379270-37-8

ChEBI: An L-alanine derivative that is isopropyl L-alaninate in which one of the amino hydrogens is replaced by an (S)-({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)( henoxy)phosphoryl group. A prodrug for tenofovir, it is used (as the fumarate salt) in combination therapy for the treatment of HIV-1 infection.

Tenofovir Alafenamide is a prodrug of Tenofovir (T018500), which is a reverse transcriptase inhibitor used to treat HIV and Hepatitis B. Antiviral.

A multikilogram synthesis of tenofovir alafenamide fumarate was described in a Gilead patent. Additional process improvements on specific steps of the Gilead process have been reported on 100 g scale, and these will be noted throughout the description of the synthesis. The synthesis was initiated with the alkylation of adenine (72) with (R)-propylene carbonate (73) to give hydroxypropyl adenine 74 in 75% yield. It should be noted that sodium hydroxide can be replaced by potassium bases with increased yields on 100 g scale.27 Alkylation of 74 with diethyl p-toluenesulfonyloxymethylphosphonate (75) gave intermediate 76, which was not isolated. Hydrolysis of the phosphonate esters with trimethylsilyl bromide followed by recrystallization from water gave phosphonic acid 77 in 50% yield. Interestingly, replacing Mg(Ot-Bu)2 with PhMgCl/t-BuOH led to improved yields for the alkylation step (74 ?ú 76) on a 100 g scale. Additionally, the authors note that conditions for hydrolyzing the phosphonate ester can be modified using HCl or HBr for improved yields on smaller scale. Dicyclohexylcarbodiimide (DCC) coupling of 77 with phenol produced phosphonate 78 in 51% yield. This step was also reported to proceed in higher yield on smaller scale by changing the solvent to cyclopentylmethyl ether. Monophosphonate ester 78 was treated with thionyl chloride followed by L-alanine isopropyl ester (79) and triethylamine to give tenofovir alafenamide rac-80 as a mixture of phosphonate diastereomers in 47% yield. The diastereomers were separated using simulated moving bed chromatography to give the desired diastereomer ent-80 in 47% yield and 99% diastereomeric purity. The diastereomers could also be separated using a crystallization-induced dynamic resolution of rac-80. Tenofovir alafenamide fumarate (VI) was prepared from ent-80 and fumaric acid in 83% yield.