JP2007291048A - MEDICINE CONTAINING 1beta-METHYLCARBAPENEM DERIVATIVE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To develop a carbapenem derivative having an excellent treatment or preventive effect on bacterial infectious diseases, especially, infectious diseases of a respiratory system. <P>SOLUTION: The present invention provides a medicine containing, as an effective ingredient, a carbapenem compound represented by general formula (I) (wherein A represents a 1-6C alkyl group which may be substituted, a substituted 2-4C alkenyl group or 3-6C cycloalkyl group, or a 4-6 membered heterocyclic group which may be substituted; a mono-substituted amino group or a di-substituted amino group, n is 1 or 2, and X represents an oxygen or sulfur atom), a pharmaceutically acceptable salt or an ester derivative thereof. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a medicament containing a carbapenem compound (I) having excellent antibacterial activity, or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient (especially bacterial infections such as infections to the respiratory system) Antibacterial agent for treating or preventing

  Development of carbapenem derivatives having an excellent therapeutic or preventive effect against bacterial infections, particularly respiratory infections, is desired. In particular, the carbapenem system for oral use that has excellent antibacterial activity against pneumococci including PRSP (penicillin-resistant pneumococci), which is resistant to the major causative bacteria of community-acquired respiratory infections, and influenza bacteria including ampicillin-resistant haemophilus Development of antibacterial agents is desired.

  Patent Document 1 discloses the following structure

A 1-methylcarbapenem compound characterized by having a catechol derivative is disclosed. On the other hand, the compound of the present invention does not have such a catechol derivative and has a different chemical structure. Therefore, based on the invention described in Patent Document 1, those skilled in the art do not conceive the compound of the present invention. Patent Document 1 describes that the compound described in Patent Document 1 exhibits excellent antibacterial activity against imipenem-resistant Pseudomonas aeruginosa, but it is resistant to the main causative bacteria of community-acquired respiratory infections. The antibacterial activity against PRSP and ampicillin-resistant Haemophilus influenzae which are bacteria is not specifically described. Therefore, it cannot be predicted by those skilled in the art based on the invention described in Patent Document 1 that the compound of the present invention has excellent antibacterial activity against PRSP and ampicillin-resistant Haemophilus influenzae.

  Patent Document 2 discloses the following structure

[In the above structure, R ¹ and R ² each independently represent a hydrogen atom or a substituted or unsubstituted lower alkyl group. 1-methylcarbapenem compounds having On the other hand, the compound of the present invention does not have the above structure and has a different chemical structure. Patent Document 2 does not describe antibacterial activity against PRSP and ampicillin-resistant Haemophilus influenzae. Therefore, it cannot be predicted by those skilled in the art based on the invention described in Patent Document 2 that the compound of the present invention has excellent antibacterial activity against these resistant bacteria.

  Non-Patent Document 1 discloses N-acetylpiperidin-3-ylthio group.

1-methylcarbapenem compounds having the following are described: On the other hand, the compound of the present invention has an N-substituted azetidin-3-ylthio group (azetidine ring is a 4-membered ring) or an N-substituted pyrrolidin-3-ylthio group (pyrrolidine ring is a 5-membered ring). The chemical structure is different. The test example shows that the antibacterial activity is improved by reducing the size of the ring (from 6-membered ring to 4-membered ring). Non-patent document 1 does not describe antibacterial activity against PRSP and ampicillin-resistant Haemophilus influenzae. Therefore, it is not predictable by those skilled in the art based on the invention described in Non-Patent Document 1 that the compound of the present invention has excellent antibacterial activity against these resistant bacteria.
JP-A-5-230061 JP 2000-86660 A J. Antibiotics 1997, 50 (7), 621-627

  As a result of various studies on the carbapenem compounds over many years, the inventors have introduced a specific functional group into the side chain at the 2-position of the 1-methylcarbapenem compound, whereby the compound (I) of the present invention is converted into a conventional carbapenem derivative. The antibacterial activity and bactericidal activity are stronger than those of the above, and it is found that the present invention is effective as a medicine (antibacterial agent) for treating or preventing (particularly treating) bacterial infections, particularly respiratory infections. It came to.

  The present invention provides a general formula

[In the formula, A, which may be substituted C ₁ -C ₆ alkyl group (the substituent is C ₁ -C ₆ alkoxy group, an amino group, selected from the group consisting of phenyl and pyridyl groups.); Substituted A C ₂ -C ₄ alkenyl group (the substituent is a phenyl group or a pyridyl group); a C ₃ -C ₆ cycloalkyl group; an optionally substituted 4- to 6-membered heterocyclic group (the heterocyclic group) Has 1 to 3 hetero atoms which are the same or different from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and the substituent is a C ₁ -C ₆ alkyl group, an amino group, a hydroxyl group or a carbamoyl group. , A morpholino group, a cyano group, and an acetyl group); a mono-substituted amino group (the substituent is a phenyl group or a pyridyl group); or a di-substituted amino group {the substituent is C ₁ -C ₆ alkyl group and a substituted A 5- or 6-membered unsaturated heterocyclic group which may have the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring. Is selected from the group consisting of C ₁ -C ₃ alkyl groups, amino groups, hydroxyl groups, carbamoyl groups and morpholino groups. }, N represents 1 or 2, and X represents an oxygen atom or a sulfur atom. ], Or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient.

In the present invention, the “C ₁ -C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl -2-methylpropyl group, preferably a linear or branched alkyl group having 1 to 4 carbon atoms (C ₁ -C ₄ alkyl group), More preferred is a linear or branched alkyl group having 1 to 3 carbon atoms (C ₁ -C ₃ alkyl group), even more preferred is a methyl or ethyl group, and particularly preferred is a methyl group. is there.

In the present invention, the “C ₁ -C ₆ alkoxy group” is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy. A straight chain or branched chain alkoxy group having 1 to 3 carbon atoms (C ₁ -C ₃ alkoxy group), and more preferably a methoxy group.

In the present invention, the “substituted C ₁ -C ₆ alkyl group (the substituent is selected from the group consisting of a C ₁ -C ₆ alkoxy group, an amino group, a phenyl group, and a pyridyl group)” refers to the above. "C ₁ -C ₆ alkoxy group", an amino group, a phenyl group and 1 to 3 substituents wherein that may be substituted with a group "C ₁ -C ₆ alkyl group same as or different selected from the group consisting of a pyridyl group In addition to the “C ₁ -C ₆ alkyl group”, for example, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, aminomethyl, aminoethyl, benzyl, phenethyl, pyridylmethyl, It may be a pyridylethyl, α-methoxybenzyl, α-aminobenzyl group, and preferably a substituted C ₁ -C ₆ alkyl group (the substituent is C _1- C ₆ alkoxy group, an amino group, selected from the group consisting of phenyl and pyridyl groups.), More preferably wherein the "C ₁ -C ₃ alkoxy group", an amino group, the group consisting of phenyl and pyridyl groups the substituted by the same or different 1 to 2 substituents selected from a "C ₁ -C ₄ alkyl group", said substituted by one of pyridyl group are more preferably from "C ₁ - a C ₃ alkyl group ", particularly preferably a 3-pyridylmethyl or 2- (3-pyridyl) ethyl group, and most preferably is 3-pyridylmethyl group.

In the present invention, the “substituted C ₂ -C ₄ alkenyl group (the substituent is a phenyl group or a pyridyl group)” is an alkenyl group having 2 to 4 carbon atoms substituted by a phenyl or pyridyl group. , and the example styryl, cinnamyl, 2-Pirijirubiniru be a group, preferably a pyridyl group substituted with number 2 or 3 alkenyl group having a carbon (C ₂ -C ₃ alkenyl group), more preferably Is a 2- (3-pyridyl) vinyl group.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably a cycloalkyl group having 3 to 5 carbon atoms (C ₃ -C ₅ cycloalkyl group). More preferably a cyclopropyl group or a cyclobutyl group, and even more preferably a cyclopropyl group.

  In the present invention, “a 4- to 6-membered heterocyclic group (the heterocyclic group has 1 to 3 different or identical heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring)”. , A 4- to 6-membered saturated or unsaturated heterocyclic group containing 1 to 3 hetero atoms which are the same or different from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, preferably 5 Or a 6-membered unsaturated heterocyclic group (the heterocyclic group has the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring) or 4 to 6-membered saturated A heterocyclic group (the heterocyclic group has the same or different 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring);

  In the above, “5- or 6-membered unsaturated heterocyclic group (the heterocyclic group has the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring)” Is a 5- or 6-membered unsaturated heterocyclic group containing 1-3 identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, such as furyl, thienyl, pyrrolyl , Azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl groups, preferably nitrogen and sulfur in the ring 5- or 6-membered saturates containing the same or different 1 to 3 heteroatoms selected from the group consisting of atoms A heterocyclic group, more preferably a pyrrolyl group, a pyrazolyl group, a thiazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group or a pyrazinyl group, and even more preferably a 2-pyrrolyl group, a 2-pyridyl group or a 3- Pyridyl group.

In the above, “a 4- to 6-membered saturated heterocyclic group (the heterocyclic group has 1 or 2 different or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring)”. A 4- to 6-membered saturated heterocyclic group containing the same or different 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, such as morpholinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl , Pyrrolinyl, imidazolidinyl, imidazolinyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl groups, preferably C ₃ -C ₅ cyclo interrupted by one oxygen atom alkyl group (the "one C ₃ -C ₅ is interrupted by oxygen atoms of a cycloalkyl group" Is a saturated monocyclic group having 3 to 5 carbon atoms containing one oxygen atom in the ring, and may be, for example, an oxetanyl, tetrahydrofuranyl, tetrahydropyranyl group, preferably a 2-tetrahydrofuryl group Or a 4-tetrahydropyranyl group, more preferably a 4-tetrahydropyranyl group.) Or the same or different 1-2 heteroatoms selected from the group consisting of nitrogen and sulfur atoms in the ring. a saturated heterocyclic group of 4 or 5-membered containing, more preferably C ₃ -C interrupted by one oxygen atom in the ₅ cycloalkyl group, azetidinyl group, pyrrolidinyl group or a thiazolidinyl group, preferably even more Is a 2-tetrahydrofuryl group, a 4-tetrahydropyranyl group, an azetidinyl group, a pyrrolidinyl group or a thiazolidinyl group, particularly preferably an azetidinyl group. A group or pyrrolidinyl group, and most preferably is azetidinyl.

In the present invention, “a 4- to 6-membered heterocyclic group which may be substituted (the heterocyclic group has 1 to 3 different or identical heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring. The substituent is selected from the group consisting of a C ₁ -C ₆ alkyl group, an amino group, a hydroxyl group, a carbamoyl group, a morpholino group, a cyano group, and an acetyl group. ”Means“ the C ₁ -C ₆ alkyl group ”. ”Said 4 to 6-membered heterocyclic group which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of amino group, hydroxyl group, carbamoyl group, morpholino group, cyano group and acetyl group The heterocyclic group has the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring.) ”, Preferably 5 or 6 membered may be substituted Unsaturated heterocyclic group Heterocyclic group. The substituent groups which have identical or different one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring is, C ₁ -C ₃ alkyl group, an amino group, The same or different one or two substituents selected from the group consisting of a hydroxyl group, a carbamoyl group and a morpholino group), or a 4- to 6-membered saturated heterocyclic group which may be substituted with a cyano group or an acetyl group ( The heterocyclic group has 1 or 2 heteroatoms which are the same or different selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and is more preferably interrupted by one oxygen atom. C ₃ -C ₅ cycloalkyl groups; methyl group, an amino group, a hydroxyl group may be substituted by a carbamoyl group or a morpholino group, pyrrolyl group, a pyrazolyl group, a thiazolyl group, an imidazolyl group, triazolyl Group, pyridyl group or pyrazinyl group; or azetidinyl group, pyrrolidinyl group or thiazolidinyl group which may be substituted by cyano group or acetyl group, and more preferably 2-tetrahydrofuryl group, 4-tetrahydropyranyl group Pyrrolyl group, thiazolyl group, imidazolyl group, pyridyl group, pyrazinyl group, 2-amino-3-pyridyl group, 6-amino-3-pyridyl group, 6-hydroxy-3-pyridyl group, azetidinyl group, pyrrolidinyl group, thiazolidinyl Group or a 3-cyano-1-azetidinyl group.

  In the present invention, “mono-substituted amino group (the substituent is a phenyl group or pyridyl group)” is an amino group substituted by one phenyl group or pyridyl group, and preferably an anilino group or N -(Pyridyl) amino group, more preferably N- (3-pyridyl) amino group.

In the substituent of the “disubstituted amino group” of the present invention, “an optionally substituted 5- or 6-membered unsaturated heterocyclic group (the heterocyclic group is the same selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring) Or the substituent is selected from the group consisting of a C ₁ -C ₃ alkyl group, an amino group, a hydroxyl group, a carbamoyl group, and a morpholino group). Or a 6-membered unsaturated heterocyclic group (the heterocyclic group has 1 to 3 different or identical heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring) "or the above" substituted A 5- or 6-membered unsaturated heterocyclic group (the heterocyclic group has the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring. C ₁ -C ₃ alkyl group, amino group, hydroxyl group, carba The same or different one or two substituents selected from the group consisting of a moyl group and a morpholino group. , Pyrrolyl group, pyrazolyl group, thiazolyl group, imidazolyl group, triazolyl group, pyridyl group or pyrazinyl group, and more preferably a pyridyl group.

In the present invention, “disubstituted amino group {the substituent is a C ₁ -C ₆ alkyl group and an optionally substituted 5- or 6-membered unsaturated heterocyclic group (the heterocyclic group is nitrogen, oxygen and sulfur in the ring) . the substituent groups which have identical or different one to three hetero atoms selected from the group consisting of atoms selected C ₁ -C ₃ alkyl group, an amino group, a hydroxyl group, from the group consisting of carbamoyl group and morpholino group Are selected from the group consisting of the above-mentioned “C ₁ -C ₆ alkyl group” and the above “optionally substituted 5- or 6-membered unsaturated heterocyclic group (the heterocyclic group is nitrogen in the ring, with oxygen and the same or different one to three hetero atoms selected from the group consisting of sulfur atom. the substituent, C ₁ -C ₃ alkyl group, an amino group, a hydroxyl group, the group consisting of carbamoyl group and morpholino group Selected from.) An amino group substituted by two identical or different substituents selected from, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, methylethylamino, N-methylanilino , N-ethylanilino, N-methyl-N-pyridylamino group, preferably two identical or different substitutions selected from the group consisting of the aforementioned “C ₁ -C ₄ alkyl group”, phenyl group and pyridyl group An amino group substituted by a group {disubstituted amino group (the substituent is the same or different substituent selected from the group consisting of a C ₁ -C ₄ alkyl group, a phenyl group and a pyridyl group)}. , more preferably the same of the amino group {disubstituted by "C ₁ -C ₃ alkyl group" (C ₁ -C ₃ Alkyl) amino group}, a N- (C ₁ -C ₃ alkyl) anilino group or N- (C ₁ -C ₃ alkyl)-N-(3- pyridyl) amino group, still more preferably a dimethylamino group , Diethylamino group or N-methyl-3-pyridylamino group, particularly preferably dimethylamino group.

  The “pharmaceutically acceptable ester derivative” of compound (I) is a group that is cleaved by a chemical or biological method such as hydrolysis in the human or animal body to form the original compound (I) or a salt thereof. An ester derivative in which the carboxyl group or hydroxyl group of compound (I) is protected, and whether or not such a derivative is administered to a laboratory animal such as a rat or a mouse by oral or intravenous injection, and then the body fluid of the animal is used. This can be determined by examining and detecting the original compound (I) or a salt thereof.

Protecting group, for example C ₁ -C ₁₀ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkyl C ₁ -C ₄ alkyl group to form an ester derivative at the carboxyl group, C ₂ -C ₁₀ Alkanoyloxy C ₁ -C ₄ alkyl group, (C ₁ -C ₁₀ alkoxy) carbonyloxy C ₁ -C ₄ alkyl group, phenyl group (the phenyl group is a halogen atom, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, a methylenedioxy group, C ₁ -C ₆ optionally substituted by 1 or 2 groups selected from an alkanoyloxy group), (C ₂ -C ₁₀ alkanoyloxy) benzyl group, phthalidyl group , A 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group.

The protecting group that forms an ester derivative at the hydroxyl group can be, for example, a C ₁ -C ₁₀ alkanoyl group, a (C ₆ -C ₁₀ aryl) carbonyl group, a (C ₁ -C ₁₀ alkoxy) carbonyl group, or an aminoacyl group.

In the above protecting group, the “C ₁ -C ₁₀ alkyl group” is a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t- butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, hexyl, 2-hexyl, 3-hexyl, isohexyl, heptyl, octyl, nonyl, be a decyl group obtained, preferably a C ₁ -C ₆ alkyl group by weight, more preferably a C ₂ -C ₄ alkyl group, preferably an ethyl group even more.

In the above protecting group, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably a cyclopentyl or cyclohexyl group.

In the above protecting group, the “C ₃ -C ₆ cycloalkyl C ₁ -C ₄ alkyl group” is a “C ₁ -C ₄ alkyl group” to which one “C ₃ -C ₆ cycloalkyl group” is bonded. Can be, for example, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl groups, suitable Is a cyclopropylmethyl group.

In the above protecting group, the “C ₂ -C ₁₀ alkanoyloxy C ₁ -C ₄ alkyl group” is a “C ₁ -C ₄ alkyl group” to which one “C ₂ -C ₁₀ alkanoyloxy” is bonded, For example, acetoxymethyl, 1- (acetoxy) ethyl, 1- (acetoxy) propyl, 1- (acetoxy) butyl, propionyloxymethyl, 1- (propionyloxy) ethyl, isopropionyloxymethyl, 1- (isopropionyloxy) ethyl , Butyryloxymethyl, 1- (butyryloxy) ethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, valeryloxymethyl, 1- ( Valeryloxy) ethyl, isovaleryloxymethyl, 1- (isovaleryloxy) ethyl, Hexanoyloxymethyl, 1- (hexanoyloxy) ethyl, octanoyloxymethyl, 1- (octanoyloxy) ethyl, decanoyloxymethyl, cyclopentylcarbonyloxymethyl, 1-methylcyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl 1-methylcyclohexylcarbonyloxymethyl group, preferably (C ₂ -C ₆ alkanoyloxy) methyl or 1- (C ₂ -C ₆ alkanoyloxy) ethyl group.

In the above-mentioned protecting group, “(C ₁ -C ₁₀ alkoxy) carbonyloxy C ₁ -C ₄ alkyl group” means “C” in which one oxygen atom to which “(C ₁ -C ₁₀ alkoxy) carbonyl” is bonded is bonded. ₁ -C ₄ alkyl group ", for example, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (Ethoxycarbonyloxy) butyl, propoxycarbonyloxymethyl, 1- (propoxycarbonyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl , Isobutoxy Carbonyloxymethyl, 1- (isobutoxycarbonyloxy) ethyl, s-butoxycarbonyloxymethyl, 1- (s-butoxycarbonyloxy) ethyl, t-butoxycarbonyloxymethyl, 1- (t-butoxycarbonyloxy) ethyl, Pentyloxycarbonyloxymethyl, 1- (pentyloxycarbonyloxy) ethyl, (1-methylbutyloxycarbonyloxy) methyl, 1- (1-methylbutyloxycarbonyloxy) ethyl, (2-methylbutyloxycarbonyloxy) methyl 1- (2-methylbutyloxycarbonyloxy) ethyl, (3-methylbutyloxycarbonyloxy) methyl, 1- (3-methylbutyloxycarbonyloxy) ethyl, (1-ethylpropyloxycarbonyloxy) methyl 1- (1-ethylpropyloxycarbonyloxy) ethyl, hexyloxycarbonyloxymethyl, 1- (hexyloxycarbonyloxy) ethyl, (1-methylpentyloxycarbonyloxy) methyl, 1- (1-methylpentyloxy) Carbonyloxy) ethyl, octyloxycarbonyloxymethyl, 1- (octyloxycarbonyloxy) ethyl, decyloxycarbonyloxymethyl, 1- (decyloxycarbonyloxy) ethyl, cyclopentylcarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, cyclohexyl carbonyl oxymethyl be a 1- (cyclohexyloxycarbonyloxy) ethyl group, preferably a (C ₁ -C ₆ alkoxy) carbonyloxy-methyl or 1 A {(C ₁ -C ₆ alkoxy) carbonyloxy} ethyl group, and more preferably 1- (isopropoxycarbonyloxy) ethyl group.

  In the above protecting group, the “substituted phenyl group” is a phenyl group which may be substituted with 1 to 5 substituents which are the same or different, for example, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4 -Difluorophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3-acetoxyphenyl, 4-acetoxyphenyl groups And is preferably an unsubstituted phenyl group.

In the above protecting group, “(C ₂ -C ₁₀ alkanoyloxy) benzyl group” is a benzyl group in which one “C ₂ -C ₁₀ alkanoyloxy” is bonded to the phenyl moiety of the benzyl group, for example, 2-acetoxy Benzyl, 3-acetoxybenzyl, 4-acetoxybenzyl, 3-propionylbenzyl, 4-propionyloxybenzyl, 4-butyryloxybenzyl, 4-valeryloxybenzyl, 4-hexanoyloxybenzyl, 4-octanoyloxybenzyl , 4-decanoyloxybenzyl group, preferably 3- or 4- (C ₂ -C ₄ alkanoyloxy) benzyl group.

In the above protecting group, the “C ₁ -C ₁₀ alkanoyl group” is a carbonyl group to which a linear or branched alkyl group having 1 to 9 carbon atoms is bonded in addition to a formyl group, such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, be a decanoyl group, preferably is C ₂ -C ₆ alkanoyl group.

In the above protecting group, the “(C ₆ -C ₁₀ aryl) carbonyl group” is a carbonyl group to which an aryl group having 6 to 10 carbon atoms is bonded, and may be, for example, a benzoyl, 1-naphthoyl, or 2-naphthoyl group. A benzoyl group is preferred.

In the above protecting group, “(C ₁ -C ₁₀ alkoxy) carbonyl group” is a carbonyl group to which “C ₁ -C ₁₀ alkoxy group” is bonded, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyl. oxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, it is a decyloxycarbonyl group, preferably a (C ₂ -C ₆ alkoxy) carbonyl group.

  In the protecting group, the “aminoacyl group” may be an amino acid group such as glycyl, alanyl, β-alanyl, leucyl, isoleucyl, phenylalanyl, histidyl, asparagyl, prolyl, lysyl, and preferably a glycyl group. It is.

  The compound (I) of the present invention and a pharmacologically acceptable ester thereof can form a “pharmacologically acceptable salt” as necessary.

  In the present invention, the “pharmacologically acceptable salt” refers to a salt thereof since the compound (I) of the present invention can be converted into a salt, and such a salt is preferably a sodium salt. Alkali metal salts such as potassium salts and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; ammonium Inorganic salts such as salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexyl Amine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, die Amine salts such as noramine salts, organic salts such as N-benzyl-phenethylamine salts, piperazine salts, tetramethylammonium salts, tris (hydroxymethyl) aminomethane salts; hydrofluoric acid salts, hydrochlorides, hydrobromides Inorganic acid salts such as hydrohalides such as hydroiodide, nitrates, perchlorates, sulfates and phosphates; such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate Lower alkanesulfonates, benzenesulfonates, arylsulfonates such as p-toluenesulfonate, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, Organic acid salts such as maleates; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, aspartates There obtained is preferably a metal salt, more preferably an alkali metal salt is more preferably sodium salt from.

  The compound (I) of the present invention, or a pharmacologically acceptable salt or ester derivative thereof includes hydrates or solvates thereof.

  The compound (I) of the present invention, or a pharmacologically acceptable salt or ester derivative thereof may have geometric isomers and optical isomers, and any isomer and a mixture of isomers in an arbitrary ratio. Included in the present invention.

In the compound (I) of the present invention, suitable compounds are
(1) A is, C ₁ -C ₆ alkyl substituted (the substituent is, C ₁ -C ₆ alkoxy group, an amino group, selected from the group consisting of phenyl and pyridyl groups.); Pyridyl group A substituted C ₂ -C ₃ alkenyl group; a C ₃ -C ₆ cycloalkyl group; a C ₁ -C ₃ alkyl group, an amino group, a hydroxyl group, a carbamoyl group and a morpholino group, the same or different 1 to 5- or 6-membered unsaturated heterocyclic group which may be substituted by two substituents (the heterocyclic group is the same or different 1 to 3 heterocycles selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring) A 4- to 6-membered saturated heterocyclic group which may be substituted by a cyano group or an acetyl group (the heterocyclic group is the same or different 1 selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring); ~ 2 heteroatoms A);. Mono-substituted amino group (the substituent is a phenyl group or a pyridyl group);., Or di-substituted amino group (the substituent is C ₁ -C ₄ alkyl group, a phenyl group, and a pyridyl group The same or different substituents selected from the group consisting of:
(2) A is, C ₁ -C ₃ alkyl group substituted by a pyridyl group; C ₃ -C ₅ cycloalkyl group; one C ₃ is interrupted by oxygen atoms -C ₅ cycloalkyl group; a methyl group, Pyrrolidyl group, pyrazolyl group, thiazolyl group, imidazolyl group, triazolyl group, pyridyl group or pyrazinyl group, which may be substituted by amino group, hydroxyl group, carbamoyl group or morpholino group; azetidinyl group which may be substituted by cyano group or acetyl group A pyrrolidinyl group or a thiazolidinyl group; an anilino group or an N- (pyridyl) amino group; a di (C ₁ -C ₃ alkyl) amino group; an N- (C ₁ -C ₃ alkyl) anilino group; ₁ -C ₃ alkyl)-N-(3- pyridyl) compound is an amino group "
(3) A is 3-pyridylmethyl group, 2- (3-pyridyl) ethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, 2-tetrahydrofuryl group, 4-tetrahydropyranyl group, pyrrolyl group, thiazolyl group Imidazolyl group, pyridyl group, pyrazinyl group, 2-amino-3-pyridyl group, 6-amino-3-pyridyl group, 6-hydroxy-3-pyridyl group, azetidinyl group, pyrrolidinyl group, thiazolidinyl group, 3-cyano- A compound which is a 1-azetidinyl group or a dimethylamino group,
(4) A compound in which A is an azetidinyl group, a pyrrolidinyl group, a 3-cyano-1-azetidinyl group or a dimethylamino group,
(5) the compound wherein n is 1,
(6) A compound in which X is an oxygen atom.

  Although this invention compound (I) is specifically illustrated in Table 1, the compound (I) of this invention is not limited to these.

In the table, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, iPr is an isopropyl group, Bu is a butyl group, iBu is an isobutyl group, tBu is a tert-butyl group, Pen is a pentyl group, Hex is a hexyl group, 3-Pyr is 3-pyridyl group, cPr is cyclopropyl group, cBu is cyclobutyl group, cPen is cyclopentyl group, cHex is cyclohexyl group, 2-Thf is 2-tetrahydrofuranyl group, 4-Thp is 4-tetrahydropyranyl group 2-Pyrr is a 2-pyrrolyl group, 4-Thiaz is a 4-thiazolyl group, 5-Imid is a 5-imidazolyl group, 2-Pyr is a 2-pyridyl group, 2-NH ₂ -3-Pyr is 2-amino- 3-pyridyl group, 4-Mor is 4-morpholinyl group, 2-Pyz is 2-pyrazinyl group, 1-Azt is 1-azetidinyl group, 1-Azo is 1-pyrrolidinyl group, 3-Thiad is thiazolidinyl group, 4- Ac represents a 4-acetyl group, 1-Piz represents a 1-piperazinyl group, and 1-Pyza represents a 1-pyrazolyl group.

  (Table 1)

―――――――――――――――――――――――――――――――――――――――
Compound No. n X A
―――――――――――――――――――――――――――――――――――――――
1 1 O Me
2 1 O Et
3 1 O Pr
4 1 O iPr
5 1 O Bu
6 1 O iBu
7 1 O tBu
8 1 O Pen
9 1 O Hex
10 1 O CH ₂ OMe
11 1 O CH (NH ₂ ) Ph
12 1 O CH ₂ -3-Pyr
13 1 O CH ₂ CH ₂ -3-Pyr
14 1 O CH = CH-3-Pyr
15 1 O cPr
16 1 O cBu
17 1 O cPen
18 1 O cHex
19 1 O 2-Thf
20 1 O 4-Thp
21 1 O 2-Pyrr
22 1 O 4-Thiaz
23 1 O 1-Me-5-Imid
24 1 O 2-Pyr
25 1 O 3-Pyr
26 1 O 2-NH ₂ -3-Pyr
27 1 O 6-NH ₂ -3-Pyr
28 1 O 6-OH-3-Pyr
29 1 O 6-CONH ₂ -3-Pyr
30 1 O 6-Mor-3-Pyr
31 1 O 4-Pyr
32 1 O 2-Pyz
33 1 O NMe ₂
34 1 O NEt ₂
35 1 O 1-Azt
36 1 O 3-CN-1-Azt
37 1 O 1-Azo
38 1 O 3-Thiad
39 1 O 4-Mor
40 1 O 4-Ac-1-Piz
41 1 O 1-Pyza
42 1 O NH-3-Pyr
43 1 O NMe-2-Pyr
44 1 O NMe-3-Pyr
45 1 O NMe-2-Thiaz
46 1 S Me
47 1 S Et
48 1 S Pr
49 1 S iPr
50 1 S Bu
51 1 S iBu
52 1 S tBu
53 1 S Pen
54 1 S Hex
55 1 S CH ₂ OMe
56 1 S CH (NH ₂ ) Ph
57 1 S CH ₂ -3-Pyr
58 1 S CH ₂ CH ₂ -3-Pyr
59 1 S CH = CH-3-Pyr
60 1 S cPr
61 1 S cBu
62 1 S cPen
63 1 S cHex
64 1 S 2-Thf
65 1 S 4-Thp
66 1 S 2-Pyrr
67 1 S 4-Thiaz
68 1 S 1-Me-5-Imid
69 1 S 2-Pyr
70 1 S 3-Pyr
71 1 S 2-NH ₂ -3-Pyr
72 1 S 6-NH ₂ -3-Pyr
73 1 S 6-OH-3-Pyr
74 1 S 6-CONH ₂ -3-Pyr
75 1 S 6-Mor-3-Pyr
76 1 S 4-Pyr
77 1 S 2-Pyz
78 1 S NMe ₂
79 1 S NEt ₂
80 1 S 1-Azt
81 1 S 3-CN-1-Azt
82 1 S 1-Azo
83 1 S 3-Thiad
84 1 S 4-Mor
85 1 S 4-Ac-1-Piz
86 1 S 1-Pyza
87 1 S NH-3-Pyr
88 1 S NMe-2-Pyr
89 1 S NMe-3-Pyr
90 1 S NMe-2-Thiaz
91 2 O Me
92 2 O Et
93 2 O Pr
94 2 O iPr
95 2 O Bu
96 2 O iBu
97 2 O tBu
98 2 O Pen
99 2 O Hex
100 2 O CH ₂ OMe
101 2 O CH (NH ₂ ) Ph
102 2 O CH ₂ -3-Pyr
103 2 O CH ₂ CH ₂ -3-Pyr
104 2 O CH = CH-3-Pyr
105 2 O cPr
106 2 O cBu
107 2 O cPen
108 2 O cHex
109 2 O 2-Thf
110 2 O 4-Thp
111 2 O 2-Pyrr
112 2 O 4-Thiaz
113 2 O 1-Me-5-Imid
114 2 O 2-Pyr
115 2 O 3-Pyr
116 2 O 2-NH ₂ -3-Pyr
117 2 O 6-NH ₂ -3-Pyr
118 2 O 6-OH-3-Pyr
119 2 O 6-CONH ₂ -3-Pyr
120 2 O 6-Mor-3-Pyr
121 2 O 4-Pyr
122 2 O 2-Pyz
123 2 O NMe ₂
124 2 O NEt ₂
125 2 O 1-Azt
126 2 O 3-CN-1-Azt
127 2 O 1-Azo
128 2 O 3-Thiad
129 2 O 4-Mor
130 2 O 4-Ac-1-Piz
131 2 O 1-Pyza
132 2 O NH-3-Pyr
133 2 O NMe-2-Pyr
134 2 O NMe-3-Pyr
135 2 O NMe-2-Thiaz
136 2 S Me
137 2 S Et
138 2 S Pr
139 2 S iPr
140 2 S Bu
141 2 S iBu
142 2 S tBu
143 2 S Pen
144 2 S Hex
145 2 S CH ₂ OMe
146 2 S CH (NH ₂ ) Ph
147 2 S CH ₂ -3-Pyr
148 2 S CH ₂ CH ₂ -3-Pyr
149 2 S CH = CH-3-Pyr
150 2 S cPr
151 2 S cBu
152 2 S cPen
153 2 S cHex
154 2 S 2-Thf
155 2 S 4-Thp
156 2 S 2-Pyrr
157 2 S 4-Thiaz
158 2 S 1-Me-5-Imid
159 2 S 2-Pyr
160 2 S 3-Pyr
161 2 S 2-NH ₂ -3-Pyr
162 2 S 6-NH ₂ -3-Pyr
163 2 S 6-OH-3-Pyr
164 2 S 6-CONH ₂ -3-Pyr
165 2 S 6-Mor-3-Pyr
166 2 S 4-Pyr
167 2 S 2-Pyz
168 2 S NMe ₂
169 2 S NEt ₂
170 2 S 1-Azt
171 2 S 3-CN-1-Azt
172 2 S 1-Azo
173 2 S 3-Thiad
174 2 S 4-Mor
175 2 S 4-Ac-1-Piz
176 2 S 1-Pyza
177 2 S NH-3-Pyr
178 2 S NMe-2-Pyr
179 2 S NMe-3-Pyr
180 2 S NMe-2-Thiaz
―――――――――――――――――――――――――――――――――――――――
Among the compounds exemplified in the above table, suitable compounds are compound numbers 12, 13, 15, 16, 17, 21, 24, 25, 26, 27, 28, 31, 32, 35, 36, 37, 38, No. 57, 60, 65, 70, 78, 80 or 84, and a more preferred compound is (1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) azetidin-3-yl ] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (compound No. 35), (1R, 5S, 6S) -2- [ 1- (Pyrrolidin-1-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (Compound No. 37) Compound), (1R, 5S, 6S) -2- [1- (pyridin-3-ylthiocarbonyl) azetidine-3- Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (compound No. 70), (1R, 5S, 6S) -2- (1-Dimethylthiocarbamoylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (Compound No. 78) , (1R, 5S, 6S) -2- [1- (1-azetidinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3-carboxylic acid (compound No. 80) or (1R, 5S, 6S) -2- [1- (4-morpholinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-me Le - a carbapen-2-em-3-carboxylic acid (Compound No. 84 No.).

  The carbapenem compound having the above general formula (I) of the present invention, or a pharmacologically acceptable salt or ester derivative thereof has an excellent antibacterial activity and is β- except for metallo-β-lactamase produced by various pathogenic bacteria It is stable against lactamase and is useful as a medicine, particularly as an antibacterial agent.

  The carbapenem derivative represented by the general formula (I) of the present invention can be produced by the methods described in the following methods A and B.

[Method A]
Method A is a method for producing compound (I) by reacting a carbapenem compound represented by formula (II) with a mercapto compound represented by formula (III), followed by deprotection reaction.

In the formula, A, X and n are as defined above, L ¹ represents a leaving group, P ¹ represents a protecting group for a carboxyl group, and Ap represents A which may have a protecting group. .

Examples of the “carboxyl-protecting group” for P ¹ include a benzyl group which may have a substituent such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl or 2-nitrobenzyl (the substituent is a nitro group) A benzhydryl group; an allyl group optionally having a substituent at the 2-position such as allyl, 2-chloroallyl or 2-methylallyl (the substituent is chlorine or methyl); A group which forms the above-mentioned pharmacologically acceptable ester can be mentioned, and a benzyl group (especially 4-nitrobenzyl group) which may have a substituent is preferable.

A “leaving group” for L ¹ is a group having the formula —OR ³ or —S (O) R ^4, for example.

R ³ is a C ₁ -C ₄ alkanesulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl group; C ₆ such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl group. -C ₁₀ arylsulfonyl group; dimethylphosphoryl, diethylphosphoryl, dipropyl phosphoryl, diisopropylphosphoryl, dibutyl phosphoryl, dipentyl phosphoryl, di C ₁ -C ₆ alkyl phosphoryl groups such as dihexyl phosphoryl group; or, diphenylphosphoryl, ditolyl phosphoryl A di (C ₆ -C ₁₀ aryl) phosphoryl group such as a group, preferably a diphenylphosphoryl group;

R ⁴ is a C ₁ -C ₄ alkyl group such as methyl, ethyl, propyl, isopropyl group; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl, Halogeno C ₁ -C ₄ alkyl group such as trifluoroethyl; 2-acetylaminoethyl group; 2-acetylaminovinyl group; optionally substituted C ₆ -C ₁₀ such as phenyl or naphthyl group An aryl group (the aryl group may have 1 to 3 substituents which may be the same or different. The substituent may be a halogen atom such as a fluorine, chlorine or bromine atom; a methyl, ethyl, propyl or isopropyl group; C ₁ -C ₄ alkyl group such as a methoxy, ethoxy, propoxy, C ₁ -C _4, such as an isopropoxy group Alkoxy group; a methoxycarbonyl, ethoxycarbonyl, t-butoxy, such as carbonyl group (C ₁ -C ₄ alkoxy) carbonyl group; a carbamoyl group; a mono- or di (C ₁ -C ₄ alkyl) carbamoyl group; a nitro group; a hydroxyl group; And a heteroaryl group which may have one or two nitrogen atoms such as pyridyl or pyrimidinyl group which may have a substituent (the heteroaryl group is selected from the group consisting of a cyano group) The groups may have 1 to 3 substituents which may be the same or different, such as halogen atoms such as fluorine, chlorine and bromine atoms, C _1- such as methyl, ethyl, propyl and isopropyl groups. C ₄ alkyl group; methoxy, ethoxy, propoxy, C ₁ -C ₄ alkoxy groups such as isopropoxy group; methoxycarbonyl, ethoxycarbonyl Carbonyl, C ₂ -C ₅ alkoxycarbonyl group such as t- butoxycarbonyl group; a carbamoyl group; a mono- or di (C ₁ -C ₄ alkyl) carbamoyl group; a nitro group; a hydroxyl group; and selected from the group consisting of cyano group Is shown).

  Examples of the “protecting group” in Ap include, in addition to the above-described protecting groups, amino protecting groups. Examples of such amino protecting groups include allyloxycarbonyl, 2-chloroallyloxycarbonyl, 2- An allyloxycarbonyl group which may be substituted at the 2-position such as a methylallyloxycarbonyl group (the substituent is a chlorine atom or a methyl group); benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4- An optionally substituted benzyloxycarbonyl group such as methoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl group (the substituent is a methyl, methoxy, nitro group or chlorine atom). Preferably allyloxycarbonyl or 4-nitrobenzyloxy A carbonyl group, more preferably a 4-nitrobenzyloxycarbonyl group.

In this method, a compound having the formula (IV) is produced by reacting a compound having the formula (II) with a compound having the formula (III) in the presence of a base (step A1), and then the protecting group is removed. To produce compound (I) (step A2). When L ¹ is a group represented by the formula —OR ³ , the starting compound (II) is, for example, a method described in DHShih et al., Heterocycles 21, 29 (1984) or a method analogous thereto. Manufactured by. When L ¹ is a group represented by the formula —S (O) R ⁴ , the starting compound (II) is produced, for example, by the method described in JP-A-62-230781 or a method analogous thereto. Hereinafter, each step will be described.

(Step A1)
Step A1 is a step for producing a compound having the general formula (IV) and is achieved by reacting compound (II) and mercaptan derivative (III) in the presence of a base in an inert solvent.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; Nitriles; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; esters such as ethyl acetate and methyl acetate; ethers such as diethyl ether, tetrahydrofuran and dioxane; Acetonitrile, N, N-dimethylformamide or tetrahydrofuran is preferred, and acetonitrile is more preferred.

  The base to be used is not particularly limited as long as it is used in a usual substitution reaction. For example, organic amines such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine; or potassium carbonate, sodium carbonate, It can be an inorganic base such as sodium bicarbonate, preferably organic amines, and more preferably diisopropylethylamine.

  The reaction temperature is usually −20 ° C. to 40 ° C., preferably −10 ° C. to 20 ° C. The reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 18 hours.

  After completion of the reaction, the target compound (IV) in this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing the mixture with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography. If desired, the target compound (IV) can be subjected to the next step without isolation.

(Step A2)
Step A2 is a step of converting compound (IV) to compound (I), and is achieved by removing the protecting group contained in compound (IV).

  Although the removal of the protecting group varies depending on the type of protecting group, a method generally used in the field of organic synthetic chemistry (for example, TWGreene, PGMWuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc. 1991).

  (1) When the protecting group is an optionally substituted benzyl group, benzhydryl group, or optionally substituted benzyloxycarbonyl group, these protecting groups are catalytic reduction catalysts in an inert solvent. It can be removed by the action of hydrogen in the presence of.

  The catalytic reduction catalyst used can be, for example, a palladium-carbon catalyst, a palladium hydroxide-carbon catalyst, a platinum catalyst, a rhodium-carbon catalyst, preferably a palladium-carbon catalyst or a palladium hydroxide-carbon catalyst.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; It can be a mixed solvent of a solvent and water, and an alkali metal salt such as sodium phosphate, sodium acetate, or sodium bicarbonate is added to the mixed solvent of water and an organic solvent, or a pH buffer such as a phosphate buffer. The liquid is preferably maintained at a pH of 6 to 8. A mixed solvent of tetrahydrofuran and water is preferred.

  The reaction temperature is usually 0 ° C. to 50 ° C., preferably 10 ° C. to 40 ° C., and the reaction time varies depending on the raw material compound and the type of the catalyst, but is usually 5 minutes to 12 hours, preferably 30 Minutes to 4 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing insoluble matter such as a catalyst from the reaction mixture and then distilling off the solvent. If necessary, the obtained compound can be purified by conventional methods such as recrystallization, preparative thin film chromatography, column chromatography and the like.

(2) When the protecting group is an optionally substituted allyl group or an optionally substituted allyloxycarbonyl group, these protecting groups are tri (C _1- C ₆ alkyl) tin hydrides or organic carboxylic acid alkali metal salts can be removed. You may add the organic base or organic substance which capture | acquires an allyl group.

  As the palladium, bis (triphenylphosphine) palladium chloride or tetrakis (triphenylphosphine) palladium is suitable. As the trialkyltin hydrides, tributyltin hydride is suitable. As the organic carboxylic acid alkali metal salt, potassium 2-ethylhexanoate or sodium 2-ethylhexanoate is preferable. As the organic base for capturing the allyl group, morpholine is preferable, and as the organic substance for capturing the allyl group, dimedone is preferable.

  A combination suitable as a deprotecting agent is a combination consisting of bis (triphenylphosphine) palladium chloride and tributyltin hydride or a combination consisting of tetrakis (triphenylphosphine) palladium and potassium 2-ethylhexanoate.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; Esters such as; ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane; nitriles such as acetonitrile; alcohols such as methanol, ethanol or propanol; water; or a mixed solvent thereof Preferably, methylene chloride, ethyl acetate or a mixed solvent thereof is used.

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

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing the insoluble matter precipitated from the reaction mixture by filtration and then distilling off the solvent. If necessary, the obtained compound can be purified by conventional methods such as recrystallization, preparative thin film chromatography, column chromatography and the like.

  (3) When the protecting group is a silyl-based protecting group, the protecting group is a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, potassium fluoride in an inert solvent. It can be removed by treatment with the resulting compound or treatment with an organic acid such as acetic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or an inorganic acid such as hydrochloric acid.

  When removing with a fluorine anion, the reaction may proceed under mild conditions by adding an organic acid such as formic acid, acetic acid or propionic acid.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether. Ethers such as acetonitrile, nitriles such as isobutyronitrile; water; organic acids such as acetic acid; and mixed solvents thereof.

  The reaction temperature is usually 0 ° C. to 100 ° C., preferably 10 ° C. to 30 ° C., and the reaction time is not particularly limited, but is usually 1 hour to 24 hours, preferably 1 hour to 4 hours. It's time.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing the mixture with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

  (4) When the protecting group is a group that forms a pharmacologically acceptable ester at the carboxyl group or hydroxyl group, these protecting groups are removed by the action of a hydrolase in water or a mixed solvent of water and an organic solvent. Is done.

  As the organic solvent mixed with water, ethers or alcohols miscible with water such as tetrahydrofuran, dioxane, methanol, ethanol and propanol are suitable.

  An alkali metal salt such as sodium phosphate, sodium acetate or sodium hydrogen carbonate is added to water or a mixed solvent of water and an organic solvent, or the pH is adjusted to 6 to 8 as a pH buffer solution such as a phosphate buffer solution. It is preferable to maintain.

  The hydrolase is not particularly limited as long as it can hydrolyze an ester bond, and examples thereof include porcine liver-derived esterase.

  The reaction temperature is 10 ° C to 50 ° C, preferably 30 ° C to 40 ° C, and the reaction time is usually 10 minutes to 8 hours, preferably 30 minutes to 2 hours.

  After completion of the reaction, the target compound can be isolated and purified by ion exchange chromatography, reverse phase column chromatography, reprecipitation, recrystallization and the like.

  When compound (IV) contains two or more types of protecting groups, the target compound (I) can be obtained by sequentially combining the above deprotection reactions. In addition, when the pharmacologically acceptable ester derivative of compound (I) is desired, it is not necessary to remove the group which forms the pharmacologically acceptable ester as a protecting group.

  The compound (I) thus obtained is converted into a pharmacologically acceptable salt or ester derivative according to a method or technique known in the field of medicinal chemistry, particularly β-lactam antibiotics, as necessary. Can be converted.

  A pharmacologically acceptable ester derivative at the carboxyl group of compound (I) is produced by reacting compound (I) with a halide corresponding to a desired ester residue in the presence of a base in an inert solvent. Can do.

  The halide used can be, for example, chloride, bromide or iodide, preferably iodide. When using chloride or bromide, the reaction can be accelerated by adding a catalytic amount of sodium iodide to the reaction solution.

  The base used can be, for example, organic amines such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine; or alkali metal carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, preferably Are organic amines, more preferably diisopropylethylamine.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, nitriles such as acetonitrile; amides such as N, N-dimethylformamide; It may be a halogenated hydrocarbon such as methylene, preferably an amide or nitrile, and more preferably dimethylacetamide or acetonitrile.

  The reaction temperature is usually −20 ° C. to 50 ° C., preferably −10 ° C. to 20 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  In addition, what was previously isolated as a salt by reacting compound (I) with a base can also be reacted with halides as described above.

  On the other hand, the pharmacologically acceptable ester derivative in the carboxyl group of compound (I) can also be obtained by reacting compound (I) with an alcohol corresponding to the desired ester residue in the presence of a condensing agent and a base. Can be manufactured.

  Examples of the condensing agent include Mitsunobu reagents such as diethyl azodicarboxylate; phosphate ester condensing agents such as diphenylphosphoryl azide; carbodiimides such as dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. A condensing agent; or an onium condensing agent such as 2-chloro-1-methylpyridinium iodide.

  The base used can be, for example, organic amines such as triethylamine, tributylamine, diisopropylethylamine, 4-dimethylaminopyridine.

  Examples of other additives include phosphines such as triphenylphosphine and tributylphosphine, and alcohols for forming active esters such as 1-hydroxybenztriazole.

  The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane; amides such as N, N-dimethylformamide; Nitriles such as acetonitrile; or ethers such as tetrahydrofuran.

  Suitable combinations of these include diethyl azodicarboxylate and triphenylphosphine; 2-chloro-1-methylpyridinium iodide and tributylamine or triethylamine; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Mention may be made of 4-dimethylaminopyridine or 1-hydroxybenztriazole.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing the mixture with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

[Method B]
Method B is a method for producing compound (III) used as a starting material in Method A.

In the above, Ap, X and n are as defined above. P ² represents a carboxyl-protecting group, and may be, for example, a t-butyl group; or an optionally substituted benzyl group such as benzyl or 4-methoxybenzyl group, preferably a t-butyl group. . L ² represents a leaving group, for example, a halogen atom such as chlorine, bromine or iodine atom; substituted with fluorine such as methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy group. good C ₁ -C be the ₄ alkylsulfonyloxy group; or alkyl substituted be also benzene sulfonyloxy group to give, preferably good C ₁ -C ₄ alkylsulfonyl is substituted with fluorine It is an oxy group. P ³ represents a mercapto protecting group, for example, a C ₁ -C ₄ alkanoyl group such as formyl, acetyl, propionyl, butyryl group; an optionally substituted benzoyl group such as benzoyl, toluoyl, anisoyl group; or it is a 4-methoxybenzyl group, preferably a C ₁ -C ₄ alkanoyl group, more preferably an acetyl group.

(Step B1)
Step B1 is a process for producing a compound having the general formula (VI), and is a method generally used in the field of organic synthetic chemistry (for example, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons by TWGreene, PGMWuts). , Inc. 1991).

(Step B2)
Step B2 is a step of producing compound (VII) by converting the hydroxyl group of compound (VI) to leaving group L ² .

(1) In the case where the leaving group L ² is a C ₁ -C ₄ alkylsulfonyloxy group which may be substituted with fluorine or a benzenesulfonyloxy group which may be substituted with alkyl. This is accomplished by reacting the sulfonylating agent in the presence of a base in an inert solvent.

  The sulfonylating agent used can be, for example, methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, preferably methanesulfonyl chloride.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform; or tetrahydrofuran, diethyl ether Such ethers can be used, preferably halogenated hydrocarbons, and more preferably methylene chloride.

  The base used can be an organic base such as, for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, preferably triethylamine.

  The reaction temperature is usually −20 ° C. to 80 ° C., preferably −10 ° C. to 40 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours. .

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing the mixture with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

(2) When the leaving group L ² is a halogen atom This step is achieved by reacting the compound (VI) with a halogenating agent in an inert solvent.

  The halogenating agent used is, for example, phosphorus pentachloride, thionyl chloride, phosphorus oxychloride, iodine, carbon tetrabromide, carbon tetrachloride, N-chlorosuccinimide, N-bromosuccinimide, diethylaminosulfur trifluoride. Preferred is carbon tetrabromide.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane; or tetrahydrofuran and diethyl ether. It may be an ether, preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature is usually −20 ° C. to 100 ° C., preferably −10 ° C. to 50 ° C., and the reaction time is usually 10 minutes to 108 hours, preferably 30 minutes to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing the mixture with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

(Step B3)
Step B3 is a step of producing compound (VIII) by converting the leaving group L ² of compound (VII) into a protected mercapto group.

  This step is achieved by allowing a mercapto agent to act on compound (VII) in an inert solvent.

  The mercapto agent used can be, for example, an alkali metal salt of a thiocarboxylic acid such as sodium thioacetate, potassium thioacetate, sodium thiopropionate, sodium thiobenzoate or an alkali metal salt of 4-methoxybenzyl mercaptan. Is potassium thioacetate.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, ethers such as tetrahydrofuran and dioxane; acetates such as ethyl acetate and methyl acetate; acetonitrile Or amides such as dimethylformamide and dimethylacetamide, preferably amides, and more preferably dimethylformamide.

  The reaction temperature is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing the mixture with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

(Step B4)
Step B4 is a step of converting compound (VIII) to compound (IX). By reacting an acid in an inert solvent, the group represented by formula CO ₂ P ² contained in compound (VIII) Is achieved by removing.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, ethers such as tetrahydrofuran, diethyl ether and dioxane; acetates such as ethyl acetate and methyl acetate Or halogenated hydrocarbons such as methylene chloride and dichloroethane.

  The acid used can be, for example, an organic acid such as trifluoroacetic acid; or an inorganic acid such as hydrochloric acid.

  After completion of the reaction, the target compound can be obtained, for example, by distilling off the solvent and drying, and can also be obtained by filtering out crystals precipitated in the solvent.

(Step B5)
Step B5 is a step for producing a desired compound (X) by introducing an acyl substituent into the amino group of compound (IX).

  This step can be achieved by applying a functional group conversion reaction usually used in the field of synthetic organic chemistry. Details will be described in the following Method C to Method H.

(Step B6)
Step B6 is a step for producing compound (III) by removing protecting group P ³ of the mercapto group of compound (X).

(1) When the protecting group P ³ is an alkanoyl group or an arylcarbonyl group This step can be achieved by allowing the salt of a hydrazine compound to act on the compound (X) in an inert solvent.

  The salt of the hydrazine compound may be, for example, hydrazine / acetic acid or N, N-dimethylhydrazine / acetic acid, and is preferably hydrazine / acetic acid.

  As a solvent to be used, the solvent used in the above-mentioned Method A, Step A1 can be used.

  The reaction temperature is not particularly limited, but is usually −10 ° C. to 40 ° C., preferably 10 ° C. to 30 ° C., and the reaction time varies depending on the type of solvent, reaction temperature and reaction reagent, but is usually 30 Minutes to 24 hours, preferably 1 to 8 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing the mixture with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

  In addition, when the salt of a hydrazine compound is used as a deprotecting agent, compound (III) can be used as a raw material of the above-mentioned Method A step A1 without isolation from the reaction solution.

  This step can also be achieved by reacting compound (X) with a base in an inert solvent.

  The base used can be an alkali metal salt such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, preferably sodium methoxide.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and diethyl ether; dimethylformamide Such amides; or halogenated hydrocarbons such as methylene chloride and dichloroethane, preferably alcohols, and more preferably methanol.

  The reaction temperature is usually −20 ° C. to 100 ° C., preferably −10 ° C. to 40 ° C., and the reaction time is usually 10 minutes to 108 hours, preferably 30 minutes to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

(2) When P ³ is a 4-methoxybenzyl group This step is achieved by reacting compound (X) with an acid in an inert solvent.

  The acid used can be sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, preferably trifluoromethanesulfonic acid. The reaction can be promoted by allowing anisole or thioanisole to coexist in the reaction system.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane; ethers such as tetrahydrofuran and diethyl ether. Or acetic acid such as acetic acid and trifluoroacetic acid, preferably acetic acid, and more preferably trifluoroacetic acid.

  The reaction temperature is usually −20 ° C. to 100 ° C., preferably −10 ° C. to 80 ° C., and the reaction time is usually 10 minutes to 108 hours, preferably 30 minutes to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

[Method C]
Method C is a method for producing compound (X-1) having an amide residue among compounds (X), which is a synthetic intermediate of method B.

In the above, Ap, P ³ and n are as defined above.

(Step C1)
This step is achieved by allowing a desired acylating agent to act on the amino group of compound (IX) in an inert solvent in the presence of a base.

  The acylating agent used can be, for example, an acid anhydride such as acetic anhydride, benzoic anhydride; or an acid chloride such as acetic acid chloride, benzoic acid chloride, preferably an acid chloride, more preferably Is acetic chloride.

  The base used can be an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine; or an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, preferably an organic base. More preferably triethylamine.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, ethers such as tetrahydrofuran and diethyl ether; or halogenated hydrocarbons such as methylene chloride and dichloroethane. Preferably ethers or halogenated hydrocarbons, more preferably tetrahydrofuran or methylene chloride.

  The reaction temperature is usually −50 ° C. to 100 ° C., preferably −20 ° C. to 50 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

  This step can also be achieved by reacting compound (IX) with a desired carboxylic acid compound represented by the formula ApCOOH in an inert solvent in the presence of a condensing agent.

  As the condensing agent used, a phosphoric ester condensing agent such as diethyl phosphoryl cyanide or a carbonate condensing agent such as carbonyldiimidazole can also be used. Preferred is diethyl phosphoryl cyanide or carbonyldiimidazole.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane; ethers such as tetrahydrofuran and diethyl ether. Amides such as dimethylformamide; or nitriles such as acetonitrile, preferably ethers, more preferably tetrahydrofuran.

  The reaction temperature is usually −50 ° C. to 100 ° C., preferably −20 ° C. to 50 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

[Method D]
Method D is a method for producing compound (X-2) having a thioamide residue among compounds (X), which is a synthetic intermediate of method B.

In the above, Ap, P ³ and n are as defined above.

(Step D1)
This step is achieved by allowing a sulfur compound to act on the carbonyl group of compound (X-1) in an inert solvent.

  Examples of sulfur compounds include phosphorus sulfide compounds such as phosphorous pentasulfide and 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4-disulfide (Lawson reagent). 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide is preferred.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and dichloroethane; Alternatively, it may be an aromatic hydrocarbon such as benzene, toluene or xylene, preferably an aromatic hydrocarbon, and more preferably toluene.

  The reaction temperature is usually −20 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  You may perform this process in presence of a base as needed.

  The base used can be, for example, an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine; or an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, preferably organic A base, more preferably pyridine.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

[E method]
Method E is a method for producing compound (X-3) having a urea residue among compounds (X), which is a synthetic intermediate of method B.

In the above, P ³ and n are as defined above. R ¹ and R ² are either a hydrogen atom and the other is a phenyl group or a pyridyl group, or the same or different, a C ₁ -C ₆ alkyl group or an optionally substituted 5- or 6-membered unsaturated heterocyclic group (said heterocyclic group is. the substituent having the same or different one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring is, C ₁ -C ₃ alkyl group, an amino group L ³ represents a leaving group, such as a halogen atom such as a chlorine atom; an azole group such as an imidazole group; or an oxysuccinimide. Oxysuccinimides, preferably a chlorine atom.

(Step E1)
Step E1 is a method for producing the desired carbonyl compound (XII) by reacting the desired amine compound (XI) with an acylating agent in the presence of a base in an inert solvent.

  The acylating agent used can be, for example, acid chlorides such as phosgene, triphosgene; or carbonates such as carbonyldiimidazole, disuccimido carbonate, preferably triphosgene.

  The base used can be, for example, an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine; or an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, preferably organic A base, more preferably diisopropylethylamine or pyridine.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, ethers such as tetrahydrofuran and diethyl ether; nitriles such as acetonitrile; methylene chloride, dichloroethane and the like. Halogenated hydrocarbons; or aromatic hydrocarbons such as benzene, toluene and xylene, preferably ethers or halogenated hydrocarbons, more preferably tetrahydrofuran or methylene chloride. .

  The reaction temperature is usually −50 ° C. to 100 ° C., preferably −20 ° C. to 50 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

  Compound (XII) can be used as a raw material for Step E2 without being isolated from the reaction solution.

(Step E2)
Step E2 is achieved by reacting carbonyl compound (XII) with compound (IX) in the presence of a base in an inert solvent.

  The base used can be, for example, an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine; or an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, preferably an organic base More preferably, it is diisopropylethylamine or pyridine.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, ethers such as tetrahydrofuran and diethyl ether; nitriles such as acetonitrile; N, N-dimethylformamide Amides such as N, N-dimethylacetamide; halogenated hydrocarbons such as methylene chloride and dichloroethane; or aromatic hydrocarbons such as benzene, toluene and xylene, preferably ethers Or halogenated hydrocarbons, more preferably tetrahydrofuran or methylene chloride.

  The reaction temperature is usually −50 ° C. to 100 ° C., preferably −20 ° C. to 50 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

[F method]
Method F is a method for producing compound (X-4) having a thiourea residue among compounds (X), which is a synthetic intermediate of method B.

In the above, R ¹ , R ² , P ³ and n are as defined above.

(Step F1)
This step can be performed according to the aforementioned D method step D1.

[G method]
Method G is a method for separately producing compound (X-4) having a thiourea residue among compounds (X), which is a synthetic intermediate of method B.

In the above, R ¹ , R ² , P ³ and n are as defined above. L ⁴ represents a leaving group, and may be, for example, a halogen atom such as a chlorine atom; or an azole group such as an imidazole group, preferably a chlorine atom.

(Step G1)
Step G1 is a method for producing the desired carbonyl compound (XIV) by reacting the desired amine compound (XI) with an acylating agent in the presence of a base in an inert solvent.

  The acylating agent can be, for example, acid chlorides such as thiocarbonyl dichloride; or carbonates such as thiocarbonyldiimidazole, preferably thiocarbonyl dichloride.

  The base used can be, for example, an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine; or an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, preferably an organic base More preferably, it is diisopropylethylamine or pyridine.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, ethers such as tetrahydrofuran and diethyl ether; nitriles such as acetonitrile; methylene chloride, dichloroethane and the like. Halogenated hydrocarbons; or aromatic hydrocarbons such as benzene, toluene and xylene, preferably halogenated hydrocarbons, more preferably methylene chloride.

  The reaction temperature is usually −50 ° C. to 100 ° C., preferably −20 ° C. to 50 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

  In addition, compound (XIV) can be used as a raw material of the G2 process, without isolating from a reaction liquid.

(Step G2)
This step can be performed according to the above-mentioned E method E2 step.

[Method H]
Method H is a method for separately producing compound (X-3) having a urea residue among compounds (X), which is a synthetic intermediate of method B.

In the above, R ¹ , R ² , P ³ , L ² and n are as defined above. P ⁴ represents an amino-protecting group such as allyloxycarbonyl group; benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc. An optionally substituted benzyloxycarbonyl group (the substituent is a methyl, methoxy, nitro group or chlorine atom); a substituent such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl or 2-nitrobenzyl A benzyl group which may have a group (the substituent is a nitro, methyl, methoxy group or chlorine atom); or a benzhydryl group, preferably a benzhydryl group. P ⁵ represents a hydroxyl-protecting group, and may be a silyl-based protecting group such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and preferably a t-butyldiphenylsilyl group.

(Step H1)
Step H1 is a step for producing compound (XVI) by introducing protective group P ⁵ into the hydroxyl group of compound (XV).

  This step is achieved by a method commonly used in the field of organic synthetic chemistry (for example, a method described by TWGreene, PGMWuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc. 1991). can do.

  The introduction of the silyl protecting group is achieved by reacting compound (XV) with a silyl halide or silyl triflate having a desired substituent in the presence of a base in an inert solvent.

  The silyl halides can be, for example, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride or t-butyldiphenylsilyl chloride, preferably t-butyldiphenylsilyl chloride.

  The silyl triflate can be, for example, trimethylsilyl triflate, triethylsilyl triflate, t-butyldimethylsilyl triflate or t-butyldiphenylsilyl triflate, preferably t-butyldiphenylsilyl triflate.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, amides such as dimethylformamide; halogenated hydrocarbons such as methylene chloride and dichloroethane; or , Tetrahydrofuran, diethyl ether and the like, preferably amides or halogenated hydrocarbons, more preferably dimethylformamide or methylene chloride.

  The base used can be an organic base such as imidazole, triethylamine, lutidine, pyridine, 4-dimethylaminopyridine, preferably imidazole or 2,6-lutidine.

  The reaction temperature is usually −20 ° C. to 50 ° C., preferably −10 ° C. to 40 ° C., and the reaction time is usually 30 minutes to 108 hours, preferably 1 hour to 24 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing the mixture with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

(Step H2)
Step H2 is a step of producing compound (XVII) by removing the amino-protecting group of compound (XVI).

  This step can be performed according to the method of the above-mentioned Method A, Step A2, Step (1) or (2). In the method according to Method A, Step A2 (1), suitable solvents are alcohols, more preferably methanol or ethanol.

(Step H3)
Step H3 is a method for producing compound (XVIII) by reacting the amino group of compound (XVII) with an acylating agent in the presence of a base in an inert solvent.

  This step can be performed according to the methods of the above-mentioned E method, E1 step and E2 step.

(Step H4)
Step H4 is a step for producing compound (XIX) by removing protecting group P ⁵ for the hydroxyl group of compound (XVIII).

  This step is achieved by a method commonly used in the field of organic synthetic chemistry (for example, a method described by TWGreene, PGMWuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc. 1991). can do.

When the hydroxyl protecting group P ⁵ is a silyl protecting group, the removal can be carried out according to the method of Method A, Step A2 (3).

(Step H5)
Step H5 is a step for producing compound (XX) by converting the hydroxyl group of compound (XIX) to leaving group L ² .

  This step can be performed according to the method of the above-mentioned method B, step B2.

(Step H6)
Step H6 is a step of producing compound (X-3) by converting the leaving group L ² of compound (XX) to a protected mercapto group.

  This step can be performed in the same manner as the above-mentioned Method B, Step B3.

  The compound having the general formula (I) of the present invention, or a pharmacologically acceptable salt or ester derivative thereof is, for example, Gram-positive bacteria such as staphylococci and Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Shigella, variant bacteria, Serratia, Has strong antibacterial activity against a wide range of pathogens including Gram-negative bacteria such as Enterobacter and anaerobes such as Bacteroides fragilis, including pneumococci (including penicillin-resistant bacteria) that are the causative agents of respiratory infections ), Strong antibacterial activity against hemophilus influenza (including β-lactamase producing bacteria). The compound (I) of the present invention has high stability against β-lactamase except metallo-β-lactamase. Since the compound (I) of the present invention is excellent in pharmacokinetics, such as giving a high maximum blood concentration and a long blood concentration half-life when administered orally or parenterally to a recipient, The effect of treating infection is expected even with a small number of administrations and a low dose compared to drugs. The compound (I) of the present invention has low toxicity to the kidney. Therefore, the compound having the general formula (I) of the present invention, or a pharmacologically acceptable salt or ester derivative thereof is useful, for example, as a medicine, and particularly treats bacterial infections caused by various pathogenic bacteria, particularly respiratory infections. Alternatively, it is useful as an antibacterial agent for prevention (preferably treatment).

  When the compound (I), or a pharmacologically acceptable salt or ester derivative thereof is used as a medicine, particularly as an antibacterial agent, itself or an appropriate pharmacologically acceptable excipient, diluent, etc. It can be mixed and administered orally by tablets, capsules, granules, powders or syrups, or parenterally by injections or the like.

  These preparations include excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose Cellulose derivatives such as low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, internally cross-linked sodium carboxymethyl cellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, metasilicate aluminate Silicate derivatives such as magnesium; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate Etc.), binders (for example, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; macrogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, etc. Modified starch, cellulose derivatives, etc.), lubricants (eg talc; stearic acid; stearic acid metal salts such as calcium stearate, magnesium stearate; colloidal silica; bee gum; waxes such as beeswax, gay wax Boric acid; Glycol; Carboxylic acids such as fumaric acid and adipic acid; Sodium carboxylate such as sodium benzoate; Sulfates such as sodium sulfate; Leucine; Lauryl such as sodium lauryl sulfate and magnesium lauryl sulfate Sulfate; None Silicic acids such as hydrosilicic acid and silicic acid hydrate; starch derivatives in the above-mentioned excipients, stabilizers (for example, para-oxybenzoic acid esters such as methylparaben and propylbaraben; chlorobutanol, benzyl alcohol, phenylethyl alcohol) Alcohols such as benzene; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.] and flavoring agents (for example, commonly used sweeteners, acidulants, flavorings, etc.) ), A suspending agent (for example, polysorbate 80, sodium carboxymethyl cellulose, etc.), a diluent, a solvent for preparation (for example, water, ethanol, glycerin, etc.) and the like, and is produced by a known method.

  The amount used varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 1000 mg), and in the case of intravenous administration, 1 It is desirable to administer a lower limit of 10 mg (preferably 100 mg) per dose and an upper limit of 3000 mg (preferably 2000 mg) to adults 1 to 6 times per day according to symptoms.

The present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Formulation Examples below, but the present invention is not limited thereto. For nuclear magnetic resonance spectra in the Examples and Reference Examples, using trimethylsilyl propionic acid sodium -d ₄ to the internal standard for the measurement of the heavy water and measured using tetramethylsilane as an internal standard in the other solvents. In the measurement in heavy water, when no internal standard was used, the signal position of proton (HOD) in heavy water was 4.65 ppm.

Example 1 (1R, 5S, 6S) -2- (1-Pivaloylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3-carboxylic acid sodium salt (salt of compound No. 7)
(1a) 3-Methanesulfonyloxy-1- (t-butoxycarbonyl) azetidine N-benzhydryl-3-hydroxyazetidine (23.9 g, 100.0 mmol) was dissolved in ethanol (1 L), and di-t- Butyl-dicarbonate (26.2 g, 100.0 mmol) and 20% palladium hydroxide-carbon (23.9 g) were added, and catalytic hydrogen reduction was performed at 50 ° C. for 1.5 hours. After completion of the reaction, the catalyst was removed by filtration, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (500 mL), methanesulfonyl chloride (17.2 g, 150.0 mmol) was added to this solution under a nitrogen atmosphere, and then triethylamine (15.2 g, 150.0 mmol) was added dropwise under ice cooling. The mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and this solution was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 7 / 3-5 / 5, V / V) to give the title compound (24.6 g, Yield 98%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 5.23-5.17 (1H, m), 4.30-4.25 (2H, m), 4.13-4.08 (2H, m), 3.07 (3H, s), 1.44 (9H, s );
MS (EI) m / z: 252 (M + H) ^<+> .

(1b) 3-acetylthio-1- (t-butoxycarbonyl) azetidine 3-methanesulfonyloxy-1- (t-butoxycarbonyl) azetidine (24.6 g, 97.7 mmol) obtained in Example 1 (1a) , N-dimethylformamide (650 mL) and acetonitrile (650 mL) dissolved in a mixed solvent, potassium thioacetate (67.0 g, 586.2 mmol) was added to the solution, and the mixture was stirred at 80 ° C. for 13.5 hours under a nitrogen atmosphere. And left at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. This solution was washed successively with 10% brine, water, dilute potassium hydrogensulfate aqueous solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. did. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 98 / 2-80 / 20, V / V) to give the title compound as a pale yellow oil (19.9 g, yield 88%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.39-4.34 (2H, m), 4.19-4.11 (1H, m), 3.83-3.79 (2H, m), 2.33 (3H, s), 1.43 (9H, s );
MS (FAB) m / z: 232 (M + H) ^<+> .

(1c) 3-Acetylthioazetidine hydrochloride 3-Acetylthio-1- (t-butoxycarbonyl) azetidine (700 mg, 3.03 mmol) obtained in Example 1 (1b) was added to 1,4-dioxane (7 mL). After dissolution, hydrogen chloride (4 mol / L, 1,4-dioxane solution) (7 mL) was added to this solution under a nitrogen atmosphere under ice cooling, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue and stirred, and the solution was concentrated under reduced pressure to obtain a crude product of the title compound as a light brown solid.

(1d) 3-acetylthio-1-pivaloylazetidine pivalic acid (371 μL, 3.63 mmol) is dissolved in tetrahydrofuran (20 mL), and 1,1′-carbonylbis is added to this solution at room temperature under a nitrogen atmosphere. -1H-imidazole (589 mg, 3.63 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. After confirming disappearance of the raw materials, a solution of 3-acetylthioazetidine hydrochloride (3.03 mmol) obtained in Example 1 (1c) in methylene chloride (10 mL) was added to the reaction solution at room temperature and stirred for 1 hour. After confirmation of completion of the reaction, methylene chloride was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 3-1 / 1, V / V) to give the title compound as a colorless oil. (513 mg, 79% yield) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.91-4.74 (1H, m), 4.52-4.30 (1H, m), 4.24-4.10 (2H, m), 4.00-3.82 (1H, m), 2.35 (3H , s), 1.18 (9H, s);
MS (EI) m / z: 215 (M) ^<+> .

(1e) p-nitrobenzyl (1R, 5S, 6S) -2- (1-pivaloylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-Em-3-carboxylate 3-Acetylthio-1-pivaloylazetidine (510 mg, 2.37 mmol) obtained in Example 1 (1d) was dissolved in dimethylformamide (15 mL). To the solution, hydrazine acetate (260 mg, 2.82 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapene-2-em-3-carboxylate (1.41 g, 2.37 mmol) in acetonitrile (45 mL) was added dropwise, followed by addition of diisopropylethylamine (1.65 mL, 9.47 mmol) and gradually to room temperature. The temperature was raised and left overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine and saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 4 / 1-1 / 0-ethyl acetate / methanol = 99/1, V / V). Purification gave the pale yellow amorphous title compound (901 mg, 73% yield).
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.80-4.65 (1H, m), 4.52-4.38 (1H, m), 4.30-4.23 (2H, m), 4.09-4.02 (2H, m), 4.04-3.90 (1H , m), 3.28 (1H, dd, J = 6.8, 2.4 Hz), 3.17 (1H, dq, J = 8.8, 7.3 Hz), 1.80-1.65 (1H, bs), 1.38 (3H, d, J = 6.3 Hz), 1.26 (3H, d, J = 7.3 Hz), 1.18 (9H, s);
MS (FAB) m / z: 518 (M + H) ^<+> .

(1f) (1R, 5S, 6S) -2- (1-Pivaloylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-pivaloylazetidin-3-yl) thio-6-[(R) obtained in Example 1 (1e) ) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (900 mg, 1.74 mmol) in tetrahydrofuran (27 mL) and 0.1 mol / L-sodium phosphate buffer pH 7.0 ( (27 mL) was dissolved in a mixed solvent, 10% palladium carbon (900 mg) was added to the solution, and catalytic hydrogen reduction was performed at room temperature for 2.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The obtained aqueous layer was concentrated under reduced pressure, and reverse phase chromatography using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Ltd.) (elution solvent: distilled water / acetonitrile = 100 / 0-96 / 4, V / V) The product was purified by lyophilization and lyophilized to obtain the target compound as a white amorphous title compound (557 mg, yield 79%).
¹ H NMR (D ₂ O, 400 MHz): δ 5.00-4.93 (1H, m), 4.46-4.38 (2H, m), 4.28-4.12 (3H, m), 3.92-3.87 (1H, m), 3.44- 3.41 (1H, m), 3.28-3.16 (1H, m), 1.30 (3H, d, J = 6.4 Hz), 1.20-1.17 (12H, m);
IR (KBr): 2966, 1751, 1606, 1403, 1390 cm ^-1 ;
MS (FAB) m / z: 405 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₈ H ₂₆ N ₂ O ₅ SNa (M + H) ⁺ : 405.14601.Found 405.14538;
Anal.calcd.for C ₁₈ H ₂₅ N ₂ O ₅ SNa ・ 3 / 2H ₂ O: C, 50.10%; H, 6.54%; N, 6.49%; S, 7.43%, Found C, 50.25%; H, 6.65 %; N, 6.59%; S, 7.25%.

Example 2 (1R, 5S, 6S) -2- (1-isobutyrylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3-carboxylic acid sodium salt (salt of compound No. 4)
(2a) 3-acetylthio-1-isobutyrylazetidine A colorless oily title in the same manner as in Example 1 (1d) except that isobutyric acid (337 μL, 3.63 mmol) was used instead of pivalic acid. A compound (434 mg, yield 71%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.64 (1H, t, J = 8.6 Hz), 4.40 (1H, t, J = 9.4 Hz), 4.26-4.18 (1H, m), 4.00 (1H, dd, J = 9.0, 5.5 Hz), 3.89 (1H, dd, J = 10.2, 5.5 Hz), 2.43-2.35 (1H, m), 2.35 (3H, s), 1.10 (6H, d, J = 7.4 Hz);
MS (FAB) m / z: 201 (M) ^<+> .

(2b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-isobutyrylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-Em-3-carboxylate 3-acetylthio-1-isobutyrylazetidine (430 mg, 2.14 mmol) obtained in Example 2 (2a) instead of the compound obtained in Example 1 (1d) ) Was used in the same manner as in Example 1 (1e) to obtain the pale yellow amorphous title compound (923 mg, yield 86%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.21 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 5.49 (1H, d, J = 13.7 Hz), 5.23 (2H , d, J = 13.7 Hz), 4.58-4.51 (1H, m), 4.92-4.85 (1H, m), 4.28-4.20 (2H, m), 4.10-4.02 (2H, m), 3.98-3.93 (1H , m), 3.28-3.23 (1H, m), 3.17-3.11 (1H, m), 2.40-2.35 (1H, m), 1.37 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.2 Hz), 1.09 (6H, d, J = 7.4 Hz);
MS (FAB) m / z: 504 (M + H) ^<+> .

(2c) (1R, 5S, 6S) -2- (1-isobutyrylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-isobutyrate) obtained in Example 2 (2b) instead of the compound obtained in Example 1 (1e) Implemented except using rilazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (920 mg, 1.83 mmol) In the same manner as in Example 1 (1f), the target compound was obtained as a pale yellow amorphous title compound (575 mg, yield 81%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.75-4.68 (1H, m), 4.46-4.40 (1H, m), 4.28-4.15 (4H, m), 3.92-3.88 (1H, m), 3.45- 3.42 (1H, m), 3.25-3.19 (1H, m), 2.63-2.53 (1H, m), 1.30 (3H, d, J = 6.3 Hz), 1.20 (1.5H, d, J = 7.3 Hz), 1.19 (1.5H, d, J = 7.3 Hz), 1.07-1.03 (6H, m);
IR (KBr): 2967, 1750, 1605, 1449, 1397 cm ^-1 ;
MS (FAB) m / z: 391 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₇ H ₂₄ N ₂ O ₅ SNa (M + H) ⁺ : 391.13036. Found 391.12771;
Anal.calcd.for C ₁₇ H ₂₃ N ₂ O ₅ SNa ・ 1 / 2H ₂ O: C, 51.12%; H, 6.06%; N, 7.01%; S, 8.03%, Found C, 51.18%; H, 6.16 %; N, 6.99%; S, 7.96%.

Example 3 (1R, 5S, 6S) -2- (1-propionylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-Carboxylic acid sodium salt (salt of compound No. 2)
(3a) 3-Acetylthio-1-propionylazetidine A colorless oily title compound in the same manner as in Example 1 (1d) except that propionic acid (271 μL, 3.63 mmol) was used instead of pivalic acid. 421 mg, yield 74%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.59 (1H, t, J = 8.4 Hz), 4.41 (1H, t, J = 9.4 Hz), 4.26-4.18 (1H, m), 3.97 (1H, dd, J = 9.0, 5.5 Hz), 3.90 (1H, dd, J = 10.4, 5.5 Hz), 2.35 (3H, s), 2.08 (2H, q, J = 7.4 Hz), 1.12 (3H, t, J = 7.4 Hz);
MS (EI) m / z: 187 (M) ^<+> .

(3b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-propionylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3-carboxylate 3-acetylthio-1-propionylazetidine (420 mg, 2.24 mmol) obtained in Example 3 (3a) was used instead of the compound obtained in Example 1 (1d). A pale yellow amorphous title compound (1.01 g, yield 93%) was obtained in the same manner as in Example 1 (1e) except for the above.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.55-4.46 (1H, m), 4.45-4.35 (1H, m), 4.31-4.22 (2H, m), 4.10-4.01 (2H, m), 4.00-3.94 (1H , m), 3.30-3.26 (1H, m), 3.21-3.12 (1H, m), 2.13-2.03 (2H, m), 1.76-1.70 (1H, m), 1.38 (3H, d, J = 6.3 Hz ), 1.26 (3H, d, J = 7.0 Hz), 1.12 (3H, t, J = 7.4 Hz);
MS (FAB) m / z: 490 (M + H) ^<+> .

(3c) (1R, 5S, 6S) -2- (1-propionylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3 -Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-propionylazetidine-) obtained in Example 3 (3b) instead of the compound obtained in Example 1 (1e) Example 1 (1f) except that 3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (1.01 g, 2.06 mmol) was used. ) To give the target compound as a pale yellow amorphous title compound (526 mg, yield 68%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.70-4.64 (1H, m), 4.46-4.40 (1H, m), 4.28-4.12 (4H, m), 3.93-3.88 (1H, m), 3.45- 3.41 (1H, m), 3.26-3.17 (1H, m), 2.19 (1H, q, J = 7.8 Hz), 2.17 (1H, q, J = 7.8 Hz), 1.30 (3H, d, J = 6.8 Hz ), 1.19 (1.5H, d, J = 7.3 Hz), 1.18 (1.5H, d, J = 7.3 Hz), 1.07 (1.5H, t, J = 7.8 Hz), 1.06 (1.5H, t, J = 7.8 Hz);
IR (KBr): 3398, 2969, 1749, 1604, 1465, 1450, 1425, 1313, 1292 cm ^-1 ;
MS (FAB) m / z: 377 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₆ H ₂₂ N ₂ O ₅ SNa (M + H) ⁺ : 377.1147. Found 377.1137;
Anal.calcd.for C ₁₆ H ₂₁ N ₂ O ₅ SNa ・ 4 / 5H ₂ O: C, 49.17%; H, 5.83%; N, 7.17%; S, 8.20%, Found C, 49.30%; H, 5.99 %; N, 7.18%; S, 8.20%.

Example 4 (1R, 5S, 6S) -2- (1-acetylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-Carboxylic acid sodium salt (sodium salt of compound No. 1)
(4a) 3-Acetylthio-1-acetylazetidine 3-Acetylthioazetidine hydrochloride (1.08 mmol) obtained in Example 1 (1c) was dissolved in methylene chloride (10 mL). Under an atmosphere and ice-cooling, acetyl chloride (127 mg, 1.62 mmol) and triethylamine (602 μL, 4.32 mmol) were added, the temperature was gradually raised to room temperature, and the mixture was allowed to stand overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the solution was washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 0-20 / 1, V / V) to give the title compound (109 mg, yield 58%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.60 (1H, t, J = 8.8 Hz), 4.47-4.36 (1H, m), 4.26-4.16 (1H, m), 3.99 (1H, dd, J = 8.6 , 5.5 Hz), 3.90 (1H, dd, J = 10.4, 5.3 Hz), 2.36-2.34 (3H, m), 1.86 (3H, s);
MS (FAB) m / z: 174 (M + H) ^<+> .

(4b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-acetylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3-carboxylate 3-acetylthio-1-acetylazetidine (0.70 g, 4.04 mmol) obtained in Example 4 (4a) was dissolved in N, N-dimethylformamide (15 mL). Hydrazine acetate (0.19 g, 2.05 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapen-2-em-3-carboxylate (1.52 g, 2.56 mmol) in acetonitrile (15 mL) was added dropwise, followed by N, N-diisopropylethylamine (0.97 mL, 5.54 mmol), Left in the refrigerator overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 10% brine, water, dilute aqueous sodium bicarbonate, water, dilute aqueous potassium hydrogen sulfate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-80 / 20, V / V) to give the title compound (606 mg, yield 74%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.23 (2H, d J = 8.8 Hz), 7.66 (2H, d J = 8.8 Hz), 5.51 (1H, d, J = 13.9 Hz), 5.25 (1H, d , J = 13.9 Hz), 4.56-3.92 (7H, m), 3.30-3.11 (2H, m), 2.16-1.84 (4H, m), 1.37 (3H, d, J = 6.6 Hz), 1.25 (3H, d, J = 7.3 Hz);
MS (FAB) m / z: 476 (M + H) ^<+> .

(4c) (1R, 5S, 6S) -2- (1-acetylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3 -Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-acetylazetidin-3-yl) thio-6-[(R) -1 obtained in Example 4 (4b) -Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (0.60 g, 1.34 mmol) in tetrahydrofuran (15 mL) and 0.1 mol / L sodium phosphate buffer pH 7.0 (15 mL). It melt | dissolved in the mixed solvent, 7.5% palladium carbon (0.60 g) was added to this solution, and catalytic hydrogen reduction was performed at 30 degreeC for 2 hours. After confirming the completion of the reaction, the catalyst was removed by filtration. The filtrate was diluted with distilled water, washed with diethyl ether, and the aqueous layer was concentrated under reduced pressure. The concentrated solution is purified by reverse phase chromatography (elution solvent: distilled water / acetonitrile = 100 / 0-99 / 1, V / V) using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Ltd.) and lyophilized. This gave the target compound as a white amorphous title compound (286 mg, yield 63%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.79-4.65 (1H, m), 4.46-4.40 (1H, m), 4.28-4.13 (4H, m), 3.93-3.89 (1H, m), 3.44- 3.42 (1H, m), 3.26-3.18 (1H, m), 1.92-1.89 (3H, m), 1.30 (3H, d, J = 6.6 Hz), 1.19 (3H, d, J = 7.3 Hz);
IR (KBr): 2967, 1748, 1605, 1461, 1396 cm ^-1 ;
MS (FAB) m / z: 339 (M-Na) ^- .

Example 5 (1R, 5S, 6S) -2- (1-methoxyacetylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt (salt of compound No. 10)
(5a) 3-acetylthio-1-methoxyacetylazetidine A colorless oily title compound in the same manner as in Example 1 (1d) except that methoxyacetic acid (279 μL, 3.63 mmol) was used instead of pivalic acid. (507 mg, 82% yield) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.74 (1H, t, J = 9.4 Hz), 4.48 (1H, t, J = 9.4 Hz), 4.29-4.22 (1H, m), 4.13 (1H, dd, J = 10.2, 5.9 Hz), 3.98 (2H, s), 3.97-3.92 (1H, m), 3.38 (3H, s), 2.35 (3H, s);
MS (FAB) m / z: 204 (M + H) ^<+> .

(5b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-methoxyacetylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylate 3-acetylthio-1-methoxyacetylazetidine (500 mg, 2.46 mmol) obtained in Example 5 (5a) was used instead of the compound obtained in Example 1 (1d). A pale yellow amorphous title compound (973 mg, yield 78%) was obtained in the same manner as in Example 1 (1e) except that it was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.21 (2H, d, J = 9.0 Hz), 7.64 (2H, d, J = 9.0 Hz), 5.50 (1H, d, J = 13.7 Hz), 5.24 (1H , d, J = 13.7 Hz), 4.71-4.64 (1H, m), 4.48-4.42 (1H, m), 4.28-4.17 (3H, m), 4.04-3.96 (1H, m), 3.98 (2H, s ), 3.37 (1.5H, s), 3.36 (1.5H, s), 3.29-3.25 (1H, m), 3.19-3.10 (1H, m), 1.80-1.76 (1H, m), 1.37 (3H, d , J = 6.3 Hz), 1.25 (3H, d, J = 6.3 Hz);
MS (FAB) m / z: 506 (M + H) ^<+> .

(5c) (1R, 5S, 6S) -2- (1-methoxyacetylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-methoxyacetylazeti) obtained in Example 5 (5b) instead of the compound obtained in Example 1 (1e) Example 1 except that din-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (970 mg, 1.92 mmol) was used. In the same manner as in (1f), the target compound was a pale yellow amorphous title compound (442 mg, yield 59%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.72-4.67 (1H, m), 4.53-4.45 (1H, m), 4.28-4.14 (4H, m), 4.07 (1H, s), 4.06 (1H, s), 4.00-3.95 (1H, m), 3.45-3.41 (1H, m), 3.40 (1.5H, s), 3.39 (1.5H, s), 3.26-3.17 (1H, m), 1.30 (3H, d, J = 6.3 Hz), 1.19 (1.5H, d, J = 7.3 Hz), 1.16 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3410, 2966, 1749, 1649, 1602, 1454, 1394, 1292 cm ^-1 ;
MS (FAB) m / z: 393 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₆ H ₂₂ N ₂ O ₆ SNa (M + H) ⁺ : 393.10963. Found 393.10909;
Anal.calcd.for C ₁₆ H ₂₁ N ₂ O ₆ SNa ・ 3 / 5H ₂ O: C, 47.66%; H, 5.55%; N, 6.95%; S, 7.95%, Found C, 47.96%; H, 5.65 %; N, 7.01%; S, 7.66%.

Example 6 (1R, 5S, 6S) -2- {1-[(S) -2-Amino-2-phenylacetyl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (Compound No. 11)
(6a) 3-acetylthioazetidine hydrochloride 3-acetylthio-1- (t-butoxycarbonyl) azetidine (1.0 g, 4.3 mmol) obtained in Example 1 (1b) was dissolved in ethyl acetate (10 mL). To this solution, hydrogen chloride (4 mol / L, ethyl acetate solution, 10 mL) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound as a light brown solid.

(6b) 3-acetylthio-1-[(S) -2- (p-nitrobenzyloxycarbonyl) amino-2-phenylacetyl] azetidine Np-nitrobenzyloxycarbonyl-phenylglycine (1.4 g, 4.3 mmol) Was dissolved in acetonitrile (30 mL), and 1,1′-carbonylbis-1H-imidazole (770 mg, 4.7 mmol) was added to this solution at room temperature under a nitrogen atmosphere, followed by stirring at room temperature for 30 minutes. After confirming disappearance of the raw materials, a solution of 3-acetylthioazetidine hydrochloride (4.3 mmol) obtained in Example 6 (6a) in acetonitrile (20 mL) was added to the reaction mixture under ice-cooling, at 0 ° C. for 10 minutes and at room temperature. For 1 hour. After confirming the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed successively with water, dilute potassium hydrogen sulfate aqueous solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 60 / 40-50 / 50, V / V) to give the amorphous title compound (1.59 g, Yield 83%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.16 (2H, d, J = 8.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.40-4.25 (5H, m), 6.28-6.23 (1H, m), 5.23-5.03 (3H, m), 4.68-3.54 (5H, m), 2.33-2.27 (3H, m);
MS (FAB) m / z: 444 (M + H) ^<+> .

(6c) p-nitrobenzyl (1R, 5S, 6S) -2- {1-[(S) -2- (p-nitrobenzyloxycarbonyl) amino-2-phenylacetyl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1-[(S) -2 obtained in Example 6 (6b) -(P-Nitrobenzyloxycarbonyl) amino-2-phenylacetyl] azetidine (1.55 g, 3.50 mmol) was dissolved in N, N-dimethylformamide (30 mL), and this solution was dissolved in a nitrogen atmosphere at room temperature. Hydrazine acetate (390 mg, 4.20 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapene-2-em-3-carboxylate (2.08 g, 3.50 mmol) in acetonitrile (30 mL) was added dropwise, followed by N, N-diisopropylethylamine (1.61 mL, 9.24 mmol), Stir at 0 ° C. for 3 hours. After confirming the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed successively with 10% brine, water, dilute aqueous sodium bicarbonate, water, dilute aqueous potassium hydrogensulfate, water and saturated brine, and dried over anhydrous magnesium sulfate. Filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-95 / 5, V / V) to give the pale yellow amorphous title compound (1.96 g, yield 75%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.24-8.08 (4H, m), 7.66-7.61 (2H, m), 7.47 (2H, d, J = 8.8 Hz), 7.37-7.15 (5H, m), 6.30-6.17 (1H, m), 5.51-5.08 (6H, m), 4.65-3.02 (9H, m), 1.36 (3H, d, J = 5.9 Hz), 1.20-1.17 (3H, m);
MS (FAB) m / z: 746 (M + H) ^<+> .

(6d) (1R, 5S, 6S) -2- {1-[(S) -2-Amino-2-phenylacetyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbapen-2-em-3-carboxylic acid p-nitrobenzyl (1R, 5S, 6S) -2- {1-[(S) -2- () obtained in Example 6 (6c) p-nitrobenzyloxycarbonyl) amino-2-phenylacetyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate ( 1.00 g, 1.34 mmol) was dissolved in a mixed solvent of tetrahydrofuran (45 mL) and distilled water (45 mL), 20% palladium hydroxide carbon (1.00 g) was added to this solution, and catalytic hydrogen reduction was performed at 35 ° C. for 5 hours. Went for hours. After confirming the completion of the reaction, the catalyst was removed by filtration, the filtrate was diluted with tetrahydrofuran-distilled water (1: 1), washed with diethyl ether, and the aqueous layer was concentrated under reduced pressure. The concentrated solution is purified by reverse phase chromatography (elution solvent: distilled water / acetonitrile = 100 / 0-85 / 15, V / V) using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Ltd.) and lyophilized. This gave the target compound as a white amorphous title compound (388 mg, yield 67%).
¹ H NMR (D ₂ O, 400 MHz): δ 7.57-7.46 (5H, m), 5.16-5.10 (1H, m), 4.70-2.85 (9H, m), 1.28 (3H, d, J = 6.6 Hz) , 1.13-0.88 (3H, m);
IR (KBr): 2967, 1754, 1665, 1591, 1456, 1389 cm ^-1 ;
MS (FAB) m / z: 432 (M + H) ^<+> .

Example 7 (1R, 5S, 6S) -2- [1- (Pyridin-3-ylacetyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid (Compound No. 12)
(7a) 3-acetylthioazetidine hydrochloride 3-acetylthio-1- (t-butoxycarbonyl) azetidine (810 mg, 3.50 mmol) obtained in Example 1 (1b) was converted to 1,4-dioxane (8 mL). To this solution, hydrogen chloride (4 mol / L, 1,4-dioxane solution, 8 mL) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. Methylene chloride and toluene were added to the residue, and the mixture was stirred and concentrated under reduced pressure to obtain a crude product of the title compound as a light brown solid.

(7b) 3-acetylthio-1- (pyridin-3-ylacetyl) azetidine 3-pyridylacetic acid hydrochloride (781 mg, 4.50 mmol) was dissolved in tetrahydrofuran (10 mL) and dimethylformamide (10 mL). Under nitrogen atmosphere, triethylamine (0.70 mL, 5.00 mmol) and 1,1′-carbonylbis-1H-imidazole (973 mg, 6.00 mmol) were sequentially added at room temperature, followed by stirring at room temperature for 2 days. After confirming disappearance of the raw materials, a solution of 3-acetylthioazetidine hydrochloride (3.50 mmol) obtained in Example 7 (7a) in methylene chloride (15 mL) was added to the reaction solution under ice cooling and stirred for 2 hours. . After confirming the completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-87.5 / 12.5, V / V) to obtain a pale yellow solid. The title compound (568 mg, yield 65%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.52 (1H, d, J = 5.1 Hz), 8.47 (1H, d, J = 2.0 Hz), 7.69-7.65 (1H, m), 7.27 (1H, dd, J = 7.4, 5.1 Hz), 4.65 (1H, t, J = 8.6 Hz), 4.46-4.41 (1H, m), 4.26-4.18 (1H, m), 4.04 (1H, dd, J = 10.0, 5.5 Hz ), 3.93 (1H, dd J = 10.6, 5.5 Hz), 3.44 (2H, s), 2.35 (3H, s);
IR (KBr): 1687, 1646, 1448, 1425 cm ^-1 ;
MS (FAB) m / z: 251 (M + H) ^<+> .

(7c) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-3-ylacetyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyridin-3-ylacetyl) azetidine (560 mg, 2.24 mmol) obtained in Example 7 (7b) was converted to dimethylformamide (16.8 mL). Hydrazine acetate (247 mg, 2.68 mmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapen-2-em-3-carboxylate (1.33 g, 2.24 mmol) in acetonitrile (40 mL) was added dropwise, followed by addition of diisopropylethylamine (0.94 mL, 5.40 mmol), and gradually to room temperature. The temperature was raised and left overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-75 / 25, V / V) to give the title compound ( 946 mg, yield 76%) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.53-8.51 (1H, m), 8.46 (1H, br s), 8.23 (2H, d, J = 8.3 Hz), 7.69-7.65 (1H, m), 7.66 (2H, d, J = 8.3 Hz), 7.28 (1H, dd, J = 7.8, 4.9 Hz), 5.50 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.59 -4.53 (1H, m), 4.46-4.40 (1H, m), 4.30-4.22 (2H, m), 4.12-4.05 (2H, m), 4.01-3.95 (1H, m), 3.46-3.43 (2H, m), 3.30-3.26 (1H, m), 3.17-3.10 (1H, m), 2.11 (1H, br s), 1.37 (3H, d, J = 6.4 Hz), 1.24 (3H, d, J = 7.8 Hz);
MS (FAB) m / z: 553 (M + H) ^<+> .

(7d) (1R, 5S, 6S) -2- [1- (Pyridin-3-ylacetyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-3-ylacetyl) azetidin-3-yl] thio- obtained in Example 7 (7c) A mixed solution of 6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (935 mg, 1.69 mmol) in tetrahydrofuran (70 mL) and distilled water (65 mL) Then, 7.5% palladium carbon (935 mg) was added to the solution, and catalytic hydrogen reduction was performed at 30 ° C. for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and diethyl ether, tetrahydrofuran and distilled water were added to the filtrate to carry out a liquid separation operation. The obtained aqueous layer was concentrated under reduced pressure, and reverse phase chromatography (elution solvent: distilled water / acetonitrile = 100 / 0-87.5 / 12.5) using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Ltd.) V / V) and lyophilized to give the title compound as a white amorphous compound (387 mg, yield 55%).
¹ H NMR (D ₂ O, 500 MHz): δ 8.64-8.62 (1H, m), 8.60 (1H, br s), 8.23 (1H, d, J = 7.8 Hz), 7.85-7.82 (1H, m), 4.83-4.75 (1H, m), 4.52-4.46 (1H, m), 4.28-4.18 (4H, m), 3.98-3.94 (1H, m), 3.83-3.73 (2H, m), 3.45-3.41 (1H , m), 3.25-3.18 (1H, m), 1.29 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 6.8 Hz);
IR (KBr): 3399, 2968, 1760, 1644, 1455 cm ^-1 ;
MS (FAB) m / z: 418 (M + H) ^<+> .

Example 8 (1R, 5S, 6S) -2- {1- [3- (pyridin-3-yl) propionyl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 13)
(8a) 3-Acetylthio-1- [3- (pyridin-3-yl) propionyl] azetidine 3-Pyridylpropionic acid (1.13 g, 7.50 mmol) was dissolved in tetrahydrofuran (20 mL), and 1,1 was added to this solution. '-Carbonylbis-1H-imidazole (1.46 g, 9.00 mmol) was added and stirred at room temperature overnight. This reaction solution was added to a solution of 3-acetylthioazetidine hydrochloride (6.00 mmol) obtained in Example 7 (7a) in methylene chloride (20 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. . After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-95 / 5, V / V) to give the title compound as a pale yellow oil ( 1.27 g, yield 80%).
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.49-8.46 (1H, m), 7.54 (1H, dd, J = 7.6, 4.7 Hz), 7.22 (1H, dd, J = 7.6, 4.7 Hz), 7.12- 7.10 (1H, m), 4.45 (1H, t, J = 8.4 Hz), 4.39 (1H, t, J = 9.4 Hz), 4.19-4.09 (1H, m), 3.89-3.85 (1H, m), 3.84 -3.80 (1H, m), 2.95 (2H, t, J = 7.4 Hz), 2.36 (2H, t, J = 7.4 Hz), 2.34 (3H, s);
MS (FAB) m / z: 265 (M + H) ^<+> .

(8b) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [3- (pyridin-3-yl) propionyl] azetidin-3-yl} thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- [3- (pyridin-3-yl) propionyl] azetidine obtained in Example 8 (8a) (395 mg, 1.49 mmol) was dissolved in dimethylformamide (12 mL), and hydrazine acetate (165 mg, 1.79 mmol) was added to the solution at room temperature under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapen-2-em-3-carboxylate (886 mg, 1.49 mmol) in acetonitrile (26 mL) was added dropwise, followed by the addition of diisopropylethylamine (1.04 mL, 5.97 mmol) and gradually to room temperature. The temperature was raised and left as it was overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-87.5 / 12.5, V / V) to give a pale yellow amorphous product. Of the title compound (596 mg, 71% yield).
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.48-8.44 (2H, m), 8.22 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.56-7.53 (1H, m), 7.25-7.21 (1H, m), 5.50 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.41-4.34 (2H, m), 4.29-4.23 (2H , m), 4.03-3.97 (1H, m), 3.96-3.89 (2H, m), 3.29-3.27 (1H, m), 3.16-3.07 (1H, m), 2.95 (2H, t, J = 7.3 Hz ), 2.44-2.31 (2H, m), 1.73 (1H, br s), 1.38-1.36 (3H, m), 1.23 (3H, d, J = 7.3 Hz);
MS (FAB) m / z: 567 (M + H) ^<+> .

(8c) (1R, 5S, 6S) -2- {1- [3- (pyridin-3-yl) propionyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- {1- [3- (pyridine-) obtained in Example 8 (8b) 3-yl) propionyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (585 mg, 1.03 mmol) Is dissolved in a mixed solvent of tetrahydrofuran (60 mL) and 0.1 mol / L-sodium phosphate buffer pH 7.0 (50 mL), and 7.5% palladium carbon (585 mg) is added to this solution and contacted at 30 ° C. Hydrogen reduction was performed for 2.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and diethyl ether and distilled water were added to the filtrate to carry out a liquid separation operation. The obtained aqueous layer was concentrated under reduced pressure, and reverse phase chromatography (elution solvent: distilled water / acetonitrile = 100 / 0-96 / 4, V / V) using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Ltd.) The product was purified by lyophilization and freeze-dried to obtain the target compound as a white amorphous title compound (359 mg, yield 77%).
¹ H NMR (D ₂ O, 500 MHz): δ 8.44 (0.5H, dd, J = 4.6, 1.2 Hz), 8.41-8.39 (1.5H, m), 7.77-7.72 (1H, m), 7.45 (0.5H , dd, J = 7.8, 4.6 Hz), 7.41 (0.5H, dd, J = 7.8, 4.6 Hz), 4.41-4.30 (2H, m), 4.27-4.21 (1H, m), 4.17 (0.5H, dd , J = 9.0, 2.2 Hz), 4.14 (0.5H, dd, J = 9.3, 2.4 Hz), 4.05-3.95 (1H, m), 3.81-3.73 (1.5H, m), 3.44-3.39 (1.5H, m), 3.17-3.10 (0.5H, m), 3.02-2.87 (2.5H, m), 2.56-2.44 (2H, m), 1.31-1.28 (3H, m), 1.13 (3H, d, J = 7.3 Hz);
IR (KBr): 3398, 2967, 1749, 1629, 1605, 1459, 1397 cm ^-1 ;
MS (FAB) m / z: 476 (M + Na) ^<+> , 454 (M + H) ^<+> .

Example 9 (1R, 5S, 6S) -2- {1-[(E) -3- (pyridin-3-yl) acryloyl] azetidin-3-yl} thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 14)
(9a) 3-acetylthio-1-[(E) -3- (pyridin-3-yl) acryloyl] azetidine 3- (3-pyridyl) acrylic acid (671 mg, 4.50 mmol) in dimethylformamide (10 mL) After dissolution, 1,1′-carbonylbis-1H-imidazole (973 mg, 6.00 mmol) was added to this solution and allowed to stand overnight at room temperature. This reaction solution was added to a solution of 3-acetylthioazetidine hydrochloride (3.00 mmol) obtained in Example 7 (7a) in methylene chloride (15 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. . After confirming the completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-92.5 / 7.5, V / V) to give a pale yellow oil. Of the title compound (378 mg, 48% yield).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.72 (1H, d, J = 2.0 Hz), 8.56 (1H, dd, J = 5.1, 1.6 Hz), 7.78 (1H, m), 7.62 (1H, d, J = 15.7 Hz), 7.30 (1H, dd, J = 7.8, 5.1 Hz), 7.09 (1H, br s), 6.47 (1H, d, J = 15.7 Hz), 4.79 (1H, t, J = 8.4 Hz ), 4.56-4.51 (1H, m), 4.29 (1H, tt, J = 8.4, 5.7 Hz), 4.17 (1H, dd, J = 8.4, 5.7 Hz), 4.05-4.00 (1H, m), 2.36 ( 3H, s);
MS (EI) m / z: 262 (M) ^<+> .

(9b) p-nitrobenzyl (1R, 5S, 6S) -2- {1-[(E) -3- (pyridin-3-yl) acryloyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1 obtained in Example 9 (9a) instead of the compound obtained in Example 7 (7b) -[(E) -3- (pyridin-3-yl) acryloyl] azetidine (370 mg, 1.41 mmol) was used in the same manner as in Example 7 (7c), except that a pale yellow amorphous title compound ( 488 mg, 61% yield).
¹ H NMR (DMSO-d ₆ , 500 MHz): δ 8.88-8.85 (1H, m), 8.58-8.55 (1H, m), 8.24 (2H, d, J = 7.8 Hz), 8.16-8.11 (1H, m ), 7.73 (2H, d, J = 7.8 Hz), 7.50 (1H, d, J = 15.6 Hz), 7.44 (1H, dd J = 7.8, 4.9 Hz), 6.90 (0.5H, d, J = 15.6 Hz) ), 6.86 (0.5H, d, J = 15.6 Hz), 5.49-5.45 (1H, m), 5.32 (1H, d, J = 13.7 Hz), 5.12-5.09 (1H, m), 4.82-4.76 (1H , m), 4.49-4.41 (1H, m), 4.36-4.29 (1H, m), 4.26-4.19 (2H, m), 4.02-3.96 (1H, m), 3.87-3.82 (1H, m), 3.41 -3.29 (2H, m), 1.18-1.13 (6H, m);
IR (KBr): 3403, 2969, 1770, 1658, 1608, 1521, 1447, 1343, 1209, 1139 cm ^-1 ;
MS (FAB) m / z: 565 (M + H) ^<+> .

(9c) (1R, 5S, 6S) -2- {1-[(E) -3- (pyridin-3-yl) acryloyl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt In place of the compound obtained in Example 8 (8b), p-nitrobenzyl (1R, 5S, 6S) -2- {1-[(E) -3- (pyridin-3-yl) acryloyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl -White amorphous (1R, 5S, 6S) which is the target compound in the same manner as in Example 8 (8c) except that carbapen-2-em-3-carboxylate (480 mg, 0.850 mmol) was used. -2- {1-[(E) -3- (pyridine-3-i ) Acrylyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt (195 mg, 51% yield) Obtained.
¹ H NMR (D ₂ O, 500 MHz): δ 8.69 (1H, br s), 8.53-8.51 (1H, m), 8.13-8.08 (1H, m), 7.53-7.48 (2H, m), 6.74-6.68 (1H, m), 4.84-4.76 (1H, m), 4.57-4.51 (1H, m), 4.33-4.20 (4H, m), 4.02-3.97 (1H, m), 3.45-3.42 (1H, m) , 3.28-3.20 (1H, m), 1.31 (3H, d, J = 6.4 Hz), 1.20 (3H, d, J = 6.8 Hz);
IR (KBr): 3418, 2969, 1748, 1656, 1598, 1456, 1397 cm ^-1 ;
MS (FAB) m / z: 452 (M + H) ^<+> .

Example 10 (1R, 5S, 6S) -2- (1-cyclopropanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3-carboxylic acid sodium salt (salt of compound No. 15)
(10a) 3-Acetylthio-1-cyclopropanecarbonylazetidine In the same manner as in Example 1 (1d) except that cyclopropanecarboxylic acid (289 μL, 3.63 mmol) was used instead of pivalic acid, white crystals The title compound (492 mg, yield 82%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.74 (1H, t, J = 8.6 Hz), 4.42 (1H, t, J = 9.8 Hz), 4.30-4.22 (1H, m), 4.12 (1H, dd, J = 8.6, 5.5 Hz), 3.90 (1H, dd, J = 9.8, 5.5 Hz), 2.36 (3H, s), 1.38-1.31 (1H, m), 0.99-0.94 (2H, m), 0.80-0.73 (2H, m);
MS (EI) m / z: 199 (M) ^<+> .

(10b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclopropanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylate 3-acetylthio-1-cyclopropanecarbonylazetidine (490 mg, 2.46 mmol) obtained in Example 10 (10a) instead of the compound obtained in Example 1 (1d) ) Was used in the same manner as in Example 1 (1e) except that a pale yellow amorphous title compound (1.14 g, yield 93%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.24 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.70-4.63 (1H, m), 4.46-4.38 (1H, m), 4.30-4.16 (3H, m), 4.14-4.06 (1H, m), 4.02-3.93 (1H , m), 3.31-3.26 (1H, m), 3.23-3.14 (1H, m), 1.90-1.80 (1H, m), 1.37 (3H, d, J = 6.3 Hz), 1.26 (3H, d, J = 7.4 Hz), 1.00-0.95 (2H, m), 0.82-0.76 (2H, m);
MS (FAB) m / z: 502 (M + H) ^<+> .

(10c) (1R, 5S, 6S) -2- (1-cyclopropanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclopropane) obtained in Example 10 (10b) instead of the compound obtained in Example 1 (1e) Carried out except using carbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (1.14 g, 2.29 mmol) In the same manner as in Example 1 (1f), the target compound was obtained as a pale yellow amorphous title compound (729 mg, yield 82%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.47-4.41 (1H, m), 4.32-4.19 (5H, m), 3.93-3.89 (1H, m), 3.45-3.42 (1H, m), 3.28- 3.19 (1H, m), 1.63-1.54 (1H, m), 1.30 (3H, d, J = 6.4 Hz), 1.20 (3H, d, J = 7.3 Hz), 0.92-0.82 (4H, m);
IR (KBr): 3387, 2966, 1749, 1606, 1484, 1457, 1395, 1339, 1292 cm ^-1 ;
MS (FAB) m / z: 389 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₇ H ₂₂ N ₂ O ₅ SNa (M + H) ⁺ : 389.11471. Found 389.11452;
Anal.calcd.for C ₁₇ H ₂₁ N ₂ O ₅ SNa ・ 2 / 3H ₂ O: C, 50.99%; H, 5.62%; N, 7.00%; S, 8.01%, Found C, 50.80%; H, 5.60 %; N, 6.88%; S, 8.11%.

Example 11 1- (Isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -2- (1-cyclopropanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl ] -1-Methyl-carbapene-2-em-3-carboxylate (ester of compound No. 15)
(1R, 5S, 6S) -2- (1-Cyclopropanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene obtained in Example 10 2-M-3-carboxylic acid sodium salt (150 mg, 0.386 mmol) was dissolved in dimethylacetamide (5 mL), and this solution was dissolved in 1-iodoethyl-isopropyl carbonate (199 mg, 0.722 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours. After completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, 5% aqueous sodium thiosulfate, 0.05 mol / L hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-97 / 3, V / V) to obtain the target compound in a white amorphous form. The title compound (167 mg, yield 87%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 6.90-6.86 (1H, m), 4.96-4.86 (1H, m), 4.68-4.62 (1H, m), 4.44-4.36 (1H, m), 4.27-4.16 (3H, m), 4.14-4.06 (1H, m), 3.99-3.92 (1H, m), 3.26-3.21 (1H, m), 3.19-3.10 (1H, m), 1.76-1.69 (1H, m) , 1.62 (1.5H, d, J = 5.7 Hz), 1.60 (1.5H, d, J = 5.7 Hz), 1.36 (1.5H, d, J = 6.3 Hz), 1.34 (3H, d, J = 6.3 Hz) ), 1.31 (1.5H, d, J = 6.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.25 (1.5H, d, J = 7.3 Hz), 1.24 (1.5H, d, J = 7.3 Hz), 1.00-0.96 (2H, m), 0.81-0.75 (2H, m);
MS (FAB) m / z: 497 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd. For C ₂₃ H ₃₃ N ₂ O ₈ S (M + H) ⁺ : 497.19576. Found 497.19521.

Example 12 (1R, 5S, 6S) -2- (1-Cyclobutanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt (salt of compound No. 16)
(12a) 3-acetylthio-1-cyclobutanecarbonylazetidine A colorless oily title in the same manner as in Example 1 (1d) except that cyclobutanecarboxylic acid (347 μL, 3.63 mmol) was used instead of pivalic acid. The compound (451 mg, yield 70%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.52 (1H, t, J = 8.4 Hz), 4.40 (1H, t, J = 9.6 Hz), 4.24-4.16 (1H, m), 3.92-3.86 (2H, m), 3.05-2.95 (1H, m), 2.34 (3H, s), 2.36-2.25 (2H, m), 2.14-2.04 (2H, m), 2.02-1.83 (2H, m);
MS (EI) m / z: 213 (M) ^<+> .

(12b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclobutanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylate 3-acetylthio-1-cyclobutanecarbonylazetidine (450 mg, 2.11 mmol) obtained in Example 12 (12a) was used instead of the compound obtained in Example 1 (1d). A pale yellow amorphous title compound (793 g, yield 73%) was obtained in the same manner as in Example 1 (1e) except that it was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.47-4.36 (2H, m), 4.29-4.22 (2H, m), 4.10-4.02 (1H, m), 3.99-3.92 (2H, m), 3.30-3.26 (1H , m), 3.19-3.11 (1H, m), 3.04-2.96 (1H, m), 2.36-2.25 (2H, m), 2.13-2.04 (2H, m), 2.00-1.86 (2H, m), 1.37 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 6.8 Hz);
MS (FAB) m / z: 516 (M + H) ^<+> .

(12c) (1R, 5S, 6S) -2- (1-Cyclobutanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclobutanecarbonylazeti) obtained in Example 12 (12b) instead of the compound obtained in Example 1 (1e) Example 1 except that din-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (790 mg, 1.53 mmol) was used. In the same manner as in (1f), the target compound was obtained as a pale yellow amorphous title compound (503 mg, yield 82%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.64-4.58 (1H, m), 4.46-4.39 (1H, m), 4.28-4.05 (4H, m), 3.91-3.87 (1H, m), 3.44- 3.41 (1H, m), 3.27-3.16 (2H, m), 3.23-2.09 (4H, m), 2.05-1.95 (1H, m), 1.86-1.77 (1H, m), 1.30 (3H, d, J = 6.4 Hz), 1.19 (1.5H, d, J = 7.3 Hz), 1.18 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3407, 2966, 1750, 1605, 1453, 1396, 1313, 1292 cm ^-1 ;
MS (FAB) m / z: 403 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₈ H ₂₄ N ₂ O ₅ SNa (M + H) ⁺ : 403.13036. Found 403.13052;
Anal.calcd.for C ₁₈ H ₂₃ N ₂ O ₅ SNa ・ H ₂ O: C, 51.42%; H, 5.99%; N, 6.66%; S, 7.63%, Found C, 51.33%; H, 6.06%; N, 6.65%; S, 7.89%.

Example 13 1- (Isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -2- (1-cyclobutanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate '(ester of compound No. 16)
(1R, 5S, 6S) -2- (1-cyclobutanecarbonylazetidin-3-yl) thio-6-[(R) -1 obtained in Example 12 instead of the compound obtained in Example 10 -Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (100 mg, 0.248 mmol) was used in the same manner as in Example 11 except that white amorphous The title compound (113 mg, yield 90%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 6.91-6.87 (1H, m), 4.96-4.86 (2H, m), 4.46-4.35 (2H, m), 4.08-4.02 (1H, m), 4.01-3.90 (2H, m), 3.25-3.21 (1H, m), 3.16-3.08 (1H, m), 3.06-2.96 (1H, m), 2.35-2.26 (2H, m), 2.13-2.05 (2H, m) , 2.02-1.93 (1H, m), 1.92-1.85 (1H, m), 1.74-1.66 (1H, m), 1.61 (1.5H, d, J = 5.4 Hz), 1.59 (1.5H, d, J = 5.4 Hz), 1.38-1.29 (9H, m), 1.25-1.21 (3H, m);
MS (FAB) m / z: 511 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd. For C ₂₄ H ₃₅ N ₂ O ₈ S (M + H) ⁺ : 511.21141. Found 511.21049.

Example 14 (1R, 5S, 6S) -2- (1-Cyclopentanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3-carboxylic acid sodium salt (salt of compound No. 17)
(14a) 3-Acetylthio-1-cyclopentanecarbonylazetidine A colorless oily form in the same manner as in Example 1 (1d) except that cyclopentanecarboxylic acid (393 μL, 3.63 mmol) was used instead of pivalic acid. Of the title compound (564 mg, yield 82%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.63 (1H, t, J = 8.4 Hz), 4.40 (1H, t, J = 9.4 Hz), 4.26-4.18 (1H, m) 4.00 (1H, dd, J = 9.0, 5.5 Hz), 3.89 (1H, dd, J = 10.4, 5.5 Hz), 2.56-2.46 (1H, m), 2.35 (3H, s), 1.82-1.62 (8H, m);
MS (EI) m / z: 227 (M) ^<+> .

(14b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclopentanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylate 3-acetylthio-1-cyclopentanecarbonylazetidine (560 mg, 2.46 mmol) obtained in Example 14 (14a) instead of the compound obtained in Example 1 (1d) ) Was used in the same manner as in Example 1 (1e), except that a pale yellow amorphous title compound (1.10 g, yield 84%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.57-4.51 (1H, m), 4.43-4.36 (1H, m), 4.30-4.22 (2H, m), 4.10-4.04 (2H, m), 3.99-3.91 (1H , m), 3.30-3.26 (1H, m), 3.21-3.12 (1H, m), 2.57-2.45 (1H, m), 1.82-1.70 (8H, m), 1.37 (3H, d, J = 6.3 Hz ), 1.26 (3H, d, J = 6.8 Hz);
MS (FAB) m / z: 530 (M + H) +.

(14c) (1R, 5S, 6S) -2- (1-cyclopentanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclopentane) obtained in Example 14 (14b) instead of the compound obtained in Example 1 (1e) Carried out except using carbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (1.10 g, 2.08 mmol) In the same manner as in Example 1 (1f), the target compound was obtained as a pale yellow amorphous title compound (530 mg, yield 61%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.73-4.68 (1H, m), 4.46-4.39 (1H, m), 4.27-4.15 (4H, m), 3.90 (1H, dd, J = 11.2, 4.4 Hz), 3.45-3.41 (1H, m), 3.25-3.19 (1H, m), 2.75-2.68 (1H, m), 1.89-1.80 (2H, m), 1.75-1.64 (2H, m), 1.64- 1.55 (4H, m), 1.30 (3H, d, J = 6.8 Hz), 1.20 (1.5H, d, J = 7.3 Hz), 1.19 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3397, 2961, 1751, 1605, 1451, 1395, 1334, 1295 cm ^-1 ;
MS (FAB) m / z: 417 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₉ H ₂₆ N ₂ O ₅ SNa (M + H) ⁺ : 417.14601.Found 417.14344;
Anal.calcd.for C ₁₉ H ₂₅ N ₂ O ₅ SNa ・ H ₂ O: C, 52.52%; H, 6.26%; N, 6.45%; S, 7.38%, Found C, 52.47%; H, 6.30%; N, 6.52%; S, 7.28%.

Example 15 1- (Isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -2- (1-cyclopentanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl ] -1-Methyl-carbapene-2-em-3-carboxylate (ester of compound No. 17)
(1R, 5S, 6S) -2- (1-cyclopentanecarbonylazetidin-3-yl) thio-6-[(R)-obtained in Example 14 instead of the compound obtained in Example 10 1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt (95 mg, 0.228 mmol) was used in the same manner as in Example 11 except that white amorphous compound as the target compound was used. Of the title compound (106 mg, 89% yield).
¹ H NMR (CDCl ₃ , 400 MHz): δ 6.92-6.85 (1H, m), 4.96-4.86 (1H, m), 4.57-4.49 (1H, m), 4.44-4.34 (1H, m), 4.28-4.18 (2H, m), 4.13-4.03 (2H, m), 3.99-3.90 (1H, m), 3.25-3.20 (1H, m), 3.18-3.10 (1H, m), 2.56-2.48 (1H, m) , 1.82-1.68 (8H, m), 1.63-1.58 (3H, m), 1.38-1.28 (9H, m), 1.24 (3H, d, J = 7.0 Hz);
MS (FAB) m / z: 525 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd. For C ₂₅ H ₃₇ N ₂ O ₈ S (M + H) ⁺ : 525.22706. Found 525.22722.

Example 16 (1R, 5S, 6S) -2- (1-Cyclohexanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt (salt of compound No. 18)
(16a) 3-Acetylthio-1-cyclohexanecarbonylazetidine Cyclohexanecarboxylic acid (769 mg, 6.00 mmol) was dissolved in tetrahydrofuran (15 mL), and 1,1′-carbonylbis-1H-imidazole (973 mg) was dissolved in this solution. , 6.00 mmol) and left at room temperature overnight. This reaction solution was added to a methylene chloride (17 mL) solution of 3-acetylthioazetidine hydrochloride (5.00 mmol) obtained in Example 7 (7a) under ice-cooling and stirred at 0 ° C. for 1 hour. . After confirming the completion of the reaction, an aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 7 / 3-4 / 6, V / V) to give a pale yellow amorphous title The compound (882 mg, yield 73%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.68-4.58 (1H, m), 4.43-4.33 (1H, m), 4.24-4.17 (1H, m), 4.04-3.82 (2H, m), 2.35 (3H , s), 2.13-2.04 (1H, m), 1.83-1.73 (2H, m), 1.73-1.61 (3H, m), 1.52-1.42 (2H, m), 1.28-1.17 (3H, m);
IR (KBr): 2925, 2853, 1693, 1648, 1436, 1361, 1135, 1112 cm ^-1 ;
MS (FAB) m / z: 242 (M + H) ^<+> .

(16b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclohexanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylate 3-Acetylthio-1-cyclohexanecarbonylazetidine (500 mg, 2.07 mmol) obtained in Example 16 (16a) was dissolved in dimethylformamide (15 mL). Hydrazine acetate (229 mg, 2.49 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapen-2-em-3-carboxylate (1.48 g, 2.49 mmol) in acetonitrile (45 mL) was added dropwise, followed by the addition of diisopropylethylamine (0.87 mL, 4.97 mmol) and 3 ° C. at 0 ° C. Stir for 1 hour at room temperature and room temperature. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol, 100 / 0-95: 5, V / V) to give the title compound (pale yellow amorphous) 1.03 g, yield 92%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.23 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz), 5.51 (1H, d, J = 14.7 Hz), 5.25 (1H , d, J = 14.7 Hz), 4.58-4.52 (1H, m), 4.42-4.35 (1H, m), 4.27-4.24 (2H, m), 4.11-4.06 (2H, m), 3.97-3.90 (1H , m), 3.29-3.26 (1H, m), 3.21-3.13 (1H, m), 2.13-2.04 (2H, m), 1.82-1.76 (2H, m), 1.66-1.63 (3H, m), 1.51 -1.41 (2H, m), 1.35 (3H, d, J = 6.3 Hz), 1.28-1.20 (3H, m), 1.26 (3H, d, J = 7.0 Hz);
MS (FAB) m / z: 566 (M + Na) ^<+> , 544 (M + H) ^<+> .

(16c) (1R, 5S, 6S) -2- (1-Cyclohexanecarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclohexanecarbonylazeti) obtained in Example 16 (16b) instead of the compound obtained in Example 8 (8b) Example 8 except that din-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (1.03 g, 1.89 mmol) was used. In the same manner as in (8c), the target compound was a pale yellow amorphous title compound (433 mg, 53% yield).
¹ H NMR (D ₂ O, 400 MHz): δ 4.75-4.69 (1H, m), 4.45-4.38 (1H, m), 4.26-4.14 (4H, m), 3.91-3.86 (1H, m), 3.44- 3.41 (1H, m), 3.24-3.19 (1H, m), 2.31-2.28 (1H, m), 1.77-1.65 (5H, m), 1.36-1.16 (5H, m), 1.30 (3H, d, J = 5.9 Hz), 1.19 (1.5H, d, J = 7.3 Hz), 1.18 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3399, 2930, 2855, 1751, 1607, 1450, 1395, 1293 cm ^-1 ;
MS (FAB) m / z: 453 (M + Na) ^<+> , 431 (M + H) ^<+> .

Example 17 (1R, 5S, 6S) -2- {1-[(R) -tetrahydrofuran-2-carbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 19)
(17a) 3-acetylthio-1-[(R) -tetrahydrofuran-2-carbonyl] azetidine Example except that (R) -tetrahydrofuran-2-carboxylic acid (421 μL, 3.63 mmol) was used instead of pivalic acid A colorless oily title compound (590 mg, yield 85%) was obtained in the same manner as 1 (1d).
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.85-4.70 (1H, m), 4.49-4.76 (2H, m), 4.28-4.12 (2H, m), 3.94-3.75 (3H, m), 3.34 (3H , s), 2.21-2.05 (2H, m) 1.95-1.83 (2H, m);
MS (EI) m / z: 229 (M) ^<+> .

(17b) p-nitrobenzyl (1R, 5S, 6S) -2- {1-[(R) -tetrahydrofuran-2-carbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl ] -1-Methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1-[(R) obtained in Example 17 (17a) instead of the compound obtained in Example 1 (1d) -Tetrahydrofuran-2-carbonyl] azetidine (590 mg, 2.57 mmol) was used in the same manner as in Example 1 (1e) to obtain the pale yellow amorphous title compound (1.24 g, yield 91%). It was.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.26 (1H , d, J = 13.7 Hz), 4.83-4.78 (0.5H, m), 4.73-4.68 (0.5H, m), 4.48-4.43 (1H, m), 4.43-4.38 (1H, m), 4.30-4.20 (3H, m), 4.11-4.04 (1H, m), 4.00-3.95 (1H, m), 3.89-3.80 (2H, m), 3.30-3.26 (1H, m), 3.19-3.11 (1H, m) , 2.22-2.07 (2H, m), 1.95-1.85 (2H, m) 1.37 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.3 Hz);
MS (FAB) m / z: 532 (M + H) ^<+> .

(17c) (1R, 5S, 6S) -2- {1-[(R) -tetrahydrofuran-2-carbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S)-obtained in Example 17 (17b) instead of the compound obtained in Example 1 (1e) 2- {1-[(R) -tetrahydrofuran-2-carbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxy A pale yellow amorphous title compound (786 mg, 81% yield) as the target compound was obtained in the same manner as in Example 1 (1f) except that the rate (1.24 g, 2.33 mmol) was used.
¹ H NMR (D ₂ O, 400 MHz): δ 4.79-4.74 (1H, m), 4.52-4.43 (2H, m), 4.28-4.18 (4H, m), 3.99-3.85 (3H, m), 3.45- 3.41 (1H, m), 3.27-3.16 (1H, m), 2.35-2.24 (1H, m), 2.01-1.88 (3H, m), 1.30 (3H, d, J = 6.4 Hz), 1.19 (1.5H , d, J = 7.3 Hz), 1.18 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3416, 2966, 1750, 1603, 1457, 1394, 1292, 1269 cm ^-1 ;
MS (FAB) m / z: 419 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₈ H ₂₄ N ₂ O ₆ SNa (M + H) ⁺ : 419.12528. Found 419.12561;
Anal.calcd.for C ₁₈ H ₂₃ N ₂ O ₆ SNa ・ 7 / 8H ₂ O: C, 49.79%; H, 5.75%; N, 6.45%; S, 7.38%, Found C, 49.88%; H, 5.99 %; N, 6.49%; S, 7.30%.

Example 18 (1R, 5S, 6S) -2- [1- (Tetrahydropyran-4-carbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 20)
(18a) 3-Acetylthio-1- (tetrahydropyran-4-carbonyl) azetidine Similar to Example 1 (1d) except that tetrahydropyran-4-carboxylic acid (472 mg, 3.63 mmol) was used instead of pivalic acid. In this manner, the title compound (565 mg, yield 77%) was obtained as pale yellow crystals.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.66 (1H, t, J = 8.6 Hz), 4.41 (1H, t, J = 10.2 Hz), 4.26-3.98 (1H, m), 4.06-3.97 (3H, m), 3.91 (1H, dd, J = 10.2, 5.7 Hz), 3.40 (2H, t, J = 11.7 Hz), 2.41-2.31 (1H, m), 2.36 (3H, s), 1.85 (2H, dq , J = 4.3, 11.7 Hz), 1.61-1.56 (2H, m);
MS (EI) m / z: 243 (M) ^<+> .

(18b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (tetrahydropyran-4-carbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- (tetrahydropyran-4-carbonyl) obtained in Example 18 (18a) instead of the compound obtained in Example 1 (1d) ) A pale yellow amorphous title compound (974 mg, yield 78%) was obtained in the same manner as in Example 1 (1e) except that azetidine (560 mg, 2.30 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.23 (2H, d, J = 8.4 Hz), 7.66 (2H, d, J = 8.4 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.61-4.54 (1H, m), 4.46-4.37 (1H, m), 4.30-4.23 (2H, m), 4.12-4.05 (2H, m), 4.04-3.93 (3H , m), 3.46-3.36 (2H, m), 3.31-3.27 (1H, m), 3.21-3.10 (1H, m), 2.41-2.40 (1H, m), 1.91-1.90 (2H, m), 1.60 -1.50 (2H, m) 1.38 (3H, d, J = 6.3 Hz), 1.26 (3H, d, J = 7.0 Hz);
MS (FAB) m / z: 546 (M + H) ^<+> .

(18c) (1R, 5S, 6S) -2- [1- (Tetrahydropyran-4-carbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 18 (18b) instead of the compound obtained in Example 1 (1e) 1- (Tetrahydropyran-4-carbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (970 mg, 1.78 The target compound was a pale yellow amorphous title compound (628 mg, yield 82%) in the same manner as in Example 1 (1f) except that mmol) was used.
¹ H NMR (D ₂ O, 400 MHz): δ 4.77-4.72 (1H, m), 4.48-4.40 (1H, m), 4.28-4.16 (4H, m), 4.04-3.99 (2H, m), 3.94- 3.90 (1H, m), 3.56-3.48 (2H, m), 3.45-3.42 (1H, m), 3.27-3.18 (1H, m), 2.71-2.59 (1H, m), 1.72-1.62 (4H, m ) 1.30 (3H, d, J = 6.3 Hz), 1.19 (1.5H, d, J = 7.3 Hz), 1.18 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3417, 2962, 1750, 1603, 1453, 1392, 1312, 1292 cm ^-1 ;
MS (FAB) m / z: 433 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₉ H ₂₆ N ₂ O ₆ SNa (M + H) ⁺ : 433.14093. Found 433.14156;
Anal.calcd.for C ₁₉ H ₂₅ N ₂ O ₆ SNa ・ H ₂ O: C, 50.66%; H, 6.04%; N, 6.22%; S, 7.12%, Found C, 50.39%; H, 6.06%; N, 6.23%; S, 6.98%.

Example 19 (1R, 5S, 6S) -2- [1- (Pyridin-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 24)
(19a) 3-Acetylthio-1- (pyridin-2-ylcarbonyl) azetidine Picolinic acid (554 mg, 4.50 mmol) was dissolved in tetrahydrofuran (10 mL), and 1,1′-carbonylbis-1H— was dissolved in this solution. Imidazole (813 mg, 5.00 mmol) was added and left overnight at room temperature. This reaction solution was added to a solution of 3-acetylthioazetidine hydrochloride (3.50 mmol) obtained in Example 7 (7a) in methylene chloride (15 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. . After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 4-4 / 6, V / V) to give a pale yellow oily title The compound (697 mg, yield 84%) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.56-8.55 (1H, m), 8.12-8.10 (1H, m), 7.82-7.78 (1H, m), 7.38-7.35 (1H, m), 5.19 (1H , dd, J = 11.2, 8.3 Hz), 4.66 (1H, dd, J = 11.2, 8.3 Hz), 4.61 (1H, dd, J = 11.2, 5.4 Hz), 4.31 (1H, tt, J = 8.3, 5.4 Hz), 4.11 (1H, dd, J = 8.3, 5.4 Hz), 2.36 (3H, s);
MS (EI) m / z: 236 (M) ^<+> .

(19b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyridin-2-ylcarbonyl) azetidine (690 mg, 2.92 mmol) obtained in Example 19 (19a) was converted to dimethylformamide (17.0 Hydrazine acetate (296 mg, 3.21 mmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 50 minutes. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapene-2-em-3-carboxylate (1.74 g, 2.93 mmol) in acetonitrile (45 mL) was added dropwise, followed by addition of diisopropylethylamine (1.20 mL, 6.89 mmol), and gradually to room temperature. The temperature was raised and left overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10, V / V) to give the title compound ( 1.49 g, 95% yield).
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.57-8.55 (1H, m), 8.23-8.20 (2H, m), 8.13-8.10 (1H, m), 7.82 (1H, td, J = 7.8, 2.0 Hz ), 7.67-7.64 (2H, m), 7.40-7.37 (1H, m), 5.52-5.48 (1H, m), 5.27-5.23 (1H, m), 5.19-5.14 (1H, m), 4.68-4.59 (2H, m), 4.30-4.25 (2H, m), 4.21-4.11 (2H, m), 3.29 (1H, dd J = 7.3, 2.9 Hz), 3.24-3.17 (1H, m), 1.66 (1H, br s), 1.38 (3H, d, J = 6.3 Hz), 1.28 (3H, d, J = 7.8 Hz);
IR (KBr): 3404, 2970, 1771, 1634, 1521, 1453, 1344 cm ^-1 ;
MS (FAB) m / z: 539 (M + H) ^<+> .

(19c) (1R, 5S, 6S) -2- [1- (Pyridin-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 19 (19b) instead of the compound obtained in Example 8 (8b) 1- (Pyridin-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (998 mg, 1.85 The target compound was a white amorphous title compound (612 mg, yield 78%) in the same manner as in Example 8 (8c) except that mmol) was used.
¹ H NMR (D ₂ O, 500 MHz): δ 8.62-8.60 (1H, m), 8.04-8.00 (1H, m), 7.85-7.82 (1H, m), 7.63-7.58 (1H, m), 4.96- 4.90 (1H, m), 4.71-4.65 (1H, m), 4.43-4.35 (1H, m), 4.31-4.20 (2.5H, m), 4.18-4.13 (1.5H, m), 3.44-3.41 (1H , m), 3.29-3.22 (0.5H, m), 3.22 -3.16 (0.5H, m), 1.30 (1.5H, d, J = 6.4 Hz), 1.29 (1.5H, d, J = 6.4 Hz), 1.20 (1.5H, d, J = 7.3 Hz), 1.18 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3384, 2967, 1749, 1612, 1454, 1396, 1290 cm ^-1 ;
MS (FAB) m / z: 448 (M + Na) ^<+> , 426 (M + H) ^<+> .

Example 20 (1R, 5S, 6S) -2- [1- (Pyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 25)
(20a) 3-Acetylthio-1- (pyridin-3-ylcarbonyl) azetidine Nicotinic acid (1.48 g, 12.0 mmol) was dissolved in tetrahydrofuran (30 mL), and 1,1′-carbonylbis-1H— was dissolved in this solution. Imidazole (1.95 g, 12.0 mmol) was added and left at room temperature overnight. This reaction solution was added to a solution of 3-acetylthioazetidine hydrochloride (10.0 mmol) obtained in Example 7 (7a) in methylene chloride (30 mL) under ice-cooling and stirred at 0 ° C. for 45 minutes. . After confirming the completion of the reaction, water was added to the reaction solution, and the aqueous layer was extracted with methylene chloride. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2 / 8-0 / 1, then ethyl acetate / methanol = 100 / 0-98 / 2). V / V) to give the title compound (2.13 g, yield 90%) as a pale yellow oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.81 (1H, d, J = 1.7 Hz), 8.68 (1H, dd, J = 4.9, 1.7 Hz), 7.95 (1H, dt, J = 7.8, 1.7 Hz) , 7.36 (1H, dd, J = 7.8, 4.8 Hz), 4.83-4.74 (1H, m), 4.67-4.59 (1H, m), 4.34-4.27 (1H, m), 4.22-4.08 (2H, m) , 2.35 (3H, s);
MS (FAB) m / z: 237 (M + H) ^<+> .

(20b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyridin-3-ylcarbonyl) obtained in Example 20 (20a) instead of the compound obtained in Example 16 (16a) ) A pale yellow amorphous title compound (1.26 g, yield 79%) was obtained in the same manner as in Example 16 (16b) except that azetidine (700 mg, 2.96 mmol) was used.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.81 (1H, br s), 8.72-8.70 (1H, m), 8.24 (2H, d, J = 8.4 Hz), 8.03 (1H, br d, J = 7.8 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 7.8, 5.1 Hz), 5.46 (1H, d, J = 14.0 Hz), 5.32 (1H, d, J = 14.0 Hz), 5.10- 5.06 (1H, m), 4.81-4.75 (1H, m), 4.61-4.51 (1H, m), 4.38-4.28 (2H, m), 4.23-4.18 (1H, m), 4.01-3.94 (2H, m), 3.39-3.27 (2H, m), 1.17-1.10 (6H, m);
IR (KBr): 3414, 2968, 1767, 1706, 1625, 1520, 1344, 1211, 1141 cm ^-1 ;
MS (FAB) m / z: 539 (M + H) ^<+> .

(20c) (1R, 5S, 6S) -2- [1- (Pyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 20 (20b) instead of the compound obtained in Example 8 (8b) 1- (Pyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (998 mg, 1.85 The target compound was a white amorphous title compound (396 mg, yield 50%) in the same manner as in Example 8 (8c) except that mmol) was used.
¹ H NMR (D ₂ O, 400 MHz): δ 8.76-8.73 (1H, m), 8.69-8.67 (1H, m), 8.09-8.04 (1H, m), 7.60-7.56 (1H, m), 4.85- 4.80 (1H, m), 4.77-4.62 (1H, m), 4.35-4.11 (5H, m), 3.44-3.41 (1H, m), 3.28-3.14 (1H, m), 1.30 (1.5H, d, J = 5.9 Hz), 1.29 (1.5H, d, J = 6.6 Hz), 1.19 (1.5H, d, J = 7.3 Hz), 1.17 (1.5H, d, J = 8.1 Hz);
IR (KBr): 3399, 2967, 1749, 1608, 1445, 1398, 1291 cm ^-1 ;
MS (FAB) m / z: 448 (M + Na) ^<+> , 426 (M + H) ^<+> .

Example 21 (1R, 5S, 6S) -2- [1- (Pyridin-4-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 31)
(21a) 3-acetylthio-1- (pyridin-4-ylcarbonyl) azetidine In the same manner as in Example 19 (19a) except that isonicotinic acid (554 mg, 4.50 mmol) was used instead of picolinic acid, The title compound (572 mg, yield 69%) was obtained as a colorless oil.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.73-8.72 (2H, m), 7.46-7.45 (2H, m), 4.78-4.74 (1H, m), 4.65-4.61 (1H, m), 4.33-4.27 (1H, m), 4.17-4.10 (2H, m), 2.36 (3H, s);
MS (EI) m / z: 236 (M) ^<+> .

(21b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-4-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyridin-4-ylcarbonyl) obtained in Example 21 (21a) instead of the compound obtained in Example 7 (7b) The pale yellow amorphous title compound (864 mg, 67% yield) was obtained in the same manner as in Example 7 (7c) except that azetidine (556 mg, 2.40 mmol) was used.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.75-8.73 (2H, m), 8.23 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 7.45-7.44 (2H, m), 5.51 (1H, d, J = 13.7 Hz), 5.26-5.22 (1H, m), 4.71-4.60 (2H, m), 4.31-4.12 (5H, m), 3.30-3.27 (1H, m) , 3.20-3.10 (1H, m), 2.04 (1H, br s), 1.38-1.35 (3H, m), 1.28-1.24 (3H, m);
IR (KBr): 3413, 2970, 1771, 1708, 1639, 1521, 1429, 1344, 1209, 1139 cm ^-1 ;
MS (FAB) m / z: 539 (M + H) ^<+> .

(21c) (1R, 5S, 6S) -2- [1- (Pyridin-4-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 21 (21b) instead of the compound obtained in Example 8 (8b) 1- (Pyridin-4-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (850 mg, 1.58 The target compound was a white amorphous title compound (522 mg, yield 78%) in the same manner as in Example 8 (8c) except that mmol) was used.
¹ H NMR (D ₂ O, 400 MHz): δ 8.70-8.67 (2H, m), 7.61-7.58 (2H, m), 4.80-4.76 (1H, m), 4.68-4.63 (1H, m), 4.32- 4.20 (3.5H, m), 4.17-4.12 (1.5H, m), 3.44-3.41 (1H, m), 3.27-3.21 (0.5H, m), 3.21-3.13 (0.5H, m), 1.30 (1.5 H, d, J = 6.8 Hz), 1.29 (1.5H, d, J = 6.8 Hz), 1.19 (1.5H, d, J = 6.8 Hz), 1.17 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3389, 2967, 1748, 1628, 1600, 1443, 1398, 1292 cm ^-1 ;
MS (FAB) m / z: 448 (M + Na) ⁺ , 426 (M + H) ⁺ ;
Anal.calcd.for C ₁₉ H ₂₀ N ₃ O ₅ SNa ・ H ₂ O: C, 51.46%; H, 5.00%; N, 9.48%; S, 7.23%; Na, 5.18%, Found C, 51.52%; H, 5.27%; N, 9.38%; S, 7.01%; Na, 5.37%.

Example 22 (1R, 5S, 6S) -2- [1- (pyrrol-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 21)
(22a) 3-Acetylthio-1- (pyrrol-2-ylcarbonyl) azetidine Similar to Example 19 (19a) except that pyrrole-2-carboxylic acid (500 mg, 4.50 mmol) was used instead of picolinic acid. By the method, the title compound (654 mg, yield 65%) as a colorless oil was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 9.58 (1H, br s), 6.92 (1H, td, J = 2.7, 1.2 Hz), 6.39 (1H, td, J = 2.7, 1.2 Hz), 6.24 (1H , dt, J = 3.9, 2.7 Hz), 4.87 (1H, br s), 4.61 (1H, br s), 4.33 (1H, tt, J = 8.2, 5.5 Hz), 4.24 (1H, br s), 4.09 (1H, br s), 2.36 (3H, s);
MS (EI) m / z: 224 (M) ^<+> .

(22b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyrrol-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyrrol-2-ylcarbonyl) obtained in Example 22 (22a) instead of the compound obtained in Example 19 (19a) ) A pale yellow amorphous title compound (1.04 g, yield 68%) was obtained in the same manner as in Example 19 (19b) except that azetidine (650 mg, 2.90 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 9.61 (1H, br s), 8.20-8.16 (2H, m), 7.64-7.60 (2H, m), 6.93 (1H, td, J = 2.7, 1.2 Hz) , 6.39-6.37 (1H, m), 6.24 (1H, dt, J = 3.6, 2.7 Hz), 5.47 (1H, d, J = 13.7 Hz), 5.23 (1H, d, J = 13.7 Hz), 4.75 ( 1H, br s), 4.62 (1H, br s), 4.30-4.12 (4H, m), 4.27 (1H, dd, J = 9.0, 2.7 Hz), 3.29 (1H, dd, J = 6.7, 2.7 Hz) , 3.22-3.14 (1H, m), 2.37 (1H, br s), 1.37 (3H, d, J = 6.3 Hz), 1.26 (3H, d, J = 7.0 Hz);
IR (KBr): 3381, 2970, 1770, 1605, 1521, 1454, 1345, 1210, 1137 cm ^-1 ;
MS (FAB) m / z: 549 (M + Na) ⁺ , 527 (M + H) ⁺ .

(22c) (1R, 5S, 6S) -2- [1- (pyrrol-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 22 (22b) instead of the compound obtained in Example 8 (8b) 1- (pyrrol-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.03 g, 1.96 The target compound was a white amorphous title compound (626 mg, yield 77%) in the same manner as in Example 8 (8c) except that mmol) was used.
¹ H NMR (D ₂ O, 500 MHz): δ 7.12 (1H, br s), 6.69-6.63 (1H, m), 6.36 (1H, br s), 4.91-4.85 (1H, m), 4.60-4.53 ( 1H, m), 4.41-4.34 (1H, m), 4.29-4.19 (3H, m), 4.07-4.01 (1H, m), 3.45-3.41 (1H, m), 3.28-3.20 (1H, m), 1.31 (3H, d, J = 5.4 Hz), 1.20 (3H, d, J = 6.8 Hz);
IR (KBr): 3378, 2967, 1748, 1598, 1473, 1395 cm ^-1 ;
MS (FAB) m / z: 436 (M + Na) ^<+> , 414 (M + H) ^<+> .

Example 23 (1R, 5S, 6S) -2- [1- (2-Aminopyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 26)
(23a) 3-acetylthio-1- (2-aminopyridin-3-ylcarbonyl) azetidine 2-aminonicotinic acid (622 mg, 4.50 mmol) was dissolved in tetrahydrofuran (10 mL) and dimethylformamide (10 mL), To this solution was added 1,1′-carbonylbis-1H-imidazole (973 mg, 6.00 mmol), and the mixture was stirred at 40 ° C. for 5 hours. This reaction solution was added to a solution of 3-acetylthioazetidine hydrochloride (3.50 mmol) obtained in Example 7 (7a) in methylene chloride (15 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. . After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride / ethyl acetate = 4 / 6-0 / 1, V / V) to give the title compound ( 625 mg, 71% yield).
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.06-8.04 (1H, m), 7.59-7.56 (1H, m), 6.75 (2H, br s), 6.56-6.52 (1H, m), 4.75- 4.40 (2H, m), 4.26-4.19 (1H, m), 4.19-3.86 (2H, m), 2.35 (3H, s);
IR (KBr): 3425, 3322, 1692, 1627, 1455 cm ^-1 ;
MS (FAB) m / z: 252 (M + H) ^<+> .

(23b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (2-aminopyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] 1-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (2-amino) obtained in Example 23 (23a) instead of the compound obtained in Example 7 (7b) A pale yellow amorphous title compound (1.20 g, yield 88%) was obtained in the same manner as in Example 7 (7c) except that pyridin-3-ylcarbonyl) azetidine (615 mg, 2.45 mmol) was used. It was.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.24-8.21 (2H, m), 8.14 (1H, dd, J = 4.7, 1.6 Hz), 7.67-7.64 (2H, m), 7.44 (1H, dd, J = 7.8, 1.6 Hz), 6.59 (1H, dd, J = 7.8, 4.7 Hz), 6.14 (2H, br s), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.66-4.62 (2H, m), 4.30-4.23 (3H, m), 4.23-4.11 (2H, m), 3.28 (1H, dd, J = 6.7, 2.7 Hz), 3.19-3.11 (1H, m), 1.71 (1H, br s), 1.37 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.0 Hz);
MS (FAB) m / z: 554 (M + H) ^<+> .

(23c) (1R, 5S, 6S) -2- [1- (2-Aminopyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S)-obtained in Example 23 (23b) instead of the compound obtained in Example 8 (8b)- 2- [1- (2-Aminopyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxy A white amorphous title compound (400 mg, yield 42%) as the target compound was obtained in the same manner as in Example 8 (8c) except that the rate (1.19 g, 2.15 mmol) was used.
¹ H NMR (D ₂ O, 500 MHz): δ 8.10-8.08 (1H, m), 7.71-7.68 (1H, m), 6.82-6.79 (1H, m), 4.73-4.66 (1H, m), 4.66- 4.58 (1H, m), 4.28-4.14 (4H, m), 4.11-4.09 (1H, m), 3.43-3.41 (1H, m), 3.27-3.20 (0.5H, m), 3.20-3.13 (0.5H , m), 1.32-1.27 (3H, m), 1.20-1.16 (3H, m);
IR (KBr): 3436, 2969, 1748, 1616, 1456, 1426, 1398, 1255 cm ^-1 ;
MS (FAB) m / z: 463 (M + Na) ^<+> , 441 (M + H) ^<+> .

Example 24 (1R, 5S, 6S) -2- [1- (6-Aminopyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 27)
(24a) 3-Acetylthio-1- (6-aminopyridin-3-ylcarbonyl) azetidine 6-Aminonicotinic acid (622 mg, 4.50 mmol) was dissolved in dimethylformamide (10 mL), and 1,1 was added to this solution. '-Carbonylbis-1H-imidazole (811 mg, 5.00 mmol) was added and stirred at 45 ° C. for 7 hours. This reaction solution was added to a solution of 3-acetylthioazetidine hydrochloride (3.50 mmol) obtained in Example 7 (7a) in methylene chloride (10 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. . After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1 / 1-0 / 1, then ethyl acetate / methanol = 100 / 0-95 / 5, V / V) to obtain the colorless amorphous title compound (415 mg, yield 47%).
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.21 (1H, br s), 7.61 (1H, dt, J = 8.6, 2.0 Hz), 6.55 (2H, br s), 6.41 (1H, dd, J = 8.6, 1.2 Hz), 4.73 (1H, br s), 4.45 (1H, br s), 4.26-4.19 (1H, m), 4.14 (1H, br s), 3.88 (1H, br s), 2.34 ( 3H, s);
IR (KBr): 3383, 3153, 1692, 1661, 1614, 1585, 1438, 1395 cm ^-1 ;
MS (EI) m / z: 251 (M) ^<+> .

(24b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (6-aminopyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] 1-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (6-amino) obtained in Example 24 (24a) instead of the compound obtained in Example 7 (7b) A pale yellow amorphous title compound (725 mg, yield 80%) was obtained in the same manner as in Example 7 (7c) except that pyridin-3-ylcarbonyl) azetidine (409 mg, 1.63 mmol) was used. It was.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.25-8.22 (3H, m), 7.72 (2H, d, J = 8.8 Hz), 7.63 (1H, dd, J = 8.8, 2.4 Hz), 6.56 ( 2H, s), 6.42 (1H, dd, J = 8.8 Hz), 5.46 (1H, d, J = 14.2 Hz), 5.32 (1H, d, J = 14.2 Hz), 5.08 (1H, d, J = 5.4 Hz), 4.76 (1H, br s), 4.49 (1H, br s), 4.34-4.28 (1H, m), 4.25 (1H, br s), 4.21 (1H, dd, J = 9.3, 2.4 Hz), 4.08-3.94 (1H, m), 3.88 (1H, br s), 3.32-3.29 (1H, m), 3.28 (1H, dd, J = 6.4, 2.9 Hz), 1.15 (3H, d, J = 6.8 Hz ), 1.12 (3H, d, J = 7.3 Hz);
IR (KBr): 3452, 3361, 3210, 2969, 1769, 1706, 1621, 1521, 1388, 1209, 1139 cm ^-1 ;
MS (FAB) m / z: 554 (M + H) ^<+> .

(24c) (1R, 5S, 6S) -2- [1- (6-Aminopyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S)-obtained in Example 24 (24b) instead of the compound obtained in Example 8 (8b)- 2- [1- (6-Aminopyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxy A white amorphous title compound (318 mg, 57% yield) as the target compound was obtained in the same manner as in Example 8 (8c) except that the rate (700 mg, 1.26 mmol) was used.
¹ H NMR (D ₂ O, 500 MHz): δ 8.23-8.22 (1H, m), 7.76-7.73 (1H, m), 6.70 (1H, d, J = 8.8 Hz), 4.87-4.78 (1H, m) , 4.63-4.57 (1H, m), 4.37-4.30 (1H, m), 4.27-4.16 (3H, m), 4.09-4.05 (1H, m), 3.44-3.40 (1H, m), 3.27-3.16 ( 1H, m), 1.31-1.29 (3H, m), 1.19 (1.5H, d, J = 6.8 Hz), 1.18 (1.5H, d, J = 6.8 Hz);
IR (KBr): 3336, 3211, 2967, 1747, 1603, 1432, 1395, 1290 cm ^-1 ;
MS (FAB) m / z: 463 (M + Na) ^<+> , 441 (M + H) ^<+> .

Example 25 (1R, 5S, 6S) -2- [1- (6-Hydroxypyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 28)
(25a) 3-acetylthio-1- (6-hydroxypyridin-3-ylcarbonyl) azetidine 6-hydroxynicotinic acid (626 mg, 4.50 mmol) is dissolved in tetrahydrofuran (10 mL) and dimethylformamide (10 mL), To this solution was added 1,1′-carbonylbis-1H-imidazole (973 mg, 6.00 mmol), and the mixture was stirred at room temperature for 26 hours. After confirming disappearance of the starting materials, a solution of 3-acetylthioazetidine hydrochloride (3.50 mmol) obtained in Example 7 (7a) in dimethylformamide (8 mL) was added to the reaction solution under ice-cooling, and 1 at 0 ° C. Stir for hours. After confirming the completion of the reaction, saturated brine was added to the reaction solution, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10, V / V) to give the title compound ( 485 mg, yield 55%).
¹ H NMR (CDCl ₃ , 500 MHz): δ 7.84 (1H, d, J = 2.4 Hz), 7.76 (1H, dd, J = 9.3, 2.4 Hz), 7.71 (1H, s), 6.58 (1H, d, J = 9.3 Hz), 4.68 (2H, br s), 4.29 (1H, tt, J = 8.3, 5.8 Hz), 4.14 (2H, br s), 2.36 (3H, s);
IR (KBr): 3383, 3153, 1692, 1661, 1614, 1585, 1438, 1395 cm ^-1 ;
MS (EI) m / z: 252 (M) ^<+> .

(25b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (6-hydroxypyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] 1-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (6-hydroxy) obtained in Example 25 (25a) instead of the compound obtained in Example 7 (7b) A pale yellow amorphous title compound (464 mg, 44% yield) was obtained in the same manner as in Example 7 (7c) except that pyridin-3-ylcarbonyl) azetidine (480 mg, 1.90 mmol) was used. It was.
¹ H NMR (DMSO-d ₆ , 500 MHz): δ 12.00 (1H, br s), 8.26-8.22 (2H, m), 7.75 (1H, d, J = 2.4 Hz), 7.74-7.71 (2H, m) , 7.66 (1H, dd, J = 9.8, 2.4 Hz), 6.34 (1H, d, J = 9.8 Hz), 5.46 (1H, d, J = 14.2 Hz), 5.32 (1H, d, J = 14.2 Hz) , 5.09 (1H, d, J = 4.9 Hz), 4.77 (1H, br s), 4.51 (1H, br s), 4.34-4.28 (1H, m), 4.25 (1H, br s), 4.21 (1H, dd, J = 9.3, 2.4 Hz), 4.00-3.95 (1H, m), 3.91 (1H, br s), 3.32-3.29 (1H, m), 3.29-3.27 (1H, m), 1.15 (3H, d , J = 6.3 Hz), 1.12 (3H, d, J = 7.3 Hz);
IR (KBr): 3427, 2971, 1771, 1657, 1627, 1522, 1432, 1346, 1210, 1138 cm ^-1 ;
MS (FAB) m / z: 557 (M + Na) ⁺ , 555 (M + H) ⁺ .

(25c) (1R, 5S, 6S) -2- [1- (6-Hydroxypyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S)-obtained in Example 25 (25b) instead of the compound obtained in Example 8 (8b)- 2- [1- (6-Hydroxypyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxy A white amorphous title compound (293 mg, yield 80%) as the target compound was obtained in the same manner as in Example 8 (8c) except that the rate (460 mg, 0.829 mmol) was used.
¹ H NMR (D ₂ O, 500 MHz): δ 7.96-7.94 (1H, m), 7.89-7.87 (1H, m), 6.67 (1H, d, J = 9.3 Hz), 4.89-4.83 (1H, m) , 4.64-4.57 (1H, m), 4.40-4.32 (1H, m), 4.29-4.16 (3H, m), 4.10-4.05 (1H, m), 3.43 (1H, dd, J = 6.3, 2.4 Hz) , 3.27-3.17 (1H, m), 1.30 (3H, d, J = 5.9 Hz), 1.20-1.17 (3H, m);
IR (KBr): 3410, 2968, 1748, 1659, 1629, 1598, 1439, 1397 cm ^-1 ;
MS (FAB) m / z: 464 (M + Na) ^<+> , 442 (M + H) ^<+> .

Example 26 (1R, 5S, 6S) -2- [1- (6-Carbamoylpyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 29)
(26a) 5-Methoxycarbonylpyridin-2-ylcarboxylic acid Pyridine-2,5-dicarboxylic acid (6.30 g, 32.3 mmol) was dissolved in methanol (107 mL), and sodium hydroxide (1.37 g) was added to this solution at room temperature. , 34.3 mmol) was added and heated to reflux for 1 hour. The temperature of the oil bath was cooled to 60 ° C., hydrochloric acid (1 mol / L, 24.3 mL) was added dropwise to the reaction solution, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction solution was cooled to room temperature, the solid produced in the reaction solution was collected by filtration and washed successively with a mixed solvent of methanol: water (2: 1) and water. The obtained solid was dried under reduced pressure (50 ° C.) to obtain the title compound (4.16 g, yield 71%) as a white solid.
¹ H NMR (CD ₃ OD, 400 MHz): δ 9.20 (1H, d, J = 2.0 Hz), 8.83 (1H, dd, J = 8.2, 2.0 Hz), 8.25 (1H, d, J = 8.2 Hz), 3.98 (3H, s);
MS (EI) m / z: 181 (M) ^<+> .

(26b) 2-carbamoyl-5-methoxycarbonylpyridine 5-methoxycarbonylpyridine-2-carboxylic acid (2.16 g, 11.9 mmol) obtained in Example 26 (26a) was suspended in tetrahydrofuran (100 mL), To this suspension was added 1,1′-carbonylbis-1H-imidazole (2.90 g, 17.9 mmol) at room temperature, and the mixture was stirred at 45 ° C. for 1.5 hours. The reaction solution was cooled to room temperature, ammonia (0.5 mol / L, 1,4-dioxane solution, 40 mL, 20.0 mmol) was added, and the mixture was stirred overnight. After confirming the completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: methylene chloride / ethyl acetate = 10 / 0-3 / 7, V / V) to give the title compound (1.87 as a white solid). g, yield 87%).
¹ H NMR (CD ₃ OD, 400 MHz): δ 9.15 (1H, dd, J = 2.0, 0.8 Hz), 8.48 (1H, dd, J = 7.8, 2.0 Hz), 8.18 (1H, dd, J = 7.8, 0.8 Hz), 3.96 (3H, s);
MS (FAB) m / z: 181 (M + H) ^<+> .

(26c) 2-carbamoylpyridin-5-ylcarboxylic acid 2-carbamoyl-5-methoxycarbonylpyridine (1.85 g, 10.3 mmol) obtained in Example 26 (26c) was dissolved in methanol (45 mL) and distilled water (5 mL). ), And sodium hydroxide (433 mg, 10.8 mmol) was added to the suspension at room temperature, followed by heating under reflux for 2 hours. The reaction solution was cooled to room temperature, hydrochloric acid (1 mol / L, 15 mL, 15.0 mmol) was added, and the solid produced in the reaction solution was collected by filtration and washed with water. The obtained solid was dried under reduced pressure (50 ° C.) to obtain the title compound (1.68 g, yield 98%) as a white solid.
¹ H NMR (DMSO, 400 MHz): δ 9.08-9.06 (1H, m), 8.45-8.41 (1H, m), 8.26 (1H, br s), 8.16-8.12 (1H, m), 7.81 (1H, br s);
MS (EI) m / z: 166 (M) ^<+> .

(26d) 3-acetylthio-1- (6-carbamoylpyridin-3-ylcarbonyl) azetidine 2-carbamoylpyridin-5-ylcarboxylic acid (748 mg, 4.50 mmol) obtained in Example 26 (26d) was converted to dimethylformamide. To this solution was added 1,1′-carbonylbis-1H-imidazole (1.12 g, 6.90 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred at 45 ° C. for 4 hours. After confirming disappearance of the raw materials, a solution of 3-acetylthioazetidine hydrochloride (3.50 mmol) obtained in Example 7 (7a) in methylene chloride (10 mL) was added to the reaction solution under ice-cooling and stirred for 0.5 hour. . After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, aqueous potassium hydrogen sulfate, aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/1/1/0, V / V) to give the title compound as a pale yellow solid. (436 mg, yield 46%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.82-8.80 (1H, m), 8.26 (1H, d, J = 8.2 Hz), 8.10 -8.07 (1H, m), 7.82 (1H, br s), 5.70 (1H, br s), 4.83-4.75 (1H, m), 4.70-4.60 (1H, m), 4.36-4.28 (1H, m), 4.23-4.12 (2H, m), 2.36 (3H, s);
IR (KBr): 3404, 3208, 1697, 1677, 1618, 1444, 1408 cm ^-1 ;
MS (FAB) m / z: 280 (M + H) ^<+> .

(26e) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (6-carbamoylpyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] 1-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (6-carbamoyl) obtained in Example 26 (26d) instead of the compound obtained in Example 7 (7b) A white amorphous title compound (500 mg, yield 56%) was obtained in the same manner as in Example 7 (7c) except that pyridin-3-ylcarbonyl) azetidine (430 mg, 1.54 mmol) was used. .
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.80 (1H, br s), 8.21 (2H, d, J = 9.0 Hz), 8.20-8.16 (2H, m), 8.06 (1H, d, J = 7.8 Hz), 7.76 (1H, br s), 7.70 (2H, d, J = 9.0 Hz), 5.45 (1H, d, J = 14.1Hz), 5.32-5.27 (1H, m), 5.09-5.05 (1H , m), 4.82-4.74 (1H, m), 4.62-4.52 (1H, m), 4.38-4.31 (2H, m), 4.23-4.16 (1H, m), 3.99-3.93 (2H, m), 3.39 -3.21 (2H, m), 1.15 (3H, d, J = 6.3 Hz), 1.13 (1.5H, d, J = 7.0 Hz), 1.11 (1.5H, d, J = 7.0 Hz);
IR (KBr): 3454, 3357, 2971, 1770, 1693, 1636, 1520, 1345, 1210, 1139 cm ^-1 ;
MS (FAB) m / z: 582 (M + H) ^<+> .

(26f) (1R, 5S, 6S) -2- [1- (6-Carbamoylpyridin-3-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapen-2-em-3carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [1- (6-carbamoylpyridin-3-ylcarbonyl) obtained in Example 26 (26e) ) Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (500 mg, 0.860 mmol) in tetrahydrofuran (200 mL), Dissolve in a mixed solvent of 0.1 mol / L-sodium phosphate buffer pH 7.0 (50 mL) and distilled water (150 mL), add 7.5% palladium carbon (950 mg) to this solution, and contact at 30 ° C. Hydrogen reduction was performed for 1 hour. After confirming the completion of the reaction, the reaction mixture was filtered, and diethyl ether, tetrahydrofuran and distilled water were added to the filtrate to carry out a liquid separation operation. The obtained aqueous layer was concentrated under reduced pressure, and reverse phase chromatography (elution solvent: distilled water / acetonitrile = 100 / 0-98 / 2, V / V) using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Ltd.) The product was purified by lyophilization and lyophilized to obtain the target compound as a white amorphous title compound (335 mg, yield 83%).
¹ H NMR (D ₂ O, 500 MHz): δ 8.85-8.83 (1H, m), 8.23-8.19 (1H, m), 8.16-8.14 (1H, m), 4.86-4.79 (1H, m), 4.71- 4.65 (1H, m), 4.36-4.21 (3.5H, m), 4.17-4.14 (1.5H, m), 3.44-3.41 (1H, m), 3.29-3.22 (0.5H, m), 3.22-3.16 ( 0.5H, m), 1.31 (1.5H, d, J = 6.8 Hz), 1.29 (1.5H, d, J = 6.8 Hz), 1.21-1.16 (3H, m);
IR (KBr): 3439, 2969, 1749, 1686, 1608, 1445, 1398 cm ^-1 ;
MS (FAB) m / z: 491 (M + Na) ^<+> , 469 (M + H) ^<+> .

Example 27 (1R, 5S, 6S) -2- {1- [6- (morpholin-1-yl) pyridin-3-ylcarbonyl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 30)
(27a) 2- (morpholin-1-yl) pyridin-5-ylcarboxylic acid 2-chloronicotinic acid (1.58 g, 10.0 mmol) and morpholine (8 mL) were mixed at room temperature and stirred at 120 ° C. for 16 hours. . The reaction mixture was cooled to room temperature, neutralized with hydrochloric acid (1 mol / L), and the solid produced in the reaction mixture was collected by filtration and washed with water. The obtained solid was dried under reduced pressure to obtain the title compound as a white solid (1.25 g, yield 60%).
¹ H NMR (DMSO-d ₆ , 500 MHz): δ 12.50 (1H, br s), 8.64 (1H, d, J = 2.0 Hz), 7.95 (1H, ddd, J = 9.3, 2.0, 1.0 Hz), 6.86 (1H, d, J = 9.3 Hz), 3.70-3.67 (4H, m), 3.61-3.58 (4H, m);
IR (KBr): 3431, 1695, 1607, 1427, 1260, 1241, 1121 cm ^-1 ;
MS (FAB) m / z: 209 (M + H) ^<+> .

(27b) 3-acetylthio-1- [6- (morpholin-1-yl) pyridin-3-ylcarbonyl] azetidine 2- (morpholin-1-yl) pyridin-5-ylcarboxylic acid (935 mg, 4.50 mmol). Dissolved in dimethylformamide (10 mL), 1,1′-carbonylbis-1H-imidazole (973 mg, 6.00 mmol) was added to the solution, and the mixture was allowed to stand overnight at room temperature. This reaction solution was added to a solution of 3-acetylthioazetidine hydrochloride (3.50 mmol) obtained in Example 7 (7a) in methylene chloride (15 mL) under ice-cooling, and the mixture was stirred at 0 ° C. for 3 hours. . After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 5-5 / 9, V / V) to give the title compound as a pale yellow solid. (691 mg, 61% yield) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.43 (1H, d, J = 2.7 Hz), 7.38 (1H, dd, J = 8.8, 2.7 Hz), 6.61 (1H, d, J = 8.8 Hz), 4.87 -4.48 (2H, m), 4.30 (1H, tt, J = 8.2, 5.7 Hz), 4.15 (1H, br s), 3.82-3.79 (4H, m), 3.62-3.59 (4H, m), 2.35 ( 3H, s);
IR (KBr): 2967, 2868, 1687, 1617, 1429, 1397, 1255. 1113 cm ^-1 ;
MS (FAB) m / z: 322 (M + H) ^<+> .

(27c) p-nitrobenzyl (1R, 5S, 6S) -2-{[6- (morpholin-1-yl) pyridin-3-ylcarbonyl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- obtained in Example 27 (27b) instead of the compound obtained in Example 7 (7b) In the same manner as in Example 7 (7c), except that [6- (morpholin-1-yl) pyridin-3-ylcarbonyl] azetidine (680 mg, 2.11 mmol) was used, the pale yellow amorphous title compound ( 1.03 g, yield 78%) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.40 (1H, d, J = 2.4 Hz), 8.23 (2H, d, J = 8.3 Hz), 7.83 (1H, dd, J = 8.8, 2.4 Hz), 7.66 (2H, d, J = 8.3 Hz), 6.62 (1H, d, J = 8.8 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.66 (2H , br s), 4.30-4.11 (5H, m), 3.82-3.80 (4H, m), 3.63-3.60 (4H, m), 3.28 (1H, dd, J = 6.4, 2.2 Hz), 3.19-3.13 ( 1H, m), 1.86 (1H, br s), 1.37 (3H, d, J = 6.4 Hz), 1.26 (3H, d, J = 6.9 Hz);
MS (FAB) m / z: 624 (M + H) ^<+> .

(27d) (1R, 5S, 6S) -2-{[6- (morpholin-1-yl) pyridin-3-ylcarbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl ] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S) obtained in Example 27 (27c) instead of the compound obtained in Example 8 (8b) , 6S) -2-{[6- (morpholin-1-yl) pyridin-3-ylcarbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene The white amorphous title compound (655 mg, yield 78), which was the target compound, was prepared in the same manner as in Example 8 (8c), except that 2-em-3-carboxylate (1.02 g, 1.64 mmol) was used. %).
¹ H NMR (D ₂ O, 500 MHz): δ 8.33 (1H, br s), 7.84-7.79 (1H, m), 6.92-6.87 (1H, m), 4.88-4.82 (1H, m), 4.64-4.57 (1H, m), 4.36-4.15 (4H, m), 4.10-4.04 (1H, m), 3.86 (1H, br s), 3.60 (1H, br s), 3.44-3.41 (1H, m), 3.26 -3.17 (1H, m), 1.30 (3H, br s), 1.22-1.16 (3H, m);
IR (KBr): 3410, 2966, 1750, 1602, 1547, 1398, 1255, 1115 cm ^-1 ;
MS (FAB) m / z: 533 (M + Na) ^<+> , 511 (M + H) ^<+> .

Example 28 (1R, 5S, 6S) -2- [1- (pyrazin-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 32)
(28a) 3-Acetylthio-1- (pyrazin-2-ylcarbonyl) azetidine Pyrazinecarboxylic acid (745 mg, 6.00 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and acetonitrile (10 mL). Under a nitrogen atmosphere, 1,1′-carbonylbis-1H-imidazole (1.30 g, 8.02 mmol) was added at room temperature, and the mixture was stirred at 45 ° C. for 6 hours. This reaction solution was added to a solution of 3-acetylthioazetidine hydrochloride (5.00 mmol) obtained in Example 7 (7a) in methylene chloride (15 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 2.5 hours. . After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed with 10% brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 4-4 / 6, V / V) to give a pale yellow oily title The compound (745 mg, yield 63%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 9.30 (1H, d, J = 1.6 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.49 (1H, dd, J = 2.4, 1.6 Hz), 5.16 (1H, ddd, J = 11.4, 8.2, 1.2 Hz), 4.67 (1H, ddd, J = 11.4, 8.2, 1.2 Hz), 4.59-4.54 (1H, m), 4.31 (1H, tt, J = 8.2, 5.5 Hz), 4.15-4.10 (1H, m), 2.34 (3H, s);
MS (EI) m / z: 237 (M) ^<+> .

(28b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyrazin-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyrazin-2-ylcarbonyl) obtained in Example 28 (28a) instead of the compound obtained in Example 7 (7b) ) A white amorphous title compound (1.07 g, 94% yield) was obtained in the same manner as in Example 7 (7c) except that azetidine (501 mg, 2.11 mmol) was used.
¹ H NMR (CDCl ₃ , 500 MHz): δ 9.34-9.32 (1H, m), 8.70 (1H, d, J = 2.4 Hz), 8.54-8.51 (1H, m), 8.23-8.21 (2H, m), 7.66 (2H, dd, J = 8.8, 2.9 Hz), 5.52-5.48 (1H, m), 5.38 (1H, m), 5.15-5.11 (1H, m), 4.68-4.63 (2H, m), 4.30- 4.25 (2H, m), 4.23-4.15 (2H, m), 3.30 (1H, dd J = 6.8, 2.4 Hz), 3.23-3.16 (1H, m), 1.72 (1H, br s), 1.38 (3H, d, J = 6.4 Hz), 1.28 (3H, d, J = 7.3 Hz);
MS (FAB) m / z: 540 (M + H) ^<+> .

(28c) (1R, 5S, 6S) -2- [1- (pyrazin-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 28 (28b) instead of the compound obtained in Example 8 (8b) 1- (pyrazin-2-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.05 g, 1.95 The target compound was a white amorphous title compound (579 mg, yield 70%) in the same manner as in Example 8 (8c) except that mmol) was used.
¹ H NMR (D ₂ O, 500 MHz): δ 9.06 (1H, br s), 8.76-8.73 (2H, m), 5.12-5.06 (1H, m), 4.73-4.67 (1H, m), 4.59-4.53 (1H, m), 4.33-4.15 (4H, m), 3.43 (1H, dd, J = 6.3, 2.4 Hz), 3.30-3.19 (1H, m), 1.31 (1.5H, d, J = 6.3 Hz) , 1.30 (1.5H, d, J = 6.3 Hz), 1.21 (1.5H, d, J = 6.3 Hz), 1.20 (1.5H, d, J = 6.3 Hz);
IR (KBr): 3398, 2967, 1749, 1633, 1601, 1455, 1390 cm ^-1 ;
MS (FAB) m / z: 449 (M + Na) +, 427 (M + H) +.

Example 29 (1R, 5S, 6S) -2- [1- (1,3-thiazol-4-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 22)
(29a) 1,3-thiazol-4-ylcarbonyl chloride 1,3-thiazole-4-carboxylic acid (418 mg, 3.24 mmol) was dissolved in methylene chloride (20 mL), and this solution was dissolved in a nitrogen atmosphere at room temperature. Dimethylformamide (0.1 mL) and oxalyl chloride (1.14 mL, 13.1 mmol) were added at rt and stirred at room temperature for 1.5 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product of the title compound as a pale yellow solid.

(29b) 3-acetylthio-1- (1,3-thiazol-4-ylcarbonyl) azetidine 1,3-thiazol-4-ylcarbonyl chloride (3.24 mmol) obtained in Example 29 (29a) was converted into methylene chloride. (3 mL) and a solution of 3-acetylthioazetidine hydrochloride (2.16 mmol) obtained in Example 7 (7a) in methylene chloride (20 mL) and triethylamine (1.82 mL, 13.0 mmol) on ice. The reaction suspension was sequentially added under cooling and stirred overnight. After confirming the completion of the reaction, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 5-4 / 6, V / V) to give a pale yellow oily title The compound (241 mg, yield 46%) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.76 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 2.0 Hz), 5.13 (1H, t, J = 10.8 Hz), 4.64 (1H , t, J = 10.7 Hz), 4.53 (1H, dd, J = 10.8, 5.4 Hz), 4.33-4.27 (1H, m), 4.10 (1H, dd, J = 10.7, 5.4 Hz), 2.36 (3H, s);
MS (FAB) m / z: 265 (M + Na) ^<+> , 243 (M + H) ^<+> .

(29c) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (1,3-thiazol-4-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- (1,1) obtained in Example 29 (29b) instead of the compound obtained in Example 16 (16a) The pale yellow amorphous title compound (498 mg, 93% yield) was prepared in the same manner as in Example 16 (16b) except that 3-thiazol-4-ylcarbonyl) azetidine (238 mg, 0.982 mmol) was used. Got.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.77-8.76 (1H, m), 8.25-8.21 (3H, m), 7.67-7.65 (2H, m), 7.27-7.26 (1H, m), 5.50 (1H , dd, J = 13.7, 3.9 Hz), 5.26 (1H, d, J = 13.7 Hz), 5.10-5.06 (1H, m), 4.61-4.58 (2H, m), 4.30-4.25 (2H, m), 4.17-4.10 (2H, m), 3.29 (1H, dd J = 6.8, 2.4 Hz), 3.22-3.18 (1H, m), 1.66 (1H, br s), 1.38 (3H, d, J = 6.3 Hz) , 1.28 (3H, d, J = 7.3 Hz);
MS (FAB) m / z: 545 (M + H) ^<+> .

(29d) (1R, 5S, 6S) -2- [1- (1,3-thiazol-4-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) obtained in Example 29 (29c) instead of the compound obtained in Example 8 (8b) 2- [1- (1,3-thiazol-4-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3 -The pale yellow amorphous title compound (183 mg, 47% yield) as the target compound was obtained in the same manner as in Example 8 (8c) except that carboxylate (490 mg, 0.900 mmol) was used. .
¹ H NMR (D ₂ O, 400 MHz): δ 9.04 (1H, s), 8.24-8.23 (1H, m), 5.06-5.00 (1H, m), 4.69-4.62 (1H, m), 4.55-4.47 ( 1H, m), 4.32-4.18 (3H, m), 4.14-4.12 (1H, m), 3.44 (1H, dd, J = 5.8, 2.0 Hz), 3.30-3.19 (1H, m), 1.30 (3H, d, J = 6.4 Hz), 1.21 (1.5H, d, J = 7.3 Hz), 1.20 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3406, 2967, 1748, 1603, 1440, 1395 cm ^-1 ;
MS (FAB) m / z: 454 (M + Na) ^<+> , 432 (M + H) ^<+> .

Example 30 (1R, 5S, 6S) -2- [1- (1-Methylimidazol-5-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 23)
(30a) 3-acetylthio-1- (1-methylimidazol-5-ylcarbonyl) azetidine 1-methylimidazole-5-carboxylic acid (757 mg, 6.00 mmol) in tetrahydrofuran (10 mL) and acetonitrile (10 mL) After dissolution, 1,1′-carbonylbis-1H-imidazole (1.29 g, 8.00 mmol) was added to this solution and stirred at 50 ° C. for 7 hours. After confirming disappearance of the raw materials, a solution of 3-acetylthioazetidine hydrochloride (3.50 mmol) obtained in Example 7 (7a) in methylene chloride (15 mL) was added to the reaction solution under ice cooling, and gradually brought to room temperature. The temperature was raised and left overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-87.5 / 12.5, V / V) to give a pale yellow oil. Of the title compound (441 mg, yield 53%).
¹ H NMR (CDCl ₃ , 500 MHz): δ 7.28 (1H, d, J = 1.0 Hz), 7.12 (1H, d, J = 1.0 Hz), 4.89 -4.52 (2H, m), 4.25-4.29 (1H, m), 3.92 (3H, s), 2.37 (3H, s);
MS (EI) m / z: 239 (M) ^<+> .

(30b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (1-methylimidazol-5-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] 1-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (1-methyl) obtained in Example 30 (30a) instead of the compound obtained in Example 7 (7b) A pale yellow amorphous title compound (564 mg, yield 58%) was obtained in the same manner as in Example 7 (7c) except that (imidazol-5-ylcarbonyl) azetidine (431 mg, 1.80 mmol) was used. It was.
¹ H NMR (acetone-d ₆ , 500 MHz): δ 8.24 (2H, d, J = 8.8 Hz), 7.81 (2H, d, J = 8.8 Hz), 7.64 (1H, s), 7.34 (1H, s) , 5.54 (1H, d, J = 13.7 Hz), 5.31 (1H, d, J = 13.7 Hz), 4.89 (1H, br s), 4.58 (1H, br s), 4.45-4.39 (1H, m), 4.33 (1H, dd, J = 9.3, 2.9 Hz), 4.25 (1H, d, J = 4.9 Hz), 4.17-4.10 (1H, m), 3.98 (1H, br s), 3.48-3.42 (1H, m ), 3.34 (1H, dd, J = 6.4, 2.4 Hz), 1.273 (3H, d, J = 7.3 Hz), 1.266 (3H, d, J = 6.4 Hz);
MS (FAB) m / z: 542 (M + H) ^<+> .

(30c) (1R, 5S, 6S) -2- [1- (1-Methylimidazol-5-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S)-obtained in Example 30 (30b) instead of the compound obtained in Example 8 (8b)- 2- [1- (1-Methylimidazol-5-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxy A white amorphous title compound (302 mg, 69% yield) as the target compound was obtained in the same manner as in Example 8 (8c) except that the rate (555 mg, 1.02 mmol) was used.
¹ H NMR (D ₂ O, 500 MHz): δ 7.76 (1H, s), 7.43-7.40 (1H, m), 4.89-4.83 (1H, m), 4.62-4.56 (1H, m), 4.37-4.19 ( 4H, m), 4.08-4.04 (1H, m), 3.83 (3H, s), 3.44 (1H, dd, J = 6.4, 2.4 Hz), 3.29-3.19 (1H, m), 1.30 (3H, d, J = 6.4 Hz), 1.20 (3H, d, J = 6.4 Hz);
IR (KBr): 3408, 2967, 1748, 1605, 1444, 1396, 1288, 1143 cm ^-1 ;
MS (FAB) m / z: 451 (M + Na) ^<+> , 429 (M + H) ^<+> .

Example 31 (1R, 5S, 6S) -2- (1-thiopivaloylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid sodium salt (salt of compound No. 52)
(31a) 3-Acetylthio-1-thiopivaloylazetidine 3-Acetylthio-1-pivaloylazetidine (670 mg, 3.11 mmol) obtained in Example 1 (1d) was added to toluene (35 mL). After dissolution, Lawson's reagent (756 mg, 1.87 mmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at 100 ° C. for 1 hr. After completion of the reaction, ethyl acetate was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/6/1/3, V / V) to give the title compound as a colorless oil. (654 mg, 91% yield) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 5.03-4.95 (1H, m), 4.69-4.60 (1H, m), 4.35-4.29 (1H, m), 4.23-4.12 (2H, m), 2.37 (1.5 H, s), 2.37 (1.5H, s), 1.35 (4.5H, s), 1.34 (1.5H, s);
MS (EI) m / z: 231 (M) ^<+> .

(31b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-thiopivaloylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylate 3-acetylthio-1-thiopivaloylazetidine (650 mg, obtained in Example 31 (31a) instead of the compound obtained in Example 1 (1d) The pale yellow amorphous title compound (1.10 g, yield 74%) was obtained in the same manner as in Example 1 (1e) except that 2.81 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.21 (2H, d, J = 8.0 Hz), 7.64 (2H, d, J = 8.0 Hz), 5.50 (0.5H, d, J = 13.7 Hz), 5.49 ( 0.5H, d, J = 13.7 Hz), 5.24 (1H, d, J = 13.7 Hz), 4.90-4.83 (1H, m), 4.68-4.60 (1H, m), 4.42-4.35 (1H, m), 4.29-4.17 (3H, m), 4.10-4.01 (1H, m), 3.30-3.26 (1H, m), 3.23-3.11 (1H, m), 1.37 (3H, d, J = 6.3 Hz), 1.35 ( 4.5H, s), 1.34 (4.5H, s), 1.28 (3H, d, J = 7.0 Hz);
MS (FAB) m / z: 534 (M + H) ^<+> .

(31c) (1R, 5S, 6S) -2- (1-thiopivaloylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-thiopivaloylazetidin-3-yl) thio-6- obtained in Example 31 (31b) [(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.10 g, 2.06 mmol) was added to tetrahydrofuran (33 mL) and 0.1 mol / L sodium phosphate buffer pH 7 0.02 (33 mL) in a mixed solvent, 20% palladium hydroxide on carbon (1.10 g) was added to the solution, and catalytic hydrogen reduction was performed at room temperature for 2.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The obtained aqueous layer was concentrated under reduced pressure, and reverse phase chromatography using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Ltd.) (elution solvent: distilled water / acetonitrile = 100 / 0-94 / 6, V / V) The product was purified by lyophilization and freeze-dried to obtain the target compound as a pale yellow amorphous title compound (421 mg, yield 49%).
¹ H NMR (D ₂ O, 400 MHz): δ 5.14-5.08 (1H, m), 4.70-4.54 (2H, m), 4.28-4.14 (4H, m), 3.46-3.43 (1H, m), 3.28- 3.21 (1H, m), 1.33 (4.5H, s), 1.32 (4.5H, s), 1.30 (3H, d, J = 6.4 Hz), 1.21 (1.5H, d, J = 7.1 Hz), 1.20 ( 1.5H, d, J = 7.1 Hz);
IR (KBr): 3399, 2966, 1750, 1601, 1470, 1447, 1436, 1395, 1258, 1147 cm ^-1 ;
MS (FAB) m / z: 421 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₈ H ₂₆ N ₂ O ₄ S ₂ Na (M + H) ⁺ : 421.12317. Found 421.12593;
Anal.calcd.for C ₁₈ H ₂₅ N ₂ O ₄ S ₂ Na ・ 2H ₂ O: C, 47.35%; H, 6.40%; N, 6.14%; S, 14.05%, Found C, 47.32%; H, 6.17 %; N, 6.17%; S, 13.93%.

Example 32 (1R, 5S, 6S) -2- [1- (Pyridin-3-ylthioacetyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 57)
(32a) 3-acetylthio-1- (pyridin-3-ylthioacetyl) azetidine 3-acetylthio-1- (pyridin-3-ylacetyl) azetidine (1.30 g, 5.19 mmol) obtained in Example 7 (7b) Was dissolved in toluene (65 mL), and Lawesson's reagent (1.26 g, 3.12 mmol) was added to this solution at room temperature under a nitrogen atmosphere, followed by stirring at 100 ° C. for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction mixture, washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1-0 / 1, V / V) to give the title compound as a colorless oil. (642 mg, 46% yield) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.55-8.52 (1H, m), 8.49 (1H, br s), 7.81-7.76 (1H, m), 7.31-7.26 (1H, m), 4.76-4.70 ( 1H, m), 4.65-4.59 (1H, m), 4.25-4.17 (1H, m), 4.15-4.07 (2H, m), 3.94-3.85 (2H, m), 2.362 (1.5H, s), 2.358 (1.5H, s);
MS (EI) m / z: 266 (M) ^<+> .

(32b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-3-ylthioacetyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyridin-3-ylthioacetyl) azetidine (635 mg, 2.38 mmol) obtained in Example 32 (32a) was converted to dimethylformamide. (19 mL) was dissolved, and hydrazine acetate (263 mg, 2.86 mmol) was added to the solution at room temperature under a nitrogen atmosphere, followed by stirring at room temperature for 0.5 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapene-2-em-3-carboxylate (1.41 g, 2.37 mmol) in acetonitrile (40 mL) was added dropwise, followed by addition of diisopropylethylamine (1.66 mL, 9.53 mmol). Ethyl acetate was added to the reaction solution, which was washed successively with 10% brine, aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 0-92.5 / 7.5, V / V) to give a pale yellow amorphous product. Of the title compound (1.24 g, yield 92%) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.55-8.52 (1H, m), 8.51-8.47 (1H, m), 8.23 (2H, d, J = 8.8 Hz), 7.80-7.74 (1H, m), 7.65 (2H, d, J = 8.8 Hz), 7.32-7.28 (1H, m), 5.52-5.47 (1H, m), 5.26-5.22 (1H, m), 4.66-4.58 (2H, m), 4.30- 4.23 (2H, m), 4.20-4.14 (2H, m), 4.11-4.05 (1H, m), 3.94-3.86 (2H, m), 3.31-3.27 (1H, m), 3.17-3.10 (1H, m ), 2.44 (1H, br s), 1.38-1.36 (3H, m), 1.26-1.23 (3H, m);
IR (KBr): 3393, 2969, 1770, 1708, 1520, 1455, 1344 cm ^-1 ;
MS (FAB) m / z: 569 (M + H) ^<+> .

(32c) (1R, 5S, 6S) -2- [1- (Pyridin-3-ylthioacetyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-3-ylthioacetyl) azetidine- obtained in Example 32 (32b) 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.23 g, 2.16 mmol) in tetrahydrofuran (90 mL) and 0.1 mol / Dissolve in a mixed solvent of L-sodium phosphate buffer pH 7.0 (80 mL), add 7.5% palladium carbon (1.2 g) to this solution, perform catalytic hydrogen reduction at 30 ° C for 2 hours, and further add 7.5% Add palladium on carbon (1.2 g) and perform catalytic hydrogen reduction for 1.5 hours. Was Tsu. After confirming the completion of the reaction, the reaction mixture was filtered, and diethyl ether and distilled water were added to the filtrate to carry out a liquid separation operation. The obtained aqueous layer was concentrated under reduced pressure, and reverse phase chromatography (elution solvent: distilled water / acetonitrile = 100 / 0-90 / 10, V / V) using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Co., Ltd.) The product was purified by lyophilization and freeze-dried to obtain the target compound as a pale yellow amorphous title compound (574 mg, yield 58%).
¹ H NMR (D ₂ O, 500 MHz): δ 8.48-8.45 (1H, m), 8.44 (1H, br s), 7.81-7.77 (1H, m), 7.47-7.43 (1H, m), 4.92-4.87 (1H, m), 4.70-4.64 (1H, m), 4.42-4.32 (1H, m), 4.28-4.15 (4H, m), 3.98-3.95 (2H, m), 3.45-3.43 (1H, m) , 3.28-3.16 (1H, m), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 7.3 Hz);
IR (KBr): 3388, 2967, 1750, 1598, 1509, 1397 cm ^-1 ;
MS (FAB) m / z: 478 (M + Na) ^<+> , 456 (M + H) ^<+> .

Example 33 (1R, 5S, 6S) -2- {1- [3- (pyridin-3-yl) thiopropionyl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 58)
(33a) 3-Acetylthio-1- [3- (pyridin-3-yl) thiopropionyl] azetidine 3-propyl obtained in Example 8 (8a) instead of the compound obtained in Example 7 (7b) The title compound as a pale yellow oil was obtained in the same manner as in Example 32 (32a) except that acetylthio-1- [3- (pyridin-3-yl) propionyl] azetidine (870 mg, 3.29 mmol) was used. 604 mg, 66% yield).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.51-8.46 (2H, m), 7.56 (1H, d, J = 7,8 Hz), 7.24 (1H, dd, J = 7.8, 4.7 Hz), 4.57 ( 1H, dd, J = 11.7, 9.0 Hz), 4.46 (1H, dd, J = 10.4, 8.4 Hz), 4.16-4.03 (2H, m), 3.81-3.76 (1H, m), 3.14 (2H, t, J = 7.4 Hz), 2.72 (2H, t, J = 7.4 Hz), 2.35 (3H, s);
MS (EI) m / z: 280 (M) ^<+> .

(33b) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [3- (pyridin-3-yl) thiopropionyl] azetidin-3-yl} thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- [] obtained in Example 33 (33a) instead of the compound obtained in Example 32 (32b) Except that 3- (pyridin-3-yl) thiopropionyl] azetidine (595 mg, 2.12 mmol) was used, the pale yellow amorphous title compound (1.06 g, yield) was obtained in the same manner as in Example 32 (32c). Rate 85%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.47-8.44 (1.5H, m), 8.43 (0.5H, dd, J = 4.7, 1.6 Hz), 7.63 (2H, d, J = 8.6 Hz), 7.57- 7.52 (1H, m), 7.22 (1H, dt, J = 7.7, 4.7 Hz), 5.51-5.46 (1H, m), 5.26-5.20 (1H, m), 4.58-4.52 (1H, m), 4.36- 4.28 (1H, m), 4.28-4.22 (2H, m), 4.14-4.07 (1H, m), 4.00-3.94 (1H, m), 3.93-3.85 (1H, m), 3.28 (1H, dd, J = 6.9, 2.5 Hz), 3.19-3.04 (3H, m), 2.74-2.69 (2H m), 2.38 (1H, br s), 1.37 (1.5H, d, J = 6.3 Hz), 1.36 (1.5H, d, J = 6.3 Hz), 1.26-1.22 (3H, m);
MS (FAB) m / z: 583 (M + H) ^<+> .

(33c) (1R, 5S, 6S) -2- {1- [3- (pyridin-3-yl) thiopropionyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 1) obtained in Example 33 (33b) instead of the compound obtained in Example 31 (31b) 6S) -2- {1- [3- (Pyridin-3-yl) thiopropionyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -The title compound as a pale yellow amorphous compound (439 mg, yield 53%) was obtained in the same manner as in Example 31 (31c) except that M-3-carboxylate (1.04 g, 1.78 mmol) was used. )
¹ H NMR (D ₂ O, 500 MHz): δ 8.45 (0.5H, d, J = 4.9 Hz), 8.42 (1H, d, J = 1.5 Hz), 8.38 (0.5H, d, J = 4.9 Hz), 7.77 (0.5H, dd, J = 8.1, 1.5 Hz), 7.74 (0.5H, dd, J = 8.1, 1.5 Hz), 7.45 (0.5H, dd, J = 8.1, 4.9 Hz), 7.40 (0.5H, dd, J = 8.1, 4.9 Hz), 4.56-4.40 (2H, m), 4.27-4.21 (1H, m), 4.20-4.12 (1H, m), 4.05-3.91 (2H, m), 3.76-3.72 ( 0.5H, m), 3.43-3.39 (1H, m), 3.34-3.29 (0.5H, m), 3.19-3.04 (2.5H, m), 2.99-2.92 (0.5H, m), 2.89-2.81 (2H , m), 1.30 (3H, d, J = 5.9 Hz), 1.14-1.11 (3H, m);
IR (KBr): 3398, 2966, 1750, 1600, 1510, 1444, 1396 cm ^-1 ;
MS (FAB) m / z: 492 (M + Na) ⁺ , 470 (M + H) ⁺ ;
Anal.calcd.for C ₂₁ H ₂₄ N ₃ O ₄ S2Na ・ 3 / 2H ₂ O: C, 50.79%; H, 5.48%; N, 8.46%; S, 12.91%; Na, 4.63%, Found C, 51.06 %; H, 5.66%; N, 8.59%; S, 12.61%; Na, 4.93%.

Example 34 (1R, 5S, 6S) -2- (1-Cyclopropanethiocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid sodium salt (salt of compound No. 60)
(34a) 3-acetylthio-1-cyclopropanethiocarbonylazetidine 3-acetylthio-1-cyclopropanecarbonylazetidine obtained in Example 10 (10a) instead of the compound obtained in Example 1 (1d) The title compound (539 mg, yield 96%) as white crystals was obtained in the same manner as in Example 31 (31a) except that (520 mg, 2.60 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.85 (1H, t, J = 9.2 Hz), 4.63 (1H, dd, J = 12.3, 8.4 Hz), 4.32-4.25 (1H, m), 4.21 (1H, dd, J = 10.6, 6.3 Hz), 4.13 (1H, dd, J = 13.3, 6.6 Hz), 2.38 (3H, s), 1.76-1.69 (1H, m), 1.29-1.25 (2H, m), 0.99 -0.93 (2H, m);
MS (EI) m / z: 215 (M) ^<+> .

(34b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclopropanethiocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylate 3-acetylthio-1-cyclopropanethiocarbonylazetidine (530 mg, obtained in Example 34 (34a) instead of the compound obtained in Example 1 (1d) The pale yellow amorphous title compound (993 mg, yield 78%) was obtained in the same manner as in Example 1 (1e) except that 2.46 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.21 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 5.49 (1H, d, J = 13.7 Hz), 5.24 (1H , d, J = 13.7 Hz), 4.78-4.72 (1H, m), 4.67-4.58 (1H, m), 4.30-4.24 (3H, m), 4.21-4.10 (2H, m), 3.32-3.26 (1H , m), 3.25-3.12 (1H, m), 1.76-1.68 (2H, m), 1.38 (1.5H, d, J = 6.3 Hz), 1.37 (1.5H, d, J = 6.3 Hz), 1.30- 1.25 (4H, m), 1.02-0.93 (2H, m);
MS (FAB) m / z: 518 (M + H) ^<+> .

(34c) (1R, 5S, 6S) -2- (1-cyclopropanethiocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclopropanethiocarbonylazetidin-3-yl) thio-6- obtained in Example 34 (34b) [(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (990 mg, 1.91 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and distilled water (30 mL). Then, 10% palladium carbon (1.5 g) was added to this solution, and catalytic hydrogen reduction was performed at room temperature for 3 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and sodium bicarbonate (60 mg), ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The obtained aqueous layer was concentrated under reduced pressure, and reverse phase chromatography using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Ltd.) (elution solvent: distilled water / acetonitrile = 100 / 0-96 / 4, V / V) The product was purified by lyophilization and freeze-dried to obtain the target compound as a pale yellow amorphous title compound (469 mg, yield 61%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.94-4.88 (1H, m), 4.68-4.61 (1H, m), 4.45-4.37 (1H, m), 4.30-4.20 (3H, m), 4.16- 4.12 (1H, m), 3.46-3.43 (1H, m), 3.30-3.23 (1H, m), 1.98-1.90 (1H, m), 1.30 (3H, d, J = 6.3 Hz), 1.22 (1.5H , d, J = 6.8 Hz), 1.21 (1.5H, d, J = 6.8 Hz), 1.10-1.04 (4H, m);
IR (KBr): 1749, 1598, 1501, 1457, 1396, 1293, 1269, 1246 cm ^-1 ;
MS (FAB) m / z: 405 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₇ H ₂₂ N ₂ O ₄ S ₂ Na (M + H) ⁺ : 405.09187. Found 405.09281;
Anal.calcd.for C ₁₇ H ₂₁ N ₂ O ₄ S ₂ Na ・ 2H ₂ O: C, 46.35%; H, 5.72%; N, 6.36%; S, 14.56%, Found C, 46.37%; H, 5.51 %; N, 6.46%; S, 14.57%.

Example 35 (1R, 5S, 6S) -2- [1- (Tetrahydropyran-4-thiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 65)
(35a) 3-acetylthio-1- (tetrahydropyran-4-thiocarbonyl) azetidine 3-acetylthio-1- () obtained in Example 18 (18a) instead of the compound obtained in Example 1 (1d) The title compound (642 mg, yield 91%) as white crystals was obtained in the same manner as in Example 31 (31a) except that tetrahydropyran-4-carbonyl) azetidine (660 mg, 2.71 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.79 (1H, t, J = 9.4 Hz), 4.64-4.56 (1H, m), 4.30-4.21 (1H, m), 4.16-4.08 (2H, m), 4.07-4.00 (2H, m), 3.43 (2H, t, J = 12.1 Hz), 2.64 (1H, tt, J = 11.7, 3.9 Hz), 2.38 (1.5H, s), 2.37 (1.5H, s) , 2.08 (2H, dq, J = 12.5, 4.3 Hz), 1.54-1.50 (2H, m);
MS (EI) m / z: 259 (M) ^<+> .

(35b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (tetrahydropyran-4-thiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (tetrahydropyran-4-) obtained in Example 35 (35a) instead of the compound obtained in Example 1 (1d) A pale yellow amorphous title compound (971 mg, yield 70%) was obtained in the same manner as in Example 1 (1e) except that (thiocarbonyl) azetidine (640 mg, 2.47 mmol) was used.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.24 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 5.46 (1H, d, J = 13.7 Hz), 5.31 (1H, d, J = 13.7 Hz), 5.10 (1H, d, J = 5.1 Hz), 4.87-4.76 (1H, m), 4.59-4.50 (1H, m), 4.36-4.20 (3H, m), 4.01-3.83 (4H, m), 3.41-3.33 (2H, m), 3.31-3.27 (1H, m), 2.83-2.74 (1H, m), 1.80-1.68 (2H, m), 1.52-1.43 (2H , m), 1.56 (3H, d, J = 5.9 Hz), 1.34 (3H, d, J = 7.4 Hz);
MS (FAB) m / z: 562 (M + H) ^<+> .

(35c) (1R, 5S, 6S) -2- [1- (Tetrahydropyran-4-thiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- obtained in Example 35 (35b) instead of the compound obtained in Example 31 (31b) [1- (Tetrahydropyran-4-thiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (970 mg , 1.73 mmol) was used in the same manner as in Example 31 (31c), to obtain the target compound as a pale yellow amorphous title compound (490 mg, yield 63%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.90-4.83 (1H, m), 4.66-4.59 (1H, m), 4.40-4.31 (1H, m), 4.29-4.20 (3H, m), 4.15- 4.10 (1H, m), 4.06-4.01 (2H, m), 3.60-3.53 (2H, m), 3.46-3.43 (1H, m), 3.29-3.22 (1H, m), 2.97-2.88 (1H, m ), 1.95-1.82 (2H, m), 1.68-1.58 (2H, m), 1.30 (3H, d, J = 6.4 Hz), 1.21 (1.5H, d, J = 7.3 Hz), 1.20 (1.5H, d, J = 7.3 Hz);
IR (KBr): 1749, 1502, 1455, 1394, 1292, 1262, 1239 cm ^-1 ;
MS (FAB) m / z: 449 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₉ H ₂₆ N ₂ O ₅ S ₂ Na (M + H) ⁺ : 449.11808. Found 449.11732;
Anal.calcd.for C ₁₉ H ₂₅ N ₂ O ₅ S ₂ Na ・ H ₂ O: C, 48.91%; H, 5.83%; N, 6.00%; S, 13.75%, Found C, 48.63%; H, 6.04 %; N, 6.00%; S, 13.72%.

Example 36 (1R, 5S, 6S) -2- [1- (Pyridin-3-ylthiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 70)
(36a) 3-acetylthio-1- (pyridin-3-ylthiocarbonyl) azetidine 3-acetylthio-1- () obtained in Example 20 (20a) instead of the compound obtained in Example 7 (7b) The title compound (826 mg, yield 56%) was obtained as a pale yellow oil in the same manner as in Example 32 (32a) except that pyridin-3-ylcarbonyl) azetidine (1.39 g, 5.88 mmol) was used. .
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.76-8.73 (1H, m), 8.65-8.62 (1H, m), 7.95-7.91 (1H, m), 7.33 (1H, dd, J = 7.8, 5.1 Hz ), 4.86-4.74 (2H, m), 4.36-4.25 (2H, m), 4.20-4.14 (1H, m), 2.37 (3H, s);
MS (FAB) m / z: 253 (M + H) ^<+> .

(36b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-3-ylthiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyridine-3-yl) obtained in Example 36 (36a) instead of the compound obtained in Example 32 (32b) A yellow amorphous title compound (1.66 g, yield 92%) was obtained in the same manner as in Example 32 (32c) except that (Luthiocarbonyl) azetidine (820 mg, 3.25 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.74-8.71 (1H, m), 8.67-8.63 (1H, m), 8.25-8.21 (2H, m), 7.96-7.92 (1H, m), 7.67-7.64 (2H, m), 7.37-7.32 (1H, m), 5.51 (0.5H, d, J = 13.7 Hz), 5.50 (0.5H, d, J = 13.7 Hz), 5.26 (0.5H, d, J = 13.7 Hz), 5.24 (0.5H, d, J = 13.7 Hz), 4.87-4.80 (1H, m), 4.72-4.67 (1H, m), 4.40-4.33 (1H, m), 4.31-4.15 (4H, m), 3.31-3.27 (1H, m), 3.23-3.16 (0.5H, m), 3.16-3.08 (0.5H, m), 1.66 (1H, br s), 1.38 (1.5H, d, J = 6.3 Hz), 1.35 (1.5H, d, J = 6.3 Hz), 1.29-1.24 (3H, m);
IR (KBr): 3394, 2969, 1770, 1708, 1520, 1495, 1451, 1343, 1279, 1209, 1140 cm ^-1 ;
MS (FAB) m / z: 555 (M + H) ^<+> .

(36c) (1R, 5S, 6S) -2- [1- (Pyridin-3-ylthiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- obtained in Example 36 (36b) instead of the compound obtained in Example 31 (31b) [1- (Pyridin-3-ylthiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.00 g , 1.80 mmol) was used in the same manner as in Example 31 (31c), to obtain the target compound as a yellow amorphous title compound (494 mg, yield 62%).
¹ H NMR (D ₂ O, 500 MHz): δ 8.72-8.69 (1H, m), 8.63-8.60 (1H, m), 8.03-7.99 (1H, m), 7.56-7.51 (1H, m), 4.88- 4.76 (2H, m), 4.38-4.14 (5H, m), 3.45-3.41 (1H, m), 3.31-3.24 (0.5H, m), 3.21-3.14 (0.5H, m), 1.30 (1.5H, d, J = 7.3 Hz), 1.29 (1.5H, d, J = 7.3 Hz), 1.20 (1.5H, d, J = 7.3 Hz), 1.17 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3397, 2966, 1749, 1600, 1497, 1451, 1396, 1279 cm ^-1 ;
MS (FAB) m / z: 464 (M + Na) ^<+> , 442 (M + H) ^<+> .

Example 37 (1R, 5S, 6S) -2- (1-Dimethylcarbamoylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt (salt of compound No. 33)
(37a) 3-acetylthio-1-dimethylcarbamoylazetidine 3-acetylthioazetidine hydrochloride (724 mg, 4.32 mmol) obtained in Example 1 (1c) was dissolved in methylene chloride (30 mL). To the solution, add N, N-dimethylcarbamoyl chloride (478 μL, 5.19 mmol) and triethylamine (1.46 mL, 10.4 mmol) under nitrogen and ice cooling, gradually warm to room temperature, and leave it overnight. did. After confirmation of completion of the reaction, methylene chloride was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-5 / 1, V / V) to give the title compound as a colorless oil. (737 mg, 84% yield) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.39 (2H, t, J = 8.6 Hz), 4.23-4.16 (1H, m), 3.86 (2H, dd, J = 8.6, 5.9 Hz), 2.84 (6H, s), 2.33 (3H, s);
MS (FAB) m / z: 203 (M + H) ^<+> .

(37b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-dimethylcarbamoylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylate 3-acetylthio-1-dimethylcarbamoylazetidine (730 mg, 3.61 mmol) obtained in Example 37 (37a) was used instead of the compound obtained in Example 1 (1d). A pale yellow amorphous title compound (1.54 g, yield 85%) was obtained in the same manner as in Example 1 (1e) except that it was used.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.39-4.34 (2H, m), 4.30-4.22 (2H, m), 4.07-4.00 (1H, m), 3.96-3.90 (2H, m), 3.27 (1H , dd, J = 7.0, 2.4 Hz), 3.17 (1H, dq, J = 7.4, 7.0 Hz), 2.84 (6H, s), 1.37 (3H, d, J = 6.3 Hz), 1.24 (3H, d, J = 7.0 Hz);
MS (FAB) m / z: 505 (M + H) ^<+> .

(37c) (1R, 5S, 6S) -2- (1-Dimethylcarbamoylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-dimethylcarbamoylazeti) obtained in Example 37 (37b) instead of the compound obtained in Example 1 (1e) Example 1 except that din-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (1.54 g, 2.08 mmol) was used. In the same manner as in (1f), the target compound was obtained as a pale yellow amorphous title compound (852 mg, yield 71%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.47 (1H, t, J = 8.4 Hz), 4.45 (1H, t, J = 8.4 Hz), 4.24 (1H, dq, J = 6.4, 6.2 Hz), 4.19 (1H, dd, J = 9.0, 2.6 Hz), 4.14-4.07 (1H, m), 3.94 (1H, t, J = 4.6 Hz), 3.92 (1H, t, J = 4.6 Hz), 3.42 (1H , dd, J = 6.2, 2.6 Hz), 3.21 (1H, dq, J = 9.0, 7.3 Hz), 2.86 (6H, s), 1.30 (3H, d, J = 6.4 Hz), 1.18 (3H, d, J = 7.3 Hz);
IR (KBr): 1749, 1607, 1504, 1455, 1396, 1286 cm ^-1 ;
MS (FAB) m / z: 392 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₆ H ₂₃ N ₃ O ₅ SNa (M + H) ⁺ : 392.12561. Found 392.12647;
Anal.calcd.for C ₁₆ H ₂₂ N ₃ O ₅ SNa ・ H ₂ O: C, 46.94%; H, 5.91%; N, 10.26%; S, 7.83%, Found C, 47.23%; H, 5.99%; N, 10.31%; S, 7.87%.

Example 38 (1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 35)
(38a) 3-Acetylthio-1- (1-azetidinocarbonyl) azetidine Azetidine (197 mg, 3.46 mmol) and diisopropylethylamine (693 μL, 3.98 mmol) were dissolved in methylene chloride (45 mL). Under an atmosphere, it was added dropwise over 3 hours to a solution of triphosgene (359 mg, 1.21 mmol) in methylene chloride (15 mL) at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature with a solution of 3-acetylthioazetidine hydrochloride (3.46 mmol) obtained in Example 1 (1c) in methylene chloride (5 mL) and diisopropylethylamine (1.27 mL, 7.27 mmol). And stirred overnight. After confirmation of completion of the reaction, methylene chloride was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3 / 1-1 / 0, V / V) to give the title compound as a colorless oil. (582 mg, 79% yield) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.34 (2H, t, J = 8.4 Hz), 4.23-4.15 (1H, m), 3.93 (4H, t, J = 7.6 Hz), 3.81 (2H, dd, J = 9.2, 5.7 Hz), 2.32 (3H, s), 2.30-2.20 (2H, m);
MS (FAB) m / z: 214 (M) ^<+> .

(38b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (1-azetidinocarbonyl) azetidine obtained in Example 38 (38a) instead of the compound obtained in Example 7 (7b) A pale yellow amorphous title compound (1.83 g, yield 80%) was obtained in the same manner as in Example 7 (7c) except that (956 mg, 4.46 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.25-8.21 (2H, m), 7.68-7.65 (2H, m), 5.50 (1H, d, J = 13.7 Hz), 5.23 (1H, d, J = 13.7 Hz), 4.33 (1H, t, J = 8.2 Hz), 4.32 (1H, t, J = 8.2 Hz), 4.28-4.21 (2H, m), 4.08-4.01 (1H, m), 3.95 (4H, t , J = 7.6 Hz), 3.89 (1H, dd, J = 8.2, 5.0 Hz), 3.88 (1H, dd, J = 8.2, 5.0 Hz), 3.26 (1H, dd, J = 7.0, 2.7 Hz), 3.19 -3.11 (1H, m), 2.26 (2H, qn, J = 7.6 Hz), 2.13 (1H, br s), 1.36 (3H, d, J = 6.3 Hz), 1.23 (3H, d, J = 7.4 Hz );
MS (FAB) m / z: 539 (M + Na) ^<+> , 517 (M + H) ^<+> .

(38c) (1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [1 obtained in Example 38 (38b) instead of the compound obtained in Example 8 (8b) -(1-Azetidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (2.28 g, 4.41 mmol) A pale yellow amorphous title compound (1.54 g, yield 87%) as the target compound was obtained in the same manner as in Example 8 (8c) except that was used.
¹ H NMR (D ₂ O, 500 MHz): δ 4.44 (1H, t, J = 8.8 Hz), 4.42 (1H, t, J = 8.8 Hz), 4.24 (1H, dq, J = 6.4, 6.4 Hz), 4.18 (1H, dd, J = 9.3, 2.4 Hz), 4.16-4.10 (1H, m), 3.89 (2H, dd, J = 8.8, 4.9 Hz), 3.42 (1H, dd, J = 6.4, 2.4 Hz) , 3.23-3.16 (1H, m), 2.27 (2H, tt, J = 7.8, 7.8 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.17 (3H, d, J = 7.3 Hz);
IR (KBr): 3379, 2966, 1749, 1604, 1434, 1398, 1296 cm ^-1 ;
MS (FAB) m / z: 426 (M + Na) ^<+> , 404 (M + H) ^<+> .

Example 39 1- (Isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (ester of compound No. 35)
(1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] obtained in Example 38 (38c) -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (999 mg, 2.48 mmol) was dissolved in dimethylacetamide (35 mL), and this solution was dissolved in 1- Iodoethyl-isopropyl carbonate (1.28 g, 4.96 mmol) was added and stirred for 2 hours. After completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, 5% aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate, then ethyl acetate / methanol = 85/15, V / V) to obtain the pale yellow amorphous compound as the target compound. The title compound (999 mg, 79% yield) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 6.91-6.86 (1H, m), 4.96-4.87 (1H, m), 4.34-4.29 (2H, m), 4.25-4.17 (2H, m), 4.07-4.00 (1H, m), 3.96 (2H, t, J = 7.8 Hz), 3.95 (2H, t, J = 7.8 Hz), 3.91-3.85 (2H, m), 3.22 (1H, dd, J = 6.8, 2.4 Hz), 3.16-3.09 (1H, m), 2.29-2.23 (2H, m), 2.02-1.99 (1H, m), 1.61 (1.5H, d, J = 5.4 Hz), 1.59 (1.5H, d, J = 5.4 Hz), 1.36-1.33 (3H, m), 1.33 (1.5H, d, J = 5.9 Hz), 1.32-1.30 (1.5H, m), 1.30 (3H, d, J = 6.4 Hz), 1.214 (1.5H, d, J = 7.3 Hz), 1.207 (1.5H, d, J = 7.3 Hz);
IR (KBr): 3382, 2973, 1763, 1626, 1432, 1375, 1271, 1073 cm ^-1 ;
MS (ESI) m / z: 550 (M + K) ⁺ , 534 (M + Na) ⁺ , 512 (M + H) ⁺ ;
HRMS (ESI) m / z: . Calcd for C 23 H 34 N 3 O 8 S (M + H) +:. 512.20666 Found 512.20763.

Example 40 (1R, 5S, 6S) -2- [1- (Pyrrolidin-1-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 37)
(40a) 3-Acetylthio-1- (pyrrolidin-1-ylcarbonyl) azetidine 3-Acetylthioazetidine hydrochloride (3.00 mmol) obtained in Example 7 (7a) was dissolved in methylene chloride (20 mL). To this solution, 1-pyrrolidinecarbonyl chloride (500 μL, 4.50 mmol) and N, N-diisopropylethylamine (2.10 mL, 12.0 mmol) were added at room temperature under a nitrogen atmosphere and stirred for 1 hour. After confirming the completion of the reaction, an aqueous potassium hydrogen sulfate solution was added to the reaction solution, extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1-1: 9, V / V) to give the title compound as a white solid ( 427 mg, yield 62%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.40 (2H, t, J = 8.4 Hz), 4.20 (1H, tt, J = 8.4, 5.8 Hz), 3.86 (2H, dd, J = 8.4, 5.8 Hz) , 3.33-3.28 (4H, m), 2.33 (3H, s), 1.85-1.81 (4H, m);
IR (KBr): 2949, 2875, 1686, 1620, 1432 cm ^-1 ;
MS (FAB) m / z: 228 (M) ^<+> .

(40b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyrrolidin-1-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyrrolidin-1-ylcarbonyl) obtained in Example 40 (40a) instead of the compound obtained in Example 7 (7b) ) A pale yellow amorphous title compound (847 mg, yield 87%) was obtained in the same manner as in Example 7 (7c) except that azetidine (420 mg, 1.84 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.23 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.37 (1H, t, J = 8.2 Hz), 4.36 (1H, t, J = 8.2 Hz), 4.29-4.22 (2H, m), 4.07-4.00 (1H, m) , 3.94 (1H, dd, J = 8.2, 5.5 Hz), 3.92 (1H, dd, J = 8.2, 5.5 Hz), 3.34-3.25 (5H, m), 3.22-3.14 (1H, m), 1.87-1.83 (4H, m), 1.77 (1H, bs), 1.37 (3H, d, J = 6.3 Hz), 1.24 (3H, d, J = 7.0 Hz);
MS (FAB) m / z: 531 (M + H) ^<+> .

(40c) (1R, 5S, 6S) -2- [1- (Pyrrolidin-1-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 40 (40b) instead of the compound obtained in Example 8 (8b) 1- (Pyrrolidin-1-ylcarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (840 mg, 1.59 The target compound was a white amorphous title compound (532 mg, yield 80%) in the same manner as in Example 8 (8c) except that mmol) was used.
¹ H NMR (D ₂ O, 500 MHz): δ 4.50-4.44 (2H, m), 4.25 (1H, dq, J = 6.4, 6.4 Hz), 4.21-4.18 (1H, m), 4.14-4.08 (1H, m), 3.96-3.91 (2H, m), 3.44-3.41 (1H, m), 3.35-3.30 (4H, m), 3.26-3.19 (1H, m) 1.88-1.84 (4H, m), 1.30 (3H , d, J = 6.4 Hz), 1.18 (3H, d, J = 7.3 Hz);
IR (KBr): 3409, 2968, 2874, 1749, 1602, 1438, 1398 cm ^-1 ;
MS (FAB) m / z: 440 (M + Na) ⁺ , 418 (M + H) ⁺ ;
Anal.calcd.for C ₁₈ H ₂₄ N ₃ O ₅ SNa3 / 2H ₂ O: C, 48.64%; H, 6.12%; N, 9.45%; S, 7.21%; Na, 5.17%, Found C, 48.84 %; H, 5.95%; N, 9.44%; S, 7.06%; Na, 5.35%.

Example 41 (1R, 5S, 6S) -2- (1-morpholinocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt (salt of compound No. 39)
(41a) 3-Acetylthio-1-morpholinocarbonylazetidine In the same manner as in Example 37 (37a) except that 4-morpholinocarbonyl chloride (606 μL, 5.19 mmol) was used instead of N, N-dimethylcarbamoyl chloride. A colorless oily title compound (947 mg, yield 90%) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 4.41 (2H, t, J = 8.8 Hz), 4.25-4.17 (1H, m), 3.88 (2H, dd, J = 8.8, 5.9 Hz), 3.64 (4H, t, J = 4.9 Hz), 3.31 (2H, t, J = 4.9 Hz), 2.33 (3H, s);
MS (FAB) m / z: 245 (M + H) ^<+> .

(41b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-morpholinocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylate 3-Acetylthio-1-morpholinocarbonylazetidine (514 mg, 2.10 mmol) obtained in Example 41 (41a) was dissolved in dimethylformamide (40 mL). Hydrazine acetate (232 mg, 2.52 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. After confirmation of completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution at −20 ° C. in a nitrogen atmosphere. A solution of 1-methyl-carbapene-2-em-3-carboxylate (1.50 g, 2.52 mmol) in acetonitrile (50 mL) was added dropwise, followed by addition of diisopropylethylamine (1.46 mL, 8.40 mmol), Left overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, saturated aqueous sodium bicarbonate, aqueous potassium hydrogen sulfate, aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2 / 1-1 / 0, then ethyl acetate / methanol = 1 / 0-15 / 1, V / V) to obtain the pale yellow amorphous title compound (0.97 g, yield 84%).
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.3 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.42-4.35 (2H, m), 4.29-4.24 (1H, m), 4.24 (1H, dd, J = 9.3, 2.4 Hz), 4.09-4.02 (1H, m), 3.97-3.91 (2H, m), 3.65 (4H, t, J = 4.9 Hz), 3.31 (4H, t, J = 4.9 Hz), 3.27 (1H, dd, J = 7.1, 2.7 Hz), 3.16 (1H , dq, J = 8.8, 7.3 Hz), 1.37 (3H, d, J = 6.4 Hz), 1.24 (3H, d, J = 7.3 Hz);
MS (FAB) m / z: 547 (M + H) ^<+> .

(41c) (1R, 5S, 6S) -2- (1-morpholinocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-morpholinocarbonylazetidin-3-yl) thio-6-[(R) obtained in Example 41 (41b) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (0.97 g, 1.77 mmol) was dissolved in a mixed solvent of tetrahydrofuran (60 mL) and distilled water (50 mL). 10% palladium carbon (0.97 g) was added, and catalytic hydrogen reduction was performed at room temperature for 1.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and sodium bicarbonate (149 mg), diethyl ether and distilled water were added to the filtrate to carry out a liquid separation operation. The obtained aqueous layer was concentrated under reduced pressure, and reverse phase chromatography using Chromatorex-ODS DM1020TT (manufactured by Fuji Silysia Co., Ltd.) (elution solvent: distilled water / acetonitrile = 100 / 0-96 / 4, V / V) The product was purified by lyophilization and freeze-dried to obtain the target compound as a pale yellow amorphous title compound (0.61 g, yield 79%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.53-4.45 (2H, m), 4.25 (1H, dq, J = 6.3, 6.3 Hz), 4.19 (1H, dd, J = 9.3, 2.5 Hz), 4.18 -4.10 (1H., M), 3.98-3.94 (2H, m), 3.71 (4H, t, J = 4.4 Hz), 3.42 (1H, dd, J = 6.3, 2.9 Hz), 3.38 (4H, t, J = 4.4 Hz), 3.24-3.17 (1H, m), 1.30 (3H, d, J = 6.3 Hz), 1.18 (3H, d, J = 7.3 Hz);
IR (KBr): 1750, 1604, 1459, 1428, 1397, 1305, 1288 cm ^-1 ;
MS (FAB) m / z: 434 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₈ H ₂₄ N ₃ O ₆ SNa ₂ (M + Na) ⁺ : 456.1181. Found 456.1187;
Anal.calcd.for C ₁₈ H ₂₄ N ₃ O ₆ SNa ・ H ₂ O: C, 47.89%; H, 5.80%; N, 9.31%; S, 7.10%; Na, 5.09%, Found C, 47.73%; H, 6.03%; N, 9.26%; S6.92%; Na, 5.26.

Example 42 (1R, 5S, 6S) -2- [1- (3-thiazolidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 38)
(42a) 3-acetylthio-1- (3-thiazolidinocarbonyl) azetidine In the same manner as in Example 38 (38a) except that thiazolidine (477 μL, 6.05 mmol) was used instead of azetidine, a colorless oily substance was used. Of the title compound (1.24 g, 84% yield).
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 4.41 (2H, t, J = 8.6 Hz), 4.41 (2H, s), 4.27-4.20 (1H, m), 3.90 (2H, dd, J = 9.2 , 5.7 Hz), 3.64 (2H, t, J = 6.3 Hz), 2.96 (2H, t, J = 6.3 Hz), 2.34 (3H, s);
MS (EI) m / z: 246 (M) ^<+> .

(42b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (3-thiazolidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (3-thiazolidinocarbonyl obtained in Example 42 (42a) instead of the compound obtained in Example 1 (1d) ) A pale yellow amorphous title compound (1.00 g, yield 91%) was obtained in the same manner as in Example 1 (1e) except that azetidine (500 mg, 2.03 mmol) was used.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.24 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 5.52 (1H, d, J = 13.7 Hz), 5.26 (1H, d, J = 13.7 Hz), 4.45-4.38 (4H, m), 4.31-4.24 (2H, m), 4.12-4.04 (1H, m), 4.01-3.95 (2H, m), 3.65 (2H , t, J = 6.3 Hz), 3.28 (1H, dd, J = 6.5, 2.0 Hz), 3.17 (1H, dq, J = 7.4, 8.2 Hz), 2.98 (2H, t, J = 6.3 Hz), 1.38 (3H, d, J = 6.3 Hz), 1.26 (3H, d, J = 7.4 Hz);
MS (FAB) m / z: 549 (M + H) ^<+> .

(42c) (1R, 5S, 6S) -2- [1- (3-Thiazolidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 42 (42b) instead of the compound obtained in Example 1 (1e) 1- (3-Thiazolidinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.00 g, 1.84 The target compound was a pale yellow amorphous title compound (538 mg, yield 67%) in the same manner as in Example 1 (1f) except that mmol) was used.
¹ H NMR (D ₂ O, 400 MHz): δ 4.52 (1H, t, J = 8.4 Hz), 4.50 (1H, t, J = 8.4 Hz), 4.45 (2H, s), 4.25 (1H, dq, J = 6.4, 6.2 Hz), 4.19 (1H, dd, J = 9.0, 2.6 Hz), 4.17-4.11 (1H, m), 4.00-3.96 (2H, m), 3.65 (2H, t, J = 6.4 Hz) , 3.43 (1H, dd, J = 6.2, 2.6 Hz), 3.22 (1H, dq, J = 9.0, 7.1 Hz), 3.05 (2H, t, J = 6.4 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.18 (3H, d, J = 7.1 Hz);
IR (KBr): 1750, 1604, 1398, 1296, 1269 cm ^-1 ;
MS (FAB) m / z: 436 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₇ H ₂₃ N ₃ O ₅ S ₂ Na (M + H) ⁺ : 436.09768. Found 436.09711;
Anal.calcd.for C ₁₇ H ₂₂ N ₃ O ₅ S ₂ Na ・ 2H ₂ O: C, 43.30%; H, 5.56%; N, 8.91%; S, 13.60%, Found C, 43.50%; H, 5.43 %; N, 9.03%; S, 13.49%.

Example 43 (1R, 5S, 6S) -2- [1- (4-Acetylpiperazinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 40)
(43a) 3-acetylthio-1- (4-acetylpiperazinocarbonyl) azetidine 4-acetylpiperazine (609 mg, 4.76 mmol) and diisopropylethylamine (954 μL, 5.47 mmol) are dissolved in methylene chloride (100 mL), and nitrogen is added. Under an atmosphere, this solution was added dropwise to a solution of triphosgene (495 mg, 1.67 mmol) in methylene chloride (50 mL) at room temperature over 2.5 hours. After completion of the dropwise addition, a solution of 3-acetylthioazetidine hydrochloride (4.32 mmol) obtained in Example 1 (1c) in methylene chloride (10 mL) and diisopropylethylamine (3.0 mL, 17.3 mmol) were added to the reaction solution. , Stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the solution was washed successively with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 3-4 / 1, V / V) to give the title compound as a white solid. (0.49 g, 40% yield) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 4.42 (2H, t, J = 8.8 Hz), 4.26-4.18 (1H, m), 3.89 (2H, dd, J = 8.8, 5.9 Hz), 3.62-3.55 ( 2H, m), 3.47-3.41 (2H, m), 3.40-3.34 (2H, m), 3.30-3.23 (2H, m), 2.34 (3H, s), 2.11 (3H, s);
MS (FAB) m / z: 286 (M + H) ^<+> .

(43b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-acetylpiperazinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-acetylpiperazinocarbonyl) azetidine (0.49 g, 1.72 mmol) obtained in Example 43 (43a) was converted to dimethylformamide. (20 mL) was dissolved, and hydrazine acetate (190 mg, 2.06 mmol) was added to the solution at room temperature under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. After confirmation of completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution at −20 ° C. in a nitrogen atmosphere. A solution of 1-methyl-carbapene-2-em-3-carboxylate (1.22 g, 2.06 mmol) in acetonitrile (25 mL) was added dropwise, followed by addition of diisopropylethylamine (1.2 mL, 6.88 mmol), Left overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 0-4 / 1, V / V) to give the title compound as a pale yellow amorphous compound ( 1.01 g, yield 100%) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.23 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H , d, J = 13.7 Hz), 4.43-4.35 (2H, m), 4.30-4.22 (2H, m), 4.10-4.03 (1H, m), 3.98-3.92 (2H, m), 3.62-3.56 (2H , m), 3.48-3.42 (2H, m), 3.38 (2H, dd, J = 6.6, 3.7 Hz), 3.30-3.23 (3H, m), 3.16 (1H, dq, J = 9.3, 7.3 Hz), 2.11 (3H, s), 1.37 (3H, d, J = 6.4 Hz), 1.25 (3H, d, J = 7.3 Hz);
MS (FAB) m / z: 588 (M + H) ^<+> .

(43c) (1R, 5S, 6S) -2- [1- (4-acetylpiperazinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- obtained in Example 43 (43b) instead of the compound obtained in Example 41 (41b) [1- (4-acetylpiperazinocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.01 g , 1.72 mmol) was used in the same manner as in Example 41 (41c), to obtain the target compound as a pale yellow amorphous title compound (0.58 g, yield 71%).
¹ H NMR (D ₂ O, 500 MHz): δ 4.57-4.43 (2H, m), 4.29-4.08 (3H, m), 4.02-3.90 (2H, m), 3.69-3.31 (9H, m), 3.27- 3.15 (1H., M), 2.15 (3H, s), 1.33-1.26 (3H, m), 1.22-1.15 (3H, m);
IR (KBr): 1749, 1617, 1429, 1295, 1260 cm ^-1 ;
MS (ESI) m / z: 475 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd. For C ₂₀ H ₂₈ N ₄ O ₆ SNa (M + H) ⁺ : 475.16272. Found 476.16425.

Example 44 (1R, 5S, 6S) -2- (1-pyrazolinocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid sodium salt (salt of compound No. 41)
(44a) 3-Acetylthio-1-pyrazolinocarbonylazetidine A colorless oily product in the same manner as in Example 43 (43a) except that pyrazole (324 mg, 4.76 mmol) was used instead of 4-acetylpiperazine. Of the title compound (0.95 g, yield 98%) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.24-8.20 (1H, m), 7.62 (1H, s), 6.35 (1H, s), 5.18-5.01 (1H, m), 4.70-4.60 (1H, m ), 4.59-4.49 (1H, m), 4.35-4.24 (1H, m), 4.17-4.01 (1H, m), 2.36 (3H, s);
MS (EI) m / z: 225 (M) ^<+> .

(44b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-pyrazolinocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylate 3-acetylthio-1-pyrazolinocarbonylazetidine (379 mg, obtained in Example 44 (44a) instead of the compound obtained in Example 43 (43a) 1.68 mmol) was used in the same manner as in Example 43 (43b), to obtain the pale yellow amorphous title compound (0.81 g, yield 91%).
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.23 (2H, d, J = 8.8 Hz), 8.22 (1H, s), 7.66 (2H, d, J = 8.3 Hz), 7.63 (1H, s), 6.37 (1H, s), 5.50 (1H, d, J = 13.7 Hz), 5.26 (1H, d, J = 13.7 Hz), 5.13-4.99 (1H, m), 4.70-4.47 (2H, m), 4.32- 4.24 (2H, m), 4.21-4.09 (2H, m), 3.29 (1H, dd, J = 6.8, 2.4 Hz), 3.17 (1H, m), 1.38 (3H, d, J = 6.4 Hz), 1.28 (3H, d, J = 7.3 Hz);
MS (FAB) m / z: 528 (M + H) ^<+> .

(44c) (1R, 5S, 6S) -2- (1-Pyrazolinocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- Em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-pyrazole) obtained in Example 44 (44b) instead of the compound obtained in Example 41 (41b) Other than using zolinocarbonylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (0.81 g, 1.54 mmol) In the same manner as in Example 41 (41c), the target compound was obtained as a white amorphous title compound (520 mg, yield 82%).
¹ H NMR (D ₂ O, 500 MHz): δ 8.23 (1H, s), 7.81 (1H, s), 6.54 (1H, s), 5.17-4.95 (1H, m), 4.74-4.43 (2H, m) , 4.34-4.00 (4H, m), 3.47-3.40 (1H, m), 3.31-3.17 (1H, m), 1.31 (3H, d, J = 5.9 Hz), 1.20 (3H, d, J = 7.3 Hz );
IR (KBr): 1750, 1686, 1600, 1446, 1399 cm ^-1 ;
MS (FAB) m / z: 415 (M + H) ⁺ ;
HRMS (ESI) m / z: . Calcd for C 17 H 20 N 4 O 5 SNa (M + H) +:. 415.10521 Found 415.10482.

Example 45 (1R, 5S, 6S) -2- [1- (Pyridin-3-ylcarbamoyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 42)
(45a) N-benzhydryl-3-t-butyldiphenylsilyloxyazetidine N-benzhydryl-3-hydroxyazetidine (5.0 g, 20.9 mmol) was dissolved in dimethylformamide (100 mL), and this solution was dissolved in a nitrogen atmosphere. Under ice-cooling, t-butyldiphenylsilyl chloride (6.53 mL, 25.1 mmol) and imidazole (2.13 g, 31.3 mmol) were added and stirred for 4 hours. After confirming the completion of the reaction, methanol (5 mL) was added to the reaction solution under ice cooling, and the mixture was stirred for 30 minutes. Subsequently, ethyl acetate was added to the reaction solution, washed with 10% brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 98-10 / 90, V / V) to give the title compound as pale yellow crystals. (10.0 g, 100% yield) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 7.60-7.55 (4H, m), 7.43-7.31 (10H, m), 7.27-7.23 (4H, m), 7.19-7.14 (2H, m), 4.46-4.39 (1H, m), 4.36 (1H, s), 3.44 (2H, dd, J = 8.2, 5.9 Hz), 2.95 (2H, dd, J = 8.2, 6.3 Hz), 1.01 (9H, s);
MS (FAB) m / z: 478 (M + H) ^<+> .

(45b) 3-t-butyldiphenylsilyloxyazetidine N-benzhydryl-3-t-butyldiphenylsilyloxyazetidine (2.08 g, 4.35 mmol) obtained in Example 45 (45a) was added to tetrahydrofuran (10 mL). And 20% palladium hydroxide carbon (2.08 g) was added to this solution, and catalytic hydrogen reduction was performed at 50 ° C. for 7.5 hours. After confirming the completion of the reaction, the catalyst was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound.

(45c) 3-t-Butyldiphenylsilyloxy-1- (pyridin-3-ylcarbamoyl) azetidine 3-aminopyridine (471 mg, 5.00 mmol) and diisopropylethylamine (1.00 mL, 5.75 mmol) in methylene chloride (40 mL) This solution was added dropwise to a solution of triphosgene (519 mg, 1.75 mmol) in methylene chloride (16 mL) at room temperature under a nitrogen atmosphere over 1 hour. After completion of the dropwise addition, a solution of 3-t-butyldiphenylsilyloxyazetidine (5.00 mmol) and diisopropylethylamine (871 μL, 5.00 mmol) obtained in Example 45 (45b) in methylene chloride (5 mL) was added to the reaction solution. Was added and stirred for 2 hours. After confirmation of completion of the reaction, methylene chloride was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3 / 1-5 / 1, V / V) to give the title compound as a white amorphous product. (1.43 g, 67% yield) was obtained.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.36 (1H, d, J = 2.7 Hz), 8.23 (1H, dd, J = 4.7, 1.6 Hz), 8.07 (1H, ddd, J = 8.2, 2.7 , 1.6 Hz), 7.61-7.58 (4H, m), 7.46-7.36 (6H, m), 7.19 (1H, dd, J = 8.2, 4.7 Hz), 5.91 (1H, s), 4.63-4.59 (1H, m), 4.18-4.00 (4H, m), 1.07 (9H, s);
MS (FAB) m / z: 432 (M + H) ^<+> .

(45d) 3-Methanesulfonyloxy-1- (pyridin-3-ylcarbamoyl) azetidine 3-tert-butyldiphenylsilyloxy-1- (pyridin-3-ylcarbamoyl) azetidine obtained in Example 45 (45c) (1.43 g, 3.33 mmol) was dissolved in tetrahydrofuran (43 mL), and this solution was added to a tetra-n-butylammonium fluoride-tetrahydrofuran solution (1.0 mol / L, 4.00 mL, 4.00 mmol) was added and stirred overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride (43 mL), and methanesulfonyl chloride (906 μL, 11.7 mmol) and triethylamine (1.64 mL, 11.7 mmol) were added to this solution under a nitrogen atmosphere under ice cooling. Stir for 4 hours. After confirming the completion of the reaction, methanol (1 mL) was added to the reaction solution under ice cooling, and the mixture was stirred for 30 minutes. Subsequently, methylene chloride was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10 / 0-9 / 1, V / V) to give the title compound (713) mg, yield 79%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.60 (1H, d, J = 2.7 Hz), 8.27 (1H, dd, J = 4.7, 1.6 Hz), 8.07 (1H, ddd, J = 8.2, 2.7, 1.6 Hz), 7.23 (1H, dd, J = 8.2, 4.7 Hz), 6.25-6.10 (1H, bs), 5.32-5.25 (1H, m), 4.49 (2H, ddd, J = 9.8, 6.6, 1.2 Hz) , 4.29 (2H, ddd, J = 9.8, 4.3, 1.2Hz), 3.10 (3H, s);
MS (FAB) m / z: 272 (M + H) ^<+> .

(45e) 3-Acetylthio-1- (pyridin-3-ylcarbamoyl) azetidine 3-Methanesulfonyloxy-1- (pyridin-3-ylcarbamoyl) azetidine (710 mg, 2.62) obtained in Example 45 (45d) mmol) was dissolved in dimethylformamide (36 mL), potassium thioacetate (1.79 g, 15.7 mmol) was added to this solution at room temperature, and the mixture was stirred at 80 ° C. for 7.5 hours. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed with 10% brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-93 / 7, V / V) to give the title compound (334 mg, yield 51%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.44 (1H, d, J = 2.7 Hz), 8.28 (1H, dd, J = 4.7, 1.6 Hz), 8.03 (1H, ddd, J = 8.6, 2.7, 1.6 Hz), 7.24 (1H, dd, J = 8.6, 4.7 Hz), 6.22 (1H, s), 4.53 (2H, t, J = 9.0 Hz), 4.32-4.24 (1H, m), 3.99 (2H, dd , J = 9.0, 5.7 Hz), 2.36 (3H, s).

(45f) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-3-ylcarbamoyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (pyridin-3-ylcarbamoyl) obtained in Example 45 (45e) instead of the compound obtained in Example 1 (1d) ) A pale yellow amorphous title compound (343 mg, yield 47%) was obtained in the same manner as in Example 1 (1e) except that azetidine (330 mg, 1.31 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.51-8.48 (1H, m), 8.31-8.28 (1H, m), 8.23 (1H, d, J = 8.8 Hz), 8.09-8.06 (1H, m), 7.66 (1H, d, J = 8.8 Hz), 7.30-7.28 (1H, m), 6.35-6.25 (1H, bs), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.53-4.47 (2H, m), 4.30-4.24 (1H, m), 4.10-4.04 (3H, m), 3.29 (1H, dd, J = 6.8, 2.5 Hz), 3.18 (1H, dq , J = 9.4, 7.0 Hz), 1.38 (3H, d, J = 6.3 Hz), 1.27 (3H, d, J = 7.0 Hz);
MS (FAB) m / z: 554 (M + H) ^<+> .

(45 g) (1R, 5S, 6S) -2- [1- (Pyridin-3-ylcarbamoyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 45 (45f) instead of the compound obtained in Example 1 (1e) 1- (Pyridin-3-ylcarbamoyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (340 mg, 0.614 The target compound was a pale yellow amorphous title compound (150 mg, yield 55%) in the same manner as in Example 1 (1f) except that mmol) was used.
¹ H NMR (D ₂ O, 400 MHz): δ 8.48 (1H, d, J = 2.4 Hz), 8.27 (1H, dd, J = 4.9, 1.5 Hz), 7.82 (1H, ddd, J = 8.3, 2.4, 1.5 Hz), 7.43 (1H, dd, J = 8.3, 4.9 Hz), 4.57-4.51 (2H, m), 4.28-4.19 (1H, m), 4.23 (1H, dq J = 6.3, 6.3 Hz), 4.21 (1H, dd, J = 8.8, 2.4 Hz), 4.02 (2H, dd, J = 8.8, 4.9 Hz), 3.44 (1H, dd, J = 6.3, 2.5 Hz), 3.25 (1H, dq J = 8.8, 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.20 (3H, d, J = 7.3 Hz);
IR (KBr): 1749, 1665, 1598, 1540, 1423, 1385, 1283 cm ^-1 ;
MS (FAB) m / z: 441 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₉ H ₂₂ N ₄ O ₅ SNa (M + H) ⁺ : 441.1209. Found 441.1206;
Anal.calcd.for C ₁₉ H ₂₁ N ₄ O ₅ SNa ・ 2H ₂ O: C, 47.01%; H, 5.40%; N, 11.54%; S, 6.60%, Found C, 46.94%; H, 5.27%; N, 11.52%; S, 6.43%.

Example 46 (1R, 5S, 6S) -2- {1- [Methyl- (pyridin-3-yl) carbamoyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 44)
(46a) 3-acetylthio-1- [methyl- (pyridin-3-yl) carbamoyl] azetidine N-methyl-3-aminopyridine (467 mg, described in Synthesis 1974, 55-56 instead of 4-acetylpiperazine) The title compound (0.41 g, yield 36%) as a light brown oil was obtained in the same manner as in Example 43 (43a) except that 4.32 mmol) was used.
¹ H NMR (CDCl ₃ , 500 MHz): δ 8.52 (1H, d, J = 2.4 Hz), 8.46 (1H, d, J = 4.9 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.32 (1H , dd, J = 8.1, 4.6 Hz), 4.05-3.96 (3H, m), 3.3.56-3.49 (2H, m), 3.28 (3H, s), 2.27 (3H, s);
MS (FAB) m / z: 266 (M + H) ^<+> .

(46b) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [methyl- (pyridin-3-yl) carbamoyl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [methyl-] obtained in Example 46 (46a) instead of the compound obtained in Example 43 (43a) (Pyridin-3-yl) carbamoyl] azetidine (0.41 g, 1.55 mmol) was used in the same manner as in Example 43 (43b), except that pale yellow amorphous title compound (0.75 g, yield 86%) Got.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.50 (1H, d, J = 2.4 Hz), 8.45 (1H, dd, J = 4.70, 1.6 Hz), 8.20 (2H, d, J = 9.0 Hz), 7.62 (2H, d, J = 8.6 Hz), 7.56-7.51 (1H, m), 7.32 (1H, dd, J = 8.0, 4.1 Hz), 5.47 (1H, d, J = 13.7 Hz), 5.22 (1H, d, J = 13.7 Hz), 4.27-4.19 (1H, m), 4.16 (1H, dd, J = 9.0, 2.7 Hz), 3.99-3.89 (2H, m), 3.88-3.79 (1H, m), 3.58 (2H, dd, J = 8.0, 6.1 Hz), 3.27 (3H, s), 3.22 (1H, dd, J = 6.7, 2.7 Hz), 3.02 (1H, dq, J = 9.0, 7.4 Hz), 1.35 ( 3H, d, J = 6.3 Hz), 1.15 (3H, d, J = 7.4 Hz);
MS (FAB) m / z: 568 (M + H) ^<+> .

(46c) (1R, 5S, 6S) -2- {1- [Methyl- (pyridin-3-yl) carbamoyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) obtained in Example 46 (46b) instead of the compound obtained in Example 1 (1e) 2- {1- [Methyl- (pyridin-3-yl) carbamoyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3 -The pale yellow amorphous title compound (401 mg, 67% yield) as the target compound was obtained in the same manner as in Example 1 (1f) except that carboxylate (750 mg, 1.32 mmol) was used. .
¹ H NMR (D ₂ O, 400 MHz): δ 8.51 (1H, dd, J = 2.6, 0.7 Hz), 8.45 (1H, dd, J = 4.9, 1.5 Hz), 7.84 (1H, ddd, J = 8.2, 2.6, 1.5 Hz), 7.53 (1H, ddd, J = 8.2, 4.9, 0.7 Hz), 4.25-4.18 (1H, m), 4.12-4.04 (3H, m), 3.96-3.89 (1H, m), 3.56 (1H, dd, J = 9.2, 4.9 Hz), 3.49 (1H, dd, J = 8.7, 4.9 Hz), 3.37 (1H, dd, J = 6.4, 2.4 Hz), 3.26 (3H, s), 3.04 ( 1H, dq, J = 9.0, 7.3 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.09 (3H, d, J = 7.3 Hz);
IR (KBr): 1749, 1603, 1483, 1439, 1421, 1388, 1297, 1268 cm ^-1 ;
MS (FAB) m / z: 455 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₂₀ H ₂₄ N ₄ O ₅ SNa (M + H) ⁺ : 455.13651. Found 455.13568;
Anal.calcd.for C ₂₀ H ₂₃ N ₄ O ₅ SNa ・ 5 / 3H ₂ O: C, 49.58%; H, 5.48%; N, 11.56%; S, 6.62%, Found C, 46.75%; H, 5.57 %; N, 11.52%; S, 6.36%.

Example 47 (1R, 5S, 6S) -2- (1-Dimethylthiocarbamoylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3-carboxylic acid sodium salt (salt of compound No. 78)
(47a) 3-Acetylthio-1-dimethylthiocarbamoylazetidine 3-acetylthio-1-dimethylcarbamoylazetidine (860) obtained in Example 37 (37a) instead of the compound obtained in Example 1 (1d) mg, 4.25 mmol) was used in the same manner as in Example 31 (31a), except that the title compound (538 mg, yield 58%) was obtained as white crystals.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.62 (2H, t, J = 8.8 Hz), 4.18-4.11 (1H, m), 4.07 (2H, dd, J = 9.4, 5.9 Hz), 3.17 (6H, s), 2.34 (3H, s);
MS (EI) m / z: 218 (M) ^<+> .

(47b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-dimethylthiocarbamoylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-Em-3-carboxylate 3-acetylthio-1-dimethylthiocarbamoylazetidine (530 mg, 2.42 mmol) obtained in Example 47 (47a) instead of the compound obtained in Example 1 (1d) ) Was used in the same manner as in Example 1 (1e) to obtain a pale yellow amorphous title compound (1.02 g, yield 81%).
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.24 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.26 (1H, d, J = 13.7 Hz), 4.61 (2H, q, J = 9.0 Hz), 4.31-4.23 (2H, m), 4.17-4.10 (2H, m), 4.04-3.97 (1H, m), 3.28 (1H, dd, J = 6.9, 1.8 Hz), 3.22-2.93 (1H, m), 3.18 (6H, s), 1.37 (3H, d, J = 6.2 Hz), 1.25 (3H, d, J = 7.4 Hz);
MS (FAB) m / z: 521 (M + H) ^<+> .

(47c) (1R, 5S, 6S) -2- (1-Dimethylthiocarbamoylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-dimethylthio) obtained in Example 47 (47b) instead of the compound obtained in Example 31 (31b) Carried out except using carbamoylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.02 g, 1.96 mmol) In the same manner as in Example 31 (31c), the target compound was a pale yellow amorphous (1R, 5S, 6S) -2- (1-dimethylthiocarbamoylazetidin-3-yl) thio-6-[(R -1- Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (543 mg, yield 68%) was obtained.
¹ H NMR (D ₂ O, 400 MHz): δ 4.76-4.64 (2H, m), 4.25 (1H, dq, J = 6.4, 6.2 Hz), 4.19 (1H, dd, J = 9.2, 2.6 Hz), 4.18 -4.06 (3H, m), 3.43 (1H, dd, J = 6.2, 2.6 Hz), 3.23 (1H, dq, J = 9.2, 7.3 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.19 ( 3H, d, J = 7.3 Hz);
IR (KBr): 1750, 1600, 1516, 1395, 1349, 1295, 1252, 1158 cm ^-1 ;
MS (FAB) m / z: 408 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₆ H ₂₃ N ₃ O ₄ S ₂ Na (M + H) ⁺ : 408.10277. Found 408.10459;
Anal.calcd.for C ₁₆ H ₂₂ N ₃ O ₄ S ₂ Na ・ 4 / 3H ₂ O: C, 44.54%; H, 5.76%; N, 9.74%; S, 14.86%, Found C, 44.34%; H , 5.88%; N, 9.77%; S, 14.76%.

Example 48 (1R, 5S, 6S) -2- [1- (1-azetidinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 80)
(48a) 3-acetylthio-1- (1-azetidinothiocarbonyl) azetidine 3-acetylthio-1- (1) obtained in Example 38 (38a) instead of the compound obtained in Example 1 (1d) -Acetidinocarbonyl) azetidine (580 mg, 2.71 mmol) was used in the same manner as in Example 31 (31a) to give the title compound (347 mg, yield 56%) as white crystals.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.57 (2H, t, J = 9.0 Hz), 4.20-4.12 (5H, m), 4.02 (2H, dd, J = 10.0, 5.7 Hz), 2.34 (3H, s), 2.28-2.21 (2H, m);
MS (EI) m / z: 230 (M) ^<+> .

(48b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (1-azetidinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (1-azetidinothiocarbonyl) obtained in Example 48 (48a) instead of the compound obtained in Example 1 (1d) ) A pale yellow amorphous title compound (683 mg, yield 87%) was obtained in the same manner as in Example 1 (1e) except that azetidine (340 mg, 1.48 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.24 (2H, d, J = 8.4 Hz), 7.66 (2H, d, J = 8.4 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.26 (1H , d, J = 13.7 Hz), 4.55 (2H, t, J = 8.6 Hz), 4.30-4.22 (1H, m), 4.24 (1H, dd, J = 9.0, 2.4 Hz), 4.18 (4H, t, J = 7.8 Hz), 4.14-4.07 (2H, m), 4.06-3.98 (1H, m), 3.28 (1H, dd, J = 6.7, 2.4 Hz), 3.15 (1H, dq, J = 9.0, 7.4 Hz ), 2.31-2.23 (2H, m), 1.37 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.4 Hz);
MS (FAB) m / z: 533 (M + H) ^<+> .

(48c) (1R, 5S, 6S) -2- [1- (1-azetidinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [obtained in Example 48 (48b) instead of the compound obtained in Example 1 (1e) 1- (1-azetidinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (680 mg, 1.28 In the same manner as in Example 1 (1f) except that mmol) was used, the target compound was obtained as a pale yellow amorphous title compound (331 mg, yield 62%).
¹ H NMR (D ₂ O, 400 MHz): δ 4.65-4.57 (2H, m), 4.28-4.18 (6H, m), 4.16-4.08 (3H, m), 3.43 (1H, dd, J = 6.2, 2.6 Hz), 3.21 (1H, dq, J = 9.0, 7.3 Hz), 2.31-2.23 (2H, m), 1.30 (3H, d, J = 6.4 Hz), 1.18 (3H, d, J = 7.3 Hz);
IR (KBr): 1749, 1601, 1499, 1457, 1442, 1373, 1311, 1287, 1248 cm ^-1 ;
MS (FAB) m / z: 420 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₇ H ₂₃ N ₃ O ₄ S ₂ Na (M + H) ⁺ : 420.10277. Found 420.10421;
Anal.calcd.for C ₁₇ H ₂₂ N ₃ O ₄ S ₂ Na ・ 10 / 7H ₂ O: C, 45.86%; H, 5.63%; N, 9.44%; S, 14.40%, Found C, 45.72%; H N, 9.47%; S, 14.3%.

Example 49 1- (Isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [1- (1-azetidinothiocarbonyl) azetidin-3-yl] thio-6-[(R)- 1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (ester of compound No. 80)
(1R, 5S, 6S) -2- [1- (1-azetidinothiocarbonyl) azetidin-3-yl] thio-6- [] obtained in Example 48 instead of the compound obtained in Example 10 (R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (120 mg, 0.286 mmol) was used in the same manner as in Example 11 except that A white amorphous title compound (127 mg, 84% yield) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 6.89 (0.5H, q, J = 5.3 Hz), 6.88 (0.5H, q, J = 5.3 Hz), 4.96-4.87 (1H, m), 4.58-4.51 ( 2H, m), 4.27-4.16 (6H, m), 4.12-4.07 (2H, m), 4.05-3.97 (1H, m), 3.23 (1H, dd, J = 6.8, 2.4 Hz), 3.13 (1H, dq, J = 7.8, 7.3 Hz), 2.30-2.24 (2H, m), 1.61 (1.5H, d, J = 5.3 Hz), 1.58 (1.5H, d, J = 5.3 Hz), 1.36-1.29 (6H , m), 1.23 (1.5H, d, J = 7.3 Hz), 1.22 (1.5H, d, J = 7.3 Hz);
MS (FAB) m / z: 528 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd. For C ₂₃ H ₃₄ N ₃ O ₇ S ₂ (M + H) ⁺ : 528.18382. Found 528.18583.

Example 50 (1R, 5S, 6S) -2- [1- (4-morpholinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt (salt of compound No. 84)
(50a) 3-acetylthio-1- (4-morpholinothiocarbonyl) azetidine 3-acetylthio-1- (4-) obtained in Example 41 (41a) instead of the compound obtained in Example 1 (1d) A colorless oily title compound (643 mg, yield 64%) was obtained in the same manner as in Example 31 (31a) except that morpholinocarbonyl) azetidine (940 mg, 3.85 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.65 (2H, t, J = 9.0 Hz), 4.22-4.14 (1H, m), 4.09 (2H, dd, J = 9.8, 5.9 Hz), 3.70 (8H, s), 2.35 (3H, s);
MS (EI) m / z: 260 (M) ^<+> .

(50b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-morpholinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-morpholinothiocarbonyl) azetidine obtained in Example 50 (50a) instead of the compound obtained in Example 1 (1d) A pale yellow amorphous title compound (1.03 g, yield 75%) was obtained in the same manner as in Example 1 (1e) except that (640 mg, 2.46 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.21 (2H, d, J = 8.8 Hz), 7.64 (2H, d, J = 8.8 Hz), 5.49 (1H, d, J = 13.7 Hz), 5.24 (1H , d, J = 13.7 Hz), 4.64-4.57 (2H, m), 4.29-4.22 (2H, m), 4.13 (2H, dd, J = 9.3, 5.3 Hz), 4.06-3.99 (1H, m), 3.70 (8H, s), 3.27 (1H, dd, J = 7.0, 2.4 Hz), 3.15 (1H, dq, J = 7.4, 7.0 Hz), 1.37 (3H, d, J = 6.3 Hz), 1.25 (3H , d, J = 7.4 Hz);
MS (FAB) m / z: 563 (M + H) ^<+> .

(50c) (1R, 5S, 6S) -2- [1- (4-morpholinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [1 obtained in Example 50 (50b) instead of the compound obtained in Example 31 (31b) -(4-morpholinothiocarbonyl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.03 g, 1.83 mmol) A pale yellow amorphous title compound (537 mg, yield 65%) as the target compound was obtained in the same manner as in Example 31 (31c) except that was used.
¹ H NMR (D ₂ O, 400 MHz): δ 4.74-4.67 (2H, m), 4.25 (1H, dq, J = 6.4, 6.2 Hz), 4.22-4.10 (4H, m), 3.76 (8H, s) , 3.43 (1H, dd, J = 6.2, 2.6 Hz), 3.22 (1H, dq, J = 9.0, 7.3 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 7.3 Hz);
IR (KBr): 1749, 1598, 1429, 1394, 1374, 1349, 1298, 1275, 1237, 1112 cm ^-1 ;
MS (FAB) m / z: 450 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₈ H ₂₅ N ₃ O ₅ S ₂ Na (M + H) ⁺ : 450.11333. Found 450.11548;
Anal.calcd.for C ₁₈ H ₂₄ N ₃ O ₅ S ₂ Na ・ 5 / 3H ₂ O: C, 45.08%; H, 5.75%; N, 8.76%; S, 13.37%, Found C, 44.86%; H , 5.81%; N, 8.82%; S, 13.07%.

Example 51 (1R, 5S, 6S) -2- {1- [1- (3-cyano) azetidinocarbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt (salt of compound No. 36)
(51a) 3-Cyano-1- (t-butoxycarbonyl) azetidine 3-Methanesulfonyloxy-1- (t-butoxycarbonyl) azetidine (4.0 g, 15.9 mmol) obtained in Example 1 (1a) was dimethylated. Dissolved in formamide (60 mL), tetraethylammonium cyanide (6.22 g, 39.8 mmol) was added to this solution at room temperature, and the mixture was stirred at 100 ° C. for 11 hours. After confirmation of completion of the reaction, ethyl acetate was added to the reaction solution, washed with 10% brine, aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 5-1 / 3, V / V) to give the title compound as a colorless oil. (2.25 g, 78% yield) was obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 4.25-4.12 (4H, m), 3.39 (1H, tt, J = 9.0, 6.2 Hz), 1.45 (9H, s).
MS (EI) m / z: 182 (M) ^<+> .

(51b) 3-Cyanoazetidine hydrochloride 3-cyano-1- (t-butoxycarbonyl) azetidine (857 mg, 4.70 mmol) obtained in Example 51 (51a) instead of the compound obtained in Example 1 (1b) ) Was used in the same manner as in Example 1 (1c) except that a crude product of the title compound as a light brown solid was obtained.

(51c) 3-tert-butyldiphenylsilyloxy-1- [1- (3-cyano) azetidinocarbonyl] azetidine 3-tert-butyldiphenylsilyloxyazetidine (1.46 g, obtained in Example 45 (45b)) 4.69 mmol) and diisopropylethylamine (0.94 mL, 5.4 mmol) are dissolved in methylene chloride (100 mL), and this solution is added dropwise to a solution of triphosgene (488 mg, 1.65 mmol) in methylene chloride (50 mL) over 4 hours. did. After completion of the dropwise addition, a solution of 3-cyanoazetidine hydrochloride (4.70 mmol) obtained in Example 51 (51b) in methylene chloride (10 mL) and diisopropylethylamine (7.4 mL, 42.5 mmol) were added to the reaction solution for 1 hour. Stir. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. This solution was washed with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 3-3 / 1, V / V) to give the title compound as a colorless oil. (0.91 g, yield 46%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 7.59 (4H, d, J = 6.8 Hz), 7.45 (2H, t, J = 7.6 Hz), 7.39 (4H, t, J = 7.3 Hz), 4.59-4.53 (1H, m), 4.19-4.08 (4H, m), 3.98-3.84 (4H, m), 3.41 (1H, tt, J = 9.0, 6.1 Hz), 1.05 (9H, s);
MS (FAB) m / z: 420 (M + H) ^<+> .

(51d) 3-Hydroxy-1- [1- (3-cyano) azetidinocarbonyl] azetidine 3-t-butyldiphenylsilyloxy-1- [1- (3-cyano] obtained in Example 51 (51c) ) Azetidinocarbonyl] azetidine (0.91 g, 2.17 mmol) was dissolved in tetrahydrofuran (30 mL), and this solution was added to a tetra-n-butylammonium fluoride-tetrahydrofuran solution (1.0 mol) under nitrogen and ice cooling. / L, 2.28 mL, 2.28 mmol) was added and stirred for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 1 / 0-8 / 1, V / V) to obtain a white solid. 3-hydroxy-1- [1- (3-cyano) azetidinocarbonyl] azetidine (0.39 g, yield 100%) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.71-4.60 (1H, m), 4.27-4.06 (6H, m), 3.83 (2H, dd, J = 9.6, 4.5 Hz), 3.45 (1H, tt, J = 8.9, 6.5 Hz);
MS (FAB) m / z: 182 (M + H) ^<+> .

(51e) 3-Methanesulfonyloxy-1- [1- (3-cyano) azetidinocarbonyl] azetidine 3-Hydroxy-1- [1- (3-cyano) azetidino obtained in Example 51 (51d) Carbonyl] azetidine (0.39 g, 2.17 mmol) was dissolved in a mixed solvent of methylene chloride (25 mL) and pyridine (5 mL), and methanesulfonyl chloride (493 mg, 4.30 mmol) and triethylamine (605 μL, 4.30 mmol) were added and stirred for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. This solution was washed with saturated aqueous ammonium chloride, aqueous potassium hydrogen sulfate solution, aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methylene chloride / methanol = 15/5 / 0-15 / 5/1, V / V / V). The title compound (0.47 g, 84% yield) was obtained as a pale yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 5.28-5.20 (1H, m), 4.30 (2H, dd, J = 11.0, 6.6 Hz), 4.25-4.10 (4H, m), 4.12 (2H, dd, J = 10.3, 4.9 Hz), 3.48 (1H, tt, J = 9.0, 6.2 Hz), 3.08 (3H, s);
MS (FAB) m / z: 260 (M + H) ^<+> .

(51f) 3-Acetylthio-1- [1- (3-cyano) azetidinocarbonyl] azetidine 3-Methanesulfonyl obtained in Example 51 (51e) instead of the compound obtained in Example 45 (45d) A pale yellow amorphous title compound (0.38) was prepared in the same manner as in Example 45 (45e) except that oxy-1- [1- (3-cyano) azetidinocarbonyl] azetidine (0.47 g, 1.81 mmol) was used. g, yield 88%).
¹ H NMR (CDCl ₃ , 500 MHz): δ 4.38 (2H, t, J = 8.6 Hz), 4.27-4.12 (5H, m), 3.84 (2H, dd, J = 9.0, 5.6 Hz), 3.45 (1H, tt, J = 9.0, 6.4 Hz), 2.34 (3H, s).
MS (EI) m / z: 239 (M) ^<+> .

(51 g) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [1- (3-cyano) azetidinocarbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- [1-] obtained in Example 51 (51f) instead of the compound obtained in Example 41 (41a) (3-Cyano) azetidinocarbonyl] azetidine (0.38 g, 1.59 mmol) was used in the same manner as in Example 41 (41b), except that a pale yellow amorphous title compound (0.77 g, yield 90%) Got.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.21 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 9.0 Hz), 5.49 (1H, d, J = 13.7 Hz), 5.23 (1H , d, J = 13.7 Hz), 4.38-4.30 (2H, m), 4.29-4.03 (7H, m), 3.89 (2H, ddd, J = 8.8, 5.3, 5.1 Hz), 3.46 (1H, tt, J = 8.9, 6.2 Hz), 3.27 (1H, dd, J = 6.9, 2.5 Hz), 3.13 (1H, dq, J = 9.2, 7.2 Hz), 1.37 (3H, d, J = 6.3 Hz), 1.24 (3H , d, J = 7.4 Hz);
MS (FAB) m / z: 542 (M + H) ^<+> .

(51h) (1R, 5S, 6S) -2- {1- [1- (3-Cyano) azetidinocarbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) obtained in Example 51 (51 g) instead of the compound obtained in Example 41 (41b) 2- {1- [1- (3-Cyano) azetidinocarbonyl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3 A pale yellow amorphous title compound (0.44 g, yield 72%) as the target compound was obtained in the same manner as in Example 41 (41c) except that -carboxylate (0.77 g, 1.42 mmol) was used. .
¹ H NMR (D ₂ O, 500 MHz): δ 4.50-4.40 (2H, m), 4.36-4.11 (7H, m), 3.97-3.86 (2H, m), 3.78-3.67 (1H, m) 3.43 (1H , d, J = 2.4 Hz), 3.25-3.14 (1H, m), 1.30 (3H, d, J = 4.9 Hz), 1.17 (3H, d, J = 6.4 Hz);
IR (KBr): 2244, 1738, 1628, 1605, 1401, 1301 cm ^-1 ;
MS (ESI) m / z: 429 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd. For C ₁₈ H ₂₂ N ₄ O ₅ SNa (M + H) ⁺ : 429.12086. Found 429.12063.

Reference Example 1 (1R, 5S, 6S) -2- [1- (Pyridin-3-ylacetyl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt (1a) 4-Methanesulfonyloxy-1- (t-butoxycarbonyl) piperidine 4-hydroxypiperidine (5.0 g, 49.4 mmol) was dissolved in methanol (100 mL). Di-t-butyl-dicarbonate (11.9 g, 54.5 mmol) was added to this solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (200 mL) .To this solution, methanesulfonyl chloride (4.21 mL, 54.4 mmol) and triethylamine (7.62 mL, 54.4 mmol) were added under nitrogen cooling under ice cooling. The mixture was gradually warmed to room temperature, allowed to stand overnight, and further added with methanesulfonyl chloride (0.38 mL, 4.9 mmol) and triethylamine (3.4 mL, 4.9 mmol) under ice cooling. And stirred for 30 minutes. After confirming the completion of the reaction, the reaction solution was diluted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 3-1 / 1, V / V) to give the title compound ( 13.8 g, 100% yield).
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.89 (1H, tt, J = 7.8, 3.8 Hz), 3.78-3.65 (2H, m), 3.35-3.25 (2H, m), 3.04 (3H, s), 2.03-1.91 (2H, m), 1.88-1.75 (2H, m), 1.47 (9H, s);
MS (FAB) m / z: 280 (M + H) ^<+> .

(1b) 4-acetylthio-1- (t-butoxycarbonyl) piperidine 4-methanesulfonyloxy-1- (t-butoxycarbonyl) piperidine (13.8 g, 49.4 mmol) obtained in Reference Example 1 (1a) was acetonitrile. (440 ml), potassium thioacetate (16.9 g, 148 mmol) was added to the solution, and the mixture was heated to reflux for 8.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with ethyl acetate. This solution was washed with 5% brine and saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2 / 98-15 / 85, V / V) to give the title compound ( 8.97 g, yield 70%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 3.96-3.73 (2H, m), 3.61 (1H, tt, J = 10.2, 4.1 Hz), 3.06 (2H, ddd, J = 13.4, 10.3, 2.9 Hz), 2.32 (3H, s), 1.95-1.84 (2H, m), 1.62-1.47 (2H, m), 1.45 (9H, s);
MS (FAB) m / z: 260 (M + H) ^<+> .

(1c) 4-acetylthiopiperidine hydrochloride 4-acetylthio-1- (t-butoxycarbonyl) piperidine (778 mg) obtained in Reference Example 1 (1b) instead of the compound obtained in Example 1 (1b) , 3.0 mmol) was used in the same manner as in Example 1 (1c) to obtain a crude product of the title compound as a light brown solid.

(1d) 4-acetylthio-1-[(pyridin-3-yl) acetyl] piperidine 3-pyridylacetic acid hydrochloride (781 mg, 4.5 mmol) in a mixed solvent of tetrahydrofuran (10 mL) and dimethylformamide (10 mL) To this suspension, triethylamine (0.63 mL, 4.5 mmol) and 1,1′-carbonylbis-1H-imidazole (730 mg, 4.5 mmol) were sequentially added at room temperature under a nitrogen atmosphere, and the mixture was heated to 45 ° C. And stirred for 5.5 hours. The reaction mixture was ice-cooled, a solution of 4-acetylthiopiperidine hydrochloride (3.0 mmol) obtained in Reference Example 1 (1c) in methylene chloride (30 mL) was added, and the mixture was stirred for 1 hr. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain the title compound (591 mg, yield 70%) as a pale yellow oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.52 (1H, dd, J = 4.7, 1.6 Hz), 8.48 (1H, d, J = 2.0 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.27 (1H, dd, J = 7.8, 4.7 Hz), 4.28-4.17 (1H, m), 3.71 (2H, s), 3.79-3.69 (2H, m), 3.29 (1H, ddd, J = 13.7, 10.4, 2.9 Hz), 3.12 (1H, ddd, J = 13.4, 10.3, 3.3 Hz), 2.32 (3H, s), 1.93 (2H, ddd, J = 17.5, 9.3, 3.7 Hz), 1.61-1.49 (1H, m ), 1.49-1.36 (1H, m);
MS (EI) m / z: 278 (M) ^<+> .

(1e) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (pyridin-3-ylacetyl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapen-2-em-3-carboxylate 4-acetylthio-1- (pyridin-3-ylacetyl) piperidine (580 mg, 2.08 mmol) obtained in Example 1 (1d) was converted to dimethylformamide (17 mL). Hydrazine acetate (230 mg, 2.50 mmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapene-2-em-3-carboxylate (1.24 g, 2.08 mmol) in acetonitrile (37 mL) was added dropwise, followed by addition of diisopropylethylamine (1.45 mL, 8.32 mmol), Left overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine, aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-82.5 / 17.5, V / V) to obtain a pale yellow amorphous state. Of the title compound (486 mg, 40% yield).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.52 (1H, d, J = 4.3 Hz), 8.47 (1H, s), 8.22 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.31-7.26 (1H, m), 5.50 (1H, d, J = 13.7 Hz), 5.22 (1H, d, J = 13.7 Hz), 4.37 -4.16 (3H, m), 3.89-3.61 (2H, m), 3.72 (2H, s), 3.42-2.92 (4H, m), 2.15-1.81 (2H, m), 1.74-1.41 (2H, m) , 1.37 (3H, d, J = 6.3 Hz), 1.27 (3H, d, J = 7.4 Hz);
MS (FAB) m / z: 518 (M + H) ^<+> .

(1f) (1R, 5S, 6S) -2- [1- (Pyridin-3-ylacetyl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [1 obtained in Reference Example 1 (1e) instead of the compound obtained in Example 1 (1e) -(Pyridin-3-ylacetyl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (480 mg, 0.83 mmol) A white amorphous title compound (291 mg, yield 75%) was obtained in the same manner as in Example 1 (1f) except that was used.
¹ H NMR (D ₂ O, 500 MHz): δ 8.46 (1H, d, J = 4.9 Hz), 8.40 (1H, s), 7.73 (1H, d, J = 7.8 Hz), 7.48-7.42 (1H, m ), 4.30-4.15 (3H, m), 4.06-3.83 (4H, m), 3.49-3.29 (3H, m), 3.19-3.02 (1H, m), 2.10-1.96 (2H, m), 1.59-1.44 (2H, m), 1.30 (3H, d, J = 6.4 Hz), 1.21 (3H, d, J = 7.3 Hz);
IR (KBr): 3408, 2966, 1748, 1628, 1603, 1450, 1395 cm ^-1 ;
MS (FAB) m / z: 468 (M + H) ^<+> .

Reference Example 2 (1R, 5S, 6S) -2- (1-cyclopentanecarbonylpiperidin-4-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt (2a) 4-acetylthio-1-cyclopentanecarbonylpiperidine Obtained in Example 1 (1c) using cyclopentanecarboxylic acid (390 μL, 3.60 mmol) instead of pivalic acid. The title compound as a brown oil (705 mg) was prepared in the same manner as in Example 1 (1d) except that 4-acetylthiopiperidine hydrochloride (3.00 mmol) obtained in Reference Example 1 (1c) was used instead of the compound. Yield 92%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.33-4.18 (1H, m), 3.91-3.76 (1H, m), 3.74-3.63 (1H, m), 3.34-3.17 (1H, m), 3.14-2.97 (1H, m), 2.93-2.81 (1H, m), 2.33 (3H, s), 2.04-1.46 (12H, m);
MS (EI) m / z: 255 (M) ^<+> .

(2b) p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclopentanecarbonylpiperidin-4-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylate 4-acetylthio-1-cyclopentanecarbonylpiperidine (700 mg, 2.74 mmol) obtained in Reference Example 2 (2a) was used instead of the compound obtained in Example 1 (1d). A pale yellow amorphous title compound (500 mg, yield 33%) was obtained in the same manner as in Example 1 (1e) except that it was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.23 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.23 (1H , d, J = 13.7 Hz), 4.43-4.16 (3H, m), 3.98-3.85 (1H, m), 3.45-2.78 (6H, m), 2.07-1.44 (12H, m), 1.38 (3H, d , J = 6.3 Hz), 1.30 (3H, d, J = 7.4 Hz);
MS (FAB) m / z: 558 (M + H) ^<+> .

(2c) (1R, 5S, 6S) -2- (1-cyclopentanecarbonylpiperidin-4-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3-Carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- (1-cyclopentanecarbonyl) obtained in Reference Example 2 (2b) instead of the compound obtained in Example 1 (1e) Example 1 except that piperidin-4-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (500 mg, 0.90 mmol) was used. In the same manner as in (1f), a pale yellow amorphous (1R, 5S, 6S) -2- (1-cyclopentanecarbonylpiperidin-4-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt (282 mg, yield 71%) was obtained.
¹ H NMR (D ₂ O, 400 MHz): δ 4.29-4.20 (3H, m), 4.06-4.02 (1H, m), 3.49-3.27 (4H, m), 3.16-2.98 (2H, m), 2.10- 1.47 (12H, m), 1.30 (3H, d, J = 6.3 Hz), 1.22 (3H, d, J = 7.3 Hz);
IR (KBr): 3399, 2959, 1750, 1632, 1608, 1446, 1392, 1265 cm ^-1 ;
MS (ESI) m / z: 445 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₂₁ H ₃₀ N ₂ O ₅ SNa (M + H) ⁺ : 445.17731. Found 445.17833;
Anal.calcd.for C ₂₁ H ₂₉ N ₂ O ₅ SNa ・ 3 / 2H ₂ O: C, 53.49%; H, 6.84%; N, 5.94%; S, 6.80%, Found C, 53.62%; H, 6.54 %; N, 5.96%; S, 6.91%.

Reference Example 3 (1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt (3a) 4-acetylthio-1- (1-azetidinocarbonyl) piperidine 4 obtained in Reference Example 1 (1c) obtained in Example 1 (1c) -The title compound (805 mg, yield 80%) as a light brown solid was obtained in the same manner as in Example 38 (38a) except that acetylthiopiperidine hydrochloride (587 mg, 3.00 mmol) was used.
¹ H NMR (CDCl ₃ , 400 MHz): δ 3.98 (4H, t, J = 7.6 Hz), 3.73-3.58 (3H, m), 3.02 (2H, ddd, J = 13.4, 10.5, 3.1 Hz), 2.32 ( 3H, s), 2.28-2.17 (2H, m), 1.96-1.87 (2H, m), 1.62-1.49 (2H, m);
MS (EI) m / z: 242 (M) ^<+> .

(3b) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-carboxylate 4-acetylthio-1- (1-azetidinocarbonyl) piperidine (800 mg, 3.30 mmol) obtained in Reference Example 3 (3a) was converted to dimethylformamide (24 mL). Hydrazine acetate (365 mg, 3.96 mmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was added to the reaction solution under a nitrogen atmosphere and ice cooling. A solution of 1-methyl-carbapene-2-em-3-carboxylate (1.96 g, 3.30 mmol) in acetonitrile (60 mL) was added dropwise, followed by diisopropylethylamine (2.30 mL, 13.2 mmol), and gradually brought to room temperature. The temperature was raised and left overnight. After confirming the completion of the reaction, ethyl acetate was added to the reaction solution, washed successively with 10% brine and saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10 / 0-9 / 1, V / V) and styrene-divinylbenzene copolymer gel chromatography (elution solvent). : Chloroform) to obtain the pale yellow amorphous title compound (659 mg, yield 37%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.20 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 5.49 (1H, d, J = 13.7 Hz), 5.22 (1H , d, J = 13.7 Hz), 4.31-4.19 (2H, m), 3.97 (4H. t, J = 7.4 Hz), 3.81-3.71 (2H, m), 3.44-3.33 (1H, m), 3.30- 3.19 (2H, m), 3.03-2.78 (2H, m), 2.29-2.15 (2H, m), 2.02-1.85 (2H, m), 1.77-1.42 (2H, m), 1.38 (3H, d, J = 6.3 Hz), 1.28 (3H, d, J = 7.4 Hz);
MS (FAB) m / z: 545 (M + H) ^<+> .

(3c) (1R, 5S, 6S) -2- [1- (1-azetidinocarbonyl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [1 obtained in Reference Example 3 (3b) instead of the compound obtained in Example 1 (1e) -(1-azetidinocarbonyl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (650 mg, 1.19 mmol) A pale yellow amorphous title compound (324 mg, yield 63%) was obtained in the same manner as in Example 1 (1f) except that was used.
¹ H NMR (D ₂ O, 400 MHz): δ 4.25 (1H, dq, J = 6.3, 6.3 Hz), 4.20 (1H, dd, J = 8.8, 2.4 Hz), 4.05 (4H, t, J = 7.8 Hz ), 3.78-3.71 (2H, m), 3.48-3.40 (2H, m), 3.40-3.31 (1H, m), 3.10-2.96 (2H, m), 2.29-2.20 (2H, m), 2.05-1.95 (2H, m), 1.59-1.47 (2H, m), 1.30 (3H, d, J = 6.3 Hz), 1.21 (3H, d, J = 6.8 Hz);
IR (KBr): 3396, 2964, 1749, 1605, 1433, 1395 cm ^-1 ;
MS (ESI) m / z: 432 (M + H) ⁺ ;
HRMS (ESI) m / z: calcd.for C ₁₉ H ₂₇ N ₃ O ₅ SNa (M + H) ⁺ : 432.15691. Found 432.15731;
Anal.calcd.for C ₁₉ H ₂₆ N ₃ O ₅ SNa ・ H ₂ O: C, 50.77%; H, 6.28%; N, 9.35%; S, 7.13%, Found C, 50.90%; H, 6.25%; N, 9.26%; S, 7.23%.

(Test Example 1) In vitro antibacterial activity The test bacteria cultured overnight at 37 ° C in the preculture medium was adjusted to about 10 ⁶ CFU / mL with Mueller Hinton broth, and one platinum ear (inner diameter 1 mm) was placed on the agar plate. After streaking and culturing at 37 ° C. for 18 to 20 hours, the minimum concentration (minimum growth inhibitory concentration (μg / mL)) of the specimen that inhibits the growth of bacteria was determined. The results are shown in Table 2. In the table, test bacteria A, B and C are as follows.
A: S. aureus 209P strain B: S. pneumoniae 10666 strain (penicillin resistant strain)
C: Hemophilus influenza 12760 strain (β-lactamase non-producing ampicillin resistant strain)
(Table 2) In vitro antibacterial activity ────────────────────────────────────────
Test compound Minimum inhibitory concentration (μg / mL)
────────────────────────────
Test bacteria A B C
───────────────────────────────────────
Compound of Example 7 0.05 0.78 0.20
Compound of Reference Example 1 0.20 1.56 0.39
───────────────────────────────────────
Compound of Example 14 0.05 0.78 0.39
Compound of Reference Example 2 0.10 0.78 0.78
───────────────────────────────────────
Compound of Example 38 0.10 0.78 0.39
Compound of Reference Example 3 0.20 1.56 0.39
───────────────────────────────────────
As described above, the compound of the present invention showed strong antibacterial activity against various bacteria.

(Formulation Example 1) Injection 500 mg of the compound of Example 38 is dissolved in 5 mL of distilled water for injection, passed through a sterilizing filter, and then freeze-dried to obtain a freeze-dried preparation for injection.

(Formulation Example 2) Capsule Compound of Example 39 50 mg
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
―――――――――――――――――――――――――――
250mg total
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg No. 3 gelatin capsule to form a capsule.

(Formulation Example 3) Tablet 50 mg of the compound of Example 39
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg

―――――――――――――――――――――――――――
Total 200mg
The powder of the above formulation is mixed, wet granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

  The carbapenem compound having the above general formula (I) of the present invention, or a pharmacologically acceptable salt or ester derivative thereof has excellent antibacterial activity, and β-lactama excluding dehydropeptidase I and metallo-β-lactamase -Stable to zea and high urine recovery. Furthermore, since it has low nephrotoxicity, it is useful as a medicine, particularly as an antibacterial agent.

Claims (9)

General formula

[In the formula, A, which may be substituted C ₁ -C ₆ alkyl group (the substituent is C ₁ -C ₆ alkoxy group, an amino group, selected from the group consisting of phenyl and pyridyl groups.); Substituted A C ₂ -C ₄ alkenyl group (the substituent is a phenyl group or a pyridyl group); a C ₃ -C ₆ cycloalkyl group; an optionally substituted 4- to 6-membered heterocyclic group (the heterocyclic group) Has 1 to 3 hetero atoms which are the same or different from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and the substituent is a C ₁ -C ₆ alkyl group, an amino group, a hydroxyl group or a carbamoyl group. , A morpholino group, a cyano group, and an acetyl group); a mono-substituted amino group (the substituent is a phenyl group or a pyridyl group); or a di-substituted amino group {the substituent is C ₁ -C ₆ alkyl group and a substituted A 5- or 6-membered unsaturated heterocyclic group which may have the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring. Is selected from the group consisting of C ₁ -C ₃ alkyl groups, amino groups, hydroxyl groups, carbamoyl groups and morpholino groups. }, N represents 1 or 2, and X represents an oxygen atom or a sulfur atom. ] Or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient. A is a substituted C ₁ -C ₆ alkyl group (the substituent is selected from the group consisting of C ₁ -C ₆ alkoxy groups, amino groups, phenyl groups and pyridyl groups); substituted with a pyridyl group C ₂ -C ₃ alkenyl group; C ₃ -C ₆ cycloalkyl group; ₁ or 2 identical or different groups selected from the group consisting of C ₁ -C ₃ alkyl group, amino group, hydroxyl group, carbamoyl group and morpholino group A 5- or 6-membered unsaturated heterocyclic group which may be substituted by a substituent (the heterocyclic group has the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring) .); 4- to 6-membered saturated heterocyclic group optionally substituted by a cyano group or an acetyl group (the heterocyclic group is the same or different one or two selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring) With heteroatoms A mono-substituted amino group (the substituent is a phenyl group or a pyridyl group); or a di-substituted amino group (the substituent is a C ₁ -C ₄ alkyl group, a phenyl group, and a pyridyl group). Or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient. 2. A medicament comprising the same or different substituents selected from the group. A is, C ₁ -C substituted by a pyridyl group ₃ alkyl group; C ₃ -C ₅ cycloalkyl group; one C ₃ is interrupted by oxygen atoms -C ₅ cycloalkyl group; a methyl group, an amino group, Pyrrolyl group, pyrazolyl group, thiazolyl group, imidazolyl group, triazolyl group, pyridyl group or pyrazinyl group, which may be substituted by hydroxyl group, carbamoyl group or morpholino group; azetidinyl group, pyrrolidinyl group which may be substituted by cyano group or acetyl group Or thiazolidinyl group; anilino group or N- (pyridyl) amino group; di (C ₁ -C ₃ alkyl) amino group; N- (C ₁ -C ₃ alkyl) anilino group; or N- (C ₁ -C ₃ alkyl)-N-(3- pyridyl) carbapenem compound of claim 1 is an amino group ", or a pharmacologically acceptable salt thereof Wakashi Ku A medicament containing an ester derivative as an active ingredient.   A is a 3-pyridylmethyl group, 2- (3-pyridyl) ethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, 2-tetrahydrofuryl group, 4-tetrahydropyranyl group, pyrrolyl group, thiazolyl group, imidazolyl group , Pyridyl group, pyrazinyl group, 2-amino-3-pyridyl group, 6-amino-3-pyridyl group, 6-hydroxy-3-pyridyl group, azetidinyl group, pyrrolidinyl group, thiazolidinyl group, 3-cyano-1-azetidinyl The carbapenem compound according to claim 1, or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient.   A medicament comprising the carbapenem compound according to claim 1, or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient, wherein A is an azetidinyl group, a pyrrolidinyl group, a 3-cyano-1-azetidinyl group or a dimethylamino group. .   6. A medicament comprising the carbapenem compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient, wherein n is 1.   X is an oxygen atom, The pharmaceutical which contains the carbapenem compound of any one of Claims 1 thru | or 6, its pharmacologically acceptable salt, or ester derivative as an active ingredient.   An antibacterial agent for treating or preventing bacterial infection, comprising the carbapenem compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient.   An antibacterial agent for treating or preventing respiratory infections comprising the carbapenem compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt or ester derivative thereof as an active ingredient.