药物合成反应实验讲义天津工业大学环境与化学工程学院制药工程专业2011年9月10日实验1、氯代叔丁烷的制备[实验目的]1.了解叔醇的卤代反应机理。
2.掌握卤化剂的种类及特点。
[反应式]C CH 3H 3C OH 3+ HClC CH 3H 3C ClCH 3+ H 2O[试剂]叔丁醇：5g 浓盐酸：16.5mL 碳酸氢钠（5%）：30mL 无水硫酸镁[实验操作]在配有搅拌、温度计、回流冷凝器的100mL 的三颈瓶中，加入叔丁醇5g 、浓盐酸16.5mL ，开动搅拌，室温下反应1小时，分出有机层，以5%碳酸氢钠洗涤两次(15mL ×2），以无水硫酸镁干燥0.5小时后，进行常压蒸馏，收集50-53℃的馏份，得产品为无色透明液体。
[思考题]1．本实验中采用5%碳酸氢钠洗涤的目的是什么？2．是否可以采用其它氯化剂？The preparation of t -butyl chloride［Aim ］To comprehend the characteristics of chlorination reaction and chlorination reagents.［Reaction equation］C CH 3H 3C OH 3+ HClC CH 3H 3C Cl3+ H 2O［Reagents］t -Butyl alcohol:5gConcentrated hydrochloric acid:16mL Sodium hydrogen carbonate (5%):30mL ［Procedure］In a 100mL three-neck flask equipped with an efficient stirrer,thermometer,and reflux condenser,place 5g of t -butyl alcohol,16mL of concentrated hydrochloric acid.Stir this solution at room temperature for 1h.Stop stirring and Lay it for a while to form two distinct layers.The organic layer is separated off with separating funnel and washed two times with 5%sodium hydrogen carbonate (15mL ×2),and dried over anhydrous calcium chloride.After the desiccant is filtered off,the product is obtained by the fraction distillation at approximately 50-52℃.［Subjects for Thinking］1.What is the reason for washing organic layer with 5%sodium hydrogen carbonate?2.Except the concentrated hydrochloric acid,what kind of chlorination reagents can also be used in this preparation?实验2、苯氧乙酸的合成[实验目的]熟悉Williamsons醚化反应的方法，了解其在药物化学结构修饰中的应用。
掌握卤代烃的反应活性顺序。
[反应式]2ClCH2COOH+Na2CO2ClCH2COONa H2O CO2ONaClCH2COONa OCH2COONaNaClOCH2COOHHCl+++++[试剂]氯乙酸：3.8g碳酸钠苯酚：2.6g浓盐酸[实验操作]将100mL三口瓶装置在磁力搅拌器上，分别装上球形冷凝器和滴液漏斗，在瓶内加入3.8g氯乙酸和5mL水，缓慢滴加饱和碳酸钠溶液至pH=7-8，然后加入2.6g苯酚，缓慢滴加30%氢氧化钠溶液至pH=12，加热回流半小时。
反应结束后，待反应混合物稍冷却后倒入锥形瓶，边搅拌边滴加浓盐酸酸化至pH=3-4，冷却结晶，析出完全后抽滤，粗产物用冷水洗涤2-3次，干燥称重，计算产率。
[注意事项]氯乙酸具有强刺激性和腐蚀性，能灼伤皮肤，使用时注意不要触及皮肤。
[思考题]1．本实验中滴加碳酸钠的目的是什么？2．反应的后处理过程中加入盐酸的作用是什么？实验3、苯亚甲基苯乙醛酮（查尔酮）的制备[实验目的]了解Aldol 缩合反应的机理、特点及反应条件。
[反应式]NaOH 2CHO COCH 3C H C HO +[试剂]苯甲醛：4.6g 苯乙酮：5.2g 乙醇（95%）：15mL氢氧化钠：2.2g （溶于20mL 水）[实验操作]在配有搅拌、温度计、回流冷凝器及滴液漏斗的100mL 的三颈瓶中，加入氢氧化钠水溶液、乙醇（95%）15mL 及苯乙酮5.2g ，水浴加热到20℃，滴加苯甲醛4.6g ，滴加过程中维持反应温度20-25℃，加毕，于该温度下继续搅拌反应0.5小时，加入少量的查尔酮做晶种，继续搅拌1.5小时，析出沉淀，抽滤、水洗至洗水呈中性，抽干得粗产品，以乙酸乙酯为溶剂重结晶，得精品为浅黄色针状结晶，熔点：55-56℃。
[思考题]1．本实验中可能的副反应有哪些？怎样可以避免？2．为什么该产品析晶较困难？The preparation of Benzalacetophenone(Chalcone)［Aim ］To comprehend the mechanism,characteristics and reaction conditions of Aldol reaction.［Reaction equation］2CHO COCH 3C H C HC O +［Reagents］Benzaldehyde:4.6g Acetophenone:5.2g Ethanol(95%):15mLSodium hydroxide:2.2g (in 20mL of water)［Procedure］In a 100mL three-neck flask equipped with an efficient stirrer,thermometer,dropping funnel and reflux condenser,place aqueous solution of sodium hydroxide,15mL of ethanol (95%)and 5.2g of acetophenone.Heat this solution to 20℃,and add 4.6g of benzaldehyde slowly with stirring,keeping the reaction temperature 20-25℃,and continue stirring 0.5h after addition at this temperature.Inoculate the mixture with a little powdered benzalacetophenone and continue stirring for additional 1.5h.The crude product is separated by filtration and washed with water.After recrystallization from ethyl acetate,the fine product is obtained,m.p 55-56℃.［Subjects for Thinking］1.Point out the side reaction in this preparation?How can we avoid it?2.Please explain the reason why the precipitation process of the product would be difficult.实验4、二苯甲醇的制备[实验目的]了解酮的还原反应机理、还原剂的种类及特点。
[反应式]O OHNaBH4[试剂]二苯酮：3.0g硼氢化钠：0.35g乙醇（95%）：20mL[实验操作]在配有搅拌、温度计、回流冷凝器的100mL的三颈瓶中，加入二苯酮3.0g、95%的乙醇20mL，水浴加热至反应物全溶，冷却至室温，搅拌下分批加入硼氢化钠0.35g，加入速度以反应温度保持在50℃以下为宜，加毕，加热反应物至回流反应1小时，冷却到室温，加入20mL水稀释反应液，再加入10%稀盐酸分解未反应的硼氢化钠，待冷却到室温后抽滤，水洗滤饼，抽干得粗产品，以石油醚（b.p30-60℃）为溶剂重结晶可制得精品。
[思考题]1．除了本实验提供的方法外可否采用其他反应途径制备二苯甲醇。
The preparation of Diphenyl carbinol［Aim］To comprehend the characteristics of reduction reaction and reduction reagents.［Reaction equation］O OH4［Reagents］Diphenyl ketone:3.0gSodium borohydride:0.35gEthanol(95%):20mL［Procedure］In a100mL three-neck flask equipped with an efficient stirrer,thermometer and reflux condenser,place3.0g of diphenyl ketone,20mL of ethanol(95%).Heat the flask on water bath. Cool the reaction mixture to room temperature after the solid is dissolved absolutely,then0.35g of sodium borohydride is added in portions by controlling the temperature below50℃.After addition,heat the mixture to reflux for1h.Then cool the mixture to room temperature and add 20mL of cold water into it,the excessive sodium borohydride will resolve.Drop10%percent hydrochloric acid to the reaction mixture slowly until sodium borohydride consumed.Cool it to room temperature and filter,wash the filtrate with water and dry it.The product may be recrystallized from ether(b.p30-60℃).［Subjects for Thinking］1.Can other method be used in this preparation?实验5 1.2-苯并吡喃酮的合成[实验目的]掌握Knoevenagel 反应制备香豆素的原理。