Premium
An Efficient Method for Synthesis of Tofacitinib Citrate
Author(s) -
Zhi Shuang,
Liu Dengke,
Liu Ying,
Liu Bingni,
Wang Donghua,
Chen Ligong
Publication year - 2016
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.2384
Subject(s) - chemistry , yield (engineering) , sodium hydride , potassium , benzaldehyde , benzyl bromide , medicinal chemistry , tosyl , combinatorial chemistry , reaction conditions , nucleophilic substitution , organic chemistry , catalysis , materials science , metallurgy
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.