Development of a Scalable Route with Efficient Stereoisomer Control to YZJ-1139, an Orexin Receptor Antagonist

An effort toward the synthesis and process development of the orexin receptor antagonist YZJ-1139(1) was described in this article. YZJ-1139(1) contains the azabicyclic nortropane structure with three chiral centers. By the original process, highly pure intermediates or API could be obtained by chromatography with a relatively low yield. To remove the undesirable stereoisomers as early as possible, intermediate 13 with (R)-α-phenethyl was synthesized by the Robinson–Schöpf reaction and easily purified as hydrochloride. The single crystal X-ray study was used to confirm the stereo configuration of 13·HCl and 18·HCl. The protecting group could be easily removed by transfer hydrogenation, resulting in enantiomerically pure intermediate 3 as a d-tartarate. The overall yield for preparing YZJ-1139(1) was significantly increased, and this cost-efficient process might be promising in future commercial productions.