Process Development of the Novel LpxC Inhibitor T-1228. Part 2: Synthesis of the Malonamide Core and the Final Intermediate

The novel LpxC inhibitor T -1228 is a candidate drug molecule for multidrug-resistant Gram-negative bacterial infection. This report describes the synthesis of the malonamide derivative,(2 S )-2-(4-iodo- N -methylbenzamido)- N 1,2-dimethyl- N 3 -((tetrahydro-2 H -pyran-2-yl)oxy)malonamide, containing the quaternary stereogenic core of the novel LpxC inhibitor T -1228 from commercially available diethyl 2-bromo-2-methylmalonate in 8 steps and 2 isolation. The quaternary stereogenic center of the malonamide core was created via enzymatic desymmetrization, by treating the malonic ester derivative, diethyl 2-(((benzyloxy)carbonyl)(methyl)amino)-2-methylmalonate, with porcine liver esterase. To control impurities that could negatively affect the quality of the drug substance, a novel approach for producing the final intermediate, ( S )-2-(4-((4-(( S )-2,2-dimethyl-1,3-dioxolan-4-yl)phenyl)ethynyl)- N -methylbenzamido)- N 1 -hydroxy- N 3,2-dimethylmalonamide, was also developed, in which a selective deprotection reaction was incorporated. Using this newly developed process chemistry route, we have successfully synthesized 38.8 kg of the malonamide derivative and 13.5 kg of the final intermediate.