Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale

Abstract

The three-step manufacturing process used in the synthesis of tenofovir disoproxil fumarate (1) was studied and optimized, leading to a more productive and robust process. The yield was improved from about 13% overall to 24%. Key process improvements identified included implementation of a telescoped process for the second stage that obviated the need for an extraction and solvent exchange, and significant optimization of the final reaction, including the beneficial effect of adding a quaternary ammonium salt to the alkylation reaction and development of a nonaqueous process for removal of NMP and triethylamine from the product mixture to decrease the level of decomposition of product during the isolation.

An Improved Process for the Preparation of Tenofovir Disoproxil Fumarate

“…This three stage process was originally patented by Gilead affording TDF in a 13 % overall yield, 5 this was more recently improved to 24 % by the Clinton Health Access Initiative (CHAI), who were able to greatly improve stage 3 from 35 % yield based upon PMPA (3) to 62 %. 6 In both instances it was not possible to isolate PPA (8) directly and crude material had to be telescoped to afford PMPA (3). The conversions of stage 2b for the Gilead and CHAI routes at 50 % and 90 % are further compromised by the loss of material in this telescoping process.…”

“…Manufacturing route for tenofovir disoproxil fumarate unwanted regioisomer where addition occurs at the exocyclic-NH 2 group, which typically accounts for 7-8 area % of the reaction mixture after completion. 6 Recrystallization from MeOH/iPrOH affords the desired HPA in 97-98 % purity with 1-2 % contamination with the unwanted NH-substituted regioisomer and a total 65 % isolated yield. 6 An assessment was undertaken to investigate the choice of catalyst, solvent, catalyst loading and reaction time on the product yield.…”

“…6 Recrystallization from MeOH/iPrOH affords the desired HPA in 97-98 % purity with 1-2 % contamination with the unwanted NH-substituted regioisomer and a total 65 % isolated yield. 6 An assessment was undertaken to investigate the choice of catalyst, solvent, catalyst loading and reaction time on the product yield. The insolubility of adenine in most solvents restricts the solvent choice to high boiling point polar aprotic solvents; DMF, NMP and DMSO and were screened against several catalysts including NaOH, KOH, K 2 CO 3 , (n-Bu) 4 NHOH, LiOH and TsOH.…”

“…Unfortunately product recovery was poor when using DMSO or NMP as solvent. In contrast, when performed in DMF, HPA (6) can be readily precipitated from the reaction mixture.…”

“…Isolation of pure HPA using the CHAI work-up and purification protocol 6 then afforded a 65 % yield of HPA with trace amounts of the unwanted regioisomer. …”