An efficient and robust synthetic route to (+)-ambrisentan ((+)-AMB) was designed by recycling the unwanted isomer from the resolution mother liquors. The racemization of AMB in the absence of either acid or base in the given solvents was reported. The recovery process was developed to produce racemates with purities over 99.5%. The mechanism of the formation of the process-related impurities of (+)-AMB is also discussed in detail. (+)-AMB was obtained in 47% overall yield with >99.5% purity and 99.8% e.e. by chiral resolution with only one recycling of the mother liquors on a 100-g scale without column purification.

中文翻译：

---

内皮素A受体拮抗剂（+）-Ambrisentan的工艺研究

通过从拆分母液中回收不需要的异构体，设计了一种高效且稳健的合成（+）-安布立坦（（+）-AMB）的合成路线。据报道，在给定的溶剂中，在不存在酸或碱的情况下，AMB的外消旋化。开发了回收工艺以生产纯度超过99.5％的外消旋体。还详细讨论了与（+）-AMB相关的过程杂质的形成机理。（+）-AMB通过手性拆分获得了47％的总收率，纯度> 99.5％，ee纯度为99.8％，仅一次循环母液即可进行100 g规模的纯化，无需柱纯化。