RESUMO
Studies of the displacement chemistry of 1,1-difluorocyclopropyldibenzosuberanyl alcohol 4 and its activated bromide derivative 6 have led to an improved approach to anti-2, a key precursor to LY335979 3HCl (1). Bromination of either syn-4 or anti-4 gave anti-oriented 6, indicating thermodynamically controlled product stereochemistry via a stabilized 1,1-difluorohomotropylium ion intermediate. Reaction of 6 with piperazine proceeded irreversibly to provide an isomeric mixture of piperazine products, with the syn:anti product ratio increased by solvent effects. Reaction of 6 with pyridine and pyrazine, on the other hand, gave anti-pyridinium and pyrazinium salts, respectively, apparently via equilibration of initially formed syn products. Reduction of pyrazinium salt 11 with lithium borohydride/TFA provided anti-2 unaccompanied by its syn isomer. A practical and expeditious approach to 1 was derived from these new results.
Assuntos
Técnicas de Química Combinatória , Dibenzocicloeptenos/síntese química , Hidrocarbonetos Fluorados/química , Quinolinas/síntese química , Dibenzocicloeptenos/farmacologia , Resistência a Múltiplos Medicamentos , Ácidos Hidroxâmicos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Quinolinas/farmacologia , EstereoisomerismoRESUMO
An efficient green chemistry approach to the synthesis of N-substituted piperidones and piperidines was developed and applied to the synthesis of 1-(2-pyridinylmethyl)-piperidin-4-one, 1, a key starting material for the synthesis of LY317615, an antiangiogenic agent currently under development at Eli Lilly and Company (Chart 1).(1) The general utility of this methodology, which presents significant advantages over the classical Dieckman approach to this class of compounds, was also demonstrated by the direct synthesis of a series of substituted piperidones and piperidines, including potential dopamine D4 receptor antagonists 2 and 3, that have been evaluated in the clinic as antipsychotic agents (Chart 2).(2)