Herein, we report further improvements to the synthesis of tenofovir 1, the precursor to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). 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 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 avoiding 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.

中文翻译：

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替诺福韦（PMPA）的有效合成：导致基于替诺福韦的HIV药物的关键中间体

在本文中，我们报告了对替诺福韦1（替诺福韦二富马酸富马酸酯（TDF）和替诺福韦阿拉芬酰胺富马酸酯（TAF）的前体）合成的进一步改进。从无环前体二氨基丙二腈12开始，到替诺福韦1的四步方案将允许更多制造商进行垂直整合。与当前的商业流程相比，关键的转变是从6开始的收敛的一步式过程，产率从59％（两步）提高到70％。进一步的改进包括消除有问题的镁叔叔的需求-丁醇盐（MTB），并通过避免中间处理显着减少溶剂。由于艾滋病毒/艾滋病治疗的费用仍然是最需要帮助的人的障碍，因此降低原材料/加工成本和增加供应安全性可以增加患者的出诊率。