Preparation method of ceftizoxime sodium

Abstract

The invention relates to a preparation method of ceftizoxime sodium. The method comprises the following steps: based on 7-acetamido-3-hydroxy-3-cephalosporin-4-formic acid-diphenyl methyl ester (II) sas a starting material, carrying out reduction, sulfoacid esterification, de-exterification sulfonation and 4-site and 7-site protective groups removal so as to obtain an important intermediate, namely, 7-amino-3-free-3-cephalosporin-4-formic acid (VI, 7-ANCA); reacting 7-amino-3-free-3-cephalosporin-4-formic acid (VI, 7-ANCA) with an active ester so as to obtain ceftizoxime acid (VIII); and generating the product, namely, ceftizoxime sodium (I), from the ceftizoxime acid (VIII) in the presence of a salt forming agent. The method for preparing ceftizoxime sodium is simple in operation, low in cost and suitable for industrial production, and the total yield can reach 52.9%. The product is white or light yellow, and rectification is not needed, thereby ensuring the quality and yield of the product.

Description

technical field

[0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method of cephalosporins, more specifically to a preparation method of ceftizoxime sodium. Background technique

[0002] Ceftizoxime sodium, English name: Ceftizoxime Sodium, chemical name: (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide Base] -8-oxo-5-thia-1-aminoheterobicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, molecular formula: C 13 h 12 N 5 NaO 5 S 2 , Molecular weight: 405.38, structural formula is

[0003]

[0004] Ceftizoxime sodium is a third-generation cephalosporin antibiotic developed by Fujisawa Pharmaceutical Co., Ltd. of Japan. It was first listed in Japan in 1982 under the trade name Ceftizox. This product is a third-generation cephalosporin antibiotic. Its mechanism of action is to achieve bactericidal effect by inhibiting the biosynthesis of bacterial cell wall mucopeptides. It has the characteristics of broa...

Examples

Embodiment 1

[0050] Synthesis of 7-phenylacetamido-3-hydroxy-4-carboxylic acid-diphenylmethyl ester (Ⅲ)

[0051] Add 50.0g (0.1mol) of 7-phenylacetamido-3-hydroxy-3-cephalosporin-4-carboxylic acid-benzhydryl (II) into a 500ml double-necked bottle, and add 250ml of dichloromethane to dissolve. Cool down to -30°C, add sodium borohydride 4.54 (0.12mol), continue to cool down to -55~-50°C, and react for 1h. After adding 300ml of pure water and stirring, separate the liquid to take the organic phase, add 100ml of toluene, stir and crystallize, and filter with suction to obtain 46.0g of 7-phenylacetamido-3-hydroxy-4-carboxylic acid-diphenylmethyl ester (Ⅲ) product , yield 91.6%.

Embodiment 2

[0053] Synthesis of 7-phenylacetamido-3-non-3-cephalosporin-4-carboxylic acid (Ⅴ)

[0054] In a 1000ml reaction bottle, add 40.2g (0.08mol) of the reaction product from the previous step, and add 500ml of dichloromethane to dissolve. Cool down to -10°C, add 13.7g (0.12mol) methanesulfonyl chloride dropwise, stir for 15min, add 13.1g (0.13g) of triethylamine dropwise, keep warm at -10~-5°C for 30min, add dropwise 20.8ml of diethylamine (0.2mol), stirred at room temperature for 2.5h, added 300ml of pure water and stirred, separated the organic layer into a 1000ml reaction bottle, cooled to -10°C, added 60ml of sulfide anisole, and added trichloride dropwise under stirring A solution of aluminum (38g) in nitromethane (200ml) was stirred at room temperature for 5h, then 500ml of pure water was added and stirred for 15min, the liquid was separated, n-hexane was added to the organic phase, stirred and crystallized, and suction filtered to obtain the product 7-benzene Acetylamino-3-...

Embodiment 3

[0056] Synthesis of 7-amino-3-anol-3-cephalosporin-4-carboxylic acid (Ⅵ)

[0057] In a 250ml reaction flask, add 12.7g (0.04mol) of 7-phenylacetamido-3-ceph-4-carboxylic acid-diphenylmethyl ester, add 80ml of dichloromethane, cool to -15°C, and add dimethyl Amine 4.0ml (0.06mol), dimethyl disulfide 15ml, stirring and dissolving, add dropwise 60ml of phosphorus pentachloride 12.5g (0.06mol) in dichloromethane solution, stir and react at -5°C for 1h, cool to -20°C ℃, 50ml of isobutanol was added dropwise, and reacted at room temperature for 3h. Extract twice with 300ml of pure water, combine the water phases, decolorize with 1g of activated carbon, adjust the pH to 4 with ammonia water, stir and crystallize, and filter with suction to obtain 7.4g of the product 7-amino-3-non-3-cephalosporin-4-carboxylic acid , yield 92.4%.

technical field

[0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method of cephalosporins, more specifically to a preparation method of ceftizoxime sodium. Background technique

[0002] Ceftizoxime sodium, English name: Ceftizoxime Sodium, chemical name: (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide Base] -8-oxo-5-thia-1-aminoheterobicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, molecular formula: C 13 h 12 N 5 NaO 5 S 2 , Molecular weight: 405.38, structural formula is

[0003]

[0004] Ceftizoxime sodium is a third-generation cephalosporin antibiotic developed by Fujisawa Pharmaceutical Co., Ltd. of Japan. It was first listed in Japan in 1982 under the trade name Ceftizox. This product is a third-generation cephalosporin antibiotic. Its mechanism of action is to achieve bactericidal effect by inhibiting the biosynthesis of bacterial cell wall mucopeptides. It has the characteristics of broa...

Examples

Embodiment 1

[0050] Synthesis of 7-phenylacetamido-3-hydroxy-4-carboxylic acid-diphenylmethyl ester (Ⅲ)

[0051] Add 50.0g (0.1mol) of 7-phenylacetamido-3-hydroxy-3-cephalosporin-4-carboxylic acid-benzhydryl (II) into a 500ml double-necked bottle, and add 250ml of dichloromethane to dissolve. Cool down to -30°C, add sodium borohydride 4.54 (0.12mol), continue to cool down to -55~-50°C, and react for 1h. After adding 300ml of pure water and stirring, separate the liquid to take the organic phase, add 100ml of toluene, stir and crystallize, and filter with suction to obtain 46.0g of 7-phenylacetamido-3-hydroxy-4-carboxylic acid-diphenylmethyl ester (Ⅲ) product , yield 91.6%.

Embodiment 2

[0053] Synthesis of 7-phenylacetamido-3-non-3-cephalosporin-4-carboxylic acid (Ⅴ)

[0054] In a 1000ml reaction bottle, add 40.2g (0.08mol) of the reaction product from the previous step, and add 500ml of dichloromethane to dissolve. Cool down to -10°C, add 13.7g (0.12mol) methanesulfonyl chloride dropwise, stir for 15min, add 13.1g (0.13g) of triethylamine dropwise, keep warm at -10~-5°C for 30min, add dropwise 20.8ml of diethylamine (0.2mol), stirred at room temperature for 2.5h, added 300ml of pure water and stirred, separated the organic layer into a 1000ml reaction bottle, cooled to -10°C, added 60ml of sulfide anisole, and added trichloride dropwise under stirring A solution of aluminum (38g) in nitromethane (200ml) was stirred at room temperature for 5h, then 500ml of pure water was added and stirred for 15min, the liquid was separated, n-hexane was added to the organic phase, stirred and crystallized, and suction filtered to obtain the product 7-benzene Acetylamino-3-...

Embodiment 3

[0056] Synthesis of 7-amino-3-anol-3-cephalosporin-4-carboxylic acid (Ⅵ)

[0057] In a 250ml reaction flask, add 12.7g (0.04mol) of 7-phenylacetamido-3-ceph-4-carboxylic acid-diphenylmethyl ester, add 80ml of dichloromethane, cool to -15°C, and add dimethyl Amine 4.0ml (0.06mol), dimethyl disulfide 15ml, stirring and dissolving, add dropwise 60ml of phosphorus pentachloride 12.5g (0.06mol) in dichloromethane solution, stir and react at -5°C for 1h, cool to -20°C ℃, 50ml of isobutanol was added dropwise, and reacted at room temperature for 3h. Extract twice with 300ml of pure water, combine the water phases, decolorize with 1g of activated carbon, adjust the pH to 4 with ammonia water, stir and crystallize, and filter with suction to obtain 7.4g of the product 7-amino-3-non-3-cephalosporin-4-carboxylic acid , yield 92.4%.

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