洛普替尼的合成研究

Study on the synthesis of repotrectinib

目的研究洛普替尼手性中间体(R)-2-(1-氨基乙基)-4-氟苯酚的合成,以制备非对映体过量(de)>99.0%的洛普替尼。方法以5-氟-2-羟基苯乙酮为起始原料,依次经甲基化、亚胺缩合、还原、脱除叔丁基亚磺酰基及脱甲基制得关键中间体,随后经取代、Mitsunobu等5步反应完成洛普替尼的手性合成。结果与结论所得中间体及终产品洛普替尼经HPLC检测纯度大于99.5%,de>99.0%。

The synthesis of chiral intermediate(R)-2-(1-aminoethyl)-4-fluorophenol(B-6)was deeply studied to prepare repotrectinib(de>99.0%).Using 1-(5-fluoro-2-hydroxyphenyl)-1-ethanone(B-1)as the starting material,B-6 was prepared by methylation,condensation,reduction,removal of tert-butylsulfinyl group,and demethylation in sequence.The target product repotrectinib was synthesized after treating B-6 with five steps:substitution,Mitsunobu,acid-catalyzed removal of tert-butoxycarbonyl,hydrolysis and cyclization.Repotrectinib can be simply and mildly synthesized with high diastereoselectivity(de>99.0%).The product was confirmed by LC-MS,HR-MS,^(1)H-NMR and ^(13)C-NMR,with the 99.5%purity as determined by HPLC area normalization method.