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Herein, we report further improvementsto the synthesis of tenofovir 1, the precursor to tenofovirdisoproxil fumarate (TDF) andtenofovir alafenamide fumarate (TAF). Starting from acyclic precursordiaminomalononitrile 12, a four-step protocol to tenofovir 1 will allow for vertical integration for more manufacturers.The key transformation is a convergent one-step procedure from 6 as compared to the current commercial process, with an improvedyield from 59% (two steps) to 70%. Further improvements include eliminatingthe need for problematic magnesium tert-butoxide(MTB) and significant solvent reduction by avoiding an intermediateworkup. With the costs of HIV/AIDS treatments remaining a barrierfor those most in need, lowering the raw material/processing costsand increasing the security of supply can increase patient access.

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