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富马酸替诺福韦酯合成路线
发布日期:2012-02-01 17:49:56

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The reaction of chloromethyl chloroformate (I) with isopropyl alcohol (II) by means of pyridine or triethylamine in ether gives the mixed carbonate (III), which is then condensed with (R)-PMPA (IV) by means of diisopropyl ethyl-amine in DMF.


























Intermediates: Serial No.
1-methyl-2-oxo-5-indolinesulfonyl chloride (I)
1-methyl-5-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)disulfanyl]-1,3-dihydro-2H-indol-2-one (II)
(2S)-2-methyltetrahydro-4H-pyran-4-one (III)
3-bromothiophene (IV)

Reference 1:
    Oliyai, R.; Dougherty, J.; Bischofberger, N.; Kim, C.U.; Mulato, A.; Shaw, J.P.; Cundy, K.C.; Arimilli, M.N.; Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs. Antivir Chem Chemother 1997, 8, 6, 557.
Reference 2:
    Sorbera, L.A.; Casta?er, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279.
Reference 3:
    Arimilli, M.N.; Cundy, K.C.; Dougherty, J.P.; Kim, C.U.; Oliyai, R.; Stella, V.J. (Gilead Sciences Inc.); Nucleotide analogs. US 5922695; WO 9804569 .