Efficient Synthesis and Resolution of Tenofovir Alafenamide

Title:Efficient Synthesis and Resolution of Tenofovir Alafenamide

Volume: 15 Issue: 1

Author(s): Bin Yang, Hongmeng Xie, Kerui Ran and Yongjun Gan*

Affiliation:

• Experimental Teaching Center, Chongqing Medical University, 400016 Chongqing,China

Keywords: Chiral phosphorus, inclusion complex, resolution, D-(-)-Tartaric acid, TADDOL, tenofovir alafenamide.

Abstract: 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.

Cite this article as:

Yang Bin, Xie Hongmeng , Ran Kerui and Gan Yongjun *, Efficient Synthesis and Resolution of Tenofovir Alafenamide, Letters in Organic Chemistry 2018; 15 (1) . https://dx.doi.org/10.2174/1570178614666170907115708