(±)-3-氨甲基-5-甲基己酸的合成

Synthesis of(±)-3-Aminomethyl-5-methylhexanoic Acid

本研究对普瑞巴林的重要中间体(±)-3-氨甲基-5-甲基己酸的合成工艺进行改进。丙二酸与异戊醛缩合后,再经酯化得5-甲基-2-己烯酸乙酯(3)。3 空间位阻小,易于与丙二酸二乙酯发生加成反应。加成反应后直接水解得3-异丁基戊二酸,再经脱水和氨解得(±)-3-氨甲酰甲基-5-甲基己酸,最后经Hofmann 重排得目标物,总收率60.3%。本工艺在优化Hofmann 重排时发现,反应温度对收率影响较大。加入次溴酸钠后,反应温度会升高至75~85℃,此时不可干预降温,应保持该温度使其自行降温,然后再加热至80~85℃反应2 h,收率高(88%)。本工艺操作简便、总收率高(60.3%),已通过中试验证。

The synthetic process of (±)-3-aminomethyl-5-methylhexanoic acid, an important intermediate of pregabalin, was improved. Malonic acid was subjected to a condensation with isovaleraldehyde and a esterification to give ethyl 5-methyl-2-hexenoate(3). Due to the small steric hindrance of 3, it was easy to carry out the addition with diethyl malonate, which was followed by a hydrolysis directly to afford 3-isobutylpentanedioic acid. Then, the latter was subjected to dehydration, ammonia hydrolysis, and Hofmann rearrangement to prepare the target compound with a total yield of 60.3%. When the Hofmann rearrangement was optimized, it was found that the reaction temperature had a great influence on the yield. When sodium hypobromite was added, the reaction temperature gone up to 75-85 ℃. Then, the temperature should be maintained and be lowered by itself. And then, the reaction temperature was raised again to 80-85 ℃ for 2 hours, a high yield(88%) was obtained for the target compound. This process was simple to operate and has high yield, and it has been tested in pilot scale.