Process Development of the Novel LpxC Inhibitor T-1228. Part 3: Optimization of the Deprotection Reaction and the Crystallization for the Final Step of API Synthesis

The novel LpxC inhibitor T-1228 is a candidate drug molecule for multidrug-resistant Gram-negative bacterial infection. We developed a process chemistry route to T-1228. The final step of T-1228 drug substance synthesis consists of a deprotection reaction under acidic conditions and a crystallization process incorporating polymorph control. The process parameters of the deprotection reaction were optimized through a Design of Experiments (DoE) study to limit the formation of a critical impurity. The production method established for the crystallization process was developed by means of process analytical technology (PAT): it controls the quality and particle size of the drug substance and selectively yields only the desired crystal polymorph. By applying the newly developed process chemistry route, we have successfully manufactured T-1228 at 24% total yield from commercially available 1,3-diethyl 2-bromo-2-methylpropanedioate.