The first attempt for the total synthesis of hydrastine was reported by Sir Robert Robinson and co-workers[3] in 1931.

The key step in the Falck synthesis was using a Passerini reaction to construct the lactonic amide intermediate 4.

Starting from a simple phenylbromide variant 1, alkylation reaction with lithium methylisocyanide gives the isocyanide intermediate 2.

The tetrahydro-isoquinolin ring was formed by first a ring-closure reaction under dehydration conditions using POCl3 and then a catalyzed hydrogenation using PtO2 as the catalyst.

Finally, hydrastine was synthesized by installing the N-methyl group via reductive amination reaction with formaldehyde.