DESCRIPTION CARBAPENEM COMPOUNDS, THEIR PRODUCTION AND USE

TECHNICAL FIELD This invention relates to a novel carbapenem compound having excellent antibacterial activities and administrable not only intravenously but also orally, a method of producing the compound and an antibacterial agent. BACKGROUND ART

There have been a number of reports on carbapenem compounds, one of the typical compounds being thienamycin. While thienamycin has excellent antibiotic activities, as it is unstable to dehydropeptidase-I (DHP-I), which is a decomposing enzyme existing in a living body, it has not been practically used in the clinical field. Imipenem, which is an analogous compound to thienamycin, has been known to display clinical effects by using combinedly with cilastatin, an inhibitor of DHP-I. A number of research works have then conducted, and it has been cleared that introduction of methyl group into lβ- position and introduction of 3-pyrrolidinylthio group into 2-position give a carbapenem compound improved both in the antibacterial activities and DHP-I stability [JPA S60 (1985)-233076 and JPA H5(1993)- 4988].

However, on carbapenem having an optionally hydrogenated 5-pyrimidylthio group at 2-position of carbapenem, very few study reports have been known, and the characteristic features of the compound has not been sufficiently clarified. For example, in JPA S57(1982)-158784, there are disclosed a carbapenem compound represented by the general formula

wherein R ¹ stands for hydrogen atom or -CR R R group

(wherein R stands for hydrogen atom, hydroxyl group or a protected hydroxyl group; R and R stand for hydrogen atom, alkyl group, alkenyl group, alkynyl group, aralkyl group or aryl group; or R and R form, taken together with the adjacent carbon atom, a ring) ; R stands for hydrogen atom or carboxyl-protective group; R ³ stands for hydrogen atom, alkyl group, alkenyl group, alkynyl, aralkyl group, aryl group or - S0 ₂ R group (wherein R stands for hydroxyl group, alkyl group, alkenyl group alkynyl group, aralkyl group or aryl group) ; Z stands for oxygen atom, sulfur atom or - N(R ⁸ )- group (wherein R is of the same meaning as R ³ ); m denotes 0 or 1; n denotes 0, 1, 2 or 3, and salts thereof, and, in the working examples, compounds having, at 2-position of the carbapenem, 2(lH)-oxo- 3,4,5,6-tetrahydropyrimidin-5-ylthio group, are described concretely.

In EP-A-72710 corresponding to JPA S58(1983)- 198486, there are disclosed a carbapenem compound represented by the general formula

wherein R ¹ stands for hydrogen atom, alkyl group, alkoxy group of RA- group (wherein R stands for hydroxyl group, alkoxy group, acyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group, trialkylsilyloxy group, mercapto group, alkylthio

group, amino group or acylamino group, and A stands for trifluoromethyl group or alkylene group optionally substituted with phenyl group) ; R stands for hydrogen atom, alkyl group, cycloalkyl group of a lower alkoxy group, cyano group, alkoxycarbonyl group or an alkyl group substituted with a halogen atom; R stands for hydrogen atom or alkyl group; R stands for hydrogen atom or a carboxyl-protecting group; X stands for methylene or sulfur atom, m denotes 0 to 3, and n denotes 1 to 3, and its pharmaceutically acceptable salts, and, among them, compounds having, at 2-position of the carbapenem, 2-methyl-3,4,5,6- tetrahydropyrimidin-5-ylthio group are concretely described. In USP 4,717,728 corresponding to JPA S60(1985)- 132985, there is disclosed a compound of the formula

wherein X stands for

R stands for hydrogen or a C _{ _ ₆ alkyl), and its pharmaceutically acceptable salts, and in the examples, compounds having, at 2-position of the carbapenem, 2- amino-3,4,5,6-tetrahydropyrimidin-5-ylthio group are described concretely.

And, in USP 5,102,997 corresponding to JPA

S60(1985)-202886, there are disclosed carbapenem derivatives having the general formula

wherein R and R independently stand for hydrogen atom

(provided that both R 1 and R2 are not hydrogen atom), ^c ι-ιo optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl or a group forming a 3- to 6- membered ring combinedly, or halogen atom; R ³ stands for optionally substituted 4- to 8-membered ring optionally having 1 to 3 nitrogen, oxygen or sulfur atom, sulfinyl, sulfonyl or carbonyl group independently interposed at the ring carbon atoms; R ⁴ stands for hydrogen atom or a carboxyl-protecting group; and R stands for hydrogen atom or a Cι. ₆ optionally substituted alkyl group or alkoxy group, and their pharmaceutically acceptable salts, but, the substituents at 2-position of the pyrimidine ring of the compound concretely described as having pyrimidine ring at 2-position of carbapenem are only methyl, ethyl, methoxymethyl, cyanomethyl, benzyl, isopropyl and fluoromethyl. While so far known carbapenem compounds show, in general, excellent antibacterial activities against gram-positive and gram-negative bacteria, the antibacterial activities are insufficient and the physico-chemical properties or the stability in a living body, especially the stability to renal dehydropeptidase-1 (DHP-1), are unsatisfactory. Circumstances being such as above, carbapenem compounds of high safety, having excellent antibacterial activities and showing excellent stable behaviors in a living body and being, depending on cases, administrable orally, have been ardently desired.

DISCLOSURE OF INVENTION As a result of extensive studies diligently conducted, the present inventors synthesized, for the first time, compounds having (1) a 2-substituted hetero atom-3,4,5,6-tetrahydropyrimidin-5-ylthio group and (2) an optionally substituted 2-oxoperhydropyrimidin-5-yl, 2-thioxoperhydropyrimidin-5-yl, 2-oxoperhydrooxazin-5- yl, 2-thioxoperhydrooxazin-5-yl, 2-oxoperhydrothiazin- 5-yl or 2-thioxoperhydrothiazin-5-yl group introduced at the 2-position of a known carbapenem, and found that the compounds, based on those specific chemical structures, show excellent antibacterial activities against a broad range of pathogenic bacteria from gram- positive bacteria to gram-negative bacteria including Pseudomonas aeruginosa, and show chemical stability and stability in a living body, especially to DHP-I, and show, depending on cases, excellent oral absorbability. Based on these findings, the present invention have been accomplished. More specifically, the present invention relates to: (1) a compound of the formula (I):

wherein R is an optionally substituted lower alkyl group, R is H or a lower alkyl group, Y is a bond or an optionally substituted lower alkylene group, and W is a group of the formula:

wherein ring A is an optionally hydrogenated pyrimidine

ring which may be substituted, X is a substituted hetero-atom, and X may form a ring taken together with the ring A-constituent nitrogen atom, or W is a group of the formula:

wherein Q is NH, 0 or S, X' is oxo group or thioxo group, and ring A' may be substituted, provided that, when Q is NH and X' is oxo group, R ² is a lower alkyl group, or an ester or salt thereof (hereinafter sometimes simply called "compound (I)"), (2) a compound described in the above (1) , which is a compound of the formula (la):

wherein each symbol is of the same meaning as defined above, or an ester or salt thereof,

(3) a compound described in the above (1) , which is a compound of the formula:

wherein each symbol is of the same meaning as defined above, an ester or salt thereof,

(4) a compound described in the above (2), which is a compound of the formula:

wherein X ¹ is a substituted hetero-atom, and the other symbols are of the same meanings as defined above, or an ester or salt thereof,

(5) a compound described in the above (2), which is a compound of the formula:

wherein X is a hetero-atom, ring B is an optionally hydrogenated heterocyclic ring, and the other symbols are of the same meanings as defined above, or an ester or salt thereof, (6) a method of producing the compound (I) which comprises reacting a compound of the formula (II):

wherein L is a leaving group, and the other symbols are of the same meanings as defined above, or an ester or salt thereof, with a compound of the formula (III):

HS-Y-W (HI)

wherein the symbols are of the same meanings as defined above, or a salt thereof, (7) an antibacterial composition which comprises the compound (I) and a pharmaceutically acceptable carrier,

diluent or excipient, etc.

The compound (I) of this invention shows excellent antibacterial activities against a broad spectrum of pathogenic bacteria ranging from gram-positive to gram- negative ones. Besides, it is excellent in chemical stability and the stability to DHP-1, and it shows antibacterial activities by subcutaneous injection or oral administration.

In the above-mentioned formulae, as lower alkyl groups of the optionally substituted lower alkyl group shown by R , use is made of, for example, straight- chain or branched C _w alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl and isobutyl) . Examples of the substituents include cyano group, amino group, mono- or di- C _X . alkylamino group (e.g. methylamino and dimethylamino) , hydroxyl group, C _x _ ₄ alkyloxy group (e.g. methoxy and ethoxy) , carbamoyloxy group, C^ alkylthio group (methylthio and ethylthio), C^ alkyl- sulfonyl group (e.g. methylsulfonyl and ethylsulfonyl) , halogen (e.g. fluoro, chloro and bromo), sulfamoyl group, Cχ. ₄ alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl) and sulfoxy group. Number of these substituents ranges preferably from 1 to 3, and, when the number of these substituents is 2 or more, they may be the same as or different from one another.

In the case where the lower alkyl group is substituted with amino group or hydroxyl group, these substituents may optionally be protected with a readily removable protective group, preferably exemplified by a silyl group such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl, allyloxycarbonyl, t- butoxycarbonyl, benzyloxycarbonyl or p- nitrobenzyloxycarbonyl. More preferable examples of R ¹ include groups representable by the formula

R ³ cu .A wherein R stands for hydrogen atom, halogen, or, respectively optionally substituted hydroxyl group or amino group. As substituents of the hydroxyl group or amino group shown by R , use is made of, for example, removable protective groups mentioned as above. More preferable examples of R include hydroxyl group. Especially preferable examples of R include (1R)- hydroxyethyl group.

When carboxyl group exists in the carboxyl group at 3-position of carbapenem or in any other substituents, they may optionally be esterified. The esterified carboxyl group is shown by COOR . As the ester residual group of carboxyl group, i.e. R , mention is made of such ester residual groups as used in the field of β-lactam such as cephalosporin, more specifically, ester residual groups usually employed as the group forming readily removable ester (ester convertible to so-called prodrug) at 4-position of the cephalosporin skeleton and groups commonly used as ester residual groups of carboxylic acid in the field of pharmaceuticals. Practically, use is made of respectively optionally substituted C alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl and t- butyl), C ₂ _ ₆ alkenyl groups (e.g. vinyl, allyl and crotyl), C ₆ . ₁₀ aryl groups (e.g. phenyl and naphthyl) or C ₇ _ ₂₀ aralkyl groups (e.g. benzyl, phenethyl, benzhydryl and trityl) .

Further, as R , use is advantageously made of, for example, groups represented by the formula:

wherein R ⁵ stands for hydrogen atom or respectively optionally substituted C ₆ alkyl groups or C ₃ . ₆ cycloalkyl groups, R stands for respectively optionally substituted Cι_ι. ₀ alkyl groups, C ₃ . ₁₀ cycloalkyl groups, C^ _o alkyloxy groups, C ₃ . ₁₀ cycloalkyloxy groups, C ₃ . ₁₀ cycloalkyl-Cj.g alkyl groups, C ₃ . ₁₀ cycloalkyl-Ci.β alkyloxy groups, C ₂ . ₆ alkenyl groups, Cβ-i _o aryl groups or C ₇ . ₁₂ aralkyl groups.

In the above formula, as the C^ alkyl groups shown by R , use is made of, for example, methyl, ethyl, propyl, isopropyl, butyl and 2,2-dimethylpropyl, and, as the C ₃ . ₆ cycloalkyl groups, use is made of, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As alkyl groups of the C _J . _J Q alkyl groups and C__ ₁₀ alkyloxy groups shown by R , use is made of, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, pentyl, 2,2-dimethylpropyl, hexyl, heptyl and decyl; as cycloalkyl groups of the C ₃ . ₁₀ cycloalkyl groups, C ₃ . ₁₀ cycloalkyloxy groups, C ₃ . ₁₀ cycloalkyl-Ci. ₆ alkyl groups and C ₃ . ₁₀ cycloalkyl-Cj.g alkyloxy groups, use is made of, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl; and, as C ₆ alkyl groups of the C ₃ . ₁₀ cycloalkyl-C^ alkyl groups and C ₃ . ₁₀ cycloalkyl-Ci.e alkyloxy groups, use is made of, for example, methyl, ethyl, propyl, butyl, pentyl and hexyl. As C ₂ . ₆ alkenyl groups, use is made of, for example, vinyl, allyl and crotyl; as C ₆ . ₁₀ aryl groups, use is made of, for example, phenyl and naphthyl; and, as C ₇ _ ₁₂ aralkyl groups, use is made of, for example benzyl and phenethyl.

As substituents in the respectively optionally substituted C ₇ alkyl groups, C ₂ . ₆ alkenyl groups, C ₆ . ₁₀ aryl groups or ^' C ₇ . ₂₀ aralkyl groups shown by R , in the respectively optionally substituted Ci_ ₆ alkyl groups or C ₃ _ ₆ cycloalkyl groups shown by R ⁵ , and in the respectively optionally substituted Cχ. _i0 alkyl groups, C ₃ -ι _o cycloalkyl groups, C _J . _I Q alkyloxy groups, C ₃ . ₁₀ cycloalkyloxy groups, C ₃ . ₁₀ cycloalkyl-Cj.β alkyl groups, C ₃ -.o cycloalkyl-Ci.β alkyloxy groups, C ₂ . ₆ alkenyl groups, C ₆ . ₁₀ aryl groups or C ₇ _ ₁₂ aralkyl groups shown by R ^δ , mention is made of, for example, cyano group, nitro group, hydroxyl group, Cj._ ₄ alkyloxy groups (e.g. methoxy, ethoxy and propoxy) , carbamoyloxy group, C alkylthio groups (e.g. methylthio) and halogen (e.g. fluoro, chloro and bromo) . Number of such substituents as above ranges preferably from 1 to 3, and when the number is 2 or more, they may be the same as or different from one another.

Especially preferable ester residual groups shown by R include groups often used in the process of preparing pharmaceuticals [e.g. methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tertiary butyl group, 2,2,2-trichloroethyl group, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, o-nitrobenzyl group, phenethyl group, bis(methoxyphenyl)methyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, benzhydryl group, trityl group, trimethylsilyl group, 2-trimethylsilylethyl group or allyl group], or groups giving biologically unstable ester derivatives suitable for oral administration [e.g. acetoxymethyl group, 1- acetoxyethyl group, 1-acetoxypropyl group, pivaloyloxymethyl group, isopropyloxycarbonyloxymethyl group, l-(isopropyloxycarbonyloxy)ethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (eyelohexyloxycarbonyloxy)ethyl group,

ethoxycarbonyloxymethyl group, 1-

(ethoxycarbonyloxy)ethyl group, phthalidyl group and (2-oxo-5-methyl-l,3-dioxol-4-yl)methyl group] .

As salts of the compounds represented by the above formulae or salts of their esters, use is preferably made of pharmacologically or chemically acceptable ones. As such salts, use is made of, for example, salts with inorganic bases, salts with organic bases, salts with organic acids and salts with basic or acid amino acid. As inorganic bases capable of producing these salts, use is made of, for example, alkali metals (e.g. sodium and potassium) and alkaline earth metals (e.g. calcium and magnesium); as organic bases, use is made of, for example, trimethylamine, triethylamine, pyridine, picoline, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, tris(hydroxymethylamino)methane and dicyclohexylamine; as inorganic acids, use is made of, for example, hydrochloric acid, hydrobromic acid, sulfuric acid nitric acid and phosphoric acid; as organic acids, use is made of, for example, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzensulfonic acid and p-toluenesulfonic acid; and as basic or acid amino acid, use is made of, for example, arginine, lysine, ornithine, aspartic acid and glutamic acid. Among these salts, salts with bases (i.e. salts with inorganic bases, salts with organic bases and salts with basic amino acids) mean salts which can be formed in such cases where the carboxyl group shown by COOH of the compounds (I), (la), (lb), (Ia-1) and (Ia-2) or an acid group such as carboxyl group exists in ester residual groups or substituents of the compounds (I), (la), (lb), (Ia-1) and (Ia-2); and salts with acids (i.e. salts with inorganic acids, salts with organic

acids and salts with acid amino acids) means salts which can be formed in such cases where a basic group such as amino group exists in the compounds (I), (la), (lb), (Ia-1) and (Ia-2) or its ester. As R of the above formulae, use is made of hydrogen atom or a lower alkyl group. As the lower alkyl group, use is preferably made of, for example, Ci. ₃ alkyl groups. Examples of the C _x . ₃ alkyl groups include methyl, ethyl, propyl and isopropyl, especially methyl being preferable.

As Y in the above formulae, use is made of a bond or an optionally substituted lower alkylene group. As the lower alkylene group, use is preferably made of Ci_ ₃ alkylene groups. As such Cj_ ₃ alkylene groups, mention is made of, for example, methylene, ethylene and propylene. As substituents of the lower alkylene groups, mention is made of, for example, halogen (e.g. fluoro, chloro and bromo), hydroxy group, C^g alkyloxy groups (e.g. methoxy and ethoxy) , amino group, and mono- or alkylamino groups (e.g. methylamino, dimethylamino) , and the number of such substituents is preferably one or two. More preferable example of Y is a bond.

The ring A of the above formula stands for an optionally hydrogenated pyrimidine ring. As the ring A, use is made of, for example, pyrimidine, 1,2- dihydropyrimidine, 1,6-dihydropyrimidine, 4,5- dihydropyrimidine, 2,6-dihydropyrimidine, 1,2,3,4- tetrahydropyrimidine, 1,2,5,6-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine or perhydropyrimidine.

Preferable examples of the ring A include pyrimidine or 1,4,5,6-tetrahydropyrimidine, more preferably 1,4,5,6- tetrahydropyrimidine. The optionally hydrogenated pyrimidine ring shown by the ring A may optionally have, other than X and Y, substituents, on the ring- constituent carbon and/or nitrogen atoms. Examples of

such substituents include Cj.g alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), C ₆ . ₁₀ aryl groups (e.g. phenyl, tolyl and naphthyl), 4- to 6-membered heterocyclic groups containing 1 to 4 hetero-atoms selected from N, 0 and S (e.g. pyridyl, thiazolyl and pyrimidinyl) and C ₇ . ₁₂ aralkyl groups (e.g. benzyl) and the number of such substituents is preferably one or two, and these substituents may optionally be further substituted with 1 to 3 substituents exemplified by halogen (e.g. fluoro, chloro and bromo), hydroxy group, C _x _ ₆ alkyloxy groups (e.g. methoxy and ethoxy) , amino group, mono- or di-C^ alkylamino groups (e.g. methylamino and di ethylamino) , cyano group.

As ring A, an optionally hydrogenated pyrimidine ring which may be substituted with 1 or 2 Ci_ ₄ alkyl groups (e.g. methyl) on ring-constituent nitrogen atoms is preferable.

The substituent X stands for a substituted hetero- atom, which may optionally form a ring, taken together with the ring A-constituent nitrogen atom. X ¹ stands for a substituted hetero-atom, and X ² stands for a hetero-atom. As the hetero-atoms in X, X and X , mention is made of, for example, 0, S and N. And, the substituted hetero-atoms of X and X include respectively substituted hydroxyl, mercapto, amino or imino group. When the "substituted hetero-atom" shown by X is a group controlling the electron density of the pyrimidine ring shown by the ring A (i.e. an electron attractive group or an electron donor group), the substituent of the "substituted hetero-atom" shown by X is not especially restricted. Practical examples of such substituents include respectively optionally substituted hydrocarbon groups or heterocyclic groups or acyl group. As the hydrocarbon group in such optionally substituted hydrocarbon groups as above, mention is

made of C^ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl and isobutyl), C ₆ . ₁₀ aryl groups (e.g. phenyl and naphthyl), C ₇ . ₁₂ aralkyl groups (e.g. benzyl and phenethyl), C ₃ . ₆ alkenyl groups (e.g. allyl and crotyl) and C ₃ . ₆ alkynyl groups (e.g. propargyl). Examples of the substituents of these hydrocarbon groups include cyano group, amino group, mono- or di- C _j . ₄ alkylamino group (e.g. methylamino and dimethylamino) , hydroxyl group, Cj. ₄ alkyloxy groups (e.g. methoxy and ethoxy) , carbamoyloxy group, C^ alkyl-thio group (e.g. methylthio and ethylthio), γ.t, alkyl-sulfonyl groups (e.g. methylsulfonyl and ethylsulfonyl) , halogen (e.g. fluoro, chloro and bromo), sulfamoyl group, C _x _ ₄ alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl), sulfoxy group or 4- to 6-membered heterocyclic groups containing 1 to 4 hetero-atoms such as nitrogen atom, oxygen atom and sulfur atom. The number of these substituents ranges preferably from 1 to 3, and when the number is two or more, those substituents may be the same as or different from one another.

As the heterocyclic groups of optionally substituted heterocyclic groups, mention is made of 4- to 6-membered heterocyclic groups containing one to four hetero-atoms such as nitrogen atom, oxygen atom and sulfur atom. These groups may optionally be condensed with the benzene ring or one or two of other heterocyclic rings (e.g. 4- to 6-membered heterocyclic rings containing one to four hetero-atoms such as nitrogen atom, oxygen atom and sulfur atom) . Examples of the substituents of these heterocyclic groups include Cj.g alkyl groups (e.g. methyl and ethyl), C ₆ . ₁₀ aryl groups (e.g. phenyl), cyano group, amino group, mono- or di-C^ alkylamino group (e.g. methylamino and

dimethylamino) , hydroxyl group, Cj_ ₄ alkyloxy groups (e.g. methoxy and ethoxy) , carbamoyloxy group, C^ alkylthio groups (e.g. methylthio and ethylthio), Cι_ ₄ alkyl-sulfonyl groups (e.g. methylsulfonyl and ethylsulfonyl) , halogen (e.g. fluoro, chloro and bromo), sulfamoyl group, C^ alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl) and sulfoxy group. The number of these substituents ranges preferably from one to three. When the number of these substituents is two or more, they may be the same as or different from one another. Examples of the 4- to 6-membered heterocyclic ring containing one to four hetero-atoms include azetidine, furan, pyrrole, thiophene, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine, morpholine, quinuclidine and structurally possible hydrogenated compounds of them.

Examples of the acyl group include C _j . ₆ alkyl- carbonyl groups (e.g. acetyl and propionyl), halogeno- C _x _ ₆ alkyl-carbonyl groups (e.g. trifluoromethylcarbonyl) , C ₆ alkoxy-carbonyl groups (e.g. methoxycarbony1, ethoxycarbony1, propoxycarbony1 and butoxycarbonyl), C ₆ . ₁₀ aryl-carbonyl groups (e.g. benzoyl), C ₇ . ₁₂ aralkyl-carbonyl groups (e.g. benzylcarbonyl), 4- to 6-membered heterocyclic-carbonyl groups containing 1 to 4 hetero-atoms selected from N, 0 and S in the heterocyclic ring, carbamoyl group, mono- or alkyl-carba oyl groups (e.g. methylcarbamoyl and dimethylcarbamoyl) , C,_ ₆ alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl) , C ₆ . ₁₀ arylsulfonyl groups (e.g. phenylsulfonyl) , C ₇ . ₁₂ aralkylsulfonyl groups (e.g. benzylsulfonyl) , 4- to 6- membered heterocyclic-sulfonyl groups containing 1 to 4

hetero-atoms selected from N, 0 and S in the heterocyclic ring.

As the "4*- to 6-membered heterocyclic groups containing 1 to 4 hetero-atoms" in the above "4- to 6- membered heterocyclic groups containing 1 to 4 hetero- atoms", "4- to 6-membered heterocyclic-carbonyl groups containing 1 to 4 hetero-atoms" and "4- to 6-membered heterocyclic-sulfonyl groups containing 1 to 4 hetero- atoms", mention is made of, for example, a group formed by eliminating a hydrogen atom from azetidine, furan, pyrrole, thiophene, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine, morpholine, quinuclidine and structurally possible hydrogenated compounds of them.

Furthermore, in the case where X and X is a substituted amino group or substituted imino group, as the substituents, use is made of, for example, in addition to those exemplified as substituents of the above X and X , C^ alkyl-sulfonyl groups (e.g. methylsulfonyl and ethylsulfonyl), mono- or di-Cj_ ₄ alkylsulfamoyl group (e.g. methylsulfamoyl and dimethylsulfamoyl) , C^ alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbony1 and butoxycarbonyl), cyano group, nitro group, amino group, mono- or di-Cj.* alkylamino groups (e.g. methylamino and dimethylamino) , hydroxyl group and C^ alkyloxy groups (e.g. methoxy, ethoxy and propoxy) . The number of the substituents of the substituted amino group is one or two, and, when the number is two, those substituents may be the same as or different from each other.

As the ring B, use is made of optionally hydrogenated 5- to 7-membered heterocyclic rings containing one to four nitrogen atoms and, besides, one to three hetero-atoms such as oxygen atom and sulfur atom. These heterocyclic rings may optionally have

substituents, which are exemplified by C^ alkyl groups (methyl, ethyl, propyl, isopropyl, butyl and t-butyl), C ₆ . ₁₀ aryl groups (phenyl and naphthyl), cyano group, amino group, mono- or di-C^ alkylamino groups (e.g. methylamino, and dimethylamino, hydroxyl group, C _A alkyloxy groups (e.g. methoxy and ethoxy), carbamoyloxy group, Cj. ₄ alkylthio groups (methylthio and ethylthio), Cj. ₄ alkylsulfonyl groups (e.g. methylsulfonyl and ethylsulfonyl), halogen (e.g. fluoro, chloro and bromo), sulfamoyl group, C^ alkoxy-carbonyl group

(e.g. methoxycarbony1, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl) and sulfoxy group. The number of these substituents ranges preferably from one to three, when the number is two or more, those substituents may be the same as or different from one another. Concrete examples of the ring B include respectively hydrogenated thiazole, oxazole, imidazole, 1,3- thiazine, 1,3-oxazine and pyrimidine, and, as the condensed ring of the ring A and the ring B, mention is made of, for example, respectively hydrogenated thiazolo[3,2-a]pyrimidine, oxazolo[3,2-a]pyrimidine, imidazo[1,2-a]pyrimidine, pyrimido[2,1-b] [1,3]thiazine, pyrimido[2,1-b] [l,3]oxazine and pyrimido[1,2- a]pyrimidine. Additionally, when X or X ¹ stands for a substituted imino group, in the above formulae

means double bond, when X and X' are any other groups, means single bond.

And, in the case where X or X stands for a mono- substituted amino group, it has an equilibrium relation with the substituted imino group, as shown by the formula

X and X are preferably (1) a substituted hydroxy group, the substituent being a Cι. _A alkyl group (e.g. methyl, ethyl, propyl and butyl) which may be substituted with amino or mono- or di-C^ alkylamino (e.g. methylamino and dimethylamino), (2) a substituted mercapto group, the substituent being a 4- to 6- membered heterocyclic group having 1 to 4 hetero-atoms selected from N, 0 and S (e.g. thiazolyl and pyridyl) or a Cj. ₄ alkyl group (e.g. methyl, ethyl, propyl and butyl) which may be substituted with hydroxyl or C _l . _il alkyloxy (e.g. methyloxy, ethyloxy, propyloxy and butyloxy), or (3) a mono- or di-substituted amino or substituted imino group, the substituent being selected from the group consisting of Ci_ ₆ alkyl-carbonyl (e.g. acetyl, propionyl and butyryl), halogeno-C^ alkyl- carbonyl (e.g. trifluoromethylcarbonyl) , C ₆ . ₁₀ aryl- carbonyl (e.g. benzoyl), carbamoyl, mono- or di-C^ alkyl-carbamoyl (e.g. methylcarbamoyl and dimethylcarbamoyl) , 4- to 6-membered heterocyclic- carbonyl having 1 to 4 hetero-atoms selected from N, 0 and S as ring-constituent atoms (e.g. thiazolylcarbonyl, pyridylcarbonyl and pyrimidinylcarbonyl) , C^ alkylsulfonyl (e.g. methylsulfonyl and ethylsulfonyl), C ₆ . ₁₀ arylsulfonyl (e.g. phenylsulfonyl) , 4- to 6-membered heterocyclic group having 1 to 4 hetero-atoms selected from N, 0 and S (e.g. thiazolyl, pyridyl and pyrimidinyl) and C^ alkyl (e.g. methyl, ethyl, propyl and butyl) which may be substituted with hydroxyl. And,

wherein D is C ₂ . alkylene group (e.g. ethylene) or C ₂ _ ₄ alkenylene group (e.g. ethenylene) .

The compound (la) is preferably a compound of the formula (la' )

wherein Ra is

Ra' is Cj. ₄ alkyl group (e.g. methyl and ethyl), Ra" is carbamoyl or mono- or di-C^ alkyl-carbamoyl (e.g. methylcarbamoyl and dimethylcarbamoyl), or an ester or salt thereof.

The ring A' of the above formulae may optionally have, other than X' and Y, substituents on the ring- constituent carbon atoms and/or nitrogen atoms.

Examples of such substituents include C _x _ ₆ alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), C ₆ . ₁₀ aryl groups (e.g. phenyl, tolyl and naphthyl), 4- to 6- membered heterocyclic groups containing 1 to 4 hetero- atoms such as N, 0 and S (e.g. pyridyl, thiazolyl and pyrimidinyl) , and C ₇ . ₁₂ aralkyl groups (e.g. benzyl).

The number of such substituents is preferably 1 to 4, and these substituents may optionally be further substituted with 1 to 3 substituents exemplified by halogen (e.g. fluoro, chloro and bromo), hydroxy group, C _χ . ₆ alkyloxy groups (e.g. methoxy and ethoxy), amino group, mono- or di- C^ alkylamino groups (e.g. methylamino and dimethylamino), cyano group.

As ring A', it is preferable that ring A' may be substituted with 1 or 2 substituents selected from the group consisting of a C^ alkyl group (e.g. methyl) and a 4- to 6-membered heterocyclic group having 1 to 4 hetero-atoms selected from N, 0 and S (e.g. pyridyl) on the ring-constituent nitrogen atoms.

Q in the above formulae stands for NH, oxygen atom or sulfur atom.

The substituent X' stands for oxo group or thioxo group.

When Q is NH and, at the same time, X' is oxo group, R stands for a lower alkyl group (e.g. C^ alkyl groups such as methyl, ethyl and propyl).

The compound (lb) is preferably a compound of the formula (lb' ) :

wherein Q' is NR , 0 or S, R" is H, a C _U4 alkyl group (e.g. methyl), a cyano- Cj_ alkyl group (e.g. cyanomethyl) or a 4- to 6-membered heterocyclic group having 1 to 4 hetero-atoms selected from N, 0 and S (e.g. pyridyl) and X' is O or S, or an ester or salt thereof. R is preferably H or a C^ alkyl group such as methyl. Production Method 1

The compound (I) can be produced by, for example,

allowing a compound represented by the formula (II)

wherein L stands for a leaving group, and other symbols are of the same meaning as defined above, or an ester or salt thereof [as the ester or salt, substantially the same one as in (I) can be used] to react with a compound represented by the formula (III)

HS-Y-W (III)

wherein symbols are of the same meaning as defined above, or a salt thereof.

As the leaving group shown by L in the compound (II), use is made of a leaving group commonly employed in the field of organic synthetic chemistry [leaving groups described in, for example, Compendium of Organic Synthetic Methods, Vol.l to Vol.7, John Wely & Sons Inc., New York (1971-1992) and R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989)]. Practical examples of L include reactive esters of hydroxyl group [e.g. Ci_ ₆ alkane- or C ₆ . ₁₀ arene-sulfonyloxy groups (e.g. methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy) or di-C^ alkyl- or di-C ₆ . ₁₀ aryl- phosphonoxy group (e.g. diphenylphosphonoxy) ] , halogen (e.g. chloro, bromo) or Ci_ ₆ alkane-, C ₂ . ₆ alkene- or C ₆ . ₁₀ arene-sulfinyl group (e.g. methanesulfinyl, benzenesulfinyl) . More preferable L is diphenylphosphonoxy group.

The salts of the compound (III) are exemplified by alkaline metal (e.g. sodium and potassium) alkaline earth metal (e.g. calcium and magnesium) salts and

ammonium salt.

When reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formulae of the compounds (II) and (III), these groups may optionally be protected, in accordance with a conventional method, with the protective groups mentioned below. After completion of the reaction, these protective groups can be removed.

The reaction between the compound (II) and the compound (III) proceeds advantageously usually in the presence of a base. Examples of the base include organic amine such as triethylamine and diisopropylethylamine and basic inorganic salts such as sodium hydrogencarbonate and potassium carbonate. When the compound (II) is allowed to react with the compound (III), in case where the mercapto group in the compound (III) is protected, the compound (III) can be allowed to react with the compound (II) after removing the protective group by using a reagent. For the removal of the protective group, conditions for the reaction with a deprotecting agent commonly used in the relevant field described, for example, T. W. Green and P. G. M Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wely & Sons Inc., New York (1991) can be employed.

And, as protective groups of mercapto group in the compound (III), those commonly used in the relevant field can be employed, which are exemplified by protective groups of mercapto group described in, for example, T. W. Green and P. G. M Wuts, Protective

Groups in Organic Synthesis, Second Edition, John Wely & Sons Inc. New York (1991). As such protective groups, readily removable silyl thioether, for example, is especially more preferable. The reaction between the compound (II) and the compound (III) can be conducted usually by stirring in

an inert solvent. As the inert solvents to be employed for the reaction, any one can be used so long as it does not hamper the reaction, which is preferably exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane and chloroform, alkyl nitriles such as acetonitrile and propionitrile, nitroalkanes such as nitromethane and nitroethane and amides such as dimethylformamide and dimethylacetamide. The amount of the compound (III) to be employed is 0.3 to 5 molar equivalents of the compound (II). While the reaction temperature varies with, among others, the starting compounds (II) and (III), kinds of bases then added and kinds of solvents then employed, it ranges usually from -40°C to 100°C, preferably from -30°C to 50°C. The reaction time ranges usually from one minute to 48 hours, preferably from about 15 minutes to about 24 hours. The method of producing the compound (II) or its esters or salts is known in the field of carbapenem (e.g. JPA S57(1982)-12318 and JPA S64(1989)-25780) .

The compounds represented by the formula (III), most of them being novel substances, can be produced by the methods described in literature references or methods analogous thereto. As such literature references, mention is made of JPA S57(1982)-158784, J. Kister et al. , Tetrahedron, Vol.32. p.1395 (1976), H. Rapoport et al. , J. Org. Chem. Vol.36, p.46 (1971), Compendium of Organic Synthetic Methods, Vol.l to

Vol.7, John Wely & Sons Inc., New York (1971-1992), Comprehensive Organic Synthesis, Vol.l-Vol.9, Pergamon Press, Oxford (1991) and Comprehensive Organic Transformation, VCH, New York (1989). When W is a group of the formula

wherein each symbol is of the same meaning as above, the compound of the formula (III) is represented by the compound of the formula (Ilia)

wherein each symbol is of the same meaning as above, When W is a group of the formula

wherein each symbol is of the same meaning as above, the compound of the formula (III) is represented by the compound of the formula (Illb)

wherein each symbol is of the same meaning as above.

The compound represented by the formula (Ilia) can be produced, practically, by allowing, for example, an optionally substituted diamino compound represented by the formula (IVa)

^Y *H ₂ < ^IVa > wherein Z is hydrogen atom or a protecting group of mercapto group, and Y is of the same meaning as above, or a salt to react with a compound represented by the

formula ( Va )

wherein X ³ stands for a substituted imino group; and L and L ² independently stand for leaving groups, or a compound represented by the formula (Via)

L ¹

L ² -C-X ⁴ (Via)

wherein X stands for respective substituted hydroxyl group, mercapto group or amino group; L ¹ , L ² and L ³ independently stand for leaving groups, if necessary, followed by removal of the protective group Z.

As substituents of the optionally substituted diamino compound represented by the above formula (IVa), use is made of groups mentioned as substituents of ring A.

As salts of the compound (IVa), use is made of similar ones to the salts of the compound (Ilia).

When the compound (IVa) is allowed to react with the compound (Va), in case where the mercapto group in the compound (IVa) is protected, the compound (IVa) can be allowed to react with the compound (Va) after removing the protective group by using a reagent. For the removal of such protective groups, reagents and reaction conditions similar to those used for the above-described deprotection of the mercapto group of the compound (Ilia) can be employed.

And, as protective groups of the mercapto group of the compound (IVa), use is made of ones similar to protective groups of the mercapto group of the compound (Ilia), and use is further made of, for example, alkyl

type protective groups (e.g. benzyl such as benzyl, p- methoxybenzyl and p-nitrobenzyl, substituted methyl such as diphenyl methyl, triphenyl methyl and methoxymethyl, and 2-tetrahydropyranyl) , acyl type protective groups (e.g. alkyloyl such as acetyl, aroyl such as benzoyl, and t-butoxycarbonyl) or silyl type protective groups (e.g. t-butyldimethylsilyl) .

As substituents of the groups shown by X and X , use is made of substituents of the groups shown by the above-mentioned X.

As the leaving groups represented by L , L and L , use can be made of removable groups commonly employed in the field of organic synthetic chemistry [removable groups described in, for example, Compendium of Organic Synthetic Methods, Vol.l to Vol.7, John Wely & Sons Inc. New York (1971-1992) and R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989)]. Practical examples of L , L and L include hydroxyl group, substituted hydroxyl groups [e.g. C__ ₆ alkyloxy (e.g. methyloxy and ethyloxy) or C ₆ . ₁₀ aryloxy (e.g. phenyloxy) or C__ ₆ alkanoyloxy (e.g. acethyloxy) or C ₆ . ₁₀ aroyloxy (e.g. benzoyloxy) ] , mercapto group, substituted mercapto groups [e.g. Ci_ ₆ alkylthio (e.g. methylthio) or C ₆ _ ₁₀ arylthio (e.g. phenylthio) or Cj.g alkanoylthio (e.g. acetylthio) or C ₆ _ ₁₀ aroylthio (e.g. benzoylthio) ] , amino group or mono- or di-substituted amino groups [e.g. mono- or di-C^g alkylamino (e.g. methylamino and dimethylamino) or mono- or di-C ₆ . ₁₀ arylamino (e.g. pheny1amino) ] . And, depending cases, L ¹ and L ² may optionally be combined to form double bond with C. Examples of such groups include oxo group and thioxo group.

The compound represented by the formula (Ilia) can be converted to a compound (Ilia) having a structure in which X is different, by subjecting to an adequate

functional group conversion reaction. For such functional group conversion reaction, use is made of conventional reactions for organic synthesis described in, for example, R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989).

And, the compound represented by the formula (Ilia) can also be produced by allowing an optionally substituted thiol compound represented by the formula (III-l) or the formula (III-2)

(III-l) (III- 2) wherein Y is of the same meaning as defined above, X 5 stands for O, S or N-Z , and Z stands for hydrogen atom or groups capable of bonding to nitrogen atom among substituents of substituted hetero-atoms shown by the above X, or a reactive derivative thereof to react with a compound represented by the formula

Z ² -L ⁴ wherein Z ² stands for substituents of the substituted hetero-atoms shown by the above X, and L stands for a leaving group. Additionally, the formula (III-l) and the formula (III-2) can be, depending on conditions, convertible to each other or in the equilibrium state. And, when a removable group group exists in Z , Z ² -L* can be shown by the formula L ⁵ -Z ³ -L ⁴ wherein Z ³ , taken together with L , stands for Z ; L stands for a leaving group; and L is of the same meaning as defined above. By subjecting L -Z -L to a similar reaction, a compound represented by the formula (Ilia) having the structure in which X, taken together

with nitrogen atom on the ring, forms a ring can be produced.

As substituents of the optionally substituted thiol compounds represented by the above formula (III- 1) or (III-2), use can be made of groups mentioned as substituents of the ring A.

As reactive derivatives of the compound (III-l) or (III-2), use is made of similar ones to those of the compound (Ilia). And, as L or L , use is made of groups similar to those shown by L .

The reaction between the compound (III-l) or (III- 2) and the compound represented by Z -L or L -Z -L can be conducted under conditions of conventional addition elimination reactions described in, for example, R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989) .

The compound (III-l) or (III-2) can be produced by allowing the compound (IVa) to react with a compound represented by the formula (V-l)

² -i=) (V-l)

wherein symbols are of the same meaning as defined above. In this reaction as well, conditions of conventional addition elimination reaction described in, for example, R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989) can be employed.

The compound represented by the formula (Illb) can be produced, practically, by allowing an optionally substituted 1,3-propanediamine, 3-aminopropan-l-ol or 3-aminopropane-l-thiol derivative, which is known from literature references or producible by reactions analogous to the methods described in those literature references, represented by the formula (IVb)

wherein Z stands for hydrogen atom or a protecting group of mercapto group, and other symbols are of the same meaning as defined above, to react with a compound represented by the formula (Vb)

(Vb)

L ² -C=X

wherein X is of the same meaning as defined above, L ¹ and L independently stand for removable groups, if necessary, followed by removal of the protective group Z.

The compound represented by the formula (III) can also be produced by allowing an optionally substituted 1,3-propanediamine, 3-aminopropan-l-ol or 3- aminopropane-1-thiol derivative, which is known from literature references or producible by reactions analogous to the methods described in those literature references, represented by the formula (IV'b)

(IV' )

wherein Z' stands for hydrogen atom or a protecting group of hydroxyl group, and other symbols are of the same meaning as defined above, to react with a compound represented by the formula (Vb), if necessary, followed by removal of the protective group Z', and by converting the resulting hydroxyl group to mercapto group. The conversion of hydroxyl group to mercapto group can be conducted by, for example, the method described in Comprehensive Organic Transformation, VCH,

New York ( 1989 ) .

In the case where Z or Z' in the compound (IVb) respectively stand' for protective groups of mercapto group or hydroxyl group, as those protecting groups, use can be made of, for example, such protecting groups commonly employed in the relevant field as described in Protective Groups in Organic Synthesis, Second Ed. John Wely & Sons Inc., New York (1991), T. W. Green and P. G. M. Wuts. Preferable examples of them include alkyl- type protective groups (e.g. benzyl such as benzyl, p- methoxybenzyl, p-methoxybenzyl and p-nitrobenzyl; substituted methyl such as diphenyl methyl, triphenyl methyl and methoxy methyl; 2-tetrahydropyranyl) , acyl- type protective groups (e.g. Ci_ ₆ alkanoyl such as acetyl; C ₆ . ₁₀ aroyl such as benzoyl; t-butoxycarbonyl) or silyl-type protective groups (e.g. t- butyldimethylsilyl) , and, among them, p-methoxybenzyl, acetyl, benzoyl and tetrahydropyran-2-yl, for example,are more preferable. As the conditions of the above reactions and the removable groups represented by L ¹ and L ² employed in the reaction, use can be made of reaction conditions and removable groups commonly employed in the field of organic synthetic chemistry. [Analogous reactions are described in, for example, S. Umezawa et al. Bull.

Chem. Soc. Japan, Vol.44, p.1411 (1971) and Y. Abe et al. J. Antibiotics, Vol.30, p.1004 (1977), or Compendium of Organic Synthetic Methods, Vol.l to Vol.7, John Wely & Sons Inc. New York (1971-1992) and R. C. Larock, Comprehensive Organic Transformation,

VCH, New York (1989)]. Practical examples of L ¹ and L ² include hydroxyl group, substituted hydroxyl groups [e.g. Cι_ ₆ alkyloxy (e.g. methyloxy) or C ₆ . ₁₀ aryloxy (e.g. phenyloxy) or Cj.g alkanoyloxy (e.g. acetyloxy) or C ₆ . ₁₀ aroyloxy (e.g. benzoyloxy) ] , mercapto group, substituted mercapto groups [e.g. d. ₆ alkylthio (e.g.

methylthio) or C ₆ . ₁₀ arylthio (e.g. phenylthio) or Cj_ ₆ alkanoylthio (e.g. acetylthio) or C ₆ . ₁₀ aroylthio (e.g. benzoylthio) ] , a iho group or mono- or di-substituted amino groups [e.g. mono- or di- C^ alkylamino (e.g. methylamino) or mono- or di- C ₆ . ₁₀ arylamino (e.g. pheny1amino) ] . And, depending cases, L and L may optionally be combined to form double bond with C. Examples of such groups include oxo group and thioxo group. Preferable examples of the compound represented by the formula (Vb) include phosgene, carbonyldiimidazole, thiophosgene, thiocarbonyl diimidazole, carbon disulfide, phenyl chlorocarbonate and p-nitrophenyl chlorocarbonate.

The compound represented by the formula (Illb) can also be produced by subjecting, for example, a 1,3- propanediamine, 3-aminopropan-l-ol or 3-aminopropane-l- thiol derivative, which is known from literature references or producible by analogous methods thereto, represented by the formula (VIb)

to adequate reaction conditions, followed by allowing cyclization to occur accompanying removal of H-L ³ . As these reaction conditions and L employable for these reactions, use can be made of such reaction conditions and removable groups commonly employed in the field of organic synthetic chemistry. [Analogous reactions are described in, for example, Compendium of Organic Synthetic Methods, Vol.l to Vol.7, John Wely & Sons Inc. New York (1971-1992) and R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989)]. Practical examples of L ³ include substituted hydroxyl groups [e.g. Cj.g alkyloxy (e.g. ethyloxy) or

C ₆ -ι _o aryloxy (e.g. phenyloxy) or C^ alkanoyloxy (e.g. acetyloxy) or C ₆ . ₁₀ aroyloxy (e.g. benzoyloxy) ] , substituted mercapto groups [e.g. C^ alkylthio (e.g. methylthio) or C ₆ . _:0 arylthio (e.g. phenylthio) or Ci_ ₆ alkanoylthio (e.g. acetylthio) or C ₆ . ₁₀ aroylthio (e.g. benzoylthio) ] , amino group or mono- or di-substituted amino groups [e.g. mono or di- C ₁ . ₆ alkylamino (e.g. methylamino) or mono- or di- C ₆ . ₁₀ arylamino (e.g. phenylamino] ] . The compound represented by the formula (Illb) can also be produced by subjecting, for example, an optionally substituted 1,3-propanediamine, 3- aminopropan-1-ol or 3-aminopropane-l-thiol derivative, which is known from literature references or producible by reactions analogous to those described therein, represented by the formula (VIlb)

wherein symbols are of the same meaning as defined above, to adequate reaction conditions to cause cyclization accompanying removal of H-L ³ , then, depending on necessity, deprotecting Z', followed by converting the resulting hydroxyl group to mercapto group. The conversion of hydroxyl group to mercapto group can be conducted by the method described in, for example, Comprehensive Organic Transformation, VCH, New York (1989). As L employable in the reaction conditions of such reactions, mention is made of similar ones to those described above.

For conducting the above-mentioned removal of the protective groups shown by Z and Z' , deprotecting reagents and reaction conditions commonly used in the relevant field, which are described in, for example, T.

W, Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wely & Sons Inc., New York (1991), can be employed.

As substituents of the optionally substituted 1,3- propanediamine, 3-aminopropan-l-ol or 3-aminopropane-l- thiol derivative represented by the above-mentioned formulae (IVb) and (VIb), use can be made of groups mentioned as substituents of the ring A. Production Method 2a The compound (Ia) of this invention can also be produced by subjecting a compound of the formula (Vila)

wherein M and Q stand for groups which form double bond by reacting with each other, in other words, groups forming a double bond by reaction of M with Q and by elimination, and, other symbols are of the same meaning as defined above] or an ester or salt thereof [as the ester or salt, use can be made of similar ones as those of (I) to ring-closure reaction. Practical examples of M and Q include, besides =0, =S and =Se, those described in JPA H4(1994)-179389.

As the ring-closure reaction, per se known reactions [for example, Annual Reports in Organic Synthesis, 1975-1993, Academic Press, Inc. San Diego, and Advanced Organic Chemistry Second Edition, Plenum Press New York and London (1983)] can be employed. Practically, Wittig type reaction (Wittig, Honer, Emonds reaction), Peterson type reaction, Aldol type reaction accompanied with dehydration and Macmary type reaction using a low-electron value metal, for example, can be employed. More desirably, a Wittig type

reaction employing, for example,

wherein R 7 and R7* stand for a lower alkoxy group, a lower alkyl group or aryl group, and, as Q, employing 0, S and Se, is mentioned. Examples of more practical methods include the following ones. Production Method 2a-l

The compound (Ia) can also be produced by allowing a compound represented by the formula (VIIa-1):

wherein Q stands for 0 or S, and other symbols are of the same meaning as defined above, or an ester or salt thereof [as the ester or salt, use can be made of similar ones to those of (I)], to react with a compound represented by the formula P(R ⁷ ) ₃ (VIII) or P(R ⁷ ) ₂ R ^7' (VIII')

(wherein R 7 and R7' are of the same meaning as defined above), followed by, depending on necessity, removing the protective groups.

When reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formula of the compound (VIIa-1), these groups may optionally be protected with the protective groups described below in accordance with a conventional method. After completion of the reaction, these protective groups can be removed by a conventional method.

As the lower alkoxy group shown by R 7 or R 7 ', use is made of, for example, C _x _ ₆ alkoxy groups such as methoxy, ethoxy, propoxy and butoxy, as the lower alkyl group, use is made of, for example, Cj_ ₆ alkyl groups such as methyl, ethyl, propyl, butyl and pentyl, and, as the aryl group, use is made of C ₆ . ₁₀ aryl groups such as phenyl.

These reactions are conducted usually under heating in the absence of solvent or in an inert solvent. While, as the inert solvent to be employed for the reaction, any one can be used so long as it does not hamper the reaction, preferable examples of such solvents include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, or halogenated hydrocarbons such as dichloromethane and chloroform. The amount of the compound (VIII) or (VIII') to be employed is 2 molar equivalents or more, preferably 2 to 10 molar equivalents, of the compound (VIIa-1). While the reaction temperature varies with the starting compounds (VIIa-1), (VIII), (VIII') and kinds of the solvent, it ranges usually from about 20 to 160°C, preferably from about 80 to 140°C. The reaction time ranges usually from 30 minutes to 100 hours, preferably from 1 to 72 hours.

Production Method 2a-2

The compound (I) can be produced by subjecting a compound represented by the formula (VIIa-2):

wherein symbols are of the same meaning as defined above, or its ester or salt [as the ester or salt, use

can be made of ones similar to those of (I)], to ring- closure reaction, followed by, depending on necessity, removing the protecting groups. Like in the case of Production Method 2a-l, when reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formula of the compound (VIIa-2), these groups may optionally be protected, in accordance with a conventional method, with any of the protecting groups mentioned below, and these protective groups may optionally be removed in accordance with a conventional method.

The ring-closure reaction is conducted in an inert solvent. Preferable examples of the inert solvent include aromatic hydrocarbons, ethers and halogenated hydrocarbons as employed in the above Production Method 2-1. The reaction is conducted under heating at temperatures ranging from about 0 to 160°C, preferably from about 30 to 140°C. While the reaction time depends on the kinds of the compound (VIIa-2) and the reaction temperature then employed, it ranges usually from about 30 minutes to 10 hours, preferably from one hour to 72 hours. Production Method 2b

The compound (lb) of this invention can also be produced by subjecting a compound of the formula (VIlb)

wherein M and G stand for groups which form double bond by reacting with each other, in other words, M reacts with G to form double bond, and, other symbols are of the same meaning as defined above, or an ester or salt thereof [as the ester or salt, use can be made of

similar ones as those of (I)] to ring-closure reaction. Practical examples of M and G include, besides =0, =S and =Se, those described in JPA H4(1994)-179389. As the ring-closure reaction, per se known reactions [for example, Annual Reports in Organic

Synthesis, 1975-1993, Academic Press, Inc. San Diego, and Advanced Organic Chemistry Second Edition, Plenum Press New York and London (1983)] can be employed. Practically, Wittig type reaction (Wittig, Honer, Emonds reaction), Peterson type reaction, Aldol type reaction accompanying dehydration and Macmary type reaction using a low-electron value metal, for example, can be employed. More desirably, a Wittig type reaction employing, for example, R ⁷

As M, 0, S, Se, P(R ⁷ ) ₃ ,pC _R 7

H ⁷ '

[wherein R 7 and R7' stand for a lower alkoxy group, a lower alkyl group or aryl group] is mentioned. Examples of more practical methods include the following ones. Production Method 2b-1

The compound (lb) can also be produced by allowing a compound represented by the formula (Vllb-1)

wherein G stands for 0 or S, and other symbols are of the same meaning as defined in the formula (I), or an ester or salt thereof [as the ester or salt, use can be made of similar ones to those of (I)], to react with a compound represented by the formula P(R ⁷ ) ₃ (VIII) or,

P(R ⁷ ) ₂ R ^7' (VIII')

(wherein R ⁷ and R are of the same meaning as defined above), followed by, depending on necessity, removing the protective ^" groups .

When reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formula of the compound (VIIb-1), these groups may optionally be protected with the protective groups described below in accordance with a conventional method. After completion of the reaction, these protective groups can be removed by a conventional method.

As the lower alkoxy group shown by R or R , use is made of, for example, Ci_ ₆ alkoxy groups such as methoxy, ethoxy, propoxy and butoxy, as the lower alkyl group, use is made of, for example, C _j _ ₆ alkyl groups such as methyl, ethyl, propyl, butyl and pentyl, and, as the aryl group, use is made of C ₆ . ₁₀ aryl groups such as phenyl.

These reactions are conducted usually under heating in the absence of solvent or in an inert solvent. While, as the inert solvent to be employed for the reaction, any one can be used so long as it does not hamper the reaction, preferable examples of such solvents include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, or halogenated hydrocarbons such as dichloromethane and chloroform. The amount of the compound (VIII) or (VIII') to be employed is 2 molar equivalents or more, preferably 2 to 10 molar equivalents, of the compound (VIIb-1) .

While the reaction temperature varies with the starting compounds (VIIb-1), (VIII), (VIII') and kinds of the solvent, it ranges usually from about 20 to 160 °C, preferably from about 80 to 140 °C. The reaction time ranges usually from 30 minutes to 100 hours, preferably from 1 to 72 hours.

Production Method 2b-2

The compound (I) can be produced by subjecting a compound represented by the formula (VIIb-2):

wherein symbols are of the same meaning as defined above, or its ester or salt [as the ester or salt, use can be made of ones similar to those of (I)], to ring- closure reaction, followed by, depending on necessity, removing the protecting groups. Like in the case of Production Method 2-1, when reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formula of the compound (VIIb-2), these groups may optionally be protected, in accordance with a conventional method, with any of the protecting groups mentioned below, and these protective groups may optionally be removed in accordance with a conventional method.

The ring-closure reaction is conducted in an inert solvent. Preferable examples of the inert solvent include aromatic hydrocarbons, ethers and halogenated hydrocarbons as employed in the above Production Method 2-1. The reaction is conducted under heating at temperatures ranging from about 0 to 160 °C, preferably from about 30 to 140 °C. While the reaction time depends on the kinds of the compound (VIIb-2) and the reaction temperature then employed, it ranges usually from about 30 minutes to 10 hours, preferably from one hour to 72 hours.

As the starting materials employed in Production Method 2a, 2a-l, 2a-2, 2b, 2b-l and 2b-2, i.e. the compounds represented by the formulae (Vila), (VIIa-1),

(VIIa-2), (Vllb), (VIIb-1) and (VIIb-2), use is made of, for example, compounds represented by the formulae (Ilia) and (Illb) , which can be produced by known methods [for example, methods disclosed in JPA S59(1984)-51286, JPA S60(1985)-19764, or Comprehensive Organic Synthesis, Vol.l to Vol.9, Pergamon Press, Oxford (1991)] or methods analogous or similar thereto. In these production steps, when an amino group is contained in the structures of the compounds represented by (Ha), (Ilia), (VIIa-1), (VIIa-2),

(lib), (Illb), (VIIb-1) and (VIIb-2) or esters of salts thereof [as the ester or salt, use can be made of ones similar those of (I)], the amino group may preferably be protected with a protecting group. As the amino- protecting group, use is conveniently made of, for example, such ones as employed in the fields of β- lactam and peptides. Among them, for example, formyl, chloroacetyl, phenyl acetyl, phenoxy acetyl, t- butoxyacetyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trityl and allyloxycarbonyl are preferable. And, when a hydroxyl group is contained in the structures of similar compounds, the hydroxyl group may optionally be protected. As the hydroxyl-protecting group, use is conveniently made of, for example, such one as employed in the fields of β-lactam and peptides. Among them, use is made of, for example, chloroacetyl, benzyl, p- nitrobenzyl, o-nitrobenzyl, methylthiomethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, 2-tetrahydropyranyl, 4-methoxy-4- tetrahydropyranyl, p-nitrobenzyloxycarbonyl, o- nitrobenzyloxycarbonyl and allyloxycarbonyl. Further, when a carboxyl group is contained in the structures of similar compounds, the carboxyl group may optionally be

protected. As the carboxyl-protecting group, use is made of, for example, such ones as employed in the fields of β-lactam and peptides. Among them, use is made of benzyl, benzhydryl, trityl, p-methoxybenzyl, p- nitrobenzyl, o-nitrobenzyl, phenethyl, 2- trimethylsilylethyl, bis(p-methoxyphenyl)methyl, tertiary butyl and allyl.

The group represented by X or X' may, when desired, optionally be converted to a different group represented by X or X' by conducting an adequate functional group conversion at the step of producing the compound represented by the formula (I) or (III) or at the stage of the compound represented by the formula (I) or (III). For the conversion reaction, a conventional reaction can be employed [e.g. R. C.

Larock, Comprehensive Organic Transformation, VCH, New York (1989)].

The carboxyl group shown by COOH of the object compound (I) may, as described above, optionally be esterified. R of the esterified carboxyl group shown by COOR may, when desired, optionally be converted to different R at the step of producing the compound represented by the formula (I) or (II) or at the stage of the compound represented by the formula (I) or (II). For this conversion, use can be made of a reaction commonly employed for a similar purpose in the field of β-lactam type antibiotics.

The object compound (I) thus produced can be isolated and purified by conventional means, for example, solvent-extraction, pH change, phasic transfer, salting out, crystallization, recrystallization and chromatography. And, when a protecting group is contained in the reaction product, the compound (I) is produced by, when so desired, removing the protecting group by a conventional method. So far, in the fields of β-lactam and peptide

synthesis, protecting groups of amino, hydroxyl or carboxyl have been sufficiently studied, and the methods of protecting and deprotecting are established. These methods can be utilized in the method of producing the object compound of this invention and in the method of producing intermediates thereof. For example, as the method of removing the said protecting group, use is made of conveniently a conventional means selected from means of using acid, means of using base, means of using palladium (0), means of using aluminum chloride, means of using hydrazine, means comprising reduction and means of using sodium N- methyldithiocarbamate.

The compound (I) shows excellent antibacterial activities against gram-positive and gram-negative bacteria including clinically separated strains, which is remarkably less toxic, shows excellent oral absorbability and is physico-chemically and biochemically stable (especially stable against DHP-I), thus being a valuable antibiotic substance. The compound (I) is, therefore, utilized as drugs for man and domestic animals, which can be safely used as an antibacterial agent for the therapy and prophylaxis of infectious diseases caused by various bacteria. Further, the compound (I) of this invention can be added to animal feed as, for example, a bactericidal agent for preservation of the feed. And, it can also be used as bactericidal agent for clearing harmful bacteria on medical and dental appliances. The compound (I) of this invention can be used, singly or in combination with any other active components (for example, any other antibiotic agents, anti-inflammatory agents, antipyretics and analgesics), and, depending on necessity, adding, besides pharmaceutically acceptable carriers, adjuvants e.g. a stabilizer and dispersant, as pharmaceutical

preparations such as injections, capsules, tablets, liquid medicines (e.g. suspensions and emulsions) formulated by conventional methods. These preparations can be administered non-orally (e.g. intravenous or intramuscular injection) or orally.

Injectable preparations can be provided in a dosage form of ampoules or vials supplemented with a preservative. These preparations may optionally be suspensions, solutions or emulsions in an oleaginous or aqueous medium, which may contain an adequate amount of conventional adjuvants such as a suspending agent, stabilizer and/or dispersant. The compound (I) of this invention can also be provided in a form of a pulverized or powdery agent, which can be used, by dissolving in sterilized water containing no pyrogenic substance.

The compound (I) can be formulated into tablets, capsules, powdery preparations or pulverized preparations by adequately mixing with a binder (e.g. syrup, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinyl pyrrolidone and methyl cellulose), a filler (e.g. lactose, sugars, corn starch, calcium phosphate, sorbitol and glycine), a lubricant (e.g. magnesium stearate, talc, polyethylene glycol and silica), a disintegrator (e.g. potato starch) or a wetting agent (e.g. sodium lauryl sulfate). Tablets, powdery preparations and the like can be film-coated by a per se known method. Orally administrable preparations may also be used as liquid preparations e.g. aqueous or oily suspensions, solutions, emulsions, syrups and elixir.

And, these preparations may be mixed with other components, for example, a known antioxidant, preservative, binder, wetting agent, lubricant, sticking agent or flavoring agent. These preparations may further be mixed with any other active components

(e.g. any other β-lactam type antibiotic substances) to give those showing a broader spectrum of antibacterial activities.

The ratio of the compound (I) in the medicinal composition containing the compound (I), though variable with forms of the composition, may be that commonly employed in general antibiotic preparations. For example, in a solid preparation such as capsules, tablets and granules, the ratio of the compound (I) ranges from about 30 to 95 weight %.

The compound (I) can be used for the therapy and prophylaxis of infectious diseases from bacteria in man and any other mammalian animals (e.g. mouse, rat, rabbit, dog, cat, cow and pig), as exemplified by respiratory infectious diseases, urinary tract infection, suppurative diseases, inflammatory diseases of biliary tract, intestinal infectious diseases, infectious diseases in the field of obsterics and gynecology, infectious diseases in the field of oto- rhino-laryngology and infectious diseases in the field of surgery. For example, in the case of respiratory infectious diseases, the dosage of the compound (I) per day, though variable with, for example, symptoms of patients, body weights and administration routes, ranges, in non-oral administration, from about 0.5 to

80 mg, preferably from about 2 to 40 mg per 1 kg of the body weight of adult patients. The administration is preferably conducted intravenously or intramuscularly divided into 1 to 4 doses daily. And, the daily dose of oral administration ranges from about 1 to 500 mg, preferably about 5 to 100 mg, in terms of the active component [i.e. the compound (I)] per 1 kg of the body weight of adult patients, divided into 1 to 3 doses.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Reference Examples and Working

Examples will describe the present invention in more detail. These are, however, mere examples and are not intended to limit the scope of this invention.

Elution in the column chromatography in the following Reference Examples and Working Examples was conducted under observation by TLC (thin-layer chromatography) . In the TLC observation, as TLC plate, 60F ₂₅₄ manufactured by Merck & Co.,Inc. was employed, as the developing solvent, use was made of the solvent employed as the eluent in the column chromatography, and, as the detection method, a UV detector was employed. As silica gel for the column, use was made of kieselguhr 60 (70-230 mesh or 230-400 mesh) manufactured by Merck & Co.,Inc. The CHP-20P resin is the product of Mitsubishi Chemical Industries, Ltd. The solvent was used, depending on necessity, after purification and drying. IR spectrum was measured by using IR-810 manufactured by Nihon Bunkosha or FT-200 manufactured by Horiba, Ltd. NMR spectrum was measured, using, as internal or external standard, tetramethyl silane or sodium 3-

(trimethylsilyl)propionate, by means of GEMINI 200 (200MHz) specrtrometer manufactured by Varian Co., and all the δ values were shown by ppm. The numerical values shown within parenthesis ( ) are mixture ratio of each solvent by volume. Percent (%) in the mixed solvents means volume %. Symbols in Reference Examples and Working Examples have the following meanings . s : singlet d : doublet t : triplet q quartet quint : quintet like dd : double doublet ddd : double double doublet m : multiplet

dt : double triplet dq : double quartet td : triple doublet tt : triple triplet br : broad

J : coupling constant

And, abbreviations in Reference Examples and Working Examples have the following meanings. THF: tetrahydrofuran DMF: dimethylformamide DMA: dimethylacetamide PNB: p-nitrobenzyl (or 4-nitrobenzyl) hexetil: l-(eyelohexyloxycarbonyloxy)ethyl Py: 2-pyridyl

Reference Example la

5-(4-Methoxybenzylthio)-3,4,5,6-tetrahydropyrimidine-

2(lH)-thione

To a THF solution (6 ml) of 2-(4- methoxybenzylthio)propane-1,3-diamine (0.5 g) produced by the method of JPA S60(1985)-132985 was added dropwise at 0°C carbon disulfide (0.26 g) . The mixture was stirred for 30 minutes at 0°C and for further one hour at room temperature. To the reaction mixture was added 6 ml of ether. Insolubles were collected by filtration, washed with ether and vacuum-dried. A THF solution (6 ml) of the resulting solid matter was stirred for 3 hours while heating under reflux. The solvent was distilled off under reduced pressure to leave the titled compound (332 mg) as a colorless solid product.

IR(KBr): 3180, 1605, 1565, 1540, 1510 cm ^"1 . ¹ H-NMR(CDC1 ₃ )6: 2.91(IH,tt,J=9.4,4.6Hz) , 3.13(2H,dd,J=12.6,9.4Hz) , 3.36(2H,dt,J=12.6,4.6Hz) , 3.76(2H,s), 3.81(3H,s), 6.56(2H,brs) ,

6.86(2H,d,J=8.8Hz) , 7.22(2H,d,J=8.8Hz) .

Reference Example 2a

5-(4-Methoxybenzylthio)-2-methylthio-l,4,5,6- tetrahydropyrimidine

To a DMF solution (3 ml) of 5-(4- methoxybenzylthio)-3,4,5,6-tetrahydropyrimidine-2(1H)- thione (314 mg) was added at 0°C sodium hydride (purity 55%, 56 mg) . The mixture was stirred for 30 minutes. To the reaction mixture was added methyl iodide (166 mg) at 0°C, and the mixture was stirred for one hour and half. To the reaction mixture was added water dropwise at 0°C to decompose sodium hydride. The reaction mixture was subjected to extraction with ether. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The solid residue was washed with a solvent (ether-hexane, 2:1), followed by drying under reduced pressure to give the titled compound (243 mg) as a white solid product. IR(KBr): 1600, 1510 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 2.32(3H,s), 2.75-3.00(lH,m) , 3.10-

3.30(2H,m), 3.40-3.65(2H,m) , 3.75(2H,s), 3.80(3H,s),

6.84(2H,d,J=8.8Hz), 7.24(2H,d,J=8.8Hz) .

Reference Example 3a

Dimethyl N-(thiazol-2-yl)dithiocarbonimidate To a DMF solution (10 ml) of 2-aminothiazole (1.0 g) were added dropwise, at 0°C, a ION solution of sodium hydroxide (1.2 ml) and, then, carbon disulfide (1.52 g) . The mixture was stirred for 30 minutes at 0°C, to which was added dropwise a 10 solution of sodium hydroxide (1.2 ml). The mixture was stirred for further 30 minutes at 0°C, to which was added dropwise methyl iodide (2.9 g), followed by stirring for one hour at 0°C. To the reaction mixture was added water (100 ml), which was subjected to extraction with ether. The extract was washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The

solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 75 g, developing solvent: ethyl acetate - hexane. 1:8) to give the titled compound (1.60 g) as a reddish oily product. IR(neat): 1540, 1520 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.60(6H,s), 7.10( lH,d,J=3.6Hz) , 1.59(lH,d,J=3.6Hz) . Reference Example 4a 5-(4-Methoxybenzylthio)-2-(thiazol-2-yl)amino-1,4,5,6- tetrahydropyrimidine

An acetonitrile solution (10 ml) of dimethyl N- (thiazol-2-yl)dithiocarbonimidate (0.39 g) and 2-(4- methoxybenzylthio)propane-l,3-diamine (0.43 g) was stirred for 2.5 hours at room temperature, then for further 2 hours at 50°C. The solvent was distilled off under reduced pressure to leave a solid residue, which was washed with ether, then dried under reduced pressure to give the titled compound (399 mg) as a yellowish solid product.

IR(KBr): 3450, 1640, 1560, 1505 cm ^"1 . ^X H-NMR(CDC1 ₃ )δ: 2.96( IH,tt,J=9.4,4.4Hz) , 3.23(2H,dd,J=12.2,9.4Hz), 3.52(2H,dd,J=12.2,4.4Hz) , 3.77(2H,s), 3.80(3H,s), 6.51( lH,d,J=3.6Hz) , 6.85(2H,d,J=8.6Hz) , 7.12( lH,d,J=3.6Hz) , 7.24(2H,d,J=8.6Hz) . Reference Example 5a 6-(4-Methoxybenzylthio)-5H-2,3,6,7- tetrahydrothiazolo[3,2-a]pyrimidine To a DMF solution (15 ml) of 5-(4- methoxybenzylthio)-3,4,5,6-tetrahydropyrimidine-2 ( IH)- thione (805 mg) was added, at 0°C, sodium hydride (purity 55%, 314 mg) . The mixture was stirred for 30 minutes. To the reaction mixture was added, at 0°C, 1,2-dibromoethane (0.31 ml). The mixture was stirred for 3 hours at room temperature, and overnight at 70°C.

To the reaction mixture was added water dropwise at room temperature to decompose excess sodium hydride. The reaction mixture was subjected to extraction with ether. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 40 g, developing solvent: methanol-dichloromethane, 1:9) to give the titled compound (370 mg) as a pale yellow solid product.

IR(KBr): 1630, 1510 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.80-3.00(lH,m) , 3.00-3.40(5H,m) , 3.40- 3.70(3H,m), 3.76(2H,s), 3.81(3H,s), 6.86(2H,d,J=8.6Hz) , 7.25(2H,d,J=8.6Hz) . Reference Example 6a

Dimethyl N-(dimethylcarbamoyl)dithiocarbonimidate

Sodium hydride (purity 55%, 1.0 g) was washed with hexane, to which was added THF (40 ml) at 0°C. To the mixture was further added 1,1-dimethylurea (1.0 g) , which was stirred for 30 minutes at room temperature. To the reaction mixture was added dropwise carbon disulfide (2.5 g) at 0°C, to which was added DMF (10 ml), followed by stirring for 30 minutes at room temperature. To the reaction mixture was added methyl iodide (4.5 g) at 0°C, which was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice-water (100 ml), which was subjected to extraction with ether. The extract solution was washed with a saturated aqueous saline solution, which was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl.hexane, 1:2) to give the titled compound (1.18 g) as a brown oily product.

IR(neat): 1650, 1565, 1525 cm ^"1 .

¹ H-NMR ( CDCl ₃ ) δ : 2 . 50 ( 6H , s ) , 3 . 02 ( 3H, s ) , 3 . 04 ( 3H , s ) .

Reference Example 7a

2-(Dimethylcarbamoylimino)-5-(4- methoxybenzylthio)perhydropyrimidine An acetonitrile solution (10 ml) of dimethyl N-

(dimethylcarbamoyl)dithiocarbonimidate (290 mg) and 2-

(4-methoxybenzylthio)propane-1,3-diamine (340 mg) was stirred for 3 hours at 80°C. The solvent was distilled off under reduced pressure to leave a solid matter, which was washed with ether, followed by drying in vacuo to give the titled compound (318 mg) as a white solid product.

IR(KBr): 1615, 1575, 1510 cm ^"1 .

^-NMRfCDCl^δ: 2.80-3.00(lH,m) , 2.94(6H,s), 3.14(2H,dd,J=11.8&9.4Hz) , 3.39(2H,dd,J=ll.8&4. Hz) ,

3.75(2H,s), 3.81(3H,s), 6.85(2H,d,J=8.8Hz) ,

7.22(2H,d,J=8.8Hz) .

Reference Example 8a

Dimethyl N-benzoyldithiocarbonimidate Starting from benzamide (1.21 g) , the titled compound (1.87 g) was produced as a yellow solid product by substantially the same procedure as in

Reference Example 6a.

IR(KBr): 1630, 1440, 1420 cm ^"1 . ^-NMRfCDCl^δ: 2.61(6H,s), 7.40-7.60(3H,m) , 8.05-

8.20(2H,m) .

Reference Example 9a

2-(Benzoylimino)-5-(4- methoxybenzylthio)perhydropyrimidine Starting from dimethyl N- benzoyldithiocarbonimidate (450 mg), the titled compound (566 mg) was produced as a white solid product by substantially the same procedure as in Reference

Example 7a. IR(KBr): 1625, 1600, 1580, 1515 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.85-3.00(lH,m) , 3.05-3.25(2H,m) , 3.30-

3.50(2H,m), 3.74(2H,s), 3.81(3H,s), 6.86 ( 2H,d, J=8.4Hz ) ,

7.22(2H,d,J=8.4Hz) , 7.30-7.50 ( 3H,m) , 8.05-8.15 (2H,m) .

Reference Example 10a

Dimethyl N-acetyldithiocarbonimidate Starting from acetamide (1.77 g) , the titled compound (859 mg) was produced as a brown oily product y substantially the same procedure as in Reference

Example 6a.

IR(neat): 1700, 1570, 1450, 1420 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 2.26(3H,s), 2.50(6H,s).

Reference Example 11a

2-(Acetylimino)-5-(4- methoxybenzylthio)perhydropyrimidine

Starting from dimethyl N-acyl dithiocarboinimidate (490 mg), the titled compound (626 mg) was produced as a white solid product by substantially the same procedure as in Reference Example 7a.

IR(KBr): 1640, 1600, 1510 cm ^"1 .

^-NMRfCDClaJδ: 1.99(3H,s), 2.80-3.00(lH,m) , 3.16(2H,dd,J=12.0&9.6Hz) , 3.43(2H,dd,J=12.0&4.6Hz) ,

3.77(2H,s), 3.81(3H,s), 6.86(2H,d,J=8.6Hz) ,

7.23(2H,d,J=8.6Hz) .

Reference Example 12a

Dimethyl N-(phenylsulfonyl)dithiocarbonimidate Starting from benzene sulfonamide (3.14 g) , the titled compound (590 mg) was produced as a white solid product by substantially the same procedure as in

Reference Example 6a.

IR(KBr): 1470, 1300, 1150 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 2.54(6H,s), 7.45-7.65(3H,m) , 7.95-

8.05(2H,m) .

Reference Example 13a

5-(4-Methoxybenzylthio)-2-

(phenylsulfonylimino)perhydropyrimidine Starting from dimethyl N-

(phenylsulfonyl)dithiocarbonimidate (734 mg) , the

titled compound (578 mg) was produced as a white solid product by substantially the same procedure as in

Reference Example 7a.

IR(KBr): 3350, 1625, 1580, 1510, 1375, 1340, 1280, 1250, 1130 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.70-3.00( lH,m) , 3.05-3.25(2H,m) , 3.35-

3.60(2H,m), 3.70(2H,s), 3.80(3H,s), 6.83(2H,d,J=8.8Hz) ,

7.19(2H,d,J=8.8Hz), 7.30-7.60( 3H,m) , 7.75-7.95(2H,m) .

Reference Example 14a Dimethyl N-(pyrimidin-2-yl)dithiocarbonimidate

Starting from 2-aminopyrimidine (1.0 g), the titled compound (940 mg) was produced as a brown oily product by substantially the same procedure as in

Reference Example 6a. IR(neat): 1580, 1550, 1530 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.58(6H,s), 7.02( IH,t,J=4.8Hz) .

8.69(2H,d,J=4.8Hz) .

Reference Example 15a

5-(4-Methoxybenzylthio)-2-[ (pyrimidin-2- yl)imino]perhydropyrimidine

Starting from Dimethyl N-(pyrimidin-2- yl)dithiocarbonimidate (400 mg), the titled compound

(559 mg) was produced as a white solid product by substantially the same procedure as in Reference Example 7a.

IR(KBr): 1640, 1580, 1560, 1505 cm ^"1 .

^-NMRfCDCl^δ: 3.00( IH,tt,J=9.6&4.4Hz) ,

3.27(2H,dd,J=12.0&9.6Hz), 3.63(2H,dd,J=12.0&4.4Hz) ,

3.79(2H,s), 3.80(3H,s), 6.54( IH,t,J=4.8Hz) , 6.86(2H,d,J=8.8Hz) , 7.26 (2H,d,J=8.8Hz) ,

8.32(2H,d,J=4.8Hz) .

Reference Example 16a

2-Cyanoimino-5-(4-methoxybenzylthio)perhydropyrimidine An acetonitrile-DMF (2:1) mixture solution (75 ml) of dimethyl N-cyanodithiocarbonimidate (1.48 g) and 2-

(4-methoxybenzylthio)propane-1,3-diamine (2.29 g) was

stirred for 4 hours at room temperature. The solvent was distilled off under reduced pressure to leave a solid matter, which was washed with a mixture of ethyl acetate and hexane (2:1), followed by drying in vacuo to afford the titled compound (2.01 g) as a white solid product.

IR(KBr): 3250, 3180, 3030, 2170, 1640, 1580, 1510 cm ^"1 .

¹ H-NMR(CDCl ₃ -DMSO-d ₆ )δ: 2.83-3.00( lH,m) , 3.00-

3.20(2H,m), 3.33-3.50(2H,m) , 3.76(2H,s), 3.79(3H,s), 6.84(2H,d,J=8.4Hz) , 7.23(2H,d,J=8.4Hz) , 7.35(2H,brs) .

Reference Example 17a

Dimethyl N-(2-thiazolin-2-yl)dithiocarbonimidate

Starting from 2-amino-2-thiazoline (1.02 g) , the titled compound (190 mg) was produced as a yellow solid product by substantially the same procedure as in

Reference Example 6a.

IR(neat): 1605, 1550, 1545, 1508 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.52(6H,s), 3.46(2H,t,J=8.0Hz) ,

4.26(2H,t,J=8.0Hz) . Reference Example 18a

5-(4-Methoxybenzylthio)-2-[ (2-thiazolin-2- yl)imino]perhydropyrimidine

Starting from dimethyl N-(2-thiazolin-2- yl)dithiocarbonimidate (185 mg) , the titled compound (172 mg) was produced as a white solid product by substantially the same procedure as in Reference

Example 7a.

IR(KBr): 1637, 1568, 1510 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.80-3.00( lH,m) , 3.17(2H,dd,J=12.2&10.4Hz) , 3.17 (2H,t,J=7.6Hz) ,

3.49(2H,dd,J=12.2&4.8Hz) , 3.75(2H,s), 3.81(3H,s),

4.06(2H,d,J=7.6Hz) , 6.85(2H,d,J=8.4Hz) ,

7.23(2H,d,J=8.4Hz) .

Reference Example 19a Dimethyl N-(methylsulfonyl)dithiocarbonimidate

Starting from methanesulfonamide (3.80 g), the

titled compound (1.68 g) was produced as a white solid product by substantially the same procedure as in

Reference Example 6a. Known compound.

Reference Example 20a 5-(4-Methoxybenzylthio)-2-

(methylsulfonylimino)perhydropyrimidine Starting from dimethyl N-

(methylsulfonyl)dithiocarbonimidate (0.88 g), the titled compound (0.8 g) was produced as a white solid product by substantially the same procedure as in

Reference Example 7a.

IR(KBr): 3350, 1640, 1610, 1580, 1510 cm ^"1 .

¹ H-NMR(CDCl ₃ -CD ₃ OD)δ: 2.91(3H,s),

2.98(lH,tt,J=8.4&4.4Hz) , 3.17 (2H,dd,J=12.4&8.4Hz) , 3.47(2H,dd,J=12.4&4.4Hz) , 3.80(2H,s), 3.82(3H,s),

6.89(2H,d,J=8.6Hz) , 7.27(2H,d,J=8.6Hz) .

Reference Example 21a

Dimethyl N-[ (pyridin-3-yl)carbonyl]dithiocarbonimidate

Starting from 3-pyridinecarboxamide (4.88 g) , the titled compound (4.5 g) was produced as a yellow solid product by substantially the same procedure as in

Reference Example 6a. Known compound.

Reference Example 22a

5-(4-memthoxybenzylthio)-2-[ (pyridin-3- yl)carbonylimino]perhydropyrimidine

Starting from dimethyl N-[ (pyridin-3- yl)carbonyl]dithiocarbonimidate (1.56 g) , the titled compound (1.89 g) was produced as a white solid product by substantially the same procedure as in Reference Example 7a.

IR(KBr): 1615, 1600, 1580, 1555, 1515 cm ^"1 .

^-NMRfCDClaJδ: 2.90-3.10( lH,m) ,

3.23(2H,dd,J=12.0&9.2Hz), 3.48(2H,dd,J=12.0&4.4Hz) ,

3.79(2H,s), 3.82(3H,s), 6.87(2H,d,J=8.8Hz) , 7.25(2H,d,J=8.8Hz), 7.30(lH,ddd,J=7.8,4.8&0.8Hz) ,

8.34(lH,dt,J=7.8&2.0Hz) , 8.64( lH,dd,J=4.8&2.0Hz) ,

9 . 30 ( lH, dd, J=2 . 0&0 . 8Hz ) .

Reference Example 23a

Dimethyl N-(pyridin-4-yl)dithiocarbonimidate

Starting from 4-aminopyridine (2.82 g) , the titled compound (1,83 g) was produced as a white solid product by substantially the same procedure as in Reference

Example 6a.

IR(KBr): 1575, 1540 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.52(6H,s), 6.79(2H,dd,J=4.6&1.6Hz) , 8.49(lH,dd,J=4.6&1.6Hz) .

Reference Example 24a

5-(4-methoxybenzylthio)-2-[ (pyridin-4- yl)imino]perhydropyrimidine

Starting from dimethyl N-(pyridin-4- yl)dithiocarbonimidate (1.83 g) , the titled compound

(1.41 g) was produced as a white solid product by substantially the same procedure as in Reference

Example 7a.

IR(KBr): 1640, 1605, 1580, 1540, 1510 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 2.90-3.05(lH,m) , 3.15(2H,dd,J-

11.8&8.8HZ), 3.39(2H,dd,J=11.8&4.4Hz), 3.76(2H,s),

3.81(3H,s) , 6.80(2H,dd,J=4.8&1.6Hz) ,

6.86(2H,d,J=8.6Hz) , 7.24(2H,d,J=8.6Hz) ,

8.34(2H,dd,J=4.8&1.6Hz) . Reference Example 25a

1,3-Bis (methylamino) propan-2-ol

To l,3-dichloropropan-2-ol (19.3 g) was added a methanol solution of methylamine (40%, 75 ml). The mixture was stirred for 3 hours at 120°C in a sealed tube. Insolubles were filtered off, and the filtrate was concentrated to afford the titled compound (20.7 g ⁾ .

Reference Example 26a

(2-Hydroxy-l,3-propanediyl)bis[ (methylimino)bis formic acid t-butyl]

To a tetrahydrofuran solution (100 ml) of 1,3-bis

(methylamino) propan-2-ol (17.7 g) were added IN NaOH (195 ml) and, subsequently, a tetrahydrofuran solution (330 ml) of bis (t-butyl carbonate)anhydride (72.0 g) at 0°C. The mixture was stirred for 2 days at room temperature. Tetrahydrofuran was distilled off under reduced pressure. The remaining solution was subjected to extraction with ether. Organic layers were combined, which was washed with a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier; silica gel, 300 g, developing solvent; ethyl acetate-hexane, 1:4) to afford the titled compound (26.7 g) as a colorless oily product.

IR(neat): 3444, 3976, 1699, 1483, 1392, 1155 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.46(18H,s), 2.04(lH,s), 2.93(6H,s), 3.10-3.42(4H,m) , 3.95-4.02(lH,m) . Reference Example 27a (2-methylsulfonyloxy-l,3- propanediyl)bis[ (methylimino)bis formic acid t-butyl]

To a tetrahydrofuran solution (150 ml) of (2- hydroxy-l,3-propanediyl)bis[ (methylimino)bis formic acid t-butyl] (26.7 g) were added, under ice-cooling, triethylamine (14.0 ml) and, subsequently, methanesulfonyl chloride (7.14 ml). The mixture was stirred for 2 hours. To the reaction mixture was added ethyl acetate (300 ml). The organic layer was washed with water, 0.5N HC1, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, successively. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave the titled compound (28.9 g) as a colorless oily product. IR(neat): 1697, 1365, 1174, 1157 cm ^"1 .

^-NMRfCDCl^δ: 1.47(18H,s), 2.95(6H,s), 2.98(3H,s),

2.98(3H,s), 3.36-3.57(4H,m) , 4.98-5.05( lH,m) . Reference Example 28a [2-(4-Methoxybenzylthio)-1, 3- propanediyl]bis[ (methylimino)bis formic acid t-butyl] To a dimethylformamide solution (240 ml) of 4- methoxybenzyl mercaptan (15.2 ml) was added sodium hydride (3.24 g) . The mixture was stirred for 10 minutes at room temperature and for 20 minutes at 80°C. The reaction mixture was cooled to -10°C, to which was then added a dimethylformamide solution (45 ml) of (2- methylsulfonyloxy-l,3-propanediyl)bis[ (methylimino)bis formic acid t-butyl] (28.9 g) . The mixture was stirred for 32 hours at room temperature. The reaction mixture was added to ice-water, which was subjected to extraction with ether. Organic layers were combined, which was washed with water, then, with an aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier; silica gel, 280 g, developing solvent; ethyl acetate-hexane, 1:5) to afford the titled compound (12.6 g) as a colorless oily product. IR(neat): 2974, 1693, 1512, 1392, 1250, 1174, 1153 cm ^"

¹ H-NMR(CDCl ₃ )δ: 1.45(18H,s), 2.82(6H,s), 3.03- 3.24(3H,m), 3.39-3.49(2H,m) , 3.71(2H,s), 3.79(3H,s). Reference Example 29a 2-(4-Methoxybenzylthio)-N,N'-dimethyl-1,3- propanediamine

Trifluoroacetic acid (15.4 ml) and anisole (15.4 ml) were added, at 0°C, to [2-(4-methoxybenzylthio)- l,3-propanediyl]bis[ (methylimino)bis formic acid t- butyl] (7 g) . The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure. To the residue was added toluene.

The solvent was gain distilled off by azeotropic distillation. To the residue was added water, and the aqueous layer was washed with haxane. The aqueous layer was adjusted to pH 10.5 with IN NaOH, which was subjected to extraction with dichloromethane. The organic layers were combined and dried over anhydrous sodium carbonate. The solvent was distilled off under reduced pressure to leave the titled compound (3.78 g) as a colorless oily product. IR(neat): 3388, 2937, 1610, 1512, 1456, 1250 cm ^'1 . ^-NMRfCDCl^δ: 1.60(2H,brs) , 2.36(6H,s), 2.59- 2.90(5H,m), 3.71(2H,s), 3.79(3H,s), 6.84(2H,d,J=8.8Hz) , 7.25(2H,d,J=8.8Hz) . Reference Example 30a 2-(Acetylimino)-1,3-dimethyl-5-(4- methoxybenzylthio)perhydropyrimidine

Using dimethyl N-acetyldithiocarbonimidate (404 mg) and 2-( -methoxybenzylthio)-N,N'-dimethyl-1,3- propanediamine (629 mg), substantially the same reaction as in Reference Example 7a was conducted to afford the titled compound (798 mg) as a pale yellow oily product.

IR(neat): 3394, 1585, 1520, 1514, 1410, 1244 cm ^"1 . ^-NMRfCDClaJδ: 2.09(3H,s), 2.96(6H,s), 3.05- 3.34(5H,m), 3.77(2H,s), 3.81(3H,s), 6.86(2H,d,J=8.8Hz) , 7.22(2H,d,J=8.8Hz) . Reference Example 31a

1, 3-Dimethyl-5-(4-memthoxybenzylthio)-2-(thiazol-2- ylimino)perhydropyrimidine Using dimethyl N-acetyldithiocarbonimidate (161 mg) and 2-(4-methoxybenzylthio)-N,N'-dimethyl-1,3- propanediamine (200 mg) , substantially the same reaction as in Reference Example 7a was conducted to afford the titled compound (286 mg) as a pale yellow foamy product.

IR(neat): 3354, 2931, 1539, 1412, 1304, 1246, 1130,

1032, 835 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.88(6H,s), 2.97-3.34(5H,m) ,

3.77(2H,s), 3. ^' 81(3H,s), 6.49(lH,d,J=4.2Hz) ,

6.86(2H,d,J=8.4Hz) , 7.12( lH,d,J=4.2Hz) , 7.24(2H,d,J=8.4Hz) .

Reference Example 32a

5-(4-Methoxybenzylthio)-1,3-dimethyl-2-

(methylsulfonylimino)perhydropyrimidine Starting from dimethyl N- (methylsulfonyl)dithiocarbonimidate (0.79 g) , the titled compound (0.98 g) was produced as a colorless oily product by substantially the same procedure as in

Reference Example 30a.

IR(neat): 3550, 3500, 1610, 1560, 1530, 1510 cm ^"1 . ^-NMRfCDClaJδ: 2.9-3.4(5H,m) , 3.00(3H,s), 3.12(6H,s),

3.77(2H,s), 3.82(3H,s), 6.88(2H,d,J=8.6Hz) ,

7.24(2H,d,J=8.6Hz) .

Reference Example 33a

2-Cyanoimino-5-(4-methoxybenzylthio)-l,3-dimethyl perhydropyrimidine

Starting dimethyl N-cyanodithiocarbonimidate (1.76 g), the titled compound (2.61 g) was produced as a white solid product by substantially the same procedure as in Reference Example 30a. IR(KBr): 2160, 1605, 1560, 1550, 1510 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.85-3.35(5H,m) , 3.12(6H,s),

3.77(2H,s), 3.82(3H,s), 6.89(2H,d,J=8.8Hz) ,

7.24(2H,d,J=8.8Hz) .

Reference Example 34a 2-[2-(N,N-dimethylamino)ethoxy]-5-(4- methoxybenzylthio)-1,4,5,6-tetrahydropyrimidine

2-(Dimethylamino)ethanol (3 ml) was added to 5-(4- methoxybenzylthio)-2-methylthio-1, ,5,6-tetrahydropy- rimidine (1.0 g) . The mixture was stirred for 3 hours while heating under reflux. Under reduced pressure, 2-

(dimethylamino)ethanol was distilled off to leave a

solid matter, which was washed with a mixture of ether and hexane (2:1), followed by drying in vacuo to afford the titled compound (1.02 g) as a white solid product.

IR(KBr): 1640, 1520 cm ^"1 . ^-NMRfCDClaJδ: 2.26(6H,s), 2.53(2H,t,J=5.6Hz) ,

2.82(lH,tt,J=9.2&4.6Hz) , 3.05-3.70(4H,m) , 3.75(2H,s),

3.81(3H,s), 4.09(2H,t,J=5.6Hz) , 6.85(2H,d,J=8.6Hz) ,

7.25(2H,d,J=8.6Hz) .

Reference Example 35a 5-(4-Methoxybenzylthio)-2-[2-[N-methyl-N-(4- nitrobenzyloxycarbonyl)amino]ethoxy]-1,4,5,6- tetrahydropyrimidine

Starting from 5-(4-methoxybenzylthio)-2- methylthio-1,4,5,6-tetrahydropyrimidine (1.0 g) and 2[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]ethanol

(0.9 g) , the titled compound (464 mg) was produced as a yellow solid product by substantially the same procedure as in Reference Example 34a.

IR(KBr): 1700, 1640, 1605, 1520, 1515 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 2.70-2.90(lH,m) , 2.99(3H,s), 3.05-

3.25(2H,m), 3.35-3.55(2H,m) , 3.55(2H,t,J=5.6Hz) ,

3.75(2H,s), 3.80(3H,s), 4.1-4.2(2H,m) , 5.21(2H,s),

6.85(2H,d,J=8.8Hz) , 7.25(2H,d,J=8.8Hz) ,

7.51(2H,d,J=8.8Hz) , 8.22(2H,d,J=8.8Hz) . Reference Example 36a

5-(Benzoylthio)-2-thioxoperhydropyrimidine

To a trifluoroacetic acid solution (65 ml) of 5-

( -methoxybenzylthio)-2-thioxoperhydropyrimidine (1.68 g) was added anisole (6.5 ml, 65 mmol.). The mixture was stirred for 2.5 hours while heating under reflux.

The solvent was distilled off under reduced pressure.

To the residue was added toluene, which was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. To a pyridine solution (25 ml) of the residue was added, at 0°C, benzoyl chloride (0.76 ml). The mixture was stirred for one

hour at 0°C. The solvent was distilled off under reduced pressure. To the residue were added ethyl acetate and water. The resulting precipitate was collected by filtration, which was washed with ethyl acetate to afford the titled compound (1.30 g) as a colorless solid product.. IR(KBr): 3174, 1655, 1558, 1209 cm ^"1 . ¹ H-NMR(DMSO-d ₆ )δ: 3.10-3.30(2H,m) , 3.50-3.70(2H,m) , 4.05-4.20(lH,m), 7.50-7.80( 3H,m) , 7.80-8.00(2H,m) , 8.16(2H,brs) .

Reference Example 37a

6-(Benzoylthio)-3-hydroxy-5H-2,3,6,7- tetrahydrothiazolo[3,2-a]pyrimidine hydrochloride

To 5-(benzoylthio)-2-thioxoperhydropyrimidine (757 mg) were added THF (20 ml) and chloroacetaldehyde (0.77 ml) successively. The mixture was heated overnight under reflux. The reaction mixture was cooled. The resulting solid matter was collected by filtration, which was washed with THF to afford the titled compound (935 mg) as a colorless solid product. IR(KBr): 3178, 1672, 1637 cm ^"1 .

¹ H-NMR(DMSO-d ₆ )δ: 3.20-4.10(8H,m) , 4.30-4.45( lH,m) , 5.60-5.75(lH,m), 7.50-7.80(3H,m) , 7.80-8.00(2H,m) . Reference Example 38a 6-(Benzoylthio)-5H,6,7-dihydrothiazolo[3,2-a]pyrimidine Dichloromethane (40 ml) was added to 6- (benzoylthio)-3-hydroxy-5H-2 ,3,6,7- tetrahydrothiazolo[3,2-a]pyrimidine hydrochloride (1.23 g) . The mixture was cooled to -78°C, to which was added dropwise diisopropyl ethylamine (3.24 ml, 18.6 mmol.). The mixture was stirred for 30 minutes at 0°C, and was again cooled to -78°C, to which was added dropwise anhydrous trifluoromethanesufIonic acid (1.24 ml). The mixture was stirred for for one hour at - 78°C. The reaction mixture was washed with a phosphate buffer solution of pH 7, which was dried over anhydrous

magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column- chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-hexane, 1:4) to afford the titled compound (550 mg) as a colorless oily product.

IR(neat): 3120, 1664, 1635, 1377, 1228, 1200 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 3.30-3.70(2H,m) , 4.00-4.30(3H,m) , 6.24(lH,d,J=5.4Hz) , 7.74(2H,d,J=5.4Hz) , 7.40- 7.70(3H,m), 7.85-8.05(2H,m) . Reference Example 39a

5-(4-Methoxybenzylthio)-2-(2-methoxyethylthio)-1,4,5,6- tetrahydropyrimidine

Sodium hydride (purity 60%, 156 mg) was added, at 0°C, to a DMF solution (8 ml) of 5-(4- methoxybenzylthio)perhydropyrimidine-2-thione (1.0 g) . The mixture was stirred for 30 minutes. To the reaction mixture was added, at 0°C, a DMF solution (2 ml) of 2-bromoethyl methyl ether (518 mg) . The mixture was stirred for 1.5 hour at 0°C then overnight at room temperature. To the reaction mixture was added dropwise water at 0°C to decompose excess sodium hydride. The reaction mixture was subjected to extraction with ether. The extract solution was washed with a saturated aqueous saline solution, which was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethanol-ethyl acetate, 1:20 - 1:4) to afford the titled compound (797 mg) as a white solid product. IR(KBr): 1600, 1510 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 2.84(IH,tt,J=9.6&4.8Hz) , 3.10(2H,t,J=6.0Hz) , 3.18(2H,dd,J=13.2&9.6Hz) , 3.37(3H,s), 3.51(2H,dd,J=13.2&4.8Hz) ,

3.58(2H,t,J=6.0Hz), 3.75(2H,s), 3.80(3H,s),

6.85(2H,d,J=8.6Hz) , 7.25(2H,d,J=8.6Hz) . Reference Example 40a

5-(4-Methoxybenzylthio)-2-(pyridin-2-yl)-1,4,5,6- tetrahydropyrimidine 2-Bromopyridine (0.48 ml) was added dropwise to a DMF solution (5 ml) of 5-(4-methoxybenzylthio)-2- thioxoperhydropyrimidine (1.34 g) . The mixture was stirred for 2 hours at 130°C. To the reaction mixture was added ethyl acetate (20 ml). The mixture was subjected to extraction with water. The aqueous layer was made to a weakly basic with a saturated aqueous solution of sodium hydrogencarbonate, which was further subjected to extraction with ethyl acetate. The extract solution was washed with water and a saturated aqueous saline solution, successively, which was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford the titled compound (1.43 g) as a yellow oily product. IR(neat): 1614, 1512, 1248 cm ^"1 . ^-NMRfCDCl- δ: 2.86-2.99(lH,m) , 3.21-3.33(2H,m) , 3.56- 3.65(2H,m), 3.76(2H,s), 3.80(3H,s), 6.85(2H,d,J=8.4Hz) , 6.95(lH,brs), 7.09-7.16(lH,m) , 7.23-7.31(3H,m) , 7.55- 7.63(lH,m), 8.41-8.44(lH,m) . Working Example la 4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-3-[ (2-methylthio-1,4,5,6-tetrahydropyrimidin-5- yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

To a trifluoroacetic acid solution (7.5 ml) of 5- (4-methoxybenzylthio)-2-methylthio-1,4,5,6- tetrahydropyrimidine (197 mg) was added anisole (0.75 g) . The mixture was stirred for 2 hours by heating under reflux. The solvent was distilled off under reduced pressure. To the residue was added toluene, and the mixture was subjected to azeotropic distillation under reduced pressure to remove

trifluoroacetic acid. To the acetonitrile solution (7 ml) was added dropwise diisopropyl ethylamine (0.49 ml) at 0°C. To the mixture was further added at 0°C 4- nitrobenzyl (4R,5R,6S)-3-[ (diphenylphosphono)oxy]-6- [ (R)-1-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (414 mg) . The mixture was stirred for 2.5 hours at 0°C. To the reaction mixture was added phosphate buffer (pH 7), which was subjected to extraction with dichloromethane, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 10 g, developing solvent: methanol-dichloromethane, 1:10) to give the titled compound (99 mg) as a yellow solid product. IR(KBr): 3400, 1770, 1710, 1600, 1520 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.27(3H,d,J=7.4Hz) , 1.34(3H,d,J=6.2Hz) , 2.34(3H,s), 3.20-3.80(6H,m) , 3.27(lH,dd,J=6.6,2.6Hz) , 4.25(lH,dd,J=9.2,2.6Hz) , 4.25(IH,quint,J=6.6Hz) , 5.22(lH,d,J=13.6Hz), 5.50(lH,d,J=13.6Hz) , 7.65(2H,d,J=8.8Hz) , 8.22(2H,d,J=8.8Hz) . Working Example 2a

Sodium (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4-methyl-3- [ (2-methylthio-1,4,5,6-tetrahydropyrimidin-5-yl)thio]- 7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The compound (30 mg) produced by the method of Working Example la was dissolved in a mixture of THF (1 ml) and a pH 7 phosphate buffer solution (0.1M, 1 ml) . To the solution was added 10% palladium-carbon (30 mg) . The mixture was stirred for one hour at ordinary temperature under hydrogen atmosphere. The catalyst was filtered off and washed with water. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography

(carrier: CHP-20P, 30 ml, developing solvent: water -

5% ethanol-water, 5:100), which was freeze-dried to give the titled compound (11.3 mg) as a white solid product.

IR(KBr): 3400, 1750, 1600 cm ^"1 . ¹ H-NMR(D ₂ 0)δ: 1.23(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) , 2.59(3H,s), 3.30-3.90(6H,m) , 3.51(lH,dd,J=6.2,2.8Hz) , 4.26(lH,quint,J=6.2Hz) , 4.28(lH,dd,J=9.4,2.8Hz) . Working Example 3a 4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-3-[ [2-[ (thiazol-2-yl)amino]-l,4,5,6- tetrahydropyrimidin-5-yl]thio]-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate

To a trifluoroacetic acid solution (12 ml) of 5- (4-methoxybenzylthio)-2-[ (thiazol-2-yl)amino]-1,4,5,6- tetrahydropyrimidine (393 mg) was added anisole (1.2 g) . The mixture was stirred for one hour at 50°C and stirred for further 2 hours while heating under reflux. The solvent was distilled off under reduced pressure. To the residue was added toluene, which was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. To an acetonitrile solution (15 ml) of the residue was added dropwise, at 0°C, diisopropylethylamine (0.38 g) . To the mixture was further added, at 0°C, 4-nitrobenzyl (4R,5R,6S)-3- [ (diphenylphosphono)oxy]-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carbox- ylate (696 mg) . The mixture was stirred for 2 hours at 0°C and for 15 minutes at room temperature. To the reaction mixture was added a pH 7 phosphate buffer solution, which was subjected to extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 50 g, developing solvent: methanol-dichloromethane, 1:20) to give the titled compound (503 mg) as a yellow solid

product .

IR(KBr): 3400, 1770, 1710, 1620, 1560, 1520 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.3 ^" 0(3H,d,J=7.2Hz) , 1.37(3H,d,J=6.2Hz) ,

3.31(lH,dd,J=6.6,2.9Hz), 3.30-3.85(6H,m) , 4.28(lH,dd,J=9.5,2.9Hz) , 4.29(IH,quint,J=6.6Hz) ,

5.23(lH,d,J=13.9Hz), 5.50(lH,d,J=13.9Hz) ,

6.55(lH,d,J=3.7Hz) , 7.15(lH,d,J=3.7Hz) ,

7.64(2H,d,J=8.4Hz) , 8.21(2H,d,J=8.4Hz) .

Working Example 4a Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-

7-oxo-3-[[2-[ (thiazol-2-yl)amino]-1,4,5,6- tetrahydropyrimidin-5-yl]thio]-1-azabicyclo[3.2.0]hept-

2-ene-2-carboxylate

The compound produced in Working Example 3a (250 mg) was dissolved in a mixture of THF (4 ml) and a pH 7 phosphate buffer solution (0.1M, 4 ml) . To the solution was added 10% palladium-carbon (250 mg) , and the mixture was stirred for one hour at ordinary temperatures under hydrogen atmosphere. The catalyst was filtered off and washed with water. The filtrate was washed with dichloromethane. The aqueous layer was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography

(carrier: CHP-20P, 70 ml, developing solvent: ethanol- water: 100 - 40:100), followed by freeze-drying to give the titled compound (140.6 mg) as a white solid product.

IR(KBr): 3400, 1750, 1610 cm ^"1 .

¹ H-NMR(D ₂ 0)δ: 1.24(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.6Hz) , 3.30-3.85(6H,m) , 3.48(lH,dd,J=6.4,2.8Hz) ,

4.26(lH,dd,J=9.4,2.8Hz) , 4.27(IH,quint,J=6.6Hz) ,

6.89(lH,d,J=3.8Hz) , 7.27(lH,d,J=3.8Hz) .

Working Example 5a

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-3-[ (RS)-5H-2,3,6,7- tetrahydrothiazolo[3.2.0]pyrimidin-6-yl)thio]-l-

azabicyclof3.2.0]hept-2-ene-2-carboxylate

To a trifluoroacetic acid solution (6.6 ml) of 6- ( -methoxybenzylthio)-5H-2,3,6,7- tetrahydrothiazolof3,2-a]pyrimidine (190 mg) was added 5 anisole (0.66 ml). The mixture was stirred for 3 hours under reflux. The solvent was distilled off under reduced pressure. To the residue was added toluene, which was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. To an

10 acetonitrile solution (6 ml) of the residue was added dropwise at 0°C diisopropylethylamine (0.28 ml). To the mixture was further added, at 0°C, 4-nitrobenzyl (4R,5R,6S)-3-[ (diphenylphosphono)oxy]-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-

15 ene-2-carboxylate (384 rag), and the mixture was stirred for 1.5 hours at 0°C. To the reaction mixture was added a pH 7 phosphate buffer solution, which was subjected to extraction with ethyl acetate. To the extract solution was added a saturated aqueous saline

2.0 solution, then the mixture was shaken. Resulting precipitates were collected by filtration to give the titled compound (220 mg) as a colorless solid product. IR(KBr): 3410, 1770, 1640, 1515 cm ^"1 . ¹ H-NMR(DMSO-d ₆ )δ: 1.10-1.30(6H,m) , 3.10-4.10(12H,m) ,

25 4.25-4.35(lH,m) , 5.15-5.25(lH,m) ,

5.39(2H,ABq,J=14.4Hz), 7.72(0.5H,d,J=8.8Hz) ,

7.73(0.5H,d,J=8.8Hz) , 8.26(lH,d,J=8.8Hz) .

Working Example 6a

(4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-3-

30 [ (RS)-(5H-2,3,5,7-tetrahydrothiazolo[3,2-a]pyrimidin-6- yl)thio]-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

The compound produced by the method of Working Example 5a (180 mg) was was dissolved in a mixture of

35 THF (10 ml) and a pH 7 phosphate buffer solution (0.1M, 10 ml). To the solution was added 10% palladium-carbon

(89 rag). The mixture was subjected to hydrogenation for one hour at room temperature under ordinary pressure. The catalyst was filtered off and washed with water. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, which was purified by means of a column chromatography (carrier: CHP-20P, 80 ml, developing solvent: water - ethanol-water, 5:95), followed by freeze-drying to give the titled compound (64 mg) as a white solid product.

IR(KBr): 3430, 1755, 1640, 1595 cm ^"1 . 1.23(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) ,

3.30-4.10(HH,m) , 4.20-4.35(2H,ra) .

Working Example 7a l-(Cyclohexyloxycarbonyloxy)ethyl ( (4R,5S,6S)-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-3-[ (RS)-(5H-2,3,6,7- tetrahydrothiazolo[3,2-a]pyriraidin-6-yl)thio]-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The compound produced by the method of Working Example 6a (20.9 rag) and sodium hydrogencarbonate (4.6 mg) were dissolved in water (1 ml). The solution was freeze-dried, which was dissolved, at -15°C, in dry N,N-dimethylacetamide (1 ml). To the solution was added 1-iodoethyl cyclohexyloxycarboxylate (21 mg) . The mixture was stirred for 30 minutes at -15°C, then for one hour at 0°C. To the reaction mixture was added ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution, successively, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 4 g, developing solvent: ethyl acetate - ethanol, 4:1 - 1:1) to give the titled compound (11 mg) as a colorless oily product.

IR(neat): 3300, 2940, 1760, 1720, 1620 cm ^'1 . ^-NMRfCDCl^δ: 1.10-2.10(19H,m) , 3.00-3.80(HH,m) , 4.10-4.30(2H,m ^" ) , 4.50-4.70(2H,m) , 5.80-6.00(lH,m) . Working Example 8-la (4R,5S,6S)-6-[ (R)-1-Hydroxyethyl]-3-[ (2-methoxy-

1,4,5,6-tetrahydropyrimidin-5-yl)thio]-4-methyl-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4- nitrobenzyl

Methyl p-toluenesulfonate (4.9 g) was added to 5- (4-methoxybenzylthio)-3,4,5,6-tetrahydropyrimidin- 2(lH)-one (800 rag). The mixture was stirred for 2 hours at 80°C. The reaction mixture was cooled to room temperature, which was washed with ether, ether- acetonitrile (8:1) and ether successively. The residue was dried in vacuo. To a trifluoroacetic acid solution (30 ml) of this residue was added anisole (3.0 g) . The mixture was stirred for one hour at 50°C. The solvent was distilled off under reduced pressure. To the residue was added toluene, which was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. The residue was dissolved in acetonitrile (20 ml), to which was added dropwise, at 0°C, diisopropylethylamine (1.51 g) . To the mixture was further added, at 0°C, an acetonitrile solution (30 ml) of (4R,5R,6S)-3-[ (diphenylphosphono)oxy]-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid 4-nitrobenzyl (1.60 g) . The mixture was stirred for 1.5 hour at 0°C. The reaction mixture was concentrated under reduced pressure, to which was added ethyl acetate. The mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 30 g, developing solvent: acetonitrile-acetonitrile:ethanol, 2:1) to afford the titled compound (879 mg) as a white solid

product .

IR(KBr): 3420, 1770, 1700, 1650, 1610 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ:- 1.29( 3H,d,J=7.4Hz) , 1.36(3H,d,J=6.2Hz) ,

3.20-3.70(6H,m) , 3.29 ( lH,dd,J=6.6&2.6Hz) , 3.66(3H,s), 4.26(lH,dd,J=9.8&2.6Hz) , 4.27 ( IH,quint,J=6.6Hz) ,

5.22(lH,d,J=13.8Hz) , 5.52(lH,d,J=13.8Hz) ,

7.66(2H,d,J=8.8Hz) , 8.23(2H,d,J=8.8Hz) .

Working Example 8-2a

(4R,5S,6S)-6-[ (R)-1-Hydroxyethyl]-3-[ (2-methoxy- 1,4,5,6-tetrahydropyrimidin-5-yl)thio]-4-methyl-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Starting from the compound (177 mg) produced by the method of Working Exaraple 8-la, the titled compound

(93.1 mg) was produced as a white solid product by substantially the same procedure as in Working Example

2a.

IR(KBr): 3420, 1755, 1660, 1620, 1590 cm ^"1 . 1.24( 3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) ,

3.35-3.60(3H,m) , 3.51( lH,dd,J=6.0&2.4Hz) , 3.65- 3.90(3H,m), 4.00(3H,s), 4.27( lH,quint,J=6.0Hz) ,

4.28(lH,dd,J=9.8&2.4Hz) .

Working Example 9a

(4R,5S,6S)-6-[ (R)-1-Hydroxyethyl]-3-[ (2-methoxy-

1,4,5,6-tetrahydropyrimidin-5-yl)thio]-4-methyl-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 1-

(cyclohexyloxycarbonyloxy)ethyl

To an aqueous solution (2 ml) of the compound

(44.4 rag) produced by the method in Working Example 8-

2a was added an aqueous solution (1 ml) of sodium carbonate (17.3 rag). The mixture was freeze-dried, which was subjected to substantially the same reaction and refining procedure as in Working Example l-3a to afford the titled compound (52 mg) as a white solid product. IR(KBr): 3400, 1760, 1650 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.20-2.30( 10H,m) , 1.27 (3H,d,J=7.2Hz) ,

1.33(3/2H,d,J=6.2Hz) , 1.35( 3/2H,d,J=6.2Hz) , 1.59(3/2H,d,J=5.4Hz), 1.61(3/2H,d,J=5.4Hz) , 3.20- 3.70(6H,m), 3.24(lH,dd,J=6.6&2.4Hz) , 3.70(3H,s), 4.16- 4.32(lH,m), 4.23( lH,dd,J=9.2&2.4Hz) , 4.55-4.75 ( lH,m) , 6.89(lH,q,J=5.4Hz) .

Working Example 10-la

(4R,5S,6S)-3-[[2-

(Dimethylcarbamoylimino)perhydropyrimidin-5-yl]thio]-6-

[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4- nitrobenzyl

Anisole (1.0 g) was added to a trifluoroacetic acid solution (10 ml) of 2-(dimethylcarbamoylimino)-5- (4-methoxybenzylthio)perhydropyrimidine (314 mg) . The mixture was stirred for 2 hours while heating under reflux. The solvent was distilled off under reduced pressure. To the residue was added toluene, which was further subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. The residue was dissolved in acetonitrile (5 ml), to which was added dropwise, at 0°C, diisopropylethylamine (0.34 g) . To the mixture was further added, at 0°C, an acetonitrile solution (10 ml) of (4R,5R,6S)-3- [ (diphenylphosphono)oxy]-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-carboxylic acid 4-nitrobenzyl (0.58 g) . The mixture was stirred for 1.5 hour at 0°C. The reaction mixture was concentrated under reduced pressure, to which was added ethyl acetate. The mixture was washed with water and a saturated aqueous solution of sodium hydrogencarbonate, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 10 g, developing solvent: ethyl acetate-ethanol, 4:1) to afford the titled compound (438 mg) as a white solid product.

IR(KBr): 3420, 1770, 1710, 1620, 1580 cm ^"1 .

¹ H-NMR(CDCl ₃ -DMSO-d ₆ )δ: 1.28(3H,d,J=7.0Hz) ,

1.33(3H,d,J=6.2Hz) , 2.96(6H,s),

3.28(lH,dd,J=7.0&2.4Hz) , 3.20-3.80(6H,m) , 4.16(lH,quint,J=7.0Hz) , 4.30( lH,dd,J=9.2&2.4Hz) ,

5.23(lH,d,J=13.6Hz) , 5.52( lH,d,J=13.6Hz) ,

7.68(2H,d,J=8.8Hz) , 8.23(2H,d,J=8.8Hz) .

Working Exaraple 10-2a

(4R,5S,6S)-3-[[2- (Diraethylcarbamoylimino)perhydropyrimidin-5-yl]thio]-6-

[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium

The compound (151 mg) produced in Working Example

10-la was dissolved in a mixture of THF (5 ml) and a phosphate buffer solution (pH 7, 0.1M, 5 ml). To the solution was added 10% palladium-carbon (151 rag) . The mixture was stirred for one hour at room temperature under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was sufficiently washed with water. From this filtrate, THF was distilled off under reduced pressure. The residue was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, which was purified by means of a column chromatography (carrier; CHP-20P, 50 ml, developing solvent: water-ethanol, 1:10), followed by freeze-drying to afford the titled compound (92 mg) as a white solid product.

IR(KBr): 3420, 1750, 1680, 1610, 1590 cm ^"1 .

^- MR^OJδ: 1.24(3H,d,J=7.2Hz), 1.30(3H,d,J=6.4Hz) , 2.95(6H,s) , _β 3.30-3.90(7H,m) , 4.26 ( lH,dd,J=8.8&2.0Hz) ,

4.27(lH,quint,J=6.6Hz) .

Working Example 10-3a

(4R,5S,6S)-3-[[2-

(Dimethylcarbamoylimino)perhydropyrimidin-5-yl]thio]6- [ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-carboxylic acid 1-

(cyclohexylcarbonyloxy)ethyl

To a DMA solution (1.5 ml) of the compound (46 mg) produced by the method of Working Example 10-2a was added, at -10°C, l-(eyelohexyloxycarbonyloxy)ethyl iodide (0.070 mg) . The mixture was warmed up to 0°C over 30 minutes, which was stirred for 2 hours at 0°C.

To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 15 g, developing solvent: acetonitrile-acetonitrile:ethanol, 4:1) to afford the titled compound (15.2 rag) as a white solid product.

IR(KBr): 3420, 1760, 1620, 1580 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.10-2.10(10H,ra) , 1.26(3H,d,J=7.2Hz) ,

1.33(3/2H,d,J=6.2Hz), 1.35(3/2H,d,J=6.4Hz) ,

1.58(3/2H,d,J=5.4Hz), 1.61(3/2H,d,J=5.4Hz) , 2.97(6H,brs) , 3.20-3.80(6H,m) , 3.26(lH,dd,J=7.0&2.6Hz) ,

4.10-4.35(lH,m), 4.24(IH,quint,J=6.6Hz) , 4.55-

4.75(lH,ra), 6.88(lH,q,J=5.4Hz) .

Working Example 11-la

(4R,5S,6S)-3-[ [2-(Benzoylimino)perhydropyriraidin-5- yl]thio]-6-[ (R)-l-hydroxyethyl]-4-raethyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4- nitrobenzyl

Starting from 2-(benzoylimino)-5-(4- methoxybenzylthio)perhydropyrimidine (560 mg) , the titled compound (708 mg) was produced as a white solid product by substantially the same procedure as in

Working Example 10-la.

IR(KBr): 3400, 1770, 1715, 1600, 1520 cm ^"1 .

^- MRfCDClaJδ: 1.23(3H,d,J=7.4Hz) , 1.37(3H,d,J=6.2Hz) , 3.10-3.60(6H,m), 3.29(lH,dd,J=6.6&2.8Hz) ,

4.21(lH,dd,J=9.6&2.8Hz) , 4.27(IH,quint,J=6.6Hz) ,

5.21(lH,d,J=13.8Hz) , 5.49(lH,d,J=13.8Hz) , 7.30- 7.55(3H,m), 7.64(2H,d,J=8.4Hz) , 8.08(2H,d,J=7.2Hz) , 8.22(2H,d,J=8.4Hz) . Working Example ll-2a Sodium (4R,5S,6S)-3-[ [2-

(benzoylimino)perhydropyrimidin-5-yl]thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

Starting from the compound (66 rag) produced by the method of Working Example 11-la, the titled compound (23.1 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-2a. IR(KBr): 3430, 1750, 1600 cm ^"1 . ¹ H-NMR(D ₂ 0)δ: 1.24(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.2Hz) , 3.35-3.55(3H,m) , 3.49(lH,dd,J=6.6&2.6Hz) , 3.65- 3.90(3H,m) , 4.26(IH,quint,J=6.6Hz) , 4.27(lH,dd,J=9.4&2.6Hz) , 7.45-7.65(3H,m) , 7.90- 8.00(2H,ra) . Working Exaraple ll-3a l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-[ [2- (benzoyliraino)perhydropyriraidin-5-yl]thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate Starting from the compound (54.3 mg) produced by the method of Working Example ll-2a. the titled compound (54.3 mg) was produced as a yellow solid product by substantially the same procedure as in Working Example 10-3a. IR(KBr): 3430, 1760, 1600 cm ^"1 .

^-NMRfCDClaJδ: 1.10-2.10(10H,m) , 1.24(3H,d,J=7.2Hz) , 1.34(3/2H,d,J=6.2Hz), 1.36(3/2H,d,J=6.2Hz) , 1.58(3/2H,d,J=5.4Hz), 1.60(3/2H,d,J=5.4Hz) , 3.15- 3.70(7H,m), 4.15-4.35(2H,m) , 4.55-4.75(lH,m) , 6.88(lH,q,J=5.4Hz), 7.30-7.55(3H,m) , 8.05-8.15(2H,m) . Working Example 12-la

4-Nitrobenzyl (4R,5S,6S)-3-[ [2-

(acetylimino)perhydropyrimidin-5-y1]thio]-6-[(R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate Starting from 2-(acetyliraino)-5-( - methoxybenzylthio)perhydropyriraidine (560 mg), the titled compound (736 mg) was produced as a yellow solid product by substantially the same procedure as in Working Example 10-la. IR(KBr): 3400, 1770, 1715, 1600, 1520 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.24(3H,d,J=7.0Hz) , 1.34(3H,d,J=6.2Hz) , 1.99(3H,s), 3.20-3.70(7H,m) , 4.15-4.35(2H,ra) , 5.21(lH,d,J=13.4Hz) , 5.49(lH,d,J=13.4Hz) , 7.63(2H,d,J=8.8Hz), 8.22(2H,d,J=8.8Hz) . Working Exaraple 12-2a

(4R,5S,6S)-3-[ [2-(Acetylimino)perhydropyrimidin-5- yl]thio]-6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Starting from the compound (262 mg) produced by the method of Working Example 12-la, the titled compound (156 mg) was produced as a white solid product

« by substantially the same procedure as in Working

Example 10-2a.

IR(KBr): 3400, 1755, 1725, 1695, 1640, 1600 era ^"1 . ^- MRfDzOJδ: 1.23(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.2Hz) ,

2.16(3H,s), 3.30-3.60(4H,ra) , 3.60-4.0(3H,ra) , 4.15-

4.35(2H,m) .

Working Example 12-3a l-(Cyclohexylcarbonyloxy)ethyl (4R,5S,6S)-3-[[2- (acetylimino)perhydropyrimidin-5-yl]thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

Starting the compound (54 mg) produced by the method of Working Example 12-2a, the titled compound (43.7 mg) was produced as a white solid product by substantially the same procedure as in Working Example

10-3a .

IR(KBr): 3400, 1750, 1600 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: ^' 1.00-2.10( 10H,m) , 1.27(3H,d,J=7.2Hz) , 1.33(3/2H,d,J=6.2Hz) , 1.35( 3/2H,d,J=6.4Hz) , 1.58(3/2H,d,J=5.4Hz) , 1.61( 3/2H,d,J=5.4Hz) , 2.05(3H,s), 3.27(lH,dd,J=6.4&2.6Hz) , 3.20-3.80(6H,ra) , 4.15- 4.35(2H,m), 4.55-4.75( lH,m) , 6.88( lH,q,J=5.4Hz) . Working Exaraple 13-la 4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- raethyl-7-oxo-3-[ [2-(phenyl¬ sulfonyliraino)perhydropyrimidin-5-yl]thio]-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from 5-(4-methoxybenzylthio)-2- (phenylsulfonylimino)perhydropyrimidine (525 mg) , the titled compound (593 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-la.

IR(KBr): 3350, 1770, 1710, 1610, 1570, 1520, 1380, 1345, 1280, 1135 cm ^"1 . ^-NMRfCDClaJδ: 1.23(3H,d,J=7.4Hz) , 1.34(3H,d,J=6.2Hz) , 3.20-3.80(6H,m), 3.27 ( lH,dd,J=7.4&2.4Hz) , 4.22(lH,quint,J=7.4Hz) , 4.28( lH,dd,J=9.2&2.4Hz) , 5.20(lH,d,J=13.6Hz) , 5.48( lH,d,J=13.6Hz) , 7.20- 7.50(3H,m), 7.60(2H,d,J=8.8Hz) , 7.74(2H,d,J=8.2Hz) , 7.86(lH,brs) , 7.97 ( lH,brs) , 8.16(2H,d,J=8.8Hz) . Working Exaraple 13-2a

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-7- oxo-3-[ [2-(phenylsulfonylimino)perhydropyrimidin-5- yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Starting from the compound (300 mg) produced by the method of Working Example 13-la, the titled compound (192.4 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-2a. IR(KBr): 3350, 1750, 1600, 1380, 1340, 1280, 1130 cm ^"1 . ^-NMRfD _j OJδ: 1.14(3H,d,J=7.4Hz) , 1.29(3H,d,J=6.6Hz) ,

3.15-3.40(3H,ra) , 3.45 ( lH,dd,J=6.2&2.6Hz) , 3.50- 3.80(3H,m) , 4.20( lH,dd,J=8.8&2.6Hz) , 4.24(lH,quint,J=6.2Hz) , 7.50-7.75( 3H,m) , 7.80- 7.95(2H,m) . Working Example 13-3a

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-3-[ [2-(phenyl- sulfonylimino)perhydropyrimidin-5-yl]thio]-1- azabicyclof3.2.0]hept-2-ene-2-carboxylate Starting from the compound (72.3 mg) produced by the method of Working Example 13-2a, the titled compound (60 mg) was produced as a white solid product by substantially the same procedure as in Working Exaraple 10-3a. IR(KBr): 3340, 1760, 1610, 1570 cm ^"1 . 1.15-2.05( 10H,m) , 1.21(3H,d,J=7.0Hz) , 1.32(3/2H,d,J=5.8Hz) , 1.33(3/2H,d,J=6.2Hz) , 1.57(3/2H,d,J=5.6Hz) , 3.20-3.80(6H,ra) , 3.23(lH,dd,J=7.0&2.6Hz) , 4.15-4.30(2H,m) , 4.55- 4.75(lH,ra), 6.87 ( lH,q,J=5.6Hz) , 7.40-7.60(4H,m) , 7.60- 7.70(lH,m), 7.75-7.90(2H,m) . Working Example 14-la

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-3-[ [2-[ (pyrimidin-2- yl)imino]perhydropyrimidin-5-yl]thio]-1-azabi- cyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from 5-(4-methoxybenzylthio)-2- [ (pyriraidin-2-yl) imino]perhydropyrimidine (554 mg) , the titled compound (527 mg) was produced as a yellow solid product by substantially the same procedure as in Working Example 10-la.

IR(KBr): 3400, 1770, 1710, 1640, 1580 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.28(3H,d,J=7.2Hz) , 1.36(3H,d,J=6.2Hz) , 3.30(lH,dd,J=7.0&2.6Hz) , 3.35-3.95(6H,m) , 4.20- 4.40(2H,m), 5.22( lH,d,J=13.8Hz) , 5.49( lH,d,J=13.8Hz) , 6.62(lH,t,J=4.8Hz) , 7.64(2H,d,J=8.8Hz) ,

8.19(2H,d,J=8.8Hz) , 8.36(2H,d,J=4.8Hz) . Working Example 14-2a

(4R,5S,6S)-6-[(R)-1-Hydroxyethyl]-4-methyl-7-oxo-3-[ [2- [ (pyrimidin-2-yl)imino]perhydropyrimidin-5-yl]thio]-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Starting from the compound (256 mg) produced by the method of Working Example 14-la, the titled compound (125 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-2a.

IR(KBr): 3420, 1755, 1650, 1600, 1580 cm ^"1 . ¹ H-NMR(D ₂ 0)δ: 1.25(3H,d,J=7.0Hz) , 1.30(3H,d,J=6.6Hz) , 3.35-3.70(4H,m) , 3.70-4.00(3H,m) , 4.27(lH,quint,J=6.2Hz) , 4.28( lH,dd,J=9.6&2.6Hz) , 7.20(lH,t,J=5.2Hz) , 8.59 (2H,d,J=5.2Hz) . Working Example 15-la 4-Nitrobenzyl (4R,5S,6S)-3-[ [2-

(carbamoyliraino)perhydropyrimidin-5-yl]thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- carboxylate

Anisole (2.0 g) was added to a trifluoroacetic acid solution (20 ml) of 2-cyanoimino-5-(4- methoxybenzylthio)perhydropyrimidine (500 mg) . The mixture was stirred for 2 hours at room temperature, then for further 2 hours under reflux. The solvent was distilled off under reduced pressure. To the residue was added toluene, which was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. The residue was dissolved in acetonitrile (20 ml), to which was added dropwise, at 0°C, isopropylethylamine (1.16 g) . To the mixture was further added, at 0°C, an acetonitrile solution (20 ml) of 4-nitrobenzyl (4R,5R,6S)-3- [ (diphenylphosphono)oxy]-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carbox- ylate. The mixture was stirred for 20 hours at 0°C.

The reaction mixture was concentrated under reduced pressure, to which was added water, followed by extraction with ethyl acetate. The extract solution was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 560 mg of a yellow solid product (a mixture of the titled compound and diphenyl phosphoric acid ester) . This yellow solid product was employed for the subsequent reaction without purification. IR(KBr): 3270, 1775, 1720, 1610, 1525 cm ^"1 . ^-NMRfCDCl- _j -DMSO-d^δ: 1.28( 3H,d,J=5.8Hz) , 1.31(3H,d,J=6.0Hz) , 3.20-3.90(7H,m) , 4.15(lH,quint,J=6.0Hz) , 4.31( lH,dd,J=9.6&2.8Hz) , 5.24(lH,d,J=14.0Hz) , 5.51( lH,d,J=14.0Hz) , 7.68(2H,d,J=8.8Hz) , 8.23(2H,d,J=8.8Hz) . Working Example 15-2a (4R,5S,6S)-3-[ [2-(Carbamoylimino)perhydropyrimidin-5- yl]thio]-6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

The yellow solid product (260 mg) produced by the method of Working Example 15-la was dissolved in a mixture of THF (4 ml) and a phosphate buffer (pH 7, 0.1M, 4 ml). To the solution was added 10% Pd-C (260 rag) , and the mixture was stirred for one hour at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with water sufficiently. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, which was purified by means of a column chromatography (carrier: CHP-20P, 80 ml, developing solvent: water to ethanol-water, 5:100), followed by freeze-drying to afford the titled compound (72.5 mg) as a white solid product.

IR(KBr): 3400, 1750, 1720, 1680, 1615 cm ^"1 .

^-NMR^OJδ: 1.24(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.4Hz) , 3.35-3.60(4H,m) , 3.60-3.90(3H,m) , 4.27(lH,dd,J=9".4&2-.8Hz) , 4.27(IH,quint,J=6.4Hz) . Working Example 15-3a l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-[ [2-

(carbamoylimino)perhydropyrimidin-5-yl]thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- ene-2-carboxylate

To the compound (49.4 mg) produced by the method of Working Example 15-2a was added an aqueous solution (4.5 ml) of potassium carbonate (19.6 mg) , which was freeze-dried. To a DMA solution (5 ml) of the solid matter thus obtained was added, at -10°C, 1- (eyelohexyloxycarbonyloxy)ethyl iodide (0.098 mg) . The mixture was stirred for 2 hours. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a flash column chromatography (carrier: silica gel, 5g, developing solvent: acetonitrile to acetonitrile-ethanol, 1:1) to afford the titled compound (13.8 mg) as a white solid product. IR(KBr): 3400, 1760, 1615, 1575 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.10-2.10(10H,m) , 1.25(3H,d,J=7.0Hz) , 1.33(3/2H,d,J=6.2Hz), 1.34(3/2H,d,J=6.2Hz) , 1.58(3/2H,d,J=5.4Hz) , 1.61(3/2H,d,J=5.4Hz) , 3.15- 3.75(7H,m), 4.15-4.30(2H,m) , 4.50-4.75(lH,m) , 6.87(lH,q,J=5.4Hz) .

Working Example 16-la

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-3-[ [2-[ (2-thiazolin-2- yl)imino]perhydropyrimidin-5-yl)thio]-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from 5-(4-methoxybenzylthio)-2-[ (2-

thiazolin-2-yl)imino]perhydropyrimidine (171 mg) , the titled compound (98 mg) was produced as a yellow solid product in accordance with substantially the same procedure. IR(KBr): 3400, 1770, 1710, 1610, 1570 cm ^"1 .

^-NMRfCDCl^δ: 1.28(3H,d,J=7.4Hz) , 1.36(3H,d,J=6.6Hz) , 3.10-3.80(9H,m) , 3.90-4.15(2H,m) , 4.15-4.35(2H,m) , 5.23(lH,d,J=13.6Hz) , 5.51( lH,d,J=13.6Hz) , 7.65(2H,d,J=8.8Hz) , 8.23(2H,d,J=8.8Hz) . Working Example 16-2a

(4R,5S,6S)-6-[ (R)-l-Hydroxyethyl]-4-methyl-7-oxo-3-[ [2- [ (2-thiazolin-2-yl)imino]perhydropyrimidin-5-yl]thio]- 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from the compound (73 mg) produced by the method of Working Example 16-la, the titled compound (43 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-2a. IR(KBr): 3400, 1750, 1590 cm ^"1 . ¹ H-NMR(D ₂ 0)6: 1.24(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) , 3.30-3.90(7H,m), 3.50(2H,t,J=7.6Hz) , 3.83(2H,t,J=7.6Hz) , 4.27 ( IH,quint,J=6.4Hz) , 4.28(lH,dd,J=9.0&2.2Hz) . Working Example 17-la 4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-3-[ [2-(methylsulfonylimino)perhydropyrimidin-5- yl]thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

Starting from 5-(4-methoxybenzylthio)-2- (methylsulfonylimino)perhydropyrimidine (750 rag), the titled compound (927 mg) was produced as a yellow solid product by substantially the same procedure as in Working Example 10-la. IR(KBr): 3350, 1770, 1705, 1610, 1570, 1520 cm ^"1 . ^-NMRfCDCl^δ: 1.29(3H,d,J=7.2Hz) , 1.37 (3H,d,J=6.4Hz) , 2.89(3H,s), 3.25-3.8(6H,ra) , 3.31( lH,dd,J=6.4&2.2Hz) ,

4 . 2-4 . 44 ( lH , m ) , 4 . 33 ( lH , dd , J=9 . 2&2 . 2Hz ) ,

5.24(lH,d,J=14.0Hz) , 5.50( lH,d,J=14.0Hz) , 7.47(lH,brs) , 7.57(lH,brs) , 7.66(2H,d,J=8.2Hz) , 8.24(2H,d,J=8.2Hz) . Working Example 17-2a Sodium (4R,5S,6S)-[ (R)-l-hydroxyethyl]-4-methyl-3-[ [2- (methy1sulfonylimino)perhydropyrimidin-5-y1]thio]-7- oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from the compound produced by the method of Working Example 17-la, the titled compound (204 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-2a. IR(KBr): 3400, 1745, 1600 cm ^"1 .

¹ H-NMR(D ₂ 0)δ: 1.23(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.6Hz) , 3.02(3H,s), 3.25-3.80(6H,m) , 3.49(lH,dd,J=6.2&2.6Hz) , 4.26(lH,dd,J=9.2&2.6Hz) , 4.26(IH,quint,J=6.2Hz) . Working Exaraple 18-la

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4- raethyl-7-oxo-3-[ [2-[ (pyridin-3- yl)carbonylimino]perhydropyrimidin-5-yl]thio]-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from 5-(4-methoxybenzylthio)-2-[ (pyridin- 3-yl)carbonylimino]perhydropyrimidine (1.0 g) , the titled compound (1.08 g) was produced as a white solid product by substantially the same procedure as in Working Example 10-la.

IR(KBr): 3380, 3250, 1765, 1705, 1600, 1540, 1515 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.24(3H,d,J=7.0Hz) , 1.38(3H,d,J=6.2Hz) , 3.0-3.75(6H,m) , 3.30(lH,dd,J=7.0&2.6Hz) , 4.17(lH,dd,J=9.2&2.6Hz) , 4.28(IH,quint,J=7.0Hz) , 5.20(lH,d,J=13.8Hz) , 5.47(lH,d,J=13.8Hz) ,

7.36(lH,dd,J=7.8&4.8Hz) , 7.62(2H,d,J=8.8Hz) , 8.19(2H,d,J=8.8Hz) , 8.35(lH,dt,J=7.8&1.6Hz) , 8.66(lH,dd,J=4.8&1.6Hz) , 9.27(lH,d,J=l.6Hz) . Working Example 18-2a Sodium (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4-methyl-7- oxo-3-[ [2-[ (pyridin-3-

y1)carbony1imino]perhydropyrimidin-5-y1]thio]-1- azabicyclo[3.2.0]hept-2-ene-carboxylate

Starting "from- the corapound (400 mg) produced by the method of Working Exaraple 18-la, the titled compound (237 mg) was produced as a white solid product by substantially the same procedure as in Working

Example 10-2a.

IR(KBr): 3430, 1750, 1600 cm ^"1 .

¹ H-NMR(D ₂ 0)δ: 1.25(3H,d,J=7.2Hz) , 1.31(3H,d,J=6.2Hz) , 3.35-3.55(3H,m) , 3.49(lH,dd,J=6.2&2.6Hz) , 3.65-

3.90(3H,m), 4.15-4.35(2H,m) , 7.53(lH,dd,J=8.0&5.2Hz) ,

8.33(lH,dt,J=8.0&2.0Hz), 8.63(lH,dd,J=5.2&2.0Hz) ,

9.04(lH,d,J=2.0Hz) .

Working Example 18-3a l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[ (R)-1- hydroxyethyl]-4-raethyl-7-oxo-3-[ [2-[ (pyridin-3- yl)carbonylimino]perhydropyrimidin-5-yl]thio]-1- azabicyclof3.2.0]hept-2-ene-2-carboxylate

Starting from the compound (68.5 mg) produced by the method of Working Example 18-2a, the titled corapound (76.9 mg) was produced as a white solid product by substantially the same procedure as in

Working Example 10-3a.

IR(KBr): 3380, 3250, 1755, 1600, 1540 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.20-2.05(10H,m) , 1.25(3H,d,J=7.4Hz) ,

1.35(3/2H,d,J=6.2Hz) , 1.37(3/2H,d,J=6.2Hz) ,

1.58(3/2H,d,J=5.2Hz) , 1.60(3/2H,d,J=5.2Hz) , 3.00-

3.75(6H,m) , 3.26(lH,dd,J=7.2&2.8Hz) ,

4.15(lH,dd,J=9.6&2.8Hz) , 4.26(IH,quint,J=6.4Hz) , 4.55- 4.75(lH,m), 6.87(lH,q,J=5.2Hz) ,

7.36(lH,dd,J=8.0&4.8Hz) , 8.36(lH,dt,J=8.0&2.0Hz) ,

8.67(lH,dd,J=4.8&2.0Hz) , 9.29(lH,d,J=2.0Hz) .

Working Example 19a

(4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-raethyl-7-oxo-3-[ [2- [ (pyridin-4-yl)imino]perhydropyrimidin-5-yl]thio]-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

hydrochloride

To a trifluoroacetic acid solution (23 ml) of 5- (4-methoxybenzylthio)-2-[ (pyridin-4- yl)imino]perhydropyrimidine (700 mg) were added, at 0°C, anisole (2.3 g) and trifluoromethanesulfonic acid (0.64 g) . The mixture was stirred for 0.5 hour at 0°C, to which was added diisopropylethylamine (1.1 g) . The solvent was then distilled off under reduced pressure. To the residue was added toluene, and the mixture was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. The residue was dissolved in acetonitrile (30 ml), to which was added dropwise, at 0°C, diisopropyl ethylamine (3.59 g) . To the mixture was added, at 0°C, an acetonitrile solution (30 ml) of 4-nitrobenzyl (4R,5R,6S)-3-

[ (diphenylphosphono)oxy]-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carbox- ylate. The mixture was stirred for 2 hours at 0°C. The solvent was distilled off under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with an aqueous solution of sodium hydrogencarbonate and water, successively, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 15 g, developing solvent: ethanol-acetonitrile, 1:1) to give a yellow solid product containing 4-nitrobenzyl (4R,5S,6S)-6-[ (R)-1- hydroxyethyl]-4-raethyl-7-oxo-3-[ [2-[ (pyridin-4- yl)imino]perhydropyrimidin-5-yl]thio]-1-azabicy- clo[3.2.0]hept-2-ene-2-carboxylate (238 mg) . This solid product was subjected to substantially the same reaction and refining process as in Working Example 10- 2a, which was adjusted to pH 5.8 with 0.IN HC1, followed by freeze-drying to afford the titled compound (84 mg) as a white solid product.

IR(KBr): 3430, 1750, 1590, 1510 cm ^"1 .

^X H-NMR(D ₂ 0) δ: 1.27 ( 3H,d,J=7.8Hz) , 1.30( 3H,d,J=6.6Hz) , 3.4-4.0(6H,m) , ^' 3.53( lH,dd,J=5.9&2.9Hz) , 4.2-4.44 (2H,m) , 7.33(2H,d,J=7.0Hz) , 8.40(2H,d,J=7.2Hz) . Working Example 20-la

4-Nitrobenzyl (4R,5S,6S)-3-[ [1,3-dimethyl-2- (methylsulfonylimino)perhydropyrimidin-5-yl]thio]-6- [ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate Starting from 5-(4-methoxybenzylthio)-l, 3- dimethyl-2-(methylsulfonylimino)perhydropyrimidine (974 rag), the titled compound (901 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-la. IR(KBr): 3430, 1770, 1710, 1600, 1560, 1520 cm ^"1 . ^l H-NMR(CDCl ₃ )δ: 1.30(3H,d,J=6.8Hz) , 1.37(3H,d,J=6.2Hz) , 2.12(lH,d,J=4.8Hz), 3.02(3H,s), 3.20(3H,s), 3.22(3H,s), 3.25-3.75(6H,m), 3.33( lH,dd,J=6.6&2.6Hz) , 4.15- 4.35(lH,m) , 4.32( lH,dd,J=9.2&2.6Hz) , 5.23(lH,d,J=13.4Hz), 5.50( lH,d,J=13.4Hz) , 7.66(2H,d,J=8.8Hz) , 8.24(2H,d,J=8.8Hz) . Working Example 20-2a Sodium (4R,5S,6S)-3-[ [l,3-dimethyl-2- (methylsulfonylimino)perhydropyrimidin-5-yl]thio]-6- [ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from the compound (400 mg) produced by the method of Working Example 20-la, the titled compound (220 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-2a.

IR(KBr): 3430, 1750, 1580, 1530 cm ^"1 .

^X H-NMR(D ₂ 0)δ: 1.23(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.6Hz) , 3.09(3H,s), 3.16(3H,s), 3.19(3H,s), 3.35-3.55(3H,ra) , 3.50(lH,dd,J=6.2&2.6Hz), 3.70-3.95(3H,m) , 4.20- 4.35(2H,m) .

Working Example 20-3a

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-[[1,3- diraethyl-2-(methylsulfonylimino)perhydropyrimidin-5- yl]thio]-6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclof3.2.0]hept-2-ene-2-carboxylate

Starting from the compound (74 mg) produced by the method of Working Example 20-2a, the titled compound (73.6 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-3a.

IR(KBr): 3430, 1760, 1560, 1530 era ^"1 . ^-NMR CDClaJδ: 1.2-2.1(10H,m) , 1.28(3H,d,J=7.4Hz) , 1.34(3/2H,d,J=6/2Hz), 1.36 (3/2H,d,J=6.2Hz) , 1.59(3/2H,d,J=5.4Hz) , 1.62 (3/2H,d,J=5. Hz) , 3.03(lH,s), 3.21(3/2H,s), 3.22(3/2H,s) , 3.23(3H,s), 3.2-3.8(7H,ra) , 4.15-4.4(2H,ra), 4.55-4.75( lH,m) , 6.88( lH,q,J=5.4Hz) . Working Example 21-la

4-Nitrobenzyl (4R,5S,6S)-3-[ [ 1,3-dimethyl-2- (trifluoromethylcarbonylimino)perhydropyrimidin-5- yl]thio]-6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from 2-cyanoimino-5-(4- methoxybenzylthio)-l, 3-dimethylperhydropyrimidine (1.3 g), the titled compound (140 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-la.

IR(KBr): 3400, 1770, 1700, 1640, 1600, 1520 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.29 (3H,d,J=7.2Hz) , 1.36(3H,d,J=6.4Hz) , 2.38(lH,brs) , 3.03(3H,s), 3.08(3H,s), 3.25-3.90(7H,m) , 4.20-4.40(2H,m) , 5.24 ( lH,d,J=13.6Hz) ,

5.51(lH,d,J=13.6Hz) , 7.67(2H,d,J=8.8Hz) ,

8.24(2H,d,J=8.8Hz) .

Working Exaraple 21-2a

Sodium (4R,5S,6S)-3-[ [1,3-dimethyl-2- (trifluoromethylearbony1imino)perhydropyrimidin-5- yl]thio]-6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-l-

azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from the compound (65.1 mg) produced by the method of Working Example 21-la, the titled compound (32 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-2a.

IR(KBr): 3420, 1750, 1640, 1595, 1520 cm ^"1 . ^X H-NMR(D ₂ 0)δ: 1.23(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.4Hz) , 3.01(3H,s), 3.04(3H,s), 3.35-4.00(7H,ra) , 4.20- 4.35(2H,m).

Working Example 21-3a l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-[ [1,3- dimethyl-2-(trifluoromethylcarbonylimino)perhydro pyrimidin-5-yl]thio]-6-[ (R)-1-hydroxyethyl]-4-methyl-7- oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from the compound (37 mg) produced by the method of Working Example 21-2a, the titled compound (33 mg) was produced as a white solid product by substantially the same procedure as in Working Example 10-3a.

IR(KBr): 3425, 1760, 1635, 1595, 1525 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.2-2.05( 10H,m) , 1.28 (3H,d,J=7.0Hz) , 1.31(3/2H,d,J=6.2Hz) , 1.35(3/2H,d,J=6.6Hz) , 1.55- 1.65(3H,m), 3.06(3/2H,s) , 3.08(3/2H,s) , 3.10(3H,s), 3.30(lH,dd,J=6.4&3.2Hz) , 3.35-3.90(6H,m) , 4.20- 4.35(lH,m) , 4.28(lH,dd,J=9.6&3.2Hz) , 6.87(l/2H,q,J=5.4Hz) , 6.88( l/2H,q,J=5.4Hz) . Working Example 22-la 4-Nitrobenzyl (4R,5S,6S)-3-[ [2-[2-(N,N- dimethylamino)ethoxy]-1,4,5,6-tetrahydropyrimidin-5- yl]thio]-6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from 2-[2-(N,N-dimethylamino)ethoxy]-5- ( -methoxybenzylthio)-1,4,5,6-tetrahydropyrimidine (500 rag), the titled compound (370 mg) was produced as a yellow oily product by substantially the same

procedure.

IR(neat): 3370, 1765, 1650, 1605, 1520 cm ^"1 .

^- MRfCDClaJδ: 1.29(3H,d,J=7.0Hz) , 1.34(3H,d,J=6.2Hz) ,

2.27(6H,s), 2.55(2H,d,J=5.6Hz), 3.2-3.8(7H,m) . 4.10(2H,t,J=5.6Hz) , 4.15-4.35(2H,m) ,

5.22(lH,d,J=13.8Hz) , 5.50( lH,d,J=13.8Hz) ,

7.66(2H,d,J=8.8Hz) , 8.22 (2H,d,J=8.8Hz) .

Working Example 22-2a

(4R,5S,6S)-3-[[2-[2-(N,N-dimethylaraino)ethoxy]-l,4,5,6- tetrahydropyrimidin-5-yl]thio]-6-[ (R)-1-hydroxyethyl]-

4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid

The compound (370 mg) produced by the method of

Working Exaraple 22-la was dissolved in a mixture of THF (20 ml) and a phosphate buffer solution (pH 7, 0.2M, 20 ml). To the solution was added 10% Pd-C (700 mg) , and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with water sufficiently. THF was distilled off under reduced pressure. Then, the aqueous solution was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, which was purified by means of a column chromatography

(carrier: CHP-20P, 120 ml, developing solvent: water to 20% ethanol-water) , whose pH was adjusted to 7.5 with hydrochloric acid, which was freeze-dried to give the titled compound (121 mg) as a white solid product.

IR(KBr): 3430, 1750, 1660, 1620, 1590 cm ^"1 .

¹ H-NMR(D ₂ 0)δ: 1.24 (3H,d,J=6.8Hz) , 1.30(3H,d,J=6.6Hz) , 2.80(6H,s), 3.35-3.90(9H,m) , 4.20-4.40(2H,m) ,

4.56(2H,t,J=4.8Hz) .

Working Exaraple 23-la

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-3-[ [2-[2-[N-methyl-N-(4- nitrobenzyloxycarbonyl)amino]ethoxy]-1,4,5,6- tetrahydropyrimidin-5-yl]thio]-7-oxo-l-

azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Starting from 5-(4-methoxybenzylthio)-2-[2-N- raethyl-N-(4-nitrobenzyloxycarbonyl)amino]ethoxy]-

1,4,5,6-tetrahydropyriraidine (325 mg), the titled compound (315 mg) was produced as a yellow solid product by substantially the same procedure.

IR(KBr): 3400, 1765, 1700, 1655, 1605, 1520 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.29(3H,d,J=7.0Hz) , 1.36(3H,d,J=6.0Hz) ,

3.00(3/2H,s), 3.01(3/2H,s), 3.2-3.75(6H,m) , 3.29(lH,dd,J=6.8&2.4Hz) , 3.57(2H,t,J=5.4Hz) ,

4.18(2H,t,J=5.4Hz) , 4.20-4.35(2H,m) ,

5.22(lH,d,J=13.8Hz), 5.23(2H,s), 5.51(lH,d,J=13.8Hz) ,

7.52(2H,d,J=8.4Hz), 7.66(2H,d,J=8.4Hz) ,

8.22(4H,d,J=8.4Hz) . Working Example 23-2a

(4R,5S,6S)-6-[ (R)-1-Hydroxyethyl]-4-methyl-3-[ [2-[2-(N- methylamino)ethoxy]-1,4,5,6-tetrahydropyrimidin-5- yl]thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid Working Example 23-3a

(4R,5S,6S)-6-[(R)-l-hydroxyethyl]-3-[[2-[N-(2- hydroxyethyl)-N-methylamino]-1,4,5,6- tetrahydropyrimidin-5-yl]thio]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Starting from the compound (314 mg) produced by the method of Working Example 23-la, the compound of

Working Example 23-2a (7.1 mg) was produced as a white solid product by substantially the same procedure as in

Working Example 10-2a. And, at the same time, the compound of Working Example 23-3a (29 mg) was produced as a white solid product.

The compound of Working Exaraple 23-2a

IR(KBr): 3420, 1750, 1660, 1620 era ^"1 .

¹ H-NMR(D ₂ 0)δ: 1.25(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.2Hz) , 2.81(3H,s), 3.30-4.00(7H,m) , 3.51(2H,t,J=5.0Hz) , 4.20-

4.35(2H,m), 4.60(2H,t,J=5.0Hz) .

The product of Working Example 23-3a IR(KBr): 3400, 1750, 1635, 1590 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.24(3H,d,J=7.0Hz) , 1.30(3H,d,J=6.2Hz) , 3.03(3H,s), 3.30-3.90(7H,m), 3.47(2H,t,J=5.2Hz) , 3.76(2H,t,J=5.2Hz) , 4.15-4.35(2H,m) . Working Exaraple 24-la 4-Nitrobenzyl (4R,5S,6S)-3-[ (5H-6,7- dihydrothiazolo[3,2-a]pyriraidin-6-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

To a THF-methanol solution (1:1,20 ml) of 6- (benzoylthio)-5H-6,7-dihydrothiazolo[3,2-a]pyrimidine (550 mg) was added, at 0°C, sodium methoxide (128 mg) . The mixture was stirred for one hour at 0°C, to which were added acetic acid )0.15 ml, 2.57 mmol.) and acetonitrile (20 ml). The mixture was concentrated under reduced pressure to make the volume of the solvent to about 5 ml. Insolubles were filtered off, and the filtrate was washed with acetonitrile (20 ml). To the filtrate were added, at 0°C, 4-nitrobenzyl (4R,5R,6S)-3-[ (diphenylphosphono)oxy]-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate (1.17 g) and diisopropyl ethylamine (0.45 ml). The mixture was stirred at 0°C for 20 minutes and at room temperature for 4 hours. To the reaction mixture was added ethyl acetate, which was washed with a pH 7 phosphate buffer solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-hexane, 1:1 - 2:1 - 3:1) to afford diastereomer-1 (21 mg) and diastereomer-2 (26 rag) of the titled corapound, respectively. Diastereomer-1

IR(neat): 3440, 3116, 1767, 1709, 1649, 1522 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.21(3H,d,J=7.2Hz) , 1.35(3H,d,J=6.4Hz) , 3.15-3.65(5H,m) , 3.85-4.10(2H,m) , 4.15-4.35(2H,m) , 5.35(2H,ABq,J=14.0Hz) , 6.24(lH,d,J=5.4Hz) , 6.67(lH,d,J=5.4Hz) , 7.64(2H,d,J=8.6Hz) , 8.22(2H,d,J=8.6Hz) . Diastereomer-2

IR(KBr): 3448, 3118, 1770, 1649, 1524 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.2 (3H,d,J=7.4Hz) , 1.36(3H,d,J=6.2Hz) , 3.15-3.75(5H,m), 3.90-4.10(2H,m) , 4.15-4.35(2H,m) , 5.37(2H,ABq,J=14.2Hz) , 6.11(lH,d,J=5.4Hz) , 6.65(lH,d,J=5.4Hz) , 7.66(2H,d,J=8.0Hz) , 8.24(2H,d,J=8.0Hz) . Working Example 24-2a Sodium (4R,5S,6S)-3-[ (5H-6,7-dihydrothiazolo[3,2- a]pyrimidin-6-yl)thio]-6-[ (R)-l-hydroxyethyl]-4-methyl- 7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Diastereomer-1

Diastereomer-1 (21 mg) produced by the method of Working Example 24-la was dissolved in a mixture of THF (1 ml) and a pH 7 phosphate buffer (0.2M, 1 ml) . To the solution was added 10% Pd-C (25 mg) . The mixture was subjected to hydrogenation for 2 hours under atmospheric pressure. The catalyst was filtered off and washed sufficiently with water. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, which was purified by means of a column chromatography (carrier: CHP-20P, 60 ml, developing solvent: water -> 5% ethanol), followed by freeze-drying to afford the titled compound (6.4 mg) as a colorless solid product. IR(KBr): 3429, 1747, 1649, 1603 cm ^"1 .

¹ H-NMR(D ₂ 0)δ: 1.02(3H,d,J=7.0Hz) , 1.29(3H,d,J=6.2Hz) , 3.10-3.25(lH,m) , 3.25-3.60(3H,m) , 3.85(lH,dd,J=14.8&10.4Hz) , 4.10-4.40(3H,m) , 6.48(lH,d,J=5.2Hz) , 7.02(lH,d,J=5.2Hz) . Diastereomer-2

The diastereomer-2 (32 mg) produced by the method of Working Exaraple 24-la was subjected to substantially the same reaction as in the case of the diastereomer-1 to afford the titled compound (7.2 mg) as a colorless solid product.

IR(KBr): 3431, 1747, 1637, 1606 cm ^"1 .

^-NMRfDzOJδ: 1.15(3H,J=7.0Hz) , 1.29 ( 3H,d,J=6.4Hz) ,

3.20-3.50(4H,m) , 3.50-3.85(2H,ra) , .00-4.10( lH,m) ,

4.15-4.35(2H,m) , 6.33( lH,d,J=5.2Hz) , 6.89(lH,d,J=5.2Hz) .

Working Example 25-la

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-3-[ [2-

(2-raethoxyethylthio)-1,4,5,6-tetrahydropyrimidin-5- yl]thio]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene- 2-carboxylate

Starting from 5-( -methoxybenzylthio)-2-(2- methoxyethylthio)-1,4,5,6-tetrahydropyrimidine (390 rag), the titled compound (446 mg) was produced as a yellow solid product by substantially the same procedure as in Working Example 10-la.

IR(KBr): 3400, 1770, 1710, 1605, 1520 cm ^"1 .

^-NMRζCDClaJδ: 1.29 (3H,d,J=7.0Hz) , 1.37(3H,d,J=6.2Hz) ,

3.12(2H,d,J=5.8Hz), 3.2-3.8(6H,m) ,

3.29(lH,dd,J=6.8,2.6Hz) , 3.39(3H,s) , 3.61(2H,t,J=5.8Hz) , 4.2-4.35(2H,m) ,

5.23(lH,d,J=13.6Hz) , 5.52( lH,d,J=13.6Hz) ,

7.66(2H,d,J=8.6Hz) , 8.23(2H,d,J=8.6Hz) .

Working Example 25-2a

(4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-3-[ [2-(2- raethoxyethylthio)-1,4,5,6-tetrahydropyrimidin-5- yl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-

2-carboxylic acid

The compound (445 rag) produced by the method of

Working Example 25-la was dissolved in a mixture of THF (17 ml) and a phosphate buffer solution (pH 7, 0.1M, 17 ml). To the solution was added 10% Pd-C (440 mg) , and

the mixture was stirred for one hour at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with water sufficiently. THF was distilled off under reduced pressure. The aqueous solution was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, which was purified by means of a column chromatography (carrier: CHP-20P, 70 ml, developing solvent: water to 20% ethanol-water) , whose pH was adjusted to 7.5 with hydrochloric acid, followed by freeze-drying to afford the titled compound (190 mg) as a white solid product. IR(KBr): 3430, 1755, 1595 cm ^"1 . 1.23(3H,d,J=7.4Hz) , 1.30( 3H,d,J=6.2Hz) , 3.30(2H,t,J=5.4Hz) , 3.35-3.95(7H,m) , 3.43(3H,s), 3.76(2H,t,J=5.4Hz) , 4.20-4.35(2H,m) . Working Exaraple 26-la

4-Nitrobenzyl (4R,5S,6S)-3-[ [2-(acetyliraino)-1,3- dimethylperhydropyrimidin-5-yl]thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

Starting from 2-(acetylimino)-l, 3-dimethyl-5-(4- methoxybenzylthio)perhydropyrimidine (797 mg) , the titled compound (811 mg) was produced as a pale yellow foamy product by substantially the sarae procedure as in Working Example 10-la.

IR(KBr): 3398, 1770, 1585, 1558, 1520 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.29(3H,d,J=6.8Hz) , 1.32 (3H,d,J=6.0Hz) , 1.66(lH,brs) , 2.04(3H,s), 2.93(3H,s), 3.05(3H,s), 3.12- 3.87(7H,s), 4.26-4.33(2H,m) , 5.20( lH,d,J=13.4Hz) , 5.54(lH,d,J=13.4Hz), 7.70(2H,d,J=8.8Hz) , 8.25(2H,d,J=8.8Hz) . Working Example 26-2a

Sodium (4R,5S,6S)-3-[[2-(acetylimino)-l,3- dimethylperhydropyrimidin-5-yl]thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

Starting from the compound (442 mg) produced by the method of Working Example 26-la, the titled compound (278 mg) was produced as a pale yellow foamy product by substantially the same procedure as in Working Example 10-2a.

IR(KBr): 3400, 1751, 1593, 1522, 1410 cm ^"1 . ¹ H-NMR(D ₂ 0)δ: 1.23( 3H,d,J=7.4Hz) , 1.30( 3H,d,J=6.2Hz) , 2.02(3H,s), 2.99(3H,s), 3.02(3H,s), 3.37-3.52 (4H,m) , 3.70-3.94(3H,m) , 4.24-4.30(2H,m) . Working Example 27-la

4-Nitrobenzyl (4R,5S,6S)-[ [ 1, 3-dimethyl-2-(thiazol-2- ylimino)perhydropyrimidin-5-yl]thio]-6-[ (R)-l- hydroxyethyl]-4-raethyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate Starting from 1,3-dimethyl-5-(4- methoxybenzylthio)-2-(thiazol-2-ylimino- )perhydropyrimidine (286 mg) , the titled compound (129 mg) was produced as a pale yellow foamy product by substantially the same method as in Working Example 10- la.

IR(KBr): 3390, 1770, 1699, 1523, 1346, 1203, 1138 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.28(3H,d,J=7.2Hz) , 1.29(3H,d,J=5.8Hz) , 2.04(lH,brs) , 2.83(3H,s), 2.99(3H,s), 3.12-3.34(3H,m) , 3.56-3.64(2H,m), 4.23-4. 7(2H,m) , 5.18( lH,d,J=14.0Hz) , 5.51(lH,d,J=14.0Hz) , 6.46( lH,d,J=4.0Hz) , 7.06(lH,d,J=4.0Hz) , 7.65(2H,d,J=8.4Hz) , 8.19(2H,d,J=8.4Hz) . Working Example 27-2a Sodium (4R,5S,6S)-3-[ [ 1,3-dimethyl-2-(thiazol-2- ylimino)perhydropyrimidin-5-yl]thio]-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

Starting from the compound (126 mg) produced by the method of Working Example 27-la, the titled compound (54.2 mg) was produced as a pale foamy product by substantially the same procedure as in Working

Exaraple 10-2a .

IR(KBr): 3400, 1755, 1591, 1531, 1412, 1392 cm ^"1 . ¹ H-NMR(D ₂ 0)δ: 1:.25(3H,d,J=7.4Hz) , 1.31( 3H,d,J=6.4Hz) , 2.96(3H,s), 3.00(3H,s), 3.32-3.52(4H,m) , 3.72- 3.87(3H,m), 4.24-4.30(2H,ra) , 6.68( lH,d,J=4.0Hz) , 7.07(lH,d,J=4.0Hz) . Working Example 28-la

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-3-[ [2-(pyridin-2-yl)-1,4,5,6- tetrahydropyrimidin-5-yl]thio]-l-azabicyclo[3.2.0]hept- 2-ene-carboxylate

Anisole (0.3 ml) was added to a trifluoroacetic acid solution (3 ml) of 5-(4-methoxybenzylthio)-2- (pyridin-2-yl)-1,4,5,6-tetrahydropyrimidine (107 mg) . The mixture was stirred for 3 hours while heating under reflux. The solvent was distilled off under reduced pressure. To the residue was added toluene. The mixture was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. An acetonitrile solution (5 ml) of the residue thus obtained was added dropwise at 0°C over 15 minutes to an acetonitrile solution (6 ml) of 4-nitrobenzyl (4R,5R,6S)-3-[ (diphenylphosphono)oxy]-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate (184.3 mg) and diisopropyl ethylamine (81 μl). The reaction mixture was stirred for further one hour at the same temperature. To the reaction mixture was added a phosphate buffer solution (pH 7), which was subjected to extraction with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was then purified by means of a flash column chromatography (carrier: silica gel, 5 g, developing solvent: ethyl acetate - dichloromethane:ethanol, 8:1) to afford the titled compound (24.9 mg) as a pale yellow foamy product.

IR(KBr): 3356, 1768, 1520, 1346, 1207, 1136 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.27 (3H,d,J=7.4Hz) , 1.34(3H,d,J=6.2Hz) , 2.05(lH,brs) , ^" 3.28(lH,dd,J=7.0..2.2Hz) , 3.36-3.83( 6H,m) , 4.14-4.28(lH,m) , 4.31( lH,dd,J=9.6&2.2Hz) , 5.27(lH,d,J=12.6Hz) , 5.49( lH,d,J=12.6Hz) , 7.07- 7.22(2H,m), 7.28-7.33( lH,m) , 7.60-7.69 (3H,ra) , 8.18(2H,d,J=8.8Hz) , 8.43-8.45( lH,m) . Working Example 28-2a Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-7- oxo-3-[ [2-(pyridin-2-y1)-1,4,5,6-tetrahydropyriraidin-5- yl]thio]-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Using the corapound obtained by the method of Working Example 28-la (203.5 mg) , the titled compound (22.7 mg) was produced as a white foamy product by substantially the same procedure as in Working Example 10-2a.

IR(KBr): 3419, 1755, 1591, 1579 cm ^"1 .

^X H-NMR(D ₂ 0)δ: 1.23(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.2Hz) , 3.37-3.62(4H,m) , 3.76-3.95(3H,ra) , 4.23-4.30(2H,m) , 7.53-7.60(lH,ra), 7.79(lH,ra), 7.96-8.04(lH,m) , 8.60- 8.63(lH,m) . Reference Example lb

5-(4-Methoxybenzylthio)perhydropyrimidine-2-thione To a THF solution (6 ml) of 2-(4- methoxybenzylthio)propane-1, 3-diamine (0.5 g) produced by the method of JPA S60( 1985)-132985 was added dropwise at 0 °C carbon disuslfide. The mixture was stirred for 30 minutes at 0 °C and for further one hour at room temperature. To the reaction mixture was added 6 ml of ether. Insolubles were collected by filtration, washed with ether and dried under reduced pressure. A THF solution (6 ml) of the resulting solid matter was stirred for 3 hours while heating under reflux. The solvent was dsitilled off under reduced pressure to leave the titled corapound (332 mg) as a colorless solid product.

IR(KBr): 3180, 1605, 1565, 1540, 1510 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 2.91( IH,tt,J=9.4,4.6Hz) , , 3.36 (2H,dt,J=12.6,4.6Hz) , 3.76(2H,s), 3.81(3H,s), 6.56(2H,brs) , 6.86(2H,d,J=8.8Hz) , 7.22(2H,d,J=8.8Hz) . Reference Example 2b 1-(t-Butoxycarbonyl)-5-( - methoxybenzylthio)perhydropyrimidin-2-one

To a DMF solution (85 ml) of N,N'-bis(t- butoxycarbonyl)-2-(4-methoxybenzylthio)propane-1, 3- diamine (3.61 g) was added at 0 °C sodium hydride (purity 55%, 0.41 g) . The mixture was stirred for 3.5 hours at room temperature. To the reaction mixture was added water dropwise at 0 °C to decompose sodium hydride. The reaction mixture was subjected to extraction with ether. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was refined by means of a flash column chromatography (carrier: silica gel, 100 g, developing solvent: methanol- dichlororaethane, 1:20) to give the titled compound (2.03 g) as a colorless solid product. IR(KBr): 3220, 3120, 1720, 1680, 1610, 1510 cm ^"1 . δ: 3.44( lH,dd,J=12.8,9.2Hz) , 3.76(2H,s), 3.81(3H,s), 3.95(lH,ddd,J=12.8,4.0,1.4Hz),

5.63(lH,brs) , 6.86(2H,d,J=8.6Hz) , 7.24 (2H,d,J=8.6Hz) .

Reference Example 3b

5-(4-Methoxybenzylthio)perhydropyriraidin-2-one

To 1-(t-butoxycarbonyl)-5-(4-methoxybenzylthio) perhydropyrimidin-2-one (705 mg) were added at 0 °C trifluoroacetic acid (2 ml) and anisole (2 ml) successively. The mixture was stirred for one hour. The solvent was distilled off under reduced pressure. To the residue was added an aqueous solution of sodium hydrogencarbonate (5%). The mixture was subjected to extraction with ethyl acetate - tetrahydrofuran. The

organic layer was taken, washed with a saturated aqueous saline solution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to leave the titled compound (430 mg) as a colorless solid product. IR(neat): 3250, 1700, 1650, 1510 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 2.80-3.05(lH,m) , 3.05-6.25(2H,m) , 3.25-3.50(2H,m) , 3.74(2H,s), 3.81(3H,s), 5.55(2H,brs) , 6.86(2H,d,J=8.6Hz) , 7.23(2H,d,J=8.6Hz) . Reference Example 4b

1-(t-Butoxycarbonyl)-5-(4-methoxybenzylthio)-3-methyl perhydropyrimidin-2-one

To a DMF solution (4 ml) of l-(t-butoxycarbonyl)- 5-(4-methoxybenzylthio)perhydropyriπιidin-2-one (500 mg) was added sodium hydride (purity 55%, 68 mg) . The raixture was stirred for 30 minutes, to which was added at 0°C methyl iodide (221 mg) . The mixture was stirred for one hour, to which was added water dropwise at 0 °C to decompose excess sodium hydride. The reaction raixture was subjected to extraction with ether. The extract was dried over anhydrous sodiura sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 40 g, developing solvent: ethyl acetate) to give the titled compound (166 mg) as a colorless oily product. IR(neat): 1755, 1700,1605, 1510 cm ^"1 . ^-N RfCDCls) δ: 1.52(9H,s), 2.91(3H,s), 2.90- 3.05(lH,m) , 3.09(lH,dd,J=11.8,8.8Hz) , 3.32(lH,ddd,J=11.8,5.6,1.4Hz),

3.45(lH,dd,J=12.8,4.0Hz) , 3.77(2H,s), 3.81(3H,s), 4.04(lH,ddd,J=12.8,4.0,1.4Hz) , 6.86(2H,d,J=8.8Hz) , 7.24(2H,d,J=8.8Hz) . Reference Exaraple 5b 1,3-Dimethyl-5-(4-methoxybenzylthio)perhydropyrimidin- 2-one

Dimethyl sulfate (0.17 ml) was added to a THF solution (2 ml) of 5-(4- methoxybenzylthio)perhydropyrimidin-2-one (126 mg) , potassium carbonate (276.4 mg) and benzyl triethylamraonium chloride (4.56 rag) . The mixture was stirred for 5 hours at 60 °C. Inorganic substances were filtered off. To the filtrate was added ethyl acetate (10 ml). The mixture was washed with water and a saturated aqueous saline solution, which was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 5 g, developing solvent: ethyl acetate : hexane, 1:1 - 5:1) to give the titled compound (49 mg) as a colorless solid product. IR(KBr): 1633, 1512, 1277, 1240 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 2.87(6H,s), 2.98-3.28(5H,m) , 3.76(2H,s), 3.81(3H,s), 6.86 (2H,d,J=8.8Hz) , 7.24(2H,d,J=8.8Hz) . Reference Example 6b

5-(4-Methoxybenzylthio)-l-methylperhydropyriraidine-2- thione

To a THF solution (10 ml) of aluminium lithium hydride (1.2 g) was added gradually at -78 °C a THF solution (5 ml) of N,N'-bis(t-butoxycarbonyl)-2-(4- methoxybenzylthio)propane-1,3-diamine. The mixture was refluxed under heating for 16 hours. To the reaction mixture was added ether (150 ml). To the mixture was added dropwise little by little a saturated aqueous solution of sodium sulfate. Resulting precipitates were filtered off, and the filtrate was dried over potassium carbonate. The solvent was distilled off under reduced pressure. To a THF solution (40 ml) of the residue was added at -10 °C carbon disulfide (0.55 ml) . The mixture was stirred for 30 minutes at the sarae temperature, which was further stirred for 14

hours under reflux. The solvent was distilled off under reduced pressure to leave a solid substance, which was washed with ethyl acetate and dried under reduced pressure to give the titled compound (640 mg) as a colorless solid product.

IR(KBr): 3205, 1608, 1551, 1510, 1304, 1269, 1248 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) 6: 2.90-3.39(5H,m) , 3.32(3H,s), 3.76(2H,s), 3.81(3H,s), 6.35(lH,brs) , 6.86(2H,d,J=8.8Hz) , 7.22(2H,d,J=8.8Hz) . Reference Example 7b

N,N'-Diformyl-2-(4-methoxybenzylthio)propane-1,3- diamine

A mixture of acetic anhydride (13.9 ml) and formic acid (5.57 ml) was stirred for 6 hours at 60 °C to make a solution. To the solution was added dropwise, while keeping the internal temperature at 40 °C or below, 2- (4-methoxybenzylthio)propane-l,3-diamine (7.6 g) . The mixture was stirred for 10 minutes at room temperature, to which was added ether (80 ral). The mixture was stirred for further 30 minutes at room temperature, which was then subjected to extraction with water. The aqueous layer was subjected to extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, followed by distilling the solvent under reduced pressure to give the titled corapound (7.3 g) as a colorless oily product. IR(neat): 1651, 1514, 1385, 1242 cm ^"1 . ^-NMRfCDCla) δ: 2.82-3.05(3H,m) , 3.73-3.86(2H,m) , 3.73(2H,s), 3.78(3H,s), 6.42(2H,brs) , 6.86(2H,d,J=8.8Hz) , 7.26(2H,d,J=8.8Hz) , 8.18(2H,s). Reference Example 8b

1,3-Dimethyl-5-(4-methoxybenzylthio)perhydropyriraidine- 2-thione

To a THF solution (3 ml) of N,N'-diformyl-2-(4- methoxybenzylthio)propane-1,3-diamine (669 mg) was added, under reflux, borane-dimethyl sulfide (0.58 ml,

6.15 mmol) dropwise over 15 minutes. The mixture was stirred for further 15 minutes while distilling off dimethyl sulfide. - From the reaction mixture, the solvent was distilled off. To the residue was added 6N HCl (1 ml), and the raixture was stirred for 30 minutes at 100 °C. The reaction mixture was adjusted to pH 10 with a 2N aqueous solution of sodium hydroxide, which was subjected to extraction with dichloromethane. The extract was washed with a saturated aqueous saline solution, which was then dried over potassium carbonate. The solvent was distilled off under reduced pressure. To a THF solution (50 ml) of the residue was added dropwise at -10 °C carbon disulfide (0.14 ml). The mixture was stirred for 30 minutes at the same temperature and for 14 hours under reflux. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 20 g, developing solvent, ethyl acetate : hexane, 1:4) to give the titled compound (117 mg) as a pale yellow oily product. IR(neat): 1512, 1346, 1271 cm ^"1 . ^-NMRfCDCla) δ: 2.92-3.39(5H,m) , 3.34(6H,s), 3.76(2H,s), 3.81(3H,s), 6.87(2H,d,J=8.8Hz) , 7.22(2H,d,J=8.8Hz) . Reference Example 9b l,3-Bis(pyridin-2-yl)-5-(4- methoxybenzylthio)perhydropyrimidine-2-thione

A mixture of 5-(4- methoxybenzylthio)perhydropyrimidine-2-thione (537 rag) and 2-chloropyridine (1.88 ral) was stirred for 5 rainutes at 150 °C. The reaction mixture was purified by means of a flash column chromatography (carrier: silica gel, 30 g, developing solvent: dichloromethane → dichloromethane:methanol, 10:1) to give the titled compound (329 mg) as a yellow solid product.

IR(KBr): 1738, 1589, 1512, 1464, 1431, 1250 cm ^"1 .

¹ H-NMR ( CDC1 ₃ ) δ : 3 . 34-3 . 47 ( lH ,ra) ,

3.75(2H,dd,J=12.4,4.6Hz) , 3.77(3H,s), 3.79(2H,s), 4.13(2H,dd,J=12.44.6Hz) , 6.78(2H,d,J=8.8Hz) , 7.17- 7.26(4H,m), 7.55-7.75(4H,m) , 8.48-8.51(2H,m) . Reference Exaraple 10b

N-(2,3-Dihydroxypropyl)phthalimide

To an anhydrous DMF solution (500 ml) of 3-chloro- 1,2-propanediol (55.3 g) was added potassium phthalimide (97.2 g) . The mixture was stirred for 5 hours at 130 °C. The reaction mixture was cooled to room temperature, then the solvent was distilled off under reduced pressure. To the residue was added water (500 ml). The mixture was subjected to extraction with ethyl acetate - THF (1:1, 100 ml). The aqueous layer was subjected to salting out with sodium chloride, which was then subjected to extraction with ethyl acetate - THF (1:1, 400 ml x 3). Organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (92.4 g) . IR(KBr): 3344, 1772, 1710 cm ^"1 .

^-NMRfCDCla) δ: 2.40-2.60( lH,m) , 2.70-2.90( lH,m) , 3.50-3.80(2H,ra), 3.80-4.10(3H,m) , 7.70-8.00(4H,m) . Reference Example lib

N-[3-(t-butyldimethylsilyloxy)-2- hydroxypropyl]phthalimide

To an anhydrous dichloromethane solution (500 ml) of N-(2,3-dihydroxypropyl)phthalimide (92.4 g) were added at 0 °C triethylamine (87.3 ml), t-butyldimethyl chlorosilane (78.7 g) and 4-dimethylaminopyridine (1.02 g) , successively. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ether. The extract was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous

solution of sodium hydrogencarbonate and a saturated aqueous saline solution, successively, followed y drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography

(carrier: silica gel, 900 g, developing solvent: ethyl acetate - hexane, 1:20 - 1:9 - 1:3) to give the titled compound (128.4 g) as a colorless solid product. IR(KBr): 3464, 1707 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 0.08(6H,s), 0.91(9H,s),

2.67(lH,d,J=6.4Hz) , 3.55-4.05(5H,m) , 7.70-7.90(4H,m) . Reference Example 12b

N-[3-(t-butyldimethylsilyloxy)-2-[ (tetrahydropyran-2- yl)oxy]propylJphthalimide To an anhydrous dichloromethane solution (150 ml) of N-[3-(t-butyldimethylsilyloxy)-2- hydroxypropyl]phthalimide (25.2 g) was added pyridinium p-toluenesulfonate (1.88 ml). The mixture was stirred for 7 hours at room temperature. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (carrier: silica gel, 300 g, developing solvent: ethyl acetate - hexane, 1:9 - 1:5) to give the titled compound (31.5 g) as a colorless oily product. IR(KBr): 2949, 1716 cm ^"1 .

^- MRfCDCla) δ: 0.05(6H,S), 0.88(9H,s), 1.10- 1.90(6H,ra), 3.10-3.60(2H,m) , 3.60-4.20(5H,ra) , 4.55- 4.75(lH,m), 7.65-7.75(2H,m) , 7.80-7.90(2H,m) . Reference Example 13b N-[3-hydroxy-2-[ (tetrahydropyran-2- yl)oxy]propyl]phthalimide

To an anhydrous THF solution (225 ml) of N-[3-(t- butyldiraethylsilyloxy)-2-[ (tetrahydropyran-2-yl)o- xy]propyl]phthaliraide (31.5 g) were added acetic acid (19.4 ml) and a THF solution of tetra n-butyl ammonium fluoride (IM, 112.5 ml), successively. The mixture was

stirred overnight at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, successively, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (carrier: silica gel, 300 g, developing solvent: ethyl acetate - hexane, 1:1) to give the titled compound (22.9 g) as a colorless solid product. IR(KBr): 3508, 1768, 1709 cm ^"1 . ^-NMRfCDCla) δ: 1.30-1.90(6H,m) , 3.30-4.20(7H,ra) , 4.60-4.75(lH,m) , 7.65-7.80(2H,m) , 7.80-7.90(2H,m) . Reference Exaraple 14b 5-[ (Tetrahydropyran-2-yl)oxy]perhydro-1,3-oxazin-2-one

In ethanol (85 ml) was dissolved N-[3-hydroxy-2- [ (tetrahydropyran-2-yl)oxy]propyl]phthalimide (8.61 g) . To the solution was added hydrazine raonohydrate (1.50 ml) , and the mixture was heated for 3 hours under reflux. The solvent was distilled off under reduced pressure. To the residue was added dichloromethane. Resulting precipitates were filtered off, and the filtrate was washed with dichloromethane. The filtrate was concentrated, which was dissolved in THF-water (1:1, 10 ml). To the solution were added at 0 °C sodium carbonate (318 mg) and phenyl chloroformate (0.14 ral), successively. The mixture was stirred for 30 minutes at 0 °C and for 6 hours at 50 °C. To the reaction mixture was added a saturated aqueous saline solution. The mixture was subjected to extraction with ethyl acetate - THF (1:1). The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (carrier: silica

gel, 150 g, developing solvent: ethyl acetate - ethanol, 20:1 - 1:1) to give the titled compound (5.63 g) as a colorless solid product. IR(KBr) : 1700 cm ^"1 . ^-NMRζCDCla) δ: 1.40-2.00(6H,m) , 3.30-3.65(3H,m) , 3.75-3.95(lH,ra) , 4.05-4.40( 3H,m) , 4.75-4.85( lH,m) , 5.40-5.80(lH,m) . Reference Example 15b 5-Hydroxyperhydro-l,3-oxazin-2-one To an ethanol solution (31 ml) of 5-

[ (tetrahydropyran-2-yl)oxy]perhydro-l,3-oxazin-2-one (0.78 g) was added pyridinium p-toluenesulfonate. The mixture was stirred for 3 hours at 50 °C. The solvent was distilled off under reduced pressure. To the residue was added dichloromethane. Resulting precipitates were collected by filtration to give the titled compound (449 mg) as a colorless solid product. IR(KBr): 3265, 3178, 1682 cm ^"1 . δ: 2.90-3.10( lH,m) , 3.20-3.50( lH,m) , 3.85-4.20(3H,m) , 5.20-5.40( lH,m) , 6.95-7.10(lH,m) . Reference Example 16b 5-Benzoylthioperhydro-l,3-oxazin-2-one

To an anhydrous THF solution of triphenyl phosphine (921 mg) was added at -20 °C diisopropyl azodicarboxylate (0.69 ml). The mixture was stirred for 30 minutes at -20 °C. To the reaction mixture were added 5-hydroxyperhydro-1, 3-oxazin-2-one (274 mg) and a hexamethyl phosphoramide solution (5 ml) of thiobenzoic acid (0.41 ml). The mixture was stirred for 2 hours at room temperature, to which was added ethyl acetate. The mixture was washed with water and a saturated aqueous saline solution, successively, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography

(carrier: silica gel, 40 g. developing solvent: ethyl

acetate - hexane, 2:1 - 4:1 - 1:10) to give the titled compound (535 mg) as a yellow solid product. IR(KBr): 1693/ 1662 cm ^"1 .

¹ H-NMR(CDC1 ₃ ) δ: 3.35-3.55(lH,m) , 3.75-3.90(lH,m) , 4.15-4.40(2H,m) , 4.50-4.65(lH,m) , 6.10(lH,brs) , 7.40- 7.70(3H,m), 7.90-8.00(2H,m) . Reference Example 17b

3-Methyl-2-oxo-5-[ (tetrahydropyran-2-yl)oxy]perhydro- 1,3-oxazine To an anhydrous THF solution (15 ml) of sodium hydride (purity 65%, 345 mg) was added at 0 °C 2-oxo-5- [ (tetrahydropyran-2-yl)oxy]perhydro-l,3-oxazine (1.71 g) . The mixture was stirred for one hour at 0 °C. To the reaction mixture was added at 0 °C methyl iodide (0.58 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was poured into water, which was subjected to salting out with sodium chloride, followed by extraction with ethyl acetate - THF (2:1) . The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (carrier: silica gel, lOOg, developing solvent: ethyl acetate - ethanol, 1:0 - 19:1) to give the titled compound (1.35 g) as a pale yellow oily product.

IR(neat): 2943, 1693 cm ^"1 .

^-N RfCDCla) δ: 1.40-1.90(6H,m) , 2.99(3H,s), 3.20- 3.40(lH,ra), 3.40-3.65(2H,m) , 3.75-3.95(lH,m) , 4.05- 4.20(lH,m), 4.20-4.35(2H,m) , 4.75-4.85( lH,ra) . Reference Example 18b

5-Hydroxy-3-methylperhydro-l,3-oxazin-2-one

To an ethanol solution (50 ml) of 3-methyl-2-oxo- 5-[ (tetrahydropyran-2-yl)oxyJperhydro-1,3-oxazine (1.35 g) was added pyridinium p-toluenesulfonate (158 mg) . The mixture was stirred for 3.5 hours at 55 °C. The solvent was distilled off under reduced pressure. To

the residue was added dichloromethane. Resulting precipitate was collected by filtration to give the titled corapound (378 mg) as a colorless solid product. Further, the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a flash column chromatography (carrier: silica gel, 15 g, developing solvent: ethyl acetate - ethanol, 4:1) to give the titled compound as a colorless solid product. IR(KBr): 3402, 1682 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 2.99(3H,s), 3.20-3.35( lH,m) , 3.45- 3.65(2H,ra), 4.10-4.35 ( 3H,ra) . Reference Example 19b

N-[3-benzoylthio-2-[ (tetrahydropyran-2-yl)oxy]- propyl]phthalimide To an anhydrous THF solution of triphenylphosphine (3.41 g) was added at -20 °C diisopropyl azodicarboxylate. The mixture was stirred for 30 minutes at -20 °C, to which were added N-[3-hydroxy-2- [ (tetrahydropyran-2-yl)oxy]propyl]phthalimide (3.05 g) and an anhydrous THF solution (17 ml) of thiobenzoic acid (1.53 ml). The mixture was stirred for one hour at -20 °C, then for 10 minutes at room temperature. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (carrier: silica gel, 200 g, developing solvent: ethyl acetate - hexane, 1:4). Further, the solvent was distilled off under reduced pressure, and the residue was washed with ether-hexane (1:10) to give the titled compound (4.26 g) as a colorless solid product.

IR(KBr): 1709, 1664 cm ^"1 .

^- MRfCDCla) δ: 1.10-1.90( 6H,m) , 3.10-3.60(4H,ra) , 3.75-4.10(2H,m) , 4.10-4.30( lH,m) , 4.60-4.70(0.6H,m) , 4.85-4.95(0.4H,m), 7.35-8.05(9H,m) . Reference Example 20b

5-[ (Tetrahydropyran-2-yl)oxy]perhydro-l,3-thiazin-2-one

In ethanol (40 ml) was dissolved N-[3-benzoylthio- 2-[ (tetrahydropyran-2-yl)oxy]propyl]phthalimide (3.48 g) . To the solution was added hydrazine monohydrate (0.99 ml), and the mixture was heated for one hour under reflux. The reaction mixture was cooled to room temperature. Resulting precipitate was filtered off and washed with ethanol. The filtrate was concentrated, which was dissolved in THF-water (1:1, 40 ml) . To the solution were added, at 0 °C, sodium carbonate (2.60 g) and 4-nitrophenyl chloroformate

(2.47 g), successively. The mixture was stirred for one hour at 0 °C, then overnight at room temperature. To the reaction mixture was added a saturated aqueous saline solution. The mixture was subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 40 g, developing solvent: ethyl acetate - hexane, 3:2 - 2:1), followed by further purification by means of a flash column chromatography (carrier: silica gel, 20 g, developing solvent: ethyl acetate - toluene, 1:1) to give the titled compound (550 mg) as a colorless oily product. IR(neat): 3277, 1649 cm ^"1 .

^-NMRfCDCl-,) δ: 1.40-2.00(6H,m) , 3.10-3.30(2H,m) , 3.40-3.55(3H,m) , 3.80-4.00(lH,m) , 4.15-4.40(lH,m) , 4.75-4.85(lH,m) , 5.85-6.15{lH,m) . Reference Example 21b 5-Hydroxy-2-oxoperhydro-l,3-thiazine

2-0x0-5-[ (tetrahydropyran-2-yl)oxy]perhydro-l,3- thiazine (580 g) was subjected to substantially the same reaction and purification as in Reference Example 15b to give the titled compound (281 mg) as a colorless solid product.

IR(KBr): 3194, 1618 cm ^"1 .

^-NMRJDMSO-d _β ) δ: 2.80-3.00( lH,ra) , 3.00-3.50(4H,m) , 3.95-4.10(lH,m) , 7.80-7.95( lH,m) . Reference Example 22b

5-Benzoylthio-2-oxoperhydro-l,3-thiazine 5-Hydroxy-2-oxoperhydro-l,3-thiazine (278 mg) was subjected to substantially the same reaction and purification as in Reference Example 16b to give the titled compound (219 mg) as a yellow solid product. IR(KBr): 1668, 1641 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 3.15-3.30( lH,m) , 3.40-3.65(2H,m) , 3.70-3.90(lH,ra) , 4.30-4.50( lH,ra) , 6.05-6.20( lH,ra) , 7.40-7.75(3H,m) , 7.90-8.00(2H,m) . Reference Example 23b 3-Methyl-5-[ (tetrahydropyran-2-yl)oxy]perhydro-l, 3- thiazin-2-one

To an anhydrous THF solution (22 ml) of sodium hydride (purity 65%, 228 mg) was added, at 0°C, 5- [ (tetrahydropyran-2-yl)oxy]perhydro-l,3-thiazin-2-one (1.22 g) . The mixture was stirred for 20 minutes at 0°C. To the reaction mixture was added, at 0°C, methyl iodide (0.39 mg) . The mixture was stirred at 0°C for one hour, and at room temperature for 30 minutes. The reaction mixture was poured into water, which was subjected to salting out with sodium chloride, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate- hexane, 1:1) to afford the titled compound (1.10 g) as a colorless oily product. IR(neat): 2939, 1633 cm ^'1 .

¹ H-NMR(CDCl ₃ )δ: 1.45-1.90(6H,m) , 3.03( 1.5H,s) , 3.04(1.5H,s) , 3.10-3.30(2H,m) , 3.40-3.65(3H,ra) , 3.80- 4.00(lH,ra), 4.20-4.40( lH,m) , 4.75-4.85( lH,m) . Reference Example 24b

- I l l -

5-Hydroxy-3-methylperhydro-l,3-thiazin-2-one

3-Methyl-5-[ (tetrahydropyran-2-yl)oxy]perhydro- l,3-thiazin-2-one (1.10 g) was subjected to substantially the same reaction and purification process as in Working Example 15b to afford the titled compound (657 mg) as a colorless solid product.

IR(KBr): 3392, 1612 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.65-1.75(lH,ra) , 3.05(3H,s), 3.05-

3.20(lH,m), 3.25-3.60(3H,ra) , 4.25-4.45(lH,m) . Reference Example 25b

5-Benzoylthio-3-methylperhydro-1,3-thiazin-2-one

5-hydroxy-3-methylperhydro-l,3-thiazin-2-one (644 mg) was subjected to substantially the same reaction and purification process as in Working Example 16b to afford the titled compound (775 mg) as a yellow solid product.

IR(KBr): 1660, 1622 cm ^"1 .

^-NMRfCDClaJδ: 3.08(3H,s), 3.15-3.30(lH,m) , 3.40-

3.65(2H,m), 3.70-3.85(lH,m), 4.35-4.55(lH,m) , 7.40- 7.70(3H,m), 7.90-8.00(2H,m) .

Reference Example 26b

3-Cyanomethyl-5-[ (tetrahydropyran-2-yl)oxy]perhydro-

1,3-thiazin-2-one

To 5-[ (tetrahydropyran-2-yl)oxy]perhydro-l,3- thiazin-2-one (1.0 g) was added, at 0°C, an anhydrous

THF solution (22 ml) of sodium hydride (purity 65%, 187 mg) . The mixture was stirred for 20 minutes at 0°C.

To the reaction mixture was added, at 0°C, chloroacetonitrile (0.32 ml). The mixture was stirred at 0°C for 10 minutes, and at room temperature for 1.5 hour. The reaction mixture was poured into water, which was subjected to salting out with sodiura chloride, followed by extraction with ethyl acetate.

The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.

The residue was was purified by means of column

chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-hexane, 2:3) to afford the titled compound as a colorless oily product.

IR(neat): 2943, 1626 cm ^"1 . ¹ H-NMR(CDCl ₃ )δ: 1.40-2.00(6H,m) , 3.15-3.40(2H,m) , 3.50-

4.00(4H,m), 4.25-4.60(3H,m) , 4.75-4.85(lH,m) .

Reference Example 27b

3-Cyanomethyl-5-hydroxyperhydro-l,3-thiazin-2-one 3-Cyanomethyl-5-[ (tetrahydropyran-2- yl)oxy]perhydro-l,3-thiazin-2-one (1.05 g) was subjected to substantially the same reaction and purification process as in Working Example 15b to afford the titled compound (570 mg) as a colorless oily product. IR(neat): 3410, 1616 cm ^"1 .

^-NMRfCDCl^δ: 3.00-3.45(2H,m) , 3.45-3.75(2H,m) , 4.30-

4.50(lH,m) , 4.42(2H,ABq,J=17.4Hz) .

Reference Example 28b

5-Benzoylthio-3-cyanomethylperhydro-l,3-thiazin-2-one 3-Cyanomethyl-5-hydroxyperhydro-l,3-thiazin-2-one

(560 mg) was subjected to substantially the same reaction and refining process as in Working Example 16b to afford the titled compound (859 mg) as a yellow oily product. IR(neat): 1662, 1632, 1209 cm ^"1 .

^-NMR(CDC1 ₃ )6: 3.30(IH,ddd,J=12.4,7.8&1.0Hz) ,

3.56(lH,ddd,J=12.4,4.0&1.0Hz) ,

3.71(lH,ddd,J=12.6,7.2&1.0Hz) ,

3.94(lH,ddd,J=12.6,3.4&1.0Hz) , 4.50(2H,ABq,17.4Hz) , 4.40-4.60(lH,m) , 7.40-7.70(3H,ra) , 7.90-8.00(2H,m) .

Working Example lb

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-3-[ (2-thioxoperhydropyriraidin-5-yl)thio]- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate To a trifluoroacetic acid solution (7.5 ml) of the compound (200 mg) produced by the method of Reference

Example lb was added anisole (0.81 g) . The mixture was stirred for 3 hours under reflux. The solvent was distilled off under reduced pressure. To the residue was added toluene, and the mixture was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. To the residue was added acetonitrile (6 ml), to which diisopropyl ethylamine (0.32 ml) was added dropwise at 0 °C. To the mixture was further added at 0 °C an acetonitrile solution (5 ml) of 4-nitrobenzyl (4R,5R, 6S)-3-

[ (diphenylphosphono)oxy]-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (443 mg) . The mixture was stirred for two hours at the same temperature. To the reaction mixture was added phosphate buffer (pH 7), which was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The solid residue was washed with ethyl acetate, followed by vacuum drying to give the titled compound (296 mg) as a pale yellow solid product.

IR(KBr): 1763, 1543, 1520, 1344, 1213 cm ^"1 . ¹ H-NMR(CDCl ₃ ,DMSO-d ₆ ) δ: 1.27 (3H,d,J=7.0Hz) , 1.32(3H,d,J=6.2Hz) , 3.12-3.65(7H,m) , 4.09-4.20(lH,m) , 4.28(lH,dd,J=2.6,9.8Hz) , 4.53( lH,d,J=5.0Hz) ,

5.22(lH,d,J=13.8Hz), 5.50( lH,d,J=13.8Hz) , 7.41(2H,brs) ,

7.67(2H,d,J=8.6Hz) . 8.23(2H,d,J=8.6Hz) .

Working Example 2b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-7- oxo-3-[ (2-thioxoperhydropyrimidin-5-yl)thio]-l- azabicyclo[3.2.0]hept-2-carboxylate

The compound (170 rag) produced by the method of Working Example lb was dissolved in a mixture of THF (7 ml) and phosphate buffer (pH 7, 0.1M, 7 ml). To the solution was added 10% palladium-carbon (180 mg) . The mixture was stirred for 3 hours at room temperature

under hydrogen atmosphere. The catalyst was filtered off and washed with water. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: CHP-20P, 60 ml, developing solvent: water - 5% ethanol-water) , which was freeze-dried to give the titled compound (81.7 mg) as a colorless solid product. IR(KBr): 3394, 1745, 1595, 1545, 1396 cm ^"1 . ^-NMR DzO) 6: 1.24(3H,d,J=7.4Hz) , 1.31(3H,d,J=6.4Hz) , 3.23-3.78(7H,m) , 4.24-4.31(2H,m) . Working Example 3b l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[ (R)-l- hydroxyethy1]-4-methy1-7-oxo-3-[ (2- thioxoperhydropyrimidin-5-yl)thio]-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

To a DMA solution (3 ml) of the compound (49 mg) produced by the method of Working Example 2b was added dropwise at -15 °C 1-iodoethyl cyclohexyloxycarboxylate. The mixture was stirred for 30 minutes at the same temperature and for further one hour at 0 °C. To the reaction mixture was added ethyl acetate, which was washed with phosphate buffer (pH 7) and a saturated aqueous saline solution, successively, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 10 g, developing solvent: ethyl acetate:ethanol, 20:1) to give the titled corapound (36.5 mg) as a colorless solid product. IR(neat): 1759, 1546, 1537, 1277, 1259 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.23-2.05( 19H,ra) , 2.50-3.00(lH,brs) , 3.24-3.67(7H,m) , 4.21- .28( lH,m) , 4.36(lH,dd,J=2.2,9.8Hz) , 4.48-4.67 ( lH,m) , 6.86(lH,q,J=6.4Hz), 7.21( lH,brs) , 7.36( lH,brs) . Working Example 4b

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-3-[ (2-oxoperhydropyrimidin-5-yl)thio]-1- azabicyclof3.2.0]hept-2-ene-2-carboxylate

To a trifluoroacetic acid solution (8 ml) of the corapound (282 mg) produced by the method of Reference Example 3b was added anisole (0.8 g) . The mixture was stirred for 30 minutes at room temperature, which was then stirred for further two hours under reflux. The solvent was distilled off under reduced pressure. To the residue was added toluene, which was subjected to azeotropic distillation under reduced pressure to remove trifluoroacetic acid. To the residue was added acetonitrile (3 ml), to which was added dropwise at 0 °C diisopropylethylamine (0.35 ml). To the mixture was further added at 0 °C an acetonitrile solution (5 ml) of 4-nitrobenzyl (4R,5R,6S)-3-[ (diphenylphosphono)oxy]- 6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (476 mg) . The mixture was stirred for one hour at the same temperature. To the reaction mixture was added phosphate buffer (pH 7), which was subjected to extraction with ethyl acetate, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave a solid matter, which was washed with ethyl acetate, followed by vacuum-drying to give the titled compound (196 mg) as a pale yellow solid product.

IR(KBr): 1772, 1699, 1680, 1519, 1344 cm ^"1 . δ: 1.26(3H,d,J=6.8Hz) , 1.28(3H,d,J=6.4Hz) , 3.18-3.31(3H,m) , 3.39-3.61(4H,m) , 4.09(lH,ra) , 4.26(lH,dd,J=2.4,9.2Hz) , 4.88(lH,d,J=4.8Hz) , 5.21(lH,d,J=13.8Hz) , 5.49(lH,d,J=13.8Hz) , 5.84(2H,m), 7.67(2H,d,J=8.6Hz) , 8.21(2H,d,J=8.6Hz) . Working Example 5b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-7-

oxo-3-[2-oxoperhydropyrimidin-5-yl)thio]-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The compound {192 mg) produced by the method of Working Example 4b was dissolved in a mixture of THF (10 ml) and phosphate buffer (pH 7, 0.1M, 10 ml). To the solution was added 10% palladium-carbon (210 mg) , which was stirred for one hour at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with water. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure. The concentrate was was purified by means of a column chromatography (carrier: CHP-20P, 100 ml, developing solvent: water - 5% ethanol-water) , followed by freeze-drying to give the titled compound (122.6 mg) as a colorless solid product.

IR(KBr): 3357, 1742, 1653, 1595, 1396 cm ^"1 . ¹ H-NMR(D ₂ 0) δ: 1.24(3H,d,J=7.2Hz) , 1.31(3H,d,J=6.4Hz) ,3.22-3.43( 3H,m) , 3.49(lH,dd,J=2.8,6.2Hz) , 3.62-3.73( 3H,ra) , 4.21- 4.31(2H,m) . Working Example 6b

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-3-[ (2- oxoperhydropyrimidin-5-yl)thio]-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

To a DMA solution (2 ml) of the compound (48.2 mg) produced by the method of Working Exaraple 5b was added dropwise at -15 °C 1-iodoethyl cyclohexyloxycarboxylate (63.3 mg) . The mixture was stirred for 30 minutes at the same temperature and for further one hour at 0 °C, to which was added ethyl acetate. The mixture was washed with phosphate buffer (pH 7) and a saturated aqueous saline solution, successively, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was

purified by means of a flash column chromatography (carrier: silica gel, 5 g, developing solvent: ethyl acetate:ethanol, 3-:l) to give the titled compound (19.1 mg) as a colorless foamy product. IR(neat): 3300, 1755, 1660, 1274 cm ^"1 .

¹ H-NMR(CDC1 ₃ ) δ: 1.16-2.04 (20H,ra) , 3.22-3.55(7H,m) , 4.09-4.27(2H,m) , 4.62-4.65(lH,m) , 5.66 (lH,brs) , 5.82(lH,brs) , 6.86( lH,q,J=5.6Hz) . Working Example 7-lb 4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4- methyl-3-[ ( l-methylperhydropyrimidine-2-thion-5- yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

The compound (300 mg) produced by the method of Reference Exaraple 6b was subjected to substantially the same reaction and refining process as in Working Example lb to give the titled compound (499.3 mg) as a pale yellow foamy product. IR(KBr): 3350, 1770, 1709, 1520 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.29(3H,d,J=7.2Hz) ,

1.37(3H,d,J=6.2Hz) , 1.63( lH,brs) , 3.21-3.79( 10H,m) , 4.26-4.35(2H,ra), 5.23(2H,d,J=13.8Hz) , 5.50(2H,d,J=13.8Hz) , 6.65(2H,d,J=8.8Hz) , 6.24(2H,d,J=8.8Hz) . Working Example 7-2b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-3- [ (l-methylperhydropyrimidine-2-thion-5-yl)thio]-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The compound (499.3 mg) produced by the method of Working Example 7-lb was subjected to substantially the same reaction and refining process as in Working Example 2b to give the diastereomer-1 (122.8 rag) and diastereomer-2 (91.8 mg) of the titled compound, respectively. Diastereoraer-1

IR(KBr): 3400, 1751, 1593, 1547 cm ^"1 .

^-NMRfDzO) δ: 1.23( 3H,d,J=7.0Hz) , 1.30(3H,d,J=6.6Hz) ,

3.22-3.84(7H,m) , 3.27(3H,s), 4.23-4.30(2H,m) .

Diastereomer-2

IR(KBr): 3369, 1751, 1593, 1544 cm ^"1 . ^-NMRfDzO) δ: 1.22 ( 3H,d,J=7.0Hz) , 1.30(3H,d,J=6.6Hz) ,

3.16-3.60(7H,m) , 3.30(3H,s), 3.77-3.88(2H,m) .

Working Example 7-3b l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[(R)-l- hydroxyethyl]-4-methyl-3-[ ( 1-methylperhydropyrimidine- 2-thion-5-yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-

2-carboxylate

The diastereomer-1 (49.6 mg) and diastereomer

(38.7 mg) of the compound produced by the method of

Working Example 7-2b were respectively subjected to substantially the same reaction and refining process as in Working Example 3b to give the diastereomer-1 (33 mg) and diastereomer-2 (22.2 mg) of the titled compound as colorless solid products, respectively.

Diastereomer-1 IR(neat): 3401, 1765, 1539, 1275, 1074 cm ^"1 .

¹ H-NMR(CDC1 ₃ ) δ: 1.21-1.96(20H,m) , 2.05-3.73( 10H,m) ,

4.22-4.31(2H,m) , 4.61-4.68( lH,m) , 6.77 ( lH,brs) ,

6.87(lH,q,J=5.2Hz) .

Diastereomer-2 IR(neat): 3400, 1759, 1537, 1277, 1074 cm ^"1 .

^X H-NMR(CDC1 ₃ ) δ: 1.17-1.95(20H,m) , 3.25-3.76( 10H,m) ,

4.18-4.24(2H,m) , 4.61-4.68( lH,m) , 4.55( lH,brs) ,

6.87(lH,q,J=3.4Hz) .

Working Example 8-lb 4-Nitrobenzyl (4R,5S,6S)-3-[ ( 1, 3-dimethyl-2- thioxoperhydropyrimidin-5-yl)thio]-6-[ (R)-1- hydroxyethy1]-4-methyl-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The compound (328.3 mg) produced by the method of Reference Example 8b was subjected to substantially the same reaction and refining process as in Working

Example lb to give the titled compound (410 mg) as a colorless solid product.

IR(KBr): 3383, 1778, 1759, 1529, 1512 cm ^"1 .

¹ H-NMR(CDC1 ₃ ) 6: 1.30(3H,d,J=7.4Hz) , 1.38(3H,d,J=6.2Hz) , 1.57 ( lH,brs) , 3.30-3.72 (7H,m) ,

3.41(3H,s), 3.43(3H,s), 4.24-4.34(2H,m) ,

5.24(lH,d,J=14.0Hz), 5.51( lH,d,J=14.0Hz) ,

7.66(2H,d,J=8.6Hz) , 8.24(2H,d,J=8.6Hz) .

Working Example 8-2b Sodium (4R,5S,6S)-3-[ ( 1,3-dimethyl-2- thioxoperhydropyriraidin-5-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

The corapound (410 mg) produced by the method of Working Example 8-lb was subjected to substantially the same reaction and refining process as in Working

Example 2b to give the titled compound (175 mg) as a colorless foamy product.

IR(KBr): 3427, 1751, 1593, 1529, 1396, 1354 cm ^"1 . ^-NMRfDzO) δ: 1.23(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.2Hz) ,

3.31-3.51(4H,m), 3.31(3H,s), 3.33(3H,s), 3.27-

3.85(3H,m), 4.23-4.30(2H,m) .

Working Exaraple 8-3b

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-[(l,3- diraethyl-2-thioxoperhydropyrimidin-5-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

The compound (51.9 mg) produced by the method of

Working Example 8-2b was subjected to substantially the same reaction and refining process as in Working

Exaraple 3b to give the titled compound (24.6 mg) as a colorless foamy product.

IR(neat): 3401, 1759, 1524, 1350, 1277 cm ^"1 .

^X H-NMR(CDC1 ₃ ) δ: 1.23-2.05(20H,m) , 3.26-3.74 ( 13H,m) , 4.18-4.30(2H,m) , 4.61-4.68( lH,ra) , 6.88( lH,q,J=5.2Hz) .

Working Example 9-lb

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-3-[ ( l-raethyl-2-oxoperhydropyrimidin-5-yl)thio]- 7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The compound (164 mg) produced by the method of Working Example 4b was subjected to substantially the same reaction and refining process as in Working Example lb to give the titled compound (140 mg) as a colorless solid product which is a mixture of diastereomers (1:1). IR(KBr): 3425, 1770, 1645, 1635, 1523 era ^"1 .

^-NMR^O) δ: 1.31(3H,d,J=7.4Hz) , 1.38(3H,d,J=6.2Hz) , 2.93(3/2H,s) , 2.96(3/2H,s) , 3.20-3.80(7H,m) , 4.20- 4.40(2H,m), 4.86(lH,brs), 5.24(lH,d,J=13.6Hz) , 5.55(lH,d,J=13.6Hz) , 7.66(2H,d,J=8.8Hz) , 8.24(2H,d,J=8.8Hz) . Working Example 9-2b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-3- [ (l-methyl-2-oxoperhydropyrimidin-5-yl)thio]-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate The compound (137 mg) produced by the method of

Working Example 9-lb was subjected to substantially the same reaction and refining process as in Working Example 2b to give diastereomer-1 (33 mg) and diastereomer-2 (24 mg) of the the titled compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3390, 1751, 1637, 1597, 1535 cm ^"1 . ¹ H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.2Hz) , 1.31(3H,d,J=6.2Hz) , 2.86(3H,s), 3.18-3.80(7H,m) , 4.20-4.32(2H,m) . Diastereomer-2

IR(KBr): 3390, 1751, 1637, 1597, 1535 cm ^"1 . ^-NMRfDzO) δ: 1.23(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) , 2.89(3H,s), 3.16-3.80(6H,m) , 3.48(lH,dd, J=6.4Hz,2.8Hz) , 4.24(lH,dd,J=8.8,2.8Hz) .4.26(IH,quint, J=6.4Hz).

Working Example 9-3b

l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[(R)-l- hydroxyethyl]-4-methyl-3-[ (l-methyl-2-oxoperhydro pyrimidin-5-yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate Diastereomer-1 (68 mg) and diastereomer-2 (71.7 mg) of the compound produced by the method of Working Example 9-2b were respectively subjected to substantially the same reaction and refining process as in Working Example 3b to give diastereomer-1 (63.6 rag) and diastereomer-2 (60 mg) of the titled compound, respectively. Diastereomer-1

IR(KBr): 3400, 1755, 1710, 1640, 1535, 1530 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.20-2.05(10H,m) , 1.28(3H,d,J=7.0Hz) , 1.34(3/2H,d,J=6.4Hz), 1.36(3/2H,d,J=6.2Hz) , 1.59(3/2H,d,J=5.2Hz), 1.61(3/2H,d,J=5.2Hz) , 2.92(3/2H,s) , 2.93(3/2H,s) , 3.20-3.80(7H,m) , 4.15- 4.35(2H,m), 4.55-4.75(lH,m) , 4.9(lH,brs), 6.88(lH,q,J=5.4Hz) . Diastereomer-2

IR(KBr): 3400, 1760, 1710, 1640, 1535, 1530 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.20-2.05(10H,m) , 1.28(3H,d,J=7.0Hz) , 1.34(3/2H,d,J=6.2Hz) , 1.36(3/2H,d,J=6.4Hz) , 1.58(3/2H,d,J=5.1Hz), 1.61(3/2H,d,J=5.1Hz) , 2.95(3H,s), 3.15-3.75(7H,m) , 4.15-4.35(2H,m) , 4.55-4.75(lH,m) , 4.8(lH,brs), 6.88(lH,q,J=5.4Hz) . Working Example 10-lb

4-Nitrobenzyl (4R,5S,6S)-3-[ (1,3-dimethyl-2-oxoperhydro pyrimidin-5-yl)thio]-6-[ [ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

The compound (300 mg) produced by the method of Reference Example 5b was subjected to substantially the sarae reaction an d refining process as in Working Example lb to give the titled compound (453 mg) as a colorless solid product.

IR(KBr): 3338, 1778, 1709, 1625, 1527 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.31(3H,d,J=7.4Hz) , 1.73(3H,d,J=6.5Hz) , 1.62( lH,brs) , 2.92(3H,s), 2.95(3H,s), 2.95-3.78(7H,m) , 4.26-4.34 (2H,ra) , 5.24(lH,d,J=13.8Hz), 5.51( lH,d,J=13.8Hz) , 7.66(2H,d,J=8.4Hz) , 8.24(2H,d,J=8.4Hz) . Working Example 10-2b

Sodium (4R,5S,6S)-3-[ ( 1,3-dimethyl-2- oxoperhydropyrimidin-5-yl)thio]-6-[ (R)-1-hydroxyethyl]- 4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

The compound (453 mg) produced by the method of Working Example 10-lb was subjected to substantially the same reaction and refining process as in Working Example 2b to give the titled corapound (257 mg) as a colorless foamy product.

IR(KBr): 3390, 1751, 1601, 1535, 1394, 1275 cm ^"1 . ¹ H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.4Hz) , 1.31( 3H,d,J=6.2Hz) , 2.87(3H,s), 2.89(3H,s), 3.21-3.79 (7H,m) , 4.22- 4.29(2H,m).

Working Example 10-3b l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-[ (1,3- dimethyl-2-oxoperhydropyrimidin-5-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

The compound (51.4 mg) produced by the method of Working Example 10-2b was subjected to substantially the same reaction and refining process as in Working Example 3b to give the titled compound (47.6 mg) as a colorless solid product.

IR(KBr): 3302, 1774, 1753, 1618, 1277, 1257, 1074 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.21-1.98(20H,ra) , 2.91-2.95(6H,m) , 3.22-3.78(7H,m), 4.22-4.28(2H,m) , 4.62-4.68( lH,m) , 6.89(lH,q,J=5.6Hz) . Working Example 11-lb

4-Nitrobenzyl (4R,5S,6S)-3-[ [ 1, 3-bis (pyridin-2-yl)-2-

thioxoperhydropyrimidin-5-yl]thio]-6-[ (R)-1-hydroxyeth- yl]-4-methyl-7-oxo-l-azabicyclo[ 3.2.0]hept-2-ene-2- carboxylate

The compound (156 mg) produced by the method of Reference Example 9b was subjected to substantially the same reaction and refining process as in Working Example lb to give the titled compound (148 mg) as a pale yellow solid product. IR(KBr): 3400, 1772, 1711, 1589, 1520 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.32(3H,d,J=7.6Hz) , 1.37(3H,d,J=6.2Hz) , 1.62(lH,brs) , 3.33(lH,dd,J=6.4,2.8Hz) , 3.43-4.48(8H,m) , 5.24(lH,d,J=13.8Hz), 5.48( lH,d,J=13.8Hz) , 7.18- 7.27(2H,m), 7.59-7.78(6H,ra) , 8.21(2H,d,J=8.8Hz) , 8.45- 8.52(2H,m).

Working Exaraple ll-2b

Sodium (4R,5S,6S)-3-[ [1,3-bis(pyridin-2-yl)-2- thioxoperhydropyrimidin-5-yl]thio]-6-[ (R)-1- hydroxyethyl]-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

The corapound (148 mg) produced by the method of Working Example 11-lb was subjected to substantially the same reaction and refining process as in Working Example 2b to give the titled compound (66.5 mg) as a colorless foamy product.

IR(KBr): 3427, 1751, 1592, 1468, 1433, 1319 cm ^"1 . ^-NMRfDzO) δ: 1.25(3H,d,J=7.2Hz) , 1.27 (3H,d,J=6.6Hz) , 3.35-3.54(2H,m) , 3.75-4.01(2H,m) , 4.12(lH,dd,J=9.4,2.4Hz) , 4.19-4.42(4H,m) , 7.45- 7.61(4H,m), 7.93-8.07 (2H,m) , 8.48-8.53(2H,m) . Working Example 12-lb

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-3-[ (2-oxoperhydro-l,3-oxazin-5-yl)thio]-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate To a THF-methanol solution (1:1, 18 ml) of the compound (416 mg) produced by the method of Reference

Example 16b was added at 0 °C sodium methoxide (95 rag). The mixture was stirred for one hour at 0 °C, to which were added acetic acid (0.22 ml) and acetonitrile (40 ml) . The mixture was concentrated under reduced pressure until the volume of the solvent was reduced to about 5 ml. Insolubles were filtered off, and washed with acetonitrile (40 ml). To the filtrate thus obtained were added at 0 °C 4-nitrobenzyl (4R,5R,6S)-3- [ (diphenylphosphono)oxy]-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (1.68 g) and diisopropyl ethylamine (0.68 ml). The mixture was stirred for one hour at 0 °C, to which was added ethyl acetate. The mixture was washed with phosphate buffer (pH 7), followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave a solid matter, which was collected by filtration and washed with ethyl acetate to give diastereomer-1 (low polarity) (427 mg) as a colorless solid product. The filtrate was concentrated under reduced pressure. The concentrate was purified by means of a flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-ethanol, 1:0 - 50:1 - 9:1) to give diastereomer-1 (low polarity) (60 mg) and diastereomer- 2 (high polarity) (327 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3521, 1761, 1703, 1524 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.10-1.25(6H,m) , 3.05-3.25(lH,m) , 3.25-3.40(lH,m) , 3.50-3.70(2H,m) , 3.70-3.90(lH,m) , 3.90-4.20(2H,m) 4.20-4.35(lH,m) , 4.35-4.50(lH,m) , 5.08(lH,d,J=5.2Hz) , 5.39(2H,ABq,J=14.4Hz) , 7.42(lH,brs) , 7.72(2H,d,J=8.6Hz) , 8.24(2H,d,J=8.6Hz) . Diastereomer-2 IR(KBr): 3402, 1768, 1708, 1521, 1346 cm ^"1 .

¹ H-NMR(DMSO-d ₆ ) δ: 1.10-1.25(6H,m) , 3.05-3.40(2H,m) ,

3.50-3.70(2H,m) , 3.80-3.90( lH,m) , 3.90-4.10( lH,m) , 4.15-4.35(2H,m) , 4.45- .55( lH,m) , 5.08( lH,d,J=5.2Hz) , 5.40(2H,ABq,J=14.0Hz), 7.35-7.45( lH,m) , 7.72(2H,d,J=8.8Hz) , 8.25(2H,d,J=8.8Hz) . Working Example 12-2b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-raethyl-7- oxo-3-[ (2-oxoperhydro-l,3-oxazin-5-yl)thio]-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The diastereoraer-1 (140 mg) and diastereomer-1 (175 mg) of the compound produced by the method of

Working Example 12-lb were respectively subjected to substantially the same reaction and refining process as in Working Example 2b to give diastereomer-1 (94 mg) and diastereomer-2 (88 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3425, 1749, 1699, 1595, 1394 cm ^"1 . ¹ H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) , 3.20-3.40(lH,ra) , 3.40-3.55(2H,m) , 3.60-3.85(2H,ra) , 4.15-4.30(3H,m) , 4.40-4.55( lH,m) . Diastereomer-2

IR(KBr): 3417, 1751, 1703, 1597, 1394 cm ^"1 . ¹ H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) , 3.20-3.50(2H,m) , 3.49 ( lH,dd,J=6.0Hz and 2.8Hz) , 3.60- 3.90(2H,m), 4.15-4.45(3H,ra) . Working Example 12-3b l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[ (R)-l- hydroxyethy1]-4-methyl-7-oxo-3-[ (2-oxoperhydro-1,3- oxazin-5-yl)thio]-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

The diastereomer-1 (38 mg) and diastereomer-2 (41 mg) of the compound produced by the method of Working Example 12-2b were respectively subjected to substantially the same reaction and refining process as in Working Example 3b to give the diastereomer-1 (37 mg) of the titled compound as a colorless solid product

and the diastereomer-2 (39 mg) as a pale yellow solid product, respectively.

Diastereomer-1

IR(KBr): 3427, 1759, 1705 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.10-2.10( 19H,m) , 3.20-3.50(3H,m) ,

3.55-3.80(2H,m) , 4.05-4.40(4H,m) , 4.55-4.75( lH,m) ,

5.35-5.45(lH,m) , 6.80-6.95( lH,m) .

Diastereomer-2

IR(KBr): 3429, 1759, 1705 cm ^"1 . ^-NMRfCDCl;,) δ: 1.10-2.10( 19H,ra) , 2.20-2.50( lH,m) ,

3.20-3.55(3H,m) , 3.55-3.80(2H,ra) , 4.05-4.40(3H,ra) ,

4.40-4.75(2H,m) , 5.94( lH,brs) , 6.80-6.95( lH,ra) .

Working Exaraple 13-lb

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4- methyl-3-[ ( 3-methyl-2-oxoperhydro-l, 3-oxazin-5- yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

The compound (717 mg) produced by the method of

Reference Example 18b was subjected to substantially the same reaction as in Reference Exaraple 16b to give

5-benzoylthio-3-raethylperhydro-l,3-oxazin-2-one as a mixture with triphenylphosphine oxide. The mixture product was then subjected to substantially the same reaction and refining process as in Working Example 12- lb to give diastereomer-1 (low polarity) (782 mg) of the titled corapound and diastereomer-2 (high polarity)

(871 mg) of the titled compound as colorless solid products, respectively.

Diastereomer-1 IR(KBr): 3462, 1776, 1686, 1523 cm ^"1 .

¹ H-NMR(DMSO-d ₆ ) δ: 1.10-1.25(6H,m) , 2.86(3H,s), 3.10-

3.40(2H,m), 3.50-3.80(2H,m) , 3.80-4.20( 3H,m) , 4.20-

4.50(2H,m), 5.10( lH,d,J=5.0Hz) , 5.40(2H,ABq,J=14.2Hz) ,

7.72(2H,d,J=8.6Hz) , 8.25(2H,d,J=8.6Hz) . Diastereomer-2

IR(KBr): 3332, 1767, 1701, 1676, 1344 cm ^"1 .

¹ H-NMR(DMSO-d ₆ ) δ: 1.10-1.30(6H,m) , 2.84(3H,s), 3.20- 3.50(2H,m), 3.50-3.85(2H,m) , 3.85-4.10(2H,m) , 4.10- 4.35(2H,m), 4.40-4.60( lH,m) , 5.10( lH,d,J=5.2Hz) , 5.40(2H,ABq,J=14.0Hz) , 7.72 (2H,d,J=8.6Hz) , 8.24(2H,d,J=8.6Hz) .

Working Example 13-2b

Sodium (4R,5S,6S)-6-[(R)-1-hydroxyethyl]-4-methyl-3- [ ( 3-methyl-2-oxoperhydro-l, 3-oxazin-5-yl)thio]-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate The diastereomer-1 (400 mg) and diastereomer-2 (400 mg) of the compound produced by the method of Working Exaraple 131b were respectively subjected to substantially the same reaction a d refining process as in Working Example 2b to give diastereomer-1 (262 mg) and diastereoraer-2 (264 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3415, 1757, 1711, 1686, 1605, 1394 cm ^"1 . ¹ H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.2Hz) , 2.96(3H,s), 3.25-3.55(3H,ra) , 3.65-3.90(2H,m) , 4.10- 4.35(3H,m), 4.35-4.50(lH,m) . Diastereomer-2

¹ H-NMR(D ₂ 0) δ: 1.22 ( 3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) , 2.94(3H,s), 3.25-3.55(3H,m), 3.70-3.90(2H,m) , 4.15- 4.40(3H,m), 4.50-4.65(lH,m) . Working Example 13-3b

1-(cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[(R)-l- hydroxyethyl]-4-methyl-3-[ ( 3-methyl-2-oxoperhydro-l, 3- oxazin-5-yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene- 2-carboxylate

The diastereomer-1 (80 mg) and diastereomer-2 (71 rag) of the compound produced by the method of Working Example 13-2b were respectively subjected to substantially the same reaction and refining process as in Working Example 3b to give diastereomer-1 (92 mg) and diastereomer-2 (86 mg) of the titled compound as

colorless solid products, respectively.

Diastereomer-1

IR(KBr): 3423, 1761, 1705 cm ^"1 .

¹ H-NMR(CDC1 ₃ ) δ: 1.10-2.10( 19H,m) , 2.20-2.50( lH,m) , 3.00(3H,s), 3.10-3.85(5H,m), 4.00-4.40(4H,m) , 4.50-

4.75(lH,ra), 6.80-7.00( lH,m) .

Diastereomer-2

IR(KBr): 3431, 1759, 1689 cm ^"1 . δ: 1.20-2.10(19H,m) , 2.25-2.55( lH,m) , 2.98(1.5H,s) , 2.99 ( 1.5H,s) , 3.20-3.65(4H,m) , 3.70-

3.85(lH,ra), 4.10-4.35(3H,ra) , 4.35-4.50( lH,m) ,

6.88(lH,q,J=5.4Hz) .

Working Example 14-lb

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-3-[ (2-oxoperhydro-l,3-thiazin-5-yl)thio]- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The compound produced by the method of Reference

Example 22b was subjected to substantially the same reaction and refining process as in Working Example 12- lb to give diastereomer-1 (low polarity) (113 mg) of the titled compound and diastereomer-2 (high polarity)

(170 mg) of the titled compound as colorless solid products, respectively.

Diastereomer-1 IR(KBr): 3425, 1768, 1705, 1641, 1522, 1344 cm ^"1 .

¹ H-NMR(DMSO-d ₆ ) δ: 1.10-1.30(6H,m) , 3.10-3.70(6H,m) ,

3.85-4.10(2H,m) , 4.20-4.35( lH,m) , 5.10( lH,d,J=5.0Hz) ,

5.60(2H,ABq,J=14.0Hz) , 7.74 (2H,d,J=8.6Hz) , 8.20-

8.30(3H,m) . Diastereomer-2

IR(KBr): 3425, 1759, 1707, 1643, 1520, 1342 era ^"1 . ^x H-NMR(DMSO-d ₆ ) δ: 1.10-1.25(6H,ra) , 3.10-3.70(6H,ra) ,

3.80-4.10(2H,m) , 4.20-4.30( lH,m) , 5.10( lH,d,J=5.2Hz) ,

5.40(2H,ABq,J=14.0Hz), 7.73(2H,d,J=8.6Hz) , 8.15- 8.30(3H,m).

Working Example 14-2b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-7- oxo-3-[ (2-oxoperhydro-l,3-thiazin-5-yl)thio]-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The diastereomer-1 (110 mg) and diastereoraer-2 (167 mg) of the compound produced by the method of

Working Example 14-lb were respectively subjected to substantially the same reaction and refining process as in Working Example 2b to give diastereomer-1 (61 mg) and diastereomer-2 (87 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3431, 1749, 1637, 1599 cm ^"1 . Working Example 14-3b 1-(cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[ (R)-1- hydroxyethyl]-4-raethyl-7-oxo-3-[ (2-oxoperhydro-l,3- thiazin-5-yl)thio]-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

The diastereomer-1 (17 mg) and diastereomer-2 (25 mg) produced by the method of Working Example 14-2b were subjected to substantially the same reaction and refining process as in Working Example 3b to afford the diastereomer-1 (18 mg) and diastereomer-2 (25 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3421, 1759, 1639 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.15-2.05(19H,m) , 2.15-2.35( lH,m) , 3.00-3.55(5H,m) , 3.55-3.90(2H,m) , 4.15-4.35(2H,m) , 4.55-4.75(lH,m) , 6.35-6.50(lH,m) , 6.88(lH,q,J=5.6Hz) . Diastereomer-2

IR(KBr): 3433, 1759, 1643 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.10-2.10(19H,m) , 2.40-2.70(lH,m) , 3.05-3.80(7H,m) , 4.10-4.35(2H,m) , 4.55-4.75(lH,m) , 6.65-6.80(lH,m) , 6.80-6.95(lH,m) . Working Example 15-lb

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-

methyl-3-[ ( 3-methyl-2-oxoperhydro-l, 3-thiazin-5- yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene- carboxylate

5-Benzoylthio-3-methylperhydro-l, 3-thiazin-2-one (763 mg) was subjected to substantially the same reaction and refining process as in Working Example 12- lb to afford the diastereomer-1 (398 rag) and diastereomer-2 (325 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3471, 1776, 1709, 1622, 1524, 1338 cm ^"1 . ¹ H-NMR(DMSO-d ₆ )δ: 1.10-1.25(6H,m) , 2.93(3H,m), 3.10- 3.35(2H,m), 3.40-3.85(4H,m) , 3.85-4.10(2H,m) , 4.25- 4.40(lH,m), 5.10(lH,d,J=5.4Hz) , 5.39(2H,ABq,J=14.0Hz) , 7.73(2H,d,J=8.8Hz) , 8.2 (2H,d,J=8.8Hz) . Diastereomer-2

IR(KBr): 3440, 1770, 1711, 1626, 1340 cm ^"1 . 1.10-1.25(6H,ra) , 2.91(3H,s), 3.10- 3.35(2H,m), 3.40-3.75(4H,m) , 3.80-4.10(2H,m) , 4.25- 4.35(lH,m), 5.11(lH,d,J=5.2Hz) , 5.39 (2H,ABq,J=14.2Hz) , 7.72(2H,d,J=8.8Hz), 8.24(2H,d,J=8.8Hz) . Working Example 15-2b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-3- [ (3-methyl-2-oxoperhydro-l, 3-thiazin-5-yl)thio]-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-carboxylate

The diastereomer-1 (393 mg) and diastereomer-2 (319 mg) produced by the method of Working Example 15- lb were subjected to substantially the same reaction and refining process as in Working Example 2b to afford the diastereomer-1 (259 mg) and diastereomer-2 (201 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1 IR(KBr): 3423, 1743, 1622, 1601 cm ^"1 . ^X H-NMR(D ₂ 0)δ: 1.24(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.6Hz) , 3.05(3H,s), 3.10-3.65(5H,m) , 3.70-4.00(2H,m) , 4.20-

4 . 35 ( 2H ,m ) .

Diastereomer-2

IR(KBr): 3408, 1745, 1641, 1599 cm ^"1 .

¹ H-NMR(D ₂ 0)δ: 1.24 ( 3H,d,J=7.2Hz) , 1.31( 3H,d,J=6.2Hz) , 3.02(3H,s), 3.23(lH,dd,J=12.2&8.2Hz) , 3.40-3.60(4H,m) ,

3.65-3.80(lH,m) , 3.80-4.00( lH,m) , 4.20-4.35(2H,m) .

Working Example 15-3b

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[(R)-l- hydroxyethyl]-4-methyl-3-[ (3-methyl-2-oxoperhydro-l,3- thiazin-5-yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-

2-carboxylate

The diastereomer-1 (70 mg) and diastereomer-2 (71 mg) produced by the method of Working Example 15-2b were subjected to substantially the same reaction and refining process as in Working Example 3b to afford the diastereomer-1 (72 mg) and diastereomer-2 (71 mg) of the titled compound as colorless solid products, respectively.

Diastereomer-1 IR(KBr): 3423, 2937, 1761, 1630, 1276 cm ^"1 .

^-NMR CDClaJδ: 1.20-2.10(20H,m) , 2.95-3.10( lH,m) ,

3.07(3H,s), 3.25-3.70(5H,m) , 3.70-3.95( lH,m) , 4.15-

4.35(2H,m), 4.55-4.75(lH,m) , 6.80-6.95( lH,m) .

Diastereomer-2 IR(KBr): 3439, 2987, 1761, 1628, 1275 cm ^"1 .

¹ H-NMR(CDCl ₃ )δ: 1.20-2.10( 19H,m) , 2.52 ( lH,brs) ,

3.04(3H,s), 3.10-3.65(6H,m) , 3.65-3.90( lH,m) , 4.15-

4.35(2H,m), 4.55-4.75( lH,m) , 6.88( lH,q,J=5.4Hz) .

Working Exaraple 16-lb 4-Nitrobenzyl (4R,5S, 6S)-3-[ (3-cyanomethyl-2- oxoperhydro-1,3-thiazin-5-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

5-Benzoylthio-3-cyanomemthylperhydro-l,3-thiazin-2-one (850 mg) was subjected to substantially the same reaction and refining process as in Working Exaraple 12-

b to afford the diastereomer-1 (544 mg) and diastereomer-2 (347 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1 IR(KBr): 3431, 1770, 1711, 1522, 1344, 1213 cm ^"1 .

^-NMRfCDCl^δ: 1.33( 3H,d,J=7.8Hz) , 1.37 (3H,d,J=6.6Hz) , 3.10-3.50(4H,m), 3.61( lH,dd,J=12.2&9.8Hz) , 3.70- 4.00(2H,m), 4.20-4.40(2H,m) , 4.42(2H,ABq,J=17.6Hz) , 5.38(2H,ABq,J=14.0Hz) , 7.66 (2H,d,J=8.4Hz) , 8.24(2H,d,J=8.4Hz) . Diastereomer-2

IR(KBr): 3431, 1770, 1711, 1629, 1522, 1344, 1213 cm ^"1 . ^-NMRfCDClaJδ: 1.33(3H,d,J=7.2Hz) , 1.36 (3H,d,J=6.2Hz) , 3.28(2H,d,J=6.6Hz) , 3.35( lH,dd,J=6.6&1.4Hz) , 3.51(lH,dq,J=9.6&7.2Hz) , 3.60-3.70(2H,m) , 3.70- 3.90(lH,m) , 4.29(lH,dq,J=7.2&6.2Hz) , 4.38(lH,dd,J=9.6.i2.8Hz) , 4.45(2H,ABq,J=17.6Hz) , 5.37(2H,ABq,J=13.6Hz) , 7.65(2H,d,J=8.8Hz) , 8.25(2H,d,J=8.8Hz) . Working Example 16-2b

Sodium (4R,5S,6S)-3-[ (3-cyanomethyl-2-oxoperhydro-l,3- thiazin-5-yl)thio]-6-[ (R)-1-hydroxyethyl]-4-methyl-7- oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The diastereomer-1 (530 mg) and diastereomer-2 (325 mg) produced by the method of Working Example 16- lb were subjected to substantially the same reaction and refining process as in Working Example 2b to afford the diastereomer-1 (310 rag) and diastereomer-2 (191 mg) of the titled compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3429, 1749, 1605, 1394 cm ^"1 .

¹ H-NMR(D ₂ 0)δ: 1.24 (3H,d,J=7.2Hz) , 1.30(3H,d,J=6.2Hz) , 3.20-3.55(4H,m), 3.71(lH,dd,J=13.4&9.0Hz) , 3.90- 4.10(2H,m), 4.20-4.30(2H,m) , 4.51(2H,s). Diastereomer-2

IR(KBr): 3431, 1751, 1605, 1394 cm ^"1 . 1.25(3H,d,J=7.2Hz) , 1.31(3H,d,J=6.4Hz) , 3.30(lH,dd,J=12.4&8.0Hz), 3.40-3.60(2H,ra) , 3.67(lH,dd,J=13.2&7.4Hz), 3.80-4.10(2H,m) , 4.20- 4.35(2H,m) , 4.49(2H,ABq,J=17.6Hz) .

The chemical structures of the Working Examples are as follows.

Examples a-1

Examples a-2

Examples a-3 2-1a 22-2a

Examples b-1

Examples b-2

[Test Example]

The compound (I) and its salts of this invention have a broad spectrum of antibacterial activity, which can be used for prophylaxis and therapy of various diseases in man and animals caused by pathogenic bacteria.

[Method of Determination] Test Example Minimal inhibitory concentration (MIC)

MIC (μg/ml) of the test compound was determined by an agar dilution method. More specifically, 0.25 ml of an aqueous solution of the test compound diluted stepwise was put into a Petri dish, which was then mixed with 9.75 ml of Muller-Hinton agar (MH medium). Or, 0.25 ml of an aqueous solution of the test compound diluted stepwise was put into a Petri dish, which was mixed with 9.75 ml of Muller-Hinton agar containing horse serum, hemin and nicotinamide adeninedinucleotide [S-MH medium. horse serum (5%), hemin (10 μg/ml) and nicotinamide adeninedinucleotide (20 μg/ml)]. On thus- prepared mixed agar plate, a suspension of the test bacteria (about 10 CFU/ml) was spread, which was incubated at 37°C overnight. The minimum concentration of the test compound to completely inhibit the growth of the test bacteria was expressed as MIC.

[Table 1]

MIC(μg/ml) 10 ⁶ CFU/ml

Bacteria Medium Impenem W.Ex.2a W.Ex.4a W.Ex.δa

E. coli NIHJ MH 0.1 0.05 0.05 0.05 JC-2

H. influenzae S-MH 0.78 0.2 0.05 0.2 NN400

Bacteria W.Ex.2b W.Ex.5b

E. coli NIHJ 0.013 0.013 JC-2

H. influenzae 0.1 0.1 NNA00

From the above results, it is clear that the carbapenem compounds of this invention have excellent antibacterial activities against bacterial strains clinically taken seriously.

INDUSTRIAL APPLICABILITY Since the novel carbapenem compounds (I) produced by the method of this invention have excellent properties, for example, having antibacterial activities of a broad spectrum, the present invention provides a novel antibacterial agent useful clinically,