JPS6236385A - 3,7-disubstituted-3-cephem compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is amino or protected amino; R<2> is carboxy, COO<->, etc., R<3> is 2-6C alkyl, 3-6C alkenyl, lower alkynyl, etc.,; R<4> is H, hydroxy-protecting group, etc.,) and its salt. EXAMPLE:7-[ 2-( 2-Tritylaminothiazol-4-yl )-2-(1-methyl-1-methoxy-ethoxyimino) acetamide]-3-methylthio-3-cephem-4-carboxylic acid benzhydryl ester. USE:An antimicrobial agent. PREPARATION:A compound shown by the formula II containing a novel compound or a reactive derivative (e.g., imino or silyl derivative of Shiff base type) at the amino group or its salt is reacted with a compound shown by the formula III or its reactive derivative (e.g., acid halide or acid anhydride) at the carboxyl group or its salt, to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to novel 3,7-disubstituted-3-cephem compounds and salts thereof.

More specifically, this invention discloses novel 3
．． The present invention relates to 7-disubstituted-3-cephem compounds and salts thereof, methods for producing them, and antibacterial agents containing them.

That is, one purpose of this invention is to treat many diseases.
An object of the present invention is to provide a novel 3,7-disubstituted-3-cephem compound and its salts that have strong antibacterial activity against bacteria and are useful as an antibacterial agent.

Another object of this invention is the novel 3,7-disubstituted-3
- To provide a method for producing cephem compounds and their salts.

Yet another object of the present invention is to provide an antibacterial agent containing the 3,7-disubstituted-3-cephem compound and its salts as active ingredients.

The 3,7-disubstituted-3-cephem compound according to the present invention is a new compound and can be represented by the following general formula (1).

[Wherein, R1 is an amino group or a protected amino group, R is a carboxy group, C0oe or a protected carboxy group, R is a (C-C) alkyl group, a (03-C6) alkenyl group, a lower alkynyl group, 1.2.3-triazolylthiomethyl group, 1.2.3-thiadiazolylthiomethyl group,
a pyridiniomethyl group which may have a suitable substituent,
Sulfo(lower)alkyltetrazolylthiomethyl group, pyridylvinyl group, bilinruvinylthio group, 1-pyridaciniomethyl group, tosu(lower)alkylammoniomethyl group, pyrrolidinylmethyl group or formula: ( In the formula, A is a group represented by -S- or 10-1 Y means a lower alkyl group, a lower alkenyl group or a heterocyclic group, and R4 means a hydrogen or hydroxy protecting group, respectively, provided that: When R is C00e, R3 means a pyridiniomethyl group, a 1-pyridaciniomethyl group, or a tri(lower)alkylammoniomethyl group which may have an appropriate substituent].

As used herein, the term "syn isomer" shall mean a compound (1) having a stereospecific partial structure represented by the formula: (wherein R4 has the same meaning as before).

Suitable salts of the target compound (I) are customary non-toxic salts, such as salts with inorganic bases, such as alkali metal salts such as sodium salts, potassium salts, alkaline earth salts such as calcium salts, magnesium salts, etc. metal salts, ammonium salts 7 Salts with organic bases, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc. organic amine salts, etc.; for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate; for example, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfone Organic carboxylic acid addition salts or organic sulfonic acid addition salts such as acid salts, benzenesulfonates, and p-toluenesulfonates; bases such as salts with basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid; and acid addition salts.

Furthermore, the symbol "R2" means a carboxy group, and the symbol "
Pyridiniomethyl group, 1-pyridacyniomethyl group or tri(lower) in which R3J may have a suitable substituent
When referring to an alkylammoniomethyl group, salts of the target compound (I) may also be used as molecules with acid residues such as chloride, bromide, fluoride, iodide, sulfate, trifluoroacetate, etc. Also includes intersalts.

The object compound (I) of this invention or its salts can be produced by the following production method.

Production method 1 or its reactive derivative in amine group or its salt or its salt production method 2 or its salt or its salt production method 3 (mV) or its salt or its salt production method 4 or its salt or its salt Pear J (In the formula, R1, R2, R3 and R4 each have the same meaning as R2 is a protected carboxy group, R is a carboxy group or C00e, R2 is an esterified carboxy group, R6 is a carboxy group or a protected carboxy group, R4 is a hydroxy protecting group, X is a halogen, R3 is a pyridiniomethyl group, a 1-pyridaciniomethyl group, or a tri(lower)alkylammoniomethyl group which may have an appropriate substituent, and X is an acid residue.

Among the raw material compounds of this invention, compound (N), compound (V'
f) and compound (I) include novel compounds, and these novel compounds can be produced by the production method shown in the reaction formula below or by a conventional method.

or a reactive derivative thereof in the amine group or a salt thereof or a salt thereof Preparation method B (EX) or a salt thereof ↑ (XI) or a salt thereof (XII) or a salt thereof (XIII) or a salt thereof or a salt thereof [in the formula , R1, R2, R2R3, R3, R4, d'
a X and X each have the same meaning as above, and Rb is pyridine, pyridazine, which may have an appropriate substituent
or tri(lower)alkylamine, R5 each means a protected amino group].

In the foregoing and following description of this specification, preferred examples and explanations of the various definitions encompassed within the scope of this invention are set forth in detail below. It shall mean 6 pieces.

"Higher" means 7 to 20 carbon atoms, unless otherwise specified.
shall mean an individual.

Suitable 1-protected amine groups include the conventional amino protecting groups used in penicillin and cephalosporin compounds, such as the following acyl groups, such as mono(or di- or Al(
(lower) alkyl group, e.g. 1-methoxycarbonyl-1
-Lower alkoxycarbonyl such as propen-2-yl (
lower) alkylidene or its enamine type tautomer,
Examples include amino groups substituted with di(lower)alkylaminomethylene such as dimethylaminomethylene.

Suitable "acyl groups" include aliphatic acyl groups, aromatic acyl groups, heterocyclic acyl groups, and aliphatic acyl groups substituted with aromatic or heterocyclic groups.

Examples of aliphatic acyl groups include formyl, acetyl,
Lower alkanoyl groups such as propionyl, butyryl, isobutyryl, valeryl, invaleryl, pivaloyl, hexanoyl, lower alkanesulfonyl groups such as mesyl, eccnesulfonyl, propanesulfonyl, etc., such as methoxycarpol, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, Lower alkoxycarbonyl groups such as tertiary butoxycarbonyl, lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl, etc. (03-C
7) Cycloalkane carbonyl acyclic or cycloaliphatic acyl group.

Examples of the aromatic acyl group include aroyl groups such as hendiyl, toluoyl, and kijiloyl, and allenesulfonyl groups such as .\zenesulfonyl and tosyl.

Examples of the heterocyclic acyl group include furoyl, thenoyl,
Examples include heterocyclic carbonyl groups such as nicotinoyl, innicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, and tetrazolylcarbonyl.

Aliphatic acyl groups substituted with aromatic groups include alkanoyl groups such as phenyl(lower)alkanoyl groups such as phenylacetyl, phenylpropionyl, phenylhexanoyl, etc., such as benzyloxycarbonyl, phenethyl, etc. Examples include alk(lower) alkyl dicarbonyl groups such as phenyl(lower) alkoxycarbonyl groups such as oxycarbonyl, and phenoxy(lower) alkanoyl groups such as phenoxyacetyl and phenoxyprobionyl.

Examples of the aliphatic acyl group substituted with a heterocyclic group include chenyl acetyl, imidazolylacetyl, furylacetyl,
Examples include tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thienylpropionyl, thiadiazolylpropionyl, and the like.

These acyl groups may further include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogens such as chlorine, bromine, iodine, fluorine, such as methoxy, ethoxy, propoxy, isopropoquine, butoxy. , lower alkoxy groups such as pentyloxy, hexyloxy, etc., such as methylthio,
may be substituted with one or more suitable substituents such as lower alkylthio groups such as ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc., nitro groups, etc., and such rM. Preferred acyl groups having substituents include, for example, mono(or tri)-halo(lower)alkanoyl groups such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc., and mono(lower)alkanoyl groups such as chloromethoxycarbonyloxycarbonylcarbonyl. (or di- or tri)-halo(lower) alkoxycarbonyl groups, such as nitro(or halo- or lower alkoxy)phenyl(lower) alkoxycarbonyl groups such as nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methoxybenzyloxycarbonyl, etc. Can be mentioned.

Suitable monoprotected carboxy groups include esterified carboxy groups commonly used in penicillin or cephalosporin compounds.

Examples of suitable primary ester moieties of mono-esterified carboxyl groups include methyl nitride, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, Lower alkyl esters such as tertiary pentyl esters and hexyl esters, lower alkenyl esters such as vinyl esters and allyl esters, lower alkynyl esters such as ethynyl esters and propynyl esters, such as methoxymethyl esters, ethoxymethyl esters, and impropoxymethyl esters. , 1-methoxyethyl Nisder, 1-ethoxyethyl ester, lower alkylthio (lower) alkyl esters such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isoprobyl thiomedel ester, etc. ) alkyl esters, such as carboxymethyl esters, 2-
Carboxy-substituted lower alkyl esters such as carboxyether esters carboxybrobyl esters, lower alkoxycarbonyls such as tertiary-butoxycarbonyl methyl ester, 2-tert-butoxycarbonyl ethyl ester, 3-tert-butoxycarbonylprobyl esters, etc. Protected carboxy-substituted (lower) alkyl esters such as substituted (lower) alkyl esters, such as 2-iodoethyl ester, 2.2.

2-1-IJ Mono (such as chloroethyl ester)
or tri) halo(lower) alkyl ester,
Examples include acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or 2)-acetoxyethyl ester, 1(or 2)-acetoxyethyl ester, 2 or 3)-acetoxypropyl ester, 1 (or 2)
or 3 or 4)-acetoxyethyl ester 1
(or 2)-propionyloxyethyl ester, 1
(or 2 or 3)-propionyloxypropyl ester, 1 (or 2)-butyryloxyethyl ester, 1 (or 2)-isobutyryloxyethyl ester, 1 (or 2)- and valeryloxymethyl ester , 1 (or 2)-hexanoyloxyethyl ester, imptyryluoquine methyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2)-pentanoyloxyethyl Lower alkanoyloxy (lower) alkyl esters such as esters, such as heptanoyloxymethyl ester, octanoyloxymethyl ester, nonanoyloxymethyl ester, decanoyloxymethyl ester, undecanoyloxymethyl ester, lauroyloxymethyl ester, tridecanoyloxymethyl ester pentadecanoyloxymethyl ester, palmitoyloxymethyl ester, heptadecanoyloxymethyl ester, stearoyloxymethyl ester, nonadecanoyloxymethyl ester, eicosanoyloxymethyl ester, 1 (or 2)- heptanoyloxyethyl ester, 1(or 2)-octanoyloxyethyl ester, 1(or 2)-nonanoyloxyethyl ester, 1(or 2)-decanoyloxyethyl ester, 1(or 2)-undecanoyloxyethyl ester Noyloxyethyl ester, 1 (or 2)-lauroyloxyethyl ester, 1 (or 2)-tridecanoyloxyethyl ester or 2)-myristoyloxyethyl ester, 1 (or 2)-pentadecanoyloxyethyl ester Ethyl ester, 1 (or 2)-heptadecanoyloxyethyl ester, 1 (or 2)-stearoyloxyethyl ester, 1 (or 2)-nonadecanoyloxymethyl ester, 1 (or 2)-diifsanoyl Higher alkanoyloxy (such as oxyethyl ester)
lower) alkyl esters, such as methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tertiary butoxycarbonyloxymethyl ester, 1 (or 2)-methoxycarbonyloxyethyl ester, 1 (or 2)-methoxycarbonyloxyethyl ester, )-ethoxycarbonyloxyethyl ester is 2)-'roboxycarbonyloxyethyl ester,
1 (or 2)-isopropoxycarbonyloxyethyl ester, 1 (or 2)-butoxycarbonyloxyethyl ester, 1 (or 2)-isobutoxycarbonyloxyethyl ester, 1 (or 2)-tertiary butoxycarbonyloxy Ethyl ester, 1 (or 2)-hexyloxycarbonyloxyethyl ester, 1 (or 2 or 3)-methoxycarbonyloxypropyl ester, 1 (or 2 or 3)-ethoxylponyloxypropyl ester, 1 (or 2 or 3)-isoproboxycarbonyl oquimbrobyl ester, 1 (or 2 or 3 or 4)-ethoxycarbonyloxybutyl ester, 1 (or 2 or 3 or 4)-butoxycarbonyloxybutyl ester,
1 (or 2 or 3 or 4 or 5)-pentyloxycarbonyloxypentyl ester, 1 (or 2
or 3 or 4 or 5)-neopentyloxycarbonyloxydipentyl ester, 1 (or 2 or 3)
or lower alkyl esters such as (5-methyl-2
-oxo-1,3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1°3-dioxol-4-yl) methyl ester, (5-propyl-2
(5-lower alkyl-2-dioxo-1,3-yl) such as -dioxo-1,3-dioxo-4-yl)ethyl ester
dioxol-4-yl) (lower) alkyl ester,
For example, lower alkanesulfonyl (lower) alkyl esters such as mesyl methyl ester, 2-mesylethyl ester, etc., such as benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydryl ester, trityl ester, bis(methoxy mono(or di- or Al(lower)alkyl esters optionally bearing one or more substituents such as tri)phenyl(lower)alkyl esters, e.g. phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityl Examples include aryl esters which may have one or more suitable substituents such as esters, cumenyl esters, and salicyl esters, and heterocyclic esters such as phthalidyl esters.

Suitable monohalogens include chlorine, bromine, iodine, and the like.

Suitable lower alkyl groups include methyl, ethyl,
Mention may be made of straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc., preferably having 1 to 3 carbon atoms. It is an alkyl group.

Suitable "(02-C6) alkyl groups" include straight-chain or branched-chain alkyl groups having 2 to 6 carbon atoms, such as ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, etc. preferred are alkyl groups having 2 to 4 carbon atoms.

Preferred 1-lower alkenyl groups are those having 2 to 6 carbon atoms, such as vinyl, allyl, isopropenyl, 1-
Examples include propenyl, 2-butenyl, 3-pentenyl, etc., and preferably one having 2 to 4 carbon atoms.

A suitable “(03-C6) alkenyl group” has 3 to 3 carbon atoms.
It has 6 pieces, allyl, isopropenyl, 1
-propenyl, 2-butenyl, 3-pentenyl and the like, preferably having 3 to 4 carbon atoms.

Suitable "lower alkynyl groups" have 2 to 6 carbon atoms, and include ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl, etc., but preferably have 2 to 6 carbon atoms. It has four pieces.

"Heterocyclic group" means a saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one petro atom such as an oxygen atom, an atom atom, a nitrogen atom, etc. Among them, particularly preferred heterocyclic groups include, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, such as 4H-1,2,4-triazolyl, IH -1,2,3-
An unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, such as triazolyl such as triazolyl and 2H-1,2,3-triazolyl, for example, tetrazolyl such as IH-tetrazolyl and 2H-tetrazolyl; Saturated 3-8 containing 1-4 nitrogen atoms such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.
Member heteromonocyclic groups; for example, indolyl, isoindolyl, intridinyl,
an unsaturated fused heterocyclic group containing 1 to 5 nitrogen atoms such as benzimidazolyl, quinolyl, isoquinolyl, imidazolyl, benzotriazolyl, tetraclopyridyl, tetraclopyridazinyl, dihydrotriazolopyridazinyl; For example, oxasilyl, isoxasilyl, e.g. 1
, 2.4-oxadiazolyl, 1.3.4-oxadiazolyl, 1.2.5-oxadiazolyl, and other unsaturated 3- to 8-membered heteromonomers containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms. Cyclic group; For example, 1 to 2 oxygen atoms such as morpholinyl and sindonyl
and a saturated 3- to 8-membered heteromonocyclic group containing 1 to 3 nitrogen atoms; For example, an unsaturated condensed group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxasilyl, benzoxadiazolyl, etc. Heterocyclic group; e.g. theacyl, isothiazolyl, e.g. 1.2
．． 3-thiadiazolyl, 1.2.4-thiadiazolyl,
Thiadiazolyl groups such as 1.3.4-thiadiazolyl and 1.2.5-thiadiazolyl; unsaturated 3- to 3-unsaturated groups containing 1 to 2 small atoms and 1 to 3 nitrogen atoms, such as dihydrothiazinyl;
8-membered heteromonocyclic group; for example, a saturated 3- to B-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl; for example, chenyl, dihydrodithionyl, dihydrodithionyl, etc. Unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 sulfur atoms; unsaturated condensed group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiasili, benzothiadiazolyl, etc. Heterocyclic group; For example, unsaturated 3 to 3 containing one oxygen atom such as furyl
8-membered heteromonocyclic group; For example, an unsaturated 3- to 8-membered heteromonocyclic group containing 1 g of oxygen atoms and 1 to 2 diatoms, such as dihydroxathinyl; For example, dihydrooxathiinyl, etc. Unsaturated fused heterocyclic groups containing 1 to 2 atoms; Examples include unsaturated fused heterocyclic groups containing 1 oxygen atom and 1 to 2 sulfur atoms such as benzoxathiinyl; It will be done.

Preferred substituents for the pyridinio group in 1. Pyridiniomethyl group which may have an appropriate substituent include lower alkyl groups such as methyl and ethyl.

Suitable "sulfo(lower)alkyltetrazolylthiomethyl groups" include 1-sulfomethyl-IH-tetrazolylthiomethyl, 2-sulfomethyl-2H-tetrazolylthiomethyl, 1-sulfoethyl-IH-tetrazolylthiomethyl, etc. can be mentioned.

Suitable pyridylvinyl groups include 2-pyridyl,
Examples include 3-pyridylvinyl.

Suitable 1-pyridylvinylthio groups include 2-pyridylvinylthio, 3-pyridylvinylthio, 4-pyridylvinylthio, and the like.

Suitable "acid residues" include acyloxy groups, azide groups, halogens, etc., and for the acyl moiety and halogen of the "acyloxy groups", refer to those exemplified above.

Regarding the suitable "esterified carboxy group", reference may be made to the above-mentioned examples of the protected carboxy group.

Suitable substituents for pyridine in "pyridine which may have a suitable substituent" include lower alkyl groups such as methyl, ethyl and the like.

Suitable "hydroxy protecting groups" include the above-mentioned acyl group,
Examples include alkyl groups such as benzyl and trityl, lower alkyl groups such as 1-methyl-1-methoxyethyl and methoxypropyl, and tetrahydropyranyl groups.

Suitable "tri(lower)alkylammoniomethyl groups" include trimethylammoniomethyl, triethylammoniomethyl, tripropylammoniomethyl, triisopropylammoniomethyl, trihexylammoniomethyl, and the like.

Suitable "tri(lower)alkylamines" include trimethylamine, triethylamine, tripropylamine, and tri-(lower)alkylamine. Examples include sobrobylamine and trihexylamine.

Preferred embodiments of the target compound (I) are as follows.

A preferred embodiment of R1 is an amine group or a (lower)
Alkylamino groups, more preferably amine groups and mono (or di or tri)-phenyl (lower) alkylamino groups, most preferably amino groups and tritylamino groups; preferred embodiments of R2 include carboxy groups, mono- or di- or A trial (lower) alkoxycarbonyl group, more preferably a carboxyl group, a penshydryloxycarbonyl group, an alkoxycarbonyl group substituted with a nitro group, still more preferably a carboxy group, a nitrobenzyloxycarbonyl group, or a lower alkanoyloxy (lower) alkoxycarbonyl group,
Most preferably carboxy group and pivaloyloxymethoxycarbonyl group; preferred embodiments of R are (02-c6) alkyl group,
(03-C6) alkenyl group, lower alkynyl group, 1.
2.3-triazolylthiomethyl group, 1.2.3-thiadiazolylthiomethyl group, pyridiniomethyl group, pyridiniomethyl group having a lower alkyl group, pyridylvinyl group, sulfomethyltetrazolylthiomethyl group, pyridylvinylthi' a 1-pyridaciniomethyl group, a lower alkoxy group, a lower alkylthio group, a lower alkenylthio group, a 1,2.3-triazolylthio group, a 1-pyrrolidinylmethyl group or a trimethylammoniomethyl group,
Most preferably ethyl, 1-propenyl, ethynyl, 1
．． 2.3-triazol-4-ylthiomethyl, 1,2
．． 3-thiadiazol-5-ylthiomethyl, 1-pyridiniomethyl, 3-methyl-1-pyridiniomethyl, 1
-Sulfomethyl-IH-tetrazol-5-ylthiomethy &.

2-(3-pyridyl)vinyl, 2-(3-pyridyl)vinylthio, 1-pyridaziniomethinotrimethylammonio, methoxy, methylthio, ethylthio, vinylthio, 1.2.3-triazol-4-ylthio or It is pyrrolidin-1-ylmethyl.

The method for producing the object compound of the present invention will be explained in detail below.

Production method 1 The target compound (I) or a salt thereof is obtained by preparing compound (I) or its reactive derivative or salt thereof in the amide 7 group,
It can be produced by reacting the compound (I[[> or a reactive derivative thereof or a salt thereof at the carboxy group).

Suitable reactive derivatives at the amino group of compound (I[) include Schiff's base type imino or its enamine type tautomer produced by the reaction of compound (If) with a carbonyl compound such as an aldehyde, ketone, etc. Silyl derivatives produced by the reaction of compound (n) with bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, etc.; derivatives produced by the reaction of compound (I) with trichloride groove or phosgene, and the like.

Suitable salts of compounds (I[) and <m> include organic acid salts such as acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, or hydrochloride, hydrobromic acid, etc. Acid addition salts such as inorganic acid salts such as salts, sulfates and phosphates; metal salts such as thorium salts, potassium salts, calcium salts and magnesium salts; ammonium salts; organic salts such as triethylamine salts and dicyclohexylamine salts. Examples include amine salts.

Suitable reactive derivatives at the carboxy group of compound (I[[) include acid halides, acid anhydrides, activated amides, activated esters, and the like.

Suitable examples thereof include acid chlorides, acid azides; substituted 8t' phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, nhenzyl phosphoric acid, and halogenated phosphoric acid;
dialkyl phosphites, sulfites, thiosulfates, sulfates, alkyl carbonates, aliphatic carboxylic acids such as pivalic acid, pentanoic acid, inpentanoic acid, 2-ethylbutyric acid or trichloroacetic acid or aromatic carboxylic acids such as benzoic acid; mixed acid anhydrides with acids such as; symmetric acid anhydrides; activated amides with imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles;
For example, cyan methyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3) 2 servings = CH-]
Estheno murmuring hinyl esteno murmuring propargyl ester,
p-nitrophenyl ester, 2.4-'; nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p
- activated esters such as nitrophenyl thioester, p-talesyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or e.g.
, N-dimethylhydroxylamine, 1-hydroxy-
2-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6
Examples include esters with N-hydroxy compounds such as -chloro-IH-benzotriazole. These reactive derivatives can be arbitrarily selected depending on the type of compound (I[[) to be used.

The reaction is usually carried out in conventional solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine,
The reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents can also be used in combination with water.

When the compound (I [ ? , N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,
N'-diisopropylcarbodiimide; N-ethyl-
N'-(3-dimethylaminopropyl)carbodiimide, N,N-carbonylbis-(2-methylimidazole); Pentamethyleneketene-N-cyclohexylimine; Diphenylketene-N-cyclohexylimine; Ethoxyacetylene; 1-Alkoxy- 1-chloroethylene; trialkyl phosphite; ether polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); trichloride groove; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxane Zolium salt; 2-ethyl-5-(m-sulfophenyl)inoxacillium hydroxide inner salt; 1(p-chlorobenzenesulfonyloxy)-6-chloro-IH-benzotriazole; dimethylformamide and thiodichloride Preferably, it is carried out in the presence of a conventional condensing agent, such as the so-called Vilsmeier reagent prepared by reaction with phosgene, phosphorus oxychloride, and the like.

The reaction also involves the presence of inorganic or organic bases such as alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorbolines, N,N-di(lower)alkylbenzylamines, etc. You can go downstairs.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature.

It is also included within the scope of this reaction if the hydroxy protecting group of R4 is removed during the reaction or post-treatment step of this process.

1. Severe Shyness Compound (Ib) or a salt thereof can be produced by subjecting Compound (Ia) or a salt thereof to an elimination reaction of the carboxy protecting group.

Suitable salts of compounds (Ia) and (Ib) include:
The same compounds as those exemplified for compound (I) can be mentioned.

Suitable methods for this elimination reaction include conventional methods such as hydrolysis and reduction.

(1) Hydrolysis Hydrolysis is preferably carried out in the presence of an acid.

Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, for example formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-
Examples include organic acids such as toluenesulfonic acid, acidic ion exchange resins, and the like. When organic acids such as trifluoroacetic acid and p-toluenesulfonic acid are used in this reaction, it is preferred to carry out the reaction in the presence of a cation scavenger, such as, for example, anisole.

Furthermore, in place of the above acids, acids such as boron trifluoride, boron trifluoride-ether adducts, aluminum trichloride, antimony pentachloride, ferric chloride, stannic chloride, titanium tetrachloride, zinc chloride, etc. Acids can also be used in this reaction, and when Lewis acid is used, the reaction is preferably carried out in the presence of a cation scavenger, such as, for example, anisole.

Hydrolysis is usually carried out using conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, furopanol, tertiary butyl alcohol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, methylene chloride, etc. It is carried out in a solvent or a mixture thereof, and the acids mentioned above can also be used as solvents if they are liquid.

The reaction temperature for this hydrolysis is not particularly limited, but the reaction is usually carried out in a temperature range of from cooling to slightly elevated temperature.

(i) Reduction Reduction is carried out by conventional methods including chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts that can be used for catalytic reduction include platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc., such as palladium sponge, palladium black, palladium oxide, palladium-carbon, colloidal palladium,
Palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, iron catalysts such as reduced iron, Raney iron, etc. Commonly used copper catalysts such as reduced steel, Raney copper, Ullmann steel, etc.

This reduction is usually carried out in conventional solvents or mixtures thereof that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide. Furthermore, if the acids used in the chemical reduction are liquids, they can also be used as solvents.

Still further, suitable solvents for use in catalytic reduction include those mentioned above and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

Although the reaction temperature for this reduction cannot be particularly limited, the reaction is usually carried out under cooling or heating.

In this elimination reaction of a carboxy protecting group, another protected carboxy group and/or a deprotected amino group is converted to the corresponding free carboxy group and/or amino group during the reaction or work-up step of this process. Variations are also included within the scope.

Production method 3 Compound (I) or a salt thereof can be produced by reacting compound (■) or a salt thereof with compound (V).

Suitable salts of compound (EV) include the same salts as exemplified for compound (I>).

This reaction usually does not adversely affect reactions such as ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, water, acetic acid, formic acid, etc. The method is carried out in any conventional solvent or mixture thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

Production method 4 Compound (Ic) or a salt thereof can be produced by subjecting compound (Ib> or a salt thereof to an esterification reaction.

For suitable salts of compounds (Ib) and (Ic),
Reference may be made to those exemplified for compound (I).

This reaction may be carried out by reacting compound (Ib) or a salt thereof with an esterifying agent.

A suitable esterifying agent has the formula: (wherein R7 is the ester moiety of the esterified carboxy group, and Z means a hydroxy group or a reactive derivative thereof)
The following compounds can be mentioned.

Suitable reactive derivatives of the hydroxy group of 2 include acid residues such as the aforementioned halogens.

This reaction is usually carried out in a solvent such as dimethylformamide, pyridine, hexamethylphosphoric triamide, or dimethyl sulfoxide, but the reaction can be carried out in any other solvent that does not adversely affect the reaction.

When compound (Ib) is used in the form of a free acid, the reaction is preferably carried out in the presence of the following base.

Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under cooling, room temperature, or heating.

In this esterification reaction, another free carboxy group of compound (Ib) may be changed to an esterified carboxy group during the reaction and/or during post-treatment of the reaction, depending on the reaction conditions and the type of protecting group. included within its scope.

1 Theft Meng 1 Compound (Ie) or a salt thereof can be produced by subjecting compound (Id) or a salt thereof to an elimination reaction of a hydroxy protecting group.

Suitable salts of compounds (Id) and (Ie) include:
The same compounds as those exemplified for compound (1) can be mentioned.

This elimination reaction of the hydroxy protecting group of compound (Id) can be carried out in the same manner as in B above, and therefore, for the reagents to be used and reaction conditions such as solvent and reaction temperature, please refer to good.

In this elimination reaction, the protected amine group and/or
or the protected carboxy group is removed during the reaction or work-up step of this preparation by the corresponding free amino group and/or
Also included within the scope are cases where it changes to a free carboxy group.

1 Production 1 Compound (Ig) or a salt thereof can be produced by subjecting compound (If) or a salt thereof to an amino-protecting group elimination reaction.

Suitable salts of compounds (If) and (Ig) include the same salts as exemplified for compound (I).

This elimination reaction can be carried out in the same manner as in the above-mentioned article, and therefore, the reagents used and the reaction conditions, such as solvent and reaction temperature, are as described in the article.

Please refer to .

The compound (Ih) or a salt thereof can be produced by reducing the compound (■) or a salt thereof.

Suitable salts of compounds (Ih) and (Vl) include the same salts as exemplified for compound (I).

For example, a method using a combination of phosphorus trichloride, tin chloride and acetyl chloride, a combination of an alkali metal iodide such as sodium iodide and a trihaloacetic anhydride such as trifluoroacetic anhydride, etc. It can be done with

This reaction is usually carried out in a solvent such as acetone, dioxane, acetonitrile, dimethylformamide, benzene, hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, but any solvent that does not adversely affect the reaction. , the reaction can be carried out in any other solvent.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature.

The method for producing the raw material compound of this invention will be explained in detail below.

Production method A-■ Compound (■) or its salt is prepared by reacting compound (n) or its reactive derivative at the amine group or its salt with compound (■) or its reactive derivative at the carboxy group or its salt. It can be manufactured by glazing.

Suitable reactive derivatives of compound (■) include acid halides such as acid chlorides, acid bromides, etc. which can be prepared by reacting diketene with a halogen.

Suitable salts for compound (■) include those similar to the bases exemplified for compound (I),
Suitable salts for compound (■) include the same salts as for compound (I).

The reaction is usually carried out using substances that may adversely affect the reaction, such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, hexamethylphosphoramide, etc. The method is carried out in any conventional solvent or mixture thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

The vapor double-layer compound (■a) or a salt thereof can be produced by reacting the compound (■) or a salt of Haso with a nitrosating agent.

Suitable salts of compound (IVa) include compound (I)
The same salts as those exemplified for are mentioned.

Suitable nitrosating agents include nitrous acid and nitrosyl halides such as nitrosyl chloride, nitrosyl bromide, alkali metal nitrites such as sodium nitrite, potassium nitrite, and isoamyl nitrite. Examples include conventional derivatives of nitrous acid such as alkyl nitrites such as nitrites and the like.

When a salt of nitrous acid or an alkali metal salt thereof is used as a nitrosating agent, it is preferable to carry out the reaction in the presence of an acid such as an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc. .

This reaction is preferably carried out in the presence of an active methylene compound such as acetylacetone, ethyl acetoacetate, and the like.

This reaction is usually carried out in conventional solvents or mixtures thereof that do not adversely affect the reaction, such as water, acetic acid, benzene, methanol, ethanol-tetrahydrofuran, methylene chloride.

Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction in the range of cooling to room temperature.

Compounds (IVa) of this reaction include syn-isomers, anti-isomers and mixtures thereof in their hydroxyimino groups, and such compounds have the substructural formula: X I ) or a salt thereof is a compound (IX
) or a salt thereof with compound (X) or a salt thereof.

For suitable salts of compounds (IX), (X) and (XI), refer to those exemplified for compound (I>).

This reaction may be carried out in a solvent such as water, phosphate sap, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, or dimethylformhokind. The reaction may be carried out in any other aqueous solvent as long as it does not adversely affect the reaction, and it is preferable to carry out the reaction in a strongly polar solvent. It may also be used as a mixture of

Preferably, the reaction is carried out in a neutral medium.

When compound (IX) is used in free form, it can be used, for example, with an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an organic base such as a trialkylamine, etc. It is preferable to carry out the reaction in the presence of a base such as a base.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature, under heating, or under heating.

This reaction is preferably carried out in the presence of an alkyl metal halide such as sodium iodide or potassium iodide, an alkali metal thiocyanate such as sodium thiocyanate or potassium thiocyanate.

[1B2■ Compound (XII) or a salt thereof is compound (X I )
Alternatively, it can be produced by reducing its salt.

For suitable salts of compound (XII), compound (I)
Please refer to the examples given below.

This reduction can be performed in the same manner as in Production Method 7 above.

This reaction can usually be produced by subjecting water, acetone, dioxane, or a salt thereof to an amine protecting group elimination reaction.

For suitable salts of compound (XI[[), compound (I
), please refer to the examples given.

This elimination reaction can be carried out in the same manner as in Production Method 2 above.

Production method C-■ Compound (XV) or a salt thereof can be produced by oxidizing compound (XIV) or a salt thereof.

For suitable salts of compounds (XIV) and (XV), refer to those exemplified for compound (I).

This oxidation reaction can be carried out by methods such as by using oxidizing agents such as m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, ozone, hydrogen peroxide, periodic acid, and the like.

The reaction is carried out in a solvent such as tetrahydrofuran or ethyl acetate, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction.

Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under cooling or at room temperature.

The single-layer and two-layer compound (Vl) or a salt thereof can be produced by reacting compound (XV) or a salt thereof with compound (X) or a salt thereof.

This reaction can be carried out in the same manner as the above-mentioned 1.

The object compound (1) of the present invention and its salts are novel, have strong antibacterial activity, inhibit the growth of a wide range of pathogenic bacteria including Durum-positive bacteria and Durum-negative bacteria, and are useful as antibacterial agents.

In order to demonstrate the usefulness of the target compounds, the antibacterial activity of representative compounds of this invention is shown below.

Antibacterial activity in a supervised in vitro test tube was measured by the following agar plate multiple dilution method.

Each test strain was cultured overnight in Tryptocase soy broth, and one platinum loop (108 viable bacteria/mule) was inoculated onto heart infusion agar (HI agar) containing a representative test compound at each concentration level. After incubation for 20 hours at 37°C, the minimum inhibitory concentration (MIC) was expressed in pgl-.

(B) Gu Kaisei Huangmu (1) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-pinyldeo-3-cephemu-4-carboxylic acid (syn isomer).

(2) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-(1,2
, 3-deadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer).

(3) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).

(C) Quadrant base 1 M, x, c, (x/mQ) When using the compound of this invention for treatment, a compound containing the compound as an active ingredient and suitable for oral, parenteral or external administration is used. They can be mixed with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients and used in the form of conventional pharmaceutical formulations. Pharmaceutical formulations may be in solid form such as tablets, granules, powders, capsules, or liquid forms such as solutions, suspensions, syrups, emulsions, lemonades, and the like.

Auxiliary agents, stabilizers, wetting agents, and lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil, and olive oil may be added to the above formulations as necessary. Other commonly used additives may also be included, such as cacao extract, ethylene glycol, and the like.

The dosage of compound (1) is selected depending on the patient's age, condition, type of disease, type of compound (1) used, etc.

In general, the compound (I) of the present invention may be administered to a patient in an amount of between 1 mg and about 4000 mg or more per day, with an average single dose of about 50 mg for the treatment of pathogenic bacterial infections. 100mg, 250mg1500mg
, 1000mg, 2000mg may be used.

The present invention will be explained below according to production examples and examples.

5/- 1st Nichiamino-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester hydrochloride (3,0g)
and N,N'-bis(trimethylsilyl)urea (4,
4-bromoacetoacetyl bromide obtained from diketene (0,81111) and bromine (0,53 fflll) in dichloromethane is added to a solution of 4 g) in tetrahydrofuran (30111) under cooling to ~20"C, and the mixture is quenched. Stir for 30 min at 15°C. Pour the reaction mixture into a mixture of ethyl acetate (150 ml) and water. Separate the organic layer, wash with water and brine and evaporate the solvent. Dissolve the residue in diisopropyl Grind in ether (20011111). The resulting precipitate is filtered and dried in vacuo to give 7-
(4-bromoacetoacetamide)-3-methoxy-3
-Cephem-4-carboxylic acid p-nitrobenzyl ester (2,78 g) is obtained.

NMR (DMSO-d6.δ): 3.53-3.9
0 (41(,m>, 3.82(3H,s), 4.
42 (IH, s), 5.12 (IH, d, J=5
Hz＞.

5.33 (2H, s), 5.48 (IH, dd,
J: 5Hz, 8Hz).

7.5-8.3 (4H, m), 9.05 (IH
, d, 8 Hz>Production Example 2 The following compound was obtained in the same manner as in "Example 2".

(1) 7-(4-bromoacetoacetamide)-3-ethylthio-3-cephem-4-carboxylic acid benzhydryl ester.

NMR (Dl'l5O-ds, δ): 1.07 (
3H, t, J near Hz), 2.83 (2H, q, J=
7Hz), 3.70 (21,ABq,J:18Hz
.

26H2), 3.50-3.87 (2H, m),
4.40 <2H, s).

5.17 (LH, d, J=5Hz), 5.43-5
．． 83 (LH, m).

6.84 (LH,s), 7.03-7.60 (1
0H, m).

9.03 (IH, d, J=8Hz> (2) 7-(4-bromoacetoacetamide)-3-ethynyl-3-cephem-4-carboxylic acid benzhydryl ester.

IR (Streak 2-L): 2900. 2g40.
1760. 1710°1520 cm-' (3) 7-(4-bromoacetoacetamide)-3-vinylthio-3-cephem-4-carboxylic acid p-nitrobenzyl ester.

IR (Xjir)' 2920. 1780.
170G, 1650°1610 cm-1 (4) 7-(4-bromoacetoacetamide)-3-(
2H-1,2,3-triazol-4-yl)thiomethyl-3-cephem-4-carboxylic acid.

NMR (ohso-ds, S)' 3.50-3
．． 80 (2H1m), 3-80-4.17 <2H
, m), 4.63 (2H,s), 5.16 (I
H,s.

J=5Hz), 5.77 (IH, dd, J:5Hz
, 8Hz>, 7.93(LH,s), 9.30
(IH, d, J=8Hz) (5) 7-(4-bromoacetoacetamide)-3-(2H-1,2,3-triazol-4-yl)thio-3-cephem-4-carboxylic acid benzene hydryl ester.

(6) 7-(4-bromoacetoacetamide)-3-ether-3-cephem-4-carboxylic acid benzhydryl ester.

(7) 7-(4-chloroacetoacetamide)-3-(
1,2,3-thiadiazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid.

IR (Streak 9-L): 2900. 1765.
1520 an-'NMR (DMSO-ds, l
') : 3.67 (2H,s), 4.33(
2H,s), 4.63 (2)1. s), 5.
23 (IH, d, J=5Hz).

5.47 (IH, dd, J=5Hz, 8Hz),
8.93 (LH,s).

9.13 (LH, d, J = 8Hz) j11 mutual 7-(4-bromoacetoacetamide)-3-(2H-
1,2,3-triazole-4-ifure)thiomethyl-
3-cephem-4-carfonic acid (1,2 g) in acetic acid (1
21119') solution, add sodium nitrite (0.28 g
) solution in water (1,2 Makoto) was added dropwise at 0°C. The mixture is stirred at room temperature for 1.5 hours.

Water (20ml) and ethyl acetate (30ml) were added to the reaction mixture.
III) and tetrahydrofuran (151+111
) mixture. The organic layer is separated, washed with water and brine, and dried over magnesium sulfate. The solvent was distilled off, the residue was ground in diisopropyl ether and collected by filtration,
Vacuum drying to give 7-(4-bromo-2-hydroxyiminoacetoacetamide)-3-(2H-1,2,3-triazol-4-yl)thiomethyl-3-cephem-4
- obtain carboxylic acid.

"Made 1".

The following compound is obtained in the same manner as in Type jL-.

7-(4-chloro-2-hydroxyiminoacetoacetamide)-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

IR(XSii-4>' 2900. 1770
．． 170G, 1530 an-INMR (DM
SO-ds, S): 3.70 (2H1s), 4.
27 (2H, ABq, J=3Hz), 4.83 (2
H, s), 5.25 (lH, d, J=5Hz), 5
．． 83 (LH, dd, J=5Hz, 8Hz>.

8.85 (IH, s), 9.36 (IH, d, J
= 8 Hz) 1 Production] 1 Gloss jL Example 1 The following compound was obtained in the same manner as in Example 1.

7-(4-chloroacetoacetamide)-3-[(z)
-1-propenyl]-3-cephemu 4-carboxylic acid benzhydryl ester.

NMR (DMSO-ds, S)' 1.37 (3
M, dJ=6Hz＞, 3.37-3.77 (4H), 4.55 (2H, s), 5.19 (LH,
d.

J=5Hz>, 5.46 (IH, dd, J=7H
z, 11Hz).

5.72 (LH, dd, J=5Hz, 8Hz)
, 6.03 (IH, d.

J=11Hz), 6.85 (LH,s),
7.07-7.77<10H, m), 9.04
(IH, d, J=8Hz) Production Example 6 (1) Triphenyl-[7-phenylacetamide-
4-Benzhydryloxycarbonyl-3-cephem-
4-yl]phosphonium iodide (1 g) in a mixture of chloroform (50 mQ) and water (50 mQ),
The pH is adjusted to 8.5 by adding IN aqueous sodium hydroxide solution and the mixture is stirred for 5 minutes. The organic layer is separated and concentrated, and acetaldehyde (3.5 ml) is added to the concentrated solution at room temperature. The mixture was stirred under the same conditions for 3 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to column chromatography using phosphoric acid gel (52 g) to obtain a mixture of ethyl acetate and n-hexane (3 nia). Elutes with Fractions containing the desired compound were collected and the solvent was distilled off to give 7-phenylacetamido-3-[(z)-1-propenyl-3
-cephem-4-carboxylic acid benzhydryl ester (
0.01 g) is obtained.

IR (methanol): 3280. 1770.
1710. 1655°1520 Cm' NMR (DMSO-ds, δ): 1.38 (3H
, d, J=6Hz).

3.55 (4H, s), 5.19 (IH, d,
J=5)1z), 5.48(IH, dd, J=1
1Hz, 7Hz), 5.72 (11, d-d
.

J=5Hz, 8Hz>, 6.06 (LH, d
, J=11Hz>, 6.88(1)1. s),
7.10-7.60 (15H, m>, 9.08
(IH, d.

J = 8 Hz) (2) A suspension of pentachloride in dichloromethane was heated at room temperature for 30
Stir for a minute. After cooling to -20 to -15°C, the mixture was charged with pyridine (0,091 nll) and 7-phenylacetamido-3-[(Z)-1-propenyl-3-
Cephem-4-carboxylic acid benzhydryl ester (0
, 4g) were added sequentially under the same conditions. The mixture was heated at the same temperature for 20 minutes.
Stir for 1 minute and then stir for 2 hours at -5°C. Then methanol CIIILII) is added to this at -20°C. The mixture is stirred at -5-0°C for 2 hours. The solvent was evaporated and the residue was triturated in water and dried over phosphorus pentoxide to give 7-amino-3-[(Z)-t-flobenyl]-3-cephemu 4-carboxylic acid benzhydryl ester hydrochloride. (1
, 2g).

NMR<DMSO-d 6. δ): 1.
46 (3)1. d, J=6Hz>, 3.33-
3.83 (2H, m), 5.15 (IH, d, 51 (z)), 5.29 (IH, d, J=5Hz),
5.61 (IH, dd, J=7Hz.

11Hz), 6.22 (IH, d, J=11Hz>
, 6.87 (IH, s).

7.07-7.53 (10H, m) Made by j11ヱ? -[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-4-
Carboxylic acid benzhydryl ester-1-oxyto (1
A 30% aqueous solution of trimedelamine (2fflD) is added to a solution of 0.0 g) in dichloromethane (100 mL) under water cooling. The mixture is stirred for 15 minutes, and the reaction product is separated, washed with isopropyl ether, and phosphorus pentoxide. to give 7-[2-(2-tetrahydropyranyl)oximino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-trimethylammoniomethyl-
3-cephem-4-carboxylic acid benzhydryl ester-1-oxyto iodide (syn isomer) (9; 9g
).

NMR (DMSO-da,S)' 1.27-2-
05 (8H1m), 2.90 (9H, s), 5.
23 (l)1. d), 5.97 (IH, dd.

J=5. 8Hz), 6.87 (LH,s),
7.10 (1)1. s).

7.10-7.70 (15)1. m), 8.8
0 (1)1. s), 9.00 (IH, d, J=
8Hz) 11 Fake 1 The following compound is obtained in the same manner as in 1-.

7-(2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamide]-3-pyrrolidin-1-ylmethyl-3-
Cephem-4-carboxylic acid benzhydryl ester-1
-Oxyto.

NMR (DMSO-ds, S)' 1.15-2.
10 (IOHlm), 2.70-3.90 (10H
, m), 5.20 (2H, m), 5.90 (I
H, dd.

J=5.8)1z), 6.90 (IH,s), 7
．． 0 (IH,s) Example 1 Phosphorous oxychloride (1
, 11111i) are added under water cooling. The mixture is stirred for 30 minutes under water cooling. 2-(2-tritylaminothiazol-4-yl)-2-(1-methyl-1-methoxyethoxyimino)acetic acid (syn isomer) (5,51 g) was added to the mixture.
) in tetrahydrofuran (samu) is added under water-cooling and stirring. The mixture is stirred at 3-5°C for 40 minutes to form an activated acid solution.

Separately, 7-amino-3-methylthio-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride (5
, 52 g) of monotrimethylsilylacetamide (Lo
The activated acid solution obtained above was added all at once to the ethyl acetate solution containing g) while cooling to -20°C, and the mixture was stirred at -20 to -10°C for 2 hours. to strengthen. Insoluble matters are removed by filtration, and the organic layer of the filtrate is separated. The aqueous layer is saturated with sodium chloride and extracted several times with ethyl acetate. The combined extracts were washed sequentially with water, an aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution.
Dry with 7 gn sulfate. The solvent was evaporated and the residue was subjected to column chromatography using silica gel (250 g) and eluted with a mixture of ethyl acetate, isopropropylene and ether (1:3). The fractions containing the target compound are combined and concentrated under reduced pressure. The residue was triturated in diisopropyl ether to give 7-[2-(2-tritylaminothiazol-4-yl)-2-(1-methyl-1-methoxyethoxyimino)acetamide]-3-methylthio-3
-cephem-4-carboxylic acid benzhydryl ester (
Syn isomer) (1.70 g) is obtained.

IR (Streak 9-L): 3300. 1780.
1670-1690°1525 cm-' NMR (DMSO-da, l;)'t, 40
(6H1s), 2-34 (3H,s), 3.13 (
3Ls), 3.80 (2H,brs).

5.18 (LH, d, J=5Hz>, 5.65 (
IH, dd, J = 5Hz.

8Hz>, 6.79 (IH,s), 6.84 (
IH,s).

7.07-7.63 (25H, m), 8.80 (
IH, br s).

9.48 (IH, d, J=8Hz) Example 2 The following compound is obtained in the same manner as in Example 1.

(L)7-[2-(2-tritylaminothiazole-4
-yl)-2-(2-tetrahydropyranyl)oxyiminoacetamide]-3-(3-methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).

IR (Sujiwor): 2900. 1770
．． 1650. 1580°1560 cm-' NMR (DMSO-ds, S)' L30-2-0
0 (8H9m), 3.57 (2H), 5.3 (I
H), 5.63 (IH), 6.87 (IH,s
).

7,H)-7,50(m), 8.10-9.10 (
5H, m) (2) 7- [2-(2-tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyl)oxyiminoacetamide]-3-(1-pyridiniomethyl)-3-cephem- 4-carboxylate (syn isomer).

IR (Stripe 9-L) i 2920. 2g50.
1785. 1610°1520 cm-1 NMR (DMSO-ds, S)' 9.13 (2H
1d, J:6Hz), 853(1)1. t, J=6)t
z), 8.2 (2H, t, J=6Hz), 7.1
0-7.60 (m), 6.80 (IH, s), ,
5.67 (LH), 5.3 (IH), 3.5
7 (2H), 1.2-2.0 (8H, m) (3
)? -[2-(2-tetrahydropyranyloxyimino)-2-(2-tritylaminothiazol-4-yl)
acetamido]-3-[(1-sulfomethyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).

(4>7-[2-(2-triple aminothiazole-4
-yl)-2-tetrahydropyranyloxyiminoacetamide]-3-[2-(3-pyridyl)vinyl]-3
-cephemu 4-carboxylic acid benzhydryl ester (
cis, trans mixture) (syn isomer).

IR (Sujoor): 2950. 2850.
1780. 1720 am-INMR (DMSO
-da, l; )'1.20-2.00' (8H
9m), 6.80 (IH, s), 7.00-7.6
5 (25H, m), 8.30-8.80 (4H, m
), 9.57 (IH, d, J=8Hz) (5)
7-[2-(2-tetrahydroviranyl ximino)
-2-(2-tritylaminothiazol-4-yl)acetamide]-3-[2-(3-pyridyl)hinylteo]-3-cephemu 4-carvone (strict benzhydryl ester).

NMR (DMSO-d6, S): 1.30-
1.85 (8H 劃＞, 5.30 (IH.d.J=5
Hz), 5.80 (IH.dd-d.J=5Hz
．． 8) tz).

6, 78 (IH.s), 6.92 (IH.s),
7.00-7.60 (10H.m), 7.63-L
83 (4H, m), 9.77 (IH, d.

J: 8 Hz> Inu wo Enyu (1) 7-[2-(2-)cutylaminothiazole-4
-yl)-2-(1-methyl-1-methoxyethoxyimino)acetamide]-3-methylthio-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (1.4 g) in dichloromethane (4.2111
Trifluoroacetic acid (8.4111Q) is added to a solution of the mixture of 1) and anisole (4.2111) under cooling, and the mixture is stirred at room temperature for 2 hours. Pour the reaction mixture dropwise into diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether, and dried. 7
-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methylthio-3-
Trifluoroacetate (syn isomer) of cephem-4-carboxylic acid (0.74 area) is obtained.

Nl'lR (DMSO-d6, ε):
2.31 (3H.s), 3.72 (2H.s)
.

br s), 5.12 (5Hz to IH.d.),
5.65 (18, dd.

J”5Hz and 8Hz), 6.79 (LH,s)
, 9.50 (LH.d.J=8Hz) (2) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-methylthio-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer') (0.74 g) is dissolved in an aqueous sodium hydrogen carbonate solution under cooling. 10 of the solution to ξ et al.
Adjust the pH to 4 with % hydrochloric acid and add HP-20 (20mQ
) column and elute with 10% isopropyl alcohol. The eluate was adjusted to -3,5 with IN hydrochloric acid and lyophilized to give 7-(2-(2-7minothiazole-4-
yl)-2-hydroxyiminoacetamide]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (0.47 g) is obtained.

ZR (striped reef): 3200-3300
．． 1740-17fiO.

152G-1660 cm-' NMR (DMSO-d6,ε): 2.2G (3
H,s), 3.33-3.87 (2H.m), 5.
0 (IH.d.J=5Hz>, 5.58 (IH.d.J=5Hz>)
dd.

J: 5Hz. 8Hz), 6.64 (18,s),
6.97-7, 20 (2H.brs), 9.30
(IH.d.J=8Hz>(3) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methylthio-3-cephem-4-carboxylic acid (synisomer 3N hydrochloric acid in n-propanol is added to a suspension of (0.30 g) in ethyl acetate under cooling. The mixture is stirred at room temperature for 1 hour and then diethyl ether is added to it. The precipitate is collected by filtration. Then, 7-[2-(2
-aminothiazol-4-yl)-2-hydroxyiminoacetamide 1,3-methylthio-3-cephem-4
-Carboxylic acid hydrochloride (syn isomer) (0.27 g) is obtained.

IR (Sujiwor): 3200-3400
．． 1750. 1640-1680.

1590 cm-1 NMR (DMSO-d6.δ): 2.35 (3
1,s), 3.77 (2H.

br s), 5, 17 (IH.d.J=5Hz)
, 5.65 (IH.dd.

J=5Hz. 8Hz), 6.93 (IH.s
), 9.67 (IH.d.

J=8Hz), 12.4 (IH.br s) Foam J
11 soil (1) 7-(4-bromoacetoacetamide)-3-methoxy-3-cephem-4-carvone 11 [p-nitrobenzyl ester (2.78 g) in dichloromethane (
30all) and acetic acid (H.IIIQ) mixture solution was added sodium nitrite (0.54g) in water (
5111) Add the solution dropwise at -20 to -15°C. Stir the mixture at -20°C for 15 minutes. Pour the reaction mixture into ice water. Separate the organic layer, wash with water and brine,
-(4-bromo-2-hydroxyiminoacetoacetamide)-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester is obtained.

A solution of 7-(4-bromo-2-hydroxyiminoacetoacetamide)-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester dissolved in N,N-dimethylacetamide (6,311111) Add thiourea (0.52 g). The solvent of the mixture was distilled off under reduced pressure at 35°C, and the residue obtained was diluted with tetrahydrofuran (z
zmt), ethyl acetate (501Q) and ice water (3
The solution was dissolved in a mixture of OfflQ) and then adjusted to pH 6.2 by adding IN aqueous sodium hydroxide solution.The 0m solution was washed twice with water and then with brine, and the solvent was distilled off. The residue was triturated in diisopropyl ether, filtered off, washed with diisopropyl ether, dried under vacuum, and ? −
Obtain [2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester (syn isomer) (2.26 g) .

IR (streak sole): 33G0. 17
60-1780. 1670.

1610 (to)-1 NMR (DMSO-d6, δ): 3.17-3.
90 (2B, m), 3.82 (3H.s), 5.
17 (IH.d.J=5Hz), 5.67 (IH.d.J=5Hz), 5.67 (IH.d.J=5Hz)
．． dd.

J=5Hz. 8Hz), 5.33 (2H.s),
6.71 (IH.s).

6, 97-7, 10 (2H, br s), 7.47
-8.33 (4H.m).

9, 30 (IH.d.J=8Hz) (2) 7-[2
-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester (syn'
A-former) (2. osg) in a hydrogen atmosphere! Tetrahydrofuran (44+1111), meta/- with 10% palladium-ff element (2.06 g) under atmospheric pressure
(1111)) and acetic acid (0.22 mm) at room temperature for 2 hours. After removing the catalyst by filtration, wash with methanol, combine the filtrate and the precipitate, and concentrate under reduced pressure. Add ethyl acetate to the residue, and adjust the mixture to -7 to 7.5 with 10% aqueous sodium hydrogen carbonate solution. After stirring, the separated aqueous layer was washed with diethyl ether and diluted with 10%
Hydrochloric acid to -3,5 all! do. HP the acidified water layer
-20 (40+111) column and 1
Elute with 0% isopropyl alcohol. Inject the eluate
The pH was adjusted to 3.0 with hydrochloric acid, and then lyophilized. −
[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer) (0.67 g) is obtained.

LR (Sujoor): 1755. 16
00-1660. 1520 cm-'NMR (
DMSO-ds,l; )' 3. 59 (2H.
br s-), 3-74(3)1. s), 5.11
(IH.d.J=5Hz), 5.54(1)1. d
d. J=5Hz. 8Hz), 6.71 (L
H. s).

7, 05 (2)1. br s), 9.32 (I
H. d. J=8Hz), 11.2(IH.br s
) (3) The following compound is obtained in the same manner as in the case of Higashiko 1 Nyu.

7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-methquin-3-
Cephem-4-carboxylic acid hydrochloride (syn isomer).

IR: 1760. 16
95. 1660. 1620-1640.

NMR (DMSO-da.l; )' 3. 58
(2H.ABq, J=18Hz.

22Hz), 3.76 (3H.s), 5.14
(IH.d.J=5Hz).

5, 49 (LH.dd.J: 5Hz. 8Hz),
6.94 (IH, s).

9, 59 (1) 1, d. C8Hz>, 12.3
(LH.br s) The following compound is obtained in the same manner as in 4-(l).

(1) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-ethylthio-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR (streak color): 32GG. 33
00. 1770. 1700. 1655.

1610 cm-1 NMR (DMSO-ds.l; ) 20. 93-
1. 33 (3H.m), 2.86 (2H.q.J=
7) Iz), 3.77 (2H.br s), 5.
23 (LH.d.J=51(z), 5.76 (IH
．． dd. J=5Hz. 8Hz).

6, 70 (IH.s), 6.84 (IH.s),
6.93-7.63 (12H.m), 9.38 (
IH. d. J=8Hz) (2)? -[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethynyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR (String confirmation): 32B0, 29
00. 1780. 1720. 1680.

1600 am-1 NMR (DMSO-d6.δ): 3.70 (2H,s
), 4.63 (LH,s), 5.23 (IH
, d, J=5Hz), 5.90(IH, dd, J=
5Hz, 8Hz), 6.63 (LH,s>
.

6.90 (IH,s), 7.0-7.67 (
15H, m), 9.47<LH, d, J=8)+2
) (3) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-vinylthio-3-cephem-4-carboxylic acid p-nitrobenyl ester (syn isomer).

IR '2950. L? ? 0.
1670. 161OCTII-INMR (DMSO
-d6. l; ): 3.63 and 3.95 (
21゜ABq, J=18Hz), 5.25 (LH
, d, J=5Hz), 5.45(LH, d, J=17
Hz), 5.56 <11(, d, J=11Hz
).

5.82 (LH, dd, J=5Hz, 8Hz)
, 6.70 (1)1. s).

7.67 and 8.21 (4H, ABq, J=8Hz
), 9.48 (LH, d, J = 8Hz> (4) 7-[2-(2-aminethiazol-4-yl)
-2-hydroxyiminoacetamide]-3-(2H-
1,2,3-triazol-4-yl)thio-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

NMR (DMSO-da, S): 5.23
<LH, d, J=5)1z), s, 82(LH,
dd, J=5Hz, 8Hz>, 6.65 (
IH,s).

6.92 (LH,s), 7.0-7.70
(25H, m), 8.18 (11, s), 9.
42 <1)1. d, J=8Hz) (5)? -[2-
(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethyl-3-cephem-4
-Carboxylic acid benzhydryl ester (syn isomer).

NMR (DI(So-d δ): 0.73-1.
23 (38, m), 1.60-6°1.93 (2)1. m>, 5.20 (IH, d,
J=5Hz>, 5.66-6.00 (11(, m>
, 6.70 (LH,s), 6.90 (IH,s
).

7.40 (12H, m>, 9.40 (IH, d,
J = 8 Hz) The following compound is obtained in the same manner as in the case of 衷本购 1 衷星贴 1nurev.

(1) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-ethynyl-3-cephem-4-carboxylic acid (syn isomer).

IR (Streak 3-L): 2920. 2350.
1760. 1610 cm-'North R (DMSO-
da, 8)' 3.99 (LHLs), 5.05
(IHld.

J=51(z), 5.65 <LH, dd, J=5H
z, 8Hz), 6.61 (IH, s), 7.10
(2H,s), 9.39 (IH,d, 8Hz>
(2) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-vinylthio-3-cephem-4-carboxylic acid (syn isomer).

IR (Streak 9-L): 2960. 1760.
1650. 1520 cm-'NMR (D1'l
5O-dS): 3.56 and 3.90 (
28゜ABqJ=18Hz＞, 5.20 (IH, d
,,c5Hz), 5.43(IH,d,J=17H2
), 5.50 (LH, d, J=11H2).

5.76 (IH, dd, J=5Hz, 8Hz),
6.70 (IH,s).

9.45 (IH, d, J = 8Hz) (3) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-(2H-
1,2,3-triazol-4-yl)thio-3-cephem-4-carvone # (syn isomer).

IR (Streak 1-L): 2920. 2850.
1750. 1600 cm-1HMR (DMSO
-9, 8): 5.01 (IH, d, J=8H
z), 5.60 (LH, dd, J=5Hz, 8Hz
), 6.62 (LH,s), 7.06(2H,s
), 7.94 (LH,s), 9.33 (LH,
d, J=8Hz) (4) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-ether-3-cephem-4-carboxylic acid (syn isomer).

IRCZ Sujiru): 2900. 1750.
1510 cm-1HMR (DMSO-d S
): 0.80-1.20 (3H, m>, L95
-6゛2.40 (2H, m>, 3.45 (2H, s),
5.05 (1) t, d.

5Hz), 5.52-5.78 (IH, n+),
6.63 (L)l,s).

7.05 (2H, s), 9.31 (IH, dJ:
8Hz) Example 7? -[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-ethylthio-3
-cephem-4-carboxylic acid benzhydryl ester (
syn isomer) (2,6 g) of dichloromethane C7,
Trifluoroacetic acid (52mM) is added to the suspension in a mixture of 8mQ) and anisole (2,s+nc) under water cooling. After stirring for 2 hours at 15° C., the reaction mixture is added dropwise to diisopropyl ether. The precipitate formed is collected by filtration and dissolved in a mixture of tetrahydrofuran and ethyl acetate. Add an aqueous sodium hydrogen carbonate solution to this to adjust the pH to 7.5. The aqueous layer is separated, adjusted to pH 2.5 with 10% hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-ethylthio-3-cephem-4-carboxylic acid (syn isomer) (1
, 7g).

IR (Snoyol); 1755. 1680.
1650. 1590°1520 c+n-' NMR (DMSO-d6.δ): 114 (3H,
t, J=7Hz), 2.77(2H,q, J=7Hz
>, 3.33 (2H, m), 5. Ll (IH,
d.

J=5Hz>, 5.63 (IH, dd, J=5Hz
, 8Hz), 6.65(LH,s), 7.07
(2H, br s), 9.37 (IH, d.

J=8Hz>, 11.40 (IH, br s) M
B, 4-lactamic (1) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-ethylthio-3-cephem-4-carlibon (syn isomer) (
0.5 g) of N,N-dimethylformamide (2011
Add cesium carbonate (0.19g) to the solution (11”),
The mixture is stirred at 25°C for 20 minutes. Pivaloyloxymethyl iodide (0.56g) is added dropwise to the reaction mixture at 0-3°C. After stirring at the same temperature for 40 minutes, the reaction mixture was poured into ethyl acetate (100 mQ) and insoluble materials were filtered off. The filtrate is washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The organic solvent was distilled off under reduced pressure and the residue was triturated in diethyl ether. −[2−
(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer) (0.56 g) is obtained.

IR (Streak 1-L): 3300. 1750-
1780. 1660°1610 cm-1 NMR (DMSO-da, S)' 1.0-1.4
5 (11H, m>, 2.90 (3H, ABq, J=
7Hz, 14Hz>, 3.78 (21,br
s).

5.21 <IH, d, J=5Hz), 5.57
-5.97 (3H, m).

6.69 (IH, s), 7.06 (2H, br
s), 9.41 (IH.

d, J=8Hz), 11.27 (IH,5)(2
)7-[2-(2-aminothiazol-4-yl)-2
-Hydroxyiminoacetamide]-3-ethylthio-
3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer) (0,5 g) in ethyl acetate (5
Isopropyl alcohol (0.27 ml) containing hydrogen chloride (0.05 g) is added to the solution under water cooling. Add diethyl ether to the reaction mixture and stir the mixture for 30 minutes under the same conditions. The precipitate was filtered, washed with diethyl ether, dried in a pentoxide groove, and ? −[2−
(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-ethylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (syn isomer) (0.32 g) obtain.

IR (Suji 5-IL)' 1770. 1?40
．． 1660. 1620゜1520 C1C11l-1N (DMSO-dS)' 0.90-1
．． 37 (12)1. m), 2.906° (2H, ABq, J=6Hz, 14Hz), 3.7
7 (2H, br s).

5.23 (1)1. dJ=5Hz), 5.50-5
．． 95 (3H, m).

6.91 (LH, s), 9.67 (IH, d, J
=8Hz>, 12.38 (IH, br s)
-yl)thiomethyl-3-cephem-4-carboxylic acid (
A solution of thiourea (0.6 g) in N,N-dimethylacetamide (5,3111 Jl), thiourea (0.1
4g) at 5°C. After stirring the mixture at room temperature for 1 hour,
Water (301111') and ethyl acetate (30
1fi11') is added at the first step, and an aqueous sodium bicarbonate solution is added thereto to adjust the pH to 6-7. The aqueous layer was concentrated under reduced pressure, and then the pH was adjusted to 4 with IN hydrochloric acid.
Adjust to 5. The solution was passed through an IP-20 column and eluted with a 10% aqueous isopropyl alcohol solution.

Fractions containing the target compound were collected, concentrated under reduced pressure, and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-
2-Hydroxyiminoacetamide]-3-(2H-1
,2,3-triazol-4-yl)thiomethyl-3-
Cephem-4-carboxylic acid (syn isomer) (0,24
g) is obtained.

IR (striped tool): 2920. 1760.
1600 cm-1 HMR (DMSO-ds, 8
)' 5-02 (IH, d, J=5Hz), 5.
58 (IH, dd, J: 5Hz, 1IHz), 6.
60 (IH, s), 7.05 (2H, s), 7.
63 (IH, s), 9.35 (IH, d, J=8
Hz) The following compound is obtained in the same manner as in JJL4U.

7-(2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-(1,2,3-
Sodium thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer).

IR (Streak 1-L): 2900. 1760.
1660. 1600°1520 CIClTl -1N (DMSO-d6.δ'): 4.41 (
2H,s), 4.98 (2)1゜d, J=5Hz)
, 5.57 (IH, dd, J=5Hz, 8H
z).

5.60 (IH, s), 7.06 (2H, s)
, 8.95 (IH,s).

9.32 (LH, d, 8Hz> Tue JL [L! i The following compound is obtained in the same manner as in Example 4-(2).

<1)? -[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamide]-3-(2H-
1,2,3-triazol-4-yl)thiomethyl-3
-Cephem-4-carboxylic acid (syn isomer).

IR (striped seal): 2920. 1760.
1600 on-1(2)7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1,2,3-deadiazol-5-yl)thiomethyl-3-cephem Sodium -4-carboxylate (syn isomer).

IR (Streak 1-L): 2900. 1760.
1660. 1600°1520■-1 The following compound is obtained in the same manner as in the procedure for 1 eye 1 deaf A.

(1) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer).

IR (X stitching rule): 1755. 1660-
1600. 1520 an-'(2)7-[2-(
2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methylthio-3-cephem-
4-carboxylic acid (syn isomer).

IR: 3300-3200.
1760-1740°1660-1520 am-' (3) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-ethyl-
3-cephem-4-carboxylic acid (syn isomer).

IR (striped seal): 2900. 1750.
1510 am-1 (4)? -[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethylthio-3-cephem-4-carboxylic acid (syn isomer).

IR (line 9-l): 17+55. 1680
．． 1650. 1590° 15206 m-' (5) 7-[2-(2-'aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinylthio-3-cephem-4-carboxylic acid (syn isomer).

IR (Stripe 1-L) = 2960. 1760.
1650. 1520 c+n-'(6)7-[2
-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethynyl-3-cephem-4-carboxylic acid (syn isomer).

IR<Z dim-4): 2920. 2350.
1760. 1610 an-1(7)7-[2-(
2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-(2)(-1,2,3-)lyazol-4-yl)thio-3-cephem-4-carboxylic acid (synisomer body).

IR (streak*-x): 2920. 2850.
1750. 1600 cm-1(8)7-[2-
(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethyl-3-cephem-4
-Carboxylic acid benzhydryl ester (syn isomer).

NMR (DMSO-da, 8)'o, 73-1
．． 23 (3H9m), 1.60-1.93 (2H,
m), 5.20 (LH, d, J=5Hz), 5.
66-6.00 (LH, m>, 6.70 (LH,
s), 6.90 (IH, s).

7.40 (12H, m), 9.40 (IH, dJ
=8Hz>(9)? -[2-(2-aminothiazole-
4-yl)-2-hydroxyiminoacetamide]-3
-nibruthio-3-setuemu 4-carboxylic acid benzhydryl ester (syn isomer).

IR (Suji Meal): 3200. 3300.
1770. 1700. 1655°1610 am
-1 (10) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-ethynyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR (z di*-r): 3280. 2900.
1780. 1720. 1680°1600 cm
-1 (11)7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-(2H
-1,2,3-triazol-4-yl)thio-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

NMR (DMSO-da, δ): 5.23 (IH
, d, J-5Hz), 5.82 (IH, dd, J:5
Hz, 8Hz), 6.65 (IH,s), 6.
92 (LH, s), 7.0-7.70 (25H, m
), 8.18 (LH,s), -9,42(LH,
d, J = 8 Hz) (12) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-vinylthio-3-cephem-4-carboxylic acid p-nitrobenzyl ester ( syn isomer).

IR(S;*-J: 2950. 1770.
1670. 1610 cm-1 (13)? -[:2
-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-ethylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (
syn isomer).

IR (striped seal): 3300. 1780-
1750. 1660°1610 an-' 2m (*13 1-membered) The following compound is obtained in the same manner as in 2U.

(1)? -[:2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

NMR(oMso-da, l;)'o, 73
-1-23 (3H1m), 1.60-1.93 (2
Lm>, 5.20 (IH, d, J=5Hz), 5
．． 66-6.00 (LH, m), 6.70 (LH
,s), 6.90 (IH,s).

7.40 (12H, m), 9.40 (IH, d,
JJHz) (2) 7-[:2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-
3-ethylthio-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR (Streak 3-L): 3200. 3300.
1770. 1700. 1655°1610 cm
-1 (3)7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-ethynyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR (Streak Rule): 32g0.2900
．． 1780. 1720. 1680゜tsoo■-
1 (4) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-(2H-
1,2,3-triazol-4-yl)thio-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

NMR (DMSO-da, δ): 5.23 (IH
, d, J: 5Hz), 5.82 (IH, dd, J: 5
Hz, 8Hz>, 6.65 (LH,s), 6.
92 (IH, s), 7.0-7.70 (25H, m
), 8.18 (LH,s).

9.42 (IH, d, J = 8Hz> (5) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester (syn isomer).

IR (Streak 1-L): 3300. 1780-
1760. 1670°1610 cm-1 (6)7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-vinylthio-3-cephemu 4-carboxylic acid p-nitrobenzyl ester (syn isomer).

IR (Sujimeal): 2950. 1770.
1670. 1610 cm-'(7)7-[2-
(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-[(Z)-1-propenyl-3-cephem-4-carboxylic acid benzhydryl ester isomer).

IR (striped seal): 3300. 177
5. 1720. 1670.

1615 cm-1 Example 14 The following compound is obtained in the same manner as in 7-.

- (1) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-ethyl-3-cephem-4-carboxylic acid (syn isomer).

IR (Suji a-L)' 2900, 17
50, 1510 CTn-'(2)? -[2-(
2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-vinylthio-3-cephem-
4-carboxylic acid (syn isomer).

IR (X-JL): 2960, 1
760. 1650, 1520 can-1 (
3) 7-[2-(2-aminothiazol-4-yl)-
2-Hydroxyiminoacetamidoco-3-ethynyl-
3-Cephem-4-carboxylic acid (syn isomer).

IR (line i-+L): 2920. 2
350, 1760. 1610 cm-1 (4
>7-[2-(2-aminothiazol-4-yl)-2
-hydroxyiminoacetamide]-3-(2H-1.
2.3-triazol-4-yl)thio-3-cephem-4-carboxylic acid (syn isomer).

IR (X Shiro-IL): 2920, 2
850. 1750. 1600 cm-1 (5
)7-[2-(2-aminothiazol-4-yl)-2
-hydroxyiminoacetamide]-3-(2H-1.
2.3-triazol-4-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR (Xjia-4): 2920. 17
60. 1600 am-'(6)7-[2-(2
-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(12.3-thiadiazole-
Sodium 5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer).

IR (Streak 1-L): 2900. 17
60, 1660. 16001520 an-' (7) 7-[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamide]-3-[(Z)
-1-propenylco-3-cephemu-4-carboxylic acid (
syn isomer).

IR (striped seal): 1760-1780
．． 1630. 1660 cm-1HMR (
DMSO-ds. S)' 1-63 (3H, d
, J=6Hz), 2.73-4, 13 (2H.m)
, 5.18 (2H, d, J=5Hz>, 5
．． 4-5, 83 (LH.m>, 5.67 (18
, d-d. , C5Hz), 6.12 (IH.d.J
=11Hz), 6.73 (IH.s), 9.
5 (IH.d.

J=8Hz), 11.83-11.97 (IH.m)
(8)? -[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamide]-3-[2-(
3-pyridyl)vinyl-3-cephem-4-carboxylic acid (cis-trans mixture) (syn isomer).

IR (Streak 1-L): 2950. 28
60. 1760. 1600 cm-'NMR
(DMSO-da.8)' 5.10 (IH,
d, J=5Hz), 5, 68 (LH, dd.J=5.
8Hz), 6.64 (IH.s), 7.20-7
, 42 (IH.m), 7.75 (IH.d),
8.34 (IH, d).

8, 52 (IH.s), 9.39 (LH, d.,
T=8Hz>(9)7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-
3-[1-Sulfomethyl-IH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).

LR(Z;1-A)' 2900. 1760.
1620 ClTl-1N MR (DMSQ-d
a, f; ) ' 3-54 (2H, A Bq
, J: 18 Hz >.

4.30 (2H, ABq, J=13Hz>, 5.7
2 (LH, dd, J=5°8Hz), 6.64 (
LH, s), 9.39 (LH, d, J=8Hz) The following compound is obtained in the same manner as in Example 4-(2).

(1) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroquiniminoacetamitoco-3-ethylthio-3-cephem-4-carboxylic acid (syn isomer).

IR (Sugitar): 1755. 1680.
1650. 1590°1520 cm-1 (2) 7-[2-(2-aminothiazol-4-yl)
-2-hydroquiniminoacetamitoco-3-[(Z)
-t-propenyl]-3-cephemu-4-carboxylic acid (
syn isomer).

ZR<Sugitar): 1760-1780.
1630. 1660 crn-1(3)7-[2-
(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-[2-(3τpyridyl)vinyl]-3-cephemu 4-carboxylic acid (cis-trans mixture) (syn isomer).

LR (Suji i4)' 2950. 2860.
1760. 1600 cm-1 (4>7-42-(
2-aminothiazol-4-yl)-2-hydroquiniminoacetamitoco-a-[(1-sulfomethyl-IH
-tetrazol-5-yl) theometelco-3-cephemu-4-carboxylic acid (syn isomer).

IR (Streak 3-L): 2900. 1760.
1620 crn-1 husband birthday? -[2-(2-Tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyloxyimino)acetamitoco-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (20
, Og) in methanol (20 ml) at 0°C is added trifluoroacetic acid (60 ml). After stirring at room temperature for 1.5 hours, the reaction mixture was added dropwise to diisopropyl ether (3QQml) under cooling. The precipitate is collected by filtration and washed with ether to obtain a powder. Powdered water (3
00+1111) and ethyl acetate (150mQ)
The suspension in the mixture was adjusted to pH with saturated aqueous sodium bicarbonate solution.
Adjust to 5. Insoluble matter was removed by filtration. The aqueous layer was separated and
Pi (2,8 to U!4t) with N-hydrochloric acid.
) was subjected to column chromatography using 5%
Elute with isopropyl alcohol aqueous solution. The eluate was lyophilized to give 7-[2-(2-aminothiazole-4-
yl)-2-hydroquiniminoacetamitoco-3-(
1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (3.20 g) is obtained.

IR (Sugitar): 2900. 1760.
1600. 1520 Low INMR (D20.δ
)' 3.42 (2H, ABq, J=18Hz),
5.28 (IH, d, J=5Hz>, 5.45 (
2H, ABq, J44Hz).

5.87 (IH, d, J=5Hz>, 6.92 (
LH, s), 8.06 (2H, t, J=6Hz),
8.55 (IH, t, J=7Hz), 8.92 (2
H, d, J=6Hz) Example 17 7-[2-(2-)cutylaminothiazol-4-yl)-2-hydroxyiminoacetamide] -3-(:
A solution of 1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (z, sog) in 50% aqueous formic acid (12, smQ) is stirred at 60'C for 20 minutes. A mixture of water and ethyl acetate is added to this mixture, and the pH is adjusted to 4.0 with a saturated aqueous solution of sodium bicarbonate.

Separate and concentrate the aqueous layer, and convert the residue into 1Diaion HP-2
Pass through a 0J column and elute with 10% isopropyl alcohol aqueous solution. The eluate was concentrated and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2
-Hydroquiniminoacetamitoco-3-(1-pyridiniomethyl)-3-t-femu-4-carboxylate (syn isomer) (0.13 g) is obtained.

IR (Streak:+-R): 2900. 1770.
1610. 1520 Cfn-INMR (DMS
O-d6. l; ) ' 3.37 (2H,ABq
j=18Hz.

27Hz), 5.24 (IH, d, J=5Hz),
5.4L <2H, d-d.

J=9Hz, 13Hz>, 7.78 (IH, d-
d,, C3Hz, 8Hz).

6.90 (IH,s), 7.90-8.70 (5
H, m>, 8.91 (tu, d, J=suz) Rice m (M 18 The following compound is obtained in the same manner as in Inuzuki Kodan.

7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-(3-methyl-
1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).

IR (Sujoor): 2920. 2850.
1760. 1600°1520 cm-' NMR (D20.S): 2.53 (3H,s
), 3.40 (2H, ABq.

J=18Hz), 5.26 (IH, d, J=5)1
z), 5.40 (2H.

ABq, J=13Hz), 5.85 (IH, d, J
=5Hz>, 6.80 (IH, s), 7.90 (
IH,t>, 8.35 (LH,d).

8.73 (2H,) and curtain 5U The following compound is obtained in the same manner as in K11.

7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-[(Z)-1-
propenyl]-3-cephemu 4-carboxylic acid benzhydryl ester (syn isomer).

IR (Suji meeting): 3300. 1775.
1720. 1670°1615 am-1 NMR (DMSO-ds, l; )' 1.40 (
3H1d, J=6Hz), 3.23-3.87 (2
H, m), 5.24 (IH, d, J=5Hz),
5.48 (IH, dd, J=7)1z, IIH2)
, 6.06 (IH, d.

J=11Hz), 6.66 (IH,s), 6.8
6 (IH, s).

6.95-7.73 (IOH, m), 9.40 (
IH, d, J = 8Hz>.

11.26 (IH, s) Tue] To a mixture of dimethylformamide (0.88 g) and tetrahydrofuran (2.66 g) was added phosphorus oxychloride (1
, 93 g) at 0°C. After stirring for 30 minutes, add 2
-(2-tritylaminodeazol-4-yl)-2-
(1-methyl-1-methoxyethoxyimino)acetic acid (5
, 25 g) in tetrahydrofuran (50111Q). The mixture is stirred at 0° C. for 1 hour to obtain an activated acid solution. Monotrimethylsilylacetamide (17g
) containing 7-amino-3-(1-pyridiniomethyl)-
The activated acid solution obtained above was added all at once to a solution of 3-cephem-4-carboxylate (3,49 g) in tetrahydrofuran (1201111) at 30°C, and the mixture was stirred at -30 to -15°C for 2 hours. The 0 reaction mixture is added to a mixture of water (1201Q') and ethyl acetate (120ml). The organic layer is separated and washed with water and brine, then dried over magnesium sulfate. The solvent was distilled off, the residue was ground with isopropyl ether and collected by filtration.
Vacuum drying to give 7-[2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1-pyridiniomethyl)-3-cephem-4
-carboxylic acid (syn isomer) (2,50 customers) is obtained.

The following compound was obtained in the same manner as in ``Hiren Koshi'' Azumaho A: Yu U and Trabao ±1.

(1) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamidoco-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).

IR (Z Dim-R): 2900. 1770.
1610. 1520 Cm″″1(2)? −[2
-(2-aminodeazol-4-yl)-2-hydroxyiminoacetamide]-3-(3-methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).

IR (Streak Indication): 2920. 2850.
1760. 160G.

1520 cm-1 (3) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide co-3-[(Z)
-1-propenyl-3-cephem-4-carboxylic acid (
syn isomer).

IR (Sujimeal): 1760-1780. 1
630. 1660 cm-1(4)7-[2-(2
-aminodeazol-4-yl)-2-hydroxyiminoacetamide]-3-[2-(3-pyridyl)vinylco-3-cephemu-4-carboxylic acid (cis-trans mixture) (syn isomer).

IR (Streak 9-L): 2950. 2860.
1760. 1600 cm-1(5)7-[2-
(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-[(1-sulfomethyl-I
H-tetrazol-5-yl)thiomethyl]-3-cephemu 4-carboxylic acid (syn isomer).

IR (Suji”) ' 2900. 1760. 1
620 cm-'X Nosebleed η W Retsu! The following compound is obtained in the same manner as -.

(t>7-[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamide]-3-[2-(
3-Pyridyl)vinylthioko 3-cephemu 4-carboxylic acid (syn isomer) (cis isomer).

IR (Streak 1-L): 3250. 1760.
1600 crn-1tnlR (DMSO-d6.
δ): 3.88 (211, ABq, J=18Hz
>.

5.22 (LH, d, J: 5Hz), 5.82 <
LH, dd, J: 5Hz.

8Hz), 6.63 (LH, d, J-12Hz),
6.90 (IH, d.

J=12Hz), 6.70 (IH,s), 7.3
5-7.55 (LH, +n).

7.75-8.00 (IH, m), 8.49 (1
B, d), 8.66 (LH, s), 9.49 (I
H, d, J = 8 Hz) (2) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1-pyridacinio)methyl-3-cephem-4-carboxy rate (syn isomer).

NMR (DMSO-d6.8): 3.40-4.
20 (2H), 5.15 (IH, d, J: 5Hz)
, 5.70-5.90 (3H), 6.65 (LH
,s), 7.10 (2H,br s), 8.60
-8.80 (21, m), 9.43 (IH, d, J
:8Hz), 9.50-9.70(LH, a+),
9.90-10. IQ (ILm), 11.33 (
11゜brs) 叉J い かえ 凰 (M4-(The following compound is obtained in the same manner as in the phantom.

(1) 7-[2-(2-tritylaminothiazole-4
-yl)-2-(2-tetrahydropyranyl)oxyiminoacetamide]-3-(3-methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).

IR (Streak 9-L): 2900. 1770.
1650. 158G.

1560 cm-' NMR (DMSO-d6.δ>' 1.30-2.0
0 (8H, m), 3.57 (2H), 5.3 (
IH), 5.63 (IH), 6.87 (IH,
s).

7.10-7.50 (m), 8.10-9.10
(5H,a+)(2)7-[2-(2-tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyl)oxyiminoacetamide]-3-(1-pyridiniomethyl)~3-cephemu 4-carboxylate (
syn isomer).

IR (Sujimeal): 2920. 2850.
17g5. 1610°NMR (DMSO-d6.ε
) 79.13 (2H, d, J=6Hz>, 8.5
3 (IH, t, , C1z), 8.2 (2H, t,
J=6Hz), 7.10-7.60 (m),
6.80 (LH,s), 5.67 (IH).

5.3 (IH), 3.57 (2H), 1.
2-2.0 (8H, m) (3) 7-[2-(2-tetrahydropyranyloxyimino)-2-(2-)rithylaminodeazol-4-yl)acetamide]-3-[
(1-sulfomethyl-IH-tetrazol-5-yl)
thiomethyl]-3-cephemu-4-carboxylic acid (syn isomer).

Dongyo Solitary Fire Cover! The following compound was obtained in the same manner as Anu U and back cover ①.

(1) 7-[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamide]-3-[2-(
3-pyridyl)vinylthio]-3-cephemu 4-carboxylic acid (syn isomer) (cis isomer).

IR (XG4): 3250. 1760.
1600 am-1(2)7-[2-(2-aminothiazol-4-yl)-2-hydroquiniminoacetamide]-3-(1-pyridacinio)methyl-3-cephem-4-carboxylate ( syn isomer).

NMR (DMSO-d6.f; ): 3.40-
4.20 (2H), 5.15 (1) 1. d, J=5
Hz>, 5.70-5.90 (3H), 6.65
(L)1. s), 7.10 <2H, br s
), 8.60-8.80 (2H, m), 9.43
(IH, d, J=8Hz), 9.50-9.70<1
)1. m), 9.9O-IQ, 10 (IH, m>,
11.33 (lH, br 9) Example 25 The following compound is obtained in the same manner as in Example 1.

(1) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroquine iminoacetamide]-3-methquine-3-cephem-4-carboxylic acid (non-isomer).

IR (Snoyor)' 1755. 1660-
1600. 1520 cm-1(2)7-[2-(
2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methylthio-3-cephem-
4-carboxylic acid (syn isomer).

IR (Stripe 1-A)' 3300-3200.
1760-1740. 1660-1520 cm-1 (3) 7-[2-(2-aminothiazol-4-yl)
-2-hydroquiniminoacetamitoco-3-ethyl-
3-cephem-4-carboxylic acid (syn isomer).

IR (X Dial): 2900. 1750.
1510 cm-' (4) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethelthio-3-cephem-4-carboxylic acid (syn isomer).

IR: 1755. 1680.
1650. 1590°1520 cm-1 (5) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-vinylthio-3-cephem-4-carboxylic acid (syn isomer).

IR (Sujimeal)' 2960. 1760.
1650. 1520 cm-1(6)7-[2-
(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-ethynyl-3-cephem-
4-carboxylic acid (syn isomer).

IR (Suf3-ru): 2920. 2350.
1760. 1610 mark-1(7)7-[2-(
2-aminodeazol-4-yl)-2-hydroxyiminoacetamide]-3-(2H-1,2,3-triazol-4-yl)1,000-3-cephemu-4-carboxylic acid (syn isomer).

IR (Streak 94): 2920. 2850.
1750. 1600 am-'(8)7-[2-(
2-Aminothiazol-4-yl)-2-hydroquiniminoacetamitoco-3-ethyl-3-cephem-4-
Carribonic acid benzhydryl ester (syn isomer).

NMR (DMSO-ds, S)'o, 73
-1.23 (3H9m), t, 60-1.93
(2)1. m), 5.20 (IH, d, J: 5H
z), 5.66-6.00 (IH, m), 6.7
0 (lH,s>, 6.90 (1) 1.s).

7.40 (12H, m), 9.40 (IH, d,
, C3Hz) (9) 7-[2-(2-aminodeazol-4-yl)-2-hydroquiniminoacetamitoco-
3-Ethylthio-3-cephem-4-carboxylic acid benzhydryl ester (Syn M type).

IR (Suji-4): 3200. 3300.
1770. 1700. 1655°1610 cm-
1 (10) 7-[2-(2-aminothiazol-4-yl)-2-hydroquiniminoacetamitoco-3-ethynyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR (Z-AR): 3280. 2900.
1780. 1720. 1680° 1600 Rho 1 (11) 7-[2-(2-aminothiazole-4--(
)-2-hydroxyiminoacetamide]-3-(2
H-1,2,3-triazol-4-yl)thio-3-
Cephem-4-carboxylic acid benzhydryl ester (syn isomer).

NMR (DMSO-d6.δ): 5.23 (IH
, d, J=5Hz), 5.82(IH, dd, J=5
Hz, 8Hz), 6.65 (LH,s), 6.
92 (LH, s), 7.0-7.70 (25H, m
), 8.18 (IH, s).

9.42 (LH, d, 8 Hz) (12>7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinylthio-3-cephem-4-carboxylic acid p -Nitrobenzyl ester (syn M type).

IR (Sujimeal): 2950. 1770.
1670. 1610 cm-1(13)7-[2-
(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-ethylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer).

IR (Stripe 9-L) 4 3300. 1780-1
750. 1660°1610 ell+' (14) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester isomers).

IR (Stripe 1-R): 3300. 1780-
1760. 1670°1610 c7n-1 (15) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-(2H
-1,2,3-1-riazol-4-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR (striped seal): 2920. 1760.
1600 cm-1(16)7-C2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-(1,2゜3-thiadiazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid sodium (syn isomer).

IR (Streak 1-L): 2900. 1760.
1660. 1600°1520 cm-1 <17)? -[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-[(Z
)-1-propenylco-3-cephemu-4-carboxylic acid (syn isomer).

IR (striped seal): 1760-1780.
1630. 1660 cm-1 (1g) 7-[2-
(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-[2-(3-pyridyl)vinyl-3-cephem-4-carboxylic acid (cis-trans mixture) (syn isomer).

IR (suji, +-ru)' 2950. 2g60
．． 1760. 1600 cm-'(19)7-
[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-[(1-sulfomethyl-IH-tetrazol-5-yl)thiomethyl]-3
- Cephemu 4-carboxylic acid (syn isomer).

IR (Streak 9-L): 2900. 1760.
1620 cm-1(20)7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-[2-(3-pyridyl)vinylthio]
-3-cephemu-4-carboxylic acid (syn isomer) ('/
isomer).

IR(7a-ru>' 3250. 1760.
1600 cm-1 (21) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer ).

IR (Suji 5-4)' 2900. 1770.
1610. 1520 cm-1(22)7-[2
-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(3-methyl-1-pyridiniomethyl)-3-cephem-4,-carboxylate (syn isomer).

IR (Stripe 3'): 2920. 2850
．． 1760. 1600°1520 ClTl-1 (23) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1-
pyridacinio) methyl-3-cephem-4-carboxylate (syn isomer).

NMR (DMSO-d6.δ): 3.40-4.2
0 (2) 1), 5.15 (IH, d, J: 5) 1z
), 5.70-5.90 (3H), 6.65 (I
H, s), 7.10 (2H, br s), 8.6
0-8.80 (2H, m), 9.43 (IH, d,
J=8Hz), 9.50-9.70(LH, m),
9.90-10.10 (IH, m), 11.33 (
IH,br 5) (24)7-[2-(2-aminothiazol-4-yl)-2-hydroxy(minoacetamido]-3-[(Z
)-1-putobenyl-3-cephem-4-carboxylic acid benzhydryl esterone isomer).

IR (Streak 1-L): 3300. 1775.
1720. 1670° 1615 mark'''1 Example 26 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamide]-3-trimethylammoniomethyl-3-
Cephem-4-carboxylic acid benzhydryl ester-1
-Oxyto iodide (syn isomer) (9.9g) in dimethylformamide (50ai) #liquid i:, EjJC
Add phosphorus (3.2 g) at -20°C. The mixture was stirred at the same temperature for half an hour, then poured into a mixture of methylene chloride and water, the organic layer was separated and washed with water and brine;
The solvent is removed under reduced pressure. The residue was dissolved in 90% tetrahydrofuran aqueous solution and anion exchange resin 'IRA-4
00.

(CF3C00-type) (trademark, manufactured by Rohm and Haas) column and eluted with 90% aqueous tetrahydrofuran. The product-containing eluate was concentrated and the resulting precipitate was collected by filtration and dried in a pentoxide groove to give 7-[2-(
2-tetrahydropyranyl)oxyimino-2-(tritylaminothiazol-4-yl)acetamide]-3
-Trimethylammoniomesole-3-cephem-4-carboxylic acid benzhydryl ester trifluoroacetate (syn isomer) (11,72 g) is obtained.

NMR (DI(So-9, δ): 1.10-
2.25 (m), 5.40 (IH.

d, J=5Hz>, 5.90 (LH, dd, J=5
．． 8Hz), 6.80 (18,s), 7.10 (
LH, s), 9.86 (IH, d, J=8Hz)K
The following compound is obtained in the same manner as in the straight p.m.

7-[2-(2-tetrahydropyranyl)oxyimino-2-(tritylaminothiazol-4-yl)acetamido]-3-pyrrolidin-1-ylmethyl-hydryl ester (syn isomer).

Tori Gosho 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamitoco-3-trimethylammoniomethyl-3-
Cephem-4-carboxylic benzhydryl ester trifluoroacetate (synisomer) (7.5 g) in 1 volume dichloromethane (22.5 ml) was mixed with anisole (7.511 LIl) and trifluoroacetic acid (
15+1111) under water cooling. After stirring for 4 hours at room temperature, pour the mixture into diisopropyl ether. The formed precipitate is collected by filtration, washed with diisopropyl ether, and dissolved in 5% aqueous sodium hydrogen carbonate solution. The aqueous solution was adjusted to p) 12.5 with IN hydrochloric acid, and nonionic adsorption m J
Subject to column chromatography using HP-20. The desired product was eluted with 5% isopropyl alcohol, the eluate was concentrated and lyophilized to give 7-
[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-trimethylammoniomethyl-3-cephem-4-carboxylate (syn isomer) (0.70 g) is obtained.

IR (Xjiv-4>: 3250.17
70. 1620 cm-'NMR (C20,l
; ) ;3. 09 (9)1. s), 3. 38.
3. 93 (2H.

ABq, C17Hz), 3.95. 4.70 (2
H. ABq.

J=12Hz), 5.33 (2H.d.J=5Hz
>, 5.84 (2H.d.

J=5Hz), 6.90 (IH, s) Jd1 average The following compound is obtained in the same manner as in Togoha Qian.

7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-pyrrolidine-1
-ylmethyl-3-cephem-4-carboxylic acid (syn isomer).

IR (suji snow rule): 3300, 17
70. 1620. 1530 cm-'NMR
(DMSO-d6.S) j 1.5G-2.1
0 (48), 2.75-3, 10 (4H), 3
．． 45 (2H.s), 3.41. 3.82 (2H
．． d, J=13Hz>, 5.95 (LH, d.J=
5Hz>, 5.58 (LH.dd-d.J=5.8H
z), 6.40 (IH,s), 9.20 (IH.
d, J=8Hz) l! 1±Yu, 1! The following compound is obtained in the same manner as in ``2'' U and Ink'' 1.

(1) 7-[2-(2-aminodeazol-4-yl)
-2-Hydroxyiminoacetamide]-3-trimethylammoniomethyl-3-cephem-4-carboxylate (syn isomer).

IR<Z9-JL): 3250. 1770.
1620 cm-'NMR(D20.S)'
3.09 (9H1s), 3.38, 3.93 (2H
0ABq, J=17Hz), 3.95. 4.70
(2H, ABQ.

J=12Hz>, 5.33 (2H, d, J=5)
1z), 5.84 (2H, d.

J: 5Hz>, 6.90 (IH, 5) (2) 7
-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-pyrrolidine-1-
ylmethyl-3-cephem-4-carboxylic acid (syn isomer).

IR (X Dial): 3300. 1770.
1620. 1530 0n-'NMR (DMSO-d
6. l; ): 1.50-2.10 (4H),
2.75-3.10 (48), 3.45 (2H
, s), 3.41.3.82 (2H, d, J=13H
z), 5.95 (IH, d, J=5Hz>, 5.
58 (IH, dd, J=5.8Hz), 6.40
(IH, s), 9.20 (LH, d, J=8Hz)

Claims (1)

[Claims] 1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is an amino group or a protected amino group,
R^2 is a carboxy group, COO^■ or a protected carboxy group, R^3 is a (C_3 to C_6) alkyl group,
(C_3 to C_6) alkenyl group, lower alkynyl group,
1,2,3-triazolylthiomethyl group, 1,2,3-
Thiadiazolylthiomethyl group, pyridiniomethyl group which may have an appropriate substituent, sulfo(lower)alkyltetrazolylthiomethyl group, pyridylvinyl group, pyridylvinylthio group, 1-pyridaziniomethyl group, tri(lower)alkylammoniomethyl group, pyrrolidinylmethyl group or formula: -A-Y (wherein A is -S- or -O-, Y is lower alkyl group, lower alkenyl group or heterocyclic group) R^4 means a hydrogen or hydroxy protecting group, respectively; however, when R^2 is COO^■, even if R^3 has an appropriate substituent. good pyridiniomethyl group, 1
- pyridaziniomethyl group or tri(lower)alkylammoniomethyl group] and salts thereof. 2) R^1 is an amino group, R^2 is a carboxy group or C
The compound according to claim 1), wherein OO^■ and R^4 are hydrogen. 3) R^3 is ethyl, 1-propenyl, ethynyl, 1,
2,3-triazol-4-ylthiomethyl, 1,2,
3-thiadiazol-5-ylthiomethyl, 1-pyridiniomethyl, 3-methyl-1-pyridiniomethyl, 1-
Sulfomethyl-1H-tetrazol-5-ylthiomethyl, 2-(3-pyridyl)vinyl, 2-(3-pyridyl)vinylthio, 1-pyridaziniomethyl, trimethylammonio, methoxy, methylthio, ethylthio, vinylthio, 1, Claim 2 which is 2,3-triazol-4-ylthio or pyrrolidin-1-ylmethyl
) Compounds described in section 2. 4) i) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^2 is a carboxy group, COO^■ or a protected carboxy group, R^3 is a (C_2-C_6) alkyl group, ( C_3 to C_6), alkenyl group, lower alkynyl group, 1,2,3-triazolylthiomethyl group, 1
, 2,3-thiadiazolylthiomethyl group, pyridiniomethyl group which may have an appropriate substituent, sulfo(lower)alkyltetrazolylthiomethyl group, pyridylvinyl group, pyridylvinylthio group, 1-pyrida diniomethyl group, tri(lower)alkylammoniomethyl group, pyrrolidinylmethyl group or formula: -A-Y (wherein A is -S- or -O-, Y is lower alkyl group, lower alkenyl group or a heterocyclic group) or a reactive derivative thereof in an amino group or a salt thereof, with the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R^1 is an amino group or a protected amino group,
(R^4 means hydrogen or hydroxy protecting group, respectively) or its reactive derivative or its salt at the carboxy group to react with the formula: ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein, (R^1, R^2, R^3 and R^4 each have the same meaning as before) or obtain a compound or its salt; ii) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula , R^1, R^3 and R^4 each have the same meaning as before, and R^2_a means a protected carboxy group) or a salt thereof in the elimination reaction of the carboxy protecting group. Attached, formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^3 and R^4 each have the same meaning as before, and R^2_b is a carboxy group or COO
^■ means) or its salt; iii) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2, R^3 and R^4 are respectively the previous and the same meaning, X means halogen) or its salt, and the compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^ has the same meaning as before). By reacting, the compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^3 and R^4 each have the same meaning as before) or its salt. iv) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2_b, R^3 and R^4 each have the same meaning as before) A compound represented by or a salt thereof is subjected to an esterification reaction, the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^3 and R^4 each have the same meaning as before, and R^2_c is the ester v) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2 and R^3 are Each has the same meaning as before, and R^4_a means a hydroxy protecting group) When the compound represented by or its salt is subjected to the elimination reaction of the hydroxy protecting group, the formula: ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2 and R^3 each have the same meaning as before) Or obtain the compound or its salt; vi) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Formula R^2, R^3, and R^4 have the same meanings as before, and R^1_a means a protected amino group) or a salt thereof is subjected to an amino-protecting group elimination reaction. To obtain the compound or its salt represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2, R^3 and R^4 each have the same meaning as before); vii) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 and R^4 each have the same meaning as before, R^2_d is a carboxy group or a protected carboxy group, R^3_a represents a pyridiniomethyl group, a tri(lower)alkylammoniomethyl group, a 1-pyridaziniomethyl group, and X_a represents an acid residue, each of which may have an appropriate substituent, or its When the salt is subjected to reduction, the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2_d, R^3_a, R^4 and X_a each have the same meaning as before). General formulas characterized by obtaining compounds that are: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2, R^3 and R^4 each have the same meaning as before, However, when R^2 is COO^■, R^3 is a pyridiniomethyl group which may have an appropriate substituent,
1-pyridaziniomethyl group or tri(lower)alkylammoniomethyl group] or a salt thereof. 5) An antibacterial agent containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.