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Method used for synthesis of atazanavir intermediate chlorhydrin via bio-enzyme catalysis

A technology of atazanavir and chlorohydrin, which is applied in the field of preparation of atazanavir intermediate chlorohydrin selectively catalyzed by biological enzymes, can solve the problem of low selectivity, complex fermentation process of Rhodococcus erythroflates, and difficulty in industrialization, etc. question

Active Publication Date: 2017-07-14
四川奇格曼药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In order to overcome the problems of low selectivity in the current chemical preparation method, complex fermentation process of Rhodococcus erythropolis, and difficulty in industrialization, the present invention provides a method for synthesizing chlorohydrin, an intermediate of atazanavir, catalyzed by biological enzymes

Method used

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  • Method used for synthesis of atazanavir intermediate chlorhydrin via bio-enzyme catalysis
  • Method used for synthesis of atazanavir intermediate chlorhydrin via bio-enzyme catalysis

Examples

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Embodiment 1

[0023] Add 300g of methyl tertiary ether, 0.5g of reductase KRED-101, and 35g of purified water into a 1L four-necked reaction flask. After adding, keep the temperature at 25-30°C for 30 minutes, then cool down to 10-15°C and add chlorine in batches. Ketone 29g, control the temperature between 10-15°C, add about 1.5 hours, maintain at 10-15°C for 24 hours, control in the middle, after the reaction is completed, add 300g of purified water at 0°C, and then add 300g of purified water at 0°C Add 50g of 18% hydrochloric acid, stir for 0.5 hours, naturally warm up to room temperature, then separate the upper layer of tertiary methyl ether, and extract the aqueous layer with methyl tertiary ether (2×80g), combine the organic layers, wash with 100g of saturated sodium chloride solution, 40g of anhydrous sodium sulfate was dried and filtered, and the filtrate was concentrated, then added 100g of n-hexane and heated to reflux for dissolution, then cooled to 15-20°C, crystals were precipi...

Embodiment 2

[0025] When other conditions are consistent with Example 1, the reductase is replaced by KRED-129, and the ratio of (1S,2R)-BOC-epoxide to (1R,2R)-BOC-epoxide obtained by reducing ketone is 35:65 .

Embodiment 3

[0027] When other conditions are consistent with Example 1, the reductase is replaced by KRED-131, and the ratio of (1S,2R)-BOC-epoxide to (1R,2R)-BOC-epoxide obtained by reducing ketone is: 59: 31.

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Abstract

The invention provides a method used for synthesis of atazanavir intermediate chlorhydrin via bio-enzyme catalysis. The method comprises following steps: 1, methyl tert-butyl ether, purified water, and a reductase are delivered into a reaction bottle, the temperature is maintained to be 25 to 30 DEG C for 30min, the temperature is reduced to 10 to 15 DEG C, chlorone is added in batches in about 1.5h while the temperature is maintained to be 10 to 15 DEG C, and then the temperature is maintained to be 10 to 15 DEG C for 24h of reaction; and 2, post-treatment is carried out. According to the method, reduction of chlorone is ensured via green environment-friendly enzyme technology, so that problems in the prior art such as low selectivity, complex fermentation technology, and applications of reducing agents, such as sodium borohydride and aluminum hydrogen, which are dangerous and are difficult to treat in an environment-friendly manner are solved.

Description

technical field [0001] The invention relates to a method for catalyzing and synthesizing an atazanavir intermediate by using a biological enzyme, in particular to a method for preparing chlorohydrin, an intermediate of atazanavir, which is selectively catalyzed by a biological enzyme. Background technique [0002] Protease inhibitors belong to polypeptide compounds, which are an important part of anti-HIV drug combination therapy. They are new products in the middle and late 1990s. The drug synthesis process is difficult, which is also the main reason for the current high cost of anti-HIV treatment. "Barriers must be crossed". Atazanavir, which belongs to the polypeptide class of protease inhibitors, is composed of three main fragments, of which (1S,2R)-BOC-epoxide contains two chiral centers, which has a complex structure and is difficult to synthesize. 60% of the cost, so the development of a process with higher synthesis efficiency and more obvious cost advantages will g...

Claims

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Application Information

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IPC IPC(8): C12P13/00
CPCC12P13/00
Inventor 杨琴飞刘念姚静胡伟李豫俭
Owner 四川奇格曼药业有限公司
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