Synthesis of Methyl 3‑Hydroxyisoxazole-5-Carboxylate Via Bromination of Dimethyl Fumarate under Photoflow Conditions and Its Safe Homologation into 3‑(3-Methoxyisoxazol-5-yl) Propanoic Acid

• Published in: Organic process research & development 2024-05, Vol.28 (5), p.1690-1703
• Main Authors: Bürki, Cédric, Künzli, Marco, Dörrwächter, Patric, Wallquist-Franke, Patrick, Wang, Larry Y., Zhang, Feng, Schäfer, Gabriel
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.3c00334

The route scouting and development activities toward a safe and scalable manufacturing route for 3-(3-methoxyisoxazole-5-yl) propanoic acid are outlined in this article. In a first step, methyl 3-hydroxy-5-isoxazolecarboxylate (CAS: 10068-07-2) was prepared on a kilogram scale via bromination of dimethyl fumarate under photoflow conditions followed by condensation with hydroxyurea. This intermediate was then two-carbon homologated by a sequence of ester reduction, chlorination, and nucleophilic substitution with commercially available triethylmethanetricarboxylate. Subsequently, a double decarboxylation event unveiled the desired building block 3-(3-methoxyisoxazole-5-yl) propanoic acid. During our development activities, a preliminary safety assessment of the intermediates by differential scanning calorimetry revealed that a high thermal decomposition energy was recorded for the isoxazole heterocycle. Therefore, our route scouting activities and isolation strategies needed to be carefully assessed under the guidance of the Oxygen balance/Rule of 6/Explosive functional group/Onset temperature/Scale (OREOS) safety assessment. Finally, to highlight our development activities, a kg-scale campaign demonstrated the scalability of the new route.