A kind of sitagliptin chiral intermediate and asymmetric synthesis method

Abstract

The invention relates to a sitagliptin chiral intermediate and an asymmetric synthesis method thereof. The asymmetric synthesis method comprises the steps: with 2,4,5-trifluorophenyl acetic acid as a starting material, carrying out a reduction reaction to obtain 2-(2,4,5-trifluorophenyl)ethanol, then carrying out a reaction with an oxidant, carrying out condensation of the product without separation and (R)-(+)-tert-butyl sulfinamide to obtain corresponding acetal, carrying out a reaction of the obtained product with dialkyl malonate to obtain a key chiral intermediate, hydrolyzing to obtain a corresponding organic amine, carrying out a reaction of the amine with caustic alkali and then acidifying to obtain a corresponding carboxylic acid, then carrying out condensation with 3-(trifluoromethyl)-5,6,7,8- tetrahydro-[1,2,4] triazolo[4,3-a]pyrazine hydrochloride to obtain sitagliptin tert-butyl oxanamide, and finally deprotecting with hydrochloric acid to obtain sitagliptin. The yields of all the steps are all higher, the used reagents are all conventional cheap reagents, no expensive chiral catalysts are used, the reaction conditions are quite mild, and the asymmetric synthesis method is suitable for industrialization.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a sitagliptin chiral intermediate and an asymmetric synthesis method. Background technique [0002] Sitagliptin is a dipeptidyl peptidase-IV inhibitor drug used in the treatment of type 2 diabetes. It controls the blood sugar level of diabetic patients by improving the ability of diabetic patients' own pancreatic β cells to produce insulin and increasing the secretion of insulin when blood sugar rises. DPP-IV inhibitors have low adverse reactions, neither weight gain nor hypoglycemia. In October 2006, sitagliptin phosphate was officially launched in the United States. [0003] At present, there are many methods for synthesizing sitagliptin at home and abroad, including chiral induction and asymmetric hydrogenation. In all syntheses of sitagliptin, the establishment method of the chiral center is the key to the synthesis process. At present, the main problem of the existing...

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Problems solved by technology

At present, the main problem of the existing sitagliptin synthesis technology is that it often needs to use very expensive noble metal catalysts and high-pressure hydrogenation conditions, the cost is very high, and unstable intermediate substances will be prepared during the synthesis of chiral centers , resulting in a low reaction yield of the synthesized chiral center, and the chemical resolution method also has a low yield. Even if the asymmetric synthesis of the above-mentioned noble metal catalyst and high-pressure hydrogenation conditions is avoided, there are still other harsh reaction conditions such as the high-risk reagent sodium hydride. The use of raw materials, rare raw materials, the use of metal reagents and other obstacles that are not conducive to the realization of industrialization

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