RESUMEN
This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr. This unprecedented process is based upon a reversible carbon-sulfur bond formation under acidic conditions.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Carbono/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Azufre/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Cristalización , Flúor/química , Cetoácidos/síntesis química , Cetoácidos/química , Magnesio/química , Estructura Molecular , Oxidación-Reducción , Inhibidores de Proteasas/química , Solubilidad , Estereoisomerismo , Sulfuros/química , TemperaturaRESUMEN
The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.
Asunto(s)
Azepinas/síntesis química , Azepinas/farmacología , Integrina alfaVbeta3/antagonistas & inhibidores , Ácidos Pentanoicos/síntesis química , Ácidos Pentanoicos/farmacología , Azepinas/química , Ciclización , Estructura Molecular , Ácidos Pentanoicos/química , Relación Estructura-ActividadRESUMEN
A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.