Study On The Process For Preparation Of The Intermediates Of Amprenavir And Darunavir

Acquired immunodeficiency syndrome(AIDS) is sort of contagious disease caused by human immunodeficiency virus(HIV). The common therapeutic drugs can be classified into three categoris: nucleotide reverse transcriptase inhibitor, nonnucleoside reverse transciptase inhibitor and proteinase inhibitor. Ampernavir, a fifth generation antiretroviral protease inhibitor, developed by Glaxo-smith Ltd. of Britian. Darunavir, a protease inhibitor, developed by Tibotec Therapeutics subsidiaries of Johns-on company.(2R,3S)-tert-butoxycarbonylamino-2-hydroxy-1-isobutylamino-4-phenylbutane is an important intermediate of the synthesis of amprenavir and darunavir. There are some obvious shortcomings in normal synthesis, step length, harsh reaction conditions, low yield, explosive material is not suitable for the industrial.In order to overcome the disadvantages of traditional technology, a novel and viable route is designed according to the literature, the optimal industrial synthesis method is selected.Starting with L-phenylalanine,through the reaction of amino group protection, esterification, the Boc-L-phenylalaninephenylesters was obtained. From Boc-L-phenylalaninephenylesters to(2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-1-isobutylamin-4-phenylbutane. Two routes were studied in this paper. Firstly, through ylide reaction,reduction, cyclization and condensation,the target compound was obtained with 41% yield. Secondly, nitro ketone was prepared firstly by Boc-Lphenylalaninediphenylesters, and the target compound was obtained through reduction, reductive amination, the total yield of the second method was 38%. The first route was easier than the second route, however, the second route described the synthesis of the(2S,3S)-1,2-Epoxy-3-(tert-butoxycarbonylamino)-4-phenylbutane, which is the key intermed-iate of navir series.Compounds of the new pathway was characterized by HPLC, MS, 1H-NMR and 13C-NMR. In summary,the novel and viable process for the synthesis of the target compound was designed and experimentaly confirmed.