An Efficient Method for Synthesis of Tofacitinib Citrate

作者：Zhi, Shuang; Liu, Dengke; Liu, Ying; Liu, Bingni; Wang, Donghua; Chen, Ligong^*

来源：Journal of Heterocyclic Chemistry, 2016, 53(4): 1259-1263.

DOI：10.1002/jhet.2384

• Tofacitinib citrate
• Synthesis
• JAK3 inhibitor
• Red-Al

An efficient and mild synthetic method was developed for tofacitinib citrate from 3-amino-4-methylpyridine and 4-chloro-7H-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.

• 出版日期2016-7
• 单位天津药物研究院有限公司; 天津大学