An Improved Process for the Preparation of Tenofovir Disoproxil Fumarate

Abstract

Abstract:The current three-step manufacturing route for the preparation of tenofovir disoproxil fumarate (1) was assessed and optimized leading to a higher yielding, simpler and greener process. Key improvements in the process route include the refinement of the second stage through the replacement of the problematic magnesium tert-butoxide (MTB) with a 1:1 ratio of a Grignard reagent and tert-butanol. The development of a virtually solvent-free approach and the establishment of a work-up and purification protocol which allows the isolation of a pure diethyl phosphonate ester (8).

An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines

“…Another issue is the base used in Stage 2a to couple the (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol (HPA) with DESMP. The base reported most often, Mg(OtBu)2, provides excellent conversions (>90%) 8 but has drawbacks including: (1) high cost, (2) poor reproducibility -lot to lot variation, and 3higher cost workup and purification. 7 We sought to create a process that avoided adenine, propylene carbonate and Mg(OtBu)2.…”

An improved synthesis of adefovir and related analogues

“…Subsequent dealkylation of 6 using trimethylsilyl bromide (TMSBr) gives adefovir ( 1 ). The related analogue tenofovir, developed as an anti-HIV agent, may be prepared in a similar manner [37–38].…”

“…The poor solubility of adenine and its derivatives in most organic solvents restricts the choice of solvent for this and subsequent reactions to polar aprotic solvents such as DMF, NMP and DMSO [38].…”

“…This resin hinders the isolation of phosphonate 6 and stymies scale-up. Finally, several byproducts, including the ethyl ether of 4 and the hemi-dealkylated ester of 6 , are produced during this reaction, further reducing the atom economy of this approach [35,38]. In an attempt to overcome these difficulties, some groups have explored telescoping the MTB-mediated alkylation of 4 with the subsequent dealkylation of 6 [38,40].…”

Continuous‐Flow Synthesis of (R)‐Propylene Carbonate: An Important Intermediate in the Synthesis of Tenofovir

“…It also induces obligate chain termination when incorporated into DNA due to the lack of a 3′-hydroxy group. [3][4][5][6][7][8] Additionally, the synthesis of the enantiomerically pure 6 by the use of enantiomerically pure templates such as lactic acid or (R)glycidol (10) has been reported, as depicted in Scheme 1. The incorporation of this chiral group into the structures of TAF (1), TDF (2) or PMPA (3) can be achieved by the substitution reaction between the corresponding (R)-propylene carbonate [(R)-PC, 6] and adenine (5), which yields adenine 4 bearing a chiral secondary hydroxy group (Scheme 1).…”