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.

中文翻译：

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光流条件下富马酸二甲酯溴化合成3-羟基异恶唑-5-甲酸甲酯及其安全同系化为3-(3-甲氧基异恶唑-5-基)丙酸

本文概述了 3-(3-甲氧基异恶唑-5-基)丙酸安全且可扩展的生产路线的探索和开发活动。第一步，通过富马酸二甲酯在光流条件下溴化，然后与羟基脲缩合，制备公斤级的 3-羟基-5-异恶唑甲酸甲酯（CAS：10068-07-2）。然后通过一系列酯还原、氯化和用市售的甲烷三甲酸三乙酯进行亲核取代，将该中间体进行二碳同系化。随后，双重脱羧事件揭示了所需的结构单元 3-(3-甲氧基异恶唑-5-基)丙酸。在我们的开发活动中，通过差示扫描量热法对中间体进行的初步安全评估表明，异恶唑杂环记录了高热分解能。因此，我们的路线探索活动和隔离策略需要在氧平衡/6规则/爆炸功能组/起始温度/规模（OREOS）安全评估的指导下仔细评估。最后，为了突出我们的开发活动，公斤级的活动展示了新路线的可扩展性。