药物合成反应(闻韧_第三版)第三章课后答案Chapter_3_Acylation_Reaction

《药物合成反应》（第三版） 闻韧主编 习题及答案 第三章 酰化反应习题及答案 1. 根据以下指定原料、试剂和反应条件，写出其合成反应的主要产物 (1) OH O O + AcONa (2) C17H35COOC2H5 + (COOC2H5)2 C2H5ONa C2H5OH heat (3) H2N OH Cl Cl O O + Et3N/CH2Cl2 (4) OH OH O ClCl + NaOH (5) S + O N HPh CH3 POCl3 (6) O OH H OH H NHAcH OH CH2OH CH3COCl CHCl3 (7) HO AC2O/Py (8) O O C2H5O OC2H5 + NaH/PhH (9) N Boc OH O + HN DCC/CH2Cl2 (10) Br O Br + NH2OH 1 gusx 打字机 武汉 工程 路基工程安全技术交底工程项目施工成本控制工程量增项单年度零星工程技术标正投影法基本原理 大学 化工与制药学院 《药物合成反应》（第三版） 闻韧主编 习题及答案 1. 根据以下指定原料、试剂和反应条件，写出其合成反应的主要产物（参考答案） 题号 答案 注释 (1) O-t-Bu O O (2) C16H33 CH CO2Et CO2Et (3) N H N H OH O O HO Org. Synth., 2006, 83: 97. (4) O O O (5) S CHO (6) O OAc H Cl H NHAcH OAc CH2OAc (7) AcO (8) O CO2Et (9) N O N Boc DCC: 二环己基碳二酰亚胺， dicyclohexylcarbodiimide Boc: 叔丁氧羰基， tert-Butoxycarbonyl (10) Br NH2 O 2 《药物合成反应》（第三版） 闻韧主编 习题及答案 2. 在下列指定原料和产物的反应式中分别填入必需的化学试剂（或反应物）和反应条件。 (1) OH O OCOPh O OH O O O O (2) O O C2H5O2C CO2C2H5 O O (3) H3CO H3CO NH2 H3CO H3CO N O O (4) OH OH CHO (5) N N H CN Ph O N H3C CN Ph O N CH3 (6) O N N N CO2CH3CO2CH3 O CO2CH3 (7) NHCOCH3 H3CO H3CO N H3CO H3CO CH3 N H3CO H3CO CH2 COCH3 (8) HN CO2C(CH3)3 N CO2C(CH3)3PhC O N O COPh H H 3 《药物合成反应》（第三版） 闻韧主编 习题及答案 (9) O N O O (CH2)8 O O O (10) OH NH2 O H N O O N O O 2. 在下列指定原料和产物的反应式中分别填入必需的化学试剂（或反应物）和反应条件。（参考答案） 题号 答案 注释 (1) 1. PhCOCl, C5H5N; 2. glycerol, △ (2) 1. 2(CH2CO2Et)2, NaOEt, EtOH, △; 2. H2O, 185~195℃ (3) O O O H H (4) CHCl3, NaOH, EtOH, △ (5) 1. PhCOCl; KOH, H2O; 2. PhLi, CH3I, Et2O, dioxane, -10℃; 3. KOH, EtOH, H2O, △ (6) 1. pyrrolidine, p-TsOH, xylene; 2. HC≡CCO2Me, Et2O; 3. H3O+ Pyrrolidine: 四氢吡咯 (7) 1. POCl3, toluene, △; 2. Ac2O, pyridine, 90~95℃ (8) 1. PhCOCl, pyridine, CH2Cl2; 2. H2SO4, 0→30℃ (9) 1. OHN , p-TsOH, toluene, △; 2. Cl (CH2)8 Cl O O , Et3N, CHCl3, 35℃ p-TsOH: 对甲苯磺酸 (10) 1. (EtO)2CO, NaOMe; 2. Ac2O, NaOAc 3. 阅读（翻译）以下有关反应操作的原文，请在理解基础上写出：（1）此反应的完整反应式（原料、试剂 和主要反应条件）；（2）此反应的反应机理（历程）。 (1) The procedure for 2-Methyl-4-ethoxalylcyclopentane-1,3,5-trione A solution of sodium ethoxide is prepared in a 2-l. three-necked, round-bottomed flask fitted with a mercury-sealed stirrer, a reflux condenser carrying a drying tube, and a stopper by the addition of 69.0 g. (3 moles) of sodium to 950 ml. of absolute ethanol. The solution is cooled to 0–5° in an ice bath and stirred. The stopper is replaced by a dropping funnel, and a cold mixture (5–15°) of 108 g. (1.50 moles) of freshly distilled 2-butanone and 482 g. (3.30 moles) of diethyl oxalate (Note 1) is added gradually over a period of 30 minutes. After the 4 《药物合成反应》（第三版） 闻韧主编 习题及答案 addition is complete, the thick, orange-red mixture is allowed to warm with continued stirring to room temperature, heated under reflux for 30 minutes, and cooled again to 0° in an ice bath. The mixture is decomposed by stirring with 165 ml. of sulfuric acid (1:1 by volume) added in portions. The sodium sulfate formed is filtered by suction and washed with ethanol (150–200 ml.) (Note 2). The washings and filtrate are combined and concentrated by evaporation at room temperature for 3–4 days in two wide-mouthed (6-in.) 1-l. crystallizing basins (Note 3). The yellowish brown product which accumulates by slow crystallization is collected by filtration, washed with small quantities of ice-cold water, and dried in air. The crude product weighs 140–150 g. Further evaporative concentration of the mother liquor followed by cooling furnishes an additional 40–50 g. of the keto ester, bringing the total yield to 180–200 g. (53–59%) (Note 2). This crude material (m.p. 120–130°) is used in the next step. A pure sample can be obtained by crystallization from ethyl acetate after treatment with Norit activated carbon, m.p. 160–162°. (2) The procedure for 2-pyrrolealdehyde In a 3-l. three-necked round-bottomed flask, fitted with a sealed stirrer, a dropping funnel, and a reflux condenser, is placed 80 g. (1.1 moles) of dimethylformamide (Note 1). The flask is immersed in an ice bath, and the internal temperature is maintained at 10–20°, while 169 g. (1.1 moles) of phosphorus oxychloride is added through the dropping funnel over a period of 15 minutes. An exothermic reaction occurs with the formation of the phosphorus oxychloride-dimethylformamide complex. The ice bath is removed, and the mixture is stirred for 15 minutes (Note 2). The ice bath is replaced, and 250 ml. of ethylene dichloride is added to the mixture. When the internal temperature has been lowered to 5°, a solution of 67 g. (1.0 mole) of freshly distilled pyrrole in 250 ml. of ethylene dichloride is added through a clean dropping funnel to the stirred, cooled mixture over a period of 1 hour. After the addition is complete, the ice bath is replaced with a heating mantle, and the mixture is stirred at the reflux temperature for 15 minutes, during which time there is copious evolution of hydrogen chloride. The mixture is then cooled to 25–30°, and to it is added through the dropping funnel a solution of 750 g. (5.5 moles) of sodium acetate trihydrate (Note 3) in about 1 l. of water, cautiously at first, then as rapidly as possible. The reaction mixture is again refluxed for 15 minutes, vigorous stirring being maintained all the while (Note 4). The cooled mixture is transferred to a 3-l. separatory funnel, and the ethylene dichloride layer is removed. The aqueous phase is extracted three times with a total of about 500 ml. of ether. The ether and ethylene chloride solutions are combined and washed with three 100-ml. portions of saturated aqueous sodium carbonate solution, which is added cautiously at first to avoid too rapid evolution of carbon dioxide. The non-aqueous solution is then dried over anhydrous sodium carbonate, the solvents are distilled, and the remaining liquid is transferred to a Claisen flask and distilled from an oil bath under reduced pressure (Note 5). The aldehyde boils at 78° at 2 mm.; there is very little fore-run and very little residue. The yield of crude 2-pyrrolealdehyde is 85–90 g. (89–95%), as an almost water-white liquid which soon crystallizes. A sample dried on a clay plate melts at 35–40°. The crude product is purified by dissolving in boiling petroleum ether (b.p. 40–60°), in the ratio of 1 g. of crude 2-pyrrolealdehyde to 25 ml. of solvent, and cooling the solution slowly to room temperature, followed by refrigeration for a few hours. The pure aldehyde is obtained from the crude in approximately 85% recovery. The over-all yield from pyrrole is 78–79% of pure 2-pyrrolealdehyde, m.p. 44–45°. 3. 阅读（翻译）以下有关反应操作的原文，请在理解基础上写出：（1）此反应的完整反应式（原料、试剂 和主要反应条件）；（2）此反应的反应机理（历程）。（参考答案） （1）反应式： 5 《药物合成反应》（第三版） 闻韧主编 习题及答案 反应机理：酮酯（三次）缩合 （2）反应式： 反应机理：傅－克反应（活性芳环的甲酰化） 6