title: Practical synthesis of capromorelin, a growth hormone secretagogue, via a crystallization-induced dynamic resolution.
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.
authors.affiliation: Department of Medicinal Sciences, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Rose
authors.affiliation: Department of Medicinal Sciences, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zawistoski
authors.affiliation: Department of Medicinal Sciences, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lefker
authors.affiliation: Department of Medicinal Sciences, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: F Michael
authors.initials: FM
authors.lastname: Mangano
authors.affiliation: Department of Medicinal Sciences, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Ann S
authors.initials: AS
authors.lastname: Wright
authors.affiliation: Department of Medicinal Sciences, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA. Electronic address: Philip.a.carpino@pfizer.com.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
mesh_terms: D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013816:Thermodynamics
chemical_list: C433143:CP 424391; D010880:Piperidines; D011720:Pyrazoles
keywords: Capromorelin; Crystallization-induced dynamic resolution; Ghrelin mimetic; Growth hormone secretagogue