JPS6210512B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 7-amino-3-substituted methyl cefemcarboxylic acids, derivatives at the carboxyl group, or salts thereof, and in particular, the general formula [In the formula, R ¹ is a hydrogen atom; R ² is an amino group; X is an acyloxy group with or without a substituent; Y means S or S→O. ] It is expressed as . To cephalosporanic acids or their carboxyl group derivatives or salts thereof,
In an organic solvent, in the presence of an acid or an acid complex, a triazole or tetrazole, or a salt thereof, in which the carbon atoms in the ring may be substituted, is reacted, and if desired, the protecting group is then removed or the carboxyl group is protected. or as a salt, the general formula [In the formula, R ¹ , R ² and Y have the above-mentioned meanings, and R ³
represents a triazolyl or tetrazolyl group in which carbon atoms in the ring may be substituted. However, −
It is assumed that CH ₂ R ³ is bonded to the carbon atom of the exomethylene group adjacent to the nitrogen atom of R ³ . ] It is related with the manufacturing method of the 7-amino-3-substituted methyl cefem carboxylic acid represented by these, its derivative in the carboxyl group, or those salts. Therefore, the object of the present invention is to obtain a 7-amino-3 compound represented by the general formula [ ] that is useful as an intermediate when producing cephalosporan compounds.
It is an object of the present invention to provide a method for obtaining -substituted methyl cefem carboxylic acids, derivatives thereof at the carboxyl group, or salts thereof in good yield and high purity by industrially easy operations. Conventionally, among the compounds represented by the general formula [],
7 ^- ACA
Replace the 3rd position with azide [The Journal of
Anti-Biotechs, 25 , No. 1.64 (1972)] followed by ring closure [Japanese Patent Publication No. 13275/1983] was known. However, this conventional method requires many reaction steps and has ^a low yield, making it unsuitable for industrial production.
1,2,3-triazolyl) or 1-(1H-1,
Only compounds that are 2,3,4-tetrazolyl) groups can be produced. Under these circumstances, the present inventors have developed a compound represented by the general formula [ ] in which the carbon atom of the exomethylene group at position 3 of the cephalosporan ring is bonded to any nitrogen atom of R ³ . As a result of intensive research aimed at developing a production method that can be obtained easily and with good yield, we found that the compound represented by the general formula [] or its carboxyl group in the presence of an acid or an acid complex in an organic solvent. If a derivative or a salt thereof is reacted with a triazole or tetrazole or a salt thereof in which the carbon atom in the ring may be substituted, and if desired, the protecting group is then removed or the carboxyl group is protected or converted into a salt. The inventors have completed the present invention by discovering that the above objects can be achieved. According to the method of the present invention, in the general formula []
R ³ is not only a 1-(1H-1,2,3-triazolyl) and 1-(1H-1,2,3,4-tetrazolyl) group, but also a 2-(2H-1,2,3-triazolyl) group. , 1-(1H-1.2.4-triazolyl), 4
-(4H-1,2,4-triazolyl) and 2-
It is also possible to obtain new compounds such as (2H-1,2,3,4-tetrazolyl) groups, and further, when 〓Y is 〓S
Not only compounds in which 〓Y is 〓S→O can also be used as starting materials, and 〓S→O can also be changed to 〓S during the reaction or in the post-treatment stage. The present invention will be explained in detail below. In the present invention, examples of the acyloxy group of halogen atom,
Nitro group, alkyl group, alkoxy group, alkylthio group, acyloxy group, acylamino group, hydroxyl group, carboxyl group, sulfamoyl group, carbamoyl group, carbalkoxycarbamoyl group, aroylcarbamoyl group, carbalkoxysulfamoyl group, aryl group, carbamoyl It may be substituted with one or more substituents such as groups. In addition, examples of the triazole or tetrazole in which carbon atoms in the ring may be substituted include a halogen atom, an alkyl group, a hydroxyl group, an aralkyl group, an alkoxy group, an alkylthio group, a cyano group, an amino group, a carboxyl group, 1,2,3-triazole in which a carbon atom in the ring may be substituted with one or more substituents such as an alkoxyalkyl group, an aminoalkyl group, an N-alkylaminoalkyl group, a haloalkyl group, an acyl group, etc.;
1,2,4-triazole or 1,2,3,4-
Examples include tetrazole. These, 1, 2, 3
- Triazole, 1,2,4-triazole, and 1,2,3,4-tetrazole have tautomers as shown below, and any isomer or mixture can be subjected to the reaction. can. (In the formula, R represents a hydrogen atom or the above-mentioned substituent, and the two Rs may be the same or different.) In the general formula [], a group represented by R ³ , 1-(1H-1, 2, 3
-triazolyl), 2-(2H-1.2.3-triazolyl), 1-(1H-1.2.4-triazolyl), 4-(4H-1.2.4-triazolyl), 1
-(1H-1.2.3.4-tetrazolyl) or 2
-(2H-1.2.3.4-tetrazolyl) group is mentioned. In the above-mentioned substituents of X, triazole and tetrazole in which carbon atoms in the ring may be substituted, the hydroxyl group, amino group and carboxyl group may be protected with a commonly used protecting group. Protecting groups for amino groups include all groups that can normally be used as amino protecting groups, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-
Toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, trifluoroacetyl, formyl, tert.-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, pyridin-1-oxide-2-yl-methoxycarbonyl, 2-pyridylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl , 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl,
Examples include acyl groups that are easily eliminated such as succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, and further examples include trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, and 2-hydroxybenzylidene. ,2
-Hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2 -butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1-
[N-(2-methoxyphenyl)carbamoyl]-
2-propylidene, 1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2-
Ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5
Examples include groups that are easily eliminated such as -oxocyclohexylidene, and protecting groups for amino groups such as di- or trialkylsilyl. In addition, the protecting group for a hydroxyl group includes all groups that can normally be used as a protecting group for a hydroxyl group, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxy Carbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, tert.-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxy Carbonyl, diphenylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclo In addition to easily leaving acyl groups such as propyl ethoxycarbonyl, 3-quinolyloxycarbonyl, trifluoroacetyl, etc., groups such as benzyl, trityl, methoxymethyl, 2-nitrophenylthio, 2,4-dinitrophenylthio, etc. Can be mentioned. Furthermore, the carboxyl group-protecting group includes all groups that can be used as ordinary carboxyl group-protecting groups, such as those whose ester moiety is methyl, ethyl, propyl, isopropyl, tert.
-butyl, butyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl,
p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-
Bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, phthalimidomethyl, trichloroethyl, 1,1-dimethyl-2-propynyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 1,1-dimethylpropyl, 1,1 -dimethyl-2-propenyl,
3-Methyl-3-butenyl, succinimidomethyl, 1-cyclopropylethyl, methylsulfenylmethyl, phenylsulfenylmethyl, methylthiomethyl, phenylthiomethyl, dimethylaminomethyl, quinoline-1-oxide-2- Esters such as methyl, pyridin-1-oxide-2-yl-methyl, bis-(p-methoxyphenyl)methyl, etc., as well as those described in JP-A-46-7073 and Dutch Publication No. 7105259 , for example, may be protected with a silyl compound such as dimethylchlorosilane. Examples of the carboxyl group derivatives of the general formula [] and the compound of the general formula [] include the following. (a) Esters: Esters include all esters that do not adversely affect the reaction, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, tert.-butyl ester, methoxymethyl ester, Ethoxymethyl ester, phenoxymethyl ester, methylthiomethyl ester, methylthioethyl ester, phenylthiomethyl ester, dimethylaminoethyl ester, diethylaminoethyl ester, morpholinoethyl ester, piperidinoethyl ester, acetylmethyl ester, phenacyl ester , toluoyl methyl ester, 4-nitrophenacyl ester, acetoxymethyl ester, pivaloyloxymethyl ester, benzoyloxymethyl ester, 1,1-diacetyl methyl ester, 1-acetyl-1-methoxycarbonyl methyl ester, methanesulfonyl Ethyl ester, toluenesulfonyl ethyl ester, bromomethyl ester, iodoethyl ester, trichloroethyl ester, cyanomethyl ester, tenoyl methyl ester,
Substituted or unsubstituted alkyl esters such as phthalimidomethyl ester; cycloalkyl esters such as cyclohexyl ester and cycloheptyl ester; alkenyl esters such as propenyl ester, allyl ester, and 3-butenyl ester; alkynyl esters such as propynyl ester; phenyl ester, tolyl ester,
Substitution or Unsubstituted aryl ester; benzyl ester, phenethyl ester, p-chlorobenzyl ester, p-nitrobenzyl ester, p-methoxybenzyl ester, 3,5-dimethoxybenzyl ester, diphenylmethyl ester, bis-(4-
methoxyphenyl) methyl ester, 3,5-
Substituted or unsubstituted aralkyl esters such as di-tert.-butyl-4-hydroxybenzyl ester and trityl ester; indanyl ester; phthalidyl ester; other substituted with carboxyl group and halogen atom, nitro group, alkoxy group, etc. or unsubstituted thioalcohol, tetrahydrofuranol, 1-cyclopropylethanol, 1-phenyl-3-methyl-
5-pyrazolone, 3-hydroxypyridine, 2
-Esters formed from hydroxypyridine-1-oxide, etc.; or carboxyl groups and methoxyacetylene, ethoxyacetylene,
tert.-butylethynyldimethylamine, ethylethynyldiethylamine, N-ethyl-5-
Mention may be made of esters formed by reaction with phenyl isoxazolium-3-sulfonate. (b) Carboxyl group and anhydride such as N-hydroxysuccinimide, N-hydroxyphthalimide, dimethylhydroxylamine, diethylhydroxylamine, 1-hydroxypiperidine, oxime, etc. (c) Amides: Amides include acid amide, N
-Includes all substituted acid amides and N/N-disubstituted amides, such as N-methyl acid amide, N-
N-alkyl acid amide such as ethyl acid amide; N
- N-aryl acid amides such as phenyl acid amide; N·N-dialkyl acid amides such as N·N-dimethyl acid amide, N·N-diethyl acid amide, N-ethyl-N-methyl acid amide; imidazole, 4 -Acid amides such as substituted imidazoles and triazolopyridones. In the present invention, general formula [] and general formula []
The salts of the compounds or derivatives or salts thereof at the carboxyl group include both salts at the acidic group and salts at the basic group. Examples of salts with acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; triethylamine, diethylamine, pyridine, N-methylpiperidine, and
- Salts with nitrogen-containing organic bases such as methylmorpholine and N.N-dimethylaniline are mentioned. Salts with basic groups include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic acids such as oxalic acid, formic acid, trichloroacetic acid, and trifluoroacetic acid; methanesulfonic acid, toluenesulfonic acid, and naphthalenesulfonic acid. Examples include salts with sulfonic acids such as. Incidentally, the salt of the compound of the general formula [] may be used after being isolated in advance, or may be prepared in-system. Triazoles and tetrazoles in which carbon atoms in the rings may be substituted may be subjected to the reaction in the form of basic salts or acidic salts, if necessary. The basic salts and acidic salts include the salt forms described above. The acid or acid complex compound used in the method of the present invention includes, for example, a protonic acid, a Lewis acid, or a complex compound of a Lewis acid. Protonic acids include, for example, sulfuric acids, sulfonic acids, or super strong acids (super strong acid means an acid stronger than 100% sulfuric acid,
Examples include sulfuric acids such as sulfuric acid, chlorosulfuric acid or fluorosulfuric acid; alkyl (mono- or sulfonic acids such as aryl (mono-, di- or tri-)sulfonic acids such as di-)sulfonic acid or p-toluenesulfonic acid; perchloric acid, magicic acid ( _FSO3H - _SbF5 ), _FSO3H −
AsF ₅ , CF ₃ SO ₃ H−SbF ₅ , HF−BF ₃ , H ₂ SO ₄ −
Examples include super strong acids such as SO ₃ . Furthermore, examples of the Lewis acid include boron trifluoride. Further, as complex compounds of Lewis acids, for example,
Dialkyl ether complex salts of boron trifluoride with diethyl ether, di-n-propyl ether, di-n-butyl ether, etc.; amine complex salts with ethylamine, n-propylamine, n-butylamine, triethanolamine, etc.; ethyl formate, Examples include carboxylic acid ester complex salts with ethyl acetate, etc.; fatty acid complex salts with acetic acid, propionic acid, etc.; and nitrile complex salts with acetonitrile, propionitrile, etc. Next, embodiments of the method of the present invention will be described. As mentioned above, the method of the present invention is based on the general formula []
A compound represented by the above, or a derivative thereof in the carboxyl group, or a salt thereof, and a triazole or tetrazole, or a salt thereof, in which a carbon atom in the ring may be substituted, in an organic solvent in the presence of an acid or a complex compound of an acid. , react. Examples of the organic solvent used in the reaction include all organic solvents that do not adversely affect the reaction, such as nitroalkanes such as nitromethane, nitroethane, and nitropropane; formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, Organic carboxylic acids such as propionic acid; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, and dimethyl cellosolve; ethyl formate, diethyl carbonate, Esters such as methyl acetate, ethyl acetate, ethyl chloroacetate, and butyl acetate; nitriles such as acetonitrile and butyronitrile; and sulfolanes such as sulfolane;
Two or more of these solvents may be used in combination.
Moreover, a complex compound formed by these organic solvents and a Lewis acid may be used as a solvent. The amount of the acid or acid complex compound to be used may be at least the equivalent molar amount relative to the compound represented by the general formula [] or its carboxyl group derivative or salt thereof, and may be increased or decreased as appropriate depending on the individual case. can. In particular, it is preferable to use 2 to 10 times the molar amount. When using an acid complex compound, it can be used by itself as a solvent, or two or more types of complex compounds may be used in combination. In addition, the amount of triazole or tetrazole, or a salt thereof, which may have a substituted carbon atom in the ring, should be used in an amount equal to or more than one molar amount based on the compound represented by the general formula [] or its carboxyl group derivative or salt thereof. 1.0 is fine, especially 1.0
It is preferable to use a molar amount of ~5.0 times. The reaction is usually carried out at a temperature of 0 to 80°C, and the reaction time is generally several minutes to several tens of hours. If moisture is present in the reaction system, there is a risk of causing undesirable side reactions such as lactonization of the raw materials or products and cleavage of the β-lactam ring, so it is desirable to maintain the reaction system in an anhydrous state. To meet this demand, a suitable dehydrating agent is added to the reaction system, such as phosphorus compounds such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, and phosphorus oxychloride; N.O-bis(trimethylsilyl)acetamide. , trimethylsilylacetamide, trimethylchlorosilane, dimethyldichlorosilane; organic acid chlorides such as acetyl chloride, p-toluenesulfonyl chloride; acid anhydrides such as acetic anhydride, trifluoroacetic anhydride; anhydrous magnesium sulfate, anhydrous chloride An inorganic desiccant such as calcium, molecular sieve, calcium carbide, etc. may be added. When a derivative of the carboxyl group of the compound represented by the general formula [] is used as a raw material,
A compound represented by the general formula [] may be obtained by treatment after the reaction, but if desired, the protecting group can be removed by a conventional method to obtain a compound represented by the general formula []. If the triazole or tetrazole or their salts, which may have substituted carbon atoms in the ring, are substituted with a hydroxyl group, amino group, carboxyl group, etc., these groups should be protected before carrying out this reaction. After the reaction is completed, the desired compound can be obtained by subjecting it to a conventional elimination reaction. Furthermore, if desired, the target compound represented by the general formula [] can be protected with a carboxyl group or converted into a salt according to a conventional method, and a corresponding compound can also be obtained. Furthermore, if the method of the present invention is carried out, a mixture in which any nitrogen atom of R ³ and the carbon atom of the exomethylene group at the 3-position of the cephalosporan ring are generally bonded may be obtained, and the reaction conditions may be adjusted as necessary. By changing, it is also possible to obtain a compound in which a specific nitrogen atom of R ³ is bonded to the carbon atom of the exomethylene group at the 3-position of the cephalosporin ring. The target compound thus obtained can be isolated and collected by conventional means. By amidating the 7-position of the cephalosporan ring with a known or new acyl group, the ^Δ3 -cephem compound of the present invention can be used to produce various useful cephalosporins that are effective against Gram-positive and Gram-negative bacteria. It is a compound that can be derived into a series of compounds and is useful as an intermediate. Next, the present invention will be specifically explained with reference to Examples. Example 1 (1) 7-aminocephalosporanic acid (hereinafter 7-
(abbreviated as ACA) was suspended in 13 ml of sulfolane, and 14.2 g of boron trifluoride diethyl ether complex salt and 5-methyltetrazole were suspended in 13 ml of sulfolane.
Add 1.0 g and react at room temperature for 17 hours. After the reaction is completed, the reaction solution is poured into 15 ml of ice water, and the pH is adjusted to 3.5 with 28% ammonia water under ice cooling. Take the precipitated crystals, wash them with 5 ml of water and 5 ml of acetone, and dry them to obtain 7-amino-3-
[2-(5-methyl-2H-1,2,3,4-tetrazolyl)methyl]-△ ³ -cephem-4-
carboxylic acid and 7-amino-3-[1-(5-
1.76 g of crystals of a mixture of methyl-1H-1,2,3,4-tetrazolyl)methyl] ^-Δ3 -cephem-4-carboxylic acid are obtained. (2) Suspend 1.76 g of the crystals obtained in (1) in 18 ml of methanol, add and dissolve 1.13 g of p-toluenesulfonic acid monohydrate, and then gradually add 4.6 g of diphenyldiazomethane. Add and react for 15 minutes at room temperature. After the reaction is completed, the solvent is distilled off under reduced pressure. The residue was dissolved in 30 ml of ethyl acetate and 30 ml of water.
Dissolve in a mixed solvent consisting of and adjust the pH to 8 with sodium hydrogen carbonate. Next, the organic layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Purification of the residue by column chromatography (Wako silica gel C-200; developing solvent, benzene:ethyl acetate = 4:1) yields 7-amino-3-[2- (5-methyl-2H-1・2・
3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid benzhydryl ester
7-Amino-3-[1-(5-methyl-1H-1.2.
3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid benzhydryl ester
Obtain 0.14g. Γ7-amino-3-[2-(5-methyl-2H-
1,2,3,4-tetrazolyl)methyl]-
△ ³ -cephem-4-carboxylic acid benzhydryl ester IR (KBr) cm ^-1 ; νC=O1770, 1720 NMR (CDCl ₃ ) ppm value; 1.75 (2H, bs, -NH ₂ ), 2.48 (3H, s, −CH ₃ ), 3.20 (2H, s,

[Formula]), 4.70 (1H, d, J=5Hz, C ₆ -H), 4.87 (1H, d, J=5Hz, C ₇ -H), 5.30, 5.72 (2H, ABq, J=16Hz,

【formula】), 6.92 (1H, s, -CH〓), 7.30 (10H, s,

[Formula]), Γ7-amino-3-[1-(5-methyl-1H-
1,2,3,4-tetrazolyl)methyl]-
^Δ3 -Cefem-4-carboxylic acid benzhydryl ester IR (KBr) cm ^-1 ; νC=O1770, 1725 NMR (CDCl ₃ ) ppm value; 1.80 (2H, s, -NH ₂ ) 2.15 (3H, s, - CH ₃ ) 3.30 (2H, s,

[Formula]), 4.70 (1H, d, j = 5Hz, C ₆ - H), 4.85 (1H, d, J = 5Hz, C ₇ - H), 5.00, 5.38 (2H, ABq, J = 16Hz,

【formula】), 6.90 (1H, s, -CH〓), 7.30 (10H, s,

[Formula]), (3) 7-amino-3-[2-(5-methyl-2H-
1,2,3,4-tetrazolyl)methyl]-△
0.462 g of ³ -cephem-4-carboxylic acid benzhydryl ester was dissolved in a mixture of 0.5 ml of anisole and 5 ml of trifluoroacetic acid, and reacted at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, 10 ml of water and 10 ml of ethyl acetate were added to the residue, and the mixture was cooled with ice.
Adjust the pH to 8 with 28% ammonia water. Next, separate the aqueous layer and adjust the pH to 3.5 with 2N hydrochloric acid while cooling on ice. Take the precipitated crystals, wash them with 5 ml of water and 5 ml of acetone, and dry them to obtain a melting point of 178.
7-amino-3-[2-(5-
0.26 g of methyl-2H-1.2.3.4-tetrazolyl)methyl] ^-Δ3 -cephem-4-carboxylic acid is obtained. IR (KBr) cm ^-1 ; νC=O1790, 1610, 1530 NMR (CF ₃ COOD) ppm value; 2.70 (3H, s, -CH ₃ ), 3.73 (2H, s,

[Formula]), 5.40 (2H, s, C ₆ -H, C ₇ -H), 5.80, 6.12 (2H, ABq, J = 16Hz,

[Formula]) Similarly, 7-amino-3-[1-(5-methyl-1H-1,2,3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid benzhydryl ester 0.462 g 0.25 g of 7-amino-3-[1-(5-methyl-1H-1,2,3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid having a melting point of 195°C (decomposition) from
get. IR (KBr) cm ^-1 ; νC=O1795, 1615, 1530. NMR (CF ₃ COOD) ppm value; 2.95 (3H, s, -CH ₃ ), 3.90 (2H, bs,

[Formula]), 5.45 (2H, s, C ₆ -H, C ₇ -H), 5.57, 5.92 (2H, ABq, J = 16Hz,

[Formula] ) Example 2 (1) The same reaction as in Example 1 (1) was carried out under the conditions shown in Table 1, and the results shown in Table 1 were obtained. (2) The product obtained in (1) was reacted and treated in the same manner as in (2) of Example 1 to obtain the results shown in Table 2. The physical properties of the compound obtained here were consistent with those of the compound obtained in Example 1 (2).

【table】

[Table] Example 3 (1) 2.72 g of 7-AC is suspended in 30 ml of ethyl acetate containing 6.78 g of boron trifluoride, 2.52 g of 5-methyltetrazole is added thereto, and the suspension is reacted at room temperature for 16 hours. After the reaction is completed, the reaction solution is poured into 30 ml of ice water, and the pH is adjusted to 3.5 with 28% ammonia water under ice cooling. The precipitated crystals were collected, washed successively with 5 ml of water and 5 ml of acetone, and dried to give 7-amino-3-[2-(5-methyl-2H-1.2.
3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid and 7-amino-3-
[1-(5-methyl-1H-1,2,3,4-tetrazolyl)methyl]-△ ³ -cephem-4-
2.34 g of crystals of a mixture of carboxylic acids are obtained. (2) If 2.34 g of the crystals obtained in (1) are reacted and treated in the same manner as in (2) of Example 1, 7-amino-3-[2
-(5-Methyl-2H-1,2,3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid benzhydryl ester 2.0g and 7
-amino-3-[1-(5-methyl-1H-1.
2,3,4-tetrazolyl)methyl]-△ ^3-
0.13 g of cefem-4-carboxylic acid benzhydryl ester is obtained. The physical properties of these compounds were consistent with those of the compound obtained in Example 1 (2). Example 4 The same reaction as in Example 3-(1) was carried out under the conditions shown in Table 3, and the results shown in Table 3 were obtained.

[Table] Example 5 (1) 2.72 g of 7-ACA is suspended in 27 ml of acetic acid, 2.5 g of concentrated sulfuric acid and 1.0 g of 5-methyltetrazole are added, and the suspension is reacted at 60°C for 4 hours. After the reaction is complete, the solvent is distilled off under reduced pressure and the residue is diluted with water.
Add 15ml and bring to PH3.5 with 28% ammonia water under ice cooling.
Adjust to. Take the precipitated crystals and add 5 ml of water and 5 ml of acetone.
After sequentially washing and drying, 7-amino-
3-[2-(5-methyl-2H-1, 2, 3, 4
-Tetrazolyl)methyl]-△ ³ -Cefem-
4-carboxylic acid and 7-amino-3-[1-
0.4 g of crystals of a mixture of (5-methyl-1H-1,2,3,4-tetrazolyl)methyl] ^-Δ3 -cephem-4-carboxylic acid are obtained. (2) If 0.4 g of the crystals obtained in (1) is reacted and treated in the same manner as in (2) of Example 1, 7-amino-3-[2
-(5-Methyl-2H-1,2,3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid benzhydryl ester 0.1g and 7
-amino-3-[1-(5-methyl-1H-1.
2,3,4-tetrazolyl)methyl]-△ ^3-
0.03 g of cefem-4-carboxylic acid benzhydryl ester is obtained. The physical properties of these compounds were consistent with those of the compound obtained in Example 1 (2). Example 6 (1) 2.72 g of 7-ACA was dissolved in 19 ml of trifluoroacetic acid, 7.1 g of boron trifluoride diethyl ether complex salt and 1.4 g of 5-acetylaminotetrazole were added thereto, and the mixture was reacted at room temperature for 7 hours. let After the reaction is complete, the solvent is distilled off under reduced pressure, 15 ml of water is added to the residue, and the pH is adjusted to 3.5 with 28% aqueous ammonia under ice cooling. Take the precipitated crystals and add 5 ml of water and 5 ml of acetone.
If washed sequentially with water and dried, 7-amino-3
-[2-(5-acetylamino-2H-1・2・
1.0 g of crude crystals of 3,4-tetrazolyl)methyl] ^-Δ3 -cephem-4-carboxylic acid are obtained. (2) Add 1.0 g of the crude crystals obtained in (1) to 10 ml of methanol.
to which p-toluenesulfonic acid 1
After adding and dissolving 0.56 g of hydrate, 2.3 g of diphenyldiazomethane was gradually added and reacted for 15 minutes at room temperature. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in a mixture of 20 ml of ethyl acetate and 20 ml of water, and the pH was adjusted to 8 with sodium hydrogen carbonate.
Adjust to. Next, the organic layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography (Wako silica gel C-200: developing solvent, benzene:
If purified with ethyl acetate = 4:1), the melting point is 106
7-Amino-3-[2-
0.35 g of (5-methyl-2H-1,2,3,4-tetrazolyl)methyl] ^-Δ3 -cephem-4-carboxylic acid benzhydryl ester is obtained. IR (KBr) cm ^-1 ; νC=O1770, 1720, 1700 NMR ( _CDCl3 ) ppm value 1.95 (2H, bs, _-NH2 ), 2.20 (3H, s, -NHCOC _H3 ), 3.20 (2H, bs ,

[Formula]), 4.67 (1H, d, J = 5Hz, C ₆ -H), 4.82 (1H, d, J = 5Hz, C ₇ -H), 5.32, 5.68 (2H, ABq, J = 16Hz,

【formula】), 6.90 (1H, s, -CH〓), 7.25 (10H, s,

[Formula]), 9.75 (1H, bs, 〓NH) (3) 7-amino-3-[2-(5-acetylamino-2H-1.2.3.4-tetrazolyl)methyl]-△ ³ − 0.505 g of cefem-4-carboxylic acid benzhydryl ester is dissolved in a mixture of 0.5 ml of anisole and 5 ml of trifluoroacetic acid, and reacted at room temperature for 1 hour. After the reaction is complete, the solvent is distilled off under reduced pressure, 10 ml of water and 10 ml of ethyl acetate are added to the residue, and the pH is adjusted to 8 with 28% aqueous ammonia under ice cooling. Next, the aqueous layer is separated and adjusted to pH 3.5 with 2N hydrochloric acid under ice cooling. The precipitated crystals were collected, washed successively with 5 ml of water and 5 ml of acetone, and dried to give 7-amino-3-[2-(5-acetylamino-2H-1.2. 3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid 0.31
get g. IR (KBr) cm ^-1 ; νC=O1790, 1690, 1610,
1530 NMR (CF ₃ COOD) ppm value; 2.42 (3H, s, -CH ₃ ), 3.70 (2H, s,

[Formula]), 5.40 (2H, s, C ₆ -H, C ₇ -H), 5.94 (2H, bs,

[Formula]) Example 7 (1) The procedure of Example 1 was carried out using other substituted tetrazole compounds in place of 5-acetylaminotetrazole.
A reaction similar to (1) or (1) of Example 6 was carried out, and the results shown in Table 4 were obtained. (2) Esterified in the same manner as in Example 6 (2), and the table
Compound 5 was obtained. The physical properties of the product are shown in Table 6. (3) Deesterified in the same manner as in Example 6 (3) and
Compound 7 was obtained.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] In the above table, products D and E, I and J, K and L,
Separation of F and G and C and M is carried out in the same manner as in Example 6 (2).
Column chromatography (Wako silica gel C-
200; developing solvent, benzene: ethyl acetate = 4:
1) Due to treatment.

【table】

【table】

[Table] Example 8 2.72 g of 7-ACA was dissolved in 19 ml of trifluoroacetic acid, and 7.1 g of boron trifluoride diethyl ether complex salt and 0.75 g of 1,2,4-triazole were added to the solution.
and react at room temperature for 7 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, 15 ml of water is added to the residue, and the pH is adjusted to 3.5 with 28% aqueous ammonia under ice cooling. Take the precipitated crystals and add 5 ml of water and 5 ml of acetone.
After sequential washing with water and drying, 7-amino-3-[1-(1H-1
2.5 g of 2,4-triazolyl)methyl] ^-Δ3 -cephem-4-carboxylic acid are obtained. IR (KBr) cm ^-1 ; νC=O1790, 1610, 1530 NMR (CF ₃ COOD) ppm value; 4.00 (2H, bs,

[Formula]), 5.47 (4H, bs, C ₆ -H, C ₇ -H,

【formula】), 8.70 (1H, s,

【formula】), 9.80 (1H, s,

[Formula]), Example 9 A reaction was carried out in the same manner as in Example 8 using another triazole compound instead of 1,2,4-triazole to obtain the compounds shown in Table 8. (7-
2.72g of ACA was used. )

【table】

【table】

[Table] Example 10 (1) 2.72 g of 7-ACA was dissolved in 20 ml of trifluoroacetic acid, and 7.1 g of boron trifluoride diethyl ether complex salt and 4-carboxy-1.2.
Add 1.24 g of 3-triazole and react at room temperature for 5 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, 15 ml of water is added to the residue, and the pH is adjusted to 3.5 with 28% ammonia water under ice cooling. Take the precipitated crystals and add 5 ml of water and 5 ml of acetone.
If washed sequentially with water and dried, 7-amino-3
-[1-(4-carboxy-1H-1,2,3-
triazolyl)methyl]-△ ³ -cephem-4
- 1.45 g of crude crystals of carboxylic acid (the structure of this product is a predicted structure) are obtained. (2) Add 1.45 g of the crude crystals obtained in (1) to 15 ml of methanol.
to which p-toluenesulfonic acid 1
After adding and dissolving 0.85 g of hydrate, 3.44 g of diphenyldiazomethane was gradually added and
Let it react for a minute. After the reaction, the solvent was distilled off under reduced pressure, and the residue was mixed with 15 ml of ethyl acetate and 15 ml of water.
Dissolve in a mixed solvent of and adjust the pH to 8 using sodium hydrogen carbonate. Next, the organic layer was separated, washed twice with 15 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography (Wako silica gel C- 200; Developing solvent, benzene:
If purified with ethyl acetate = 5:1), the melting point is 96.
7-Amino-3-[1-
(4-diphenylmethoxycarbonyl)-1H-
1,2,3-triazolyl)methyl]-△ ^3-
Cefem-4-carboxylic acid benzhydryl ester (The structure of this product is a predicted structure.)
Obtain 0.24g. IR (KBr) cm ^-1 ; νC=O1770, 1720 NMR ( _CDCl3 ) ppm value; 2.33 (2H, bs, _-NH2 ), 2.78, 3.21 (2H, ABq, J=18Hz,

[Formula]), 4.71 (1H, d, J = 5Hz, C ₆ -H), 4.90 (1H, d, J = 5Hz, C ₇ -H), 5.32, 5.92 (2H, ABq, J = 16Hz,

[Formula]), 6.86 (2H, s, -COOC H (C ₆ H ₅ ) ₂ × 2), 7.20 (20H, s,

[Formula] × 4), 8.11 (1H, s,

[Formula]) Example 11 Substituted-1,2,4-triazoles in Example 1
The reaction was carried out in the same manner as in (1) and (2) to obtain the compounds shown in Table 9.

【table】

【table】

[Table] Example 12 The compounds shown in Table 10 were obtained by reacting in the same manner as in Example 10 (1). Physical properties of the products in Table 10 (IR and
NMR) was consistent with that of Example 8. In the table, 7-amino-3-acetoxymethyl- ^Δ3 -cephem-4-carboxylic acid-1-oxide was used as the raw material marked with *.

[Table] Example 13 (1) p-nitrobenzyl ester of 7-ACA
Dissolve 4.07g in 30ml of trifluoroacetic acid, and add 7.1g of boron trifluoride/diethyl ether complex salt to this.
and 0.69 g of 1,2,4-triazole were added, and the mixture was allowed to react at room temperature for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was added with 30% water.
ml and 30 ml of ethyl acetate, and then the pH was adjusted to 7.0 with sodium hydrogen carbonate under ice cooling, and the organic layer was separated. The separated organic layer was washed with water, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 7-Amino-3-[1-(1H-1・2・4
-Triazolyl)methyl]-△ ³ -Cefem-
4-Carboxylic acid p-nitrobenzyl ester
Obtain 0.67g. IR (KBr) cm ^-1 ; νC=O1770, 1708 NMR (CDCl ₃ ) ppm value; 1.99 (2H, s, -NH ₂ ), 3.50 (2H, s,

[Formula]), 4.79 (1H, d, J = 5Hz, C ₆ -H), 4.86 (1H, d, J = 5Hz, C ₇ -H), 4.95, 5.28 (2H, ABq, J = 15Hz,

[Formula]), 5.24 (2H, s,

【formula】), 7.53, 8.15 (4H, ABq, J=8Hz,

【formula】), 7.86 (1H, s,

【formula】), 8.30 (1H, s,

[Formula]) (2) 7-Amino-3-[1-(1H-1・2・4-
triazolyl)methyl]-△ ³ -cephem-4
-Carboxylic acid p-nitrobenzyl ester
4.16 g was dissolved in a mixed solvent of 40 ml of methanol and 20 ml of tetrahydrofuran, 3.0 g of 10% palladium on carbon was added thereto, and a hydrogenation reaction was carried out at room temperature. After the reaction is completed, the reaction mixture is filtered and concentrated under reduced pressure. Then, add 30 ml of ethyl acetate and 30 ml of water to the residue, adjust the pH to 7 with sodium hydrogen carbonate under ice cooling, and separate the aqueous layer.
This was adjusted to pH 3.5 with 2N hydrochloric acid under ice cooling. Take the precipitated crystals and add 5 ml of water and 5 ml of acetone.
If washed sequentially with ml and dried, the melting point is 149℃.
(decomposition) 7-amino-3-[1-(1・
2.56 g of 2,4-triazolyl)methyl- _Δ3 -cephem-4-carboxylic acid are obtained. The physical properties (IR and NMR) of this compound were consistent with those of Example 8. Example 14 3.0 g of 7-amino-3-acetoxymethyl-△ ³ -cephem-4-carboxylic acid ethyl ester and 0.76 g of 1,2,4-triazole were added to Example 13.
If the reaction is carried out in the same manner as in (1), 7-amino-3-[1-(1H-1・
1.02 g of 2,4-triazolyl)methyl] ^-Δ3 -cephem-4-carboxylic acid ethyl ester is obtained. IR (KBr) cm ^-1 ; δC=O 1770, 1720 NMR (CDCl ₃ ) ppm value; 0.89 (3H, t, J=7Hz, -COOCH ₂ CH ₃ ), 2.68 (2H, bs, -NH ₂ ) , 3.51 (2H, s,

[Formula]), 4.47 (2H, q, J=7Hz, -COOC H ₂ CH ₃ ), 4.82 (1H, d, J=5Hz, C ₆ -H), 4.98 (1H, d, J=5Hz, C ₇ −H) 4.98, 5.35 (2H, ABq, J=15Hz,

【formula】), 7.93 (1H, s,

【formula】), 8.39 (1H, s,

[Formula]) Example 15 7-amino-3-acetoxymethyl- ^Δ3 -cephem-4-carboxylic acid benzhydryl ester
4.38 g was dissolved in 30 ml of trifluoroacetic acid, 7.1 g of boron trifluoride/diethyl ether complex salt and 0.9 g of 1,2,4-triazole were added thereto, and the mixture was reacted at room temperature for 5 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, 30 ml of water and 30 ml of ethyl acetate are added to the resulting residue, the pH is adjusted to 7 with sodium bicarbonate under ice cooling, and the aqueous layer is separated. The pH of this was adjusted to 3.5 using 2N hydrochloric acid under ice cooling again. Take the precipitated crystals, wash them with 5 ml of water and 5 ml of acetone, and then dry them to obtain 7-amino-3-[1-(1H-1.2.4-triazolyl)methyl], which has a melting point of 149°C (decomposed). -Δ 1.12 g of ³ -cephem-4-carboxylic acid is obtained. The physical properties (IR and NMR) of this compound were consistent with those obtained in Example 8.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom; R ² is an amino group; X is an acyloxy group with or without a substituent; Y means S or S→O. ] In an organic solvent, in the presence of an acid or an acid complex compound, the cephalosporanic acids represented by the above or their carboxyl group derivatives or their salts are added to triazoles or tetrazoles in which carbon atoms in the ring may be substituted, or their salts. A general formula characterized by reacting a salt and optionally removing a protecting group or protecting a carboxyl group or converting it into a salt. [In the formula, R ¹ , R ² and Y have the above-mentioned meanings,
R ³ represents a triazolyl or tetrazolyl group in which carbon atoms in the ring may be substituted. However, it is assumed that _-CH2R3 is bonded to ^the carbon atom of the exomethylene group adjacent to the nitrogen atom of ^R3 . ] A method for producing a 7-amino-3-substituted methyl cefemcarboxylic acid represented by the following formula, a derivative in its carboxyl group, or a salt thereof. 2. 7-amino-3-substituted methyl cefemcarboxylic acids or derivatives thereof in the carboxyl group according to claim 1, wherein the acid or the acid complex is a protonic acid, a Lewis acid, or a complex of Lewis acids; How those salts are made. 3. The method for producing 7-amino-3-substituted methylcefemcarboxylic acids or their carboxyl group derivatives or salts thereof according to claim 2, wherein the protonic acid is a sulfate, sulfonic acid, or super strong acid. . 4 Claim 2 in which the Lewis acid or the complex compound of a Lewis acid is boron trifluoride or a complex compound thereof
A method for producing 7-amino-3-substituted methylcefemcarboxylic acids or derivatives at the carboxyl group or salts thereof as described in 2. 5 Claim 1 in which X is an acetoxy group
A method for producing a 7-amino-3-substituted methyl cefemcarboxylic acid, a carboxyl group derivative thereof, or a salt thereof according to any one of items 1 to 4. 6 Claims 1 to 5 in which the organic solvent is an organic carboxylic acid, ether, ester, nitrile, nitroalkane, or sulfolane.
A method for producing a 7-amino-3-substituted methyl cefemcarboxylic acid or a carboxyl group derivative thereof or a salt thereof according to any of the above items. 7 R ³ is 2-(2H-1.2.3-triazolyl), 1- in which the carbon atom in the cold may be substituted.
(1H-1,2,4-triazolyl), 4-(4H-
1,2,4-triazolyl) or 2-(2H-1.
7-amino- according to any one of claims 1 to 6, which is a 2,3,4-tetrazolyl) group.
A method for producing 3-substituted methyl cefem carboxylic acids, derivatives at the carboxyl group, or salts thereof.