(±)-3-氨甲基-5-甲基己酸的合成
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摘要
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2h,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 to80-85℃ 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.
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 to80-85℃ 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.
引文
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[3]张桂森,杨相平,刘笔锋.普瑞巴林的合成[J].中国医药工业杂志,2007,38(9):617-618.
[4]李景,田铁牛,李秀峰.抗惊厥药物普瑞巴林的合成工艺改进[J].中国药物化学杂志,2007,17(1):44-46.
[2]陈敖,张建军.普瑞巴林的合成[J].中国医药工业杂志,2004,35(4):195-196.
[3]张桂森,杨相平,刘笔锋.普瑞巴林的合成[J].中国医药工业杂志,2007,38(9):617-618.
[4]李景,田铁牛,李秀峰.抗惊厥药物普瑞巴林的合成工艺改进[J].中国药物化学杂志,2007,17(1):44-46.