Practical synthesis of capromorelin, a growth hormone secretagogue, via a crystallization-induced dynamic resolution

[Display omitted] 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 f...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2017-02, Vol.25 (3), p.1000-1003
Main Authors: Rose, Colin R., Zawistoski, Michael P., Lefker, Bruce A., Mangano, F. Michael, Wright, Ann S., Carpino, Philip A.
Format: Article
Language:English
Subjects:
Capromorelin
Crystallization-induced dynamic resolution
Crystallography, X-Ray
Ghrelin mimetic
Growth hormone secretagogue
Models, Molecular
Molecular Structure
Piperidines - chemical synthesis
Piperidines - chemistry
Pyrazoles - chemical synthesis
Pyrazoles - chemistry
Thermodynamics
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2016.12.015