Aryl bromide 36 was subjected to Ullman coupling reaction with 3-methyl-1H-1,2,4-triazole using CuI and N,N-dimethylcyclohexanediamine as catalyst and ligand to generate piperazine 37. Residual copper in the reaction was removed by the addition of ammonium pyrrolidine dithiocarbamate (APDTC). The Ullman coupling product was treated with potassium hydroxide (KOH) and then lithium iodide (LiI) hydrate was added to precipitate the target lithium salt 37 in 67% yield. The phosphoryloxymethyl prodrug group was installed on 37 using di-tert-butyl (chloromethyl) phosphate 38 and triethyl sodium (Et4NI) and potassium carbonate (K2CO3). After the reaction, quenching and extraction were carried out by adding toluene, followed by treatment with brine and sodium bisulfate (NaHSO4) to consume the unwanted N-6 isomer byproduct. Through the above steps, the key intermediate 39 was isolated in 70% yield. The final step was the deprotection of the tert-butyl phosphate ester group in 39, which was hydrolyzed by treatment with acetic acid to expose the phosphate group in fostemsavir. The TRIS salt of fostemsavir was precipitated as a white crystalline solid in 88% yield by adding tris(hydroxymethyl)aminomethane (TRIS) in acetonitrile.
