Title:Efficient Synthesis and Resolution of Tenofovir Alafenamide
VOLUME: 15 ISSUE: 1
Author(s):Bin Yang, Hongmeng Xie, Kerui Ran and Yongjun Gan*
Affiliation:Department of Pharmacy, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, 400014 Chongqing, Department of Pharmacy, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, 400014 Chongqing, Department of Pharmacy, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, 400014 Chongqing, Experimental Teaching Center, Chongqing Medical University, 400016 Chongqing
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.
