Stereoselective Synthesis of Mirogabalin via 1,4-Selective Addition of Lithioacetonitrile to Alkylidene Malonate

The synthesis of mirogabalin was studied for industrial production, and an alternative to the Daiichi–Sankyo’s method was established. The developed synthesis involves the introduction of a two-carbon unit with the stereoselective 1,4-selective addition of lithioacetonitrile to alkylidene malonate and one-carbon degradation by Hofmann rearrangement. The precursor for the Hofmann rearrangement was readily prepared from the 1,4-adduct via a one-pot reaction involving decarboxylation, hydrolysis, and hydration.