Background: Tenofovir alafenamide (TAF) is an oral antiviral prodrug of tenofovir (TFV),
we have developed a facial and efficient method for the synthesis and chiral resolution of TAF.
Method: The practical synthetic route of a mixed two diastereomers at phosphorous could start from
(R)-9-[2-(Phosphonomethoxy)propyl]adenine (PMPA), the esterification reaction between PMPA and
phenol occurred under the catalysis of dicyclohexylcarbodiimide (DCC) in 1-methyl-2-pyrrolidinone
(NMP) at the temperature of 100°C to afforded 1. Phosphonochloridate was synthesized from 1 by
chloride acetylation with thionyl chloride, and then react with an excess of L-Alanine isopropyl ester
hydrochloride to give the diastereomer mixture of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl]
amino]-phenoxyphosphinyl]methoxy]propyl]adenine (2). The antipodes of 2 were separated in a satisfactory
yield and diastereomeric excess (99% de) by resolution via formation diastereoisomer salt or
inclusion complex to afford the more potent diastereomer (3). Tenofovir Alafenamide hemifumarate
could be afforded by 3 and fumaric acid in a 1:0.5 ratio.
Results: The diastereomeric excess of 3 could reach to 99% de.
Conclusion: In a word, we have developed an efficient and chromatography-free route for the preparation
of TAF. In consideration of the expensive equipment and higher operation cost of SMBC, we
chose a traditional resolution route to obtain chiral phosphorus.