Preparation of the HIV Attachment Inhibitor BMS-663068. Part 8. Installation of the Phosphonoxymethyl Prodrug Moiety

The reaction optimization of an alkylation to enable the production of the penultimate intermediate of an HIV-attachment inhibitor candidate is described. To address the challenges associated with the reactivity and stability of di-tert-butyl (chloromethyl) phosphate (2), and the poor solubility and reactivity of the starting BMS-626529-Li salt (1), strategic selection of Et4NI and 325 mesh K2CO3 as additives, and wet CH3CN as solvent were required. An aqueous workup protocol was also developed to selectively remove an undesired N-6 alkylation isomer. The final processing conditions resulted in the isolation of the penultimate compound 3 in 70% yield with high purity.