酮基布洛芬的合成工艺研究及手性拆分

发布时间：2018-06-10 11:22

本文选题：非甾体抗炎药 + 酮基布洛芬　；参考：《浙江理工大学》2017年硕士论文

【摘要】：酮基布洛芬作为一种优良的非甾体抗炎镇痛药,具有剂量小、疗效高、副作用少等特点。当前酮洛芬生产中所面临的因生产技术落后引起的制备成本高和污染严重等问题引起了业内的高度关注和重视。随着有机化工方法学的发展,对原有的合成路线进行改进以及开发出工艺路线简便、条件温和、生产绿色环保的新工艺具有非常大的经济价值和一定的学术意义。本论文在参考文献基础上对酮基布洛芬的合成路线进行了改进和优化。即以间苯二甲酸为原料,采用一锅法连续投料的方式,通过氯化、单酯化、缩合步骤生成间甲氧羰基苯甲酰丙二酸二乙酯,然后水解脱羧为间乙酰基苯甲酸,收率为68.3%;间乙酰基苯甲酸先经氯化,然后和苯在三氯化铝作用下发生Friedel-Crafts反应得到间乙酰基二苯甲酮,收率为80.5%;间乙酰基二苯甲酮在异丙醇钠和氯乙酸乙酯作用下发生Darzens反应得到3-苯甲酰基-α-甲基苯乙醛,收率为64.3%;最后经H_2O_2-N_aClO_2氧化得到酮基布洛芬,收率为82.4%。该合成方法的总收率为29.1%。该方法与原路线相比操作更流畅,反应条件更温和。同时本论文又探索出了一种新的工艺路线:以对氨基苯丙酮为原料,经间氯过氧苯甲酸氧化得到对硝基苯丙酮,收率为85.4%;然后经乙二醇保护,在苯乙腈和氢氧化钠作用下成环,再在铁粉和盐酸作用下还原开环得到4-氨基-3-苯甲酰基苯丙酮,收率为76.4%;4-氨基-5-苯甲酰基苯丙酮再经去氨基化得到3-苯甲酰基苯丙酮,收率为81.3%;3-苯甲酰基苯丙酮经溴化得到2-溴-3'-苯甲酰基苯丙酮,收率为90.2%;2-溴-3'-苯甲酰基苯丙酮与新戊二醇发生缩酮化反应得到2-溴-3'-苯甲酰基苯丙酮新戊二醇缩酮,收率为75.2%;2-溴-3'-苯甲酰基苯丙酮新戊二醇缩酮再在乙酸钾作用下发生1,2-芳基重排,最后直接水解得到酮基布洛芬,收率为77.6%。该新工艺路线的总收率为27.9%,操作简便,后处理简单。此外,本论文还对葡辛胺和S-α-苯乙胺两种拆分剂拆分外消旋酮基布洛芬的工艺进行了进行了初步探究。本论文的目标产物和它所涉及的中间体的相关图谱数据均符合各化合物的结构特征。
[Abstract]:Ketoprofen is an excellent non-steroidal anti-inflammatory analgesics with low dose, high efficacy and less side effects. At present, ketoprofen production is faced with the problems of high production cost and serious pollution caused by backward production technology, which has aroused great concern and attention in the industry. With the development of organic chemical industry methodology, it is of great economic value and academic significance to improve the original synthetic route and develop a simple and mild process for the production of green and environmental protection. The synthesis route of ketoprofen was improved and optimized on the basis of reference. Using isophthalic acid as raw material, a one-pot method of continuous feeding was used to produce diethyl m-methoxycarbonyl benzoyl malonate by chlorination, monoesterification, condensation, and then hydrolysis decarboxylation to m-acetylbenzoic acid. The yield of m-acetylbenzoic acid was 68.3%. The m-acetyl benzophenone was synthesized by Friedel-Crafts reaction with benzene under the action of aluminum trichloride. The yield was 80.5; the Darzens reaction of m-acetylbenzophenone with sodium isopropanol and ethyl chloroacetate gave 3benzoyl 伪 -methylphenylacetaldehyde in 64.3% yield; finally, ketoprofen was oxidized by H2O2-NaClO2 to ketoprofen in 82.4%. The overall yield of the synthetic method is 29.1g. Compared with the original route, the method operates more smoothly and the reaction conditions are more mild. At the same time, a new technological route was explored: p-nitrophenylacetone was oxidized by m-chloro-peroxybenzoic acid, and the yield was 85.4%, then was protected by ethylene glycol to form ring under the action of acetonitrile and sodium hydroxide. Under the action of iron powder and hydrochloric acid, 4-amino-3-benzoyl acetone was obtained by ring opening. The yield of 4amino-5-benzoyl acetone was 76.4. The 3-benzoyl benzoacetone was synthesized by deaminination of 4-amino-5-benzoyl acetone. The yield of 2-bromo-3-benzoyl phenylacetone was 81.3%, and the yield was 90.2%. The reaction of 2-bromo-3-benzoyl phenylacetone and neopentanediol was carried out in the yield of 90.2% to give 2-bromo-3-benzoyl acetone new pentanediol Ketal, and the yield was 90.2%, and the yield was 90.2% for the Ketal reaction between 2-bromo-3-benzoyl-benzoyl phenylacetone and neopentanediol (neopentanediol). The yield was 75.2 / 2 / 2-bromo-3-benzoylbenzoyl acetone neopentanediol Ketal was rearranged with potassium acetate, finally ketoprofen was directly hydrolyzed to give ketoprofen in the yield of 77.6%. The total yield of the new process is 27.9, the operation is simple and the post-treatment is simple. In addition, the separation of racemic ketoprofen with two resolution agents, glucoctylamine and S- 伪 -phenylethylamine, was studied. Both the target product and the related spectra of the intermediates are in accordance with the structural characteristics of the compounds.
【学位授予单位】：浙江理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ463

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