奈必洛尔关键中间体的合成新工艺

New Synthetic Process of the Key Intermediate of Nebivolol

本研究采用新路线合成奈必洛尔关键中间体2-氯-1-(6-氟-3,4-二氢-2H-1-苯并吡喃-2-基)乙酮。以6-氟-3,4-二氢-2H-1-苯并吡喃-2-羧酸为原料,经与氯甲酸乙酯缩合、与重氮甲烷重氮化、氯代反应"一锅法"制得目标化合物,收率85%,纯度≥99%。本工艺对产物的手性几乎没有影响,最终合成的产物与所选用的原料手性一致,手性纯度≥99.5%。本工艺已经过中试放大验证。

2-Chloro- 1- （6-fluoro-3,4-dihydro-2H- 1-benzopyran-2-yl） ethan- 1 -one, the key intermcdiate of nebivolol, was synthesized by a new synthetic process. The target compound was prepared by ＂one-pot＂ method of condensation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid with ethyl chloroformate, followed by diazotization and chlorination. The yield was 85% and the purity was more than 99% with a chiral purity of 99.504. The chirality of the target product was identical to the starting material＇s. This process has been proven by pilot-scale test.