An Efficient Method for Synthesis of Tofacitinib Citrate

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• 作者：Shuang Zhi ; Dengke Liu ; Ying Liu ; Bingni Liu ; Donghua Wang and Ligong Chen
• 刊名：Journal of Heterocyclic Chemistry
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：53
• 期：4
• 页码：1259-1263
• 全文大小：879K
• ISSN：1943-5193

文摘

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 made the reaction proceed effectively to present compound 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 enhanced the nucleophilic substitution of with compound dramatically. Thus, under the optimized conditions, tofacitinib citrate was obtained in 13.3% yield (based on compound ) 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.