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Technology for preparing medicine intermediate D-7-ACA by two enzyme carriers one-step method

A technology of D-7-ACA and preparation process, which is applied in the technical field of preparing D-7-ACA by two-enzyme one-step method, can solve the problems of low production safety, long production cycle, poor product quality and the like, and shorten production The effect of cycle time, less by-products and low cost

Active Publication Date: 2012-12-19
AMICOGEN CHINA BIOPHARM CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] In order to overcome the deficiencies of the existing technology and solve the problems of poor product quality, high energy consumption and heavy pollution caused by alkaline hydrolysis at ultra-low temperature in the preparation of D-7-ACA by the chemical method in the prior art; the production cycle of the three-enzyme and two-step enzymatic method is long , the use of liquid oxygen in the preparation process leads to problems such as low production safety and difficult operation. The invention provides a two-enzyme one-step method for preparing the pharmaceutical intermediate D-7-ACA. The cephalosporin C sodium salt concentrate As the substrate, immobilized CPC acylase and immobilized deacetyl esterase are used, and the two enzyme carriers are mixed in a certain ratio to directly convert the cephalosporin C extract into D-7-ACA

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  • Technology for preparing medicine intermediate D-7-ACA by two enzyme carriers one-step method

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Effect test

Embodiment 1

[0044] The process for preparing pharmaceutical intermediate D-7-ACA by two-enzyme one-step method, the specific steps include:

[0045] (1) According to the potency of cephalosporin C sodium salt concentrate determined by high performance liquid chromatography, dilute the cephalosporin C sodium salt concentrate to 28000u / mL, and adjust the pH value to 6.5 with 5% ammonia water Finally, add 500mL of the above dilution into an enzyme cleavage tank containing 40.23g of immobilized CPC acylase (enzyme activity 87u / g) and 8.75g immobilized deacetylesterase (enzyme activity 400u / g) , at 20°C, the pH value of the lysate was adjusted to 8.2 by using ammonia water with a mass fraction of 5.5% through an enzyme cleavage tank, and the final lysate was obtained after the reaction was completed;

[0046] (2) Transfer the final lysate obtained in step (1) to a crystallization tank, cool down to 3°C, add dropwise a 12% hydrochloric acid solution to adjust the pH to 3.5, grow crystals at 0°C...

Embodiment 2

[0048] The process for preparing pharmaceutical intermediate D-7-ACA by two-enzyme one-step method, the specific steps include:

[0049] (1) According to the titer of cephalosporin C sodium salt concentrate determined by high performance liquid chromatography, dilute the cephalosporin C sodium salt concentrate to 30000u / mL, and adjust the pH value to 7.0 with 5% ammonia water Finally, add 500mL of the above dilution into an enzyme cleavage tank containing 41.05g of immobilized CPC acylase (enzyme activity: 87 u / g) and 8.93g immobilized deacetylase (enzyme activity: 400 u / g) At 18°C, the pH of the lysate was adjusted to 8.0 by using ammonia water with a mass fraction of 8% through an enzyme cleavage tank, and the reaction was completed to obtain the final lysate;

[0050] (2) Transfer the final lysate obtained in step (1) to a crystallization tank, cool down to 0°C, add dropwise a 20% hydrochloric acid solution to adjust the pH to 3.0, grow crystals at 5°C for 1.5 hours, filter...

Embodiment 3

[0052] The process for preparing pharmaceutical intermediate D-7-ACA by two-enzyme one-step method, the specific steps include:

[0053] (1) According to the potency of cephalosporin C sodium salt concentrate determined by high performance liquid chromatography, dilute the cephalosporin C sodium salt concentrate to 32000u / mL, and adjust the pH value to 7.5 with 5% ammonia water Finally, add 500mL of the above dilution into an enzyme cleavage tank containing 40.87g of immobilized CPC acylase (enzyme activity: 87 u / g) and 8.89g immobilized deacetylase (enzyme activity: 400 u / g) In 25 ° C, the pH of the lysate was adjusted to 8.5 by using ammonia water with a mass fraction of 4.5% through the enzyme cleavage tank, and the final lysate was obtained after the reaction was completed;

[0054] (2) Transfer the final lysate obtained in step (1) to a crystallization tank, cool down to 10°C, add dropwise hydrochloric acid solution with a mass fraction of 10% to adjust the pH to 5.0, gro...

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Abstract

The invention discloses a technology for preparing a medicine intermediate D-7-ACA by a two enzyme carriers one-step method, a cephalosporin C sodium salt concentrate is taken as a substrate, immobilization CPC acylase and immobilization deacetylase are employed, two enzyme carriers are mixed according to certain proportion so that a cephalosporin C extract is directly conversed to D-7-ACA. The technology for preparing the medicine intermediate D-7-ACA is capable of simplifying the technology route, raising the utilization rate of the cephalosporin C fermentation components, shortening the production period, avoiding the usage of liquid oxygen in a three enzyme carriers two-step method and enhancing the production security, the whole technology employs the enzyme method production technology and has the advantages of mild condition, simple equipment, no pollution, high yield, less by-product, low cost and the like, and is in favor of development of the national green pharmacy industry and is a sustainable technology route.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a new enzymatic preparation process of a pharmaceutical intermediate, in particular to a two-enzyme one-step process for preparing D-7-ACA. Background technique [0002] D-7-ACA (3-deacetyl-7-aminocephalosporanic acid) as a new intermediate of cephalosporin antibiotics, and 7-ACA (7-aminocephalosporanic acid) and 7-ADCA (7-amino -3-desacetoxycephalosporanic acid) compared with the hydroxyl group on the 3-position, the reactivity is higher, which is conducive to the synthesis of new cephalosporin products. When synthesizing some cephalosporin varieties, the production process route is simplified and modified Simple, easy to purify, good product quality, while reducing production costs and other advantages, the development of D-7-ACA will provide a new method for the development of the third generation, fourth generation and upcoming fifth generation cephalosporins in China. Selection; th...

Claims

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Application Information

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IPC IPC(8): C12P35/02
Inventor 赵新祥王玲罗文军李树英江照洋
Owner AMICOGEN CHINA BIOPHARM CO LTD
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