Darunavir derivatives

The synthesis of darunavir (1) is shown in Scheme 12. Optically active bis-THF alcohol (-)-ll was converted to activated mixed carbonate 46 by treatment with N,N-disuccinimidyl carbonate (DSC) in the presence of triethylamine.30 For the synthesis of the hydroxyethylsulfonamide isostere, epoxide 38 was treated with isobutyl amine (47) in 2-propanol at reflux to provide the corresponding amino alcohol. Reaction of the resulting amino alcohol with p-nitrophenylsulfonyl chloride in the presence of aqueous NaHC03 afforded the sulfonamide derivative 48 in 95% yield for the two steps. This was converted to darunavir in a three-step process, involving (1) catalytic hydrogenation of nitro to an amine, (2) removal of the Boc group by exposure to trifluoroacetic acid in... 

That product (17) is then converted to the activated A -hydoxysuccinimide derivative 18 as in the case of the monocyclic furan. Reaction with the primary amine 10 used to prepare amprenavir then leads to the urethane (19). Reduction of the nitro group then affords darunavir" (20). 

Clinically important, potentially hazardous interactions with alprazolam, astemizole, clindamycin, darunavir, dasatinib, dihydroergotamine, eplerenone, ergot derivatives, fentanyl, garlic, ixabepilone, ketoconazole, lapatinib, methysergide, midazolam, phenytoin, pimozide, rifampin, ritonavir, sildenafil, solifenacin, St John s wort, temsirolimus, tolvaptan... 

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