JPH0121150B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 7-amino-3-substituted methylcefemcarboxylic acid or a salt thereof, and specifically relates to a method for producing 7-amino-3-substituted methylcefemcarboxylic acid or a salt thereof, and in particular, [In the formula, R ¹ represents a hydrogen atom; X represents an acetoxy group. ] In an organic solvent, in the presence of a protonic acid, a Lewis acid, or a complex compound of a Lewis acid, a compound represented by the general formula R ² −H [] [wherein R ² may be substituted] phenyl,
Indicates an indanyl, thienyl or furyl group. ] A general formula characterized by reacting a compound represented by [In the formula, R ¹ and R ² have the above-mentioned meanings. However, it is assumed that -CH ₂ R ² is bonded to the carbon atom of the exomethylene group adjacent to the carbon atom of R ² . ] It is related with the manufacturing method of 7-amino-3-substituted methyl cefem carboxylic acid or its salt represented by these. The purpose is to use 7-amino-3-substituted methyl cefemcarboxylic acid or its salt as an intermediate in the production of various cephalosporin compounds in an industrially easy manner. The object of the present invention is to provide a method for obtaining it in good yield and high purity. Conventionally, 7-amino- represented by the general formula []
A method for producing 3-substituted methyl cefemcarboxylic acid, its salt, or its ester is a method in which the ring of penicillins is opened, a group corresponding to R ² is introduced, and then the ring is closed (Japanese Patent Application Laid-Open No. 1972-
No. 76888; No. 48-76889; No. 50-5393) and a method for producing using ^Δ2 -cephalosporins in which the amino group at the 7th position is an acyl group as starting materials (Japanese Patent Application Laid-open No. 47-2582) has been reported. but,
All of these methods require a very large number of reaction steps and have poor yields, making them unsuitable for industrial production. The inventors of the present invention have conducted intensive research to find a method for producing the compound represented by the general formula [] industrially with ease and good yield. The present invention has been completed by discovering that the above object can be achieved by reacting a compound represented by the general formula [] or a salt thereof with a compound represented by the general formula [] in the presence of a complex compound. The present invention will be explained in detail below. In the present invention, phenyl, indanyl, thienyl or furyl group in R ² is, for example,
Halogen atom, alkyl group, nitro group, hydroxyl group, alkoxy group, amino group, alkylamino group, dialkylamino group, acylamino group, acyl group, acyloxy group, carboxyl group, carbamoyl group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, hydroxyalkyl group, alkoxyalkyl group, carboxyalkyl group, sulfoalkyl group, sulfo group, sulfamoyl group or carbamoylalkyl group. . Among the above substituents, the hydroxyl group, amino group and carboxyl group may be protected with a commonly used appropriate protecting group. Here, the hydroxyl group-protecting group includes all groups that can normally be used as hydroxyl group-protecting groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl,
tert.-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-
Examples include acyl groups that are easily eliminated such as cyclopropylethoxycarbonyl, 3-quinolyloxycarbonyl, or trifluoroacetyl, and benzyl, trityl, methoxymethyl, 2-nitrophenylthio, and 2,4-dinitrophenylthio groups. . In addition, 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, o-nitrophenylsulfenyl,
(mono-, di-, tri-)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-dimethylpropoxy Easily eliminated acyl groups include carbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, and trityl, 2-nitrophenylthio. ,2,4
-dinitrophenylthio, 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-
Examples include groups that are easily eliminated such as dimethyl-5-oxocyclohexylidene, and protecting groups for amino groups such as di- or trialkylsilyl. Furthermore, the carboxyl group-protecting group includes all groups that can be used as ordinary carboxyl group-protecting groups, such as methyl, ethyl, n-
Propyl, isopropyl, tert.-butyl, n-butyl, benzyl, diphenylmethyl, trityl,
p-nitrobenzyl, p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl,
p-methanesulfonylbenzoylmethyl, phthalimidomethyl, trichloroethyl, 1,1-dimethyl-2-propenyl, 1,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 1,1-dimethyl-2 -propenyl, 3-methyl-3-putenyl,
Succinimidomethyl, 1-cyclopropylethyl, methylsulfenylmethyl, phenylthiomethyl, dimethylaminomethyl, quinolin-1-oxide-2-yl-methyl, pyridin-1-oxide-2-yl-methyl, bis When protected with a group such as (p-methoxyphenyl)methyl, or with a non-metallic compound such as titanium tetrachloride, furthermore, JP-A-46-7073 and Dutch Publication No. 7105259 Examples include the case where the compound is protected with a silyl compound such as dimethyldichlorosilane, as described in the above. Further, as the salts of the compounds represented by the general formulas [] and [], commonly known salts can be mentioned. Salts at amino groups include, for example, salts with mineral acids such as hydrochloric acid or sulfuric acid; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid or trifluoroacetic acid; methanesulfonic acid, p-toluenesulfonic acid. or salts with sulfonic acids such as naphthalenesulfonic acid, and salts at the carboxyl group, such as salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; Ammonium salt; triethylamine, diethylamine, pyridine, N-methylpiperidine, N-methylmorpholine or N,N
- Salts with nitrogen-containing organic bases such as dimethylaniline can be mentioned. Further, if desired, the compound represented by the general formula [] may be an ester, and esters of the compound represented by the general formula [] include esters formed by commonly known ester-forming groups, Examples of the ester-forming group include the same groups as those listed above as the carboxyl group-protecting group. The protonic acid, Lewis acid, or complex compound of Lewis acid used in the reaction of the present invention will be explained in detail.
Examples of protonic acids include sulfuric acids, sulfonic acids, and super strong acids (super strong acids refer to acids stronger than 100% sulfuric acid, and include some of the above sulfuric acids and sulfonic acids). teeth,
Examples of sulfuric acids include sulfuric acid, chlorosulfuric acid, and fluorosulfuric acid; examples of sulfonic acids include alkyl (mono- or di-)sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid;
-Aryl (mono-,
Super strong acids such as di- or tri-)sulfonic acids include perchloric acid and magicic acid (FSO ₃ H-
SbF ₅ ), FSO ₃ H−AsF ₅ , CF ₃ SO ₃ H−SbF ₅ , HF
-BF ₃ , H ₂ SO ₄ -SO ₃ and the like. Examples of Lewis acids include boron trifluoride, zinc chloride, and stannic chloride. Examples of complex compounds of Lewis acids include the above-mentioned Lewis acids, diethyl ether, di-n-
Dialkyl ether complex salts with propyl ether, di-n-butyl ether, etc.; ethylamine, n
- Amine complex salts with propylamine, n-butylamine, triethanolamine, etc.; fatty acid complex salts with acetic acid, propionic acid, etc.; or phenol complex salts with phenols. Next, embodiments of the method of the present invention will be described. The method of the present invention involves reacting a compound represented by the general formula [] or a salt thereof with a compound represented by the general formula [] in the presence of a protonic acid, a Lewis acid, or a complex compound of a Lewis acid in an organic solvent. Implemented. In addition, when the salt of the compound represented by the above general formula [] is used as a starting material, it may be isolated beforehand and used, or it may be used for the reaction without being isolated. As organic solvents that can be used in the reaction, mention may be made of all organic solvents or reaction reagents themselves that do not adversely affect the reaction, for example,
Nitroalkanes such as nitromethane, nitroethane, and nitropropane; Organic carboxylic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid;
Examples include ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and anisole; and mixtures of two or more of these solvents. The amount of protonic acid, Lewis acid, or complex compound of Lewis acid to be used should be at least the equivalent molar amount of the compound represented by the general formula [] or its salt, and can be increased or decreased as appropriate depending on the individual case. . In particular, it is preferable to use 2 to 10 times the molar amount. When a Lewis acid complex compound is used, 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 the compound represented by the general formula [] may be at least equivalent molar to the compound represented by the general formula [] or its salt, but in particular,
It is preferable to use 1.0 to 1.5 times the molar amount. This reaction is
It is usually carried out at a temperature of 0°C to 80°C and is completed in several minutes to several tens of hours. The presence of moisture in the reaction system of the present invention may cause undesirable side reactions such as lactonization of 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 requirement, a suitable dehydrating agent is added to the reaction system, such as a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, or 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 sieves, calcium carbide, etc. may be added. After the reaction is completed, if desired, esterification is carried out by a conventional method, and the ester of the target compound is isolated and purified. ^R2
When a hydroxyl group, an amino group, or a carboxyl group that is a substituent of It can also be carried out continuously without isolating. Next, the present invention will be explained by examples, but these are not intended to limit the present invention. Example 1 2.72 g of 7-aminocephalosporanic acid was mixed with 25 g of acetic acid.
ml, 4.26 g of boron trifluoride-diethyl ether (1/1) was added and dissolved, and then 0.9 g of benzene was added and reacted at room temperature for 5 hours. After the reaction, the solvent is distilled off under reduced pressure, the resulting residue is dissolved in 15 ml of water, and the pH is adjusted to 3.5 using 28% aqueous ammonia under ice cooling. The precipitated crystals were collected, washed successively with 5 ml of water and 5 ml of acetone, and then dried to yield 2.4 g of 7-amino-3-benzyl-△ ³ -cephem-4-carboxylic acid (decomposition) having a melting point of 189-192°C (decomposition). Yield: 83%). IR (KBr) cm ^-1 ; νc=o1790, 1610, 1520 NMR ( _D2O - _CF3COOD ) ppm value; 3.38 (2H, s,

[Formula]) 3.90, 4.23 (2H, ABq J=14cps,

[Formula]) 5.16 (1H, d J = 5cps, C ₆ - H) 5.29 (1H, d J = 5cps, C ₇ - H) 7.30 (5H, s,

[Formula]) Example 2 2.72 g of 7-aminocephalosporanic acid was dissolved in 20 ml of trifluoroacetic acid, and boron trifluoride-
7.1g of diethyl ether (1/1) and furan
Add 1.6 g of 2-carboxylic acid and react at room temperature for 5 hours. After the reaction, the solvent is distilled off under reduced pressure, the resulting residue is dissolved in 15 ml of water, and the pH is adjusted to 3.5 using 28% aqueous ammonia under ice cooling. If you take the precipitated crystals, wash them with 5 ml of water and 5 ml of acetone, and then dry them, they will show a melting point of 190-197°C (decomposition).
7-amino-3-(5-carboxy-furfuryl)
-△ ³ -Cefem-4-carboxylic acid 2.37g (yield
73%). IR (KBr) cm ^-1 ; νc=o1790, 1660, 1610, 1510 NMR ( _D2O − _CF3COOD ) ppm value; 3.60 (2H, s,

【formula】) 4.13 (2H, s,

[Formula]) 5.17 (1H, d J = 5 cps, C ₆ - H) 5.28 (1H, d J = 5 cps, C ₇ - H) 6.40 (1H, d J = 4 cps,

[Formula]) 7.10 (1H, d J = 4cps,

[Formula]) The following compound was obtained in the same manner. Γ7-amino-3-(4-chlorobenzyl)-△ ³
-Cefem-4-carboxylic acid Melting point 198-204℃ (decomposed) IR (KBr) cm ^-1 ; νc=o1780, 1610, 1520 NMR (d ₆ -DMSO) ppm value; 3.05, 3.53 (2H, ABq J=18cps ,

[Formula] 3.50, 3.95 (2H, ABq J=14cps,

[Formula]) 4.75 (1H, ABq J=5cps, C ₆ −H) 4.97 (1H, ABq J=5cps, C ₇ −H) 7.30 (4H, s,

[Formula]) Γ7-amino-3-(3-chloro-4-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid Melting point 186-190℃ (decomposition) IR (KBr) cm ^-1 ; νc=o1790, 1610, 1530 NMR ( _D2O - _CF3COOD ) ppm value; 3.40 (2H, s,

[Formula]) 3.90, 4.10 (2H, ABq J=14cps,

[Formula]) 5.16 (1H, d J = 5 cps, C ₆ - H) 5.29 (1H, d J = 5 cps, C ₇ - H) 6.75 - 7.40 (3H, m,

[Formula]) Γ3-(3-acetyl-2-hydroxybenzyl)
-7-amino-△ ³ -cephem-4-carboxylic acid Melting point 180-185℃ (decomposed) IR (KBr) cm ^-1 ; νc=o1790, 1615, 1530 NMR (D ₂ O-CF ₃ COOD) ppm value; 2.65 (3H, s, −COCH ₃ ) 3.45 (2H, s,

[Formula]) 4.10, 4.17 (2H, ABq J=14cps,

[Formula]) 5.16 (1H, d J = 5 cps, C ₆ - H) 5.29 (1H, d J = 5 cps, C ₇ - H) 7.00 - 7.80 (3H, m,

[Formula]) Γ7-amino-3-(5-carboxy-2-tenyl)-△ ³ -cephem-4-carboxylic acid Melting point 180-185℃ (decomposition) IR (KBr) cm ^-1 ; νc=o1790, 1690 , 1610,
1530 NMR ( _d6 -DMSO) ppm value; 3.15, 3.55 (2H, ABq J=18cps,

[Formula]) 3.53, 3.90 (2H, ABq J=14cps,

[Formula]) 4.80 (1H, d J = 5 cps, C ₆ - H) 5.03 (1H, d J = 5 cps, C ₇ - H) 7.60 (2H, m,

[Formula]) Γ7-amino-3-(5-methoxycarbonyl-
2-tenyl)-△ ³ -cephem-4-carboxylic acid Melting point 208-215℃ (decomposition) IR (KBr) cm ^-1 ; νc=o1790, 1710, 1605,
1520 NMR ( _D2O − _CF3COOD ) ppm value; 3.30, 3.68 (2H, ABq J=18cps,

[Formula]) 3.90 (3H, s, CH ₃ ) 3.80~4.30 (2H, m,

[Formula]) 5.15 (1H, d J = 5 cps, C ₆ - H) 5.30 (1H, d J = 5 cps, C ₇ - H) 7.50 (1H, d J = 3.5 cps,

[Formula]) 7.70 (1H, d J = 3.5cps,

[Formula]) Γ7-amino-3-[5-(4-nitrobenzyloxycarbonyl)-2-tenyl]-△ ³ -cephem-4-carboxylic acid Melting point 200-205℃ (decomposition) IR (KBr) cm ^{- 1} ; νc=o1790, 1710, 1600,
1510 NMR (CF ₃ COOD) ppm value; 3.40, 3.72 (2H, ABq J = 18cps,

[Formula]) 4.10, 4.41 (2H, ABq J=14cps,

[Formula]) 5.37 (1H, d J = 5 cps, C ₆ - H) 5.47 (1H, d J = 5 cps, C ₇ - H) 5.52 (2H, s,

[Formula]) 7.10 (1H, d J = 4cps,

[Formula]) 7.70, 8.30 (4H, ABq J=9cps,

【formula】) 7.87 (1H, dJ=4cps,

[Formula]) Γ7-amino-3-(5-methoxycarbonylfurfuryl)-△ ³ -cephem-4-carboxylic acid Melting point 180-185℃ (decomposition) IR (KBr) cm ^-1 ; νc=o1800, 1730, 1610,
1530 NMR ( _d6 -DMSO) ppm value; 3.18, 3.55 (2H, ABq J=18cps,

[Formula]) 3.75 (3H, s, CH ₃ ) 3.84 (2H, s,

[Formula]) 4.65 (1H, d J = 5 cps, C ₆ - H) 4.90 (1H, d J = 5 cps, C ₇ - H) 6.30 (1H, d J = 4 cps,

【formula】) 7.15 (1H, dJ=4cps,

[Formula]) Example 3 (i) 2.72 g of 7-aminocephalosporanic acid was dissolved in 20 ml of trifluoroacetic acid, and 5.6 g of boron trifluoride/diethyl ether (1/1) and 1.2 g of phenol were added thereto. React at room temperature for 4 hours.
After the reaction, the solvent is distilled off under reduced pressure, the resulting residue is dissolved in 15 ml of water, and the pH is adjusted to 3.5 using 28% aqueous ammonia under ice cooling. The precipitated crystals are washed with 5 ml of water and 5 ml of acetone and dried to form 7-amino-3-(4-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid and 7-amino-3-(2 2.8 g of crude crystals of a mixture of -hydroxybenzyl)-Δ ³ -cephem-4-carboxylic acids are obtained. (ii) 2.8g of the crude crystals obtained in (i) were added to 30ml of methanol.
to which p-toluenesulfonic acid 1
After adding and dissolving 1.75 g of hydrate, 8.8 g of diphenyldiazomethane was gradually added and reacted for 15 minutes at room temperature. After the reaction is complete, the solvent is distilled off under reduced pressure, and the residue is dissolved in a mixed solvent of 15 ml of ethyl acetate and 15 ml of water, and the pH is adjusted to 7 using sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (Wako silica gel C-200; developing solvent, benzene: ethyl acetate = 5:1). If purified, the melting point
7-Amino-3-(2
-Hydroxybenzyl)-△ ³ -Cefem-4-
7-amino-3 showing 1.39 g of carboxylic acid benzhydryl ester and a melting point of 85-90°C (decomposition)
-(4-Hydroxybenzyl)-△ ³ -Cefem-4-carboxylic acid benzhydryl ester 2.31
g was obtained. Γ7-amino-3-(2-hydroxybenzyl)-
△ ³ -Cefem-4-carboxylic acid benzhydryl ester IR (KBr) cm ^-1 ; νc = o1760, 1725 NMR (d ₆ -DMSO) ppm value; 2.70-3.10 (2H, m, NH ₂ ) 3.08, 3.50 ( 2H, ABq J=18cps,

[Formula]) 3.50, 3.78 (2H, ABq J=14cps,

[Formula]) 4.75 (1H, d J = 5 cps, C ₆ - H) 4.98 (1H, d J = 5 cps, C ₇ - H) 6.65 - 7.45 (15 H, m,

【formula】

[Formula] -COOCH~-) Γ7-amino-3-(4-hydroxybenzyl)-
△ ³ -Cefem-4-carboxylic acid benzhydryl ester IR (KBr) cm ^-1 ; νc = o1760, 1720 NMR (d ₆ -DMSO) ppm value; 2.70-3.10 (2H, m, NH ₂ ) 3.08, 3.50 ( 2H, ABq J=18cps,

[Formula]) 3.37, 3.65 (2H, ABq J=14cps,

[Formula]) 4.76 (1H, d J = 5 cps, C _{6 -} H) 5.00 (1H, d J = 5 cps, C ₇ - H) 6.63, 6.90 (4H, ABq J = 9 cps,

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

[Formula]) The following compound was obtained in the same manner. Γ7-amino-3-(4-hydroxy-3-methylbenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 83-85℃ (decomposed) IR (KBr) cm ^-1 ; νc=o1760, 1720 NMR (CDCl ₃ ) ppm value; 2.05 (3H, s, CH ₃ ) 2.95, 3.27 (2H, ABq J=18cps,

[Formula]) 3.29, 3.74 (2H, ABq J=14cps,

[Formula]) 4.57 (1H, d J = 5 cps, C ₆ - H) 4.80 (1H, d J = 5 cps, C ₇ - H) 6.42 - 7.47 (13 H, m,

【formula】

[Formula]) 6.95 (1H, s, CH) Γ7-amino-3-(2-hydroxy-3-methylbenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 78-81℃ (decomposed) IR (KBr) cm ^-1 ; νc=o1760, 1720 NMR (CDCl ₃ ) ppm value; 2.17 (3H, s, CH ₃ ) 3.13, 3.45 (2H, ABq J=18cps,

[Formula]) 3.53, 4.05 (2H, ABq J=14cps,

[Formula]) 4.64 (1H, d J = 5 cps, C ₆ - H) 4.87 (1H, d J = 5 cps, C ₇ - H) 6.48 - 7.58 (14 H, m,

【formula】

[Formula] CH) Γ3-(3-acetamido-4-hydroxybenzyl)-7-amino-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 88-90℃ (decomposition) IR (KBr) cm ^-1 ; νc=o1763, 1720, 1650 NMR (CDCl ₃ ) ppm value; 1.98 (2H, s, NH ₂ ) 2.08 (3H, s, CH ₃ ) 2.92, 3.24 (2H, ABq J=18 cps,

[Formula]) 3.21, 3.74 (2H, ABq J=14cps,

[Formula]) 4.44 (1H, d J = 5 cps, C ₆ - H) 4.67 (1H, d J = 5 cps, C ₇ - H) 6.48 - 7.52 (14 H, m,

【formula】

[Formula] CH) 8.65 (1H, bs, -NHCO-) Γ3-(4-acetamido-2-hydroxybenzyl)-7-amino-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 100-101℃ ( decomposition) IR (KBr) cm ^-1 ; νc=o1768, 1720, 1632 NMR (CDCl ₃ ) ppm value; 1.96 (2H, s, NH ₂ ) 2.01 (3H, s, CH ₃ ) 3.04, 3.36 (2H, ABq J=18cps,

[Formula]) 3.54, 3.91 (2H, ABq J=14cps,

[Formula]) 4.57 (1H, d J = 5 cps, C ₆ - H) 4.79 (1H, d J = 5 cps, C ₇ - H) 6.48 ~ 7.50 (14 H, m,

【formula】

[Formula] CH) 8.66 (1H, bs, -NHCO-) Γ7-amino-3-(2,4-dihydroxy-3
-Methylbenzyl)-△ ³ -Cefem-4-carboxylic acid benzhydryl ester Melting point 93-95℃ (decomposition) IR (KBr) cm ^-1 ; 1760, 1720 NMR (CDCl ₃ ) ppm value; 2.01 (2H, s, NH ₂ ) 2.07 (3H, s, CH ₃ ) 3.14, 3.46 (2H, ABq J=18cps,

[Formula]) 3.52, 4.05 (2H, ABq J=14cps,

[Formula]) 4.64 (1H, d J = 5cps, C ₆ -H) Γ7-amino-3-(2,6-dimethyl-4-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 89-91℃ (decomposition) IR (KBr) cm ^-1 ; νc=o1762, 1718 NMR (CDCl ₃ ) ppm value; 2.02 (6H, s, CH ₃ ×2) 2.84 (2H, s,

[Formula]) 3.40 (2H, bs, NH ₂ ) 3.88 (2H, s,

[Formula]) 4.58 (1H, d J = 5 cps, C ₆ - H) 4.78 (1H, d J = 5 cps, C ₇ - H) 6.44 (2H, s,

[Formula]) 6.99 (1H, s, -CHCH~~) 7.02~7.58 (10H, m,

[Formula]) Γ7-amino-3-(4-hydroxy-3-methoxybenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 73-75℃ (decomposition) IR (KBr) cm ^-1 ; νc = o1762, 1720 NMR (CDCl ₃ ) ppm value; 3.04, 3.36 (2H, ABq J = 18cps,

[Formula]) 3.64 (3H, s, -OCH ₂ ) 3.76 (2H, s,

[Formula]) 4.60 (1H, d J = 5 cps, C ₆ - H) 4.83 (1H, d J = 5 cps, C ₇ - H) 6.38 - 7.48 (14 H, m,

【formula】

[Formula] CH) Γ7-amino-3-(5-chloro-2-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 113-115℃ (decomposition) IR (KBr) cm ^-1 ; νc=o1758, 1720 NMR ( _CDCl3 ) ppm value; 3.14, 3.46 (2H, ABq J=18cps,

[Formula]) 3.26, 3.74 (2H, ABq J=14cps,

[Formula]) 4.77 (1H, d J = 5 cps, C ₆ - H) 5.01 (1H, d J = 5 cps, C ₇ - H) 6.63 - 7.52 (13 H, m,

【formula】

[Formula]) 6.88 (1H, s, CH) Γ7-amino-3-(4-methoxybenzyl)-△
³ -Cefem-4-carboxylic acid benzhydryl ester Melting point 169-174℃ (decomposed) IR (KBr) cm ^-1 ; νc=o1760, 1720 NMR (d ₆ -DMSO) ppm value; 3.16 (2H, bs, NH ₂ ) 3.09, 348 (2H, ABq J=18cps,

[Formula]) 3.41, 3.70 (2H, ABq J=14cps,

[Formula]) 3.70 (3H, s, -OCH ₃ ) 4.78 (1H, d J = 5 cps, C _{6 -} H) 5.01 (1H, d J = 5 cps, C ₇ - H) 6.76 ~ 7.05 (4H, ABq J =8cps,

【formula】) 6.92 (1H, s, CH) 7.32 (10H, s,

[Formula]) Γ7-amino-3-(4-hydroxy-3-nitrobenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 80-83℃ (decomposition) IR (KBr) cm ^-1 ; νc = o1765, 1725 NMR ( _d6- DMSO) ppm value; 3.45 (2H, bs, _NH2 ) 3.00, 3.54 (2H, ABq J=18cps,

[Formula]) 3.34, 3.76 (2H, ABq J=14cps,

[Formula]) 3.69 (1H, d J = 5 cps, C ₆ - H) 3.91 (1H, d J = 5 cps, C ₇ - H) 6.62 ~ 7.02 (2H, m, CH,

【formula】) 7.20 (11H, s,

【formula】

【formula】) 7.90 (1H, dJ=2cps,

[Formula]) Γ7-amino-3-[4-(diphenylmethyloxycarbonylmethyl)benzyl]-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 120-125℃ (decomposition) IR (KBr) cm ^{- 1} ; νc=o1765, 1720 NMR ( _d6 -DMSO) ppm value; 3.20, 3.60 (2H, ABq J=18cps,

[Formula]) 3.45, 3.80 (2H, ABq J=14cps,

【formula】) 3.55 (2H, s,

[Formula]) 4.20 (1H, d J=5cps, C ₆ −H) 4.90 (1H, d J=5cps, C ₇ −H) 6.80 (1H, s, −COOCHCH) 7.00 (1H, s, −COOCHCH) 6.95~7.55 (24H, m,

【formula】

[Formula]) Γ3-(5-acetamido-2-hydroxybenzyl)-7-amino-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 104-106℃ (decomposition) IR (KBr) cm ^-1 ; νc = o1760, 1720, ₁₆₅₀ NMR (CDCl3) ppm value; 1.98 (2H, s, _-NH2 ) 2.09 (3H, s, -NHCOCH~~ ₃ ) 3.03, 3.35 (2H, ABq J=18cps,

[Formula]) 3.35, 3.85 (2H, ABq J=14cps,

[Formula]) 4.46 (1H, d J = 5 cps, C ₆ - H) 4.74 (1H, d J = 5 cps, C ₇ - H) 6.48 - 7.51 (13 H, m,

【formula】

[Formula]) 6.88 (1H, s, -CHCH) 8.09 (1H, bs, -NH~CO-) Γ7-amino-3-(3,5-di-tert.-butyl-4-hydroxybenzyl) -△ ³ -Sefuem-
4-Carboxylic acid benzhydryl ester Melting point 78-81℃ (decomposed) IR (KBr) cm ^-1 ; νc=o1762, 1720 NMR (CDCl ₃ ) ppm value; 1.23 (18H, s, CH ₃ ×6) 3.21 (2H ,s,

[Formula]) 3.27, 3.91 (2H, ABq J=14cps,

[Formula]) 4.47 (1H, d J = 5 cps, C ₆ - H) 4.75 (1H, d J = 5 cps, C ₇ - H) 6.55 - 7.57 (13 H, m,

【formula】

[Formula] -CH) Γ7-amino-3-(5-hydroxy-4-indanylmethyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester Melting point 84-85℃ (decomposition) IR (KBr) cm ^{- 1} ; νc=o1760, 1720 NMR ( _CDCl3 ) ppm value; 1.70-2.28 (2H, m,

【formula】) 2.36~3.37 (4H, m,

【formula】) 3.26 (2H, s,

[Formula]) 3.53, 3.88 (2H, ABq J=14cps,

[Formula]) 4.53 (1H, d J = 5 cps, C ₆ - H) 4.79 (1H, d J = 5 cps, C ₇ - H) 6.40 ~ 7.01 (13 H, m,

【formula】

[Formula] -CHCH~~) Example 4 7-amino-3-(4-hydroxybenzyl)-
4.72 g of ^Δ3 -cephem-4-carboxylic acid benzhydryl ester is dissolved in a mixture of 20 ml of anisole and 25 ml of trifluoroacetic acid, and reacted at room temperature for 30 minutes. After the reaction is complete, the solvent is distilled off under reduced pressure, and the residue is dissolved in 20 ml of water and 20 ml of ethyl acetate. Next, adjust the pH to 3.5 using 28% ammonia water while cooling on ice. If the precipitated crystals are collected, washed successively with 6 ml of water and 6 ml of acetone, and then dried, 7-amino-3-(4-hydroxybenzyl)-△ ³ -cephem-4-, which has a melting point of 173-183°C (decomposed), is obtained. 2.9 g (95% yield) of carboxylic acid are obtained. IR (KBr) cm ^-1 ; νc=o1790, 1610, 1530 NMR ( _D2O - _CF3COOD ) ppm value; 3.38 (2H, s,

[Formula]) 3.85, 4.15 (2H, ABq J=14cps,

[Formula]) 5.13 (1H, d J = 5 cps, C _{6 -} H) 5.25 (1H, d J = 5 cps, C ₇ - H) 6.85, 7.13 (4H, ABq J = 9 cps,

[Formula]) In the same manner, 7-amino-3-(2-hydroxybenzyl)-Δ ^{3 -cephem} -4-carboxylic acid was obtained. Melting point 168℃ (decomposed) IR (KBr) cm ^-1 ; νc=o1785, 1610, 1550 NMR (D ₂ O−CF ₃ COOD) ppm value; 3.40 (2H, s,

[Formula]) 4.00, 4.10 (2H, ABq J=14cps,

[Formula]) 5.16 (1H, d J = 5 cps, C ₆ - H) 5.29 (1H, d J = 5 cps, C ₇ - H) 6.65 - 7.20 (4 H, m,

[Formula]) Example 5 (i) 2.72 g of 7-aminocephalosporanic acid was dissolved in acetic acid.
Suspend in 25 ml and add anhydrous stannic chloride 7.8
After adding and dissolving 1.2 g of phenol, the mixture was allowed to react at room temperature for 8 hours. After the reaction is complete,
The solvent was distilled off under reduced pressure, 20 ml of water was added to the residue, and the pH was adjusted using 28% ammonia water under ice cooling.
Adjust to 3.5. At this time, remove the crystals that precipitate and wash them with water. Pour the obtained crystals back into 15 ml of water.
and adjust the pH to 7 using sodium bicarbonate.
Adjust to. Next, insoluble matter was removed and the solution was diluted with ice for 2N.
- Adjust the pH to 3.5 using hydrochloric acid. The precipitated crystals are collected, washed successively with 5 ml of water and 5 ml of acetone, and then dried to form 7-amino-3-(4-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid and 7-amino-3- 2.1 g of crude crystals of a mixture of (2-hydroxybenzyl)-Δ ³ -cephem-4-carboxylic acid are obtained. (ii) Suspend 2.1 g of the crude crystals obtained in (i) in 21 ml of methanol, add and dissolve 1.32 g of p-toluenesulfonic acid monohydrate, and then gradually add 6.7 g of diphenyldiazomethane. and react for 15 minutes at room temperature. After the reaction is complete, the solvent is distilled off under reduced pressure, the residue is dissolved in a solvent consisting of 15 ml of ethyl acetate and 15 ml of water, and sodium hydrogen carbonate is added to this solution to adjust the pH to 7. Then,
The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (Wako Silica Gel C-200;
When purified using a developing solvent (benzene: ethyl acetate = 5:1), it exhibits a melting point of 98-102°C (decomposition).
-Amino-3-(2-hydroxybenzyl)-△
1.05 g of ³ -cephem-4-carboxylic acid benzhydryl ester and 1.70 g of 7-amino-3-(4-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester having a melting point of 85-90°C (decomposition). get g. The physical properties (IR and NMR) of these compounds were consistent with those obtained in Example 3. Example 6 (i) 2.72 g of 7-aminocephalosporanic acid was dissolved in acetic acid.
Suspend in 25 ml, add 10 g of concentrated sulfuric acid to dissolve it, add 1.2 g of phenol, and stir at room temperature for 5 minutes.
Allow time to react. After the reaction is complete, the solvent is distilled off under reduced pressure, 20 ml of water is added to the residue, and the pH is adjusted to 3.5 using 28% aqueous ammonia under ice cooling. The precipitated crystals were collected, washed successively with 5 ^ml of water and 5 ml of acetone, and then dried. 2.5 g of crude crystals of a mixture of 2-hydroxybenzyl)-Δ ³ -cephem-4-carboxylic acid are obtained. (ii) Suspend 2.5 g of the crude crystals obtained in (i) in 25 ml of methanol, add and dissolve 1.55 g of p-toluenesulfonic acid monohydrate, and then gradually add 7.9 g of diphenyldiazomethane. Add and react for 15 minutes at room temperature. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 15 ml of ethyl acetate and 15 ml of water, and the pH was adjusted using sodium hydrogen carbonate.
Adjust to 7.0. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Wako silica gel C-200; developing solvent, benzene: ethyl acetate = 5:1). For example, 1.27 g of 7-amino-3-(2-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester with a melting point of 98-102°C (decomposition) and a melting point of 85-90°C.
2.08 g of 7-amino-3-(4-hydroxybenzyl)-Δ ^{3 -cephem} -4-carboxylic acid benzhydryl ester showing (decomposition) was obtained. In addition, the physical properties of these compounds (IR and
NMR) was consistent with that obtained in Example 3. Example 7 (i) 2.72 g of 7-aminocephalosporanic acid was dissolved in acetic acid.
Suspend in 25 ml and add fluorosulfonic acid 7 to this.
After adding and dissolving 1.2 g of phenol, the mixture was allowed to react at room temperature for 8 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, 20 ml of water is added to the residue, and the pH is adjusted to 3.5 using 28% aqueous ammonia under ice cooling. Take the precipitated crystals and add 5 ml of water and 5 ml of acetone.
7-amino-
3-(4-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid and 7-amino-3-(2-
2.5 g of crude crystals of a mixture of hydroxybenzyl)-Δ ³ -cephem-4-carboxylic acid are obtained. (ii) Suspend 2.5 g of the crude crystals obtained in (i) in 25 ml of methanol, add and dissolve 1.55 g of p-toluenesulfonic acid monohydrate, and then gradually add 7.9 g of diphenyldiazomethane. Add and react for 15 minutes at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure.
The residue was dissolved by adding 15 ml of ethyl acetate and 15 ml of water, and the pH was adjusted to 7.0 using sodium bicarbonate.
Adjust to. The organic layer was separated and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (Wako silica gel C-200; developing solvent, benzene: ethyl acetate =
5:1), the melting point is 98-102℃ (decomposition).
1.30 g of 7-amino-3-(2-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester and 7-amino-3-(4-hydroxy 2.0 g of benzyl)-Δ ³ -cephem-4-carboxylic acid benzhydryl ester are obtained. In addition, the physical properties of these compounds (IR and
NMR) was consistent with that obtained in Example 3. Example 8 (i) 2.72 g of 7-aminocephalosporanic acid was dissolved in acetic acid.
Suspend in 25 ml, add 12 g of trifluoromethanesulfonic acid and dissolve, then add 1.2 g of phenol and react at room temperature for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was diluted with water.
ml and pH using 28% ammonia water under ice cooling.
Adjust to 3.5. Take the precipitated crystals, wash them sequentially with 5 ml of water and 5 ml of acetone, and then dry them.
7-amino-3-(4-hydroxybenzyl)-
2.3 g of crude crystals of a mixture of △ ³ -cephem-4-carboxylic acid and 7-amino-3-(2-hydroxybenzyl)-△ ^{3 -cephem} -4-carboxylic acid
get. (ii) Suspend 2.3 g of the crude crystals obtained in (i) in 23 ml of methanol, add and dissolve 1.42 g of p-toluenesulfonic acid monohydrate, and then gradually add 7.3 g of diphenyldiazomethane. Add and react for 15 minutes at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure.
The residue was dissolved by adding 15 ml of ethyl acetate and 15 ml of water, and the pH was adjusted to 7.0 using sodium bicarbonate.
Adjust to. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (Wako silica gel C-
200; developing solvent, benzene: ethyl acetate = 5:
Purification by step 1) yields 1.14 g of 7-amino-3-(2-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester with a melting point of 98-102°C (decomposition) and a melting point of 85-90°C. (Disassembly)
1.88 g of 7-amino-3-(4-hydroxybenzyl)-Δ ³ -cephem-4-carboxylic acid benzhydryl ester having the following formula is obtained. In addition, the physical properties of these compounds (IR and
NMR) was consistent with that obtained in Example 3. Example 9 (i) 2.72 g of 7-aminocephalosporanic acid was suspended in 25 ml of trifluoroacetic acid, 13 g of p-toluenesulfonic acid monohydrate was added and dissolved, and 1.2 g of phenol was added. React for 5 hours at room temperature. After the reaction is complete, the solvent is distilled off under reduced pressure, 20 ml of water is added to the residue, and the pH is adjusted to 3.5 using 28% aqueous ammonia under ice cooling. Remove the precipitated crystals and wash with water. The obtained crystals are suspended again in 15 ml of water, and the pH is adjusted to 7.0 using sodium hydrogen carbonate. Next, after removing insoluble matter, the solution was adjusted to pH 3.5 using 2N hydrochloric acid 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-
(4-Hydroxybenzyl)-△ ³ -Cefem-
2.2 g of crude crystals of a mixture of 4-carboxylic acid and 7-amino-3-(2-hydroxybenzyl)-Δ ³ -cephem-4-carboxylic acid are obtained. (ii) Suspend 2.2 g of the crude crystals obtained in (i) in 22 ml of methanol, add and dissolve 1.35 g of p-toluenesulfonic acid monohydrate, and then gradually add 6.9 g of diphenyldiazomethane. Add and react for 15 minutes at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure.
The residue was dissolved by adding 15 ml of ethyl acetate and 15 ml of water, and the pH was adjusted to 7.0 using sodium bicarbonate.
Adjust to. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (Wako silica gel C-200; developing solvent, benzene: ethyl acetate =
5:1), the melting point is 98-102℃ (decomposition).
1.10 g of 7-amino-3-(2-hydroxybenzyl)-△ ³ -cephem-4-carboxylic acid benzhydryl ester exhibiting 1.80 g of benzyl)-Δ ³ -cephem-4-carboxylic acid benzhydryl ester are obtained. In addition, the physical properties of these compounds (IR and
NMR) was consistent with that obtained in Example 3.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, and X represents an acetoxy group. ] In an organic solvent, in the presence of a protonic acid, a Lewis acid, or a complex compound of a Lewis acid, a compound represented by the formula R ² −H [wherein R ² is an optionally substituted phenyl ,
Indicates an indanyl, thienyl or furyl group. ] A general formula characterized by reacting a compound represented by [In the formula, R ¹ and R ² have the above-mentioned meanings. However, it is assumed that -CH ₂ R ² is bonded to the carbon atom of the exomethylene group adjacent to the carbon atom of R ² . ] A method for producing 7-amino-3-substituted methyl cefemcarboxylic acid or a salt thereof. 2. The method for producing 7-amino-3-substituted methyl cefem carboxylic acid or a salt thereof according to claim 1, wherein the organic solvent is an organic carboxylic acid. 3. The method for producing 7-amino-3-substituted methyl cefemcarboxylic acid or a salt thereof according to claim 1 or 2, wherein the protonic acid is sulfuric acid, sulfonic acid, or super strong acid. 4. 7-amino-3 according to claim 1 or 2, wherein the Lewis acid or a complex compound of a Lewis acid is boron trifluoride, zinc chloride, stannic chloride, or a complex compound of these Lewis acids. - A method for producing substituted methyl cefem carboxylic acid or a salt thereof.