Novel Synthetic Industrial Approach for Efficient Synthesis of Baclofen via C-C Bond formation

Abstract Baclofen is an active pharmaceutical ingredient (API) used for the treatment of muscle spasticity. We describe our efforts to develop a novel synthetic approach via C-C bond formation and the cost-effective process of Baclofen. The synthesis involved a two-step approach via C-C bond formation using the extensively and commercially available starting material 4-chlorobenzyl cyanide and chloroacetic acid as a reagent in an aprotic solvent, followed by reduction of the nitrile functional group. The synthetic route of baclofen has been demonstrated to be commercially viable, cost-effective, and environmentally friendly. Execution of the developed process led to the isolation of (+) baclofen in an overall yield of 60% at a multi-kilogram scale > 99.5 % HPLC purity. This article also discusses the cost-effectiveness of the process, impurity profiling, material quality, and polymorphic form. Key words Baclofen, polymorph, C- alkylation, Nitrile reduction.