Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.
J Org Chem
; 84(12): 8006-8018, 2019 06 21.
Article
en En
| MEDLINE
| ID: mdl-31124362
ABSTRACT
A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Receptores de Péptido Relacionado con el Gen de Calcitonina
/
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina
Idioma:
En
Revista:
J Org Chem
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos