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)

There is an urgent demand for 5‐fluorocytosine (5‐FC) due to its activity against HIV‐induced fungal infections as well as its use as a key intermediate in the synthesis of the clinically highly important anti‐HIV drug emtricitabine (FTC). We report a simple, low‐cost five steps synthesis of 5‐FC starting from chloroacetamide. Overall yields up to 46 % were achieved and the route is devoid of any chromatographic purifications. The previously unknown key intermediate (Z)‐2‐cyano‐2‐fluoroethenolate is obtained through a Claisen‐type condensation from fluoroacetonitrile. As the direct cyclization with urea only gave poor yields, 5‐fluoro‐2‐methoxypyrimidin‐4‐amine, 5‐fluoro‐2‐(methylsulfanyl)pyrimidin‐4‐amine and 5‐fluoropyrimidine‐2,4‐diamine served as synthetic intermediates.

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<p>Abstract: Herein, we report further improvements to the synthesis of tenofovir <b>1</b>, the precursor to tenofovir disoproxil fumarate and tenofovir alafenamide fumarate. Starting from acyclic precursor diaminomalononitrile <b>12</b>, a four-step protocol to tenofovir <b>1 </b>will allow for vertical integration for more manufacturers. The key transformation is a more convergent one step procedure from <b>6</b> 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 <i>tert</i>-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.</p>

<p>Abstract: Herein, we report further improvements to the synthesis of tenofovir <b>1</b>, the precursor to tenofovir disoproxil fumarate and tenofovir alafenamide fumarate. Starting from acyclic precursor diaminomalononitrile <b>12</b>, a four-step protocol to tenofovir <b>1 </b>will allow for vertical integration for more manufacturers. The key transformation is a more convergent one step procedure from <b>6</b> 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 <i>tert</i>-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.</p>