JPH05345787A - New cephem compound - Google Patents

Abstract

PURPOSE:To obtain a new compound useful for infectious diseases, having excellent antimicrobial activity. CONSTITUTION:A compound of formula I [R<1> is amino or acylamino; R<5> is (protected) carboxy; R<3> is (substituted) saturated heteromonocyclic, amino (lower) alkyl, protected amino (lower) alkyl, hydroxy (lower) alkyl, etc.] such as diphenylmethyl=7beta-tertiary-butoxycarbonylamino-3-[(E)-2-[(3S)-1-for mylpyrrolidin-3-yl)thio}vinyl]-3-cephem-4-carboxylate. The compound of formula I is obtained by reacting a compound of formula II (X<1> is eliminable group) with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cephem compound having high antibacterial activity and is used in the medical field.

[0002]

BACKGROUND OF THE INVENTION Many cephem compounds are known, but no cephem compound represented by the following general formula (I) of the present invention is known.

[0003]

Although many cephem compounds having antibacterial activity and useful as medicines are known,
This invention was made with the intention of developing even more excellent pharmaceutical products.

[0004]

The target compound, the cephem compound, is novel and is represented by the following general formula (I).

[Chemical 2] [Wherein R ¹ is amino or acylamino, R ² is carboxy or protected carboxy, R ³ is a ^{3- to} 8-membered saturated heteromonocyclic group which may have a suitable substituent, a suitable substituent is 3-8 membered saturated heterocyclic monocyclic (lower) alkyl, amino (lower) alkyl, protected amino (lower) alkyl, N- (lower) alkylamino (lower) alkyl, N- (lower ) Alkyl-N-amino protecting group represents substituted amino (lower) alkyl, N, N-di (lower) alkylamino (lower) alkyl, hydroxy (lower) alkyl, or protected hydroxy (lower) alkyl] respectively. Cephem compound (I)
Can be produced by the following methods. Method (1)

[Chemical 3]

Method (2)

[Chemical 4]

Method (3)

[Chemical 5]

Method (4)

[Chemical 6]

Method (5)

[Chemical 7]

Method (6)

[Chemical 8] Wherein R ¹ , R ² and R ³ are each as defined above, R ¹ _a has acylamino, R ¹ _b has acylamino with a protected hydroxy group and R ¹ _c has a hydroxy group. Acylamino, R ² _a is a protected carboxy, R ³ _a is an N-imino protecting group-substituted 3-8 membered saturated heteromonocyclic group containing at least one nitrogen atom,
N- (lower) alkyl-N-amino protecting group substituted amino (lower) alkyl or protected amino (lower) alkyl, wherein R ³ _b contains at least one nitrogen atom, a 3-8 member A saturated heteromonocyclic group, N- (lower) alkylamino (lower) alkyl or amino (lower) alkyl, and X ¹ represents a leaving group.

The starting compound (III) can be produced by a method similar to the method shown in the production examples described below or by a conventional method. In the above and subsequent description of the present specification, preferable examples and specific examples of various definitions that the present invention includes within the scope thereof will be described in detail below. The term "lower" means 1 to 6 carbon atoms unless otherwise specified. Unless otherwise noted, the word "luxury"
It means 7 to 20 carbon atoms. Suitable "acyl" moieties in the expressions "acylamino", "acylamino having a protected hydroxy group" and "acylamino having a hydroxy group" are derived from organic carboxylic acids, organic carbonic acids, organic sulfonic acids or organic carbamic acids. And a carbamoyl group, an aliphatic acyl group, an aromatic ring-containing acyl group (referred to as aromatic acyl), or a heterocyclic ring-containing acyl group (referred to as heterocyclic acyl).

Specific preferred examples of the acyl are shown below: carbamoyl; lower or higher alkanoyl (eg formyl, acetyl, succinyl, hexanoyl, heptanoyl, valeryl, stearoyl etc.); lower or higher alkoxycarbonyl (eg methoxycarbonyl). , Ethoxycarbonyl, t-butoxycarbonyl, t
-Pentyloxycarbonyl, heptyloxycarbonyl, etc.); Lower or higher alkanesulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); Aliphatic acyl, such as lower or higher alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.); Aroyl (eg, benzoyl) , Toluoyl, naphthoyl etc.); alk (lower) alkanoyl such as phenyl (lower) alkanoyl (eg phenylacetyl, phenylpropionyl etc.); aryloxycarbonyl (eg phenoxycarbonyl, naphthyloxycarbonyl etc.); aryloxy (lower) alkanoyl ( For example, phenoxyacetyl, phenoxypropionyl, etc.); arylglyoxyloyl (eg, phenylglyoxyloyl) Naphthyl glyoxyloyl yl, etc.); arylsulfonyl (e.g. phenylsulfonyl, p- tolyl sulfonyl) aromatic acyl and the like;

Heterocyclic carbonyl; heterocyclic (lower) alkanoyl (eg, heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanoyl, etc.); heterocyclic acyl such as heterocyclic glyoxyloyl; the above "heterocyclic carbonyl", "heterocyclic" The preferred heterocyclic moiety in the expressions (lower) alkanoyl "and" heterocyclic glyoxyloyl "is, more specifically, a monocyclic compound containing at least one hetero atom such as oxygen atom, sulfur atom or nitrogen atom. Or a polycyclic saturated or unsaturated heterocyclic group. Particularly preferred heterocyclic groups are 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and the like. N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,3-triazolyl, 1H-1,2,
3-triazolyl, 2H-1,2,3-triazolyl, etc., tetrazolyl (for example, 1H-tetrazolyl, 2
H-tetrazolyl etc.); 3-8-membered (more preferably 5- or 6-membered) saturated heteromonocyclic group containing 1-4 nitrogen atoms, such as pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc .; 1-
Fused unsaturated heterocyclic groups containing 4 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; 1-2 oxygen atoms and 1
A 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group containing 3 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4-oxadiazolyl, 1,3,3). 4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) and the like;

3 to 8 member (more preferably 5 or 6 member) containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms
Saturated heteromonocyclic groups such as morpholinyl, cydonyl and the like; fused unsaturated heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as benzoxazolyl, benzooxadiazolyl and the like; A 3-8 membered (more preferably 5 or 6 membered) unsaturated heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl (e.g. , 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), dihydrothiazinyl, etc .; 1-2 sulfur atoms and 1-3 nitrogen atoms And a 3 to 8-membered (more preferably 5 or 6-membered) saturated heteromonocyclic group, such as thiazolidinyl; 3 to 8-membered containing 1 to 2 sulfur atoms (more preferably Is a 5- or 6-membered) unsaturated heteromonocyclic group, such as thienyl, dihydrodithiynyl, dihydrodithionyl, etc .; fused unsaturated heterocycles containing 1-2 sulfur atoms and 1-3 nitrogen atoms. Groups such as benzothiazolyl, benzothiadiazolyl, etc .; 3-8 member containing 1-2 oxygen atoms (more preferably 5-6
Member) unsaturated heteromonocyclic group such as furyl, dioxolyl, etc .; 3-8 membered (more preferably 5 or 6 membered) saturated heteromonocyclic group containing 1-2 oxygen atoms, such as tetrahydrofuryl, tetrahydropyrani 3-8-membered (more preferably 5- or 6-membered) saturated heteromonocyclic group containing 1-2 sulfur atoms, such as tetrahydrothienyl; 1 oxygen atom and 1-2 sulfur atoms A 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group containing and, for example, dihydrooxathiynyl;
A fused unsaturated heterocyclic group containing two sulfur atoms, such as benzothienyl, benzodithynyl, etc .;

A fused unsaturated heterocyclic group containing one oxygen atom and one to two sulfur atoms, for example, a heterocyclic group such as benzooxathinyl can be mentioned. Regarding the above heterocyclic group, the following points should be noted. That is, when the heterocyclic group is, inter alia, a thiazolyl or thiadiazolyl having amino or protected amino as a substituent in its molecule, the thiazolyl or thiadiazolyl group results in a specific behavior of the thiazole ring or thiadiazole ring. Includes tautomers.
Thus, for example, the amino or protected amino-substituted thiazolyl or thiadiazolyl group has the formula

[Chemical 9] (Wherein R ⁴ is amino or protected amino, Z is C
H or N) and the group of formula (Q) is

[Chemical 10] (Wherein R ⁴ and Z are as defined above)
When the group of formula (Q ′) is

[Chemical 11] Where Z is as defined above and R ^{4 ′} represents imino or protected imino). That is, both groups of the formulas (Q ′) and (Q ″) are in a tautomeric equilibrium state that can be represented by the following equilibrium formula.

[Chemical formula 12] (In the formulae, R ⁴ , Z and R ^{4 ′} are each as defined above.)

These types of tautomerism between 2-aminothiazole or 5-aminothiadiazole compounds and 2-iminothiazoline or 5-iminothiadiazoline compounds as described above are well known in the art and both It is obvious to a person skilled in the art that the tautomers are in equilibrium and in the mutually convertible state, and it is therefore understood that such isomers are included in the compounds themselves of the same category. . It is therefore clear that both tautomeric forms are included within the scope of the invention. In the present specification, a target compound and a starting compound containing such a tautomeric group are, for convenience, one of the expressions,
2-amino (or protected amino) thiazole or 5-amino (or protected amino) thiadiazolyl and a formula

[Chemical 13] It will be expressed using only. The above-mentioned acyl moiety is lower alkyl, lower alkoxy (eg methoxy, ethoxy, propoxy etc.), lower alkylthio (eg methylthio, ethylthio etc.), lower alkylamino (eg methylamino etc.), cyclolower alkyl (eg cyclopentyl, cyclohexyl etc.). ), Cyclo lower alkenyl (eg, cyclohexenyl, cyclohexadienyl, etc.), halogen, amino,
Protected amino, hydroxy, protected hydroxy, cyano, nitro, carboxy, protected carboxy, sulfo, sulfamoyl, imino, oxo, amino (lower) alkyl (eg aminomethyl, aminoethyl etc.), carbamoyloxy, hydroxy (Lower) alkyl (eg hydroxymethyl, 1- or 2-hydroxyethyl, 1- or 2- or 3-hydroxypropyl etc.), cyano (lower) alkenylthio (eg cyanovinylthio etc.), formula = N-OR ⁵ It may have 1 to 10 suitable substituents which are the same or different, such as a group (in the formula, R ⁵ is hydrogen or an organic group exemplified below).

In this connection, the acyl moiety has the formula ═NO
When having a group R ⁵ (where R ⁵ is as defined above) as a substituent, geometric isomers (syn and anti isomers) due to the presence of double bonds are present. For example, the syn isomer has the formula

[Chemical 14] Means one isomer having a group of

[Chemical 15] And other geometric isomers having the group Suitable "lower alkyl" as well as "3 to 8-membered saturated monocyclic (lower) alkyl", "amino (lower) alkyl", "protected amino (lower) alkyl", "N- (lower) alkylamino ( Lower) alkyl "," N- (lower) alkyl-N
-Amino-protecting group-substituted amino (lower) alkyl "," N,
N-di (lower) alkylamino (lower) alkyl ",
Suitable "lower alkyl" moieties in "hydroxy (lower) alkyl" and "protected hydroxy (lower) alkyl" include direct groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like. Examples thereof include chain-like or branched-chain ones, and more preferable examples thereof are C ₁ -C ₄ alkyl. Suitable "protected amino" as well as suitable "protected amino" moiety in "protected amino (lower) alkyl" may be acylamino as described above or may have an appropriate substituent. Mention may be made of amino substituted with conventional protecting groups such as good ar (lower) alkyl (eg benzyl, trityl etc.).

Examples of the "amino protecting group" include acyl as described above or ar (lower) alkyl which may have a suitable substituent (eg, benzyl, trityl, etc.) and the like. Suitable "organic groups" include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.),
Mono (or di or tri) halo lower alkyl (eg chloromethyl, dichloromethyl, trichloromethyl,
Bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc.), lower alkenyl (eg vinyl, 1-propenyl, allyl, 1-methylallyl, 1- or 2- or 3-butenyl, 1- or 2- Or 3- or 4-pentenyl, 1- or 2- or 3- or 4- or 5-hexenyl, etc., lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1- or 2-or 3) -Butynyl, 1- or 2- or 3- or 4-pentynyl, 1- or 2- or 3- or 4- or 5-hexynyl), aryl (e.g. phenyl, naphthyl, etc.),
Al (lower) alkyl such as phenyl (lower) alkyl (eg, benzyl, phenethyl, phenylpropyl, etc.), hydroxy protecting groups exemplified below, carboxy (lower) alkyl (lower alkyl moieties may include those exemplified above. ), A protected carboxy (lower) alkyl (the lower alkyl moiety includes those exemplified above,
Examples of the protected carboxy moiety include those exemplified below) and the like.

Suitable "protected carboxy" and "protected carboxy (lower) alkyl" in the expression "protected carboxy moiety" include esterified carboxy and the like. Preferable examples of the ester include lower alkyl ester (eg, methyl ester, ethyl ester, propyl ester,
Isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-
Pentyl ester, hexyl ester etc.), lower alkenyl ester (eg vinyl ester, allyl ester etc.), lower alkynyl ester (eg ethynyl ester, propynyl ester etc.), lower alkoxyalkyl ester (eg methoxymethyl ester, ethoxymethyl ester, isopropoxy) Methyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.), lower alkylthioalkyl ester (eg, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.), mono (or di- or tri-). ) Halo (lower) alkyl ester (eg, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkyl ester Canoyloxy (lower) alkyl ester (for example, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 1- Propanoyloxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.), cyclo-lower alkoxycarbonyloxy (lower) alkyl ester (for example, 1- (cyclopentyloxycarbonyloxy) ethyl ester, 1- (cyclohexyloxycarbonyl) Oxy) ethyl ester, etc.), cyclo-lower alkylcarbonyloxy (lower) alkyl ester (eg 1- (cyclohexylcarboxyl) Niruokishi)
Ethyl ester, etc.), lower alkoxycarbonyloxy (lower) alkyl ester (eg, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-methoxycarbonyloxyethyl ester, 2-methoxycarbonyloxyethyl ester) 1
-Ethoxycarbonyloxyethyl ester, 2-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, 2-isopropoxycarbonyloxyethyl ester, etc.), dioxolyl optionally having a suitable substituent (lower) Alkyl ester (for example, 5-methyl-2-oxo-1,3
-Dioxolylmethyl ester, etc.), lower alkanesulfonyl (lower) alkyl ester (eg, mesylmethyl ester, 2-methylethyl ester, etc.), and one or more appropriate substituents (lower) Alkyl esters such as phenyl (lower) alkyl esters (eg benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4
-Dimethoxybenzyl ester, 4-hydroxy-3,
5-di-t-butylbenzyl ester, etc.), an aryl ester which may have one or more appropriate substituents,
For example, substituted or unsubstituted phenyl ester (eg, phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.), tri (lower) alkyl. Examples include silyl ester, lower alkyl thioester (eg, methyl thioester, ethyl thioester, etc.).

Suitable "hydroxy-protecting group", "protected hydroxy" as well as suitable "protecting hydroxy" in "protected hydroxy (lower) alkyl" include suitable "protecting group". The same acyl as described above, phenyl lower alkyl optionally having one or more suitable substituents (eg, benzyl, 4-methoxybenzyl, etc.), tetrahydropyranyl and the like can be mentioned.
Suitable "3 to 8-membered saturated heteromonocyclic group" and suitable "3 to 8-membered saturated heterocyclic monocyclic group" in "3 to 8-membered saturated heteromonocyclic (lower) alkyl" are 1 to 4 groups. A 3- to 8-membered (more preferably 5- or 6-membered) saturated heteromonocyclic group containing a nitrogen atom such as pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl;
3 to 8 membered (more preferably 5 or 6 membered) saturated heteromonocyclic group containing 1 oxygen atom, such as tetrahydrofuryl, tetrahydropyranyl, etc .; 3 to 8 membered containing 1 to 2 sulfur atoms ( More preferably a 5- or 6-membered) saturated heteromonocyclic group such as tetrahydrothienyl; 1-
3 to 2 containing 2 oxygen atoms and 1 to 3 nitrogen atoms
8-membered (more preferably 5- or 6-membered) saturated heteromonocyclic group,
For example, morpholinyl, sydnonyl, etc .; a 3- to 8-membered (more preferably 5- or 6-membered) saturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl; Can be mentioned. "3- to 8-membered saturated heteromonocyclic group containing at least one nitrogen atom" and "N-imino-protecting group-substituted 3- to 8-membered saturated heteromonocyclic group containing at least one nitrogen atom" Suitable "3 to 8-membered saturated heteromonocyclic group" in the expression "cyclic group" is a 3- to 8-membered (more preferably 5 or 6-membered) saturated heterocyclic monocyclic ring containing 1 to 4 nitrogen atoms. Groups such as pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc .; 1-2 oxygen atoms and 1-3
3 to 8 members containing nitrogen atoms (more preferably 5
Or 6-membered) saturated heteromonocyclic groups such as morpholinyl,
Cydnonyl, etc .; 3-8 member containing 1-2 sulfur atoms and 1-3 nitrogen atoms (more preferably 5 or 6)
Member) saturated heteromonocyclic group, for example, thiazolidinyl and the like;

Suitable "imino protecting group" may be the same acyl as mentioned above. Suitable “leaving group” includes acyloxy such as halogen (eg chlorine, bromine, iodine etc.), sulfonyloxy (eg benzenesulfonyloxy, tosyloxy, mesyloxy etc.), lower alkanoyloxy (eg acetyloxy, propionyloxy etc.). And so on. The expressions "3 to 8-membered saturated heteromonocyclic group optionally having suitable substituents" and "3 to 8-membered saturated heteromonocyclic (lower) alkyl optionally having substituents" Suitable "substituent" in
Are, for example, lower alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl etc.), lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, Isobutoxy, tertiary butoxy, pentyloxy, neopentyloxy,
Tertiary pentyloxy, hexyloxy, etc.), lower alkenyl (eg vinyl, 1-propenyl, allyl,
1-methylallyl, 1- or 2- or 3-butenyl, 1- or 2- or 3- or 4-pentenyl,
1- or 2- or 3- or 4- or 5-hexenyl, etc.), lower alkynyl (eg ethynyl, 1-
Propynyl, propargyl, 1-methylpropargyl,
1- or 2- or 3-butynyl, 1- or 2- or 3- or 4-pentynyl, 1- or 2- or 3- or 4- or 5-hexynyl, etc.), mono (or di or tri) halo ( Lower) alkyl (eg fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl etc.), halogen (eg chlorine, bromine, fluorine, iodine), carboxy, protected carboxy, hydroxy, protected Hydroxy, aryl (eg, phenyl, naphthyl, etc.), phenyl lower alkyl (eg, benzyl, phenethyl, phenylpropyl, etc.), lower alkyl, carboxy (lower) alkyl, protected carboxy (lower) alkyl, nitro, amino,
Protected amino, di (lower) alkylamino (eg, dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylisopropylamino, etc.), acyl as exemplified above, acyl (lower) alkyl (acyl) Moieties and lower alkyl moieties may include those exemplified above),
Imino protecting groups, as exemplified above, hydroxy (lower)
Alkyl (eg, hydroxymethyl, hydroxyethyl, etc.), protected hydroxy (lower) alkyl,
Examples thereof include cyano, mercapto, lower alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.) and imino.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg salt). Metal salts such as calcium salts, magnesium salts, etc., ammonium salts, organic base salts (eg trimethylamine salts, triethylamine salts, etc.)
Pyridine salt, picoline salt, dicyclohexylamine salt,
N, N′-dibenzylethylenediamine salt, etc.), organic acid salts (eg formate, acetate, trifluoroacetate,
Maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), inorganic acid salts (eg hydrochloride, hydrobromide, sulfate, phosphate, etc.), salts with amino acids (For example, arginine salt, aspartate, glutamate, etc.) and the like.
Preferred specific examples of the target compound (I) are as follows.

Preferred examples of the target compound (I) are as follows. R ¹ is amino, lower alkoxycarbonylamino or the formula:

[Chemical 16] Wherein R ⁴ is amino or protected amino (more preferably acylamino) R ⁵ is hydrogen or an organic group (more preferably lower alkyl or acyl; most preferably lower alkyl or lower alkanoyl), Z is CH or N , R ² is carboxy, or esterified carboxy [more preferably ar (lower) alkoxycarbonyl (more preferably phenyl (lower) optionally having a suitable substituent] Alkoxycarbonyl; most preferably benzhydryloxycarbonyl), optionally substituted dioxolyl (lower) alkoxycarbonyl (more preferably dioxolyl (lower) alkoxycarbonyl having oxo and lower alkyl; most preferably 5-methyl-2-oxo-1 3-benzodioxolyl methoxycarbonyl), lower alkanoyloxy (lower) alkoxycarbonyl, cyclo (lower) alkyloxycarbonyloxy (lower) alkoxycarbonyl or lower alkoxycarbonyloxy (lower) alkoxycarbonyl,], R ³ is pyrrolidinyl, Piperidyl or tetrahydrofuryl, each of which may have 1 to 3 suitable substituents [more preferably pyrrolidinyl, piperidyl or tetrahydrofuryl, each of which is lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, Mono (or di or tri) halo (lower) alkyl, halogen, carboxy, protected carboxy, hydroxy, protected hydroxy, aryl, ar (lower) alkyl, carboxy (low Primary) alkyl, protected carboxy (lower) alkyl, nitro, amino, protected amino, di (lower) alkylamino, acyl, acyl (lower) alkyl, imino protecting group, hydroxy (lower) alkyl, protected A substituent selected from the group consisting of hydroxy (lower) alkyl, cyano, mercapto, lower alkylthio and imino is 1
Or may have 2 or more; most preferably, pyrrolidinyl optionally has 1 or 2 substituents selected from the group consisting of lower alkyl, lower alkanoyl, lower alkoxycarbonyl and di (lower) alkylcarbamoyl. Lower alkyl, hydroxy (lower) alkyl,
Acyloxy (lower) alkyl, carbamoyl (lower)
Piperidyl optionally having 1 or 2 substituents selected from the group consisting of alkyl and lower alkoxycarbonyl; or tetrahydrofuryl], pyrrolidinyl (lower) optionally having 1 to 3 substituents Alkyl [more preferably lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, mono (or di or tri) halo (lower) alkyl, halogen, carboxy, protected carboxy, hydroxy, protected hydroxy, aryl, ar (Lower) alkyl, carboxy (lower) alkyl, protected carboxy (lower)
Alkyl, nitro, amino, protected amino, di (lower) alkylamino, acyl, acyl (lower) alkyl, imino protecting group, hydroxy (lower) alkyl, protected hydroxy (lower) alkyl, cyano, mercapto, lower Pyrrolidinyl (lower) alkyl optionally having 1 or 2 substituents selected from the group consisting of alkylthio and imino; most preferably pyrrolidinyl (lower) alkyl optionally having lower alkyl, amino (lower ) Alkyl, acylamino (lower) alkyl (more preferably lower alkoxycarbonylamino (lower) alkyl), N- (lower) alkylamino (lower)
Alkyl, N- (lower) alkyl-N-acylamino (lower) alkyl [more preferably N- (lower) alkyl-N- (lower) alkoxycarbonylamino (lower) alkyl], N, N-di (lower) Alkylamino (lower) alkyl, hydroxy (lower) alkyl, tetrahydropyranyloxy (lower) alkyl, or acyloxy (lower) alkyl (more preferably carbamoyloxy (lower) alkyl).

The method for producing the object compound of the present invention is described in detail below. Method (1) Compound (I) or a salt thereof can be produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof. This reaction is usually carried out with water, alcohol (eg methanol, ethanol, etc.), benzene,
N, N-dimethylformamide, tetrahydrofuran,
It is carried out in a solvent such as toluene, methylene chloride, ethylene dichloride, chloroform, dioxane or diethyl ether, or any other solvent which does not adversely influence the reaction. These conventional solvents may be used as a mixture with water.
The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating. The reaction is usually an alkali metal hydroxide (eg sodium hydroxide, potassium hydroxide, etc.),
Alkali metal hydrogen carbonates (eg sodium hydrogen carbonate, potassium hydrogen carbonate etc.), Alkali metal carbonates (eg sodium carbonate, potassium carbonate etc.), Tri-lower alkylamines (eg trimethylamine, triethylamine, diisopropylethylamine etc.), Alkali metal hydrides (Eg, sodium hydride), alkali metal lower alkoxide (eg, sodium methoxide, sodium ethoxide, etc.), pyridines (eg, pyridine, lutidine, picoline, dimethylaminopyridine, etc.), N-lower alkylmorpholine, N, N
It is carried out in the presence of an inorganic or organic base such as di-lower alkylbenzylamine, N, N-di-lower aniline. When the base and / or the starting compound are liquid,
They can also be used as solvents.

Method (2) Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to a deacylation reaction.
Suitable methods for this reaction include conventional methods such as hydrolysis and reduction. (I) Hydrolysis The hydrolysis is preferably carried out in the presence of a base or an acid including a Lewis acid. Suitable bases include alkali metals (eg sodium, potassium etc.), alkaline earth metals (eg magnesium, calcium etc.), their hydroxides or carbonates or bicarbonates,
Trialkylamine (eg, trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo Inorganic and organic bases such as [5.4.0] undec-7-ene are mentioned. Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide etc.). . The elimination using a Lewis acid such as trihaloacetic acid (eg trichloroacetic acid, trifluoroacetic acid etc.) is preferably carried out in the presence of a cation trapping agent (eg anisole, phenol etc.). The reaction is usually
It is carried out in a solvent such as water, alcohol (eg, methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, a mixture thereof, or any other solvent that does not adversely influence the reaction. A liquid base or acid may be used as a solvent. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

(Ii) In the case of reduction The reduction is carried out by a conventional method including chemical reduction and catalytic reduction. Suitable reducing agents to be used in the chemical reduction include metals (eg tin, zinc, iron etc.) or metal compounds (eg chromium chloride, chromium acetate etc.) and organic or inorganic acids (eg formic acid, acetic acid, propionic acid, tri-acid etc.). Fluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts to be used for catalytic reduction are platinum catalysts (eg platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg spongy palladium, palladium black, palladium oxide). , Palladium charcoal, colloidal palladium, palladium / barium sulfate, palladium / barium carbonate, etc.), nickel catalysts (eg reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalysts (eg reduced cobalt, Raney cobalt etc.), iron catalysts (eg (Reduced iron, Raney iron, etc.), copper catalyst (for example, reduced copper, Raney copper, Ullmann copper, etc.) and the like. The reduction is usually water, methanol,
It is carried out in a conventional solvent which does not adversely influence the reaction, such as ethanol, propanol, N, N-dimethylformamide, diethyl ether, dioxane, tetrahydrofuran and a mixture thereof. When the above acids to be used for chemical reduction are liquid, they can also be used as a solvent. The reaction temperature for this reduction is not particularly limited, but the reaction is usually carried out under cooling or heating. The present invention is also included in the scope of the present invention when the protected carboxy in R ² is changed to carboxy or the protected hydroxy (lower) alkyl in R ³ is changed to hydroxy (lower) alkyl during the reaction.

Method (3) Compound (Ia) or a salt thereof can be produced by subjecting compound (Ib) or its reactive derivative at the amino group or a salt thereof to an acylation reaction. Suitable reactive derivative at the amino group of the compound (Ib) is an imine-type isomer of a Schiff base formed by the reaction of the compound (Ib) with a carbonyl compound such as an aldehyde or a ketone, or an enamine-type isomer thereof. Body, compound (Ib) and bis (trimethylsilyl) acetamide,
Examples thereof include a silyl derivative formed by a reaction with a silyl compound such as mono (trimethylsilyl) acetamide and bis (trimethylsilyl) urea, and a derivative formed by a reaction between compound (Ib) and phosphorus trichloride or phosgene. Suitable acylating agents to be used in the present acylation reaction include those conventionally used, and are represented by the formula R ⁶ -OH
(IV) (R ⁶ in the formula is acyl), a reactive derivative thereof or a salt thereof. Suitable reactive derivatives of compound (IV) include acid halides, acid anhydrides, active amides, active esters and the like. Suitable examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid. , Sulfonic acid (eg methanesulfonic acid), aliphatic carboxylic acid (eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.)
Or a mixed acid anhydride with an acid such as an aromatic carboxylic acid (eg, benzoic acid); a symmetrical acid anhydride; imidazole,
Active amides with 4-substituted imidazoles, 1-hydroxy-1H-benzotriazoles, dimethylpyrazoles, triazoles or tetrazoles; active esters (eg cyanomethyl esters, methoxymethyl esters, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH) -] Ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethylthio Ester, benzothiazolyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), N-hydroxy compound ( For example if N, N- dimethylhydroxylamine, 1-hydroxy -2 (IH) - pyridone, N-
Hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.)
And ester and the like. These reactive derivatives can be appropriately selected from these depending on the type of compound (IV) to be used.

The reaction is usually water, alcohol (eg methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N.
-It is carried out in a conventional solvent such as dimethylylformamide, pyridine or any other organic solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water. In this reaction, when compound (IV) is used in the form of a free acid or a salt thereof, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-
Morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-dimethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N,
N'-diisopropylcarbodiimide, N-ethyl-
N '-(3-dimethylaminopropyl) carbodiimide, N, N'-carbonylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1-alkoxy- 1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, lower alkyl haloformates (eg ethyl chloroformate, isopropyl chloroformate, etc.) ), Triphenylphosphine, 2-ethyl-7
-Hydroxybenzisoxazolium salt, 2-hydroxy hydroxide
Ethyl-5- (m-sulfophenyl) isoxazolium inner salt, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, N, N
It is preferred to carry out the reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by reaction of dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride and the like. The reaction also includes alkali metal bicarbonates, tri (lower) alkylamines, pyridines, N-lower alkylmorpholines,
It may be carried out in the presence of an inorganic or organic base such as N, N-di (lower) alkylbenzylamine. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Method (4) Compound (Id) or a salt thereof can be produced by subjecting compound (Ic) or a salt thereof to elimination reaction of an imino protecting group or an amino protecting group. This reaction can be carried out in the same manner as in method (2) above, therefore, for the reagents to be used and the reaction conditions (for example, solvent, reaction temperature, etc.), refer to those in method (2). You can Method (5) Compound (If) or a salt thereof can be produced by subjecting compound (Ie) or a salt thereof to a reaction for eliminating a hydroxy protecting group. This reaction can be carried out in the same manner as in the above method (2), and therefore, regarding the reagents to be used and the reaction conditions (for example, solvent, reaction temperature, etc.),
One can cite them in method (2).

Method (6) Compound (Ih) or a salt thereof can be produced by introducing a carboxy protecting group into compound (Ig) or a salt thereof. Examples of the carboxy-protecting group-introducing agent to be used in this reaction include conventional esterifying agents such as alcohols and reactive equivalents thereof (for example, halides, sulfonates, sulfates, diazo compounds, etc.). This reaction is usually performed in the presence of a base. Suitable bases include, for example, alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkaline earth metal hydroxides (eg magnesium hydroxide, calcium hydroxide etc.), alkali metal carbonates (eg Sodium carbonate, potassium carbonate, cesium carbonate, etc., alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), alkali metal bicarbonates (eg sodium bicarbonate, potassium bicarbonate etc.), alkali metal (lower) alkanes Inorganic bases such as acid salts (eg sodium acetate, potassium acetate etc.), alkaline earth metal phosphates (eg magnesium phosphate, calcium phosphate etc.), alkali metal hydrogen phosphates (eg disodium hydrogen phosphate, dipotassium hydrogen phosphate etc.) And trialkylamine ( Trimethylamine, triethylamine, etc.) For example, picoline, N- methylpyrrolidine, N- methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2]
Organic bases such as octane and 1,5-diazabicyclo [5.4.0] undecene-5 can be mentioned.

This reaction is usually carried out using benzene, N, N-dimethylformamide, tetrahydrofuran, toluene,
It is carried out in a solvent such as methylene chloride, ethylene dichloride, chloroform or any other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating. Suitable salts of the target compounds and their reactive derivatives in the methods (1) to (6) may be the same as those exemplified for the compound (I). The object compound (I) and a pharmaceutically acceptable salt thereof are novel and have high antibacterial activity, inhibit growth of a wide range of pathogenic bacteria including Gram-positive and Gram-negative bacteria, and are useful as antibacterial agents, It is particularly useful as an oral preparation. Now, in order to show the usefulness of the target compound (I), the minimum inhibitory concentration (MIC) test data of a representative compound belonging to the compound (I) is shown below. Test method In vitro antibacterial activity was measured by the following agar plate multiple dilution method. Each test strain was cultivated overnight in tryptocase-soy-broth, and 1 platinum loop (viable cell count: 10 ⁸ cells / ml) was
Heart infusion agar (HI-agar) containing representative test compounds at each concentration step was inoculated and incubated at 37 ° C. for 20 hours, after which the minimum inhibitory concentration (MIC) was expressed in μg / ml.

Test compound 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
{((3S) -pyrrolidin-3-yl) thio} vinyl]
-3-Cephem-4-carboxylic acid (syn isomer) test results

[Table 1] When the object compound (I) of the present invention and a pharmaceutically acceptable salt thereof are used for therapeutic purposes, an organic or inorganic solid or liquid suitable for oral administration, parenteral administration or external use is used as the active ingredient. It is administered as a usual preparation mixed with a pharmaceutically acceptable carrier such as an excipient. These formulations may be solid dosage forms such as tablets, granules, powders, capsules, or solutions,
It may be a liquid dosage form such as a suspension, syrup, emulsion or lemonade. If necessary, various auxiliaries, stabilizers, wetting agents, and other commonly used additives in the above-mentioned preparations such as lactose, citric acid, tartaric acid, stearic acid,
Magnesium stearate, white clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil,
Olive oil, cocoa butter, ethylene glycol and the like can be added. The dose of compound (I) will vary depending on the age and other conditions of the patient, the type of disease, the type of compound used, etc., but generally, about 1 mg to about 4,000 mg or more per day is administered to each patient. be able to. For the treatment of infectious diseases caused by pathogenic bacteria, the target compound (I) has an average dose of about 50 mg,
100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg can be administered.

The following Production Examples and Examples are provided to describe the present invention in more detail. Production Example 1 To a solution of (S) -1-formyl-3-acetylthiopyrrolidine (50.90 g) in acetonitrile (150 ml) was added a 28% sodium methoxide-methanol solution (51.9 ml) dropwise at 5 ° C. Mix the mixture at 5 ° C for 2.5
Stir for hours. To this mixture is carefully added 6N hydrochloric acid (45 ml), the mixture is poured into a mixture of ethyl acetate and ice water and 6N hydrochloric acid is added to adjust the pH to 2. The separated organic layer was washed with brine, dried over magnesium sulfate,
Evaporate the solvent under reduced pressure. The residue is purified by silica gel column chromatography to give (S) -1-formyl-3-mercaptopyrrolidine (18.50 g) as a brown oil. IR (film): 3450, 2930, 2860, 2510, 1640 cm ^-1 NMR (DMSO-d ₆ , δ): 1.75-2.0 and 2.2-2.4 (2H, m),
2.95-4.0 (5H, m), 8.16 (1H, s)

Production Example 2 Triethylamine (125.8 g) was added dropwise to a solution of 3-hydroxytetrahydrofuran (100 g) in tetrahydrofuran (500 ml) at 5 ° C. under a nitrogen atmosphere, and then methanesulfonyl chloride ( 142.
4 g) is added dropwise over 4 hours. After stirring the mixture at 5 ° C for 1 hour, the insoluble matter is filtered off and washed with tetrahydrofuran.
The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography to give 3-methylsulfonyloxytetrahydrofuran (187.1 g) as an oil. IR (film): 2930, 2860, 1330 cm ^-1 NMR (DMSO-d ₆ , δ): 2.0-2.3 (2H, m), 3.22 (3H, s), 3.
7-3.9 (4H, m), 5.2-5.4 (1H, m)

Production Example 3 3-methylsulfonyloxytetrahydrofuran (20
To a solution of 8.0 g) in acetonitrile (3 l) was added Thio-S.
-Potassium acetate (171.3 g) is added and the mixture is heated to reflux under a nitrogen atmosphere for 4 hours. After cooling, the insoluble matter is filtered off and washed with acetonitrile. The filtrate is concentrated under reduced pressure,
The residue was purified by silica gel column chromatography to give 3-acetylthiotetrahydrofuran (13
3.4 g) is obtained as an oil. IR (film): 2960, 2910, 2850, 1680 cm ^-1 NMR (DMSO-d ₆ , δ): 1.65-1.8 and 2.2-2.4 (2H, m),
2.32 (3H, s), 3.45-4.0 (5H, m)

Production Example 4 A solution of 3-acetylthiotetrahydrofuran (82.7 g) in acetonitrile (165 ml) was added with a 28% sodium methoxide-methanol solution (103.8 ml) at 5 ° C. under a nitrogen atmosphere for 1 hour. And drip. The mixture is stirred at 5 ° C. for 3.6 hours. 6N hydrochloric acid (90 ml) was added dropwise to this mixture, the mixture was poured into a mixture of ethyl acetate and ice water, and 6N hydrochloric acid was added to adjust the pH to 2.
The separated organic layer is washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 3-mercaptotetrahydrofuran (30.13g) as an oil. NMR (DMSO-d ₆ , δ): 1.6-1.8 and 2.2-2.4 (2H, m),
3.3-4.1 (5H, m)

Example 1 Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylate (75.56 g) To a solution of (S) -1-formyl-3-mercaptopyrrolidine (18.01 g) and N, N-dimethylformamide (500 ml) was added diisopropylethylamine (14.74 g) dropwise at 5 ° C., and the mixture was heated to 5 ° C. Stir for 1.5 hours and room temperature for 3 hours. The mixture is poured into ice water (3 l), the precipitate is filtered off and washed with ice water.
This powder is dissolved in a mixture of tetrahydrofuran and ethyl acetate, the solution washed with brine, dried over magnesium sulphate and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give diphenylmethyl = 7β-tertiary butoxycarbonylamino-
3-[(E) -2-{((3S) -1-formylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-
Carboxylate (50.05 g) is obtained as an amorphous solid. IR (Nujol): 1770, 1700, 1650 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.8-2.0 and 2.2
-2.4 (2H, m), 3.2-3.9 (7H, m), 5.16 (1H, d, J = 4.6Hz),
5.47 (1H, dd, J = 9.0 and 4.6Hz), 6.83 (1H, d, J = 15.9H
z), 6.91 (1H, s), 7.14 (1H, d, J = 15.9Hz), 7.3-7.6 (10
H, m), 8.05 (1H, d, J = 9.0Hz), 8.14 and 8.16 (1H, s
x 2)

Example 2 Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylate (66.3 g) And 3-mercaptotetrahydrofuran (15.6 g) in N, N-dimethylformamide (4
00 ml) solution is cooled to 5 ° C. Diisopropylethylamine (17.4 ml) is added dropwise to this solution over 30 minutes. The mixture is stirred at 5 ° C. for 1.5 hours and at room temperature for 4 hours. The reaction mixture is added dropwise to ice water (3.51).
The precipitate was filtered off, dried and chromatographed on silica gel to diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-[(tetrahydrofuran-3-yl) thio] vinyl]- 3-Cephem-4
-A carboxylate (18.69 g) is obtained. IR (nujor): 1765, 1700, 1500 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.6-1.8 (1H, m), 2.
1-2.3 (1H, m), 3.4-4.0 (7H, m), 5.15 (1H, d, J = 5Hz),
5.46 (1H, dd, J = 5, 9Hz), 6.76 and 6.79 (Total 1
H, d, J = 16Hz), 6.90 (1H, s), 7.16 (1H, d, J = 16Hz), 7.3-
7.6 (10H, m), 8.05 (1H, d, J = 9Hz)

Example 3 Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-{((3S) -1-formylpyrrolidin-3-yl) thio} vinyl] -3-cephem Trifluoroacetic acid (80 ml) was added dropwise at 5 ° C. to a dichloromethane (200 ml) -anisole (40 ml) mixture solution of -4-carboxylate (50.02 g),
The mixture is stirred at room temperature for 3.2 hours. The mixture was concentrated under reduced pressure and triturated with isopropyl ether,
7β-amino-3-[(E) -2-{((3S) -1-
Formylpyrrolidin-3-yl) thio} vinyl] -3-
Cephem-4-carboxylic acid / trifluoroacetic acid salt (3
9.61 g) are obtained. NMR (DMSO-d ₆ , δ): 1.8-2.0 and 2.2-2.4 (2H, m),
3.3-4.0 (7H, m), 5.10 (1H, d, J = 4.7Hz), 5.23 (1H, d, J =
4.7Hz), 7.1-7.4 (2H, m), 8.18 (1H, s)

Example 4 Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-[(tetrahydrofuran-3
-Yl) thio] vinyl] -3-cephem-4-carboxylate (18.0 g) and anisole (18 ml)
A methylene chloride (90 ml) solution of is cooled to 5 ° C. To this mixture is added trifluoroacetic acid (36 ml) and the mixture is stirred at room temperature for 4 hours. Methylene chloride and trifluoroacetic acid are removed by evaporation under reduced pressure. The residue is added dropwise to diisopropyl ether (600 ml).
The precipitate was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give 7β-amino-3-[(E) -2-
[(Tetrahydrofuran-3-yl) thio] vinyl]-
3-Cephem-4-carboxylic acid / trifluoroacetic acid salt (10.94 g) is obtained. NMR (DMSO-d ₆ , δ): 1.7-1.9 (1H, m), 2.2-2.4 (1H, m),
3.5-4.2 (7H, m), 4.84 (1H, d, J = 5Hz), 5.05 (1H, d, J = 5H
z), 6.84 and 6.89 (1H, d, J = 16Hz in total), 7.00
(1H, d, J = 16Hz)

Example 5 7β-Amino-3-[(E) -2-{((3S) -1-
Formylpyrrolidin-3-yl) thio] vinyl] -3-
Cephem-4-carboxylic acid / trifluoroacetic acid salt (9.
389 g) in methylene chloride (140 ml) at 35 ° C.
And bis (trimethylsilyl) acetamide (12.21
Melt by adding g). 5 in the resulting solution
2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl chloride hydrochloride (syn isomer) at ℃
(6.147 g) is added and the mixture is stirred at 5 ° C. for 1.8 hours. The mixture is poured into isopropyl ether (1.6 l), the precipitate is filtered off and dried under reduced pressure. This crude product was used as Diaion HP-20 (trademark; manufactured by Mitsubishi Kasei).
Purify by column chromatography using (400 ml). Elute with 10% aqueous isopropyl alcohol. When the eluate was freeze-dried, 7β- [2- (2
-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-{((3S) -1
-Formylpyrrolidin-3-yl) thio} vinyl] -3
-Cephem-4-carboxylic acid (syn isomer) (4.50
3 g) are obtained. NMR (DMSO-d ₆ , δ): 1.8-2.0 and 2.2-2.4 (2H, m),
3.2-4.0 (7H, m), 3.84 (3H, s), 5.03 (1H, d, J = 4.8Hz),
5.57 (1H, dd, J = 8.1 and 4.8Hz), 6.33 (1H, d, J = 15.8H
z), 6.74 (1H, s), 7.12 (1H, d, J = 15.8Hz), 7.24 (2H, br
s), 8.16 (1H, s), 9.55 (1H, d, J = 8.1Hz)

Example 6 7β-Amino-3-[(E) -2-{(tetrahydrofuran-3-yl) thio} vinyl] -3-cephem-4-
To a suspension of carboxylic acid trifluoroacetic acid salt (2.37 g) in methylene chloride (50 ml) is added bis (trimethylsilyl) acetamide (3.97 ml). The mixture is stirred at room temperature for 10 minutes and cooled to 5 ° C. 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl chloride hydrochloride (syn isomer) was added to this solution.
(1.65 g) is added. The mixture is stirred at 5 ° C. for 2 hours. The reaction mixture is isopropyl ether (500 ml)
Drop in. The precipitate is filtered off, washed with isopropyl ether and dried under reduced pressure to give a crude product (3.4 g). A suspension of the crude product (3.4 g) in water (250 ml) is adjusted to pH 7. The solution is adjusted to pH 5, chromatographed using Diaion HP-20 (100 ml) and eluted with 30% aqueous isopropyl alcohol. Concentrate the eluate. The precipitate was collected by filtration and dried under reduced pressure in the presence of phosphorus pentoxide to give 7β- [2- (2
-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-{(tetrahydrofuran-3-yl) thio} vinyl] -3-cephem-4
-Carboxylic acid (syn isomer) (847 mg) is obtained. IR (nujor): 1755, 1650, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.7-1.9 (1H, m), 2.2-2.5 (1H, m),
3.5-4.2 (7H, m), 3.84 (3H, s), 5.17 (1H, d, J = 5Hz), 5.
72 (1H, dd, J = 5, 8Hz), 6.77 (1H, s), 6.84 and 6.88
(1H, d, J = 16Hz in total), 7.01 (1H, d, J = 16Hz), 7.23
(2H, br s), 9.62 (1H, d, J = 8Hz)

Example 7 7β-Amino-3-[(E) -2-{(tetrahydrofuran-3-yl) thio} vinyl] -3-cephem-4-
To a suspension of carboxylic acid trifluoroacetic acid salt (4.42 g) in methylene chloride (90 ml) is added bis (trimethylsilyl) acetamide (7.4 ml). The mixture is stirred at room temperature for 10 minutes and cooled to 5 ° C. To this solution is added 2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetyl chloride hydrochloride (syn isomer) (3.41 g). The mixture is stirred at 5 ° C. for 3 hours. The reaction mixture was mixed with isopropyl ether (800 m
l) into it. The precipitate was collected by filtration, washed with isopropyl ether, and dried under reduced pressure to give 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3-[(E) -2- {. (Tetrahydrofuran-3-yl) thio} vinyl] -3-cephem-4-
A carboxylic acid (syn isomer) (7.13 g) is obtained. IR (nujol): 1780, 1740, 1630 cm ^-1 NMR (DMSO-d ₆ , δ): 1.7-1.8 (1H, m), 2.15 (3H, s), 2.
2-2.4 (1H, m), 3.4-4.1 (7H, m), 5.17 (1H, d, J = 5Hz),
5.72 (1H, dd, J = 5, 8Hz), 6.80 and 6.84 (Total 1
H, d, J = 16Hz), 6.98 (1H, d, J = 16Hz), 7.12 (1H, s), 9.91
(1H, d, J = 8Hz)

Example 8 7β-Amino-3-[(E) -2-{((3S) -1-
Formylpyrrolidin-3-yl) thio} vinyl] -3-
Cephem-4-carboxylic acid / trifluoroacetic acid salt (9.
389 g) in dichloromethane (190 ml) and 35
Bis (trimethylsilyl) acetamide (12.2
Dissolve by adding 1 g). In this solution,
2- (2-Aminothiazol-4-yl) -2-acetoxyiminoacetyl chloride hydrochloride (syn isomer)
(5.682 g) is added at 5 ° C. and the mixture is stirred at 5 ° C. for 40 minutes and room temperature for 2.2 hours. The mixture is poured into isopropyl ether (1 l), the precipitate is filtered off and dried under reduced pressure. This crude product was used as Diaion HP-20 (35
0 ml) purified by column chromatography. 1
Elute with 0% aqueous isopropyl alcohol. The eluate is concentrated to a volume of 150 ml, cooled to 5 ° C. and adjusted to pH 3 with 1N hydrochloric acid. The precipitate was collected by filtration, washed with ice water, and dried under reduced pressure to give 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3-[(E) -2-{( (3S) -1-Formylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) (4.35 g) is obtained. IR (nujor): 1750, 1635, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.0 and 2.2-2.4 (2H, m),
2.18 (3H, s), 3.2-4.0 (7H, m), 5.22 (1H, d, J = 4.7Hz),
5.78 (1H, dd, J = 8.1 and 4.7Hz), 6.88 (1H, d, J = 15.8H
z), 7.04 (1H, d, J = 15.8Hz), 7.10 (1H, s), 7.40 (2H, br
s), 8.17 (1H, s), 9.90 (1H, d, J = 8.1Hz)

Example 9 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
A solution of {((3S) -1-formylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) (4.48 g) in methanol (20 ml) at 10 ° C. Concentrated hydrochloric acid (10.4 ml) is added and the mixture is stirred at room temperature for 5.5 hours. Mix the mixture with ice water (300 m
l), poured into saturated aqueous sodium hydrogen carbonate solution to adjust the pH to 1.8, and the methanol is evaporated off under reduced pressure. The residue was adjusted to pH 2.3 and Diaion HP
Purify by column chromatography at -20 (300 ml). Elution with a 10% aqueous isopropyl alcohol solution gave 7β- [2- (2-aminothiazole-4.
-Yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{((3S) -pyrrolidin-3-yl)
Thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) (1.35 g) is obtained. IR (Nujor): 3300, 1750, 1660, 1580, 1520 cm
^-1 NMR (DMSO-d ₆ , δ): 1.8-2.0 and 2.2-2.4 (2H, m),
3.1-3.9 (7H, m), 3.84 (3H, s), 5.06 (1H, d, J = 4.8Hz),
5.63 (1H, dd, J = 8.2 and 4.8Hz), 6.47 (1H, d, J = 15.8H
z), 6.75 (1H, s), 6.95 (1H, d, J = 15.8Hz), 7.23 (2H, br
s), 9.56 (1H, d, J = 8.2Hz)

Example 10 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3-[(E) -2
-{((3S) -1-formylpyrrolidin-3-yl)
To a suspension of thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) (985 mg) in methanol (8 ml) was added concentrated hydrochloric acid (3.27 ml) at 10% and the mixture was allowed to come to room temperature. Stir for 20 hours. The resulting solution was ice water (10
(0 ml) and add saturated aqueous sodium hydrogen carbonate solution to adjust the pH to 3.5. The mixture is evaporated under reduced pressure to remove methanol, adjusted to pH 2.9 and purified by column chromatography on Diaion HP-20 (100 ml). By eluting with 10% isopropyl alcohol aqueous solution and freeze-drying the eluate, 7β- [2
-(2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-{((3
S) -Pyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) (496 mg)
Is obtained. IR (nujol): 1750, 1660, 1610, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 1.7-2.0 and 2.2-2.4 (2H, m),
2.8-3.8 (7H, m), 5.06 (1H, d, J = 4.8Hz), 5.66 (1H, dd, J =
8.2 and 4.8Hz), 6.44 (1H, d, J = 15.8Hz), 6.66 (1H,
s), 6.97 (1H, d, J = 15.8Hz), 7.13 (2H, br s), 9.40 (1H,
(d, J = 8.2Hz)

Example 11 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3 [(E) -2-
{((3S) -1-Formylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) (1.0 g, 1.76 mmol) in water (50 m
ammonium chloride (282 mg, 5.28 mmol) was added to a suspension of the mixture of l) -methanol (5 ml),
The mixture is stirred at room temperature for 2 hours, keeping the pH at 8 by addition of saturated aqueous sodium hydrogen carbonate solution. The mixture is adjusted to pH 6.5 with 6N hydrochloric acid and the methanol is evaporated off under reduced pressure. The residue was adjusted to pH 5.1 by adding 1N hydrochloric acid, and was added to Diaion HP-20.
Purify by column chromatography using (100 ml). Elute with 10% aqueous isopropyl alcohol and concentrate the eluate under reduced pressure to a volume of 30 ml.
Cool to 0 ° C. and adjust to pH 3 by adding 1N hydrochloric acid. The precipitate was collected by filtration and dried under reduced pressure to give 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-{((3S)-. 1-
Formylpyrrolidin-3-yl) thio} vinyl] -3-
Cephem-4-carboxylic acid (syn isomer) (402m
g) is obtained. IR (nujor): 1750, 1640, 1525 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.8-2.0 and 2.2-2.4 (2H, m),
3.2-4.0 (7H, m), 5.17 (1H, d, J = 4.7Hz), 5.73 (1H, dd, J =
8.1 and 4.7Hz), 6.68 (1H, s), 6.88 (1H, d, J = 15.8H
z), 7.02 (1H, d, J = 15.8Hz), 7.13 (2H, br s), 8.17 (1H,
s), 9.47 (1H, d, J = 8.1Hz), 11.31 (1H, s)

Example 12 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3-[(E) -2
-{(Tetrahydrofuran-3-yl) thio} vinyl]
-3-Cephem-4-carboxylic acid (syn isomer) (7.
01 g) water (200 ml) -methanol (20 ml)
Ammonium chloride (2.09 g) is added to the medium suspension. The mixture is adjusted to pH 8 by addition of aqueous sodium hydrogen carbonate solution and stirred at room temperature for 2.5 hours. The reaction mixture is adjusted to pH 6. The methanol of the reaction mixture is evaporated under reduced pressure. The mixture is adjusted to pH 7 and the insoluble matter is filtered off. The filtrate was adjusted to pH 5.5 and Diaion HP
Chromatography at -20 (200 ml),
Elute with 10 to 15% isopropyl alcohol aqueous solution. The eluate is concentrated and freeze-dried. PH of lyophilizate
Dissolve in 7 of water (50 ml). Adjust the solution to pH 3,
The precipitate was collected by filtration and dried under reduced pressure in the presence of phosphorus pentoxide to give 7β- [2- (2-aminothiazol-4-yl).
-2-Hydroxyiminoacetamide] -3-[(E)
-2-{(tetrahydrofuran-3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer)
(1.37 g) are obtained. IR (nujol): 3400-3200, 1760, 1640, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 1.7-1.9 (1H, m), 2.2-2.4 (1H, m),
3.5-4.2 (7H, m), 5.17 (1H, d, J = 5Hz), 5.73 (1H, dd, J =
5, 8Hz), 6.68 (1H, s), 6.84, 6.88 (total 1H, d, J = 1
6Hz), 7.01 (1H, d, J = 16Hz), 7.14 (2H, br s), 9.47 (1H,
d, J = 8Hz), 11.3 (1H, s)

Example 13 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
To a solution of {((3S) -1-formylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) (1.077 g) in N, N-dimethylformamide (10 ml). , Powdered potassium carbonate (152m
g) is added at 5 ° C. and the mixture is stirred at 5 ° C. for 40 minutes.
The mixture was added to iodomethyl pivalate (484) at 5 ° C.
mg) and the mixture is stirred at 5 ° C. for 3 hours. The mixture is poured into a mixture of ethyl acetate and ice water, the separated organic layer is washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave pivaloyloxymethyl =
7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
This gives {((3S) -1-formylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) (710 mg). IR (nujor): 1770, 1690, 1615, 1515 cm ^-1 NMR (DMSO-d ₆ , δ): 1.16 (9H, s), 1.8-2.0 and 2.2
-2.4 (2H, m), 3.2-4.0 (7H, m), 3.87 (3H, s), 5.22 (1H,
d, J = 4.6Hz), 5.76 (1H, dd, J = 8.1 and 4.6Hz), 5.80
And 5.90 (2H, ABq, J = 5.9Hz), 6.78 (1H, s), 6.79 (1
H, d, J = 15.7Hz), 7.19 (1H, d, J = 15.7Hz), 7.23 (2H, br
s), 8.18 (1H, s), 9.62 (1H, d, J = 8.1Hz)

Example 14 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
{(Tetrahydrofuran-3-yl) thio} vinyl]-
3-Cephem-4-carboxylic acid (syn isomer) (307
Powdered calcium carbonate (46 mg) is added to a solution of (mg) in N, N-dimethylformamide (3 ml). The mixture is stirred at room temperature for 10 minutes and cooled to 5 ° C. To the mixture is added iodomethyl pivalate (145 mg). The mixture is stirred at 5 ° C for 45 minutes. Pour the reaction mixture into ethyl acetate and ice water. Separate the organic layer, water,
Wash with dilute aqueous sodium hydrogen carbonate solution and brine, dry over magnesium sulfate, and concentrate under reduced pressure. The residue is dissolved in tetrahydrofuran (3 ml) and isopropyl ether (100 ml) is added to the solution. The precipitate was collected by filtration and dried under reduced pressure to give pivaloyloxymethyl = 7.
β- [2- (2-aminothiazol-4-yl) -2-
Methoxyiminoacetamide] -3-[(E) -2-
{(Tetrahydrofuran-3-yl) thio} vinyl]-
3-Cephem-4-carboxylate (syn isomer)
(312 mg) is obtained. IR (Nujor): 3200, 1760, 1665, 1605, 1520 cm
^-1 NMR (DMSO-d ₆ , δ): 1.16 (9H, s), 1.7-1.9 (1H, m), 2.
2-2.5 (1H, m), 3.5-4.2 (7H, m), 3.84 (3H, s), 5.22 (1
H, d, J = 5Hz), 5.75 (1H, dd, J = 5,8Hz), 5.85 and 5.90
(2H, ABq, J = 6Hz), 6.76 and 6.80 (Total 1H, d, J =
16H), 6.78 (1H, s), 7.18 (1H, d, J = 16Hz), 7.24 (2H, br
s), 9.63 (1H, d, J = 8Hz)

Production Example 5 Lithium aluminum hydride (18.98 g, 500 m)
2- (tertiary butoxycarbonylamino) in a suspension of a solution of (mol) and tetrahydrofuran (700 ml) at room temperature.
A tetrahydrofuran solution (300 ml) of ethanethiol (85.63 g, 500 mmol) is added dropwise. The mixture is refluxed for 4.5 hours in a nitrogen atmosphere and cooled to 5 ° C.
Sodium fluoride (83.78 g, 2 mo)
1) was added, followed by cold water (27.02 g, 1.5 mo)
l) is added dropwise and the mixture is stirred vigorously for 1.1 hours at room temperature. The insoluble matter is collected by filtration and washed with tetrahydrofuran. The filtrate is concentrated under reduced pressure and dichloromethane is added to the residue. The insoluble material was filtered and concentrated under reduced pressure to obtain crude oily 2- (methylamino) ethanethiol (27.42 g). IR (film): 2210, 1650 cm ^-1 NMR (DMSO-d ₆ ,, δ): 2.26 (3H, s), 2.5-2.8 (4H, m), 3.
3-3.55 (1H, m)

Production Example 6 Crude 2- (methylamino) ethanethiol (27.40)
g, 301 mmol) of dichloromethane (200 ml)
Triethylamine (33.45 g, 331 mmo)
l) followed by dropwise addition of a solution of di-tert-butyl dicarbonate (72.26 g, 331 mmol) in dichloromethane (100 ml) at 5 ° C. The mixture is stirred at room temperature for 62 hours and concentrated under reduced pressure. . Ethyl acetate and water are added to the residue, and the mixture is adjusted to pH 2 with 6N hydrochloric acid. The organic layer is separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain N, S-bis (tertiary butoxycarbonyl) -2- (methylamino) ethanethiol (2
5.79 g) are obtained. This compound was added to acetonitrile (2
A suspension of 28% sodium methoxide in methanol (17.1 ml) is added dropwise at 5 ° C and the mixture is stirred for 2.5 hours at 5 ° C. Ethyl acetate and cold water are added to the mixture and the pH is adjusted to 2 with 6N hydrochloric acid. The organic layer is separated, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2- (N-tertiary butoxycarbonyl-N-
Methylamino) ethanethiol (13.06 g) is obtained. IR (Film): 2960, 2930, 2550, 1680 cm ^-1 NMR (DMSO-d ₆ , δ): 1.39 (9H, s), 2.28 (1H, t, J = 7.9H
z), 2.5-2.7 (2H, m), 2.79 (3H, s), 3.29 (2H, t, J = 7.6H
z)

Production Example 7 Diphenylmethyl = 7β-amino-3-[(E) -2-
{P-Tolylsulfonyloxy} vinyl] -3-cephem-4-carboxylate (13.75 g, 24.4 m
mol) in tetrahydrofuran (130 ml) solution, bis (trimethylsilyl) acetamide (9.93 g, 4
8.8 mmol) and stir for 20 minutes at room temperature. 2- (2-aminothiazol-4-yl) -2 was added to this solution.
-Acetoxyiminoacetyl chloride hydrochloride (syn isomer) (8.331 g, 29.3 mmol) is added at 5 ° C and the mixture is stirred at 5 ° C for 1.5 hours and then at room temperature for 1.5 hours. The mixture is poured into a mixture of ethyl acetate and cold water and adjusted to pH 6 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure, pulverized with diisopropyl ether, and diphenylmethyl = 7β- [2- (2
-Aminothiazol-4-yl) -2-acetoxyiminoacetamido] -3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylate (syn isomer) (16 0.09 g) is obtained. IR (Nujor): 3250, 1770, 1710, 1640, 1530 cm
^-1 NMR (DMSO-d ₆ , δ): 2.16 (3H, s), 2.41 (3H, s), 3.64
And 3.94 (2H, ABq, J = 17.8Hz), 5.28 (1H, d, J = 4.8H
z), 5.93 (1H, dd, J = 8.1 & 4.8Hz), 6.51 (1H, d, J = 12.1H
z), 6.90 (1H, s), 7.12 (1H, s), 7.3-7.5 (13H, m), 7.49
(2H, d, J = 8.1Hz), 7.84 (2H, d, J = 8.1Hz), 9.94 (1H, d, J
= 8.1Hz)

Production Example 8 The following compound was obtained in the same manner as in Production Example 7. (1) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3- Cephem-4-carboxylate (syn isomer) IR (nujol): 1770, 1715, 1660, 1515 cm ^-1 NMR (DMSO-d ₆ , δ): 2.41 (3H, s), 3.61 and 3.88
(2H, ABq, J = 18.6Hz), 3.84 (3H, s), 5.23 (1H, d, J = 4.8H
z), 5.88 (1H, dd, J = 8.2 & 4.8Hz), 6.50 (1H, d, J = 12.1H
z), 6.76 (1H, s), 6.89 (1H, s), 7.2-7.5 (11H, m), 7.4
9 (2H, d, J = 8.2Hz), 7.84 (2H, d, J = 8.2Hz), 9.66 (1H, d, J
= 8.2Hz) (2) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1765, 1655, 1630, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 2.43 (3H, s), 3.63 and 3.82
(2H, ABq, J = 17.7Hz), 3.87 (3H, s), 5.18 (1H, d, J = 4.8H
z), 5.79 (1H, dd, J = 8.0 & 4.8Hz), 6.65 (1H, d, J = 12.1H
z), 6.79 (1H, s), 7.21 (1H, d, J = 12.1Hz), 7.51 (2H, d,
J = 8.2Hz), 7.88 (2H, d, J = 8.2Hz), 9.67 (1H, d, J = 8.0Hz)

Production Example 9 Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylate (100 g, 151 mmol) And dichloromethane (3
To a solution of a mixture of 00 ml) and anisole (100 ml) was added trifluoroacetic acid (200 ml) dropwise at 5 ° C and the mixture was stirred at room temperature for 3.1 hours. The mixture was poured into diisopropyl ether (3 l), the precipitate was filtered off, washed with diisopropyl ether and concentrated under reduced pressure to 7
β-amino-3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylic acid
Trifluoroacetic acid salt (66.18 g) is obtained. IR (nujor): 1780, 1610, 1590, 1510 cm ^-1 NMR (DMSO-d ₆ , δ): 2.43 (3H, s), 3.58 and 3.82
(2H, ABq, J = 17.5Hz), 4.92 (1H, d, J = 5.1Hz), 5.07 (1H, d,
J = 5.1Hz), 6.67 (1H, d, J = 12.2Hz), 7.21 (1H, d, J = 12.2H)
z), 7.51 (2H, d, J = 8.4Hz), 7.88 (2H, d, J = 8.4Hz)

Production Example 10 Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylate (75.1 g, 113 mmol of ethyl acetate (450
4N to a mixed solution of (ml) and ethanol (112 ml).
A solution of hydrochloric acid-1,4-dioxane (113 ml) was added dropwise and the mixture was stirred at room temperature for 17 hours. The mixture is poured into tetrahydrofuran (450 ml), cold water (2 l) and a mixture of sodium hydrogen carbonate (37.97 g). The insoluble material is filtered off, the organic layer is separated, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain diphenylmethyl =
7β-Amino-3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylate (26.49 g) is obtained. IR (nujor): 1755, 1710 cm ^-1 NMR (DMSO-d ₆ , δ): 2.40 (2H, br s), 2.41 (3H, s), 3.
55 and 3.87 (2H, ABq, J = 17.9Hz), 4.87 (1H, d, J = 5.1
Hz), 5.05 (1H, d, J = 5.1Hz), 6.45 (1H, d, J = 12.1Hz), 6.8
9 (1H, s), 7.24 (1H, d, J = 12.1Hz), 7.3-7.6 (10H, m),
7.48 (2H, d, J = 8.6Hz), 7.88 (2H, d, J = 8.6Hz)

Production Example 11 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
(P-Tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylic acid (syn isomer) (18.68 g, 3
Potassium carbonate (2.45 g, 17.7 mmol) is added to an N, N-dimethylformamide solution (2.3 mmol), and the mixture is stirred at 5 ° C for 1.5 hours. Iodomethyl pivalate (7.79 g, 32.2 mmol) is added dropwise to the mixture and stirred at 5 ° C. for 3.6 hours. Mix the mixture with water (650 m
l), the precipitate is filtered off and washed with water. The powder is dissolved in tetrahydrofuran and ethyl acetate and water is added. The organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain pivaloyloxymethyl = 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3-[(E) -2
-(P-Tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylate (syn isomer) (9.21
g) is obtained. IR (Nujol): 3280, 1780, 1760, 1665, 1620, 15
25 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.13 (9H, s), 2.44 (3H, s), 3.62
And 3.93 (2H, ABq, J = 18.0Hz), 3.83 (3H, s), 5.20
(1H, d, J = 4.8Hz), 5.82 (1H, dd, J = 8.1 & 4.8Hz), 5.75 and 5.88 (2H, ABq, J = 6.0Hz), 6.53 (1H, d, J = 12.0Hz) ,
6.75 (1H, s), 7.32 (1H, d, J = 12.0Hz), 7.24 (2H, br s),
7.52 (2H, d, J = 8.2Hz), 7.88 (2H, d, J = 8.2Hz), 9.63 (1
(H, d, J = 8.1Hz)

Production Example 12 4-hydroxypiperidine (5.06 g, 50.0 mm
Ethyl bromoacetate (5.54 ml, 50.0 mmol) is added dropwise to an ethanol (50 ml) solution of ol). The mixture is refluxed for 2 hours. The reaction mixture is cooled to 5 ° C. Triethylamine (6.97 ml, 5
0.0 mmol) is added dropwise. The mixture is concentrated under reduced pressure.
Tetrahydrofuran is added to the residue. The insoluble material is filtered off, and the filtrate is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-ethoxycarbonylmethyl-4-hydroxypiperidine (6.16 g, 32.9).
mmol) is obtained. IR (film): 3300, 2800, 1730 cm ^-1 NMR (DMSO-d ₆ , δ): 1.18 (3H, t, J = 7Hz), 1.2-1.4 (2H,
m), 1.6-1.8 (2H, m), 2.21 (2H, dt, J = 3, 11Hz), 2.6-2.8
(2H, m), 3.15 (2H, s), 3.41 (1H, m), 4.07 (2H, q, J = 7H
z), 4.54 (1H, d, J = 4Hz)

Preparation Example 13 1-Ethoxycarbonylmethyl-4-hydroxypiperidine (10.0 g, 53.4 mmol) and triphenylphosphine (14.0 g, 53.4 mmol) in tetrahydrofuran (100 ml) was dissolved in diethyl azodicarboxylate. A solution of (8.4 ml, 53.4 mmol) in tetrahydrofuran (30 ml) is added dropwise at 5 ° C. The mixture is stirred at 5 ° C for 20 minutes. Thio-S in the mixture
-Add a solution of benzoic acid (6.2 ml, 53.4 mmol) in tetrahydrofuran dropwise. The mixture is stirred at room temperature for 20 hours. The reaction mixture is concentrated under reduced pressure, and acetic acid-diisopropyl ether (1: 1) is added to the residue. The insoluble material is filtered off and the filtrate is subjected to silica gel column chromatography to obtain a yellow oily substance. After standing overnight at room temperature, the yellow crystals were collected by filtration, washed with diisopropyl ether-n-hexane (1: 2) and dried to give 1-ethoxycarbonylmethyl-4-benzoylthiopiperidine (4.95 g).
To get IR (Film): 2800, 1730, 1655 cm ^-1 NMR (DMSO-d ₆ , δ): 1.20 (3H, t, J = 7Hz), 1.6-1.8 (2H,
m), 1.9-2.0 (2H, m), 2.4-2.5 (2H, m), 2.7-2.9 (2H, m),
3.24 (2H, s), 3.5-3.7 (1H, m), 4.09 (2H, q, J = 7Hz), 7.
5-7.6 (2H, m), 7.7-7.8 (1H, m), 7.9-8.0 (2H, m)

Production Example 14 In the same manner as in Production Example 13, the following compound was obtained. 1-carbamoylmethyl-4-benzoylthiopiperidine IR (nujol): 1650 cm ^-1 NMR (DMSO-d ₆ , δ): 1.6-1.8 (2H, m), 1.9-2.2 (2H, m),
2.2-2.4 (2H, m), 2.7-2.8 (2H, m), 2.87 (2H, s), 3.63
(1H, m), 7.14 (1H, br s), 7.21 (1H, br s), 7.5-7.6 (2
H, m), 7.6-7.7 (1H, m), 7.9-8.0 (2H, m)

Production Example 15 Lithium aluminum hydride (2.17 g, 57.2 m)
mol) and a suspension of tetrahydrofuran at 5 ° C., a solution of 1-ethoxycarbonylmethyl-4-benzoylthiopiperidine (11.7 g, 38.1 mmol) in tetrahydrofuran (35 ml) is added. The mixture is stirred at 5 ° C. for 1 hour and at room temperature for 2 hours. Sodium fluoride (9.61 g, 229 mmol) and water (3.09 m) were added to the reaction mixture.
1, 172 mmol) is added. The mixture is stirred at 5 ° C for 1 hour. The insoluble matter is filtered off. The filtrate is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1
-(2-Hydroxyethyl) -4-mercaptopiperidine (1.49 g, 9.23 mmol) is obtained. IR (film): 3300, 2800 cm ^-1 NMR (DMSO-d ₆ , δ): 1.4-1.6 (2H, m), 1.8-2.1 (4H, m),
2.34 (3H, t, J = 6Hz), 2.7-2.8 (3H, m), 3.3-3.5 (3H, m),
4.35 (1H, br s)

Production Example 16 4-hydroxypiperidine (100 g, 989 mmo
To a solution of l) in ethanol (750 ml) is added iodoacetamide (183 g, 989 mmol). The mixture is stirred at room temperature for 2 days. The precipitate of the reaction mixture was collected by filtration, washed with ethanol and diisopropyl ether, and dried under reduced pressure to give 1-carbamoylmethyl-4-hydroxypiperidine hydroiodide (214 g, 748 mmo).
l) is obtained. IR (nujor): 3300, 1670 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.5-1.7 (2H, m), 1.8-2.0 (2H, m),
3.0-3.4 (4H, m), 3.88 (2H, s), 4.98 (1H, br s), 7.68
(1H, s), 7.91 (1H, s), 9.43 (1H, br s)

Production Example 17 1-carbamoylmethyl-4-hydroxypiperidine
To a suspension of hydroiodide (195 g, 682 mmol) and ethanol (3 l) triethylamine (95 ml,
682 mmol) is added dropwise. The mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The residue was washed with dichloromethane, collected by filtration, and dried under reduced pressure to give 1-carbamoylmethyl-4-hydroxypiperidine (100.4 g, 63
5 mmol) is obtained. IR (nujor): 3300, 3200, 1650 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.4-1.6 (2H, m), 1.6-1.8 (2H, m),
2.32 (2H, m), 2.7-2.9 (2H, m), 3.02 (2H, s), 3.4-3.6
(1H, m), 4.65 (1H, d, J = 4Hz), 7.22 (1H, s), 7.28 (1H,
s)

Production Example 18 1-carbamoylmethyl-4-benzoylthiopiperidine (1.9 g, 6.83 mmol) in acetonitrile (9.5 ml) was added at 28 ° C. to a solution of 28% sodium methoxide in methanol (1.3 ml, 1.3 ml, (6.83 mmol)
Add. The mixture is stirred for 1 hour. 6N in the reaction mixture
Hydrochloric acid (1.1 ml, 6.83 mmol) is added. The mixture is poured into a mixture of ethyl acetate and water and adjusted to pH2. The aqueous layer is separated, adjusted to pH 7, and concentrated under reduced pressure. Chloroform-methanol (10: 1) is added to the residue, and the insoluble matter is filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 1-carbamoylmethyl-4-mercaptopiperidine (318 m
g, 1.82 mmol). IR (nujol): 3400, 3200, 1620 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.4-1.7 (2H, m), 1.8-2.0 (2H, m),
2.0-2.2 (2H, m), 2.7-2.8 (3H, m), 2.81 (2H, s), 7.10
(2H, br s)

Production Example 19 In the same manner as in Production Example 18, the following compound was obtained. 2-[(tetrahydropyran-2-yl) oxy] ethanethiol IR (film): 2930, 2860, 1715 cm ^-1 NMR (DMSO-d ₆ , δ): 1.4-1.8 (6H, m), 2.3-2.4 (1H, m),
2.6-2.7 (2H, m), 3.4-3.8 (3H, m), 4.55-4.65 (1H, m)

Production Example 20 Potassium tertiary butoxide (51.75 g, 461 mm)
ol) N, N-dimethylformamide (600 ml)
The solution was treated with thio-S-benzoic acid (63.
71 g, 461 mmol) was added dropwise to bring the mixture to 40
Stir for 1 minute at the same temperature. 2 to this mixture over 1 hour
[(Tetrahydropyran-2-yl) oxy] ethyl bromide (87.66 g, 419 mmol) is added and the mixture is stirred for 2.5 hours at room temperature. The mixture is poured into a mixture of ethyl acetate and cold water, the organic layer is separated, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure.
The residue is subjected to silica gel column chromatography to obtain crude 1-benzoylthio-2-[(tetrahydropyran-2-yl) oxy] ethane (76.92 g) as a red oil. IR (film): 2940, 2860, 1655, 1590, 1575 cm ^-1 NMR (DMSO-d ₆ , δ): 1.4-1.8 (6H, m), 3.2-3.8 (6H, m),
4.6-4.7 (1H, m), 7.5-8.0 (5H, m)

Example 15 The following compound was obtained in the same manner as in Examples 3 and 4. (1) 7β-amino-3-[(E) -2-{(1-methylpiperidin-4-yl) thio} vinyl] -3-cephem-4-carboxylic acid / 2-trifluoroacetate IR (nujol) : 1765, 1660, 1560 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.1 and 2.2-2.4 (4H, m),
2.70 (3H, s), 3.0-3.9 (7H, m), 5.09 (1H, d, J = 4.8Hz),
5.22 (1H, d, J = 4.8Hz), 7.0-7.4 (2H, m) (2) 7β-amino-3-[(E) -2-{((3
S) -1-Methylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylic acid / 2-trifluoroacetate IR (nujol): 1770, 1660 cm ⁻¹ NMR (DMSO-d ₆ , δ) ): 1.9-2.1 and 2.5-2.7 (2H, m),
2.88 (3H, s), 3.6-4.0 (7H, m), 5.09 (1H, d, J = 4.8Hz),
5.21 (1H, d, J = 4.8Hz), 6.98 (1H, d, J = 12.8Hz), 7.11 (1
(H, d, J = 12.8Hz) (3) 7β-amino-3-[(E) -2-[{2-
(Dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylic acid ・ 2 trifluoroacetate NMR (DMSO-d ₆ , δ): 2.89 (6H, s), 3.1-3.45 (4H, m) ,
3.7-3.85 (2H, m), 5.11 (1H, d, J = 4.8Hz), 5.22 (1H, d, J =
4.8Hz), 6.9-7.3 (2H, m) (4) 7β-amino-3-[(E) -2-{((2
S) -1-Methylpyrrolidin-2-yl) methylthio}
Vinyl] -3-cephem-4-carboxylic acid-2 trifluoroacetate IR (nujol): 1770, 1650 cm ^-1 NMR (DMSO-d ₆ , δ): 1.70-2.13 (3H, m), 2.16-2.40 (1
H, m), 2.91 (3H, s), 3.0-3.25 (2H, m), 3.54-3.64 (2H,
m), 3.7-3.8 (3H, m), 5.10 (1H, d, J = 4.8Hz), 5.22 (1H,
d, J = 4.8Hz), 7.13 (1H, d, J = 15.9Hz), 7.29 (1H, d, J = 15.
9Hz)

(5) 7β-amino-3-[(E) -2
- [{3- (dimethylamino) propyl} thio] vinyl] -3-cephem-4-carboxylic acid 2 trifluoroacetate _{NMR (DMSO-d 6, δ} ): 1.9-2.1 (2H, m), 2.78 (6H, s), 2.
9-3.0 (2H, m), 3.1-3.2 (2H, m), 3.7-3.8 (2H, m), 5.08
(1H, d, J = 4.7Hz), 5.21 (1H, d, J = 4.7Hz), 7.08 (1H, d, J
= 15.8Hz), 7.16 (1H, d, J = 15.8Hz) (6) 7β-amino-3-[(E) -2-{(1-
(2-Hydroxyethyl) piperidin-4-yl) thio} vinyl] -3-cephem-4-carboxylic acid / 2-trifluoroacetate NMR (DMSO-d ₆ , δ): 1.8-2.0 (2H, m), 2.1-2.3 (2H, m),
2.9-3.5 (8H, m), 3.5-3.9 (2H, m), 5.11 (1H, d, J = 5Hz),
5.23 (1H, d, J = 5Hz), 7.11 (1H, d, J = 16Hz), 7.23 (1H,
d, J = 16Hz) (7) 7β-amino-3-[(E) -2-{(1-carbamoylmethylpiperidin-4-yl) thio} vinyl] -3-cephem-4-carboxylic acid-2tri Fluoroacetate NMR (DMSO-d ₆ , δ): 1.8-2.0 (2H, m), 2.1-2.3 (2H, m),
3.0-3.6 (4H, m), 3.74 (2H, s), 3.8-3.9 (1H, m), 3.8-
4.0 (2H, m), 5.11 (1H, d, J = 5Hz), 5.23 (1H, d, J = 5Hz),
7.0-7.2 (2H, m), 7.72 (1H, br s), 7.99 (1H, br s) (8) 7β-amino-3-[(E) -2-{(2-hydroxyethyl) thio} vinyl ] -3-Cephem-4-
Carboxylic acid / trifluoroacetic acid salt IR (nujol): 1765, 1605, 1505 cm ^-1 NMR (DMSO-d ₆ , δ): 2.89 (2H, t, J = 6.5Hz), 3.21 (2H,
t, J = 6.5Hz), 3.61 and 3.81 (2H, ABq, J = 17.1Hz), 4.
58 (1H, t, J = 6.3Hz), 4.81 (1H, d, J = 4.9Hz), 5.04 (1H,
d, J = 4.9Hz), 6.86 (1H, t, J = 15.9Hz), 6.99 (1H, d, J = 15.
9Hz) (9) 7β-amino-3-[(E) -2-{(2-carbamoyloxyethyl) thio} vinyl] -3-cephem-4-carboxylic acid / trifluoroacetate IR (nujol): 3300 , 3160, 1780, 1700, 1610, 15
90, 1510 cm ^-1 NMR (DMSO-d ₆ , δ): 3.03 (2H, t, J = 6.3Hz), 3.62 and 3.84 (2H, ABq, J = 17.2Hz), 4.10 (2H, t, J = 6.3Hz), 4.
86 (1H, d, J = 4.9Hz), 5.06 (1H, d, J = 4.9Hz), 6.5-6.7 (2
H, br s), 6.70 (1H, d, J = 15.9Hz), 7.00 (1H, d, J = 15.9H)
z)

Example 16 The following compound was obtained in the same manner as in Examples 5, 6, 7 and 8. (1) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{((3S) -1-methylpyrrolidine-
3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1760, 1715, 1560 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.0 and 2.4 -2.6 (2H, m),
2.56 (3H, s), 2.8-3.2 and 3.4-3.6 (5H, m), 3.52 and 3.72 (2H, ABq, J = 17.4Hz), 3.84 (3H, s), 5.11 (1H,
d, J = 4.7Hz), 5.66 (1H, dd, J = 8.1 & 4.7Hz), 6.66 (1H, d,
J = 15.8Hz), 6.75 (1H, s), 6.93 (1H, d, J = 15.8Hz), 7.22
(2H, br s), 9.58 (1H, d, J = 8.1Hz) (2) 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3-
[(E) -2-{((3S) -1-methylpyrrolidine-
3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) NMR (DMSO-d ₆ , δ): 1.9-2.1 (1H, m), 2.3-2.5 (1H, m),
2.23 (3H, s), 2.75 (3H, t-like), 2.9-3.1 (2H, m), 3.4-
3.9 (4H, m), 5.18 (1H, d, J = 5Hz), 5.73 (1H, dd, J = 5, 8H
z), 6.85 (1H, d, J = 16Hz), 7.10 (1H, s), 7.13 (1H, d, J = 1
6Hz), 9.90 (1H, d, J = 8Hz) (3) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{(1-methylpiperidin-4-yl)
Thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1745, 1650, 1590, 1525 cm ^-1 NMR (DMSO-d ₆ , δ): 1.7-1.95 and 2.0-2.25 (4H,
m), 2.61 (3H, s), 2.7-3.0 and 3.1-3.4 (5H, m), 3.
51 and 3.73 (2H, ABq, J = 17.2Hz), 3.84 (3H, s), 5.10
(1H, d, J = 4.8Hz), 5.66 (1H, dd, J = 8.1 & 4.8Hz), 6.63
(1H, d, J = 15.8Hz), 6.76 (1H, s), 6.96 (1H, d, J = 15.8H)
z), 7.25 (2H, br s), 9.59 (1H, d, J = 8.1Hz) (4) 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3-
[(E) -2-{(1-methylpiperidin-4-yl)
Thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) NMR (DMSO-d ₆ , δ): 1.8-2.0 (4H, m), 2.12 (3H, s), 2.
64 (3H, m), 2.8-3.0 (2H, m), 3.1-4.0 (5H, m), 5.17 (1
H, d, J = 5Hz), 5.72 (1H, dd, J = 5, 8Hz), 6.9-7.3 (5H, m),
9.86 (1H, d, J = 8Hz) (5) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -2-[{2- (Dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3280, 1750, 1655, 1590, 1525 cm
^-1 NMR (DMSO-d ₆ , δ): 2.47 (6H, s), 2.8-3.0 (4H, m), 3.
53 and 3.71 (2H, ABq, J = 17.1Hz), 3.84 (3H, s), 5.1
1 (1H, d, J = 4.7Hz), 5.66 (1H, dd, J = 8.1 & 4.7Hz), 6.67
(1H, d, J = 15.8Hz), 6.76 (1H, s), 6.94 (1H, d, J = 15.8H)
z), 7.24 (2H, br s), 9.59 (1H, d, J = 8.1Hz) (6) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -2-{((2S) -1-methylpyrrolidine-
2-yl) methylthio} vinyl] -3-cephem-4-
Carboxylic acid (syn isomer) IR (nujol): 3275, 1755, 1650 cm ^-1 NMR (DMSO-d ₆ , δ): 1.6-1.92 (3H, m), 2.0-2.18 (1H,
m), 2.50-2.72 (1H, m), 2.59 (3H, s), 2.85-3.03 (2H,
m), 3.10-3.40 (2H, m), 3.52 and 3.69 (2H, ABq, J = 1
7.1Hz), 5.11 (1H, d, J = 4.7Hz), 5.67 (1H, dd, J = 8.1Hz,
4.7Hz), 6.70 (1H, d, J = 15.7Hz), 6.98 (1H, d, J = 15.7H)
z), 7.14 (2H, brs), 9.43 (1H, d, J = 8.1Hz), 11.33 (1H,
br s)

(7) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide]
-3-[(E) -2-{((2S) -1-methylpyrrolidin-2-yl) methylthio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3300, 1755, 1650 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.68-1.99 (3H, m), 2.08-2.22 (1
H, m), 2.80 (3H, s), 2.92-3.07 (2H, m), 3.21-3.78 (5H,
m), 3.84 (3H, s), 5.16 (1H, d, J = 4.7Hz), 5.70 (1H, dd,
J = 8.1Hz, 4.7Hz), 6.77 (1H, s), 6.87 (1H, d, J = 15.7H
z), 6.97 (1H, d, J = 15.7Hz), 7.24 (2H, br s), 9.60 (1
(H, d, J = 8.1 Hz) (8) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoceatamide] -3-
[(E) -2-[{3- (dimethylamino) propyl}
Thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1740, 1650, 1575, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.0 (2H, m ), 2.61 (6H, s), 2.
75-3.05 (4H, m), 3.50 and 3.69 (2H, ABq, J = 17.0Hz),
3.84 (3H, s), 5.09 (1H, d, J = 4.7Hz), 5.64 (1H, dd, J =
8.2 & 4.7Hz), 6.58 (1H, d, J = 15.8Hz), 6.88 (1H, d, J = 1
5.8Hz), 7.24 (2H, br s), 9.57 (1H, d, J = 8.2Hz) (9) 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3 −
[(E) -2-[{3- (dimethylamino) propyl}
Thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1760, 1635, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.1 (2H, m), 2.14 (3H, s), 2.
65 (6H, s), 2.7-3.1 (4H, m), 3.60 and 3.74 (2H, AB
q, J = 18Hz), 5.17 (1H, d, J = 5Hz), 5.71 (1H, dd, J = 8 & 5H
z), 6.8-7.3 (5H, m), 9.88 (1H, t, J = 8Hz) (10) 7β- [2- (2-aminothiazole-4-
) -2-Methoxyiminoacetamide] -3-
[(E) -2-{(1- (2-hydroxyethyl) piperidin-4-yl) thio} vinyl] -3-cephem-4
-Carboxylic acid (syn isomer) IR (nujol): 3300, 1750, 1650, 1590, 1525 cm
^-1 NMR (DMSO-d ₆ , δ): 1.7-1.9 (2H, m), 2.0-2.2 (2H, m),
2.7-3.0 (4H, m), 3.1-3.4 (3H, m), 3.53 and 3.82
(2H, ABq, J = 17Hz), 3.7-3.8 (2H, m), 5.11 (1H, d, J = 5H),
5.65 (1H, dd, J = 8 & 5Hz), 6.65 (1H, d, J = 16Hz), 6.76 (1
H, s), 7.00 (1H, d, J = 16Hz), 7.23 (2H, br s), 9.59 (1
H, d, J = 8Hz) (11) 7β- [2- (2-aminothiazole-4-
) -2-Methoxyiminoacetamide] -3-
[(E) -2-{(1-carbamoylmethylpiperidin-4-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3300, 1750, 1680 cm ^-1 NMR (DMSO-d ₆ , δ): 1.7-1.9 (2H, m), 2.0-2.2 (2H, m),
2.6-2.8 (2H, m), 3.0-3.2 (3H, m), 3.14 (2H, s), 3.61
And 3.85 (2H, ABq, J = 17Hz), 3.84 (3H, s), 5.18 (1H,
d, J = 5Hz), 5.71 (1H, dd, J = 5, 8Hz), 6.77 (1H, s), 6.90
(1H, d, J = 16Hz), 7.00 (1H, d, J = 16Hz), 7.24 (2H, br
s), 7.42 (1H, s), 7.58 (1H, s), 9.62 (1H, d, J = 8Hz) (12) 7β- [2- (2-aminothiazole-4-
) -2-Methoxyiminoacetamide] -3-
[(E) -2-{(2-hydroxyethyl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3260, 1745, 1650, 1580, 1520 cm
^-1 NMR (DMSO-d ₆ , δ): 2.78 (2H, t, J = 6.7Hz), 3.3-3.6 (2
H, m), 3.56 (2H, t, J = 6.7Hz), 3.84 (3H, s), 5.02 (1H,
d, J = 4.7Hz), 5.55 (1H, dd, J = 8.2 & 4.7Hz), 6.33 (1H, d,
J = 15.9Hz), 6.74 (1H, s), 7.04 (1H, d, J = 15.9Hz), 7.24
(2H, br s), 9.56 (1H, d, J = 8.2Hz) (13) 7β- [2- (2-aminothiazole-4-
) -2-Methoxyiminoacetamide] -3-
[(E) -2-{(2-carbamoyloxyethyl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3250, 1740, 1655, 1590, 1520 cm
^-1 NMR (DMSO-d ₆ ,, δ): 2.91 (2H, t, J = 6.4Hz), 3.30 and 3.50 (2H, ABq, J = 17.0Hz), 3.84 (3H, s), 4.06 (2H,
t, J = 6.4Hz), 5.01 (1H, d, J = 4.8Hz), 5.56 (1H, dd, J = 8.1
& 4.8Hz), 6.29 (1H, d, J = 15.9Hz), 6.74 (1H, s), 7.08
(1H, d, J = 15.9Hz), 7.24 (2H, br s), 9.56 (1H, d, J = 8.1H
z) (14) 7β- [2- (2-aminothiazole-4-
Il) -2-acetoxyiminoacetamide] -3-
[(E) -2-{(2-carbamoyloxyethyl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) NMR (DMSO-d ₆ , δ): 2.14 (3H, s), 2.97 (2H, t, J = 6Hz),
3.59 and 3.81 (2H, ABq, J = 17Hz), 4.00 (2H, t, J = 6H
z), 5.16 (1H, d, J = 5Hz), 5.71 (1H, dd, J = 8 & 5Hz), 6.8
4 (1H, d, J = 16Hz), 6.97 (1H, d, J = 16Hz), 9.91 (1H, d, J =
8Hz)

Example 17 The following compound was obtained in the same manner as in Examples 1 and 2. (1) Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-{((3S) -1-
Methylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate IR (nujol): 1760, 1710, 1555 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.4-1.6 and 2.1
-2.3 (2H, m), 2.3-2.8 (4H, m), 3.3-3.5 (1H, m), 3.64
And 3.80 (2H, ABq, J = 16.8Hz), 5.16 (1H, d, J = 4.5Hz),
5.45 (1H, dd, J = 8.9 & 4.5Hz), 6.77 (1H, d, J = 15.8Hz),
6.90 (1H, s), 7.16 (1H, d, J = 15.8Hz), 7.3-7.6 (10H,
m), 8.05 (1H, d, J = 8.9Hz) (2) Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-{(1-methylpiperidin-4-yl) thio } Vinyl] -3-Cephem-4
-Carboxylate IR (nujol): 1765, 1700 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.4-1.5 and 1.8
-2.2 (4H, m), 2.49 (3H, s), 3.0-3.5 (5H, m), 3.65 and 3.88 (2H, ABq, J = 17.0Hz), 5.15 (1H, d, J = 4.6Hz), 5.4
5 (1H, dd, J = 9.0 & 4.6Hz), 6.86 (1H, d, J = 15.8Hz), 6.89
(1H, s), 7.12 (1H, d, J = 15.8Hz), 7.3-7.5 (10H, m), 8.
05 (1H, d, J = 9.0Hz) (3) Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-{((2S) -1-
Methylpyrrolidin-2-yl) methylthio} vinyl]-
3-Cephem-4-carboxylate IR (nujol): 3350, 1770, 1700 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.48-1.70 (3H, m),
1.78-1.95 (1H, m), 2.1-2.3 (1H, m), 2.24 (3H, s), 2.72
-2.83 (2H, m), 2.83-3.0 (2H, m), 3.64 and 3.78 (2
H, ABq, J = 16.6Hz), 5.15 (1H, d, J = 4.5Hz), 5.41 (1H, dd, J
= 4.5Hz, 9.0Hz), 6.91 (1H, d, J = 14.1Hz), 6.88 (1H, s),
7.22 (1H, d, J = 14.1Hz), 7.2-7.51 (11H, m), 8.04 (1H,
d, J = 9.0Hz) (4) Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-[{2- (dimethylamino) ethyl} thio] vinyl] -3-cephem- 4-
Carboxylate NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 2.13 (6H, s), 2.4-
2.5 (2H, m), 2.8-2.9 (2H, m), 3.64 and 3.80 (2H, AB
q, J = 16.7Hz), 5.14 (1H, d, J = 4.5Hz), 5.43 (1H, dd, J = 9.1
& 4.5Hz), 6.86 (1H, d, J = 15.7Hz), 6.89 (1H, s), 7.2-
7.5 (11H, m), 8.05 (1H, d, J = 9.1Hz)

(5) Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-[{3
-(Dimethylamino) propyl} thio] vinyl] -3-
Cephem-4-carboxylate IR (nujol): 1760, 1690 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.7-1.8 (2H, m), 2.
24 (6H, s), 2.4-2.5 (2H, m), 2.7-2.8 (2H, m), 3.64 and 3.81 (2H, ABq, J = 16.6Hz), 5.15 (1H, d, J = 4.5Hz) ,
5.43 (1H, dd, J = 9.0 & 4.5Hz), 6.87 (1H, d, J = 15.7Hz),
6.89 (1H, s), 7.14 (1H, d, J = 15.7Hz), 7.3-7.6 (10H,
m), 8.05 (1H, d, J = 9.0Hz) (6) Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-{(1- (2-hydroxyethyl) piperidine- 4-yl) thio} vinyl]
-3-Cephem-4-carboxylate NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.5-1.7 (2H, m), 1.
9-2.0 (2H, m), 2.2-2.4 (2H, m), 2.8-3.0 (2H, m), 3.4-
3.6 (3H, m), 3.65 and 3.86 (2H, ABq, J = 17Hz), 4.12
(1H, br s), 5.15 (1H, d, J = 5Hz), 5.45 (1H, dd, J = 9 & 5H
z), 6.86 (1H, d, J = 16Hz), 6.89 (1H, s), 7.19 (1H, d, J =
16Hz), 7.2-7.5 (10H, m), 8.05 (1H, d, J = 9Hz) (7) Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-{(1- Carbamoylmethylpiperidin-4-yl) thio} vinyl] -3-
Cephem-4-carboxylate IR (nujol): 1760, 1690, 1670 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.5-1.7 (2H, m), 1.
8-2.0 (2H, m), 2.0-2.3 (2H, m), 2.6-2.8 (2H, m), 2.9-
3.0 (1H, m), 2.83 (2H, s), 3.65 and 3.85 (2H, ABq,
J = 17Hz), 5.14 (1H, d, J = 5Hz), 5.30 (1H, dd, J = 5, 9Hz),
6.8-7.0 (1H, d, J = 16Hz), 6.89 (1H, s), 7.0-7.5 (11H,
m), 8.04 (1H, d, J = 9Hz) (8) Diphenylmethyl = 7β-tertiary butoxycarbonyl-3-[(E) -2-[{2- (tetrahydropyran-2-yl) oxyethyl}} Thio] vinyl] -3-
Cephem-4-carboxylate IR (nujol): 1760, 1695 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.4-1.8 (6H, m), 2.
94 (2H, t, J = 6.2Hz), 3.4-3.8 (6H, m), 4.55-4.65 (1H,
m), 5.15 (1H, d, J = 4.5Hz), 5.41 (1H, dd, J = 8.9 & 4.5H
z), 6.89 (1H, s), 6.91 (1H, d, J = 15.5Hz), 7.2-7.6 (11
H, m), 8.04 (1H, d, J = 8.9Hz)

Example 18 Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide]-
3-[(E) -2- (p-tolylsulfonyloxy) vinyl] -3-cephem-4-carboxylate (syn isomer) (12.20 g, 16.4 mmol) and (3S).
-1-Tertiary butoxycarbonyl-3-mercaptopyrrolidine (3.99 g, 19.6 mmol) in N, N-dimethylformamide (80 ml) solution at 5 ° C. diisopropylethylamine (2.12 g, 16.4 mmol)
Is added dropwise and the mixture is stirred at 5 ° C. for 2 hours and at room temperature for 1 hour. The mixture is poured into cold water (400 ml), the precipitate is filtered off and dissolved in tetrahydrofuran. Ethyl acetate and water are added to the solution, the organic layer is separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and diphenylmethyl = 7β
-[2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-
{((3S) -1-tert-Butoxycarbonylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) (5.36 g) is obtained. IR (nujol): 3280, 1770, 1670, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 1.39 (9H, s), 1.75-1.95 and
2.05-2.25 (2H, m), 3.2-3.9 (7H, m), 3.86 (3H, s), 5.26
(1H, d, J = 4.6Hz), 5.82 (1H, dd, J = 8.2 & 4.6Hz), 6.79
(1H, d, J = 15.7Hz), 6.81 (1H, s), 6.92 (1H, s), 7.15 (1
H, d, J = 15.7Hz), 7.2-7.6 (12H, m), 9.67 (1H, d, J = 8.2H
z)

Example 19 The following compound was obtained in the same manner as in Example 18. (1) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-{((3S) -1-tertiary butoxy Carbonylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 1770, 1665, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.39 ( 9H, s), 1.6-1.9 (1H, m), 2.
1-2.3 (1H, m), 3.1-3.9 (7H, m), 5.25 (1H, d, J = 5Hz),
5.83 (1H, dd, J = 5, 8Hz), 6.71 (1H, s), 6.78 (1H, d, J = 16
Hz), 6.91 (1H, s), 7.14 (2H, s), 7.14 (1H, d, J = 16Hz),
7.2-7.6 (10H, m), 9.52 (1H, d, J = 8Hz), 11.3 (1H, s) (2) Pivaloyloxymethyl = 7β- [2- (2-
Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-{((3S) -1-
Tertiary butoxycarbonylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3380, 3280, 1760, 1670, 1610, 15
20 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.16 (9H, s), 1.40 (9H, s), 1.8-
2.0 and 2.2-2.4 (2H, m), 3.2-3.9 (5H, m), 3.65 and 3.95 (2H, ABq, J = 17.5Hz), 3.84 (3H, s), 5.21 (1H,
d, J = 4.7Hz), 5.76 (1H, dd, J = 8.1 & 4.7Hz), 5.80 and 5.90 (2H, ABq, J = 5.9Hz), 6.78 (1H, s), 6.77 (1H, d,
J = 15.7Hz), 7.18 (1H, d, J = 15.7Hz), 7.23 (2H, br s), 9.
63 (1H, d, J = 8.1Hz) (3) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2- { (1-tertiary butoxycarbonylpiperidin-4-yl) thio} vinyl] -3-
Cephem-4-carboxylate (syn isomer) IR (nujol): 1750, 1670, 1510 cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s), 1.3-1.5 and 1.8
-2.0 (4H, m), 2.8-3.0 and 3.6-3.9 (7H, m), 3.85 (3
H, s), 5.25 (1H, d, J = 4.6Hz), 5.80 (1H, dd, J = 8.2 & 4.6H
z), 6.80 (1H, s), 7.2-7.5 (12H, m), 9.65 (1H, d, J = 8.2
Hz) (4) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-{(1-tertiary butoxycarbonylpiperidine -4-yl) thio} vinyl] -3
-Cephem-4-carboxylate (syn isomer) IR (nujol): 3300, 1770, 1760, 1740, 1670, 15
25 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.40 (9H, s), 1.8-2.0 (2H, m), 2.
7-2.9 (2H, m), 3.6-3.9 (7H, m), 5.25 (1H, d, J = 5Hz),
5.82 (1H, dd, J = 5, 8Hz), 6.72 (1H, s), 6.91 (1H, s),
7.1-7.6 (12H, m), 9.50 (1H, d, J = 8Hz) (5) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [(E) -2- {2- (tertiary butoxycarbonylamino) ethylthio} vinyl] -3-cephem-4-carboxylate (syn isomer) NMR (DMSO-d ₆ , δ): 1.37 (9H, s), 2.7-2.9 (2H, m), 3.
0-3.2 (2H, m), 3.6-3.7 (2H, m), 3.85 (3H, s), 5.25 (1
H, d, J = 5Hz), 5.79 (1H, dd, J = 5, 8Hz), 6.81 (1H, s), 6.9
1 (1H, s), 7.0-7.5 (14H, m), 7.82 (1H, d-like), 9.65 (1
H, d, J = 8Hz) (6) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2- {2- ( Tertiary butoxycarbonylamino) ethylthio} vinyl] -3-cephem-4-carboxylate (syn isomer) NMR (DMSO-d ₆ , δ): 1.37 (9H, s), 2.79 (2H, t-like) , 3.
14 (2H, m), 3.64 and 3.82 (2H, ABq, J = 17Hz), 5.25
(1H, d, J = 5Hz), 5.81 (1H, dd, J = 5, 8Hz), 6.72 (1H, s),
6.91 (1H, s), 7.0-7.5 (12H, m), 7.79 (1H, d-like), 9.50
(1H, d, J = 8Hz), 11.3 (1H, s)

(7) Diphenylmethyl = 7β- [2-
(2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-[{2-
(Dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3350, 1755, 1650, 1510 cm ^-1 NMR (DMSO-d ₆ , δ): 2.12 (6H, s), 2.3-2.5 (2H, m), 2.
6-2.8 (2H, m), 3.65 and 3.82 (2H, ABq, J = 17.1Hz),
5.25 (1H, d, J = 4.6Hz), 5.80 (1H, dd, J = 8.3 & 4.6Hz),
6.72 (1H, s), 6.83 (1H, d, J = 15.8Hz), 6.90 (1H, s), 7.0
-7.6 (13H, m), 9.50 (1H, d, J = 8.3Hz), 11.32 (1H, s) (8) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2- Methoxyiminoacetamido] -3-[(E) -2-{((3R) -1-tertiary butoxycarbonylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer ) IR (nujol): 1770, 1675, 1520 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.39 (9H, s), 1.8-2.0 and 2.1
-2.3 (2H, m), 3.0-3.9 (7H, m), 3.85 (3H, s), 5.25 (1H,
d, J = 4.6Hz), 5.80 (1H, dd, J = 8.3 & 4.6Hz), 6.5-7.2 (2
H, m), 6.80 (1H, s), 6.91 (1H, s), 7.2-7.6 (12H, m), 9.
67 (1H, d, J = 8.3Hz) (9) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2- { ((3R) -1-tertiary butoxycarbonylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3280, 3170, 1760, 1665, 1600 , 15
20 cm ^-1 NMR (DMSO-d ₆ , δ): 1.39 (9H, s), 1.7-1.9 and 2.1
-2.3 (2H, m), 3.0-3.9 (7H, m), 5.24 (1H, d, J = 4.7Hz),
5.83 (1H, dd, J = 8.4 & 4.7Hz), 6.71 (1H, s), 6.91 (1H,
s), 6.8-7.1 (2H, m), 7.3-7.6 (12H, m), 9.52 (1H, d, J =
8.4Hz), 11.34 (1H, s) (10) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-{( (2S, 4S) -1
-Tertiary butoxycarbonyl-2-dimethylcarbamoylpyrrolidin-4-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 1770, 1660, 1520 cm ^-1 NMR ( DMSO-d ₆ , δ): 1.31 (9H, s), 1.37 (9H, s), 1.5-
1.7 and 2.1-2.3 (2H, m), 2.81 and 2.84 (3H, s),
2.89 (3H, s), 3.4-4.0 (5H, m), 3.85 (3H, s), 4.7-4.8
(1H, m), 5.25 (1H, d, J = 4.6Hz), 5.81 (1H, d, J = 8.2 & 4.
6Hz), 6.7-7.6 (14H, m), 6.92 (1H, s), 9.67 (1H, d, J =
8.2Hz) (11) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-((2S, 4S) -1
-Tertiary butoxycarbonyl-2-dimethylcarbamoyl-pyrrolidin-4-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) NMR (DMSO-d ₆ , δ): 1.31 (9H, 9H, s), 1.37 (9H, s), 1.5-
1.7 and 2.0-2.2 (2H, m), 2.8 and 2.84 (3H, s),
3.00 (3H, s), 3.4-4.0 (5H, m), 4.5-4.8 (1H, m), 5.25
(1H, d, J = 4.7Hz), 5.83 (1H, dd, J = 8.2 & 4.7Hz), 6.71 (1
H, s), 6.91 (1H, s), 7.0-7.6 (14H, m), 9.52 (1H, d, J =
8.2Hz), 11.33 (1H, s) (12) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-{( 2- (N-tertiary butoxycarbonyl-N-methylamino) ethyl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) NMR (DMSO-d ₆ , δ): 1.37 (9H, s), 2.75 (3H, s), 2.7-
2.9 (2H, m), 3.2-3.4 (2H, m), 3.6-3.9 (2H, m), 5.25 (1
H, d, J = 5Hz), 5.81 (1H, dd, J = 8 & 5Hz), 6.72 (1H, s), 6.
87 (1H, d, J = 16Hz), 6.90 (1H, s), 7.0-7.6 (13H, m), 9.5
1 (1H, d, J = 8Hz), 11.33 (1H, s) (13) Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[( E) -2-[{2- (Tetrahydropyran-2-yl) oxyethyl} thio] vinyl]-
3-Cephem-4-carboxylate (syn isomer) IR (nujol): 3270, 1750, 1660, 1605, 1510 cm
^-1 NMR (DMSO-d ₆ , δ): 1.4-1.8 (6H, m), 2.9-2.95 (2H,
m), 3.2-3.8 (6H, m), 4.59 (1H, s), 5.25 (1H, d, J = 5Hz),
5.80 (1H, dd, J = 8 & 5Hz), 6.72 (1H, s), 6.90 (1H, s),
7.0-7.6 (14H, m), 9.51 (1H, d, J = 8Hz), 11.34 (1H, s)

Example 20 Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide]
-3-[(E) -2-{(2-tertiary butoxycarbonylaminoethyl) thio} vinyl] -3-cephem-4-
Carboxylate (syn isomer) (1.4 g, 1.90)
Trifluoroacetic acid (2.8 ml) is added to a dichloromethane (7 ml) solution of (mmol) and anisole (1.4 ml). The mixture is stirred at 5 ° C. for 1 hour and at room temperature for 2 hours. Pour the reaction into diisopropyl ether (100 ml). The precipitate is collected by filtration and concentrated under reduced pressure. Precipitate (1.3
g) in a solution of water (120 ml) at pH 7 followed by p
Adjust to H2.5. Insoluble matter is filtered. The filtrate is subjected to column chromatography using Diaion HP-20 (50 ml) and eluted with 5-10% aqueous isopropanol solution. The eluate was lyophilized to 7β- [2- (2-
Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-{(2-aminoethyl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) ( 489 mg, 1.04 mmol) are obtained. IR (nujol): 3200, 1760, 1600, 1525 cm ^-1 NMR (DMSO-d ₆ , δ): 3.02 (4H, br s), 3.46 and 3.6
5 (2H, ABq, J = 17Hz), 5.08 (1H, d, J = 5Hz), 5.68 (1H, dd, J
= 5, 8Hz), 6.49 (1H, d, J = 16Hz), 6.66 (1H, s), 6.98 (1
H, d, J = 16Hz), 7.14 (2H, br s), 9.42 (1H, d, J = 8Hz)

Example 21 The following compound was obtained in the same manner as in Example 20. (1) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{(2S, 4S) -2-Dimethylcarbamoylpyrrolidin-4-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1750, 1640 , 1580, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.6-1.8 and 2.2-2.4 (2H, m),
2.88 and 2.98 (6H, s), 2.8-4.0 (5H, m), 4.42 (1H,
t, J = 8.1Hz), 5.11 (1H, d, J = 4.7Hz), 5.66 (1H, dd, J = 8.1
& 4.7Hz), 6.67 (1H, d, J = 15.8Hz), 6.76 (1H, s), 6.89
(1H, d, J = 15.8Hz), 7.24 (2H, br s), 9.59 (1H, d, J = 8.1H
z) (2) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{((3R) -pyrrolidin-3-yl)
Thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1750, 1655, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.0 and 2.3-2.5 (2H , m),
3.1-3.9 (7H, m), 3.84 (3H, s), 5.10 (1H, d, J = 4.8Hz),
5.66 (1H, dd, J = 8.0 & 4.8Hz), 6.63 (1H, d, J = 15.8Hz),
6.75 (1H, s), 6.98 (1H, d, J = 15.8Hz), 7.24 (2H, br s),
9.59 (1H, d, J = 8.0Hz) (3) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -2-{(piperidin-4-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3200, 1750, 1650, 1610, 1580, 15
20 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.72 (2H, m), 2.09 (2H, m), 2.92
(2H, m), 3.2-3.6 (3H, m), 3.47 and 3.65 (2H, ABq, J =
17Hz), 5.07 (1H, d, J = 5Hz), 5.66 (1H, dd, J = 5, 8Hz), 6.
45 (1H, d, J = 16Hz), 6.66 (1H, s), 7.00 (1H, d, J = 16Hz),
7.14 (2H, br s), 9.43 (1H, d, J = 8Hz) (4) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
{(E) -2-{(piperidin-4-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1750, 1660, 1520 cm ^-1 NMR (DMSO- d ₆ , δ): 1.6-1.9 and 2.0-2.2 (4H, m),
2.8-3.9 (7H, m), 3.84 (3H, s), 5.07 (1H, d, J = 4.8Hz),
5.62 (1H, dd, J = 8.1 & 4.8Hz), 6.43 (1H, d, J = 15.7Hz),
6.74 (1H, s), 7.01 (1H, d, J = 15.7Hz), 7.22 (2H, brs),
9.56 (1H, d, J = 8.1Hz) (5) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -2-{((3S) -pyrrolidin-3-yl)
Thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3300, 1750, 1580, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.0 (1H, m ), 2.2-2.4 (1H, m),
3.0-3.8 (7H, m), 5.07 (1H, d, J = 5Hz), 5.66 (1H, dd, J =
5, 8Hz), 6.47 (1H, d, J = 16Hz), 6.66 (1H, s), 6.95 (1H,
d, J = 16Hz), 7.15 (2H, br s), 9.43 (1H, d, J = 8Hz)

(6) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide]
-3-[(E) -2-{((3S) -pyrrolidine-3-
(Il) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1750, 1660, 1580, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.0 and 2.25 -2.45 (2H,
m), 3.05-3.9 (7H, m), 3.84 (3H, s), 5.07 (1H, d, J = 4.8H
z), 5.63 (1H, dd, J = 8.1 & 4.8Hz), 6.45 (1H, d, J = 15.9H)
z), 6.75 (1H, s), 6.95 (1H, d, J = 15.9Hz), 7.23 (2H, br
s), 9.56 (1H, d, J = 8.1Hz) (7) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{(2-aminoethyl) thio} vinyl]
-3-Cephem-4-carboxylic acid (syn isomer) IR (nujol): 3200, 1760, 1660, 1525 cm ^-1 NMR (DMSO-d ₆ , δ): 3.03 (4H, br s), 3.51 and 3.7
1 (2H, ABq, J = 17Hz), 3.84 (3H, s), 5.11 (1H, d, J = 5Hz),
5.67 (1H, dd, J = 5, 8Hz), 6.60 (1H, d, J = 16Hz), 6.75 (1
H, s), 6.98 (1H, d, J = 16Hz), 7.24 (2H, br s), 9.59 (1H,
d, J = 8Hz) (8) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -2-[{2- (methylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) NMR (DMSO-d ₆ , δ): 2.57 (3H, s ), 2.5-2.7 (2H, m), 3.
0-3.2 (2H, m), 3.50 and 3.70 (2H, ABq, J = 18Hz), 5.1
0 (1H, d, J = 5Hz), 5.69 (1H, dd, J = 8 & 5Hz), 6.60 (1H, d,
J = 16Hz), 6.67 (1H, s), 6.95 (1H, d, J = 16Hz), 7.15 (2H,
br s), 9.45 (1H, d, J = 8Hz) (9) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -2-{((3R) -pyrrolidin-3-yl)
Thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3170, 1745, 1660, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.7-2.0 and 2.2-2.5 (2H, m),
3.0-3.9 (7H, m), 5.10 (1H, d, J = 4.8Hz), 5.68 (1H, dd, J =
8.1 & 4.8Hz), 6.58 (1H, d, J = 15.8Hz), 6.67 (1H, s),
6.98 (1H, d, J = 15.8Hz), 7.15 (2H, br s), 9.44 (1H, d, J =
8.1Hz) (10) 7β- [2- (2-aminothiazole-4-
Il) -2-hydroxyiminoacetamide] -3-
[(E) -2-{((2S, 4S) -2-Dimethylcarbamoylpyrrolidin-4-yl) thio} vinyl] -3-
Cephem-4-carboxylic acid (syn isomer) IR (nujol): 3270, 1755, 1645, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.5-1.7 and 2.1-2.3 (2H, m),
2.88 and 2.98 (6H, s), 2.6-4.0 (8H, m), 5.11 (1H,
d, J = 4.8Hz), 5.09 (1H, dd, J = 8.1 & 4.8Hz), 6.67 (1H,
s), 6.66 (1H, d, J = 15.8Hz), 6.89 (1H, d, J = 15.8Hz), 7.1
4 (2H, br s), 9.45 (1H, d, J = 8.1Hz)

Example 22 Pivaloyloxymethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-{((3S)- 1-tertiary butoxycarbonylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) (490 mg, 0.676 mmol) in dichloromethane (5 ml) and anisole (0.5 ml). Trifluoroacetic acid (1 ml) is added to the mixed solution of at 5 ° C., and the mixture is stirred at 5 ° C. for 2.5 hours and at room temperature for 30 minutes. The mixture was poured into diisopropyl ether, the precipitate was collected by filtration, washed with diisopropyl ether, dried under reduced pressure, and pivaloyloxymethyl = 7β- [2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{((3S) -pyrrolidin-3-yl)
Thio} vinyl] -3-cephem-4-carboxylate.2 trifluoroacetate salt (419 mg) is obtained. IR (nujol): 1750, 1675, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 1.17 (9H, s), 1.8-2.0 and 2.3
5-2.55 (2H, m), 3.1-3.8 (5H, m), 3.65 and 3.96 (2
H, ABq, J = 18.2Hz, 2Hz), 3.85 (3H, s), 5.23 (1H, d, J = 4.7
Hz), 5.75 (1H, dd, J = 8.0 & 4.7Hz), 5.81 and 5.91
(2H, ABq, J = 6.0Hz), 6.76 (1H, d, J = 15.7Hz), 6.80 (1H,
s), 7.16 (1H, d, J = 15.7Hz), 9.18 (2H, br s), 9.65 (1
(H, d, J = 8.0Hz)

Example 23 The following compound is obtained in the same manner as in Examples 13 and 14. (1) Pivaloyloxymethyl = 7β- [2- (2-
Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-{((3S) -1-
Methylpyrrolidin-3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 1770, 1740, 1655, 1605, 1510 cm
^-1 NMR (DMSO-d ₆ , δ): 1.16 (9H, s), 1.55-1.7 and 2.
25-2.35 (2H, m), 2.26 (3H, s), 2.3-2.65 (3H, m), 2.8-
3.0 and 3.35-3.5 (2H, m), 3.65 and 3.89 (2H, A
Bq, J = 18.7Hz), 3.84 (3H, s), 5.21 (1H, d, J = 4.6Hz), 5.
73 (1H, dd, J = 8.2 & 4.6Hz), 5.81 and 5.89 (2H, ABq,
J = 5.9Hz), 6.78 (1H, d, J = 15.7Hz), 6.78 (1H, s), 7.18
(1H, d, J = 15.7Hz), 7.23 (2H, brs), 9.62 (1H, d, J = 8.2H
z) (2) (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3 -[(E) -2-[{2- (dimethylamino)
Ethyl} thio] vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3300, 1805, 1770, 1660, 1520 cm
^-1 NMR (DMSO-d ₆ , δ): 2.18 (3H, s), 2.18 (6H, s), 2.5-
2.6 (2H, m), 2.94 (2H, t, J = 6Hz), 3.63 and 3.90 (2
H, ABq, J = 17Hz), 3.84 (3H, s), 5.0-5.2 (3H, m), 5.75 (1
H, dd, J = 8 & 5Hz), 6.76 (1H, d, J = 16Hz), 6.77 (1H, s),
7.13 (1H, d, J = 16Hz), 7.24 (2H, br s), 9.62 (1H, d, J = 8
Hz) (3) 1-propionyloxyethyl = 7β- [2-
(2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-[{2- (dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylate (Syn isomer) IR (nujol): 1760, 1670, 1605, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 0.9-1.1 (3H, m), 1.46 and 1.4
7 (total 3H, d, J = 5Hz), 2.17 (6H, s), 2.36 (2H, q, J = 7H
z), 2.5-2.6 (2H, m), 2.9-3.0 (2H, m), 3.63 and 3.9
2 (2H, ABq, J = 17Hz), 3.84 (3H, s), 5.19 and 5.21
(Total 1H, d, J = 5Hz), 5.7-5.8 (1H, m), 6.7-7.0 (3H, m),
7.1-7.3 (3H, m), 9.61 and 9.63 (total 1H, d, J = 8Hz) (4) 1-acetoxyethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyimino Acetamide] -3-[(E) -2-[{2- (dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3270, 3120, 1755 , 1655, 1610, 15
30 cm ^-1 NMR (DMSO-d ₆ , δ): 1.45 and 1.47 (total 3H, d, J = 5
Hz), 2.06 (3H, s), 2.17 (6H, s), 2.4-2.5 (2H, m), 2.9-
3.0 (2H, m), 3.63 and 3.92 (2H, ABq, J = 17Hz), 3.84
(3H, s), 5.19 and 5.21 (total 1H, d, J = 5Hz), 5.7-
5.8 (1H, m), 6.7-7.0 (3H, m), 7.1-7.3 (3H, m), 7.61
And 7.63 (total 1H, d, J = 8Hz) (5) 1- (cyclopentyloxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazole-4
-Yl) -2-methoxyiminoacetamide] -3-
[(E) -2-[{2- (Dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3280, 1750, 1665, 1610, 1525 cm
^-1 NMR (DMSO-d ₆ , δ): 1.47 (3H, d, J = 5Hz), 1.5-1.9 (8H,
m), 2.17 (6H, s), 2.4-2.5 (2H, m), 2.9-3.0 (2H, m), 3.
65 and 3.92 (2H, ABq, J = 18Hz), 3.84 (3H, s), 5.0-5.
1 (1H, m), 5.19 and 5.22 (total 1H, d, J = 5Hz), 5.7-
5.8 (1H, m), 6.7-6.9 (3H, m), 7.1-7.3 (3H, m), 9.61
And 9.62 (total 1H, d, J = 8Hz)

(6) 1- (isopropoxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
-[(E) -2-[{2- (dimethylamino) ethyl}}
Thio] vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3290, 1750, 1660, 1525 cm ^-1 NMR (DMSO-d ₆ , δ): 1.24 (6H, d, J = 6Hz), 1.48 (3H, d, J
= 5Hz), 2.17 (6H, s), 2.4-2.6 (2H, m), 2.8-3.0 (2H, m),
3.64 and 3.92 (2H, ABq, J = 17Hz), 3.84 (3H, s), 4.7
-4.9 (1H, m), 5.19 and 5.22 (total 1H, d, J = 5Hz), 5.
7-5.8 (1H, m), 6.7-6.9 (2H, m), 7.0-7.2 (3H, m), 9.60
And 9.62 (total 1H, d, J = 8Hz) (7) 1- (cyclohexyloxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazole-4
-Yl) -2-methoxyiminoacetamide] -3-
[(E) -2-[{2- (dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 1750, 1665, 1525 cm ^-1 NMR ( DMSO-d ₆ , δ): 1.2-1.6 (6H, m), 1.48 (3H, d, J = 5.
4Hz), 1.6-1.7 (2H, m), 1.8-2.0 (2H, m), 2.17 (6H, s),
2.4-2.5 (2H, m), 2.8-3.0 (2H, m), 3.64 and 3.92
(2H, ABq, J = 17.1Hz), 3.87 (3H, s), 4.5-4.6 (1H, m), 5.1
9 and 5.22 (total 1H, d, J = 4.8Hz), 5.7-5.85 (1H,
m), 6.8-7.2 (4H, m), 7.24 (2H, br s), 9.59 and 9.6
4 (total 1H, d, J = 8.2Hz) (8) 1- (isopropoxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide] -3-[(E)-
2-{(1-methylpiperidin-4-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3280, 3110, 1750, 1655, 1605, 15
25 cm ^-1 NMR (DMSO-d ₆ , δ): 1.24 (6H, d, J = 6.1Hz), 1.47 and 1.48 (total 3H, d, J = 5Hz), 1.4-1.65 (2H, m), 1.8 -2.
05 (4H, m), 2.15 (3H, s), 2.6-2.8 (2H, m), 3.0-3.2 (1
H, m), 3.64 and 3.97 (2H, ABq, J = 17.2Hz), 3.84 (3H,
s), 4.75-4.9 (1H, m), 5.19 and 5.21 (total 1H, d, J
= 4.7Hz), 5.65-5.85 (1H, m), 6.8-7.0 (3H, m), 7.23 (2
H, br s), 9.60 and 9.63 (total 1H, d, J = 8.1Hz) (9) 1- (cyclohexyloxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazole-4
-Yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{(1-methylpiperidin-4-yl)
Thio} vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3290, 3100, 1750, 1660, 1605, 15
25 cm ^-1 NMR (DMSO-d ₆ , δ): 1.1-2.0 (14H, m), 1.47 and 1.
48 (total 3H, d, J = 5Hz), 2.17 (3H, s), 2.6-2.8 (2H, m),
3.0-3.2 (3H, m), 3.63 and 3.96 (2H, ABq, J = 17.1H
z), 3.84 (3H, s), 4.5-4.7 (1H, m), 5.19 and 5.21
(Total 1H, t, J = 4.7Hz), 5.7-5.9 (1H, m), 6.7-6.9 (4H,
m), 7.24 (2H, br s), 9.59 and 9.64 (total 1H, t, J =
8.0Hz) (10) 1- (cyclohexyloxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazole-4
-Yl) -2-methoxyiminoacetamide] -3-
[(E) -2-{((3S) -1-methylpyrrolidine-
3-yl) thio} vinyl] -3-cephem-4-carboxylate (syn isomer) IR (nujol): 3280, 3100, 1750, 1665, 1605, 15
25 cm ^-1 NMR (DMSO-d ₆ , δ): 1.1-2.0 (12H, m), 1.48 and 1.
49 (Total 3H, d × 2J = 5Hz), 2.25 (3H, s), 2.2-2.7 (3
H, m), 2.8-3.0 (1H, m), 3.5-3.7 (1H, m), 3.64 and
3.92 (2H, ABq, J = 17Hz), 3.84 (3H, s), 4.5-4.6 (1H, m),
5.20 and 5.22 (total 1H, d, J = 5Hz), 5.7-5.8 (1H,
m), 6.8-6.9 (3H, m), 7.1-7.2 (1H, m), 7.24 (2H, br
s), 9.61 and 9.63 (total 1H, d, J = 8Hz)

Example 24 The following compound was obtained in the same manner as in Examples 11 and 12. (1) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -2-{(1-methylpiperidin-4-yl)
Thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3300, 1745, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 1.6-2.0 (2H, m), 2.0-2.2 (2H, m),
2.65 (3H, s), 2.8-3.0 (2H, m), 3.1-3.4 (3H, m), 3.52
And 3.73 (2H, ABq, J = 17Hz), 5.11 (1H, d, J = 5Hz), 5.
69 (1H, dd, J = 5, 8Hz), 6.65 (1H, d, J = 16Hz), 6.67 (1H,
s), 6.96 (1H, d, J = 16Hz), 7.14 (2H, s), 9.46 (1H, d, J =
8Hz), 11.4 (1H, br s) (2) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -2-{((3S) -1-methylpyrrolidine-
3-yl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3200, 1750, 1650, 1590, 1520 cm
^-1 NMR (DMSO-d ₆ , δ): 1.87 (1H, m), 2.40 (1H, m), 2.59
(3H, s), 2.9-3.2 (3H, m), 3.43 (1H, m), 3.51 and 3.
71 (2H, ABq, J = 17Hz), 3.80 (1H, m), 5.11 (1H, d, J = 5H
z), 5.68 (1H, dd, J = 5, 8Hz), 6.66 (1H, d, J = 16Hz), 6.67
(1H, s), 6.92 (1H, d, J = 16Hz), 7.13 (2H, br s), 9.43
(1H, d, J = 8Hz), 11.3 (1H, br s) (3) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -2-[{3- (dimethylamino) propyl]]
Thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1745, 1650, 1580, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.8-2.0 (2H, m ), 2.57 (6H, s), 2.
75-3.0 (4H, m), 3.48 and 3.66 (2H, ABq, J = 16.9Hz),
5.08 (1H, d, J = 4.8Hz), 5.65 (1H, dd, J = 8.0 & 4.8Hz),
6.55 (1H, d, J = 15.7Hz), 6.69 (1H, s), 6.86 (1H, d, J = 1
5.7Hz), 9.42 (1H, d, J = 8.0Hz), 11.33 (1H, br s) (4) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3 −
[(E) -2-{(2-carbamoyloxyethyl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 3280, 1750, 1650, 1595, 1530 cm
^-1 NMR (DMSO-d ₆ , δ): 3.03 (2H, t, J = 6Hz), 3.60 and
3.82 (2H, ABq, J = 17Hz), 4.10 (2H, t, J = 6Hz), 5.16 (1H,
d, J = 5Hz), 5.73 (1H, dd, J = 8 & 5Hz), 6.58 (2H, br s),
6.69 (1H, s), 6.88 (1H, d, J = 16Hz), 7.00 (1H, d, J = 16H
z), 7.14 (2H, br s), 9.48 (1H, d, J = 8Hz), 11.31 (1H,
s)

Example 25 1- (Cyclohexyloxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3-[(E) -2
-[{2- (Dimethylamino) ethyl} thio] vinyl]
-3-Cephem-4-carboxylate (syn isomer)
(400 mg, 0.586 mmol) ethyl acetate (1
2 ml) solution at room temperature with 4N hydrochloric acid-ethyl acetate solution (0.
29 ml) and stirred at 5 ° C. for 1 hour. The precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether, and dried under reduced pressure to give 1- (cyclohexyloxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazol-4-yl) -2- Methoxyiminoacetamide]
-3-[(E) -2-[{2- (dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylic acid
The dihydrochloride salt (421 mg) is obtained. IR (nujor): 1750, 1660, 1625, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 1.2-1.5 (6H, m), 1.4-1.5 (3H, m),
1.6-1.8 (2H, m), 1.8-2.0 (2H, m), 2.77 and 2.79
(Total 6H, s), 2.7-2.9 (2H, m), 3.1-3.3 (2H, m), 3.69
And 3.97 (2H, ABq, J = 17Hz), 3.91 (3H, s), 4.5-4.6
(1H, m), 5.23 and 5.26 (total 1H, d, J = 5Hz), 5.8-5.
9 (1H, m), 6.8-7.0 (3H, m), 7.22 (1H, d, J = 16Hz), 9.76
(1H, d, J = 8Hz)

Example 26 The following compound was obtained in the same manner as in Example 25. (1) 1- (Cyclopentyloxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazole-4
-Yl) -2-methoxyiminoacetamide] -3-
[(E) -2-[{2- (dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylate.
Dihydrochloride (syn isomer) IR (nujol): 1750, 1660, 1625, 1550 cm ^-1 NMR (DMSO-d ₆ , δ): 1.03 (3H, d, J = 6Hz), 1.5-1.9 (8H,
m), 2.77 and 2.80 (total 6H, s), 3.1-3.3 (4H, m),
3.67 and 3.94 (2H, ABq, J = 18Hz), 3.90 (3H, s), 5.0
-5.1 (1H, m), 5.23 and 5.26 (total 1H, d, J = 5Hz),
5.7-5.8 (1H, m), 6.7-6.9 (3H, m), 7.19 (1H, d, J = 16H
z), 9.74 (1H, d, J = 8Hz) (2) 1-acetoxyethyl = 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-{{2- (dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylate dihydrochloride (syn isomer) IR (nujol): 1750, 1660, 1620, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.46 and 1.48 (total 3H, d, J = 5
Hz), 2.06 and 2.07 (total 3H, s), 2.77 and 2.79
(Total 6H, s), 3.1-3.4 (4H, m), 3.68 and 4.03 (2H,
ABq, J = 18Hz), 3.92 (3H, s), 5.23 and 5.26 (total 1
H, d, J = 5Hz), 5.7-5.9 (1H, m), 6.8-7.0 (3H, m), 7.20
(1H, d, J = 16Hz), 9.80 (1H, d, J = 8Hz) (3) 1- (isopropoxycarbonyloxy) ethyl = 7β- [2- (2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide] -3-[(E)-
2-[{2- (Dimethylamino) ethyl} thio] vinyl] -3-cephem-4-carboxylate dihydrochloride (syn isomer) IR (nujol): 1755, 1670, 1620, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.24 (6H, d, J = 6Hz), 1.48 and
1.49 (total 3H, d, J = 5Hz), 3.1-3.4 (4H, m), 3.68 and 3.97 (2H, ABq, J = 18Hz), 3.91 (3H, s), 4.7-4.9 (1H,
m), 5.23 and 5.26 (total 1H, d, J = 5Hz), 5.7-5.9 (1
H, m), 6.7-6.9 (3H, m), 7.21 (1H, d, J = 16Hz), 9.76 (1
(H, d, J = 8Hz)

Example 27 Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-[{2- (tetrahydropyran-2-yl) oxyethyl} thio] vinyl] -3-cephem- 4-carboxylate (5.0 g, 7.06 m
To a solution of (mol) in methanol (25 ml) at room temperature is added 6N hydrochloric acid (2.55 ml), and the mixture is stirred at the same temperature for 45 minutes. The mixture is poured into a mixture of ethyl acetate and cold water, the organic layer is separated, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-
{(2-Hydroxyethyl) thio} vinyl] -3-cephem-4-carboxylate (2.41 g) is obtained. IR (nujol): 3300, 1760, 1695, 1500 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 2.82 (2H, t, J = 6.3H
z), 3.56 (2H, t, J = 6.3Hz), 3.63 and 3.79 (2H, ABq,
J = 16.7Hz), 4.93 (1H, br), 5.14 (1H, d, J = 4.5Hz), 5.42
(1H, dd, J = 9.0 & 4.5Hz), 6.89 (1H, s), 6.90 (1H, d, J = 1
5.7Hz), 7.23 (1H, d, J = 15.7Hz), 7.3-7.5 (10H, m), 8.0
4 (1H, d, J = 9.0Hz)

Example 28 Diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-[(E) -2-{(2-hydroxyethyl)
A solution of thio} vinyl] -3-cephem-4-carboxylate (17.83 g, 31.4 mmol) in dichloromethane (180 ml) was added at 5 ° C. to trichloroacetyl isocyanate (7.10 g, 37.7 mmol) in dichloromethane (20 ml). The solution is added dropwise and stirred for 1.6 hours at the same temperature. The mixture is concentrated under reduced pressure and the residue is dissolved in a mixture of chloroform (167 ml) and methanol (33 ml). Silica gel (30 g) is added to the mixture and the mixture is stirred at room temperature for 1.6 hours. The silica gel is filtered off and the filtrate is concentrated under reduced pressure. The residue was purified by subjecting it to silica gel column chromatography to diphenylmethyl = 7β-tertiary butoxycarbonylamino-3-.
[(E) -2-{(2-carbamoyloxyethyl) thio} vinyl] -3-cephem-4-carboxylate (16.75 g) is obtained. IR (nujor): 3300, 1760, 1690, 1510 cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 2.94 (2H, t, J = 6.2H
z), 3.64 and 3.82 (2H, ABq, J = 16.8Hz), 4.05 (2H, t,
J = 6.2Hz), 5.14 (1H, d, J = 4.6Hz), 5.45 (1H, dd, J = 8.9 and 4.6Hz), 6.5-6.7 (2H, br s), 6.86 (1H, d, J = 15.3H
z), 6.90 (1H, s), 7.18 (1H, d, J = 15.3Hz), 7.3-7.5 (10
H, m), 8.05 (1H, d, J = 8.9Hz)

Example 29 Diphenylmethyl = 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide]
-3-[(E) -2-[{2- (tetrahydropyran-
2-yl) oxyethyl} thio] vinyl] -3-cephem-4-carboxylate (syn isomer) (8.05
g, 11.2 mmol) and dichloromethane (40 ml)
Trifluoroacetic acid (16 ml) was added dropwise to a mixture solution of aniline and anisole (8 ml), and the mixture was stirred at room temperature for 5 hours. The mixture is poured into isopropyl ether (500 ml), the precipitate is filtered off, washed with isopropyl ether and dried under reduced pressure. The powder is dissolved in water (300 ml) at pH 7 and the insoluble material is filtered off. The pH of the filtrate was adjusted to 4 with 1N hydrochloric acid and the pH was adjusted to 3
Purify by column chromatography using Diaion HP-20 (100 ml) eluting with 0% aqueous isopropyl alcohol. Lyophilize the eluate,
7β- [2- (2-aminothiazol-4-yl) -2
-Hydroxyiminoacetamide] -3-[(E) -2
-{(2-hydroxyethyl) thio} vinyl] -3-cephem-4-carboxylic acid (syn isomer) (148 mg)
To get IR (Nujol): 3300, 1745, 1640, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 2.89 (2H, t, J = 7Hz), 3.4-3.6 (2H,
m), 3.58 and 3.79 (2H, ABq, J = 17Hz), 4.95 (1H, br
s), 5.16 (1H, d, J = 5Hz), 5.71 (1H, dd, J = 8 & 5Hz), 6.6
9 (1H, s), 6.87 (1H, d, J = 16Hz), 7.02 (1H, d, J = 16Hz),
7.14 (2H, br s), 9.47 (1H, d, J = 8Hz), 11.31 (1H, s)

Example 30 The following compound was obtained as in Example 29. 7β- [2- (2-aminothiazol-4-yl) -2
-Hydroxyiminoacetamide] -3-[(E) -2
-[{2- (Dimethylamino) ethyl} thio] vinyl]
-3-Cephem-4-carboxylic acid (syn isomer) IR (nujol): 1750, 1645, 1580, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 2.63 (6H, s), 3.08 (4H, br s), 3.
54 and 3.74 (2H, ABq, J = 17.2Hz), 5.13 (1H, d, J = 4.7H
z), 5.71 (1H, dd, J = 8.1 & 4.7Hz), 6.68 (1H, s), 6.74
(1H, d, J = 15.8Hz), 6.94 (1H, d, J = 15.8Hz), 7.14 (2H, br
s), 9.45 (1H, d, J = 8.1Hz)

Claims (1)

[Claims] 1. A general formula: [Wherein R ¹ is amino or acylamino, R ² is carboxy or protected carboxy, R ³ is a ^{3- to} 8-membered saturated heteromonocyclic group which may have a suitable substituent, a suitable substituent 3-8 membered saturated heterocyclic monocyclic (lower) alkyl, amino (lower) alkyl, protected amino (lower) alkyl, N- (lower) which may have
Alkylamino (lower) alkyl, N- (lower) alkyl-N-amino protective group-substituted amino (lower) alkyl,
N, N-di (lower) alkylamino (lower) alkyl,
A hydroxy (lower) alkyl or a protected hydroxy (lower) alkyl, respectively] and a pharmaceutically acceptable salt thereof.