s)
The residue obtained by concentrating the crystallization filtrate was recrystallized from chloroform-methanol-hexane to give 4-methoxycarbonyl-5-((E) -2-tritylthioethen-1-yl) thiazole. 502 mg was obtained.
NMR (CDCl ₃ ) δ: 3.93 (3H, s), 6.35 (1H, d, J = 15.9 Hz), 7.25-7.35 (15H, m), 7.70 (1H, d, J = 15.9 Hz), 8.38 (1H , s)

b) 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole
To a suspension of 7.31 g of 4-methoxycarbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole in THF was added 8.30 ml of 5N aqueous sodium hydroxide solution, and the mixture was stirred at 60 ° C. for 1 hour. After cooling to room temperature, 5.50 ml of 5N hydrochloric acid, 100 ml of ethyl acetate and 50 ml of water were added and concentrated to 150 ml. 100 ml of hexane was added, and the precipitated solid was collected by filtration and washed with ethyl acetate-hexane (2: 1) to give 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole. 8.30 g was obtained.
NMR (DMSO-d ₆ ) δ: 6.24 (1H, d, J = 11.0 Hz), 7.23-7.41 (15H, m), 7.58 (1H, d, J = 11.0 Hz), 9.04 (1H, s)

c) 4-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole 7.34 g of DMF in 100 ml suspension in 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride 3.91 g and 3.14 g of 1-hydroxybenzotriazole were added and stirred at room temperature for 30 minutes. 25.6 ml of 2M-dimethylamine THF solution was added and stirred at the same temperature for 9 hours. 400 ml of ethyl acetate was added to the reaction solution, washed 4 times with 400 ml of brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was recrystallized from ethyl acetate-hexane to obtain 5.73 g of the title compound. NMR (CDCl ₃ ) δ: 2.96 (3H, s), 3.09 (3H, s), 6.06 (1H, d, J = 10.8 Hz), 6.86 (1H, d, J = 10.8 Hz), 7.23-7.34 (15H , m), 8.69 (1H, s)

Example 4 4-Hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4-Ethoxycarbonyl-2-iodothiazole A solution of 6.0 ml of t-butyl nitrite in 120 ml of acetonitrile was ice-cooled in an argon atmosphere, and 9.64 g of diiodomethane and 5.16 g of 2-amino-4-ethoxycarbonylthiazole were added. After stirring at room temperature for 1 hour, brine was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-3: 1). By purification, 5.58 g of 4-ethoxycarbonyl-2-iodothiazole was obtained.
NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.2 Hz), 4.43 (2H, q, J = 7.2 Hz), 8.14 (1H, s)

b) 2-ethynyl-4-methoxycarbonylthiazole
6.39 g of 4-ethoxycarbonyl-2-iodothiazole was suspended in 60 ml of triethylamine, 253 mg of palladium acetate, 592 mg of triphenylphosphine and 6.37 ml of ethynyltrimethylsilane were added under an argon atmosphere, and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and brine were added, and 1N aqueous hydrochloric acid was added to adjust to pH 3.0. Extracted twice with ethyl acetate, washed with brine, dried the organic layer over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). By purification, 3.97 g of 2- (2-trimethylsilylethynyl) -4-ethoxycarbonylthiazole was obtained. This was dissolved in 30 ml of methanol, 220 mg of potassium carbonate was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added brine, extracted twice with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.50 g of 2-ethynyl-4-methoxycarbonylthiazole.
NMR (CDCl ₃ ) δ: 3.51 (1H, s), 3.97 (3H, s), 8.20 (1H, s)

c) 4-Methoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
2.50 g of 2-ethynyl-4-methoxycarbonylthiazole was dissolved in 70 ml of THF, and 4.96 g of triphenylmethyl mercaptan and 336 mg of potassium tert-butoxide were added at −60 ° C. under an argon atmosphere. After stirring at the same temperature for 1 hour, an aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the desired product. Ethyl acetate and hexane were added from the crude purified product containing and the precipitate was collected by filtration to obtain 3.88 g of 4-methoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole.
NMR (CDCl ₃ ) δ: 3.96 (3H, s), 6.46 (1H, d, J = 11.1 Hz), 6.85 (1H, d, J = 11.1 Hz), 7.2-7.4 (15H, m), 8.22 (1H , s)

d) 4-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
4-Methoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 3.48 g of 70 ml of dichloromethane was ice-cooled, and 18.7 ml of 1.0 M diisobutylaluminum hydride / toluene solution was added in an argon atmosphere. It was dripped. After stirring at the same temperature for 1 hour, water was added to the reaction solution, and the pH was adjusted to 2.5 with 1N aqueous hydrochloric acid. Insoluble material was removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2.88 g of the title compound.
NMR (CDCl ₃ ) δ: 4.79 (2H, s), 6.35 (1H, d, J = 10.8 Hz), 6.68 (1H, d, J = 10.8 Hz), 7.21 (1H, s), 7.25-7.4 (15H , m)

Example 5 4-Methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
From 1.14 g of 4-methyl-5-ethynylthiazole, 1.98 g of the title compound was obtained in the same manner as in Example 1-e).
NMR (CDCl ₃ ) δ: 2.45 (3H, s), 5.90 (1H, d, J = 10.8 Hz), 6.53 (1H, d, J = 10.8 Hz), 7.26-7.35 (15H, m), 8.66 (1H , s)

Example 6 4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4-carbamoyl-5-ethynylthiazole
4-carbamoyl-5-iodothiazole 5.02 g in dioxane solution bis (benzonitrile) palladium (II) dichloride 227 mg, tri-tert-butylphosphine 239 mg, copper (I) iodide 75 mg, trimethylsilylacetylene 5.55 ml, N, N -4.14 ml of diisopropylamine was added and it stirred at 40 degreeC for 1 day. Ethyl acetate and half-saturated saline were added to the reaction solution, and after separation, the organic layer was dried over anhydrous magnesium sulfate. From the residue obtained by distilling off the solvent under reduced pressure, 20 ml of 30% aqueous ammonia and 10 ml of THF were added to a light brown solid obtained by recrystallization from dichloromethane-hexane. After stirring at room temperature for 1 hour, the solvent was concentrated and recrystallized from dichloromethane-ethyl acetate to obtain 474 mg of 4-carbamoyl-5-ethynylthiazole.
NMR (DMSO-d ₆ ) δ: 4.95 (1H, s), 7.65 (1H, br s), 7.77 (1H, s), 9.08 (1H, s)

b) 4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
From 740 mg of 4-carbamoyl-5-ethynylthiazole, 1.77 g of the title compound was obtained in the same manner as in Example 1-e).
NMR (DMSO-d ₆ ) δ: 6.14 (1H, d, J = 11.0 Hz), 7.20-7.43 (15H, m), 7.58 (1H, br s), 7.81-7.90 (2H, m), 9.05 (1H , s)

Example 7 4-N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
In the same manner as in Example 3-c), 397 mg of the title compound was obtained from 430 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 1.0 ml of 2.0 M methylamine THF solution.
NMR (CDCl ₃ ) δ: 2.97 (3H, d, J = 5.1 Hz), 6.20 (1H, d, J = 11.0 Hz), 7.25-7.33 (15H, m), 7.54 (1H, br s), 7.99 ( 1H, d, J = 11.0 Hz), 8.57 (1H, s)

Example 8 4-N-cyanomethyl-N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
781 mg of the title compound was obtained in the same manner as in Example 3-c) from 1.10 g of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.392 ml of 2-methylaminoacetonitrile.
NMR (DMSO-d ₆ ) δ: 2.97-3.07 (3H, m), 4.48-4.58 (2H, m), 6.13 (1H, d, J = 10.9 Hz), 6.82-6.96 (2H, m), 7.22- 7.43 (15H, m), 9.12-9.17 (1H, m)

Example 9 4-N-cyanomethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
1.24 g of the title compound was obtained in the same manner as in Example 3-c) from 1.41 g of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 609 mg of aminoacetonitrile (hydrochloride). .
NMR (DMSO-d ₆ ) δ: 4.23 (2H, d, J = 5.9 Hz), 6.25 (1H, d, J = 11.2 Hz), 7.23-7.43 (15H, m), 7.83 (1H, d, J = 10.8 Hz), 9.12 (1H, s), 9.18 (1H, t, J = 5.9 Hz)

Example 10 4-N- (2-cyanoethyl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
From 430 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.148 ml of 2-cyanoethanol, 439 mg of the title compound was obtained in the same manner as in Example 3-c).
NMR (CDCl ₃ ) δ: 2.70 (2H, t, J = 6.6 Hz), 3.68 (2H, m), 6.25 (1H, d, J = 11.2 Hz), 7.27-7.34 (15H, m), 7.90 (1H , d, J = 11.2 Hz), 7.96 (1H, br t, J = 6.3 Hz), 8.60 (1H, s)

Example 11 4-Cyanomethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 4-chloromethyl-5-((Z) -2-trityl obtained in Example 2-a) A suspension of 350 mg of thioethen-1-yl) thiazole in 7 ml of DMF was ice-cooled, and 94 mg of sodium cyanide was added under an argon atmosphere. After stirring at room temperature for 2.5 hours, brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 132 mg of the title compound.
NMR (CDCl ₃ ) δ: 3.87 (2H, s), 6.13 (1H, d, J = 10.8 Hz), 6.47 (1H, d, J = 10.8 Hz), 7.2-7.4 (15H, m), 8.72 (1H , s)

Example 12 4- (2-methoxyethoxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 2-a) in the same manner as Example 2-b) From 436 mg of 4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole and 7 ml of 2-methoxyethanol, 461 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 3.34 (3H, s), 3.5-3.6 (2H, m), 3.6-3.7 (2H, m), 4.74 (2H, s), 6.00 (1H, d, J = 11.1 Hz) , 6.77 (1H, d, J = 11.1 Hz), 7.2-7.4 (15H, m), 8.69 (1H, s)

Example 13 4- (3-Cyanoazetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
In the same manner as in Example 3-c), 716 mg of the title compound was obtained from 859 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 237 mg of 3-cyanoazetidine hydrochloride.
NMR (CDCl ₃ ) δ: 3.44-3.52 (1H, m), 4.34-4.39 (1H, m), 4.41-4.47 (1H, m), 4.77-4.81 (1H, m), 4.86-4.91 (1H, m ), 6.24 (1H, d, J = 11.2 Hz), 7.27-7.34 (15H, m), 7.78 (1H, d, J = 11.2 Hz), 8.61 (1H, s)

Example 14 4-N- (2-hydroxyethyl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
In the same manner as in Example 3-c), 871 mg of the title compound was obtained from 859 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.24 ml of 2-aminoethanol.
NMR (CDCl ₃ ) δ: 2.80 (1H, br t, J = 5.4 Hz), 3.56-3.61 (2H, m), 3.79-3.83 (2H, m), 6.23 (1H, d, J = 11.0 Hz), 7.26-7.33 (15H, m), 7.95 (1H, d, J = 11.0 Hz), 7.96 (1H, br s), 8.59 (1H, s)

Example 15 4-N- (3-hydroxypropan-1-yl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
644 mg of the title compound was obtained from 644 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.137 ml of 3-aminopropanol in the same manner as in Example 3-c).
NMR (CDCl ₃ ) δ: 1.75 (2H, m), 3.41 (1H, br t, J = 6.6Hz), 3.55-3.60 (2H, m), 3.61-3.66 (2H, m), 6.23 (1H, d , J = 11.2 Hz), 7.26-7.33 (15H, m), 7.80 (1H, br t), 7.96 (1H, d, J = 11.2 Hz), 8.59 (1H, s)

Example 16 4-N- (2-hydroxyethyl) -N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
In the same manner as in Example 3-c), 651 mg of the title compound was obtained from 644 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.145 ml of 2- (methylamino) ethanol. .
NMR (CDCl ₃ ) δ: 3.05 & 3.11 (total 3H, both s, N-Me conformer), 3.46-3.48 (2H, m), 3.82-3.84 (2H, m), 5.25 (1H, br t), 6.13 (1H, d, J = 11.0 Hz), 7.07 (1H, d, J = 11.0 Hz), 7.27-7.32 (15H, m), 8.68 (total 1H, both s, thiazole H (2) conformer)

Example 17 4- (azetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
644 mg of the title compound was obtained from 644 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 168 mg of azetidine hydrochloride in the same manner as in Example 3-c).
NMR (CDCl ₃ ) δ: 2.24-2.32 (2H, m), 4.15-4.19 (2H, m), 4.48-4.52 (2H, m), 6.15 (1H, d, J = 11.0 Hz), 7.24-7.31 ( 15H, m), 7.73 (1H, d, J = 11.0 Hz), 8.61 (1H, s)

Example 18 4- (3-Hydroxyazetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
From 0.757 g of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.757 g of 3-hydroxyazetidine tartrate, 0.742 g of the title compound was prepared in the same manner as in Example 3-c). Obtained.
NMR (CDCl ₃ ) δ: 2.68 (1H, d, J = 6.1 Hz), 3.99 (1H, m), 4.31-4.41 (2H, m), 4.60-4.74 (2H, m), 6.18 (1H, d, J = 11.2 Hz), 7.23-7.33 (15H, m), 7.71 (1H, d, J = 11.1 Hz), 7.57 (1H, 2s)

Example 19 4- (3-Hydroxypropan-1-yloxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole In the same manner as in Example 2-b), Example 2-a The title compound 674 mg was obtained from 665 mg of 4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole and 3 ml of 1,3-propanediol.
NMR (CDCl ₃ ) δ: 1.8-1.9 (2H, m), 3.6-3.8 (4H, m), 4.68 (2H, s), 6.02 (1H, d, J = 11.1 Hz), 6.68 (1H, d, J = 11.1 Hz), 7.2-7.4 (15H, m), 8.71 (1H, s)

Example 20 2-Amino-4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
a) 2-Amino-4-ethoxycarbonyl-5-ethynylthiazole 1.40 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole obtained in Example 1-a) was dissolved in 20 ml of N-methyl-2-pyrrolidinone. Under an argon atmosphere, 1.63 ml of tri-n-butylethynyltin, 127 mg of tri (2-furyl) phosphine, 127 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.27 g of zinc chloride were added, and the mixture was stirred at room temperature for 2.5 hours. did. Brine and ethyl acetate were added to the reaction solution, insolubles were filtered off through celite, the filtrate was extracted twice with ethyl acetate, and the organic layers were combined and washed with brine. The residue obtained after drying over anhydrous magnesium sulfate, filtration, and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2-amino-4-ethoxycarbonyl-5-ethynyl. 597 mg of thiazole was obtained.
NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 6.9 Hz), 3.67 (1H, s), 4.39 (2H, q, J = 6.9 Hz), 5.55 (2H, br s)

b) 2-amino-4-ethoxycarbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole In the same manner as in Example 1-e), 2-amino-4-ethoxycarbonyl-5- From 992 mg of ethynylthiazole, 1.93 g of 2-amino-4-ethoxycarbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole was obtained.
NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 6.9 Hz), 4.35 (2H, q, J = 6.9 Hz), 5.03 (2H, br s), 5.94 (1H, d, J = 11.1 Hz) , 7.2-7.4 (15H, m), 7.52 (1H, d, J = 11.1 Hz), 8.02 (1H, s)

c) 2-Amino-4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 2-amino-4-ethoxy as in Examples 3-b) and 3-c) The title compound was obtained from 501 mg of carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole and 8 ml of 0.5 M ammonia / dioxane solution.
NMR (CDCl ₃ ) δ: 4.87 (2H, br s), 5.42 (1H, br s), 5.88 (1H, d, J = 11.1 Hz), 7.06 (1H, br s), 7.2-7.4 (15H, m ), 7.77 (1H, d, J = 11.1 Hz)

Example 21 4-Hydroxymethyl-5-((E) -2-tritylthioethen-1-yl) thiazole 4-methoxycarbonyl-5-((E) -2-trityl obtained in Example 3-a) 330 mg of the title compound was obtained from 480 mg of thioethen-1-yl) thiazole in the same manner as in Example 4-d).
NMR (CDCl ₃ ) δ: 2.25 (1H, t, J = 5.8 Hz), 4.62 (2H, d, J = 5.8 Hz), 6.11 (1H, d, J = 15.6 Hz), 6.78 (1H, d, J = 15.6 Hz), 7.24-7.35 (15H, m), 8.71 (1H, s)

Example 22 2-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
a) 2-carbamoyl-5-ethynylthiazole
From 1.70 g of 2-carbamoyl-5-iodothiazole, 1.11 g of 2-carbamoyl-5-ethynylthiazole was obtained in the same manner as in Example 1-c).
NMR (DMSO-d ₆ ) δ: 4.97 (1H, s), 8.90 (1H, br s), 8.23 (1H, s), 8.29 (1H, br s)

b) 2-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
In the same manner as in Example 1-e), 2.88 g of the title compound was obtained from 1.11 g of 2-carbamoyl-5-ethynylthiazole.
NMR (DMSO-d ₆ ) δ: 6.06 (1H, d, J = 11 Hz), 6.88 (1H, d, J = 11 Hz), 7.22-7.43 (15H, m), 7.85 (1H, br s), 8.00 (1H, s), 8.16 (1H, br s)

Example 23 2-Amino-5-((Z) -2-tritylthioethen-1-yl) thiazole
a) 2-Amino-5-ethynylthiazole
Add 1.93 ml of tri-n-butylethynyltin and 292 mg of bis (triphenylphosphine) palladium (II) dichloride to 30 ml of xylene suspension of 1.00 g of 2-amino-5-bromothiazole at 80 ° C for 1 hour, 100 ° C For 30 minutes and at 120 ° C. for 30 minutes. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain 1.70 mg of 2-amino-5-ethynylthiazole.
NMR (CDCl ₃ ) δ: 3.30 (1H, s), 5.20 (2H, br s), 7.25 (1H, s)

b) 2-Amino-5-((Z) -2-tritylthioethen-1-yl) thiazole
In the same manner as in Example 1-e), 616 mg of the title compound was obtained from 275 mg of 2-amino-5-ethynylthiazole.
NMR (CDCl ₃ ) δ: 4.93 (2H, br s), 5.56 (1H, d, J = 10.5 Hz), 6.41 (1H, d, J = 10.5 Hz), 7.07 (1H, s), 7.23-7.36 ( 15H, m)

Example 24 2-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
a) 2-N, N-dimethylcarbamoyl-5-ethynylthiazole
According to the same procedure as in Example 4-b), 3.13 g of 2-N, N-dimethylcarbamoyl-5-ethynylthiazole was obtained from 5.69 g of 2-N, N-dimethylcarbamoyl-5-iodothiazole.
NMR (CDCl ₃ ) δ: 3.15 (3H, s), 3.52 (1H, s), 3.58 (3H, s), 7.92 (1H, s)

b) 2-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole
From 2.80 g of 2-N, N-dimethylcarbamoyl-5-ethynylthiazole, 5.27 g of the title compound was obtained in the same manner as in Example 1-e).
NMR (CDCl ₃ ) δ: 3.15 (3H, s), 3.58 (3H, s), 6.08 (1H, d, J = 10.7 Hz), 6.54 (1H, d, J = 10.7 Hz), 7.23-7.34 (15H , m), 7.79 (1H, s)

Example 25 4-carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
a) 2-Bromo-4-carbamoylthiazole
To 1.51 g of 2-bromo-4-ethoxycarbonylthiazole, 10 ml of THF and 20 ml of 30% aqueous ammonia were added and stirred at room temperature for 3 days. The reaction solution was concentrated to obtain 1.31 g of 2-bromo-4-carbamoylthiazole.
NMR (DMSO-d ₆ ) δ: 7.65 (1H, br s), 7.85 (1H, br s), 8.27 (1H, s)

b) 4-carbamoyl-2-ethynylthiazole
From 2.3 g of 2-bromo-4-carbamoylthiazole, 209 mg of 4-carbamoyl-2-ethynylthiazole was obtained in the same manner as in Example 4-b).
NMR (CDCl ₃ ) δ: 3.54 (1H, s), 5.67 (1H, br s), 7.15 (1H, br s), 8.18 (1H, s)

c) 4-carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
In the same manner as in Example 1-e), 417 mg of the title compound was obtained from 209 mg of 4-carbamoyl-2-ethynylthiazole.
NMR (CDCl ₃ ) δ: 5.58 (1H, br s), 6.45 (1H, d, J = 11.1 Hz), 6.59 (1H, d, J = 11.1 Hz), 7.22 (1H, br s), 7.26-7.34 (15H, m), 8.11 (1H, s)

Example 26 4-N- (2-hydroxyethyl) carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 4-methoxycarbonyl-2-obtained in Example 4-c) 443 mg of ((Z) -2-tritylthioethen-1-yl) thiazole was dissolved in 8 ml of THF, 1.2 ml of 2-aminoethanol was added, and the mixture was stirred at 50 ° C. for 8 hours. THF was distilled off under reduced pressure, and water and aqueous hydrochloric acid were added to adjust to pH 2, followed by extraction twice with dichloromethane.
The residue obtained by drying over anhydrous magnesium sulfate, filtration, and concentration under reduced pressure was added with ethyl acetate, and the resulting solid was collected by filtration to give 396 mg of the title compound.
NMR (DMSO-d ₆ ) δ: 3.3-3.6 (4H, m), 4.83 (1H, t, J = 5.4 Hz), 6.43 (1H, d, J = 10.8 Hz), 6.86 (1H, d, J = 10.8 Hz), 7.2-7.4 (15H, m), 8.11 (1H, t, J = 6.0 Hz), 8.28 (1H, s)

Example 27 4-N, N-dimethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4-Carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole 4-methoxycarbonyl-2-((Z) -2-tritylthioethene obtained in Example 4-c) In the same manner as in Example 3-b), 2.33 g of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole was obtained from 2.65 g of 1-yl) thiazole.
NMR (CDCl ₃ ) δ: 6.38 (1H, d, J = 10.8 Hz), 6.85 (1H, d, J = 10.8 Hz), 7.23-7.42 (15H, m), 8.45 (1H, s)

b) 4-N, N-dimethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 4-carboxy-2-((Z)- From 1.32 g of 2-tritylthioethen-1-yl) thiazole and 4.6 ml of 2M-dimethylamine / THF solution, 854 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 3.11 (3H, s), 3.40 (3H, s), 6.39 (1H, d, J = 11.1 Hz), 6.61 (1H, d, J = 11.1 Hz), 7.2-7.4 (15H , m), 7.93 (1H, s)

Example 28 4-N-methylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 4-carboxy-2-((Z) -2 obtained in Example 27-a) -Tritylthioethen-1-yl) thiazole To 625 mg of THF solution was added 0.136 ml of oxalyl dichloride and 3 drops of DMF, and the mixture was stirred at room temperature for 15 minutes. 5 ml of 2M-methylamine / THF solution was added at the same temperature and stirred for 30 minutes, and then 50 ml of ethyl acetate and half-saturated saline were added. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-hexane to obtain 400 mg of the title compound.
NMR (CDCl ₃ ) δ: 3.00 (3H, d, J = 5.1 Hz), 6.43 (1H, d, J = 10.7 Hz), 6.58 (1H, d, J = 10.7 Hz), 7.25-7.35 (15H, m ), 8.06 (1H, s)

Example 29 4-N-cyanomethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
69 mg of the title compound was obtained from 85 mg of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole and 46 mg of aminoacetonitrile sulfate in the same manner as in Example 3-c).
NMR (CDCl ₃ ) δ: 4.34 (2H, d, J = 5.8 Hz), 6.48 (1H, d, J = 10.9 Hz), 6.58 (1H, d, J = 10.9 Hz), 7.25-7.40 (15H, m ), 7.76 (1H, t, J = 6.0 Hz), 8.13 (1H, s)

Example 30 4-N-cyanomethyl-N-methylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
91 mg of the title compound was obtained from 85 mg of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole and 21 mg of N-methylaminoacetonitrile in the same manner as in Example 3-c).
NMR (CDCl ₃ ) δ: 3.20, 3.61 (total 3H, both s), 4.44, 5.38 (total 2H, both s), 6.44 (1H, d, J = 10.9 Hz), 6.56 (1H, d, J = 11.0 Hz), 7.24-7.32 (15H, m), 8.09, 8.18 (total 1H, both s)

Example 31 4-Cyanomethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
From 2.801 g of 4-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole, 2.614 g of the title compound was obtained in the same manner as in Example 2-a) and Example 11.
NMR (CDCl ₃ ) δ: 3.92 (2H, s), 6.40 (1H, d, J = 11.0 Hz), 6.64 (1H, d, J = 10.9 Hz), 7.26-7.38 (15H, m), 8.02 (1H , s)

Example 32 4- (3-Hydroxyazetidin-1-yl) carbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
From 1.300 g of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole and 1.028 g of 3-hydroxyazetidine tartrate, 1.169 g of the title compound was prepared in the same manner as in Example 3-c). Obtained.
NMR (CDCl ₃ ) δ: 4.05 (1H, m), 4.44 (1H, m), 4.65 (2H, m), 5.08 (1H, m), 6.37 (1H, d, J = 11.0 Hz), 6.48 (1H , d, J = 10.9 Hz), 7.25-7.37 (15H, m), 8.09 (1H, s)

Example 33 4- (3-Cyanoazetidin-1-yl) carbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
0.271 g of the title compound was obtained in the same manner as in Example 3-c) from 0.356 g of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole and 0.149 g of 3-cyanoazetidine hydrochloride. .
NMR (CDCl ₃ ) δ: 3.48 (1H, m), 4.39-4.52 (2H, m), 5.14 (2H, m), 6.40 (1H, d, J = 11.0 Hz), 6.48 (1H, d, J = 11.0 Hz), 7.26-7.36 (15H, m), 8.13 (1H, s)

Example 34 5-Hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
a) 5-Ethoxycarbonyl-2-iodothiazole In the same manner as in Example 4-a), 1.10 g of 5-ethoxycarbonyl-2-iodothiazole was obtained from 935 mg of 2-amino-5-ethoxycarbonylthiazole.
NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.2 Hz), 4.36 (2H, q, J = 7.2 Hz), 8.10 (1H, s)

b) 5-Ethoxycarbonyl-2-ethynylthiazole In the same manner as in Example 20-a), 218 mg of 5-ethoxycarbonyl-2-ethynylthiazole was obtained from 997 mg of 5-ethoxycarbonyl-2-iodothiazole.
NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.2 Hz), 3.59 (1H, s), 4.39 (2H, q, J = 7.2 Hz), 8.37 (1H, s)

c) 5-Ethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole In the same manner as in Example 1-e), from 395 mg of 5-ethoxycarbonyl-2-ethynylthiazole, 5-ethoxycarbonyl As a result, 531 mg of -2-((Z) -2-tritylthioethen-1-yl) thiazole was obtained.
NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.2 Hz), 4.38 (2H, q, J = 7.2 Hz), 6.52 (1H, d, J = 11.1 Hz), 6.69 (1H, d, J = 11.1 Hz), 7.2-7.4 (15H, m), 8.40 (1H, s)

d) 5-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
A solution of 5-ethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 257 mg in THF 10 ml was ice-cooled, and 1.069 ml of a 1.0 M diisobutylaluminum hydride / toluene solution was added dropwise under an argon atmosphere. . After stirring at room temperature for 2 hours, water was added to the reaction mixture, and the pH was adjusted to 2.5 with 1N hydrochloric acid. Insoluble material was removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined and washed with brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (234 mg).
NMR (CDCl ₃ ) δ: 4.90 (2H, s), 6.33 (1H, d, J = 11.1 Hz), 6.64 (1H, d, J = 11.1 Hz), 7.2-7.4 (15H, m), 7.70 (1H , s)

Example 35 4,5-Dicarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4,5-Diethoxycarbonyl-2-iodothiazole In the same manner as in Example 4-a), from 900 mg of 2-amino-4,5-diethoxycarbonylthiazole, 4,5-diethoxycarbonyl-2-iodothiazole 662 mg was obtained.
NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.2 Hz), 1.40 (3H, t, J = 7.2 Hz), 4.36 (2H, q, J = 7.2 Hz), 4.44 (2H, q, J = 7.2 Hz)

b) 4,5-Diethoxycarbonyl-2-ethynylthiazole 1.16 g of 4,5-diethoxycarbonyl-2-iodothiazole in the same manner as in Example 4-b) except that ethanol was used instead of methanol as the solvent. From this, 539 mg of 4,5-diethoxycarbonyl-2-ethynylthiazole was obtained.
NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.2 Hz), 1.41 (3H, t, J = 7.2 Hz), 3.60 (1H, s), 4.38 (2H, q, J = 7.2 Hz), 4.45 (2H, q, J = 7.2 Hz)

c) 4,5-diethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 4,5-diethoxycarbonyl-2-ethynylthiazole as in Example 1-e) From 389 mg, 440 mg of 4,5-diethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole was obtained.
NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.2 Hz), 1.41 (3H, t, J = 7.2 Hz), 4.38 (2H, q, J = 7.2 Hz), 4.45 (2H, q, J = 7.2 Hz), 6.58 (1H, d, J = 11.1 Hz), 6.77 (1H, d, J = 11.1 Hz), 7.2-7.4 (15H, m)

d) 4,5-Dicarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 4,5-diethoxycarbonyl-2 as in Examples 3-b) and 3-c) 102 mg of the title compound was obtained from 200 mg of-((Z) -2-tritylthioethen-1-yl) thiazole and 3 ml of 0.5 M ammonia / dioxane solution.
NMR (DMSO-d ₆ ) δ: 6.58 (1H, d, J = 11.1 Hz), 6.80 (1H, d, J = 11.1 Hz), 7.2-7.4 (15H, m), 8.04 (1H, br s), 8.11 (1H, br s), 8.34 (1H, br s), 10.47 (1H, br s)

Example 36 4-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4-Ethynylthiazole To 100 ml of a THF suspension of 7.27 g of potassium-t-butoxide under ice cooling, 9.83 g of bromomethyltriphenylphosphonium bromide was added and stirred at the same temperature for 10 minutes. 2.44 g was added. After stirring at room temperature for 2 hours, 100 ml each of ethyl acetate and half-saturated saline was added, and the organic layer after separation was washed with half-saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane: hexane = 3: 2) to obtain 614 mg of 4-ethynylthiazole. .
NMR (CDCl ₃ ) δ: 3.15 (1H, s), 7.58 (1H, d, J = 2.0 Hz), 8.78 (1H, d, J = 2.0 Hz)

b) 4-((Z) -2-tritylthioethen-1-yl) thiazole
From 561 mg of 4-ethynylthiazole, 1.22 g of the title compound was obtained in the same manner as in Example 1-e).
NMR (CDCl ₃ ) δ: 6.10 (1H, d, J = 11.2 Hz), 6.54 (1H, d, J = 11.2 Hz), 7.09-7.34 (15H, m), 7.47 (1H, s), 8.80 (1H , s)

Example 37 2-carbamoyl-4-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4-Bromo-2-carbamoylthiazole
1.61 ml of oxalyl dichloride was added to 100 ml of a mixed solution of 4-bromo-2-carboxythiazole in THF-dichloromethane 2: 1, and the mixture was stirred at 60 ° C. for 2 hours. Under ice-cooling, 15 ml of 30% aqueous ammonia was added to the reaction solution and stirred at the same temperature for 30 minutes. 50 ml each of ethyl acetate and half-saturated saline was added, and the separated organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: methanol = 40: By purification in 1), 1.36 g of 4-bromo-2-carbamoylthiazole was obtained.
NMR (DMSO-d ₆ ) δ: 7.98 (1H, br s), 8.16 (1H, s), 8.33 (1H, br s)

b) 2-carbamoyl-4-ethynylthiazole
694 mg of 2-carbamoyl-4-ethynylthiazole was obtained from 1.22 g of 4-bromo-2-carbamoylthiazole in the same manner as in Example 4-b).
NMR (DMSO-d ₆ ) δ: 7.98 (1H, br s), 8.16 (1H, s), 8.33 (1H, br s)

c) 2-carbamoyl-4-((Z) -2-tritylthioethen-1-yl) thiazole
The title compound (1.38 g) was obtained from 597 mg of 2-carbamoyl-4-ethynylthiazole in the same manner as in Example 1-e).
NMR (CDCl ₃ ) δ: 5.55 (1H, br s), 6.16 (1H, d, J = 11.0 Hz), 6.43 (1H, d, J = 11.0 Hz), 7.25-7.36 (15H, m), 7.61 ( 1H, s)

Example 38 5-Hydroxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole
a) 4-Ethoxycarbonyl-5-hydroxymethylthiazole
7.13 g of 4,5-diethoxycarbonylthiazole was dissolved in 100 ml of ethanol, and 2.20 g of sodium borohydride was added under an argon atmosphere under ice cooling, followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, 1N hydrochloric acid was added to adjust the pH to 4.5, and then the organic solvent was distilled off under reduced pressure. The remaining aqueous solution was extracted five times with chloroform, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, ethyl acetate and hexane were added to the resulting residue, and the resulting solid was collected by filtration to give 4-ethoxycarbonyl. 2.29 g of -5-hydroxymethylthiazole was obtained.
NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.2 Hz), 3.65 (1H, t, br t), 4.47 (2H, q, J = 7.2 Hz), 5.09 (2H, d, J = 5.1 Hz), 8.69 (1H, s)

b) 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole
282 mg of 4-ethoxycarbonyl-5-hydroxymethylthiazole was dissolved in 5 ml of DMF, 123 mg of imidazole and 250 mg of t-butyldimethylsilyl chloride were added under ice cooling under an argon atmosphere, and the mixture was stirred at room temperature for 1.5 hours. Brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 5-t-butyldimethylsilyloxymethyl-4- 374 mg of ethoxycarbonylthiazole was obtained.
NMR (CDCl ₃ ) δ: 0.14 (6H, s), 0.95 (9H, s), 1.43 (3H, t, J = 7.2 Hz), 4.42 (2H, q, J = 7.2 Hz), 5.23 (2H, s ), 8.66 (1H, s)

c) 5-t-butyldimethylsilyloxymethyl-4-formylthiazole
To a 10 ml toluene solution of 578 mg of 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole, 2.4 ml of a 1.0 M diisobutylaluminum hydride / toluene solution was added dropwise at −60 ° C. in an argon atmosphere. After stirring at the same temperature for 2 hours, water and ethyl acetate were added to the reaction solution, and the pH was adjusted to 5.5 with 1N aqueous hydrochloric acid. Insoluble material was removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined and washed with brine. The residue obtained after drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to ethyl acetate only) to give 5-t-butyldimethylsilyloxy. 308 mg of methyl-4-formylthiazole was obtained.
NMR (CDCl ₃ ) δ: 0.14 (6H, s), 0.95 (9H, s), 5.24 (2H, s), 8.70 (1H, s), 10.17 (1H, s)

d) 5-t-butyldimethylsilyloxymethyl-4-ethynylthiazole As in Example 36-a), 5-t-butyldimethylsilyloxyl from 104 mg of 5-t-butyldimethylsilyloxymethyl-4-formylthiazole 47 mg of methyl-4-ethynylthiazole was obtained.
NMR (CDCl ₃ ) δ: 0.12 (6H, s), 0.92 (9H, s), 3.31 (1H, s), 4.98 (2H, s), 8.65 (1H, s)

e) 5-t-butyldimethylsilyloxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole In the same manner as in Example 1-e), 5-t-butyldimethylsilyloxymethyl- From 165 mg of 4-ethynylthiazole, 392 mg of 5-t-butyldimethylsilyloxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole was obtained.
NMR (CDCl ₃ ) δ: 0.06 (6H, s), 0.89 (9H, s), 4.84 (2H, s), 6.07 (1H, d, J = 11.1 Hz), 6.17 (1H, d, J = 11.1 Hz ), 7.2-7.4 (15H, m), 8.76 (1H, m)

f) 5-hydroxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole
392 mg of 5-t-butyldimethylsilyloxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole was dissolved in 10 ml of THF, 0.7 ml of 5N hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours. . Brine was added to the reaction solution, and the pH was adjusted to 8 with sodium bicarbonate water, followed by extraction twice with ethyl acetate and washing with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (5 ml) and hexane (5 ml) were added to the resulting residue, and the resulting solid was collected by filtration to give the title compound (180 mg).
NMR (DMSO-d ₆ ) δ: 4.65 (2H, d, J = 5.4 Hz), 5.57 (1H, t, J = 5.4 Hz), 5.91 (1H, d, J = 10.8 Hz), 6.39 (1H, d , J = 10.8 Hz), 7.2-7.4 (15H, m), 9.05 (1H, s)

Example 39 4-Ethoxycarbonyl-5- (2-trimethylsilylethynyl) thiazole
a) 2-Amino-5-bromo-4-ethoxycarbonylthiazole In the same manner as in Example 1-a), 43.05 g of 2-amino-4-ethoxycarbonylthiazole and 48.95 g of N-bromosuccinimide were used to give 2-amino- 46.27 g of 5-bromo-4-ethoxycarbonylthiazole was obtained.
NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.1 Hz), 4.36 (2H, q, J = 7.1 Hz), 6.05 (H, br s)

b) 5-bromo-4-ethoxycarbonylthiazole In the same manner as in Example 1-b), 31.31 g of 5-bromo-4-ethoxycarbonylthiazole was obtained from 48.65 g of 2-amino-5-bromo-4-ethoxycarbonylthiazole. Obtained.
NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.1 Hz), 4.46 (2H, q, J = 7.1 Hz), 8.79 (1H, s)

c) 4-Ethoxycarbonyl-5- (2-trimethylsilylethynyl) thiazole
Dissolve 18.64 g of 5-bromo-4-ethoxycarbonylthiazole in 80 ml of DMF, add 22 ml of triethylamine, 16.7 ml of ethynyltrimethylsilane, 960 mg of copper (I) iodide, and 1.11 g of bis (triphenylphosphine) palladium (II) dichloride sequentially. The mixture was stirred at 90 ° C. for 1 hour under an argon atmosphere. Water (80 ml), ethyl acetate (160 ml) and hexane (160 ml) were added to the reaction mixture, and the mixture was washed successively with (brine + aqueous hydrochloric acid), aqueous sodium bicarbonate, and brine. Activated carbon and anhydrous magnesium sulfate were added to the organic layer, which was filtered and concentrated under reduced pressure to obtain 16.45 g of the title compound.
NMR (CDCl ₃ ) δ: 0.29 (9H, s), 1.44 (3H, t, J = 7.2 Hz), 4.45 (2H, q, J = 7.2 Hz), 8.65 (1H, s)

Example 40 4-Ethoxycarbonyl-5-ethynylthiazole
1.45 g of 4-ethoxycarbonyl-5-iodothiazole is dissolved in 25 ml of N-methyl-2-pyrrolidinone and 1.78 ml of tri-n-butylethynyltin, 143 mg of tri (2-furyl) phosphine, tris (di Benzylideneacetone) dipalladium (0) (143 mg) and zinc chloride (1.43 g) were added and the mixture was stirred at room temperature for 40 minutes. Brine and ethyl acetate were added to the reaction solution, insolubles were filtered off through celite, the filtrate was extracted twice with ethyl acetate, and the organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 750 mg of the title compound.
NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 3.86 (1H, s), 4.47 (2H, q, J = 7.2 Hz), 8.70 (1H, s)

Example 41 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium
a) 4-hydroxymethyl-5-((Z) -2-mercaptoethen-1-yl) thiazole silver salt
Add 0.511 ml of pyridine and 6.6 ml of 1N silver nitrate aqueous solution to 50 ml of THF solution of 2.5 g of 4-hydroxymethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 1 for 30 minutes at room temperature. And stirred. The precipitated solid was collected by filtration, washed successively with 50 ml of acetone, 150 ml of 50% acetone-water, and 100 ml of acetone to give a crude 4-hydroxymethyl-5-[(Z) -2-mercaptoethen-1-yl] thiazole silver salt. 2.15 g (78% purity) of crystals were obtained.

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] 4-nitrobenzyl thio] -1-methyl-1-carbapene-2-em-3-carboxylate
(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl 599 mg Into 10 ml of dry acetone solution of 4 mg of 4-hydroxymethyl-5-[(Z) -2-mercaptoethen-1-yl] thiazole silver crystals, and then 303 mg of sodium iodide at 4 ° C. under an argon atmosphere It was. After stirring for 18 hours at the same temperature, 20 ml each of ethyl acetate and half-saturated brine was added, and the mixture was filtered through celite and washed with ethyl acetate. After the filtrate was separated, the organic layer was washed with half-saturated saline. The extract was dried over anhydrous magnesium sulfate and filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[( Z) -2- (4-Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl 298 mg was obtained.
NMR (DMSO-d ₆ ) δ: 1.09 (3H, d, J = 7.3 Hz), 1.15 (3H, d, J = 6.3 Hz), 3.36 (1H, dd, J ₁ = 6.1 Hz, J ₂ = 2.9 Hz ), 3.83 (1H, m), 4.00 (1H, m), 4.26 (1H, dd, J ₁ = 10.0 Hz, J ₂ = 3.0 Hz), 4.67 (2H, d, J = 4.6 Hz), 5.12 (1H , d, J = 5.4 Hz), 5.29-5.38 (2H, m), 5.51 (1H, d, J = 13.8 Hz), 6.86 (1H, d, J = 10.5 Hz), 7.33 (1H, d, J = 10.5 Hz), 7.75 (2H, d, J = 8.7 Hz), 8.25 (2H, d, J = 8.7 Hz), 9.04 (1H, s)

c) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylate
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1-Methyl-1-carbapene-2-em-3-carboxylate 4-nitrobenzyl 957 mg of 1/15 M sodium phosphate buffer (pH 6.8) 40 ml, THF 40 ml solution with 10% Pd-C (hydrous, (Moisture 53%) 1.42 g was added, and the mixture was stirred under a hydrogen atmosphere for 1.5 hours. 10% palladium carbon was filtered and washed with water, and saturated aqueous sodium hydrogen carbonate was added to the filtrate to adjust to pH 6.6. The resultant was washed with 40 ml of ethyl acetate, the aqueous layer was concentrated to about 5 ml, and purified by column chromatography (2% aqueous methanol) of Cosmosil 40C18-PREP to obtain 360 mg of the title compound.
NMR (DMSO-d ₆ ) δ: 0.98 (3H, d, J = 7.3 Hz), 1.15 (3H, d, J = 6.4 Hz), 3.08 (1H, dd, J ₁ = 6.8 Hz, J ₂ = 2.7 Hz ), 3.38-3.51 (1H, m), 3.84-3.96 (1H, m), 4.02 (1H, dd, J ₁ = 9.7 Hz, J ₂ = 2.7 Hz), 4.64 (2H, d, J = 5.6 Hz) , 5.00 (1H, d, J = 5.1 Hz), 5.24 (1H, t, J = 5.6 Hz), 6.80 (1H, d, J = 10.7 Hz), 7.04 (1H, d, J = 10.7 Hz), 8.99 (1H, s)

Example 42 (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium
a) 4- (2-hydroxyethoxy) methyl-5-((Z) -2-mercaptoethen-1-yl) thiazole silver salt 4- (2-hydroxyethoxy) methyl-5- ( 4- (2-hydroxyethoxy) methyl-5-((Z) -2-mercaptoethene- was prepared by the same procedure as Example 41-a) from 4.83 g of (Z) -2-tritylthioethen-1-yl) thiazole. 1.97 g (purity 85%) of 1-yl) thiazole silver salt was obtained.

b) (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-6 4- (Nitrobenzyl)-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylate
(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylic acid 4-nitro Crude crystals of 4- (2-hydroxyethoxy) methyl-5-((Z) -2-mercaptoethen-1-yl) thiazole silver salt in 60 ml of a dry acetonitrile solution of 6.20 g of benzyl at room temperature under an argon atmosphere 3.97 g followed by 3.30 g sodium iodide. After stirring at the same temperature for 18 hours, 200 ml each of ethyl acetate and half-saturated brine was added, filtered through Celite, and washed with ethyl acetate. After the filtrate was separated, the organic layer was washed with half-saturated saline. The extract was dried over anhydrous magnesium sulfate and filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy ) Methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylic acid 4- 4.17 g of nitrobenzyl was obtained.
NMR (CDCl ₃ ) δ: 0.61 (6H, q, J = 7.5 Hz), 0.95 (9H, t, J = 7.5 Hz), 1.20 (3H, d, J = 7.5 Hz), 1.27 (3H, d, J = 6.3 Hz), 3.29 (1H, dd, J ₁ = 5.7 Hz, J ₂ = 2.7 Hz), 3.45-3.6 (1H, m), 3.65-3.7 (2H, m), 3.7-3.8 (2H, m) , 4.2-4.35 (2H, m), 4.81 (2H, s), 5.29 (1H, d, J = 13.8 Hz), 5.50 (1H, d, J = 13.8 Hz), 6.54 (1H, d, J = 10.2 Hz), 7.17 (1H, d, J = 10.2 Hz), 7.67 (2H, d, J = 8.7 Hz), 8.22 (2H, d, J = 8.7 Hz), 8.77 (1H, s)

c) (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6-((1R ) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate
(1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-6- ( (1R) -1-Triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl (3.82 g) was dissolved in 170 ml of THF and 70 ml of water, and 2.8 ml of 1N-hydrochloric acid was added at room temperature. Stir for 50 minutes. After adding saturated sodium bicarbonate water to the reaction solution to adjust the pH to 3.0, 170 ml of 1/15 M sodium phosphate buffer (pH 6.8) and 3.10 g of 10% Pd-C (containing water, water 53%) were added, and hydrogen was added. Stir for 1.5 hours under atmosphere. 10% Pd—C was filtered and washed with water, and saturated aqueous sodium hydrogen carbonate was added to the filtrate to adjust to pH 7.0. The resultant was washed with 300 ml of ethyl acetate, the aqueous layer was concentrated to about 20 ml, and purified by column chromatography (5% aqueous methanol) of Cosmosil 40C18-PREP to obtain 1.91 g of the title compound.
NMR (DMSO-d ₆ ) δ: 0.99 (3H, d, J = 7.2 Hz), 1.15 (3H, d, J = 6.3 Hz), 3.11 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.4 Hz ), 3.4-3.6 (5H, m), 3.8-4.0 (1H, m), 4.05 (1H, dd, J ₁ = 9.6 Hz, J ₂ = 2.4 Hz), 4.6-4.7 (3H, m), 5.0- 5.1 (1H, m), 6.84 (1H, d, J = 10.8 Hz), 7.01 (1H, d, J = 10.8 Hz), 9.02 (1H, s)

Example 43 (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-(( 1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium
a) 4-N, N-dimethylcarbamoyl-5-((Z) -2-mercaptoethen-1-yl) thiazole silver salt 4-N, N-dimethylcarbamoyl-5-((Z 4-N, N-carbamoyl-5-((Z) -2-mercaptoethen-1-yl) in the same manner as in Example 41-a) from 6.54 g of) -2-tritylthioethen-1-yl) thiazole 5.73 g of crude thiazole silver salt (purity 80%) was obtained.

b) (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl
(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl 8.51 In a solution of 100 g of dry acetonitrile, 5.73 g of a crude crystal of 4-N, N-dimethylcarbamoyl-5-((Z) -2-mercaptoethen-1-yl) thiazole silver salt at room temperature under an argon atmosphere, Then 4.29 g of sodium iodide was added. After stirring at the same temperature for 13 hours, 300 ml of ethyl acetate and 200 ml of half-saturated saline were added, and the mixture was filtered through celite and washed with ethyl acetate. After the filtrate was separated, the organic layer was washed with half-saturated saline. The extract was dried over anhydrous magnesium sulfate and filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1-20: 1) to give (1R, 5S, 6S) -2-[[(Z) -2- (4-N , N-Dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid 4 -4.60 g of nitrobenzyl was obtained.
NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.3 Hz), 1.37 (3H, d, J = 6.3 Hz), 3.03 (3H, s), 3.14 (3H, s), 3.33 (1H, dd , J ₁ = 6.7 Hz, J ₂ = 2.8 Hz), 3.53-3.63 (1H, m), 4.23-4.33 (2H, m), 5.29 (1H, d, J = 13.9 Hz), 5.55 (1H, d, J = 13.9 Hz), 6.56 (1H, d, J = 10.5 Hz), 7.40 (1H, d, J = 10.5 Hz), 7.69 (2H, d, J = 8.8 Hz), 8.24 (2H, d, J = 8.8 Hz), 8.75 (1H, s)

c) (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate
(1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 2.25 g of the title compound was obtained in the same manner as in Example 41-c) from 4.60 g of 4-hydroxybenzyl 4-hydroxyethyl) -1-methyl-1-carbapent-2-em-3-carboxylate.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.14 (3H, d, J = 7.2 Hz), 1.29 (3H, d, J = 6.3 Hz), 2.97 (3H, s), 3.15 (3H, s ), 3.47 (1H, dd, J ₁ = 6.2 Hz, J ₂ = 2.6 Hz), 3.57-3.67 (1H, m), 4.21-4.29 (2H, m), 6.94 (1H, d, J = 10.5 Hz) , 6.97 (1H, d, J = 10.5 Hz), 9.04 (1H, s)

Example 44 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-2-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 4-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) obtained in Example 4 90.7 mg of the title compound was obtained from 370 mg of thiazole in the same manner as in Example 42.
N MR (D ₂ O) δ (HOD = 4.80 ppm): 1.15 (3H, d, J = 6.9 Hz), 1.28 (3H, d, J = 6.3 Hz), 3.4-3.5 (1H, m), 3.6- 3.7 (1H, m), 4.2-4.3 (2H, m), 4.71 (2H, s), 7.00 (1H, d, J = 10.8 Hz), 7.14 (1H, d, J = 10.8 Hz), 7.52 (1H , s)

Example 45 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-methylthiazol-5-yl) ethene -1-yl] thio] -1-carbapene-2-em-3-carboxylate sodium 4-methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 1.95 obtained in Example 5 From 240 g, 240 mg of the title compound was obtained in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.11 (3H, d, J = 7.4 Hz), 1.25 (3H, d, J = 6.6 Hz), 2.45 (3H, s), 3.41 (1H, dd , J ₁ = 6.2 Hz, J ₂ = 2.6 Hz), 3.51-3.60 (1H, m), 4.15-4.28 (2H, m), 6.65 (1H, d, = 10.5 Hz), 7.05 (1H, d, J = 10.5 Hz), 8.88 (1H, s)

Example 46 (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole 2.03 obtained in Example 6 287 mg of the title compound was obtained from g in the same manner as in Example 42.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.15 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 3.47 (1H, dd, J ₁ = 6.1 Hz, J ₂ = 2.7 Hz), 3.60-3.71 (1H, m), 4.21-4.30 (2H, m), 6.97 (1H, d, = 10.7 Hz), 7.78 (1H, d, J = 10.7 Hz), 8.95 ( 1H, s)

Example 47 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-N-methylcarbamoylthiazole-5- Yl) ethen-1-yl] thio] -1-carbapene-2-em-3-carboxylate 4-N-methylcarbamoyl-5-((Z) -2-tritylthioethene- obtained in Example 7 In the same manner as in Example 42, 86 mg of the title compound was obtained from 394 mg of 1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.00 (3H, d, J = 7.1 Hz), 1.15 (3H, d, J = 6.3 Hz), 2.80 (3H, s), 3.32 (1H, d , J = 3.7 Hz), 3.48-3.52 (1H, m), 4.07-4.12 (2H, m), 6.80 (1H, d, = 10.7 Hz), 7.61 (1H, d, J = 10.7 Hz), 8.79 ( 1H, s)

Example 48 (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethyl-N-methylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6 ((1R) -1-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4-N-cyanomethyl-N-methylcarbamoyl-5-((Z 487 mg of the title compound was obtained from 1.24 g of) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.00 (3H, d, J = 7.3 Hz), 1.15 (3H, d, J = 6.3 Hz), 2.98, 3.10 (total 3H, both s), 3.33 (1H, dd, J ₁ = 6.1 Hz, J ₂ = 2.7 Hz), 3.43-3.53 (1H, m), 4.07-4.15 (2H, m), 4.32, 4.47 (total 2H, both s), 6.75-6.96 (2H, m), 8.91-8.93 (1H, m)

Example 49 (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R ) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylate example obtained in 9 4-N-cyanomethylcarbamoyl -5 - ((Z) -2-tritylthio In the same manner as in Example 43, 487 mg of the title compound was obtained from 1.24 g of ethen-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.00 (3H, d, J = 7.3 Hz), 1.16 (3H, d, J = 6.4 Hz), 3.33 (1H, dd, J ₁ = 6.1 Hz, J ₂ = 2.7 Hz), 3.46-3.56 (1H, m), 4.07-4.15 (2H, m), 4.26 (2H, s), 6.87 (1H, d, = 10.7 Hz), 7.67 (1H, d, J = 10.7 Hz), 8.79 (1H, s)

Example 50 (1R, 5S, 6S) -2-[[(Z) -2- [4-N- (2-cyanoethyl) carbamoylthiazol-5-yl] ethen-1-yl] thio] -6 Sodium ((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 4-N- (2-cyanoethyl) carbamoyl-5-((Z 183 mg of the title compound was obtained from 415 mg of) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.15 (3H, d, J = 7.5 Hz), 1.31 (3H, d, J = 6.3 Hz), 2.8-2.9 (2H, m), 3.48 (1H , dd, J ₁ = 6.0 Hz, J ₂ = 2.4 Hz), 3.6-3.8 (3H, m), 4.2-4.3 (2H, m), 6.98 (1H, d, J = 10.5 Hz), 7.77 (1H, d, J = 10.5 Hz), 8.95 (1H, s)

Example 51 (1R, 5S, 6S) -2-[[(Z) -2- (4-cyanomethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 -Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 4-cyanomethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 11 From 305 mg, 117 mg of the title compound was obtained in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.15 (3H, d, J = 6.9 Hz), 1.32 (3H, d, J = 6.3 Hz), 3.48 (1H, dd, J ₁ = 6.3 Hz, J ₂ = 3.0 Hz), 3.55-3.7 (1H, m), 4.16 (2H, s), 4.2-4.3 (2H, m), 6.85 (1H, d, J = 10.5 Hz), 6.98 (1H, d, J = 10.5 Hz), 9.00 (1H, s)

Example 52 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4- (2-methoxyethoxy) methylthiazol-5-yl ] Ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4- (2-methoxyethoxy) methyl-5-((Z)- In the same manner as in Example 43, 159 mg of the title compound was obtained from 434 mg of 2-tritylthioethen-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.16 (3H, d, J = 7.2 Hz), 1.32 (3H, d, J = 6.3 Hz), 3.38 (3H, s), 3.45-3.5 (1H , m), 3.6-3.7 (2H, m), 3.7-3.8 (2H, m), 4.2-4.3 (2H, m), 6.82 (1H, d, J = 10.5 Hz), 7.18 (1H, d, J = 10.5 Hz), 8.99 (1H, s)

Example 53 (1R, 5S, 6S) -2-[[(Z) -2- [4- (3-cyanoazetidin-1-yl) carbonylthiazol-5-yl] ethen-1-yl] thio]- 6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid sodium 4- (3-cyanoazetidin-1-yl) carbonyl-5 obtained in Example 13 63 mg of the title compound was obtained from 694 mg of-((Z) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.00 (3H, d, J = 7.1 Hz), 1.15 (3H, d, J = 6.4 Hz), 3.32-3.34 (1H, m), 3.46-3.54 (1H, m), 3.64-3.72 (1H, m), 4.07-4.14 (2H, m), 4.30-4.44 (2H, m), 4.48-4.58 (2H, m), 6.84 (1H, d, J = 10.5 Hz), 7.31 (1H, d, J = 10.5 Hz), 8.84 (1H, s)

Example 54 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthiazole-5 -Yl] ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4-N- (2-hydroxyethyl) carbamoyl-5- (obtained in Example 14 In the same manner as in Example 42, 289 mg of the title compound was obtained from 870 mg of (Z) -2-tritylthioethen-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.04 (3H, d, J = 7.2 Hz), 1.19 (3H, d, J = 6.3 Hz), 3.34-3.38 (1H, m), 3.43-3.47 (2H, m), 3.50-3.56 (1H, m), 3.65-3.70 (2H, m), 4.10-4.15 (2H, m), 6.85 (1H, d, = 10.5 Hz), 7.65 (1H, d, J = 10.5 Hz), 8.83 (1H, s)

Example 55 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (3-hydroxypropan-1-yl) Carbamoylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 4-N- (3-hydroxypropane-1 obtained in Example 15 In the same manner as in Example 42, 284 mg of the title compound was obtained from 643 mg of -yl) carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.15 (3H, d, J = 7.2 Hz), 1.32 (3H, d, J = 6.6 Hz), 1.8-2.0 (2H, m), 3.4-3.55 (3H, m), 3.6-3.8 (3H, m), 3.7-3.8 (2H, m), 4.2-4.35 (2H, m), 6.93 (1H, d, J = 10.5 Hz), 7.74 (1H, d , J = 10.5 Hz), 8.92 (1H, s)

Example 56 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) -N-methyl Carbamoylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4-N- (2-hydroxyethyl) -obtained in Example 16 105 mg of the title compound was obtained from 628 mg of N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 42.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 0.99 (3H, d, J = 6.8 Hz), 1.15 (3H, d, J = 6.1 Hz), 2.85, 3.03 (total 3H, both s), 3.29 -3.33 (2H, m), 3.45-3.50 (2H, m), 3.58-3.62 (1H, m), 3.73-3.77 (1H, m), 4.09-4.13 (2H, m), 6.72-6.77 (1H, m), 6.84 (1H, d, J = 10.5 Hz), 8.89, 8.91 (total 1H, both s)

Example 57 (1R, 5S, 6S) -2-[[(Z) -2- [4- (azetidin-1-yl) carbonylthiazol-5-yl] ethen-1-yl] thio] -6 Sodium ((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylate 4- (azetidin-1-yl) carbonyl-5-((Z 230 mg of the title compound was obtained from 569 mg of) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 0.98 (3H, d, J = 7.6 Hz), 1.15 (3H, d, J = 6.4 Hz), 2.13-2.27 (2H, m), 3.31 (1H , dd, J ₁ = 6.4 Hz, J ₂ = 2.7 Hz), 3.42-3.53 (1H, m), 4.00-4.18 (6H, m), 6.77 (1H, d, = 10.8 Hz), 7.14 (1H, d , J = 10.8 Hz), 8.82 (1H, s)

Example 58 (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-hydroxyazetidin-1-yl) carbonylthiazol-5-yl) ethen-1-yl] thio ] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid sodium 4- (3-hydroxyazetidin-1-yl obtained in Example 18 0.282 g of the title compound was obtained from 0.742 g of carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 42.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 0.98 (3H, d, J = 7.4 Hz), 1.14 (3H, d, J = 6.4 Hz), 3.31 (1H, dd, J ₁ = 6.0 Hz, J ₂ = 2.6 Hz), 3.49 (1H, m), 3.88 (1H, m), 4.02 (1H, m), 4.10 (2H, m), 4.34 (2H, m), 4.54 (1H, m), 6.78 (1H, 2d, J = 10.6 Hz), 7.17 (1H, 2d, J = 10.5 Hz), 8.81 (1H, s)

Example 59 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4- (3-hydroxypropan-1-yloxy) methylthiazole -5-yl] ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylate 4- (3-hydroxypropan-1-yloxy) methyl obtained in Example 19 210 mg of the title compound was obtained from 903 mg of -5-((Z) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 42.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.10 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.75-1.85 (2H, m), 3.4-3.5 (1H, m), 3.5-3.7 (5H, m), 4.15-4.3 (2H, m), 4.68 (2H, s), 6.75 (1H, d, J = 10.2 Hz), 7.69 (1H, d, J = 10.2 Hz), 8.92 (1H, s)

Example 60 (1R, 5S, 6S) -2-[[(Z) -2- (2-amino-4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R ) -1-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 2-amino-4-carbamoyl-5-((Z) -2-tritylthio obtained in Example 20 In the same manner as in Example 42, 37 mg of the title compound was obtained from 182 mg of ethene-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.15 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3 Hz), 3.42 (1H, dd, J ₁ = 6.0 Hz, J ₂ = 2.7 Hz), 3.45-3.6 (1H, m), 4.15-4.3 (2H, m), 6.51 (1H, d, J = 10.5 Hz), 7.67 (1H, d, J = 10.5 Hz)

Example 61 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(E) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 4-hydroxymethyl-5-((E) -2-tritylthioethen-1-yl) obtained in Example 21 36 mg of the title compound was obtained from 330 mg of thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.01 (3H, d, J = 7.1 Hz), 1.14 (3H, d, J = 6.0 Hz), 3.27-3.31 (1H, m), 3.40-3.58 (1H, m), 4.05-4.14 (2H, m), 4.60 (2H, s), 6.81 (1H, d, J = 15.3 Hz), 7.03 (1H, d, J = 15.4 Hz), 8.67 (1H, s)

Example 62 (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylate example 22 obtained in 2-carbamoyl -5 - ((Z) -2-tritylthiopyrrolidine ethene-1-yl) thiazole 2.88 158 mg of the title compound was obtained from g in the same manner as in Example 42.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.14 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.6 Hz), 3.48 (1H, dd, J ₁ = 6.1 Hz, J ₂ = 2.7 Hz), 3.59-3.70 (1H, m), 4.22-4.30 (2H, m), 6.90 (1H, d, = 10.5 Hz), 7.12 (1H, d, J = 10.5 Hz), 8.03 ( 1H, s)

Example 63 (1R, 5S, 6S) -2-[[(Z) -2- (2-aminothiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 2-amino-5-((Z) -2-tritylthioethen-1-yl) thiazole 596 mg obtained in Example 23 39 mg of the title compound was obtained in the same manner as in Example 42.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.13 (3H, d, J = 7.3 Hz), 1.29 (3H, d, J = 6.3 Hz), 3.45-3.60 (2H, m), 4.14-4.30 (2H, m), 6.25 (1H, d, = 9.5 Hz), 7.03 (1H, d, J = 9.5 Hz), 7.22 (1H, s)

Example 64 (1R, 5S, 6S) -2-[[(Z) -2- (2-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-(( 1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 2-N, N-dimethylcarbamoyl-5-((Z) -2- In the same manner as in Example 43, 295 mg of the title compound was obtained from 3.15 g of tritylthioethen-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 0.99 (3H, d, J = 7.3 Hz), 1.15 (3H, d, J = 6.6 Hz), 3.06 (3H, s), 3.20 (3H, s ), 3.32 (1H, dd, J ₁ = 6.1 Hz, J ₂ = 2.6 Hz), 3.43-3.52 (1H, m), 4.06-4.15 (2H, m), 6.72 (1H, d, = 10.5 Hz), 6.96 (1H, d, J = 10.5 Hz), 7.85 (1H, s)

[Example 65] (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1- Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4-carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 92 mg obtained in Example 25 In the same manner as in Example 43, 24 mg of the title compound was obtained.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.19 (3H, d, J = 7.3 Hz), 1.31 (3H, d, J = 6.3 Hz), 3.50 (1H, dd, J ₁ = 6.1 Hz, J ₂ = 2.7 Hz), 3.70-3.81 (1H, m), 4.23-4.32 (1H, m), 6.96 (1H, d, J = 10.7 Hz), 7.24 (1H, d, J = 10.7 Hz), 8.24 (1H, s)

Example 66 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthiazole-2 - yl] ethene-1-yl] thio] -1-methyl-1-carbapen-2-em-3-4-N-(2-hydroxyethyl) obtained in carboxylic acid sodium example 26-carbamoyl-2- ( In the same manner as in Example 43, 75 mg of the title compound was obtained from 371 mg of (Z) -2-tritylthioethen-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.15 (3H, d, J = 7.5 Hz), 1.27 (3H, d, J = 6.3 Hz), 3.4-3.6 (3H, m), 3.65-3.8 (3H, m), 4.2-4.3 (2H, m), 6.93 (1H, d, J = 11.1 Hz), 7.19 (1H, d, J = 11.1 Hz), 8.17 (1H, s)

Example 67 (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-(( 1R) -1-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4-N, N-dimethylcarbamoyl-2-((Z) -2- In the same manner as in Example 43, 273 mg of the title compound was obtained from 854 mg of tritylthioethen-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.80ppm): 1.19 (3H, d, J = 6.9 Hz), 1.32 (3H, d, J = 6.3 Hz), 3.14 (3H, s), 3.23 (3H, s ), 3.5-3.55 (1H, m), 3.7-3.8 (1H, m), 4.2-4.35 (2H, m), 7.00 (1H, d, J = 10.5 Hz), 7.24 (1H, d, J = 10.5 Hz), 7.98 (1H, s)

Example 68 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-N-methylcarbamoylthiazole-2- Yl) ethen-1-yl] thio] -1-carbapene-2-em-3-carboxylate 4-N-methylcarbamoyl-2-((Z) -2-tritylthioethene- obtained in Example 28 130 mg of the title compound was obtained from 745 mg of 1-yl) thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.03 (3H, d, J = 7.3 Hz), 1.16 (3H, d, J = 6.3 Hz), 2.82 (3H, s), 3.34 (1H, dd , J ₁ = 6.1 Hz, J ₂ = 2.7 Hz), 3.54-3.65 (1H, m), 4.07-4.16 (2H, m), 6.77 (1H, d, = 10.8 Hz), 7.05 (1H, d, J = 10.8 Hz), 8.00 (1H, s)

Example 69 (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R ) -1-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4-N-cyanomethylcarbamoyl-2-((Z) -2-tritylthio obtained in Example 29 18 mg of the title compound was obtained from 68 mg of ethen-1-yl) thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.11 (3H, d, J = 7.3 Hz), 1.16 (3H, d, J = 6.4 Hz), 3.33 (1H, dd, J ₁ = 6.0 Hz, J ₂ = 2.3 Hz), 3.55-3.63 (1H, m), 4.08-4.13 (2H, m), 4.29 (2H, s), 6.73 (1H, d, J = 10.7 Hz), 7.03 (1H, d, J = 10.7 Hz), 8.07 (1H, s)

Example 70 (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethyl-N-methylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6 ((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid sodium 4-N-cyanomethyl-N-methylcarbamoyl-2-((Z 15 mg of the title compound was obtained from 90 mg of) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.04 (3H, d, J = 7.3 Hz), 1.16 (3H, d, J = 5.6 Hz), 3.10, 3.30 total (3H, both s), 3.35 (1H, dd, J ₁ = 6.0 Hz, J ₂ = 2.1 Hz), 3.57-3.63 (1H, m), 4.09-4.16 (2H, m), 4.43, 4.89-5.02 (total 2H, s & m), 6.82 (1H, d, J = 10.7 Hz), 7.08 (1H, d, J = 10.7 Hz), 7.99, 8.05 (total 1H, both s)

Example 71 (1R, 5S, 6S) -2-[[(Z) -2- (4-cyanomethylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1 4-hydroxymethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4-cyanomethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 31 From 1.48 g, 739 mg of the title compound was obtained in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 0.98 (3H, d, J = 7.1 Hz), 1.15 (3H, d, J = 5.8 Hz), 3.32 (1H, m), 3.54 (1H, m ), 3.89 (2H, s), 4.08-4.13 (2H, m), 6.76 (1H, d, J = 10.8 Hz), 6.99 (1H, d, J = 10.2 Hz), 7.37 (1H, s)

Example 72 (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-hydroxyazetidin-1-yl) carbonylthiazol-2-yl) ethen-1-yl] thio ] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid sodium 4- (3-hydroxyazetidin-1-yl obtained in Example 32 208 mg of the title compound was obtained from 1.28 g of carbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 0.98 (3H, d, J = 7.3 Hz), 1.14 (3H, d, J = 6.6 Hz), 3.30 (1H, dd, J ₁ = 5.9 Hz, J ₂ = 2.5 Hz), 3.54-3.60 (1H, m), 3.84 (1H, m), 4.07-4.13 (2H, m), 4.27 (1H, m), 4.42-4.49 (1H, m), 4.53- 4.63 (1H, m), 4.85-4.92 (1H, m), 6.62 (1H, 2d, J = 10.8 Hz), 6.91 (1H, 2d, J = 11.0 Hz), 7.87 (1H, 2s)

Example 73 (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-cyanoazetidin-1-yl) carbonylthiazol-2-yl) ethen-1-yl] thio]- 6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid sodium 4- (3-cyanoazetidin-1-yl) carbonyl-2 obtained in Example 33 In the same manner as in Example 43, 21 mg of the title compound was obtained from 50 mg of-((Z) -2-tritylthioethen-1-yl) thiazole.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.02 (3H, 2d, J = 7.1 Hz), 1.15 (3H, d, J = 6.3 Hz), 3.33 (1H, dd, J ₁ = 5.9 Hz, J ₂ = 2.7 Hz), 3.61 (1H, m), 3.73 (1H, m), 4.12 (2H, m), 4.28 (1H, m), 4.37 (1H, m), 4.86 (1H, m), 5.08 (1H, m), 6.73 (1H, 2d, J = 10.9 Hz), 7.01 (1H, d, J = 11.0 Hz), 7.99 (1H, s)

Example 74 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (5-hydroxymethylthiazol-2-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium 5-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) obtained in Example 34 38 mg of the title compound was obtained from 234 mg of thiazole in the same manner as in Example 43.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.13 (3H, d, J = 7.2 Hz), 1.29 (3H, d, J = 6.3 Hz), 3.4-3.5 (1H, m), 3.6-3.8 (1H, m), 4.2-4.3 (2H, m), 4.84 (2H, s), 6.91 (1H, d, J = 10.8 Hz), 7.09 (1H, d, J = 10.8 Hz), 7.69 (1H, s)

Example 75 (1R, 5S, 6S) -2-[[(Z) -2- (4,5-dicarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 4,5 -dicarbamoyl- 2-((Z) -2-tritylthioethene- obtained in Example 35 13 mg of the title compound was obtained from 102 mg of 1-yl) thiazole in the same manner as in Example 42.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.21 (3H, d, J = 6.9 Hz), 1.34 (3H, d, J = 6.0 Hz), 3.5-3.6 (1H, m), 3.7-3.8 (1H, m), 4.2-4.4 (2H, m), 6.83 (1H, d, J = 10.8 Hz), 7.36 (1H, d, J = 10.8 Hz)

Example 76 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (thiazol-4-yl) ethene-1- Yl] thio] -1-carbapene-2-em-3-carboxylic acid sodium salt As in Example 42 from 1.20 g of 4-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 36 The procedure yielded 354 mg of the title compound.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.18 (3H, d, J = 7.3 Hz), 1.31 (3H, d, J = 6.3 Hz), 3.45-3.50 (1H, m), 3.61-3.77 (1H, m), 4.22-4.31 (2H, m), 6.85 (1H, d, = 10.7 Hz), 6.91 (1H, d, J = 10.7 Hz), 7.77 (1H, s), 9.01 (1H, s )

[Example 77] (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-4-yl) ethen-1-yl] thio] -6-((1R) -1- Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium 2-carbamoyl-4-((Z) -2-tritylthioethen-1-yl) thiazole 1.38 obtained in Example 37 174 mg of the title compound was obtained from g in the same manner as in Example 42.
NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.03 (3H, d, J = 7.3 Hz), 1.16 (3H, d, J = 6.3 Hz), 3.30-3.35 (1H, m), 3.55-3.62 (1H, m), 4.07-4.15 (2H, m), 6.62 (1H, d, = 11.0 Hz), 6.72 (1H, d, J = 11.0 Hz), 7.70 (1H, s)

Example 78 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (5-hydroxymethylthiazol-4-yl) ethene-1- [Ill] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium 5-hydroxymethyl-4-((Z) -2-tritylthioethen-1-yl) obtained in Example 38 In the same manner as in Example 43, 9 mg of the title compound was obtained from 180 mg of thiazole.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.16 (3H, d, J = 7.2 Hz), 1.29 (3H, d, J = 6.3 Hz), 3.45 (1H, dd, J ₁ = 6.0 Hz, J ₂ = 2.7Hz), 3.6-3.75 (1H, m), 4.2-4.3 (2H, m), 4.86 (2H, s), 6.74 (1H, d, J = 10.5 Hz), 6.83 (1H, d, J = 10.5 Hz), 8.97 (1H, s)

Example 79 (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 -Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium
a) (1R, 5S, 6S) -2-[[(Z) -2- (4-Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-6-((1R) 4-Trinitrosilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl 4-hydroxymethyl-5-((Z) -2-mercaptoethene obtained in Example 41-a) (1R, 5S, 6S) -2-[[((Z) -2- (4-Hydroxymethylthiazole-5- Yl) ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl 582 mg was obtained. . _{NMR (CDCl 3) δ: 0.55-0.65} (6H, m), 0.9-1.0 (9H, m), 1.20 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3 Hz), 3.29 (1H, dd, J ₁ = 5.7 Hz, J ₂ = 2.7 Hz), 3.45-3.6 (1H, m), 4.2-4.35 (2H, m), 4.85 (2H, s), 5.29 (1H, d, J = 13.8 Hz), 5.50 (1H, d, J = 13.8 Hz), 6.53 (1H, d, J = 10.5 Hz), 7.12 (1H, d, J = 10.5 Hz), 7.68 (2H, d, J = 8.7 Hz), 8.22 (2H, d, J = 8.7 Hz), 8.76 (1H, s)

b) (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl
(1R, 5S, 6S) -2-[[(Z) -2- (4-Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-6-((1R) -1 N-N-dimethylaminopyridine 37 mg, pyridine 0.133 ml, acetic anhydride 0.114 ml was added to 3 ml of THF solution of 695 mg of 4-nitrobenzyl 4-carbbenzyl-2-em-3-carboxylate. For 1.5 hours. Ethyl acetate was added to the reaction solution, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was filtered with 5 g of silica gel, and the filtrate was concentrated under reduced pressure to give (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethene-1 There was obtained 730 mg of 4-nitrobenzyl 4-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 0.55-0.65 (6H, m), 0.9-1.0 (9H, m), 1.21 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.4 Hz), 2.10 (3H, s), 3.30 (1H, dd, J ₁ = 6.0 Hz, J ₂ = 2.9 Hz), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 5.25-5.35 (3H, m ), 5.50 (1H, d, J = 13.7 Hz), 6.59 (1H, d, J = 10.5 Hz), 7.19 (1H, d, J = 10.5 Hz), 7.68 (2H, d, J = 9.0 Hz), 8.23 (2H, d, J = 9.0 Hz), 8.79 (1H, s)

c) (1R, 5S, 6S) -2-[[(Z) -2- (4-Acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxy (Ethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium as in Example 42-c), (1R, 5S, 6S) -2-[[(Z) -2- (4 -Acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylic acid 4 -305 mg of the title compound was obtained from 725 mg of nitrobenzyl.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.12 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3 Hz), 2.09 (3H, s), 3.44 (1H, dd , J ₁ = 6.3 Hz, J ₂ = 2.7 Hz), 3.5-3.65 (1H, m), 4.2-4.3 (2H, m), 5.29 (2H, s), 6.81 (1H, d, J = 10.5 Hz) , 7.12 (1H, d, J = 10.5 Hz), 8.96 (1H, s)

Example 80 (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium
a) (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-6 -((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl Example 42-b) (1R, 5S, 6S) -2- [ [(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) (1R, 5S, 6S) -2-[[((Z) -2- [4-) from 270 mg of 4-nitrobenzyl-1-carbapent-2-em-3-carboxylate by the same procedure as in Example 79-b) (2-Acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3 -319 mg of 4-nitrobenzyl carboxylate was obtained.
NMR (CDCl ₃ ) δ: 0.55-0.65 (6H, m), 0.9-1.0 (9H, m), 1.20 (3H, d, J = 7.3 Hz), 1.28 (3H, d, J = 6.3 Hz), 2.07 (3H, s), 3.29 (1H, dd, J ₁ = 5.8 Hz, J ₂ = 2.9 Hz), 3.5-3.6 (1H, m), 3.7-3.75 (2H, m), 4.2-4.3 (4H, m ), 4.81 (2H, s), 5.30 (1H, d, J = 14.2 Hz), 5.51 (1H, d, J = 14.2 Hz), 6.53 (1H, d, J = 10.5 Hz), 7.24 (1H, d , J = 10.5 Hz), 7.68 (2H, d, J = 8.8 Hz), 8.23 (2H, d, J = 8.8 Hz), 8.75 (1H, s)

b) (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6-((1R ) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium as in Example 42-c), (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-Acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene -135 mg of the title compound was obtained from 315 mg of 4-nitrobenzyl 2-m-3-carboxylate.
NMR (D ₂ O) δ (HOD = 4.80 ppm): 1.21 (3H, d, J = 7.2 Hz), 1.29 (3H, d, J = 6.3 Hz), 2.07 (3H, s), 3.4-3.5 (1H , m), 3.55-3.65 (1H, m), 3.75-3.85 (2H, m), 4.2-4.3 (4H, m), 6.80 (1H, d, J = 10.5 Hz), 7.13 (1H, d, J = 10.5 Hz), 8.96 (1H, s)

Example 81 (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
(1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6-((1R)- 1-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 51.8 mg of N, N-dimethylacetamide in 2 ml of solution in argon atmosphere at −10 ° C. at 1- (cyclohexyloxy) Carbonyloxy) ethyl iodide 0.147 mg of hexane solution 2 ml was added. After stirring at the same temperature for 1 hour, 2 ml of hexane was added to the reaction solution, and the upper layer and the lower layer were separated. Brine was added to the lower layer, extracted twice with ethyl acetate, and the combined organic layer was washed twice with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration, and concentration under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 61.7 mg of the title compound.
NMR (CDCl ₃ ) δ: 1.2-2.0 (19H, m), 3.2-3.3 (1H, m), 3.5-3.6 (1H, m), 3.65-3.8 (4H, m), 4.2-4.3 (2H, m ), 4.6-4.7 (1H, m), 4.81 (2H, s), 6.52 (1H, d, J = 10.2 Hz), 6.85-7.0 (1H, m), 7.1-7.2 (1H, m), 8.77, 8.78 (total 1H, 2s)

Example 82 (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-(( 1R) -1-Hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers) obtained in Example 43 (1R, 5S , 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) In the same manner as in Example 81, 969 mg of the title compound was obtained from 667 mg of sodium -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.3 Hz), 1.20-2.00 (16H, m), 3.03 (3H, m), 3.14 (3H, m), 3.26-3.31 (1H, m) , 3.50-3.60 (1H, m), 4.21-4.30 (2H, m), 4.60-4.71 (1H, m), 6.55 (1H, d, J = 10.5 Hz), 6.90-6.96 (1H, m), 7.36 -7.40 (1H, m), 8.76 (1H, m)

Example 83 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-2-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-2-yl) ethene The title compound was obtained in an amount of 52.7 mg from 42.9 mg sodium 1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 48 mg 1- (cyclohexyloxycarbonyloxy) ethyl iodide.
NMR (CDCl ₃ ) δ: 1.2-2.0 (19H, m), 3.25-3.35 (1H, m), 3.6-3.75 (1H, m), 4.2-4.3 (2H, m), 4.6-4.7 (1H, m ), 4.7-4.9 (2H, m), 6.8-7.0 (3H, m), 7.26 (1H, s)

[Example 84] (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
(1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R)- In the same manner as in Example 81, 54 mg of the title compound was obtained from 70 mg of 1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 6.7 Hz), 1.21-2.00 (16H, m), 3.26-3.32 (1H, m), 3.53-3.65 (1H, m), 4.20-4.31 ( 2H, m), 4.60-4.71 (1H, m), 5.63 (1H, brs), 6.69 (1H, d, J = 10.5 Hz), 6.88-6.96 (1H, m), 7.43 (1H, brs), 8.37 -8.42 (1H, m), 8.69 (1H, m)

Example 85 (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R ) -1-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
(1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6- ( In the same manner as in Example 81, 57 mg of the title compound was obtained from 60 mg of (1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.3 Hz), 1.21-2.00 (16H, m), 3.26-3.32 (1H, m), 3.53-3.66 (1H, m), 4.22-4.32 ( 2H, m), 4.34-4.38 (2H, m), 4.60-4.71 (1H, m), 6.69 (1H, d, J = 10.7 Hz), 6.89-6.96 (1H, m), 7.91-7.97 (1H, m), 8.31-8.36 (1H, m), 8.70 (1H, m)

Example 86 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthiazole-5 -Yl] ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
Similar to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoyl] The title compound (85.6 mg) was obtained from 69 mg of sodium thiazol-5-yl] ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.2-2.0 (19H, m), 3.25-3.3 (1H, m), 3.5-3.6 (3H, m), 3.8-3.9 (2H, m), 4.2-4.3 (2H, m ), 4.6-4.7 (1H, m), 6.69 (1H, d, J = 10.8 Hz), 6.9-7.0 (1H, m), 8.0-8.1 (1H, m), 8.39 (1H, d, J = 10.8 Hz), 8.67, 8.68 (total 1H, both s)

[Example 87] (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- (Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid pivaloyloxymethyl (1R, 5S, 6S) -2-[[(Z) -2- ( 2-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 74 mg 78 mg of the title compound was obtained from 0.031 ml of iodomethyl pivalate in the same manner as in Example 81.
NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.3 Hz), 1.23 (9H, s), 1.34 (3H, d, J = 6.4 Hz), 3.28-3.34 (1H, m), 3.46-3.62 (1H, m), 4.22-4.33 (2H, m), 5.55 (1H, brs), 5.88 (1H, d, J = 5.6 Hz), 6.00 (1H, d, J = 5.6 Hz), 6.61 (1H, d, J = 10.3 Hz), 6.98 (1H, d, J = 10.3 Hz), 7.10 (1H, brs), 7.91 (1H, s)

Example 88 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthiazole-2 -Yl] ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
Similar to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoyl] From 38.5 mg sodium thiazol-2-yl] ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 123 mg 1- (cyclohexyloxycarbonyloxy) ethyl iodide, the title 45 mg of compound was obtained.
NMR (CDCl ₃ ) δ: 1.1-2.0 (19H, m), 3.25-3.4 (2H, m), 3.6-4.0 (4H, m), 4.2-4.35 (2H, m), 4.6-4.7 (1H, m ), 6.78 (1H, d, J = 10.5 Hz), 6.85-7.0 (2H, m), 7.9-8.0 (1H, m), 8.06, 8.08 (total 1H, 2s)

[Example 89] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene The title compound was obtained from 379 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.1-2.0 (19H, m), 2.6-2.7 (1H, m), 3.2-3.3 (1H, m), 3.45-3.6 (1H, m), 4.2-4.3 (2H, m ), 4.6-4.75 (1H, m), 4.8-4.9 (2H, m), 6.51 (1H, d, J = 10.2 Hz), 6.9-7.0 (1H, m), 7.05-7.15 (1H, m), 8.77, 8.78 (total 1H, 2s)

Example 90 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate acetoxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl)- Sodium 2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and acetic acid In the same manner as in Example 81, 146 mg of the title compound was obtained from 0.047 ml of bromomethyl.
NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.3 Hz), 1.35 (3H, d, J = 6.3 Hz), 1.83 (1H, d, J = 4.8 Hz), 2.14 (3H, s), 2.50 (1H, t, J = 5.9 Hz), 3.29 (1H, dd, J ₁ = 6.8 Hz, J ₂ = 2.8 Hz), 3.51-3.61 (1H, m), 4.22-4.31 (2H, m), 4.86 (2H, d, J = 5.9 Hz), 5.89 (1H, d, J = 5.6 Hz), 5.97 (1H, d, J = 5.6 Hz), 6.52 (1H, d, J = 10.5 Hz), 7.13 (1H , d, J = 10.5 Hz), 8.79 (1H, s)

Example 91 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (isopropyloxycarbonyloxy) ethyl (mixture of diastereomers)
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-] obtained in Example 41 137 mg of the title compound was obtained from 133 mg of 1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 110 mg of 1- (isopropyloxycarbonyloxy) ethyl iodide in the same manner as in Example 81. .
NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.3 Hz), 1.26-1.37 (9H, m), 1.61-1.65 (3H, m), 1.80 (1H, d, J = 4.7 Hz), 2.50 (1H, t, J = 5.9 Hz), 3.28 (1H, dd, J ₁ = 6.7 Hz, J ₂ = 2.8 Hz), 3.51-3.61 (1H, m), 4.22-4.30 (2H, m), 4.85 ( 2H, d, J = 5.9 Hz), 4.87-4.96 (1H, m), 6.52 (1H, d, J = 10.2 Hz), 6.90-6.95 (1H, m), 7.09-7.14 (1H, m), 8.78 (1H, m)

Example 92 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (ethoxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene 167 mg of the title compound was obtained from 145 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 148 mg of 1- (ethoxycarbonyloxy) ethyl iodide.
NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 6.9 Hz), 1.3-1.4 (6H, m), 1.6-1.7 (3H, m), 2.05-2.2 (1H, m), 2.8-2.9 ( 1H, m), 3.05-3.1 (1H, m), 3.45-3.6 (1H, m), 4.2-4.3 (4H, m), 4.8-4.9 (2H, m), 6.51 (1H, d, J = 10.5 Hz), 6.9-7.0 (1H, m), 7.1-7.2 (1H, m), 8.77, 8.78 (total 1H, both s)

Example 93 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- [I]] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid pivaloyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxy Ethyl) -2-[[((Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 93 mg of the title compound was obtained from 104 mg and 0.049 ml of iodomethyl pivalate in the same manner as in Example 81.
NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.2 Hz), 1.23 (9H, s), 1.34 (3H, d, J = 6.4 Hz), 1.80 (1H, d, J = 4.8 Hz), 2.45 (1H, t, J = 5.8 Hz), 3.29 (1H, dd, J ₁ = 6.4 Hz, J ₂ = 2.6 Hz), 3.50-3.60 (1H, m), 4.22-4.30 (2H, m), 4.86 (2H, d, J = 5.6 Hz), 5.89 (1H, d, J = 5.6 Hz), 6.00 (1H, d, J = 5.6 Hz), 6.51 (1H, d, J = 10.4 Hz), 7.13 (1H , d, J = 10.4 Hz), 8.78 (1H, m)

Example 94 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid cyclohexyloxycarbonyloxymethyl
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] In the same manner as in Example 81, 372 mg of the title compound was obtained from 374 mg of sodium -1-methyl-1-carbapene-2-em-3-carboxylate and 336 mg of cyclohexyloxycarbonyloxymethyl iodide.
NMR (DMSO-d ₆ ) δ: 1.08 (3H, d, J = 7.3 Hz), 1.14 (3H, d, J = 6.4 Hz), 1.20-1.88 (10H, m), 3.78-3.86 (1H, m) , 3.94-4.03 (1H, m), 4.24 (1H, dd, J ₁ = 9.8 Hz, J ₂ = 2.9 Hz), 4.56-4.64 (1H, m), 4.67 (2H, d, J = 5.6 Hz), 5.13 (1H, d, J = 5.1 Hz), 5.33 (1H, t, J = 5.6 Hz), 5.78 (1H, d, J = 6.2 Hz), 5.89 (1H, d, J = 6.2 Hz), 6.86 ( 1H, d, J = 10.4 Hz), 7.37 (1H, d, J = 10.4 Hz), 9.07 (1H, s)

Example 95 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (isobutyloxycarbonyloxy) ethyl (mixture of diastereomers)
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-- obtained in Example 41 In the same manner as in Example 81, 334 mg of the title compound was obtained from 346 mg of sodium 1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 278 mg of 1- (isobutyloxycarbonyloxy) ethyl iodide. .
NMR (CDCl ₃ ) δ: 0.92-0.96 (6H, m), 1.19 (3H, d, J = 7.3 Hz), 1.32-1.37 (3H, m), 1.64-1.71 (3H, m), 1.79 (1H, m), 1.92-2.04 (1H, m), 2.48 (1H, t, J = 6.1 Hz), 3.26-3.31 (1H, m), 3.49-3.60 (1H, m), 3.93-3.99 (2H, m) , 4.22-4.30 (2H, m), 4.85 (2H, d, J = 6.1 Hz), 6.51 (1H, d, J = 10.3 Hz), 6.89-6.96 (1H, m), 7.08-7.14 (1H, m ), 8.78 (1H, m)

Example 96 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene From 367 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 300 mg of 1- (cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl iodide, the title compound 84 mg Got.
NMR (CDCl ₃ ) δ: 1.1-2.2 (23H, m), 3.2-3.3 (1H, m), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 4.6-4.7 (1H, m ), 4.8-4.9 (2H, m), 6.5-6.6 (1H, m), 6.6-6.7 (1H, m), 7.1-7.2 (1H, m), 8.75-8.8 (1H, m)

Example 97 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid isobutyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid From 344 mg of sodium and 264 mg of isobutyloxycarbonyloxymethyl iodide, 294 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 0.94 (6H, d, J = 6.6 Hz), 1.19 (3H, d, J = 7.2 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.9-2.05 (1H, m ), 2.1-2.25 (1H, m), 2.75-2.9 (1H, m), 3.28 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.7 Hz), 3.5-3.6 (1H, m), 3.98 ( 2H, d, J = 6.6 Hz), 4.2-4.3 (2H, m), 4.8-4.9 (2H, m), 5.91 (1H, d, J = 5.4 Hz), 5.97 (1H, d, J = 5.4 Hz) ), 6.51 (1H, d, J = 10.5 Hz), 7.15 (1H, d, J = 10.5 Hz), 8.78 (1H, s)

[Example 98] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate isopropyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid From 348 mg of sodium and 252 mg of isopropyloxycarbonyloxymethyl iodide, 203 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.2 Hz), 1.3-1.4 (9H, m), 2.05-2.1 (1H, m), 2.7-2.8 (1H, m), 3.28 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.7 Hz), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 4.85 (2H, d, J = 5.4 Hz), 4.9-5.0 (1H , m), 5.89 (1H, d, J = 5.4 Hz), 5.97 (1H, d, J = 5.4 Hz), 6.51 (1H, d, J = 10.5 Hz), 7.14 (1H, d, J = 10.5 Hz) ), 8.78 (1H, s)

Example 99 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid isobutyryloxymethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid The title compound (360 mg) was obtained from sodium (325 mg) and isobutyryloxymethyl iodide (220 mg).
NMR (CDCl ₃ ) δ: 1.05-1.25 (9H, m), 1.33 (3H, d, J = 6.3 Hz), 2.55-2.7 (1H, m), 3.28 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.4Hz), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 4.84 (2H, s), 5.89 (1H, d, J = 5.4 Hz), 5.99 (1H, d, J = 5.4 Hz), 6.52 (1H, d, J = 10.5 Hz), 7.16 (1H, d, J = 10.5 Hz), 8.78 (1H, s)

Example 100 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid (pentan-1-yl) oxycarbonyloxymethyl
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] In the same manner as in Example 81, 168 mg of the title compound was obtained from 150 mg of sodium -1-methyl-1-carbapene-2-em-3-carboxylate and 162 mg of (pentan-1-yl) oxycarbonyloxymethyl iodide.
NMR (CDCl ₃ ) δ: 0.87-0.91 (3H, m), 1.20 (3H, d, J = 7.4 Hz), 1.27-1.36 (7H, m), 1.65-1.74 (3H, m), 2.41 (1H, t, J = 6.1 Hz), 3.28 (1H, dd, J ₁ = 6.7 Hz, J ₂ = 2.8 Hz), 3.55 (1H, m), 4.19 (2H, t, J = 6.7 Hz), 4.22- 4.28 (2H, m), 4.85 (2H, d, J = 5.9 Hz), 5.91 (1H, d, J = 5.6 Hz), 5.97 (1H, d, J = 5.6 Hz), 6.51 (1H, d, J = 10.2 Hz), 7.14 (1H, dd, J ₁ = 10.2Hz, J ₂ = 1.0 Hz), 8.78 (1H, s)

Example 101 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid (butan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6- ( (1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2- From 175 mg of sodium M-3-carboxylate and 164 mg of (butan-1-yl) oxycarbonyloxymethyl iodide, 223 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.5 Hz), 1.20 (3H, d, J = 7.2 Hz), 1.3-1.5 (5H, m), 1.6-1.7 (2H, m), 3.28 (1H, dd, J ₁ = 6.9 Hz, J ₂ = 2.7 Hz), 3.5-3.6 (1H, m), 4.15-4.3 (4H, m), 4.86 (2H, s), 5.90 (1H, d, J = 5.7 Hz), 5.97 (1H, d, J = 5.7 Hz), 6.51 (1H, d, J = 10.2 Hz), 7.14 (1H, d, J = 10.2 Hz), 8.79 (1H, s)

Example 102 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid (1-ethylpropan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S)- 6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene The title compound (154 mg) was obtained from 149 mg of sodium 2-m-3-carboxylate and 120 mg of (1-ethylpropan-1-yl) oxycarbonyloxymethyl iodide.
NMR (CDCl ₃ ) δ: 0.85-0.95 (6H, m), 1.20 (3H, d, J = 7.2 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.55-1.7 (4H, m), 1.8 -1.9 (1H, m), 2.45-2.55 (1H, m), 3.28 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.4 Hz), 3.5-3.6 (1H, m), 4.2-4.3 (2H , m), 4.6-4.7 (1H, m), 4.86 (2H, d, J = 5.7 Hz), 5.91 (1H, d, J = 5.4 Hz), 5.98 (1H, d, J = 5.4 Hz), 6.50 (1H, d, J = 10.5 Hz), 7.13 (1H, d, J = 10.5 Hz), 8.78 (1H, s)

EXAMPLE 103 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid isopentyloxycarbonyloxymethyl as in Example 81, (1R, 5S, 6S) -6-((1R) -1 -Hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carvone The title compound (153 mg) was obtained from 150 mg of sodium acid and 120 mg of isopentyloxycarbonyloxymethyl iodide.
NMR (CDCl ₃ ) δ: 0.91 (6H, d, J = 6.6 Hz), 1.20 (3H, d, J = 7.2 Hz), 1.34 (3H, d, J = 6.0 Hz), 1.5-1.6 (2H, m ), 1.6-1.8 (1H, m), 1.8-1.9 (1H, m), 2.45-2.55 (1H, m), 3.28 (1H, dd, J ₁ = 6.9 Hz, J ₂ = 2.7 Hz), 3.5- 3.6 (1H, m), 4.2-4.3 (4H, m), 4.8-4.85 (2H, m), 5.90 (1H, d, J = 5.7 Hz), 5.97 (1H, d, J = 5.7 Hz), 6.51 (1H, d, J = 10.2 Hz), 7.14 (1H, d, J = 10.2 Hz), 8.78 (1H, s)

[Example 104] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid (propan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6- ( (1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2- The title compound (177 mg) was obtained from 150 mg of sodium M-3-carboxylate and 109 mg of (propan-1-yl) oxymethyl iodide.
NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7.5 Hz), 1.20 (3H, d, J = 6.9 Hz), 1.35 (3H, d, J = 6.3 Hz), 1.65-1.75 (2H, m ), 1.75-1.85 (1H, m), 2.45-2.55 (1H, m), 3.28 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.7 Hz), 3.5-3.6 (1H, m), 4.1- 4.35 (4H, m), 4.86 (2H, d, J = 6.0 Hz), 5.91 (1H, d, J = 5.7 Hz), 5.97 (1H, d, J = 5.7 Hz), 6.51 (1H, d, J = 10.2 Hz), 7.14 (1H, d, J = 10.2 Hz), 8.78 (1H, s)

Example 105 (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 -Hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl] thio] obtained in Example 79 From 130 mg of 6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate and 104 mg of 1- (cyclohexyloxycarbonyloxy) ethyl iodide, 159 mg of the title compound Got.
NMR (CDCl ₃ ) δ: 1.2-2.1 (19H, m), 2.10 (3H, s), 3.25-3.3 (1H, m), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 4.6-4.75 (1H, m), 5.31 (2H, s), 6.57 (1H, d, J = 10.5 Hz), 6.9-7.0 (1H, m), 7.1-7.2 (1H, m), 8.80, 8.81 ( total 1H, 2s)

Example 106 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid ethoxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxy Ethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate From 214 mg and ethoxycarbonyloxymethyl iodide 146 mg, 203 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.3 Hz), 1.30-1.35 (6H, m), 1.74 (1H, d, J = 4.6 Hz), 2.42 (1H, t, J = 6.1 Hz ), 3.28 (1H, dd, J ₁ = 6.8 Hz, J ₂ = 2.7 Hz), 3.5-3.6 (1H, m), 4.2-4.3 (4H, m), 4.8-4.9 (2H, m), 5.91 ( 1H, d, J = 5.6 Hz), 5.98 (1H, d, J = 5.6 Hz), 6.51 (1H, d, J = 10.2 Hz), 7.29 (1H, d, J = 10.2 Hz), 8.78 (1H, s)

Example 107 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate neopentyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1 -Hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carvone The title compound (193 mg) was obtained from 160 mg of sodium acid and 129 mg of neopentyloxycarbonyloxymethyl iodide.
NMR (CDCl ₃ ) δ: 0.95 (9H, s), 1.19 (3H, d, J = 7.2 Hz), 1.34 (3H, d, J = 6.3 Hz), 2.2-2.3 (1H, m), 2.9-3.0 (1H, m), 3.28 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.4 Hz), 3.5-3.6 (1H, m), 3.89 (2H, s), 4.2-4.3 (2H, m), 4.85 (2H, d, J = 4.8 Hz), 5.92 (1H, d, J = 6.0 Hz), 5.97 (1H, d, J = 6.0 Hz), 6.52 (1H, d, J = 10.2 Hz), 7.15 ( 1H, d, J = 10.2 Hz), 8.78 (1H, s)

Example 108 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid methoxycarbonyloxymethyl
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene 148 mg of the title compound was obtained from 160 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 103 mg of methoxycarbonyloxymethyl iodide.
NMR (CDCl ₃ ) δ: 1.18 (3H, d, J = 7.2 Hz), 1.32 (3H, d, J = 6.3 Hz), 2.75-2.9 (1H, m), 3.28 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.7Hz), 3.35-3.5 (1H, m), 3.5-3.6 (1H, m), 3.84 (3H, s), 4.2-4.3 (2H, m), 4.8-4.9 (2H, m ), 5.90 (1H, d, J = 5.4 Hz), 5.97 (1H, d, J = 5.4 Hz), 6.52 (1H, d, J = 10.2 Hz), 7.16 (1H, d, J = 10.2 Hz), 8.79 (1H, s)

[Example 109] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid cyclopentyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid The title compound (167 mg) was obtained from 160 mg of sodium and 128 mg of cyclopentyloxycarbonyloxymethyl iodide.
_{NMR (CDCl 3) δ: 1.19} (3H, d, J = 6.9 Hz), 1.33 (3H, d, J = 6.0 Hz), 1.5-1.9 (8H, m), 2.4-2.5 (1H, m), 3.0 -3.2 (1H, m), 3.28 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.4 Hz), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 4.85 (2H, s ), 5.1-5.2 (1H, m), 5.88 (1H, d, J = 5.7 Hz), 5.96 (1H, d, J = 5.7 Hz), 6.52 (1H, d, J = 10.2 Hz), 7.15 (1H , d, J = 10.2 Hz), 8.79 (1H, s)

[Example 110] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid t-butoxycarbonyloxymethyl
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene From 176 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 135 mg of t-butoxycarbonyloxymethyl iodide, 214 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 1.18 (3H, d, J = 7.2 Hz), 1.33 (3H, d, J = 6.3 Hz), 1.49 (9H, s), 2.5-2.6 (1H, m), 3.2-3.3 (2H, m), 3.5-3.6 (1H, m), 4.26 (1H, dd, J ₁ = 9.3 Hz, J ₂ = 2.4 Hz), 4.84 (2H, d, J = 3.3 Hz), 5.84 (1H, d, J = 5.7 Hz), 5.93 (1H, d, J = 5.7 Hz), 6.52 (1H, d, J = 9.9 Hz), 7.15 (1H, d, J = 9.9 Hz), 8.78 (1H, s)

EXAMPLE 111 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid phthalidyl (diastereomeric mixture)
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z)-), except that the solvent was only DMA and the reaction was carried out at room temperature. 2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 162 mg and 3-bromophthalide 128 mg 122 mg of compound was obtained.
NMR (CDCl ₃ ) δ: 1.20-1.24 (3H, m), 1.30-1.34 (3H, m), 1.69 & 1.75 (total 1H, br sx 2), 2.43 (1H, m), 3.28-3.31 (1H , m), 3.54-3.61 (1H, m), 4.24-4.27 (total 1H, dx 2, J = 2.9 Hz), 4.2 & 4.8 (total 1H, br sx 2), 4.82-4.87 (total 1H, dx 2, J = 5.2 Hz), 6.45-6.53 (total 1H, dx 2, J = 10.3 Hz), 7.07-7.17 (total 1H, dx 2, J = 10.3 Hz), 7.52 & 7.56 (total 1H, sx 2 ), 7.64-7.77 (3H, m), 7.91-7. 95 (total 1H, m), 8.73 & 8.79 (total 1H, sx 2)

[Example 112] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (methoxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene 163 mg of the title compound was obtained from 163 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 140 mg of 1- (methoxycarbonyloxy) ethyl iodide.
NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.2 Hz), 1.3-1.4 (3H, m), 1.6-1.7 (3H, m), 2.1-2.3 (1H, m), 2.8-3.0 ( 1H, m), 3.25-3.3 (1H, m), 3.5-3.6 (1H, m), 3.81, 3.83 (total 3H, 2s), 4.2-4.3 (2H, m), 4.85 (2H, d, J = 3.9 Hz), 6.52 (1H, d, J = 10.2 Hz), 6.9-7.0 (1H, m), 7.1-7.2 (1H, m), 8.79 (1H, s)

[Example 113] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (cyclopentyloxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene 187 mg of the title compound was obtained from 162 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 148 mg of 1- (cyclopentyloxycarbonyloxy) ethyl iodide.
NMR (CDCl ₃ ) δ: 1.18 (3H, d, J = 7.2 Hz), 1.3-1.4 (3H, m), 1.5-2.0 (11H, m), 2.2-2.4 (1H, m), 2.9-3.05 ( 1H, m), 3.25-3.35 (1H, m), 3.45-3.6 (1H, m), 4.2-4.3 (2H, m), 4.85 (2H, d, J = 4.8 Hz), 5.1-5.2 (1H, m), 6.52 (1H, d, J = 10.5 Hz), 6.85-7.0 (1H, m), 7.1-7.2 (1H, m), 8.77, 8.78 (total 1H, 2s)

[Example 114] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid (tetrahydropyran-4-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2 -194 mg of the title compound was obtained from 160 mg of sodium em-3-carboxylate and 136 mg of (tetrahydropyran-4-yl) oxycarbonyloxymethyl iodide.
NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6.0 Hz), 1.7-1.9 (2H, m), 1.9-2.05 (2H, m), 2.4 -2.6 (1H, m), 3.0-3.2 (1H, m), 3.25-3.3 (1H, m), 3.45-3.6 (3H, m), 3.85-4.0 (2H, m), 4.2-4.3 (2H, m), 4.8-4.95 (3H, m), 5.88 (1H, d, J = 5.7 Hz), 6.00 (1H, d, J = 5.7 Hz), 6.52 (1H, d, J = 10.5 Hz), 7.16 ( 1H, d, J = 10.5 Hz), 8.79 (1H, s)

Example 115 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (neopentyloxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene 100 mg of the title compound was obtained from 160 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 170 mg of 1- (neopentyloxycarbonyloxy) ethyl iodide.
NMR (CDCl ₃ ) δ: 0.95 (9H, s), 1.19 (3H, d, J = 6.9 Hz), 1.3-1.4 (3H, m), 1.6-1.7 (3H, m), 2.0-2.1 (1H, m), 2.7-2.85 (1H, m), 3.25-3.3 (1H, m), 3.5-3.6 (1H, m), 3.8-3.95 (2H, m), 4.2-4.3 (2H, m), 4.85 ( 2H, s), 6.51 (1H, d, J = 10.5 Hz), 6.9-7.0 (1H, m), 7.1-7.2 (1H, m), 8.78 (1H, s)

Example 116 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid (piperidin-1-yl) carbonyloxymethyl (1R, 5S, 6S) -6-(( 1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em The title compound (192 mg) was obtained from sodium -3-carboxylate (160 mg) and (piperidin-1-yl) carbonyloxymethyl iodide (130 mg).
NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6.0 Hz), 1.45-1.65 (6H, m), 2.25-2.4 (1H, m), 2.75 -2.9 (1H, m), 3.27 (1H, dd, J ₁ = 6.9 Hz, J ₂ = 2.7 Hz), 3.4-3.6 (5H, m), 4.2-4.3 (2H, m), 4.85 (2H, d , J = 5.1 Hz), 5.92 (1H, d, J = 5.7 Hz), 5.99 (1H, d, J = 5.7 Hz), 6.51 (1H, d, J = 10.5 Hz), 7.13 (1H, d, J = 10.5 Hz), 8.78 (1H, s)

Example 117 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- [I]] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid allyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2 -[[(Z) -2- (4-Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 1.00 g and allyl In the same manner as in Example 81, 984 mg of the title compound was obtained from 538 mg of bromide and 415 mg of allyl iodide.
NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.3 Hz), 1.35 (3H, d, J = 6.1 Hz), 3.29 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.7 Hz), 3.54 (1H, m), 4.25-4.28 (2H, m), 4.73 (1H, m), 4.85-4.89 (3H, m), 5.28 (1H, d, J = 10.5 Hz), 5.48 (1H, m) , 5.95-6.04 (1H, m), 6.53 (1H, d, J = 10.5 Hz), 7.11 (1H, d, J = 10.2 Hz), 8.77 (1H, s)

Example 118 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (L-valyloxymethyl) thiazole -5-yl) ethen-1-yl] thio] -1-carbapen-2-em-3-carboxylic acid
a) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl- L-valyloxymethyl) thiazol-5-yl) ethen-1-yl] thio] -1-carbapene-2-em-3-carboxylate
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -Dissolve 970 mg of allyl 1-methyl-1-carbapene-2-em-3-carboxylate in 10 ml of N, N-dimethylacetamide, 281 mg of 4-dimethylaminopyridine, 1- [3- (dimethylamino) propyl] 441 mg of 3-ethylcarbodiimide hydrochloride and 681 mg of N-4-nitrobenzyloxycarbonyl-L-valine were added and stirred overnight at room temperature. The reaction mixture was poured into 20% brine (50 ml) and ethyl acetate (50 ml) for liquid separation, and the organic phase was dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: normal hexane = 2: 1, then ethyl acetate: normal hexane = 5: 1) to obtain (1R, 5S, 6S) -6-((1R)- 1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl-L-valyloxymethyl) thiazol-5-yl) ethen-1-yl 517 mg of allyl thio] -1-carbapene-2-em-3-carboxylate were obtained.
NMR (CDCl ₃ ) δ: 0.83 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 1.20 (3H, d, J = 7.3 Hz), 1.36 (3H, d, J = 6.3 Hz), 2.05 (1H, m), 3.30 (1H, dd, J ₁ = 6.8 Hz, J ₂ = 2.7 Hz), 3.55 (1H, m), 4.27-4.35 (3H, m), 4.71-4.76 (1H, m), 4.84-4.89 (1H, m), 5.16-5.50 (6H, m), 5.94-6.04 (1H, m), 6.61 (1H, d, J = 10.5 Hz), 7.15 (1H, d , J = 10.5 Hz), 7.51 (2H, d, J = 8.5 Hz), 8.22 (2H, d, J = 8.8 Hz), 8.79 (1H, s)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl- L-valyloxymethyl) thiazol-5-yl) ethen-1-yl] thio] -1-carbapene-2-em-3-carboxylic acid
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl-L- Valinyloxymethyl) thiazol-5-yl) ethen-1-yl] thio] -1-carbapene-2-em-3-carboxylate 500 mg and dimedone 250 mg were dissolved in tetrahydrofuran 10 ml and tetrakistriphenylphosphine palladium 82 mg was dissolved. In addition, the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The reaction mixture was poured into 50 ml of 20% brine and 50 ml of ethyl acetate, and the pH was adjusted to 0.6 with 1N aqueous hydrochloric acid solution, followed by liquid separation. The organic phase was dried over anhydrous magnesium sulfate, the solid was filtered off, and the solvent was distilled off under reduced pressure. Purification by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to produce (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [ [(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl-L-valyloxymethyl) thiazol-5-yl) ethen-1-yl] thio] -1-carbapen-2-em-3 -317 mg of carboxylic acid was obtained.
NMR (CDCl ₃ ) δ: 0.82-0.85 (6H, m), 1.03 (3H, d, J = 7.3 Hz), 1.14 (3H, d, J = 6.3 Hz), 1.99-2.04 (1H, m), 3.29 (1H, dd, J ₁ = 6.2 Hz, J ₂ = 2.8 Hz), 3.73 (1H, m), 3.92-3.98 (1H, m), 4.19 (1H, dd, J ₁ = 10.0 Hz, J ₂ = 2.7 Hz), 5.09 (1H, d, J = 4.9 Hz), 5.19 (2H, s), 5.29 (1H, d, J = 12.4 Hz), 5.40 (1H, d, J = 12.4 Hz), 6.94 (1H, d, J = 10.5 Hz), 7.21 (1H, d, J = 10.5 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.25 (2H, d, J = 8.8 Hz), 8.32 (1H, s), 9.12 (1H, s)

c) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (L-valyloxymethyl) thiazole-5 -Yl) ethen-1-yl] thio] -1-carbapen-2-em-3-carboxylic acid
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl-L- (1R, 5S, 6S) from 150 mg of (valyloxymethyl) thiazol-5-yl) ethen-1-yl] thio] -1-carbapene-2-em-3-carboxylic acid in the same manner as in Example 41-c) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (L-valyloxymethyl) thiazol-5-yl) ethen-1-yl] 27 mg of thio] -1-carbapene-2-em-3-carboxylic acid was obtained.
NMR (CDCl ₃ ) δ: 0.75 (3H, d, J = 7.1 Hz), 0.77 (3H, d, J = 7.1 Hz), 0.96 (3H, d, J = 7.3 Hz), 1.14 (3H, d, J = 6.3 Hz), 2.07-2.15 (1H, m), 3.29 (1H, dd, J ₁ = 6.1 Hz, J ₂ = 2.7 Hz), 3.44 (1H, m), 3.85 (1H, d, J = 4.4 Hz ), 4.06-4.12 (2H, m), 5.26 (1H, d, J = 12.4 Hz), 5.42 (1H, d, J = 12.7 Hz), 6.71 (1H, d, J = 10.5 Hz), 7.00 (1H , d, J = 10.5 Hz), 8.82 (1H, s)

[Example 119] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (t-butoxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene The title compound (89 mg) was obtained from 160 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 162 mg of 1- (t-butoxycarbonyloxy) ethyl iodide.
NMR (CDCl ₃ ) δ: 1.1-1.2 (3H, m), 1.3-1.4 (3H, m), 1.49 (9H, s), 1.55-1.7 (3H, m), 2.0-2.1 (1H, m), 2.7-2.85 (1H, m), 3.27 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.7 Hz), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 4.85 (2H, s), 6.51 (1H, d, J = 10.5 Hz), 6.8-6.9 (1H, m), 7.1-7.2 (1H, m), 8.78, 8.79 (total 1H, 2s)

Example 120 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (t-butoxycarbonyloxy) ethyl (mixture of diastereomers)
Analogously to Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene The title compound (89 mg) was obtained from 160 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate and 162 mg of 1- (t-butoxycarbonyloxy) ethyl iodide.
NMR (CDCl ₃ ) δ: 1.15-1.25 (3H, m), 1.3-1.4 (3H, m), 1.49 (9H, s), 1.55-1.7 (3H, m), 2.0-2.1 (1H, m), 2.7-2.85 (1H, m), 3.27 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.7 Hz), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 4.85 (2H, s), 6.51 (1H, d, J = 10.5 Hz), 6.85-6.95 (1H, m), 7.05-7.15 (1H, m), 8.78, 8.79 (total 1H, 2s)

[Example 121] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate In the same manner as in Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl)- 2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate sodium 265 mg and iodine 143 mg of the title compound was obtained from 0.063 ml of ethyl iodide. NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.3 Hz), 1.34-1.41 (6H, m), 1.80 (1H, d, J = 4.6 Hz), 2.51 (1H, t, J = 6.0 Hz ), 3.29 (1H, dd, J ₁ = 6.8 Hz, J ₂ = 2.7 Hz), 3.48-3.59 (1H, m), 4.23-4.44 (4H, m), 4.85 (2H, d, J = 6.0 Hz) , 6.53 (1H, d, J = 10.5 Hz), 7.10 (1H, d, J = 10.5 Hz), 8.78 (1H, s)

Example 122 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- [I]] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl , 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1 -156 mg of the title compound was obtained from 160 mg of sodium methyl-1-carbapene-2-em-3-carboxylate and 122 mg of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl bromide.
NMR (DMSO-d ₆ ) δ: 1.08 (3H, d, J = 6.9 Hz), 1.14 (3H, d, J = 6.3 Hz), 2.20 (3H, s), 3.25-3.35 (1H, m), 3.75 -3.9 (1H, m), 3.9-4.05 (1H, m), 4.2-4.3 (1H, m), 4.67 (2H, d, J = 5.4 Hz), 5.1-5.2 (3H, m), 5.25-5.35 (1H, m), 6.86 (1H, d, J = 10.8 Hz), 7.33 (1H, d, J = 10.8 Hz), 9.05 (1H, s)

Example 123 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid phenyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid From 226 mg of sodium and 243 mg of phenyloxycarbonyloxymethyl iodide, 278 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.5 Hz), 1.34 (3H, d, J = 6.3 Hz), 2.05-2.25 (1H, m), 2.7-2.9 (1H, m), 3.30 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.4 Hz), 3.5-3.6 (1H, m), 4.2-4.35 (2H, m), 4.85 (2H, d, J = 5.4 Hz), 5.98 ( 1H, d, J = 5.7 Hz), 6.11 (1H, d, J = 5.7 Hz), 6.51 (1H, d, J = 10.5 Hz), 7.15 (1H, d, J = 10.5 Hz), 7.2-7.35 ( 3H, m), 7.35-7.45 (2H, m), 8.72 (1H, s)

EXAMPLE 124 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid N, N-di (propan-1-yl) aminocarbonyloxymethyl in the same manner as in Example 81, (1R, 5S, 6S ) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1 From 159 mg of sodium -carbapen-2-em-3-carboxylate and 135 mg of N, N-di (propan-1-yl) aminocarbonyloxymethyl iodide, 179 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 0.8-0.95 (6H, m), 1.19 (3H, d, J = 7.5 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.45-1.6 (4H, m), 2.1 -2.25 (1H, m), 2.6-2.8 (1H, m), 3.1-3.3 (5H, m), 3.5-3.6 (1H, m), 4.2-4.3 (2H, m), 4.85 (2H, d, J = 4.8 Hz), 5.92 (1H, d, J = 5.7 Hz), 5.99 (1H, d, J = 5.7 Hz), 6.50 (1H, d, J = 10.5 Hz), 7.12 (1H, d, J = 10.5 Hz), 8.77 (1H, s)

Example 125 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl
a) (cis-2,6-Dimethylpiperidin-1-yl) carbonyloxymethyl chloride
To 46 ml of a toluene solution of 9.11 ml of cis-2,6-dimethylpiperidine, 24 ml of a toluene solution of 2.39 ml of chloromethyl chloroformate was added dropwise over 10 minutes under ice cooling, and the mixture was stirred at room temperature for 16 hours. After 60 ml of 1N hydrochloric acid was added for liquid separation, the organic layer was washed with 60 ml each of 5% aqueous sodium hydrogen carbonate solution and 20% brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain 12.7 g of (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl chloride.
NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 7.1 Hz), 1.46-1.81 (6H, m), 4.34 (2H, m), 5.83 (2H, s)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[((1R, 5S, 6S) -6- (5R) was added to 5 ml of DMSO solution of 183 mg of (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl chloride. Z) -2- (4-Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate (300 mg) was added at room temperature for 18 Stir for hours. After adding 20 ml each of ethyl acetate and 20% brine and separating the layers, the organic layer was washed twice with 20% brine. The extract was dried over anhydrous magnesium sulfate and filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 15: 1) to give the title compound (273 mg).
NMR (CDCl ₃ ) δ: 1.19-1.22 (9H, m), 1.34 (3H, d, J = 6.3 Hz), 1.44-1.76 (6H, m), 2.10 (1H, d, J = 4.4 Hz), 2.63 (1H, t, J = 6.0Hz), 3.28 (1H, dd, J ₁ = 2.8 Hz, J ₂ = 6.7 Hz), 3.54 (1H, m), 4.25-4.35 (4H, m), 4.85 (2H, d, J = 5.8 Hz), 5.94 (1H, d, J = 5.6 Hz), 6.02 (1H, d, J = 5.6 Hz), 6.51 (1H, d, J = 10.5 Hz), 7.12 (1H, d, J = 10.5 Hz), 8.78 (1H, s)

Example 126 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid N, N-di- (butan-1-yl) aminocarbonyloxymethyl
a) Chloromethyl N, N-di-n-butylcarbamate Triethylamine 11.7 ml, N, N-di-n-butylamine 11.3 ml cyclopentyl methyl ether solution 100 ml And stirred at room temperature for 13 hours. After 100 ml of 2N hydrochloric acid was added for liquid separation, the organic layer was washed with 100 ml each of 5% aqueous sodium hydrogen carbonate solution and half-saturated saline. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain 12.7 g of chloromethyl N, N-di-n-butylcarbamate.
NMR (CDCl ₃ ) δ: 0.92 (6H, t, J = 7.3 Hz), 1.25-1.37 (4H, m), 1.47-1.58 (4H, m), 3.18-3.30 (4H, m), 5.79 (2H, m)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid N, N-di (butan-1-yl) aminocarbonyloxymethyl N, N- 154 mg of chloromethyl di-n-butylcarbamate and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 -Ill) ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 233 mg gave the title compound 220 mg.
NMR (CDCl ₃ ) δ: 0.86-0.94 (6H, m), 1.19 (3H, d, J = 7.3 Hz), 1.23-1.36 (7H, m), 1.43-1.57 (4H, m), 1.98 (1H, d, J = 4.6 Hz), 2.57 (1H, t, J = 6.0 Hz), 3.14-3.31 (5H, m), 3.49-3.59 (1H, m), 4.21-4.30 (2H, m), 4.86 (2H , d, J = 6.0 Hz), 5.92 (1H, d, J = 5.6 Hz), 5.99 (1H, d, J = 5.6 Hz), 6.51 (1H, d, J = 10.2 Hz), 7.12 (1H, d , J = 10.2 Hz), 8.77 (1 H, s)

Example 127 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid hexane-1-yl In the same manner as in Example 81, (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 162 mg of the title compound was obtained from 218 mg of sodium and 0.095 ml of 1-iodohexane.
NMR (CDCl ₃ ) δ: 0.86-0.91 (3H, m), 1.20 (3H, d, J = 7.3 Hz), 1.24-1.37 (7H, m), 1.38-1.48 (2H, m), 1.70-1.79 ( 2H, m), 3.29 (1H, dd, J ₁ = 6.6 Hz, J ₂ = 2.6 Hz), 3.48-3.59 (1H, m), 4.19-4.39 (4H, m), 4.85 (1H, s), 6.53 (1H, d, J = 10.2 Hz), 7.09 (1H, d, J = 10.2 Hz), 8.77 (1H, s)

[Example 128] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl
a) Chloromethyl Nn-hexyl-N-methylcarbamate Chloromethyl Nn-hexyl-N-methylcarbamate from 3.17 g Nn-hexyl-N-methylamine and 2.22 ml chloromethyl chloroformate using the same procedure as in Example 126-a) 4.64 g of methyl was obtained.
NMR (CDCl ₃ ) δ: 0.86-0.94 (3H, m), 1.25-1.37 (6H, m), 1.47-1.60 (2H, m), 2.91, 2.94 (total 3H, s each), 3.65-3.81 (2H , m), 5.78, 5.80 (total 2H, s each)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N- (Hexane-1-yl) -N-methylaminocarbonyloxymethyl Nn-hexyl by a method similar to Example 125-b) 134 mg of chloromethyl-N-methylcarbamate and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl ) Ethen-1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 217 mg gave the title compound 206 mg.
NMR (CDCl ₃ ) δ: 0.83-0.91 (3H, m), 1.19 (3H, d, J = 7.3 Hz), 1.22-1.31 (6H, m), 1.34 (3H, d, J = 6.3 Hz), 1.45 -1.56 (2H, m), 1.93-1.99 (1H, m), 2.56 (1H, t, J = 5.9 Hz), 2.90, 2.91 (total 3H, each s), 3.20-3.31 (3H, m), 3.49 -3.60 (2H, m), 4.21-4.30 (2H, m), 4.86 (2H, d, J = 5.9 Hz), 5.90-5.94 (1H, m), 5.96-6.00 (1H, m), 6.51 (1H , d, J = 10.2 Hz), 7.12 (1H, d, J = 10.2 Hz), 8.78 (1H, s)

[Example 129] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N, N-diisobutylaminocarbonyloxymethyl
a) Chloromethyl N, N-diisobutylcarbamate Using the same procedure as in Example 126-a), 3.54 g of N, N-diisobutylamine and 4.64 g of chloromethyl N, N-diisobutylcarbamate from 2.22 ml of chloromethyl chloroformate Obtained.
NMR (CDCl ₃ ) δ: 0.75-0.94 (12H, m), 1.87-2.05 (2H, m), 3.06 (1H, d, J = 7.6 Hz), 3.12 (1H, d, J = 7.6 Hz), 5.80 (2H, s)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N, N-diisobutylaminocarbonyloxymethyl In a manner similar to Example 125-b), 159 mg of chloromethyl N, N-diisobutylcarbamate (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 241 mg of the title compound was obtained from 241 mg of sodium -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 0.82-0.90 (12H, m), 1.19 (3H, d, J = 7.3 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.85-2.02 (3H, m), 2.57 -2.62 (1H, m), 3.00-3.17 (4H, m), 3.27 (1H, dd, J ₁ = 6.8 Hz, J ₂ = 2.7 Hz), 3.46-3.59 (1H, m), 4.19-4.30 (2H , m), 4.86 (2H, d, J = 5.9 Hz), 5.93 (1H, d, J = 5.5 Hz), 5.98 (1H, d, J = 5.5 Hz), 6.51 (1H, d, J = 10.2 Hz) ), 7.12 (1H, d, J = 10.2 Hz), 8.78 (1H, s)

Example 130 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N, N-diisopropylaminocarbonyloxymethyl Chloromethyl N, N-diisopropylcarbamate by a method similar to Example 125-b) 133 mg and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] 150 mg of the title compound was obtained from 231 mg of sodium thio] -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.18-1.23 (15H, m), 1.34 (3H, d, J = 6.4 Hz), 1.99 (1H, d, J = 4.4 Hz), 2.57 (1H, t, J = 5.9 Hz) ), 3.27 (1H, dd, J ₁ = 6.8 Hz, J ₂ = 2.6 Hz), 3.48-3.59 (1H, m), 3.78 (1H, brs), 4.06 (1H, brs), 4.21-4.30 (2H, m), 4.86 (2H, d, J = 5.9 Hz), 5.93 (1H, d, J = 5.6 Hz), 5.98 (1H, d, J = 5.6 Hz), 6.51 (1H, d, J = 10.2 Hz) , 7.12 (1H, d, J = 10.2 Hz), 8.78 (1H, s)

Example 131 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid N-cyclohexyl-N-methylaminocarbonyloxymethyl
a) N-cyclohexyl-N-methylcarbamate chloromethyl Chloroformate 2.67 ml of toluene solution 27 ml of toluene solution The solution was added dropwise over a period of time and stirred at room temperature for 17 hours. After adding 60 ml of 1N hydrochloric acid for liquid separation, the organic layer was washed with 60 ml each of 5% aqueous sodium hydrogen carbonate solution and 20% brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain 5.76 g of chloromethyl N-cyclohexyl-N-methylcarbamate.
NMR (CDCl ₃ ) δ: 1.06-1.80 (10H, m), 2.79, 2.85 (total 3H, s each), 3.82, 4.00 (total 1H, m each), 5.80, 5.82 (total 2H, s each)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-cyclohexyl-N-methylaminocarbonyloxymethyl Chloroform N-cyclohexyl-N-methylcarbamate in the same manner as in Example 125-b) 122 mg of methyl and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[((Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl The title compound (165 mg) was obtained from 200 mg of thio] -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.04-1.41 (6H, m), 1.20 (3H, d, J = 7.3 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.67 (2H, m), 1.78 (2H , m), 1.99 (1H, m), 2.56 (1H, m), 2.78, 2.82 (total 3H, s each), 3.28 (1H, dd, J ₁ = 2.7 Hz, J ₂ = 6.8 Hz), 3.54 ( 1H, m), 3.85, 3.98 (total 1H, m each), 4.25-4.28 (2H, m), 4.86 (2H, d, J = 5.6 Hz), 5.92-6.01 (2H, m), 6.51 (1H, d, J = 10.2 Hz), 7.12 (1H, d, J = 10.2 Hz), 8.78 (1H, s)

Example 132 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid N-pentan-1-ylaminocarbonyloxymethyl
a) Chloromethyl N-pentan-1-ylcarbamate Chloromethyl chloroformate 2.39 ml of toluene solution 24 ml of toluene solution 3.38 ml of n-pentylamine and 5.02 ml of triethylamine 38 ml over 15 minutes while cooling in an ice bath The solution was added dropwise and stirred at room temperature for 15 hours. After 60 ml of 1N hydrochloric acid was added for liquid separation, the organic layer was washed with 60 ml each of 5% aqueous sodium hydrogen carbonate solution and 20% brine. After drying over anhydrous magnesium sulfate and filtering, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give 3.31 chloromethyl N-pentan-1-ylcarbamate. g was obtained.
NMR (CDCl ₃ ) δ: 0.89-0.92 (3H, m), 1.27-1.39 (4H, m), 1.49-1.60 (2H, m), 3.16-3.25 (2H, m), 4.86 (1H, m), 5.75 (2H, s)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-pentan-1-ylaminocarbonyloxymethyl N-pentan-1-yl-N by a method analogous to Example 125-b) 160 mg of chloromethyl-methylcarbamate and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene 125 mg of the title compound was obtained from 300 mg of sodium -1-yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 0.89 (3H, m), 1.19 (3H, d, J = 7.3 Hz), 1.24-1.30 (4H, m), 1.34 (3H, d, J = 6.1 Hz), 1.50 (2H , m), 2.62 (1H, m), 3.19 (2H, m), 3.28 (1H, dd, J ₁ = 2.6 Hz, J ₂ = 6.7 Hz), 3.55 (1H, m), 4.24-4.27 (2H, m), 4.85 (2H, m), 4.92 (1H, m), 5.88 (1H, d, J = 5.9 Hz), 5.96 (1H, d, J = 5.9 Hz), 6.51 (1H, d, J = 10.5 Hz), 7.12 (1H, d, J = 10.2 Hz), 8.78 (1H, s)

Example 133 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-cyclohexyl-N-ethylaminocarbonyloxymethyl
a) Chloromethyl N-cyclohexyl-N-ethylcarbamate N-cyclohexyl-N-ethylcarbamic acid from 10 ml N-ethyl-N-cyclohexylamine and 2.68 ml chloromethyl chloroformate using the same procedure as in Example 125-a) 6.44 g of chloromethyl was obtained.
NMR (CDCl ₃ ) δ: 1.04-1.82 (13H, m), 3.16-3.29 (2H, m), 3.74, 3.92 (total 1H, m each), 5.82 (2H, s)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-cyclohexyl-N-ethylaminocarbonyloxymethyl N-cyclohexyl-N-ethylcarbamic acid by a method similar to Example 125-b) 190 mg of chloromethyl and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- From 300 mg of [Il] thio] -1-methyl-1-carbapene-2-em-3-carboxylate, 285 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 1.05-1.42 (6H, m), 1.20 (3H, d, J = 7.3 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.72-1.78 (4H, m), 1.96 (1H, m), 2.54 (1H, m), 3.15-3.29 (3H, m), 3.54 (1H, m), 3.76, 3.91 (total 1H, m), 4.24-4.27 (2H, m), 4.85 ( 2H, d, J = 5.9 Hz), 5.93 (1H, d, J = 5.6 Hz), 6.02 (1H, d, J = 5.6 Hz), 6.51 (1H, d, J = 10.2 Hz), 7.12 (1H, d, J = 10.2 Hz), 8.77 (1H, s)

Example 134 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-isobutyl-N-isopropylaminocarbonyloxymethyl
a) Chloromethyl N-isobutyl-N-isopropylcarbamate
To 870 mg of N-isobutylisopropylamine, 9 ml of toluene, 1.42 ml of N, N-diisopropylethylamine, and 0.56 ml of chloromethyl chloroformate were sequentially added and stirred at room temperature for 16 hours. After 15 ml of 1N hydrochloric acid was added for liquid separation, the organic layer was washed with 15 ml each of 5% aqueous sodium hydrogen carbonate solution and 20% brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain 1.23 g of chloromethyl N-isobutyl-N-isopropylcarbamate.
NMR (CDCl ₃ ) δ: 0.90 (6H, d, J = 6.6 Hz), 1.19-1.27 (6H, m), 1.86-2.00 (1H, m), 3.00, 3.07 (total 2H, d each, J = 7.3 Hz), 3.94-3.99 (1H, m), 5.79, 5.82 (2H, s each)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-isobutyl-N-isopropylaminocarbonyloxymethyl N-isobutyl-N-isopropylcarbamic acid by a method similar to Example 125-b) 177 mg of chloromethyl and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- From yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate 300 mg, the title compound 279 mg was obtained.
NMR (CDCl ₃ ) δ: 0.85-0.89 (6H, m), 1.18-1.28 (9H, m), 1.34 (3H, d, J = 6.3 Hz), 1.85-1.95 (2H, m), 2.55 (1H, t, J = 6.0 Hz), 2.99-3.04 (2H, m), 3.27 (1H, dd, J ₁ = 2.7 Hz, J ₂ = 6.8 Hz), 3.54 (1H, m), 3.94-4.00 (1H, m ), 4.23-4.26 (2H, m), 4.86 (2H, d, J = 5.6 Hz), 5.91-6.03 (2H, m), 6.51 (1H, d, J = 10.2 Hz), 7.12 (1H, d, J = 10.2 Hz), 8.77 (1H, s)

EXAMPLE 135 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid Nt-butyl-N-ethylaminocarbonyloxymethyl
a) Chloromethyl Nt-butyl-N-ethylcarbamate Using the same procedure as Example 125-a), 9.15 ml of Nt-butylethylamine and 2.67 ml of chloromethyl chloroformate, 5.54 chloromethyl Nt-butyl-N-ethylcarbamate g was obtained.
NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 6.9 Hz), 1.43 (9H, s), 3.40 (2H, q, J = 7.1 Hz), 5.80 (2H, s)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-Methyl-1-carbapene-2-em-3-carboxylic acid Nt-butyl-N-ethylaminocarbonyloxymethyl Nt-butyl-N-ethylcarbamic acid by a method similar to Example 125-b) 180 mg of chloromethyl and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- From 300 mg of [Il] thio] -1-methyl-1-carbapene-2-em-3-carboxylate, 273 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.1 Hz), 1.19 (3H, d, J = 7.3 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.41 (9H, s), 2.06 (1H, m), 2.63 (1H, m), 3.27 (1H, dd, J ₁ = 2.7 Hz, J ₂ = 6.8 Hz), 3.39 (2H, q, J = 7.0 Hz), 3.50-3.58 (1H , m), 4.24-4.27 (2H, m), 4.85 (2H, d, J = 4.6 Hz), 5.91 (1H, d, J = 5.6 Hz), 6.00 (1H, d, J = 5.6 Hz), 6.51 (1H, d, J = 10.2 Hz), 7.12 (1H, d, J = 10.2 Hz), 8.77 (1H, s)

Example 136 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 1- (N, N-diisopropylaminocarbonyloxy) ethyl (mixture of diastereomers)
a) 1-chloroethyl N, N-diisopropylcarbamate 1-chloroethyl N, N-diisopropylcarbamate from 15.4 ml N, N-diisopropylamine and 5.40 ml 1-chloroethyl chloroformate in the same manner as in Example 125-a) 10.2 g was obtained.
NMR (CDCl ₃ ) δ: 1.23 (12H, d, J = 6.8 Hz), 1.83 (3H, d, J = 5.9 Hz), 3.76 (1H, m), 4.11 (1H, m), 6.65 (1H, q , J = 5.8 Hz)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1- (N, N-diisopropylaminocarbonyloxy) ethyl N, N-diisopropylcarbamic acid by a method similar to Example 125-b) 247 mg of 1-chloroethyl and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1 The title compound (92 mg) was obtained from 400 mg of -yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.16-1.22 (15H, m), 1.32-1.35 (3H, m), 1.60-1.64 (3H, m), 1.86 (1H, m), 2.55 (1H, m), 3.25- 3.29 (1H, m), 3.48-3.56 (1H, m), 3.75 (1H, m), 4.08 (1H, m), 4.22-4.26 (2H, m), 4.84, 4.86 (total 2H, s each), 6.50-6.53 (1H, m), 7.00-7.11 (2H, m), 8.76, 8.77 (total 1H, s each)

[Example 137] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl (mixture of diastereomers)
a) 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl chloride In a manner similar to Example 125-a), 8.45 g of cis-2,6-dimethylpiperidine, chloroformate-1 -6.01 g of 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl chloride was obtained from 3.66 ml of chloroethyl.
NMR (CDCl ₃ ) δ: 1.21-1.29 (6H, m), 1.45-1.86 (9H, m), 4.28-4.38 (2H, m), 6.60-6.68 (1H, m)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl (mixture of diastereomers)
In the same manner as in Example 125-b), 283 mg of 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl chloride and (1R, 5S, 6S) -6-((1R)- 1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbapen-2-em-3- The title compound (98 mg) was obtained from 404 mg of sodium carboxylate.
NMR (CDCl ₃ ) δ: 1.15-1.27 (9H, m), 1.31-1.37 (3H, m), 1.40-1.81 (9H, m), 1.92 (1H, brs), 2.59 (1H, brs), 3.25- 3.30 (1H, m), 3.47-3.58 (1H, m), 4.18-4.39 (4H, m), 4.82-4.87 (2H, m), 6.51 (1H, d, J = 10.5 Hz), 6.97-7.13 ( 2H, m), 8.78 (1H, m)

Example 138 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-ethyl-N-isoamylaminocarbonyloxymethyl
a) Chloromethyl N-ethyl-N-isoamylcarbamate Using the same procedure as in Example 125-a), N-ethyl-N-isoamylcarbamate from 228 mg of N-ethyl-N-isoamylamine and 0.089 ml of chloromethyl chloroformate 207 mg of chloromethyl was obtained.
NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.4 Hz), 1.10-1.19 (3H, m), 1.44-1.49 (2H, m), 1.55-1.62 (1H, m), 3.18-3.38 ( 4H, m), 5.80 (2H, s)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N-ethyl-N-isoamylaminocarbonyloxymethyl N-ethyl-N-isoamylcarbamic acid by a method similar to Example 125-b) 202 mg of chloromethyl and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- From 328 mg of sodium [yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate, 213 mg of the title compound was obtained.
NMR (CDCl ₃ ) δ: 0.83-0.94 (6H, m), 1.07-1.13 (3H, m), 1.19 (3H, d, J = 7.2 Hz), 1.23-1.42 (3H, m), 1.34 (3H, d, J = 6.4 Hz), 1.87-1.95 (1H, m), 2.48 (1H, t, J = 5.9 Hz), 3.19-3.34 (5H, m), 3.48-3.59 (1H, m), 4.21-4.30 (2H, m), 4.86 (2H, d, J = 5.6Hz), 5.90-5.94 (1H, m), 5.97-6.02 (1H, m), 6.51 (1H, d, J = 10.2 Hz), 7.12 ( 1H, d, J = 10.2 Hz), 8.77 (1H, s)

[Example 139] 29.4 g of calcium chloride dihydrate, 11.80 g of ethyl 5-bromothiazole-4-carboxylate and 30 ml of THF were sequentially added to 60 ml of (5-bromothiazol-4-yl) methanol water and stirred. After adjusting the reaction solution temperature to 0-2 ° C, 3.78 g of sodium borohydride was added at a reaction solution temperature of 5 ° C or less. After stirring at a reaction solution temperature of 2-7 ° C. for 2 hours, 22 ml of acetone and 20 ml of 5 N hydrochloric acid were sequentially added at a reaction solution temperature of 7 ° C. or less. After stirring at the same temperature for 30 minutes, the pH was adjusted to 5 with a 5N aqueous sodium hydroxide solution. The reaction mixture was extracted with 120 ml of ethyl acetate, the separated aqueous layer was extracted with 120 ml of ethyl acetate, and the organic layers were combined. The organic layer was washed sequentially with 5% aqueous sodium bicarbonate 60 ml, 30 ml, and 20% brine 30 ml, the aqueous layers were combined, extracted with ethyl acetate 120 ml, and the organic layers were combined. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off to separate the solid obtained to obtain 7.64 g of (5-bromothiazol-4-yl) methanol.
NMR (CDCl ₃ ) δ: 2.73 (1H, t, J = 6.3 Hz), 4.76 (2H, d, J = 6.3 Hz), 8.78 (1H, s)

Example 140 [5- [2- (Trimethylsilyl) ethynyl] thiazol-4-yl] methanol
Into 25 ml of DMF, 6.15 g of (5-bromothiazol-4-yl) methanol, 8.9 ml of triethylamine, 61 mg of copper (I) iodide, 5.4 ml of trimethylsilylacetylene, 223 mg of bis (triphenylphosphine) palladium (II) dichloride are sequentially added. The atmosphere was replaced with argon by stirring. The reaction mixture was heated and stirred at 90 ° C. for 90 minutes and then released. 74 ml of toluene and 25 ml of water were added to the reaction mixture, and the aqueous layer was separated. After 25 ml of water was added to the organic layer and adjusted to pH 2 with 5 N hydrochloric acid, the aqueous layer was separated. The organic layer was washed successively with 25 ml of 5% aqueous sodium bicarbonate and 25 ml of 10% brine and treated with 1.4 g of activated carbon and anhydrous magnesium sulfate. The solid obtained by distilling off the solvent was separated to obtain 5.35 g of [5- [2- (trimethylsilyl) ethynyl] thiazol-4-yl] methanol.
NMR (CDCl ₃ ) δ: 0.26 (9H, s), 2.75 (1H, t, J = 6.3 Hz), 4.83 (2H, d, J = 6.3 Hz), 8.64 (1H, s)

[Example 141] 5-Ethynyl-4-hydroxymethylthiazole
To a solution of 6.05 g of [5- [2- (trimethylsilyl) ethynyl] thiazol-4-yl] methanol, 39 mg of potassium carbonate was added and stirred at room temperature for 10 minutes. After adding 6 ml of 10% aqueous citric acid solution and stirring for 30 minutes, the reaction mixture was extracted with 90 ml of ethyl acetate. The organic layer was washed sequentially with 12 ml of 5% sodium bicarbonate water and 12 ml of 20% brine and treated with 0.8 g of activated carbon and anhydrous magnesium sulfate. To the obtained organic layer, 15 ml of toluene was added and concentrated, and the precipitated solid was collected by filtration to obtain 3.11 g of 5-ethynyl-4-hydroxymethylthiazole.
NMR (CDCl ₃ ) δ: 3.48 (1H, t, J = 6.32 Hz), 3.60 (1H, s), 4.85 (2H, d, J = 6.32 Hz), 8.69 (1H, s)

Example 142 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N, N-diisopropylaminocarbonyloxymethyl
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Add 1.81 g of chloromethyl N, N-diisopropylcarbamate and 2.76 g of triethylbenzylammonium chloride to 50 ml of N, N-dimethylacetamide solution of 4.89 g of sodium 1-methyl-1-carbapene-2-em-3-carboxylate And stirred at 30 ° C. for 5 hours. The reaction solution was washed twice with 180 ml of heptane, and 125 ml each of ethyl acetate and 20% brine were added. After separation, the organic layer was washed 3 times with 125 ml of 10% brine. After drying over anhydrous magnesium sulfate and filtration, ethyl acetate was distilled off under reduced pressure to obtain 6.01 g of the title compound.

Example 143 (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-carbapene-2-em-3-carboxylate sodium salt
a) (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1-Carbapen-2-em-3-carboxylic acid 4-nitrobenzyl Example 41-b) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-((1R) -1-hydroxyethyl ) -1-Methyl-1-carbapene-2-em-3-carboxylate instead of using 4-nitrobenzyl (5R, 6S) -2- (diphenylphosphoryloxy) -6-((1R) -1- (5R, 6S) -6-((1R) -1-Hydroxyethyl) In substantially the same manner except that 4.13 g of 4-nitrobenzyl 4-hydroxybenzyl) (hydroxyethyl) -1-carbapene-2-em-3-carboxylate was used ) -2-[[(Z) -2- (4-Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-carbapene-2-em-3-carboxylate g was obtained.
NMR (DMSO-d ₆ ) δ: 1.14 (3H, d, J = 6.4 Hz), 3.30-3.39 (1H, m), 3.41-3.54 (2H, m), 3.93-4.03 (1H, m), 4.18- 4.27 (1H, m), 4.66 (2H, d, J = 5.8 Hz), 5.13 (1H, d, J = 5.1 Hz), 5.31 (1H, t, J = 5.8 Hz), 5.36 (1H, d, J = 13.8 Hz), 5.50 (1H, d, J = 13.8 Hz), 6.83 (1H, d, J = 10.5 Hz), 7.27 (1H, d, J = 10.5 Hz), 7.75 (2H, d, J = 8.7 Hz), 8.26 (2H, d, J = 8.7 Hz), 9.03 (1H, s)

b) (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] Sodium -1-carbapene-2-em-3-carboxylate (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z ) -2- (4-Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-carbapene-2-em-3-carboxylate 4-nitrobenzyl 1.10 g gave the title compound 259 mg. .
NMR (DMSO-d ₆ ) δ: 1.13 (3H, d, J = 6.3 Hz), 2.95-3.04 (1H, m), 3.12-3.24 (2H, m), 3.84-3.95 (1H, m), 3.97- 4.06 (1H, m), 4.63 (2H, d, J = 5.8 Hz), 5.02 (1H, d, J = 4.8 Hz), 5.23 (1H, t, J = 5.8 Hz), 6.79 (1H, d, J = 10.0 Hz), 6.99 (1H, d, J = 10.0 Hz), 9.00 (1H, s)

Example 144 (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] Thio] -1-carbapene-2-em-3-carboxylic acid N, N-diisopropylaminocarbonyloxymethyl
(5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1 -Carbapent-2-em-3-carboxylate 100 mg in N, N-dimethylacetamide solution 2 ml, N, N-diisopropylcarbamate chloromethyl 54 mg and n-tetrabutylammonium bromide 75 mg were added, and 3 Stir for 30 minutes. 10 ml each of ethyl acetate and half-saturated saline were added to the reaction solution, and after separation, the organic layer was washed three times with 10 ml of half-saturated saline. The extract was dried over anhydrous magnesium sulfate and filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 15: 1) to give 108 mg of the title compound.
NMR (CDCl ₃ ) δ: 1.22 (12H, d, J = 6.8 Hz), 1.33 (3H, d, J = 6.3 Hz), 3.07-3.22 (2H, m), 3.30-3.40 (1H, m), 3.79 (1H, brs), 4.07 (1H, brs), 4.19-4.30 (2H, m), 4.84 (2H, s), 5.94 (1H, d, J = 5.6 Hz), 6.02 (1H, d, J = 5.6 Hz), 6.50 (1H, d, J = 10.3 Hz), 7.08 (1H, d, J = 10.3 Hz), 8.77 (1H, s)

Example 145 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapen-2-em-3-carboxylic acid
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] To 120 ml of an aqueous solution of 2.73 g of sodium -1-methyl-1-carbapene-2-em-3-carboxylate, 7.10 ml of 1N hydrochloric acid was added at room temperature and stirred for 3 minutes. The mixture was extracted twice with 150 ml of ethyl acetate, dried over anhydrous magnesium sulfate and filtered, and then ethyl acetate was distilled off to 50 ml under reduced pressure. 1.63 g of the title compound was obtained by adding 200 ml of hexane and collecting the precipitated solid by filtration.
NMR (DMSO-d ₆ ) δ: 1.16 (3H, d, J = 7.3 Hz), 1.14 (3H, d, J = 6.3 Hz), 3.28 (1H, dd, J ₁ = 6.2 Hz, J ₂ = 2.8 Hz ), 3.69-3.80 (1H, m), 3.93-4.01 (1H, m), 4.19 (1H, dd, J ₁ = 10.0 Hz, J ₂ = 2.7 Hz), 4.66 (2H, s), 5.09 (1H, brs), 5.32 (1H, brs), 6.84 (1H, d, J = 10.7 Hz), 7.29 (1H, d, J = 10.7 Hz), 9.05 (1H, s)

Example 146 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylate potassium
(1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl 1.00 g water 2.5 ml, THF 7.5 ml mixed solution 10% Pd-C catalyst (water content, water 53%) 500 mg And stirred for 3 hours under a hydrogen atmosphere while maintaining the temperature at 30 to 35 ° C. The catalyst was filtered, and 1.7 ml of 1 M aqueous potassium hydrogen carbonate solution and 0.061 ml of 2-ethylhexanoic acid were added to the filtrate. The mixture was washed with 80 ml of ethyl acetate, and the aqueous layer was concentrated to about 10 ml. The precipitated insoluble matter was removed by filtration, and the filtrate was further concentrated to about 8 ml. 60 ml of acetone was added and stirred for 1 hour under ice cooling. The precipitated solid was collected by filtration to give 432 mg of the title compound.
NMR (DMSO-d ₆ ) δ: 0.96 (3H, d, J = 7.3 Hz), 1.14 (3H, d, J = 6.4 Hz), 3.06 (1H, dd, J ₁ = 6.8 Hz, J ₂ = 2.7 Hz ), 3.37-3.48 (1H, m), 3.86-3.94 (1H, m), 4.01 (1H, dd, J ₁ = 9.6 Hz, J ₂ = 2.7 Hz), 4.63 (2H, d, J = 5.4 Hz) , 5.00 (1H, d, J = 5.1 Hz), 5.24 (1H, t, J = 5.4 Hz), 6.78 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 10.7 Hz), 8.99 (1H, s)

Example 147 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(E) -2- (4-hydroxymethylthiazol-5-yl) ethene-1- Yl] thio] -1-methyl-1-carbapene-2-em-3-carboxylic acid N, N-diisopropylaminocarbonyloxymethyl In the same manner as in Example 144, 50.4 mg of chloromethyl N, N-diisopropylcarbamate was obtained. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(E) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] 90.8 mg of the title compound was obtained from 87.8 mg of sodium -1-methyl-1-carbapene-2-em-3-carboxylate.
NMR (CDCl ₃ ) δ: 1.14-1.26 (15H, m), 1.34 (3H, d, J = 6.4 Hz), 3.27 (1H, dd, J ₁ = 7.0 Hz, J ₂ = 2.6 Hz), 3.49-3.57 (1H, m), 3.79 (1H, brs), 4.07 (1H, brs), 4.21-4.29 (2H, m), 4.81 (2H, s), 5.90 (1H, d, J = 5.6 Hz), 6.00 ( 1H, d, J = 5.6 Hz), 6.74 (1H, d, J = 15.2 Hz), 7.12 (1H, d, J = 15.2 Hz), 8.64 (1H, s)

Hereinafter, Table 1 to Table 10 are Example compounds.
In the table, Me is a methyl group, Et is an ethyl group, iPr is an isopropyl group, nPr is an n-propyl group, nBu is an n-butyl group, tBu is a tert-butyl group, Tr is a trityl (triphenylmethyl) group, TMS Represents a trimethylsilyl group, and E / Z represents a stereo of the thioethenyl moiety.

[Test Example 1] Antibacterial activity The following are the minimum inhibitory concentrations (MIC, μg / ml) of representative compounds of the novel carbapenem derivatives of the present invention against various pathogens, CHEMOTHERAPY, vol. 16, No. 1,99, 1968. Measured according to the method described in Table 1, and the results are shown in Table 11. The measurement medium is SensitivityDisk agar-N + 5% Horse blood, and the amount of inoculum is 10 ⁶ CFU / ml.
The comparative substance was IPM (imipenem).

Claims (22)

A compound of the following formula (I), or a pharmaceutically acceptable salt thereof:

[Where:
R ¹ represents a hydrogen atom or a methyl group,
R ² and R ³ may be the same or different,
Hydrogen atom,
Halogen atoms,
An amino group,
A substituted amino group,
A lower alkyl group,
A substituted lower alkyl group,
A carbamoyl group,
A substituted aminocarbonyl group,
A lower alkoxycarbonyl group,
A substituted lower alkoxycarbonyl group,
A heterocyclic carbonyl group, or
Represents a substituted heterocyclic carbonyl group,
R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo]. In which R ² and R ³ may be the same or different,
Hydrogen atom,
Halogen atoms,
An amino group,
A substituted amino group,
A lower alkyl group,
A hydroxy lower alkyl group,
A cyano lower alkyl group,
A lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkyl group,
Lower alkoxy lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkoxy lower alkyl group,
An acyloxy lower alkyl group,
A substituted acyloxy lower alkyl group,
A carbamoyl group,
A mono-lower alkylcarbamoyl group,
A substituted mono-lower alkylcarbamoyl group,
Di-lower alkylcarbamoyl group,
A substituted di-lower alkylcarbamoyl group,
A lower alkoxycarbonyl group,
An azetidinylcarbonyl group, or
The compound according to claim 1, which represents a substituted azetidinylcarbonyl group, or a pharmaceutically acceptable salt thereof. In which R ² and R ³ may be the same or different,
Hydrogen atom,
Halogen atoms,
An amino group,
Methyl group,
A cyanomethyl group,
A hydroxymethyl group,
An acetoxymethyl group,
(2-hydroxyethoxy) methyl group,
(3-hydroxypropyloxy) methyl group,
(2-methoxyethoxy) methyl group,
(2-acetoxyethoxy) methyl group,
L-valyloxymethyl group,
A carbamoyl group,
An N-methylcarbamoyl group,
An N-cyanomethylcarbamoyl group,
An N- (2-cyanoethyl) carbamoyl group,
An N- (2-hydroxyethyl) carbamoyl group,
An N- (3-hydroxypropyl) carbamoyl group,
An N, N-dimethylcarbamoyl group,
An N- (2-hydroxyethyl) -N-methylcarbamoyl group,
An N-cyanomethyl-N-methylcarbamoyl group,
A methoxycarbonyl group,
An ethoxycarbonyl group,
(Azetidin-1-yl) carbonyl group,
(3-cyanoazetidin-1-yl) carbonyl group, or
The compound according to claim 1, which represents a (3-hydroxyazetidin-1-yl) carbonyl group, or a pharmaceutically acceptable salt thereof. A compound of the following formula (II), or a pharmaceutically acceptable salt thereof:

[Where:
R ¹ represents a hydrogen atom or a methyl group,
Ring A is
4-hydroxymethylthiazole,
5-hydroxymethylthiazole,
4- (2-hydroxyethoxy) methylthiazole,
4-N, N-dimethylcarbamoylthiazole,
2-N, N-dimethylcarbamoylthiazole,
4-methylthiazole,
4-carbamoylthiazole,
2-carbamoylthiazole,
4-N-methylcarbamoylthiazole,
4-N-cyanomethyl-N-methylcarbamoylthiazole,
4-N-cyanomethylcarbamoylthiazole,
4-N- (2-cyanoethyl) carbamoylthiazole,
4-cyanomethylthiazole,
4- (2-methoxyethoxy) methylthiazole,
4- (3-cyanoazetidin-1-yl) carbonylthiazole,
4-N- (2-hydroxyethyl) carbamoylthiazole,
4-N- (3-hydroxypropan-1-yl) carbamoylthiazole,
4-N- (2-hydroxyethyl) -N-methylcarbamoylthiazole,
4- (azetidin-1-yl) carbonylthiazole,
4- (3-hydroxyazetidin-1-yl) carbonylthiazole,
4- (3-hydroxypropan-1-yloxy) methylthiazole,
2-amino-4-carbamoylthiazole,
2-aminothiazole,
4,5-dicarbamoylthiazole,
4-acetoxymethylthiazole,
4- (2-acetoxyethoxy) methylthiazole,
4- (L-valyloxymethyl) thiazole,
4-methoxycarbonylthiazole,
4-ethoxycarbonylthiazole,
2-amino-4-methoxycarbonylthiazole, or
2-amino-4-ethoxycarbonylthiazole,
Represents
R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo]. In the formula, R ¹ is a methyl group, or a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. Where R ⁴ is
Hydrogen atom,
A lower alkyl group,
A lower alkenyl group,
A lower alkylcarbonyloxy lower alkyl group,
A lower cycloalkylcarbonyloxy lower alkyl group,
A lower cycloalkylmethylcarbonyloxy lower alkyl group,
A lower alkenylcarbonyloxy lower alkyl group,
An arylcarbonyloxy lower alkyl group,
Tetrahydrofuranylcarbonyloxymethyl group,
A lower alkoxy lower alkyl group,
Lower alkoxy lower alkoxy lower alkyl group,
An arylmethyloxy lower alkyl group,
Arylmethyloxy lower alkoxy lower alkyl group,
A lower alkoxycarbonyloxy lower alkyl group,
Lower alkoxycarbonyloxy lower alkoxy group,
A lower cycloalkoxycarbonyloxy lower alkyl group,
A lower cycloalkylmethoxycarbonyloxy lower alkyl group,
Aryloxycarbonyloxy lower alkyl group,
3-phthalidyl group optionally having a substituent on the aromatic ring,
2- (3-phthalidylidene) ethyl group optionally having a substituent on the aromatic ring,
2-oxotetrahydrofuran-5-yl group,
4-tetrahydropyranyloxycarbonyloxy lower alkyl group,
Mono lower alkylaminocarbonyloxy lower alkyl group,
Di-lower alkylaminocarbonyloxy lower alkyl group,
2-oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl group,
An optionally substituted piperidinylcarbonyloxy-lower alkyl group, or
Lower alkyl lower cycloalkylaminocarbonyloxy lower alkyl group,
The compound as described in any one of Claims 1-5 which represents these, or its pharmaceutically acceptable salt. In the formula, R ⁴ represents an ethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, acetoxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, pivaloyloxy. Methyl group, cyclohexyloxycarbonyloxymethyl group, 1- (isobutyloxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl group, isobutyloxycarbonyloxymethyl group, isopropyloxycarbonyl Oxymethyl group, isobutyryloxymethyl group, (pentan-1-yl) oxycarbonyloxymethyl group, (butan-1-yl) oxycarbonyloxymethyl group, (1-ethylpropan-1-yl) oxycarbonyloxy Methyl group, isopentyloxycarbonyloxymethyl group, (propan-1-yl) oxymethyl group, ethoxycarbonyloxymethyl group, neopentyloxycarbonyloxymethyl group, methoxycarbonyloxymethyl group, cyclopentyloxycarbonyloxymethyl group, t -Butoxycarbonyloxymethyl group, phthalidyl group, 1- (methoxycarbonyloxy) ethyl group, 1- (cyclopentyloxycarbonyloxy) ethyl group, (tetrahydropyran-4-yl) oxycarbonyloxymethyl group, 1- (neopentyl) Oxycarbonyloxy) ethyl group, (piperidin-1-yl) carbonyloxymethyl group, allyl group, 1- (t-butoxycarbonyloxy) ethyl group, N, N-di (propan-1-yl) aminocarbonyl Oxymethyl group, phenyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3dioxolen-4-yl) methyl group, (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl group N, N-di- (butan-1-yl) aminocarbonyloxymethyl group, hexane-1-yl group, N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl group, N, N- Diisobutylaminocarbonyloxymethyl group, N, N-diisopropylaminocarbonyloxymethyl group, N-cyclohexyl-N-methylaminocarbonyloxymethyl group, N-pentan-1-ylaminocarbonyloxymethyl group, N-cyclohexyl-N- Ethylaminocarbonyloxymethyl group, N-isobutyl-N-isopropyl Ruaminocarbonyloxymethyl group, Nt-butyl-N-ethylaminocarbonyloxymethyl group, 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl group, 1- (N, The compound according to claim 6, which represents an (N-diisopropylaminocarbonyloxy) ethyl group or an N-ethyl-N-isoamylaminocarbonyloxymethyl group, or a pharmaceutically acceptable salt thereof. A compound of the following formula (III), or a pharmaceutically acceptable salt thereof:

[Where:
One of R ² ′ and R ^{3 ′} is
A hydroxy lower alkyl group,
A hydroxy lower alkyl group protected with a hydroxyl protecting group,
A lower alkoxy lower alkyl group, or
Represents a lower alkoxycarbonyl group, and the other is a hydrogen atom,
R ⁵ represents a hydrogen atom or an alkynyl protecting group. In formula (III), one of R ^{2 ′} and R ^{3 ′} is
A hydroxymethyl group,
An acetoxymethyl group,
A methoxycarbonyl group,
An ethoxycarbonyl group,
And the other is a hydrogen atom, or a pharmaceutically acceptable salt thereof. A compound of the following formula (IV), or a pharmaceutically acceptable salt thereof:

[Where:
R ^{2 ′} and R ^{3 ′} may be the same or different,
Hydrogen atom,
Halogen atoms,
An amino group,
A substituted amino group,
A hydroxy lower alkyl group,
A cyano lower alkyl group,
A lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkyl group,
Lower alkoxy lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkoxy lower alkyl group,
An acyloxy lower alkyl group,
A substituted acyloxy lower alkyl group,
A carbamoyl group,
A mono-lower alkylcarbamoyl group,
A substituted mono-lower alkylcarbamoyl group,
Di-lower alkylcarbamoyl group,
A substituted di-lower alkylcarbamoyl group,
A lower alkoxycarbonyl group,
An azetidinylcarbonyl group, or
Represents a substituted azetidinylcarbonyl group,
R ⁶ is
R ⁷ —S—C═C—
Wherein R ⁷ represents a hydrogen atom, a metal ion, or a protecting group for a thiol]. In formula (IV), one of R ^{2 ′ and} R ^{3 ′} is
A hydroxy lower alkyl group,
A hydroxy lower alkyl group protected with a hydroxyl protecting group,
A lower alkoxy lower alkyl group, or
The compound according to claim 10, which represents a lower alkoxycarbonyl group, and the other represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. In formula (IV), one of R ^{2 ′} and R ^{3 ′} is
A hydroxymethyl group,
An acetoxymethyl group,
A methoxycarbonyl group, or
An ethoxycarbonyl group,
The compound according to claim 11, wherein the other represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 10 to 12, or a pharmaceutically acceptable salt thereof, having R ⁶ at the 5-position on the thiazole ring of the formula (IV). A process for the preparation of a compound of formula (I) according to claim 1,
A method comprising reacting a compound of the following formula (V) with a compound of the following formula (IVc):

[Where:
R ¹ represents a hydrogen atom or a methyl group,
R ⁸ represents a hydrogen atom or a hydroxyl-protecting group,
R ⁹ represents a protecting group for a carboxyl group, and
L represents a leaving group];

[Where:
R ^7c represents a metal ion,
R ^{2 ′} and R ^{3 ′} may be the same or different,
Hydrogen atom,
Halogen atoms,
An amino group,
A substituted amino group,
A hydroxy lower alkyl group,
A cyano lower alkyl group,
A lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkyl group,
Lower alkoxy lower alkoxy lower alkyl group,
A substituted lower alkoxy lower alkoxy lower alkyl group,
An acyloxy lower alkyl group,
A substituted acyloxy lower alkyl group,
A carbamoyl group,
A mono-lower alkylcarbamoyl group,
A substituted mono-lower alkylcarbamoyl group,
Di-lower alkylcarbamoyl group,
A substituted di-lower alkylcarbamoyl group,
A lower alkoxycarbonyl group,
An azetidinylcarbonyl group, or
Represents a substituted azetidinylcarbonyl group]. 15. The method of claim 14, further comprising obtaining a compound of formula (IVc) by reacting a compound of formula (III) below with a corresponding thiol represented by formula ^R7bSH :

[Where:
One of R ² ′ and R ^{3 ′} is
A hydroxy lower alkyl group,
A hydroxy lower alkyl group protected with a hydroxyl protecting group,
A lower alkoxy lower alkyl group, or
Represents a lower alkoxycarbonyl group, and the other is a hydrogen atom,
R ⁵ represents a hydrogen atom or a protecting group for an alkynyl group], and R ^7b in the corresponding thiol may be a triphenylmethyl group, a diphenylmethyl group, an acyl-based protecting group, or a substituted group. It is a group selected from the group consisting of a good benzyl group and a silyl protecting group.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.   The pharmaceutical composition according to claim 16 or 17, which is used as an antibacterial agent.   Bacterial infection or symptoms associated therewith comprising administering an effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof to a patient in need thereof. How to treat or prevent.   The method according to claim 19, wherein the bacterium is selected from the group consisting of pneumococci, Haemophilus influenzae, catalucoccus, and β-lactamase producing bacteria.   Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a bacterial infection or a symptom associated therewith.   The use according to claim 21, wherein the bacterium is selected from the group consisting of pneumococci, Haemophilus influenzae, catalucoccus, and β-lactamase producing bacteria.