Preparation of 5-(2-methoxy-4-nitrophenyl)oxazole: A key intermediate for the construction of VX-497

A process for the multigram preparation of 5-(2-methoxy-4-nitrophenyl)oxazole, a key intermediate for the preparation of the hepatitis C drug candidate VX-497 (merimepodib), has been achieved in good yield from a commercially available dye. Early studies focused on the preparation of the requisite aldehyde by the Beech reaction. A second approach utilized a palladium (0)-catalyzed formylation of an aryl diazonium species, which was followed by condensation of the aldehyde with tosylmethyl isocyanide (TosMIC) to provide the required oxazole. This two-step method has been carried out to provide multigram samples of this key intermediate in 75 % overall yield and > 95 % purity from the commercially available Fast Red B tetrafluoroborate salt.