Safety Guided Process Development and Scale-Up of the Highly Energetic Compound 4-Methyl-1,2,5-oxadiazole-3-carboxylic Acid

Abstract

The synthesis of the highly energetic pharmaceutical intermediate 4-methyl-1,2,5-oxadiazole-3-carboxylic acid via cyclization of (2E,3E)-butane-2,3-dione dioxime followed by selective oxidation of the resulting 3,4-dimethyl-1,2,5-oxadiazole was developed to support the sample production for clinical trials. Rigorous process safety evaluations revealed many potential safety risks associated with the involved highly energetic compounds and the high exothermicity of the oxidation reaction. A continuous flow process was developed for the synthesis of 3,4-dimethyl-1,2,5-oxadiazole to mitigate the potential safety risks associated with the thermal instability of starting material (2E,3E)-butane-2,3-dione dioxime and product 3,4-dimethyl-1,2,5-oxadiazole. A much safer process for the highly exothermic oxidation of 3,4-dimethyl-1,2,5-oxadiazole involving portion-wise addition of potassium permanganate was developed to avoid accumulation of reactive chemicals. The desired product was isolated as N-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to avoid handling of potentially explosive 4-methyl-1,2,5-oxadiazole-3-carboxylic acid in its solid form. The developed process was successfully scaled up to afford a total of 93.52 kg of N-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to support the production of a drug substance.