Practical synthesis of capromorelin, a growth hormone secretagogue, via a crystallization-induced dynamic resolution.
Rose CR1, Zawistoski MP1, Lefker BA1, Mangano FM1, Wright AS1, Carpino PA2.
Bioorg Med Chem. 2016 Dec 10. pii: S0968-0896(16)31398-0. doi: 10.1016/j.bmc.2016.12.015. [Epub ahead of print]
A practical synthesis of capromorelin (1), a growth hormone secretagogue, is described that utilizes as a key step a crystallization-induced dynamic resolution (CIDR) of (±)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3(3aH)-one [(±)-2] by L-tartaric acid salt formation, yielding (R)-2.L-tartaric acid in high chemical yield (>85%) and with diastereomeric excess (de) of ∼98%. Treatment of (R)-2.L-tartaric acid with ammonium hydroxide provided (R)-2 without loss of chiral purity. In situ generated (R)-2 was coupled with (R)-3-(benzyloxy)-2-(2-(tert-butoxycarbonyl)-2-methylpropanamido)propanoic acid [(R)-3] to give predominantly a single diastereomer of N-Boc-protected capromorelin [(1R,3aR)-4]. This process was used to prepare bulk quantities of capromorelin from (±)-2 to support preclinical toxicology studies.Copyright © 2016 Elsevier Ltd. All rights reserved.
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