Preparation method of sitagliptin impurity

Abstract

The invention provides a preparation method of a sitagliptin impurity compound, belonging to the field of chemical pharmacy. According to the method, racemic and / or chiral sitagliptin is taken as a substrate, reductive amination is performed firstly, and then Cpe elimination is performed, so the sitagliptin impurity compound is obtained; and the starting material is easy to obtain, operation is simple, generation of double-bond isomeric impurities in a reaction process can be effectively controlled, and purification is convenient. The method is rigorous, practical, scientific and reliable in operation, the required materials are easy to store and free of harm, the product is easy to purify, the yield and the purity of the product are high, the preparation requirements of the impurity can be met, a new thought is provided for synthesis of the sitagliptin impurity (XGT062-05), and the method has important significance in research of the sitagliptin impurity.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a preparation method of sitagliptin impurities. Background technique [0002] Sitagliptin is a new orally administered dipeptidyl peptidase-4 (Dipeptidyl peptidase-4, DPP-4) inhibitor drug developed by Merck and Co. of the United States, as a second-line treatment for type 2 diabetes after metformin treatment Hypoglycemic drugs have the same status as other effective anti-hyperglycemic drugs (such as sulfonylureas, GLP-1 receptor agonists, thiazolidinediones, insulin, etc.), are highly selective DPP-4 inhibitors, and are used worldwide The first DPP-4 inhibitor to be marketed in China was approved for marketing by the State Food and Drug Administration of China in 2009. The trade name is JANUVIA. Sitagliptin alone can improve blood sugar, and combined with metformin, insulin, sulfonylureas, and thiazolidinediones can enhance the efficacy without increasing the risk of hypoglycem...

AI Technical Summary

Problems solved by technology

[0015] Through verification, it is found that the first step of operation uses format reagents and CoBr 2 , need to strictly control anhydrous and anaerobic conditions, the operation is cumbersome and difficult to repeat

The third step repeats its optimal conditions, and the production of double bond isomers cannot be avoided, the cost of purification is greatly increased, and the purity is difficult to reach more than 95%, which cannot meet the quality research requirements

[0016] PCT application WO2015120111A2 discloses a report on the impurity of sitagliptin, but the structure obtained in the report is a mixture of double bond cis-trans isomerism of the sitagliptin impurity or four compounds containing double bond positional isomerism and cis-trans isomerism, because These four compounds have similar properties and cannot be separated by conventional means, and the purification cost is greatly increased

The experimental process uses acetic anhydride, a precursor auxiliary material, and sodium borohydride, a dangerous chemical, so the scope of application of this method is limited

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