脱羧
化学
卤化
丙酸
甲醇
异恶唑
亲核细胞
有机化学
组合化学
催化作用
作者
Cédric Bürki,Marco Künzli,Patric Dörrwächter,Patrick Wallquist-Franke,Larry Y. Wang,Zhihai Feng,Gabriel Schäfer
标识
DOI:10.1021/acs.oprd.3c00334
摘要
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.
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