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.
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