替格瑞洛的合成工艺改进
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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.
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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[9]M·博林,S·科斯格洛夫,B·拉森.三唑并[4,5-D]嘧啶化合物的新晶形和非晶形:CN 01810582.3[P].2001.
[2]Ulf Larsson,Magnusson,Musil,et al.Novel triazolo pyrimidine compounds:US 20030148888[P].2003.
[3]Anil S K,Vignesh N,Nikhil T.Improved process for preparing eyelopentylamine derivatives and intermediates thereof:WO 2012172426[P].2012.
[4]David H,Anthony I,Brian S,et al.Triazolo(4,5-D)pyrimidine:US 6525060[P].2003.
[5]Zhang H,Liu J,Zhang L Y,et al.Synthesis and biological evaluation of cyclopentyl-triazolopyrimidine derivatives as novel antiplatelet agents[J].Bioorganic&Medicinal Chemistry Letters,2012,22(11):3598-3602.
[6]曾志旋,曹胜华,陈林,等.替格瑞洛的合成工艺改进[J].化学研究与应用,2015,27(3):373-377.
[7]缪世峰,蔺宇,张海波,等.新型抗凝血药替格瑞洛的合成[J].海峡药学,2015,27(4):249-251.
[8]胡晨阳,任芳俊,盛晓霞,等.替格瑞洛晶型及其制备方法和用途:CN 201310118496.8[P].2013.
[9]M·博林,S·科斯格洛夫,B·拉森.三唑并[4,5-D]嘧啶化合物的新晶形和非晶形:CN 01810582.3[P].2001.