WO2004067532A1 - Novel carbapenem derivatives - Google Patents

Abstract

A carbapenem derivative represented by the following general formula (I) which has a potent antimicrobial effect on pneumococci including MRSA, VRE and PRSP, influenza viruses including BLNAR and β-lactamase-producing strains from among resistant strains bringing about clinical problems at present.

Description

 Novel potato derivatives [Background of the invention]

 Field of the invention

 Light

 The present invention relates to a compound having excellent antibacterial activity and a broad spectrum, and more particularly, to a substituted (thiazole-5-yl) thio group at the 2-position on the compound. The present invention relates to a novel derivative of the compound.

 Background art

Because of its strong antibacterial activity and excellent antibacterial spectrum over a wide range, research on virucanem derivatives has been actively conducted as a highly useful ^ -lactam agent, and iminemene and panipenem have already been studied. And meropenem are used in clinical settings. Furthermore, a group of compounds using various bonding modes at the 2-position of the carbane ring have been studied (Expert Opinion on Therapeutic Patents, (UK), 2001, 11 (8) ₅ pl2 67-1276), Above all, research has been conducted on a group of compounds having a heterocyclic ring via a sulfur atom at the 2-position of the ring. However, antimicrobial activity against various resistant bacteria is not always satisfactory. For example, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), penicillin-resistant pneumococcus (PRSP), which are major clinical problems today, ^ It is not necessarily sufficient antibacterial activity against ampicillin-resistant H. influenzae (BLN AR) and resistant Pseudomonas aeruginosa, which do not produce lactose. There is a need for effective drugs against these infectious disease-causing bacteria.

 Therefore, an object of the present invention is to provide a potent rubenem derivative having a strong antibacterial activity against pneumococci including MRSA, VRE and PRSP, influenza bacteria including BLNAR and / or -lactamase-producing bacteria. And

[Overview of the invention]

The present inventors have recently proposed a new S-carbane derivative represented by the following formula (I): It has a broad and strong antibacterial activity against rum-positive and gram-negative bacteria, and has a strong antibacterial activity against MRSA, PRSP, H. influenzae and / or lactamase-producing bacteria. Was. The present invention is based on such findings. Further, the carbane derivative according to the present invention is a compound of the following general formula (I) or a pharmaceutically acceptable salt thereof:

[In the above formula,

R ¹ represents a hydrogen atom or a methyl group,

R ² and R ³ may be the same or different;

 Hydrogen atom,

 Halogen atom,

 Formyl group,

 Nitrile group,

 An amino group which may be substituted,

 An optionally substituted lower alkyl group,

 Optionally substituted rubamoyl group,

 An optionally substituted lower alkylcarbonyl group,

 An optionally substituted lower alkoxycarbonyl group,

 An arylcarbonyl group which may be substituted,

 An optionally substituted heteroarylcarbonyl group,

 Carboxyl group,

 An aryl group which may be substituted,

An optionally substituted heteroaryl group, A lower alkylthio group, or.

 Lower alkylsulfonyl group,

 Represents

However, R ² and R ³ do not both represent a hydrogen atom,

R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo. ].

 The rubanem derivative of the general formula (I) according to the present invention has a broad and strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria. In particular, it has strong antibacterial activity against various pathogens including pneumococci including MRSA, VHE and PRSP, influenzae including BLNAR, and / or lactobacillus producing bacteria. In particular, the potent rubanem derivatives of the general formula (I) according to the invention show a particularly pronounced antibacterial activity against pneumococci containing PRSP.

Furthermore, among the compounds of the general formula (I) according to the present invention, the carbane derivative of the compound (I) in which R ⁴ is a group that is hydrolyzed in vivo, exhibits excellent oral absorbability, and It is metabolically deesterified in the body to produce a drug substance with antibacterial activity (compound of general formula (I ')). Therefore, the compound of the general formula (I) of the present invention is useful not only as an injection but also as an ester thereof as an oral preparation. Furthermore, the carbane derivative of the present invention is excellent in that it has low toxicity and high safety.

[Specific description of the invention]

Definition

 In the present specification, the term “lower alkyl group” or “lower alkoxy group” as a group or a part of a group preferably means that the group has a linear or branched carbon number of 1 to 6, more preferably 1 to 6 carbon atoms. 4 means an alkyl group or an alkoxy group.

 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-propyloxy, i-propyloxy, n-butyloxy, s-butyloxy, t-butyloxy, n-pentyloxy, neopentyloxy, i-pentyloxy, t-pentyloxy, n-hexyloxy, i-hexyloxy, etc. Is mentioned.

 As used herein, the term “lower cycloalkyl group” as a group or a part of a group means a monocyclic alkyl group having 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl Is mentioned.

 In the present specification, the “halogen atom” indicates each atom of fluorine, chlorine, bromine, and iodine.

 As used herein, the term “aryl group” as a group or part of a group means a phenyl group or a naphthyl group.

 As used herein, the term “heteroaryl group” as a group or part of a group is the same or different and has 5 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. It means a 6-membered aromatic heterocyclic ring. Preferably, it represents furan, pyrrole, imidazole, thiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, or pyrazine, and more preferably, furan, imidazole, thiazole, or the like. Pyridine and the like can be mentioned.

 Compound

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

According to a preferred embodiment of the present invention, there is provided a preferred compound of formula (I) wherein R ¹ is a methyl group.

R ² and R ³ may be the same or different and each is a hydrogen atom, a halogen atom, a formyl group, a nitrile group, an optionally substituted amino group, an optionally substituted lower alkyl group, Optionally substituted rubamoyl group, optionally substituted lower alkylcarbonyl group, optionally substituted lower alkoxylation group, optionally substituted arylcarbonyl group, substituted A heteroarylcarbonyl group, a carboxyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a lower alkylthio group, or a lower alkylaryl group. Represents a lower alkylsulfonyl group, provided that both R ² and R ³ do not represent a hydrogen atom.

In the optionally substituted amino group represented by R ² and R ³ , examples of one or more substituents of the amino group include 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 alkyl group, a rubamoyl group, a hydroxy lower alkyl group, an amino lower alkyl group, an aryl group, or a heteroaryl group. Preferably, a formyl group, a lower alkoxycarbonyl group, an aminocarbonyl group, and an aminosulfonyl group can be mentioned, and more preferably, a formyl group and a methoxycarbonyl group can be mentioned. Therefore, preferred examples of the optionally substituted amino group represented by R ² and R ³ include a formylamino group and a methoxycarbonylamino group. Examples of one or more substituents of the lower alkyl group represented by R ² and R ³ include a hydroxyl group, a lower alkoxy group, a lower alkylthio group, an amino group, an aryl group, a heteroaryl group, and a carbamoyl group. Group, lower alkylaminocarbonyl group, formylamino group, lower alkylcarbonylamino group, aminosulfonylamino group, and aminocarbonylamino group, and preferably a hydroxyl group.

Accordingly, a preferable example of the optionally substituted lower alkyl group represented by R ² and: ³ is a hydroxymethyl group.

Examples of one or more substituents of the optionally substituted rubamoyl group represented by R ² and R ³ include an optionally substituted lower alkyl group, a lower cycloalkyl group, and an optionally substituted lower group. Alkoxy group, lower alkoxyalkyl group, lower alkylcarbonyl group, lower alkoxycarbonyl group, formyl group, aminocarbonyl group, aminosulfonyl group, lower alkyl group rubamoyl group, hydroxy lower alkyl group, amino lower alkyl group, aryl group Or a heteroaryl group, preferably an optionally substituted lower alkyl group, a lower cycloalkyl group, an aryl group, a heteroaryl group, or an optionally substituted lower alkoxy group. More preferred substituents include a lower alkyl group (at least one hydrogen atom of the alkyl group is a hydroxyl group, an amino group, a carbamoyl group, an amino lower alkyl group). , A formylamino group, a lower alkylcarbonylamino group, an aminosulfonylamino group, an aminocarbonylamino group, a lower alkoxy group, a thiazolyl group, a furyl group, a pyridyl group, or a lower alkylthio group Good), lower cycloalkyl group, phenyl group, naphthyl group, thiazolyl group, furyl group, pyridyl group and lower alkoxy group. Particularly preferred are a methyl group, an ethyl group and a 1,1 -yl group. , Isopropyl group, butane-1-yl group, pentane-11-yl group, hexane-1-yl group, cyclopropyl group, cyclohexyl group, dimethyl group, N-hydroxylbamoylmethyl group, 2-hydroxyethyl Group, 3-hydroxypropane-1-yl group, 2-aminoethyl group, 2-formylaminoethyl group, 2-base Aminoethyl group, 2-aminosulfonylaminoethyl group, 2-aminocarbonylaminoethyl group, 2-methoxethyl group, (pyridine-2-yl) methyl group, (pyridine-3-yl) methyl group, 1-yl) methyl group,

(Furan-2-yl) methyl, methoxy, 2-methylthioethyl, phenyl, and thiazo-1-yl.

One or more hydrogen atoms of the lower alkylcarbonyl group represented by R ² and R ³ may be substituted, and examples of the substituent include a hydroxyl group, a lower alkoxy group, a lower alkylthio group, an amino group, an aryl group, Examples include a heteroaryl group, a carbamoyl group, a lower alkylaminocarbonyl group, a formylamino group, a lower alkylcarbonylamino group, an aminosulfonylamino group, and an aminocarbonylamino group, preferably a hydroxyl group or an N— And a methylcarbamoyl group.

Accordingly, in the optionally substituted lower alkyl carbonyl group represented by R ² and R ³ , preferred examples of the optionally substituted lower alkyl include a methyl group, an ethyl group, and an N-methylcarbamoyl. Examples include a methyl group, a 3-hydroxypropane-1-yl group, and a 3,4-dihydroxybutane-1-yl group.

One or more hydrogen atoms of the lower alkoxycarbonyl group represented by R ² and R ³ may be substituted, and examples of the substituent include a hydroxyl group, a lower alkoxy group, a lower alkylthio group, an amino group, and an aryl group. , A heteroaryl group, a carbamoyl group, a lower alkylaminocarbonyl group, a formylamino group, a lower alkylcarbonylamino group, an aminosulfonylamino group, and an aminocarbonylamino group. Examples are a hydroxyl group, a sulfamoyl group, a lower alkoxy group, and a lower alkylthio group. Accordingly, in the optionally substituted lower alkoxycarbonyl group represented by R ² and R ³ , preferred examples of the optionally substituted lower alkoxy group include a methoxy group, an ethoxy group, and a Yl) oxy, isopropyloxy, (butane-11-yl) oxy, carbamoylmethoxy, 2-hydroxyethoxy, (3-hydroxypropane-11-yl) oxy, 2,3-dihydroxypropane_1-yl) oxy group, (4-hydroxybutane_1-yl) oxy group, (3-hydroxybutane-1-yl) oxy group, (5-hydroxypentane-1 1-yl) oxy group, (2,2-dimethyl-13-hydroxypropan-1-yl) oxy group, (3-hydroxy-13-methylbutane-11-yl) oxy group, 2-methoxy Examples include a ethoxy group, a 2-ethoxyethoxy group, a (3-methoxypropanol) -ethoxy group, a 2- (2-hydroxyethoxy) ethoxy group, or a 2-methylthioethoxy group.

R ² and: One or more hydrogen atoms on the aryl or heteroaryl of the arylaryl, heteroarylcarbonyl, aryl and heteroaryl groups represented by R ³ are substituted. Examples of the substituent include a hydroxyl group, an amino group, a lower alkyl group and a lower alkoxy group.

The heteroaryl of the heteroarylcarbonyl group represented by R ² and R ³ is preferably a 5- or 6-membered aromatic having one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur. It is a heterocyclic ring, and more preferably, furan, pyrrole, thiazol, and pyridine.

The heteroaryl group represented by R ² and R ³ is preferably a 5- or 6-membered aromatic heterocyclic ring having one hetero atom selected from the group consisting of nitrogen, oxygen, and sulfur, more preferably And furan, pyrrol, thiazole and pyridine, and particularly preferably a pyridine-3-yl group, a pyridine-14-yl group, a thia, and a J-ru-2-yl group.

Preferred examples of the lower alkylthio group represented by R ² and R ³ include a methylthio group.

Preferred examples of the lower alkylsulfonyl group represented by R ² and are: And a methanesulfonyl group.

Further, according to a preferred embodiment of the present invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom and R ³ is a carbamoyl group.

According to another preferred embodiment of the present invention, there is provided a preferable compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom and R ³ is an acetyl group. You.

According to another preferred embodiment of the present invention, preferred compounds of the formula (I) or a pharmaceutically acceptable salt thereof are those wherein R ² is a hydrogen atom and R ³ is an ethoxycarbonyl group. Provided.

According to another preferred embodiment of the present invention, preferred compounds of the formula (I) or a pharmaceutically acceptable salt thereof are those wherein R ² is a hydrogen atom and R ³ is a methoxycarbonyl group. Provided.

According to another preferred embodiment of the present invention, as a preferable compound of the formula (I) or a pharmaceutically acceptable salt thereof: R ² is a hydrogen atom and R ³ is (2-hydroxy) ethoxycarbonyl The base is provided.

According to another preferred embodiment of the present invention, as a preferable compound of the formula (I) or a pharmaceutically acceptable salt thereof, is a hydrogen atom, and R ³ is (3-hydroxypropane-1-yl) Are provided which are oxycarbonyl groups.

According to another preferred embodiment of the present invention, there is provided a preferable compound of the formula (I), wherein R ⁴ is a group capable of being hydrolyzed in a living body.

When R ⁴ is a group that is hydrolyzed in a living body, the group is preferably an ester residue, for example, a lower alkylcarbonyloxy lower alkyl group, a lower cycloalkylcarbonylcarbonyloxy lower alkyl group, a lower cycloalkyl Methylcarbonyl lower alkyl group, lower alkenylcarbonyloxy lower alkyl group, arylcarbonyl lower alkyl group, tetrahydrofuranylcarbonyloxymethyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, a Reel methyloxy lower alkyl group, arylmethyl lower alkoxy group, lower alkyl group, lower alkyloxycarbonyl lower alkyl group A lower alkyl group, a lower cycloalkyloxycarbonyloxy lower alkyl group, a lower cycloalkylmethoxycarbonyloxy lower alkyl group, an aryloxycarbonyloxy lower alkyl group, or a substituent on the aromatic ring. Phthalidyl group, 2 _ (3-phthalidylidene) ethyl group which may have a substituent on the aromatic ring, 2-oxotetrahydrofuran-1-yl group, 2-oxo-15-lower alkyl-1, Commonly used ones such as 3-dioxolen-4-ylmethyl group are exemplified.

Further, specific examples of R ⁴ include a bivaloyloxymethyl group, a 1- (bivaloyloxy) ethyl group, an isobutyryloxymethyl group, a 1- (isobutyryloxy) ethyl group, an acetoxmethyl group, and a 1- (acetoxymethyl group. ) Ethyl group, (1-methylcyclohexane-1-yl) carbonyloxymethyl group, (1-ethylpropan-1-yl) carbonyloxymethyl group, isobutylcarbonyloxymethyl group, 11- (cyclo Hexyloxycarbonyloxy) ethyl group, 1- (cyclohexylmethoxycarbonyloxy) ethyl group, 1- (2-cyclohexylethoxycarbonylcarbonyloxy) ethyl group, 1- (neopentyloxycarbonyloxy) Xy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, cyclohexyloxycarbonyloxymethyl group, 1- [(2 —Methylcyclohexane-1-yl) oxycarbonyloxy] ethyl group, cyclopentyloxycarboxyloxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, (1 R, 2 S, 5 R ) ― (1) -menthyloxycarbonyloxymethyl group, (1 S, 2 R, 5 S) ― (d) 1-menthyloxycarbonyloxymethyl group, 1-(phenyloxycarbonyloxy) Ethyl group, phenyloxycarbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) — n-propyl group, 1 — [(hexan-1-yl) oxycarbonyloxy] Ethyl group, isopropyloxycarbonyloxymethyl group, 1- (isobutyloxycarbonyloxy) ethyl group, isopentyloxycarbonyloxymethyl group, (5-methyl-2-oxo13-3) Oxolene 1-yl) methyl group, 3-furidylidyl group, and (Z) -2- (3-phthalidylidene) ethyl group, preferably, bivaloyloxymethyl group, 1- (cyclo- Xyloxycarbonyloxy) ethyl group, 1- (isopropylpyroxycarbonyloxy) ethyl group, acetoxymethyl group, (5-methyl —2—oxo — 1,3-dioxolen-1-yl) methyl group, 11- (neopentyloxycarbonyloxy) ethyl group, 11- (2-cyclohexylethoxycarbonyloxy) ethyl group, 1— [(Hexane-1-yl) oxycarbonyldioxy] ethyl group, isopropyloxycarbonyloxymethyl group, cyclohexyloxycarbonyloxymethyl group, 1_ (isobutyloxycarbonyloxy) ethyl group, It is an isopentyloxycarbonyloxymethyl group, a (1-ethylpropan-1-yl) carbonyloxymethyl group, or an isobutylcarbonyloxymethyl group.

 Salts of general formula (I) are pharmaceutically acceptable salts, for example inorganic salts such as lithium, sodium, potassium, calcium, magnesium, or ammonium salts, triethylamine, diisopropylethylamine Salts with organic bases such as, or salts with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or acids such as acetic acid, carbonic acid, citric acid, malic acid, oxalic acid, methanesulfonic acid. And a salt with an organic acid, preferably a sodium salt, a potassium salt, or a hydrochloride.

 Next, specific examples of the carbane derivative of the general formula (I) according to the present invention will be illustrated, but the present invention is not limited thereto.

 1. (IE, 5S, 6S)-2- (4-Lumbamoylthiazol-5-yl) thio-6-((1R) -1 -Hydroxityl) -1-methyl-1-L-lubapen-2 -Em-3-sodium sodium carboxylate

 2. (1R, 5S, 6S)-2- (4-force rubamoylthiazol-5-yl) thio-6-((1R) -1-hydroxyxethyl) -1-methyl-1-force lubapen-2 -Em-3-Bivaloyloxymethyl carboxylate

 3. (1R, 5S, 6S)-2- (2-Aminothiazol-5-yl) thio-6-((lR) -l-hydroxy-shetyl) -1-methyl-1-butyrubapen-2 -Em-3-sodium carboxylate

 4. (1R, 5S, 6S) -2- [4- (N, N-dimethyl) -powerbamoylthiazol-5-yl] thio-6-((lR) -l-hydroxyethyl) -1- Methyl 1-l-r-bapene-2-em-3-sodium carboxylate

5. (1R, 5S ₅ 6S)-2- [4- (N-ethyl) rubamoylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl- 1-potassium lvapen-2-em-3-sodium carboxylate _{6. (1R 5 5S, 6S)} -2- (4- formylthiazole - 5-I le) Chio - 6- ((1R) -1-hydro Kishechiru) -1-methyl-1 force Rubapen - 2- E Sodium 3-carboxylate

 7. (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (2-hydroxyethyl) aminocarborylthiazol-5-yl] thio-1-methyl -1-force Lubapen-2-em-3-force sodium rubonate

_{8. (1R 5 5S 5 6S)} -2- [4- (2- aminoethyl) Aminokarubo two Ruchiazo Ichiru 5-I le] Chio - 6- ((1R) - 1- hydroxy E chill) -1- Methyl 1-l-l-bapene-2-em-3-carbonate sodium

 9. (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -trimethyl-2- [4- (N-phenyl) -capsulebamoylthiazol-5-yl] thio- 1-Carpapen-2-em-3-potassium sodium

 10. (1R, 5S, 6S) -6-(-Trihydroxyethyl) -2- (4-methoxycarbonylaminothiazol-5-yl) thio-1-methyl-1-hexylbapen-2- Sodium -3-carboxylate

 1 1. (1R, 5S, 6S)-2- (4-Acetylthiazol-5-yl) thio-6-((lR) -1-Hydroxityl)-:!-Methyl-1-capryl- Sodium 2-em-3-carboxylate

 12. (1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -l-hydric quichetyl) -1-methyl-1-carpapen-2- Bivaloyloxymethyl 3-carboxylate

_{13. (1R 3 5S, 6S)} -6 - ((lR) - 1- hydroxy E chill) -1-methyl -2- [4- (N- methyl force Rubamoiru) thiazole Ichiru - 5-I le] Chio -1-potassium lvapen-2-em-3-sodium carboxylate

_{14. (1R 5 5S, 6S)} - 2- (4- ethoxycarbonyl two Ruchiazoru - 5-I le) Chio -6- ((1 R) -l- hydroxy E chill) -1-methyl-1- force Rubapen -Sodium 2-em-3-carboxylate

_{15. (1R, 5S 5 6S)} - 2- (4- ethoxycarbonyl two Ruchiazo Ichiru 5-I le) Chio -6- ((1 R) -l- hydroxy E chill) -1-methyl-1- Levapen-2-em-3-carboxylate Bivaloy Roxymethyl

_{16. (1R, 5S 5 6S)} -2- [4- (N- force Rubamoirumechiru) force Rubamoiruchiazo Ichiru -5 -Yl] thio-6-((lR) -l-hydroxyethyl) -1-methyl-1-force rubapene-2-em-3-force sodium ribonate

 17. (1R, 5S, 6S) -2- (4-formylaminothiazol-5-yl) thio-6-((lR) -1-hydroxyethyl) -1-methyl-1-force Lubapen-2-em-3-carboxylate sodium

18. (1R ₃ 5S, 6S) -6-((11-1-hydroxyethyl) -2- [4- [N- (2-methoxethyl) -lubamoyl] thiazolyl-5-yl] Thio-1-methyl-1-force Lubapen-2-em-3-force Sodium rubonate

 19. (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -2- [4- (N-methoxy) -rubamoylthiazol-5-yl] thio-1-methyl 1-force lubapen-2-em-3-carboxylate sodium

 20. (1R, 5S, 6S) -2- (4-Aminothiazol-5-yl) thio-6-((1R) -1-hydroxyl) -1-methyl-1-hexarubapene-2- EM-3-Sodium carboxylate

_{2 1. (1R 5 5S, 6S} ) - 6- ((1R) - Bok hydroxy E Chill) - 2- [4- [N- ( 3- hydroxy-flop port pan - 1-I le) force Rubamoiru] thiazole - 5-yl] thio-1-methyl-1-potassium lvapen-2-em-3-carboxylate sodium

_{22. (1R, 5S 5 6S)} - 6- ((1R) - 1- hydroxy E Chill) - 1-methyl - 2- [4- [N- (propane - 1-I le) force Rubamoiru] thiazole one Le-5-yl] thio-1-force Lubapen-2-em-3-force Sodium rubonate-

23. (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- [4- [N- (pyridin-2-yl) methyl] potassium Le-5-yl] thio-1-potassium lvapen-2-em-3-sodium carboxylate

 24. (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-methyl-1-force Lubapen-2-em-3-carboxylate.

_{25. (IE, 5S 5 6S)} - 2- (4- Karubokishichiazo Ichiru - 5-I le) Chio -6- ((1R) -1 - heat Dorokishechiru) - methyl-1 Power Rubapen - 2- EM-3-Carboxylic acid sodium

26. (5R ₃ 6S) -2- (4-Lumbamoylthiazol-5-yl) thio-6-((1R) -1-Hyd-mouth quichetyl) -1-Lumbapent-2-em-3 -Sodium carboxylate

27. (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl)-1-methyl-2- (4-propio Nilthiazole-5-yl) thio-1-potassium lvapen-2-em-3-sodium carboxylate

28. (1R, 5S, 6S) -2- (4-Cyanothiazol-5-yl) thio-6-((lR) -trihydroxitytyl) -1-methyl-1-butyrrappen-2-e Sodium-3-carboxylate

 29. (1R, 5S, 6S) -6-((1R) -Trihydroxyethyl) -2- [4- (N-isopropyl power rubamoyl) thiazolyl-5-yl] thio-1-methyl- 1-potassium lvapen-2-em-3-sodium carbonate

 30. (1R, 5S, 6S)-2- [4- (N-cyclohexylcarbamoyl) thiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1- Methyl 1-l-l-bapene-2-em-3-carbonate sodium

 3 1. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- [N- (thiazol-2-yl) methylcarbamoyl ] Thiazol-5-yl] thio-1-potassium 2-carbene-3-carboxylate

_{32. (1R 5 5S, 6S)} -2- [4- ( force Rubamoirume butoxy) carbonylation Ruchiazo Ichiru 5-I le] Chio -6 - ((lR) - 1- hydroxy E chill) -1-methyl -1-force Lubapen-2-em-3 -force sodium rubonate

 33. (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- (4-Methanesulfonylthiazol-5-yl) thio-1-methyl-1- L-Lapapen-2-em-3-carboxylate sodium

34. (1R, 5S, 6S) -2- [4- (2-Hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -l-hydroxyethyl) -1- Methyl-1-force rubapene-2-em-3-force sodium rubonate

 35. (1R, 5S, 6S) -2- [4- (N-Cyclopropylcapsulebamoyl) thiazole-5-yl] thio-6-((11 -1-hydroxyethyl) -1-methyl-1 -Kirubapen-2-em-3-sodium carbonate

 36. (1R, 5S, 6S) -2- (2-force rubamoylthiazole-5-yl) thio-6-((lR) -1-hydroxyethyl) -1-methyl-1-force rubapene- Sodium 2-em-3-carboxylate

37. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2--2- [4- (propan-1-yl) oxycarbonylthiazol-5- Yl] thio-1-potassium 2-baem-3-sodium carboxylate

38. (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -1-methyl-2- (4-methylthio Thiothiazol-5-yl) thio-1-potassyl-2-ene-3-carboxylate sodium

39. (1R, 5S, 6S) -2- [4- [N- (Hexane-1-yl) caprolbumoyl] thiazol-5-yl] thio-6-((lR) -l- (Hydroxyethyl) -trimethyl-1-force Lubapen-2-em-3-force Sodium rubonate

 40. (1R, 5S, 6S) -6-((1R) -1-Hydroxyethyl) -1-methyl-2- [4- [N- (thiazol-2-yl) potumbamoyl] thiazole- 5-yl] thio-1-potassium 2-carb-3-carboxylate

 4 1. (1R, 5S, 6S) -2- [4- [N- (furan-2-yl) methylcarbamoyl] thiazolyl-5-yl] thio-6-((lR) -l- (Hydroxyethyl) -trimethyl-1-ketorubapene-2-em-3-carboxylate sodium

_{42. (1R 5 5S 3 6S)} -6 - ((lR) - 1- hydroxy E Chill) - 1-methyl - 2- [4- [N- (pyrimidin Jin - 3-I le) methylcarbamoyl] thiazole one Le-5-yl] thio-1-potassium 2-baem-3-sodium carboxylate

 43. (1R, 5S, 6S) -2- [4- (2-Hydroxyethoxycarbonyl) thiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1-methyl -1-force Lubapen-2-em -3-force Bivaloyloxymethyl rubonate

 44. (1R, 5S, 6S) -2- [4- [N- (2-formylaminoethyl) carbamoyl] thiazo-yl-5-yl] thio-6-((1R) -1-hydroxy Tyl) -1-methyl -1-caproluvene-2-em-3-sodium carboxylate

_{45. (1R 5 5S 3 6S)} -2- [4- [N- (2- aminosulfonyl aminoethyl) force Rubamoi le] thiazole Ichiru -5- I le] Chio -6 - ((lR) -l- (Hydroxyethyl) -1-methyl-1-potassium pen-2-em-3-carboxylate sodium

 46. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-hydroxymethylthiazol-5-yl) thio-1-methyl-1- L-Lapapen-2-em-3-carboxylate sodium

47. (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2--2- [4- (pyridin-3-yl) thiazol-5-yl] Thio-1-caproluben-2-em-3-carboxylate sodium

48. (1R, 5S, 6S)-2- [4- [N- (2-Aminocarbonylaminoethyl) -lubamoyl] thiazol-5-yl] thio-6-((1R) -1-hydroxy Ethyl) -1-methyl -1- Sodium pen-2-em-3-carboxylate

 49. (1R, 5S, 6S) -2- [4- [N- (2-acetylamino) ethyl] rubamoyl] thiazo-yl-5-yl] thio-6-((1R) -1-hydr N-quichetyl) -1-methyl-1-potassium 2-carbamate-3-carboxylate

 50. (1R, 5S, 6S) -6-((1R) -1-Hydroxydityl) -2- [4- [N- (2-hydroxyethyl) caprubamoyl] thiazolyl-5-yl ] Thio-1-methyl-1-carbyl-2-em-3-bivaloyloxymethyl carboxylate

 5 1. (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (2-methoxetoxy) carbonylthiazol-5-yl] thio- 1-methyl-1-butyric acid 2-sodium 3-carbonate

 52. (1R, 5S, 6S) -6-((. LR) -1-Hydroxyethyl) -1-methyl-2- [4- [N- (Pen-Yuin-1-yl) -capsulebamoyl] Thiazolyl-5-yl] thio-1-force Lubapen-2-em-3-force Sodium rubonate

 53. (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-methyl-tolubapine -2-val-3-methyl carboxylate

 54. (1R, 5S, 6S) -6-((lR)-: l-hydroxyethyl) -1-methyl-2- [4- (propane-1-yl) oxycarbonylthiazol-5- Yl] thio-1-force lubapen-2-em-3-force bivaloyloxymethyl rubonate

_{55. (1R, 5S 3 6S)} - 2- [4- [N- ( butane - 1-I le) force Rubamoiru] thiazole-5-I le] Chio -6 - ((lR) -l- hydroxy E Chill 1)-1-Methyl-1-levapen-2-hem-3-sodium carbonate.

 5 6. (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -trimethyl-2- 2- [4- [N- (2-methylthioethyl) rubamoyl] thiazole-5-y Le] thio-1-Luvapene-2-Em-3 -Sodium rubonate

 5 7. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazole-5-yl ] Thio-1-methyl -1-caproluvene sodium 2-carboxylate

_{58. (1R 5 5S, 6S)} - 6- ((1R) - 1- hydroxy E chill) -1-methyl - 2- [4- (thiazo one Le-2-yl) thiazol-5-yl] thio-1-potassium 2-baem-3-carboxylate sodium salt

 59. (1R, 5S, 6S)-2- [4- (Butane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl)- 1-methyl-1-butyric acid 2-sodium 3-carbonate

60. ( ₁₅ 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2- [4- (2-methoxyethoxycarbonyl) thiazol-5-yl] thiomethyl 1-Levapen-2-em-3-bivaloyloxymethyl carboxylate

 6 1. (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -methyl-2- (4- (N-methylpotamoylacetyl) thiazolyl-5-yl ] Cho-1-Levapen-2-em-3-Sodium carbonate

62. (5R ₅ 6S) -6-((1R) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-butyrolpine-2 Sodium-3-carboxylate

 63. (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazole-5-yl] Bivaloyloxymethyl thio-1-methyl-1-carbyl-2-em-3-carboxylate

 64. (5R, 6S) -6-((lR) -Trihydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-potassyl-2-ene-3 -Bivaloyoxymethyl carboxylate

_{65. (1R, 5S 5 6S)} -6- ((1R) - 1- hydroxy E Chill) - 2- (4-main-butoxycarbonyl thiazole Ichiru 5-I le) Chio - 1-methyl-1-forces Lubapen-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (a mixture of diastereomers)

 66. (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-methyl-1-force Lubapen-2-em-3-carboxylic acid 1- (isopropyloxycarbonyloxy) ethyl (a mixture of diastereomers)

_{67. (1R 5 5S, 6S)} - 6- ((1R) - 1- hydroxy E chill) -2- (4-main-butoxycarbonyl thiazole Ichiru - 5-I le) Chio - 1-methyl-1-forces Lubapen-2-em-3-carboxymethyl carboxylate

_{68. (1R 3 5S, 6S)} -6 - ((lR) - Bok hydroxy E Chill) - 2- (4-main-butoxycarbonyl Thiazolyl-5-yl) thio-1-methyl-1-methyl-2-carbene-3-carboxylate (5-methyl-2-oxo-1,3dioxolen-4-yl) carboxylate

 69. (5R, 6S)-2- (4-Acetylthiazol-5-yl) thio-6-((1R) -1-hydroxystyl) -1-carbyl-2-em-3-carvone Sodium acid

 70. (1R, 5S, 6S) -2- [4- (2-Hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -l-hydroxyethyl) -1- 1- (cyclohexyloxycarbonyloxy) ethyl (1-dicyclohexyloxycarbonyloxy) ethyl (diastereomeric mixture)

 7 1. (1R, 5S, 6S) -2- [4- (2-Hydroxyethoxy) carbonyldithiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) 1- (neopentyloxycarbonyloxy) ethyl methyl -1-l-lubapen-2-em-3 -l-rubonate (a mixture of diastereomers)

_{72. (1R, 5S 5 6S)} -2- [4- (2- hydroxyethoxy) carbonylation Ruchiazo Ichiru 5-I le] Chio -6 - ((lR) -l- hydroxy E chill) -1- 1- (2-cyclohexylethoxycarbonyloxy) ethyl methyl -1-l-rubapene-2-em-3-rhrubonate (mixture of diastereomers)

 73. (1R, 5S, 6S) -2- [4- (2-Hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1- Methyl-1-force rubapen-2-em-3-force Methyl rubonate (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl

 74. (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -1-methyl-2- [4- (pyridine-4-yl) thiazol-5-yl] Thio-1-caproluvene-2-em-3-sodium carboxylate

75. (1R ₃ 5S ₃ 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -1-Hyd-guchixethyl) -1-Methyl-1-hexarubapene-2 -Em-3-carboxylate (isopropyloxycarbonyloxy) ethyl (a mixture of diastereomers)

 76. (1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -1-hydrexyl) -1-methyl-1-hexarubapene-2 -Em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (a mixture of diastereomers)

77. (1R, 5S, .6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -l-hydride Mouth xicetyl) -1-methyl -1-force lubapen-2-em-3-acetoxymethyl carboxylate 78. (1R, 5S, 6S)-2- [4- (2-ethoxyethoxy) carbonyl thiazole- 5-yl] thio-6-((lR) -1-hydroxyethyl) -1-methyl-1_potassyl-2-am-3-sodium carbonate

 79. (1R, 5S, 6S) -2- (4-Acetylthiazolyl-5-yl) thio-6-((1R) -1-Hydrochexethyl) -1-Methyl-1-hexarubapene-2 -Em-3-carboxylate (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl

 80. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- (2-methylthioethoxy) carbonylthiazole-5-yl] thio- 1-force lubapen-2-em-3-carbonate sodium

 8 1. (1R, 5S, 6S) -2- [4- (4-Hydroxybutane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((1R)- 1-Hydroxyethyl) -1-methyl-1-potassium 2-baem-3-carboxylate

 82. (1R, 5S, 6S) -6-((lR)-; l-hydroxyethyl)-2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazol-5- 1- (neopentyloxycarbonyloxy) ethyl (diastereomeric mixture)

 83. (1R, 5S, 6S) -6-((1R) -1-Hydroxyethyl) -2- [4- (3-methoxypropan-1-yl) oxycarbonylthiazol-5-y Le] thio-1-methyl-1-sodium rubapene-2-em-3-carboxylate

 84. (1R, 5S, 6S) -6-((1R) -Trihydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazoyl-5-yl 1- (2-cyclohexylethoxycarbonyloxy) ethyl 2-thio-1-methyl-1-carbapene-2-carboxylate (a mixture of diastereomers)

_{85. (1R, 5S 3 6S)} -6 - ((lR) -: l- hydroxy E chill) -2- [4- (3-hydroxy propane - 1-I le) Okishikarubo two Ruchiazoru 5- I le ] Thio-1-methyl-1-hexyllvapen-2-em-3-carboxylate (cyclohexyloxycarbonyloxy) ethyl (a mixture of diastereomers)

86. (1R, 5S, 6S) -6-((lR)-; l-hydroxyethyl)-2- [4- (5-hydroxypen Ethyl-1-yl) oxycarbonylthiazole-5-yl] thio-1-methyl-1-butyrolpine -2 -em-3-carboxylate sodium

_{87. (1R 5 5S, 6S)} -6 - ((lR) - Bok hydroxy E Chill) - 2- [4- (isopropyl O key sheet) carbonylation Ruchiazo Ichiru - 5-I le] Chio - 1-methyl 1-Levapen-2-em-3-sodium carbonate

_{88. (1R, 5S 5 6S)} - 2- [4- [2- (2- hydroxyethoxy) ethoxy] carbonyl Chi § zone Ichiru 5-I le] Chio -6- ((1R) - 1- hydroxy Ethyl) 1-methyl-1-sodium lubapen-2-em-3-carboxylate

 89. (lR, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazole-5-yl] Thio-1-methyl-1-carbapene-2-acemoxymethyl-3-carboxylate

 90. (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazol-5-yl] Thio-1-methyl-1-capryl-2-ene-3-carboxylate 1-[(hexane-1-yl) oxycarbonyloxy] ethyl (a mixture of diastereomers)

 9 1. (lR, 5S, 6S) -6-((lR)-: l-Hydroxyethyl) -2- (4- (3-hydroxypropan-1-yl) oxycarbonylthiazole-5-y L] thio-1 -Methyl-1-potassium lvapen-2-em-3-carboxylic acid; I- (isopropyloxycarbonyloxy) ethyl (mixture of diastereomers)

 92. (lR, 5S, 6S) -6-((lR)-: L-hydroxyethyl) -2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazole-5-yl ] Thio-1-methyl-1-carbyl-2-em-3-carboxylate

 93. (1R, 5S, 6S) -6-((1R) -Hydroxyethyl) -2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazole-5-yl] thio- 1-Methyl-1-carbyl-2-carboxy-3-cyclohexyloxycarbonyloxymethyl

94. (1R, 5S, 6S) -6-((1R) -1-Hydroxyethyl) -2- 2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazol-1-yl 1]-(Isobutyloxycarbonyloxy) ethyl (diesteromer mixture) 95. (1R, 5S, 6S)-2- [4- (2,2-Dimethyl-3-hydroxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((1R ) -1-Hydroxyethyl) -methyl-1-potassium levapen-2-em-3-carboxylate

 96. (1R, 5S, 6S)-2- [4- (2,3-Dihydroxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((lR) -l- Hydroxyethyl) -1-methyl-1-carbazine-2-em-3-sodium carboxylate (a mixture of diastereomers)

 97. (lR, 5S, 6S) -6-((lR) -lbdroxityl) -2- 2- [4- (3-Hydroxypropan-1-yl) oxycarbonylthiazol-5-yl] thio -1-Methyl-1-capryl-2-ene-3-carboxylate

 98. (1R, 5S, 6S) -6-((lR) -l-Hydroxyethyl) -2- (4- (3-hydroxypropan-1-yl) oxycarbonylthiazol-5-y L] thio-1-methyl-1-l-lubapen-2-em-3-carboxylate (1-ethylpropane-1-yl) carbonyloxymethyl

 99. (lR, 5S, 6S) -6-((1R) -Trihydroxyethyl) -2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazoyl-5-yl ] Thio-1-methyl-1-butyrolpine-2-2-em-3-carboxylate

 100. (1R, 5S, 6S)-2- [4- (3-Hydroxybutane-1-yl) oxycarbonylthiazole-5-yl] thio-6-((lR) -l-hydroxyethyl ) -1-Methyl -1-caproluvene-2-em-3-carboxylate sodium (a mixture of diastereomers)

 10 1. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxy-3-methylbutyn-1-yl) oxycarbonylthiazo Le-5-yl] thio-1-methyl-1-force sodium lubapen-2-em-3-carboxylate

 102. (5R, 6S) -6-((lR)-: l-hydroxyethyl) -2- [4- (3-hydroxypropan-1-yl) oxycarbonylthiazole-5-yl] thio -1-Levapen-2-em-3-sodium carboxylate

 103. (lR, 5S, 6S) -2- [4- (4-Hydroxybutanoyl) thiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl- 1-force lubapen-2-em-3-carboxylate sodium

104. (lR, 5S, 6S) -2- [4- (4,5-dihydroxypentyl) thiazol-5-yl] thio-6-((1R) -1-hydroxyethyl)- 1-Methyl-1-caproluben-2-em-3-cal Sodium Bonate (Diastereomer mixture)

Among the compounds of the general formula (I) according to the present invention, a compound wherein R ⁴ is a hydrogen atom, or a salt thereof (1 ′) can be preferably produced according to the following scheme.

[In the above scheme, RR ² and R ³ represent the same meaning as defined in the general formula (I), and R ⁵ represents a hydrogen atom or a hydroxyl protecting group (for example, t-butyldimethylsilyl group, Represents a trimethylsilyl group, a triethylsilyl group, a 4-nitrobenzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, an aryloxycarbonyl group, etc .: R ⁶ is a carboxyl protecting group (for example, 412 base Njiru group, 4-methoxybenzyl group, Jifuenirumechiru group, t-butyl di methylsilyl group, an Ariru group), the functional group R ⁷ and R ⁸ are contained in R ² and R ³ the same or R ² and R ³ (For example, a hydroxyl group, an amino group, a carboxyl group, etc.) are those protected by ordinary protecting groups (here, ordinary protecting groups are defined as Protective Groups in Or ganic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc.).), R ⁹ represents a hydrogen atom or a metal ion such as potassium or sodium. ]

The compound of the formula (II) in the scheme in the first step can be synthesized by a conventional method (for example, JP-A-57-123182, JP-A-64-25779). In the first step, the conversion of (II) into (III) can be performed by the following method. That is, one equivalent or an excess of trifluoromethanesulfonic anhydride relative to (II) is used, and one equivalent or an excess of an organic base (preferably, diisopropylethylamine) is used relative to tri'fluorenesulfonic acid anhydride. Min) in the presence of an inert solvent such as acetate nitrile, tetrahydrofuran, dichloromethane, toluene, or a mixture of these at 150 ° C to 150 ° C for 10 minutes to 24 hours, followed by the usual reaction. (III) can be obtained by separation and purification. Next, in the second step, the conversion of (III) to (V) can be performed by the following method. That is, one equivalent or an excess amount of (IV) or a salt thereof is added to (III), and, if necessary, one equivalent or an excess amount of an organic base (preferably diisopropyl ester) to (III). Tylamine) in the presence of acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dioxane, methanol, ethanol, dichloromethane, toluene, hexamethylphosphoroditriamide, etc. In these mixed solvents, 0 ° C to 100 ° C (here, after reacting for 10 minutes to 7 days, (V) can be obtained by subjecting to normal post-treatment.

 Finally, in the third step, the protecting group of the compound (V) is removed by a deprotection reaction in one or more steps depending on the kind of the protecting group to give the compound represented by the general formula (I) of the present invention. obtain.

At this time, the deprotection reaction for removing the protecting group varies depending on the type of the protecting group used, but can be generally carried out according to a usual method known in the art. If any or all of them can be deprotected under acidic conditions, use a mineral acid such as hydrochloric acid, an organic acid such as formic acid, acetic acid, citric acid, or a Lewis acid such as aluminum chloride. When it is removed below, catalytic reduction using various catalysts or a metal reducing agent such as zinc or iron can be used. When R ⁵ is a silyl protecting group (eg, t-butyldimethylsilyl group, trimethylsilyl group, triethylsilyl group, etc.), a fluorine ion reagent (eg, tetrabutylammonium fluoride, etc.) ) Can further be used when R ⁵ is an aryloxycarbonyl group and R ⁶ is an aryl group. It can be easily removed by using Lakis (triphenylphosphine) palladium (0) or the like.

 The compound of the general formula (1 ′) thus obtained may be crystallized or chromatographed using a non-ionic Mac-mouth hypoporous resin, gel filtration using Sephadex, etc., reverse phase silica gel column chromatography. Can be used for isolation and purification.

Further, among the compounds of the general formula (I) according to the present invention, the compound (1 ′,) 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 the general formula (I), R ⁹ represents a hydrogen atom or a metal ion such as potassium or sodium, ¹ "represents a group that is hydrolyzed in the living body (has the same meaning as defined in the section of compounds when“ R ⁴ is a group that is hydrolyzed in the living body ”), and X represents Cl, br, I, - OS_〇 _{2 CF 3, - OS0 2 CH} 3, to the table a leaving group such as one _{0 S 0 2 P h CH 3} . ]

If necessary, 1 equivalent or an excess of base (1), (as an organic base, an inorganic base such as diisopropylethylamine, diazabicyclo [2,2,2] indene, 2,6-lutidine, etc.) Is the presence of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. in the presence of one equivalent or an excess of an alkyl halide (R ¹¹¹ — X: 1- (Bivaloyloxy) ethyl iodide, Isobutyryloxymethyl iodide, 1- (Isobutyryloxy) ethyl 1- (acetoxy) ethyl chloride, 1- (acetoxy) ethyl chloride, (1-methylcyclohexane-1-yl) carbonyloxymethyl chloride, (1-ethylpropane) B) Carbonyloxymethyl chloride, isobutylcarbonyloxymethyl chloride, 1- (cyclohexyloxycarbonyloxy) ethyl, 11- (cyclohexylmethoxycarbonyloxy) ethyl chloride, 1- (2-cyclohexylethoxycarboxy) ethyl, 1- (neopentyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, cyclohexyloxycarboxy Dioxymethyl chloride, 1-[(2-methylcyclohexan-1-yl) Oxycarbonyloxy] ethyl chloride, cyclopentyloxy carboxycarbonyl methyl oxide, 1- (isopropyloxycarbonyl) ethyl, (1R, 2S, 5)-(1) 1-menthyloxyca L-Polyroxymethyl chloride, (1 S, 2 R, 5 S) _ (d) —Mentyloxyloxycarboxylic acid methyl chloride, 1-(Phenoxyloxycarboxylic acid) ethyl chloride, phenylol 1- (cyclohexyloxycarbonyloxy) 1-n-propyl oxide, 1-[(Hexane-1-yl) oxycarbonyloxy] ethyl oxide, isop Mouth piloxycarboxymethyloxy, 1- (isobutyloxy carboxy) ethyl chloride, isopench Oxycarbonyloxymethyl chloride, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl bromide, 3-furisylrubide, (Z) -2-( 3-Fuyridylidene) ethylpromide, etc.), alone or in combination with an inert solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-getylformamide) , N, N-Getylacetamide, N-methylpyrrolidinone, N, N—Dimethylimidazolidinone, Dimethyl sulfoxide, Sulfolane, Acetonitrile, Acetone, Ethyl acetate, Tetrahydrofuran, 1,4-Dioxane, Ter, anisol, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, hexamethylphosphoric tri Mi de, methanol, ethanol, etc.), one 7 0 tens 5 0 ° C (preferably, + 2 0 from a 3 0 ° C (1,,) can be obtained by reacting at (° C) for 10 minutes to 24 hours.

 The ester thus obtained can be isolated and purified by precipitation, crystallization, gel filtration using Sephadex or the like, silica gel column chromatography, or the like.

 Compound Use / Pharmaceutical Composition

 The compound according to the present invention has a broad and strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and is also pneumococcal including MRSA, VRE and PRSP; It has a strong antibacterial activity against evening production bacteria. Further, the compounds according to the present invention have low toxicity and are stable against DHP-1. Therefore, the compounds according to the present invention can be used for treating infectious diseases caused by various pathogenic bacteria in animals including humans. Thus, according to the present invention there is provided an antimicrobial comprising the compound according to the present invention. Further, according to another aspect of the present invention, there is provided the use of a pharmaceutical composition of a compound according to the present invention for the manufacture of an antimicrobial agent. Further, according to another aspect of the present invention, there is provided a method for preventing or treating infectious diseases, comprising administering a compound according to the present invention to an animal including a human.o

The compound according to the invention can be in a pharmaceutical composition. In particular, a compound in which R ⁴ in the formula (I) is a group that is hydrolyzed in a living body is excellent in oral absorbability and has an advantage that it can be used as an oral preparation. Thus, according to the present invention there is provided a pharmaceutical composition comprising a compound according to the present invention. According to a further aspect of the present invention there is provided the use of a compound according to the present invention for the manufacture of a pharmaceutical composition. Pharmaceutical compositions containing the compound according to the present invention and a pharmacologically acceptable salt thereof as an active ingredient are orally or parenterally (eg, intravenous, intramuscular, subcutaneous, rectal, transdermal) ) Can be administered to humans and non-human animals. Therefore, the pharmaceutical composition comprising the compound according to the present invention as an active ingredient is made into an appropriate dosage form depending on the administration route. Specifically, injections such as intravenous injection and intramuscular injection, capsules, tablets, and granules are mainly used. , Powders, pills, fine granules, lozenges and other oral preparations, rectal preparations, oily suppositories, etc. it can. These formulations contain commonly used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, preservatives, It can be produced by a conventional method using a flavoring agent, a soothing agent, a stabilizer and the like. The non-toxic additives that can be used include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose or salts thereof, gum arabic, polyethylene glycol And syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, and sodium phosphate. The dosage will be determined as appropriate, taking into account the usage, patient age, gender, degree of symptoms, etc. For treatment of infectious diseases, usually about 25 mg to 200 mg / day per adult per day: Preferably, the dose is from 5 Omg to: L00 Omg, which can be administered once or several times a day.

[Example]

 Hereinafter, the present invention will be described with reference to Examples and Synthesis Examples, but the present invention is not limited thereto.

 [Example 1] (1R, 5S, 6S)-2- (4-forcerubamoylthiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -1-methyl-1- L-Lapapen-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S)-2- (4-L-rubamoylthiazol-5-yl) thio-6-((1R)-1-hydroxystyl) -1-methyl-1-l-lubapen-2 -Em-3-carboxylic acid

(lR ₅ 3R ₃ 5R, 6S) -6-((lR) -l-fcdroxityl) -1-methyl-2-oxo-1-carbazane-3-carboxylate 4-nitrobenzyl 873 mg of dry acetonitrile To a 24 mL solution were added dropwise N, N-diisopropylethylamine 0.628 mL and then anhydrous trifluoromethanesulfonic acid 0.404 mL at -30 ° C under argon atmosphere. After stirring at the same temperature for 30 minutes, add ethyl acetate lOOinL, and add a half-saturated saline solution, a mixed solution of half-saturated saline and 1N-hydrochloric acid solution (p H 1.1), a mixed solution of half-saturated saline and saturated aqueous sodium bicarbonate (pH 8.9), and sequentially washed with half-saturated saline. After drying over anhydrous magnesium sulfate and filtration, 20 mL of DMF was added, and ethyl acetate was distilled off under reduced pressure. To the obtained DMF solution was added 512 mg of 5-mercaptothiazol-4-carboxylic acid amide ammonium salt, and the mixture was stirred at 40 ° C for 1 hour under an argon atmosphere. To the reaction solution was added 100 mL of half-saturated saline, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic layers were combined, washed twice with 100 mL of half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 1: 1 to dichloromethane: methanol = 20: 1) to give (1R, 5S, 6S) -2- (4-force 914 mg of rubamoylthiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-forcelvapen-2-em-3-carboxylic acid 4-nitrobenzyl Was.

Hz), 1.34(3H， d， J=6.3 Hz)， 3.2-3.4(2H, m)， 4.2- 4.4(2H， m), 5.28(1H, d,J=13.5 Hz), 5.52(1H, d, J=13.5 Hz), 5.68 (1H₅ br s)， 7.18(1H, br s), 7.64(2H₅ d,J=9.0 Hz), 8.22(2H, d， J=9.0 Hz), .8.71(1H₃ s)

Hz), 1.34 (3H, d, J = 6.3 Hz), 3.2-3.4 (2H, m), 4.2- 4.4 (2H, m), 5.28 (1H, d, J = 13.5 Hz), 5.52 (1H, d , J = 13.5 Hz), 5.68 (1H ₅ br s), 7.18 (1H, br s), 7.64 (2H ₅ d, J = 9.0 Hz), 8.22 (2H, d, J = 9.0 Hz), .8.71 ( 1H ₃ s)

_{b) (1R 5 5S, 6S} ) -2- (4- force Rubamoiruchiazo Ichiru - 5-I le) Chio -6 - ((lR). -l- hydrin port Kishechiru) -1-methyl-1- force Rubapen -Sodium 2-Em-3-carboxylate

 (1R, 5S, 6S) -2- (4-L-rubamoylthiazol-5-yl) thio-6-((lR) -l-hydroxyl) -1-methyl-1-l-lubapen-2-e To a solution of 914 mg of 0.1N phosphate buffer (pH 6.8) in 54 mL of THF and 54 mL of THF, add 1.5 g of 10% Pd-C (water-containing, 53 I in water) and hydrogen atmosphere The mixture was stirred for 1.5 hours. 10% palladium carbon was filtered and washed with water, and the filtrate was adjusted to pH 7.5 by adding saturated aqueous sodium hydrogen carbonate. After washing with 25 mL of ethyl acetate, the aqueous layer was concentrated to about 2 mL, and purified by Cosmoseal 40C18-PREP column chromatography (2% aqueous methanol) to obtain 432 mg of the title compound. .

_{NMR (D 2 0) d (} H0D = 4.80ppm):. 1.08 (3H 5 d, J = 7.2 Hz), 1.26 (3H, d, J = 6.3 Hz), 3 2-3.3 (lH 3 m), 3.49 (1H, dd, JF5.1 Hz, J? 2.7 Hz), 4.2-4.3 (2H, m), 8.97 (1H, s)

[Example 2] (1R, 5S, 6S) -2- (4-kerbamoylthia.zol-5-yl) thio-6-((lR) -trihydroxyethyl) -1-methyl-1 -Kirubapen-2-em-3-bivaloyl carboxylate Oxymethyl

 (lR, 5S, 6S) -2- (4-Lubamoylthiazol-5-yl) thio-6-((1R) -1-hydroxystyl) -trimethyl-1-l-lubapen-2-em 138 mg of sodium 3-carboxylate was dissolved in 5 mL of DMF, and under argon atmosphere, -30. C, 6 mg of sodium hydrogencarbonate and 0.083 mL of odomethylrubinate were added, and the mixture was stirred for 1 hour. To the reaction solution was added 50 mL of half-saturated saline, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, washed twice with 50 mL of half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: mesanol = 20: 1) to give 155 mg of the title compound.

_{NMR (CDC1 3) d: 1.10} (3H, d 5 J = 7.5 Hz), 1.22 (9H, s), 1.31 (3H, d, J = 6.0 Hz), 3.2-3.4 (2H, m), 4.2- 4.3 (2H, m), 5.85 (1H ₃ d, J = 5.4 Hz), 5.99 (1H, d, J = 5.4 Hz), 7.20 (1H, br s), 8.74 (1H ₃ s)

 [Example 3] (1R, 5S, 6S) -2- (2-Aminothiazol-5-yl) thio-6-((1R) -1-hydridoxicetyl) -1-methyl-1-force Lubapen-2-em-3-carboxylate sodium

 a) (lR, 5S, 6S) -2- (2-Aminothiazol-5-yl) thio-6-((lR) -1-hydroxyethyl) -1-methyl-1-methyllvapen-2 -Em-3-carboxylic acid 4-nitrobenzil

(lR ₅ 3R, 5R ₅ 6S) -6-((lR) -lh-droxityl) -trimethyl-2-oxo-1-hexarubenam-3-carboxylic acid 4-dibenzobenzene 345 mg of dry acetonitrile 0.29 mL of N, N-diisopropylethylamine at -30 ° C under argon atmosphere in 10 mL solution, then 0.160 mL of trifluoroacetic anhydride was added dropwise. After stirring at the same temperature for 30 minutes, 50 mL of ethyl acetate was added, and a half-saturated saline solution, a mixed solution of half-saturated saline and 1N-hydrochloric acid solution (pH 1.1), a mixed solution of half-saturated saline and saturated sodium bicarbonate solution ( pH 8.9), and washed sequentially with half-saturated saline. After drying over anhydrous magnesium sulfate and filtration, DMFlOmL was added, and ethyl acetate was distilled off under reduced pressure. To the obtained DMF solution, 151 mg of 2-amino-5-mercaptothiazole and 0.249 mL of N, N-diisopropylethylamine were added, and the mixture was stirred at 40 ° C. for 3 hours under an argon atmosphere. 50 mL of half-saturated saline was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, washed twice with 50 mL of half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give (1R, 5S, 6S) -2- (2-aminothiazol-5-yl) thio. 133 mg of -6-((1R) -1-kisethyl) -l-methyl-1--1-l-lubapen-2-em-3-carboxylate 4-nitrobenzil was obtained.

NMR (CDCl ₃ ) ^: 1.18 (3H ₅ d, J = 7.2 Hz), 1.34 (3H, d, J = 6.0 Hz), 3.2-3.3 (2H, m), 4.1-4.3 (2H, m), 5.18 (2H, s), 5.27 (1H ₃ d, J = 13.8 Hz), 5.53 (1H, d, J = 13.8 Hz), 7.24 (1H, s), 7.67 (2H, d, J = 9.0 Hz) , 8.23 (2H, d, J = 9.0 Hz)

 b) (lR, 5S, 6S) -2- (2-Aminothiazole-5-yl) thio-6-((lR) -l-hydroxyethyl) -1-methyl-1-methyll-bapene-2 -Em-3-sodium carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -2- (2-aminothiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -1-methyl -The title compound (75.6 mg) was obtained from 173 mg of 4-nitrobenzyl 2-carboxy-3-carboxylate.

_{NMR (D 2 0) d (} H0D = 4.80ppm): 1.14 (3H, d, J = 7.2 Hz), 1.29 (3H, d, J = 6.0 Hz), 3. 1-3.2 (1H, m), 3.1 -3.2 (lH, m), 3.3-3.4 (lH ₃ m), 4.1-4.3 (2H, m), 7.26 (lH, s)

[Example _{4] (lR 5 5S 5 6S} ) -2- [4- (N, N- dimethyl) force Luba Moi thiazole-5-I le] Chio -6 - ((lR) - 1- hydroxy E chill) 1-methyl-1-l-l-bapene-2-em-3-sodium carbonate COONa

 a) (lR, 5S, 6S) -2- [4- (N, N-dimethyl) force rubamoylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl)-:! -Methyl-1-butyl-2-ene-3-carboxylic acid 4-carboxylic acid benzyl

 (LR, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-carbazin-3-carboxylic acid in the same manner as in Example 3a) From 74.5 mg of 4-nitrobenzoyl and 42.0 mg of 5-mercaptothiazol-4-carboxylic acid (N, N-dimethyl) amide, (1R, 5S 6S) -2- [4- (N, N-Dimethyl) -l-bamoylthiazol-5-yl] thio-6-((lR) -l-hydroxyxethyl) -1-methyl-l-l-l-bapene-2-em-3-carboxylic acid 4--2 71.6 mg of trobenzil were obtained.

_{NMR (CDC1 3) d: 1.12} (3H 3 d, J = 7.5 Hz), 1.32 (3H, d, J = 6.3 Hz), 2.92 (3H, s), 3.08 (3H, s), 3.2-3.3 (2H , M), 4.2-4.3 (2H, m), 5.27 (1H, d, J = 13.5 Hz), 5.5 3 (1H, d, J = 13.5 Hz), 7.66 (2H, d, J = 8.7 Hz), 8.23 (2H, d, J = 8.7 Hz), 8.92 (1 H, s)

 b) (lR, 5S, 6S) -2- [4- (N, N-dimethyl) -rubamoylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1- Sodium methyl-1-carbap-2-em-3-carboxylate

 In the same manner as in Example lb), (lR, 5S, 6S) -2- [4- (N, N-dimethyl) forcerubamoylthiazol-5-yl] thio-6-((1R) -1 -Hydroxyethyl) -1-methyl-1-forcelvapen-2-em-3-carboxylate From 71.6 mg of 4-nitrobenzene, 27.9 mg of the title compound was obtained.

_{NMR (D 2 0) d (} H0D = 4.80ppm): 1.13 (3H 5 d, J = 7.2 Hz), 1.29 (3H, d, J = 6.3 Hz), 3. 0-3.K1H, m), 3.04 (3H ₅ s), 3.12 (3H, s), 3.4-3.5 (1H, m), 4.1- 4.3 (2H,), 9.17 (1H ₃ s)

[Example 5] (lR, 5S, 6S) -2- [4- (N-ethyl) potassium rubamoylthiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1 -Methyl-1-hexarubapene-2-em-3-sodium carboxylate COONa

 a) (lR, 5S, 6S) -2- [4- (N-Ethyl) force rubamoylthiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1-methyl 1-Levapen-2-em-3-carboxylate 4-nitrobenzyl

 In the same manner as in Example la), (1R, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- (1R, 5S, 6S) -2- [4- (N-ethyl) carboxylate 4-ditrobenzyl 209mg and 5-mercaptothiazol-4-carboxylic acid (N-ethyl) amidoethylamine salt 161m L-rubamoylthiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1-methyl-1-l-lubapen-2-em-3-carboxylic acid 4-2-butene 111.5 mg of Jill was obtained.

_{NMR (CDC1 3) d: 1.10} (3H, d, J = 7.2 Hz), 1.25 (3H, t, J = 6.9 Hz), 1.34 (3H 3 d, J = 6.3 Hz), 3.2-3.3 (2H, m ), 3.4-3.5 (2H, m), 4.2-4.3 (2H, m), 5.27 (1H, d, J = l 3.8 Hz), 5.51 (1H, d, J = 13.8 Hz) ₃ 7.3-7.4 (1H , m), 7.64 (2H, d, J = 8.7 Hz), 8.21 (2H ₅ d, J = 8.7 Hz), 8.70 (1H, s)

 b) (1R, 5S, 6S)-2- [4- (N-ethyl) rubamoylthiazol-5-yl] thio-6-((lR) -l-hydroxyethyl) -1-methyl 1-force lubapen-2-em-3-carboxylate sodium

 In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- (N-ethyl) forcerubamoylthiazol-5-yl] thio-6-((lR) -1- 58.8 mg of the title compound was obtained from 111.5 mg of 4-hydroxybenzene.

_{NMR (D 2 0) d (} H0D = 4.80ppm):. 1.08 (3H 5 d, J = 6.9 Ηζ), 1 · 23 (3Η, t, J = 7.2 Hz) 5 l 29 (3H, d, J = 6.3 Hz) ₅ 3.0-3.2 (1H ₅ m), 3.4-3.5 (3H, m), 4.2-4.3 (2H, m), 9.02 (1H, s)

[Example 6] (1R, 5S, 6S) -2- (4-Formylthiazol-5-yl) thio-6-((lR) -l-hydroxyxethyl) -1-methyl-1-butarubene -2-Em-3-sodium carboxylate

 a) (lR, 5S, 6S) -2- (4-Formylthiazol-5-yl) thio-6-((lR) -l-hydroxyethyl) -1-methyl-1-methyll-bapene-2-e M-3-carboxylate 4-nitrobenzyl

In the same manner as in Example 3a), (lR ₃ 3R, 5R, 6S) -6-((lR) -lbdroxityl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid 4 (1R, 5S, 6S) -2- (4-formylthiazo-l-5-yl) thio-6-((2-Ritropenyl) 209mg and 4-formyl-5-mercaptothiazol 92m lR) -1-Hydroxyethyl) -1-methyl-1-forcelvapen-2-em-3-carboxylic acid 4-nitrobenzil 150 mg was obtained.

NMR (CDCl ₃ ) d: 1.10 (3H ₅ d, J = 1.Z Hz), 1.33 (3H, d, J = 6.3 Hz), 3.2-3.4 (2H, m), 4.2-4.3 (2H, m) , 5.30 (lH, d, J = 13.8 Hz), 5.54 (1H, d, J = 13.8 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.24 (2H, d, J = 8.4 Hz), 8.88 (1H, s), 10.21 (1H, s)

 b) (1R, 5S, 6S) -2- (4-Formylthiazol-5-yl) thio-6-((lR) -1-hydroxy) 6S)-2- (4-Formylthiazol-5-yl) thio-6-((111) -1-hydroxyethyl) -1-methyl-1-butyrolpine-2-em-3-carboxylic acid 25.5 mg of the title compound was obtained from 150 mg of 4-nitrobenzyl.

NMR (D ₂₀ ) d (HOD = 4.80 ppm): 1.0-1.2 (3H ₅ m.), 1.2-1.4 (3H, m), 3.2-3.6 (2H, m), 4.1-4.4 (ZH,), 9.13 (lH, s), 10.10 (1H, s)

 [Example 7] (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- [N- (2-hydroxyethyl) rubamoyl] thiazol-5- Yl] thio-1-methyl-1-potassium lvapen-2-em-3-carboxylate sodium

a) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- [N- (2-hydroxyethyl) ylbamoyl] thiazol-5-yl ] Cho-1-methyl-1-caproluben-2-em-3-cal 4-nitrobenzyl borate

In the same manner as in Example _{3a), (lR, 3R 3} 5R, 6S) -6 - ((lR) -lb Dorokishechiru) -1 - methyltransferase 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 (1R, 5S, 6S) -6-((1R) -1 from 85 mg of 2-nitrobenzil 137m and 5-mercaptothiazol-4-carboxylic acid [N- (2-hydroxyethyl)] amide -Hydroxyethyl) -2- [4- [N- (2-hydroxyethyl) carbamoyl] thiazolyl-5-yl] thio-1-methyl-1-hexyl-2-ene-3 -108 mg of 4-nitrobenzyl carboxylate was obtained.

NMR (CDCl ₃ ) d: 1.10 (3H, d, J 5 Hz), 1.34 (3H, d, J = 6.3 Hz), 3.2-3.3 (2H, m), 3.5-3.7 (2H ₅ m), 3.8- 3.9 (2H, m), 4.2-4.3 (2H, m) ₅ 5.28 (1H, d, J = 13.5 Hz), 5.51 (1H, d, J = 13.5 Hz), 7.65 (2H, d, J = 9.0 Hz), 7.7-7.8 (lH, m), 8.22 (2 H, d, J = 9.0 Hz), 8.71 (1H, s)

_{b) (lR, 5S 3 6S} ) -6 - ((lR) -lt: Dorokishechiru) -2- [4- [N- (2- hydroxy E chill) force Rubamoiru] thiazole-5-I le] Chio - 1 1-Methyl-1-potassium lvapen-2-em-3-sodium carbonate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- [N- (2-hydroxyethyl) potassium] thiazo [1-5-yl] thio-1-methyl-1-force Lubapen-2-em-3-carboxylic acid 62.5m of the title compound was obtained from 4-nitrobenzene.

_{NMR (D 2 0) d (} H0D = 4.80ppm):. 1.06 (3H, d, J = 6.9 Hz), 1.26 (3H, d, J = 6.3 Hz), 3 1-3.2 (1H, m), 3.4 -3.6 (3H, m), 3.7-3.8 (2H, m), 4.2-4.3 (2H 3 m), 8.99 (lH, s)

[Example 8] (lR, 5S, 6S) -2- [4- [N- (2-aminoethyl) caprubamoyl] thiazol-5-yl] thio-6-((1R) -1- Hydroxyethyl) -1-methyl-1-force Lubapen-2-em-3- force Sodium rubonate

[4-[N- (2-アジドエ ィル] チォ- 6-((lR)- 1-ヒドロキシェチル） -1-メチル -1-力ルバペン- 2-ェム- 3-カルボン 酸 4-二トロべンジル a) (1R, 5S, 6S)-2-

[4- [N- (2-azidoyl) thio-6-((lR) -1-hydroxyethyl) -1-methyl-1-hexyl-2-ene-3-carbone 4-Nitrobenzyl acid

In the same manner as in Example _{3a), (lR 3 3R 3} 5R, 6S) -6 - ((lR) -lb Dorokishechiru) -1-methylation-2 Okiso - carba Bae Nam - 3- carboxylic acid 4 two From 139 mg of trobenzil and 97 mg of 5-mercaptothiazol-4-carboxylic acid [N- (2-azidoethyl)] amide, (1R, 5S, 6S) -2- [4- [N- (2-azidoethyl) 76) 4-nitrobenzyl 4-carboxyyl] thiazole-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl-tolulbapene-2-em-3-carboxylate Got.

NMR (CDCl ₃ ) d: l.ll (3H ₅ d ₃ J = 7.2 Hz), 1.34 (3Η, d, J = 6.3 Hz), 3.2-3.3 (2H, m), 3.5-3.7 (4H, m), 4.2-4.3 (2H, m) ₃ 5.28 (1H, d, J = 13.8 Hz), 5.52 (1H, d, J = 13.8 Hz), 7.65 (2H, d, J = 8.7 Hz), 8.22 ( 2H, d, J = 8.7 Hz), 8.72 (1H ₅ s) b) (lR, 5S, 6S) -2- [4- [N- (2-aminoethyl) rubamoyl] thiazol-5-y Ru] thio-6-((lR) -1-Hydroxyethyl) -1-methyl-1-caphyllvapen-2-em-3-carboxylate

In the same manner as in Example _{lb), (1R 5 5S,} 6S) -2- [4- [N- (2- azidoethyl) force Rubamoi le] thiazole Ichiru - 5-I le] Chio - 6 - ((lR 16.7 mg) of the title compound was obtained from 76 m))-l-Hydroxyethyl) -trimethyl-1-forcelvapen-2-em-3-carboxylic acid 4-dibenzobenzene.

_{NMR (D 2 0) d (} H0D = 4.80ppm):. 1.09 (3H 3 d, J = 7.5 Hz), 1.27 (3H, d, J = 6.3 Hz), 3 2 - 3.3 (3H, m), 3.50 (1H, dd, JF6.3 Hz, J? 3.0 Hz), 4.2-4.3 (2H ₅ m), 8.97 (1H, s)

 [Example 9] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- (N-phenyl) potene rubamoylthiazole-5-y Le] thio-1-sodium lubapen-2-em-3-carboxylate

a) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- (N-phenyl) force rubamoylthiazol-5-yl] thio- 1-force Lubapen-2-em-3-carboxylic acid 4-dito Mouth Benzil

In the same manner as in Example 3a), (lR, 3R, 5R 3 6S) -6 - ((lR) -lb Dorokishechiru) -1-methylation - 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 Starting from 460 mg of -nitrobenzyl and 300 mg of 5-mercaptothiazol-4-carboxylic acid (N-phenyl) amide, (1R, 5S, 6S) -6-((1R) -1-hide mouth quichetyl) -1 497 mg of 4-methyl-2- [4- (N-phenyl) -rubamoylthiazo-l-5-yl] thio-1-l-rubapen-2-em-3-carboxylate were obtained.

NMR (CDCl ₃ ) d: 1.13 (3H, d ₅ J = 7.5 Hz), 1.34 (3H ₅ d, J = 6.3 Hz), 3.2-3.4 (2H,), 4.2-4.4 (2H, m), 5.29 ( lH, d, J = 13.5 Hz), 5.52 (1H, d, J = 13.5 Hz), 7.1-7.2 (1H, m), 7.3-7.4 (2H, m), 7.6-7.8 (4H, m) , 8.22 (2H, d, J = 9.0 Hz), 8.76 (1H, s), 9.26 (1H, s)

 b) (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- [4- (N-phenyl) force rubamoylthiazol-5-yl] thio- 1-force lubapen-2-em-3-carboxylate sodium

 In the same manner as in Example lb), (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- [4- (N-phenyl) potene rubamoylthiazol- From the 497 mg of 5-yl] thio-1-thiol-levapen-2-em-3-carboxylate 4-dibenzobenzene, 222 mg of the title compound was obtained.

Hz), 4.2-4.3(2H, m), 7.2-7.3 (1H， m),7.4-7.5(2H, m), 7.5-7.6(2H, m)， 9.02(1H, s) R (D ₂₀ ) d (H0D = 4.80ppm): 1.08 (3H, d, J = 1.Z Hz), 1 · 26 (3Η, d, J = 6.3 Hz), 3.2-3.3 (1H, m), 3.48 (1H,

Hz), 4.2-4.3 (2H, m), 7.2-7.3 (1H, m), 7.4-7.5 (2H, m), 7.5-7.6 (2H, m), 9.02 (1H, s)

 [Example 10] (lR, 5S, 6S) -6-((lR)-;!-Hydroxyethyl) -2- (4-methoxycarbonylnylaminothiazol-5-yl) thio-1-methyl 1-force lubapen-2-em-3-carboxylate sodium

a) (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- (4-methoxycarbonylaminothiazol-5-yl) thio-1-methyl-1- L-Lapapen-2-Em-3-carboxylic acid 4-Nito Mouth Benzil

In the same manner as in Example 3a), (lR, 3R, 5R 3 6S) -6 - ((lR) -lt Dorokishechiru) -1-methylation-2 Okiso - carba Bae Nam - 3- carboxylic acid 4 two (1R, 5S, 6S) -6-((1R)-: 1-Hydroxyethyl) -2- (from trobenzil 256m and 148mg of 5-mercapto-4-methoxycarbonylaminothiazol) There were obtained 198 mg of 4-methoxybenzyl 4-methoxycarbonylaminothiazol-5-yl) thio-methyl-1-carbyl-2-em-3-carboxylate.

NMR (CDCL) d: 1.08 (3H, d, J = 7.5 Hz), 1.32 (3H, d, J = 6.3 Hz), 3.0-3.K1H, m), 3.25 (1H, dd, JF6.6HZ, J ^ 2.7 HZ), 3.81 (3H, S), 4.2-4.3 (2H, m), 5.29 (1H, d, J = 13.5 Hz), 5.56 (lH, d, J = 13.5 Hz), 7.11 (1H, br s), 7.68 (2H, d, J = 9.0 Hz), 8.Z5 (ZH ₅ d, J = 9.0 Hz), 8.89 (1H, s)

 b) (lR, 5S, 6S) -6-((lR) -Trihydroxyethyl) -2- (4-methoxycarbonylthiominothiazol-5-yl) thio-1-methyl-1-force Lubapen-2-em-3-carboxylate sodium

 In the same manner as in Example lb), (lR, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- (4-methoxycarbonylaminothiazole-5-yl) thio- The title compound (120 m) was obtained from 198 m of 1-methyl-1-forcelvapen-2-em-3-carboxylic acid 4-nitrobenzil.

Hz), 4.1-4.3(1H₃ m), 9.03(1H， s) _{NMR (D 2 0) d (} H0D = 4.80ppm):. 1.02 (3H 5 d, J = 7.2 Hz), 1.23 (3H, d, J = 6.3 Hz), 2 8-3.0 (lH, m), 3.38 (1H, dd, J? 6.0 Hz, J * 2.7 Hz), 3.77 (3H, s), 4.09 (1H, dd,

Hz), 4.1-4.3 (1H ₃ m), 9.03 (1H, s)

 [Example 11] (lR, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((1R) -l-hydroxyxethyl) -l-methyl-l-capryl -Sodium 2-Em-3-carboxylate

 a) (1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -l-hydroxyethyl) -trimethyl-1-butyl-2-ene -3-carboxylic acid

In the same manner as in Example 3a), (lR ₃ 3R ₃ 5R, 6S) -6-((lR) -lb-droxityl) (1R, 5S, 6S) -2- (4) from 569m of 4-ditrobenzyl tyl-2-oxo-tricarbazane-3-carboxylate and 275mg of 4-acetyl-5-mercaptothiazol -Acetylthiazo-l-5-yl) thio-6-((lR) -l-hydroxyethyl) -1-methyl-l-caphyl-2-ene-3-carboxylate 4-nitrobenzyl 458 mg were obtained.

_{NMR (CDC1 3) d: 1.12} (3H 3 d, J = 7.2 Hz), 1.34 (3H, d, J = 6.3 Hz), 2.69 (3H, s), 3.3-3.4 (2H, m), 4.2- 4.4 (2H, m), 5.29 (1H, d, J = 13.8 Hz), 5.51 (1H, d, J = 13.8 Hz), 7.64 (2H, d, J = 9.0 Hz) ₃ 8.22 (2H, d, J = 9.0 Hz), 8.72 (1H, s)

 b) (lR, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-methyll-bapen-2- EM-3-Sodium carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -2- (4-acetylthiazol-5-yl) thio-6-((lR) -1-hydroxyethyl) -1- 238 mg of the title compound was obtained from 458 mg of 4-dimethoxybenzyl 2-methyl-3-carboxylate.

_{NMR (D 2 0) δ (} H0D = 4.80ppm): 1.10 (3H, d, J = 7.5 Hz), 1.27 (3H, d, J = 6.3 Hz), 2. 65 (3H, s), 3.3-3.4 (lH, m), 3.55 (lH, dd, J? 6.0 Hz, J ¾ 3.0 Hz), 4.Z-4.3 (1H, m), 4.34 (lH ₅ dd, J 9.9 HZ, J? 3.0 Hz), 8.88 (1H, s)

 [Example 12] (1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -l-hide mouth quichetyl) -trimethyl-1-force Lubapen-2-em-3-carboxylate methyl carboxylate

 (LR, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((1R) -trihydroxyethyl) -1-methyl-1 in the same manner as in Example 2. 120 mg of the title compound was obtained from 108 mg of sodium lubapen-2-em-3-carboxylate.

_{NMR (CDC1 3) d: l.ll} (3H, d 3 J = 7.2 Hz), 1.21 (9H, s), 1.32 (3H, d, J = 6.3 Hz), 2.69 (3H, s), 3.2-3.4 (2H, i), 4.2-4.3 (2H, m), 5.85 (1H, d, J = 5.4 Hz), 5.98 (1H, d, J-5.4 Hz), 8.72 (1H, s) Example _{13] (lR, 5S 3 6S} ) -6 - ((lR) -lt Dorokishechiru) - 1-methyl - 2-[4-(N-menu Chi carbamoyl) thiazole Ichiru -5- I le] Chio -1-potassium lvapen-2-em-3-carboxylate sodium

 a) (lR, 5S, 6S) -6-((lR) -ltdroxityl) -trimethyl-2- [4- (N-methylcarbamoyl) thiazolyl-5-yl] thio-1-caprylbapene -2-Em-3-carboxylic acid 4-to-2 mouth benzyl

In the same manner as in Example la), (lR ₃ 3R, 5R, 6S) -6-((lR) -lhdroxityl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid 4 - from the two Torobe Njiru 217mg and 5 main Rukaputochiazo Ichiru 4-carboxylic acid (N- methyl) amino Domechiruamin salts _{135m, (1R, 5S 3 6S} ) -6 - ((lR) -lh Dorokishechiru) -1- 116 mg of methyl-2- [4- (N-methylcarbamoyl) thiazol-5-yl] thio-1-butyrubapen-2-em-3-carboxylate 4-nitrobenzoyl were obtained.

NMR (DMSO-d ₆ ) d: 0.97 (3H, d ₅ J = 7.2 Hz), 1.10 (3H, d, 3 = 6 Λ Hz), 2.75 (3H ₅ d, J = 4.8 Hz), 3.2-3.4 ( 2H, m), 3.9-4.0 (lH, m), 4.22 (1H, dd, 10 Hz,

Hz), 5.06 (lH, d, J = 5.2 Hz), 5.35 (1H, d, J = 13.6 Hz), 5.49 (1H, d, J = 13.6 Hz), 7.71 (2H, d, J = 8.8 Hz) , 8.21 (2H, d, J = 8.8 Hz), 8.49 (1H ₃ d, J = 4.8 Hz), 9.19 (1H, s)

 MS (FAB); m / z 519 (M ++ 1)

 b) (lR, 5S, 6S) -6-((lR) -lbdroxityl) -trimethyl-2- [4- (N-methylcarbamoyl) thiazolyl-5-yl] thio-1-capryl -Sodium 2-em-3-carboxylate

 In the same manner as in Example lb), (lR, 5S, 6S) -6-((lR) -lbdroxityl) -1-methyl-2- [4- (N-methylcarbamoyl) thiazol-5-y [L] thio-l-Levapen-2-em-3-l-lulphonic acid 4-Nitrobenzyl, 114 mg, to give the title compound (48 mg).

_{NMR (D 2 0) d (} HOD = 4.80ppm): 0.92 (3H 5 d, J = 1.2 Hz), 1.12 (3H, d, J = 6 Hz), 2. 79 (3H, s), 2.9-3.0 (1Η, m), 3.3-3, 4 (1H, m), 4.0-4.K2H, m), 8.85 (1H, s) MS (FAB); m / z 406 (M ++ 1)

 [Example 14] (lR, 5S, 6S) -2- (4-Ethoxycarbonylthiazol-5-yl) thio-6-((1R) -hydroxyethyl) -1-methyl-1- Sodium Lubapen-2-em-3-carboxylate.

 a) (1R, 5S, 6S) -2- (4-Ethoxycarbonylthiazol-5yl) thio-6-((1R) -1-hydroxyethyl) -trimethyl-1-butyrubapen-2 -Em-3-carboxylic acid 4-nitrobenzene

In the same manner as in Example _{3a), (lR, 3R 5} 5R, 6S) -6 - ((lR) -lt Dorokishechiru) -1 - methyltransferase 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 (1R, 5S, 6S) -2- (4-ethoxycarbonylthiazol-5-yl) thio-6 from 217m of 2-nitrobenzil and 125mg of 5-mercaptothiazol-4-ethyl carboxylate 193m of 4- (2-l-hydroxyethyl) -1-methyl-toluene-lubapen-2-em-3-carboxylate 4-nitrobenzyl were obtained.

_{NMR (CDC1 3) d: l.ll} (3H, d 5 J = 7.2 Hz), 1 · 33 (3Η, d, J = 6 Hz), 1.41 (3H, t, J = 7.2 Hz), 3.2-3.3 (2H, m), 4.2-4.3 ( 2H, m), 4.43 (2H, q, J = 7.2 Hz), 5.29 (lH, d, J = 13.6 Hz), 5.53 (1H, d 3 J = 13.6 Hz) , 7.66 (2H, d, J = 8.8 Hz), 8.23 (2H, d, J = 8.8 Hz), 8.84 (1H, s)

 MS (FAB); m / z 534 (M ++ 1)

 b) (1R, 5S, 6S)-2- (4-Ethoxycarbonylthiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-methyl-lvapen- Sodium 2-em-3-carboxylate In the same manner as in Example lb), (1R, 5S, 6S) -2- (4-ethoxycarbonylthiazol-5-yl) thio-6-(( 1R)-1-Hyd mouth xicetyl) -1-methyl-1-force lubapen-2-em-3-carboxylate 4-nitrobenzyl, 193 mg, gave the title compound (76 mg).

NMR (D ₂ 0) δ (H0D = 4.80 ppm): 0.56 (3H, d, J = 6.8 Hz), 0.75 (3H, d, J = 6 Hz), 0.87 (3H, t, J = 7.2 Hz) ), 2.6-2.7 (1H, m), 2.9-3 · 0 (1Η, m), 3.6-3.7 (2H, m), 3.91 (2H, q, J = 7.2 Hz), 8.48 (lH, s)

 MS (FAB); m / z 421 (M ++ 1)

 Example 15 (lR, 5S, 6S) -2- (4-ethoxycarbonylthiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -1-methyl-1- Levapen-2-em-3-carboxylate

 In the same manner as in Example 2, (lR, 5S, 6S) -2- (4-ethoxycarbonylthiazol-5-yl) thio-6-((lR) -l-hydroxyethyl) -1- 129 mg of the title compound was obtained from sodium methyl-1-captor-2-ap-3-em-3-carbonate.

NMR (CDCL) d: 1.10 (3H ₅ d, 3 = 1.2 Hz), 1.22 (9Η, s), 1.31 (3H, d, J = 6.4 Hz), 1.41 (3H ₃ t, J = 7.2 Hz) , 3.2-3.3 (2H, m), 4.2-4.3 (2H, m), 4.43 (2H, q, J = 7.2 Hz), 5.87 (1H, d, J = 5.2 Hz), 6.00 (lH, d, J = 5.2 Hz), 8.84 (1H, s)

 MS (FAB); m / z 513 (M ++ 1)

 [Example 16] (1R, 5S, 6S) -2- [4- (N-rubamoylmethyl) rubamoylthiazol-5-yl] thio-6-((lR) -1-hydroxyethyl ) 1-Methyl-1-caproluvene-2-em-3-carboxylate sodium

a) (1R, 5S, 6S)-

Le] thio-6-((lR) -l-hydroxyethyl) -1-methyl-1-methyll-bapene-2-em-3-carbone 4-nitrobenzene

In the same manner as in Example _{3a), (lR, 3R 3} 5R 3 6S) -6 - ((lR) -lb Dorokishechiru) -1 - methyltransferase - 2 Okiso - Bok carba Bae Nam - 3- carboxylic acid 4- Nitrobenzil 250 mg and 5-me Rucaptothiazol-4-carboxylic acid (from 155 mg of N-mid, (1

ル]チォ-R, 5S, 6S) -2- [4- (N-

Le] Chio-

170 mg of 6-((lR)-: l-hydroxyethyl) -l-methyl-l-caproluben-2-em-3-carvone 4-ditrobenzil was obtained.

NMR (DMS0-da) d: 0.98 (3H ₃ d ₅ J = 7.2 Hz), 1.11 (3H ₅ d ₅ J = 6.3 Hz), 3.3-3.4 (2H, m), 3.7-3.8 (2H, m), 3.9- 4.0 (1H, m), 4.2-4.3 (1H, m), 5.06 (1H, d, J = 4.8 Hz), 5.35 (1H, d, J = 13.8 Hz), 5.50 (lH, d, J = 13.8 Hz), 7.09 (1H, br s), 7.43 (1H, br s), 7.72 (2H, d, J = 8.4 Hz), 8.23 (2H, d, J = 8.4 Hz), 8.4-8.5 (lH , m), 9.22 (1H, s)

 b) (1R, 5S, 6S)-2- [4- (N-forcerubamoylmethyl) forcerubamoylthiazole-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl 1-Levapen-2-em-3-sodium carbonate

 In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- (N-forcerubamoylmethyl) forcerubamoylthiazol-5-yl] thio-6-((lR) -l- 99.4 mg of the title compound were obtained from 170 m of benzyl dihydrol-l-methyl-1-carbap-2-ene-3-em-3-carboxy.

Hz, J 2.7 HZ), 4.1-4.2(2H, m)， 4.2-4.3 (2H, m)，9.01(lH, s) ■ R (D) d (H0D = 4.80ppm): l.ll (3H, d, J = 6.9 Hz), 1.30 (3H, d, J = 6.3 Hz), 3.2-3.4 (1H, m), 3.52 (1H,

Hz, J 2.7 HZ), 4.1-4.2 (2H, m), 4.2-4.3 (2H, m), 9.01 (lH, s)

 [Example 17] (lR, 5S, 6S) -2- (4-Formylaminothiazol-5-yl) thio-6-((1R) -l-hydroxyethyl) -1-methyl 1-force lubapen-2-em-3-carboxylate sodium

a) (1R, 5S, 6S) -2- (4-Formylaminothiazol-5-yl) thio-6-((1R) -1-hydrexyl) -trimethyl-1-caproluvene-2- in the same manner as E arm 3-carboxylic acid 4 two Torobe Njiru example _{3a), (lR, 3R 3} 5R 3 6S) -6 - ((lR) -l-fc Dorokishechiru) -1 - main From 542 mg of 4-ditrobenzyl tyl-2-oxo-carbazin-3-carboxylate and 73 mg of 4-formylamino-5-mercaptothiazol, (IR, 5S, 6S) -2- (4- Formyl aminothiazol-5-yl) thio-6-((1R) -1-hid mouth kissille) -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl 47m was obtained.

NMR (CDCl ₃ ) d: l.ll (3H ₃ d, J = 7.2 Hz), 1.33 (3H, d, J = 6.3 Hz), 2.9-3.1 (lH, m), 3.26 (1H ₃ dd, J 6.9 HZ, J? 2.7 Hz), 4.2-4.3 (2H, m), 5.31 (1H, d, J = 13.8 Hz), 5.55 (1H, d, J = 13.8 Hz), 7.68 (2H, d, J = 9.0 Hz), 8.07, 8.10 (total 1H, 2s), 8.25 (2H 5 d, J = 9.0Hz), 8.84 (1H, s), 9.28, 9.31 (total 1H, 2s) b) (lR, 5S, 6S) -2- (4-formylaminothiazol-5-yl) thio-6-((lR)-; l-hide kisshethyl) -1-methyl -1-capryl-2-ene-3 -Sodium carboxylate

 (1R, 5S, 6S) -2- (4-formylaminothiazol-5-yl) thio-6-((1R) -1-hide mouth quichetyl) The title compound (27.5 mg) was obtained from 47-m-nitrobenzyl 1-methyl-1-carbyl-2-em-3-carboxylate

_{NMR (D 2 0) d (} H0D = 4.80ppm): 1.04 (3H, d, J = 7.2 Hz), 1.24 (3H, d, J = 6.3 Hz), 2. 9-3.0 (lH, m), 3.3 -3.4 (lH, m), 4.1-4.3 (2H, m), 8.35, 9.03, 9.05, 9.10 (tota

1 2H, 4s)

 [Example 18] (111,58,68) -6-((^)-; 1-hydroxyethyl) -2- [4- | ^-(2-methoxyethyl) carpamoyl] thiazole-5-y Le] thio-1-methyl-1-carpapen-2-em-3-carboxylate

 a) (1R, 5S, 6S) -6-((1R) -1-Hydroxyethyl) -2- [4- [N- (2-Methoxyxyl) force rubamoyl] thiazol-5-yl] Thio-1-methyl-1-carbyl-2-em-3-carboxylate 4-nitrobenzyl

In the same manner as in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -lbdroxityl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid 4 From 145 mg of 2-nitrobenzil and 87 mg of 5-mercaptothiazole-4-carboxylic acid [N- (2-methoxethyl)] amide, (1R 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- 2- [4- [N- (2-methoxethyl) lvamoyl] thiazolyl-5-yl] thio-1- There was obtained 56 mg of methyl-1-butyr-2-ene-3-carboxylate 4-benzyl benzyl.

NMR (CDCl ₃ ) ^: 1.10 (3H ₅ d ₃ 3 = 1.Z Hz), 1.33 (3H, d, J = 6.4 Hz), 3.2-3.3 (2H, m), 3.5-3.6 (2H, m) , 3.6-3.7 (2H, m), 4.2-4.3 (2H, m), 5.29 (1H, d, J = 13.6 Hz), 5.51 (1H, d, J = 13.6 Hz), 7.64 (2H, d, J = 8.8 Hz), 8.22 (2H, d, J = 8.8 Hz), 8.72 (1H, s)

 MS (FAB); m / z 563 (M ++ 1)

 b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- [N- (2-methoxethyl) rubamoyl] thiazole-5-yl] thio- 1-methyl-1-caproluvene-2-em-3-carbonate sodium

In the same manner as in Example _{lb), (1R 3 5S,} 6S) -6 - ((lR) - Bok hydroxy E Chill) - 2- [4 - [N - (2- main Tokishechiru) force Rubamoiru] thiazole Ichiru [5-5-yl] thio-1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzoyl (88 m) gave the title compound (23 mg).

_{NMR (D 2 0) δ (} H0D = 4.80ppm): 0.90 (3H, d, J = 7.2 Hz), 1.11 (3H, d, J = 6.4 Hz), 3. 0-3.K1H, m), 3.25 (3H, s), 3.3-3, 4 (1H ₅ m), 3.4-3.5 (2H, m), 3.5-3.6 (2H, m), 4.0-4.K2H, m) ₃ 8.85 (1H, s)

 MS (FAB); m / z 450 (M ++ 1)

 [Example 19] (lR, 5S, 6S) -6-((ll-Trihydroxyethyl) -2- [4- (N-methoxy) force rubamoylthiazol-5-yl] thio-1- Sodium methyl-1-carba-2-em-3-carboxylate

メ トキシ）力ルバモイ ルチアゾール -5-ィル]チォ- 1-メチル -1-力ルバペン- 2-ェム- 3-カルボン酸 4-二ト 口べンジル 実施例 3a)と同様にして、 (lR₅3R₃5R₅6S)-6-((lR)-l-t:ドロキシェチル） -1 -メ チル- 2-ォキソ -1-カルバぺナム- 3-カルボン酸 4-二トロべンジル 469mgおよび 5-メ ルカプトチアゾ一ル- 4-カルボン酸 (N-メ トキシ）アミ ド 270mgより、' (1R, 5S，6S) - 6-((lR)-:l-ヒドロキシェチル） -2-[4- (N-メ トキシ）力ルバモイルチアゾ一ル -5 -ィ ル]チォ- 1-メチル -1-力ルバペン- 2-ェム -3-カルボン酸 4-二トロべンジル 112mgを 得た。 a) (1R, 5S, 6S)-6- (

Methoxy) -l-bamoyl luthiazole-5-yl] thio-1-methyl-1-l-lupapen-2-em-3-carboxylic acid 4-t-benzyl In the same manner as in Example _{3a), (lR 5 3R 3} 5R 5 6S) -6 - ((lR) -lt: Dorokishechiru) -1 - methyltransferase - 2 Okiso-carba Bae Nam - 3- carboxylic acid From (469 mg of 4-ditrobenzil and 270 mg of 5-mercaptothiazol-4-carboxylic acid (N-methoxy) amide, '(1R, 5S, 6S) -6-((lR)-: l-hydroxy Ethyl) -2- [4- (N-methoxy) potassyl-5-yl] thio-1-methyl-1-potassyl-2-ene-3-carboxylate 4-carboxylic acid 112 mg was obtained.

NMR (CDCL) d: 1.1-1.2 (3H ₅ m), 1.3-1.4 (3H, m), 3.1-3.3 (2H, m), 3.90 (3H, s), 4.1-4.4 (2H ₃ m), 5.2 -5.6 (2H, m), 7.6-7.7 (2H ₃ m), 8.2-8.3 (2H, m), 8.73 (1H, s), 9.73 (1H, s)

 b) (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -2- [4- (N-methyoxy) -rubamoylthiazolyl-5-yl] thio-1- Sodium methyl-1-carbyl-2-em-3-carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- 2- [4- (N-methy) sylvamoylthiazol-5 From the 112 mg of 4- (2-yl) thio-1-methyl-1-forcelvapen-2-em-3-carboxylate 4-nitrobenzene, 29.2 mg of the title compound was obtained.

_{NMR (D 2 0) d (} H0D = 4.80ppm):. 1.04 (3H 5 d, J = 7.2 Hz), 1.23 (3H 5 d, J = 6.3 Hz), 3 0-3.K1H, m), 3.41 (1H ₅ dd, J? 6.0 Hz, J? 2.4 Hz), 3.75 (3H, s), 4.1-4.3 (2H, m), 9.00 (lH, s)

 [Example 20] (lR, 5S, 6S) -2- (4-Aminothiazol-5-yl) thio-6-((lR)-; l-hydridoxicetyl) -1-methyl-1- Sodium Lubapen-2-em-3-carboxylate

_{a) (lR, 5S 3 6S} ) -6 - ((lR) -lt: Dorokishechiru) -1-methyl-2- [4- (4-Nitoroben Jill O alkoxycarbonyl § mino) thiazole Ichiru -5- I le ] Cho-1-L-Levapen-2-Em-3-Carboxylic acid 4-Nitrobenzil

In the same manner as in Example _{3a), (lR 5 3R 3} 5R, 6S) -6 - ((lR) -lh Dorokishechiru) -1-methylation - 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 -Nitrobenzil 117 mg and 5-me Mercapto - 4- (4-two Torobe Nji Ruo alkoxycarbonyl § mino) from thiazole Ichiru _{169mg, (lR, 5S 5 6S} ) -6 - ((lR) -lb Dorokishechiru) - 1-methyl-2- [4 There was obtained 74 mg of 4- (2-nitrobenzyloxycarbonylamino) thiazol-5-yl] thio-1-thiol-l-bapene-2-em-3-carbonic acid 4-dibutenyl.

NMR (CDCl ₃ ) d: 1.07 (3H ₃ d ₃ J = 7.2 Hz), 1.31 (3Η, d, J = 6.0 Hz), 3.0-3.1 (1H, m), 3.24 (1H, dd, JF6. 6HZ, J 2.7 HZ), 4.1-4.3 (2H, m), 5.26 (1H, d, J = 14.1 Hz), 5.55 (1H, d, J = 14.1 Hz), 7.56 (2H, d, J = 8.1 Hz) ), 7.67 (2H, d, J = 8.1 Hz), 8.2-8.3 (4H, m), 8.91 (lH, s)

_{b) (1R, 5S 5 6S} ) - 2- (4- Aminochiazo Ichiru 5-I le) Chio - 6 - ((1R) -; - hydroxy Echiru) - Bok-methyl-1 force Rubapen - 2- E Sodium 3-carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR)-: l-hydroxyethyl) -1-methyl-2- [4- (4-ditrobenzylo) 28.2 mg of the title compound were obtained from 74 mg of xycarbonylamino) thiazolyl-5-yl] thio-1 -l-levapen-2-em-3-carboxylic acid 4-dibutenyl.

_{NMR (D 2 0) d (} H0D = 4.80ppm):. 1.07 (3H 5 d, J 2 Hz), 1.24 (3H, d, J = 6.3 Hz), 2 9-3.0 (lH, m), 3.36 ( 1H, dd ₅ J-6.3 Hz, J-2.7 Hz), 4.1-4.3 (2H, m), 8.82 (1H, s)

 [Example 21] (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- [N- (3-hydroxypropane-1-yl) -capsulebamoyl] thiazo 1-yl-5-yl] thio-1-methyl-1-potassium sodium 2-carboxy-3-carboxylate

_{a) (lR 5 5S 3 6S} ) -6 - ((lR) -lh Dorokishechiru) -2- [4- [N- (3- hydroxy propane -; I- I le) force Rubamoiru] thiazole Ichiru -5 -Yl] thio-1-methyl-1-potassyl-2-ene-3-carboxylate 4-nitrobenzyl

In the same manner as in Example 3a), (lR, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- Carboxylic acid 4-Nitrobenzil 254mg and 5-medium From 16 mg of rucaptothiazol-4-carboxylic acid [N- (3-hydroxypropane-1-yl)] amide, (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- [N- (3-Hydroxypropane-1-yl) capsulebamoyl] thiazolyl-5-yl] thio-1-methyl-1-carbazane-2-em-3 -225 mg of 4-carboxylic acid 2-nitrobenzil were obtained.

NMR (CDCl ₃ ) d: 1.09 (3H, d, J = 7.6 Hz), 1.33 (3H, d, J = 6.4 Hz), 1.7-1.8 (2H, m), 3.2-3.3 (2H, m), 3.5 -3.6 (lH ₅ m), 3.6-3.7 (lH, m), 3.6-3.7 (2H, br s), 4.2-4.3 (lH, m), 4.28 (1H, dd, J? 9.6 Hz, J * 2.8 Hz), 5.27 (1H, d, J = 14 Hz), 5.52 (1H, d, J = 14 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.70 (1H, t, J = 6.8 Hz), 8.22 (2H, d, J = 8.4 Hz), 8.72 (1H, s)

 MS (FAB); m / z 563 (M ++ 1)

 b) (lR, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -2- [4- [N- (3-hydroxypropan-1-yl) -capsulebamoyl] thiazol -5-yl] thio-1-methyl-1-potassium 2-bamate-3-carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- [N- (3-hydroxypropane-1-yl)] L-Bamoyl] thiazol-5-yl] thio-1-methyl-1-l-lubapen-2-em-3-carboxylate 4-Nitrobenzyl 225 mg to give 89 mg of the title compound Was.

NMR (D ₂₀ ) d (HOD = 4.80 ppm): 0.91 (3H ₃ d, J = 7.2 Hz), 1.12 (3H, d, J = 6.4 Hz), l. 6-1.7 (2H, m), 3.0 -3.1 (lH, m), 3.3-3, 4 (3H, m), 3.55 (2H, t, J = 6 Hz), 4.0-4.1 (2H, m), 8.87 (1H, s)

 MS (FAB); m / z 450 (M ++ 1)

Example _{22] (lR 5 5S 5 6S} ) -6 - ((lR) -l-fc Dorokishechiru) - 1-methyl-2-[4-[N-(flop port Pan - 1-I le) force Rubamoiru ] Thiazol-5-yl] thio-1-potassium 2-baem-3-carboxylate

a) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- [N- (propane Le-5-yl] thio-1-potassium 2-baem-3-carbonic acid 4-nitrobenzil

In the same manner as in Example _{la), (lR, 3R 5} 5R, 6S) -6 - ((lR) -lb Dorokishechiru) -1-methylation - 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 From 254 mg of 2-nitrobenzil and 201 mg of 5-mercaptothiazol-4-carboxylic acid [N- (propane-1-yl) amide] (1-propyl) amine salt, (lR, 5S, 6S) -6-((lR) -ltdroxityl) -Methyl-2- [4- [N- (propane-1-yl) -lubamoyl] thiazolyl-5-yl] thio-1-l-lubapen-2 198 mg of 4-emtrobenzil -em-3-carboxylic acid were obtained.

_{NMR (CDC1 3) d: 0.98} (3H, d, J = 7.2 Hz), 1.10 (3H, d, J = 7.2 Hz), 1.34 (3H, d, J = 6.4 Hz), 1.6-1.7 (2H, m ), 3.2-3.3 (2H, m), 3.39 (2H, q, J = 7.2 Hz), 4.2-4.3 (1H, m), 4.28 (1H, dd, J 9.6 HZ, J 2.8HZ), 5.28 (1H _{5 d, J = 13.6 Hz)} , 5.51 (1H, d, J = 13.6 Hz), 7.3-7.4 (lH 5 br s), 7.64 (2H, d, J = 8.8 Hz), 8.22 (2H, d, J = 8.8 Hz), 8.70 (1H, s)

 MS (FAB); m / z 547 (M ++ 1)

 b) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2- [4- [N- (propane-

1-yl) Rubamoyl] thiazolyl-5-yl] thio-1-Lubapen-2-em-3-sodium carbonate

In the same manner as in Example lb), (1R, 5S, 6S) -6-((lIl) -1-hydroxyethyl) -1-methyl-2- [4- [N- (propane-1-yl) ) Carpamoyl] thiazol-5-yl] thio-1-carbazin-2-em-3-carboxylate 4-Nitrobenzyl From 198 m, 78 mg of the title compound were obtained.

_{NMR (D 2 0) δ (} H0D = 4.80ppm):. 0.79 (3H, d, J = 7.2 Hz), 0.89 (3H 5 d, J = 6.8 Hz), l 10 (3H, d, J = 5.6 Hz ), 1.45 (2H, q, J = 7.2 Hz), 2.9-3 · 0 (1Η, m), 3.1-3.2 (2H, m), 3.2-3.3 (1H, m), 4.0-4.1 (2H, m ), 8.86 (1H, s)

 MS (API); m / z 434 (M ++ 1)

 [Example 23] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl- [4- [N- (pyridin-2-yl) methyl] forcerubamoylthiazo 1-L-5-Il] Cho-1

a) (1R, 5S,6S)-6-((lR)-:l-ヒドロキシェチル） -1-メチル -2- [4-[N- (ピリジン- 2-ィル）メチル]力ルバモイルチアゾ一ル -5-ィル]チォ -1-力ルバペン- 2-ェム- 3 - カルボン酸 4-ニトロべンジル ■ Sodium 2-em-3-carboxylate

a) (1R, 5S, 6S) -6-((lR)-: l-hydroxyethyl) -1-methyl-2- [4- [N- (pyridin-2-yl) methyl] potassium Ru-5-yl] thio-1-caproluban-2-em-3-carboxylate 4-nitrobenzyl ■

 In the same manner as in Example 3a), (1R, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazinam-3- From 398mg of carboxylic acid 4-ditrobenzyl 361m and 5-mercaptothiazol-4-carboxylic acid [N- (pyridin-2-yl) methyl] amide trifluoroacetate (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -1-methyl -2-[4- [N- (pyridine-2-yl) methyl] methyl-l-bamoylthiazol-5-yl] thio -1 -Carbapene-2-em-3-carboxylic acid 4- (2-butoxybenzyl) 208 mg was obtained.

NMR (CDCl ₃ ) d: 1.09 (3H ₅ d, J = 6.9 Hz), 1.33 (3H, d, J = 6.3 Hz), 3.2-3.3 (2H, m), 4.2-4.3 (2H, m), 4.7 -4.8 (2H, m), 5.28 (1H, d, J = 14.1 Hz), 5.51 (1H, d, J. = 14.1 Hz), 7.2-7.4 (2H ₃ m), 7.6-7.7 (3H, m) , 8.21 (2H, d, J = 9.0 Hz), 8.4-8.5 (1H, m) ₅ 8.5-8.6 (1H, m), 8.76 (lH, s)

 b) (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -1-methyl-2- [4- [N- (pyridin-2-yl) methyl] -capillobamoylthiazol -5-yl] thio-1-L-capulene-2-em-3-sodium carboxylate

In the same manner as in Example _{lb), (1R, 5S 5} 6S) - 6- ((1R) - hydroxy E chill) -1-methylation - 2- [4- [N- (pyridin-2-I-le) From the 208 mg of methyl 2-butyrolbazoylthiazol-5-yl] thio-1-butyrolbapene-2-em-3-carboxylate, 70 mg of the title compound was obtained.

NR (D ₂₀ ) δ (H0D = 4.80ppm): 0.97 (3H, d, J = 7.1 Hz), 1.24 (3H, d, J = 6.6 Hz), 3.1.3.2. (1H, m), 3.42 (1H, dd, Jf6.1 Hz, J? 2.9 Hz), 4.11 (1H, dd, 9.5 Hz, J 2 = 2.9 Hz), 3.75 (3H 5 s), 4.2-4.3 (2H 3 m), 4.68 ( 2H ₅ s), 7.3-7.4 (lH, m), 7.4-7.5 (1H, m), 7.8-7.9 (1H, m), 8.4-8.5 (1H, m), 9.01 (1H, s) [Example 24] (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- (4-methoxyponylthiazol-5-yl) thio-1-methyl-1 -Kirubapen-2-Em-3-Sodium carboxylate

 a) (1R, 5S, 6S) -6-((lR)-: l-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-methyl-1 -Kyrubapene-2-Em-3-Carboxylic acid 4-Nitrobenzyl

 As in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- From 153 mg of 4-carboxylic acid dinitrobenzil and 81 mg of methyl 5-mercaptothiazol-4-carboxylate, (1R, 5S, 6S) -6-((1R) -1-hydroxystyl)-2- (4 83 mg of -Methoxycarbonylthiazol-5-yl) thio-1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzil were obtained.

NMR (CDC1 ₃ ) <5: l.ll (3H, d, J = 7.2 Hz), 1.34 (3H, d, J = 6.3 Hz), 3.2-3.3 (2H, m), 3.97 (3H, s), 4.2-4.3 (2H, m), 5.29 (1H, d, J = 13.8 Hz), 5.54 (1H, d, J = 13.8 Hz), 7.66 (2H, d, J = 8.7 Hz), 8.24 (2H , D, J = 8.7 Hz), 8.83 (1H, s)

b) (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -2- (4-Methoxycarbonylthiazol-5-yl) thio-1-methyl-1-capryl - 2-E arm - in the same manner as 3-carboxylate example _{lb), (1R, 5S 5} 6S) -6 - ((lR) - 1- hydroxy E chill) -2- (4-menu Tokishikarubo two Luthiazole-5-yl) thio-1-methyl-1-forcelvapen-2-em-3 -carbo NMR (D ₂₀ ) δ (H0D = 4.80 ppm): 1.09 (3H, d, J = 7.2 Hz ), 1.26 (3H ₅ d, J = 6.6 Hz), 3.2-3.3 (1H, m), 3.51 (1H, dd ₅ J? 5.7 Hz, J * 2.7 Hz), 3.94 (3H ₅ s), 4.2-4.3 (2H, m), 8.96 (lH, s)

[Example 25] (1R, 5S, 6S) -2- (4-carboxythiazol-5-yl) thio-6-((lR) -1-hydroxyethyl) -trimethyl-1- L-Lapapen-2-em-3-carboxylic acid 2 sodium

 a) (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- [4- (4-nitrobenzyroxycarbonyl) thiazolyl-5-yl ] Cho-1-Levapen-2-em-3-Carbonate 4-Nitrobenzil

In the same manner as in Example _{3a), (lR 3 3R,} 5R 5 6S) -6 - ((lR) -lt Dorokishechiru) -1-methylation-2 Okiso-carba Bae Nam - 3-carboxylic acid 4 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -trimethyl from 310 mg of 2-nitrobenzil and 253 m of 4-nitrobenzyl 5-carboxythiazol-4-carboxylate -2- [4- (4-Nitro-benzyloxycarbonyl) thiazolyl-5-yl] thio-1-thiol-lubapen-2-em-3-carboxylic acid 172 mg of benzyl were obtained.

_{NMR (CDC1 3) d: 1.07} (3H, d 5 J = 7.6 Hz), 1.32 (3H, d, J = 6 Hz), 1.80 (1H, d, J = 4.4 Hz), 3.20-3.25 (lH, m ) ₅ 3.27-3.29 (1H, m), 4.18 (1H ₅ dd, J = iO Hz, J = 2.8 Hz), 4.23- 4.27 (1H, m), 5.25-5.30 (lH, m), 5.49-5.55 ( 3H ₅ m), 7.63- 7.67 (4H, m), 8.23 (4H, d, 3 = 7.6 Hz), 8.85 (1H, s)

 MS (FAB); m / z 641 (M ++ 1)

_{b) (1R 5 5S, 6S} ) - 2- (4- carboxy-5-I le) Chio -6 - ((lR) -l- hydro Kishechiru) -1-methyl-1 force Rubapen - 2- E -3-carboxylic acid 2 sodium

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- [4- (4-ditrobenzoyloxy) From 172 m of carbonyl) thiazol-5-yl] thio-1-carbapene-2-em-3-carboxylate, 4172 mg of the title compound was obtained.

_{NMR (D 2 0) d (} HOD = 4.80ppm):. 0.90 (3H, d, J = 7.2 Hz), 1.10 (3H, d, J = 6.4 Hz), 2 96-3.00 (lH, m), 3.29 (lH, dd, J? 5.6 Hz, J? 2.4 Hz), 4.03-4.09 (2H, m), 8.79 (1H, s)

 MS (FAB); m / z 415 (M ++ 1)

[Example 26] (5R, 6S) -2- (4-force rubamoylthiazole-5-yl) thio-6-((1R) -1- (Hydroxyethyl) -1-sodium lvapen-2-em-3-carboxylate

 a) (5R, 6S)-2- (4-Rubamoylthiazol-5-yl) thio-6-((lR) -1 -Hydroxyethyl) -Luvapene-2-em-3-carvone 4-Nitrobenzyl acid

 In the same manner as in Example la), (3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2-oxo-1-carbazin-3-carboxylic acid 4-nitrobenzene (5R, 6S) -2- (4-carbamoylthiazol-5-yl) thio-6-((1R) from 696 mg of benzyl and 372 mg of 5-mercaptothiazol-4-carboxylic acid amide ammonium salt 788 mg of 4-ditrobenzyl-1--1-hydroxyl-l-pent-2-em-3-carboxylate were obtained.

NMR (CDCL) d: 1.32 ( 3H, d 5 J = 6.3 Hz), 2.9- 3 · 0 (2Η, m), 3 · 19 (1Η, dd, J 6.9 Hz, «L = 3.0Hz), 4.1- 4.3 (2H, m), 5.29 (1H, d, J = 14.1 Hz), 5.53 (1H 3 d, J = 14. 1 Hz), 5.62 (lH 5 br s), 7.20 (1H, br s), 7.66 (2H, d, J = 8.7 Hz), 8.23 (2H, d, J = 8.7 Hz), 8.79 (lH, s)

 b) (5R, 6S) -2- (4-L-rubamoylthiazol-5-yl) thio-6-((1R) -trihydroxyl) -1-l-lubapen-2-em-3-carvone Sodium acid

 In the same manner as in Example lb), (5R, 6S) -2- (4-force rubamoylthiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -toluene rubapene- 416 mg of the title compound was obtained from 788 mg of 2-em-3-carboxylic acid 4-nitrobenzene.

Hz), 4.1-4.2(2H₅ m), 9.03(1H, s) _{NR (D 2 0) δ (} H0D = 4.80ppm): 1.23 (3H, d, J = 6.6 Hz), 2.7-3.0 (2H 5 m), 3.40 (1H, dd,

Hz), 4.1-4.2 (2H ₅ m), 9.03 (1H, s)

[Example 27] (lR, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (4-propionylthiazol-5-yl) thio-1- L-Levapen-2-em-3-carboxylate sodium

a) (lR, 5S, 6S) -6-((lR) -ltdroxityl) -trimethyl-2- (4-propionylthiazol-5-yl) thio-1--1-l-lubapen-2-em- in the same manner as 3-carboxylic acid 4 two preparative port base Njiru example 3a), (lR, 3R, 5R 3 6S) -6 - ((lR) -lh Dorokishechiru) -1-methylation - 2- Okiso - From 188 mg of 4-nitrobenzoyl 1-carbazin-3-carboxylate and 121 mg of 5-mercapto-4-propionylthiazol, (lR, 5S, 6S) -6-((lR) -1- Hydroxyl) -trimethyl-2- (4-propionylthiazol-5-yl) thio-1-carban-2-em-3-carboxylate 4-nitrobenzoyl 97m was obtained.

MR (CDCl ₃ ) d: 1.10 (3H, d, J = 7.4 Hz), 1.21 (3H, dd, J-7.4 Hz, JA Hz), 1.35 (3H, d, J = 6.3 Hz), 1.68 (1H, d, J = 4.7 Hz), 3.02- 3.24 (2H, m), 3.26-3.3 4 (2H, m), 4.27-4.33 (2H ₃ m), 5.29 (1H, d, J = 13.6 Hz), 5.51 ( 1H, d, J = 13.6 Hz, 7.64 (2H ₅ d, J = 8.5 Hz), 8.22 (ZH, d, J = 8.8 Hz), 8.75 (1H, s)

 b) (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- (4-propionylthiazol-5-yl) thio-1-force Lubapen-2-em-3-carboxylate sodium

In the same manner as in Example _{lb), (lR 5 5S,} 6S) -6 - ((lR) -lt: Dorokishechiru) -1-methyl - 2- (4-propionic two Ruchiazoru 5-I le) Chio -1 18-m title compound 18m was obtained from 97-m-l-lappaen-2-em-3-carboxylic acid 4-nitrobenzil.

NMR (D ₂₀ ) d (H0D = 4.65 ppm): 0.95 (3H ₃ d, J = 7.3 Hz), 1.00 (3H, dd, J 7.3 Hz, J ₂ = 7.3 Hz), 1.12 (3H ₃ d, J = 6.3 Hz), 2.90-3.01 (2H, m), 3.17-3.25 (1H, m), 3.40 (1H, dd, J 2.9 Hz, '5.9 Hz), 4.08-4.14 (1H, m), 4.18 (1H , dd, J 3.0 Hz, J ₂ = 9.8 Hz), 8.74 (1H, s)

MS (FAB); m / z 405 (M ⁺⁺ 1)

[Example 28] (1R, 5S, 6S) -2- (4-cyanothiazol-5-yl) thio-6-((lR) -l-hydroxyxethyl) -1-methyl-l-caprolubene -2-Em-3-carboxylate sodium.

 a) (1R, 5S, 6S) -2- (4-cyanothiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-methyll-bapen-2- EM-3-carboxylic acid

 (1R, 35R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid in the same manner as in Example la). From 237m of 4-nitrobenzoyl and 93m of 4-cyano-5-mercaptothiazole, (1R, 5S, 6S) -2- (4-cyanothiazol-5-yl) thio-6- ( 81 mg of (lR) -l-hydroxyethyl) -1-methyl-1-force lubapen-2-em-3-carboxylate

_{NMR (CDC1 3) d: 1.15} (3H 3 d, J = 7.2Hz), 1.33 (3H, d, J = 6Hz), 3. Bok 3.2 (lH, m), 3. 31 (1H, dd, J 2.4 HZ, JF6.4HZ), 4.2-4.3 (lH, m), 4.32 (1H, dd, J 2.4Hz, J¾9.2Hz), 5.31 (1H, d, J = 13.6Hz), 5.55 (1H, d, J = 13.6Hz), 7.67 (2H, d, J = 8.8Hz), 8.24 (2H, d, J = 8.8Hz), 8.96 (1H, s)

MS (FAB); m / z 487 (M ⁺⁺ 1)

 b) (lR, 5S, 6S) -2- (4-Cyanothiazol-5-yl) thio-6-((lR) -l-hydroxyethyl) -1-methyl-1-methyll-bapene-2 -Em-3-sodium sodium carboxylate

In the same manner as in Example _{lb), (1R, 5S 5} 6S) - 2- (4- Shianochiazo Ichiru 5-I le) Chio - 6 - ((lR) - Bok hydroxy E Chill) - Bok methyl -1 From the 108 mg of 4-nitro-4-benzyl-3-carb-3-ylcarboxylate, 39 mg of the title compound was obtained.

NMR (D ₂₀ ) d (H0D = 4.65 ppm): 0.96 (3H ₃ d, J = 7.2 Hz), 1.11 (3H, d, J = 6.4 Hz), 2.9-3.0 (lH, m), 3.3 -3.4 (1H, m), 4.1-4.1 (2H, m), 9.03 (1H, s)

MS (FAB); m / z 374 (M + + l)

Example 29 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (N-isopropylcarbamoyl) thiazolyl-5-yl] thio-1 -Methyl-1-force Lubapen-2-Em-3-force Sodium rubonate CONHCH (CH ₃ ) ₂

COONa

 a) (1R, 5S, 6S) -6-((lR) -Hydroxyethyl) -2- (4- (N-Isopropyl rubamoyl) thiazol-5-yl] thio-1-methyl- 1-Luvapene-2-em-3-carboxylic acid 4-nitrobenzil

In the same manner as in Example _{3a), (1R 5 3R,} 5R, 6S) - 6- ((1R) - 1- hydroxy We Chill) -1-methyl-2-Okiso-carba Bae Nam - 3- carboxylic (1R, 5S6S) -6-((1R) -1-hydroxyethyl) from 181mg of 4- (2-butoxy) benzene and N-isopropylamide of 5-mercaptothiazol-4-carboxylic acid -2- [4- (N-Isopropyl-rubamoyl) thiazol-5-yl] thio-1-methyl-1-l-rubapen-2-em-3-carboxylic acid lOOmg was obtained.

NMR (CDCl ₃ ) d: 1.10 (3H, d, J = 7.6 Hz), 1.2-1.3 (6H, m), 1.34 (3H, d, J = 6.4 Hz), 3.2-3.3 (2H, m), 4.2-4.3 (3H, m), 5.28 (1H, d, J = 13.6Hz), 5.51 (1H 5 d, J = 13.6Hz), 7.19 (1H 5 d, J = 8Hz), 7.64 (2H, d, J = 8.8Hz), 8.21 (2H, d, J = 8.8Hz), 8.70 (1H, s)

MS (FAB); m / z 547 (M ⁺⁺ 1)

_{b) (1R 5 5S, 6S} ) -6- ((1R) -1- hydroxy E Chill) - 2- [4- (N- isopropyl force Luba moil) thiazol-5-I le] Chio -1-methyl - 1-force lubapen-2-em-3-sodium carboxylate

 (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (N-isopropylcapillubamoyl) thiazol-5-yl] 47 mg of the title compound were obtained from 99 mg of 4-nitrobenzyl, thio-1-methyl-1-l-lubapen-2-em-3-carboxylate.

_{NMR (D 2 0) d (} H0D = 4.65ppm):. 1.09 (3H, d, J = 6.8 Hz), 1.2 - 1 · 3 (9Η, m), 3.1-3 2 (1H, m), 3.4- 3 ₃ 5 (lH ₅ m), 4.1-4.3 (3H, m), 9.06 (1H, s)

MS (FAB); m / z 434 (M ⁺ +1)

Example 30 (1R, 5S, 6S) -2- [4- (N-cyclohexylcarbamoyl) thiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1 -Methyl-1-L-l-bapene-2-Em-3- Sodium carboxylate

ル] チォ- 6-((lR)- 1-ヒドロキシェチル） -1-メチル -1-力ルバペン- 2-ェム -3-カルボン 酸 4-ニトロべンジル a) (1R, 5S, 6S)-

Le] thio-6-((lR) -1-hydroxyethyl) -1-methyl-1-butyl-2-ene-3-carboxylate 4-nitrobenzyl

In the same manner as in Example 3a), (1R, 3R, 5R 5 6S) -6- ((1R) - 1- hydroxy E Chill) - 1-methyl-2-Okiso - Bok carba Bae Nam - 3- carboxylic acid (1R, 5S, 6S) -2- (4- (N-cyclohexyl) from 181mg of 4-nitrobenzyl and 121m of 5-mercaptothiazol-4-carboxylic acid N-cyclohexylamide Rucarbamoyl) thiazole-5-yl) thio-6-((1R) -trihydroxyethyl) -trimethyl-1-forcelvapen-2-em-3-carboxylic acid 4-nitrobenzoyl 52mg Obtained.

 NMR (CDCl3) d: 1.09 (3H, d, J = 7.6 Hz), 1.2-1.3 (4H, m), 1.34 (3H, d, J = 6.4 Hz), 1.4-1.5 (2H, m), 1.7 -1.8 (2H m), 1.9-2.0 (2H, m), 3.2-3.3 (2H, m), 3.9-4. 0 (1H, m), 4.2-4.3 (2H, m), 5.27 (1H, d , J = 14 Hz), 5.51 (1H, d, J = 14Hz), 7.64 (2H, d, J = 8.8Hz), 8.21 (2H, d, J = 8.8Hz), 8.70 (1H, s)

MS (FAB) m / z 587 (M ⁺ +1)

 b) (1R, 5S, 6S) -2- [4- (N-cyclohexylcarbamoyl) thiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1- Sodium methyl-1-carbyl-2-em-3-carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- (N-cyclohexylcarbamoyl) thiazol-5-yl] thio-6-((lR) -1-hydroxy) Tyl) -1-methyl-1-methyl-4-pent-3-em-3-carboxylate 4-nitrobenzyl, 52 mg, yielded 19 mg of the title compound

NMR (D ₂₀ ) d (H0D = 4.65 ppm): 0.87 (3H ₃ d, J = 7.6 Hz), 1.0-1.1 (2H ₅ m), 1.09 (3 H, d, J = 6.4 Hz), 1.1- 1.2 (4H, m) ₅ 1.5-1.6 (2H, m), 1.7-1.8 (2H ₅ m), 2.8-2.9 (1H, m), 3.27 (1H, dd, JF2.4HZ, J? 6HZ), 3.6 -3, 7 (1H, m), 4.00 (1H, dd, J 9.2Hz, J 2.4HZ) ₃ 4.1- 4.2 (1H, m), 8.87 (1H, s)

MS (FAB); m / z 474 (M ⁺⁺ 1)

 [Example 31] (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2- [4- [N- (thiazol-2-yl) methylcarbamoyl] Thiazolyl-5-yl] thio-1-carbazine-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- [N- (thiazolyl-2-yl) methylcarbamoyl] thiazo 1-yl-5-yl] thio-1-potassium 2-baem-3-carboxylic acid 4-benzyl

 In the same manner as in Example 3a), (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-tricarbazin-3-carboxylic acid From 152m of 4-nitrobenzyl and 5-156m of 5-mercaptothiazol-4-carboxylic acid N- (thiazol-2-yl) methylamidotrifluoroacetate, (1R, 5S, 6S) -6- ( (1R) -Hydroxyethyl)-;!-Methyl-2- [4- [N- (thiazol-2-yl) methylcarbamoyl] thiazol-5-yl] thio-1 130 mg of 2-em-3-carboxylic acid 4-nitrobenzil were obtained.

_{NMR (DMS0-d 6) (} 5: 0.97 (3H, d, J = 7.6Hz), 1.10 (3H 3 d, J = 6Hz), 3.2- 3.3 (2H, m), 3.9- 4.0 (1H, m) , 4.2-4.3 (lH, m), 4.70 (2H, d, J = 7.2Hz), 5.07 (1H, d, J = 4.8Hz), 5.34 (1H, d, J = 14Hz), 5.48 (1H, d , J = 14Hz), 7.59 (1H, d, J = 3.2Hz), 7.6-7.7 (3H, m), 8.21 (2H, d, J = 8.4Hz), 9.24 (1H, s), 9.4-9.5 ( lH ₅ m)

MS (FAB); m / z 602 (M ⁺⁺ 1)

 b) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -trimethyl-2- [4- [N- (thiazol-2-yl) methylcarbamoyl] thiazole-5 -Yl] thio-1-potassium 2-baem-3-sodium rubonate

In the same manner as in Example _{lb), (1R, 5S 5} 6S) - 6- ((1R) - 1- hydroxy E chill) -1-methylation - 2- [4- [N- (thiazole Ichiru -2 -Yl) methylcarbamoyl] thiazole-5-yl] thio-toluene-l-bapene-2-em-3-carboxylic acid 4-nitrobenzyl, from 128 mg to the title compound 6 got ling.

_{NMR (D 2 0) d (} H0D = 4.65ppin): 0.84 (3H, d, J = 7.6Hz), 1.09 (3H, d, J = 6.4Hz), 2. 9 - 3.0 (lH, m), 3.2 -3.3 (1H, m), 3.9-4.0 (1H, m), 4.0-4.1 (1H, m), 4.73 (2H, s), 7.38 (1H, d, J = 3.6Hz), 7.58 (1H, d , J = 3.6Hz) ₃ 8.57 (lH, s)

MS (FAB); m / z 489 (M ⁺⁺ 1)

 [Example 32] (1R, 5S, 6S) -2- [4- (Irubamoylmethoxy) carbonylthiazole-5-yl] thio-6-((lR) -l-hydroxyethyl) -1 -Methyl-1-potassium-2-em-3 -Sodium rubonate

 a) (1R, 5S, 6S) -2- [4- (Rubamoyl methoxy) propyl-2-thiazol-5-yl] thio-6-((lR) -l-hydroxyethyl) -1- Methyl 1-l-r-bapene-2-em-3-carbonic acid 4-nitrobenzil

 As in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- (1R, 5S, 6S) -2- (4-Rutromobyl methoxy) carboryl thiazol 5-yl] thio-6-((lR) -l-hydroxyethyl) -1-methyl-1-forcelvapen-2-em-3-carboxylic acid .

_{NMR (CD 3 0D) d:} 1.10 (3H 5 d, J = 7.2 Hz), 1.25 (3H, d, J = 6.4 Hz) 3.3- 3.4 (2H, m), 4.1- 4.2 (1H, m), 4.3 -4.4 (lH, m), 4.7-4.8 (2H, m), 5.33 (1H, d, J = 14 Hz), 5.49 (1H, d, J = 14 Hz), 7.70 (2H, d, J = 8.8 Hz), 8.21 (ZH, d, J = 8.8 Hz), 9.08 (1H, s)

MS (FAB); m / z 563 (M ⁺⁺ 1)

b) (1R, 5S, 6S)-2- [4- (pothambyl methoxy) carbonyl dithiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl 1-Levapen-2-em-3-sodium carbonate In the same manner as in Example _{lb), (1R, 5S 3} 6S) - 2- [4- ( force Rubamoirume butoxy) carbonylation Ruchiazo Ichiru 5-I le] Chio - 6 - ((lR) -l- hydroxy Ethyl) -1-methyl-1-forcelva-Pen-2-em-3-carboxylic acid 18 mg of the title compound was obtained from 65 mg of 4-nitrobenzyl.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.71 (3H, d, J = 7.6 Hz), 0.87 (3H, d, J = 6 Hz), 2. 9-3.0 (lH, m), 3.0 -3.1 (1H, m), 3.8-3.9 (2H ₅ m), 4.51 (2H, s), 8.62 (1H, s)

MS (FAB); m / z 450 (MM)

[Example _{33] (1R 5 5S, 6S} ) - 6- ((1R) -1- hydroxy E Chill) - 2- (4-methanesulfonate two Ruchiazo Ichiru - 5-I le) Chio - methyl-1 -Kirubapen-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- (4-methanesulfonylthiazol-5-yl) thio-1-methyl-1-force Lubapen-2-em-3-carboxylic acid 4-nitrobenzyl

In the same manner as in Example _{3a), (lR 3 3R,} 5R 3 6S) -6 - ((lR) -lt: Dorokishechiru) -1-methylation-2 Okiso - Bok carba Bae Nam - 3-carboxylic acid 4 -(1R, 5S, 6S) -6-((1R) -Hydrochekisekil) from 516m of 2-nitrobenzil and 94mg of 5-mercapto-4-methanesulfonylthiazole There was obtained 181 mg of 4-nitrobenzoyl sulfonylthiazol-5-yl) thio-1-methyl-l-caproluben-2-em-3-carboxylate.

_{NMR (CDC1 3) d: 1.15} (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6.3 Hz), 3.2-3.3 (2H, m), 3.32 (3H, s), 4.2-4.4 (2H, m), 5.29 (1H ₃ d, J = 13.8 Hz), 5.54 (1H, d, J = 13.8 Hz), 7.66 (2H, d, J = 9.0 Hz), 8.23 (2H, d, J- 9.0 Hz), 8.89 (1H, s)

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-methanesulfonylthiazol-5-yl) thio-1-methyl-1-force Rubapen - 2 E beam - 3-carboxylate example lb) and in the same _{manner, (1R 3 5S, 6S)} -6- ((1R) -1- hydroxy We chill) - 2- (4- main evening Sulphonylthiazole-5-yl) thio-1-methyl-1-force rubapene-2-em-3-force rubonic acid 4- (2-to-butenyl) 181 mg to give 64.Omg of the title compound. NMR (D ₂₀ ) d (HOD = 4.80 ppm): 1.13 (3H ₃ d, J = 7.2 Hz), 1.26 (3H, d, J = 6.3 Hz), 3.2-3.4 (1H ₃ m), 3.40 (3H , s), 3.52 (1H, dd, J? 5.7 Hz, J 2.7 Hz), 4.2-4.3 (2H, m), 9.10 (1H, s)

 [Example 34] (1R, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) 1-methyl-1-l-lubapen-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S)-2- [4- (2-Hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -l-hydroxyethyl)-:! -Methyl -1-caproluvene-2-em-3-carbonic acid 4-nitrobenzil

In the same manner as in Example _{3a), (lR, 3R 5} 5R 3 6S) -6 - ((lR) -lt Dorokishechiru) -1-methylation - 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 (1R, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonithiazol from 290 mg of 2-nitrobenzil and 164 mg of 2-hydroxyethyl 4-carboxylate -5-yl] thio-6-((lR) -l-'hydroxyethyl) -1-methyl-1-forcelvapen-2-em-3-carboxylic acid Obtained.

NMR (CDCL) (J: 1.10 (3H, d, J = 7.2 Hz), 1.33 (3H, d, J = 6.4 Hz), 3.2-3.3 (2H, m), 3.9-4.0 (2H, m), 4.2 -4.3 (2H, m), 4.4-4.5 (2H, m), 5.Z9 (1H ₅ d, J = 13.6 Hz), 5.53 (1H ₃ d, J = 13.6 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.23 (2H, d, J = 8.4 Hz), 888 (1Η, s)

MS (FAB); m / z 550 (M ⁺⁺ 1)

_{b) (1R 3 5S, 6S} ) -2- [4- (2- hydroxyethoxy) carbonylation Ruchiazoru - 5-I le] Chio - 6- ((lR) -l- hydroxy E Chill) - 1-methyl - 1-Luvapene-2-em-3 -Sodium carboxylate

In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -l-hydroxye Chill) -1-methyl-1-butane The title compound 107m was obtained from 192 mg of pen-2-em-3-carboxylic acid 4-dibenzyl.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.94 (3H, d, J = 1.2 Hz), 1.11 (3H, d, J = 6.4 Hz), 3.1-3.2 (1H, m), 3.3-3.4 (lH, m) ₅ 3.8-3.9 (2H, m), 4.0-4.1 (2H, m), 4.3-4.4 (2H, m), 8.84 (1H, s)

 MS (FAB); m / z 437 (M ++ 1)

 [Example 35] (1R, 5S, 6S) -2- [4- (N-cyclopropylcapsulebamoyl) thiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) 1-methyl-1-force rubapene 2-em-3-force sodium rubonate

 a) (1R, 5S, 6S) -2- [4- (N-cyclopropyllubamoyl) thiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1- Methyl 1-l-r-bapene-2-em-3-carboxylate 4-nitrobenzyl

 In the same manner as in Example 3a), (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3-carbone (1R, 5S, 6S) -2- [4- (N-cyclopropylrubamoyl) thiazolate from 156m of 4- (2-butoxy) benzene and 86mg of 5-mercaptothiazolcarboxylic acid N-cyclopropylamide 1-yl-5-yl] thio-6-((li)-1-hydroxyethyl) -1-methyl-1-forcelvapen-2-em-3-carboxylic acid 4-nitrobenzene 84mg Got.

_{NMR (CDC1 3) 0.6-0.7 (2H} , m) 5 0.8-0.9 (2H, m), 1.10 (3H, d, J = 7.2Hz), 1.3 4 (3H, d, J = 6.4Hz), 2.8- 2.9 (1H, m), 3.2-3.3 (2H, m), 4.2-4.3 (2H 5 m), 5.28 (1H, d, J = 14Hz), 5.5K1H, d, J = 14Hz), 7.4-7.5 ( lH ₅ m), 7.65 (2H ₅ d, J = 8.8 Hz), 8.22 (2H, d, J = 8.8 Hz), 8.68 (1H, s)

MS (FAB); m / z 545 (M ⁺⁺ 1)

_{b) (1R, 5S 5 6S} ) -2- [4- (N- cyclopropyl force Rubamoiru) thiazole Ichiru -5- I le] Chio - 6 - ((lR) - 1- hydroxy E chill) -1- Methyl 1-l-r-bapene-2-em-3-carvone Sodium acid

 In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- (N-cyclopropyl-l-bamoyl) thiazol-5-yl] thio-6-((lR) -1 -Hydroxyethyl) -1-methyl-1-forcelva-pent-2_em-3-carboxylate 4-Methoxybenzyl To obtain 26 mg of the title compound from 84 m.

NMR (D ₂ 0) δ (H0D = 4.65ppm): 0.6-0.7 (2H, m), 0.8-0.9 (2H, m), 1.03 (3H, d, J = 7.2Hz), 1.25 (3H, d, J = 6.4Hz), 2.7-2.8 (lH, m), 3.0-3.1 (1H, m), 3.4-3, 5 (1H, m), 4.1-4.3 (2H, m), 8.99 (1H ₅ s)

 MS (FAB); m / z 432 (M)

[Example _{36] (1R, 5S 3 6S} ) -2- (2- force Rubamoiruchiazo Ichiru 5-I le) Chio -6- ((1 R) - 1- hydroxy E chill) -1-methyl -1 -Kyrubapene-2-Em-3-Sodium carboxylate

a) (1R, 5S, 6S) -2- (2-kelbamylthiazol-5-yl) thio-6-((lR) -1-hydrexyl) -1-methyl-1-kerbapene- 2-E arm 3-carboxylic acid 4 two Torobe Njiru example 3a) and in the same _{manner, (lR 5 3R 5 5R,} 6S) -6 - ((lR) -lt Dorokishechiru) -1-methylation - (1R, 5S, 6S) -2- (2R) from 2-oxo-1-carbazane-3-carboxylic acid 4-nitrobenzyl 56m and 5-mercaptothiazol-2-carboxylic acid amide 26mg -Ketylvamoylthiazol-5-yl) thio -6-((lR) -l-hydroxyethyl) -methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzil 24.6 mg were obtained.

_{NMR (CDC1 3) d: 1.12} (3H, d, J = 7.5 Hz), 1.32 (3H, d, J = 6.0 Hz), 3.1-3.2 (1H, m), 3.28 (1H, dd, J 6.6 HZ, _{JF2.7 HZ), 3.32 (3H 5} S), 4.2-4.3 (2H, m), 5.2 9 (1H, d, J = 13.5 Hz), 5.55 (1H, d, J = 13.5 Hz), 6.83 (1H , Br s), 7.10 (1H, br s), 7.67 (2H, d, J = 8.7 Hz), 7.93 (lH ₃ s), 8.24 (2H, d, J = 8.7 Hz)

b) (1R, 5S, 6S)-2- (2-L-bulmoylthiazol-5-yl) thio-6-((lR) -l-Hyd- mouth-kisechil) -1-methyl-1-L-lubapen- Sodium 2-em-3-carboxylate In the same manner as in Example lb), (1R, 5S, 6S) -2- (2-pothamylthiazol-5-yl) thio-6-((lR) -1-hydroxyethyl) -1- 11.4 mg of the title compound was obtained from 24.6 mg of methyl-1--1-l-lubapen-2-em-3-carboxylate 4-nitrobenzyl.

_{NMR (D 2 0) d (} HOD = 4.80 ppm): 1.06 (3H, d, J = 6.9 Hz), 1.23 (3H, d, J = 6.6 Hz), 3.0-3.1 (1H, m), 3.4-3.5 (lH, m), 4.1-4.3 (2H, m), 8.07 (1H, s)

 Example 37 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2--2- [4- (p-pan-1-yl) oxycarbonylthiazo Le-5-yl] thio-1-potassium lvapen-2-em-3-carboxylate sodium

_{a) (1R, 5S 5 6S} ) - 6 - ((lR) - Bok hydroxy E Chill) - 1-methyl - 2- [4- (propane - 1 - I le) Okishikarubo two Ruchiazo Ichiru 5- I le ] Cho-1-Levapen-2-em-3-Carbonic acid 4-Nitrobenzil

In the same manner as in Example _{3a), (lR 3 3R,} 5R 5 6S) -6 - ((lR) -l-ti Dorokishechiru) -1-methylation-2 Okiso-carba Bae Nam - 3- carboxylic acid 4 two Torobe Njiru 296mg and 5 main Rukaputochiazo Ichiru - from 4-carboxylic acid propyl _{183mg, (1R, 5S 5 6S} ) - 6 - ((1 R) -l- hydrin port Kishechiru) -1 - methyl -2- [4- (propane-1-yl) oxycarbonylthiazol-5-yl] thio-1-caphyl-2-ene-3-carboxylate 4-nitrobenzil 379 mg were obtained.

NMR (CDCl3) d: 1.01 (3H ₅ t, J = 7.5 Hz), 1.11 (3H, d, J = 7.3 Hz), 1.34 (3H, d, J = 6.4 Hz), 1 ・ 80 (2Η, m) , 3.22-3.32 (2H, m), 4.23-4.39 (4H, m), 5.29 (1H ₃ d, J = 13.6 Hz), 5.54 (1H, d, J2 13.6 Hz), 7.67 (2H, d, J = 8.8 Hz), 8.24 (2H, d, J = 8.8 Hz), 8.84 (1H, s)

_{b) (1, 5S 3 6S} ) - 6 - ((1R) - 1- hydroxy E Chill) - 1-methyl - 2- [4- (propane - 1 - I le) Okishikarubo two Ruchiazoru 5-I le] Thio-1-l-Levapen-2-em-3-sodium carbonate

In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-me Tyl-2- [4- (propane-: l-yl) oxycarbonylthiazol-5-yl] thio-carbapene-2-em-3-carboxylate 4-Nitrobenzil From 379 mg, 163m of the title compound were obtained.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.83 (3H, t, J = 7.3 Hz), 0.9Z (3H 3 d, J = 7.1 Hz), 1.1K3H, d, J = 6.3 Hz), 1.61 (2H, m), 3.06 (1H, m), 3.33 (1H, m), 3.04 (3H, s), 4.06-4.12 (lH, m), 4.17-4.24 (2H, m), 8.85 (1H 5 s)

 Example 38 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (4-methylthiothiazol-5-yl) thio-1- L-Levapen-2-em-3-carboxylate sodium

a) (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- (4-methylthiothiazol-5-yl) thio-hydrolbapen-2-e arm 3 in the same manner as carboxylic acid 4 two preparative port base Njiru example _{3a), (lR, 3R 3} 5R, 6S) -6 - ((lR) -lb Dorokishechiru) -1-methylation-2- (1R, 5S, 6S) -6-((1R) from oxo-:!-Carbazum-3-carboxylic acid 4-mg 2-nitrobenzil and 71 mg 5-mercapto-4-methylthiothiazol -; 1-Hydroxystyl) -1-methyl-2- (4-methylthiothiazole-5-yl) thio-1-butarubene-2-hem-3-carboxylic acid Obtained.

_{NMR (CDC1 3) d: 1.10} (3H, d, J = 7.5 Hz), 1.33 (3H 5 d, J = 6.3 Hz), 2.68 (3H, s), 3.0-3.1 (1H, m), 3.24 (1H , dd, JF6.6 HZ, J * 2.7 HZ), 4.2-4.3 (2H ₅ m), 5.29 (1H, d, J = 13.5 Hz), 5.56 (1H, d, J = 13.5 Hz), 7.68 (2H ₃ d, J = 9.0 Hz), 8.24 (2H, d, J = 9.0 Hz), 8.89 (1H, s)

 b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (4-methylthiothiazol-5-yl) thio-1-capryl -Sodium 2-Em-3-carboxylate

In the same manner as in Example _{lb), (1R 5 5S,} 6S) -6 - ((lR) - 1- hydroxy E Chill) - 1-methylcarbamoyl-2-(4 Mechiruchiochiazo Ichiru 5- I 1) 17.3 mg of the title compound was obtained from 65 mg of 4-nitrobenzoyl 4-thiol-l-bapene-2-em-3-carboxylate.

NMR (D ₂ 0) 5 (H0D = 4.80 ppm): 1.05 (3H ₅ d, J 2 7.2 Hz), 1.23 (3H, d, J = 6.3 Hz), 2.59 (3H, s), 2.8-3.0 (lH, m), 3.3-3.4 (lH, m), 4.1-4.3 (2H, m), 9.09 (1H, s)

 [Example 39] (1R, 5S, 6S) -2- [4- [N- (Hexane-1-yl) forcerubamoyl] thiazol-5-yl] thio-6-((11-1 -Hydroxyethyl) -trimethyl-1-potassium-2-em-3 -Sodium rubonate

 a) (1R, 5S, 6S) -2- [4- (N-hexyl) force rubamoylthiazol-5-yl] thio-6-((1R) -trihydroxyethyl) -trimethyl-1 -Kirubapen-2-em-3-carboxylic acid 4-2

 As in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- From 226 mg of carboxylic acid 4-nitrobenzoyl and 168 mg of 5-mercaptothiazol-4-carboxylic acid N- (trihexyl) amide, (1R, 5S, 6S)-2- [4- [N- (Hexane-1-yl) caproluvyl] thiazolyl-5-yl] thio-6-((lR) -trihydroxyethyl) -1-methyl-1-captoryl-2-ene- 284 mg of 3-carboxylic acid 4-nitrobenzene were obtained.

Thigh (CDCl ₃ ) d: 0.89 (3H, m), 1.10 (3H, d, J = 7.3 Hz), 1.25-1.40 (9H, m), 1.60 (2H, m), 3.24-3.33 (2H, m m), 3.38-3.45 (2H, m ), 4.20-4. 9 (2H, m), 5.28 (1H, d, J = 13.7 Hz), 5.5K1H, d, J = 13.7 Hz), 7.65 (2H 5 d, J = 8.8 Hz), 8.23 (2H, d, J = 8.8 Hz), 8.70 (1H, s)

 b) (1R, 5S, 6S)-2- [4- [N- (Hexane-1-yl) caprolbumoyl] thiazolyl-5-yl] thio-6-((lR) -l- (Hydroxyethyl) -1-methyl -1-caproluvene-2-em-3-sodium carbonate

In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- [N- (hexane-1-yl) carbamoyl] thiazolyl-5-yl] thio-6 109 mg of the title compound was obtained from 289 mg of-((lR) -l-hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl. NMR (D ₂₀ ) d (H0D = 4.65 ppm): 0.69 (3H, m), 0.87 (3H ₃ d, J = 7.3 Hz), 1.09 (3H, d, J = 6.6 Hz), 1.11-1.25 (6H , m), 1.44 (2H, m), 2.88-2.96 (1H, m), 3.20-3.30 (3H, m), 4.00-4.10 (2H, m), 8.87 (1H, s)

 Example 40 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- [N- (thiazolyl-2-yl) force Rubamoyl] thiazole-5-yl] thio-1-potassium rubapene-2-em-3-carboxylate

 a) (1R, 5S, 6S) -6-((lR) -Trihydroxyethyl) -1-methyl-2- [4- [N- (thiazol-2-yl) -lubamoyl] thiazol -5-yl] thio-1-L-capulene-2-em-3-carboxylic acid 4-nitrobenzil

 In the same manner as in Example 3a), (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3-rubon (1R, 5S, 6S) -6 from 156 mg of 4- (2-butoxy) benzyl and 5- (mercaptothiazol) -4-carboxylic acid N- (thiazol-2-yl) amidotrifluoroacetate -((lR) -l-Hydroxyethyl) -1-methyl-2- [4- [N- (thiazolyl-2-yl) capsulebamoyl] thiazolyl-5-yl] thio-1 -L-lubapen-2-em-3-carboxylic acid 4-m-butene benzyl 70m was obtained.

_{NMR (CDC1 3) d: 1.13} (3H, d, J = 7.6Hz), 1.34 (3H, d, J = 6Hz), 3.2- 3.3 (2H, m), 4.2-4.3 (2H, m), 5.30 ( 1H, d, J = 13.6Hz), 5.53 (1H, d, J = 13.6Hz), 7.06 (1H, d, J = 3.6Hz) ₃ 7.52 (1H, d, J = 3.6Hz) ₅ 7.66 (2H, d, J = 8.4Hz), 8.23 (2H, d, J = 8.4Hz), 8.80 (1H, s), 10.5-10.6 (lH, br s)

MS (FAB); m / z 588 (M ⁺⁺ 1)

 b) (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -1-methyl-2- (4- [N- (thiazol-2-yl) caprolbumoyl] thiazole- 5-yl] thio-1-potassium lvapen-2-em-3-sodium carbonate

In the same manner as in Example lb), (1R, 5S, 6S 6-((lR) -trihydroxyethyl) -trimethyl-2- [4- [N- (thiazolyl-2-yl)) Lubamoyl] thiazole-5-yl] thio-1-cal 28 mg of the title compound was obtained from 70 mg of 4-nitrobenzyl, pent-2-em-3-carboxylate.

_{NMR (D 2 0) δ (} H0D = 4.65ppm): 0.94 (3H, d, J = 7.2Hz), 1.11 (3H, d, J = 6.4Hz), 3. 1-3.2 (1H 5 m), 3.3 -3.4 (lH ₃ m), 4.0-4.1 (2H, m), 7.10 (1H, d, J = 3.6Hz), 7.38 (1H, d, J = 3.6Hz), 8.86 (1H, s)

MS (FAB); m / z 475 (M ⁺⁺ 1)

 Example 41 (1R, 5S, 6S) -2- [4- [N- (furan-2-yl) methylcarbamoyl] thiazol-5-yl] thio-6-((11- 1-Hydroxyethyl) -1-methyl-1-caproluvene-2-em-3-sodium carboxylate

 a) (lR, 5S, 6S) -2- [4- [N- (furan-2-yl) methylcarbamoyl] thiazolyl-5-yl] thio-6-((1R) -1-hydr 1-methyl-1-1-lubapen-2-em-3-force rubonic acid 4-nitrobenzene

 In the same manner as in Example 3a), (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3-carboxylic From 391m of 4-hydroxybenzyl acid and 260mg of N- (furan-2-yl) methylamide 5-mercaptothiazol-4-carboxylate. (1R, 5S, 6S) -2- [4- [N- (furan-2-yl) methylcarbamoyl] thiazolyl-5-yl] thio-6-((1R) -1-hydroxyethyl) -trimethyl-1-butyrrappen-2-e 230 mg of 4-ditrobenzyl mu-3-carbonate were obtained.

_{NMR (CDC1 3) ^: 1.09} (3H, d, J = 7.2Hz) 5 1.34 (3H, d, J = 6.4Hz), 3.2- 3.3 (2H, m), 4.2-4.3 (2H, m), 4.6 -4.7 (2H, m), 5.28 (1H, d, J = 13.6Hz), 5.52 (1H, d, J = 13.6Hz), 6.30 (1H, d, J = 3.2Hz), 6.33 (1H, d, J = 3.2Hz), 7.38 (1H, s), 7.65 (2H, d, J = 8.8Hz), 8.22 (2H, d, J = 8.8Hz), 8.70 (1H, s)

MS (FAB); m / z 585 (M ⁺⁺ 1)

b) (1R, 5S, 6S) -2- [4- [N- (furan-2-yl) methylcarbamoyl] thiazol-5-yl] thio-6-((1R) -1-hydroxyethyl ) -1-Methyl-1-force Lubapen-2-Em-3-force Sodium rubonate

 In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- [N- (furan-2-yl) methylcarbamoyl] thiazol-5-yl] thio-6-((1R 78 mg of the title compound were obtained from 230 mg of) -1-methyl-1-kisethyl) -1-methyl-1-caphylbapene-2-em-3-carboxylate.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.81 (3H, d, J = 7.2Hz), 1.09 (3H 3 d, J = 6.4Hz), 2.9- 3.0 (1H, m), 3.2- 3.3 (1H, m), 3.9- 4.0 (1H, m), 4.0-4.1 (1H, m), 4.40 (2H, d, J = 4.4Hz), 6.1-6.2 (1H, brs), 6.3-6.4 ( 1H, br s), 7,30 (1H, s), 8.82 (1H, s)

MS (FAB) m / z 472 (M ⁺⁺ 1)

 Example 42 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -trimethyl-2- [4- [N- (pyridin-3-yl) methylcarbamoyl] thiazo 1-yl-5-yl] thio-1-potassium rubapene-2-em-3-carboxylate

a) (1R， 5S, 6S)-6-((lR)-l-ヒドロキシェチル） - 1-メチル -2-[4- [N- (ピリジン -3-ィル）メチルカルバモイル]チアゾール -5-ィル]チォ- 1-力ルバペン- 2-ェム- 3- カルボン酸 4-二トロべンジル

a) (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- [4- [N- (pyridin-3-yl) methylcarbamoyl] thiazole-5 -Ill] thio-1-Lyvapene-2-Em-3-Carboxylic acid 4-Nitrobenzil

 In the same manner as in Example 3a), (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3-carbone (1R, 5S, 6S) -6 -((1R) -1-hydroxyethyl)-1-methyl-2- [4- [N- (pyridin-3-yl) methylcarbamoyl] thiazol-5-yl] thio-1-carbapene- 89 mg of 2-em-3-carboxylic acid 4-nitrobenzil were obtained.

NR (DMSO-de) d: 0.95 (3H, d, J = 7.2Hz) 3 1.00 (3H, d, J = 6Hz), 3.2-3.3 '(2H, m), 3.9- 4.0 (1H, m), 4.1-4.2 (1Η, m), 4.44 (2H ₅ d, J = 6.4 Hz), 5.34 (1H ₃ d, J = _{13.6Hz), 5.48 (1H 5 d} , J = 13.6Hz), 7.3-7.4 (lH, m), 7.70 (2H, d, J = 8.8Hz), 8. 21 (2H, d, J = 8.8Hz) , 8.4-8.5 (lH, m), 8.52 (1H, s), 9.22 (1H, s)

MS (FAB); m / z 596 (M ⁺⁺ 1)

 b) (IR, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2- [4- [N- (pyridin-3-yl) methylcarbamoyl] thiazol -5-yl] thio-1-caproluben-2-em-3-sodium carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- [N- (pyridine-3-y L) Methylcarbamoyl] thiazolyl-5-yl] thio-l-caproluvene-2-em-3-carboxylate 4-Nitrobenzyl From 88 nig, 41 mg of the title compound was obtained.

NMR (D ₂ 0) d (H0D = 4.65 ppm): 0.77 (3H, d, J = 7.2Hz), 1.09 (3H, d, J = 6.4Hz)

2.9-3.0 (1H, m), 3.2-3.3 (lH ₅ m), 3.9-4.0 (lH, m), 4.0-4.1 (1H, m), 4.46 (2H, s), 7.2-7.3 (lH, m ), 7.7-7.8 (1H, m), 8.2-8.3 (1H, m), 8.39 (1H, s), 8.86 (1H, s)

MS (FAB); m / z 483 (M ⁺ +1)

[Example _{43] (1R 3 5S, 6S} ) -2- [4- (2- hydroxyethoxy carbonyl) thiazole one Le - 5-I le] Chio - 6- ((1R) - 1-hydroxy E Chill) - Trimethyl-1-caproluvene-2-em-3-bivaloyoxymethyl 3-carboxylate

 In the same manner as in Example 2, (IR, 5S, 6S) -2- [4- (2-hydroxyethoxycarbonyl) thiazole-5-yl] thio-6-((IR) -1-hydroxy) 32 mg of the title compound were obtained from 65 mg of sodium thiol) -1-methyl-1-forcelvapen-2-em-3-carboxylate.

_{NMR (CDC1 3) 5: 1.10} (3H 5 d, J = 7.2Hz), 1.22 (9H, s), 1.30 (3H, d, J = 6.4Hz), 3.2-3.4 (2H, m), 3.9- 4.0 (2H, m), 4.2-4.3 (2H ₅ m), 4.4-4.5 (2H ₅ m), 5.86 (1H, d, J = 5.6 Hz), 6.00 (1H, d, J = 5.6 Hz), 8.91 ( 1H, s) MS (FAB); m / z 529 (M ⁺⁺ 1)

 [Example 44] (1R, 5S, 6S) -2- [4- [N- (2-formylaminoethyl) -capsulebamoyl] thiazolyl-5-yl] thio-6-((lR) -l -Hydroxyethyl) -1-methyl-1-carno pen-2-em-3-carboxylate

 a) (1R, 5S, 6S) -2- [4- [N- (2-formylaminoethyl) carbamoyl] thiazolyl-5-yl] thio-6-((lR) -1-hydroxy) Tyl) -1-methyl -1-caproluvene-2-em-3-carboxylate 4-nitrobenzyl

 As in Example 3a), (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazinam-3- From 248 mg of carboxylic acid 4-nitrobenzoyl and 164 g of 5-mercaptothiazol-4-carboxylic acid N- (2-formylaminoethyl) amide, (1R, 5S, 6S) -2- [4- [N -(2-formylaminoethyl) -l-bamoyl] thiazol-5--yl] thio- 6-((lR) -l-hydroxyethyl) -1-methyl-1-l-lappa-2--2-em- 3-force 114 mg of a crude product of benzyl 4-butanol was obtained.

 b) (1R, 5S, 6S) -2- [4- [N- (2-formylaminoethyl) rubamoyl] thiazol-5-yl] thio-6-((lR) -l-hydroxy Tyl) -1-methyl-1-caproluvene-2-em-3-carboxylate sodium

 In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- [N- (2_formylaminoethyl) force rubamoyl] thiazol-5-yl] thio-6-(( 54 mg of the title compound was obtained from 114 mg of a crude product of 4-nitrobenzyl lR) -l-hydroxyethyl) -1-methyl-l-potassyl-2-em-3-carboxylate.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.90 (3H, d, J = 7.3 Hz), 1.10 (3H, d, J = 6.3 Hz), 3.01 (2H, m), 3.27-3.47 (6H , m), 4.03-4.12 (2H, m), 7.91 (1H, s), 8.82 (1H,

[Example 45] (1R, 5S, 6S) -2- [4- [N- (2-aminosulfonylaminoethyl) -capsulebamoyl] thiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1-methyl-1 -force Lubapen-2-em-3-carboxylate sodium

_{a) (1R 5 5S, 6S} ) - 6 - ((lR) - 1- hydroxy E chill) -1-methyl - 2- [4- [N- [2- (4 - two preparative port base Nji Ruo alkoxycarbonyl ) Aminosulfonylaminoethyl] pothamamoyl] thiazolyl-5-yl] thio-1-potumbyl-2-em-3-carboxylic acid 4-nitrobenzyl In the same manner as in Example 3a), (lR, 3R ₅ 5R ₅ 6S) -6-((lR) -lhdroxityl) -1-methyl-2-oxo-1-carbazane-3-carboxylate 245 mg and 5-ditrobenzyl From 343 mg of crudely purified mercaptothiazol-4-carboxylic acid N- [2- (4-nitrobenzyloxycarbonyl) aminosulfonylaminoethyl] amide, (1R, 5S, 6S) -6- ( (1R)-: 1-Hydroxyethyl) -trimethyl-2- [4- [N- [2- (4-nitrobenzyloxycarbonyl) aminosulfonylaminoethyl] aminosulfonyl]] thiazol- 5-yl] thio-1-caproluben-2-em-3-carboxylic acid 4-nitrobenzene 83 mg of crude product was obtained. b) (1R, 5S, 6S)-2- [4- [N- (2-aminosulfonylaminoethyl) -capsulebamoyl] thiazolyl-5-yl] thio-6-((1R) -1-hydroxy Ethyl) -1-methyl -1-caproluvene sodium 2- dimethyl-3-carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl)-; 1-methyl-2- [4- [N- [2- (4 -Nittobenzyloxycarbonyl) aminosulfonylaminoethyl] lubamoyl] thiazol-5-yl] thio-1-l-lubapen-2-em-3-carbonic acid 4-nitobenzyl 24 mg of the title compound was obtained from 83 mg of the crude product of the above.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.90 (3H 5 d, J = 7.3 Hz), 1.10 (3H, d, J = 6.3 Hz), 3.0K1H, m), 3.10- 3.20 (2H, m), 3.31 (1H, m), 3.35-3.50 (2H ₅ m), 4.04-4.11 (2H, m), 8.83 (1H, s)

Example 46 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-hydroxymethyl Thithiazol-5-yl) thio-1-methyl-1-butyrolpine-2-em-3-carboxylate sodium

_{a) (1R 3 5S, 6S} ) -6 - ((lR) -l- hydroxy E chill) -2- (4-hydroxymethyl-thiazolium Ichiru - 5-I le) Chio -1-methyl-1-forces Lubapen-2-em-3-carboxylic acid 4-nitrobenzyl

_{(1R, 5S 3 6S) -2-} (4- Horumiruchiazo Ichiru - 5-I le) Chio -6 - (. (LR) - 1- hydroxy Echiru) -1-methyl - Bokuryoku Rubapen - 2- E arm Dissolve 109 mg of -3-carboxylic acid 4-nitrobenzene in 1.5 mL of dichloromethane and 1.5 mL of methanol, add 0.019 mL of acetic acid and 4.0 mg of sodium borohydride at -20 ° C under an argon atmosphere. Stir for 20 minutes. To the reaction solution was added lOmL of a half-saturated saline solution, and the mixture was extracted twice with lOmL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane: methyl alcohol = 20: 1) to give (1R, 5S, 6S) -6-((1R) -hydroxyethyl ) 2- (4-Hydroxymethylthiazol-5-yl) thio-1-methyl-1-forcerbapen-2-em-3-carboxylic acid 4--2-toventil benzyl 73 mg was obtained.

_{NMR (CDC1 3) d: 1.07} (3H, d, J = 7.2 Hz), 1.31 (3H, d, J-6.3 Hz), 2.89 (1H, t, J = 6.0 Hz), 3.0- 3.2 (1H, m ), 3.25 (1H, dd, J ^ 6.3 Hz, J 2.7 Hz), 4.2-4.3 (2 H, m), 4.7-4.9 (2H, m), 5.28 (1H, d, J = 13.8 Hz), 5.56 (1H, d, J = 13.8 Hz), 7.68 (2H, d, J = 8.7 Hz), 8.24 (2H, d, J = 8.7 Hz), 8.95 (1H, s)

 b) (1R, 5S, 6S) -6-((1R) -Trihydroxyethyl) -2- (4-hydroxymethylthiazol-5-yl) thio-1-methyl-1-methyllvapen -Sodium 2-em-3-carboxylate Example 1 lb), (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl)-2- (4-hydroxymethylthiazo 49.7 mg of the title compound was obtained from 84 mg of 4- (2-yl) thio-1-methyl-1-force rubapene-2-em-3-force rubonic acid 4-butene benzyl.

_{NMR (D 2 0) d (} HOD-4.80 ppm): 1.04 (3H, d, J = 7.5 Hz), 1.24 (3H, d, J two 6.3 Hz), 2.9- 3.0 (1H, m), 3.39 (1H, dd, J? 6.0 Hz, J? 2.7 Hz), 4.1-4.3 (ZH ₅ m), 9.11 (1H, s)

 Example 47 (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2- [4- (pyridin-3-yl) thiazol-5 -Yl] thio-1-potassium lvapen-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2- [4- (pyridin-3-yl) thiazol-5-yl] Thio-1-l-Levapen-2-em-3-carboxylic acid 4-nitrobenzyl

 Analogously to Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- From 362 mg of 4-nitrobenzyl carboxylate and 323 mg of 5-mercapto-4- (pyridine-3-yl) thiazole, (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl)- 1-Methyl-2- [4- (pyridin-3-yl) thiazolyl-5-yl] thio-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzil 427m Got.

_{NMR (CDC1 3) d: 0.90} (3H, d, J = 7.2 Hz), 1.29 (3H, d, J = 6.3 Hz), 2.9-3.1 (1H, m), 3.18 (1H, dd, J 6.6 HZ, J 2.7 HZ), 4.07 (1H, dd, JF9.6 HZ, JF2.7 Hz), 4.1-4.2 (1H ₅ m), 5.28 (1H, d, J = 13.8 Hz), 5.55 (1H, d, J = 13.8 Hz), 7.3-7.4 (1H, m), 7.67 (2H, d, J = 8.7 Hz), 8.2-8.3 (3H, m), 8.6-8.7 (1H, 'm), 9.02 (1H, s), 9.2-9.3 (lH, m)

 b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2--2- [4- (pyridine-3-yl) thiazol-5-yl] thio- (1-R, 5S, 6S) -6-((IR) -1-hydroxyethyl) -1-methyl -2- [4- (Pyridin-3-yl) thiazole-5-yl] thio-1-l-rubapene-2-em-3-l-rubonic acid 142 mg of the compound were obtained.

NMR (D ₂₀ ) d (HOD = 4.80 ppm): 0.86 (3H ₅ d, J = 7.2 Hz), 1.18 (3H ₃ d, J = 6.3 Hz), 2.7-2.8 (1H, m), 3.2-3.3 (1H, m), 3.7- 3.8 (1H, m), 4.0-4.2 (lH ₅ m) ₅ 7.5-7.6 (1H, m), 8.2- 8.3 (1H, m), 8.5- 8.6 (1H, m), 8.90 (1H, s), 9.1-9.2 (1H, m)

 [Example 48] (1R, 5S, 6S) -2- [4- [N- (2-aminocarbonylaminoethyl) -capsulebamoyl] thiazolyl-5-yl] thio-6-((1R ) -1-Hydroquichetyl) -1-methyl-1-force Lubapen-2-em-3-force Sodium ruponate

 a) (1R, 5S, 6S) -6-((110-1-hydroxyethyl) -1-methyl-2- [4- [N- [2- (4-dimethoxybenzyloxycarbonyl)] Aminocarbonylaminoethyl] caphambyl] thiazolyl-5-yl] thio-1-carboxyl-2-em-3-carboxylate 4-nitrobenzyl In the same manner as in Example 3a), lR, 3H, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazane-3-carboxylate 314 mg From 406 mg of N- [2- (4-nitrobenzoyloxycarbonyl) aminocarbonylaminoethyl] amide 5-mercaptothiazol-4-carboxylate, (1R, 5S, 6S) -6-(( lR) -l-Hyd mouth kissille) -1-Methyl-2- [4- [N- [2- (4-dimethoxybenzoyloxycarbonyl) aminocarbonylaminoethyl] potumbamoyl] thiazole-5- Yl] thio-1-carbazin-2-em-3-carboxylate To give things 90mg.

 b] (1R, 5S, 6S) -2- [4- [N- (2-aminocarbonylaminoethyl) thiol-bamoyl] thiazolyl-5-yl] thio-6-((lR) -l- Hydroxyethyl) -1-methyl-1-caproluvene-2-em-3-carboxylate sodium

 In the same manner as in Example lb], (1R, 5S, 6S) -6-((lR)-; l-hydroxyethyl) -trimethyl-2- [4--[2- (4-ditoyl) Benzyloxycarbonyl) aminocarbonylaminoethyl] lubamoyl] thiazole-5-yl] thio-1-l-lubapen-2-em-3-carboxylate 4-nitrobenzyl 5.5 mg of the title compound were obtained.

Hz), 1.23(3H, d, J=6.6 Hz), 3.1-3.2(1H, m), 3.3-3.4(2H, m)， 3.4-3.6(3H, m)， 4.1-4.3(2H, m), 8.97(1H, s)

Hz), 1.23 (3H, d, J = 6.6 Hz), 3.1-3.2 (1H, m), 3.3-3.4 (2H, m), 3.4-3.6 (3H, m), 4.1-4.3 (2H, m) , 8.97 (1H, s)

[Example 49] (1R, 5S, 6S) -2- [4- [N- (2-acetylaminoethyl) potassium] Thiazolyl-5-yl] thio-6-((ll-l-hydroxyethyl) -1-methyl-1-sodium lubapen-2-em-3-carboxylate

 a) (1R, 5S, 6S) -2- [4- [N- (2-acetylamino) ethyl] rubamoyl] thiazol-5-yl] thio-6-((1Ιί) -1-hydroxy) Cyl) -trimethyl-1-l-rubapen-2-em-3-l-rubonic acid

As in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- carboxylic acid 4 two Torobe Njiru 323mg and 5 main Rukaputochiazo Ichiru 4-carboxylic acid N-(2-§ cetyl-aminoethyl) amino-de 219mg than _{(1R 5 5S, 6S) -} . 2- [4- [ N- (2-Acetylaminoethyl) l-rubamoyl] thiazole-5-yl] thio-6-((lR) -l-hydroxyethyl) -1-methyl-1-l-lubapen-2-em- 3-force Rubonic acid 4-Nitoguchi benzyl 90 mg was obtained.

NMR (CDC1 ₃ ) (^: 1.06 (3H ₃ d, J = 1A Hz), 1.34 (3Η, d, J = 6.3 Hz), 198 (3Η, s), 3.16-3.26 (2H, m ), 3.33-3.52 (2H, m), 3.58-3.72 (2H, m), 4.23 (1H, m), 4.33 (1H, dd, J 9.5 HZ, J 2.7 HZ), 5.28 (1H, d, J = 13.7 Hz), 5.52 (1H, d, J = 13.7 Hz), 6.06 (1H, m), 7.65 (2H, d, J = 8.7 Hz), 7.84 (1H, m), 8.23 (2H, d, J = 8.7 Hz), 8.73 (1H, s)

 b) (1R, 5S, 6S)-2- [4- [N- (2-Acetylaminoethyl) rubamoyl] thiazolyl-5-yl] thio-6-((1R) -1-hydroxy Ethyl) -1-methyl -1-caproluvene-2-em-3-sodium carboxylate

 (1R, 5S, 6S) -2- [4- [N- (2-acetylaminoethyl) force rubamoyl] thiazol-5-yl] thio-6- ( (lR) -l-Hydroxyethyl) -1-methyl-1 -l-lubapen-2-em-3-carboxylic acid 48 mg of the title compound was obtained from 90 mg of 4-nitrobenzyl.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.91 (3H, d, J = 7.3 Hz), 1.11 (3H, d, J = 6.6 Hz), 1.83 (3H, s), 3.03 (1H, m ), 3.20-3.46 (5H, m), 4.05- 4.13 (2H, m), 8.87 (1H, s)

 [Example 50] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- [N- (2-hydroxyshetyl) potassium] thiazole-5-yl ] Thio-1-methyl-1-caproluvene-2-em-3-carboxylate bivaloyloxymethyl

 In the same manner as in Example 2, (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- [N- (2-hydroxyethyl)] lubamoyl] thiazo 86 mg of the title compound was obtained from 87 m of sodium [5-yl] thio-1-methyl-1-carbapene-2-em-3-carboxylate.

_{NMR (CDC1 3) ί: 1.09} (3H 5 d, J = 7.5 Hz), 1.22 (9H, s), 1.31 (3H, d, J = 6.0 Hz), 3.2-3.3 (2H, m), 3.5-3.7 (2H, m), 3.8-3.9 (2H, m), 4.2-4.3 (2H, m), 5.85 (1H, d, J = 5.4 Hz), 5.98 (1H, d, J = 5.4 Hz), 7.7- 7.8 (lH, m), 8.73 (1H, s)

Example _{51] (1R 5 5S, 6S} ) -6 - ((lR) -l- hydroxy E chill) -2- [4- (2-menu Tokishe butoxy) carbonylation Ruchiazoru 5 I le] Chio - 1-methyl-1-butyric acid 2-sodium-3-carboxylate

 a) (1R, 5S, 6S) -6-((1R) -Trihydroxyethyl) -2- [4- (2-methoxetoxy) carbonylthiazolyl-5-yl] thio-1-methyl 1-Levapen-2-em-3-carboxylic acid 4-nitrobenzil

As in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -ltdroxityl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid 4 - 4-carboxylic acid 2 main Tokishechiru _{213mg, (1R, 5S 5 6S} ) -6 - - two Torobe Njiru 352mg and 5 main Rukaputochiazo Ichiru ((1R) - 1-hydroxy E chill) -2- [ 4- (2-methoxyxetoxy) carborylthiazole 277 mg of [5-5-yl] thio-1-methyl-1-forcelvapen-2-em-3-carboxylate 4-nitrobenzil were obtained.

NMR (CDCL) d: 1.10 (3H, d, 3 = 7.2 Hz), 1.33 (3H ₅ d, J = 6.4 Hz), 1.70 (1H, d, J = 4.8 Hz), 3.2-3.3 (2H, m) , 3.39 (3H, s), 3.7-3.8 (2H ₅ m), 4.2-4.3 (2H ₅ m), 4.5-4.6 (2H, m), 5.Z9 (1H, d, J = 13.6 Hz), 5.53 (1H, d, J = 13.6 Hz), 7.66 (2H ₅ d, J = 8.8 Hz), 8.24 (2H, d, J = 8, 8 z), 8.84 (1H, s)

MS (FAB); m / z 564 (M ⁺ +1)

 b) (1R, 5S, 6S) -6-((lR)-; l-hydroxyethyl) -2- [4- (2-methoxetoxy) carbonyldithiazole-5-yl] thio-1-methyl 1-Sodium lubapen-2-em-3-carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (2-methoxetoxy) carbonylthiazole-5-yl ] Thio-1-methyl-1-carban-2-em-3-carboxylate 4-nitrobenzyl, 277 mg, gave the title compound (88 mg).

NMR (D ₂₀ ) d (H0D = 4.65 ppm): 0.93 (3H, d, 3 = 1.2 Hz), 1.11 (3H, d, J = 6.4 Hz), 3.1-3.2 (1H, m), 3.28 (3H , s), 3.3-3.4 (lH, m), 3.6-3.7 (2H, m), 4.0- 4.1 (2H, m), 4.3-4.4 (2H, m), 8.85 (1H, s)

 MS (FAB); m / z 451 (MM)

Example _{52] (1R, 5S 5 6S} ) -6 - ((lR) -l- hydroxy E chill) -1-methyl - 2- [4- [N - (pen Yun-1-I le) Power Lubamoyl] thiazolyl-5-yl] thio-1-Lycapen-2-em-3 -Sodium rubonate

 a) (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -1-methyl-2- [4- [N- (penn-1-yl) -capsulebamoyl] thiazo 1-yl-5-yl] thio-1-l-l-bapene-2-em-3-carboxylate 4-dibenzoyl

In the same manner as in Example la), (lR, 3R, 5R, 6S) -6-((lR) -lt: droxityl) -1-methyl-2-oxo-tricarbazinam-3-carboxylic acid 4 -Nitoguchi Benzil IIOmg and 5-me From 70 mg of L-captothiazole-4-carboxylic acid N- (l-pentyl) amide, (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- [ 4- [N- (pentan-1-yl) potassium thiol] -5-yl] thio-1-potassyl-2-ene-3-carboxylic acid Was.

NMR (CDCl ₃ ) d: 0.8-0.9 (3H, m), 1 · 10 (3Η, d, J = 7.2 Hz), 1.3-1.4 (7H, m), 1.6-1.7 (2H, m), 3.2-3.3 (2H, m), 3.41 (2H, q, J = 6.8 Hz), 4.2-4.3 (2H ₃ m), 5.28 (1H, d, J = 14 Hz), 5.50 (1H, d, J = 14 Hz), 7.3-7.4 (lH ₃ m) ₅ 7.64 (2H ₃ d, J = 8.4 Hz), 8.22 (2H, d, J = 8.4 Hz), 8.71 (1H ₅ s)

MS (FAB); m / z 575 (M ⁺⁺ 1)

 b) (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -trimethyl-2- [4- [N- (pentane-1-yl) potumbamoyl] thiazole-5- Yl] thio-1-potassium lvapen-2-em-3-sodium carbonate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2- [4- [N- (pentane-1-y L) Capsulebamoyl] thiazol-5-yl] thio-1-capsyl 2-pent-3-em-3-carboxylate From 105 mg of 4-nitrobenzil, 21 mg of the title compound was obtained.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.6-0.7 (3H, m), 0.87 (3H, d, J = 7.2 Hz), 1.09 (3 H, d, J = 6.4 Hz), 1.1- 1.2 (4H, m), 1.4- 1.5 (2H, m), 2.9-3.0 (lH 5 m), 3.23 (2H, t, J = 6.8Hz), 3.2-3.3 (lH, m), 4.0- 4.1 ( 2H, m), 8.86 (1H, s)

MS (API); m / z 440 (M ⁺ +1)

 Example 53 (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- (4-methoxycarbonylylthiazol-5-yl) thio-1-methyl-1- L-Balpen-2-em-3-carboxylate

In the same manner as in Example _{2, (1R, 5S 3 6S} ) - 6- ((1R) -1- hydroxy E Chill) - 2- (4-menu Toxcarbonylthiazol-5-yl) thio-1-methyl-1-force rubapene-2-em-3-force Sodium sodium ribonate From lOOmg, the title compound 78m was obtained.

_{NMR (CDC1 3) d: 1.10} (3H 5 d, J = 7.2 Hz), 1.22 (9H 5 s), 1.31 (3H, d, J = 6.3 Hz), 3.2-3.3 (2H, m), 3.97 (3H , s), 4.2-4.3 (2H ₃ m), 5.87 (1H, d, J = 5.4 Hz), 6.0 1 (1H, d, J = 5.4 Hz), 8.83 (1H, s)

Example _{54] (1R 5 5S 5 6S} ) -6 - ((lR) -; l- hydroxy E chill) -1-methyl - 2- [4- (flop port Pan - 1-I le) Okishikarubo two Ruchiazoru -5-yl] thio-1-b-ylbapen-2-em-3-carboxylate bivaloyloxymethyl

In the same manner as in Example _{2, (1R, 5S 5 6S} ) -6- ((1R) -: L- hydroxy E chill) -1-methyl-2- [4- (propane - 1-I le) Okishi force The title compound (64 mg) was obtained from 120 mg of sodium rupropenylthiazol-5-yl] thio-1-carban-2-em-3-carboxylate.

_{NMR (CDC1 3) d: 1.01} (3H, t, J = 7.5 Hz), 1.10 (3H, d, J = 7.5 Hz), 1.22 (9H, s), 1.32 (3H, d, J = 6.0 Hz), 1.9- 2.1 (2H, m), 3.2-3.3 (2H, m), 4.Z-4.4 (4H ₅ m), 5.87 (1H ₅ d, J = 5.4 Hz), 6.00 (1H, d, J = 5.4 Hz), 8.84 (1H, s)

[Example _{55] (1R 5 5S, 6S} ) - 2- [4- [N- ( butane - 1-I le) force Rubamoiru] thiazole Ichiru -5- I le] Chio -6 - ((lR) - 1-Hydroxyethyl) -1-methyl -1-caproluvene-2-em-3 -Sodium carboxylate

- [4-[N- (ブタン- 1- ル] チォ- 6- ((1R)-1-ヒドロキシェチル） -1-メチル -1-力ルバペン- 2-ェム -3-カルボン 酸 4-二トロべンジル 実施例 la)と同様にして、 (lR,3R,5R,6S)-6-((lR)-l-ヒドロキシェチル） -1-メ チル -2-ォキソ -1-カルバぺナム- 3-カルボン酸 4-ニトロべンジル 543mgおよび 5-メ ルカプトチアゾ一ル- 4-カルボン酸 [N- ( 1 -プチル）アミ ド] -プチル）ァミン塩 434 mgから、 (1R, 5S, 6S)-2- [4-[N -(ブタン- 1-ィル）力ルバモイル]チアゾ一ル -5 -ィ ル]チォ -6-((lR)- 1-ヒドロキシェチル） -1-メチル -1-力ルバペン- 2-ェム- 3 -カル ボン酸 4-ニトロべンジル 402mgを得た。 _{a) (1R, 5S 5 6S} ) -2

-[4- [N- (Butane-1-yl) thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-methyllvapen-2-em-3-carboxylic acid 4- Nitrobenzil In the same manner as in Example la), (lR, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- From 434 mg of carboxylic acid 4-nitrobenzyl and 434 mg of 5-mercaptothiazol-4-carboxylic acid [N- (1-butyl) amide] -butyl) amine, (1R, 5S, 6S) -2- [4- [N- (Butane-1-yl) caprolubamoyl] thiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1-methyl-1-capryl This gave 402 mg of 4-nitrobenzyl 2-nitro-3-carboxylate.

_{NMR (CDC1 3) 5: 0.95} (3H, d, J = 7.6Hz), 1.10 (3H, d, J = 7.2Hz), 1.34 (3H, d, J = 6.4Hz), 1.3-1.4 (2H, m ), 1.5- 1.6 (2H, m ), 3.2 - 3.3 (2H, m), 3.41 (2H, q, J = 7.2Hz), 4.2-4.3 (2H 3 m), 5.28 (1H, d, J = 14Hz ) ₃ 5.50 (1H, d, J = 14Hz), 7.3-7.4 (1H, m), 7.64 (2H, d, J = 8.4Hz), 8.22 (2H, d, J = 8.4Hz), 8.71 ( 1H, s)

MS (FAB); m / z 561 (M ⁺ +1)

 b) (1R, 5S, 6S) -2- [4- [N- (butan-1-yl) caprolubamoyl] thiazolyl-5-yl] thio-6-((lR) -1-hydroxy -Ethyl) -trimethyl-1-ketorubapene-2-Em-3-sodium carboxylate

In the same manner as in Example _{lb), (1R 5 5S,} 6S) -2- [4- [N - ( butane - 1-I le) force Rubamoi le] thiazole Ichiru - 5-I le] Chio - 6- 116 mg of the title compound were obtained from 396 mg of ((1R) -1-hydroxyethyl) -1-methyl-1-forcelvapen-2-em-3-carboxylate 4-nitropentyl.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.91 (3H, d, J = 7.2 Hz), 1.02 (3H, d, J = 7.2 Hz), 1.25 (3H, d, J = 6Hz), 1.3 -1.4 (2H, m), 1.4-1.5 (2H, m), 2.9-3.0 (lH, m), 3.4-3.5 (3H, m), 4.0-4.1 (2H, m), 9.00 (1H, s)

MS (FAB); m / z 448 (M ⁺ +1)

[Example 56] (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -trimethyl-2- [4- [N- (2-methylthioethyl) potassium] thiazo Le-5-yl] thio-1-potassium lvapen-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S) -6-((lR)-; l-hydroxyethyl)-1-methyl-2- [4- [N- (2-methylthioethyl) rubamoyl] thiazol- 5-yl] thio -1-force rubapene-2-em-3 -force rubonic acid

 As in Example la), (lR, 3R, 5R, 6S) -6-((lR) -l-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- From 360 mg of 4-carboxylic acid nitrobenzene and 232 mg of 5-mercaptothiazole-4-carboxylic acid N- (2-methylthioethyl) amide, (1R, 5S, 6S) -6-((lR) -l-Hydroxyethyl)-1-methyl-2- [4- [N- (2-methylthioethyl)] lubamoyl] thiazol-5-yl] thio-1-l-lubapen-2-e 334 mg of 4-nitrobenzyl -3-carboxylate were obtained.

_{NMR (CDC1 3) d: 1.10} (3H, d, J = 7.2Hz), 1.34 (3H, d, J = 6Hz), 2.16 (3H, s), 2. 7-2.8 (2H, m), 3. Z-3.3 (2H, m), 3.6-3.7 (2H, m), 4.2-4.3 (2H, m), 5.28 (1H, d, J = 14Hz), 5.50 (1H, d, J = 14Hz), 7.64 (2H, d, J = 8.4Hz), 7.3-7.4 (lH ₃ m), 8.2 2 (2H, d, J = 8.4Hz), 8.71 (1H, s)

MS (API); m / z 579 (M ⁺ +1)

ル- 5-ィル]チォ- 1-力ルバペン- 2-ェム -3-力 ルボン酸ナトリウム b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (4- [N- (2-methyl

Le-5-yl] thio-1-potassium rubapene-2-em-3-potassium sodium rubonate

ル]チォ- 1-力 ルバペン- 2-ェム- 3-カルボン酸 4-二ト口べンジル 334mgから、 表題の化合物 40mg を得た。 In the same manner as in Example lb), (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- [4- [N- (2

[Ruthio-1-force Lubapen-2-em-3-carboxylic acid 4-dimethoxybenzene 334 mg to give the title compound 40 mg.

_{NMR (D 2 0) d (} H0D-4.65 ppm): 0.91 (3H, d, J = 7.2 Hz), 1.10 (3H, d, J = 6.4 Hz), 2.00 (3H, s), 2.62 (2H, t , J = 6.4Hz), 2.9-3.0 (1H, m), 3.4-3.5 (1H, m), 3.48 (2H, t, J = 6.4Hz)) ₅ 4.0-4.K2H, m), 8.85 (1H , S)

MS (FAB); m / z 466 (M ⁺⁺ 1) Example 57 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-tolyl) oxycarbonylthiazol-5- Yl] thio-1-methyl-1-potassium pen-2-em-3-sodium carboxylate

 a) (1R, 5S, 6S) -6-((IR)-;!-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazole-5-yl] Thio-1-methyl-1-capryl-2-ene-3-carboxylate 4-nitrobenzyl

 (LR, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-tricarbazin-3-carboxylic 827m of 4-Nitrobenzyl acid and 323mg of 5-mercaptothiazol-4-carboxylic acid (3-hydroxypropane-1-yl) were obtained from (1R, 5S, 6S) -6-((lR) -l -Hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-1-methyl-1-hexyl-2-ene-3-em-carvone 267 mg of the acid 4-nitrobenzoyl were obtained.

_{NMR (CDC1 3) d: l.ll} (3H, d, J = 7.2 Hz), 1.34 (3H, d, J = 6.3 Hz), 2.0-2.1 (2H, m), 3.2-3.3 (2H, m) , 3.7-3.8 (2H, m), 4.2-4.3 (2H, m), 4.5-4.6 (2H, m), 5.29 (1H, d, J = 13.8 Hz), 5.54 (1H, d, J = 13.8 Hz), 7.66 (2H, d, J = 9.0 Hz), 8.23 (2H ₅ d, J = 9.0 Hz), 8.83 (1H, s)

_{b) (1R 5 5S, 6S} ) -6 - ((lR) - 1- hydroxy E chill) -2- [4- (3-hydroxy-propane - 1 - I le) Okishikarubo two Ruchiazo Ichiru - 5- I le ] Thio-1-methyl-1-caproluvene-2-em-3-carboxylate sodium

 (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazole 128 mg of the title compound were obtained from 267 mg of 4--2-yl] thio-1-methyl-1-caphyllappen-2-em-3-carboxylate 4-nitrobenzil.

_{NMR (D 2 0) d (} H0D = 4.80 ppm): 1.07 (3H 5 d, J = 7.2 Hz), 1.26 (3H, d, J = 6.3 Hz), 1.9-2.1 (2H 5 m), 3.2-3.3 (lH ₅ m), 3.49 (1H, dd, J ^ 6.0 Hz, Js2.7 Hz), 3.7- 3.8 (2H, m), 4.2-4.3 (2H, m), 4.4-4.6 (2H, m), 8.98 (1H, s)

 [Example 58.] (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -methyl-2- [4- (thiazol-2-yl) thiazol -5-yl] thio-1-sodium lubapen-2-em-3-carboxylate sodium

_{a) (1R 5 5S, 6S} ) - 6 - ((lR) - 1- hydroxy E Chill) - Bok methyl - 2- [4- (thiazol - 2-I le) thiazole Ichiru -5- I le] Chio -Ururubabapen-2-em-3-carboxylic acid 4-benzyl

 As in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3- From 443 mg of 4-nitrobenzyl carboxylate and 260 m of 5-mercapto-4- (thiazol-2-yl) thiazol, (1R, 5S, 6S) -6-((lR)-

1-Hydroxyethyl) -1-methyl-2- [4- (thiazol-2-yl) thiazol-5-yl] thio-1-butyl-2-en-3-carboxylic acid 4 -Obtained 469m.

_{NMR (CDC1 3) d: 1.05} (3H, d, J = 7.2 Hz), 1.31 (3H, d, J = 6.3 Hz), 3.1-3.2 (1H, m), 3.22 (1H, dd, J 6.6 HZ, 2.7 Hz), 4.14 (1H, dd, JF9.3 HZ, J? 2.7 Hz), 4.2-4.3 (1H, m), 5.31 (1H, d, J = 13.5 Hz), 5.58 (1H, d, J = 13.5 Hz), 7.45 (1H, d, J = 3.0 Hz), 7.69 (2H, d, J = 8.7 Hz), 7.93 (1H, d, J = 3.0 Hz), 8.23 (2H, d, J = 8.7 Hz), 8.92 (1H, s)

 b) (1R, 5S, 6S) -6-((lR) -l-hydroxyethyl)-1-methyl-2- (4- (thiazolyl-

2-yl) thiazol-5-yl] thio-1-caproluvene-2-em-3-carboxylic acid sodium salt In the same manner as in Example lb), (1R, 5S, 6S) -6- ((lR) -l-hydroxyethyl) -1-methyl-2- [4- (thiazol-2-yl) thiazol-5-yl] thio-1 thiolbapen 2-hem- From 469 mg of 3-carboxylic acid 4-nitrobenzil, 277 mg of the title compound was obtained.

_{NMR (D 2 0) d (} H0D = 4.80 ppm): 0.94 (3H, d, J = 7.5 Hz), 1.20 (3H, d, J = 6.3 Hz), 2.8-3.0 (1H, m), 3.3-3.4 (lH ₅ m), 3.9-4.0 (lH, m), 4.1-4.2 (1H, m), 7.7-7.8 (1H, m), 7.9-8.0 (lH, m), 9.15 (1H, s) Example 59 (1R, 5S, 6S) -2- [4- (Butane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((lR) -1-hydroxy) Tyl) -1-methyl-1-force rubapene-2-em-3-force sodium rubonate

 a) (lR, 5S, 6S) -2- [4- (Butane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((lH) -1-hydroxyethyl) 1-methyl-1-l-lubapen-2-em-3-carboxylic acid 4-nitrobenzyl

 754 ml of 5-butyltylthiothiazol-4-carboxylate was dissolved in 9.5 ml of dichloromethane, and 0.42 ml of triethylsilane was added. While cooling in an ice bath, 1.36 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 40 minutes in an alcohol atmosphere. After adding 2 mL of methanol, the solvent was distilled off under reduced pressure to obtain a residue containing 1-butyl 5-mercaptothiazol-4-carboxylate.

 The above residue containing 1-butyl 5-mercaptothiazol-4-carboxylate and (111,311,511,6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1 In the same manner as in Example 3a), from (638 mg of 4-nitrobenzyl) -carbazum-3-carboxylate, (1R, 5S, 6S) -2- [4- (butan-1-yl) oxycarbo N-Lthiazolyl-5-yl] thio-6-((lR) -l-hydroxyethyl) -trimethyl-toluene-lvapen-2-em-3-carboxylic acid 4-ditrobenzil (419 mg) was obtained. Was.

_{NMR (CDC1 3) d: 0.95} (? 3H, dd, J 7.3 HZ, J 7.6HZ), 1.11 (3H, d, J = 7.3 Hz), 1.34 (3H 3 d, J = 6.4 Hz), 1.40-1.49 (2H ₅ m), 1.73- 1.80 (2H, m), 3.23-3.31 (2H ₅ m), 4.24- 4.29 (2H, m), 4.33-4.43 (2H, m), 7.66 (2H, d, J = 8.8 Hz), 8.24 (2H, d, J = 9.0 Hz), 8.84 (1H, s)

 b) (lR, 5S, 6S) -2- [4- (Butane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -Trimethyl-1-butyric acid 2-sodium-3-carboxylate

In the same manner as in Example lb), (lR, 5S, 6S) -2- [4- (butan-1-yl) oxycarbonyl Thiazolyl-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-butyric lappene-2-em-3-carboxylate From 419 mg of 4-nitrobenzyl 120 g of the title compound were obtained.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.77 (? 3H, dd, J 7.3 HZ, J 7.6 Hz), 0.90 (3H, d, J = 7.3 Hz), 1.10 (3H, d, J = 6.3 Hz), 1.23-1.32 (ZH, m), 1.54-1.61 (2H, m), 3.00-3.08 (lH, m), 3.30 (1H, dd, JF2.7 Hz, J? 5.6 Hz), 4.06-4.11 (2H, m), 4.19-4.29 (2H, m), 8.84 (1H, s)

MS (FAB); m / z 449 (M ⁺⁺ 1)

 [Example 60] (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- (2-methoxyethoxycarbonyl) thiazolyl-5-yl] thio Bivaloyloxymethyl carboxylate

 In the same manner as in Example 2, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (2-methoxyethoxycarbonyl) thiazole-5-yl 94 mg of the title compound were obtained from 173 mg of sodium thio-1-methyl-1-caprol-2-en-3-empyronic acid.

_{NMR (CDC1 3) d: 1.10} (3H, d, J = 7.2Hz), 1.22 (9H, s), 1.30 (3H, d, J = 6Hz), 3. 2-3.4 (2H, m), 3.40 ( 3H, s), 3.72 (2H, t, J = 4.8Hz), 4.2-4.3 (2H, m), 4.4-4.5 (2H, m), 5.86 (1H, d, J = 5.6Hz), 6.00 (1H , d, J = 5.6Hz), 8.85 (1H, s)

MS (FAB); m / z 543 (M ⁺⁺ 1)

[Example _{61] (lR, 5S 5 6S} ) -6 - ((lR) -lt Dorokishechiru) -1-methyl - 2-[4-(N - Main switch carbamoyl § cetyl) thiazole Ichiru - 5- I le ] Cho-1-force Lubapen-2-em-3-force sodium rubonate COCH ₂ CONHCH _: a) (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -trimethyl-2- [4- (N-methylcarbamoylacetyl) thiazol-5-yl ] Cleaning Lubapen-2-Em-3-carboxylic acid 4-Nitoguchi Benzinole

 427 mg of 4-((N-methylcarbamoylacetyl) -5-tritylthiothiazol and (1R, 3R 5R, 6S) -6-((lR) -1-hydroxyethyl) -trimethyl-2-oxo (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-Methyl-2- [4- (N-methylcarbamoylacetyl) thiazol-5-yl] thio-1-l-lubapen-2-em-3-carboxylic acid 4-nitrobe Waited for 143 mg

_{NMR (CDC1 3) d: 1.12} (3H, d, J = 7.3 Hz), 1.35 (3H, d, J = 6.4Hz), 2.87 (3H 3 d, J = 4.9 Hz), 3.30-3.38 (2H, m ), 4.04 (1H, d, J = 16.6 Hz), 4.18 (1H, d, J = 16.6 Hz), 4.24-4.34 (2H, m) ₅ 5.29 (1H, d, J = 13.4 Hz), 5.52 (1H , d, J = 13.6 Hz), 7.65 (2H, d, J = 9.0 Hz), 8.23 (2H, d, J = 8.7 Hz), 8.71 (1H, s)

 b) (1R, 5S, 6S) -6-((lR) -1-Hydroxyethyl) -1-methyl-2- [4- (N-methylcarbamoylacetyl) thiazol-5-yl] thio- 1-potassium lvapen-2-em-3-carboxylate sodium

In the same manner as in Example lb), (lR ₅ 5S, 6S) -6-((lR) -l-tidroxityl) -1-methyl-2-[4- (N-methylcarbamoylacetyl) thiazole-5 [-Yl] thio-l-cap-lubapen-2-em-3-carboxylic acid 30 mg of the title compound was obtained from 140 mg of 4-dibenzyl.

NMR (D ₂₀ ) d (H0D = 4.65 ppm): 0.96 (3H ₅ d, J = 7.3 Hz), 1.12 (3H, d, J = 6.3 Hz), 2.62 (3H, s), 3.21-3.29 (1H , m), 3.41 (1H ₅ m), 4.08-4.14 (lH, m), 4.20 (1H, dd, Hz, JF9.7 HZ), 4.65 (2H, S) ₃ 8.73 (1H, S)

MS (FAB); m / z 448 (M ⁺ +1)

[Example 62] (5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-alkenyl-2-ene Sodium-3-carboxylate COOCHg a) (5R, 6S) -6-((lR) -l-hydroxyethyl) -2- (4-methoxycarbonylthiazo-l-5-yl) thio-1--1-l-lubapen-2-e -3-carboxylic acid

In the same manner as in Example _{3a), (3R 3 5R,} 6S) -6 - ((lR) -lb Dorokishechiru) -2 Okiso-carba Bae Nam - 3- carboxylic acid 4 two Torobe Njiru 192mg and From (96 mg) of methyl 5-mercaptothiazole-4-carboxylate, (5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazole-5-yl) thio 197 mg of 4-nitrobenzyl, -1-l-lubapen-2-em-3-carbonic acid, were obtained.

NMR (CDCL) d: 1.07 (3H, d, J-6.4 Hz), 2.8-2.9 (1H, m), 2.9-3.0 (lH, m), 3.2-3.3 (1H, m), 3.84 (3H, s _{), 3.9-4.0 (lH 5, m} ), 4.2-4.3 (1H, m), 5.03 (1H, d, J = 4.4 Hz), 5.38 (1H, d, J = 13.8 Hz), 5.51 (1H, d , J = 13.8 Hz), 7.73 (2H, d, J = 8.8 Hz), 8.24 (2H, d, J = 8.8 Hz), 9.29 (1H, s)

MS (FAB); m / z 506 (M ⁺⁺ 1)

 b) (5R, 6S) -6-((1R) -1-Hydroxyethyl) -2- (4-methoxycarbonylthiazo-l-5-yl) thio-1-caprolubapen-2-em Sodium 3-carboxylate

 "T :, (5R, 6S) -6-((lR)-; l-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) as in Example lb) 76 mg of the title compound were obtained from 195 mg of thio-1-forcelvapen-2-em-3-carboxylic acid 4-nitrobenzyl.

_{NMR (D 2 0) d (} H0D = 4.65 ppm):. 1.27 (3H 5 d, J = 6.4 Hz), 2.8-3.0 (2H, m), 3.2-3 3 (1H, m), 3.94 (3H, s), 4.2-4.3 (2H ₃ m), 8.96 (1H, s)

 MS (FAB); m / z 393 (M)

[Example 63] (1R, 5S, 6S) -6-((lR)-;! -Hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazole-5- Yl] thio-1-methyl-1-potene pen-2-em-3-carboxylate bivaloyloxymethyl

 In the same manner as in Example 2, (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonyldithiazole From 53 mg of sodium 5- (5-yl) thio-1-methyl-1-caproluvene-2-em-3-carboxylate, 43 mg of the title compound was obtained.

NMRiCDCls) d: 1.10 (3H ₃ d, J = 7.2 Hz), 1.23 (9H, s), 1.31 (3H, d, J = 6.3 Hz), 2.0-2.1 (2H, m), 3.2-3.3 (2H, m), 3.7-3.9 (2H, m), 4.2-4.3 (2H, m), 4.5-4.6 (2H, m), 5.87 (1H, d, J = 5.4 Hz), 6.00 (1H, d, J = 5A Hz), 8.84 (1H, s)

 [Example 64] (5R, 6S) -6-((lR) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-hexarubapene-2-e Bivaloyloxymethyl-3-carboxylate ''

 In the same manner as in Example 2, (5R, 6S) -6-((lR)-: l-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1 30 mg of the title compound was obtained from 70 mg of sodium lubapen-2-em-3-carboxylate.

NMR (CDCl ₃ ) d: 1.24 (9H ₅ s), 1.30 (3H, d, J = 6.4 Hz), 2.88 (2H ₅ d, J = 9.2 Hz), 3.1-3.2 (1H ₅ m), 3.98 (3H , s), 4.2-4.3 (2H, m), 4.4-4.5 (2H, m), 5.89 (1H, d, J = 5.4Hz), 6.00 (1H, d, J = 5.4Hz), 8.91 (1H, s)

MS (FAB) m / z 485 (M ⁺ +1)

[Example 65] (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-methyl-1- L-Lupapen-2-em-3-carboxylic acid 1- (Cyclohexyloxycarbonyloxy) ethyl (a mixture of diastereomers)

ォキシ）ェチルョ一ダイ ド llOm を加え、 2時間 撹拌した。 反応液に半飽和食塩水 50mLを加え、 酢酸ェチル 50mLで 2回抽出した。 有機層を合わせて半飽和食塩水 50mLで 2回洗浄し、 無水硫酸マグネシウムで乾燥、 溶媒を減圧； f留去した。 得られた残渣をシリカゲルカラムクロマトグラフィ一 (へキサン：酢酸ェチル =1:9)で精製することにより、 表題の化合物 82m を得た。 (1R, 5S, 6S) -6-((1R) -Hydroxyethyl) -2- (4-methoxycarbonylthiazo-l-5-yl) thio-1-methyl-1-methyll-bapen-2- Dissolve 114 mg of hem-3-carboxylate in 2 mL of DMF, and in an argon atmosphere, at -30 ° C, sodium hydrogen carbonate 71 mg, 1-

(Oxy) ethyl ether llOm was added and stirred for 2 hours. To the reaction solution was added 50 mL of half-saturated saline, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, washed twice with 50 mL of half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 9) to give the title compound (82m).

_{NMR (CDC1 3) d: 1.10} (3H 5 d, J = 7.2Hz), 1.2-1.3 (7H 5 m), 1.4-1.5 (2H, m), 1.6 - 1.7 (3H, m), 1.7- 1.8 ( 2H, m), 1.8-1.9 (2H, m), 3.2-3.3 (2H, m), 3.97 (3H ₅ s), 4.2-4.3 (2H, m) ₅ 4.6-4.7 (lH, m), 6.92 ( 1H, q, J = 5.2 Hz), 8.82 (1H, s)

MS (FAB); m / z 555 (M ^÷ +1)

 [Example 66] (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-trimethyl-;!- 1- (Isopropyloxycarbonyloxy) ethyl (diastereomeric mixture)

_{(1R, 5S 3 6S) -6} - ((lR) - 1- hydroxy E Chill) - 2- (4-methoxy carbonylation Ruchiazo Lumpur - 5-I le) Chio - 1-methyl-1-Power Rubapen - Dissolve 130 mg of sodium 2-em-3-carboxylate in 2.6 niL of DMF, and add 81 mg of sodium bicarbonate at -30 ° C under argon atmosphere. 107 mg of-(isopropyloxycarbonyloxy) ethyl ester was added, and the mixture was stirred for 2 hours. To the reaction solution was added 50 mL of half-saturated saline, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, washed twice with 50 mL of half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 9) to give the title compound (llmg). Thigh (CDC1: 1.10 (3H, d, J = 7.2Hz), lZ-1.3 (6H, m), 1.5-1.6 (6H, m), 3.2-3.3 (2H, m), 3.97 (3H, s), 4.2-4.3 (2H ₅ m), 4.9-5.0 (1H, m), 6.9-7.0 (lH, m), 8.82 (1H ₅ s)

MS (FAB); m / z 515 (M ⁺⁺ 1)

 [Example 67] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-methyl-1- Levapen-2-em-3-carboxylate acetoxymethyl

 In the same manner as in Example 2, (1R, 5S, 6S.)-6-((1R) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio- 1-Methyl-1-potassyl-2-em-3-potassium 132 mg of the sodium ribonate and 113 mg of acetoxymethyl chloride gave 113 mg of the title compound.

_{NMR (CDC1 3) d: 1.10} (3H, d, J = 7.2 Hz), 1.32 (3H, d, J = 6.3 Hz), 2.14 (3H, s), 3.2-3.3 (2H 5 m), 3.98 (3H , s), 4.2-4.3 (2H, m), 5.88 (1H, d, J = 5.4 Hz), 5.97 (1H, d, J = 5.4 Hz), 8.84 (1H, s)

実施例 2と同様にして、 （1R, 5S， 6S)- 6-((lR)-l-ヒドロキシェチル） -2-(4-メ トキシカルボ二ルチアゾ一ル -5-ィル）チォ -1-メチル -1-力ルバペン- 2-ェム -3-力 ルボン酸ナトリゥム 150mgと（5-メチル -2-ォキソ -1,3ジォキソレン- 4-ィル）メチ ルブロマイ ドより表題の化合物 138m を得た。 [Example 68] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazol-5-yl) thio-1-methyl-1- L-Bapen-2-em-3-carboxylate (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl

In the same manner as in Example 2, (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- (4-methoxycarbonylthiazolyl-5-yl) thio-1 -Methyl-1-force lubapen-2-em-3-force Sodium rubonate 150mg and (5-methyl-2-oxo-1,3dioxolen-4-yl) methylbromide gave 138m of the title compound. Was.

_{NMR (CDC1 3) d: 1.10} (3H, d, J = 7.3 Hz), 1.33 (3H, d, J = 6.3 Hz), 2.22 (3H, s), 3.23-3.30 (2H, m), 4.20-4.30 (2H, m), 5.04 (2H, d, J = 3.4 Hz), 8.84 (1H, s)

[Example 69] (5R, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -l-hydric quichetil) Sodium 3-carboxylate

 a) (5R, 6S) -2- (4-Acetylthiazo, 1-5-yl) thio-6-((lR) -1-hydroxyethyl) 4-Nitrobenzyl carboxylate

 In the same manner as in Example 3a), (3R, 5R, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid 4 (5R, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR ) -l-Hydroxyethyl) -1-mg lubapen-2-em-3-carboxylic acid 4-nitrobenzil 155 mg was obtained.

NMR (CDCL) d: 1.32 (3H ₅ d, J = 6.4 Hz), 2.71 (3H, s), 2.9-3.0 (2H, m), 3.2-3.3 ((2H, m), 4.2-4.3 ( 2H, m), 5.29 (1H, d, J = 13.6Hz), 5.53 (1H, d, J = 13.6Hz), 7.66 (2H, d, J = 8.8Hz), 8.23 (2H, d, J = 8.8 Hz), 8.84 (1H, s) MS (FAB); m / z 490 (M ⁺⁺ 1)

b) (5R ₅ 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lIl) -l-hydroxyethyl) -toluylbapene-2-em-3-carvone Sodium acid

 (5R, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -1-caproluvene From 154 mg of 2-em-3-carboxylic acid 4-nitrobenzene, the title compound 53m was obtained.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): l.10 (3H, d, J = 6 Hz), 2.52 (3H, s), 2.83 (2H, d, J = 9.2Hz), 3.3-3.4 (lH, m), 4.0-4, l (2H, m), 8.81 (1H, s)

MS (FAB); m / z 377 (M ⁺ +1)

 [Example 70] (1R, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) 1-methyl-1--1-l-lubapen-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (diastereomeric mixture)

 In the same manner as in Example 2, (1R, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -l-hydroxy 37 mg of the title compound was obtained from 60 mg of sodium 1-methyl-1-carbazane-2-em-3-carboxylate and 315 mg of 1- (cyclohexyloxycarbonyloxy) ethyl ester. Was.

NMR (CDCL) (5: 1.10 (3H, d, J = 7.5 Hz), 1.2-2.0 (16H, m), 3.2-3.3 (2H, m), 3.9-4.0 (2H, m), 4.2- 4.3 (2H ₅ m), 4.4-4.6 (2H, m), 4.6-4.7 (lH ₅ m), 6.8-7.0 (1H, m), 8.85, 8.86 (total 1H, 2s)

[Example 71] (1R, 5S, 6S) -2- 2- [4- (2-Hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((1R) -l-hide mouth quichetyl) -1 1- (Neopentyloxycarbonyloxy) ethyl (methyl diastereomer mixture)

実施例 2と同様にして、 （lR，5S,6S)-2- [4-(2-ヒドロキシエトキシ）カルボニル チアゾ一ル -5-ィル]チォ -6-((lR)- 1-ヒドロキシェチル） -1-メチル -1-力ルバペン - 2-ェム- 3-カルボン酸ナトリウム lOOmgおよび卜（ネオペンチルォキシカルボニル ォキシ）ェチルョ一ダイ ド 107m より、 表題の化合物 35m を得た。

In the same manner as in Example 2, (lR, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonyl thiazol-5-yl] thio-6-((lR) -1-hydroxy) The title compound 35m was obtained from lOOmg of sodium thiol) -1-methyl-1-l- levapen-2-em-3-carboxylate and 107m of tri (neopentyloxycarbonyloxy) ethyl iodide.

_{NMR (CDC1 3) d: 0.94} , 0.96 (total 9H, 2s), 1.09 (3H, d, J = 7.3 Hz), 1.30, 1. 32 (total 3H, 2d, J = 6.3 Hz), 1.62, 1.65 ( total 3H, 2d, J = 5.3 Hz), 3.19-3.2 7 (2H, m), 3.83-3.96 (4H, m), 4.20-4.27 (2H, m), 4.42-4.55 (2H, m), 6.91, 6.91 (total 1H, 2q, J = 5.3 Hz), 8.88, 8.89 (total 1H, 2s)

MS (FAB); m / z 573 (M + + l)

[Example _{72] (1R 5 5S, 6S} ) - 2- [4- (2- hydroxyethoxy) carbonylation Ruchiazo one-5-I le] Chio -6- ((1R) -1- hydroxy E chill) -Trimethyl-1-capryl-2-em-3-carboxylic acid tri (2-cyclohexylethoxycarbonyloxy) ethyl (a mixture of diastereomers)

 In the same manner as in Example 2, (1R, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonylthiazole-5-yl] thio-6-((lR) -l-hydroxyethyl 121 mg of the title compound was obtained from 151 mg of sodium 1-methyl-1-carbazin-2-em-3-carboxylate and 358 m of 1- (2-cyclohexylethoxycalponyloxy) ethyl monohydrate. .

_{NMR (CDC1 3) (5:} 0.8-1.8 (22H 3 m), 3.2-3.3 (2H, m), 3.8- 4.0 (2H, m), 4.1-4.3 (4H, m), 4.4-4.6 (2H ₃ m), 6.90 (1H, q, J = 5.4 Hz), 8.90 (1H, s)

 [Example 73] (lR, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonylthiazol-

5-yl] thio-6-((110-1-hydroxyethyl) -trimethyl-1-hexylbapen-2-em-3-carboxylic acid (5-methyl-2-oxo-1,3dioxolen) -4-yl) methyl

実施例 2と同様にして、 （lR,5S,6S)-2-[4-(2-ヒドロキシエトキシ）カルボニル チアゾ一ル -5-ィル]チォ -6-((lR)- 1-ヒドロキシェチル） -1-メチル -1-力ルバペン - 2-ェム- 3-カルボン酸ナトリゥム lOOmgと（5-メチル -2-ォキソ -1，3ジォキソレン- 4 -ィル）メチルプロマイ ド 90mgより表題化合物 30mgを得た。

In the same manner as in Example 2, (lR, 5S, 6S) -2- [4- (2-hydroxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -1-hydroxy) Tyl) -1-methyl-1-methyll-balpene-2-em-3-sodium sodium carboxylate lOOmg and (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylpromide 90mg 30 mg of the compound were obtained.

NMR (CDCL) (: 1.11 (3H ₅ d, J = 7.3 Hz), 1.32 (3H ₅ d, J = 6.3 Hz), 2.21 (3H, s), 3.20-3.30 (2H ₅ m), 3.90-3.97 ( 2H, m), 4.20-4.30 (2H, m), 4.42-4.58 (2H, m), 5.03 (1H, ABq, J = 13.6 Hz), 5.07 (1H, ABq, J = 13.6Hz), 8.88 (lH , s)

 Example 74 (1R, 5S, 6S) -6-((ll-1-hydroxyethyl) -trimethyl-2- [4- (pyridin-4-yl) thiazol-5-y Le] thio-1-potassium 2-baem-3-carboxylate

_{a) (1R 5 5S, 6S} ) -6 - ((lR) - 1- hydroxy E chill) -1-methyl - 2- [4- (pyridin - 4-I le) thiazole Ichiru - 5-I le] Thio-l-pentyl-2-ene-3-carboxylate 4-nitrobenzyl

In the same manner as in Example _{la), (1R, 3R 5} 5R, 6S) - 6 - ((lR) - 1- hydroxy E chill) -1- Methyl-2-oxo-1-carbazinam-3-carburonic acid 4-Nitrobenzyl 623m and 5-mercapto-4- (pyridine-4-yl) -thiazoyl 334mg from (1R, 5S , 6S) -6-((lR) -1-Hydroxyethyl)-:!-Methyl-2- [4- (pyridine-4-yl) thiazol-5-yl] thio-1- There were obtained 561 mg of 4-l-benzyl 2-carbene-2-carboxylate.

_{NMR (CDC1 3) ^: 0.90} (3H, d, J = 7.2Hz) 5 1.29 (3H, d, J = 6.4Hz), 2.9-3.0 (lH, m), 3.1- 3.2 (lH, m), 4.1 -4.2 (2H, m), 5.29 (1H, d, J = 14Hz), 5.57 (1H, d, J = 14Hz), 7.68 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 6Hz), 8.24 (2H, d, J = 8.8Hz), 8.70 (2H, d, J = 6Hz), 9.01 (1H ₅ s)

 MS (FAB); m / z 539 (M ++ 1)

 b) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -trimethyl-2- [4- (pyridine-4-yl) thiazol-5-yl] thio 1-force sodium lubapen-2-em-3-carboxylate In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR) -hydroxyethyl) -trimethyl-2 -[4- (Pyridin-4-yl) thiazolyl-5-yl] thio-1-L-ruben-2-em-3 -L-Rubonic acid 277 mg of the compound were obtained.

_{NMR (D 2 0) 5 (} H0D = 4.65ppm): 0.71 (3H, d, J = 7.2Hz), 1.02 (3H, d, J = 6Hz), 2.5- 2.6 (lH, m), 3.1- 3.2 ( 1H, m), 3.5-3.6 (1H, m), 3.9-4 · 0 (1Η, m), 7.71 (2H ₅ d, J = 6 Hz), 8.46 (2H, d, J = 6 Hz), 9.03 (1H ₅ s)

 MS (FAB); m / z 426 (M ++ 1)

 [Example 75] (lR, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((1R) -1 -hydroxyxethyl) -1-methyl-l-capryl -2-Em-3-carboxylate (isopropyloxyl-ponyloxy) ethyl (a mixture of diastereomers)

(LR, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((1R) -1-hydroxyethyl) -trimethyl-1 in the same manner as in Example 2. 1- (Isopropyloxycarbonyloxy) ethyl iodide 2 From 7 mg, 35 mg of the title compound was obtained.

_{NMR (CDC1 3) d: 1.10} , l.ll (total 3H, 2d, J = 7.3 Hz), 1.26- 1.34 (9H, m), 1.5, 1.61 (total 3H, 2d, J = 5.3 Hz), 2.69 ( 3H, s), 3.26-3.35 (2H ₃ m), 4.21-4.3 (2H, m), 4.86-4.93 (1H ₅ m), 6.89, 6.90 (total 1H, 2q ₅ J = 5.3 Hz), 8.72 (1H , s)

MS (FAB); m / z 499 (M + + l)

 [Example 76] (1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -l-hide mouth quichetyl) -trimethyl-1-capryl -2-Em-3-carboxylate (cyclohexyloxycarbonyloxy) ethyl (a mixture of diastereomers)

In the same manner as in Example 2, (1R, 5S, 6S) -2- (4-acetylthiazol-5-yl) thio-6-((11-trihydroxyethyl) -1-methyl-1- Compound 116 NMR (CDCl ₃ ) d: l.ll from 116 mg of sodium levapene-2-em-3-carboxylate and 223 mg of 1- (cyclohexyloxycarbonyloxy) ethyl ester (3H, d, J = 7.5 Hz), 1.2-2.0 (16H, m), 2.69 (3H, s), 3.2-3.4 (2H, m), 4.2-4.3 (2H, m), 4.6-4.7 (lH, m), 6.8-6.9 (1H ₅ m), 8.71 (1H ₅ s)

 [Example 77] (1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -l-hydroxyethyl) -trimethyl-1-capryl -2-ethoxy-3-acetoxymethyl carboxylate

(1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio- 6-((1R) -1 -Hydroxyethyl) -1-methyl-1-forcelvapen-2-em-3-carboxylate sodium salt 92 mg and acetooxymethyl chloride 115 mg from the title compound 83 mg were obtained.

NMR (CDCl3) d: l.ll (3H, d, J = 7.2 Hz), 1.33 (3H, d, J = 6.3 Hz), 2.12 (3H, s), 2.69 (3H, s), 3.2-3.4 ( 2H ₅ m) ₅ 4.2-4.4 (2H, m), 5.85 (1H, d, J = 5.4 Hz), 5.94 (1H, d, J = 5.4 Hz), 8.74 (1H, s)

 [Example 78] (1R, 5S, 6S) -2- [4- (2-ethoxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -1-l-hide mouth quichetyl) 1-methyl-1-carbyl-2-em-3-sodium carboxylate

 a) (1R, 5S, 6S) -2- [4- (2-ethoxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1- Methyl 1-l-Levapen-2-em-3-carboxylic acid 4-nitrobenzil

In the same manner as in Example _{3a), (lR, 3R 5} 5R, 6S) -6 - ((lR) -lt Dorokishechiru) -1-methylation - 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 -(1R, 5S, 6S) -2--[4- (2-ethoxyethoxy) carbonylthiazole-5-yl from 400 mg of 2-nitrobenzil and 345 mg of 2-ethoxyxetyl-4-carboxylic acid 5-mercaptothiazol [L] thio-6-((IR) -l-hydric quichetyl) -trimethyl-1-force lubapen-2-em-3-carboxylic acid 4-nitrobenzil (189 mg) was obtained.

_{NMR (CDC1 3) d: 1.10} (3H, d, J = 7.Z Hz), 1.19 (3H, t, J = 7.2Hz) 5 1.33 (3H, d, J = 6.4 Hz), 3.2-3.3 (2H , m), 3.55 (2H ₅ q, J = 7.2 Hz), 3.76 (2H ₅ t, J = 4.8 Hz), 4.2-4.3 (2H ₅ m), 4.51 (2H, t, J = 4.8 Hz) ₃ 5.29 (1H, d, J = 13.6 Hz), 5.53 (1H ₃ d, J = 13.6 Hz), 7.66 (2H, d, J = 8.8 Hz), 8.24 (2H ₅ d, J = 8.8 Hz), 8.84 (1H, s)

MS (FAB); m / z 577 (M ⁺ )

b) (IR, 5S, 6S) -2- [4- (2-ethoxyethoxy) carbonylthiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) -1-methyl- 1-Power Lubapen-2-Em-3-Carbon Sodium acid

 In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- (2-ethoxyethoxy) dicarboxylthiazol-5-yl] thio 6-((1R) -1-hydroxy) The title compound (52 mg) was obtained from 189 m of 4-nitrobenzyl, tyl) -trimethyl-1-carbazin-2-em-3-carboxylate.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.93 (3H, d, J = 6.8 Hz), 1 · 03 (3Η, t, J = 7.2Hz), 1.1K3H, d, J = 5.6 Hz) , 3.1-3.2 (1H, m), 3.3-3.4 (lH, m), 3.49 (2H ₃ q, J = 7.2 Hz), 3.6-3.7 (ZH, m), 4.0-4.1 (2H, m), 4.3 -4.4 (2H, m), 8.85 (1H, s)

MS (FAB); m / z 465 (M + + l)

 [Example 79] (1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((lR) -l-hydroxyethyl) -1-methyl-1-force Lubapen-2-em-3-carboxylate (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl

実施例 2と同様にして、 （1R， 5S， 6S)- 2- (4-ァセチルチアゾ一ル -5-ィル）チォ- 6- ((1R)- ヒドロキシェチル） -1-メチル -1-力ルバペン- 2-ェム -3-カルボン酸ナ トリゥムと 150mgと（5-メチル -2-ォキソ -1，3ジォキソレン- 4-ィル）メチルブロマ ィ ド 150m より表題化合物 35m gを得た。

(1R, 5S, 6S) -2- (4-Acetylthiazol-5-yl) thio-6-((1R) -hydroxyethyl) -1-methyl-1- 35 mg of the title compound was obtained from sodium levapene-2-em-3-carboxylate, 150 mg and 150 mg of (5-methyl-2-oxo-1,3 dioxolen-4-yl) methyl bromide.

NMR (CDCL) d: l.ll (3H ₅ d, J = 7.3 Hz), 1.33 (3H, d, J = 6.3 Hz), 2.20 (3H, s), 2.70 (3H, s), 3.20-3.35 ( 2H, m), 4.20-4.33 (2H, m), 5.03 (2H, s), 8.74 (1H,

[Example 80] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -trimethyl-2- [4- (2-methylthioethoxy) carbonylthiazole-5-yl ] Cho-1-Portable Lubapen-2-Em-3-Portable Sodium Rubonate

_{a) (1R, 5S 3 6S} ) -6 - ((lR) - 1- hydroxy E chill) -1-methyl - 2- [4- (2-Mechiruchi Oetokishi) carbonylation Ruchiazo Ichiru 5-I le] Thio-1-l-L-bapene-2-em-3-carboxylate 4-dibenzobenzene

In the same manner as in Example _{3a), (lR 5 3R,} 5R 3 6S) -6 - ((lR) -lb Dorokishechiru) -1-methylation-2 Okiso-carba Bae Nam - 3-carboxylic acid 4 From 424 mg of 2-nitrobenzil and 331 mg of 2-methylthioethyl 5-carboxythiazole-4-carboxylate, (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -trimethyl There was obtained 220 mg of 2-nitrobenzyl-2- [4- (2-methylthioethoxy) carborylthiazole-5-yl] thio-1-caproluben-2-em-3-carboxylate.

_{NMR (CDC1 3) d: l.ll} (3H 5 d, J = 7.2 Hz), 1.34 (3H, d, J = 6.4Hz), 2.18 (3H, s), 2.86 (2H, t, J = 7.2Hz ), 3.2-3.3 (2H, m), 4.2-4.3 (2H, m), 4.5-4.6 (2H ₅ m), 5.29 (1H, d, J = 13.6 Hz), 5.53 (1H, d, J = 13.6 Hz), 7.66 (2H, d, J = 8.8Hz), 8.24 (2H, d, J = 8.8Hz), 8.84 (1H ₅ s)

MS (FAB); m / z 580 (M ⁺ )

 b) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2- [4- (2-methylthioethoxy) carbonylthiazole-5-yl] thio- 1-potassyl 2-pent-3-carbonate sodium carbonate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((lR)-; l-hydroxyethyl) -methyl-2- [4- (2-methylthioethoxy) carbonyldiazo The title compound (60 mg) was obtained from 220 mg of [l-5-yl] thio-1-potassium 2-pent-3-em-3-carboxylate.

_{NMR (D 2 0) d (} H0D = 4.65 ppm): 0.93 (3H, d, J = 6.8 Hz), 1.11 (3H, d, J = 6 Hz), 2. 02 (3H, s), 2.77 (2H , t, J = 6Hz), 3.1-3.2 (1H, m), 3.3-3.4 (lH, m), 4.0-4.1 (2H, m), 4.42 (2H, t, J = 6Hz), 8.85 (1H , s)

MS (FAB); m / z 467 (M ++ 1) [Example _{81] (1R, 5S 5 6S} ) -2- [4- (4- hydroxy-butane - 1-I le) Okishikarubo two Ruchiazo Ichiru - 5-I le] Chio -6 - ((lR) -l -Hydroxyethyl) -1-methyl-1-carbazine-2-em-3-sodium carboxylate

 a) (1R, 5S, 6S) -2- [4- (4-Hydroxybutane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((lR) -l-hydroxy) Tyl) -1-methyl -1-caproluvene-2-em-3-carboxylic acid 4-nitrobenzil

In the same manner as in Example _{3a), (lR, 3R 3} 5R, 6S) -6 - ((lR) -lt Dorokishechiru) -1-methylation - 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 (1R5S, 6S) -2- [4- (4-hydroxy-4-dihydroxybenzil 536 mg and 5-415-mercaptothiazol-4-carboxylic acid (4-hydroxybutane-1-yl) Butane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-hexyl-bapene-2-em-3- There was obtained 126 mg of 4-ditrobenzyl rubinate.

_{NMR (CDC1 3) d: 1.10} (3H 5 d, J-7.2 Hz), 1.33 (3H, d, J = 6.4 Hz), 1.6-1.7 (2H, m), 1.8-1.9 (2H, m), 3.2 -3.3 (2H, m), 3.69 (2H, t, J = 6.4Hz), 4.2-4.3 (2H, m), 4.4-4.5 (2H, m), 5.29 (1H, d, J = 13.6 Hz), 5.53 (1H ₃ d, J = 13.6 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.23 (2H, d, J = 8.4 Hz), 8.85 (1H, s)

MS (FAB); m / z 578 (M ⁺⁺ 1)

 b) (1R, 5S, 6S) -2- [4- (4-Hydroxybutane-1-yl) oxycarbonylthiazo-l-5-yl] thio-6-((lR) -1-hydroxy) Tyl) -1-methyl -1-caproluban-2-em-3-sodium carboxylate

In the same manner as in Example _{lb), (1R, 5S 3} 6S) -2- [4- (4- hydroxy-butane - 1-I le) O Kishikarubo two Ruchiazoru - 5-I le] Chio - 6 - ((lR ) -l-Hydroxyethyl) -1-methyl-1-force lubapen-2-em-3-carboxylic acid 4- (2-butenyl) benzene 170 mg to obtain 56 mg of the title compound.

NMR (D ₂₀ ) d (H0D = 4.65 ppm): 0.91 (3H ₅ d, J = 7.2 Hz), 1.11 (3H, d, J = 6.4 Hz), 1.5- 1.6 (2H, m), 1.6-1.7 (2H, m), 3.1- 3.2 (1H, m), 3.3-3.4 (lH, m) ₅ 3.49 (2H, t, J = 6.4Hz), 4.0- 4.K2H, m), 4.3-4.4 (2H ₃ m), 8.83 (1H ₅ s)

 MS (FAB); m / z 465M)

[Example _{82] (lR, 5S 5 6S} ) -6 - ((lR) -lt Dorokishechiru) - 2- [4- (3-hydroxy-flop port pan - 1-I le) Okishikarubo two Ruchiazo Ichiru - 5- [Yl] thio-1-methyl-1-carbazine-2-em-3-carboxylate (neopentyloxycarbonyloxy) ethyl (a mixture of diastereomers)

実施例 2と同様にして、 (lR,5S,6S)-6-((lR)-l-t:ドロキシェチル） - 2-[4- (3-ヒ ドロキシプロパン- 1-ィル）ォキシカルボ二ルチアゾール -5-ィル]チォ -1-メチル- 1-力ルバペン- 2-ェム- 3-カルボン酸ナトリウム 79mgおよび卜（ネオペンチルォキ シカルボニルォキシ）ェチルョ一ダイ ド 229mgより、 表題の化合物 39mgを得た。

In the same manner as in Example 2, (lR, 5S, 6S) -6-((lR) -lt: droxityl)-2- [4- (3-hydroxypropane-1-yl) oxycarbonyldithiazole- 39 mg of the title compound was obtained from 79 mg of sodium 5-yl] thio-1-methyl-1-methyllvapen-2-em-3-carboxylate and 229 mg of tri (neopentyloxycarbonyloxy) ethyl chloride. .

_{NMR (CDC1 3) d: 0.94} 3 0.96 (total 9H, 2s), 1.09, 1.09 (total 3H, 2d, J = 7.3 Hz), 1.30, 1.32 (total 3H, 2d, J = 6.3 Hz), 1.62, 1.65 (total 3H, 2d, J = 5.4 Hz), 1.97-2.05 (2H ₅ m), 3.20-3.28 (2H, m), 3.75-3.80 (2H, m), 3.83-3.91 (2H, m), 4.20- 4.26 (2H, m), 4.46-4.62 (2H, m), 6.92 (1H, q, J = 5.3 Hz), 8.84, 8.85 (total 1H, 2s)

[Example 83] (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-methoxypropane-1-yl) oxycarbonyldithiazole-5- Yl] thio-1-methyl-1-carpapen-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- (3-methoxypropane-1-yl) oxycarbonylthiazol-5-y Le] thio-trimethyl-1-ketorubapene-2-em-3-carboxylic acid 4-nitrobenzil

In the same manner as in Example 3a), (lR ₃ 3R, 5R, 6S) -6-((lR) -lhdroxityl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid 4 From 727 mg of 2-nitrobenzil and 468 mg of 5-mercaptothiazol-4-carboxylic acid (3-methoxypropane-1-yl), (1R 5S, 6S) -6-((1R) -1-hydroxy 2-Ethyl) -2- [4- (3-methoxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-1-methyl-1-butyrolpine-2-2-em-3-cal 339 mg of 4-nitrobenzyl borate was obtained.

_{NMR (CDC1 3) d: 1.10} (3H, d, J = 7.2 Hz), 1.33 (3H, d, J = 6.4 Hz), 2.0-2.1 (2H, m), 3.2-3.3 (2H, m), 3.33 (3H, s), 3.51 ( 2H, t, J = 6.4Hz), 4.2-4.3 (2H, m), 4.4-4.5 (2H, m), 5.29 (1H 5 d, J = 13.6 Hz), 5.53 ( 1H, d, J = 13.6 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.23 (2H, d, J = 8.4 Hz), 8.84 (1H, s)

 MS (FAB); m / z 578 (M)

_{b) (1R 5 5S 5 6S} ) - 6- ((1R) -1- hydroxy E Chill) - 2- [4- (3-main Tokishipuropan - 1 - I le) Okishikarubo two Ruchiazoru 5-I le] Thio-1-methyl-1-butyric acid 2-sodium-3-carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-methoxypropane-1-yl) oxycarbonyl 135 mg of the title compound was obtained from 33 g of luthiazole-5-yl] thio-1-methyl-1-force lubapen-2-em-3-carboxylic acid 4-nitrobenzil.

_{NMR (D 2 0) d (} H0D = 4.80 ppm): 1.08 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.4 Hz), 2.0-2.1 (2H, m), 3.2- 3.3 (1H, m), 3.37 (3H, s), 3.4-3.5 (lH, m), 3.6-3.7 (2H, m), 4.2-4.3 (2H, m), 4.4-4.5 (2H, m), 9.01 (1H, s)

MS (FAB); m / z 465M ⁺ +1) Example 84 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazole-5 -Yl] thio-1-methyl-1-carbazine-2-em-3-carboxylic acid 1- (2-cyclohexylethoxycarbonyloxy) ethyl (a mixture of diastereomers)

In the same manner as in Example _{2, (lR 5 5S, 6S} ) -6 - ((lR) -lh Dorokishechiru) - 2- [4- (3-arsenide Dorokishipuroban - 1-I le) Okishikarubo two Ruchiazoru -5- I [Ru] thio-1-methyl-1-methyllvapen-2-em-3-carboxylate sodium (154 mg) and (2-cyclohexylethoxycarbonyloxy) ethyl ester (360 m) gave 94 mg of the title compound. .

 NMR (CDCL) d: 0.8-2.3 (24H, m), 3.2-3.3 (2H, m), 3.7-3.8 (2H, m), 4.1-4.3 (4H, m), 4.5-4.7 (2H, m ), 6.90 (1H, q, J = 5.1 Hz), 8.84, 8.85 (total 1H, 2s)

[Example 85] (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazol -5-yl] thio-1-methyl-1-carbazine-2-em-3-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)

In the same manner as in Example _{2, (lR, 5S 3 6S} ) -6 - ((lR) -lh Dorokishechiru) - 2- [4- (3 - hydroxycarboxylic propane - 1-I le) Okishikarubo two Ruchiazo Ichiru -5-yl] thio-1-methyl-toluene-lvapen-2-em-3-carboxylate (67 mg) and tri (cyclohexyloxycarbonyloxy) ethyl ester (290 mg) gave 44 mg of the title compound. Obtained. _{NR (CDC1 3) d: 1.09} (3H, d, J = 7.5 Hz), 1.2-2.2 (18H, m), 3.2-3.3 (2H, m), 3. 7- 3.8 (2H, m), 4.2- 4.3 (2H, m), 4.5-4.7 (3H 3 m), 6.91 (1H, q, J = 5.1 Hz), 8.8 3, 8.84 (total 1H, 2s)

 Example 86 (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- (5-hydroxypenten-1-yl) oxycarbonylthiazole-5 -Yl] thio-1-methyl-1-potassium pen-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- (4- (5-hydroxypentane-1-yl) oxycarbonylthiazoyl-5-yl ] Thio-1-methyl-1-caproluben-2-em-3-carboxylic acid 4-benzyl

In the same manner as in Example _{3a), (lE 3 3R 3} 5R 5 6S) -6 - ((lR) -lh Dorokishechiru) -1-methylation - 2 Okiso-carba Bae Nam - 3-carboxylic acid 4 From 1.09 g of 2-nitrobenzil and 742 mg of 5-mercaptothiazol-4-carboxylic acid (5-hydroxypentanol-; I-yl), (1R, 5S, 6S) -6-((lR) -l-Hydroxyethyl) -2- [4- (5-hydroxypentan-1-yl) oxycarbonylthiazol-1-5-yl] thio-1-methyl-1-methyll-bapen-2-em There was obtained 361 m of 4-nitrocarbenyl 3-carboxylate.

_{NMR (CDC1 3) d: 1.10} (3H 5 d, J = 7.6 Hz), 1.33 (3H, d, J = 6 Hz), 1.51- 1.54 (2H, m), 1.58- 1.61 (2H, m), 1.79 -1.83 (2H, m), 3.21-3.29 (2H, m), 4.26-4.29 (2H ₃ m) ₃ 4.36-4.51 (2H ₅ m), 5.29 (1H, d, J = U Hz), 5.53 (1H , D, J = 14 Hz), 7.66 (2H, d, J = 8 Hz), 8.23 (2H ₅ d, J = 8 Hz), 8.85 (1H, s)

MS (FAB); m / z 592 (M ⁺⁺ 1)

 b) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- 2- [4- (5-hydroxypentane-1-yl) oxycarbonylthiazole-5-yl] thio -1-Methyl-1-caprolubene-2-Em-3-Sodium carboxylate

In the same manner as in Example _{lb), (1R 5 5S,} 6S) -6 - ((lR) - 1- hydroxy E Chill) - 2- [4- (5-hydroxy-pentane - 1-I le) Okishikarubo two Ruchiazoru -5-yl] cho -1-me 135 mg of the title compound was obtained from 360 mg of tyl-1-carbyl-2-em-3-carboxylic acid 4-nitrobenzil.

NMR (D ₂ 0) δ (H0D = 4.80ppm): 1.08 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.4 Hz), 1.48-1.50 (2H, m), 1.57-1.63 (2H, m), 1.78-1.81 (2H, m), 3.19-3.24 (1H, m), 3.47-3.49 (1H, m), 3.60-3.63 (2H, m), 4.23-4.27 (2H, m) , 4.38-4.44 (2H, m), 9.01 (1H, s)

MS (FAB); m / z 479 (M ⁺⁺ 1)

 [Example 87] (1R, 5S, 6S) -6-((lR) -trihydroxyethyl) -2- [4- (isopropyloxy) carbonylthiazol-5-yl] thio-1- Sodium methyl-1-carbyl-2-em-3-carboxylate

 a) (1R, 5S, 6S) -6-((lR)-: l-hydroxyethyl) -2- [4- (isopropyloxy) carbonyl-2-thiazol-5-yl] thio-1- Methyl 1-l-r-bapene-2-em-3-carboxylate 4-nitrobenzyl

In the same manner as in Example _{3a), (lR, 3R 5} 5R, 6S) -6 - ((lR) -lt Dorokishechiru) - methyltransferase 2 Okiso-carba Bae Nam - 3- carboxylic acid 4 two From 482 mg of trobenzil and 350 mg of isopropyl 5-mercaptothiazol-4-carboxylate, (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- (isopropyl 397 mg of carboxylic acid carbonyltriazoyl-5-yl] thio-trimethyl-1-forcelvapen-2-em-3-carboxylate 4-dioctylbenzene.

R (CDC1 ₃ ) 5: 1.10 (3H, d, J = 7.6 Hz), 1.33 (3H ₃ d, J = 6 Hz), 1 ・ 38 (6Η, d, J = 6 Hz), 3.23-3.3K2H, m ), 4.26-4.29 (2H ₅ m), 5.28- 5.32 (2H, m), 5.53 (1H ₃ d, J2 13.6 Hz), 7.66 (2H, d, J = 8.8 Hz), 8.Z3 (2H, d, J = 8.8 Hz), 8.85 (1H, s) MS (FAB); m / z 548 (M ⁺⁺ 1)

b) (1R ₃ 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (isopropyloxy) carbonylthiazol-5-yl] thio-1-methyl -1-Capacyl-2-ene-3-carvone Sodium acid

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (isopropyloxy) carbonylthiazol-5 115 mg of the title compound were obtained from 397 mg of 4- [2-yl] thiomethyl-1-forcelvapen-2-em-3-carboxylic acid 4-nitrobenzil.

NMR (D ₂ 0) δ (H0D = 4.80 ppm): 1.08 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.4 Hz), 1.38 (6H, t, J = 5.ZHz) , 3.16- 3.20 (1H, m), 3.7-3.49 (1H, m), 4.23-4.27 (2H, m), 5.25-5.29 (lH, m), 9.01 (1H, s)

MS (FAB); m / z 435 (M ⁺⁺ 1)

 [Example 88] (1R, 5S, 6S) -2- [4- [2- (2-hydroxyethoxy) ethoxy] carbonylthiazol-5-yl] thio-6-((lR) -l-hydroxy Ethyl) -1-methyl -1-caprolene pen-2-em-3-carboxylate sodium

 a) (1R, 5S, 6S) -2- [4- [2- (2-Hydroxyethoxy) ethoxy] carbonylthiazol-5-yl] thio-6-((lR) -l-hydroxy Ethyl) -1-methyl -1-caproluvene-2-em-3-carboxylic acid

In the same manner as in Example 3a), (lR, 3R, 5R 3 6S) -6 - ((lR) -ll: Dorokishechiru) -1-methylation - 2 Okiso - Bok carba Bae Nam - 3-carboxylic acid 4 837m-Ditrobenzil and 748mg of 2- (2-hydroxyethoxy) ethyl 5-mercaptothiazole-4-carboxylate give (1R, 5S, 6S) -2- [4- [2- (2-hydroxy Ethoxy) ethoxy] carbonylthiazol-5-yl] thio-6-((1R) -1-hid mouth kisshethyl) -1-methyl-1-butyl-2-ene-3-carboxylic acid 4 -257 mg of nitrobenzil were obtained.

NMR (CDCl ₃ ) d: 1.10 (3H, d, J = 7.6 Hz), 1.33 (3H, d, J = 6 Hz), 3.21- 3.29 (2H, m), 3.62-3.64 (2H, m), 3.72 -3.74 (2H ₃ m), 3.79-3.85 (2H, m), 4.25-4.32 (2H ₃ m), 4.52-4.56 (2H ₅ m) ₅ 5.29 (1H, d, J = 14 Hz), 5.53 (1H , d, J = 14 Hz), 7.66 (2H, d, J = 8.8 Hz), 8.23 (2H, d, J = 8.8 Hz), 8.85 (1H, s) MS (FAB); m / z 594 (M)

 b) (1R, 5S, 6S)-2- [4- [2- (2-Hydroxyethoxy) ethoxy] carbonylthiazol-5-yl] thio-6-((1R) -1-hydroxy Ethyl) -1-methyl -1-caproluvene-2-em-3-sodium carboxylate

 In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- [2- (2-hydroxyethoxy) ethoxy] carbonyldithiazol-5-yl] thio-6- ( 69 mg of the title compound was obtained from 254 mg of (1R) -1-hydroxyethyl) -1-methyl-1-methyllvapen-2-em-3-carboxylate 4-nitropentyl.

_{NMR (D 2 0) d (} HOD = 4.80ppi): 1.08 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.4 Hz), 3.26-3.30 (1H, m), 3.50-3.52 (1H, m), 3.70-3.73 (4H, m), 3.90-3.92 (2H, m), 4.24-4.30 (2H, m), 4.54-4.57 (2H, m), 9.00 (1H, s)

MS (FAB); m / z 481 (M ⁺ +1)

[Example _{89] (lR 3 5S, 6S} ) -6 - ((lR) -lh Dorokishechiru) -2- [4- (3-hydroxy-flop port pan -; I- I le) Okishikarubo two Ruchiazo Ichiru - 5 -Yl] thio-1-methyl-1-carbazine-2-em-3-acetoxymethyl-3-carboxylate

In the same manner as in Example _{2, (lR 5 5S 5 6S} ) -6 - ((lR) -l-ti Dorokishechiru) -2- [4- (3-hydroxycarboxylic propane - 1-I le) Okishikarubo two Ruchiazoru 92 mg of the title compound were obtained from 200 mg of sodium-5-yl] thio-1-methyl-toluene-lubapen-2-em-3-carboxylate and 203 mg of bromomethyl acetate.

 NMR (CDCL) d: 1.09 (3 H, d, J = 7.3 Hz), 1.32 (3 H, d, J = 6.3 Hz), 2.04 (2 H, m), 2.14 (3 H, s), 3.21-3.27 (2 H, m), 3.79-3.80 (2 H, m), 4.24 -4.27 (2 H, m), 4.50-4.61 (2 H, m), 5.88 (1 H, d, J = 5.9 Hz), 5.96 (1 H, d, J = 5.6 Hz), 8.84 (1 H, s)

MS (FAB +); m / z 501 (M ^ l) [Example _{90] (lR 3 5S 5 6S} ) -6 - ((lR) -lh Dorokishechiru) -2- [4- (3-hydroxy-flop port pan - 1-I le) Okishikarubo two Ruchiazoru 5- I le ] Thio-1-methyl-1-carban-2-em-3-carboxylic acid 1-[(hexane-1-yl) oxyl-ponyloxy] ethyl (mixture of diastereomers)

In the same manner as in Example _{2, (lR, 5S 5 6S} ) -6 - ((lR) -lt Dorokishechiru) -2- [4- (3-hydroxycarboxylic propane - 1-I le) Okishikarubo two Ruchiazo Ichiru -5-yl] thio-1-methyl-toluene-lubapen-2-em-3-carboxylate 150 mg and 1-[(hexan-1-yl) oxycarbonyloxy] ethylyl ide 225 mg As a result, 49 mg of the title compound was obtained.

_{NMR (CDC1 3) d: 0.88} (3 H, m), 1.08-1.10 (3 H, m), 1.24-1.33 (6 H, m), 1. 54-1.76 (8 H, m), 1.99-2.04 (2 H, m), 3.21-3.27 (ZH, m), 3.78 (2 H, m), 4.15-4.25 (4 H, m), 4.48-4.61 (2 H, m), 6.90 (1 H, q , J = 5.4 Hz), 8.83, 8.84 (total 1H, 2 s)

 MS (FAB +); m / z 601 (M ^ l)

 [Example 91] (lR, 5S, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazole-5 -Yl] thio-1-methyl-1-carbazine-2-em-3-carboxylate (isopropyloxycarbonyloxy) ethyl (diastereomeric mixture)

In the same manner as in Example _{2, (lR 5 5S 3 6S} ) -6 - ((lR) -lb Dorokishechiru) -2- [4- (3 - arsenate Droxypropane-1-yl) oxycarbonylthiazole-5-yl] thio-1-methyll-lubapen-2-em-3-sodium carboxylate 139mg and 1- (isopropyloxycarbonyloxy) ethylol 79.9 mg of the title compound was obtained from 396 mg of one dyde.

NMR (CDCl ₃ ) d: 1.09 (3H ₃ d, J = 7.2 Hz), 1.2-1.4 (9H, m), 1.6-1.7 (3H, m), 1.9-2.K2H, m), 3.2- 3.3 (2H, m), 3.7-3.8 (2H, m), 4.2-4.3 (2H, m), 4.4-4.6 (2H, m), 4.8-5.0 (lH, m), 6.9-7.0 (1H, m ), 8.84, 8.85 (total 1H, 2s)

Example 92 (lR ₃ 5S, 6S) -6-((lR) -l-tidroxityl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazol- 5-yl] thio-1-methyl-1-carbazine-2-em-3-carboxylate isopropyloxycarbonyloxymethyl

 In the same manner as in Example 2, (lR, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonyl The title compound 90m was obtained from 150 mg of sodium ruthiazol-5-yl] thio-1-methyl-toluene-lubapen-2-em-3-carboxylate and 121 mg of isopropyloxycarbonyloxymethyl chloride. Was.

Thigh (CDCl ₃ ) d: 1.09 (3 H, d, J = 7.3 Hz), 1.30-1.33 (9 H, m), 2.02 (2 H, m), 3.20-3.28 (2 H, m) ₅ 3.78 ( 2 H, m), 4.24-4.27 (2 H, m), 4.48-4.61 (2 H, m), 4.93 (1 H, m), 5.89 (1 H, d, J = 5.8 Hz), 5.96 (1 H, d, J = 5.6 Hz), 8.86 (1 H, s)

 MS (FAB +); m / z 545 (M ^ l)

[Example _{93] (lR 5 5S, 6S} ) -6 - ((lR) -lh Dorokishechiru) -2- [4- (3-hydroxy-flop port pan - 1-I le) Okishikarubo two Ruchiazo Ichiru 5- Yl] thio-1-methyl-1-carbazine-2-em-3-carboxylate cyclohexyloxycarbonyloxymethyl

 In the same manner as in Example 2, (lR, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonyl From luthiazole-5-yl] thio-1-methyl-toluene-lvapen-2-em-3-carboxylate sodium salt 150mg and cyclohexyloxycarbonyloxymethyl oxide 122m, 104mg of the title compound was obtained. .

_{NMR (CDC1 3) d: 1.09} (3 H, d, J = 7.3 Hz), 1.31 (3 H, d, J = 6.4 Hz), 1. 24-1.96 (10 H, m), 2.02 (2 H, m), 2.1-2.2 (1 H, m), 2.2-2.3 (1 H, m), 3.20-3.28 (2 H, m), 3.78 (2 H, m), 4.24-4.27 (2 H, m), 4.48-4.61 (2 H, m), 4.67 (1 H, m), 5.89 (1 H, d, J = 5.6 Hz), 5.96 (1 H, d, J = 5.9 Hz), 8, 85 (1 H, s)

 MS (FAB +); m / z 585 (M41)

 Example 94 (lR, 5S, 6S) -6-((lR) -ltdroxitytyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazole-5-yl ] Thio-1-methyl-1-carbazine-2-em-3-carboxylate 1- (isobutyloxycarbonyloxy) ethyl (a mixture of diastereomers)

実施例 2と同様にして、 (lR₃5S,6S)-6-((lR)-l-hドロキシェチル） - 2-[4-(3 -ヒ ドロキシプロパン- 1 -ィル）ォキシカルボ二ルチアゾ一ル- 5-ィル]チォ- 1 -メチル- 卜力ルバペン- 2-ェム- 3-カルボン酸ナトリゥム 169mgおよび卜（イソプチルォキシ カルボニルォキシ）ェチルョーダイ ド 330mgより、 表題の化合物 lllmgを得た。 NMR(CDC1₃) d :0.9-1.0(6H, )₅ 1.09(3H, d, J=7.2 Hz), 1.2-1.4(3H₅ m), 1. 6 - 1.8(3H， m), 1.9-2.1(3H， m), 3.2-3.3(2H， m)， 3.7-3.8(2H, m)， 3.95(2H, d， J=6.6Hz)₅ 4.2-4.3(2H, m)， 4.4- 4.6(2H, m)， 6.9-7.0(lH₃ m), 8.84， 8.85(to tal 1H， 2s)

In the same manner as in Example _{2, (lR 3 5S, 6S} ) -6 - ((lR) -lh Dorokishechiru) - 2- [4- (3 - hydroxycarboxylic propane - 1 - I le) Okishikarubo two Ruchiazo Ichiru The title compound, lllmg, was obtained from 169 mg of sodium 5-isobutyl-3-carboxylate and 330 mg of tri (isobutyloxycarbonyloxy) ethyl iodide. _{NMR (CDC1 3) d: 0.9-1.0} (6H,) 5 1.09 (3H, d, J = 7.2 Hz), 1.2-1.4 (3H 5 m), 1. 6 - 1.8 (3H, m), 1.9-2.1 (3H, m), 3.2-3.3 (2H, m), 3.7-3.8 (2H, m), 3.95 (2H, d, J = 6.6Hz) ₅ 4.2-4.3 (2H, m), 4.4- 4.6 (2H , m), 6.9-7.0 (lH ₃ m), 8.84, 8.85 (total 1H, 2s)

 [Example 95] (1R, 5S, 6S) -2- [4- (2,2-dimethyl-3-hydroxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-6- ((1R) -1-Hydroxyethyl) -sodium 1-methyl-1-carba-2-em-3-carboxylate

 a) (1R, 5S, 6S) -2- [4- (2,2-dimethyl-3-hydroxypropane-1-yl) oxycarbonylthiazole-5-yl] thio-6-((lR) -l-Hydroxyethyl) -1-methyl-1 -l-ravenpene-2-em-3-carboxylate 4-nitrobenzil

 In the same manner as in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -lhdroxityl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid 4 -(2R, 5S, 6S) -2-[(2R, 5S, 6S) -2-[]-[2-methylbenzyl] and 323m of 5-mercaptothiazol-4-carboxylic acid (2,2-dimethyl-3-hydroxypropane-1-yl) 4- (2,2-dimethyl-3-hydroxypropane-: I-yl) oxycarbonylthiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl 248 mg of 1-force lubapen-2-em-3-carboxylic acid 4-nitrobenzil were obtained.

 NR (CDCL) d: 1.00 (6H, s), 1.10 (3H, d, J = 7.6 Hz), 1.33 (3H, d, J = 6.4 Hz), 3.21-3.29 (2H, m), 3.42 (2H, s), 4.18-4.31 (4H, m), 5.29 (1H, d, J = 14 Hz), 5.53 (1H, d, J = 14 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.23 ( 2H, d, J-8.4 Hz), 8.84 (1H, s)

MS (FAB); m / z 592 (M ⁺⁺ 1)

 b) (1R, 5S, 63> -2- [4- (2,2-dimethyl-3-hydroxypropan-1-yl) oxycarbonylthiazol-5-yl] thio-6-(( 1R) -1-Hydroxyethyl)-; [-methyl-1-sodium lubapen-2-em-3-carboxylate

(1R, 5S, 63) -2- [4- (2,2-dimethyl-3-hydroxypropyl) Mouth-pan-1-yl) oxycarbonylthiazol-5-yl] thio-6-((1R) -1-hydroxystyl) -trimethyl-1-butyl-2-ene-3-carvone The title compound (102 mg) was obtained from 248 mg of the acid 4-butene benzyl.

NMR (D ₂ 0) δ (H0D = 4.80 ppm): 1.01 (6H, s), 1.08 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.4 Hz), 3.28-3.32 (1H , M), 3.50-3.53 (3H, m), 4.17-4.19 (1H, m), 4.25-4.30 (3H, m), 9.00 (1H, s)

MS (FAB); m / z 479 (M ⁺⁺ 1)

 [Example 96] (lR, 5S, 6S) -2- [4- (2,3-dihydroxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((lR)- l-Hydroxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate sodium (a mixture of diastereomers)

 a) (1R, 5S, 6S) -2- [4- (2,3-dihydroxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((lR) -l-Hydroxyethyl) -1-methyl-1-potassium 2-carbene-3-carboxylate 4-dibenzobenzene (a mixture of diastereomers)

In the same manner as in Example _{3a), (1R, 3R 5} 5R 5 6S) -6- ((1R) -1- hydroxy E Chill) - 1-methyl-2-Okiso-carba Bae Nam - 3- carboxylic From 156 mg of 4-dibenzoic acid benzyl and 174 mg of 5-mercaptothiazol-4-carboxylic acid (2,3-dihydroxypropane-yl), (1R, 5S, 6S) -2- [4- ( 2,3-dihydroxypropane-1-yl) oxycarbonyl thiazolyl-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-butyrupene-2 There was obtained 154 mg of 4-nitrobenzyl (a diastereomer mixture).

_{NMR (CDC1 3) d: 1.1-1.2} (3H, m), 1.3-1.4 (3H, m), 3.2-3.4 (2H, m), 3.3-4.6 (7 H, m), 5.29 (1H, d, J = 13.8 Hz), 5.53 (1H, d, J = 13.8 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.22 (ZH, d, J = 8.4 Hz), 8.86, 8.89 (total 1H, 2s )

b) (1R, 5S, 6S) -2- [4- (2,3-dihydroxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((lR) -1- (Hydroxyethyl) -trimethyl-1-potassyl-2-ene-3-carboxylate sodium (a mixture of diastereomers) In the same manner as in Example lb), (1R, 5S, 6S) -2- [4- (2,3-dihydroxypropane-1-yl) oxycarbonylthiazolyl-5-yl] thio-6- 53 mg of the title compound were obtained from 154 mg of ((110-1-hydroxyethyl) -1-methyl-1-butyl-l-pent-2-em-3-carboxylate 4-dipentenyl (diastereomeric mixture). .

NMR (D ₂₀ ) δ (HOD = 4.80 ppm): 1.10 (3H, d, J = 7.5 Hz), 1.28 (3H, d J = 3.6 Hz), 3.Z-3.4 (1H, m), 3.5- 3.6 (1H, m), 3.6-3.9 (2H, m), 4.1-4.6 (5H ₅ m), 8.99, 9.00 (total 1H, 2s)

 [Example 97] (lR, 5S, 6S) -6-((lR) -lhdroxityl) -2- 2- [4- (3-Hydroxypropane-1-yl) oxycarbonylthiazole-5-yl ] Thio-1-methyl-1-carban-2-em-3-carboxylate isopentyloxycarbonyloxymethyl

 In the same manner as in Example 2, (lR, 5S, 6S) -6-((lR) -lhdroxityl) -2- 2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazol 109 mg of the title compound was obtained from 165 mg of sodium 5- (yl) thio-1-methyl-toluene-lubapen-2-em-3-carboxylate and 150 m of isopentyloxycarbonyloxymethyl chloride. .

NMR (CDCL) d: 0.92 (6H, d, J = 6.6 Hz), 1.09 (3H, d, J = 6.9 Hz), 1.31 (3H, d, J = 6.3 Hz), 1.5-1.8 (3Η, m), 1.9- 2.1 (2H, m), 3.2-3.3 (2H, m), 3.7-3.9 (2H, m), 4.2-4.3 (6H, m), 4.4-4.6 (2H, m), 5.90 ( 1H, d, J = 6.0 Hz), 5.96 (1H ₅ d, J = 6.0 Hz), 8.85 (1H, s)

[Example 98] (lR, 5S, 6S) -6-((lR) -lhdroxityl) -2- [4- (3-hydroxypropane-; I-yl) oxycarbonyldithiazole-5-i L] thio-1-methyl-1-carbazine-2-em-3-carboxylate (1-ethylpropane-1-yl) carbonyloxymethyl

 In the same manner as in Example 2, (lR, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonyl [Ruthiazol-5-yl] thio-1-methyl-1-l-lubapen-2-em-3-carboxylate sodium 150m and (1-ethylpropane-1-yl) carboxyloxymethyl chloride from 128mg, 12 g of the title compound were obtained.

NMR (CDC1 ₃ ) 5: 0.89 (6 H, t, J = 7.3 Hz), 1.09 (3 H, d, J = 7.3 Hz), 1.-32 (3 H, d, J = 6.3 Hz), 1.51 -1.70 (4 H, m), 2.03 (2 H, m), 2.25-2.31 (1 H, m), 3.22-3.26 (2 H, m), 3.79 (2 H, m), 4.23-4.25 (2 H, m), 4.50-4.59 (2 H, m), 5.93 (1 H, d, J = 5.6 Hz), 5.97 (1 H, d, J = 5.6 Hz), 8.84 (1 H, s)

 MS (difficult); m / z 557 (M ^ l)

 Example 99 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazol [5-yl] thio-1-methyl-1-carbazine-2-em-3-carboxylate isobutylcarbonyloxymethyl

 In the same manner as in Example 2, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonyl 142 mg of the title compound was obtained from 200 mg of sodium ruthiazol-5-yl] thio-1-methyl-! 1-forcervapen-2-em-3-carboxylate and 160 mg of isobutylcarboxy-l-methoxymethylazide.

_{NMR (CDC1 3) 0.92 (6} H, d, J = 6.6 Hz), 1.09 (3 H, d, J = 7.3 Hz), 1. 29 (3 H, d, J = 6.3 Hz), 2.02 (2 H, m), 2.12 (1 H, m), 2.27 (2 H, d, J = 7.0 Hz), 2.62 (1 H, br s) , 2.75 (1 H, br s), 3.20-3.27 (2 H, m), 3.76-3.79 (2 H, m), 4.22-4.28 (2 H, m), 4.47-4.59 (2 H, m ), 5.89 (1 H, d, J = 5.8 Hz), 5.96 (1 H, d, J = 5.6 Hz), 8.87 (1 H, s)

 MS (FAB +); m / z 543 (M ^ l)

[Example _{100] (1R 3 5S, 6S} ) - 2- [4- (3- hydroxybutanoic - 1-I le) Okishikarubo two Ruchiazoru 5-I le] Chio -6 - ((lR) - 1-hydroxy Ethyl) -1-methyl -1-potene pen-2-em-3-carboxylate sodium (a mixture of diastereomers)

 a) (1R, 5S, 6S) -2- [4- (3-Hydroxybutane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((lR) -1-hide mouth Quichetyl) -1-methyl-1-l-caphyl-2-em-3-carboxylate 4-nitrobenzyl (diastereomeric mixture)

 In the same manner as in Example 3a), (lR, 3R, 5R, 6S) -6-((lR) -ltdroxityl) -1-methyl-2-oxo-tricarbazin-3-carboxylic acid 4- From 219 mg of ditrobenzil and 169 mg of 5-mercaptothiazole-4-carboxylic acid (3-hydroxybutane-1-yl), (1R 5S, 6S) -2- [4- (3-hydroxybutane-1 -Yl) oxycarbonylthiazolyl-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl-1-hexylcarbene-2-em-3-carbonic acid 183 mg of 4-nitrobenzyl (a mixture of diastereomers) were obtained.

_{NMR (CDC1 3) d: 1.09-1.12} (3H, in), 1.25 (3H, d, J = 6.4 Hz), 1.33 (. 3H, d, J = 6 4 Hz), 1.85-1.90 (1H 3 m) , 1.93-1.95 (1H ₃ m), 3.25-3.31 (2H ₃ m), 3.96-4.01 (1 H, m), 4.27-4.30 (2H, m), 4.40-4.50 (1H, m), 4.57-4.66 (1H, m), 5.29 (1H, d, J = 14 Hz), 5.53 (1H, d, J = 14 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.23 (2H, d, J = 8.4 Hz), 8.84 (1H, s)

MS (FAB); m / z 578 ( ⁺ +1)

b) (1R, 5S, 6S) -2- 2- [4- (3-Hydroxybutane-1-yl) oxycarbonylthiazol-5-yl] thio-6-((111) -1-hydroxy) Chill) -trimethyl-1-kerubapen-2-e Sodium-3-carboxylate (a mixture of diastereomers)

In the same manner as in Example _{lb), (1R, 5S 5} 6S) -2- [4- (3- hydroxybutanoic - 1-I le) O Kishikarubo two Ruchiazo Ichiru 5-I le] Chio 6- ( (lR) -l-Hydroxyethyl) -1-methyl-1-butyric lappen-2-em-3-carboxylic acid 4-dibenzobenzene (mixture of diastereomers) From 200 mg to 78 mg of the title compound Got.

_{NMR (D 2 0) d (} H0D = 4.80ppm): 1.06 - 1.10 (3H, m), 1.24-1.28 (6H, m), 1.89-1.97 (2H, m), 3.21-3.27 (1H, m), 3.47-3.51 (1H, m), 4.04- 4.08 (1H, m), 4.24-4.27 (2H, m), 4.44-4.53 (2H, m), 9.00-9.02 (lH, m)

MS (FAB); m / z 465 (M ⁺⁺ 1)

 Example 101 (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxy-3-methylbutane-1-yl) oxycarbo N-Lthiazolyl-5-yl] thio-1-methyl-1-methyll-bapene-2-em-3-carboxylate sodium

a ~ S COO (CH2) ₂ C (CH ₃ ) ₂ OH

 . I

 COONa

 a) (1R, 5S, 6S) -6- ((11-Trihydroxyethyl) -2- [4- (3-hydroxy-3-methylbutane-1-yl) oxycarbonylthiazole-5- Yl] thio-1-methyl-1-methyll-pentene-2-em-3-carboxylic acid 4-nitrobenzene

 (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-carbazin-3-carboxylic acid in the same manner as in Example 3a) From 536 mg of 4-nitrobenzene and 366 mg of 5-mercaptothiazol-4-carboxylic acid (3-hydroxy-3-methylbutane-1-yl), (1R, 5S, 6S) -6-((lR )-1-'Hydroxyethyl)-2- [4- (3-hydroxy-3-methyl-1-enyl) oxycarbonylthiazol-5-yl] thio-1-methyl-1 518 mg of 4-l-pent-3-enyl carboxylic acid 4-diene benzyl were obtained.

NMR (CDCl ₃ ) d: 1.10 (3H ₅ d, J = 7.6 Hz), 1.30 (6H, s), 1.33 (3H, d, J = 6.4 Hz), 1.99 (2H, t, J = 6.8 Hz), 3.23-3.32 (2H, m), 4.28-4.30 (2H, m), 4.51-4.62 (2H, m), 5.29 (1H, d, J = 14 Hz), 5.53 (1H ₅ d, J = 14 Hz) , 7.66 (2H, d, J = 8.4 Hz), 8.23 (2H, d, J = 8.4 Hz), 8.82 (1H, s) MS (FAB) m / z 592 (M ⁺⁺ 1)

 b) (1R, 5S, 6S) -6-((lR) -1-hydroxyethyl) -2- [4- (3-hydroxy-3-methylbutane-1-yl) oxycarbonylthiazo Ru-5-yl] thio-trimethyl-1-potassium pen-2-em-3-carboxylate sodium

 In the same manner as in Example lb), (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-.hydroxy-3-methylbutane-1-yl) ) Oxycarbonylthiazol-5-yl] thio-l-methyl-l-caphyl-2-en-3-em-3-carboxylic acid From 518 mg of 4-nitrobenzil, 279 mg of the title compound were obtained.

_{NMR (D 2 0) d (} H0D = 4.80ppm): 1.08 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.8 Hz),

1.29 (6H, s), 2.02 (2H, t, J = 7.6 Hz), 3.21- 3.25 (1H, m), 3.48-3.50 (1H, m), 4.25-4.27 (2H, m), 4.49-4.54 ( 2H, m), 9.00 (1H, s)

MS (FAB); m / z 479 (M ⁺⁺ 1)

 [Example 102] (5R, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazol-5 -Yl] thio-1-potassium 2-baem-3 -potassium sodium rubonate

ドロキシプロパン- 1- ィル）ォキシカルボ二ルチアゾ一ル -5-ィル]チォ- 1-力ルバペン- 2-ェム- 3-カルボ ン酸 4-二ト口べンジル a) (5R, 6S)-6- ((

Droxypropane-1-yl) oxycarbonylthiazol-5-yl] thio-1-carbyl-2-em-3-carbonic acid 4-benzyl-2-benzyl

 In the same manner as in Example 3a), (3R, 5R, 6S) -6-((1R)-: 1-hydroxyethyl) -2-oxo-carbazin-3-carboxylic acid From 559 mg of oral benzyl and 352 mg of 5-mercaptothiazol-4-carboxylic acid (3-hydroxypropane-: I-yl), (5R, 6S) -6-((1R) -1-hydroxyethyl ) -2- [4- (3-Hydroxypropane-1-yl) oxycarboxylthiazolyl-5-yl] thio-1-caphylbapene-2-em-3-carboxylate 4-nitrobenzoyl 527 mg were obtained.

_{NMR (CDC1 3) d: 1.31} (3H 3 d, J = 6.4 Hz), 2.00 (2H, t, J = 6 Hz), 2.87-2.90 (2H 5 m), 3-19-3321 (1Η, m), 3.74-3.78 (2H,, m), 4.20-4.24 (2H ₅ m), 4.54 (2H, t: J = 6 Hz), 5.29 (1H , d, J = 14 Hz), 5.53 (1H, d, J = 14 Hz), 7.66 (2H, d, J = 8.8 Hz), 8.23 (2H, d, J = 8.8 Hz), 8.91 (1H, s )

MS (FAB); m / z 550 (M ⁺⁺ 1)

 b) (5R, 6S) -6-((lR) -l-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonylthiazolyl-5-yl] thio -1-potassium lvapen-2-em-3-carbonate sodium

 In the same manner as in Example lb), (5R, 6S) -6-((1R) -1-hydroxyethyl) -2- [4- (3-hydroxypropane-1-yl) oxycarbonyldithiazole 243 mg of the title compound was obtained from 520 mg of 4-nitrobenzyl-2-thio] thiol-l-pent-2-em-3-carboxylate.

 NMR (M)) d (H0D = 4.80 ppm): 1.24 (3H, d, J = 6 Hz), 1.97-2.01 (2H, m), 2.85-2.91 (2H, m), 3.36-3.40 (1H , M), 3.75 (2H, t, J = 6 Hz), 4.18-4.22 (2H, m), 4.48 (2H, t, J = 6 Hz), 9.08 (1H, s)

MS (FAB); m / z 437 (M ⁺⁺ 1)

 Example 103 (1R, 5S, 6S) -2- [4- (4-Hydroxybutanoyl) thiazol-5-yl] thio-6-((lR) -1-hydroxyethyl) 1-methyl-1-sodium lubapen-2-em-3-carboxylate

 a) (1R, 5S, 6S)-2- [4- (4-Hydroxybutanoyl) thiazol-5-yl] thio-6-((1R) -1-hydroxyethyl) -trimethyl 1-Levapen-2-em-3-carboxylic acid 4-2

In the same manner as in Example _{3a), (1R, 3R 5} 5R, 6S) -6- ((1R) -1- hydroxy E Chill) - 1-methyl-2-Okiso - Bok carba Bae Nam - 3- carboxylic acid From 45 mg of 4-Nitrobenzil and 25 mg of 4- (4-hydroxybutanol) -5-mercaptothiazol, (lR, 5S, 6S) -2- [4--(4-hydroxybutanol) Thiazolyl-5-yl] thio-6- ((1R) -1 -hydroxyethyl L) -Trimethyl-1-force lubapen-2-em-3-carboxylic acid 4-nitrobenzoyl llmg was obtained. NMR (CDCl3) d: l.ll (3H, d, J = 1.2 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.9-2.'1 (2H, m), 3.1-3.4 (4H, m), 3.7-3.8 (2H, m), 4.2-4.4 (2H ₃ m), 5.28 (1H, d, J = 13.8 Hz), 5.5K1H, d, J = 13.8 Hz), 7.64 (2H, d, J = 9.0 Hz), 8.22 (2H, d, J = 9.0 Hz), 8.73 (1H, s)

 b) (lR, 5S, 6S) -2- [4- (4-hydroxybutanol) thiazole-5-yl] thio-6-((1R) -1-hydroxyethyl) -1-methyl- 1-force lubapen-2-em-3-sodium carboxylate

 In the same manner as in Example lb), (lR, 5S, 6S) -2- [4- (4-hydroxybutanoyl) thiazo-l-5-yl] thio-6-((lR) -l- 10.8 mg of the title compound was obtained from llmg of hydroxyethyl)-; 1-methyl-1-forcelvapen-2-em-3-carboxylate 4-nitrobenzyl.

NMR (D ₂ 0) δ (H0D = 4.80ppm): 1.08 (3H, d, 3 = 1.2 Hz), 1.26 (3H, d, J = 6.3 Hz), 1.8-2.0 (2H, m), 3.0-3.2 _{(2H 5 m), 3.3-3.4 (} lH, m), 3.53 (1H, dd, 6.0 Hz, J 2 = 2.7 Hz), 3.6-3.7 (2H, m), 4.2-4.4 (2H 3 m), 8.87 (1H, s)

 [Example 104] (1R, 5S, 6S) -2- [4- (4,5-dihydroxypentanoyl) thiazol-5-yl] thio-6-((lR) -1-hydroxy) Tyl) -1-methyl -1-force rubapene-2-em -3-force sodium ribonate (a mixture of diastereomers)

 a) (lR, 5S, 6S) -2- [4- (4,5-dihydroxypentyl) thiazol-5-yl] thio-6-((lR) -l-hydroxyethyl) 1-Methyl-1-l-levapen-2-em-3-carboxylic acid 4-dibenzobenzene (diastereomeric mixture)

In the same manner as in Example 3a), (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxydityl) -1-methyl-2-oxo-1-carbazin-3-carboxylic acid (LR, 5S, 6S) -2- [4- (4,5-dihydroxypentanoyl) from 308 mg of 4-dibenzopentyl acid and 4- (4,5-dihydroxypentanoyl) -5-mercaptothiazole L) Thiazol-5-yl] thio-6-((1R) -1-hydroxyl) -1-methyl-1-butyrolene-2-em-3-carboxylic acid Njiru 36m was obtained.

_{NMR (CDC1 3) d: l.ll} (3H, d, J = 7.5 Hz), 1.3-1.4 (3H, m), 1.8 - 2.0 (2H, m), 3. 1-3.8 (7H 5 m), 4.2- 4.4 (2H, m), 5.29 (1H, d, J = 13.8 Hz), 5.51 (1H, d, J = 13.8 Hz), 7.64 (2H, d, J = 8.4 Hz), 8.22 (2H, d , J = 8.4 Hz), 8.73 (1H, s)

 b) (lR, 5S, 6S) -2- [4- (4,5-dihydroxypentyl) thiazol-5-yl] thio-6-((lR) -l-hydroxyethyl) 1-methyl-1-l-lubapen-2-em-3-carboxylic acid sodium (a mixture of diastereomers)

 In the same manner as in Example lb), (lR, 5S, 6S) -2- [4- (4,5-dihydroxypentanoyl) thiazol-5-yl] thio-6-((1R)- 10.5 mg of the title compound were obtained from 36 m of 1-hydroxyethyl) -1-methyl-1-methyll-bapene-2-em-3-carboxylate 4-nitrobenzil (a mixture of diastereomers).

_{NMR (D 2 0) δ (} H0D = 4.65ppm): 1.08 (3H, d, J = 6.0 Hz), 1.25 (3H, d, J = 5.7 Hz), 1.7-2.0 (2H, m), 3.1 - 3.8 (7H, m), 4.2-4.4 (2H, m), 8.88 (1H, s)

[Synthesis Example 1] 5-mercaptothiazol-4-ethyl carboxylate

 5.2 g of potassium-1-butoxide was suspended in 50 mL of THF, and a solution of 5.0 g of ethyl isocyanoacetate in 40 mL of THF was added dropwise at -40 ° C under an argon atmosphere. After stirring for 10 minutes, the reaction solution was cooled to −60 ° C., and a solution of 2.66 mL of carbon disulfide in 40 mL of THF was added dropwise. After stirring for 2 hours while gradually raising the temperature to 0 ° C, 44 mL of 1N hydrochloric acid and 300 mL of water were added, and the mixture was extracted twice with 300 mL of dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 7.99 g of the title compound.

 NMR (DMSO-de) d: 1.34 (3H, t, J = 7.2 Hz), 4.36 (2H, q, J = 7.2 Hz), 9.01 (1H, s)

[Synthesis Example 2] 5-mercaptothiazol-4-carboxylic acid amide ammonium salt

To 1.98 g of 5-ethyl mercaptothiazol-4-carboxylate was added 30 mL of 28% aqueous ammonia, and the mixture was stirred at 50 ° C for 4 days in a sealed tube. The reaction solution was concentrated under reduced pressure to dryness to obtain 1.84 g of the title compound.

_{NMR (DMS0-d 6) d} : 6.8-7.4 (5H, m), 8 · 00 (1Η, s), 9.96 (1H, br s)

 [Synthesis Example 3] 2-Amino-5-mercaptothiazole

It was synthesized from 2-aminothiazole according to the method described in W09617850.

[Synthesis Example 4] 5-Mercaptothiazol-4-carboxylic acid (N, N-dimethyl) amide

 a) 5-Tritylthiothiazole-4-ethyl carboxylate

 A solution of 3.15 g of ethyl 5-mercaptothiazole-4-carboxylate in 60 mL of dichloromethan was cooled on ice, and thereto was added pyridine 1.621111 and 5.11 g of trityl chloride in an argon atmosphere, followed by stirring at the same temperature for 1 hour. 300 mL of water was added to the reaction solution, and extracted twice with 300 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.774 g of 5-ethyltriethylthiothiazol-4-carboxylate.

Thigh (CDC1: 1.40 (3H ₃ t, J = 7.2 Hz), 4.39 (2H, q, 3 = 1.2 Hz), 7.2-7.4 (15 H, m), 8.36 (1H, s)

 b) sodium 5-tritylthiothiazole-4-carboxylate

To a suspension of 534 mg of ethyl 5-tritylthiothiazol-4-carboxylate in 10 mL of ethanol was added 1.24 mL of a 1N aqueous sodium hydroxide solution, and the mixture was stirred at 40 ° C for 4 hours. Decompress the solvent By distilling off under reduced pressure, 536 mg of sodium 5-tritylthiothiazol-4-carboxylate was obtained.

_{NMR (DMS0-d 6) d} : 7.2-7.4 (15H, m), 8.42 (1H, s)

 c) 5-Tritylthiothiazol-4-carboxylic acid (N, N-dimethyl) amide

 To a suspension of 227m of sodium 5-tritylthiothiazole-4-carboxylate in 10mL of DMF was added 108mg of trihydroxybenzotriazole and 154m of tri [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride. Was added and stirred at room temperature for 20 minutes. 0.35 mL of a 2M-dimethylamine THF solution was added, and the mixture was stirred at the same temperature for 22 hours. 100 mL of saline was added to the reaction solution, and extracted twice with 100 mL of ethyl acetate. The organic layers were combined, washed with 100 mL of brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). This gave 174 mg of 5-tritylthiothiazole-4-carboxylic acid (N, N-dimethyl) amide.

_{NMR (CDC1 3) d: 2.69} (3H, s), 3.08 (3H, s), 7.2-7.5 (15H, m), 8.48 (1H, s) d) 5- Merukaputochiazo Ichiru 4-carboxylic acid (N, N-dimethyl) amide

 To a solution of 174 mg of 5-tritylthiothiazol-4-carboxylic acid (N, N-dimethyl) amide in 3 mL of dichloromethane was added 1 mL of trifluoroacetic acid and 0.097 mL of triethylsilane, and the mixture was stirred at room temperature for 40 minutes. The residue obtained by evaporating the solvent under reduced pressure is to be purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1), followed by Sephadex LH-20 (dichloromethane: methanol = 1: 1). Gave 42 mg of the title compound.

_{NMR (CDC1 3) (J:} 3.13 (3H, s), 3.32 (3H, s), 8.64 (1H, s)

 [Synthesis Example 5] 5-mercaptothiazol-4-carboxylic acid (N-ethyl) amidoethylamine salt

合成例 2と同様にして、 5-メルカプトチアゾ一ル -4-カルボン酸ェチル 1.89 お よび 35%ェチルァミン水溶液より表題の化合物 2.33 gを得た。 NMR(DMS0-d₆) 1.1-1.2(6H, m)， 2.84(2H, q J=7.2 Hz), 3.2-3.3(2H, m), 7. 75(3H₃ br s), 8.05(1H, s)， 10.60(1H， br s)

In the same manner as in Synthesis Example 2, 1.89 g of ethyl 5-mercaptothiazol-4-carboxylate and 2.33 g of the title compound were obtained from a 35% aqueous solution of ethylamine. _{NMR (DMS0-d 6) 1.1-1.2} (6H, m), 2.84 (2H, q J = 7.2 Hz), 3.2-3.3 (2H, m), 7. 75 (3H 3 br s), 8.05 (1H, s), 10.60 (1H, br s)

[Synthesis Example 6] 4-Formyl-5-mercaptothiazol

 a) 4-formyl-5-tritylthiothiazole

 Dissolve 1.017 g of 5-tritylthiothiazole-4-ethyl carboxylate in 60 mL of dichloromethane, add 5.5 mL of 1.0M diisobutylaluminum hydride in THF at -50 ° C under an argon atmosphere, and raise to -30 ° C. Stir for 3 hours while warming. After adding 10 mL of a saturated aqueous sodium sulfate solution to the reaction mixture, the mixture was filtered through celite and washed with dichloromethane. The filtrate is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (dichloromethane: ethyl acetate = 10:;! To 5: 1). 712 mg of 4-formyl-5-tritylthiothiazole were obtained.

 NMR (CDCL) 7.2-7.4 (15H, m), 8.57 (1H, s), 9.72 (1H, s)

 b) 4-formyl-5-mercaptothiazole

 In the same manner as in Synthesis Example 4d), 46.2 mg of the title compound was obtained from 295 mg of 4-formyl-5-tritylthiothiazol.

 NMR (CDCL) d: 8.70 (1H, s), 10 · 15 (1Η, s)

[Synthesis Example 7] 5-mercaptothiazole-4-carboxylic acid [N- (2-hydroxyethyl)] ad,

 a) 5-Tritylthiothiazol-4-carboxylic acid [N- (2-hydroxyethyl)] amide 5-Tritylthiothiazol-4-carboxylic acid was prepared in the same manner as in Synthesis Example 4c). Nursery

From 425 mg and 0.078 iiiL of 2-aminoethanol, 121 mg of [N- (2-hydroxyethyl)] amide 5-tritylthiothiazol-4-carboxylate was obtained.

NMR (CDC1: 3.5-3.6 (2H, m), 3.7-3.8 (2H, m), 7.2-7.4 (15H ₅ m) ₅ 7.58 (1H, br t), 8.24 (1H, s)

 b) 5-Mercaptothiazole-4-carboxylic acid [N- (2-hydroxyethyl)] amide 'Similar to Synthesis Example 4d), 5-tritylthiothiazol-4-carboxylic acid [N- (2-Hydroxityl)] amide (499 mg) gave the title compound (85 mg).

NMR (DMSO-de) δ: 3.3-3.4 (2H, m), 3.5-3.6 (2H 5 m), 9.02 (1H, s), 10.02 (1H,

[Synthesis Example 8] 5-mercaptothiazol-4-carboxylic acid [N- (2-azidoethyl)] amide

 a) 5-Tritylthiothiazol-4-carboxylic acid [N- (2-azidoethyl)] amide sodium 5-tritylthiothiazole-4-carboxylate as in Synthesis Example 4c)

From 495 mg and 178 mg of 2-azidoethylamine hydrochloride, 492 mg of 5-tritylthiothiazole-4-carboxylic acid [N- (2-azidoethyl)] amide was obtained.

NMR (CDCL) 5: 3.5-3.6 (4H,), 7.2-7.4 (15H, m), 7.50 (1H, brt), 8.26 (1H ₃ s)

 b) 5-Mercaptothiazol-4-carboxylic acid [N- (2-hydroxyethyl)] amide In the same manner as in Synthesis Example 4d), 5-tritylthiothiazol-4-carboxylic acid [ 97 mg of the title compound was obtained from 492 mg of [N- (2-azidoethyl)] amide.

_{NMR (CDCl 3) d: 3.5-3.7} (4H, m), 7.26 (1H 5 s), 7.47 (1H, br t), 8.54 (1H, s)

[Synthesis Example 9] 5-mercaptothiazol-4-carboxylic acid (N-phenyl) amide

8 mL of aniline was added to 420 m of 5-mercaptothiazol-4-carboxylate, and the mixture was stirred at 100 ° C for 1.5 hours. 30 mL of dichloromethane, 30 mL of water and aqueous hydrochloric acid were added to the reaction solution to adjust the pH to 0.5, and the insoluble material was collected by filtration to obtain 74.8 mg of the title compound. The organic layer of the filtrate was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, 5 mL of dichloromethane was added to the obtained residue, and the insoluble material was collected by filtration to give the title compound. An additional 226 mg of compound was obtained.

NMR (CDCl ₃ ) d: 7.1-7.2 (lH ₅ m), 7.3-7.4 (2H, m), 7.6-7.7 (2H, m), 9.2-9.3 (1 H, m), 12.34 (1H, s)

[Synthesis Example 10] 5-Mercapto-4-methoxycarbonylaminothiazole

 a) 4-Methoxycarbonylamino-5-tritylthiothiazole

 Suspend 544m of sodium 5-tritylthiothiazol-4-carboxylate in 10 mL of THF, add 0.14mL of ethyl ethyl chloroformate and 0.2OmL of triethylamine at -20 ° C under argon atmosphere, and stir for 1 hour did. To the reaction mixture was added a solution of 92 mg of sodium azide in 2.5 mL of water, and the mixture was stirred for 1 hour while heating to 10 ° C. To the reaction solution was added 30 mL of saline, and the mixture was extracted twice with 30 DIL of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of toluene and 1 mL of methanol were added, and the mixture was stirred at 70 ° C for 1 hour. To the reaction solution was added 30 mL of saline, and the mixture was extracted twice with 30 mL of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 4-methoxycarbonyl. 417 mg of amino-5-tritylthiothiazole were obtained.

_{NMR (CDC1 3) 5: 3.67} (3H, s), 6.21 (1H, br s), 7.2-7.4 (15H 3 m), 8.65 (1H, s) b) 5- mercapto - 4-methoxycarbonyl § Mino Chia Sol

 In the same manner as in Synthesis Example 4d), 148 mg of the title compound was obtained from 383 m of 5-tritylthio-4-methoxycarbonylaminothiazole.

NMR (CDCL) d: 3.80 (3H ₅ s), 7.19 (1H, br s), 885 (1Η, s)

[Synthesis Example 11] 4-Acetyl-5-mercaptothiazol

a) 4- (1-Hydroxyethyl) -5-tritylthiothiazole 2.87 g of 4-formyl-5-tritylthiothiazole was dissolved in 60 mL of THF, and 9.57 mL of 0.93M-methylmagnesium bromide / THF solution was added dropwise at -35 ° C under an argon atmosphere. After stirring at the same temperature for 40 minutes, 200 mL of a half-saturated ammonium chloride solution was added to the reaction solution, and extracted twice with 150 mL of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography-(dichloromethane: ethyl acetate = 10: 1 to 5: 1). 2.69 g of 4-U-hydroxyshethyl) -5-tritylthiothiazole was obtained.

_{NMR (CDC1 3) 5: 1.25} (3H, d, J = 6.6 Hz), 4.6-4.7 (1H, m), 7.2-7.4 (15H, m), 8. 66 (1H, s)

 b) 4-Acetyl-5-tritylthiothiazole

 338 mg of 4- (1-hydroxyethyl) -5-tritylthiothiazole was dissolved in 8 mL of dichloromethane, and heated to reflux for 50 hours while adding 300 mg of activated manganese dioxide in six portions. The manganese dioxide was filtered off on celite, and the filtrate was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 157 mg of 4-acetyl-5-tritylthiothiazole.

 NMR (CDCL) d: 2.63 (3H, s), 7.2-7.4 (15H, m), 8.28 (1H, s)

 c) 4-Acetyl-5-mercaptothiazole

 In the same manner as in Synthesis Example 4d), the title compound (58m) was obtained from 157 mg of 4-acetyl-5-tritylthiothiazol.

_{NMR (CDC1 3) d: 2.71} (3H 3 s), 7 · 96 (1Η, s), 8.48 (lH, s)

[Synthesis Example 12] 5-mercaptothiazol-4-carboxylic acid (N-methyl) amidomethylamine salt

-CH ₃ NH ₂

568 mg of 5-mercaptothiazol-4-carboxylate was dissolved in 5 mL of a 40% methylamine-methanol solution and stirred at 40 ° C. for 22 hours under an argon atmosphere. The reaction solution was distilled off under reduced pressure to obtain 604 mg of the title compound. NMR (DMSO-de) δ: 2 · 40 (3Η, s), 2.73 (3Η ₃ br s), 7.73 (3H, br s), 8.05 (1H, s), 10.48 (1H, br s)

MS (EI ⁺ ): m / z = 174 (M ⁺ ) (5-mercaptothiazole-4-carboxylic acid-N-methylamide)

[Synthesis Example 13] 5-Mercaptothiazonyl-4-carboxylic acid (N-caproluvamoylmethyl) amide

 a) 5-Tritylthiothiazol-4-carboxylic acid

 6.74 g of ethyl 5-tritylthiothiazol-4-carboxylate was suspended in 30 mL of ethanol, 30 mL of THF and 30 mL of water, 31 mL of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at 40 ° C for 4 hours. The organic solvent was distilled off under reduced pressure, the pH was adjusted to 1 by adding a 1N aqueous hydrochloric acid solution, and the mixture was extracted three times with 50 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.58 g of 5-tritylthiothiazol-4-carboxylic acid.

_{NMR (CDC1 3) d:.} 7.2-7 (15H, m), 8.34 (1H, s)

 b) 5-Tritylthiothiazole-4-carboxylic acid (N-carbamoylmethyl) amide 548 mg of 5-tritylthiothiazole-4-carboxylic acid and 2-aminoacetamide as in Synthesis Example 4c) From 225 mg of the hydrochloride, 286 mg of 5-tritylthiothiazol-4-carboxylic acid (N-potumbamoylmethyl) amide was obtained.

_{NMR (CDC1 3) d: 4.09} (2H, d, J = 6.0 Hz)), 5.37 (1H, br s), 6.24 (1H, br s), 7. 2-7.4 (15H 3 m), 7.75 (1H , br t), 8.Z9 (1H, s)

 c) 5-Mercaptothiazol-4-carboxylic acid (N-potamoylmethyl) amide 5-Tritylthiothiazole-4-carboxylic acid (N-potamoylmethyl) amide as in Synthesis Example 4d) From 286 mg, 155 mg of the title compound was obtained.

 NMR (DMSO-de) 5: 3.94 (2H, d, J = 5.7 Hz), 7.12 (1H, br s), 7.44 (1H, br s), 9.13 (1H, s), 10.03 (1H, br t)

[Synthesis Example 14] 4-Formylamino-5-mercaptothiazole HS NHCHO a) 4-aryloxycarbonylamino-5-tritylthiothiazo

 By using 0.8 inL of aryl alcohol in place of methanol in Synthesis Example 10a), 1.16 g of 5-tritylthiothiazol-4-carboxylic acid was obtained from 4-aryloxycarbonylamino-5-tritylthiothione. 852m of azol were obtained.

 NMR (CDCL) d: 4.5-4.6 (2H, m), 5.2-5.4 (2H, m), 5.8- 6.0 (1H, m), 6.27 (1H, brs), 7.2-7.4 (15H, m), 8.65 (1H, s)

 b) 4-Amino-5-tritylthiothiazole

 Dissolve 307m of 4-aryloxycarbonylamino-5-tritylthiothiazole in 6 mL of dichloromethane, and add 18 mg of triphenylphosphine, 0.112 mL of pyrrolidine and 39 mg of tetrakistriphenylphosphine palladium under an argon atmosphere. The mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 20 mL of water, extracted twice with 30 mL of dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1). ) To give 232m of 4-amino-5-tritylthiothiazol.

_{NM (CDC1 3) d: 7.2-7.4} (15H 3 m), 8.41 (1H, s)

 c) 4-formylamino-5-tritylthiothiazole

 A solution of 232 mg of 4-amino-5-tritylthiothiazole in 4 mL of dichloromethane was ice-cooled. 0.3 mL of formic acid and 0.3 mL of acetic anhydride, which had been heated at 50 ° C for 5 minutes in advance, were added, followed by stirring for 2 hours. The reaction solution was adjusted to pH 7.5 by adding 10 mL of water and aqueous sodium hydrogen carbonate, and extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 10: 1) to give 4-formylamino- 200 mg of 5-tritylthiothiazole were obtained.

_{NMR (CDC1 3) 7.2-7.4 (15H} , m), 8.58 (1H, s), 8.86, 8.90 (total 1H, 2s) d) 4- Horumiruamino - 5- Merukaputochiazo Ichiru

In the same manner as in Synthesis Example 4d), 4-formylamino-5-tritylthiothiazol 200 mg Thus, 73 mg of the title compound was obtained.

_{NMR (CDC1 3) d: 3.15} (lH, br s), 8.15 (1H, br s), 8.70 (1H, s), 9.23, 9.27 (t otal 1H, 2s)

 [Synthesis Example 15] 5-mercaptothiazol-4-carboxylic acid [N- (2-methoxyethyl)] a

 a) 5-Tritylthiothiazol-4-carboxylic acid [N- (2-methoxyethyl)] amide 5-Tritylthiothiazol-4-carboxylic acid 605 mg of DMF lOinL solution was added to 1-hydroxybenzotriazolate. After adding 345 mg of toluene and 431 mg of tri [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 0.315 mL of triethylamine, the mixture was stirred at 30 ° C. for 50 minutes in an argon atmosphere, and then treated with 2-methoxy. 0.195 mL of ethylamine was added, and the mixture was stirred at the same temperature for 18 hours. 50 mL of half-saturated saline was added to the reaction solution, and extracted twice with 50 mL of ethyl acetate. The organic layers were combined, washed successively with a saturated saline solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 20 mL of ethyl acetate. After 5 g of silica gel 60 (Merck No. 9385) was added and stirred, the mixture was filtered and the solvent was distilled off under reduced pressure to give 5-tritylthiothiazol-4-carboxylic acid [N- (2-methyl Tokishetil)] amide was obtained in an amount of 690 mg.

Anonymous (CDCl ₃ ) d: 3.37 (3H, s), 3.5-3.6 (4H, m), 7.2-7.4 (15H, m), 7.48 (1H, brt), 8.25 (1H ₅ s)

 MS (FAB): m / z = 459 (M-1)

 b) 5-mercaptothiazole-4-carboxylic acid [N- (2-methoxyethyl)] amide

To a solution of 690 mg of 5-tritylthiothiazol-4-carboxylic acid [N- (2-methoxyethyl)] amide in lOmL of dichloromethane was added 1.16 mL of trifluoroacetic acid and 0.360 mL of triethylsilane, followed by stirring at room temperature for 15 minutes. A small amount of n-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, subjected to ultrasonic treatment, and allowed to stand. Then, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 304 mg of the title compound.

_{NMR (CDC1 3) d: 3.40} (3H, s), 3.55-3.64 (4H, m), 7: 8-7.9 (1H, m), 8.44 (1H, s)

 MS (FAB-): m / z = 217 (M-1)

[Synthesis Example 16] 5-mercaptothiazol-4-carboxylic acid (N-methoxy) amide

 a) 5-Tritylthiothiazol-4-carboxylic acid (N-methoxy) amide

 To a solution of 605m of 5-tritylthiothiazol-4-carboxylic acid in 10mL of DMF was added 1-hydroxybenzotriazol, 345mg of 1-yl, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimid hydrochloride 431mg, and Then, 0.315 mL of triethylamine was added, and the mixture was stirred at 30 ° C. for 50 minutes under an argon atmosphere, and then 188 mg of methoxylamine hydrochloride and 0.315 mL of triethylamine were added, followed by stirring at the same temperature for 18 hours. To the reaction solution was added 50 mL of half-saturated saline, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, washed successively with a saturated saline solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 20 mL of ethyl acetate. After adding 5 g of silica gel 60 (Merck No.9385) and stirring, the mixture was filtered and the solvent was distilled off under reduced pressure to give 5-tritylthiothiazol-4-carboxylic acid (N-methoxy) amide. 648 mg were obtained.

NMR (CDC1 ₃ ) d: 3.85 (3H ₃ s), 7.2-7. (15H, m), 8.26 (lH, s), 9.47 (1H, br s)

MS (FAB '): m / z = 431 (MM)

 b) 5-mercaptothiazol-4-carboxylic acid (N-methoxy) amide

 To a solution of 648 mg of 5-tritylthiothiazol-4-carboxylic acid (N-methoxy) amide in 100 mL of dichloromethane was added 1.16 mL of trifluoroacetic acid and 0.360 mL of triethylsilane, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, a small amount of n-hexane was added to the residue obtained, and the mixture was subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 294 mg of the title compound.

_{NMR (CDC1 3) 3.90 (3H} , s), 8.47 (1H, s), 9.9 (1H, br s)

MS (FAB ⁺ ): m / z = 191 (M ⁺⁺ 1)

[Synthesis Example 17] 5-mercapto-4- (4-ditrobenzyloxycarponylamino) thiazole

 a) 4- (4-nitrobenzoyloxycarbonylamino) -5-tritylthiothiazol In Synthesis Example 10a), 390 mg of 4-nitrobenzoyl alcohol was used instead of methanol. 466 mg of 4- (4-nitrobenzoyloxycarbonylamino) -5-tritylthiothiazole was obtained from 544 mg of sodium-tritylthiothiazole-4-carboxylate.

NMR (CDCL) d: 5.19 ( 2H, s), 6.29 (1H, br s), 7.2-7.4 (15H 5 m), 7.51 (2H, d 3 J = 8.7 Hz), 8.23 (2H, d, J = 8.7 Hz), 8.67 (1H, s)

 b) 5-Mercapto-4- (4-dibenzobenzyloxycarbonylamino) thiazolyl In the same manner as in Synthesis Example 4d), 4- (4-nitrobenzoyloxycarbonylamino)- 55 m of the title compound was obtained from 466 m of 5-tritylthiothiazole.

_{NMR (CDC1 3) d: 5.31} (2H, s), 7.57 (2H, d, J = 7.5 Hz), 8.23 (2H, d, J = 7.5 Hz), 8.78 (1H, br s)

[Synthesis Example 18] 5-mercaptothiazol-4-carboxylic acid [N- (3-hydroxypropane-1-yl)] amide

After 568m of 5-mercaptothiazole-4-ethyl carboxylate was dissolved in 1mL of ethanol, 2mL of 3-amino-1-propanol was added, and the mixture was stirred at 70 ° C for 2 days under an argon atmosphere. After neutralization with 1N-hydrochloric acid, the mixture was adjusted to pH 2 and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 195 mg of the title compound.

NMR (DMS0-d ₆ ) δ: 1.63-1.70 (2H, m), 3.32 (1H ₅ t, J = 6.3 Hz), 3.35-3.41 (2H, m), 3.46-3.52 (2H, m), 9.07 ( 1H, s), 9.98 (1H, br t)

MS (ES ⁺ ): m / z = 219 (M ⁺ +1)

MS (ES-): m / z = 217 (M-1) [Synthesis Example 19] 5-Mercaptothiazo, mono-4-carboxylic acid [N- (propyl) amide] (1-propyl) amine salt

■ CH ₃ (CH2) ₂ NH ₂

After 379 mg of ethyl 5-mercaptothiazol-4-carboxylate was dissolved in 1 mL of methanol, 2 mL of propylamine was added, and the mixture was stirred under an argon atmosphere at 40 ° C for 31 hours. The reaction solution was evaporated under reduced pressure to obtain 523 mg of the title compound.

NMR (DMSO-de) d: 0.89-0.97 (6H ₅ m), 1.47-1.61 (4H, m), 2.76 (2H, t, J = 7.5 Hz), 3.19-3.26 (2H, m), 7.7 (3H , br s), 803 (1Η, s), 10.64 (1H, br t)

MS (FAB ⁺ ): m / z = 203 (M ⁺ +1) (5-mercaptothiazol-4-carboxylic acid-Nl-propylamide)

 [Synthesis Example 20] 5-mercaptothiazole-4-carboxylic acid [N- (pyridine-2-yl) methyl] amide trifluoroacetate

 a) [N- (Pyridin-2-yl) methyl] adide 5-tritylthiothiazol-4-carboxylate

In a DMF lOmL solution of 605 mg of 5-tritylthiothiazol-4-carboxylic acid, 345 mg of trihydroxybenzotriazol, 431 mg of tri [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, and 0.315 mL of triethylamine After stirring at 30 ° C. for 50 minutes under an argon atmosphere, 0.230 mL of 2-pyridylamine was added, and the mixture was stirred at the same temperature for 18 hours. To the reaction solution was added 50 mL of half-saturated saline, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, washed successively with a saturated saline solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 20 mL of ethyl acetate. 5 g of silica gel 60 ^ 6 ^! ^. 9385), stirred, filtered, and the solvent was distilled off under reduced pressure to give 5-tritylthiothiazol-4-carboxylic acid [N- (pyridine -2-Y 7) m was obtained.

NMR (CDCL) (J: 4.72 (2H, d, J = 5.3 Hz), 7.17-7.20 (1H, m), 7.33 (1H, br d, J = 8.0 Hz), 7.25-7.42 (15H ₅ m), 7.63-7.67 (lH, m) ₅ 8.16 (1H, br s), 8.28 (1H, s), 8.55-8.56 (lH, m)

MS (FAB ⁺ ): m / z = 494 (M ⁺⁺ 1).

 b) 5-Mercaptothiazole-4-carboxylic acid [N- (pyridin-2-yl) methyl] amide trifluoroacetate

 5-Tritylthiothiazol-4-carboxylic acid [N- (pyridin-2-yl) methyl] amide To a solution of 646 mg of 646 mg in 10 mL of dichloromethane was added l.OlmL of trifluoroacetic acid and 0.315 mL of triethylsilane, and the solution was added at room temperature. Stirred for minutes. A small amount of n-hexane was added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 453 mg of the title compound.

NMR (DMS0-d ₆ ) δ: 4.66 (1H ₅ d, J = 5.6 Hz), 4.76 (2H, d, J = 5.8 Hz), 7.52-7.72 (2H, m), 8.08 (1H, m), 8.65-8.66 (1H, m), 9.08 (1H, s), 10.57 (1H, br t)

MS (FAB ⁺ ): m / z = 252 (M ⁺ +1) (5-mercaptothiazol-4-carboxylic acid-N- (2-methoxethyl) amide)

[Synthesis Example 21] Methyl 5-mercaptothiazol-4-carboxylate

 After 379 mg of 5-mercaptothiazol-4-ethyl carboxylate was dissolved in 10 mL of methanol, 0.5 mL of 4N-dioxane hydrochloride was added, and the mixture was stirred at 50 ° C for 3 days under an argon atmosphere. The residue obtained by evaporating the reaction solution under reduced pressure was dissolved in 40 mL of half-saturated saline and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, the obtained oil was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to obtain 81 mg of the title compound.

Thigh _{(CDC1 3) 5: 3.97 (} 3H, s), 6.3 (1H, br s), 8.59 (1H, s)

S (FAB ⁺ ): m / z = 176 (M ⁺⁺ 1)

[Synthesis Example 22] 4-Nitropentyl 5-mercaptothiazol-4-carboxylate

 a) 5-Tritylthiothiazole-4-carboxylic acid 4-nitrobenzyl

 To a solution of 414m of 5-tritylthiothiazole-4-carboxylic acid in 8mL of DMF were added 377mg of 4-nitrobenzoylbromide and 0.179mL of N, N-diisopropylethylamine, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 25 mL of half-saturated saline, and the mixture was extracted with 25 mL of ethyl acetate. The organic layer was washed three times with 25 mL of half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain 461 mg of 5-tritylthiothiazol-4-carboxylic acid 4-nitrobenzene. .

NMR (CDCl3) (5: 5.45 (2H 5 s), 7.26-7.34 (15H, m), 7.62 (2H 5 d, J = 8.8 Hz), 8. 18 (2H, d, J = 8.8 Hz), 8.40 (1H, s)

 b) 5-Mercaptothiazol-4-carbonic acid 4-dibenzyl

 In the same manner as in Synthesis Example 4d), the title compound 253m was obtained from 461 mg of 4-nitrobenzyl 5-tritylthiothiazol-4-carboxylate.

_{NMR (CDC1 3) d: 5.49} (2H, s), 7.65 (2H, d, J = 8.8 Hz), 8.24 (2H 3 d, J = 8.8 Hz), 8.74 (1H, s)

 MS (API); m / z 295 (M-1)

[Synthesis Example 23] 5-Mercapto-4-propionylthiazol

 a) 5-Tritylthiothiazole-4-carboxylic acid (N-methoxy-N-methyl) amide

In a DMFlOmL solution of 807 mg of 5-tritylthiothiazol-4-carboxylic acid, 460 mg of 1-hydroxybenzotriazole, 574 mg of [3- (dimethylamino) propyl] -3-ethylcarbodiimid hydrochloride, and 0.840 mL of triethylamine After stirring at room temperature for 15 minutes under an argon atmosphere, 293 mg of Ν, Ο-dimethylhydroxylamine hydrochloride was added, and the mixture was stirred at the same temperature for 22 hours. Add 100 mL of half-saturated saline to the reaction mixture, and add ethyl acetate. And extracted twice with 100 mL. The organic layers were combined, washed successively with a saturated saline solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.A small amount of n-hexane was added to the obtained residue. After sonication and standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 885 mg of 5-tritylthiothiazol-4-carboxylic acid (N-methoxy-N-methyl) amide.

_{NMR (CDC1 3) 5: 3.24} (3H, br s), 3.65 (3H, br s), 7.2-7.4 (15H, m), 8.47 (1H, s)

MS (FAB ⁺ ) (with Nal): 469 (M ÷ Na)

 b) 4-propionyl-5-tritylthiothiazole

 Under an argon atmosphere, add 0.66 mL of a THF solution (0.89 mol / l) of ethyl ethyl bromide to a THF solution of 5-tritylthiothiazole-4-carboxylic acid (N-methoxy-N-methyl) amide cooled in an ice bath under an argon atmosphere. The mixture was stirred at room temperature for 1 hour. 0.66 mL of a THF solution (0.89 mol / l) of ethyl magnesium bromide was further added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into a saturated aqueous solution of ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL). After drying the organic phase over anhydrous magnesium sulfate, the solid was filtered off. The solvent of the filtrate was distilled off under reduced pressure to obtain 214m of 4-propionyl-5-tritylthiothiazol.

_{NMR (CDC1 3) d: 1.19} (3H 3 t, J = 7.3 Hz), 3.05 (2H, q, J = 7.3 Hz), 7.24-7.37 (1 5H, m), 8.28 (lH, s)

 c) 5-mercapto-4-propionylthiazole

 To a solution of 214 mg of 4-propionyl-5-tritylthiothiazole in 3 mL of dichloromethane was added 0.40 mL of trifluoroacetic acid and 0.082 mL of triethylsilane, and the mixture was stirred at room temperature for 40 minutes. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane: methyl alcohol = 30: 1) to obtain 121 mg of the title compound.

NMR (CDCL) d: 1.23 ( 3H, t, J = 7.3 Hz), 3.16 (2H, q, J = 7.3 Hz), 7.77 (1H 3 s), 8.48 (1H, s)

[Synthesis Example 24] 4-cyano-5-mercaptothiazole

 a) 5-Tritylthiothiazol-4-carboxylic acid amide

 104 m of 5-mercaptothiazol-4-carboxylic acid amide ammonium salt was dissolved in 5 mL of DMF, and 0.115 mL of triethylamine and 162 mg of trityl chloride were added under ice-cooling. After stirring at room temperature for 20 hours, water was added to the reaction solution, and the insoluble portion was collected by filtration to obtain 117 mg of 5-tritylthiothiazol-4-carboxylic acid amide.

NMRiCDaOD) d: 7.2-7.4 (16H ₅ m), 753 (1Η, s), 8.40 (1Η, s)

 b) 4-Cyano-5-tritylthiothiazole

 779m of 5-tritylthiothiazole-4-carboxylic acid amide was dissolved in 15mL of N, N-dimethylformamide, and 484mg of phosphorus pentachloride was added, followed by stirring at 40 ° C for 2 hours. The reaction solution was added to 70 mL of water, and extracted with 70 mL of ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain 319m of 4-cyano-5-tritylthiothiazole.

_{NMR (CDC1 3) d: 7.28-7.37} (15H, m), 8.58 (1H, s)

 MS (EI); m / z 384 (M)

 c) 4-Cyano-5-mercaptothiazole

 In the same manner as in Synthesis Example 15b), 93 mg of the title compound was obtained from 319 m of 4-cyano-5-tritylthiothiazol.

 MS (EI); m / z 142 (M)

[Synthesis example 25] 5-mercaptothiazol-4-carboxylic acid N-isopropylamide

 a) 5-Tritylthiothiazol-4-carboxylic acid N-isopropylamide

To a solution of 605 mg of 5-tritylthiothiazol-4-carboxylic acid in 10 mL of DMF was added 345 mg of 1-hydroxybenzotriazol, 1- [3- (dimethylamino) propyl] -3-ethylcarbo. 431 mg of diimide hydrochloride and 0.315 mL of triethylamine were added, and the mixture was stirred at room temperature for 15 minutes in an argon atmosphere, and then 0.192 mL of isopropylamine was added, and the mixture was stirred at room temperature for 22 hours. To the reaction solution was added 100 mL of half-saturated saline, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, washed successively with half-saturated saline and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue and subjected to sonication. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 623 mg of N-isopropylamide 5-tritylthiothiazole-4-carboxylate.

Country CDCl ₃ ) d: 1.23 (6H, d, J = 6.3 Hz), 4.18-4.25 (1H, m), 7.02 (1H, br d, J = 7.7 Hz), 7.2-7.4 (15H, m), 8.23 (1H, s)

MS (FAB ⁺ ) (with Nal): 467 (M ^ Na)

MS (FAB ⁺ ) (with KI): 467 (MH)

 b) 5-mercaptothiazole-4-carboxylic acid N-isopropylamide

 To a solution of 535 mg of 5-tritylthiothiazol-4-carboxylic acid N-isopropylamide in 9 mL of dichloromethane was added 0.93 mL of trifluoroacetic acid and 0.288 mL of triethylsilane, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, a small amount of n-hexane was added to the residue obtained, and the mixture was subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 249 mg of the title compound.

Thigh (CDCl ₃ ) d: 1.29 (6H, d, J = 6.3 Hz), 4.17-4.25 (1H, m), 8.42 (1H, s)

MS (FAB ⁺ ) (with KI): 241 (MH)

[Synthesis Example 26] 5-mercaptothiazol-4-carboxylic acid N- (cyclohexyl) amide

a) 5-Tritylthiothiazole-4-carboxylic acid N- (cyclohexyl) amide 5-Tritylthiothiazol-4-carboxylic acid 605 mg in a DMF 10 mL solution, trihydroxybenzotriazol 345 mg,:! -[3- (Dimethylamino) propyl]-431 mg of 3-ethylcarbodiimide hydrochloride and 0.315 mL of triethylamine are added, and the mixture is stirred at room temperature for 1 hour under an argon atmosphere, and 0.257 mL of cyclohexylamine is added. At room temperature Stir for 21 hours. 100 mL of half-saturated saline was added to the reaction solution, and extracted twice with 100 mL of ethyl acetate. The organic phases were combined, washed successively with a saturated saline solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue, and the mixture was subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 671 mg of N- (cyclohexyl) amide 5-tritylthiothiazol-4-carboxylate.

NMR (CDCl ₃ ) d: 1.11-1.43 (6H, m), 1.62 (1Η, br d), 1.73 (2H ₃ m), 1.98 (2H, br d), 3.92 (1H, m), 7.06- 7.14 (lH, br d), 7.25-7.42 (15H 3 m), 8.23 (1H, s) MS (FAB +): 485 (M + +1)

 b) 5-mercaptothiazol-4-carboxylic acid N- (cyclohexyl) amide

 To a solution of 561 mg of 5-tritylthiothiazol-4-carboxylic acid N- (cyclohexyl) amide in 9 mL of dichloromethane was added 0.89 mL of trifluoroacetic acid and 0.277 mL of triethylsilane, followed by stirring at room temperature for 20 minutes. A small amount of n-hexane was added to the residue obtained by evaporating the solvent under reduced pressure, subjected to ultrasonic treatment, and allowed to stand. Then, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 247 mg of the title compound.

_{NMR (CDC1 3) d: 1.13-1.47} (6H, m), 1.64 (1H, m), 1.78 (2H, m), 1.98 (2H, m), 2.93 (1H, m), 3.91 (1H, m) , 8.45 (1H, s), 9.00 (2H, br s)

MS (FAB ⁺ ) (with Nal): 265 (M Na)

[Synthesis Example 27] 5-Mercaptothiazol-4-carboxylic acid N- (thiazol-2-yl) methylamidotrifluoroacetate

 a) N- (Thiazol-2-yl) methylamide 5-tritylthiothiazole-4-carboxylate

To a solution of 605 mg of 5-tritylthiothiazole-4-carboxylic acid in 10 mL of DMF, 345 iiig of trihydroxybenzotriazole, 431 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, and 0.315 mL of triethylamine After stirring at 30 ° C for 1 hour in an argon atmosphere, 257 mg of 2-aminomethylthiazole was added, and the mixture was heated at the same temperature. For 21 hours. To the reaction solution was added 100 mL of half-saturated saline, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, washed successively with a saturated saline solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue and subjected to sonication. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 674 mg of 5-tritylthiothiazol-4-carboxylic acid N- (thiazo'-1-yl) methylamide.

_{NMR (CDC1 3) 5:.} 4 · 92 (2Η, d, J = 6.1 Hz), 7.26-7.40 (16H, m), 7.73 (1H, d, J = 3.6 Hz), 7.92 (1H, br s) , 8.27 (1H, s)

MS (FAB ⁺ ) (with Nal): 522 (MWa)

MS (FAB ⁺ ) (with KI): 538 (MH)

 b) 5-Mercaptothiazol-4-carboxylic acid N- (thiazol-2-yl) methylamide trifluoroacetate

 5-Tritylthiothiazol-4-carboxylic acid N- (thiazol-2-yl) methylamide To a solution of 537 mg of dichloromethane in 8 mL, add 0.83 mL of trifluoroacetic acid and 0.257 mL of triethylsilane, and add Stirred for minutes. A small amount of n-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, subjected to ultrasonic treatment, and allowed to stand. Then, the supernatant was removed. The obtained residue was dissolved in a mixed solution of methylene chloride-methanol (7: 3), and about 4 g of silica gel 60 (No. 9385, manufactured by Merck) was added. After stirring, the mixture was filtered off and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue and subjected to sonication. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 129 mg of the title compound.

2.1 Hz), 7.62(1H, d, J = 3.3 Hz), 7.74(1H, d, J = 3.3 Hz), 9.14(1H, s), 10.61(1H， br t) NMR (DMSO-de) δ: 4.86 (2H, dd,

2.1 Hz), 7.62 (1H, d, J = 3.3 Hz), 7.74 (1H, d, J = 3.3 Hz), 9.14 (1H, s), 10.61 (1H, brt)

MS (FAB ⁺ ): 258 (M ⁺⁺ 1)

[Synthesis Example 28] 5-mercaptothiazole-4-carboxylate rubamoylmethyl

 a) 5-tritylthiothiazol-4-carboxylate rubamoylmethyl

To a solution of 605m of 5-tritylthiothiazol-4-carboxylic acid in 10 mL of DMF, Then, 208 mg of ethanol and 555 mg of potassium acetate were added successively, and the mixture was stirred at 30 ° C. for 16 hours under an argon atmosphere. To the reaction solution was added 100 mL of half-saturated saline, and the mixture was extracted with 100 mL of ethyl acetate. The organic layer was washed twice with half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was added with a small amount of n-hexane and subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 667 m of 5-tritylthiothiazol-4-carboxylic acid.

_{NMR (CDC1 3) 4.76 (2H} , s), 5.46 (1H, br s), 6.69 (1H, br s), 4.18-4.25 (1 H, m), 7.24-7.35 (15H, m), 8.44 (1H , s)

MS (FAB ⁺ ): 461 (MM)

 b) 5-mercaptothiazol-4-carboxylate rubamoylmethyl

 In the same manner as in Synthesis Example 15b), 468 mg of the title compound was obtained from 632 mg of rubamoylmethyl 5-tritylthiothiazol-4-carboxylate.

_{NMR (DMS0-d 6) d} : 4.70 (2H, s), 7.2-7.3 (1H, br s), 7.5-7.6 (1H, br s)

MS (API); m / z 219 (M ⁺ +1)

[Synthesis Example 29] 5-Mercapto-4-methylsulfonylthiazol

 a) Ν, Ν-dimethylaminomethylformamide

 It was synthesized by the method described in Chem. Ber. 103, 2775 (1970).

 b) Formylaminomethyltrimethyl ammonium hydroxide

 7.30 g of Ν, Ν-dimethylaminomethylformamide was suspended in 140 mL of dimethyl ether, 5.4 mL of methyl iodide was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure to about half, and the insoluble matter was collected by filtration to obtain 10.88 g of formylaminomethyltrimethylammonium monohydrate.

NMR (DMS0-de) d: . 2.95 (9H 5 s), 4.61 (2H, d, J = 7.5 Hz), 8.31 (1H 5 s), 9.3-9 4 (1H, m)

 c) Methanesulfonylmethylformamide

691 mg of formylaminomethyltrimethylammonium amide The suspension was suspended in 15 mL of ril, to which 289 mg of sodium methanesulfinate was added, followed by heating under reflux for 1.5 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain 224 mg of methanesulfonylmethylformamide.

NMR (DMS0-de) d: 2.91 (3H ₃ s), 4.57 (2H, d, J = 6.6 Hz), 8.19 (1H, s), 9.1-9.2 (1H ₅ m) Methanesulfonylmethylformamide A suspension of 224 mg of dichloromethane in 3 mL was ice-cooled, and 0.57 mL of triethylamine and 0.152 mL of phosphorus oxychloride were added, followed by stirring for 40 minutes. To the reaction solution was added a solution of 350 mg of sodium carbonate in 5 mL of water, extracted 5 times with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 72 mg of isocyanomethyl sulfonylamine.

_{NMR (CDC1 3) d: 3.15} (3H, s), 4.56 (2H, s)

 e) 5-mercapto-4-methyl sulfonylthiazole

 In the same manner as in Synthesis Example 1, 94 mg of the title compound was obtained from 72 mg of isocyanomethanesulfonylmethane.

_{NMR (CDC1 3) d: 3.27} (3H 5 s), 5.60 (1H, br s), 8.63 (1H, s)

[Synthesis Example 30] 2-Hydroxyethyl 5-mercaptothiazol-4-carboxylate

 To a solution of 1.893 g of 5-mercaptothiazol-4-ethyl carboxylate in 20 mL of ethylene glycol was added 1.497 g of sodium ethoxide, and the mixture was stirred at 60 ° C for 24 hours. The reaction solution was diluted with 100 mL of distilled water and washed with 100 mL of toluene. The aqueous phase was adjusted to pH 2 with 5N hydrochloric acid, and extracted three times with 100 mL of ethyl acetate. The combined organic phase was washed with 100 mL of saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue, subjected to sonication, allowed to stand, and the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 1.556 g of the title compound.

Original (DMS0-d ₆ ) d: 3.72 (2H, s), 4.34 (2H ₅ s), 4.40 (1H ₅ br s), 8.73 & 9.01 (1H, sx 2, comformer mixture), 8.97 (1H, s)

MS (FAB ⁺ ): 206 (M ⁺⁺ 1).

[Synthesis Example 31] 5-mercaptothiazol-4-carboxylic acid N- (cyclopropyl) amide

 a) 5-Tritylthiothiazole-4-carboxylic acid (N-cyclopropyl) amide

 To a solution of 605m of 5-tritylthiothiazol-4-carboxylic acid in 10mL of DMF was added 345mg of hydroxybenzotriazole, 431mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, and 0.315 mL of triethylamine was added, and the mixture was stirred at room temperature for 1 hour under an atmosphere of argon. Then, 0.156 mL of cyclopropylamine was added, and the mixture was stirred at room temperature for 23 hours. 80 mL of half-saturated saline was added to the reaction solution, and extracted with 80 mL of ethyl acetate. The organic phase was washed twice with 40 mL of a half-saturated saline solution, dried over anhydrous magnesium sulfate, added with about 5 g of Silica Gel 60 (Merck, No. 9385), and stirred. After filtration, the solvent was distilled off under reduced pressure, a small amount of n-hexane was added to the obtained residue, ultrasonic treatment was performed, and after allowing to stand, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 557 mg of 5-tritylthiothiazole-4-carboxylic acid N- (cyclopropyl) amide.

_{NMR (CDC1 3) d: 0.57-0.65} (2H, m), 0.77-0 · 84 (2Η, m), 2.81-2.89 (1H, m), 7. 23 (1H, br s), 7.25-7.40 ( 15H, m), 8.22 (1H, s)

MS (FAB ⁺ ) (with Nal): 465 (M Na)

 b) 5-mercaptothiazol-4-carboxylic acid N- (cyclopropyl) amide

 To a solution of 471 mg of 5-tritylthiothiazol-4-carboxylic acid N- (cyclopropyl) amide in 8 mL of dichloromethane was added 0.82 mL of trifluoroacetic acid and 0.255 mL of triethylsilane, and the mixture was stirred at room temperature for 15 minutes. A small amount of n-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, subjected to ultrasonic treatment, and allowed to stand. Then, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 168 mg of the title compound.

_{NMR (CDC1 3) 0.64-0.68 (2H} , m), 0.82-0.90 (2H, m), 2.84-2.90 (1H, m), 7. 60 (1H, br s), 8.40 (1H, s)

MS (FAB ⁺ ): 201 (M ⁺⁺ 1) [Synthesis Example 32] 5-mercaptothiazol-2-carboxylic acid amide

a) 2-ァミノ- 5-チオシアナ一トチアゾ一ル

a) 2-Amino-5-thiocyanatotothiazole

 It was synthesized from 2-aminothiazole by the method described in W09617850.

 b) 5-thiocyanatotothiazole

 A DMFlOmL solution of 2.18 mL of t-butyl nitrite was ice-cooled, and a DMFlOmL solution of 1.71 g of 2-amino-5-thiocyanatotothiazol was added dropwise under an argon atmosphere. The mixture was stirred at room temperature for 20 minutes and at 5.0 ° C for 1 hour. Hydrochloric acid solution was added to the reaction solution, extracted twice with ethyl acetate, and the organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 474 mg of 5-thiocyanatotothiazole. .

_{NMR (CDC1 3) d: 8.16} (lH, s), 9.07 (1H, s)

 c) 5-Tritylthiothiazole

 A solution of 474 mg of 5-thiocyanatothiazole in 4 mL of THF was cooled with ice, 3.3 mL of a 1N aqueous solution of sodium hydroxide was added, and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 3.3 mL of 1N aqueous hydrochloric acid, and the mixture was extracted twice with dichloromethane. The residue obtained by drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure was dissolved in 10 mL of dichloromethane, 0.35 mL of pyridine and 1.12 g of trityl chloride were added, and the mixture was stirred at room temperature for 1 hour. Dichloromethane and water were added to the reaction solution, and the mixture was adjusted to pH 3.5 with aqueous hydrochloric acid, and then extracted twice with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 5-trityl titanate. 158 mg of thiazole were obtained.

_{NMR (CDC1 3) d: 7.2-7.4} (15H 3 m), 7.46 (1H, s), 8.64 (1H, s)

 d) 5-Tritylthiothiazol-2-carboxylic acid

158 mg of 5-tritylthiothiazole was dissolved in 3 mL of THF, and 0.292 mL of a 1.56 Nn-butyllithium / hexane solution was added dropwise at -60 ° C under an argon atmosphere. Stir at the same temperature for 15 minutes After that, the reaction vessel was replaced with carbon dioxide and stirred at the same temperature for 2 hours. Dichloromethane and water were added to the reaction solution, the pH was adjusted to 2 with hydrochloric acid, and then the solution was extracted three times with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 136 mg of 5-tritylthiothiazole-2-carboxylic acid.

_{NMR (CDC1 3) (5:} 7.2-7.4 (16H, m)

 e) 5-Tritylthiothiazol-2-carboxylic acid amide

 In the same manner as in Synthesis Example 4c), 136 mg of 5-tritylthiothiazol-2-carboxylic acid and 0.25 mL of a 2M ammonia / ethanol solution were used to prepare 5-tritylthiothiazol-2-carboxylic acid amide. De 73m.

_{NMR (CDC1 3) d: 5.42} (lH, br s), 6.95 (1H, br s), 7.2-7.4 (16H, m)

 f) 5-mercaptothiazol-2-carboxylic acid amide

 26 mg of the title compound was obtained from 73 mg of 5-tritylthiothiazol-2-carboxylic acid amide in the same manner as in Synthesis Example 4d).

_{NMR (CDC1 3) d: 5.58} (lH, br s), 7.02 (1H, br s), 7.73 (1H 3 s)

[Synthesis Example 33] 1-propyl 5-mercaptothiazole-4-carboxylate

 a) 5-Tritylthiothiazol-4-propyl carboxylate

 To a solution of 605 mg of 5-tritylthiothiazole-4-carboxylic acid in 10 mL of DMF were added 208 mg of carbon dioxide and 0.295 mL of 1-propyl iodide, and the mixture was stirred at 30 ° C. for 17.5 hours under an argon atmosphere. To the reaction solution was added half-saturated aqueous sodium bicarbonate (100 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed once with 50 mL of a 5% aqueous sodium thiosulfate solution and twice with 50 mL of half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue and subjected to sonication. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 582 mg of 5-tritylthiothiazol-4-carboxylic acid propyl.

NMR (CDCl ₃ ) d: 1.00 (3H, t ₅ J = 7.2 Hz), 1.80 (2H, dd, Ji- 7.2 Hz, J ₂ = 6.6 Hz), 4.29 (2H, d, J = 6.6 Hz) , 7.27-7.45 (15H, m), 8.36 (1H, s) MS (FAB ⁺ ): 446 (MM)

 b) 5-Propyl 5-mercaptothiazole-4-carboxylate

 To a solution of 492 mg of 1-propyl 5-tritylthiothiazole-4-carboxylate in 9 mL of dichloromethane was added 0.85 mL of trifluoroacetic acid and 0.265 mL of triethylsilane, and the mixture was stirred at room temperature for 25 minutes. The solvent was distilled off under reduced pressure, and a small amount of n-hexane was added to the residue, which was subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 8 g of a crude product of the title compound. The n-hexane supernatant was distilled off and purified by silica gel column chromatography (methylene chloride: ethyl acetate = 20: 1) to obtain 231 mg of a solid. By purifying both of them by Sephadex LH-20 column chromatography (methylene chloride: methanol = 1: 1), 183 mg of the title compound was obtained as a solid.

7.3 Hz, J₂= 6. 8 Hz), 3.52(1H， br s)， 4.34(2H, t， J = 6.8 Hz), 8.70(1H, s) _{NMR (CDC1 3) d: 1.03} (3H 5 t, J = 7.3 Hz), 1.83 (2H, dt,

7.3 Hz, J ₂ = 6.8 Hz), 3.52 (1H, br s), 4.34 (2H, t, J = 6.8 Hz), 8.70 (1H, s)

MS (FAB ⁺ ): 204 (M ⁺⁺ 1)

[Synthesis example 34] 5-mercapto-4-methylthiothiazol

 a) Methylthiomethylformamide

 In the same manner as in Synthesis Example 29c), methylthiomethylformamide (334 mg) was obtained from formylaminomethyltrimethylammonium hydroxide (1.22 g) and sodium thiomethoxide (350 mg).

_{NMR (CDC1 3) d: 2.18} (3H, s), 4.41 (2H 3 d, J = 6.3 Hz), 8.28 (1H, s) Synthesis Example 29d) in analogy to Isoshia Nomechiruchiome than methylthiomethyl formamidine de 334mg Evening 215 mg was obtained.

NR (CDCL) (5: 2.33 (3H ₅ s), 4.31 (2H, s)

 c) 5-mercapto-4-methylthiothiazole

In the same manner as in Synthesis Example 1, the title compound was obtained from 215 mg of isocyanomethylthiomethane. 71m was obtained.

 NMR (CDCla) d: 2.59 (3H, s), 8.87 (1H, s)

[Synthesis Example 35] 5-Mercaptothiazol-4-carboxylic acid NU-hexyl) amide

 a) N- (Trihexyl) amide 5-tritylthiothiazol-4-carboxylate

 To a solution of 605 mg of 5-tritylthiothiabul-4-carboxylic acid in 10 mL of DMF was added 345 mg of trihydroxybenzotriazole, 431 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, and 0.315 mL of triethylamine. In addition, after stirring at 30 ° C. for 1 hour in an argon atmosphere, 0.300 mL of 1-hexylamine was added, and the mixture was stirred at the same temperature for 23 hours. 80 mL of half-saturated saline was added to the reaction solution, and extracted with 80 mL of ethyl acetate. The organic phase was washed twice with 40 mL of a half-saturated saline solution, dried over anhydrous magnesium sulfate, added with about 5 g of silica gel 60 (Merck, No.9385) and stirred. After filtration, the solvent was distilled off under reduced pressure, a small amount of n-hexane was added to the obtained residue, and the mixture was subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 572 mg of N- (1-hexyl) amide 5-tritylthiothiazol-4-force.

NMR (CDCla) 0.88 (3H ₃ t, J = 6.7 Hz), 1.30-1.38 (6H, m), 1.54-1.61 (2H ₅ m), 3.38 (2H, dd, Ji = 6.8 Hz, J ₂ = 6.6 Hz ), 7.18 (1H, br s), 7.25-7.40 (15 H, m), 8.24 (1H, s)

S (FAB ⁺ ) (with Nal): 509 (MWa)

 b) 5-mercaptothiazol-4-carboxylic acid N- (l-hexyl) amide

6.6 Hz), 7.45(1H, br s), 8.40(1H, s) To a solution of 510 mg of 5-tritylthiothiazol-4-carboxylic acid N- (hexyl) amide in 8 mL of dichloromethane was added 0.81 mL of trifluoroacetic acid and 0.25 mL of triethylsilane, and the mixture was stirred at room temperature for 15 minutes. To the residue obtained by evaporating the solvent under reduced pressure, 6 mL of n-hexane was added, and the mixture was subjected to ultrasonic treatment. After standing, the supernatant was separated. This operation was performed twice more, the supernatants from the three times were combined, and the solvent was distilled off. The remaining powder was purified by silica gel column chromatography (ethyl acetate) to give the title compound (168 mg). NMRiCDCDd:. 0.89 (3H, t , J = 6.8 Hz), 1.29-1 0 (6H, m), 1.58-1.65 (2H, m), 1.8K1H, br s), 3.41 (2H 3 dd,

6.6 Hz), 7.45 (1H, br s), 8.40 (1H, s)

MS (FAB ⁺ ): 245 (M ⁺⁺ 1)

a) 5-トリチルチオチアゾ一ル- 4-カルポン酸 N- (チアゾ一ル -2-ィル）アミ ド[Synthesis Example 36] 5-Mercaptothiazole-4-carboxylic acid N- (thiazol-2-yl) amidotrifluoroacetate

a) 5-Tritylthiothiazol-4-carbonic acid N- (thiazol-2-yl) amide

To a DMF lOmL solution of 605 mg of 5-tritylthiothiazole-4-carboxylic acid was added 345 mg of trihydroxybenzotriazole, 431 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, and 0.315 mL of triethylamine. After stirring at 30 ° C. for 1 hour in an argon atmosphere, 225 mg of 2-aminothiazole was added, and the mixture was stirred at the same temperature for 21 hours. To the reaction solution was added 100 mL of half-saturated saline, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, washed successively with a saturated saline solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue, and the mixture was subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was generated by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give 5-tritylthiothiazol-4-carboxylic acid N- (thiazol-2-yl). ) 254 mg of amide was obtained.

_{NMR (CDC1 3) d: 7.00} (2H, d, J = 3.5 Hz), 7.23-7.32 (9H, m), 7.38-7.41 (6H, m), 7.49 (1H, d = 3.5 Hz), 8.37 (1H , s) ₅ 10.45 (1H, br s)

MS (FAB ⁺ ): 486 (M ⁺ 1)

 b) 5-Mercaptothiazol-4-carboxylic acid N- (thiazol-2-yl) amidotrifluoroacetate

To a solution of 254 mg of 5-tritylthiothiazol-4-carboxylic acid N- (thiazol-2-yl) amide in 4 mL of dichloromethane, 0.405 mL of trifluoroacetic acid and 0.125 mL of triethylsilyl were added. Stirred at room temperature for 15 minutes. The residue obtained by evaporating the solvent under reduced pressure, A small amount of n-hexane was added thereto, subjected to ultrasonic treatment, allowed to stand, the supernatant was removed, and the obtained residue was dried under reduced pressure to obtain the title compound 139m.

_{NMR (DMS0-d 6) δ} : 7.00 (2H, d 5 J = 3.6 Hz), 7.50 (1H, d = 3.6 Hz), 8.93 (1H, s), 14.00 (1H, br s)

MS (FAB ⁺ ): 244 (M ⁺ + 1,5-mercaptothiazol-4-carboxylic acid N- (thiazol-2-yl) amide)

[Synthesis Example 37] 5-Mercaptothiazol-4-carboxylic acid N- (furan-2-yl) methyl adduct

 a) 5-Tritylthiothiazol-4-carboxylic acid N- (furan-2-yl) methylamide 5-Tritylthiothiazol-4-carboxylic acid 605m in a DMF 7.5mL solution was added to 1- 345 mg of hydroxybenzotriazole, 431 mg of tri [3- (dimethylamino) propyl] -3-ethylcarboimide hydrochloride and 0.315 mL of triethylamine were added, and the mixture was stirred at 30 ° C. for 1 hour in an argon atmosphere. Thereafter, 0.200 mL of furfurylamine was added, and the mixture was stirred at the same temperature for 19 hours. To the reaction solution was added 40 mL of half-saturated saline, and the mixture was extracted with 40 mL of ethyl acetate. The organic layer was successively washed with 40 mL of a half-saturated aqueous sodium bicarbonate solution, 40 mL of a 0.05 M hydrochloric acid aqueous solution, and 40 mL of a half-saturated saline solution, dried over anhydrous magnesium sulfate, and added with about 5 g of silica gel 60 (Merck Co. No. 9385) and stirred. . After filtration, the solvent was distilled off under reduced pressure, a small amount of n-hexane was added to the obtained residue, and the mixture was subjected to ultrasonic treatment. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 544 mg of N- (furan-2-yl) methylamide 5-tritylthiothiazol-4-carboxylate.

Thigh (CDCl ₃ ) d: 4.58 (2H, d, J = 5.6 Hz), 6.27 (1H, d, J = 2.7 Hz), 6,32 (1 H, d, J = 2.0 Hz), 7.25-7.39 ( 16H ₃ m), 7.48 (1H, br s), 8.24 (1H, s)

MS (FAB ⁺ ): 483 (MM)

 b) 5-Mercaptothiazol-4-carboxylic acid N- (furan-2-yl) methylamide 5-tritylthiothiazole-4-carboxylic acid N- (furan-2

-Yl) Methylamide (523 mg) gave the title compound (260 mg). Thigh (D images _{- d 6) d: 4.09 (} 2H, d, J = 5.6Hz), 5.87 (1H, s, J = 2.8Hz), 5.95 (1H, d, J = 2.8Hz), 7.15 (1H, s), 8.70 (1H, s), 9.7-9.8 (lH, br s)

a) 5-トリチルチオチアゾ一ル -4-カルボン酸 N-(ピリジン -3-ィル）メチルァミ ド、 [Synthesis Example 38] 5-mercaptothiazol-4-carboxylic acid N- (pyridine-3-yl) methyl amide trifluoroacetate

a) 5-tritylthiothiazol-4-carboxylic acid N- (pyridin-3-yl) methylamide,

 To a solution of 605 mg of 5-tritylthiothiazol-4-carboxylic acid in 7.5 mL of DMF, 345 mg of 1-hydroxybenzotriazole and 431 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride Then, 0.315 mL of triethylamine was added, and the mixture was stirred at 30 ° C. for 1 hour in an argon atmosphere, and then 0.230 mL of 3-aminomethylviridine was added, followed by stirring at the same temperature for 17 hours. To the reaction solution was added 40 mL of half-saturated saline, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was successively washed with 40 mL of a half-saturated aqueous sodium bicarbonate solution and 40 mL of a half-saturated saline solution, dried over anhydrous magnesium sulfate, added with about 3 g of silica gel 60 (Merck, No. 9385) and stirred. After filtration, the solvent was distilled off under reduced pressure, and a small amount of n-hexane was added to the obtained residue, subjected to ultrasonic treatment, and allowed to stand. Then, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 512 mg of N- (pyridin-3-yl) methylamide 5-tritylthiothiazol-4-carboxylate.

_{NMR (CDC1 3) 4.59 (2H} , d, J = 6.3 Hz), 7.20-7.23 (lH 3 m), 7.25-7.39 (15H, m), 7.54 (1H, br t), 7.70 (1H, d, J = 7.6 Hz), 8.24 (1H, s), 8.52 (1H, d = 4.4 Hz), 8.58 (1H, br s)

MS (FAB ⁺ ): 494 (M ⁺⁺ 1).

 b) 5-mercaptothiazol-4-carboxylic acid N- (pyridine-3-yl) methylamide trifluoroacetate

 197 mg of the title compound was obtained from 486 mg of 5-tritylthiothiazol-4-carboxylic acid N (pyridin-3-yl) methylamide in the same manner as in Synthesis Example 15b).

NMR (DMS0-d6) d: 4.71 (2H, d, J = 5.6Hz), 7.8-7.9 (1H 3 m), 8.2-8.3 (1Η, i), 8. 7-8.8 (1H, m), 8.80 (1H, s), 9.07 (1H, s), 10.5-10.6 (1H, br s)

[Synthesis Example 39] 5-Mercaptothiazol-4-carboxylic acid N- (2-formylaminoethyl) amide

 a) N- (2-formylaminoethyl) amide 5-tritylthiothiazol-4-carboxylate '

 In a DMF lOmL solution of 807 mg of 5-tritylthiothiazol-4-carboxylic acid, 459 mg of trihydroxybenzotriazole, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride 574 mg, and triethylamine 0.42 mL was added, and the mixture was stirred at 30 ° C. for 1 hour in an argon atmosphere, and then stirred at the same temperature for 13.5 hours with 264 mg of 2-formylaminoethylamine. 50 mL of half-saturated saline was added to the reaction solution, and extracted with 50 niL of ethyl acetate. The organic phase was successively washed with 50 mL of a half-saturated aqueous sodium bicarbonate solution and 50 mL of a half-saturated saline solution, dried over anhydrous magnesium sulfate, added with about 4 g of silica gel 60 (Merck Co., No. 9385) and stirred. After filtration, the solvent was distilled off under reduced pressure, a small amount of n-hexane was added to the obtained residue, ultrasonic treatment was performed, and after allowing to stand, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 697 mg of N- (2-formylaminoethylamide) 5-tritylthiothiazol-4-carboxylate.

_{NMR (CDC1 3) d: 3.43-3.50} (2H 5 m), 3.53-3.57 (2H, m), 6.74 (1H 5 br s), 7.25 -7.30 (9H, m), 7.35-7.39 (6H 5 m) , 7.56 (1H, brt), 7.70 (1H, d, J = 7.6 Hz), 8.14 (1H, s), 8.25 (1H ₅ s)

MS (FAB ⁺ ): 474 (M ⁺⁺ 1)

 b) 5-Mercaptothiazol-4-carboxylate N- (2-formylaminoethyl) amide 5-Tritylthiothiazol-4-carboxylate N- (2-formylaminoethyl) amide 6

To a solution of 72 mg of dichloromethane in 11 mL of dichloromethane was added 1,095 mL of trifluoroacetic acid and 0.34 mL of triethylsilane, and the mixture was stirred at room temperature for 25 minutes. A small amount of n-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, subjected to ultrasonic treatment, and allowed to stand. Then, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 170 mg of the title compound. _{NMR (CDCl 3) d: 3.54-3.69} (4H, m), 5.19 (1H, br s), 6.90 (1H, br s), 8.05 (1 H, br t), 8.25 (1H, s), 8.48 ( 1H, s)

MS (FAB ⁺ ): 232 (M ⁺⁺ 1)

a) 5-トリチルチオチアゾ一ル- 4-カルボン酸 N-[2-(4-ニトロベンジルォキシカ ルボニル）アミノスルホニルアミノエチル]アミ ド [Synthesis example 40] 5-mercaptothiazol-4-carboxylic acid N- [2- (4-nitrobenzyloxycarbonyl) aminosulfonylaminoethyl] amide

a) N- [2- (4-nitrobenzyloxycarbonyl) aminosulfonylaminoethyl] amide 5-tritylthiothiazol-4-carboxylate

 In the same manner as in Synthesis Example 16a>, 605 m of 5-tritylthiothiazole-4-carboxylic acid and 1.57 g of N- [N- (4-nitrobenzyloxycarbonyl) aminosulfonyl] ethylenediamine were used to obtain 5-tritylthione. 772 mg of a crude purified product of N- [2- (4-nitrobenzoylcarbonyl) aminosulfonylaminoethyl] amide of thiazol-4-carboxylic acid was obtained.

 b) 5-Mercaptothiazol-4-carboxylic acid N- [2- (4-dibenzobenzyloxycarbonyl) aminosulfonylaminoethyl] amide

 In the same manner as in Synthesis Example 4d), the title was obtained from 772 mg of a crude product of 5-tritylthiothiazole-4-carboxylate N- [2- (4-dibenzyloxycarbonyl) aminosulfonylaminoethyl] amide. 343 mg of a crude product of the compound was obtained.

[Synthesis Example 41] 5-mercapto-4- (pyridine-3-yl) thiazol

a) 3-ホルミルアミノメチルビリジン

a) 3-formylaminomethylviridine

 In the same manner as in Synthesis Example 14c), 1.33 g of 3-formylaminomethylpyridine was obtained from 1.02 mL of 3-aminomethylpyridine.

NMR (CDCl ₃ ) d: 4.51 (2H, d, J = 6.0 Hz), 6.1-6.3 (1H ₅ m), 7.2-7.4 (lH, m), 7. 6-7.7 (1Η ₅ m), 8.3-8.4 (lH, m), 8.5-8.6 (2H, m)

 b) 3-Isocyanomethylpyridine

 In the same manner as in Synthesis Example 29d), 337m of 3-isocyanomethylpyridine was obtained from 1.33 g of 3-formylaminomethylpyridine.

NR (CDCL) d: 4.69 ( 2H, s), 7.3-7.4 (1Η, m), 7.7-7.8 (1Η 5 m), 8.6-8.7 (2H, m)

 d) 5-Mercapto-4- (pyridine-3-yl) thiazole

 In the same manner as in Synthesis Example 1, 432 mg of the title compound was obtained from 337 mg of 3-isocyanomethylpyridine.

 NMR (DMSO-de) δ: 7.9-8.0 (2H, m), 8.31 (1H, s), 8.5-8.6 (2H, m), 9.6-9.7 (1H, m)

[Synthesis Example 42] 5-mercaptothiazol-4-carboxylic acid N- [2- (4-nitrobenzyloxycarbonyl) aminocarbonylaminoethyl] amide

 a) 5-Tritylthiothiazol-4-carboxylic acid N- [2- (4-nitrobenzyloxycarbonyl) aminocarbonylaminoethyl] amide

 In the same manner as in Synthesis Example 16a), from 609 mg of 5-tritylthio-4-carboxylic acid and 480 mg of N- (4-diopentobenzyloxycarbonylaminocarbonyl) ethylenediamine hydrochloride, 5-tritylthiothiazol- There was obtained 647m of 4-carboxylic acid N- [2- (4-dimethoxybenzyloxycarbonyl) aminocarbonylaminoethyl] amide.

_{NMR (CDC1 3) d: 3.50-3.60} (4H, m), 5.23 (2H 5 s), 7.26-7.40 (15H 5 m), 7.54 (2H, d, J = 8.8 Hz), 8.22 (2H, d, J = 8.8 Hz), 8.24 (1H ₃ s)

 b) 5-Mercaptothiazol-4-carboxylic acid N- [2- (4-dibenzyloxycarbonyl) aminocarbonylaminoethyl] amide

0.735 mL of trifluoroacetic acid and 0.23 mL of triethylsilane in a solution of 637 mg of N- [2- (4-ditrobenzoyloxycarbonyl) aminocarbonylaminoethyl] amide 5-tritylthiothiazol-4-carboxylate in 18 mL of dichloromethane And add at room temperature for 25 minutes For a while. A small amount of n-hexane was added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was subjected to sonication. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to give the title compound 406m.

_{NMR (CDC1 3) 3.52-3.6Z (4H} 3 m), 4.38 (1H, br s), 5.24 & 5.28 (2H, s, com former), 7.37 (1H 5 m), 7.50 (2H, m), 8.18 -8.30 (1H + 2H, m), 8.25-8.51 (lH, m)

MS (FAB ⁺ ): 426 (M ⁺⁺ 1)

[Synthesis Example 43] 5-Mercaptothiazol-4-carboxylic acid N- (2-acetylaminoethyl) amide

 a) N- (2-acetylaminoethyl) amide 5-tritylthiothiazole-4-carboxylate,

 Analogously to Synthesis Example 16a), from 1.21 g of 5-tritylthiothiazol-4-carboxylic acid and 0.431 mL of N-acetylethyldiamine, 5-tritylthiothiazol-4-carbonic acid N- 1.06 g of (2-acetylaminoethyl) amide was obtained.

_{NMR (CDC1 3) d: 2.83} (3H 3 s), 3.40-3.47 (2H, m), 3.49-3.56 (2H, m), 6.26 (1H, br s), 7.24-7.34 (15H, m), 8.26 (1H, s)

 b) N- (2-Acetylaminoethyl) amide 5-mercaptothiazol-4-carboxylate N- (2-Acetylaminoethyl) amide 5-tritylthiothiazol-4-carboxylate 1.

To a solution of 06 g of dichloromethane in 17 mL, 1.675 inL of trifluoroacetic acid and 0.52 mL of triethylsilane were added, and the mixture was stirred at room temperature for 35 minutes. A small amount of n-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, subjected to ultrasonic treatment, and allowed to stand. Then, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 214 mg of the title compound.

Marauder (CDCl ₃ ) d: 2.08 (3H, s), 3.50-3.58 (2H, m), 3.59-3.62 (2H ₅ m), 4.44 (1H ₅ br s), 6.75 (1H, br s), 8.00 ( 1H, br s), 8.47 (1H, s)

MS (FAB ⁺ ): 246 (MM)

[Synthesis example 44] 2-Methoxyxetyl 5-mercaptothiazol-4-carboxylate

 To a solution of 379 m of 5-mercaptothiazol-4-carboxylate in 10 mL of 2-methoxyethanol was added 300 m of sodium ethoxide, and the mixture was stirred at 60 ° C for 5 hours. The reaction solution was added to a mixture of 50 mL of ethyl acetate and 50 mL of 0.1N-hydrochloric acid, followed by stirring. After standing, the organic phase was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue and subjected to sonication. After standing, the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 243 mg of the title compound.

_{NMR (CDC1 3) 5: 3.4K3H} , s), 3.75- 3 · 77 (2Η, m), 4.53 (2H, t, J = 4.9 Hz), 6.19 (1H, br s), 8.58 (1H, s)

MS (FAB ⁺ ): 220 (MM)

[Synthesis Example 45] 5-Mercaptothiazol-4-carboxylic acid N- (topopentyl) amide

 a) 5-Tritylthiothiazol-4-carboxylic acid N-U-pentyl) amide

 In the same manner as in Synthesis Example 15a), 500 mg of 5-tritylthiothiazol-4-carboxylic acid and

From 1-pentylamine, 216 mg of 5-tritylthiothiazol-4-carboxylic acid N- (l-pentyl) amide was obtained.

NR (CDC1 ₃ ) d: 0.8-0.9 (3H, m), 1.3-1.4 (4H ₃ m), 1.5-1.6 (2H, m), 3.38 (2H ₅ q, J = 6.8 Hz), 7.1-7.2 ( 1H, br s), 7.2-7.3 (9H ₅ m), 7.3-7.4 (6H ₅ m), 8.24 (1H ₅ b) 5-mercaptothiazol-4-carboxylic acid N- (l-pentyl) amide

 70 mg of the title compound was obtained from 215 mg of 5-tritylthiothiazol-4-carboxylic acid N- (toppentyl) amide in the same manner as in Synthesis Example 15b).

_{NMR (CDC1 3) d: 0.8-0.9} (3H 5 m) 3 1.3-1.4 (4H, m), 1.6-1.7 (2H, m), 3.42 (2H, q, J = 6.8Hz), 8.41 (1H, s)

MS (FAB): m / z = 231 (MM) [Synthesis Example 46] 5-mercaptothiazol-4-carboxylic acid [N-butyl] amide] (1-butyl) amine salt

- to obtain a CH ₃ (CH2) ₃ NH ₂ Synthesis Example 19 in analogy to 5-Merukaputochiazo Ichiru 4-carboxylic acid Echiru 284mg than title compound 560 m. '

_{NMR (CD 3 0D) (J} : 0.9-1.0 (6H, m), 1.3-1.4 (4H, m), 1.5-1.6 (8H, m), 2.83 (4H, t, J = 7.6 Hz), 3.3- 3.4 (lH, m), 8.18 (1H, s)

 MS (FAB-): m / z = 215 (M-1)

[Synthesis Example 47] 5-mercaptothiazol-4-carboxylic acid N- (2-methylthioethyl) amid K

 a) 5-Tritylthiothiazole-4-carboxylic acid N- (methylthioethyl) amide 500 mg of 5-tritylthiothiazol-4-carboxylic acid as in Synthesis Example 15a)

From 0.116 mL of 2- (methylthio) ethylamine, 476 mg of N- (2-methylthioethyl) amide 5-tritylthiothiazole-4-carboxylate was obtained.

_{NMR (CDC1 3) ^: 2.15} (3H, s), 1.5-1.6 (2H 5 m), 2.72 (2H, t, J = 6.8Hz), 3.61 (2 H, q, J = 6.8Hz), 7.2- 7.3 (9H, m), 7.3-7.4 (6H ₅ m), 7.5-7.6 (1H, br s), 8.24 (1H, s)

 MS (FAB): m / z = 477 (M-1)

 b) 5-Mercaptothiazol-4-carboxylic acid N- (2-methylthio) amide

 In the same manner as in Synthesis Example 15b), 232 mg of the title compound was obtained from 474 mg of N- (2-methylthioethyl) amide 5-tritylthiothiazol-4-carboxylate.

_{NMR (CDC1 3) (^:} 2.16 (3H 5 s), 2.75 (2H, t, J = 6.8Hz), 3.6-3.7 (2H, m), 8.44 (1 H, s) MS (FAB): m / z = 235 (M-1)

[Synthesis Example 48] 5-Mercaptothiazol-4-carboxylic acid (3-hydroxypropane-1-yl)

 To a solution of 1.893 g of 5-ethyl mercaptothiazol-4-carboxylate in 20 mL of 1,3-propanediol was added 1.497 g of sodium ethoxide, and the mixture was stirred at 60 ° C for 24 hours. The reaction solution was diluted with 100 mL of distilled water and washed with 100 mL of toluene. The aqueous phase was adjusted to pH 2 with 5N hydrochloric acid and extracted three times with 100 mL of ethyl acetate. The combined organic phase was washed with 100 mL of saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. A small amount of n-hexane was added to the obtained residue, subjected to sonication, allowed to stand, and the supernatant was removed. The remaining powder was dried under reduced pressure to obtain 2.182 g of the title compound.

NMR (DMS0-d ₆ ) δ: 1.56 (2H, m), 3.43-3.46 (4H, m), 4.38 (1H, brt), 5.2 (1H, brs), 8.77 & 8.98 & 9.01 (1H, sx 3, comformer mixture)

MS (FAB ⁺ ): 220 (MM)

[Synthesis Example 49] 5-mercapto-4- (thiazol-2-yl) thiazol

 In the same manner as in Synthesis Example 29d), 415 mg of 2-isocyanomethylthiazole was obtained from 1.29 g of 2-formylaminomethylthiazole.

_{NMR (CDC1 3) d: 4.97} (2H, s), 7.42 (1H, d, J = 3.3 Hz), 7.79 (1H, d, J = 3.3 Hz) b) 5- mercapto - 4- (thiazole Ichiru - 2-yl) thiazole

 In the same manner as in Synthesis Example 1, 64 mg of the title compound was obtained from 415 mg of 2-isocyanomethylthiazole.

NMR (DMSO-de) d: 7.51 (lH, d, J = 3.6 Hz), 7.86 (1H, d, J = 3.6 Hz), 8.65 (1H, s)

 [Synthesis Example 50] Butyl 5-tritylthiothiazol-4-carboxylate

 to s

(C ₆ H ₅ ) ₃ CS COO (CH2) ₃ CH ₃

 DMFlOmL was added to 807 mg of 5-tritylthiothiazol-4-carboxylic acid, 86 mg of potassium iodide, and 276 mg of carbon dioxide, and 0.43 mL of I-butane bromide was added, followed by stirring at room temperature for 21 hours. The reaction solution was poured into 50 mL of a 10 I aqueous sodium chloride solution and extracted with 50 mL of ethyl acetate. 10 The organic phase was washed twice with 50 mL each of an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solid matter was removed by filtration. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain 754 mg of the title compound.

_{NMR (CDCl 3) d: 0.94} (3H, t, J = 7.3 Hz), 1.41-1.50 (2H, m), 1.72-1.79 (2H, m), 4.34 (2H, t 5 J = 6.8 Hz), 7.25 -7.38 (15H, m), 8.37 (1H, s)

[Synthesis Example 51] 4- (N-methylcarbamoylacetyl) -5-tritylthiothiazol

 a) Ethylthiocarbonylacetic acid

 To 15 g of diphosphorus pentoxide was added 30 mL of chloroform and 15 mL of getyl ether, and the mixture was stirred at an external temperature of 60 ° C for 19 hours. After evaporating the reaction solvent under reduced pressure, 5.97 g of malonic acid, 68 mL of chloroform, 11 mL of tetrahydrofuran, and 2 mL of ethanethiol were added, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was diluted with 200 mL of getyl ether, and extracted with 150 mL of 5% sodium hydrogencarbonate and 100 mL. The combined aqueous phase was adjusted to pH 2 with a 5N aqueous hydrochloric acid solution and then extracted with 200 mL of ethyl acetate. After drying over anhydrous magnesium sulfate, the solid was filtered off, and the solvent was distilled off under reduced pressure to obtain 2.95 g of ethyl thiocarbonylacetic acid.

 Country CDC1: 1.30 (3H, t, J = 7.3 Hz), 2.98 (2H, q, J = 7.3 Hz), 3.64 (2H, s) b) 4-Ethylthiocarbonylacetyl-5-tritylthiothiazo One liter

To a solution of 1.21 g of 5-tritylthiothiazol-4-carboxylic acid in 15 mL of THF was added 1, 535-Carbonylbis-1H-imidazole (535 mg) was added, and the mixture was stirred at room temperature for 15 hours under an argon atmosphere. Separately, 0.98 g of ethylthiocarbonylacetic acid was dissolved in 15 mL of THF, 0.38 g of magnesium ethoxide was added, the mixture was stirred at room temperature for 1 hour under an argon atmosphere, the solvent was distilled off under reduced pressure, and 5 mL of tetrahydrofuran was added. This tetrahydrofuran solution of magnesium ethyl thiocarbonyl acetate was added to the above-mentioned THF solution of 4-[(imidazole-1-yl) carbonyl] -5-tritylthiothiazol, and the mixture was stirred at room temperature for 20 hours under an argon atmosphere. The reaction solution was opened with 80 niU of a 1 N aqueous hydrochloric acid solution, and extracted with 80 mL of ethyl acetate. The organic phase was washed with 80 mL of 5% aqueous sodium hydrogen carbonate solution and 80 mL of 20% brine, dried over anhydrous magnesium sulfate, and the solid was filtered off. The solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) gave 567 mg of 4-ethylthiocarbonylacetyl-5-tritylthiothiazol.

NMR (CDCl ₃ ) d: 1.27 (3H, t, J = 7.4 Hz), 2.94 (2H ₃ q, J = 7.3 Hz), 4 · 32 (2Η, s), 7.27-7.36 (15H, m), 8.26 (1H ₅ s)

 c) 4- (N-methylcarbamoylacetyl) -5-tritylthiothiazole

 10 mL of 40% methylamine solution in methylamine was added to 1.22 g of 4-ethylthiocarbonacetyl-5-tritylthiothiazol, and the mixture was heated at an external temperature of 40 in a sealed tube for 17.5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 226 mg of the title compound.

_{NMR (CDC1 3) d: 2.85} (3H, d, J = 4.9 Hz), 4.09 (2H, s), 7.29-7.35 (15H, m), 8. 28 (1H, s)

 [Synthesis Example 52] 5-mercapto-4- (pyridine-4-yl) thiazol

a) 4- (ホルミルアミノメチル）ピリジン

a) 4- (Formylaminomethyl) pyridine

4-Aminomethylviridine 1. OmL was dissolved in lOmL of ethyl formate and stirred at 40 ° C for 2 days. The solvent was distilled off and the residue was dried under reduced pressure to obtain 1.515 g of 4- (formylaminomethyl) pyridin. Thigh (CDCl ₃ ) d: 4.52 (2H, d, J = 6.1 Hz), 6.15, 6.38 (total 1H, 2brs, conformer), 7.24-7.27 (2H, m), 8.20, 8.55 (total 1H, 2s, confomer), 8.55-8.6 2 (2H, m)

MS (FAB ⁺ ): 137 (M ⁺⁺ 1)

 b) 4-Isocyanomethylpyridine

 In the same manner as in Synthesis Example 29d), 322 m of 4-isosianomethylpyridine was obtained from 1.51 of 4- (formylaminomethyl) pyridine.

_{NMR (CDC1 3) cJ: 4.70} (2H 5 s), 7.31 (2H, d, J = 5Hz), 8.67 (2H, d, J = 5Hz)

MS (EI): m / z = 118 (M ⁺ )

 b) 5-Mercapto-4- (pyridine-4-yl) thiazole

 The title compound 334m was obtained from 4-isocyanomethyl pyridine 322m in the same manner as in Synthesis Example 1.

_{NMR (CDC1 3) <5:} 8.35 (1H, s), 8.47 (2H, d, J = 7.2 Hz), 9.2- 9.3 (2H, br s) MS (FAB): m / z = 195 (M + + 1)

[Synthesis Example 53] 5-Ethoxytyl 5-mercaptothiazol-4-carboxylate

 In the same manner as in Synthesis Example 44, 379 mg of the title compound was obtained from 379 mg of ethyl 5-mercaptothiazole-4-carboxylate and 2-ethoxyethanol.

 MS (FAB-): m / z = 232 (M-1)

[Synthesis Example 54 2-Methylthioethyl 4-mercaptothiazol-4-carboxylate]

 In the same manner as in Synthesis Example 30, 379 mg of the title compound was obtained from 379 mg of ethyl 5-mercaptothiazol-4-carboxylate and 5 mL of 2-methylthioethanol.

 MS (FAB "): m / z = 236 (M-1)

[Synthesis Example 55] 5-mercaptothiazole-4-carboxylic acid (4-hydroxybutane-;

 The title compound 495m was obtained from 473 mg of ethyl 5-mercaptothiazol-4-carboxylate and 4.4 mL of 1,4-butanediol in the same manner as in Synthesis Example 30.

 NMR (DMSO-de) δ: 1.5-1.6 (2H, m), 1.7-1.8 (2H, m), 3.44 (2H, t, J = 6.4Hz), 4.33 (2H, t, J = 6.4Hz), 8.68 (1H, s)

 MS (FAB '): m / z = 234 (M-1)

[Synthesis Example 56〗 5-Mercaptothiazol-4-carboxylic acid (3-methoxypropane-1-yl)

 In the same manner as in Synthesis Example 30, 568 mg of 5-mercaptothiazol-4-carboxylate and 472 mg of 3-methoxy-1-propanol were obtained to obtain 472 mg of the title compound.

 NMR (DMSO-de) δ: 1.9-2.0 (2H, m), 3.25 (3H, s), 3.46 (2H, t, J = 6.4Hz), 4.3-4.4 (2H, m), 8.69 (1H, s )

MS (FAB-): m / z = 234 (M ⁺ -1)

[Synthesis Example 57] 5-Mercaptothiazol-4-carboxylic acid (5-hydroxypentan-1-yl)

 In the same manner as in Synthesis Example 44, 472 mg of the title compound was obtained from 568 mg of ethyl 5-mercaptothiazol-4-carboxylate and 8 mL of 1.5-pentanediol.

MS (FAB): m / z 2 248 (M ⁺ +1)

[Synthesis Example 58] 5-mercaptothiazole-4-isopropyl carboxylate COOCH (CH ₃ ) ₂

 In the same manner as in Synthesis Example 44, 464 mg of the title compound was obtained from 568 mg of ethyl 5-mercaptothiazol-4-carboxylate and 10 mL of 2-propanol.

MS (FAB): m / z = 204 (M ⁺ +1)

[Synthesis Example 59] 2- (2-hydroxyethoxy) ethyl 5-mercaptothiazole-4-carboxylate

 In the same manner as in Synthesis Example 44, 702 mg of the title compound was obtained from 568 mg of ethyl 5-mercaptothiazol-4-carboxylate and 8 mL of di (ethylene glycol).

[Synthesis Example 60] 5-mercaptothiazol-4-carboxylic acid (2,2-dimethyl-3-hydroxypropane-1-yl)

 a) 5-Tritylthiothiazol-4-carboxylic acid (2,2-dimethyl-3-hydroxypropan-1-yl)

605 mg of 5-tritylthiothiazol-4-carboxylic acid was dissolved in 3 mL of dichloromethane, and [3- (dimethylamino) propyl] -3-ethylcarbodiimid hydrochloride 345 mg, 4- (N ₅ N-dimethylamino) ) 55 mg of pyridine and 344 mg of 2,2-dimethyl-1,3-propanediol were added, and the mixture was stirred at room temperature overnight. The reaction solution was added to 70 mL of water, and extracted with 70 mL of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5-tritylthiothiazol-1-carboxylic acid (2,2-dimethyl-3-hydroxypropane). -Toil) 347 mg were obtained.

_{NMR (CDCl 3) d: 0.99} (6H, s), 3.37-3.39 (2H, br s), 4.18 (2H 5 s), 7.25-7.36 (15H, m), 8.38 (1H, s)

MS (API); m / z 490 (M ⁺ +1)

 b) 5-Mercaptothiazol-4-carboxylic acid (2,2-dimethyl-3-hydroxypropan-1-yl)

 In the same manner as in Synthesis Example 4d), 308 mg of the title compound was obtained from 610 mg of 5-tritylthiothiazol-4-carboxylic acid (2,2-dimethyl-3-hydroxypropane-tolyl).

NMR (CDCl ₃ ) d: 1.02 (6H, s), 3.50 (2H, s), 425 (2Η, s), 8.74 (1H, s)

 MS (FAB) m / z 248 (M)

[Synthesis example 61] 5-mercaptothiazol-4-carboxylic acid (2,3-dihydroxypropane-1-yl)

 a) 5-Tritylthiothiazole-4-carboxylic acid (2,3-dihydroxypropane-1-yl)

 156 mg of glycerol was suspended in 5 mL of THF, 403 mg of 5-tritylthiothiazole-4-carboxylic acid, 586 mg of triphenylphenylphosphine, and 0.354 mL of getyl azodicarboxylate were added, and the mixture was stirred at room temperature for 2.5 hours. The residue obtained by concentrating the reaction solution to dryness under reduced pressure was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give 5-tritylthiothiazol-4-carboxylic acid (2 , 3-dihydroxypropane-1-yl) 225m.

 b) 5-Mercaptothiazole-4-carboxylic acid (2,3-dihydroxypropane-1-yl)

 In the same manner as in Synthesis Example 4d), 174 mg of the title compound was obtained from 225 mg of 5-tritylthiothiazol-4-carboxylic acid (2,3-dihydroxypropane-1-yl).

[Synthesis Example 62] 5-mercaptothiazole-4-carboxylic acid (3-hydroxybutane-1-yl)

 a) 5-Tritylthiothiazol-4-carboxylic acid (3-hydroxybutan-1-yl) Dissolve 807 mg of 5-tritylthiothiazol-4-carboxylic acid in 4 mL of dichloromethane. Add 460 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarposimid hydrochloride, 73 mg of 4- (N, N-dimethylamino) pyridine and 0.359 mL of 1,3-butanediol and terminate at room temperature. Stirred at night. The reaction solution was added to 70 mL of water, and extracted with 70 mL of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5-tritylthiothiazol-4-carboxylic acid (3-hydroxybutane-1-yl). ^ 85mg was obtained.

NMR (CDCl ₃ ) d: 1.22 (3H, d, J = 6 Hz), 1.80-1.88 (1H, m), 1.92-1.98 (1H, m), 3.95-3.99 (lH, m), 4.34-4.40 (1H, m), 4.59-4.65 (lH, m), 7.28-7.37 (15H,), 8.37 (1H, s) '

MS (API); m / z 476 (M ⁴ +1)

 a) 5-Mercaptothiazol-4-carboxylic acid (3-hydroxybutan-1-yl) In the same manner as in Synthesis Example 4d), 5-tritylthiothiazol-4-carboxylic acid (3-hydroxybutane) -: I-yl) From 580 m, 284 mg of the title compound was obtained.

NMR (CDCl ₃ ) d: 1.27 (3H ₅ d, J = 6 Hz), 1.86-191 (1Η, m), 1.93-2.04 (1H, m), 4.01-4.09 (1H, m) ₅ 4.41- 4.47 (1H, m), 4.63-4.69 (lH, m), 8.65 (1H, s)

 MS (O); m / z 234 (M ++ 1)

[Synthesis Example 63] 5-mercaptothiazole-4-carboxylic acid (3-hydroxy-3-methylbut-1-yl)

a) 5-Tritylthiothiazole-4-carboxylic acid (3-hydroxy-3-methylbutane-1-yl) W

Dissolve 807 mg of 5-tritylthiothiazole-4-carboxylic acid in 4 mL of dichloromethane.

 [460 mg of 3- (dimethylamino) propyltriethylcarbodiimide hydrochloride, 73 mg of 4- (N, N-dimethylamino) pyridine and 417 mg of 3-methyl-1,3-butanediol were added, and the mixture was stirred at room temperature overnight. . The reaction solution was added to 70 mL of water, and extracted with 70 mL of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5-tritylthiothiazol-4-carboxylic acid (3-hydroxy-3-methylbutane). -Il) 729 mg were obtained.

_{NMR (CDC1 3) d: 1.29} (6H 3 s), 1.98 (2H, t, J = 6.8 Hz), 4.51 (2H, t, J = 6.8 Hz), 7.26-7.29 (9H, m), 7.34-7.36 (6H, m), 8.35 (1H, s)

MS (FAB); m / z 490 (M ⁺⁺ 1)

 b) 5-Mercaptothiazol-4-carboxylic acid (3-hydroxy-3-methylbutane-1-yl)

 366 mg of the title compound was obtained from 725 mg of 5-tritylthiothiazole-4-carboxylic acid (3-hydroxy-3-methylbutane-; I-yl) in the same manner as in Synthesis Example 4d).

_{NMR (CDC1 3) (5:} 1.35 (6H, s), 2.04 (2H, t, J = 6.4 Hz), 4.56 (2H, t, J = 6.4 Hz), 8.75 (1H 5 s)

MS (FAB); m / z 248 (M ⁺ +1)

[Synthesis example 64] 4- (4-Hydroxybutanol) -5-mercaptothiazol

 a) 4- (4-pentenyl) -5-tritylthiothiazole

To 2.2 g of magnesium was added 4 mL of getyl ether, and a solution of 4.6 mL of 4-bromo-1-butene in 20 mL of getyl ether was added dropwise at a rate at which the solvent was slowly refluxed under an argon atmosphere. A solution of 4.07 g of 5-tritylthiothiazol-4-carboxylic acid (N-methoxy-N-methyl) amide in 80 mL of THF was ice-cooled under an argon atmosphere, and 11.5 mL of the above Grignard solution was added dropwise. After stirring at the same temperature for 2 hours, an aqueous solution of ammonium chloride was added, and the mixture was extracted twice with ethyl acetate. Combine the organic layers and wash with brine, anhydrous magnesium sulfate W

The residue obtained by drying under reduced pressure and the solvent was concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4- (4-pentenyl) -5-tritylthio. 2.89 g of thiazole were obtained.

NMR (CDCl ₃ ) d: 2.4-2.6 (2H, m), 3.1-3.2 (2H ₃ m), 5.0-5.2 (2H ₅ m), 5.8-6.0 (1 H, m), 7.2-7.4 (15H ₅ m), 8.28 (1H ₅ s)

 b) 4- (4,5-dihydroxypentyl) -5-tritylthiothiazole

 2.61 g of 4- (4-pentenyl) -5-tritylthiothiazol is suspended in 40 mL of acetone, 80 mL of acetonitrile, and 40 mL of water, and 1.38 g of .4-methylmorpholine-N-oxide 1.38 g of 4% -tetraoxide An osmium aqueous solution (l.OmL) was added, and the mixture was stirred at 40 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, brine was added, and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give 4- 1.21 g of (4,5-dihydroxypentyl) -5-tritylthiothiazole was obtained.

 NMR (CDCL) d: 1.8-2.0 (2H, m), 3.0-3.8 (5H, m), 7.2-7.4 (15H, m), 8.29 (1H, s)

 c) 4-oxo-4- (5-tritylthiothiazol-4-yl) butyraldehyde

 Dissolve 1.01 g of 4- (4,5-dihydroxypentyl) -5-tritylthiothiazol in 20 mL of dichloromethane and add 1.80 g of sodium carbonate and 1.88 g of lead tetraacetate at 30 ° C under an argon atmosphere. The mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction solution, the mixture was filtered through celite, the organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 4-oxo-4- (5-tritylthiothiazol-4-yl) butyraldehyde (806 mg). Got.

_{NMR (CDC1 3) d: 2.8-2.9} (2H, m), 3.4-3.5 (2H, m), 7.2-7.4 (15H, m), 8.29 (1H, s), 9.89 (1H, s)

 d) 4- (4-hydroxybutanol) -5-tritylthiothiazole

To a solution of 735 mg of 4-oxo- 4- (5-tritylthiothiazol-1-yl) butyraldehyde in 15 mL of THF at -40 ° C under argon atmosphere was added 31 mg of sodium borohydride, and -20 ° The mixture was stirred for 30 minutes while heating to C. Water was added to the reaction solution, and the pH was adjusted to 3 with aqueous hydrochloric acid. The residue obtained by extracting twice with ethyl acetate, washing with brine and drying over anhydrous magnesium sulfate was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 5: 1) to give 4- ( 436 mg of 4-hydroxybutanol) -5-tritylthiothiazole was obtained.

NMR (CDCl ₃ ) d: 1.9-2.0 (2H, m), 2.19 (1H, t, J = 5.7 Hz), 3.1-3.2 (2H, m), 3.6-3.7 (2H, m), 7.2- 7.4 (15H ₃ ), 8.29 (1H, s)

 e) 4- (4-hydroxyphenyl) -5-mercaptothiazole

 In the same manner as in Synthesis Example 4d), the title compound was obtained from 4- (4-hydroxybutanol) -5-tritylthiothiazole 205m.

[Synthesis Example 65] 4- (4,5-dihydroxypentyl) -5-mercaptothiazole

 In the same manner as in Synthesis Example 4d), the title compound was obtained from 177 mg of 4- (4,5-dihydroxypentyl) -5-tritylthiothiazole.

 [Test Example 1] Antibacterial activity

In the following, the minimum inhibitory concentrations (MIC, zg) of various representative compounds of the novel potent rubanem derivatives of the present invention against various pathogens were determined by the method described in CHEMOTHERAPY, vol. 16, No. 1, 99, 1968. The results were shown in Table 1 below. Measurements media are SensitivityDisk agar-N + 5¾ Horse blood , inoculum amount is 10 ⁶ CFU.

Test Organisms Example 1 Example 11 Example 14 Example 24 Example 33

 Compound of compound of compound of compound of compound of compound

 S. aureus 209P JC-1 0.063 0.016 0.063 0.031 0.063

 S. pneumoniae R6 0.016 0.008 0.016 0.016 0.016

 S. pneumoniae 197 * 0.5 0.25 0.25 0.5 0.5

 S. pneumoniae PRC53 * 0.063 0.063 0.063 0.063 0.125

 E. coli W4680 0.25 0.5 4 1 0.5

 . pneumoniae GN69 0.25 0.5 4 1 0.25

 M. catarrhal is W-0500 0.016 0.016 0.031 0.031 0.016

 H. influenzae Rd 0.031 0.016 0.031 0.016 0.031

 H. influenzae 870 ** 0.125 0.063 0.125 0.063 0.125

 H. influenzae PRC44 ** 0.125 0.063 0.125 0.125 0.125

 * PRSP

 ** BLNAR

Test Organisms Example 34 Example 57 Example 58 Example 62 Imidenem Compound A

 Compound of compound compound of compound compound of

 S. aureus 209P JC-1 0.063 0.063 0.031 0.031 0.016 0.031

S. pneumoniae E6 0.016 0.016 0.016 0.008 0.008 0.016

S. pneumoniae 197 * 0.5 0.25 0.25 0.25 1 2

S. pneumoniae PRC53 * 0.125 0.063 0.063 0.063 0.125 0.25

E. coli W4680 1 2 16 0.25 0.125 1.pneumoniae GN69 1 2 16 0.25 0.125 1.catarrhal is W-0500 0.031 0.031 0.031 0.016 0.063 0.031

H. influenzae Rd 0.031 0.031 0.016 0.031 1 0.031

H. influenzae 870 ** 0.063 0.063 0.031 0.063 4 0.125

H. influenzae PRC44 ** 0.063 0.125 0.125 0.063 16 0.125

* PRSP

 ** BLNAR

 Compound A: (m, 5S, 6S) -6-((lR) -1-hydroxyethyl) -1-methyl-2- (thiazol-5-yl) thio

 -1-Carpapen-2-em-3-potassium sodium

The present invention provides a compound of formula (I) which is useful for pneumococci including PRSP, influenzae including LNAR, and various pathogens including LnAR-producing mamase-producing bacteria, in particular, pneumococci including PRSP. It shows strong antibacterial activity.

Claims

 Scope of Claim Compound of general formula (I) or a pharmaceutically acceptable salt thereof:

 (I)  [In the above formula, R ¹ represents a hydrogen atom or a methyl group, R ² and R ³ may be the same or different and are each a hydrogen atom,  Halogen atom,  Formyl group,  Nitrile group,  An amino group which may be substituted,  An optionally substituted lower alkyl group,  Optionally substituted rubamoyl group,  An optionally substituted lower alkylcarbonyl group,  An optionally substituted lower alkoxycarbonyl group, an optionally substituted arylcarbonyl group,  An optionally substituted heteroarylcarbonyl group, a carboxyl group,  An aryl group which may be substituted,  An optionally substituted heteroaryl group,  A lower alkylthio group, or Lower alkylsulfonyl group, Represents However, R ² and R ³ do not both represent a hydrogen atom, R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo. ] 2. R ² and IT, which may be the same or different, it it,  Hydrogen atom,  Halogen atom,  Formyl group,  Nitrile group,  Optionally substituted amino group (at least one hydrogen atom of this amino group may be substituted with a formyl group, a lower alkoxycarbonyl group, an aminocarbonyl group, or an aminosulfonyl group)  An optionally substituted lower alkyl group,  An optionally substituted carbamoyl group (one or more hydrogen atoms of the carbamoyl group may be a substituted lower alkyl group, a lower cycloalkyl group, an aryl group, a heteroaryl group, or a substituted (May be substituted with a good lower alkoxy group)  An optionally substituted lower alkylcarbonyl group,, an optionally substituted lower alkoxycarbonyl group,  Phenylcarbonyl group, naphthylcarbonyl group  An optionally substituted heteroarylcarbonyl group (the heteroaryl is a 5- or 6-membered aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur) ,  Carboxyl group,  Phenyl, naphthyl,  An optionally substituted heteroaryl group, wherein the heteroaryl is a 5- or 6-membered aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur; A lower alkylthio group, or Lower alkylsulfonyl group  Represents However, unless R ² and R ³ are both hydrogen atoms, A compound according to claim 1 or a pharmaceutically acceptable salt thereof. ' 3. R ² and R ³ may be the same or different,  Hydrogen atom,  Halogen atom,  Formyl group,  Nitrile group,  An optionally substituted amino group (one or more hydrogen atoms of the amino group may be substituted with a formyl group, a lower alkoxycarbonyl group, an aminocarbonyl group, or an aminosulfonyl group),  An optionally substituted lower alkyl group (at least one hydrogen atom of the alkyl group may be substituted with a hydroxyl group),  Optionally substituted rubamoyl group (at least one hydrogen atom of the rubamoyl group is a lower alkyl group (at least one hydrogen atom of the alkyl group is a hydroxyl group, an amino group, an alkamoyl group, an amino lower alkyl group) Group, formylamino group, lower alkylcarbonylamino group, aminosulfonylamino group, aminocarbonylamino group, lower alkoxy group, thiazolyl group, furyl group, pyridyl group, or lower alkylthio group Or lower cycloalkyl, phenyl, naphthyl, thiazolyl, furyl, pyridyl, or lower alkoxy).  An optionally substituted lower alkylcarbonyl group (at least one hydrogen atom of the alkyl group may be substituted with a hydroxyl group or an N-methylcarbamoyl group) an optionally substituted lower alkoxycarbonyl group (the alkoxy group At least one hydrogen atom of the group may be substituted by a hydroxyl group, a carbamoyl group, a lower alkoxy group, a lower alkylthio group), Heteroarylcarbonyl group (The heteroaryl is furan, pyrrole, A heterocycle selected from the group consisting of azoles and pyridines)  Carboxyl group,  Phenyl, naphthyl,  Heteroaryl groups (the heteroaryl is a heterocycle selected from the group consisting of furan, pyrrole, thiazol, and pyridine),  A lower alkylthio group, or  Lower alkylsulfonyl group  Represents However, unless R ² and R ³ are both hydrogen atoms, A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 4. R ² and R ³ may be the same or different,  Hydrogen atom,  Formyl group,  Nitrile group,  An amino group which may be substituted (at least one hydrogen atom of the amino group may be substituted with a formyl or methoxycarbonyl group),  Hydroxymethyl group,  Optionally substituted labamoyl groups (at least one hydrogen atom of the labamoyl group may be a methyl group, an ethyl group, a propane-1-yl group, an isopropyl group, a butane- 1-yl group, pentyl-1-yl group, hexane-11-yl group, cyclopropyl group. Cyclohexyl group, dimethyl group, N-hydroxylmethyl group, 2-hydroxyethyl group, 3-hydroxy group Propane 1-yl, 2-aminoethyl, 2-formylaminoethyl, 2-acetylaminoethyl, 2-aminosulfonylaminoethyl, 2-aminocarbonylaminoethyl, 2-methyl Toxityl group, (Pyridine-1-yl) methyl group, (pyridine-1-yl) methyl group, (thiazo-1-yl) methyl group, (furan-2-yl) methyl group, methoxy group, 2 — May be substituted by methylthioethyl, phenyl or thiazo-1-yl) An optionally substituted lower alkylcarbonyl group (where the optionally substituted lower alkyl is a methyl group, an ethyl group, an N-methylcarbamoylmethyl group, a 3-hydroxypropane-1-yl group, or 3, 4-dihydroxybutane-1-yl group)  An optionally substituted lower alkoxycarbonyl group (here, an optionally substituted lower alkoxy group refers to a methoxy group, an ethoxy group, a (propan-1-yl) oxy group, an isopropyloxy group, — 1-yl) oxy, carbamoylmethoxy, 2-hydroxyethoxy, (3-hydroxypropane-1-yl) oxy, (2,3-dihydroxypropane-11-yl) oxy, (4-hydroxybutane-11-yl) oxy, (3-hydroxybutane-1-yl) oxy, (5-hydroxypent-1-yl) oxy, (2,2-dimethyl-3-) Hydroxypropane (11-yl) oxy group, (3-hydroxy-3-methylbutane-11-yl) oxy group, 2-methoxetoxy group, 2-ethoxyethoxy group, (3-methoxy) Shipuropan one 1 one I le) Okishi group, 2 - represents a (2-hydroxyethoxy) ethoxy group or 2methylthioethoxy group,),  Carboxyl group,  A heteroaryl group (where the heteroaryl group is a heterocyclic ring selected from the group consisting of a pyridine-13-yl group, a pyridine-14-yl group, and a thiazo-l-2-yl group),  Methylthio group,  Or a methanesulfonyl group, The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. 5. R ² is a hydrogen atom, those wherein R ³ is a force Rubamoiru group, compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4. 6. R ² is a hydrogen atom, R ³ is one that is Asechiru group, compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4. 7. R ² is a hydrogen atom, is R ³ is ethoxycarbonyl group, compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4. 8. R ² is a hydrogen atom, R ³ is as methoxycarbonyl group, compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4. 9. R ² is a hydrogen atom, R ³ is one that is (2-t Dorokishi) ethoxycarbonyl group, a compound according to any one of claims 1-4. 10. The compound according to claim 1, wherein R ² is a hydrogen atom, and R ³ is a (3-hydroxypropane-11-yl) oxycarbonyl group. Or a pharmaceutically acceptable salt thereof. 1 1. R ¹ is as a methyl group, according to claim 1-1 0 any one the title compound or a pharmaceutically acceptable salt thereof for mounting the. 1 2. R ⁴ are those a group which can be hydrolyzed in vivo, the compounds of any one of claims 1-1 1. 1 3. R ⁴ is a bivaloyloxymethyl group, a 1- (cyclohexyloxyl-carbonyloxy) ethyl group, a 1 _ (isopropoxycarbonyloxy) ethyl group. 1,3 dioxolene 4-yl) methyl group, 1 (neopentyloxycarbonyloxy) ethyl group, 1 1 (2-cyclohexylethoxycarbonyloxy) ethyl group, 11-[(hexane-11-yl) oxycarbonyloxy] ethyl group, isopropyloxycarboxyloxymethyl group, cyclohexyloxycarbonyloxy group Xymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, isopentyloxycarbonyloxymethyl group, (1-ethylpropane-11-yl) carbonyloxymethyl group, The compound according to any one of claims 1 to 12, which represents an isobutyl carbonyldioxymethyl group. 14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 16. The pharmaceutical composition according to claim 14 or 15, which is used as an antibacterial agent. 17. An antibacterial agent comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 18. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition. 19. Use of a pharmaceutical composition of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of an antibacterial agent. 20. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 14 to 16 includes a human. A method for preventing or treating an infectious disease, comprising administering to an animal.