An Improved Synthetic Route to Drotaverine and Papaverine Using Substituted Nitrostyrenes as Key Intermediates

An improved synthetic process for isoquinoline-based antispasmodic drugs (drotaverine and papaverine) has been developed that avoids the bulk use of metal cyanides traditionally employed in the preparation of arylacetonitrile intermediates. The industrial-scale synthesis of arylacetonitrile typically involves highly toxic metal cyanides, which pose significant safety and environmental hazards. The improved process replaces the low-yielding arylacetonitrile intermediate with a substituted nitrostyrene, thereby eliminating the need for metal cyanides on the industrial scale. Additionally, the implementation of in situ reactions at the n–1 and n–2 stages, coupled with an aqueous-phase reaction in the initial step, enhances sustainability both economically and environmentally. This approach results in 83% overall yields from substituted nitrostyrene 11 and 55.5% yield of nitrostyrene 11 from catechol 3, concise synthetic route, and reduced use of bulk solvents compared to the previously opted lengthy, lower-yielding routes through nitrile claiming 31% overall yield of nitrile 5 from catechol 3 and 56.5% overall yield from nitrile 5 to the active pharmaceutical ingredient.