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Practical Synthesis of Capromorelin, a Growth Hormone Secretagogue, via a Crystallization-Induced Dynamic Resolution

Practical Synthesis of Capromorelin, a Growth Hormone Secretagogue, via a Crystallization-Induced Dynamic Resolution

Colin R Rose, Michael P Zawistoski, Bruce A Lefker, F Michael Mangano, Ann S Wright, Philip A Carpino

Bioorg Med Chem. 2017 Feb 1;25(3):1000-1003.

PMID: 28012686

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP870718073	3-Benzyloxy-2,6-difluorophenylboronic acid		870718-07-3	Price

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