Indinavir (Crixivan) is a potent and specific inhibitor of the HIV-1 for the treatment of AIDS. Pharmacokinetic studies revealed that oxidative metabolism via CYP3A4 are the major routes of elimination for indinavir in human. The identified metabolites of indinavir include M2, M3, M4a, M4b, M5 and M6. Indinavir M5 and M6 were found to be major metabolites in urine. The metabolic profile in plasma is similar to that in urine. The extensive inter- patient pharmacokinetic variabilities are seen with HIV drugs. Drug-drug interactions, dosing errors and noncompliance may be improved by therapeutic drug monitoring.

In the development of an immunoassay for indinavir, we initially produced indinavir metabolites via microsomal methods, but this approach provided us with insufficient quantities. This prompted us to investigate total synthetic approaches to prepare indinavir metabolites. In this report we describe the total syntheses of indinavir M3 and M5. We also obtained indinavir M6 by one step hydrogenation process from indinavir and used this to prepare indinavir M4a.