Preparation method of cefcapene lactone compound or hydrochloride thereof

A technology for cefcapine and compound, which is applied in the field of preparation of cefcapine lactone compound or its hydrochloride, can solve problems such as difficulty in extraction, achieve good yield and purity requirements, is beneficial to industrial application, and guarantees impurities Effects of Control and Purity Quality Analysis

Inactive Publication Date: 2020-04-14
浙江东邦药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] And the synthetic process report that relates to this impurity is quite few, simultaneously, for its content of the impurity that exists in the synthesis of cefcarpine pivoxil hydrochloride, it is very small, is difficult to separate therefrom, and this just is difficult to extract this impurity of high quality as standard substance to be used as a control

Method used

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  • Preparation method of cefcapene lactone compound or hydrochloride thereof
  • Preparation method of cefcapene lactone compound or hydrochloride thereof
  • Preparation method of cefcapene lactone compound or hydrochloride thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0038] The formula V compound cefcarpine lactone hydrochloride structural formula of the present embodiment is as follows:

[0039]

[0040] The synthesis of above-mentioned cefcarpine lactone compound hydrochloride adopts the following method to obtain:

[0041] At room temperature, mix 30.2g (0.096mol, 1.2eq) (Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid with 18.4g (0.08mol, 1eq) methylol Dissolve 7-aminocephalosporanic acid in 300mL of ethyl acetate, slowly cool down to 5-10°C, control the temperature, start to add 10.5g (0.104mol, 1.3eq) of triethylamine dropwise, after the drop, control the temperature at Stir at 5-10°C and carry out condensation reaction for 3 hours; after the condensation reaction is completed, add triethylamine dropwise to the reaction solution to adjust the pH value of the reaction solution system to 9.0-9.5. After the pH value is basically stable, control the temperature at Stir at about 15°C for sufficient lactonization reactio...

Embodiment 2

[0067] At room temperature, mix 37.7g (0.12mol, 1.5eq) (Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid with 18.4g (0.08mol, 1eq) methylol Dissolve 7-aminocephalosporanic acid in 400mL of dichloromethane, slowly cool down to 5-10°C, control the temperature, start to add 10.5g (0.104mol, 1.3eq) triethylamine dropwise, after the drop, control the temperature at 0~5℃ and stirring for condensation reaction for 4 hours; after the condensation reaction is completed, add dropwise to the reaction solution, and then add dropwise triethylamine to the reaction solution, adjust the system pH of the reaction solution to 9.0-9.5, wait for the pH After the value is basically stable, control the temperature at about 15°C and stir for a full lactonization reaction for 3.0 hours. After the end of lactonization, carry out vacuum concentration to a certain volume to remove part of the solvent, and then slowly cool down to -10~-5°C for stirring Crystallize for 2 hours. After the cry...

Embodiment 3

[0071] At room temperature, mix 27.7g (0.088mol, 1.1eq) (Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid with 18.4g (0.08mol, 1eq) methylol Dissolve 7-aminocephalosporanic acid in 400mL of ethyl acetate, slowly cool down to 5-8°C, control the temperature, start to add 12.1g (0.12mol, 1.5eq) of triethylamine dropwise, after the dropping, control the temperature at 0~5℃ and stirring for 3.5 hours for condensation reaction; after the condensation reaction is over, add triethylamine dropwise to the reaction solution to adjust the pH value of the reaction solution system to 9.0-9.5. After the pH value is basically stable, control the temperature at Stir at around 20°C for 3 hours for sufficient lactonization reaction. After the end of lactonization, carry out vacuum concentration to a certain volume to remove part of the solvent, then slowly cool down to -8~-5°C for 2.5 hours of stirring and crystallization, and crystallization After finishing, filter and wash the fi...

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PUM

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Abstract

The invention relates to a preparation method of a cefcapene lactone compound or a hydrochloride thereof, and belongs to the technical field of synthesis of drug-related impurities. In order to solvethe problems of few synthesis routes and low yield in the prior art, the invention provides a preparation method of a cefcapene lactone compound or a hydrochloride thereof. The method comprises the following steps: carrying out a condensation reaction on (Z)-2-(2-tert-butyloxycarbonylaminothiazole-4-yl)-2-pentenoic acid and hydroxymethyl-7-aminocephalosporanic acid in an organic solvent in the presence of an organic alkali I, continuously adding an organic alkali II to adjust the pH value to 9.0-9.5 after the reaction is finished, and performing lactonization to obtain a compound represented by a formula IV; performing a deprotection reaction on the compound represented by the formula IV in a non-water-soluble organic solvent under the action of a Lewis acid to obtain a compound represented by a formula I; and carrying out a reaction on the compound represented by the formula I and hydrochloric acid to obtain a cefcapene lactone compound hydrochloride when the cefcapene lactone compound hydrochloride is synthesized. The synthetic route is easy to operate, and the yield and the purity are high.

Description

technical field [0001] The invention relates to a preparation method of a cefcarpine lactone compound or its hydrochloride, belonging to the technical field of synthesis of drug-related impurities. Background technique [0002] Cefcapene Pivoxil Hydrochloride Hydrochloride (Cefcapene Pivoxil Hydrochloride Hydrochloride) was developed by Shionogi Co., Ltd. of Japan, and was listed for the first time in 1997 under the trade name of Flomox. Cefcarpine pivoxil is a third-generation oral cephalosporin antibiotic. The results of pharmacological studies have shown that cephalocarpine pivoxil has stronger antibacterial activity and lower dosage than the existing oral cephalosporins, and has achieved good clinical and bacteriological effects and good safety for adults and children. , is an oral cephalosporin with high efficacy. [0003] There are many methods for synthesizing cefcarpine pivoxil hydrochloride currently reported, but most of the processes are similar to the synthetic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/12C07D501/06
CPCC07D501/06C07D501/12C07D501/34
Inventor 周军荣张云华池瀛肖建平张佳
Owner 浙江东邦药业有限公司
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