Process Development toward a Pro-Drug of R‑Baclofen

This paper describes the process development conducted toward the multi-kilogram synthesis of a novel transported pro-drug of R-baclofen. The key steps in the synthesis were the enzyme-catalyzed kinetic resolution of isopropyl­(methylthiocarbonyloxy)­methyl-2-methylpropionate using Candida antarctica lipase A to provide the desired (S)-enantiomer. This was followed by the reaction with sulfuryl chloride and N-hydroxysuccinimide to produce (S) 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate. The synthesis of (S) 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate enabled the efficient use of R-baclofen in the final coupling stage of the synthesis. The new route reported here is more efficient and sustainable than those reported previously and had the potential to become the commercial route of manufacture.