Method for preparing paroxetine intermediate through enzymatic resolution in ionic liquid

A technology of ionic liquids and intermediates, applied in the field of biocatalysis, can solve the problems of potential danger in operation, environmental pollution, strong toxicity, etc., and achieve the effects of less environmental pollution, easy separation of products, and high conversion rate

Inactive Publication Date: 2011-02-16
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to resolve and prepare paroxetine intermediates in the prior art using organic solvents as reaction media, which are highly toxic, f

Method used

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  • Method for preparing paroxetine intermediate through enzymatic resolution in ionic liquid
  • Method for preparing paroxetine intermediate through enzymatic resolution in ionic liquid
  • Method for preparing paroxetine intermediate through enzymatic resolution in ionic liquid

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Add the substrate compound (IIA) at a concentration of 30mmol / L, use the ionic liquid [BMIm][PF6] as the reaction medium, add the acyl donor according to the compound (IIA):vinyl acetate ratio of 1:10, add 5g / L lipase from Porcine pancreatic was used to start the reaction, and the reaction was carried out at 30°C and the shaker speed was 200rpm for 12h. After the reaction, the lipase was removed by centrifugation to obtain a supernatant. The supernatant was extracted with a mixed solution of n-hexane / isopropanol (90:10, v / v) to obtain an organic phase, which was filtered and analyzed by HPLC. The reaction conversion rate was 38%, and the optical purity was 79%.

Embodiment 2

[0041] Add the substrate compound (IIA) with a concentration of 30mmol / L, use the ionic liquid [BMIm][PF6] as the reaction medium, add the acyl donor according to the ratio of compound (IIA):vinyl acetate in the amount of 1:10, add 5g / L lipase A from Candidaantarctica was used to start the reaction, and the reaction was carried out at 30°C and the shaker speed was 200rpm for 10h. After the reaction, the lipase was removed by centrifugation to obtain a supernatant. The supernatant was extracted with a mixed solution of n-hexane / isopropanol (90:10, v / v) to obtain an organic phase, which was filtered and analyzed by HPLC. The reaction conversion rate was 52%, and the optical purity was 92%.

Embodiment 3

[0043] Add the substrate compound (IIA) with a concentration of 30mmol / L, use the ionic liquid [BMIm][PF6] as the reaction medium, add the acyl donor according to the ratio of compound (IIA):vinyl acetate in the amount of 1:10, add 5g / L lipase B from Candidaantarctica was used to start the reaction, and the reaction was carried out at 30°C and the shaker speed was 200rpm for 8h. After the reaction, the lipase was removed by centrifugation to obtain a supernatant. The supernatant was extracted with a mixed solution of n-hexane / isopropanol (90:10, v / v) to obtain an organic phase, which was filtered and analyzed by HPLC. The reaction conversion rate was 46%, and the optical purity was 98%.

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Abstract

The invention belongs to the technical field of biocatalysis and discloses a method for preparing a paroxetine intermediate through enzymatic resolution in an ionic liquid, which comprises the following step of: preparing (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-R-piperidine by using the ionic liquid as a reaction medium and utilizing the transesterification reaction of racemic 4-(4-fluorophenyl)-3-hydroxymethyl-1-R-piperidine (II) as a lipase-catalyzed substrate and an acyl donor. The preparation method provided by the invention has the advantages of mild reaction conditions, simple operation and high conversion ratio, the highest optical purity can reach 98 percent, and the enzyme can be repeatedly utilized and is environmentally-friendly. The (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-R-piperidine is a key intermediate for preparing paroxetine as an antidepressant, and the invention supplies a feasible approach for the preparation of the paroxetine.

Description

technical field [0001] The invention belongs to the technical field of biocatalysis, and relates to a method for preparing paroxetine intermediates by enzymatic resolution in ionic liquids, in particular to a method for preparing (3S, 4R)-4-(4-fluorophenyl) by enzymatic resolution in ionic liquids )-3-hydroxymethyl-1-R-piperidine method. Background technique [0002] With the progress of society and the development of economy, depression, a new type of disease, is perplexing the life of modern people and seriously affecting people's health. At present, depression patients have reached 340 million people in the world, and it is the fourth largest disease in the world. It is predicted that it will rise to the second largest disease in the world (after cardiovascular and cerebrovascular diseases) by 2020. A joint study by the World Health Organization, the World Bank and Harvard University shows that depression has become the second largest disease burden in China, but only ab...

Claims

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Application Information

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IPC IPC(8): C12P17/12C12P41/00
Inventor 胡燚刘维明黄和邹彬
Owner NANJING UNIV OF TECH
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