JPH0631258B2 - Method for producing cefalosporin derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [In the formula, X represents a halogen atom, R ₃ represents —CH ₂ R ₅ (R
₅ is a hydrogen atom or a residue of a nucleophilic compound), an optionally substituted hydroxyl group, a thiol group or an amino group (provided that the substituent of the hydroxyl group is a carboxyl group, a sulfo group or a hydroxyl group). Optionally aralkyl, aryl or acyl groups are used) or (Y is an oxygen atom, a sulfur atom or an optionally substituted imino group, Z is a hydrogen atom or an optionally substituted hydroxyl group, amino group, thiol group or hydrocarbon group), and -COOR ₄ is an ester. R ₆ represents an optionally converted carboxyl group and R ₆ represents an alkyl group. ] 7- (4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative represented by the formula, synthetic intermediates thereof, salts thereof and a process for producing them, and further the above compound (I) and thiol Formula for reacting with urea [Wherein the symbols in the formula have the same meanings as defined above] 7- [2-
(2-Aminothiazol-4-yl) -2- (syn)-
Alkoxyiminoacetamide] cephalosporin derivative manufacturing method.

As a result of various studies, the present inventors have found that a new 7- (4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative represented by the general formula (I) is represented by the formula (III). [Wherein the symbols in the formula have the same meanings as defined above] 7- (4-
Alkylate the halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative,
Or formula (IV) 4-halogeno-3-oxo-2-alkoxyiminobutyric acid or a reactive derivative thereof represented by the formula [V] By reacting with a 7-aminocephalosporin derivative represented by [the symbols in the formula are as defined above], or Compound (VII) obtained by reacting 3-oxo-2-alkoxyiminobutyric acid or a reactive derivative thereof represented by [the symbols in the formula are as defined above] with compound (V) [Wherein the symbols in the formula have the same meanings as defined above], and the formula (I) thus obtained
It was found that a derivative (II) having an excellent antibacterial activity was produced by reacting the compound of 1) with thiourea, and the present invention was completed based on these. That is, the present invention provides (1) 7- (4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative (I), (2) 4-halogeno-3-oxo-2-alkoxy. Iminobutyric acid (IV), (3) 7- (3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative (VII), (4) 3-oxo-2-alkoxyiminobutyric acid (VI), (5 ) 7- (4-halogeno-3-oxo-2-hydroxyiminobutyrylamino) cephalosporin derivative (III)
7. A method for producing a compound represented by the formula (I), characterized in that the compound (I) is reacted with thiourea, 7- [2- (2-aminothiazole -4-yl) -2
-(Syn) -alkoxyiminoacetamido] cephalosporin derivative (II), (7) 4-halogeno-3-oxo-2-alkoxyiminobutyric acid (IV) or its reactive derivative and compound (V) (8) a method for producing a compound (IV), which comprises halogenating 3-oxo-2-alkoxyiminobutyric acid (VI), ) 3-oxo-2-alkoxyiminobutyric acid (VI) or its reactive derivative and 7-aminocephalosporin derivative
A method for producing a 7- (3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative (VII), characterized by reacting with (V), (10) 7- (3-oxo-2- 7- (4-halogeno-3-oxo-, characterized by halogenating an alkoxyiminobutyrylamino) cephalosporin derivative (VII)
Method for producing 2-alkoxyiminobutyrylamino) cephalosporin derivative (III), (11) 4-halogeno-3-oxo-2-obtained by halogenating 3-oxo-2-alkoxyiminobutyric acid (VI) 7- (4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) obtained by reacting an alkoxyiminobutyric acid (IV) with a 7-aminocephalosporin derivative (V)
7- [2- (2-aminothiazole-, characterized by reacting a cephalosporin derivative (I) with thiourea
4-yl) -2- (syn) -alkoxyiminoacetamido] cephalosporin derivative (II), (12) 3-oxo-2-alkoxyiminobutyric acid (VI) and 7-
7- (4-halogeno-3-oxo obtained by halogenating the 7- (3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative (VII) obtained by reacting with an aminocephalosporin derivative -2-Alkoxyiminobutyrylamino) cephalosporin derivative (I)
And thiourea are reacted with 7- [2-
(2-Aminothiazol-4-yl) -2- (syn)-
Alkoxyiminoacetamido] cephalosporin derivative (II), (13) 7- (4-halogeno-3-oxo-2-hydroxyiminobutyrylamino) cephalosporin derivative (III)
7- [2- (2- (2- (4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative (I) obtained by alkylation of 7- [2- ( 2-Aminothiazol-4-yl) -2- (syn) -alkoxyiminoacetamide]
The present invention relates to a method for producing a cephalosporin derivative (II).

X in the formulas (I), (III) and (IV) represents a halogen atom such as chlorine, bromine, fluorine and iodine, and chlorine and bromine are often used. The substituent R ₃ on the cephem ring in the formulas (I), (II), (III), (V) and (VII) is —CH ₂ R ₅ (R ₅
Is a hydrogen atom or a residue of a nucleophilic compound), a halogen atom, an optionally substituted hydroxyl group, a thiol group or an amino group, or (Y is an oxygen atom, a sulfur atom or an optionally substituted imino group, and Z is a hydrogen atom or an optionally substituted hydroxyl group, amino group, thiol group or hydrocarbon group). Here, R ₅ represents hydrogen or a residue of a nucleophilic compound, and as the nucleophilic compound residue R ₅ ,
For example, substituted with hydroxyl group, mercapto group, acetyloxy group, propionyloxy group, 3-oxobutyryloxy group, 3-carboxypropionyloxy group, 3-ethoxycarbamoylpropionyloxy group, 4-carboxybutyryloxy group, etc. Optionally substituted lower aliphatic carboxylic acid acyloxy group having 2 to 4 carbon atoms, mandryloxy group, 2-carboxybenzoyloxy group,
Aromatic carboxylic acid acyloxy group which may be substituted such as 2- (carboethoxycarbamoyl) benzoyloxy group and 2- (carboethoxysulfamoyl) benzoyloxy group, carbamoyloxy group, cyano, azido, amino, carbamoylthio group , Thiocarbamoyloxy, amino-protected carbamoyloxy groups (eg,
N-mono-, di- and trihalogenoacetylcarbamoyloxy groups, N-chlorosulfonylcarbamoyloxy groups, N-, such as N-chloroacetylcarbamoyloxy group, N-dichloroacetylcarbamoyloxy group and N-trichloroacetylcarbamoyloxy group. A trimethylsilylcarbamoyloxy group), a phenylglycyloxy group, or a residue of a nucleophilic compound thereof may be an alkyl group (eg, a lower alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl), an acyl group ( Eg acetyl,
A lower aliphatic carboxylic acid acyl group having 2 to 4 carbon atoms such as propionyl and butyryl, and an aromatic carboxylic acid acyl group such as benzoyl, p-chlorobenzoyl, p-methylbenzoyl, and mandeloyl). In this case, the number of substituents is usually 1-2. Alternatively, the nucleophilic compound residue R ₅ may be a quaternary ammonium group, and the nucleophilic compound residue R ₅ also represents a heterocycle linked via S, ie a heterocyclic thio group. The heterocycle is a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from O, S or N, and the nitrogen atom may be oxydated. Examples of these heterocyclic rings include pyridyl, N-oxidepyridyl, pyrimidyl,
Pyridazinyl, N-oxidepyridazivir, pyrazolyl, diazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,
2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl,
2-Tetrazolyl and the like are often used. Further, on these heterocycles, for example, a lower alkyl group having 1 to 3 carbon atoms such as methyl, ethyl and propyl, a lower alkoxy group having 1 to 3 carbon atoms such as methoxy, ethoxy and propoxy, chloro,
Halogen atom such as bromine, trihalogeno-substituted lower alkyl such as trifluoromethyl, trichloroethyl, hydroxyl group, mercapto group, amino group, carboxyl group,
It may have a carbamoyl group, for example, a di-lower alkylamino-lower alkyl group having 1 to 3 carbon atoms such as dimethylaminoethyl or dimethylaminomethyl, or a substituent such as carboxymethyl. When these substituents are substituted on the heterocycle, the number of substituents is usually 1-2. Examples of the quaternary ammonium group represented by R ₅ include pyridinium, 3-methylpyridinium, 4-methylpyridinium, 3-chloropyridinium, 3-bromopyridinium, 3-iodopyridinium, 4-carbamoylpyridinium, 4- (N -Hydroxymethylcarbamoyl) pyridinium, 4- (N-carbomethoxycarbamoyl)
Pyridinium, 4- (N-cyanocarbamoyl) pyridinium, 4- (carboxymethyl) pyridinium, 4-
(Hydroxymethyl) pyridinium, 4- (trifluforomethyl) pyridinium, quinolinium, picolinium or rutidinium are commonly used. When R ₃ represents a hydroxyl group, a thiol group or an amino group,
The hydroxyl group, thiol group or amino group may be substituted, and examples of the substituent include alkyl such as methyl and ethyl (preferably C _1-4 ), aralkyl such as benzyl (preferably C _7-9 ), A hydrocarbon group such as aryl such as phenyl, an acyl group such as acetyl and benzoyl (preferably C _2-8 ), and the like are used, and these substituents are further substituted with a carboxyl group, a sulfo group, a hydroxyl group and the like. (However,
As the substituent of the hydroxyl group, a carboxyl group, a sulfo group or an aralkyl group optionally substituted by a hydroxyl group, an aryl group or an acyl group is used).
Further, in the case of an amino group, a case where it is bonded to an N atom to form a pyrrolidino, morpholino, thiomorpholino group or the like is also included. That is, specific examples thereof include a hydroxyl group, a methoxy group, an ethoxy group, a methylthio group, a carboxymethylthio group, a phenylthio group, an amino group, a dimethylamino group, an ethylamino group, a 2-dimethylaminoethyl group, chlorine and bromine. . Also R ₃ When Y represents an oxygen atom, a sulfur atom or an optionally substituted imino group, examples of the substituent of the optionally substituted imino group include a lower alkyl group such as methyl and ethyl (preferably a carbon atom). 1 to 3), or hydroxyl group, mercapto group, amino group, morpholino group, carboxyl group, sulfo group, carbamoyl group, alkoxycarbonyl group (preferably having 2 to 6 carbon atoms), lower alkylcarbamoyl group (preferably having carbon number) 2-6),
Alkoxy group (preferably having 1 to 4 carbon atoms), alkylthio group (preferably having 1 to 4 carbon atoms), alkylsulfonyl group (preferably having 1 to 4 carbon atoms), acyloxy group (preferably having 2 to 4 carbon atoms), morpholino A lower alkyl group (preferably having a carbon number of 1 to 4) substituted with a carbonyl group, an aryl group such as a phenyl group, an aralkyl group such as a benzyl group,
An acyl group (preferably having 1 to 5 carbon atoms) such as an acetyl group, a propionyl group, a benzoyl group is used. Also, Z
A hydroxyl group, an amino group, a thiol group or a hydrocarbon group (for example, an alkyl group (preferably having 1 to 4 carbon atoms) such as methyl, ethyl, propyl, isobutyl and tertiary butyl, an aralkyl group such as benzyl, phenyl ，
As the substituent of the aryl group such as naphthyl), a lower alkyl group, an acyl group, an aralkyl group, an aryl group and the like as described above are used. Further, these substituents may be substituted with a carboxyl group, a sulfo group, a hydroxyl group or the like. Further, in the case of an amino group, a case where a pyrrolidino, morpholino, thiomorpholino group or the like is formed together with an N atom is also included. That is, As specific examples of, 5-azetylamino-1,3,4-
Thiadiazol-2-yl, 5-amino-1,3,4-
Thiadiazol-2-yl, 5-dimethylamino-1,
3,4-thiadiazol-2-yl, 5-methyl-1,
3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 5-acetamido-1,3,4
-Triazol-2-yl, 5-acetamido-1,
3,4-oxadiazol-2-yl and the like can be mentioned.

The optionally esterified carboxyl group represented by —COOR ₄ is a carboxyl group or an alkali salt such as sodium, potassium or triethylamine salt thereof, an inorganic salt such as an alkaline earth metal, an organic salt, or an esterified carboxyl group. It means a carboxyl group. Examples of such esters include methyl, ethyl, tertiary butyl, tertiary amyl, benzyl, p-nitrobenzyl, alkanoyloxymethyl (acetoxymethyl, etc.), di- or trialkylsilyl (trimethylsilyl, etc.), alkoxy. Lil, benzhydryl, 1-indanyl, phthalidyl, 5-indanyl, phenacyl, phenyl, p-nitrophenyl, alkoxyalkyl (methoxymethyl, ethoxymethyl, etc.), alkenyl, trichloroethyl, methylsulfonylethyl, benzoylmethyl, benzyloxymethyl, t-butyl, methoxybenzyl, trityl, methylthiomethyl, pivaloyloxymethyl, α-
Acetoxybutyl, α-ethoxycarbonyloxy-α
-Α-acyloxy-α-substituted methyl-ester such as methylmethyl is used. These esters are β
-A compound capable of leading to a free form under a mild condition that does not cleave a lactam ring or the like is desirable, and for example, R ₄
Is a group that can be converted to hydrogen under mild acidity or alkalinity, such as diphenylmethyl, substituted phenyl, lower alkylsulfonylethyl, pivaloyloxymethyl, etc., or a group that can be removed by an oxidation / reduction reaction such as trichloroethyl group, A benzyl group or the like is used. Also, −COOR ₄ The group which can be easily hydrolyzed and converted into —COOH is also included.

As the alkyl group represented by R ₆ in the formulas (I), (II), (IV), (VI) and (VII), for example, a lower alkyl group such as methyl or ethyl group is used.

It should be noted that the wavy lines in formulas (I), (III), (IV), (VI) and (VII) may be such that the group OH or OR ₆ is in one or the other position of the two possible syn or anti configurations. Indicates that.

Next, the reaction of the present invention will be described. Compound (I) is produced by alkylating compound (III).
The alkylation reaction is usually carried out in a solvent under ice cooling or around room temperature and is often completed within a few minutes to a few hours. Any solvent may be used as long as it does not inhibit this reaction, for example, tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene dichloride, ethyl acetate, butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, Water or the like or a mixture thereof is used. As the alkylating agent,
For example, methyl iodide, methyl bromide, ethyl iodide, methyl halide of ethyl bromide, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane or methyl p-toluenesulfonate is used. Compounds in the presence of alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and bases such as triethylamine, pyridine and dimethylaniline, except for diazomethane and diazoethane. It is carried out by reacting (III) with the above-mentioned alkylating agent. Thus obtained
Although (I) can be isolated and purified by a known means, it can also be used as a starting material for the next reaction without separation.

The reaction for reacting compound (I) with thiourea to produce compound (II) is usually carried out in a solvent. Any solvent may be used as long as it does not inhibit this reaction, for example, water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N, N-dimethylformamide,
A solvent such as N, N-dimethylacetamide, N-methylpiperidone or a mixture thereof is used.
The reaction is carried out under ice-cooling or room temperature or warming. Usually, 1 to several equivalents of thiourea are used with respect to compound (I). The reaction time is 1 to 48 hours, preferably 1 to 1
It's 0 hours. The thus obtained (II) can be isolated and purified by known means such as concentration, concentration under reduced pressure, crystallization, recrystallization, solvent extraction, liquid conversion, salting out, fractional distillation, distillation and chromatography.

Compound (IV) or (VI) is reacted with 7-aminocephalosporin derivative (V) to obtain compounds (I) and (VII), respectively. Compound (IV) or (VI) is used as it is in a free state or its reactive derivative is used as an acylating agent for the 7-position amino group of compound (V). That is, the compound (IV) or (VI) is
As a free salt or as a salt with an alkali or alkaline earth metal such as sodium, potassium or calcium having a carboxyl group, or an organic amine such as trimethylamine or pyridine, or its acid halide (eg, acid chloride, acid bromide), acid anhydride , Mixed acid anhydrides, activated amides, activated esters and the like are used for the acylation reaction. As the activated ester, for example, p
-Nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester or N-hydroxyphthalimide ester is used. Examples of the mixed acid anhydride include mixed acid anhydrides with carbonic acid monoesters such as carbonic acid monomethyl ester and carbonic acid monoisobutyl ester, and mixed acid anhydrides with lower alkanoic acid which may be substituted with halogen such as pivalic acid and trichloroacetic acid. Things etc. are used. When the compound (IV) or (VI) is used in a 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,
Azolide compounds such as N, N'-carbonylimidazole, N, N'-thionyldiimidazole, dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride and alkoxyacetylene, 2 -Halogenopyridinium salts (eg, 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyl iodide) and the like are used. When these condensing agents are used, the reaction is considered to proceed via the reactive derivative of compound (IV) or (VI). The reaction is generally carried out in a suitable solvent. Examples of such a solvent include halogenated hydrocarbons such as chloroform and methylene dichloride, ethers such as tetrahydrofuran and dioxane, dimethylformamide, dimethylacetamide,
Acetone, water, etc., or a mixture thereof are often used.
The amount of compound (IV) or (VI) used is usually about 1 to several moles per 1 mole of compound (V). The reaction is generally -50
It is performed in the range of -40 ° C. The reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 10 hours.
The thus obtained (I) is isolated by a known means as described above, and (VII) is similarly isolated by a known means, but it is usually used as a starting material for the next step without separation. it can.

The reaction used for halogenating active hydrogen in ordinary organic chemistry is applied to the reaction of halogenating compound (VI) and (VII) to lead to compound (IV) and (I), respectively. Examples of the halogenating agent include chlorine, bromine, sulfuryl chloride and the like. The reaction may proceed smoothly by performing it in a solvent. As such a solvent,
For example, chloroform, methylene chloride, dichloroethane, dichloroethylene, carbon tetrachloride, acetic acid, benzene,
Toluene or the like is used. The reaction is carried out under ice cooling or under heating, but is usually carried out in the range of 0 to 60 ° C. The reaction time is generally 5 minutes to 48 hours, preferably 10 minutes to 10 hours. The obtained (IV) and (I) can be isolated and purified by the known means as described above. The compound (IV) may be provided as a raw material for the reaction with the compound (V) as it is as a reaction mixture without separation.

Among the raw material compounds used in the present invention, for 3-oxo-2-alkoxyiminobutyric acid represented by the formula (VI), those esters are described in, for example, Journal.
Obj Indian Chemical Society (J.
Indian Chem. Soc.), 42 , 677 (1965); Journal of the American Chemical Society (J. Am. Chem. Soc.), 60 , 1328 (193).
8) and can be obtained by removing the ester group from the corresponding ester under conditions such as ordinary ester hydrolysis. This (VI) is usually a compound without purification.
Used as a raw material for the production of (IV) or (VII). Other raw material compounds (III) are chemical and pharmaceutical-butylene (Chem.Pharm.Bull.), 25 , 311.
7 (1977) or a method similar thereto. Further, the 7-aminocephalosporin derivative represented by the formula (V) can be obtained, for example, from West German Patent Application Publication No. 246.
No. 1478, West German Patent Application No. p260706
No. 4.4, West German patent application No. p26192243.8
No. 5, JP-A-50-52083, West German Application Publication Nos. 2460331 and 2460332, and JP-A-51-138696 and 50-12.
9590, 50-95485, 51-11059
3, 51-138697, 51-108087, Journal of the American Chemicals.
Society (J. Am. Chem. Soc.), 96 , 4986 (1
974), Helvetica Kimika Actor (Helv.Chim.Ac
ta.), 57 , 1919 (1974), ibid. 58 , 243.
7 (1975), and JP-A-49-116090, J. Am.Chem.Soc., 98 , 2342 (197)
6) ,: Helv.Chim.Acta., 55 , 408 (1972).
It can be produced by an appropriate method selected from the methods described in, etc., or a method according to these methods.

The compounds (IV) and (VI) thus obtained are excellent synthetic intermediates for useful novel compounds, and the compounds (I) and (VII) are novel cephalosporin derivatives having antibacterial activity. And it can be an advantageous synthetic intermediate for synthesizing the compound (II).

The cephalosporin derivative represented by the formula (II) is It is considered that the compound has a tautomeric structure of a 2-aminothiazole body and a 2-iminothiazoline body as described above, but in the present specification, it is described as a thiazole type.

Examples of the compound (I) produced by the method of the present invention include 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-5-yl ) Thiomethyl-3-cephem-4-carboxylic acid 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-4-yl) thiomethyl-3- Cephem-4-carboxylic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid Acid benzhydryl ester 7- (4-bromo-3-oxo-2-ethoxyiminobutyrylamino) cephalosporanic acid 7- (4-bromo-3-oxo-2-ethoxy) Minobutyrylamino) cephalosporanic acid t-butyl ester 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) cephalosporanic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyryl) Amino) cephalosporanic acid 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3- (2-methyl-1,3,4-liadiazol-5-yl) thiomethyl-3- Cephem-4
-Carboxylic acid 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3- [1- (2-N, N-dimethylaminoethyl) -1H-tetrazol-5-yl] thiomethyl- 3-Cephem-4-carboxylic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3-carbamoyloxymethyl-3-
Cephem-4-carboxylic acid 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3-carbamoyloxymethyl-3-
Cephem-4-carboxylic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) desacetoxycephalosporanic acid 7- (4-Bromo-3-oxo-2-methoxyiminobutyrylamino)- 3- (5-acetamide-1,3,4
-Thiadiazol-2-yl) -3-cephem-4-carboxylic acid 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3- (5-methyl-1,3,4-thiadiazole -2-yl) -3-cephem-4-carboxylic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1,3,4-thiadiazole-
2-yl) -3-cephem-4-carboxylic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (5-acetamido-1,3,4
-Triazol-2-yl) -3-cephem-4-carboxylic acid 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3- (5-acetamido-1,3,4
-Oxadiazol-2-yl) -3-cephem-4-
Carboxylic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (5-dimethylamino-1,3,3
4-thiadiazol-2-yl) -3-cephem-4-
Carboxylic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (5-N-methylacetamide-
1,3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3-methylthio-3-cephem-4 −
For example, carboxylic acid.

As the compound (VII) produced by the method of the present invention,
For example, 7- (3-oxo-2-methyliminobutyrylamino)
-3- (1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-4-yl) thiomethyl-3-cephem-4-carboxylic acid Sodium 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester 7- (3 -Oxo-2-ethoxyiminobutyrylamino) cephalosporanic acid 7- (3-oxo-2-ethoxyiminobutyrylamino) cephalosporanic acid t-butyl ester 7- (3-oxo-2-methoxyiminobutyrylamino) ) Cephalosporanic acid 7- (3-oxo-2-methoxyiminobutyrylamino) cephalosporanic acid Natri Mu 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid 7- (3 -Oxo-2-methoxyiminobutyrylamino) -3- [1- (2-N, N-dimethylaminoethyl) -1H-tetrazol-5-yl] thiomethyl-3
-Cephem-4-carboxylic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3-carbamoyloxymethyl-3-cephem-
4-Carboxylic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3-carbamoyloxymethyl-3-cephem-
Sodium 4-carboxylate 7- (3-oxo-2-methoxyiminobutyrylamino) desacetoxycephalosporanic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (5-acetamido-1, 3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (5-methyl-1,3,4-thiadiazole- 2-yl) -3-cephem-4-carboxylic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (1,3,4-thiadiazol-2-yl)
-3-Cephem-4-carboxylic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (5-acetamido-1,3,4-triazol-2-yl) -3-cephem-4 -Carboxylic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (5-acetamido-1,3,4-oxadiazol-2-yl) -3-cephem-4-carboxylic acid 7 -(3-Oxo-2-methoxyiminobutyrylamino) -3- (5-dimethylamino-1,3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid 7- (3-oxo 2-Methoxyiminobutyrylamino) -3- (5-N-methylacetamide-1,3,4
-Thiadiazol-2-yl) -3-cephem-4-carboxylic acid 7- (3-oxo-2-methoxyiminobutyrylamino) -3-methylthio-3-cephem-4-carboxylic acid and the like.

Examples of the compound (IV) include 4-bromo-3-oxo-2-methoxyiminobutyric acid 4-chloro-3-oxo-2-methoxyiminobutyric acid 4-bromo-3-oxo-2-ethoxyiminobutyric acid 4-chloro. -3-Oxo-2-ethoxyiminobutyric acid and the like.

Example 1 20.3 g of methyl 3-oxo-2-methoxyiminobutyrate
Is dissolved in 100 m of methanol, and 1N-NaO is added to this.
200 m of H aqueous solution is dripped for about 30 minutes. A little heat is generated during this period. After completion of the dropwise addition, stirring is continued for 1 hour at room temperature, then methanol is distilled off under reduced pressure and the residue is washed with ethyl acetate. The aqueous layer is adjusted to pH 2.0 with 3N-HCl under ice cooling, sodium chloride is added, and the mixture is extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and then concentrated to obtain a crude product of 3-oxo-2-methoxyiminobutyric acid as a viscous oil. This is recrystallized from chloroform-n-hexane to obtain colorless crystals (16.0 g). Melting point 81-82 [deg.] C.

NMR (CDCl ₃ ): 2.40 ppm (3H, s, CH ₃ CO), 4.10 ppm
(3H, s, OCH ₃ ), 10.87ppm (1H, s, COOH) Elemental analysis value C ₅ H ₇ NO ₄ Calculated value: C 41.38; H 4.86; N 9.65 Measured value: C 41.71; H 4.87; N 9.49 Example 2. Methyl 3-oxo-2-ethoxyiminobutyrate 1.87 g
Is dissolved in 80 m of methanol and 1N-NaOH aqueous solution 4
0 m is dropped. After completion of the dropwise addition, stirring was continued for 1 hour at room temperature and then the same treatment as in Example 1 was performed to obtain a crude product of 3-oxo-2-ethoxyiminobutyric acid in the form of colorless crystals. _{1.3g NMR (CDCl 3): 1.35ppm} (3H, t, CH 2 CH 3), 2.42ppm
(3H, s, CH ₃ CO), 4.40ppm (2H, q, CH ₂ CH ₃ ), 7.82ppm (1H, s, COO
H). Example 3 590 mg of 3-oxo-2-ethoxyiminobutyric acid was dissolved in 10 m of methylene chloride, a solution of 640 mg of bromine in 5 m of methylene chloride was added dropwise, and the mixture was stirred at 40 ° C. for 30 minutes. Wash the reaction mixture with ice water and concentrate under reduced pressure to 4-
A crude product of bromo-3-oxo-2-ethoxyiminobutyric acid is obtained. 750 mg.

_{NMR (CDCl 3): 1.40ppm (} 3H, t, CH 2 CH 3), 4.37ppm
(2H, s, BrCH ₂ ), 4.45 ppm (2H, q, CH ₂ CH ₃ ). Example 4 7.0 g of 3-oxo-2-methoxyiminobutyric acid was dissolved in 50 m of methylene chloride, and 7.71 g of bromine was added thereto. When a small amount of a solution dissolved in 10 m of methylene chloride is added and heated in a hot water bath at 50 ° C and the color of bromine begins to disappear, remove the hot water bath and drop the remaining bromine solution at room temperature at a rate at which the color of bromine disappears. To do. After the dropwise addition, when the color of bromine disappears, the stirring is stopped and the mixture is concentrated under reduced pressure to obtain a crude product of 4-bromo-3-oxo-2-methoxyiminobutyric acid as an oil. 11.1 g.

NMR (CDCl ₃ ): 4.17 ppm (3H, s, OCH ₃ ), 4.37 ppm (2
H, s, BrCH ₂ ). Example 5 320 mg of 3-oxo-2-ethoxyiminobutyric acid was dissolved in 10 m of methylene chloride, a solution of 400 mg of bromine in 3 m of methylene chloride was added dropwise, and the mixture was stirred at room temperature for 2 hours. Then, 500 mg of phosphorus pentachloride was added thereto and stirred at room temperature for 1 hour to obtain a methylene chloride solution of 4-bromo-3-oxo-2-ethoxyiminobutyric acid chloride. On the other hand, t-butyl 7-aminocephalosporanate 660 mg
Then, 500 mg of pyridine is dissolved in 10 m of methylene chloride, cooled to -30 ° C, and the solution of the above acid chloride is added dropwise over about 15 minutes while stirring. After completion of the dropping, the mixture is returned to room temperature and stirred for 2 hours, then concentrated under reduced pressure and the residue is dissolved in ethyl acetate. The ethyl acetate layer was washed with 3N-HCl, washed with water, then with 5% NaHCO ₃ aqueous solution and water, dried, and the ethyl acetate was distilled off to obtain a semi-solid, which was purified by silica gel chromatography to give 7- (4- Bromo-3-oxo-2
-Ethoxyiminobutylamino) cephalosporanic acid
t-Butyl is obtained as a foamy solid. 620 mg.

_{NMR (CDCl 3): 1.36ppm (} 3H, t, CH 2 CH 3), 1.50ppm
(9H, s, -C (CH ₃ ) ₃ ), 2.05ppm (3H, s, CH ₃ CO), 3.44ppm (2H, q, 2
-CH ₂ ), 4.37ppm (2H, q, CH ₂ CH ₃ ), 4.55ppm (2H, s, BrCH ₂ ), 4.9
0ppm (2H, q, 3-CH ₂ ), 4.99ppm (1H, d, 6-H), 5.83ppm (1H, dd, 7
-H), 7.12 ppm (1H, d, CONH) Example 6 t-Butyl 200 7- (4-bromo-3-oxo-2-ethoxyiminobutyrylamino) cephalosporanate
m is dissolved in 5 m of ethanol, 100 mg of thiourea is added, and the mixture is stirred at room temperature for 2 hours. Ethanol is distilled off under reduced pressure, ethyl acetate and water are added, and the mixture is shaken. The ethyl acetate layer is washed with water and dried. The oily substance obtained by distilling off ethyl acetate was purified by silica gel chromatography to obtain 7- [2-
(2-Aminothiazol-4-yl) -2- (syn)-
Ethoxyiminoacetamide] cephalosporanic acid t
-Butyl is obtained as a foamy solid. _{152mg NMR (CDCl 3): 1.22ppm} (3H, t, CH 2 CH 3), 1.43ppm
(9H, s, C (CH ₃ ) ₃ ), 1.97ppm (3H, s, CH ₃ COO), 3.36ppm (2H, q, 2
-CH ₂ ), 4.19ppm (2H, q, CH ₂ CH ₃ ), 4.82ppm (2H, q, 3-CH ₂ ), 4.9
3ppm (1H, d, 6- H), 5.55ppm (2H, bs, NH 2), 5.86ppm (1H, dd, 7-
H), 6.74 ppm (1 H, s, thiazole 5-H), 7.32 ppm (1 H, d, CONH). Example 7 290 mg of 3-oxo-2-methoxyiminobutyric acid is dissolved in 10 m of methylene chloride. A solution prepared by dissolving 320 mg of bromine in 1 m of methylene chloride was added thereto, and the mixture was stirred at room temperature for 1 hour, then 500 mg of dicyclohexylcarbodiimide and 7-
Amino-3- (1-methyl-1H-tetrazole-5-
Il) Thiomethyl-3-cephem-4-carboxylic acid 495 mg of benzhydryl is added, and the mixture is stirred at room temperature for 3 hours. Methylene chloride was distilled off under reduced pressure, ethyl acetate was added to the residue and the insoluble matter was filtered off. The filtrate was washed with a 5% NaHCO ₃ aqueous solution and then with water and dried, and ethyl acetate was distilled off to obtain an oily substance. Purify by silica gel chromatography 7- (4
-Bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazole-5-
Yl) Thiomethyl-3-cephem-4-carboxylic acid benzhydryl is obtained. 480 mg NMR (CDCl ₃ ): 3.70 ppm (2H, s, 2-CH ₂ ), 3.80 ppm
(3H, s, N-CH ₃ ), 4.11ppm (3H, s, OCH ₃ ), 4.29ppm (2H, q, 3-C
H ₂ ), 4.53ppm (2H, s, BrCH ₂ ), 4.99ppm (1H, d, 6-H), 5.85ppm
(1H, dd, 7-H), 6.88ppm (1H, s, 7.31ppm (10H, s, Example 8 7- (4-Bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid Benzhydryl (610 mg) 20m ethanol,
After dissolving in a mixture of 10 m of tetrahydrofuran, 304 mg of thiourea was added and the mixture was stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, washed with water and dried. The residue obtained by distilling off ethyl acetate was purified by silica gel chromatography to obtain 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- (1- Methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid benzhydryl is obtained. 540 mg NMR (CDCl ₃ ): 3.70 ppm (2H, s, 2-CH ₂ ), 3.78 ppm
(3H, s, N-CH ₃ ), 3.97ppm (3H, s, OCH ₃ ), 4.28ppm (2H, q, 3-C
H ₂ ), 5.02ppm (1H, d, 6-H), 5.97ppm (1H, dd, 7-H), 6.77ppm (1
H, s, thiazole 5-H), 6.90ppm (1H, s, 7.31ppm (10H, s, 7.77ppm (1H, d, CONH). 50mg of this product was added to a mixture of 0.5m of anisole and 2.5m of trifluoroacetic acid and stirred at room temperature for 30 minutes, then anhydrous ether was added thereto and the precipitate was collected by filtration. . This was dissolved in a small amount of 5% NaHCO ₃ aqueous solution, passed through a column of Sephadex LH-20 (registered trademark; manufactured by Pharmacia Fine Chemicals Co., Ltd.) and purified to obtain 7- [2- (2-aminothiazol-4-yl) -2-. (Syn) -methoxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-
35 mg of sodium carboxylate are obtained.

NMR (D ₂ O): 3.59ppm (2H, q, 2-CH ₂ ), 3.93ppm (3H,
s, OCH ₃ ), 3.98ppm (3H, s, N-CH ₃ ), 4.08ppm (2H, q, 3-CH ₂ ), 5.
12ppm (1H, d, 6-H), 5.72ppm (1H, d, 7-H), 6.93ppm (1H, s, thiazole 5-H). Example 9 Chlorinated 145mg of 3-oxo-2-methoxyiminobutyric acid Dissolve in 10 m of methylene, add 250 mg of phosphorus pentachloride and stir at room temperature for 1 hour to obtain a solution of 3-oxo-2-methoxyiminobutyric acid chloride. On the other hand, 7-amino-3- (1
-Methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid benzhydryl 49
5 g and pyridine (240 g) are dissolved in methylene chloride (10 m), cooled to -30 ° C, and the above acid chloride solution is added dropwise over about 20 minutes. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours, then 100 m of ethyl acetate was added, and water, 1N-HCl, water and 5% Na were added.
It is washed with an aqueous solution of HCO _{3 and} then with water, and dried. The solvent was evaporated and the obtained residue was purified by silica gel chromatography to give 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazole-5.
-Yl) thiomethyl-3-cephem-4-carboxylic acid
Benzhydryl is obtained. _{440mg NMR (CDCl 3): 2.38ppm} (3H, s, CH 3 CO), 3.72ppm
(2H, s, 2-CH ₂ ), 3.80ppm (3H, s, N-CH ₃ ), 4.10ppm (3H, s, OC
H ₃ ), 4.28ppm (2H, q, 3-CH ₃ ), 5.00ppm (1H, d, 6-H), 5.88ppm
(1H, dd, 7-H), 6.88ppm (1H, s, 6.92ppm (1H, d, CONH), 7.31ppm (10H, s Example 10 3-Oxo-2-ethoxyiminobutyric acid (160 mg) was dissolved in methylene chloride (5 m), phosphorus pentachloride (250 mg) was added, and the mixture was stirred at room temperature for 1 hour to obtain a solution of acid chloride. Meanwhile, t-butyl 7-aminocephalosporanate 330 mg,
Dissolve 240 mg of pyridine in 5 m of methylene chloride-50
After cooling to ℃, the above acid chloride solution is added dropwise, and after completion of the addition, the mixture is stirred at room temperature for 2 hours. Ethyl acetate (100 m) is added to this, washed with water, 3N-HCl, water, 5% NaHCO ₃ aqueous solution, and then with water, and dried. The residue obtained by distilling off the solvent was purified by silica gel chromatography to give 7- (3-
Oxo-2-ethoxyiminobutyrylamino) -t-butyl cephalosporanate is obtained. _{340mg NMR (CDCl 3): 1.34ppm} (3H, t, CH 2 CH 3), 1.50ppm
(9H, s, C (CH ₃ ) ₃ ), 2.04ppm (3H, s, CH ₃ COO), 2.37ppm (3H, s, C
H ₃ CO), 3.42ppm (2H, q, 2-CH ₂ ), 4.33ppm (2H, q, CH ₂ CH ₃ ), 4.8
9ppm (2H, q, 3-CH ₂ ), 4.97ppm (1H, d, 6-H), 5.83ppm (1H, dd, 7
-H), 6.84 ppm (1H, d, CONH). Example 11 t-Butyl tert-butyl 7- (3-oxo-2-ethoxyiminobutyrylamino) cephalosporanate 235 mg was dissolved in 10 m of methylene chloride, and this was heated to 35 ° C. After warming, a solution of 88 mg of bromine in 3 m of methylene chloride is added and stirred. When the color of bromine starts to disappear, stop heating and stir at room temperature until it almost completely fades. Ice water is added to the reaction solution, which is then shaken and then separated, and the methylene chloride layer is further washed with ice water and dried. The residue obtained by distilling off methylene chloride is purified by silica gel chromatography to obtain t-butyl 7- (4-bromo-3-oxo-2-ethoxyiminobutyrylamino) cephalosporanate. 190 mg.
This product was identified by comparing with that obtained in Example 5 by NMR and the like.

Example 12 7- (4-chloro-3-oxo-2-hydroxyiminobutyrylamino) cephalosporanic acid 419 mg in water 7
m and acetone 7 m, and 300 ml of sodium carbonate was added to the mixture under ice cooling with stirring to dissolve it, and 600 mg of dimethyl sulfate was added dropwise. After 30 minutes, add 300 mg of sodium carbonate and 300 mg of dimethyl sulfate, and then add 30 mg.
Continue stirring for a minute. Add 20m of ice water to the reaction mixture and add 10%
The pH is adjusted to 2.0 by adding hydrochloric acid and the mixture is extracted with ethyl acetate.
The extract layer was washed with water, dried and concentrated to give 7- (4-chloro-3-
A crude product of oxo-2-methoxyiminobutyrylamino) cephalosporanic acid is obtained in powder form. 280 mg NMR (δ ₆ -DMSO): 2.00 ppm (3H, s, CH ₃ COO), 3.5
0ppm (2H, bs, 2-CH ₂ ), 4.01ppm (3H, s, OCH ₃ ), 4.76ppm (2H, s,
ClCH ₂ CO), 4.81ppm (2H, q, 3-CH ₂ ), 5.11ppm (1H, d, 6-H), 5.7
3ppm (1H, dd, 7-H), 9.53ppm (1H, d, CONH). Example 13 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) cephalosporanic acid 210mg was added to N, N.
-Dissolve in 4 m of dimethylacetamide, add 100 mg of thiourea thereto, and stir at room temperature for 4 hours. 30 m of ether was added to the reaction solution, and the precipitated oily matter was separated by decantation and dissolved in a 5% NaHCO ₃ aqueous solution, and Amberlite XAD-2 (registered trademark; manufactured by Rohm & Haas Co.)
Purified by column chromatography using 7- [2-
(2-Aminothiazol-4-yl) -2- (syn)-
Methoxyiminoacetamide] cephalosporanate sodium is obtained as a white powder. 141 mg NMR (D ₂ O): 2.07 ppm (3H, s, COCH ₃ ), 3.53 ppm (2H,
q, 2-CH ₂ ), 3.98ppm (3H, s, OCH ₃ ), 4.75ppm (2H, q, 3-CH ₂ ), 5.
21 ppm (1H, d, 6-H), 5.81ppm (1H, d, 7-H), 7.01ppm (1H, s, thiazole 5-H). Example 14 Combination of Examples 12, 13 or 7,8 The compounds produced according to the combination method or the combination method of 10, 11, and 6 are exemplified in the table.

Claims (6)

[Claims] 1. A formula [In the formula, X represents a halogen atom, R ₃ represents —CH ₂ R ₅ (R
₅ is a hydrogen atom or a residue of a nucleophilic compound), an optionally substituted hydroxyl group, a thiol group or an amino group (provided that the substituent of the hydroxyl group is a carboxyl group, a sulfo group or a hydroxyl group). Optionally aralkyl, aryl or acyl groups are used) or (Y is an oxygen atom, a sulfur atom or an optionally substituted imino group, Z is a hydrogen atom or an optionally substituted hydroxyl group, an amino group, a thiol group or a hydrocarbon group), and -COOR ₄ is an ester. R ₆ represents an optionally converted carboxyl group and R ₆ represents an alkyl group. ] A 7- (4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative represented by the formula or a salt thereof is reacted with thiourea. [In the formula, R ₃ , —COOR ₄ , and R ₆ are the same as defined above] 7- [2- (2-aminothiazol-4-yl) -2- (syn) -alkoxyiminoacetamide]
A method for producing a cephalosporin derivative or a salt thereof. 2. A formula [In the formula, X represents a halogen atom, R ₃ represents —CH ₂ R ₅ (R
₅ is a hydrogen atom or a residue of a nucleophilic compound), an optionally substituted hydroxyl group, a thiol group or an amino group (provided that the substituent of the hydroxyl group is a carboxyl group, a sulfo group or a hydroxyl group). Optionally aralkyl, aryl or acyl groups are used) or (Y is an oxygen atom, a sulfur atom or an optionally substituted imino group, Z is a hydrogen atom or an optionally substituted hydroxyl group, an amino group, a thiol group or a hydrocarbon group), and -COOR ₄ is an ester. Indicates a carboxyl group which may be compounded. ] 7- (4-halogeno-3-oxo-2-hydroxyiminobutyrylamino) cephalosporin derivative or its salt represented by the formula 7- (4-halogeno-3-oxo-2-alkoxy) The production method according to claim 1, wherein an iminobutyrylamino) cephalosporin derivative or a salt thereof is reacted with thiourea. 3. A formula [Wherein X and R ₆ have the same meanings as in claim 1] and 4-halogeno-3-oxo-2-alkoxyiminobutyric acid or a reactive derivative thereof [Wherein, R ₃ and —COOR ₄ have the same meanings as in claim 1], and 7- (4-halogeno-3 obtained by reacting with a 7-aminocephalosporin derivative or a salt thereof. The method according to claim 1, wherein the -oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or a salt thereof is reacted with thiourea. 4. A formula [In the formula, R ₃ , -COOR ₄ , and R ₆ have the same meanings as in claim 1] 7- (3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or a salt thereof 7. The process according to claim 1, wherein the 7- (4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or its salt obtained by halogenating is reacted with thiourea. . 5. A formula [Wherein R ₆ has the same meaning as in claim 1] and is obtained by halogenating 3-oxo-2-alkoxyiminobutyric acid. [Wherein X and R ₆ have the same meanings as in claim 1] and 4-halogeno-3-oxo-2-alkoxyiminobutyric acid or a reactive derivative thereof [Wherein, R ₃ and —COOR ₄ have the same meanings as in claim 1], and 7- (4-halogeno-3 obtained by reacting with a 7-aminocephalosporin derivative or a salt thereof. The method according to claim 1, wherein the -oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or a salt thereof is reacted with thiourea. 6. A formula [Wherein, R ₆ has the same meaning as in claim 1] and is represented by the formula 3-oxo-2-alkoxyiminobutyric acid or a reactive derivative thereof. [Wherein R ₃ and -COOR ₄ have the same meanings as in claim 1] and are reacted with a 7-aminocephalosporin derivative or a salt thereof. [In the formula, R ₃ , -COOR ₄ , and R ₆ have the same meanings as in claim 1] 7- (3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or a salt thereof 7. The process according to claim 1, wherein the 7- (4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or its salt obtained by halogenating is reacted with thiourea. .