JPH0696562B2 - Process for producing aminothiadiazoleacetic acid derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to 2- (5-amino-1,2,4-, which is useful as a raw material for acylation of amino groups of cephalosporin compounds, penicillin compounds and azetidinone compounds. Thiadiazol-3-yl) -2 (Z) -hydroxyiminoacetic acid derivative, ie, general formula [Wherein R ₂ represents a hydrogen atom or an optionally substituted hydrocarbon group], or a salt thereof.

As a method for producing an aminothiadiazoleacetic acid derivative represented by the general formula (I), for example, 2- (5-amino-1,2,4-thiadiazol-3-yl)-is obtained from dimethyl malonate through about 9 steps. A method for obtaining 2-ethoxyiminoacetic acid (described in JP-A-56-633988) or 2- (5-protected amino-1,2,4) from acetamidine hydrochloride through about 6 steps
-Thiadiazol-3-yl) -2-alkoxyiminoacetic acid (JP-A-53-53691, JP-A-54-1064)
91, JP-A-55-11600, JP-A-55-105689, etc.) are known.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention In these conventional techniques, the process for producing an aminothiadiazoleacetic acid derivative from a raw material is long, and the yield from the initial raw material is 10% or less, which is extremely low. Is also poor in purity. Further, a special reagent that cannot be used for industrial production (for example, diisopropylaminolithium, zelenium oxide, etc.) is required, and it cannot be said to be a method suitable for industrial mass production.

Means for Solving the Problems The inventors of the present invention have been conducting research on a method for industrially and easily producing the target compound (I) or a salt thereof, and found that the target compound of high yield and high purity ( The present invention has been completed as a result of discovering a method for producing I) or a salt thereof and further conducting various studies.

That is, the present invention has the general formula [Wherein ring A represents an optionally substituted benzene ring] or a salt thereof is hydrolyzed in the presence of a base, and then subjected to an acylation reaction and / or a neutralization reaction to obtain General formula [Wherein, ring A has the same meaning as defined above, R ₁ represents a hydrogen atom or an acyl group], and the compound is obtained by subjecting it to an oxidation reaction. And a salt thereof represented by the general formula R ₂ ONH ₂ (II) [wherein R ₂ represents a hydrogen atom or an optionally substituted hydrocarbon group] or a salt thereof is reacted. General formula characterized by The present invention relates to a method for producing a compound represented by the formula [wherein the symbols are as defined above] or a salt thereof.

In the method of the present invention, the production process is short, and the target compound (I) is produced from the starting compound (V) in good yield and high purity.
Moreover, it is a method suitable for industrial production because it uses readily available and inexpensive raw materials and reagents.

Furthermore, in this method, the starting compounds (V), (IV),
The amino group on the thiadiazole ring of (III) does not need to be protected, and no amino group protection reaction or deprotection reaction is required unlike conventional known reactions, and the number of steps is shortened, which is extremely advantageous. That's the method.

In the starting material (V) of the present invention, ring A is, for example, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group,
The benzene ring which may be substituted with 1 to 4 substituents selected from nitro group, cyano group, acyl group and the like is shown. Here, as the halogen atom, for example, fluorine, chlorine, bromine, iodine and the like are used, and as the alkyl group, a linear or branched alkyl group having 1 to 8 carbon atoms, specifically, for example, methyl, Ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-
Hexyl, isohexyl, sec-hexyl, neohexyl, tert-hexyl, n-heptyl, isoheptyl, sec-
Heptyl, neoheptyl, tert-heptyl, n-octyl, isooctyl, sec-octyl, neooctyl, tert
-Octyl and the like, preferably an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-
Propyl, i-butyl, sec-butyl, t-butyl and the like are used, and the alkoxy group is a linear or branched alkoxy group having 1 to 8 carbon atoms, specifically, for example, methoxy, ethoxy, n-propoxy. , Isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, sec-pentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, neohexyloxy , tert-hexyloxy, n-heptyloxy, isoheptyloxy, sec-heptyloxy, neoheptyloxy, tert-heptyloxy, n-octyloxy, isooctyloxy, sec-octyloxy, neooctyloxy, tert-octyl Oxy or the like, preferably an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy is used, and the acyl group is an organic group. An acyl group derived from a carboxylic acid, for example, an alkyl group having 1 to 7 carbon atoms. Yl group (eg, formyl, acetyl, propionyl, butyrin, isobutyryl, pentanoyl, hexanoyl, heptanoyl, etc.), aryl-carbonyl group having 6 to 14 carbon atoms (eg, benzoyl, naphthalenecarbonyl, etc.), alkoxy having 1 to 4 carbon atoms -Carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, sec-butoxycarbonyl, ter
t-butoxycarbonyl, etc.), an aryloxy-carbonyl group having 6 to 14 carbon atoms (eg, phenoxycarbonyl, etc.), an aralkyl-carbonyl group having 7 to 19 carbon atoms (eg, benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, naphthyl) Ethylcarbonyl, etc.), 5- to 6-membered heterocyclic carbonyl group (eg, 2-pyrrolylcarbonyl, 4-, 2- or 3-pyrrolylcarbonyl, 3-, 4
-Or 5-pyrazolylcarbonyl, 2-, 4- or 5-
Imidazolylcarbonyl, 1,2,3- or 1,2,4-triazolylcarbonyl, 1H- or 2H-tetrazolylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2-, 4- or 5-oxazolylcarbonyl, 3-, 4- or 5-isoxazolylcarbonyl,
1,2,3-oxadiazol-4- or 5-ylcarbonyl, 1,2,4-oxadiazol-3- or 5-ylcarbonyl, 1,2,5- or 1,3,4-oxa Diazole carbonyl, 2-, 4- or 5-thiazolyl carbonyl, 3-, 4
-Or 5-isothiazolylcarbonyl, 1,2,3-thiadiazol-4- or 5-ylcarbonyl, 1,2,4-thiadiazol-3- or 5-ylcarbonyl, 1,2,5-or 1, 3,4-thiadiazolylcarbonyl, 2- or 3-
Pyrrolidinylcarbonyl, 2-, 3- or 4-pyridylcarbonyl, 2-, 3- or 4-pyridyl-N-oxidecarbonyl, 3- or 4-pyridazinylcarbonyl, 3- or 4-pyridazinyl-N -Oxidecarbonyl, 2-, 4
-Or 5-pyrimidinylcarbonyl, 2-, 4- or 5
-Pyrimidinyl-N-oxidecarbonyl, pyrazinylcarbonyl, 2-, 3- or 4-piperidinylcarbonyl, piperazinylcarbonyl, 3H-indol-2- or 3-ylcarbonyl, 2-, 3- or 4 -Pyranylcarbonyl, 2-, 3- or 4-thiopyranylcarbonyl,
Benzopyranylcarbonyl, quinolylcarbonyl, pyrido [2,3-d] pyrimidinylcarbonyl, 1,5-, 1,6-, 1,
7,1,8-, 2,6- or 2,7-naphthyridinylcarbonyl,
Thieno [2,3-d] pyridylcarbonyl, pyrimidopyridylcarbonyl, pyrazinoquinolylcarbonyl, benzopyranylcarbonyl, etc., 5- to 6-membered heterocyclic acetyl group (eg, 2-pyrrolylacetyl, 3-imidazolylacetyl) , 5-isoxazolylacetyl, etc.), halogenoalkanoyl groups (C1 to C7) (eg, chloroacetyl, difluoroacetyl, trifluoroacetyl, 3-chloropropionyl), substituted aryl having 6 to 14 carbons −
Carbonyl group (eg, 2,4-dichlorobenzoyl, 3,4-diacetoxybenzoyl, 3,4-dihydroxybenzoyl,
3,4-dimethoxybenzoyl, 4-nitrobenzoyl, 4-
Methylbenzoyl) and the like are used.

Next, the method of the present invention will be described step by step.

Compound (IV) can be produced by hydrolyzing compound (V) or a salt thereof in the presence of a base, and then subjecting it to an acylation reaction and / or a neutralization reaction.

As the acyl group represented by R ₁ in the compound (IV), the same acyl group as the substituent of the ring A of the compound (V) can be used. Examples of the salt of compound (V) include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, such as acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, tartaric acid, oxalic acid, propionic acid and maleic acid. , Malic acid,
Acid addition salts with organic acids such as malonic acid, fumaric acid, mandelic acid and ascorbic acid are used.

In this reaction, compound (V) or a salt thereof is hydrolyzed in the presence of a base and then subjected to an acylation reaction, a neutralization reaction, or an acylation reaction and a neutralization reaction. It is done by either method.

The hydrolysis reaction is carried out in the presence of a base.

Suitable bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate.

The base is usually about 2 to the compound (V) or a salt thereof.
It is used in a 10-fold molar amount, preferably about a 2- to 5-fold molar amount, but a large excess can be used. This hydrolysis reaction is carried out in water alone or in a mixed solvent of water and a hydrophilic solvent shown below. Examples of the hydrophilic solvent include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, nitriles such as acetonitrile, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethyl sulfoxide. Kinds are used.

Water and the hydrophilic solvent may be mixed and used at an appropriate ratio.

In this reaction, water is required in at least an equimolar amount with respect to compound (V) or a salt thereof, but a large excess is preferably used.

The reaction temperature is about 15 to 100 ° C, preferably about 20 to 60 ° C. A reaction time of 10 minutes to 3 hours is sufficient.

The compound thus obtained has the general formula [Wherein ring A has the same meaning as described above, and M represents an alkali metal]. As the alkali metal represented by M, lithium, sodium, potassium and the like are used.

The compound (IV ′) may be subjected to the subsequent reaction of the reaction solution, or may be isolated and purified by known means such as concentration, concentration under reduced pressure, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization. It may be isolated and purified by chromatography, etc. and used as a starting material for the next reaction.

(Acylation Reaction) The acylation reaction is a compound obtained by hydrolyzing the compound (V) or a salt thereof in the presence of a base [eg compound (I
V ')] is reacted with an acylating agent. The acylating agent used in this reaction organic carboxylic acids containing the acyl group represented by R ₁ [i.e. formula R ₁ '
Compounds represented by OH (wherein R ₁ ′ represents an acyl group)]
Alternatively, it may be a reactive derivative thereof.

As the reactive derivative of the organic carboxylic acid R ₁ ′ OH, for example, carboxylic acid halide, carboxylic acid anhydride, active amide of carboxylic acid, active ester of carboxylic acid, carboxylic acid azide, active thioester of carboxylic acid and the like are used. The reactive derivative of such a carboxylic acid is specifically described as follows.

(1) Carboxylic acid halide: For example, an aliphatic carboxylic acid halide (eg, acetyl chloride, acetyl bromide), an aromatic carboxylic acid halide (eg, benzoyl chloride, benzoyl bromide) or the like is used.

(2) Carboxylic acid anhydride: For example, aliphatic carboxylic acid anhydride (eg, acetic anhydride), aromatic carboxylic acid anhydride (eg, benzoic anhydride), mono (C 1 to C 6) alkyl carbonic acid (eg, Monomethyl carbonate, monoethyl carbonate, monobutyl carbonate) mixed acid anhydride, aliphatic carboxylic acid having 1 to 6 carbon atoms (eg, formic acid, acetic acid, pivalic acid, valeric acid, isopentanoic acid, trichloroacetic acid) mixed acid anhydride (eg, Acetic formic anhydride), aromatic carboxylic acid (eg, benzoic acid, p-toluic acid, p-chlorobenzoic acid) mixed acid anhydride and the like are used.

(3) Active amide of carboxylic acid: For example, an acid amide with a nitrogen-containing heterocyclic compound such as pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole or benzotriazole is used.

(4) Active ester of carboxylic acid: For example, esters such as methoxymethyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester and mesylphenyl ester are used. Further, 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, 1-hydroxybenztriazole, N-hydroxy-5-norbornene-2,
Esters and the like of 3-dicarboximide, N-hydroxyphthalimide and the like and the above-mentioned carboxylic acid, that is, the compound represented by the general formula, R ₁ ′ OH, are used.

(5) Active thioester of carboxylic acid: For example, an ester with an aromatic heterocyclic thiol compound (for example, 2-pyridylthiol, 2-benzothiazolylthiol) or the like is used.

The heterocycle of the heterocyclic compound represented by the above (3) to (5) is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom or an alkylthio group having 1 to 8 carbon atoms ( (Eg, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, octylthio)
It may be replaced with.

The acylating agent is used in an amount of about 0.8 to 5 times, preferably about 1 to 2 times the molar amount of the compound (V) or a salt thereof.

This reaction is carried out in a solvent that does not inhibit the reaction. As a suitable solvent, the solvent used for the hydrolysis reaction may be used as it is, and for example, water, alcohols such as methanol, ethanol, n-propanol and isopropanol, ethers such as dioxane and tetrahydrofuran, acetone and the like. A solvent inert to the reaction such as ketones, nitriles such as acetonitrile, and amides such as dimethylformamide and dimethylacetamide is used. These solvents may be used alone or as a mixture of two or more kinds at an arbitrary ratio, if necessary. Of these, water, a mixed solvent of water and ethanol,
A mixed solvent of water and dimethylformamide is preferable.

A base may be further added to promote the reaction smoothly. Suitable bases include, for example, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide, and alkaline earth hydroxides such as potassium hydroxide. Inorganic bases such as alkali metals such as group metals, potassium carbonate and sodium carbonate, alkali metals such as potassium hydrogencarbonate and sodium hydrogencarbonate, and alkaline earth metals such as calcium carbonate are used.

Although the reaction temperature is not particularly limited, it is usually preferably carried out at about -10 to 30 ° C. The reaction time is about 30 minutes to 3 hours.

The compound thus obtained may be subjected to the subsequent reaction of the reaction solution, or may be isolated and purified by known methods such as concentration, concentration under reduced pressure, distillation under reduced pressure, liquid conversion, phase transfer, solvent extraction,
It may be isolated and purified by crystallization, recrystallization, chromatography, etc. and then used in the next reaction.

(Neutralization reaction) This reaction is carried out according to a conventional method.

The neutralization reaction is carried out by hydrolyzing the compound (V) or a salt thereof in the presence of a base, or by adding an acid to an alkaline solution obtained by the hydrolysis followed by an acylation reaction.

Here, as the acid for neutralization, hydrochloric acid, sulfuric acid,
An inorganic acid such as phosphoric acid is preferably used.

The neutralization reaction is carried out in water alone or in a mixed solvent of water and a hydrophilic solvent. The same hydrophilic solvent as that used in the above hydrolysis reaction is used.

Since the present invention may generate heat, it is preferably carried out under cooling. Usually, it is suitable to keep the reaction solution at about 0 to 10 ° C. The reaction time is about 15 minutes to 3 hours.

The end of the reaction can be easily confirmed with a pH meter, litmus test paper, etc.

The reaction product (compound (IV)) is usually precipitated as a solid or crystal by the neutralization reaction. The precipitate may be extracted and transferred to a suitable organic solvent (preferably a solvent suitable for carrying out the oxidation reaction described below) according to a conventional method and then subjected to the next reaction, or if desired, once isolated and purified. Good.

Compound (III) or a salt thereof is produced by oxidizing compound (IV) with an oxidizing agent. Examples of the oxidizer include sodium perchlorate, potassium perchlorate, calcium perchlorate, sodium perbromate, perhalogenates such as potassium periodate, permanganates such as potassium permanganate, and dichromium. Dichromates such as potassium acid, ozone, etc. are used. Of these, ozone is particularly preferable. Electrolytic oxidation is also used.

The oxidizing agent may be appropriately used in an amount necessary for producing the compound (III), and theoretically, an amount that generates an equimolar amount of active oxygen is used with respect to 1 molar amount of the compound (IV) as a raw material. The amount is usually 0.8 to 5 times the molar amount. However, there is no problem in using a large excess.

The reaction is generally performed in a solvent that does not interfere with the reaction. Suitable solvents include solvents inert to the reaction, for example, water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, chloroform, 1,2-dichloroethane, tetrachloride. Carbon, halogenated hydrocarbons such as tetrachloroethane, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide and dimethylacetamide, methyl acetate, ethyl acetate, butyl acetate, etc. And the like are used. These solvents may be used alone or as a mixture of two or more kinds at an arbitrary ratio, if necessary.

Of the above, halogenated hydrocarbons and esters are preferable.

The reaction temperature may be selected at a temperature at which the reaction proceeds in the range of about -80 to 25 ° C, but generally about -70 to 0 ° C is suitable. The reaction time varies depending on the amount of the reaction substrate and, for example, the capacity of the ozone generator, but is generally about 5 minutes to 12 hours.

The completion of the reaction can be easily confirmed by thin layer chromatography, high performance liquid chromatography and the like.

After the completion of the reaction, when ozone is used as the oxidant, nitrogen gas is introduced into the reaction solution to remove the ozone gas remaining in the solution. Then, the reaction solution is mixed with sodium acetate or an inorganic base (eg, alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or lithium hydroxide, alkaline earth metal hydroxide such as calcium hydroxide, alkali carbonate such as potassium carbonate or sodium carbonate). The compound (III) may be converted into a salt with a base by adding a metal, an alkali metal hydrogencarbonate such as potassium hydrogencarbonate and sodium hydrogencarbonate, an inorganic base such as an alkaline earth metal carbonate such as calcium carbonate) and the like by a conventional method.

When a halogenated hydrocarbon is used as the reaction solvent, after completion of the reaction, water and sodium acetate, sodium carbonate or the like are added to the reaction solution to make it alkaline, and then the compound (II
The salt of I) with a base may be extracted with water, and this extracted aqueous solution may be subjected to the next reaction. When water, alcohols, ketones, nitriles, amides, and esters are used as reaction solvents, the solvent is distilled off after the reaction, and then water and sodium acetate (or sodium carbonate) and halogenated hydrocarbons are used. After adding the components and mixing well, the mixture may be separated into two layers and the aqueous layer may be separated and used as a raw material for the next reaction. Further, the compound (III) or a salt thereof can be isolated and purified by known means,
For example, it may be isolated and purified by concentration, concentration under reduced pressure, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, chromatography, etc., and then subjected to the next reaction.

Compound (I) or a salt thereof can be produced by reacting compound (III) or a salt thereof with compound (II) or a salt thereof.

In the compound (II), R ₂ represents a hydrogen atom or an optionally substituted hydrocarbon group. Examples of the hydrocarbon group include a linear or branched alkyl group having 1 to 8 carbon atoms (hereinafter sometimes abbreviated as C _1-8 alkyl group), a linear or branched carbon atom having 2 carbon atoms. 6 alkenyl groups (hereinafter C _2-6
Alkenyl group), straight-chain or branched alkynyl group having 2 to 6 carbon atoms (hereinafter also abbreviated as C _2-6 alkynyl group), cycloalkyl group having 3 to 10 carbon atoms (Hereinafter sometimes abbreviated as C _3-10 cycloalkyl group), a cycloalkenyl group having 5 to 6 carbon atoms (hereinafter C
_5-6 cycloalkenyl group), 6 carbon atoms
To 14 aryl groups (hereinafter sometimes abbreviated as C _6-14 aryl groups), C 7 to C 19 aralkyl groups (hereinafter C
_7-19 aralkyl group may be abbreviated) etc. are used.
Particularly, a lower alkyl group having 1 to 3 carbon atoms (hereinafter, C
_(Although abbreviated as _1-3 alkyl group) or a C _1-3 alkyl group substituted with a carboxyl group is preferable. As the C _1-8 alkyl group, the same one as defined for the substituent of ring A in compound (V) is used.

As the C _2-6 alkenyl group, vinyl, allyl, isopropenyl, methallyl, 1,1-dimethylallyl, 2-butenyl, 3-butenyl and the like are used. C _2-6 alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl)
Are used. As the C _3-10 cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and the like are used. As the C _5-6 cycloalkenyl group, 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-
Cyclohexenyl, cyclopentadienyl, cyclohexadienyl and the like are used. Phenyl, biphenylyl, naphthyl, anthryl and the like are used as the C _6-14 aryl group. Benzyl as the aralkyl group for C _7-19 ,
Phenethyl, phenylpropyl, naphthylmethyl, naphthylethyl, anthrylmethyl and the like are used. Substituents for these hydrocarbon groups include, for example, hydroxyl group, C _1-8 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C
_3-10 cycloalkyl group, C _5-6 cycloalkenyl group, C
_6-14 aryl group, C _7-19 aralkyl group, heterocyclic group, C _1-8 alkoxy group (hereinafter sometimes abbreviated as C _1-8 alkoxy group), C _3-10 cycloalkyloxy group, C _6-14
Aryloxy group, C _7-19 aralkyloxy group, heterocyclic oxy group, mercapto group, C _1-8 alkylthio group, C _3-10
Cycloalkylthio group, C _6-14 arylthio group, C _7-19 aralkylthio group, heterocyclic thio group, amino group, mono C _1-8 alkylamino group, di C _1-8 alkylamino group, tri C _1-8 Alkylammonium group, C _3-10 cycloalkylamino group, C _6-14 arylamino group, C _7-19 aralkylamino group, heterocyclic amino group, cyclic amino group, azido group, nitro group, halogen atom, cyano group, Optionally protected carboxyl group, C _1-8 alkoxy-carbonyl group, C _6-14
Aryloxy-carbonyl group, C _7-19 aralkyloxycarbonyl group, carbamoyl group, carbamoyloxy group, phthalimido group, alkanoyl having 1 to 7 carbon atoms (hereinafter sometimes abbreviated as C _1-7 alkanoyl) amino group,
A C _6-14 aryl-carbonylamino group, a C _1-8 alkoxy-carboxamide group, a C _7-19 aralkyloxy-carboxamide group or the like is used, and the same or different 1 to 3
Individuals may exist.

As the substituent of the carbon-hydrogen group, a C _1-8 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _5-6 cycloalkenyl group, C _6-14 Aryl group, C _7-19
As the aralkyl group, those described above are used, and as the C _1-8 alkoxy group, those described above, that is, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy,
n-pentyloxy, n-hexyloxy, etc., C _3-10 cycloalkyloxy groups such as cyclopropyloxy, cyclohexyloxy, etc., C _6-14 aryloxy groups such as phenoxy, naphthyloxy, etc., C _7-19 aralkyl Oxy groups include benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy, C
_1-8 alkylthio groups include methylthio, ethylthio, n-propylthio, n-butylthio, etc., C _3-10 cycloalkylthio groups include cyclopropylthio, cyclohexylthio, etc., C _6-14 arylthio groups include phenylthio, naphthylthio, anthrylthio, etc. , C _7-19 aralkylthio group is benzylthio, phenylethylthio, benzhydrylthio, etc., mono C _1-8 alkylamino group is methylamino,
Ethylamino, n-propylamino, n-butylamino, etc., di C _1-8 alkylamino groups are dimethylamino, diethylamino, methylethylamino, di- (n-propyl)
Amino, di- (n-butyl) amino, etc., tri C _1-8 alkylammonium group is trimethylammonium, triethylammonium, etc., C _3-10 cycloalkylamino group is cyclopropylamino, cyclopentylamino,
Cyclohexylamino, etc., C _6-14 arylamino groups such as anilino, N-methylanilino, etc., C _7-19 aralkylamino groups such as benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, etc. , Cyclic amino groups are pyrrolidino, piperidino, piperazino, morpholino, 1-pyrrolyl, 2-oxo-3-pyrrolidinyl, halogen atoms are fluorine, chlorine, bromine and iodine, and protected carboxyl groups are C _1-8. An alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.) can be _substituted with C _6-14 Aryloxy- Carbonyl group (e.g. phenoxycarbonyl, naphthyl etc. chill oxycarbonyl) a, C _7-19 aralkyloxy - carbonyl group benzyloxycarbonyl, benzhydryloxy carbonyl, etc., C _1-6 alkanoylamino groups such as acetylamino, propionylamino , Butyrylamino, valerylamino, pivaloylamino, etc., C _6-14 aryl-carbonylamino groups such as benzamide, naphthoylamide, phthalimide, etc., C _1-8 alkoxy-carboxamide groups such as methoxycarboxamide (CH
₃ OCONH-), ethoxycarboxamide, tert-butoxycarboxamide and the like, and the C _7-19 aralkyloxy-carboxamide group represents, for example, benzyloxycarboxamide (C ₆ H ₅ CH ₂ OCONH-), benzhydryloxycarboxamide and the like.

The heterocyclic group of the heterocyclic group, the heterocyclic oxy group, the heterocyclic thio group and the heterocyclic amino group has, for example, one to several heteroatoms such as nitrogen atom (which may be oxidized), oxygen atom and sulfur atom. , Preferably a 5- to 8-membered ring group containing 1 to 4 or a condensed ring group thereof. As such a heterocyclic group, 2- or 3-pyrrolyl, 3-, 4- or 5-
-Pyrazolyl, 2-, 4- or 5-imidazolyl, 1,2,3-
Or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4
-Or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,
2,5- or 1,3,4-oxadiazolyl, 2-, 4- or 5
-Thiazolyl, 3-, 4- or 5-isothiazolyl, 1,2,3
-Thiadiazol-4- or 5-yl, 1,2,4-thiadiazol-3- or 5-yl, 1,2,5- or 1,3,4-
Thiadiazolyl, 2- or 3-pyrrolidinyl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide, 3- or 4-pyridazinyl, 3- or 4-pyridazinyl-N-oxide , 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5-pyrimidinyl-N-oxide, pyrazinyl, 2-, 3- or 4-piperidinyl, piperazinyl, 3H-indol-2- or 3-yl, 2-, 3- or 4-pyranyl, 2-, 3- or 4-thiopyranyl, benzopyranyl, quinolyl, pyrido [2,3-d] pyrimidinyl, 1,5-, 1,6-, 1,7-, 1 , 8-, 2,6- or 2,7-naphthyridinyl, thieno [2,3-d] pyridyl, pyrimidopyridyl, pyrazinoquinolyl, benzopyranyl and the like are used.

More preferred substituted hydrocarbon group is hydroxyl group, C
_3-10 cycloalkyl group, C _1-8 alkoxy group, C _1-8 alkylthio group, amino group, tri-C _1-8 alkylammonium group, halogen atom, carboxyl group, C _1-8 alkoxy-
Carbonyl group, carbamoyl group, cyano group, azido group,
A C _1-3 alkyl group (C _1-3 alkyl group refers to methyl, ethyl, n-propyl, isopropyl, etc.) substituted with 1 to 3 heterocyclic groups and the like, and specific examples thereof include: Cyclopropylmethyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-hydroxyethyl, methylthiomethyl, 2
-Aminoethyl, 2- (trimethylammonium) ethyl, 2- (triethylammonium) ethyl, fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, chloromethyl, 2-chloroethyl, 2,2-dichloro Ethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxy Propyl, 1-
Carboxybutyl, 1-carboxybenzyl, 1-carboxy-4'-hydroxybenzyl, cyanomethyl, 1-carboxy-1-methylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-ethoxycarbonyl-1- Methylethyl, 1-ethoxycarbonyl-1-methylethyl, 1-tert
-Butoxycarbonyl-1-methylethyl, 1-benzyloxycarbonyl-1-methylethyl, 1-pivaloyloxycarbonyl-1-methylethyl, carbamoylmethyl, 2-azidoethyl, 2- (pyrazolyl) ethyl, 2- ( Imidazolyl) ethyl, 2- (2-oxopyrrolidine-3-
Yl) ethyl, 2-amino-4-thiazolylmethyl, 4-imidazolylmethyl, 2-oxo-3-pyrrolidinyl, (5
-Amino-1,2,4-thiadiazolyl-3-yl) methyl and the like. The most preferable hydrocarbon group among the listed hydrocarbon groups is a linear chain such as methyl, ethyl or n-propyl.
C _1-3 alkyl group and 2-fluoroethyl, 2-chloroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, carboxymethyl, cyclopropylmethyl, ter
halogen atom such as t-butoxycarbonylmethyl, 1-carboxy-1-methylethyl, 1-tert-butoxycarbonyl-1-methylethyl, hydroxyl group, C _1-8 alkoxy group, carboxyl group, C _1-8 alkoxy-carbonyl Basis,
A linear or branched C _1-3 alkyl group substituted with a cyano group, an allyl group, and a propargyl group.

As the salt of the compound (II), for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid, or an acid addition salt such as an organic acid such as oxalic acid, trifluoroacetic acid or p-toluenesulfonic acid is used.

When an amino group or a substituted amino group is present in the optionally substituted hydrocarbon group represented by R ₂ in the compound (II), these groups form an acid addition salt with the above-mentioned inorganic acid or organic acid. When a carboxyl group, a sulfo group and the like are present, for example, an alkali metal such as sodium and potassium, an alkaline earth metal such as calcium and magnesium, such as triethylamine, trimethylamine, pyridine, collidine, picoline and lutidine. May form a salt with a base such as an organic amine.

Since the compound (III) has an amino group in the molecule, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, such as oxalic acid,
It may be used as an acid addition salt of an organic acid such as trifluoroacetic acid or p-toluenesulfonic acid, and since it has a carboxyl group in the molecule, it is an alkali metal such as sodium or potassium, such as calcium or magnesium. Alkaline earth metal, for example, a salt with a base such as an organic amine such as triethylamine, trimethylamine, pyridine, collidine and lutidine may be used.

In this reaction, the compound (II) or its salt is
The molar amount is about 0.8 to 5 times, preferably about 1 to 2 times the molar amount of I) or a salt thereof.

This reaction is carried out in a solvent that does not inhibit the reaction. Suitable solvents include, for example, water, methanol, ethanol, n-
Propanol, isopropanol, n-butanol, tert
-Alcohols such as butanol, benzene, toluene,
Aromatic hydrocarbons such as xylene, nitrobenzene, chlorobenzene, halogenated carbon hydrogens such as dichloromethane, chloroform, tetrachloroethane, carbon tetrachloride, ethers such as ethyl ether, dioxane, isopropyl ether, tetrahydrofuran, acetone, methyl ethyl ketone Such as ketones, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, dimethylacetamide and hexanemethylphosphoric triamide, esters such as methyl acetate, ethyl acetate and butyl acetate, sulfoxides such as dimethyl sulfoxide, Aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, etc., tertiary organic amines such as pyridine, γ-collidine, quinoline, triethylamine, tri-n-propylamine, N, N-dimethylaniline, etc. Used. These solvents may be used alone or as a mixture of two or more kinds at an arbitrary ratio, if necessary. Of these, water, a mixed solvent of water and ethanol, and a mixed solvent of water and dimethylformamide are preferable.

This reaction may be carried out in the presence of a base to allow the reaction to proceed smoothly. Suitable bases include, for example, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as potassium carbonate and sodium carbonate, potassium hydrogen carbonate and hydrogen carbonate. An inorganic base such as an alkali metal hydrogen carbonate such as sodium and an alkaline earth metal carbonate such as calcium carbonate is used.

In this reaction, when the acid addition salt of compound (II) is used, it is preferable to carry out the reaction in the presence of the above base.

Although the reaction temperature is not particularly limited, it is usually preferably carried out at about -20 to 30 ° C.

The salt of compound (I) has an amino group in the molecule, and therefore, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, such as acetic acid, benzenesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, tartaric acid, oxalic acid, propionic acid, maleic acid, malic acid, malonic acid, fumaric acid, mandelic acid,
An addition salt with an organic acid such as ascorbic acid is used.

Further, since it has a carboxyl group in the molecule, for example, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, such as triethylamine, trimethylamine, pyridine, collidine,
A salt with a base such as an organic amine such as picoline or lutidine is used. When compound (I) is obtained as a free form, it can be converted into the above-mentioned acid addition salt or salt with a base according to a method known per se. When the compound (I) is obtained as a salt, it can be converted into a free form according to a method known per se.

The thus-obtained compound (I) or a salt thereof is isolated and purified by a known method, for example, concentration, vacuum concentration, vacuum distillation, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, chromatography and the like. It can be isolated and purified by.

The object compound (I) of the present invention or a salt thereof has an antibacterial action or β
An azetidinone compound having a lactamase inhibitory action,
It is useful as a raw material for cephalosporin compounds and penicillin compounds (eg, cephalosporin compounds described in JP-A-53-53691 and JP-A-56-18988).

These azetidinone, hofalosporin and penicillin compounds can be produced using compound (I) or a salt thereof according to a method known per se (for example, the method described in JP-A-57-156495; JP-A-54-48790). . For example, a cephalosporin compound is produced by the method shown in the following scheme.

In the above formula, Z is S, S → O, O or CH₂, R₃Is a hydrogen atom,
R is a methoxy group or a formamide group._FourIs a hydrogen atom,
A chill group, hydroxyl group or halogen atom Is replaced
Optionally form a condensed ring at the 2,3-position or 3,4-position
The imidazolium-1-yl groups are shown respectively. here
R_FourThe halogen atom represented by is fluorine, chlorine, bromine, or iodine.
Say elementary. Substitution A The fused ring is an imidazole ring
And a 5- to 6-membered aromatic heterocycle are condensed,
This fused ring is condensed with another aromatic ring or aromatic heterocycle.
You may match. Also added to the right shoulder of the substituent A is
It shows that the substituent A has a monovalent positive charge. Replaced
Optionally forming a condensed ring at the 2,3-position or the 3,4-position.
Midarium-1-yl group (A ) Example above
Hydrocarbon group (R₂) And acyl groups (R₁) Has been replaced
Good imidazo [1,2-a] pyridinium-1-yl groupImidazo [1,2-b] pyridazinium-1-yl groupImidazo [1,5-a] pyridinium-2-yl groupCan be given.

The method represented by the above scheme is a method of acylating compound (VI) or a salt thereof with compound (I) or a salt or a reactive derivative thereof. In this method, compound (I)
Is used as it is or as a salt or a reactive derivative thereof as an acylating agent for the 7-position amino group of the compound (VI). That is, the reactive derivative such as the compound (I) or an inorganic base salt, an organic base salt, an acid halide, an acid azide, an acid anhydride, a mixed acid anhydride, an active amide, an active ester or an active thioester of compound (I) is acylated. Subject to the reaction. Inorganic base salts include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, etc.), and organic base salts include, for example, trimethylamine salt, triethylamine salt, ter.
t-Butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt and the like, and acid halides such as acid chloride and acid bromide are mixed acid anhydrides. Examples of the compound include monoalkyl carbonic acid mixed acid anhydride, aliphatic carboxylic acid mixed acid anhydride, aromatic carboxylic acid mixed acid anhydride, and the like, and active amides include amides with nitrogen-containing heterocyclic compounds (eg, benzotriazole). Is used. As the active ester, all those used for this purpose in the field of β-lactam and pebutide synthesis can be used, and examples thereof include organic phosphoric acid esters as well as p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentaester. Chlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester, 1-hydroxy-1H-2-pyridone ester and the like are used. As the active thioester, an ester with an aromatic heterocyclic thiol compound is used. Compound (V
I) is used as a free salt or as a salt thereof.
As the salt of the compound (VI), an inorganic base salt, an organic base salt, an inorganic acid addition salt, an organic acid addition salt and the like are used. Inorganic base salts include alkali metal salts (eg sodium salt, potassium salt, etc.), alkaline earth metal salts (eg calcium salt, etc.), and organic base salts include, for example, trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt. , Dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt, and the like, and inorganic acid addition salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphorus. As the organic acid addition salt, formate salt, acetate salt, trifluoroacetate salt, methanesulfonate salt, p-toluenesulfonate salt and the like are used. The reactive derivative of compound (I) can be easily produced by a known method or a method analogous thereto. The reactive derivative of compound (I) may be reacted with compound (VI) or a salt thereof as a substance isolated from the reaction mixture, or a reaction containing the reactive derivative of compound (I) before isolation. The mixture can be directly reacted with the compound (VI) or a salt thereof. When the compound (I) is used in the free acid or salt form, a suitable condensing agent is used. Examples of the condensing agent include N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide, such as N, N'-carbonyldiimidazole, N, N '.
-Azolides such as thiocarbonyldiimidazole,
For example, N-ethoxycarbonyl-2-ethoxy-1,2
A dehydrating agent such as dihydroquinoline, phosphorus oxychloride, or alkoxyacetylene, for example, 2-halogenopyridinium salt such as 2-chloro-1-methylpyridinium iodide or 2-fluoro-1-methorpyridinium iodide is used. The reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol-
Ethers such as dimethyl ether, esters such as ethyl formate, ethyl acetate, n-butyl acetate, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane, such as n-hexane. , Hydrocarbons such as benzene and toluene, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, such as acetonitrile and propionitrile In addition to nitriles such as dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water, etc. are used alone or as a mixed solvent. The amount of compound (I) or its salt or reactive derivative used is usually about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound (VI) or its salt. The reaction is about -80 to 80 ° C, preferably about -40 to 50
C., most preferably in the temperature range of about -30 to 30.degree. The reaction time is usually about 1 minute to 72 hours, preferably about 15
3 minutes to 3 hours. When an acid halide is used as the compound (I), the reaction can be carried out in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system. Examples of such a deoxidizing agent include inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate and sodium hydrogen carbonate, such as triethylamine, tri (n-propyl) amine, tri (n-butyl) amine,
Tertiary amines such as diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, pyricon, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine, eg propylene oxide, epichlorohydrin, etc. Alkylene oxides and the like are used.

Thus obtained azetidinone compound, cephalosporin compound and penicillin compound or salts thereof (for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, for example, maleic acid, acetic acid, citric acid, tartaric acid, malic acid, malonic acid, Fumaric acid, benzoic acid, mandelic acid, ascorbic acid, salts with organic acids such as methanesulfonic acid) are isolated and purified by a known isolation and purification means (eg, crystallization, recrystallization, chromatography, etc.). be able to.

The azetidinone compound, cephalosporin compound and penicillin compound thus obtained are used for human and mammalian bacteria (for example, Gram-positive bacteria such as Staphylococcus aureus, Gram-negative bacteria such as Escherichia coli). co
li), Klebsiella p.
neumoniae), Proteus vulga
ris), Proteus mirabili
s), Proteus morganii,
Pseudomonas aerugino
sa)) It is effective for the treatment of infectious diseases such as bacterial respiratory respiratory infections and urinary tract infections.

The raw material compound (V) or a salt thereof is produced, for example, by the following method. That is, 3-amidinocoumarin compound (VII
It is produced by reacting I) with a halogenating agent to give an N-haloamidinocoumarin compound (IX), and then reacting with thiocyanate.

[In the formula, X is a halogen atom such as chlorine and iodine, and other symbols have the same meanings as described above] The halogenation reaction of (VIII) is performed by using a solvent such as methanol,
In alcohols such as ethanol, esters such as ethyl acetate, ethers such as dioxane, dimethoxyethane, diethyl ether, tetrahydrofuran, halogenated carbon hydrogen such as methylene chloride, and a mixed solvent of these and water (methanol is preferable among them) Can be performed by reacting equimolar halogenating agents. As halogenating agents, halogens such as chlorine and bromine, N
-Chlorosuccinimide, chloramine T, N-halogenamides such as N-chlorophthalimide, hypochlorous acid and its salts (calcium salt, sodium salt, potassium salt) and its aqueous solution, tert-butyl hypochlorite, iodobenzene dichloride Active halogen donors such as (VIII) can be used as a free base or as a salt (hydrochloride, acetate). (VIII)
When used in the form of a salt, equimolar amounts of organic tertiary amines such as triethylamine, metal alkoxides such as sodium methoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, acetic acid are used in the reaction solution. An inorganic base such as sodium or potassium acetate may be added. The reaction is carried out at -10 to 30 ° C, preferably -5 to 20 ° C. The produced (IX) may be used for the reaction in the next step of the reaction solution, but can also be taken out from the reaction solution by a usual means such as filtration or extraction.

(IX) is then reacted with an equimolar amount of thiocyanate (eg potassium thiocyanate, sodium thiocyanate, ammonium thiocyanate, etc.). The reaction is preferably carried out in a solvent. As the solvent, alcohols (eg, methanol, ethanol, etc.), ketones (eg, acetone, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), amides (eg, dimethyl) Formamide, dimethylacetamide, etc.), acetonitrile, dimethylsulfoxide, sulfolane, etc. and a mixed solvent thereof are used, and among them, methanol-acetone, methanol-dimethylformamide and the like are preferable. The reaction temperature is 0 to 100 ° C, preferably 0 to 60 ° C, and the reaction time depends on the solvent, the reaction temperature, etc., but is generally 0.5 hours to 24 hours (for example, about 1 hour at a reaction temperature of 40 ° C in a methanol-dimethylformamide solvent). Approximately 8 to 16 hours when the reaction is carried out at room temperature with a methanol-acetone solvent).

The compound (IX), (V) or a salt thereof thus obtained can be isolated and purified by a known means (eg, crystallization, recrystallization,
It can be isolated and purified by chromatography).

Examples and Reference Examples The symbols in the examples have the following meanings.

s: singlet d: doublet t: triplet q: quartet AB q: AB type quartet dd: double doublet m: multiplet br : Broad J: coupling constant DMSO: dimethyl sulfoxide Reference Example 1 3- (N-chloroamidino) coumarin 3-amidinocoumarin hydrochloride ^* 224 g, N-chlorosuccinimide 130 g suspended in 2.5 l of methanol. It becomes cloudy and vigorously stirred. Keeping the internal temperature at 10 to 16 ℃, triethylamine
Add 140 ml dropwise. After stirring for 30 minutes under ice cooling, the precipitated powder was collected by filtration and dried to obtain 140 g of 3- (N-chloroamidino) coumarin powder. mp 180-185 ° C (decomposition) Elemental analysis: Calculated as C ₁₀ H ₇ N ₂ O ₂ Cl (%): C, 53.95; H, 3.17; N, 12,58 Measured value (%); C, 53.81 H, 3.07; N, 12.59 ^* Bulletin of the Chemical Society of Japan (Bull.Chem.Soc.Jap.) 1970 4319 Vol. 2925
Reference Example 2 3- (5-amino-1,2,4-thiadiazol-3-yl) coumarin 140 g of 3- (N-chloroamidino) coumarin, 76 g of potassium thiocyanate, 1.26 l of methanol and 630 ml of acetone The suspension is stirred for 16 hours at room temperature. The reaction solution was filtered and the precipitated crystals were collected by filtration, washed well with water, and dried to give 109 g of the title compound. m.p 220-228 ℃ (decomposition) Elemental analysis value: Calculated as C ₁₁ H ₇ N ₃ O ₂ S (%): C, 53.87; H, 2.88; N, 17.13 Measured value (%); C, 53.99; H, 2.77; N, 17.13 NMR spectrum (d ₆ -DMSO) δ: 7.23 to 7.57 (4H, m), 7.9
7 (2H, s), 8.58 (9H, s) Reference Example 3 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl) -2 (Z) -methoxyiminoacetamide]
-3- (3-oxobutyryloxymethyl) -3-cephem-4-carboxylic acid 7β-amino-3- (3-oxobutyryloxymethyl) -3-cephem-4-carboxylic acid 9.06 g of dichloromethane 200 ml 28.9 g of bistrimethylsilylacetamide, and stir at room temperature until it becomes a solution. Then, it was ice-cooled, and 2- (5-amino-1,2,
4-Thiadiazol-3-yl) -2 (Z) -methoxyiminoacetyl chloride solution in dichloromethane (2-
(5-amino-1,2,4-thiadiazol-3-yl)-
2 (Z) -methoxyiminoacetic acid (5.83 g) and phosphorus pentachloride (6.02 g) prepared in 90 ml of dichloromethane) were added, and the mixture was stirred for 1 hour under ice cooling. Dichloromethane is distilled off, the residue is dissolved in methyl ethyl ketone and water, the organic layer is separated, washed with water and dried, and then the solvent is distilled off. Diethyl ether was added to the residue to give a powder, which was collected by filtration to give the title compound 1
1.8 g (82% yield) are obtained.

NMR spectrum (d₆−DMSO) δ: 2.19 (3H, s), 3.40 and 3.6
5 (2H, ABq, J = 18Hz), 3.63 (2H, s), 3.95 (3H, s), 4.78
And 5.09 (2H, ABq, J = 14Hz), 5.14 (1H, d, J = 4.8Hz), 5.8
4 (1H, d.d, J = 8Hz and 4.8Hz), 8.11 (2H, br.), 9.59 (1H,
d, J = 8 Hz) Reference Example 4 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl) -2 (Z) -methoxyiminoacetamide]
-3-[(imidazo [1,2-b] pyridazinium-1-
Iyl) methyl] -3-cephem-4-carboxylate 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl) -2 (Z) -methoxyiminoacetamide]
-3- (3-oxobutyryloxymethyl) -3-cef
Em-4-carboxylic acid 1.1 g, imidazo [1,2-b] pyridy
1.0 g of potassium iodide and 1.1 g of potassium iodide 50% hydrous acetonitrile 3
Dissolve in 0 ml and stir at 60-70 ° C for 2 hours. After cooling, anti
Apply the reaction solution to silica gel column chromatography and
Fraction containing the desired product, eluting sequentially with seton and hydrous acetone
And the solvent is concentrated under reduced pressure. The residue is MCI gel CHP 2
0P Column chromatography with resin (manufactured by Mitsubishi Kasei)
And elute with water and then with hydrous alcohol to obtain the desired product.
The fractions containing were combined and concentrated under reduced pressure, and the residue was freeze-dried.
Dry to obtain the title compound.

Elemental _{analysis: C 19 H 17 N 9 O} 5 S 2 · 3H 2 O Calculated (%): C, 40.07; H, 4.07; N, 22.13 Found (%): C, 39.75; H, 3.51; N, 21.89 NMR spectrum (d ₆ -DMSO) δ: 3.03 and 3.44 (2H, ABq, J =
18Hz), 3.86 (3H, s), 4.99 (1H, d, J = 4.5Hz), 5.27 and 5.
51 (2H, ABq, J = 14Hz), 5.63 (1H, dd, J = 4.5Hz and 8Hz),
7.8-8.32 (1H, m), 8.12 (2H, br.s), 8.76 (2H, s), 9.04
(1H, d, J = 4Hz), 9.31 (1H, d, J = 9Hz), 9.44 (1H, d, J =
8 Hz) Example 1 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -methoxyiminoacetic acid (1) 3- (5-Amino-1,2,4-thiadiazole -3
-Yl) -Coumarin (12 g) is suspended in 100 ml of ethanol, 100 ml of a 1N sodium hydroxide aqueous solution is added, and the mixture is stirred at room temperature for 60 minutes. 250 ml of ethyl acetate was added, and 100 ml of 1N hydrochloric acid was added under ice cooling.
Neutralize with. Saturate the salt, separate the ethyl acetate layer, and
-(5-amino-1,2,4-thiadiazol-3-yl)
A solution of -2 (Z)-(2-hydroxybenzylidene) -acetic acid in ethyl acetate is obtained.

(2) Ozone is passed while cooling the solution obtained above in a dry ice-acetone (-78 ° C) bath. After the reaction is complete, add 90 ml of water and stir vigorously. Separate the water layer 2
-(5-amino-1,2,4-thiadiazol-3-yl)
A 2-oxoacetic acid aqueous solution is obtained.

(3) While stirring, add 5 g of O-methylhydroxylamine hydrochloride and 8 g of sodium acetate at once, and stir at room temperature for 3 hours.
Stir for hours. After washing with ether, the aqueous layer is concentrated under reduced pressure, 300 ml of methyl ethyl ketone is added, and the mixture is stirred under ice cooling. 50 ml of 1N hydrochloric acid is added to saturate the salt, and the organic layer is separated. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The crystallized residue is triturated with a small amount of ethyl acetate and collected by filtration to obtain 6.1 g of the title compound.

m.p178 ℃ (decomposition) NMR spectrum (d ₆ -DMSO) δ: 3.97 (3H, s), 8.10 (2H,
br.s) Example 2 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -methoxyiminoacetic acid (1) 3- (5-amino-1,2,4 -Thiadiazole-3
-Yl) -Coumarin 24.5 g suspended in 200 ml of ethanol,
Add 200 ml of 1N caustic soda. 60 on a hot water bath at about 40 ℃
Stir while heating for a minute to obtain a uniform bath liquid. After ice cooling, 11 g of chlorocarbonic acid ethyl ester was added all at once and the mixture was stirred for 5 minutes under ice cooling. Add 300 ml of dichloromethane and add 100 ml of 1N hydrochloric acid under ice cooling. The dichloromethane layer was separated, the aqueous layer was extracted with 200 ml of dichloromethane, the dichloromethane layers were combined, and 2- (5-amino-1,2,4-thiadiazole-3 was used.
A solution of -yl) -2 (Z)-(2-ethoxycarbonyloxybenzylidene) acetic acid in dichloromethane is obtained.

(2) Dry ice-acetone bath (-78 ° C)
Cool with and let ozone flow until the reaction liquid turns blue. 8.2 g of sodium acetate was added, the cold bath was removed, and after nitrogen gas was evacuated, the dichloromethane layer was extracted twice with 200 ml of water and 100 ml of water. The aqueous layer was washed with 200 ml of ethyl acetate to give 2- (5-amino-1,2,4
An aqueous solution of -thiazol-3-yl) -2-oxoacetic acid is obtained.

(3) While stirring at room temperature, 9.1 g of O-methylhydroxylamine hydrochloride and 9 g of sodium acetate were added to the above solution,
After stirring for 3 hours, leave overnight at room temperature. Acid sodium sulfite 1.
Add 2 g and concentrate under reduced pressure to about 150 ml. Add 200 ml of methyl ethyl ketone and add 10 ml of concentrated hydrochloric acid while stirring under ice cooling. The aqueous layer is extracted twice with 100 ml of methyl ethyl ketone, the organic layers are combined and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the crystals obtained are triturated with a small amount of ethyl acetate and collected by filtration. The second crystals obtained by concentrating the mother liquor are combined to obtain 10.2 g of the title compound. m.p178 ℃
(Disassembly) NMR spectrum (d ₆ -DMSO) δ: 3.97 (3H, s), 8.10 (2H,
br.s) Example 3 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-ethoxycarbonyloxybenzylidene) acetic acid 3- (5-amino-1, Suspension of 4.9 g of 2,4-thiadiazol-3-yl) -coumarin in 40 ml of ethanol, and addition of 40 ml of 1N caustic soda. Heat on a hot water bath at about 60 ℃ for 15 minutes,
A solution of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-hydroxybenzylidene) -acetic acid disodium salt is obtained. To this, 2.2 g of ethyl chloroformate was added under ice-cooling under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. Add 60 ml of ethyl acetate and 20 ml of 1N hydrochloric acid and stir vigorously. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystals are triturated with ether and filtered to obtain 4.6 g of the title compound. mp 175
℃ (decomposition) Elemental analysis value: Calculated as C ₁₄ H ₁₃ N ₃ O ₅ S (%): C, 50.14; H, 3.91; N, 12.53 Measured value (%): C, 49.63; H, 3.84; N , 12.30 NMR spectrum (d ₆ -DMSO) δ: 1.32 (3H, t, J = 7.5Hz),
4.30 (2H, q, J = 7.5Hz), 7.20 ~ 7.80 (4H, m), 7.55 (1H,
s), 8.00 (2H, s) Example 4 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-acetoxybenzylidene) acetic acid (1) 3- ( 5-amino-1,2,4-thiadiazole-3
-Yl) -Coumarin 4.9 g is suspended in 40 ml of ethanol, and 40 ml of 1N caustic soda is added. Warm for 15 minutes on a hot water bath at about 60 ° C to give 2- (5-amino-1,2,4-thiadiazole-3-
An alkaline solution of (yl) -2 (Z)-(2-hydroxybenzylidene) acetic acid is obtained.

(2) Then, 2.2 g of acetic anhydride was added to the above solution under ice cooling, and 5
Stir under ice cooling for 1 minute. Ethyl acetate 60 ml, 1N hydrochloric acid 20 m
Add l and stir vigorously. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
The crystals are triturated with ether and collected by filtration to obtain 4.8 g of the title compound.

mp 186-187 ℃ (decomposition) Elemental analysis value: Calculated as C ₁₃ H ₁₁ N ₃ O ₄ S (%): C, 51.14; H, 3.63; N, 13.76 Measured value (%): C, 51.06; H , 3.51; N, 13.58 NMR spectrum (d ₆ -DMSO) δ: 2.33 (3H, s), 7.03 to 7.7
3 (4H, m), 7.50 (1H, s), 7.93 (2H, s) Example 5 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-oxoacetic acid (1) 3- (5-amino-1,2,4-thiadiazole-3
-Yl) Coumarin 2.45 g, 1N caustic soda 20 ml, ethanol 20 ml A mixture was stirred for 30 minutes at 50 ℃,
(5-amino-1,2,4-thiadiazol-3-yl)-
An alkaline solution of 2 (Z)-(2-hydroxybenzylidene) acetic acid is obtained.

(2) Then add 1.1 g of ethyl chlorocarbonate under ice cooling,
Stir under ice cooling for 10 minutes. 40 ml of dichloromethane was added, and then neutralized with 10 ml of 1N hydrochloric acid to give 2- (5-amino-1,2,
A solution of 4-thiadiazol-3-yl) -2 (Z)-(2-ethoxycarbonyloxybenzylidene) acetic acid in dichloromethane is obtained.

(3) Ozone is passed while cooling this dichloromethane solution in a dry ice-acetone bath (-78 ° C). 0.82 g of sodium acetate is added to the bluish solution, the mixture is degassed with nitrogen, 20 ml of water is added, and the mixture is vigorously stirred. The aqueous layer was separated and washed with ethyl acetate, then polystyrene resin Amberlite XA
Subject to column chromatography using D-2 and elute with water. After concentrating the eluate, lyophilize it to give 2- (5
-Amino-1,2,4-thiadiazol-3-yl) -2-
1.6 g of sodium oxoacetate is obtained.

Elemental analysis value: Calculated as C ₄ H ₂ N ₃ O ₃ SNal.5H ₂ O (%): C, 21.63; H, 2.27; N, 18.91 Measured value (%): C, 21.83; H, 2.34; N , 15.03 (4) 2- (5-amino-1,2,4-thiadiazole-3
-Yl) -Sodium 2-oxoacetate (320 mg) is dissolved in ice (2 ml), and 1N hydrochloric acid (ml) is added under ice cooling. After freeze-drying, add 6 ml of methanol and filter. Concentrate the filtrate,
2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-oxoacetic acid 200 mg
To get

Claims (1)

[Claims] 1. A general formula [Wherein ring A represents an optionally substituted benzene ring] or a salt thereof is hydrolyzed in the presence of a base, and then subjected to an acylation reaction and / or a neutralization reaction to obtain General formula [Wherein, ring A has the same meaning as defined above, R ₁ represents a hydrogen atom or an acyl group], and the compound is obtained by subjecting it to an oxidation reaction. Characterized by reacting a compound represented by or a salt thereof with a compound represented by the general formula R ₂ ONH ₂ [wherein R ₂ represents a hydrogen atom or an optionally substituted hydrocarbon group] or a salt thereof. General formula A method for producing a compound represented by the formula [wherein the symbols are as defined above] or a salt thereof.