Method for purifying orlistat

Abstract

The invention belongs to the field of pharmaceutical synthesis and discloses a method for purifying orlistat. Two-step refining is performed by crystallization of a polar solvent and a non-polar solvent, according to the high performance liquid chromatography (HPLC) measurement, the content of the orlistat is above 99%, the maximum single impurity of the orlistat is within 0.1%, and the orlistat accords with United States pharmacopoeia (USP) 35 standards. The method for purifying the orlistat has the advantages of being simple, small in equipment investment, low in production costs, high in product quality, stable in process and suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of high-purity 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. Its structural formula is shown in formula I. [0003] [0004] Formula I [0005] At present, orlistat can be produced by two methods: total synthesis and fermentation. Chinese patent CN319596A discloses a method for producing orlistat through a twelve-step chemical synthesis route. The method has low yield, high reagent cost and no p...

AI Technical Summary

Problems solved by technology

Chinese patent CN319596A discloses a method for producing orlistat through a twelve-step chemical synthesis route, which has low yield, high reagent cost and no practicality

Chinese patent CN1765892A discloses a method for obtaining chiral hydroxyhexadecanone by condensation of enol lauryl ether and lauryl aldehyde under the action of several chiral catalysts. Although there are only eight steps in the reaction, there is still no cost advantage

[0006] U.S. Patent No. 4,598,089 reported in 1986 the technology of producing orlistat intermediates through microbial fermentation. The intermediates were extracted and purified using silica gel as a carrier, eluted with chloroform, and silica gel, n-hexane and ethyl acetate for the second time. Reversed-phase column chromatography, methanol elution method to obtain orlistat intermediate, this process intermediate purification requires multiple column chromatography, low purification yield, not suitable for industrial promotion

Chinese patent CN1266058A invented the combination of liquid-liquid extraction and back extraction to purify trypsin. After the product was hydrogenated, it was crystallized with heptane or hexane to obtain the final product of orlistat. The disadvantage is that the extraction process is relatively expensive. The content of the initial intermediate is relatively high, and the content of the final refined product is too low to meet the pharmaceutical standards of the preparation

Although the purification and crystallization yield of this process is as high as 85%, the product quality is not high, with a maximum of 0.17% impurity, which does not meet the pharmaceutical standards stipulated in USP35.

[0008] Publication No. CN102070567A uses reversed-phase high-performance liquid chromatography to prepare high-purity orlistat. Although the refined product has a purity of more than 99.5% and a single impurity within 0.1%, the preparation of liquid phase technology requires a large investment in equipment and high cost of fillers. in industrial production

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