A Stereoselective Process for the Manufacture of a 2鈥?Deoxy-尾-d-Ribonucleoside Using the Vorbr眉ggen Glycosylation

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• 作者：Julian P. Henschke ; Xiaoheng Zhang ; Xiaohong Huang ; Lijun Mei ; Guodong Chu ; Kun Hu ; Qingping Wang ; Guoyang Zhu ; Mingfeng Wu ; Chihying Kuo ; Yungfa Chen
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：November 15, 2013
• 年：2013
• 卷：17
• 期：11
• 页码：1419-1429
• 全文大小：472K
• 年卷期：v.17,no.11(November 15, 2013)
• ISSN：1520-586X

文摘

A practical and scalable process for the manufacture of cladribine (1) is described. Vorbr眉ggen glycosylation of doubly silylated 2-chloroadenine 2 with protected 1-O-acetyl-2-deoxy-伪,尾-d-ribofuranose 3 under reversible conditions in the presence of 20 mol % triflic acid in a solvent that selectively precipitated the desired 尾-anomer 尾-4a whilst leaving the unwanted 伪-anomer 伪-4a in solution to isomerise allowed good overall stereoselectivity with exclusive regioselectivity. An aging step allowed anomerisation of 伪-4a to 尾-4a, thereby improving the isolable yield of the 尾-anomer. Direct filtration of the product mixture without a catalyst quench or aqueous workup furnished the crude 尾-anomer 尾-4a in good yield (up to 68%) and purity (>95% by HPLC) with no regioisomers detected and only 1鈥?% (by HPLC) of the undesired 伪-anomer. Deprotection of the crude, unpurified intermediate 尾-4a followed by recrystallisation provided drug-grade cladribine (1). The process includes three isolation steps and was demonstrated on kilogram scales using cGMP providing 99.8鈥?9.9% pure cladribine in up to an overall 43% yield based on 2-chloroadenine (5). In contrast to previous methods, column chromatography and/or bulky directing groups were not required in the glycosylation step, a high pressure vessel was not needed in the deprotection step, and only one dedicated recrystallisation step was necessary.