【作者】 端振英；

【导师】 颜廷仁；

【作者基本信息】 河北医科大学 ， 药物化学， 2003， 硕士

【摘要】 巴氯芬(Baclofen)，商品名力奥来素(Lioresal)，化学名β-4-氯-苯基-γ-氨基丁酸，是γ-氨基丁酸的取代衍生物。γ-氨基丁酸(GABA)是哺乳动物中枢神经系统(CNS)最重要的抑制性氨基酸递质，通过与其三个特异性受体GABA_A、GABA_B和GABA_C相互作用而发挥重要的生理活性。巴氯芬是第一个应用于临床的选择性的GABA_B受体激动剂，曾作为肌松药用于临床，近年来又发现了许多新的应用，如镇咳、抗癫痫、治疗顽固性呃逆、中风及脊髓损伤引起的疼痛、三叉神经痛等。在脑血管病康复期应用巴氯芬也取得良好效果，采用巴氯芬治疗胃食管反流病开辟了非抑胃酸治疗胃食管反流病的新途径。还有报道巴氯芬在治疗可卡因成瘾上也非常有效，这在药物成瘾的治疗上将会有重要意义。 巴氯芬是一种手性药物，存在一对对映异构体，目前，临床使用的仍是其外消旋体。据文献报道R(-)-巴氯芬的生理活性是S(+)-巴氯芬的100倍。近年来，随着对其药理作用及作用机制等方面的研究和进展，人们对R(-)-巴氯芬的研制越来越感兴趣。R(-)-巴氯芬的成功研制可为多种疾病的治疗提供新的途径，研究表明R(-)-巴氯芬具有广泛的应用前景。 目的：通过化学合成和对中间体(±)-3-(对氯苯基)戊二酸单酰胺((±)-GAM)的拆分，合成具有广泛应用中文摘要前景的R一(一)p一4一氯苯基一Y一氨基丁酸(R(一)一巴氯芬)，对其合成路线和工艺进行改进，寻找一条简便可行，适于大规模生产R(一)一巴氯芬的合成路线;通过对拆分后剩余的S(一)一GAM异构体进行外消旋化处理，再拆分回收，提供一条可循环再利用的途径，从而节省原料、降低成本、缩短反应周期。 方法:在3一(对氯苯基)戊二酸醉制备中，采用两条不同的合成路线:①以对氯苯甲醛和乙酞乙酸乙醋为原料经酷化、酸式分解、再经脱水缩合;②以对氯苯甲醛和丙二酸二乙醋为原料经醋化、水解脱梭、脱水缩合。第二条路线未见文献报道。 在(士)一3一(对氯苯基)戊二酸单酞胺制备中，按文献路线为，3一(对氯苯基)戊二酸醉在185℃反应，生成酞亚胺，再经碱性水解得单酞胺，操作复杂。改进路线为3一(对氯苯基)戊二酸配在较低温度下氨解，一步反应即可得单酞胺产品。 在R(一)一巴氯芬合成中，以S(一)一Q一苯乙胺(S(一)一PEA)为拆分剂，甲醇为溶剂，将(士)GAM拆分得R(+)GAM和S(一)GAM两种光学异构体，将分离后的R(+)GAM用次氯酸钠处理，经Hofmann降解得产品R(一)巴氯芬。剩余的S(一)一GAM经处理，转化成3一(对氯苯基)戊二酞亚胺，碱性水解后得(士)一GAM，再进行拆分，又得R(一)一巴氯芬。 R(一)一巴氯芬的比旋光度的测定中，由于其比旋光度较小(ra]220=一1 .2(c=0.24 in HZo))，为此，将R(一)一巴氯芬在无水乙酸钠存在下，脱水缩和得其相应的内酞2中文摘要胺R一(一)一4(对氯苯基)毗咯烷一2一酮衍生物([。户D-一39(c=0.5 in EtoH))，再测该衍生物的比旋光度。 结果:(士)一3一(对氯苯基)戊二酸单酞胺的熔点、UV、xR与文献一致，xR(KBr，cm一’):3425.55，3221.42，2928.13，1709.70，1649.87。 R(十)一3一(对氯苯基)戊二酸单酞胺比旋光度十9.31。 R(一)一巴氯芬的熔点与文献一致，UV、IR、’HNMR、Ms等波一谱及元素分析均符合其结构特征，IR(KB:，cm一’):3000一2500，1625.9，1531.4，1496.7;IHNMR(6)7.32一7.46(4H，q，苯环氢)，3.35一3.43(ZH，ABx体系的AB部分，一C丛NHZ)，3 .19一3 .27(IH，m，一C旦)，2.48一2.67(ZH，ABX体系的AB部分，一C旦ZCOOH);MSm/e (%):2 1 3.2(M+，10)，195.2(50)，138.1(100);元素分析:C，。H!ZNOZCI，计算值(%):C，56.21;H，5.66;N，6.56;CI，16.60;实验值①(%):C，56.30;H，5.65;N，6.46;CI，16.89;实验值②(%):C，56.42;H，5 .69;N，6.51;Cl，1 6.90。 R(一)一4一(对氯苯基)毗咯烷一2一酮的比旋光度一38.36。 结论:1.在3一对氯苯基戊二酸的合成中，试用了两条路线进行 合成，改进的路线以内二酸二乙酝替代乙酞乙酸乙配 为原料，原料价廉易得，中间体不需纯化即可直接进 行下步反应，该路线未见文献报道。2.在3一对氯苯基戊二酸单酞胺((士)GAM)的合成中， 原文献将原料经185℃反应生成酞亚胺后，再水解成 产物，操作复杂，副产物较多。改进的一步合成法，3中文摘要 操作简便，产品收率及质量都优于前者，未见文献报 道。3.由(士)一3一对氯苯基戊二酸单酞胺((士)一GAM)拆分 为R(+)一GAM的过程中，对原料与拆分剂的摩尔比 及拆分溶剂进行了优化选择，认为原料与拆分剂较理 想的摩尔比为1:1.2，最佳拆分溶剂为甲醇。4.在将R(+)一GAM降解为R(一)一巴氯芬的过程中，以 次氯酸钠替代澳液和氢氧化钠，避免了使用强腐蚀性 试剂澳、降低了成本，此路线更适于工业生产。5.R(一)一巴氯芬比旋光度数值较低，为此，将其转化成 其内酞胺R一(一)一4一(对氯苯基)毗咯烷一2一酮衍生物， 该化合物在乙醇更多还原

【Abstract】 Baclofen, [β - (p-chlorophenyl) -γ -amino-butyric acid], or Lioresal for its commercial name , is the first selective GABAB receptor agonist in clinical. Y -aminobutyric acid (GAB A), the major inhibitory amino acid transmitter in the central nervous system of mammalians, exerts its physiological actions through the interaction with three receptor subtypes, that is GABAA, GABAB and GABAC. Baclofen is the first liophilic analogue of GABA and is used clinically for the treatment of spasticity of spinal and cerebral origin. Some more recent studies have described many new uses of baclofen , including antitussis , antiepilepty, treating intractable hiccup, pain caused by apoplexy and myelopathy, trigeminal neuralgia, etc. Baclofen can also improve the hypermyotonia and myoclonia in case of cerebrovascular diseases. Beside , it was applied successfully to cure gastroesophageal reflux, which opened up a new way to treat gastroesophageal reflux whithout inhibitting gastric secretion. There is another report that baclofen has effective application in the treatment of the cocaine addication, which has great significance in treating drug addication.The biological activity and physical properties of racemic baclofen are well documented in the literature. Further extensive pharmacological tests have concluded that biological activity of the drug resides with the R-enantiomer (R (-) baclofen) . These selective activites have led to extensive research concerning methods of separating the optical isomers of baclofen. It is very important in augmenting effect, reducing toxic and secondary action and treating many other diseases.Objective: To synthese R- (-) - β - (p-chlorophenyl) - Y -aminobutyric acid (R (-) -baclofen ) through resolution of its intermediate, (± )-GAM. To deveplop a modification of the general route for the synthesis of R (-) -baclofen and find a suitable method for industrialization. For purpose of saving raw material, reducing production costs and shortening reaction cycle and exploring a reusable route through racemization of S (-) -GAM.Methods: 3- ( p-chlorophenyl ) glutaric acid was synthesized by using two different compounds as raw materials through two different synthetic routes respectively: (1)3- (p-chlorophenyl) glutaric acid was synthesized by using p-chlorobenzaldehyde and ethyl acetoacetate as raw materials through esterification , acid-decomposition , dehydration and condensation. (2) 3- ( p-chlorophenyl ) glutaric acid was obtained through esterification , hydrolysis , decarboxylation , and condensation withp-chlorobenzaldehyde and diethyl malonate as raw materials. The second route was not reported previously.3- (p-chlorophenyl) glutaramic acid was synthesized through two different synthetic routes respectively. According to the literature, 3- (p-chlorophenyl) -glutaric anhydride reacted with ammonia at 185癈 to gave 3-( p-chlorophenyl) glutarimide, then subjected to basic hydrolysis to obtain 3- (p-chlorophenyl) glutaramic acid. It was synthesized only through one step in the improved method.R- (-) - 0 - (p-chlorophenyl) - y -aminobutyric acid (R(-) -baclofen) was synthesized as follows: (±) -GAM was resolved by the reaction with S- (-) -a -phenylethylamine(S-PEA) to form two enantioners R ( + ) -GAM and S (-) -GAM. The R(+)-GAM was subsepuently converted to R( -) -baclofen with sodium hypochlorite via a Hoffmann degradation. S ( - ) -GAM was racemizated through dehydration and condensation to afford 3- (p-chlorophenyl) glutarimide followed the basic hydrolysis to obtain (±) -GAM.Owing to the very low value of the optical rotation of R(-)-baclofen, ([alpha]22D= - 1.2(c=0.24 in H2O)), its optical purity was assessed by the transformation of a sample into the corresponding lactame: R- (-) -4- (p-chlorophenyl) pyrrolidin-2-one, ([alpha]25D= -39 (c=0.5 in EtOH) ) . Results: (±)-3- (p-chlorophenyl) glutaramic acid IR(KBr, cm-1) : 3428.55, 32更多还原