New Routes to Antiviral Molnupiravir against SARS-CoV-2 Infection

Molnupiravir is an oral drug against SARS-CoV-2 infection approved by Britain and America in 2021. Currently, the reported synthetic methods of molnupiravir have disadvantages, such as long steps, limited yield and high cost. Efficient methods for the synthesis of molnupirovir through direct acylation of low-price cytidine are developed. In different proportions of aqueous tetrahydrofuran solution, selective isobutyrylation of hydroxyl of cytidine and further 2',3'-deprotection of 2',3',5'-tri-O-isobutyrylcytidine could be realized, which successfully gave 5'-O-isobutyrylcytidine. Finally, N-4-hydroxylation of 5'-O-isobutyrylcytidine yielded molnupirovir. Using this straightforward and high-yielding three-step approach, molnupirovir was obtained from cytidine in 82% overall yield.