An Efficient Method for Synthesis of Tofacitinib Citrate

An efficient and mild synthetic method was developed for tofacitinib citrate from 3‐amino‐4‐methylpyridine and 4‐chloro‐7 H ‐pyrrolo[2,3‐d]pyrimidine. The related reactions were systematically optimized. Sodium hydride instead of potassium tert ‐butoxide employed in the methoxycarbonylation reaction of compound 9 made the reaction proceed effectively to present compound 8 in a better yield. The replacement of benzaldehyde with benzyl bromide simplified the protection process of amino group. Red‐Al provided a cost‐effective method for the reduction of amides . The introduction of tosyl group into compound 10 enhanced the nucleophilic substitution of 10 with compound 4 dramatically. Thus, under the optimized conditions, tofacitinib citrate was obtained in 13.3% yield (based on compound 9 ) with a purity of 99.9%, much better than the reported yield 8.6%. This cost‐effective and environmental friendly process is more suitable for scale‐up production.