JPS5989689A - 7-substituted-3-vinyl-3-cephem compound, its production and antimicrobial agent containing the same - Google Patents

Abstract

NEW MATERIAL:A syn isomer of a compound expressed by formula I [R<1> is (protected) amino; R<2> is (protected)carboxyl] and a salt thereof. EXAMPLE:7-[ 2-( 2-Amiothiazol-4-yl )-2-hydroxyiminoacetamido ]-3-vinyl-3-cephem- 4-carboxylic acid (syn isomer). USE:An antimicrobial agent against Gram-positive and Gram-negative bacteria, etc. useful particularly for oral administration. PROCESS:A compound expressed by formula II (X is halogen) or a salt thereof is reacted with a compound expressed by formula III usually in an inert solvent, e.g. ethyl acetate, to give the compound expressed by formula I . The compound expressed by formula II is a novel substance, and can be obtained by reacting a compound expressed by formula IV with a compound expressed by the formula X-CH2COCH2COOH to form a compound expressed by formula V, and reacting the resultant compound expressed by formula V with a nitrosating agent.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel 7-substituted-3-vinyl-3-cephem compounds and pharmaceutically acceptable salts thereof.

More specifically, the present invention discloses a novel i.7
f! The present invention relates to 1%-3-vinyl-3-cephem compounds and pharmaceutically acceptable salts thereof, methods for producing them, and antibacterial agents containing them.

That is, an object of the present invention is to develop antibacterial agents having high activity against various pathogenic bacteria, particularly novel 7 antibacterial agents useful for oral administration.
- Substituted-3-vinyl-3-cephem compounds and pharmaceutically acceptable salts thereof.

Another object of this invention is the novel 7-substituted-3-vinyl-3
- To provide a method for producing cephem compounds and salts thereof.

Yet another object of the present invention is the 7-substituted-3
An object of the present invention is to provide an antibacterial agent containing a vinyl-3-cephem compound and a pharmaceutically acceptable salt thereof.

The 7-substituted-3-vinyl-3-cephem compound of this invention is a new compound and is represented by the following general formula CI).

(In the formula, R1 is an ami 7 group or a protected ami 7 group, R
2 means a carboxy group or a protected carboxy group, respectively).

In this specification, "syn isomer" refers to the group 1 -OH It means a compound (I) having the steric structure shown below.

Suitable pharmaceutically acceptable salts of compound (I) are customary non-toxic salts, such as alkali metal salts such as IJcum salts, potassium salts, alkaline earth metal salts such as calcium salts, and potassium salts. , salts with inorganic bases such as ammonium salts, organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ehnolamine salts, triethanolamine salts, dicyclohexylamine salts, NIN'-dibenzylethylenediamine salts, etc. Inorganic acid addition salts such as salts with bases, such as hydrochlorides, hydrobromides, sulfates, phosphates, such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates. Organic acid addition salts such as organic carboxylic acid addition salts or organic sulfonic acid addition salts such as benzenesulfonate, p-toluenesulfonate; for example, salts with basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid. etc.

Compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be produced by the method shown in the reaction formula below.

0) Manufacturing method I ([1) or its salt (I) or its salt (2) Manufacturing method 2 Rλ (Ia) or its salt (Ib) or its salt (3) Manufacturing method 3 or its salt (4) Manufacturing method 4 (Ic ) or a salt thereof or a salt thereof 1 In the formula, R1 and R2 each have the same meaning as before, X is a halogen, 零 is a protected carboxy group, RA is a protected carboxy (lower) alkoxycarbonyl group, and the cursor is a carboxy group. (lower)alkoxycarbonyl group].

The raw material compound used in Production II Method 1 is new and can be produced, for example, by the following method.

Production method A A reactive derivative at the carboxyl group or a salt thereof, or a salt thereof (C) Production method B 2 or a reactive derivative at the amino group or a salt thereof l (6 or a salt thereof (where R2 and X are It has the same meaning as before, “C0O
The group RJ means a protected carboxy group).

Suitable examples and explanations of the various definitions used in this invention are discussed in detail below.

"Lower" means a group having 1 to 6 carbon atoms, unless otherwise specified.

"High-grade" means 7 to 20 carbon atoms, unless otherwise specified.
means a group having .

"Protected amino" groups include amine groups substituted with conventional amino protecting groups used in penicillin and cephalosporin compounds; examples of such amine protecting groups include the acyl groups described below. Groups, such as mono (or di or trip) phenyl (lower) alkyl, such as benzyl, benzhydryl, trityl, etc.! Al(lower)alkyl groups such as, for example, lower alkoxycarbonyl(lower)alkylene such as 1-methoxycarbonyl-1-propen-2-yl or its enamine-type tautomer, e.g. di(lower)alkylene such as dimethylaminomethylene, (lower) alkylaminomethylene and the like.

"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, imbutyryl, valeryl, invaleryl, piparoyl, hexanoyl, lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary Lower alkoxycarbonyl groups such as butoxycarbonyl, lower alkenoyl groups such as acryloyl, methacryloyl, tarotonoyl, etc. (03-
C7) - Saturated or unsaturated cyclic or acyclic aliphatic acyl groups such as cycloalkadicarbonyl groups, amidino groups and the like.

Examples of aromatic acyl groups include aroyl groups such as benzoyl, toluoyl, and xyloyl, benzenesulfonyl,
Examples include arenesulfonyl groups such as tosyl.

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

As an aliphatic acyl group substituted with an aromatic group,
Al(lower)alkanoyl groups such as phenyl(lower)alkanoyl groups such as phenylacetyl, phenylpropionyl, quenylhexanoyl, and phenyl(lower)alkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, etc. (
(lower) alkoxycarbonyl group, such as 7-enoxy (lower) such as phenoxyacetyl, phenoxypropionyl, etc.
Examples include alkanoyl groups.

As an aliphatic acyl group substituted with a heterocyclic group,
Examples include thenyl acetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thenylpropionyl, thiadiazolylpropionyl, and the like.

These acyl groups may further include lower alkyl groups such as methyl, engineered, propyl, isopropyl, butyl, pentyl, hexyl, halogens such as chlorine, bromine, iodine, fluorine, methoxy, ethoxy, propoxy, impropoxy, etc. , ti-alkoxy groups such as butoxy, pentyloxy, hexyloxy, lower alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, nitro groups, etc. Examples of the acyl group having such a substituent include taloloacetyl, bromoacetyl,
Mono (or di or tri) halo (lower) alkanoyl groups such as dichloroacetyl, trifluoroacetyl, etc., mono (or di or tri) halo (lower) alkanoyl groups such as thalolomethoxycarbonyl, dichloromethoxycarbonyl, 2,2.2-trichloroethoxycarbonyl, etc. Halo (lower) alkoxycarbonyl groups, such as nitro (or halo or lower alkoxy) phenyl (lower) alkoxycarbonyl groups such as nitrobenzyloxycarbonyl, thalolopenzyloxycarbonyl, methoxybenzyloxycarbonyl, etc. .

The "protected carboxy" group and the "protected carboxy" moiety in "protected carboxy(lower)alkoxycarbonyl" include esterified carboxy groups used in penicillin compounds and cephalosporin compounds. It will be done. Examples of the "ester moiety" of such "esterified carboxy" include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, and tertiary pentyl ester. Lower alkyl esters such as esters and hexyl esters, lower alkenyl esters such as vinyl esters and allyl esters, lower alkynyl esters such as ethynyl esters and flovinyl esters, such as methoxymethyl esters, ethoxymethyl esters, and impropoxymethyl esters. , 1-methoxyethyl ester, 1-ethoxyethyl ester, lower alkoxy (lower) alkyl ester, such as lower alkylthio (lower) alkyl ester, such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc. , carboxy (lower) alkyl esters such as carboxymethyl ester, 2-carboxyethyl ester, 3-carboxypropyl ester, e.g. Lower alkoxycarbonyl (lower) such as tertiary butoxycarbonylpropyl ester
protected carboxy (lower) alkyl esters such as alkyl esters, e.g. 2-iodoethyl ester, 2.2.2-') ) alkyl esters such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester,
valeryloxymethyl ester, piparoyloxymethyl ester, hexanoyloxymethylethyl ester, 1 (or 2)-acetoxyethyl ester, 1 (still 2)-acetoxypropyl ester,
l(or 2 but not 3 or 4)-acetoxybutyl ester, 1(but not 2)-propionyloxyethyl ester, 1(or 2 or 3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1 (or 2)-isobutyryloxyethyl ester, 1 (!, or 2)-piparoyloxyethyl ester, 1 (t or 2)-hexanoyloxyethyl ester, imbutyryloxymethyl ester ,2
-Ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2)-
Lower alkanoyloxy (lower) alkyl esters such as pentanoyloxyethyl ester, such as heptanoyloxymethyl ester, octanoyloxymethyl ester, nonanoyloxymethyl ester, decanoyloxymethyl ester, Kundecanoyloxymethyl ester, lauroyl Oxymethyl ester, tridecanoyloxymethyl ester, myristoyloxymethyl ester, pentadecanoyloxymethyl ester, palmitoyloxymethyl ester, hepucdecanoyloxymethyl ester, stearoyloxymethyl ester, nonadecanoyloxymethyl ester, eicosa Noyloxymethyl ester, 1('! or 2)-heptanoyloxyethyl ester, ■(or 2)-octanoyloxyethyl ester, 1(j or 2)-nonanoyloxyethyl ester, l(or 2)- )-decanoyloxyethyl ester, ■(or 2)-cundecanoyloxyethyl ester, 1(or 2)-lafuroyloxyethyl ester, 1(or 2)-tridecanoyloxyethyl ester, 1(t)-decanoyloxyethyl ester, 2)-Myristoyloxyethyl ester, 1 (or 2)-pentadecanoyloxyethyl ester, 1 (or 2)-valmitoyloxyethyl ester, 1 (or 2)-hepkudecanoyloxyethyl ester , 1 (or 2) −
Stearoyloxyethyl ester, 1 (!, daha 2)
-7 Nadecanoyloxyethyl ester - higher alkanoyloxy (lower) alkyl esters such as eicosanoyloxyethyl ester, e.g. methoxycarbonyloxymethyl ester ethoxycarbonyloxymethyl ester, propoquine carbonyloxymethyl ester, impropoxycarbonyloxymethyl ester ester, tertiary butoxycarbonyloxymethyl ester, 1 (or 2)-methoxycarbonyloxyethyl ester, ■ (straight 2)-ethoxycarbonyloxyethyl ester, 1 (or 2)-propoxycarbonyloxyethyl ester, 1 ( or 2)-isopropoxycarbonyloxyethyl ester, 1 (or 2)
) Butoxycarbonyloxyethyl ester, 1 (or 2)-isobutoxycarbonyloxyethyl ester, 1 (or 2)-tertiary butoxycarbonyloxyethyl ester, 1 (or 2)-hexyloxycarbonyloxyethyl ester, 1 (or 2 or 3) -
Methoxycarbonyloxypropyl ester Nyloxypropyl ester, 1(4 or 2 or 3)-isopropoxycarbonyloxypropyl ester, l(still 2 or 3 or 4)-ethoxycarbonyloxyph or 2 or 3 or 4)-Butoxycarbonyloxybutyl ester, 1 (or 2 or 3 but 4 or 5) pentyloxycarbonyloxypentyl ester, 1 (or 2 or 3 or tri4? or 5)-neopentyloxycarbonyloxypentyl ester ,
1 (or 2″!. 3 straddles, 4 straddles 5, 6 straddles)
-lower alkoxycarbonyloxy(lower)alkyl esters such as ethoxycarbonyloxyhexyl ester, e.g. (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl ester, (5-ethyl-2-
(5-lower alkyl-2-oxo-1) such as oxo-1,3-dioxo-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxo-4-yl)ethyl ester, etc. .3-dioxol-4-yl) (
(lower) alkyl esters, e.g. mesyl methyl ester, lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester, e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydryl ester, trityl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4
one or more mono(or di- or tri)phenyl (lower) alkyl esters which may have one or more suitable substituents such as -hydroxy-3.5-cy91 tertiary butyl benzyl esters Al (lower) alkyl esters which may have substituents such as phenyl esters, tolyl esters, tertiary butyl phenyl esters,
Allinyl esters which may have one or more substituents such as xylyl esters, mesityl esters, cumenyl esters, and salicyl esters; for example, heterocyclic esters such as phthalidyl esters; and the like.

Examples of "halogen" include chlorine, bromine, and iodine.

"Protected carboxy(lower)alkoxycarbonyl" and "carboxy(lower)alkoxycarbonyl"
Examples of the "lower alkoxycarbonyl" group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and the like.

[Lower alkoxycarbonyloxy (lower) alkyl]
The groups include methoxycarbonyloxymethyl, ethoxyl-levonyloxymethylpoxycarbonyloxymethyl, impropoxycarbonyloxymethyl, tert-butoxycarbonyloxymethyl, 1 (and 2)-methoxycarbonyloxyethyl, 1 (or 2)-Ethoxycarbonyloxyethyl, 1 (or 2)-propoxycarbonyloxyethyl, 1 (or 2)-isopropoxycarbonyloxyethyl, 1 (or 2)-butoxycarbonyloxyethyl, 1 (or 2)- Imbutoxycarboxyloxyethyl, 1 (or 2)-tert-butoxycarbonyloxyethyl, l (or 2)
-hexyloxycarbonyloxyethyl, ■(still 2 or 3)-methoxycarbonyloxypropyl, ■
(or 2 or 3)-ethoxycarbonyloxypropyl, 1 (or 2 or 3)-isopropoxycarbonyloxypropyl, 1. (4 or 2 or 3 or 4
)-Ethoxycarbonyloxybutyl, 1 (I!. is 2 or 3 or 4)-butoxycarbonyloxybutyl, 1 (or 2 or 3 or 4 or 5)-pentyloxycarbonyloxypentyl, Examples include 1 (or 2 or 3 or 4 or 5)-neopentyloxycarbonyloxypentyl, 1 (or 2 or 3 or 4 or 5 or 6)-ethoxycarbonyloxyhexyl.

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

A preferred example of R1 is amino, and a preferred example of R2 is carboxy or esterified carboxy, more preferably carboxy (lower) alkoxycarbonyl, lower alkoxycarbonyl (lower) alkoxycarbonyl, lower alkanoyloxy (lower) alkoxycarbonyl. , higher alkanoyloxy (lower) alkoxycarbonyl, lower alkoxycarbonyloxy (
(lower) alkoxycarbonyl, (5-[&alkyl-2
-oxo-1,3-dioxo-ruyl) ([9) Al(lower)alkoxycarbonyl such as alkoxycarbonyl, diphenyl(lower)alkoxycarbonyl, or tutaridyloxycarbonyl.

The method for producing the compound (Il or its salt) will be explained in detail below.

(1) Production method 1 Compound (11 or a salt thereof) can be produced by reacting compound (II) or a salt thereof with compound (III).

Examples of the salt of compound (II) include the salts with bases exemplified for compound (I) as they are.

This reaction is usually carried out using any conventional solvent that does not adversely affect the reaction, such as ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, N-dimethylacetamide, dioxane, water, acetic acid, or formic acid. solvent or mixtures thereof.

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

Production method 2 Compound [Ibl or a salt thereof can be produced by subjecting compound [Ia] or a salt thereof to an elimination reaction of a carboxy protecting group.

Salts of compounds (Ia) and (Ib) include compounds (Ia) and (Ib);
1) What about the salt exemplified in Fu? It is raised as it is.

Methods for removing the carboxy protecting group in this reaction include conventional methods such as hydrolysis, reduction and the like.

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

Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. , acidic ion exchange resins, and the like. When using organic acids such as trifluoroacetic acid and p-)luenesulfonic acid among these acids, it is desirable to carry out the reaction in the presence of a cation scavenger such as anisole.

Furthermore, in place of the above acids, boronate trifluoride, borofluoride etherate, aluminum trichloride, antimony pentachloride, ferric chloride, stannic chloride, titanium tetrachloride, zinc chloride, etc. Lewis acids can also be used, and even when Lewis acids are used, the reaction can be carried out in the presence of a cation scavenger such as anisole.

Hydrolysis is typically performed using water, methanol, ethanol, propatool, tertiary butyl alcohol, tetrahydrofuran, N,N-dimethylformamide, N.

Customary solvents which do not adversely affect this reaction, such as N-dimethylacetamide, dioxane, etc., can also be used in mixtures thereof, and also when the acid is liquid.

The reaction temperature for this hydrolysis is not particularly limited, but it is usually carried out under cooling or heating.

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

Reducing agents used in chemical reduction include metals such as soot, zinc, and iron, or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid, trifluoroacetic acid, and p-toluenesulfonic acid. , a combination with an organic or inorganic acid such as hydrochloric acid or hydrobromic acid.

Catalysts used in catalytic reduction include platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, and platinum wires, such as palladium black cotton, palladium black, palladium oxide, baladicum carbon, and colloidal palladium. , palladium black media such as palladium pallicum sulfate and palladium pallicum carbonate, nickel catalysts such as reduced nickel, nickel oxide and Raney nickel, reduced cobalt,
Common catalysts include cobalt catalysts such as Raney cobalt, eg reduced iron, iron catalysts such as Raney iron, copper catalysts such as reduced copper, Raney copper, Kulmann copper, and the like.

The 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. ′! ! Furthermore, the solvent used in the catalytic reduction includes, in addition to the above-mentioned solvents, conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

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

Production method 3 Compound (Ia) or a salt thereof can be produced by introducing a carboxy protecting group into compound (Ib) or a reactive derivative thereof at a carboxy group or a salt thereof.

Mention may be made of the customary reactive derivatives applicable to this reaction, such as genides.

The carboxy protecting group introducing agent used in this reaction includes conventional esterifying agents such as reactive equivalents of alcohols or their halides, sulfonic acid esters, sulfuric esters, diazo compounds and the like.

This reaction can be carried out using alkali metals such as lithium, sodium, potassium, etc., alkaline metals such as calcium, alkali metal hydrides such as sodium hydride, alkaline metals hydrides such as lucium hydroxide, e.g. Alkali metal hydroxides such as sodium, potassium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, e.g. sodium methoxide, sodium cum ethoxide,
Alkali metal alkoxides such as potassium tertiary butoxide, alkali metal alkanoates such as sodium acetate, trialkylamines such as triethylamine, ■,8-diazabicyclo[5,4,0]untes-
7-enes, such as pyridine, lutidine, picoline, etc., pyridine and its derivatives, quinoline, etc. can also be carried out in the presence of an organic base type or an inorganic group, such as sodium iodide, potassium iodide, etc. It can also be carried out in the presence of metal iodides.

When alcohol is used as a carboxy protecting group introducing agent, for example, N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N, Carbodiimide compounds such as N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, e.g.
It can be carried out in the presence of a condensing agent such as a sulfonic acid ester of an N-hydroxybenzotriazole derivative such as -(4-chlorobenzenesulfonyloxy)-6-chloro-IH-benzotriazole.

This reaction is typically performed using acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-
It is carried out in a solvent or mixture thereof that does not adversely affect the reaction, such as dimethylacetamide, pyridine, hexamethylphosphoramide, etc.

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

Production Method 4 Compound (Id) or its salt can be produced by subjecting Compound (Ic) or its salt to an elimination reaction of the carboxy protecting group of R.

This reaction is carried out by conventional methods such as hydrolysis and reduction.

Hydrolysis and reduction methods and e.g. reaction temperatures,
The reaction conditions such as solvent are as follows for compound (Ia) detailed in Production Method 2.
is substantially the same as the elimination reaction of the carboxy protecting group of
Therefore, that explanation can be used.

The target compound CI+ can be converted into its pharmaceutically acceptable salt by conventional methods.

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

Production method A Compound (■b) or its salt is reacted with compound (IVa) or its reactive derivative at the carboxy group or its salt with compound (v) or its reactive derivative at the hydroxy group or its salt. It can be manufactured by

As the reactive derivative at the carboxy group of compound (IVa), the same examples as the reactive derivative of compound (Ib) in Koji Making Method 3 can be mentioned.

Reactive derivatives at the hydroxyl group of the compound (■) are compounds in which the hydroxyl group is substituted with an acid residue such as a halogen such as chlorine, bromine, iodine, etc.
v).

Examples of the salts of compounds (IVa) and (Ivb) include the salts exemplified for compound (I), and examples of the salts of compound (v) include the salts with bases exemplified for compound (I). It will be done.

This reaction is substantially the same as the esterification method described in Production Method 3, and therefore, the explanation can be referred to for reaction conditions such as reaction temperature, solvent, base, etc.

Production method B-■ Compound (Vl) or its salt is prepared by reacting compound (■) or its reactive derivative at the amino group or its salt with compound (W) or its reactive derivative at the carboxyl group or its salt. Can be manufactured.

Reactive derivatives at the amine 7 group of compound (■) include conventional derivatives such as those obtained by reaction of compound (■) with silyl compounds such as trimethylsilylacetamide, bis(trimethylsilyl)acetamide, bis(trimethylsilyl)urea, etc. Examples of reactive derivatives of compound (Vl) include acid halides such as acid chlorides, acid bromides, etc.
These acid halides can be produced by reacting diketene with halogen.

Examples of the salt of compound (IT) include the same examples of the salt of compound (I), and compounds (W) and (to)
Examples of the salt include the salts of compound (I) with bases.

The reaction is usually carried out using chemicals that adversely affect this reaction, such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, nehexamethylphos≠misakiruamide, etc. Only conventional solvent evaporation with no effect is carried out on these mixtures.

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

Production method B-① Compound (nl or its salt) can be produced by reacting compound (2) or its salt with a nitrosating agent.

As nitrosating agents, nitrous acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide, alkali metal nitrites such as sodium nitrite and potassium nitrite, such as butyl nitrite, pentyl nitrite, nitrous acid When using an inkali metal salt, the reaction is preferably carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, or acetic acid.

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

This reaction is usually carried out in a conventional solvent or mixture thereof that does not adversely affect the reaction, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, methylene chloride, etc.

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

The hydroxyimino group of compound (II) obtained by this reaction may contain a syn isomer, an anti isomer, and a mixture thereof, and such a compound is represented by the following partial structure.

1 H Compound (I) and its pharmaceutically acceptable salts are novel compounds, have high antibacterial activity that inhibits the growth of many pathogenic bacteria including Durum-positive bacteria and Durum-negative bacteria, and have antibacterial properties. It is useful as an antibacterial agent, especially for oral administration.

Next, in order to demonstrate the usefulness of the target compound (I), the results of a urinary excretion test of a representative compound of this invention are shown.

Urinary excretion test (1) Test method 100 μ/lv of the test compound was orally administered to 3 rats per group, and urine samples were collected for 0 to 24 hours.

(2) Test compound (A+ Piparoyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylate (syn isomer ) (hereinafter referred to as compound A) (B) 7- (2-(2-aminothiazole-4-
(3) Test results: Urinary excretion Values are expressed as percentages.

When administering the object compound (I) of this invention or its pharmaceutically acceptable salts for therapeutic purposes, the compound (I) or its pharmaceutically acceptable salts is prepared using the above-mentioned compound as a main ingredient, a pharmaceutically acceptable carrier,
For example, they can be administered in the form of conventional preparations with organic or inorganic, solid or liquid excipients suitable for oral, parenteral or topical use. Such preparations include solids such as tablets, granules, powders, and capsules, as well as liquids, powders,
Includes liquids such as syrups, emulsions, and lemonade.

Furthermore, if necessary, adjuvants, stabilizers,
Wetting agents, as well as lactose, citric acid, tartaric acid, fumaric acid,
Commonly used additives such as stearic acid, magnesium stearate, clay, sucrose, cornstarch, curcum, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, etc. can be included.

The dosage of compound CI) varies depending on the patient's age, condition, type of disease, and type of compound (I) to be administered, but generally an amount of 1 to about 4000 or more can be administered to the patient per day. . The average dose of the compound (I) of the present invention is about 50 tn, 1100 tn, 2
50■, 500■, 1000■, 2000mg can be used to treat diseases caused by pathogenic microorganisms.

Next, the present invention will be explained in detail using examples.

Production example 1 Ethyl carbonate 1-DL-iodoethyl (7,32y)
, 7-amino-3-vinyl-3--t! Femme 4-
Carboxylic acid (4,52y) and 1,8-diazabicyclo[5,4,0]cundes-7-ene (4,5me)
N,N-dimethylacetamide (C45me) solution under water cooling. After stirring the mixture at 0-3°C for 45 minutes, the reaction mixture is poured into ice water (200me) and extracted with ethyl acetate (200me).

The extracted organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated to 1/4 volume of the original volume. Add the concentrate to concentrated hydrochloric acid (2me). The formed precipitate was collected, washed with ethyl acetate, and air-dried to obtain 7-asanino-3-
Vinyl-3-cephem-4-carboxylic acid DL'-1-ethoxycarbonyloxyethyl hydrochloride (2,669)
get.

Engineering R (nujol) 礪-1: 3400. 1775
．． 1755°72O NMR (DMSO-d6) δ: 1.27 (3H, t
, J=7Hz).

1.53 (3H, d, J=6Hz), 3.93 (
2H, m), 4.23 (2H, q, J=7)Iz)
, 5.06.0 (4H, m), 6.7-7.2
(2H, m), 8.0-40.0 (2H, broad m) Production Example 2 7-amino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl hydrochloride jlK (150y) and trimethylsilylacetamide (189y) ) to ethyl acetate (
1,5/) and cooled to -20°C. To this was added 4-bromoacetoacetate bromide obtained from diketene (39p) and bromine (75y) in methylene chloride (200ml) at -20°C, and the mixture was stirred at -10°C for 1 hour. ) and water (I), and the organic layer is separated and water and salted.
Wash with J cum aqueous solution. After distilling off the solvent under reduced pressure, the resulting precipitate was washed with ethyl acetate and dried to give 7-(4
-bromoacetoacetamide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl (171y) is obtained. Melting point 133-137°C (decomposition).

Engineering R (nujol) ffl-1: 3270. 17
65. 1705°1650, 155O NMR (DMSO-d6) l: 3.5-4.
5 (6H, m), 5.2-6.0 (4H, m), 6
．． 83 (IH, m), 7.00 (IH, s).

7.45 (IOH, m), 9.25 (LH, d, J=8
Hz) Production Example 3 The following compound was obtained according to the method of Production Example 2.

7-(4-bromoacetoacetamide)-3-vinyl-
3-cephem-4-carboxylic acid DL-1 = ethoxycarbonyloxyethyl.

IR (Nujol) cm: 1780. 1760
．． 1270°08O NMR (DMSO-a6)a Hl, 27(3H,t,
J=7Hz), 1.53 (3H, d, J='6Hz)
, 3.93 (2H, m), 4.17 (2H, s
), 4.23 (2H, q, J=7Hz), 4
．． 33 (2H, s), 5.0-6.0 (4H, m)
, 6.5-7.2 (2H, m), 9.17 (I
H, d, J-8Hz) Production example 4 7-(4-bromoacetoacetamide)-3-vinyl-
Benzhydryl 3-cephem-4-carboxylate (40?
) of methylene chloride (400 ml') and acetic acid (20 ml')
0d) In a solution, add sodium nitrite (7,5y) to water (5y).
Add the solution dissolved to 0 ml dropwise at -10 to -5°C, and -
Stir for 30 minutes at 5°C.

After adding urea (7y) and stirring at room temperature for 30 minutes, water (400 mt') was added to the reaction mixture. The organic layer is separated, washed with water and 10% aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off, and the resulting solid was dried in vacuo to give 7-(4-bromo-2-hydroxyiminoacetoacetamide)-3-vinyl-3-cephem-4-
Benzhydryl carboxylate (48y) is obtained. melting point 10
5-108°C.

Engineering R (nujol) σ-1: 3250. 1770
．． 1705°1655, 154O NMR (DMSO-d6) δ: 3.80 (2H, m
), 4.67 (2H.

s), 5.2 6.2 (4H, m), 6.80 (L
H, m).

7.00 (IH, s), 7.45 (IOH, m),
9.42 (LH.

d, J=8Hz), 13.20 (IH,s) Example 1 N of 7-(4-bromo-2-hydroxyiminoacetoacetamide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl (48y) , Thiourea (7,1') was added to a solution of N-dimethylacetamide (200m+') at 5°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was
% sodium bicarbonate aqueous solution (lI), then add sodium chloride (150y). A precipitate was obtained, and then acetone (200m) and ethyl acetate (500m) were added.
) is dissolved in a mixture with

The organic layer is washed with an aqueous sodium chloride solution, and then the solvent is distilled off. The resulting precipitate was collected, washed with ethyl acetate and diethyl ether, and dried in vacuo to give 7-(2-(
2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-
Benzhydryl carboxylate (syn isomer) (16,9y
).

Melting point 133-136°c.

IR (nuji r-ru) (2-1: 3200+ 17
80. 1720+1670, 161O NMR (DMSO-d6) δ: 3.75 (2H, m
), 5.2-6.1 (4H, m), 6.67 (
IH, s), 6.75 (IH, m).

7.00 (LH, s), 7.20 (2H, m)+
7.34 (IOH, m).

9.50 (IH, d, J=8Hz) Example 2 According to the method of Example 1, the following compound is obtained.

+1+ 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid DL-1 = ethoxycarbonyloxyethyl (syn isomer).

Engineering R (Nujoor) am, 3300. 1780
．． 1750°67O NMR (DMSO-a6)a: 1.17(3H,t
, J=7Hz).

1, 50 (3Hld, J=6Hz), 3-75 (
2H+m).

4.13 (2H,, q, J=7Hz), 5.176
．． 0 (4H, m).

6.63(IH,s), 6.7-7.3(4f(,
m).

9.45 (1, H, d, J=8Hz), 11.3
3(IH,5)(217-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]
-3-vinyl-3-cephem-4-carboxylic acid tertiary-butoxycarbonylmethyl (syn isomer).

IR (Nujol) cm-1: 3300. 3170
．． 1780°1730, 1665. 1620 (3) DL-1-propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]=3-vinyl-3-cephem-4-carboxylate (syn-X body).

Engineering R (nujol) am-1: 3300. 320
0. 1780°1.765. 172Q, 171
0. 1660. 1630 (417-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid pivaloyloxymethyl (syn isomer).

IR (Nujol) □-1: 3400. 1785
．． 1750°1670, 1615. 1530.
1310. 1220+5) Palmitoyloxymethyl 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer).

Engineering R (nujol) c+++-1: 3300. 1
775. 1670°1615, 1530. 130
5. 1210 (617-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide)
-3-vinyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxo-4-yl)
Methyl (syn isomer).

IR (Nujol) cIn': 3300. 18
12. 1772°1730, 1668. 1611 +7+ 7- C2-(2-aminothiazole-4-
yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid phthalid-3-yl (syn isomer).

IR (Nujol) am-1: 3200 (broad), 1772 (broad), 1728 (shoulder),
1660. 1620+81 7- [2-(2-
Carboxymethyl aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylate (syn isomer).

Engineering R (nujol) cm': 1765 (broad), 1720°1660 (broad) +91 7-[2'-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3- Sodium cephem-4-carboxylate (syn isomer).

IR (nujol) σ-1: 3200. 1760
．． 1660°600 Example 3 7-(2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl (syn isomer)
(68,5y), 2.2.2-)lifluoroacetic acid (
60+++e) and anisole (60me) little by little at 5-7°C and stirred at 5°C for 1 hour. The reaction mixture was diisopropyl ether (1,!M)
and collect the precipitate.

Tetrahydrofuran (100ml?) and ethyl acetate (1
After dissolving in a mixed solvent of 00+++1, it is extracted with an aqueous sodium bicarbonate solution. The resulting aqueous layer was diluted with 10% hydrochloric acid.
After adjusting to H5.0 and washing with ethyl acetate, it is subjected to chromatography using aluminum oxide. Elute with aqueous sodium trithiacetate solution and collect both fractions containing the desired compound. After adjusting the pH to 6.0 with 10% hydrochloric acid, the aqueous solution was again subjected to chromatography using activated carbon. Elute with a 20-liter acetone aqueous solution, collect both fractions containing the target compound, concentrate under reduced pressure, and lyophilize to obtain 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3 - Sodium vinyl-3-cephem-4-carboxylate (syn isomer) (14, B) is obtained. Decomposed at 220°C or higher.

Engineering R (Nujol) (2-1: 3200. 176
0. 1660°60O NMR (D20) δ: 3.67 (2H, s), 5
．． 2-5.7 (3H, m).

5.83 (IH, d, J=5Hz), 6.80 (I
H, m).

7,00(IH,s) Example 4 Ethyl carbonate 1-DL-iodoethyl (22-yl-hydroxyiminoacetamide)-3-vinyl-3-
Sodium cephem-4-carboxylate (syn isomer) (
15y) N,N-dimethylacetamide (1'20m
Add dropwise to the solution at 5-7°C and stir at 5°C for 30 minutes. Add ethyl acetate (200me) to the reaction mixture,
Forgive. Solution F is washed with water and an aqueous sodium chloride solution, and dried over magnesium sulfate. After distilling off the solvent, the remaining liquid was washed with ethyl acetate and dried in vacuum to give 7-[2-(
2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-
Carboxylic acid DL-1-ethoxycarbonyloxyethyl (syn isomer X7.4 f;!) 41 l.

Melting point: 126-130°C.

Engineering R (nujikor) (to), 3300. 1780
．． 1750°1670, 162O NMR (DMSO-d6) δ: 1.17 (3H, t,
J=7Hz).

1.50 (3H, d, J=6Hz), 3.75 (2
H, m), 4.13 (2H, q, J=7Hz),
5.1-6.0 (4H, m), 6.65 (LH2
s) + 6.7 7.3 (4H, m), 9.45
(IHld.

J=8Hz), 11.33 (IH, s) Example 5 Cesium carbonate (2,06y), ? -[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (5y) N,N-dimethylacetamide ( 50me) solution at 25°C. The mixture is stirred for 1 hour at ambient temperature and then cooled in a water bath. Add ethyl carbonate 1-DL-iodoethyl (9,2
Add y) all at once and stir at 0-3°C for 40 minutes. Add ethyl acetate (300ml) to the reaction mixture and filter.

The P solution is washed twice with water and then with saline, treated with activated carbon and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with diisopropyl ether, air-dried,
7-(2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid DL-1-ethoxycarbonyloxyethyl (syn isomer) (4,6y) is obtained. Melting point: 126-130°C.

Engineering R (nujol) cIn': 3300. 17
80. 1750°67O NMR (DMSO-d6) δ: 1.17 (3H, t,
J'=7Hz).

1.50 (3H, d, J=6Hz), 3.75 (2
H, m).

4.13 (2H, (1, J=7H2), 5.1-6.0
(4H, m).

6.63 (IHLs) + 6.7 7.3 (4H1m
).

9.45 (LH, d, J = 8Hz), 11.33 (
LH,s) Example 6 Potassium iodide (4,0y) was converted into N,N-dimethylacetamide (50
mff) solution and stir for 40 minutes at room temperature. Remove the precipitate. Add 7- [2-3 I5-nothiazole-4 to the furnace solution.
-yl)-2-hydroxyiminoacetamide]-3-
Potassium vinyl-3-cephem-4-carboxylic acid (syn-U type) (3,2y) was added at room temperature, and at the same temperature 1.5
Stir for an hour. A mixture of water and ethyl acetate was added to the reaction mixture, and the pH was adjusted to 7.0 with a 20% aqueous potassium carbonate solution. The organic layer is separated, washed with water, dried over magnesium sulfate, and the solvent is distilled off. -(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid tert-butoxycarbonylmethyl (syn isomer) (
2, OF) is obtained.

Engineering R (nujol) cm-': 3300. 317
0. 1780°1730, 1665. 162O NMR (DMS 0-a6) δ: 1.43 (9H, s
), 3.76 (2H, q+J-18,0Hz),
4.73 (2H, s), 5.24 (IH, d.

J=5.0Hz), 5.38(IH,d, J=1
1.0H2), 5.68(LH,d,,J-18,
0Hz), 5.82 (IH, dd, J=5.0Hz
.

8.0Hz), 6.66(LH,s), 7.0
3 (IH, dd, J-11, OHz, 18.0Hz
), 9.46 (IH, d, J = 8.0 Hz) Example 7 According to the method of Example 5, 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide )']-]3-vinyl-3-yahuemu 4carboxylic acid (syn isomer) (5y) was reacted with DL-1-bromoethyl propionate (4,56y) to form 7-(2-(2
-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid DL-1-propionyloxyethyl (syn isomer) (1,38y) is obtained.

IR (Nujol) cm-1: 3300. 320
0. 1780°1765, 1720. 1710.
1660. 163ONMR(DMSO-d6)δ
: 1.03 (3H, t, J=7Hz).

1.48 (3H, d, J=6Hz), 2.38 (2
H, q, J = 7Hz).

3.53 and 3.97 (2H, ABq, J-18H
z), 5.23 (IH, d, J=5Hz), 5.
4 (IH, d, J=11Hz).

5.65 (IH, d, T=18Hz), 5.85
(IH, dd.

J=8Hz, 5Hz), 6.67(LH,s),
6.83(LI(.

dd, J=18Hz, 11Hz), 6.93(
IH, q, J=6Hz).

7.1 (2H, broad s), 9.43 (IH,
d, J=8Hz).

11.33(LH,s) Example 8 According to the method of Example 5, 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-- T! Iodomethyl piperate (5
, React ') to 05, ? -[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-pinyl-3-cephem-4-carboxylic acid piparoyloxymethyl (syn isomer) (1,24y) 4
do.

Melting point 90-100°C (decomposition).

Engineering R (nujol) a: 3400. 178'5
．． 1750°1670, 1615. 1530.
1310. 122ONMR (DMSO-d6) δ:
1.14 (9H, s), 3.58 and 3.97
(2H, ABq, J=18I(z), 5.24(
IH, d.

J-5Hz), 5.39 (IH, d, J=11Hz
), 5.7-6.0 (3H, m), 5.77 (
IH, d, J-17Hz), ' 6.70 (IH,
8), 6.83'(1)i, cld, J=11
Hz, 17Hz).

7.12 (2H, broad s), 9.49 (IH
, d, J=8Hz).

16, 24 (IH, s) Su Kunmawari 1 According to the method of Example 5, ? -(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (3y) and iodomethyl valmitate (4,
13y) to form palmitoyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylate (syn isomer). (1,86y)t[
Ru. Melting point 90-105°C3 1R (Nujol) c+++-1: 3300. 1
775. 1670°1615, 1530. 130
5. 121ONMR('DMSO-d6)δ:1.1
-1.7 (26H, m), 2.3-2.5 (2H,
m), 3.56 and 3.95 (2H, ABq.

J=18Hz), 5.21(IH,d,,T=5Hz
), 5.37 (IH, d, J=11Hz),
5.7-6.0 (3H, m) + 5゜75 (IH, d, J
=17Hz), 6.66(iH,s).

6.7-7.0 (IH, m) Example 10? -(2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid potassium (syn isomer) (2,
4-Bromomethyl-5-methyl-1,3-dioxol-2-one (1,0y) is added to a solution of 1') in N,N-dimethylacetamide (30 mf) while stirring under water cooling. The reaction mixture is stirred for 30 minutes at the same temperature. The mixture was poured into 200 ml of ethyl acetate and washed three times with water. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (SO?). and 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-vinyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1, 3-dioxol-4-yl)methyl (syn isomer) (0,62y) is obtained.

IR (Nujol) Ko-1: 3300. 1812
．． 1772°1730, 1668. 1611 NMR (DMSO-d6) δ: 2.17 (3H, s)
, 3.52. 3.98 (2H, ABq, J-17
Hz), 5.15 (2H, s), 5.20 (I
H, (1, J=5H2), 5.30 (IH,, d,
, J=11Hz).

5.63 (IH, d, J = 17Hz), 5.76 (
IH, dd, J = 5Hz.

8H2), 6.63 (IH28), 6.83 (IHld
d, J-1IH2°17Hz), 9.42 (IH;
d, J=8Hz), 11.3(IH,s) Example 11 According to the method of Example 1.0, 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide ]-3-vinyl-3-cephem-4-carboxylic acid potassium (syn isomer) (1,0y) was reacted with 3-bromotuclide (0,91) to form 7-[2-(2-aminothiazole-4 -yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid phthalid-3-yl (syn isomer) (1,osy) is obtained.

IR (nujol) σ-1:3200 (broad),
1772 (broad), 1728 (shoulder), 1
660. 162ONMR (DMSO-d6) δ:3
．． 70 (2H, m), 5.18 (IH.

d, J=5Hz), 5.43(IH, d, J=11
H2), 5.73 (IH, d, J=17H2),
5.83 (LH, dd, J=5Hz.

8Hz), 6.75 (IH, s), 6.7-7
．． 2 (2H, m).

7.66-'8.0 (6H, m), 9.87 (IH
, d, J=8 Hz) Example 12 Trifluoroacetic acid (5.4 ml?) was added to 7-[2-(2
-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid tertiary-butoxyluponylmethyl (synisomer) (1,8y) in methylene chloride (4mt) and a suspension in anisole (1,8me) at room temperature.
Stir for an hour. Add diisopropyl ether to this solution and stir.

Separate the resulting precipitate and wash with diisopropyl ether. This precipitate is added to a mixture of ethyl acetate and water, and the pH is adjusted to 7 with 20% aqueous sodium carbonate solution while stirring. Add 10% hydrochloric acid to the separated aqueous layer while cooling with water to adjust the pH to 2.2. The precipitate was separated, washed with ice water, and vacuum dried over phosphorous pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4. -Carboxymethyl carboxylate (
syn isomer) (0,73y) is obtained.

Engineering R (nujol) cm': 1765 (broad), 1720°1660 (broad) NMR (DMSO-d, )δ: 3.76 (2H,q
, J=18.0E(z).

, t7s(2u,s)+5.24(la,d,,
r=s, oaz).

5.37 (IH, d, , T=11.0Hz), 5
．． 86 (1, H, d.

J=17.0H2), 7.83(IHldd, J-5,
0H2, 8, 0H2).

6.69 (IH, s), 6.61-7.67 (3H
,' m).

9.50 (IH, d, J-8,0 Hz) Example 13 7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid DL-1-ethoxycarbonyloxyethyl (syn isomer) (1y), ethyl acetate (
Concentrated hydrochloric acid (0.3me) was added to a mixture of 50m(') and ethanol (2+++f) under water cooling, and the mixture was stirred at 0 to 3°C for 10 minutes. Add diimpropyl ether (50%
7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide) was added, the resulting precipitate was collected, washed with ethyl acetate, and air-dried.
-3-vinyl-3-cephem-4-carboxylic acid DL-1
-Ethoxycarbonyloxyethyl hydrochloride (syn isomer) (0,8y) is obtained.

Engineering R (nujol) α: 3100. 1780
．． 1750°64O NMR (DMso-a6) δ: 1.23 (3H, t,
J = 7Hz) + 1.53 (3H, d, J = 6Hz
), 3.75 (2H, m), 4.20 (2H.

q, J=7Hz), 5.0-6.0 (6H, m),
6.83(1)I, B).

6.7-7.2 (2H, m), 9.7 (IH, d,
J=8Hz).

12.5 (IH, Broad 8) Example 14 Benzhydryl 7-(4-bromoacetoacetami)')-3-vinyl-3-cephem-4-carboxylate (10
y) methylene chloride (70me) and acetic acid (25mt
') Add isoamyl nitrite (3,5rne) to the mixture.
Add dropwise at 3 to -5°C. The mixture was stirred at -5°C for 40 min, then acetylacetone (4y) was added and the mixture was stirred at 5°C for 30 min.
Stir for a minute. Add thiourea (3y) to the reaction mixture,
After stirring for 3 hours, ethyl acetate (70me) and diisopropyl ether (100me) are added dropwise. The resulting precipitate was collected and dried under vacuum to obtain 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide F] & Mu4-carboxylic acid benzhydryl hydrobromide ( syn isomer) lt, 7y) is obtained. Of this product, 3y was heated to 2,2°2- at 5-7°C.
Add portionwise to the mixture of trifluoroacetic acid (5yd) and anisole (5-). After stirring for 1 hour at 5°C, the reaction mixture is added dropwise to diisopropyl ether (150me). The resulting precipitate was mixed with tetrahydrofuran (
10me) and ethyl acetate (10-). This solution is extracted with an aqueous sodium bicarbonate solution.

The aqueous extract was washed with ethyl acetate while keeping the pH at 5, and then adjusted to pH 2.2 with 10% hydrochloric acid. This solution is 0
After stirring at ℃ for 1 hour, the resulting crystals were separated and dried under vacuum to give 7-[2-(2-aminothiazol-4-yl).
-2-Hydroxyiminoacetamide]-3-vinyl-
3-cephem-4-carboxylic acid (syn isomer) (0,7
9y) is obtained.

IR(nujia-#)am-1: 3300. 178
0. 1665+1180, 1130 Example 15 7-(4-bromoacetoacetamide)-3-vinyl-
Benzhydryl 3-cephem-4carboxylate (15y)
methylene chloride (100 Wd) and acetic acid (30 me
) Add sodium nitrite (2,8y) to the mixture (5me)
The solution is added dropwise at -10 to -15°C. The reaction mixture is stirred at -5°C for 40 minutes, acetoacetone (4y) is added, and then stirred at ambient temperature for 15 minutes. The reaction mixture was diluted with water (
200me) and methylene chloride (200+++e), and the organic layer is separated and washed with water. The solvent was distilled off and the residue was dissolved in N,N-dimethylacetamide (40me
) dissolves in Thiourea (3,4y) was added to this solution, stirred at room temperature for 1 hour, and tetrahydrofuran (150m
e), ethyl acetate (300mE) and water (300mE)
e) Pour into the mixture. The mixture was adjusted to pH 6.0 with 20% aqueous sodium hydroxide solution. The organic layer is separated, washed with a 20% aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the precipitate is taken and washed with ethyl acetate and diisopropyl ether. This precipitate was dried under vacuum, and the benzhydryl 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) ( 8,5f;”) is obtained.

Engineering R (Nujol) Qm-1: 3200. 1780
．． 1720°1670, 1610 Example 16 7-(2-(2-aminothiazol-4-yl)=2-
Hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl (syn isomer)
Boron trifluoride etherate (5me) is added dropwise to a mixture of anisole (20me) and acetic acid (5+++Il') of (5f/ ) at 10°C. After stirring for 20 minutes at 10°C, the reaction mixture was diluted with tetrahydrofuran (100mf
? ), ethyl acetate (loOml') and water (100 m
f? ) and then adjusted to pH 6.0 with 20% aqueous sodium hydroxide solution. Separate the aqueous layer and adjust the pH
Wash with ethyl acetate while maintaining the temperature at 6.0. This solution is subjected to chromatography using aluminum oxide.

Extract with a 3% aqueous sodium acetate solution, collect both fractions containing the target product, and adjust the pH to 4.0 with 10% hydrochloric acid. This solution was further mixed with a nonionic adsorption resin “Diaion HP-20”.
Chromatography using J (trademark, manufactured by Mitsubishi Kasei Corporation). The fractions eluted with the 20% acetone aqueous solution are collected, concentrated under reduced pressure, and adjusted to pH 2.0 with 10% hydrochloric acid. The resulting precipitate was dried in vacuum several times to give 7-(2-(2
-aminothiazol-4-yl)-2-hydroxyiminoacetami1')-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1,23y) is obtained.

IR (nujol) c+++': 3300. 17
80. 1665°1180, 113O NMR (DMSO-d6) δ: 3.76 (2H, ABq
, J=18Hz).

5.2-6.0 (4H, m), 6.73 (IH, s
), 6.8-7.50 (3H1m), 9.5 (IH
, d, J=8Hz), 11.4 (IH.

Broad 8) Example 17 (1) 7-Amino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl hydrochloride (1 kg) and 1
．． 3-bis(trimethylsilyl)urea (1,4'6k
Dissolve f) in tetrahydrofuran (81)! and -20°
Cool to C. To this solution is added 4-bromoacetoacetyl bromide obtained from diketene (224me) and bromine (147me) in methylene chloride at -20°C and stirred for 30 minutes at -15°C. The reaction mixture is poured into a mixture of ethyl acetate (121) and water (6I). The organic layer is separated and washed with an aqueous sodium chloride solution, and then the solvent is distilled off under reduced pressure. The precipitate is poured into diisopropyl ether (10I). The crystals obtained were stirred at 0°C for 1 hour and dried under vacuum to give benzhydryl 7-(4-bromoacetoacetami)')-3-vinyl-3-cephem-4-carboxylate. (1,27 kg) is obtained.

Melting point 133-137°C (decomposed).

(2) Benzhydryl 7-(4-bromoacetoacetamide)-3-vinyl-3-cephem-4-carboxylate (
50'Oy) of methylene chloride (4,5/) and acetic acid (
1,71) A solution of sodium nitrite (93,2y) in water (450me) is added dropwise to the mixed solution at -15 to -22°C. The reaction mixture is stirred at -15° C. for 7 minutes, then ethyl acetoacetate (117y) is added and stirred at room temperature for 5 minutes. The reaction mixture is washed with water (6I!, twice) and aqueous sodium chloride solution (6e). Add N to the separated organic layer.
, thiourea (82,2,p) dissolved in N-dimethylacetamide (II) is added and stirred at 36°C for 1 hour. After distilling off the methylene chloride under reduced pressure, the remaining oil is dissolved in tetrahydrofuran (3, 51, and poured into a mixture of ethyl acetate (71) and ice water (41). The mixture was adjusted to pH 6.0 with an aqueous solution of 10% sodium hydroxide. The organic layer was separated and diluted with water (4I!, twice). ) and diisopropyl ether (2,47?) at 0 °C. Stir for 1 hour at
3-vinyl-3-cephem-4-carboxylic acid benzhydryl (syn isomer) (394,5y) is obtained.

IR (Nujol) cm-1: 3200. 1780
．． 1720° 1670, 1610 Example 18 According to the method of Example 5, 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamyl']-]3-vinyl-3-cephemu 4-carboxylic acid syn isomer) (5y), cesium carbonate (2,01'
) in the presence of DL-1-bromoethyl acetate (3,42y)
7-[2-(2-aminothiazole-4-
yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid DL-1-acetoxyethyl (1,12y) is obtained.

Engineering R (nujol) c+++ -1: 3300. 1
780. 1760°1670, 121O NMR (DMS O-d 6) δ: 1.50 (3H,
d, J=6Hz), 2.03(3H,s),
3.75 (2H, ABq, J=18Hz), 5.
0-6.0 (4H, m), 6.67 (IH, s),
6.5-7.5 (4H.

m), 9.22 (IH, d, J=8Hz),
11.37 (LH, s) Patent applicant Fujisawa Pharmaceutical Co., Ltd. Agent Patent attorney Aomizu High procedural amendment (spontaneous) 1. Indication of the case 1982 Patent Application No. 184036 2. Name of the invention 7-f! Convert-3-vinyfiy-3-cephem compound, process for producing it, and antibacterial agent containing the same 3, person making the amendment Patent applicant: 4-3 Doshomachi, Higashi-ku, Osaka (524) Representative, Fujisawa Pharmaceutical Co., Ltd. Fujisawa Tomoyoshibe 4, Agent Address: 2-1-6 Kashima, Yodoyou-ku, Osaka 532 Fujisawa Pharmaceutical Co., Ltd. Osaka Factory (6300) Patent attorney Aoki High School 5, Details of the invention in the specification to be amended Insert the following statement in column 6 of ``Explanation'', page 72 of the specification of the amendment, in the second line from the bottom, before ``Patent applicant: Fujisawa Pharmaceutical Co., Ltd.''.

"In an ethyl acetate solvent, the above compound is treated with isopropyl alcohol (V) containing heptahydrogen chloride in a conventional manner to obtain the hydrochloride of the above compound.

IR (, (di g/l/) 1 m, 1780.1760
．． 1620.1210°07DJ or more

Claims (1)

[Claims] 1) General formula: (wherein R1 is atri) group or protected. amine group,
R2 means a carboxy group or a protected carboxy group, respectively) and a pharmaceutically acceptable salt thereof. 2) The compound according to claim 1), wherein R1 is an amino group. 3) 7-(2-(2-aminothiazol-4-yl)-
2-Hydroxyiminoacetamide]-3-vinyl-3
-Cephem-4-carboxylic acid (syn isomer), its sodium salt or its potassium salt, the compound according to claim 2). 4) The compound according to claim 2), wherein R2 is an esterified carboxy group. 5) The compound according to claim 4), wherein R2 is a lower alkoxycarbonyloxy(lower) alkoxycarbonyl group. 6) 7-[2-(2-aminothiazol-4-yl)-
2-Hydroxyiminoanadamide]-3-vinyl-3
The compound according to claim 5), which is 1-ethoxyluponyloxyethyl -cephem-4-carboxylate (syn isomer) or its hydrochloride. 7) The compound according to claim 4), wherein R2 is a lower alkoxycarbonyl group. 8) 7-(2-(2-aminothiazol-4-yl)-
2-Hydroxyiminoacetamide]-3-vinyl-3
-Cephem-4-carboxylic acid tertiary ptoxyl methylbenzene (syn isomer). 9) The compound according to claim 4), wherein R2 is a carboxy(lower)alkoxycarbonyl group. 10)"7-(' 2-(2-aminothiazole-4-
The compound according to claim 9, which is carboxymethyl (syn isomer)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylate. 11) The compound according to claim 4), wherein R2 is a lower alkanoyloxy(lower)alkoxycarbonyl group. 12) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-vinyl-
The compound according to claim 11, which is 1-propionyloxyethyl 3-cephem-4-carboxylate (syn isomer). 13) 7-(2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-vinyl-
The compound according to claim 11), which is piparoyloxymethyl 3-cephem-4-carboxylate (syn isomer). 14) Claim 4) in which R2 is a higher alkanoyloxy (lower) alkoxycarbonyl group
Section, Compounds Listed. 15) The claimed compound is palmitoyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylate (syn isomer). A compound according to range 14). 16) R2 is (5-lower alkyl-2-oxo-1
The compound according to claim 4, which is a ゜3-dioxol-4-yl)(lower)alkoxycarbonyl group. 17) 7-[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-vinyl-
The compound according to claim 16, which is (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl 3-cephem-4-carboxylic acid (syn isomer). 18) The compound according to claim 4), wherein R2 is a phthalidyloxycarbonyl group. 19)? -[2-(2-aminothiazol-4-yl)
-2-Hydroxyiminoacetamide]-3-vinyl-
The compound according to claim 18, which is phthalid-3-yl 3-cephem-4-carboxylate (syn isomer). 20) +11 Formula: (In the formula, R2 means a carboxy group or a protected carboxy group, and X means a halogen, respectively.) (2) A compound represented by the formula: (wherein R1 has the same meaning as before and RA means a protected carboxy group) or a salt thereof is subjected to an elimination reaction of the carboxy-protecting group, and the compound represented by the formula: (formula (wherein, R1 has the same meaning as above) or a salt thereof, or obtain a compound of formula (3): (wherein, R1 has the same meaning as before) or a reactive derivative at its carboxy group, or its Introducing a carboxy protecting group to the salt,
Formula: (In the formula, R1 and R2 each have the same meaning as before) To obtain a salt of a compound represented by the formula (4), where R1 and R2 have the same meanings as before, RA is means a protected carboxy(lower)alkoxycarbonyl group] or a salt thereof is subjected to a reaction for eliminating the carboxy protecting group in RA, and the formula: [wherein R1 has the same meaning as before] and R2 means a carboxy (lower) alkoxycarbonyl group] or a salt thereof. Process for producing syn isomer and its salts. 21) General formula (wherein, R1 is an amino group protected by 7 amino groups, R
2 means a carboxy group or a protected carboxy group, respectively) An antibacterial agent characterized by containing a syn isomer of the compound represented by the formula (2) and a pharmaceutically acceptable salt thereof.