Cefcapene pivoxil hydrochloride synthesis method

A cefcapene hydrochloride and synthetic method technology, applied in the direction of organic chemistry, etc., can solve the problems of unsuitability for large-scale production, complicated operation, low total yield, etc., and achieve saving of drying process, simplified operation steps, and short process cycle Effect

Active Publication Date: 2018-05-15
湖北凌晟药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is complicated to operate, and the cost is high, so it is not suitable for large-scale production
[0008] CN102775425A: Discloses a one-pot preparation method of cefcapene diisopropylamine salt, a key intermediate of cefcapene axetil. Although the operation is simple, the yield is not high, and the two-step reaction product is only 67% when the purity is unknown. %
[0009] CN105254649A: discloses the preparation of cefcapene etexilate with 7-HACA as raw material, wherein the esterification process is carried out in the presence of potassium phosphate and ketone acetate, and then reacted with hydrochloric acid to remove the protecting group. The two-step total yield is 68.82%. This patented process High-salt wastewater is produced, and the total yield of the two steps is low

Method used

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  • Cefcapene pivoxil hydrochloride synthesis method
  • Cefcapene pivoxil hydrochloride synthesis method
  • Cefcapene pivoxil hydrochloride synthesis method

Examples

Experimental program
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Embodiment 1

[0033] In a 250ml four-necked flask, add 12.1g (0.0185mol) of BCN solids, 50ml of dichloromethane, add 9.06g (0.00925mol) of 10wt% dilute sulfuric acid to adjust the pH (5.0) to dissolve, stir at room temperature for 10 minutes, and let stand layer, the organic layer was added with 5g of anhydrous sodium sulfate and dried for 8 hours, the water layer was discarded, and after removing the anhydrous sodium sulfate by filtration, 2.7g (0.037mol) of formic acid was added, 18.76g (0.185mol) of 36wt% concentrated hydrochloric acid, and the temperature was controlled 0-5 ℃, insulated and stirred for 7 hours, after the completion of the reaction, add 30ml of water, separate layers, add 4.47 grams (0.0185mol) of iodomethyl pivalate dropwise to the organic layer and maintain pH=6.0 with 7wt% sodium bicarbonate aqueous solution, in React at 25°C for 4 hours. After the reaction is over, add 10ml of ethanol and 30ml of water to wash and separate the layers, discard the water layer, then add...

Embodiment 2

[0035] In a 250ml four-neck flask, add 12.1g (0.0185mol) of BCN solids and 50ml of dichloromethane, stir at room temperature, add 9.07g of 10wt% dilute sulfuric acid to adjust the pH (5.01) to dissolve, let stand and separate, add 5g to the organic layer Anhydrous sodium sulfate was left to stand for 8 hours, the water layer was discarded, and after removing anhydrous sodium sulfate by filtration, 2.7 g (0.037 mol) of formic acid and concentrated hydrochloric acid (22.51 g, 0.222 mol) were added, and the temperature was controlled at 0-5°C, and kept stirring for 7 Hours, add 30ml of water, separate layers, add 4.47 grams (0.0185mol) of iodomethyl pivalate (0.0185mol) and 7wt% sodium bicarbonate aqueous solution to the organic layer dropwise, maintain pH = 6, react at 25 ° C for 5h, after the reaction, wash with ethanol 10ml Wash and separate with 30ml of water, then add 10ml of ethanol, adjust the pH to neutral with 7wt% sodium bicarbonate aqueous solution (23g), separate layer...

Embodiment 3

[0037]In a 250ml four-neck flask, add 12.1g (0.0185mol) of BCN solids and 50ml of dichloromethane, stir at room temperature, add 6.75g (0.0185mol) of 10wt% dilute hydrochloric acid to adjust the pH (5.02) to dissolve and clear, let stand and separate, Add 5 g of magnesium sulfate to the organic layer to dry, filter to remove anhydrous magnesium sulfate, add 2.7 g (0.037 mol) of formic acid, 24.6 g (0.246 mol) of concentrated hydrochloric acid, control the temperature at 0-5 ° C, keep stirring for 7 hours, add 30 ml of water, divide layer, the organic layer was added dropwise with iodomethyl pivalate 4.47 grams (0.0185mol) and 7wt% sodium bicarbonate aqueous solution (40 milliliters), to maintain pH = 5, 30 ° C reaction 3h, after the reaction, with ethanol 10ml and water 30ml Wash and separate the layers, then add 10ml of ethanol, adjust the pH to neutral with 7wt% sodium bicarbonate aqueous solution (26g), separate the layers, concentrate the organic layer under reduced pressur...

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Abstract

The invention discloses a cefcapene pivoxil hydrochloride synthesis method, and belongs to the technical field of synthesis of cephalosporin medicines. The cefcapene pivoxil hydrochloride synthesis method comprises the following steps: (1) using BCN as a starting material, reacting with an inorganic acid aqueous solution in a solvent to obtain a dissolved clarified solution, standing, layering, abandoning a water layer, collecting an organic layer comprising a compound I, and drying; (2) adding a formic acid and a concentrated hydrochloric acid, reacting at the temperature of 0-5 DEG C, washing with water after finishing reacting, layering, and collecting an organic layer comprising a compound II; (3) adding a sodium bicarbonate aqueous solution and iodomethyl pivalate, maintaining the pHvalue to 5-6, layering after finishing reacting, collecting the organic layer, adding ethanol, washing with water, layering, additionally adding the ethanol in the organic layer, regulating the pH value to 7-8 by using an inorganic base, layering, and collecting an organic layer comprising a compound III; and (4) conducting vacuum concentration until no liquid drop is distilled, adding a solvent,adding a diluted hydrochloric acid, regulating the crystallization, cooling, growing the crystal, conducting suction filtration, and drying to obtain cefcapene pivoxil hydrochloride. The process of the method is simple, the reaction condition is mild, the method is environmentally friendly, the yield is high, the purity is high, and the method is easy for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of cephalosporins, in particular to a synthesis method of cefcapene hydrochloride. Background technique [0002] Cefcapene Proxil Hydrochloride, chemical name: (6R,7R)-3-(((carbamoyl)oxy)methyl)-7-(((2Z)-2-(2-amino-4-thiazolyl) -1-oxo-2-pentene)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-ene-2-carboxylic acid-2,2-di Methyl pivaloyloxymethyl ester hydrochloride monohydrate, its structural formula is: [0003] [0004] Cefcapene pivoxil hydrochloride is a broad-spectrum cephalosporin antibiotic. It was first developed by Shionogi Pharmaceutical Co., Ltd. in Japan. It was listed in Japan for the first time in 1997 under the trade name Flomox. Spectrum antibiotics. [0005] Since multiple parts of the β-lactam ring in the structure of cefcapene pivoxil hydrochloride are prone to degradation reactions, the stability of cefcapene pivoxil hydrochloride is poor. The impurities in the finished...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/04C07D501/34
CPCC07D501/04C07D501/34
Inventor 金联明门万辉罗云石林邹菁
Owner 湖北凌晟药业股份有限公司
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