Preparation method of cefditoren pivoxil

Abstract

The invention relates to a preparation method of cephalosporin, particularly to a preparation method of cefditoren pivoxil. 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl) vinyl]-3-cephem-4-carboxylic acid and 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic are taken as initial raw materials, and the cefditoren pivoxil is obtained through condensation and esterification reactions. The method is simple in process, high in yield, free of highly corrosive solvents and suitable for industrial production.

Description

technical field

[0001] The invention relates to a preparation method of cephalosporins, in particular to a preparation method of cefditoren pivoxil. Background technique

[0002] Cefditoren pivoxil is the third-generation oral cephalosporin, pioneered by Japan's Meiji Seika Co., Ltd. It went on the market in Japan in April 1994 and in China in April 2001 under the trade name of Miac. The dosage form currently on the market in China is film-coated tablets. Indications are Staphylococcus, Streptococcus, Peptostreptococcus, Branham catarrhalis, Propionibacterium acnes, Escherichia coli, Citrobacter, Klebsiella, Enterobacter, Serratia The following infections caused by bacteria sensitive to cefditoren in the genus Proteus (Proteus mirabilis, Proteus vulgaris), Morganella, Providencia, Haemophilus influenzae, and Bacteroides: ①Folliculitis, furuncle, furunculosis, carbuncle, contagious impetigo, erysipelas, cellulitis, lymphangio (node) inflammation, suppurative paronychia, wh...

Examples

Embodiment 1

[0026] (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methyl Preparation of lithium-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

[0027] Put 200g of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, 2-methoxyimino into the reaction flask - 240g of 2-(2-amino-4-thiazolyl)-(z)-benzothiazolyl thioacetate, 2000ml of dichloromethane, lower the temperature to 0°C, and add 120g of ethylamine dropwise. Add water, separate the layers, adjust the pH of the aqueous layer to 2.8 with dilute hydrochloric acid, and centrifuge until dry. The filter cake was completely dissolved with 5000ml of acetone, 130g of lithium tert-butoxide was added to react for 1 hour, filtered, and the product was dried to obtain 270g of the title compound with a yield of 80.0%.

Embodiment 2

[0029] Put 200g of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, 2-methoxyimino into the reaction flask - 240 g of 2-(2-amino-4-thiazolyl)-(z)-benzothiazolyl thioacetate, 2000 ml of dichloromethane, lower the temperature to 0°C, and add 145 g of triethylamine dropwise. Add water, separate the layers, adjust the pH of the aqueous layer to 2.8 with dilute hydrochloric acid, and centrifuge until dry. The filter cake was completely dissolved with 5000ml of acetone, 130g of lithium tert-butoxide was added to react for 1 hour, filtered, and the product was dried to obtain 276g of the title compound with a yield of 82.1%.

Embodiment 3

[0031] Put 200g of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, 2-methoxyimino into the reaction flask - 240 g of 2-(2-amino-4-thiazolyl)-(z)-benzothiazolyl thioacetate, 2000 ml of dichloromethane, lower the temperature to 0°C, and add 157 g of triethanolamine dropwise. Add water, separate the layers, adjust the pH of the aqueous layer to 2.8 with dilute hydrochloric acid, and centrifuge until dry. The filter cake was completely dissolved with 5000ml of acetone, 130g of lithium tert-butoxide was added to react for 1 hour, filtered, and the product was dried to obtain 254g of the title compound with a yield of 74.3%.

technical field

[0001] The invention relates to a preparation method of cephalosporins, in particular to a preparation method of cefditoren pivoxil. Background technique

[0002] Cefditoren pivoxil is the third-generation oral cephalosporin, pioneered by Japan's Meiji Seika Co., Ltd. It went on the market in Japan in April 1994 and in China in April 2001 under the trade name of Miac. The dosage form currently on the market in China is film-coated tablets. Indications are Staphylococcus, Streptococcus, Peptostreptococcus, Branham catarrhalis, Propionibacterium acnes, Escherichia coli, Citrobacter, Klebsiella, Enterobacter, Serratia The following infections caused by bacteria sensitive to cefditoren in the genus Proteus (Proteus mirabilis, Proteus vulgaris), Morganella, Providencia, Haemophilus influenzae, and Bacteroides: ①Folliculitis, furuncle, furunculosis, carbuncle, contagious impetigo, erysipelas, cellulitis, lymphangio (node) inflammation, suppurative paronychia, wh...

Examples

Embodiment 1

[0026] (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methyl Preparation of lithium-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

[0027] Put 200g of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, 2-methoxyimino into the reaction flask - 240g of 2-(2-amino-4-thiazolyl)-(z)-benzothiazolyl thioacetate, 2000ml of dichloromethane, lower the temperature to 0°C, and add 120g of ethylamine dropwise. Add water, separate the layers, adjust the pH of the aqueous layer to 2.8 with dilute hydrochloric acid, and centrifuge until dry. The filter cake was completely dissolved with 5000ml of acetone, 130g of lithium tert-butoxide was added to react for 1 hour, filtered, and the product was dried to obtain 270g of the title compound with a yield of 80.0%.

Embodiment 2

[0029] Put 200g of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, 2-methoxyimino into the reaction flask - 240 g of 2-(2-amino-4-thiazolyl)-(z)-benzothiazolyl thioacetate, 2000 ml of dichloromethane, lower the temperature to 0°C, and add 145 g of triethylamine dropwise. Add water, separate the layers, adjust the pH of the aqueous layer to 2.8 with dilute hydrochloric acid, and centrifuge until dry. The filter cake was completely dissolved with 5000ml of acetone, 130g of lithium tert-butoxide was added to react for 1 hour, filtered, and the product was dried to obtain 276g of the title compound with a yield of 82.1%.

Embodiment 3

[0031] Put 200g of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, 2-methoxyimino into the reaction flask - 240 g of 2-(2-amino-4-thiazolyl)-(z)-benzothiazolyl thioacetate, 2000 ml of dichloromethane, lower the temperature to 0°C, and add 157 g of triethanolamine dropwise. Add water, separate the layers, adjust the pH of the aqueous layer to 2.8 with dilute hydrochloric acid, and centrifuge until dry. The filter cake was completely dissolved with 5000ml of acetone, 130g of lithium tert-butoxide was added to react for 1 hour, filtered, and the product was dried to obtain 254g of the title compound with a yield of 74.3%.

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