{Author}:黄杨威 陈 忠 魏宗有 赵学清 徐敏华 徐燕和

　　{Year}:2013

　　{Title}:氯法拉滨的工艺改进

　　{Journal}:《今日药学》

　　{Volume}:23

　　{Issue}:11

　　{Pages}: 730-732

　　{ISBN/ISSN}: 1674-229X

　　{Keywords}:氯法拉滨 合成 TiCl 4 PBSF-Et 3 N·3HF

　　{Abstract}: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-Dribofuranose was treated with the solution of TiCl 4 in CH 2 Cl 2,followed by the addition of water. Instead of extremely corrosive sulfuryl chloride,the rearranged product was fluorinated by novel PBSF-Et 3 N·3HF to give 1,3,5-di-O-benzoyl- 2-deoxy-2-fluoro-α-D-arabinose in 86. 2% yield. The ratio of the β isomer to α isomer reached 19 ∶ 1 in the optimized condensation of the brominated arabino...