药物合成习题课

1、镇静催眠药物异戊巴比妥的合成方法：丙二酸二乙酯法OOOOCH3CH3Me2CHCH2CH2BrEtONaOOOOCH3CH3CH3CH3EtBrEtONaOOOOCH3CH3CH3CH3CH3NH2CONH2EtONaNNHOOONaCH3CH3CH3HClNHNHOOOCH3CH3CH3C-烃化C-烃化缩合酸化2、镇静催眠药物酒石酸唑吡坦(ZolpidemTartrate)的合成方法：由2-氨基-5-甲基吡啶与4-甲基-2-溴苯乙酮经过缩合、曼尼希反应、季铵盐反应、取代水解、酰胺化得到。NCH3NH2+OBrCH3NCH3NCH3HCHONCH3NNCH3CH3CH3CH3INCH3NN+CH3CH3CH3CH3HNMe2NaCNNCH3NCNCH3HCl/HOAcNCH3NCOOHCH3POCl3HNMe2C4H6O6NCH3NCH3NMe2OOHOHCOOHCOOH.1/2环缩合曼尼希反应季铵盐反应取代水解酰化卤化3、盐酸美沙酮（Methadone,6）为镇痛、镇咳药物，试以环丙烷为原料合成之。OCH3HNMe220-30CH3OHNCH3CH3SOCl2PhCH3CH3ClNCH3CH3.HClPh2CHCNPhCH3/ref.CNPhPhNCH3CH3CH3+CNPhPhNCH3CH3CH31)EtMgBr2)H3+OPhPhNCH3CH3CH3OCH3不溶于正己烷的异构体分离℃胺化卤化缩合格林反应水解4、溴新斯的明属于可逆性胆碱酯酶抑制剂，合成方法：OHNH2(CH3)2SO4OHNCH3CH3NaOHNaONCH3CH3Me2NCOClONCH3CH3NOCH3CH3MeBrON+CH3CH3NOCH3CH3CH3.Br甲基化成盐酯化季铵盐化5、由化合物（3）合成抗组胺药物盐酸赛庚定（4）OOO（3）（4）NCH3.HCl.3/2H2OOOOPhCH2COOHOOPhKOHOOOHPhZn/HClOOHOHPhKOHOOHPhH2合成路线：水解还原脱水氢化.HCl.3/2H2OOOHPh1)SOCl22)AlCl3ONBSOEt3NONCH3MgClTHFOHNCH3Ac2OAcOHHClNCH3酰化付克环合卤化消除格林反应脱水酸化6、盐酸普鲁卡因（ProcaineHydrochloride）为局部麻醉药物，试以对硝基甲苯为原料进行合成。CH3NO2Na2Cr2O7H2SO4COOHNO2HOCH2CH2NEt2C6H4(CH3)2COOCH2CH2NEt2NO21)Fe/HCl2)HClCOOCH2CH2NEt2NO2.HCl氧化酯化还原酸化7、吉非罗齐（Gemfibrozil）为典型的苯氧基烷酸类循环系统药物，可以降低甘油三酯、VLDL、LDL，同时还能升高HDL。试对它进行合成。CH3CH3OBr+CH3CH(CO2Et)2CH3CH3OOOOOCH3CH3CH31)NaOH/ref2)HClCH3CH3OOHOCH31)CH3I2)HClCH3CH3OOHOCH3CH3水解酸化甲基化酸化C-烃化8、利尿药氨苯蝶啶（Triamterene）是以氰乙酸乙酯为原料合成的，试合成之。CNOCH3ONH4OHCNNH2OPOCl3/NaClPy/ClCH2CH2ClNCCNNH2NH2NH.HNO3EtONaNNNH2NH2NH2NaNO2/HClNNNH2NH2NH2ONPhCH2CNEtONaNNNNNH2NH2NH2Ph胺解消除环合亚硝化环合9、格列本脲（Glibenclamide，５）为第二代磺酰脲类口服降血糖药，试以邻羟基苯甲酸为原料合成之。（5）ClNHOSNHONHOOOCH3OHCOOHCl2OHCOOHClCH3IOCOOHClCH3氯化甲基化SOCl2OCOClClCH3PhCH2CH2NH2OCONHCH2CH2PhClCH3ClSO3HOClCH3NHOSClOONH3OClCH3NHOSNH2OONCOTM酰化缩合氯磺化氨化缩合10、吡喹酮（2）为一种新型的广谱抗寄生虫药物，试以异喹啉为原料合成之。NPhCOClKCNNCNPhOH2/Ni703kPa,90NHPhONHClCH2COCl/C6H6C5H5NNPhONHOClMe3COK60-70NPhONOH3PO4100NNHOCOClNONO℃℃℃Reissert反应氢化分子内重排缩合脱HCl环合水解酰化吡喹酮11、硝酸益康唑（1）是一种抗真菌药物，试以间苯二酚为原料合成之。ClOClClNN.HNO3ClOClClNNClClClCH2COClAlCl3ClClOClLiAlH4ClClOHClNNHCH3ONaClClOHNNClCl傅克反应还原缩合缩合12、盐酸环丙沙星（6）为抗菌药物，试从2,4-二氯氟苯和丙二酸二乙酯等为原料合成之。傅克反应氧化酰氯化FClClAlCl3CH3COClNaOClFClClCOOHSOCl2Mg(OEt)2FClOOOClOCH3CH3Op-CH3PhSO3HCH2(CO2Et)2缩合水解脱羧缩合酯化缩合水解环合FClOClOCH3OHC(OEt)3Ac2OFClOOClOCH3CH3ONH2FClONHClOCH3ONaOHNaHFClNOHOONHNHFNNOHOONHDMSO缩合13、喹诺酮类抗菌药物吡哌酸（PipemidicAcid）合成是由丙二酸二乙酯、原甲酸三乙酯和脲缩合、环合、氯化，再与β-乙胺基丙酸甲酯缩合、环合、溴代、消除，最后与哌嗪缩合得到，试合成之。HC(OEt)3NH2NH2O+CH2(CO2Et)2+CH3OHNNOHOOCH3OHCH3ONaPOCl3NNClOOCH3ClEtNHCH2CH2CO2Et缩合、环合氯化缩合NNClOOCH3NCH3OCH3Ot-BuOHt-BuOKNNClOONCH3OCH31)Br22)HBrNNClOONCH3OCH3NHNHNaOHNNNOONCH3OHNH环合溴代消除缩合14、巯嘌呤（Mercaptopurine,6-MP）为嘌呤类抗肿瘤药物常用于白血病的治疗，试对之进行合成。NH2SNH2+CNCH2COOEtEtONaEtOHNNSHNH2OHNaNO2/HClpH=3-4NNSHNH2OHNONa2S2O4NaOHNNSHNH2OHNH2Na2CO3/NiNNNH2OHNH2缩合环合亚硝化还原脱硫HCOOHNNNHOHNPS5NNNHSHNI2NNNHSNNNNHSNNa2SO3H2ONNNSNSO3NaNaNNNHSHN.2H2O+缩合环合取代氧化成盐15、氟尿嘧啶（Fluorouracil,5-FU）为嘧啶类广谱抗肿瘤药物，试对之进行合成。ClCH2COOEtKFAcNH2FCH2COOEtHCOOEtCH3ONaFOCH3OOCH3ONaFOCH3OONaCH3ONHNH2CH3OHNNOHOCH3FHClH2ONHNHOOF氟化缩合烯醇化缩合环合水解16、环磷酰胺(Cyclophosphamide)是一种广谱抗肿瘤药物主要用于淋巴瘤、白血病等。试合成之。NHOHOHPOCl3PyNClClPClClONH2CH2CH2CH2OHPNHOONClClH2O/CH3COCH3PNHOONClCl.H2O氯代磷酰化缩合水合17、萘普生（Naproxen）是一种抗炎镇痛药物，试从化合物（4）为原料合成化合物（5）。COOHCH3HOCH3OH（4）（5）OHMe2SO4NaOHOCH3(CH3CO)2OAlCl3甲基化酰化OCH3CH3OClCH2COOCH3CH3ONaOCH3CH3OOOCH3BF3EtOEtOCH3CH2OHOOCH3OCH3CH3OOHO1)H2O2/NaOH2)HClOCH3CH3OOHOCH3CH3OOHH达则斯反应酸性开环异构化氧化脱羰酸化拆分18、布洛芬（Ibuprofen）为非甾体镇痛抗炎药物，试进行合成。CH3CH=CH2Na-C(CH3CO)2OAlCl3CH3OCH3CH3ClCH2COOCH3CH3CH2ONaCH3OOOCH3CH3CH31)NaOH2)HClCH3CH3CH3CH3CHOCH3CH3CH3COOHCH3CH31)AgNO3/OH2)H+烃化酰化达则斯反应水解脱羧重排氧化中和19、吲哚美辛（Indomethacin）为强力镇痛消炎药物，试对它进行合成。OCH3NH21)NaNO2/HCl2)SnCl2OCH3NHNH2CH3CHOOCH3NHNCH3ClCOClNOCH3NNCH3OClHClOCH3NNH2OCl重氮化还原酰化缩合水解CH3COCH2CH2COOHHAcOCH3NOClCH3OHO缩合20、吡罗昔康（Piroxicam）为解热镇痛抗炎药物，试合成之。SOOOHNHONCH3NNSOOONaClCH2CO2EtDMFNSOOOOCH3OCH3CH2ONaSOOOHOCH3ONHMe2SO4NaOHSOOOHOCH3ONCH3NNH2TM21、卡马西平（Carbamazepine）为中枢神经系统药物，用于治疗癫痫大发作和综合性局灶性发作。是从化合物（1）为原料合成的，试进行合成。NHNHCOCl2NOClBr2NOClBrEtOH/KOHNOClNH3NONH2NONH2甲酰化卤化脱卤氨解22、盐酸氯丙嗪（5）是一种抗精神病药物，以邻氯苯甲酸和间氯苯胺为原料通过Ullman反应合成，试合成之。SNClCH3CH3NH2Cl+ClCOOHCu/pH=5-6150NHClCOOHFe200NHClS/I2170NHClSClCH2CH2CH2NMe2NaOHNClSNCH3CH3HClTM℃℃℃Ullmann脱羧环合缩合酸化成盐23、肾上腺素（Adrenaline）为周神经系统药物，用于过敏性休克、心脏骤停和支气管哮喘的急救。试以邻苯二酚为原料进行合成。OHOHNHCH3OHOHOHPOCl3/ClCH2COOHOHOHOClCH3NH2/HClOHOHONHCH3.HClH2/Pd-COHOHOHNHCH3.HClNH3OHOHOHNHCH3OHOHOHNHCH3缩合胺化酸化还原中和拆分（R）-（-）Adrenaline24、马来酸氯苯那敏（Chlorphenamine）为丙胺类抗组胺药物是以2-甲基吡啶为原料合成的，试进行合成。NNCH3CH3ClOHOHOO.NCH3Cl2/Na2CO3CCl4NClPhNH2/HClNNH21)NaNO2/HCl1)Cu2Cl2/HClNClBrCH2CH(OEt)2NaNH2/PhCH3NClCH2CH(OEt)2HCOOH/DMFH2ONClCH2CH2NMe2COOHCOOHPhCH3/CH3CH2CH3TM氯化缩合Sandmeyer缩合水解Leuckart反应酸化成盐24、盐酸利多卡因（LidocaineHydrochride）为局部麻醉和抗心律失常作用的药物，试以间二甲苯为原料进行合成。CH3CH3HNO3H2SO4CH3CH3NO2Fe/HClCH3CH3NH2ClCH2COClHAc/NaAcCH3CH3NHClOEt2NHC6H6CH3CH3NHONCH3CH3HCl/MeCOMeCH3CH3NHONCH3CH3.HCl.H2O硝化还原酰化缩合成盐25、一、1,1-二官能团化合物例1：分析香料丁香素C6H5CH2CH（OCH3）2的合成路线。PhCH2CH(OCH3)2PhCH2CHO+2CH3OHPhCH2CHOPhCH2CH2OHPhMgBr+O例2、试分析化合物（1）的合成路线。OHCOOEt缩醛反应OHCOOEtOHCOOHOHCNO+HCNOHCOOEtOHCOOHOHCNOHCNOHCOOHNH2EtOCOOHNH2EtOCNOHEtOCHOEtOCH2OHEtOH+OH+CrO3HCN1)NH32)H2O,H+HI例3、试分析丝氨酸HOCH2CH(NH2)COOH的合成路线。OHCOOHNH2EtOCOOHNH2EtOCNOHEtOCHOEtOCH2OHEtO