Novel preparation process of linagliptin

Abstract

The invention discloses a novel preparation process of linagliptin. 8-bromine-3-methyl xanthine (SM1) is used as an initial raw material, DMF is used as a solvent to react with 1-bromine-2-butyne (SM2) under an alkaline condition to obtain an intermediate I, then the intermediate I reacts with 2-chloromethyl-4-methyl quinazol (SM3) under the solvent system to obtain an intermediate II, and the solvent system reacts with (R)-3-Boc-aminopiperidine (SM4) under the alkaline condition to obtain an intermediate III; and the protecting group is dissociated by using acid to obtain the linagliptin (I) for resisting type 2 diabetes mellitus. By adopting a one-pot method, the method has the advantages that the raw material cost is low, the yield is high, the post-treatment operation of each step of chemical reaction in multi-step reaction is reduced, the production period is greatly shortened, few impurities are generated in the reaction, the product quality is high, the use amount of chemical reagents is relatively reduced, and the method is relatively green and environment-friendly, and is beneficial to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a new preparation process of linagliptin, a medicine for treating type 2 diabetes. Background technique [0002] Linagliptin, an inhibitor of the serine protease dipeptidyl peptidase IV (DPP-IV), maintains the levels of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in vivo , to promote the secretion of insulin, so as to exert a hypoglycemic effect, and has a good therapeutic effect on the treatment of type 2 diabetes. [0003] Linagliptin tablets are developed and manufactured by Boehringer Ingelheim-Eli Lilly, trade name Specification 5mg / tablet, used for the treatment of type 2 diabetes, first launched in 2011. [0004] This product was approved by the FDA for marketing in the United States in May 2011, and was approved for marketing in Europe by EMP in June 2011. In addition, in October 2010, EMA approved lina...

AI Technical Summary

Problems solved by technology

[0013] 1) The cost of starting materials and reagents; 2) The cost of equipment, safety, and environmental protection; 3) The cost of three wastes treatment; 4) Labor cost

[0014] After a comprehensive analysis, 2-4 are the key points of cost, and one of the keys is the problem of the three wastes: the generation of the three wastes directly leads to the treatment cost of the three wastes, the cost of safety and environmental protection, and the cost of labor

In the traditional synthesis method of linagliptin, potassium carbonate and the like need to be added as an acid-binding agent during the reaction process, and acid-base neutralization produces a large amount of salt, and the waste water has obvious defects;

[0016] ②Microchannel reaction: Among the emerging synthesis methods in recent years, microchannel reaction has undergone a lot of publicity and reports, and it is still in the preliminary stage in China, and it is still immature, and there are many areas that need to be improved. There are still fewer varieties produced by channel reaction, and the cost is very high, which does not match the current demand for centralized procurement;

[0018] In the current relevant literature reports, there is no report on the three-step reaction "one-pot stew" preparation method of linagliptin

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