An Efficient Method for Synthesis of Tofacitinib Citrate. (30th July 2015)

• Record Type: Journal Article
• Authors: Zhi, Shuang; Liu, Dengke; Liu, Ying; Liu, Bingni; Wang, Donghua; Chen, Ligong
• Is Part Of: Journal of heterocyclic chemistry. Volume 53:Number 4(2016:Jul.)
• Page Start: 1259
• Page End: 1263
• Publication Date: 2015-07-30
• Subjects: Tofacitinib citrate -- Synthesis -- JAK3 inhibitor -- Red‐Al; Heterocyclic compounds -- Periodicals; 547.59
• DOI: 10.1002/jhet.2384
• Languages: English
• ISSNs: 0022-152X

Abstract

Abstract : 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 compound9 made the reaction proceed effectively to present compound8 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 thereduction of amides . The introduction of tosyl group into compound10 enhanced thenucleophilic substitution of10 with compound4 dramatically. Thus, under the optimized conditions, tofacitinib citrate was obtained in 13.3% yield (based on compound9 ) 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. Abstract :