Improved Synthetic Process of an Intermediate of Tofacitinib
An improved synthetic process of the intermediate of tofacitinib,4-chloro-7H-pyrrolo[2,3-d]-pyrimidine(1),was described in this paper.Started from malononitrile,the desired product 1 was synthesized via a-alkylation with bromoacetaldehyde diethyl acetal(2),cyclization with thiourea,deprotection,cyclization,acidification,removal of the thiol group,as well as Sandmeyer chlorination,with an overall yield of 49％(based on 2)and a purity of 99.10％.The improved process had three apparent advantages compared with previously reported procedures,including:① direct precipitation of the potassium 4,6-diamino-5-(2,2-diethoxyethyl)pyrimidine-2-thiolate(4),from the reaction solvent ethanol as a salt with a high yield of 85％,overcoming the technical difficulties in purifying the thiol compound;② preparation of the 4-amino-7H-pyrrolo[2,3-d]pyrimidine-2-thiol(5)via a one-pot sequential three-step reaction of deprotection,cyclization,and acidification in the presence of hydrochloric acid,simplifying the process;③ elimination toxic reagents such as phosphorus oxychloride,2-methyl-3,3-dichloroacrylonitrile,and 2-chloroacetaldehyde,which ensured process safety and improved environmental friendliness,especially the elimination of phosphorus oxychloride.All the raw materials and reagents used in the improved syntheses are inexpensive and readily available,and the operation is simple with mild conditions and high yield,which is suitable for industrial production.
JAK inhibitortofacitinibintermediate4-chloro-7H-pyrrolo[2,3-d]pyrimidineprocess improvement
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