RESUMO
The practical and highly diastereoselective syntheses of CF(3)-substituted dihydroquinazolinones via 1,4-additions of nucleophiles to chiral auxiliary substituted 2(3H)-quinazolinones is described. This methodology is applied to the syntheses of the NNRTIs (nonnucleoside reverse transcriptase inhibitors) DPC 961 (1) and DPC 083 (2), which are useful for the treatment of HIV (human immunodeficiency virus). The synthesis of DPC 961 (1) requires three steps, proceeds in >55% overall yield from the keto-aniline 9, and gives synthetic access to DPC 083 (2). In addition, the scope of the new diastereoselective 1,4-addition chemistry is investigated. The first preparation of DPC 961 (1) described in this paper is a derivatization fractional crystallization protocol.
Assuntos
Fármacos Anti-HIV/síntese química , Técnicas de Química Combinatória , Quinazolinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/análise , Catálise , HIV/efeitos dos fármacos , Humanos , Estrutura Molecular , Quinazolinas/análise , Quinazolinonas , Inibidores da Transcriptase Reversa/análise , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C(2) symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led to intermediates which were easily purified without chromatography. Additionally, a one-pot, high yield process was developed to prepare the alkylating agent, 4-[(triphenylmethoxy)methyl]benzyl chloride from 1,4-benzenedimethanol.
