An Improved and Efficient Process for the Preparation of Tofacitinib Citrate

Abstract

The present invention is related to a simple and efficient process for the preparation of tofacitinib citrate 1, a Pfizer molecule approved for the treatment of rheumatoid arthritis. The process relies upon an improved process for the preparation of a key intermediate (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methylamine as tartarate salt 3 and its simple and impurity-free conversion to tofacitinib citrate 1. The current invention is aimed at addressing process development issues related to quality and yields. The disclosed process is capable of delivering much higher yield compared to the prior state-of-the-art process and is able to yield very highly pure compound.

Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis

“…Comparison to the complex synthetic procedures of tofacitinib and PF‐06651600 , III‐4 was simply prepared according to five common reactions in a good yield (Scheme ). Commercially available 6‐chloro‐9 H ‐purine ( 1 ) was first protected by 3,4‐dihydro‐2 H ‐pyrane to give 2 , which was allowed to react with ( R )‐ tert ‐butyl‐3‐aminopiperidine‐1‐carboxylate completely to provide 3 in a high yield about 90%.…”

Tofacitinib Synthesis – An Asymmetric Challenge

“…Patil et al also employed 11 as starting material to produce 5 in a “two‐step process” with an overall yield of 26 % (Scheme ) . The first step comprised the formation in situ of the N ‐acylated intermediate 25 .…”

“…In order to enhance the reaction yield and reduce undesired impurities, several groups employed a tosyl‐protection for intermediate 88 , , , . Indeed, heating the tosylated 88 with 5 in water in the presence of K 2 CO 3 , yielded 89 in 85 % (Scheme ) . This protection‐deprotection methodology does not have a detrimental effect on yield, which may be higher than the observed for direct substitution with the piperidine intermediate.…”

“…Patil et al also employed 11 as starting material to produce 5 in a "two-step process" with an overall yield of 26 % (Scheme 5). [19] The first step comprised the formation in situ of the N-acylated intermediate 25. Despite the resemblance to the carbamate derivatives 22 described on the previous method, the alternative N-acylation of 11 seems to influence the reaction sequence efficiency, since 25 was obtained in 82 % in high purity (95 %, assessed by HPLC) without requiring the intermediates isolation.…”

“…[18] However, it was observed that water could promote undesired racemization, which could be prevented by using methanol. [19] Debenzylation of 84 was performed under standard conditions. The original hydrogenation conditions used 20 % Pd/C in ethanol in the presence of HCl.…”