Large-Scale Preparation of 3-Methyl-4H-[1,2,4]oxadiazol-5-one, Potassium or Sodium Salt

Abstract

The development of a safe and practical process for the potassium and sodium salts of 3-Methyl-4H-[1,2,4]oxadiazol-5-one 1A and 1B is described. The focus of the report is how the scale-up issues of the original procedure are overcome, in particular, the thermal hazards of the starting material, hydroxylamine, and the intermediate, acetamidoxime 4. The final process was demonstrated multiple times on a 600-L scale with consistent yields (70%) and purities (95%).

Process Research Towards a Scalable Synthesis of the Muscarinic M1 Receptor Subtype Selective Agonist MCD-386

“…The crude Boc-protected ester 11 could be carried forward to the next step without purification. Two improvements were made regarding the oxadiazole formation step; first, the preparation of propionamide oxime was simplified by replacing hydroxylamine hydrochloride with aqueous hydroxylamine, which eliminated salt formation and facilitated slow hydroxylamine addition . Second, highly flammable sodium hydride was replaced with potassium carbonate as the base to promote oxadiazole ring formation.…”

Process Development and Large-Scale Synthesis of a PDE4 Inhibitor

“…Methylamidoxime Preparation and Oxadiazole Synthesis. The first step in the preparation of the oxadiazole 8 is the formation of methylamidoxime 8a from hydroxylamine and acetonitrile. , This step is complicated by the energetic nature of the starting material, hydroxylamine, and the product 8a . In the process, acetonitrile is heated to 70−72 °C and a 50 wt % aqueous solution of hydroxylamine is added slowly over at least 4 h to avoid the accumulation of the reagents.…”

“…CAUTION: Hydroxylamine is a possible mutagen and is known to cause severe skin, eye, and respiratory tract burns. Heating hydroxylamine solutions may result in an exothermic decomposition, see ref .…”