【作者】 余疆江；

【导师】 梁渠； 闫书一；

【作者基本信息】 成都理工大学 ， 矿产资源化学， 2010， 硕士

【摘要】 异喹啉及其衍生物是一类重要的医药化工中间体,以它为先导合成的化合物具有多种药理作用。不但具有降压、抗心律失常、抗炎、降血糖等作用,还能够替代吗啡作为镇痛药物进行使用。因此异喹啉及其衍生物是目前国内外研究的热门方向。本文旨在提供一种异喹啉衍生物中间体的合成方法。以苯丙酮为起始原料,依次经过硝化、还原、重氮化、水解、Williamson反应、Mannich反应得到目标产物——1-(3-甲氧苯基)-2-甲基-3-二甲氨基-1-丙酮。1.对硝化反应进行了实验改进,改变了以往高温高压硝化的方法,探索使用了低温常压硝化合成法。这是本文的创新点所在。通过条件实验,得出了苯丙酮在常压条件下硝化反应的最佳温度和最佳混酸[n(硫酸)/n(硝酸)]配比。即在温度低于-5℃,混酸比大于5的条件下产物产率达到85 %。2.对3-硝基苯丙酮的还原条件进行了探讨,最终选用硫化钠作为还原剂来还原3-硝基苯丙酮。通过条件实验,得出了3-硝基苯丙酮的最佳还原条件。即在n(硫化钠):n(3-硝基苯丙酮)为2:1,反应时间大于4 h的条件下,3-氨基苯丙酮的产率为73 %。3.3-氨基苯丙酮的重氮化反应是在水溶液中进行的,得到的重氮盐不必从水溶液中分离纯化,进行加热分解后即得到3-羟基苯丙酮。通过条件实验,得出了3-氨基苯丙酮的最佳重氮化条件。即反应温度在0℃,n(硫酸)/n(3-羟基苯丙酮)为4:1时,产物产率为84 %。4.利用Williamson反应可将3-羟基苯丙酮合成3-甲氧基苯丙酮。通过条件实验,得出了Williamson反应的最佳条件:反应温度70~75℃,反应时间3 h,反应溶剂为DMSO,产物产率为82 %。5.利用Mannich反应可以得到目标产物1-(3-甲氧苯基)-2-甲基-3-二甲氨基-1-丙酮(T·M·)。通过条件实验,得出了Mannich反应的最佳反应条件。即反应温度为70℃;反应物的摩尔比,n(3-甲氧基苯丙酮):n(甲醛):n(二甲胺盐酸盐)为1:1:1;反应时间16 h;盐酸的用量为6倍于T·M·,产物产率为86 %。更多还原

【Abstract】 Isoquinoline and its derivatives are an important class of pharmaceutical and chemical intermediate, by which many compounds are synthesized. These compounds have lots of pharmacological effects, which include blood pressure, anti-arrhythmia, anti-inflammatory, blood sugar lowering and even can replace morphine as an analgesic drugs. The research of isoquinoline is the hot topic both at home and abroad. The intent of this paper is to provide a synthesis method of intermediate of isoquinoline derivatives. First of all, propiophenone is selected as the starting material, then the target products, 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1 -one, can be synthesized by six steps which include nitration, reduction, diazotization, hydrolysis, Williamson reaction, Mannich reaction.1. Some experimental improvement has been used for the nitration. The low temperature and common pressure condition have been explored to instead of high temperature and high pressure condition for the nitration. Such is where the innovation of this paper. From the condition experiment, the optimum reaction temperature and the optimum ratio of mixture acid [n(Sulfuric acid)/n(Nitrate)] are obtained. that is, the temperature is lower than -5℃, the molar ratio of mixture acid is greater than 5, the yield will up to 85 %.2. Reduction condition of 1-(3-nitrophenyl)propan-1-one have been discussed firstly, then sodium sulfide has been chosen for reductive reagent. From the condition experiment, the optimum reducing conditions are founded. that is, the molar ratio of sodium sulfide to 1-(3-nitrophenyl)propan-1-one is 2:1, the reaction time is greater than 4 h, the yield of 1-(3-aminophenyl)propan-1-one will up to 73 %.3. The diazotization of 1-(3-aminophenyl)propan-1-one is carried out in the water. The diazonium salt which is produced from diazotization should not be separated from the water, and can be decomposed directly to the 1-(3-hydroxyphenyl)propan-1-one with heating. From the condition experiment, the optimum diazotizating conditions are achieved. That is, the temperature is maintained at 0℃, the molar ratio of sulfuric acid to 1-(3-hydroxyphenyl)propan-1-one is 4:1, the yield will up to 84 %.4. 1-(3-methoxyphenyl)propan-1-one can be got from Williamson reaction. From the condition experiment, the optimum Williamson reaction conditions are acquired. That is, the reaction temperature is maintained at 70~75℃, the reaction time is greater than 3 h and the reaction solvent is DMSO, the yield will up to 82 %.5. The traget compounds of 3-(dimethylamino)-1-(3-methoxyphenyl)-2- methylpropan-1-one (T·M·) can be produced by Mannich reaction. From the condition experiment, the optimum Mannich reaction conditions are attained. That is, the temperature is maintained at 70℃, the molar ratio of reactants [n(1-(3-methoxyphenyl)propan-1-one):n(formaldehyde):n(dimethylamine hydrochlo- ride)] is 1:1:1, the reaction time is greater than 16 h, the use level of hydrochloric acid is six times than T·M·, the yield will up to 86 %.更多还原