替格瑞洛的合成工艺改进

以2-丙硫基-4,6-二氢-5-氨基嘧啶和2-{［(3aR,4S,6R,6aS)-6-氨基-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇L-酒石酸盐为原料，经C-N偶联,亲核取代和环合反应制得2-{［(3aR,4S,6R,6aS)-6-(7-氯-5-丙硫基-3H-［1,2,3］三唑［4,5-d］嘧啶-3-基)-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇(4); 4与(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐经亲核取代反应后酸解脱除丙酮叉保护基合成替格瑞洛,总收率58.7%，纯度99.2%，其结构经¹H NMR, MS(ESI)和XRD确证。

Process Improvement for Synthesis of Ticagrelor

2-6-(7-Chloro-5-propylsulfanyl-1,2,3] triazolo4,5-d] pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-cyclopenta1,3] dioxol-4-yloxy]-ethanol (4) was prepared by the reaction of C—N cou-pling, nucleophilic substitution and cyclization, using 4,6-dichloro-2-( propylthio)-5-pyrimidinamine and 2-{(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopentad]1,3]-dioxol-4-yl] oxy}-1-ethanol and L-tartrate acid salt as materials. Ticagrelor with total yield of 58. 7% and purity of 99. 2% was synthesized by nucleophilic substitution of 4 with (1R,2S)-2-(3, 4-difluorophenyl) cy-clopropylamine D-mandelic acid salt, then removal of the protecting group of acetone fork. The struc-ture was confirmed by 1 H NMR, MS( ESI) and XRD.