Method for synthesizing cefcapene pivoxil hydrochloride by using enzyme method and synthesized intermediate of cefcapene pivoxil hydrochloride

A technology of cefcapine and enzymatic synthesis, applied in organic chemistry, fermentation, etc., can solve the problems of unstable cephalosporin antibiotic compounds, difficulty in removing phenol impurities, and easy occurrence of side reactions, so as to facilitate industrial production and improve product purity , the effect of reducing production costs

Active Publication Date: 2022-05-27
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

In the reaction of deamination protecting group, phenol is used for cleavage reaction. Because cephalosporin antibiotic compound is unstable, at high temperature of 80°C, phenol is used as a cleavage agent to remove amino Boc protecting group, which is prone to side reactions and impurities, and phenol itself as a It is also difficult to remove impurities, which will eventually affect the quality of the product

Method used

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  • Method for synthesizing cefcapene pivoxil hydrochloride by using enzyme method and synthesized intermediate of cefcapene pivoxil hydrochloride
  • Method for synthesizing cefcapene pivoxil hydrochloride by using enzyme method and synthesized intermediate of cefcapene pivoxil hydrochloride
  • Method for synthesizing cefcapene pivoxil hydrochloride by using enzyme method and synthesized intermediate of cefcapene pivoxil hydrochloride

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Experimental program
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Embodiment 1

[0114] The preparation of compound shown in embodiment 1 formula (V)

[0115] At room temperature, 200 mL of dichloromethane was added to a clean reaction flask, and then 15 g (0.07 mol, 1 eq) of the compound of formula VI was added, and the mixture was stirred to dissolve. The material was gradually cooled, and the temperature was controlled at 5-10° C., 17.3 g (0.112 mol, 1.6 eq) of phenylacetyl chloride was added, and the mixture was stirred uniformly. Then, the temperature was controlled at 5-10° C., and 12.0 g (0.119 mol, 1.7 eq) of triethylamine was added dropwise. After the dropwise addition, the temperature was controlled at 5-10°C, and the acylation reaction was stirred for 3 hours. After the reaction, 1.5% dilute hydrochloric acid solution was added to the feed solution, the pH value was adjusted to be neutral, the temperature was controlled at 10-15° C., stirred and washed for 5 minutes, and stood for 30 minutes for liquid separation. The aqueous layer was discard...

Embodiment 2

[0120] The preparation of compound shown in embodiment 2 formula (IV)

[0121] At room temperature, 150 mL of dichloromethane was added to a clean three-necked flask, and 18.0 g (0.057 mol, 1.0 eq) of the compound represented by formula (V) and 7.8 g (0.068 mol, 1.2 eq) of methanesulfonyl chloride were added, and the mixture was stirred. Cool down to 0°C. The temperature was controlled at 0°C-10°C, 7.5 g (0.074 mol, 1.3 eq) of diisopropylamine was added, and the reaction was stirred for 30 minutes. After the reaction, the reaction solution A was obtained, which was kept at 0°C to 10°C for use. At room temperature, 100 mL of methanol was added to another clean three-necked flask, 13.1 g (0.057 mol, 1.0 eq) of D-7-ACA was added, stirred and cooled to 0°C. The temperature was controlled at 0°C-10°C, 6.4 g (0.063 mol, 1.1 eq) of diisopropylamine was added, and the reaction was stirred for 20 minutes. After the reaction was completed, a reaction solution B was obtained, and the ...

Embodiment 3

[0122] Example 3 Preparation of compound represented by formula (II)

[0123] At room temperature, 200 mL of dichloromethane and 150 mL of water were added to a dry and clean three-necked flask, and 30.0 g (0.045 mol, 1.0 eq) of the compound of formula IV was added, stirred and cooled to 10°C. Control the temperature below 15°C, add 10% sulfuric acid solution, adjust the pH value to 4.0-4.5, and stir to dissolve. Let stand for 30 minutes. The aqueous layer was discarded during liquid separation, and the organic layer feed liquid was collected for use. Add 200 mL of water to the organic layer, control the temperature to 10-15° C., add 10% aqueous sodium hydroxide solution, adjust the pH to 7.0-7.5, and stir for 10 minutes. Let stand for 30 minutes. During the separation, the organic layer was discarded, and the aqueous solution of the compound of formula (III) was collected for use. The temperature was controlled at 25°C-30°C, 15 g of IPA-750 enzyme was added to the above-m...

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Abstract

The invention belongs to the technical field of antibiotic drug synthesis, and relates to a method for synthesizing cefcapene pivoxil hydrochloride by an enzymic method, the method comprises the following steps: treating a compound shown in a formula (IV) with acid and alkali in sequence to obtain a compound shown in a formula (III), performing enzymolysis on the compound shown in the formula (III) to obtain a compound shown in a formula (II), the enzyme used for enzymolysis being IPA-750 enzyme; and (2) in the presence of an acid-binding agent, carrying out esterification reaction on the compound as shown in the formula (II) and iodomethyl pivalate, and salifying with hydrochloric acid to obtain the compound cefcapene pivoxil hydrochloride as shown in the formula (I). The invention also provides a synthetic intermediate for synthesizing cefcapene pivoxil hydrochloride by an enzymic method. According to the method for synthesizing the cefcapene pivoxil hydrochloride through the enzyme method and the synthetic intermediate of the cefcapene pivoxil hydrochloride, the reaction conditions are milder, and the obtained product is higher in purity and more environmentally friendly.

Description

technical field [0001] The invention belongs to the technical field of antibiotic drug synthesis, and relates to a method for enzymatically synthesizing cefcapipil hydrochloride and a synthetic intermediate thereof. Background technique [0002] The chemical name of cefcapipil hydrochloride is 2,2-dimethylpropionyloxymethyl(6R,7R)-7-[(2Z)-2-(2-aminothiazol-4-yl)pentane-2 -Enamido]-3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate hydrochloride- Hydrate, its chemical structural formula is shown in formula (I): [0003] [0004] Cefcapene Pivoxil Hydrochloride Hydrate was developed by Shionogi Company of Japan. It was first listed under the trade name of Flomox in 1997. The patent expired in 2005, and there is no administrative protection in my country. Carpinipate is a third-generation oral cephalosporin antibiotic. The results of pharmacological studies show that cefcapipil pivoxil has stronger antibacterial activity and smaller dose than the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/02C12P35/06C07D501/12C07D501/08C07D501/34C07D277/46
CPCC12P35/02C12P35/06C07D501/12C07D501/08C07D501/34C07D277/46
Inventor 周军荣池骋王胜卢荣桂芮立涛王干
Owner 浙江东邦药业有限公司
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