Practical Synthesis of Tenofovir Alafenamide Fumarate Inspired by New Retrosynthetic Disconnection Featuring a Novel Carbon–Phosphorus Bond Construction Methodology

Abstract

Tenofovir alafenamide fumarate (TAF) is rising as a mainstay antiretroviral agent for the treatment of HIV and chronic HBV infections. A de novo practical synthesis of TAF circumventing tenofovir (PMPA) has been accomplished on a 7 g scale. This reimagined synthesis of TAF, inspired by a hitherto uncharted retrosynthetic disconnection, centers on the P-alkylation of silylated diphenyl phosphonate 11 (as acceptor) with methylthiomethyl (MTM) ether derivative 12 (as donor) in the presence of NIS/TfOH combination as a promoter to construct the strategic carbon–phosphorus bond. This PMPA-free synthesis of TAF not only removes the intrinsic drawbacks encountered by the PMPA-dependent commercial process but also is beneficial to the diversification of the synthetic portfolio of TAF. Furthermore, this type of P-alkylation reaction with defined stereochemistry could be deployed for the late-stage modification of druglike molecules and natural products to access valuable phosphonate derivatives.

Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

“…Following the production of the scandium isotopes, the recovery of the calcium, titanium, and vanadium target materials is a very important process, owing both to their high cost and their potential for use as stable long-term supply sources [ 40 ]. The separation of the target source from scandium usually involves several processes of selective precipitation, filtration, and washing, aimed at maximizing extraction and purification [ 124 , 125 , 126 , 127 , 128 ] ( Table 3 ). Different approaches have been used by various research teams in the course of these processes [ 129 , 130 , 131 , 132 ].…”