替格瑞洛的合成工艺优化

Improved Synthesis of Ticagrelor

本研究对替格瑞洛的合成工艺进行了优化。4,6-二氯-5-氨基-2-丙硫基嘧啶(2)与2-[[(3aR,4S,6R,6aS)-6-氨基-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二氧杂环戊-4-基]氧基]-1-乙醇以N,N-二异丙基乙胺为缚酸剂于100℃反应得2-[[(3aR,4S,6R,6aS)-6-[[5-氨基-6-氯-2-(丙硫基)-4-嘧啶基]氨基]-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二氧杂环戊-4-基]氧基]-1-乙醇,收率87.1%;通过"一锅法"使重氮化环合反应和脱保护反应同时进行制得(1S,2S,3R,5S)-3-[7-氯-5-(丙硫基)-3H-[1,2,3]三唑[4,5-d]嘧啶-3-基]-5-(2-羟乙氧基)环戊烷-1,2-二醇,再与(1R,2S)-2-(3,4-二氟苯基)-环丙胺经氨基化得目标化合物。优化后的工艺缩减了反应步骤,简化了实验操作,总收率由文献的32.3%提高至61.8%(以2计)。

The synthetic process of ticagrelor was improved. 2- [[（3aR,4S,6R,6aS） -6- E E5-Amino-6-chloro-2- （propylthio）pyrimidin-4-yl]amino]-2,2-dimethyltetrahydro-4H-cyclopenta[d] E1,3]dioxol-4-yl]oxy]ethan-1-ol （4） was synthesized via nucleophilic substitution of 4,6-dichloro-5-amino-2-propylthiopyrimidine （2） and 2-[ [（3aR,4S,6R,6aS）- 6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d] [1,31dioxol-4-yl]oxy]ethan-l-ol in the presence of N, N- diisopropylethylamine at 100℃ with a yield of 87.1%. Then compound 4 was converted to （1S,2S,3R,5S）-3-E7-chloro- 5- （propylthio） -3 H- [1,2,31 triazolo [4,5-d] pyrimidin-3-yl]-5- （2-hydroxyethoxy） cyclopentane- 1,2-diol by ＂one-pot＂ reaction （diazo-cyclization and deprotection） with a yield of 83.5%. Then the latter was subjected to amination with （1R,2S）-2-（3,4-difluorophenyl） cyclopropan-1-amine to provide the target compound. This improved synthetic route had less reaction steps and simplified operation procedures, and also gave a better overall yield of 61.8 % （based on 2）.