坎格雷洛的合成工艺改进

Improved Synthetic Process of Cangrelor

本研究对坎格雷洛(1)的合成工艺进行了改进。鸟嘌呤核苷(2)经乙酰化反应、2步氯代反应得2,6-二氯-9-(2,3,5-三-O-乙酰基-β-D-呋喃核糖基)嘌呤(5),5经氨基取代、脱保护和硫代反应得N6-(2-甲硫基乙基)-2-(3,3,3-三氟丙硫基)腺嘌呤核苷(8)。硫代反应中,采用自制的三氟丙硫醇代替过硫醚试剂,提高了反应活性,6步总收率由15%提高至33%。由8合成1时,使用“一锅法”3步连续反应,并且后处理时采用正丁醇萃取纯化代替离子交换分离纯化,操作简便,产物1纯度达到99.10%。

The synthetic process of cangrelor(1)was improved in this report.2,6-Dichloro-9-(2,3,5-tris-Oacetyl-β-D-ribofuranyl)purine(5)was obtained by acetylation and two-step chlorination from guanine nucleoside(2),and N6-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)adenine nucleus glycoside(8)was obtained by amino substitution,deprotection and thiolation from compound 5.In the thiolation,the self-prepared trifluoro propanethiol was used to replace the persulfide reagent,which increased the reaction activity,and the yield of the 6-step reacction was increased from 15%to 33%.When synthesizing 1 from 8,a"one-pot"three-step continuous reaction was used,and n-butanol extraction was used instead of ion exchange separation in the work-up.In this process,the operation was simple and the purity of 1 was 99.10%.