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

Abstract

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

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

“…At 60 °C, dealkylation was already complete after 2 h. The pH was adjusted to 2.8–3.0 with NaOH solution to precipitate PMPA·H 2 O, which was dried afterward, as described in the literature. 10 On a 1 g scale, the conversion of HPA was slightly higher when using 1.7 equiv of 14 instead 1.5 equiv, while the isolated yields were similar (64 and 65%, respectively, Table 5 , entries 1 and 2). Despite the high conversions of HPA, large amounts of PMPA·H 2 O did not precipitate and remained in the mother liquor.…”

“…Derstine et al have carefully observed that NaCl, which forms during pH adjustment, has a large effect on keeping PMPA in solution. 10 Therefore, in a further experiment, aqueous H 2 SO 4 was used for dealkylation and the pH was adjusted with conc. aqueous NH 3 (25 wt %) in order to see how (NH 4 ) 2 SO 4 formation affects the solubility of PMPA.…”

“…In the case of tosylate 13 , the method affords an alternative to the recently reported synthesis by Derstine et al , where the diethyl ester 5 was dealkylated with TMSBr. 10 …”