本文選題：非甾體抗炎藥 + 酮基布洛芬��； 參考：《浙江理工大學(xué)》2017年碩士論文

【摘要】：酮基布洛芬作為一種優(yōu)良的非甾體抗炎鎮(zhèn)痛藥,具有劑量小、療效高、副作用少等特點(diǎn)。當(dāng)前酮洛芬生產(chǎn)中所面臨的因生產(chǎn)技術(shù)落后引起的制備成本高和污染嚴(yán)重等問(wèn)題引起了業(yè)內(nèi)的高度關(guān)注和重視。隨著有機(jī)化工方法學(xué)的發(fā)展,對(duì)原有的合成路線進(jìn)行改進(jìn)以及開(kāi)發(fā)出工藝路線簡(jiǎn)便、條件溫和、生產(chǎn)綠色環(huán)保的新工藝具有非常大的經(jīng)濟(jì)價(jià)值和一定的學(xué)術(shù)意義。本論文在參考文獻(xiàn)基礎(chǔ)上對(duì)酮基布洛芬的合成路線進(jìn)行了改進(jìn)和優(yōu)化。即以間苯二甲酸為原料,采用一鍋法連續(xù)投料的方式,通過(guò)氯化、單酯化、縮合步驟生成間甲氧羰基苯甲酰丙二酸二乙酯,然后水解脫羧為間乙�；郊姿�,收率為68.3%;間乙�；郊姿嵯冉�(jīng)氯化,然后和苯在三氯化鋁作用下發(fā)生Friedel-Crafts反應(yīng)得到間乙�；郊淄�,收率為80.5%;間乙�；郊淄诋惐尖c和氯乙酸乙酯作用下發(fā)生Darzens反應(yīng)得到3-苯甲酰基-α-甲基苯乙醛,收率為64.3%;最后經(jīng)H_2O_2-N_aClO_2氧化得到酮基布洛芬,收率為82.4%。該合成方法的總收率為29.1%。該方法與原路線相比操作更流暢,反應(yīng)條件更溫和。同時(shí)本論文又探索出了一種新的工藝路線:以對(duì)氨基苯丙酮為原料,經(jīng)間氯過(guò)氧苯甲酸氧化得到對(duì)硝基苯丙酮,收率為85.4%;然后經(jīng)乙二醇保護(hù),在苯乙腈和氫氧化鈉作用下成環(huán),再在鐵粉和鹽酸作用下還原開(kāi)環(huán)得到4-氨基-3-苯甲�；奖�,收率為76.4%;4-氨基-5-苯甲�；奖俳�(jīng)去氨基化得到3-苯甲�；奖�,收率為81.3%;3-苯甲�；奖�(jīng)溴化得到2-溴-3'-苯甲�；奖�,收率為90.2%;2-溴-3'-苯甲�；奖c新戊二醇發(fā)生縮酮化反應(yīng)得到2-溴-3'-苯甲�；奖挛於伎s酮,收率為75.2%;2-溴-3'-苯甲�；奖挛於伎s酮再在乙酸鉀作用下發(fā)生1,2-芳基重排,最后直接水解得到酮基布洛芬,收率為77.6%。該新工藝路線的總收率為27.9%,操作簡(jiǎn)便,后處理簡(jiǎn)單。此外,本論文還對(duì)葡辛胺和S-α-苯乙胺兩種拆分劑拆分外消旋酮基布洛芬的工藝進(jìn)行了進(jìn)行了初步探究。本論文的目標(biāo)產(chǎn)物和它所涉及的中間體的相關(guān)圖譜數(shù)據(jù)均符合各化合物的結(jié)構(gòu)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 偽 -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- 偽 -phenylethylamine, was studied. Both the target product and the related spectra of the intermediates are in accordance with the structural characteristics of the compounds.
【學(xué)位授予單位】：浙江理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：TQ463

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