Large-scale asymmetric synthesis of a cathepsin S inhibitor.
J Org Chem
; 75(4): 1155-61, 2010 Feb 19.
Article
en En
| MEDLINE
| ID: mdl-20102230
ABSTRACT
A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Urea
/
Compuestos de Vinilo
/
Catepsinas
/
Alquenos
/
Inhibidores Enzimáticos
Idioma:
En
Revista:
J Org Chem
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos