石杉碱甲关键中间体的新方法研究
发布时间：2018-10-10 07:36
【摘要】：石杉碱甲是一种高效的乙酰胆碱酯酶抑制剂。2-甲氧基-6-羟基-7,8-二氢-5-喹啉羧酸甲酯是合成石杉碱甲的关键中间体，本文综述了该中间体已有的合成方法，在此基础上提出并验证了自己的新合成方法。 (1):以1,4-环己二酮缩乙二醇为起始原料，用N,N-二甲基甲酰胺二甲基缩醛在羰基的α位进行取代。取代产物在氰基乙酸甲酯的作用下关环，，此反应为本路线的创新点。关环产物通过已知的方法得到中间体化合物1。 (2):以2-甲氧基-6-甲基吡啶为原料，与1,3-二溴-5,5-二甲基海因反应，得到3-溴代吡啶衍生物。吡啶衍生物再进一步与N-溴代丁二酰亚胺（NBS）反应，得到多溴代的混合物。通过与亚磷酸二乙酯还原生成3-溴-2-(溴甲基)-6-甲氧基吡啶。乙酰乙酸甲酯与碱作用生成双负离子，端基碳上的负离子优先与3-溴-2-(溴甲基)-6-甲氧基吡啶反应得到化合物(3-溴-6-甲氧基吡啶-2-基)-3-羰基戊酸甲酯，这步反应是本路线的创新点。化合物(3-溴-6-甲氧基吡啶-2-基)-3-羰基戊酸甲酯经钯或CuI/氨基酸催化关环得到所需的化合物1。这步反应是本路线的另一创新之处。 总之，两种新的合成方法都避免了易致敏试剂丙炔酰胺的使用；相对于方法一,方法二避免了碳酸银等贵试剂的使用，且路线较短，收率稳定，总收率为46%。
[Abstract]:Huperzine A is a highly effective inhibitor of acetylcholinesterase. Methyl 2-methoxy-6-hydroxy-7-dihydro-5-quinoline carboxylate is the key intermediate for the synthesis of Huperzine A. On this basis, a new synthetic method is proposed and validated. The results are as follows: (1) using 1-hexamethylene glycol as starting material, N-dimethylformamide dimethyl acetal was substituted at the 伪 -site of carbonyl group. The substitution product under the action of methyl cyanoacetate, this reaction is the innovation point of this route. Intermediate 1 was obtained by the known method. (2) 3-bromopyridine derivatives were synthesized by the reaction of 2-methoxy-6-methylpyridine with 1-dibromo-5-dimethyl hydantoin. Pyridine derivatives further reacted with N-bromosuccinimide (NBS) to obtain a polybrominated mixture. 3-bromo-2-(bromomethyl)-6-methoxy pyridine was synthesized by reduction with diethyl phosphite. Methyl acetoacetate reacted with alkali to form dianion, and the anion on the terminal carbon preferentially reacted with 3-bromo-2- (bromomethyl) -6-methoxy pyridine to form a compound (3-bromo-6-methoxypyridyl-2-yl) -3-carbonyl valerate. This reaction is the innovation of this route. The compound (3-bromo-6-methoxy pyridine-2-yl) -3-carbonyl valerate was synthesized by palladium or CuI/ amino acid catalyzed ring closure. This reaction is another innovation in this route. In a word, the two new synthetic methods have avoided the use of propylidene, a sensitive reagent, and the second method has avoided the use of expensive reagents such as silver carbonate in comparison with the first method, and the route is relatively short, the yield is stable, and the total yield is 46%.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914
[Abstract]:Huperzine A is a highly effective inhibitor of acetylcholinesterase. Methyl 2-methoxy-6-hydroxy-7-dihydro-5-quinoline carboxylate is the key intermediate for the synthesis of Huperzine A. On this basis, a new synthetic method is proposed and validated. The results are as follows: (1) using 1-hexamethylene glycol as starting material, N-dimethylformamide dimethyl acetal was substituted at the 伪 -site of carbonyl group. The substitution product under the action of methyl cyanoacetate, this reaction is the innovation point of this route. Intermediate 1 was obtained by the known method. (2) 3-bromopyridine derivatives were synthesized by the reaction of 2-methoxy-6-methylpyridine with 1-dibromo-5-dimethyl hydantoin. Pyridine derivatives further reacted with N-bromosuccinimide (NBS) to obtain a polybrominated mixture. 3-bromo-2-(bromomethyl)-6-methoxy pyridine was synthesized by reduction with diethyl phosphite. Methyl acetoacetate reacted with alkali to form dianion, and the anion on the terminal carbon preferentially reacted with 3-bromo-2- (bromomethyl) -6-methoxy pyridine to form a compound (3-bromo-6-methoxypyridyl-2-yl) -3-carbonyl valerate. This reaction is the innovation of this route. The compound (3-bromo-6-methoxy pyridine-2-yl) -3-carbonyl valerate was synthesized by palladium or CuI/ amino acid catalyzed ring closure. This reaction is another innovation in this route. In a word, the two new synthetic methods have avoided the use of propylidene, a sensitive reagent, and the second method has avoided the use of expensive reagents such as silver carbonate in comparison with the first method, and the route is relatively short, the yield is stable, and the total yield is 46%.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914
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3 闫q谒
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