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

Abstract

Herein, we report further improvements to the synthesis of tenofovir 1, the precursor to tenofovir disoproxil fumarate and tenofovir alafenamide fumarate. Starting from acyclic precursor diaminomalononitrile 12, a four-step protocol to tenofovir 1 will allow for vertical integration for more manufacturers. The key transformation is a more convergent one step procedure from 6 as compared to the current commercial process, with an improved yield from 59% (two steps) to 70%. Further improvements include eliminating the need for problematic magnesium tert-butoxide (MTB) and significant solvent reduction by eliminating the need for an intermediate workup. With the costs of HIV/AIDS treatments remaining a barrier for those most in need, lowering the raw material/processing costs and increasing the security of supply can increase patient access. File list (2) download file view on ChemRxiv An_Efficient_Synthesis_of_Tenofovir_(PMPA)_Derstine... (803.91 KiB) download file view on ChemRxiv An_Efficient_Synthesis_of_Tenofovir_(PMPA)_Derstine_... (1.96 MiB)

Di-tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir

“…18−23 Chemoselectivity (triester 10 vs diester 9, Figure 2) also proved to be an issue. 24 Mark and Van Wazer, who focused their investigations on the selective synthesis of tri-tert-butyl phosphite (10), enlightened more details about the reaction of PCl 3 and tertbutanol. They proved that almost only triester 10 forms in the reaction.…”

“…It should be mentioned that only commercial or freshly distilled di-tert-butyl phosphite was used up to this point. When using the crude di-tert-butyl phosphite obtained through the newly developed protocol mentioned above, the purity was 9), tri-tert-butyl phosphite (10), and tri-tert-butyl phosphate (11). determined first by 31 P NMR spectroscopy in order to adjust the amount of paraformaldehyde.…”

“…This very efficient process gave PMPA in 70% yield. 10 It is conspicuous that all reports investigating the challenging synthesis of PMPA focused only on DESMP or the derived free acid 7 as alkylating agents with HPA. One big selling point is of course the fact that DESMP can be made from cheap commodity chemicals and has an industrial well-established process.…”

Orthoesters in heterocycle synthesis

“…One last report detailed a complementary approach to prepare Tenofovir, an HIV/AIDs and hepatitis B drug. 96 In this application, the imidazole ring of the purine was assembled first followed by annulation of the aromatic ring to give the adenine nucleus. Thus, reaction of diaminomaleonitrile (193) was condensed with trimethyl orthoformate in DMF containing catalytic TFA to give formidate 194 (93%).…”

Quality by design‐assisted development of a capillary electrophoresis method for the enantiomeric purity determination of tenofovir

“…TEN is applied in therapy in the form of prodrugs such as tenovovir disoproxil or tenofovir alafenamide either alone or in combination with other antivirals, for example, dolutegravir and lamivudine. Since TEN is the active metabolite as well as the synthetic precursor of tenofovir disoproxil and related prodrugs [3,4], its chiral purity should be controlled in order to ensure the chiral purity of the final product.…”