(S)-1-(2,6-二氯-3-氟苯基)乙醇的合成

Synthesis of(S)-1-(2,6-Dichloro-3-fluorophenyl)ethanol

本文报道了一种用化学拆分法合成克里唑替尼关键中间体(S)-1-(2,6-二氯-3-氟苯基)乙醇的新方法。以2,6-二氯-3-氟苯乙酮为原料,经硼氢化钠还原得1-(2,6-二氯-3-氟苯基)乙醇,然后与邻苯二甲酸酐反应得2-[[1-(2,6-二氯-3-氟苯基)乙氧基]羰基]苯甲酸(4),再与(S)-1-苯乙胺选择性成盐,得(S)-2-[[1-(2,6-二氯-3-氟苯基)乙氧基]羰基]苯甲酸单[(S)-1-苯乙胺]盐(5),最后经酸化、水解得目标化合物,总收率43%,纯度99.8%,ee值99.9%。其中,化合物4和5为未见文献报道的新化合物。本工艺已实现百公斤级中试生产,邻苯二甲酸和(S)-1-苯乙胺可回收。

A new synthetic method for（S）-1-（2,6-dichloro-3-fluorophenyl）ethanol, the key intermediate of crizotinib, by chemical resolution was reported.（2,6-Dichloro-3-fluorophenyl）ethanone was reduced by sodium borohydride to give 1-（2,6-dichloro-3-fluorophenyl）ethanol, which was followed by reacting with phthalic anhydride to afford 2-[[1-（2,6-dichloro-3-fluorophenyl）ethoxy]carbonyl]benzoic acid（4）. Then the latter reacted with（S）-1-phenylethanamine to prepare（S）-1-phenylethanaminium（S）-2-[[1-（2,6-dichloro-3-fluorophenyl）ethoxy]carbonyl]-benzoate（5）, which was subjected to acidification and hydrolysis to give the target compound with an overall yield of 43%, a purity of 99.8% and an ee value of 99.9%. In this method, compound 4 and 5 are new compounds which have not yet been reported in literatures. This process has been carried out in 100 kilograms pilot production, and both phthalic acid and（S）-1-phenylethanamine were recovered.