(R)-3-氨基丁醇的合成研究
|
摘要
(R)-3-氨基丁醇(1)是合成抗HIV/AIDS新药度鲁特韦的重要中间体。以(R)-(+)-α-苯乙胺(2)和乙酰乙酸乙酯(3)为原料,经过缩合、烯胺还原、差向异构体分离、酯还原和脱保护,得到纯品(R)-3-氨基丁醇,总收率达到39.3%。产品经过核磁氢谱和核磁碳谱表征。该路线能有效减少副产物。
(R)-3-amino-1-butanol,an important intermediate of dolutegravir,was prepared in a total yield of 39.3% from(R)-α-phenylethylamine and ethyl acetoacetate by sequential condensation,enamine reduction,separation of lepimers and deprotection.The structures of all the intermediates and the final product were confirmed by ~1H NMR and ~(13)C NMR.This synthetic route could effectively reduce the formation of by-products.
(R)-3-amino-1-butanol,an important intermediate of dolutegravir,was prepared in a total yield of 39.3% from(R)-α-phenylethylamine and ethyl acetoacetate by sequential condensation,enamine reduction,separation of lepimers and deprotection.The structures of all the intermediates and the final product were confirmed by ~1H NMR and ~(13)C NMR.This synthetic route could effectively reduce the formation of by-products.
引文
[1]B.A约翰斯,段茂圣,箱木敏和.氨甲酰基吡啶酮HIV整合酶抑制剂的方法和中间体[P].CN:102245572 A,2009-12-09.
[2]B.A约翰斯,川筋孝,大司照彦,等.具有HIV整合酶抑制活性的多环氨基甲酰基吡啶酮衍生物[P].CN:101212903 A,2006-04-28.
[3]Johns B A,Kawasuji T,Taishi T,et al.Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity[P].WO:2006/116764 A1,2006-02-11.
[4]孙建军,沈银忠,卢洪洲.第二代整合酶链转移抑制剂dolutegravir[J].上海医药,2014,35(21):24-27.
[5]Rhyne D N,Byrd E S,Klibanov O M.Dolutegravir(Tivicay)for HIV infection[J].Nurse Pract,2014,39(6):11-15.
[6]Cada D J,Levien T L,Baker D E.Dolutegravir[J].Hosp Pharm,2014,49(2):184-195.
[7]Hare S,Smith S J,Metifiot M,et al.Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir(S/GSK 1349572)[J].Mol Pharmacol,2011,80(4):565-572.
[8]Cooper D A,Steigbigel RT,Gatell J M,et al.Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection[J].N Engl J Med,2008,359(4):355-365.
[9]毛龙飞,毛伸,蒋涛,等.4-甲氧基乙酰乙酸甲酯的合成研究[J].化学研究与应用,2016,28(7):1 030-1 033.
[10]叶菲,赵李霞,付颖.手性化合物S-(+)-和R-(-)-2-氨基丁醇的制备方法[P].CN:101863779 A,2010-10-20.
[11]吴生文,田重威,胡四明,等.一种光学活性的3-氨基丁醇和3-氨基丁醇的制备方法[P].CN:104370755A,2015-02-25.
[12]范文超,丁鹏.一种R-3氨基丁醇的生物制备方法[P].CN:104131048 A,2014-11-05.
[13]范文超,丁鹏.一种R-3氨基丁醇的生产方法[P].CN:104178533 A,2014-12-03.
[2]B.A约翰斯,川筋孝,大司照彦,等.具有HIV整合酶抑制活性的多环氨基甲酰基吡啶酮衍生物[P].CN:101212903 A,2006-04-28.
[3]Johns B A,Kawasuji T,Taishi T,et al.Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity[P].WO:2006/116764 A1,2006-02-11.
[4]孙建军,沈银忠,卢洪洲.第二代整合酶链转移抑制剂dolutegravir[J].上海医药,2014,35(21):24-27.
[5]Rhyne D N,Byrd E S,Klibanov O M.Dolutegravir(Tivicay)for HIV infection[J].Nurse Pract,2014,39(6):11-15.
[6]Cada D J,Levien T L,Baker D E.Dolutegravir[J].Hosp Pharm,2014,49(2):184-195.
[7]Hare S,Smith S J,Metifiot M,et al.Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir(S/GSK 1349572)[J].Mol Pharmacol,2011,80(4):565-572.
[8]Cooper D A,Steigbigel RT,Gatell J M,et al.Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection[J].N Engl J Med,2008,359(4):355-365.
[9]毛龙飞,毛伸,蒋涛,等.4-甲氧基乙酰乙酸甲酯的合成研究[J].化学研究与应用,2016,28(7):1 030-1 033.
[10]叶菲,赵李霞,付颖.手性化合物S-(+)-和R-(-)-2-氨基丁醇的制备方法[P].CN:101863779 A,2010-10-20.
[11]吴生文,田重威,胡四明,等.一种光学活性的3-氨基丁醇和3-氨基丁醇的制备方法[P].CN:104370755A,2015-02-25.
[12]范文超,丁鹏.一种R-3氨基丁醇的生物制备方法[P].CN:104131048 A,2014-11-05.
[13]范文超,丁鹏.一种R-3氨基丁醇的生产方法[P].CN:104178533 A,2014-12-03.