Production method suitable for enzymatic synthesis of sitagliptin phosphate

Abstract

The invention discloses a production method suitable for enzymatic synthesis of sitagliptin phosphate. The method is characterized by comprising the following steps: (1) carrying out fermentation culture on transaminase cells with catalytic activity, performing centrifuging to obtain bacterial sludge, performing crushing twice, and directly putting crushed powder into a reaction kettle to carry out catalytic reaction with a substrate, wherein the addition amount is 45-85 wt% (based on the amount of the bacterial sludge / the substrate); (2) using partially-recovered DMSO in the catalytic reaction, wherein the total impurity content is less than or equal to 5%, the specific gravity is required to be 1.0-1.1, and the ratio of the DMSO to added fresh DMSO is 1:(0.2-0.8); (3) adding ethyl acetate for extraction after adjusting the acidity to ensure that the impurity content in mother liquor is lower than 0.1%; and (4) adding recycled isopropanol (the content is 70%-90%) into a salifying reaction. Compared with common reported enzyme catalysis methods, the process method can ensure that the finished product meets the quality requirements of raw material medicines, saves the production cost to the maximum extent, and is suitable for large-scale production and application.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to an improved production process suitable for enzymatically synthesizing sitagliptin phosphate. Background technique [0002] Sitagliptin is the first DPP-IV inhibitor drug developed by Merck in the United States. It is a drug for the treatment of type 2 diabetes. Its medicinal form is sitagliptin phosphate monohydrate, which has the following structure : [0003] [0004] At present, the synthesis of sitagliptin in the international market is generally based on the total chemical synthesis method. During the production process, noble metal catalytic hydrogenation is used under high temperature and high pressure conditions. The catalyst is not easy to recycle, and the operation risk factor is high. Difficulty is big, is difficult to separate, and yield is low, causes cost higher. As Merck first developed the route of synthesizing sitagliptin by transaminase method...

AI Technical Summary

Problems solved by technology

Through the research on its process, it is found that: (1) the purification of enzymes will lead to low catalytic efficiency, long cycle, and a large increase in waste water and cost; A large number of other impurities (such as substrates, intermediates, coenzymes, protein fat-soluble impurities, etc.) are produced, resulting in later salt formation and crystallization that cannot meet the quality requirements of raw materials; (3) waste solvents (DMSO, isopropyl Alcohol) reuse plan

Other relevant literature and patent reports use bio-enzymatic synthesis of sitagliptin, but there is no consistent content with the process method reported in this patent

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