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Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid

An ionic liquid and selective technology, applied in the field of biocatalysis, can solve problems such as the unfavorable environmental protection of organic solvents, and achieve the effects of good chemical and thermal stability, low environmental pollution, and stereoselectivity maintenance.

Inactive Publication Date: 2011-02-16
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this route adopts a mixed system of buffer and organic solvent in order to increase the substrate concentration during the hydrolysis process, and the use of organic solvent is not conducive to environmental protection.

Method used

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  • Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid
  • Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid
  • Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Get 0.5g of compound (IIA) in the reactor, add 5.0ml, pH7.0, 0.2M phosphate buffer, 1.5g of ionic liquid [BMIm][PF 6 ] and 10mg of Lipase A from Candida antarctica were reacted in a water bath shaker at 30°C and 200rpm for 24h, during which TLC tracked and detected the reaction process. After the reaction, the supernatant was obtained by centrifuging to remove the biological enzyme, and the supernatant was rotary evaporated to remove water and ethanol generated, then added ethyl acetate for extraction, and the raffinate recovered the ionic liquid, and the extract was added with a small amount of anhydrous Na 2 SO 4 After drying, the reaction conversion and product purity were analyzed by gas chromatography.

[0044] (4R,5S)-5-Ethyl carboxylate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidine-3-carboxylic acid, the conversion rate is 87%, and the purity is 79%.

Embodiment 2

[0046] Get 0.5g of compound (IIA) in the reactor, add 5.0ml, pH7.0, 0.2M phosphate buffer, 1.5g of ionic liquid [BMIm][PF 6 ] and 10mg of Lipase B from Candida antarctica were reacted in a water-bath shaker at 30°C and 200rpm for 18h, during which TLC tracked and detected the reaction process. After the reaction, the supernatant was obtained by centrifuging to remove the biological enzyme, and the supernatant was rotary evaporated to remove water and ethanol generated, then added ethyl acetate for extraction, and the raffinate recovered the ionic liquid, and the extract was added with a small amount of anhydrous Na 2 SO 4 After drying, the reaction conversion and product purity were analyzed by gas chromatography.

[0047] (4R,5S)-5-Ethyl carboxylate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidine-3-carboxylic acid, conversion rate 97%, purity 91%.

Embodiment 3

[0049] Get 0.5g of compound (IIA) in the reactor, add 5.0ml, pH7.0, 0.2M phosphate buffer, 1.5g of ionic liquid [BMIm][PF 6 ] and 15mg of Esterase from Porcine Liver were reacted in a water-bath shaker at 30°C and 200rpm for 24h, during which TLC tracked and detected the reaction process. After the reaction, the supernatant was obtained by centrifuging to remove the biological enzyme, and the supernatant was rotary evaporated to remove water and ethanol generated, then added ethyl acetate for extraction, and the raffinate recovered the ionic liquid, and the extract was added with a small amount of anhydrous Na 2 SO 4 After drying, the reaction conversion and product purity were analyzed by gas chromatography.

[0050] (4R,5S)-5-Ethyl carboxylate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidine-3-carboxylic acid, conversion rate 98%, purity 88%.

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Abstract

The invention discloses a method for preparing a paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid, and relates to a method for preparing a chiral medicament intermediate based on bio-enzyme catalysis, in particular to a method for preparing (4R,5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxypiperidine-3-carboxylic acid (I) through biocatalysis. In the method, 4-(4-fluorophenyl)-1-R-2,6-dioxypiperidine-3,5-diethyl phthalate (II) is taken as a raw material, a bio-enzyme in a cosolvent-containing buffer solution system is taken as a catalyst, and the (4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxypiperidine-3-carboxylic acid (I) is prepared at the temperature of between 15 and 60 DEG C and the rotating speed of 100-250 revolutions per minute of a table concentrator. The provided preparation method has mild reaction condition, the maximum conversion rate of 98 percent, the highest purity of 96 percent and high atom utilization rate, meets the requirements of green chemistry and greatly reduces the production cost. The compound in the formula (I) can be prepare into an important paroxetine intermediate through decarboxylation, reduction and other steps, namely (3R,4S)-4-(4-fluorophenyl)-3-hydroxymethyl-1-R-piperidine (III).

Description

technical field [0001] A new method for the preparation of paroxetine intermediates by enzymatic selective hydrolysis in ionic liquids, especially the preparation of (4R, 5S)-5-ethyl carboxylate-4-(4-fluoro) by enzymatic selective hydrolysis in ionic liquids The method of phenyl)-1-R-2,6-dioxopiperidine-3-carboxylic acid belongs to the technical field of biocatalysis. 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 disea...

Claims

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Application Information

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IPC IPC(8): C12P17/12
Inventor 沈文和黄和刘维明车大庆胡燚邹彬
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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