Preparation method of vildagliptin intermediate

Abstract

Belonging to the technical field of heterocyclic compounds, the invention provides a preparation method of a vildagliptin intermediate. The preparation method includes: adding prolinamide into a solvent, performing stirring and heating to dissolve prolinamide; performing cooling, adding propylene oxide as an acid-binding agent, and adding chloroacetyl chloride dropwise under stirring; carrying outcondensation reaction at the end of adding; lowering the temperature and performing heat preservation; conducting filtering, washing the filter residue, and performing drying to obtain (S)-1-(2-chloracetyl)pyrrolidine-2-amide. The method has the advantages of simple process, mild reaction conditions, high product purity and the like.

Description

technical field [0001] The application relates to a preparation method of vildagliptin intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-amide, which belongs to the technical field of heterocyclic compounds. Background technique [0002] Diabetes mellitus (DM) is one of the most important non-communicable diseases currently threatening human health. In 2015, the number of patients worldwide reached 415 million. As a big country with diabetes, the prevalence of diabetes in my country continues to rise and has reached 11.6% of the total population, of which more than 90% are type 2 diabetes mellitus (T2DM). Diabetes and its complications seriously affect the quality of life of patients, and bring a heavy burden to patients, the national economy, and medical insurance. Current interventions for T2DM mainly include diet control and the use of oral and / or injectable hypoglycemic agents on the basis of exercise therapy. Dipeptidyl peptidase-4 (dipeptidyl peptidase-4, DPP-4) inhib...

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Problems solved by technology

[0013] Zhejiang Guobang Pharmaceutical Co., Ltd. found that the intermediate (S)-1- (2-Chloroacetyl) pyrrolidine-2-amide yields are very low, the main reason is: (S)-1-(2-chloroacetyl) pyrrolidine-2-amide has a high polarity, and in general solvent tetrahydrofuran , ethyl acetate, and dichloromethane have low solubility, and have high solubility in water. During the post-treatment process, it is involved in the removal of salts in the reaction system (such as potassium carbonate, potassium chloride or triethylamine hydrochloride). large, low yield

[0014] In response to the above technical problems, Tianjin Minxiang Biomedical Co., Ltd. used potassium carbonate as an acid-binding agent and acetonitrile as a solvent to synthesize (S)-1-(2-chloroacetyl)pyrrolidine-2-amide, filtered to remove salt, and the mother liquor was directly Synthesize (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (CN106045891A) by dehydration with trifluoroacetic anhydride, the yield is 92%, but the cost of dehydration with trifluoroacetic anhydride is too high; Qingdao Huanghai Pharmaceutical Co., Ltd. uses triethylamine as the acid-binding agent, ethyl acetate and DMSO as the mixed solvent to synthesize (S)-1-(2-chloroacetyl)pyrrolidine-2-amide, and then uses DMF and phosphorus oxychloride in one pot (S)-1-(2-chloroacetyl)pyrrolidine-2-nitrile group (CN106699627A) was synthesized by method, and the yield was 78%, but there was also the troublesome problem of phosphorus-containing wastewater treatment; Yantai Wanrun Pharmaceutical Co., Ltd. adopted Triethylamine is used as an acid-binding agent, dichloromethane is used as a solvent to synthesize (S)-1-(2-chloroacetyl)pyrrolidine-2-amide, and DMF and phosphorus oxychloride are added to synthesize (S)- 1-(2-chloroacetyl) pyrrolidine-2-nitrile group (CN104945299A), yield 80%, also has the troublesome problem of phosphorus-containing wastewater treatment; Zhejiang Prokangyu Pharmaceutical Co., Ltd. uses excessive chloroacetyl chloride as reagent and Dehydrating agent, DMF as solvent, one-pot synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (CN107501154A), yield 78%, the method is novel but the yield is low; Tianjin Tasly Diyi Pharmaceutical Co., Ltd. directly synthesized (S)-1-(2-chloroacetyl)pyrrolidine-2-amide hydrochloride by reacting prolineamide and chloroacetyl chloride in tetrahydrofuran solution, and filtered it while hot to obtain Product (CN107793341A), yield 87.9%, but product quality is on the low side, and HPLC detects only 97.7%

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