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Preparation method of orlistat

A technology for orlistat and intermediates, applied in the field of preparation of orlistat, can solve the problems of low yield, high production cost, and high investment, and achieve the effects of high yield, easy operation, and low equipment investment

Active Publication Date: 2014-08-20
鲁南新时代生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In order to solve the technical problem of purifying orlistat to the high quality standard required by ICH, and overcome the shortcomings of high production equipment investment, high production cost and low yield in the prior art, the inventor has optimized a A method for preparing orlistat, comprising pretreatment of fermentation broth, extraction, concentration, non-polar solvent extraction, concentration, medium-grade solvent extraction, concentration, to obtain an orlistat intermediate with a content of more than 80%, and then Then dissolve and hydrogenate with a non-polar solvent, filter to obtain a hydrogenated solution, add a medium-grade organic solvent aqueous solution to the hydrogenated solution to backwash and remove impurities, and then carry out non-polar solvent crystallization and recrystallization until the product content exceeds 99% , maximum simplex within 0.1%

Method used

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  • Preparation method of orlistat

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Effect test

Embodiment 1

[0051] 1) Fermentation broth pretreatment: to 1.5m 3 Add 45kg of diatomaceous earth to the fermentation broth (fermentation unit 8.5g / L), adjust the pH to 4.5 with hydrochloric acid, stir for 1h, plate and frame press filter, and collect 360kg of filter cake;

[0052] 2) Leaching: use 2.88m 3 Industrial acetone extracts the filter cake obtained in step 1), extracts for 3h, and filters to obtain a clear, light red transparent filtrate containing orlistat intermediate 3.2m 3 ;

[0053] 3) Concentration and adjustment of solvent volume concentration: Concentrate the acetone solution of orlistat intermediate obtained in step 2) under reduced pressure with a falling film evaporator, and concentrate to a product concentration of 20g / L at a temperature of 30°C, add 150L of drinking water Regulate the volume concentration of aqueous acetone to be 65%;

[0054] 4) Non-polar solvent extraction: Add 480L of petroleum ether to the acetone / water solution of the orlistat intermediate pre...

Embodiment 2

[0062] 1) Fermentation broth pretreatment: to 1.45m 3 Add 70kg of perlite to the fermentation broth (fermentation unit 9.2g / L), adjust the pH to 4.7 with oxalic acid, stir for 2 hours, plate and frame filter, and collect 350kg of filter cake;

[0063] 2) Extraction: use 3.5m 3 Industrial methanol leached the filter cake obtained in step 1), leached for 5h, and plate-and-frame press-filtered to obtain a clear, light red transparent solution containing the orlistat intermediate 4m 3 ;

[0064] 3) Concentration and adjustment of solvent volume concentration: Concentrate the orlistat intermediate methanol solution obtained in step 2) under reduced pressure with a falling film evaporator, and concentrate it to a product concentration of 20g / L under temperature control at 30°C, add 170L for drinking Water regulates the volume concentration of methanol aqueous solution to be 62%;

[0065] 4) Non-polar solvent extraction: Add 670L heptane to the methanol / water solution of the orlis...

Embodiment 3

[0074] 1) Fermentation broth pretreatment: to 1.5m 3 Add 60kg of magnesium oxide to the fermentation broth (fermentation unit 8.8g / L), adjust the pH to 5.0 with oxalic acid, stir for 3h, filter, and collect 375kg of filter cake;

[0075] 2) Leaching: use 1.88m 3 Industrial ethanol extracts the filter cake obtained by filtering in step 1), extracts for 3h, and plate and frame press filter to obtain a clear, light red transparent solution containing orlistat intermediate 2.1m 3 ;

[0076] 3) Concentration and adjustment of solvent volume concentration: use a falling film evaporator to concentrate the orlistat intermediate ethanol solution obtained in step 2) under reduced pressure, and concentrate to a product concentration of 25g / L at a temperature of 30°C, and add 200L of drinking water Regulating the volumetric concentration of ethanol aqueous solution is 67%;

[0077] 4) Non-polar solvent extraction: Add 840L n-hexane to the ethanol / water solution of the orlistat intermed...

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a preparation method of orlistat, which specifically comprises the steps of pre-processing a fermentation solution, extracting through a filter cake, concentrating, extracting through a non-polar solvent, concentrating, extracting through a polar solvent, freezing to remove impurity, concentrating, crystallizing through a non-polar solvent, hydrogenating, backwashing, crystallizing and re-crystallizing. The content of orlistat prepared by adopting the preparation method disclosed by the invention is above 99%; the maximum individual impurity is within 0.1% and is higher than medicine standard; the preparation method disclosed by the invention is short in route, good in quality, convenient to operate, low in equipment investment and low in solvent use amount; furthermore, all solvents can be recycled and reused; and the production cost and the environmental pollution of orlistat are greatly reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of orlistat. Background technique [0002] Orlistat is the first new weight-loss drug developed by Roche and the only non-central nervous weight-loss drug. It is a long-acting and potent specific gastrointestinal lipase inhibitor. The gastric lipase in the small intestine combines with the active serine site of pancreatic lipase to form a covalent bond, which inactivates the lipase and prevents the decomposition, absorption and utilization of fat in food, thereby achieving the goal of weight loss. [0003] [0004] At present, there are two methods for domestic production of orlistat: one is chemical total synthesis, with many reaction steps, low yield, and poor environmental compatibility; the other is microbial fermentation to obtain orlistat intermediates, and then the intermediates are processed Orlistat is synthesized by one-step hydroge...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/12
CPCC07D305/12
Inventor 闫同顺赵军杰赵桂芳
Owner 鲁南新时代生物技术有限公司
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