药物化学实验讲义.doc

THE EXPERIMENTS OFMEDICINAL CHEMISTRY（供药学、药剂、制药工程用）实验一 苯佐卡因（Benzocaine）的合成 苯佐卡因为局部麻醉药，外用为撒布剂，用于手术后创伤止痛、溃疡痛、一般性痒等。化学结构式 化学名 对氨基苯甲酸乙酯性 状 白色结晶性粉末，味微苦而麻，熔点8890，易溶于乙醇，极微溶于水。实验目的通过苯佐卡因的合成，了解药物合成的基本过程，掌握酯化反应和还原反应的原理及基本操作。实验原理（主要合成路线）1.还原反应2.酯化反应实验步骤1.对氨基苯甲酸的制备（还原） 称取4g对硝基苯甲酸、9g锡粉加入到100ml三颈瓶中，装上回流冷凝管和滴液漏斗，从漏斗中分批加入20ml浓盐酸，边加料边搅拌，反应立即开始（如有必要可用温火加热至反应发生）。必要时可再微热片刻以保持反应正常进行，反应液中锡粉逐渐减少。当反应接近终点时（约30分钟），反应液呈透明状，稍冷，将反应液倾入250ml烧杯中，加少量水消除留存的锡块固体。反应液冷至室温时，慢慢滴加浓氨水，边滴加边搅拌，使溶液刚好呈碱性。抽滤除去析出的Sn(OH)4沉淀，用少量水洗涤沉淀，合并滤液和洗液（若总体积超过550ml，可在水浴上浓缩）。向滤液中小心地滴加冰醋酸，有白色固体析出。再滴加少量冰醋酸，有更多的固体析出。用蓝色石蕊试纸检验到呈酸性为止。在冷水浴上冷却，过滤得白色固体，晾干后称重，计算产率。2对氨基苯甲酸乙酯的制备（酯化）将自制的2g对氨基苯甲酸放入干燥的100ml圆底瓶中，加入20ml无水乙醇和2.5ml浓硫酸。振摇使混合均匀，投入沸石，装上附有氯化钙干燥管的球形冷凝管，油浴加热回流6080分钟（油浴温度控制在100120）；稍冷，将反应液倾入到85ml水中，在搅拌下，慢慢加入碳酸钠固体粉末（使碳酸钠粉末充分溶解），当液面有少量白色沉淀出现时，慢慢加入10%碳酸钠溶液，将溶液PH值调至呈中性，抽滤得固体产品，用少量水洗涤固体，抽干，干燥，称重，计算产率。3对氨基苯甲酸乙酯的精制将粗品置于装有球形冷凝管的100ml圆底瓶中，加入1015倍（ml/g）50%乙醇，在水浴上加热溶解。稍冷，加入活性炭脱色（活性炭用量视粗品颜色而定），加热回流20分钟，趁热抽滤。将滤液趁热转入烧杯中，自然冷却，待结晶完全后，抽滤，用少量50%乙醇洗涤两次，抽干，干燥，称重，计算收率。思考题1.如何判断还原反应已经结束？为什么？2.酯化反应为什么需要无水操作？Experiment 2SYNTHESIS OF SODIUM PHENYTOINRequirement：To master the synthesis technique of sodium phenytoin.To understand coenzyme chemistry,benzoin condensation,oxidation,benzilic acid rearrang-ement and some other reactions.To learn the purification technique of phenytoin sodium.Experiment：1.Coenzyme Synthesis of Benzoin(i)Materials:thiamine nitrate2g 0.032molH2O4ml95% ethanol 12ml3M Na0H 约3.2ml0.01molbenzaldehyde8ml 0.079mol(ii)Procedure:Dissolve 2g of thiamine nitrate in about 4ml of water in a 100ml round bottom flask equipped with a condenser for reflux. Add 12ml of 95% ethanol and cool the solution by swirling the flask in an ice-water bath. Meanwhile, Place about 3.2 ml of 3M sodium hydroxide solution in a small test tube. Cool this solution in the ice bath also. Then, over a period of about 10 minutes,add the cold sodium hydroxide solution to the thiamine solution. Then adjust the solution to pH 89 using 10% hydrochloric acid. Measure 8ml of benzaldehyde and add it to the reaction mixture. Then heat the mixture gently on a steam bath at 6570 for about 90 minutes. Allow the mixture to cool to room temperature, and then cool the mixture in an ice-water bath. If the product separates as an oil, reheat the mixture until it is once again homogeneous, and then allow it to cool more slowly than before. Scratching of the flask with a glass rod may be required.Collect the product by vacuum filtration using a Buchner funnel. Wash the product with two 20ml portions of 10% ethano1.Weigh the crude product and then recrystallize it from 95% ethanol. Dry and weigh the product, calculate the percentage yield, and determine its melting point(mp 134 to 136).Note:(1)The benzaldehyde used for this experiment must be free of benzoic acid. Benzaldehyde is oxidized easily in air. Dont expose it to the air too long when taking it.(2)Thiamine is a heat sensitive reagent. It should be stored in a refrigerator when not in use. Since it may decompose on heating, you should take care not to heat the reaction mixture too vigorously.Question:(i) Why is sodium hydroxide added to the solution of thiamine nitrate? What is the theoretical quantities of NaOH? What reaction will occur and what compound will produce if we use excess NaOH?(ii)Theoretically, does benzoin have colour?2、preparation of Benzil(i)Materials:Benzoin 3g 0.014molNH4NO3 6.4g 0.08molCuSO4 0.1g80% acetic acid 20ml(ii)procedure:Put all the materials in a flask fitted with a reflux condenser, heat to reflux and keep refluxing for 2 hours. Allow to cool to the room temperature, a layer of oil forms on the surface. Rub the oil against the wall of the flask with a glass rod or introduce some crystal seed to induce crystallizing. Break the crystal then filter with suction on a Buchner funnel. Wash with water until the washings are neutral. Dry the crystal in infrared light. The yellow crystal can be used directly for the next step.Note:Using TLC to observe the procedure of the reaction.3. Preparation of phenytoin or phenytoin Sodium (i)Materialsbenzil 2g0.009mol15% NaOH 6mlurea 0.7g 0.0116mol50% ethanol 10ml(ii)procedure:Equip a flask with a reflux condenser, heat directly,place all materials above sequently in it. Heat gently to reflux, keep refluxing for half an hour until the oil layer (benzil)disappears completely. Pour the reaction mixture into 60ml of cold water, add a small amount of active-carbon, boil for several minutes allow to cool,then filter with suction while hot. Adjust the filtrate to pH 6, phenytoin precipitates. Filter with suction on a Buchner funnel. The solid is dissolved in a solution of 2 ml of 15% NaOH and 20 ml of water, add some active carbon and warm for three minutes with stirring. Filter as fast as possible while hot and wash with a small amount of hot water.Add 6g of NaCl in the filtrate and warm to solve. Allow to cool with stirring, a white crystal (phenytoin sodium) forms. Filter with suction ,press as dry as possible, then dry under reduced pressure.Identification of phenytoin sodium:1.The water solution of phenytoin(1:20)is basic to litmus.2.Take about 0.1g of phenytoin sodium, add 10ml of distilled water, shake to solve, add 0.2ml of HgCl2 test solution, a white precipitate produces which will not solve in an ammonia solution.Note:(i)Keep gentle reflux while refluxing.(ii)During preparing the sodium phenytoin, dont use too much water or filter repeatedly that will cause the loss of the product considerablly.(iii)The insoluble compound that is filtered off is possibly the product of condensation of one molecule of benzil with 2 molecules of urea.Question:(1)Compare the condensation reaction in phenytoin preparation with that in barbitals,give out the common points and the differences.(2)Compare phenytoin sodium with phenobarbitone sodium,bring out the common points and differences of their chemical properties.Reference:(1)Org. React. Vol. IV/269304(2)L.F. Fieser: Experiment in Organic Chemistry 170,174(1955)(3)J. Amer. Chem. Soc. 70 3666(1984)(4)王殿翔编:实用有机制药化学173页(1954)(5)于燕孙编:制药化学 491页(1963)(6)顾可权编:重要有机反应及其应用6页(二苯羟乙酸重排)64页(