Abstract:
This paper described a practical process for the preparation of bicyclic pyrrolidine intermediate of telaprevir. The racemate, (3α
R, 6α
S)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid hydrochloride(
4 )was synthesized from 3-azabicyclo[3. 3. 0]nonane hydrochloride(
9 )
via chlorination of an imine, basic elimination, sulfonation, cyanation, and acid hydrolysis. The target product, (1
S, 3α
R, 6α
S)-octahydrocyclopenta[c]pyrrole-1-carboxylic-
t-butylester oxalate(
1 )was synthesized in an overall yield of about 26. 4% from the free amino acid of compound
4 via Boc protection of the imino, chemical resolution,
t-butyl esterification of the carboxyl group, imino deprotection, and formation of the oxalate salt. The convergent synthetic process of compound
1 highlights the ease of operation and high stereoselectivity, and thus should be applicable for large-scale production.