氯法拉滨的工艺改进

Improvement of Process of Clofarabine Synthesis

目的改进氯法拉滨的化学合成路线。方法采用TiCl4的二氯甲烷溶液代替通气(HCl或HBr)处理1-O-乙酰基-2,3,5-三-O-苯甲酰基-β-D-呋喃核糖再加水重排;采用新型的羟基氟代试剂PBSF-Et3N·3HF替代了强腐蚀的硫酰氯等试剂,在温和反应条件下得到1,3,5-二-O-苯甲酰基-2-脱氧-2-氟-α-D-阿拉伯糖(收率86.2%),优化工艺后溴代糖与2-氯嘌呤缩合时β体与α体比例可达19∶1,经氢氧化锂水解得氯法拉滨。结果纯度达到要求,氯法拉滨α体杂质含量小于0.1%,总收率21.2%。结论与文献合成工艺比较,其重排步骤操作简便,氟代反应条件温和、无腐蚀,缩合与水解步骤严格控制了产品质量。

Objective To improve the synthesis process of Clofarabine. Methods 1-O-acetyl-2,3,5-tri-O- benzoyl- β-D-ribofuranose was treated with the solution of WiCl4 in CH2 C12, followed by the addition of water. Instead of extremely corrosive sulfuryl chloride, the rearranged product was fluorinated by novel PBSF-Et3N·3HF to give 1,3,5-di-O-benzoyl- 2-deoxy-2-fluoro-ot-D-arabinose in 86.2% yield. The ratio of the 13 isomer to ot isomer reached 19：1 in the optimized condensation of the brominated arabinose with 2-chloropurine, and the final hydrolysis in methanol by LiOH led to Clorofarabine. Results The total yield of Clofarabine was 21.2%, with the same quality as the reported （α isomer 〈 0.1% ）. Conclusion A simple workup, cost-effective process with mild conditions was provided.