Mechanochemical Reductive Amination of Aldehydes and Ketones: Solid-State Synthesis of the Antiparkinsonian Drugs Rasagiline and Safinamide

A general two-step, one-pot mechanochemical procedure for carrying out reductive amination under solvent-free conditions is described. The method involves milling the starting materials in stainless steel jar and balls in the presence of zinc chloride and sodium cyanoborohydride, and was applied to a broad range of carbonyl compounds, including aromatic and aliphatic aldehydes and ketones, and also two drug molecules (benzocaine and sulphathiazole) and four natural products (vainillin, menthone, cinnamaldehyde andtryptamine). Its use in target-oriented synthesis was demonstrated by the fully mechanochemical preparation of two active pharmaceutical ingredients, the anti-Parkinson monoamino oxidase B inhibitors rasagiline and safinamide, with improved green metrics in comparison with solution chemistry.