Method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine

Abstract

The invention provides a method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine, which belongs to the technical field of chemical medicine midbody preparation methods. The preparation method comprises the steps: (1) L-proline and thionyl chloride generate acylation reaction to obtain L-proline chloride; (2) the L-proline chloride and ammonia water generate reaction to produce L-proline amide; (3) the L-proline amide and chloroacetyl chloride generate reaction to obtain (2S)-N-chloracetyl-2-carbamoyl pyrrole; and (4) (2S)-N-chloracetyl-2-carbamoyl pyrrolidine and phosphorus oxychloride generate dehydration reaction under low temperature condition to obtain the (2S)-N-chloracetyl-2-cyano-group pyrrolidine. The method has the advantages of saving material cost, being simple in technological process, moderate in reaction condition, low in operation difficulty, convenient in aftertreatment, stable in quality and suitable for mass industrial production, having operability, and improving yield of prepared products by a large margin.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of pharmaceutical intermediates, and in particular relates to a method for preparing (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole. Background technique [0002] (2S)-N-Chloroacetyl-2-cyanotetrahydropyrrole is the key intermediate of vildagliptin, a new hypoglycemic drug. Currently adopted synthetic methods require relatively high production equipment, high cost, and lower yields of (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole, domestic related literature reports, published Research on the synthesis of dipeptidyl peptidase-IV inhibitor vildagliptin, which uses L-proline to acetylate first, then uses expensive DCC, and dehydrates with phosphorus oxychloride to obtain (2S) -N-chloroacetyl-2-cyanotetrahydropyrrole, its yield is very low cost and too expensive, it is difficult to realize industrial production; In addition, foreign related documents US6166063, WO0034241, Beilstein Journal o...

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Problems solved by technology

Currently adopted synthetic methods require relatively high production equipment, high cost, and lower yields of (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole, domestic related literature reports, published Research on the synthesis of dipeptidyl peptidase-IV inhibitor vildagliptin, which uses L-proline to acetylate first, then uses expensive DCC, and dehydrates with phosphorus oxychloride to obtain (2S) -N-chloroacetyl-2-cyanotetrahydropyrrole, its yield is very low cost and too expensive, it is difficult to realize industrial production; In addition, foreign related documents US6166063, WO0034241, Beilstein Journal of Organic Chemistry 2008, 4, No.20 .J.Med.Chem.2002,45,2362-2365, Journal of Medicinal Chemistry, 2003, Vol.46, No.13 2775, US20080167479, etc. all disclose (2S)-N-chloroacetyl-2-cyano The synthesis reports of tetrahydropyrrole are all acetylation of proline amide first, and expensive trifluoroacetic anhydride or expensive DCC is used for amidation during dehydration. It is difficult to realize industrial production, and the yield is very low and too expensive. , it is difficult to realize industrial production. In addition, there are no reports in the literature on the synthesis of L-proline amide and its subsequent amination.

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