摘要
以2-丙硫基-4,6-二氢-5-氨基嘧啶和2-{[(3aR,4S,6R,6a S)-6-氨基-2,2-二甲基四氢-3a H-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,6a S)-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-3a H-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。
2-[6-( 7-Chloro-5-propylsulfanyl-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-cyclopenta[1,3]dioxol-4-yloxy]-ethanol( 4) was prepared by the reaction of C—N coupling,nucleophilic substitution and cyclization,using 4,6-dichloro-2-( propylthio)-5-pyrimidinamine and 2-{ [( 3aR,4S,6R,6a S)-6-amino-2,2-dimethyltetrahydro-3a H-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol and L-tartrate acid salt as materials.Ticagrelor with total yield of 58.7% and purity of99.2% was synthesized by nucleophilic substitution of 4 with( 1R,2S)-2-( 3,4-difluorophenyl) cyclopropylamine D-mandelic acid salt,then removal of the protecting group of acetone fork.The structure was confirmed by1 H NMR,MS( ESI) and XRD.
引文
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