Practical Synthesis of PGI2 Agonist: Resolution-Inversion-Recycle Approach of Its Chiral Intermediate

摘要

Practical synthesis of ((2R)-5-benzylo:sy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol ((R)-7b), a key chiral intermediate for the synthesis of the novel PGI2 agonist, (Jl)-[6-[(diphenylcarbamoyloxy)methyl]-6-hydroxy-5,6,7,8-tetrahydronaph-thalen-l-yloxy]acetic acid (1), was achieved via optical resolution by diastereoselective crystallization of ester derivative 18 of racemic (S-benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol (7b) with (lS,4R)-(-)-camphanlc acid ((-)-CpOH) followed by saponification. Starting from commercially available 5-hydroxy-l-tetralone (2), this process features recycling of the undesired enantiomer (S)-7b via inversion of the C2 hydroxyl group by acid-catalyzed hydrolysis of its epoxide derivative (S)-ll. Performing this resolution-inversion-recycle approach provided a 44% overall yield of (R)-7b (>99% ee) from racemic 7b. The enantiopure (R)-7b synthesized by this approach was then used to prepare 1. This robust, reproducible, and scalable synthesis of 1 was successfully demonstrated on a pilot scale.