牛磺熊去氧胆酸的合成工艺及工业化设计
|
摘要
牛磺熊去氧胆酸(TUDCA)属于胆酸类药物,具有溶解胆固醇结石和保护肝细胞等多项生理功能。
本文在文献阅译和工艺原理分析的基础上,尝试与评估了合成TUDCA的各条工艺路线。研究了以熊去氧胆酸(UDCA)为原料,首先在三乙胺作用下与氯甲酸苯酯形成羧酸-碳酸苯酯的混酐,再与牛磺酸钠发生氨解反应合成TUDCA的工艺。确定了较优合成工艺过程为：1当量UDCA溶解于4倍质量体积的四氢呋喃中,加入1.5当量的三乙胺,在0～5℃下滴加1.5当量的氯甲酸苯酯,10℃以下反应60～80min,过滤,滤液降温在5℃以下滴加入2当量的牛磺酸钠(1.27mo1/L)水溶液,在15℃反应100～160min,盐酸酸化之后浓缩,加乙醇溶解之后过滤,滤液浓缩即可得到收率为75%的TUDCA。
在小试研究基础上,设计了工艺流程、操作方法、物料回收套用措施等。为生产工艺流程及操作的进一步设计优化提供了良好的理论依据和可参考的工艺参数。
Tauroursodeoxycholic acid(TUDCA) is a kind of bile acid drugs. It has many physiological functions such as dissolved cholesterol stone and protective liver cell and so on.
Based on the relevant literature and the analysis of the principle of reactions, several synthesis routes are collected and the synthesis route that is suitable for industrial production is selected. In this paper, the TUDCA was synthesized by aminolysis of sodium taurine with carboxy-carbonate mixed anhydride prepared by reacting UDCA with phenyl chloroformate at the present of triethylamine. substitution. The influences of anhydride reaction and aminolysis reaction were investigated in molar ratio, temperature, time and so on. on. Optimum reaction conditions were selectred as follows:1 equivalent UDCA dissolved in four times,in the size of the quality, tetrahydrofuran. Then joined 1.5 equivalent of triethylamine.1.5 equivalent of the chlorine acid benzene ester was droped in the solution should be keeped at 0-5℃. This solution was keeped in 10℃for 60-80min,then filter. The filtrate under 5℃droped join 2 equivalent of taurine sodium aqueous solution(1.27mol/L), then keeped in 15℃for 100-160min. The alkaline liquor was acidize by hydrochloric acid. The absolute ethyl alcohol dissolve the residue that get by moved water in reduced pressure distillation. After filter, the ethyl alcohol was moved out from filtrate in reduced pressure distillation. According to the conditions described,TUDCA yields 75%.
Based on the results of experiments, the rational scheme for the renovating of the process was discussed. The technological process、operational approach material recycling etc. were designed. It provided the theoretical basis and process parameters for the industrial production of TUDCA.
本文在文献阅译和工艺原理分析的基础上,尝试与评估了合成TUDCA的各条工艺路线。研究了以熊去氧胆酸(UDCA)为原料,首先在三乙胺作用下与氯甲酸苯酯形成羧酸-碳酸苯酯的混酐,再与牛磺酸钠发生氨解反应合成TUDCA的工艺。确定了较优合成工艺过程为：1当量UDCA溶解于4倍质量体积的四氢呋喃中,加入1.5当量的三乙胺,在0～5℃下滴加1.5当量的氯甲酸苯酯,10℃以下反应60～80min,过滤,滤液降温在5℃以下滴加入2当量的牛磺酸钠(1.27mo1/L)水溶液,在15℃反应100～160min,盐酸酸化之后浓缩,加乙醇溶解之后过滤,滤液浓缩即可得到收率为75%的TUDCA。
在小试研究基础上,设计了工艺流程、操作方法、物料回收套用措施等。为生产工艺流程及操作的进一步设计优化提供了良好的理论依据和可参考的工艺参数。
Tauroursodeoxycholic acid(TUDCA) is a kind of bile acid drugs. It has many physiological functions such as dissolved cholesterol stone and protective liver cell and so on.
Based on the relevant literature and the analysis of the principle of reactions, several synthesis routes are collected and the synthesis route that is suitable for industrial production is selected. In this paper, the TUDCA was synthesized by aminolysis of sodium taurine with carboxy-carbonate mixed anhydride prepared by reacting UDCA with phenyl chloroformate at the present of triethylamine. substitution. The influences of anhydride reaction and aminolysis reaction were investigated in molar ratio, temperature, time and so on. on. Optimum reaction conditions were selectred as follows:1 equivalent UDCA dissolved in four times,in the size of the quality, tetrahydrofuran. Then joined 1.5 equivalent of triethylamine.1.5 equivalent of the chlorine acid benzene ester was droped in the solution should be keeped at 0-5℃. This solution was keeped in 10℃for 60-80min,then filter. The filtrate under 5℃droped join 2 equivalent of taurine sodium aqueous solution(1.27mol/L), then keeped in 15℃for 100-160min. The alkaline liquor was acidize by hydrochloric acid. The absolute ethyl alcohol dissolve the residue that get by moved water in reduced pressure distillation. After filter, the ethyl alcohol was moved out from filtrate in reduced pressure distillation. According to the conditions described,TUDCA yields 75%.
Based on the results of experiments, the rational scheme for the renovating of the process was discussed. The technological process、operational approach material recycling etc. were designed. It provided the theoretical basis and process parameters for the industrial production of TUDCA.
引文
[1]曹东林,陈晓文,周思朗.胆结石患者胆汁对人胆管癌细胞增殖的影响[J].中国民康医学杂志.2005,17(10)：51-562
[2]王玉君,严钟德.老年Ⅱ型糖尿病患者胆结石发生的高危因素[J].中国老年学杂志.1999,19(3)：147-149
[3]侯俊岭,李朝战,鲍广建,杨峰,张超.老年胆石症的临床特征及外科治疗分析[J].中国基层医药.2009,7：1277-1277
[4]吴东进.肝硬化合并胆囊结石的临床研究(附50例报道)[J].中国医药指南.2009,7(24)：72-73
[5]Sridhar A, Sandeep Y, Krishnakishore C, Sriramnaveen P, Manjusha Y, Sriram P, Lakshmi B V, Lakshmi A Y, Sivakumar V. Gall Stone Ileus with Acute Kidney Injury-A Case Report[J].Renal failure.2011,33(9):908-909
[6]唐俊.胆结石与消化性溃疡的关系[J].临床医药实践.2009,18(5)：362-363
[7]方干.结石的化学成份分类方法[J].中华外科杂志.1964,(2)：71
[8]孙颖,杨展澜,申国荣,周勇,吴瑾光,徐光宪.胆结石组成和形成机理的研究进展[J].中国科学(B辑).2001,31(5)：385-393
[9]潘其金.超声诊断肝胆结石的临床意义[J].国际医药卫生导报(半月刊).2005,11(16)：60-61
[10]吴在德.外科学(第5版)[M].人民卫生出版社.2000,616-617
[11]Huang ZQ, Huang XQ. Evolution of surgical treatment of intrahepatic lithiasis in China[J]. China Natl J New Gastroenterol.1997,3:131-133
[12]Stokes C S, Krawczyk M, Lammert F. Gallstones:Environment, Lifestyle and Genes[J]. Digestive diseases.2011,29(2):191-201
[13]徐闫军.胆结石患病率的发展趋势分析[J].内蒙古中医药.2011,30(14)：71-73
[14]孙运峰.飞行人员1020例胆石症患病率及相关因素调查[J].中国误诊学杂志.2008,8(33)：8314
[15]叶忻,王保钢,项晓宇等.上海江湾地区成年人胆囊结石发病情况调查[J].肝胆胰外科杂志.2003,15：28-30
[16]施维锦,姜广杰,谢敏等.上海地区“健康人”胆石发生率的调查报告[J].中华消化杂志.1989,9：105
[17]蒋兆彦,韩天权,张圣道.从胆石成因研究谈胆石病预防的新策略[J].中华肝胆外科杂志.2011,17(9)：697-700
[18]赵国臣,周春祥.胆结石成石机制研究概况[J].广西中医学院学报.2007,10(2)：76-78
[19]Somien GJ, Gilar T.A non-micellar mode of cholesterol transport in human bile[J].FBRS Lett.1983,156:256-268
[20]王学军,李玉民,李世雄.细菌在胆固醇结石中的作用研究[J].中国现代医学杂志.2003,13(3)：4-7
[21]Afdhal NH, Niu N, Gantz D, et al. Bovine gallbladder mucin acceerates cholesterol monohydrate crystal growth in modelbile[J].Gatroenterology.1993,104(5):1515-1523
[22]朱雷明,赵洪,蔡端等.胆固醇结石中细菌对人胆汁胆固醇晶体形成的作用[J].中华肝胆外科杂志.2005,11(3)：182
[23]朱雷明,蔡端,吕元等.模拟胆汁体系中胆固醇结石内细菌对胆固醇晶体形成的作用[J].中华外科杂志.2004,42(24)：1503
[24]Stokes C S, Krawczyk M, Lammert, F. Gallstones:Environment, Lifestyle and Genes[J]. DIGESTIVE DISEASES.2011,29(2):191-201
[25]潘其金.超声诊断肝胆结石的临床意义[J].国际医药卫生导报(半月刊).2005,11(16),60-61
[26]皋岚雅,焦成文,王坚,蔡珍福,刘存官,张大治,郝立校.胆石病患者术前MRCP检查价值探讨[J].肝胆胰杂志.2006,18(3)：165-166
[27]卢盛贞,袁青.内窥镜治疗胆结石84例护理体会[J].实用临床医学.2004,5(3)：16-17
[28]李庆怀,高静涛,曹嘉华,熊剑平,何效东,秦建伟.肝切除治疗肝胆管结石[J].中华肝胆外科杂志.2003,9(11)：645-646
[29]植传雄.两种方法治疗胆结石的临床效果分析[J].中国现代药物应用.2010,4(16),66-67
[30]卢景雾,杨正红,陈立新,王夔,沈韬,林丛,傅贤波,周孝思.人体胆结石的电子顺磁共振波谱研究[J].科学通报.1992,(8)：738-741
[31]刘刚,滕秀萍,王华,汪禄祥.胆结石的磁性研究[J].生物磁学.2004,4(2)：25-27
[32]黄鹤,史亦飞.磁场综合治疗胆石症3866例观察[J].生物磁学.2002,2(2)：28-29
[33]颜莉,金祥瑞,陈飞明,余练红,张沪生.综合磁场治疗胆结石及其测试分析[J].武汉科技学院学报.2008,21(3)：9-12
[34]裴莉,孙立巍.高压氧治疗泥沙样胆结石疗效观察[J].中国煤炭工业医学杂志.2008,11(11)：1740-1741
[35]陈进洪,蔡端,马保金.利胆冲剂对胆汁成石趋势的影响[J].肝胆胰外科杂志.2006,18(3)：142-143
[36]林长春.利胆排石汤治疗肝胆湿热型胆结石的临床研究[J].吉林中医药.2009,29(12)：1039-1040
[37]韩金山,宝龙.蒙医药治疗胆结石体会[J].中国民族医药杂志.2008,11：10
[38]尕藏才让,王成,普化加.藏药治疗胆结石的临床观察[J].医药信息(下旬版).2011,24(5)：190
[39]刘嘉,万春艳.熊胆粉溶胆结石的作用研究[J].中国林副特产.2007,4：37-39
[40]顾树南,蔡珍福,王坚.胆结石灌注药物溶石的治疗进展[J].中华现代外科学杂志.2005,2(5)：431-434
[41]向伟.胆结石治疗方法的研究状况综述[J].中外健康文献.2009,8(19)：227-228
[42]谢广静.黄伟华.输尿管结石的现代微创治疗[J].中华腔镜泌尿外科杂志.2008,2(2)：60-63
[43]俞亚红.卢兴培,丁志强等.液电碎石仪治疗肝内外胆管难取性结石[J].华中科技大学学报(医学版).2005,34(1)：72-73
[44]谢广静,陈光,沈思等.输尿管镜钬激光碎石术治疗输尿管结石536例报告[J].中华腔镜泌尿外科杂志.2008,2(2)：33-35
[45]谭德福,陈涛,黄利呜等.胆穴刺血抑制豚鼠胆囊结石的实验研究[J].中国中医药科技.1996,3(3)：5
[46]邱昌.按摩治疗胆结石二法[J].中国民间疗法.2005,9(13)：14-15
[47]王洪玲.电针治疗胆结石268例[J].上海针灸杂志.2004,23(7)：25
[48]冯西园.不吃早饭易患胆结石[J].快乐养生.2010,6(中)：35
[49]刘清,刘钰,刘萍,罗晓梅胆结石患者膳食营养状况调查及相关性分析[J].卫生职业教育.2005,23(10)：86-87
[50]钟美,陈黄锰,刘浩丹等.茶叶中咖啡碱的功效与提取方法概述[J].中国民族民间医药.2008,17(1])：16-17
[51]PalanduzA,YalcinmI,TongueE,etal.Sonographicassessment of ceftriaxone-associated biliary pseudolithiasis in children[J].J Clin Ultrasound.2000,28(4):166-168
[52]马伟军,董萍.头孢曲松钠致胆结石1例[J].中国综合临床.2008,,24(13)：76
[53]朱红,刘治军.影响胆结石形成的药物及使用注意事项[J].中国全科医学.2007,10(18)：1536-1537
[54]马洪娟.警惕药源性胆结石[J].杭州科技双月刊.2001,3：43
[55]白文林,张玲霞.药物性肝胆淤积[J].肝脏.2001,6(1)：47-48
[56]Michihiro Nonaka,Susumu Tazuma,Hideyuki Hyogo,Keishi Kanno and Kazuaki Chayama. Cytoprotective effect of tauroursodeoxycholate on hepatocyte apoptosis induced by peroxisome proliferator-activated receptor gamma ligand[J].Journal of Gastroenterology and Hepatology.2008,23:198-206
[57]Carmela Fimognari, Monia Lenzi, Giorgio Cantelli-Forti, and Patrizia Hrelia. Apoptosis and Modulation of Cell Cycle Control by Bile Acids in Human Leukemia T Cells[J]. Ann. N.Y. Acad. Sci.2009,1171:264-269
[58]黄延风.胆汁酸的毒性作用[J].国际检验医学杂志.2006,27(2)：152-157
[59]Joana D Amaral, Ricardo J. S. Viana, Rita M. Ramalho, Clifford J. Steer, and Cecilia M. P. Rodrigues. Bile acids:regulation of apoptosis by ursodeoxycholic acid[J].Journal of Lipid Research.2009,50:1721-1734
[60]Vijayalakshmi N,Martia U.Hydroxyl-terminated dndritic oligomers from bile acids.Synthesis and properties[J].J Org Chem.2006,71(2):768-774
[61]Wess G,Kramer W. Dissecting G-protein-coupled receptors:Structure,function.and ligand interaction[J].Chembiochem.2002,3(10):915-919
[62]靳雪源,王慧芬.以胆酸为载体的肝靶向疗法[J].军事医学科学院院刊.2007,31(3)：287-290
[63]李培锋,关红,赵红霞,斯琴.鹅去氧胆酸的平喘及抗炎作用机理研究[J].中国中药杂志.2004,29(4)：349-352
[64]中国药典2000年版二部：1006
[65]张铭,田辉.熊去氧胆酸在胆汁淤积性肝病中的作用机制和治疗指征[J].肝脏.2007,12(1)：64-66
[66]罗强,陈全成,吴瑶,姜苗苗,陈志鸿,张晓坤,陈海峰.熊胆的化学成分研究[J].中国中药杂志.2010,35(18)：2416-2419
[67]Michihiro Nonaka,Susumu Tazuma,Hideyuki Hyogo,Keishi Kannoand Kazuaki Chayama. Cytoprotective effect of tauroursodeoxycholate on hepatocyte apoptosis induced by peroxisome proliferator-activated receptor gamma ligand[J] Journal of Gastroenterology and Hepatology.2008,23:198-206
[68]Neuman M G,Cameron R G,Shear N H,Bellentani S,Tiribelli C. Effect of tauroursodeoxycholic and ursodeoxycholic acid on ethanol-induced cell injuries in the human hep G2 cell line[J].Gastroenterology.1995,109(2):555-563
[69]蒋欣桐,蔡可丽,郭媛媛,王荣.牛磺酸熊脱氧胆酸对高糖环境下晶状体上皮细胞的保护作用[J].山东大学学报(医学版).2010,48(3)：74-82
[70]Leonardo Baiocchi,Giuseppe Tisone,Mario Antonio Russo,Chiara Longhi,Gianpiero Palmieri,Antonio Volpe,Cristiana Almerighi,Claudia Telesca,Marco Carbone,Luca Toti,Francesco De Leonardis and Mario Angelico.TUDCA prevents cholestasis and canalicular damage induced by ischemia-reperfusion injury in the rat, modulating PKCa-ezrin pathway[J]. European Society for Organ Transplantation.2008,21:792-800
[71]Paumgartner G. Medical treatment of cholestatic liver diseases:From pathobiology to pharmacological targets[J].World J Gastroenterol.2006,12 (28):4445-4451
[72]李继珩,刘士忠,姚文庄.牛磺熊去氧胆酸镇静与镇痛作用的动物实验[J].医药导报.2002,21(1)：11-12
[73]Angelico M,Tisone G, Baiocchi L,Palmieri G,Pisani F, Negrini S,Anselmo A,Vennarecci G,Casciani C U. One-year pilot study on tauroursodeoxycholic acid as an adjuvant treatment after liver transplantation [J]. Italian journal of gastroenterology and hepatology,1999,31(6):462-468.
[74]Hert1 M,Hertl M C,Kunkel P,Schilling S,Prevot B,Kluth D,Malago M,Broelsch C E. Tauroursodeoxycholate ameliorates reperfusion injury after pig liver transplantation[J].Transplant international:official journal of the European Society for Organ Transplantation.1999,12(6):454-62
[75]翟钰栋,张晓坤,曾锦章,储瑞蔼.一种可用于皮肤创伤修复的药物[P].CN101732325
[76]Yoshikawa Kunihiko,Itami Akira,Yamaguchi Hiroshi.Therapeutics for psoriasis containing tauroursodeoxycholic acid [P]. JP10017474
[77]王丹,杨玲,黄金明,王保永,李靓,钱伟,叶进,侯晓华.牛磺熊去氧胆酸抑制四氯化碳诱导的大鼠肝纤维化[J].世界华人消化杂志.2010,18(19)：1979-1984
[78]Bataller R,Brenner DA.Liver fibrosis[J].J Clin Invest.2005,115(2):209-218姚光弼.慢性病毒性肝炎治疗的策略及实施[J].现代实用医学.2003,15(1)：2-11
[79]Crosignani A,Budillon G, Cimino L,Del Vecchio Blanco C,Loguercio C,Ideo G,Raimondo G,Stabilini R,Podda M. Tauroursodeoxycholic acid for the treatment of HCV-related chronic hepatitis: a multicenter placebo-controlled study [J]. Hepato-gastroenterology.1998,45:1624-1629
[80]雷陵,艾书眉.神农肝酶安胶囊治疗慢性病毒性肝炎转氨酶升高的临床观察[J].中国中医药信息杂志.2003,10(12)：44
[81]Leonardo Furio,Pasquale Tomaiuolo,Raffaele Gatta,Michele Tomaiuolo,Serafino Talarico,Vittorio Beverelli,Domenico Prencipe. Treatment of virus-associated liver cirrhosis with tauroursodeoxycholic acid:Evaluation of cytolysis and cholestasis indexes and selected immunologic variables[J].Current Therapeutic Research.1994,5(11):1355-1361
[82]蒋欣桐,蔡可丽,郭媛媛,王荣.牛磺酸熊脱氧胆酸对高糖环境下晶状体上皮细胞的保护作用[J].山东大学学报(医学版).2010,48(3)：74-82
[83]王晓黎,戚朝秀,曹良启,杨晖,钱益勇,张振平.毒胡萝卜内酯对人晶状体上皮细胞HLE-B3生长抑制作用的研究[J].中国病理生理杂志.2008,24(4)：692-696
[84]A. Malo,B. Kruger,E. Seyhun,C. Schafer,R. T. Hoffmann,B. Goke,and C. H. Kubisch. Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini[J].Am J Physiol Gastrointest Liver Physiol.2010,299:877-886
[85]Emanuel Berger,Dirk Haller. Structure-function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic reticulum stress in intestinal epithelial cells[J].Biochemical and Biophysical Research Communications.2011,409:610-615
[86]Yeon Yi Lee,Shin Hee Hong,Ye Jin Lee,Sung Soo Chung,Hye Seung Jung,Sang Gyu Park,Kyong Soo Park. Tauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stress[J].Biochemical and Biophysical Research Communications.2010,397:735-739
[87]Asli F. Ceylan-Isik,Nair Sreejayan,Jun Ren. Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction[J].Journal of Molecular and Cellular Cardiology.2011.(50):107-116
[88]Susana Sola, Joana D. Amaral,Pedro M. Borralho.Rita M. Ramalho,Rui E. Castro,Ma' rcia M. Aranha,Cifford J. Steer,and Ceciia M. P. Rodrigues. Functional Modulation of Nuclear Steroid Receptors by Tauroursodeoxycholic Acid Reduces Amyloid-β-Peptide-Induced Apoptosis[J].Molecular Endocrinology.2006,20(10):2292-2303
[89]Stanley D.W. Miller, Catherine M. Greene, Caitriona McLean, Matthew W. Lawless,Clifford C. Taggart,Shane J. O'Neill,and Noel G. McElvaney. Tauroursodeoxycholic Acid Inhibits Apoptosis Induced by Z Alpha-1 Antitrypsin via Inhibition of Bad[J].HEPATOLOGY.2007,46(2):496-503
[90]Ahmet Colak,Bilal Kelten,Ayhan Sagmanligil,Osman Akdemir,Alper Karaoglan,Elife Sahan,Ozge Celik,Seref Barut. Tauroursodeoxycholic acid and secondary damage after spinal cord injury in rats [J] Journal of Clinical Neuroscience.2008,15:665-671
[91]R J S Viana,A F Nunes,R E Castro,R M Ramalho,J Meyerson,S Fossatib,J Ghiso,A Rostagno and C M PRodrigues. Tauroursodeoxycholic acid prevents E22Q Alzheimer's Aβ toxicity in human cerebral endothelial cells[J].Cellular and Molecular Life Sciences. 2009,66:1094-1104
[92]Florian Schulz Ingo Just, and Harald Genth. Prevention of Clostridium sordellii Lethal Toxin-Induced Apoptotic Cell Death by Tauroursodeoxycholic Acid[J]. Biochemistry.2009, 48:9002-9010
[93]Brian C.Oveson,Takeshi Iwase,Sean F Hackett,Sun Young Lee,Shinichi Usui,Thomas W Sedlak,Solomon H Snyder,Peter A Campochiaro and Jennifer U Sung. Constituents of bile,bilirubin and TUDCA,protect against oxidative stress-induced retinal degeneration [J]. Journal of Neurochemistry.2011,116:144-153
[94]Ozcan U,Yilmaz E,Ozcan L,Furuhashi M,Vaillancourt E,Smith RO,Gorgun CZ,Hotamisligil GS.Chemical chaperoncs reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes[J]. Science.2006,313:1137-1140
[95]Asli F Ceylan-Isik,Nair Sreejayan,Jun Ren. Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction[J].Journal of Molecular and Cellular Cardiology.2011, (50):107-116
[96]Sancia Gaetani. A sideway glance:a new role for endoplasmic reticulum chemical chaperones as leptin sensitizers[J].Genes Nutr.2009(4):157-159
[97]Michael J Bull,Gottfried H Kellermann,Kelly L Olson.Methods for reducing cravings and impulses associated with addictive and compulsive behaviors[P].2011, US20110098265A1
[98]傅贤波,林三仁,范竹平,邱德凯.牛磺熊去氧胆酸溶解胆囊胆固醇结石有效性和安全 性——随机、双盲、安慰剂对照、多中心临床研究[J].中国微创外科杂志.2007,7(12)：1159-1163
[99]A Larghi,A Crosignani,P M Battezzati,G DE Valle.M Allocca,P Invernizzi,M Zuin,M Podda. Ursodeoxycholic and tauroursodeoxycholic acids for the treatment of primary billiary cirrhosis:a pilot crossover study[J].Aliment Pharmacol Ther.1997,11:409-414
[100]Pietro Invernizzi,Kenneth D. R. Setchell.Andrea Crosignani. Differences in the Metabolism and Disposition of Ursodeoxycholic Acid and of its Taurine-Conjugated Species in Patients With Primary Biliary Cirrhosis[J]. HEPATOLOGY.1999,29(2):320-327
[101]Ulrich Baumgartner,Jorgen Scholmerich,Markus Sellinger,Martina Reinhardt,Gunter Ruf,and Eduard-Heinrich Farthmann. Different Protective Effects of Tauroursodeoxycholate, Ursodeoxycholate, and 23-Methyl-Ursodeoxycholate Against Taurolithocholate-Induced Cholestasis[J]. Digestive Diseases and Sciences.1996,41(2):250-255
[102]Loria P,Bozzoli M,Angelico M,Bertolotti M,Carubbi F,Concari M.Baiocchi L,Nistri A,Della Guardia P,et al. Effect of taurohyodeoxycholic acid on biliary lipid secretion in man: Preliminary report[J]. Italian Journal of Gastroenterology.1996,28(7):391-392
[103]Balandraud-PieriNathalie,QueneauPierre-Edouard,Caroli-BoscFrancois-Xavier, Bertault-Peres Pierre,Montet Anne-Marie,Durand Alain,Montet Jean-Claude. Effects of tauroursodeoxycholate solutions on cyclosporin A bioavailability in rats[J].Drug Metabolism and Disposition.1997,25(8):912-916
[104]Sawada. Producing conjugated ursodeoxycholic acids[P].EP0119040A1.1984
[105]章贵荣,韩成光,万平,陈峰.一种牛磺熊去氧胆酸的禽胆制取法[P].2002,CN1357551A
[106]Parentl Massimo.Procedimentd per la sintesi di acido ursodesossicolico coniugato con la taurina[P].1983,IT1167038
[107]Parentl Massimo. Process for the preparation of taurousodesoxycholic acid[P]. 2007, EP1985622A1
[108]Reiner Alberto.Ursodeoxycholic acid derivatives and their inorganic and organic salts having therapeutic activity,and process for preparing the same[P].1987,EP0272462A1
[109]1990,EP400695;1993, US5260462
[110]Parentl Massimo. Process for the preparation of taurousodesoxycholic acid[P]. 2007,EP1985622A1
[111]卓超,冯炜,吴达俊,熊志刚.牛磺熊去氧胆酸的合成[J].合成化学.2002,10(5)：444-446
[112]Aroso Roberto,Rossetti Vittorio.Process for the preparation of taurocholic acids[P]. 1993,EP629634
[113]Parentl Massimo. Process for the preparation of taurousodesoxycholic acid[P]. 2008,WO2008128844A1.2007,EP1985622A1
[114]Bonaldi Antonio.Process for the preparation of taurine-conjugated bile acids[P]. 1993,EP0582891A2
[115]Arosio Roberto.Process for the preparation of taurocholic acid[P].1994,EP0629634A2. 1996,US5508453
[116]荣国斌.华东理工大学出版社.大学有机化学(第二版)[M].2000：441
[117]朱强,石朝周,孙汉清.牛黄胆酸钠的合成及其药理作用[J].中国药学杂志.1997,32(4)：236-238
[118]B Dayal,K R Rapole,G Salen,S Shefer,G S Tint,S R Wilson.Microwave-induced rapid synthesis of bile acid conjugate[J].Synlett.1995:861-862
[119]Bishambar Dayal, Jalpa Bhojawala.Keshava R Rapole, Birendra N Pramanik, Norman H Ertel,Sarah Shefer,Gerald Salen. Chemical Synthesis, structural analysis,and decomposition of N-nitroso bile acid conjugates[J].Bioorganic&Medicinal Chemistry.1996,4(6):885-890
[120]邓勇,沈怡,严忠勤,钟裕国.一种胆酸偶联物的制备方法[P].2008,CN101307088A
[121]王海龙,吴成龙,邓勇.牛磺熊去氧胆酸的合成[J].中国工业医药杂志.2009,40(2)：88-89
[122]邓勇,沈怡,王海龙,吴成龙.胆酸类偶合物、其制备方法和用途[P].2010,CN201010139549.0
[123]邓勇,王海龙,沈怡,钟裕国.用于制备胆酸偶联物的化合物、其制备方法和用途[P]2009,CN101503454
[124]Morteza Montazerozohori,Shiva Joohari,Bahador Karami and Nasrin Haghighat.Fast and Highly Efficient Solid State Oxidation of Thiols[J].Molecules.2007,12:694-702
[125]Abd El-Wareth and A O Sarhan. On Acidification of Thiols to Produce the Corresponding Disulfides[J].Heteroatom Chemistry.2000,11(6):399-402
[126]于韬,张珂良,王晖,赵燕芳,宫平.盐酸头孢唑兰的合成[J].中国药物化学杂志.2006,16(2)：91-92
[127]李爱军,周雪琴,李巍,刘东志.头孢地嗪钠的合成研究[J].中国抗生素杂志.2005,30(6)：332-335
[128]唐双强,刘建辉,张会欣,孙凤卿.头孢噻肟酸的合成工艺研究[J].河北化工.2007,30(7)：27-28
[129]黄君强.头孢地尼侧链酸及其活性硫酯的工艺研究[D].河北科技大学.2008
[130]Seema Kanwar and S. D. Sharma. Use of 2,2'-Dibenzothiazolyl Disulfide-Triphenylphosphine and Lawesson's Reagent in the Cyclization of β-Amino Acids[J]. Bull.Chem.Soc.Jpn.2006,79(11):1748-1752
[131]A. Armstrong. N,N'-Carbonyldiimidazole[J].Encyclopedia of Reagents for Organic Synthesis.2001, DOI:10.1002/047084289X.rc024
[132]朱强,石朝周,孙汉清.牛黄胆酸钠的合成及其药理作用[J].中国药学杂 志.1997,32(4)：236-238
[134]Rotenoids. XX, Masateru Miyano. Total Synthesis of Rotenone[J]. Journal of the American Chemical Society.1965,87(17):3958-3962
[135]Roger Adams, L. H. Ulich. The use of oxalyl chloride and bromide for producing acid chlorides, acid bromides or acid anhydrides[J]. J.Am. Chem. Soc.1920,42 (3):599-611
[136]余龙江.生物制药工厂工艺设计[M].化学工业出版社.2008;张衍.制药工程工艺设计[M].化学工业出版社.2006;赵临襄.化学制药工艺学[M].中国医药科技出版社.2003
[2]王玉君,严钟德.老年Ⅱ型糖尿病患者胆结石发生的高危因素[J].中国老年学杂志.1999,19(3)：147-149
[3]侯俊岭,李朝战,鲍广建,杨峰,张超.老年胆石症的临床特征及外科治疗分析[J].中国基层医药.2009,7：1277-1277
[4]吴东进.肝硬化合并胆囊结石的临床研究(附50例报道)[J].中国医药指南.2009,7(24)：72-73
[5]Sridhar A, Sandeep Y, Krishnakishore C, Sriramnaveen P, Manjusha Y, Sriram P, Lakshmi B V, Lakshmi A Y, Sivakumar V. Gall Stone Ileus with Acute Kidney Injury-A Case Report[J].Renal failure.2011,33(9):908-909
[6]唐俊.胆结石与消化性溃疡的关系[J].临床医药实践.2009,18(5)：362-363
[7]方干.结石的化学成份分类方法[J].中华外科杂志.1964,(2)：71
[8]孙颖,杨展澜,申国荣,周勇,吴瑾光,徐光宪.胆结石组成和形成机理的研究进展[J].中国科学(B辑).2001,31(5)：385-393
[9]潘其金.超声诊断肝胆结石的临床意义[J].国际医药卫生导报(半月刊).2005,11(16)：60-61
[10]吴在德.外科学(第5版)[M].人民卫生出版社.2000,616-617
[11]Huang ZQ, Huang XQ. Evolution of surgical treatment of intrahepatic lithiasis in China[J]. China Natl J New Gastroenterol.1997,3:131-133
[12]Stokes C S, Krawczyk M, Lammert F. Gallstones:Environment, Lifestyle and Genes[J]. Digestive diseases.2011,29(2):191-201
[13]徐闫军.胆结石患病率的发展趋势分析[J].内蒙古中医药.2011,30(14)：71-73
[14]孙运峰.飞行人员1020例胆石症患病率及相关因素调查[J].中国误诊学杂志.2008,8(33)：8314
[15]叶忻,王保钢,项晓宇等.上海江湾地区成年人胆囊结石发病情况调查[J].肝胆胰外科杂志.2003,15：28-30
[16]施维锦,姜广杰,谢敏等.上海地区“健康人”胆石发生率的调查报告[J].中华消化杂志.1989,9：105
[17]蒋兆彦,韩天权,张圣道.从胆石成因研究谈胆石病预防的新策略[J].中华肝胆外科杂志.2011,17(9)：697-700
[18]赵国臣,周春祥.胆结石成石机制研究概况[J].广西中医学院学报.2007,10(2)：76-78
[19]Somien GJ, Gilar T.A non-micellar mode of cholesterol transport in human bile[J].FBRS Lett.1983,156:256-268
[20]王学军,李玉民,李世雄.细菌在胆固醇结石中的作用研究[J].中国现代医学杂志.2003,13(3)：4-7
[21]Afdhal NH, Niu N, Gantz D, et al. Bovine gallbladder mucin acceerates cholesterol monohydrate crystal growth in modelbile[J].Gatroenterology.1993,104(5):1515-1523
[22]朱雷明,赵洪,蔡端等.胆固醇结石中细菌对人胆汁胆固醇晶体形成的作用[J].中华肝胆外科杂志.2005,11(3)：182
[23]朱雷明,蔡端,吕元等.模拟胆汁体系中胆固醇结石内细菌对胆固醇晶体形成的作用[J].中华外科杂志.2004,42(24)：1503
[24]Stokes C S, Krawczyk M, Lammert, F. Gallstones:Environment, Lifestyle and Genes[J]. DIGESTIVE DISEASES.2011,29(2):191-201
[25]潘其金.超声诊断肝胆结石的临床意义[J].国际医药卫生导报(半月刊).2005,11(16),60-61
[26]皋岚雅,焦成文,王坚,蔡珍福,刘存官,张大治,郝立校.胆石病患者术前MRCP检查价值探讨[J].肝胆胰杂志.2006,18(3)：165-166
[27]卢盛贞,袁青.内窥镜治疗胆结石84例护理体会[J].实用临床医学.2004,5(3)：16-17
[28]李庆怀,高静涛,曹嘉华,熊剑平,何效东,秦建伟.肝切除治疗肝胆管结石[J].中华肝胆外科杂志.2003,9(11)：645-646
[29]植传雄.两种方法治疗胆结石的临床效果分析[J].中国现代药物应用.2010,4(16),66-67
[30]卢景雾,杨正红,陈立新,王夔,沈韬,林丛,傅贤波,周孝思.人体胆结石的电子顺磁共振波谱研究[J].科学通报.1992,(8)：738-741
[31]刘刚,滕秀萍,王华,汪禄祥.胆结石的磁性研究[J].生物磁学.2004,4(2)：25-27
[32]黄鹤,史亦飞.磁场综合治疗胆石症3866例观察[J].生物磁学.2002,2(2)：28-29
[33]颜莉,金祥瑞,陈飞明,余练红,张沪生.综合磁场治疗胆结石及其测试分析[J].武汉科技学院学报.2008,21(3)：9-12
[34]裴莉,孙立巍.高压氧治疗泥沙样胆结石疗效观察[J].中国煤炭工业医学杂志.2008,11(11)：1740-1741
[35]陈进洪,蔡端,马保金.利胆冲剂对胆汁成石趋势的影响[J].肝胆胰外科杂志.2006,18(3)：142-143
[36]林长春.利胆排石汤治疗肝胆湿热型胆结石的临床研究[J].吉林中医药.2009,29(12)：1039-1040
[37]韩金山,宝龙.蒙医药治疗胆结石体会[J].中国民族医药杂志.2008,11：10
[38]尕藏才让,王成,普化加.藏药治疗胆结石的临床观察[J].医药信息(下旬版).2011,24(5)：190
[39]刘嘉,万春艳.熊胆粉溶胆结石的作用研究[J].中国林副特产.2007,4：37-39
[40]顾树南,蔡珍福,王坚.胆结石灌注药物溶石的治疗进展[J].中华现代外科学杂志.2005,2(5)：431-434
[41]向伟.胆结石治疗方法的研究状况综述[J].中外健康文献.2009,8(19)：227-228
[42]谢广静.黄伟华.输尿管结石的现代微创治疗[J].中华腔镜泌尿外科杂志.2008,2(2)：60-63
[43]俞亚红.卢兴培,丁志强等.液电碎石仪治疗肝内外胆管难取性结石[J].华中科技大学学报(医学版).2005,34(1)：72-73
[44]谢广静,陈光,沈思等.输尿管镜钬激光碎石术治疗输尿管结石536例报告[J].中华腔镜泌尿外科杂志.2008,2(2)：33-35
[45]谭德福,陈涛,黄利呜等.胆穴刺血抑制豚鼠胆囊结石的实验研究[J].中国中医药科技.1996,3(3)：5
[46]邱昌.按摩治疗胆结石二法[J].中国民间疗法.2005,9(13)：14-15
[47]王洪玲.电针治疗胆结石268例[J].上海针灸杂志.2004,23(7)：25
[48]冯西园.不吃早饭易患胆结石[J].快乐养生.2010,6(中)：35
[49]刘清,刘钰,刘萍,罗晓梅胆结石患者膳食营养状况调查及相关性分析[J].卫生职业教育.2005,23(10)：86-87
[50]钟美,陈黄锰,刘浩丹等.茶叶中咖啡碱的功效与提取方法概述[J].中国民族民间医药.2008,17(1])：16-17
[51]PalanduzA,YalcinmI,TongueE,etal.Sonographicassessment of ceftriaxone-associated biliary pseudolithiasis in children[J].J Clin Ultrasound.2000,28(4):166-168
[52]马伟军,董萍.头孢曲松钠致胆结石1例[J].中国综合临床.2008,,24(13)：76
[53]朱红,刘治军.影响胆结石形成的药物及使用注意事项[J].中国全科医学.2007,10(18)：1536-1537
[54]马洪娟.警惕药源性胆结石[J].杭州科技双月刊.2001,3：43
[55]白文林,张玲霞.药物性肝胆淤积[J].肝脏.2001,6(1)：47-48
[56]Michihiro Nonaka,Susumu Tazuma,Hideyuki Hyogo,Keishi Kanno and Kazuaki Chayama. Cytoprotective effect of tauroursodeoxycholate on hepatocyte apoptosis induced by peroxisome proliferator-activated receptor gamma ligand[J].Journal of Gastroenterology and Hepatology.2008,23:198-206
[57]Carmela Fimognari, Monia Lenzi, Giorgio Cantelli-Forti, and Patrizia Hrelia. Apoptosis and Modulation of Cell Cycle Control by Bile Acids in Human Leukemia T Cells[J]. Ann. N.Y. Acad. Sci.2009,1171:264-269
[58]黄延风.胆汁酸的毒性作用[J].国际检验医学杂志.2006,27(2)：152-157
[59]Joana D Amaral, Ricardo J. S. Viana, Rita M. Ramalho, Clifford J. Steer, and Cecilia M. P. Rodrigues. Bile acids:regulation of apoptosis by ursodeoxycholic acid[J].Journal of Lipid Research.2009,50:1721-1734
[60]Vijayalakshmi N,Martia U.Hydroxyl-terminated dndritic oligomers from bile acids.Synthesis and properties[J].J Org Chem.2006,71(2):768-774
[61]Wess G,Kramer W. Dissecting G-protein-coupled receptors:Structure,function.and ligand interaction[J].Chembiochem.2002,3(10):915-919
[62]靳雪源,王慧芬.以胆酸为载体的肝靶向疗法[J].军事医学科学院院刊.2007,31(3)：287-290
[63]李培锋,关红,赵红霞,斯琴.鹅去氧胆酸的平喘及抗炎作用机理研究[J].中国中药杂志.2004,29(4)：349-352
[64]中国药典2000年版二部：1006
[65]张铭,田辉.熊去氧胆酸在胆汁淤积性肝病中的作用机制和治疗指征[J].肝脏.2007,12(1)：64-66
[66]罗强,陈全成,吴瑶,姜苗苗,陈志鸿,张晓坤,陈海峰.熊胆的化学成分研究[J].中国中药杂志.2010,35(18)：2416-2419
[67]Michihiro Nonaka,Susumu Tazuma,Hideyuki Hyogo,Keishi Kannoand Kazuaki Chayama. Cytoprotective effect of tauroursodeoxycholate on hepatocyte apoptosis induced by peroxisome proliferator-activated receptor gamma ligand[J] Journal of Gastroenterology and Hepatology.2008,23:198-206
[68]Neuman M G,Cameron R G,Shear N H,Bellentani S,Tiribelli C. Effect of tauroursodeoxycholic and ursodeoxycholic acid on ethanol-induced cell injuries in the human hep G2 cell line[J].Gastroenterology.1995,109(2):555-563
[69]蒋欣桐,蔡可丽,郭媛媛,王荣.牛磺酸熊脱氧胆酸对高糖环境下晶状体上皮细胞的保护作用[J].山东大学学报(医学版).2010,48(3)：74-82
[70]Leonardo Baiocchi,Giuseppe Tisone,Mario Antonio Russo,Chiara Longhi,Gianpiero Palmieri,Antonio Volpe,Cristiana Almerighi,Claudia Telesca,Marco Carbone,Luca Toti,Francesco De Leonardis and Mario Angelico.TUDCA prevents cholestasis and canalicular damage induced by ischemia-reperfusion injury in the rat, modulating PKCa-ezrin pathway[J]. European Society for Organ Transplantation.2008,21:792-800
[71]Paumgartner G. Medical treatment of cholestatic liver diseases:From pathobiology to pharmacological targets[J].World J Gastroenterol.2006,12 (28):4445-4451
[72]李继珩,刘士忠,姚文庄.牛磺熊去氧胆酸镇静与镇痛作用的动物实验[J].医药导报.2002,21(1)：11-12
[73]Angelico M,Tisone G, Baiocchi L,Palmieri G,Pisani F, Negrini S,Anselmo A,Vennarecci G,Casciani C U. One-year pilot study on tauroursodeoxycholic acid as an adjuvant treatment after liver transplantation [J]. Italian journal of gastroenterology and hepatology,1999,31(6):462-468.
[74]Hert1 M,Hertl M C,Kunkel P,Schilling S,Prevot B,Kluth D,Malago M,Broelsch C E. Tauroursodeoxycholate ameliorates reperfusion injury after pig liver transplantation[J].Transplant international:official journal of the European Society for Organ Transplantation.1999,12(6):454-62
[75]翟钰栋,张晓坤,曾锦章,储瑞蔼.一种可用于皮肤创伤修复的药物[P].CN101732325
[76]Yoshikawa Kunihiko,Itami Akira,Yamaguchi Hiroshi.Therapeutics for psoriasis containing tauroursodeoxycholic acid [P]. JP10017474
[77]王丹,杨玲,黄金明,王保永,李靓,钱伟,叶进,侯晓华.牛磺熊去氧胆酸抑制四氯化碳诱导的大鼠肝纤维化[J].世界华人消化杂志.2010,18(19)：1979-1984
[78]Bataller R,Brenner DA.Liver fibrosis[J].J Clin Invest.2005,115(2):209-218姚光弼.慢性病毒性肝炎治疗的策略及实施[J].现代实用医学.2003,15(1)：2-11
[79]Crosignani A,Budillon G, Cimino L,Del Vecchio Blanco C,Loguercio C,Ideo G,Raimondo G,Stabilini R,Podda M. Tauroursodeoxycholic acid for the treatment of HCV-related chronic hepatitis: a multicenter placebo-controlled study [J]. Hepato-gastroenterology.1998,45:1624-1629
[80]雷陵,艾书眉.神农肝酶安胶囊治疗慢性病毒性肝炎转氨酶升高的临床观察[J].中国中医药信息杂志.2003,10(12)：44
[81]Leonardo Furio,Pasquale Tomaiuolo,Raffaele Gatta,Michele Tomaiuolo,Serafino Talarico,Vittorio Beverelli,Domenico Prencipe. Treatment of virus-associated liver cirrhosis with tauroursodeoxycholic acid:Evaluation of cytolysis and cholestasis indexes and selected immunologic variables[J].Current Therapeutic Research.1994,5(11):1355-1361
[82]蒋欣桐,蔡可丽,郭媛媛,王荣.牛磺酸熊脱氧胆酸对高糖环境下晶状体上皮细胞的保护作用[J].山东大学学报(医学版).2010,48(3)：74-82
[83]王晓黎,戚朝秀,曹良启,杨晖,钱益勇,张振平.毒胡萝卜内酯对人晶状体上皮细胞HLE-B3生长抑制作用的研究[J].中国病理生理杂志.2008,24(4)：692-696
[84]A. Malo,B. Kruger,E. Seyhun,C. Schafer,R. T. Hoffmann,B. Goke,and C. H. Kubisch. Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini[J].Am J Physiol Gastrointest Liver Physiol.2010,299:877-886
[85]Emanuel Berger,Dirk Haller. Structure-function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic reticulum stress in intestinal epithelial cells[J].Biochemical and Biophysical Research Communications.2011,409:610-615
[86]Yeon Yi Lee,Shin Hee Hong,Ye Jin Lee,Sung Soo Chung,Hye Seung Jung,Sang Gyu Park,Kyong Soo Park. Tauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stress[J].Biochemical and Biophysical Research Communications.2010,397:735-739
[87]Asli F. Ceylan-Isik,Nair Sreejayan,Jun Ren. Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction[J].Journal of Molecular and Cellular Cardiology.2011.(50):107-116
[88]Susana Sola, Joana D. Amaral,Pedro M. Borralho.Rita M. Ramalho,Rui E. Castro,Ma' rcia M. Aranha,Cifford J. Steer,and Ceciia M. P. Rodrigues. Functional Modulation of Nuclear Steroid Receptors by Tauroursodeoxycholic Acid Reduces Amyloid-β-Peptide-Induced Apoptosis[J].Molecular Endocrinology.2006,20(10):2292-2303
[89]Stanley D.W. Miller, Catherine M. Greene, Caitriona McLean, Matthew W. Lawless,Clifford C. Taggart,Shane J. O'Neill,and Noel G. McElvaney. Tauroursodeoxycholic Acid Inhibits Apoptosis Induced by Z Alpha-1 Antitrypsin via Inhibition of Bad[J].HEPATOLOGY.2007,46(2):496-503
[90]Ahmet Colak,Bilal Kelten,Ayhan Sagmanligil,Osman Akdemir,Alper Karaoglan,Elife Sahan,Ozge Celik,Seref Barut. Tauroursodeoxycholic acid and secondary damage after spinal cord injury in rats [J] Journal of Clinical Neuroscience.2008,15:665-671
[91]R J S Viana,A F Nunes,R E Castro,R M Ramalho,J Meyerson,S Fossatib,J Ghiso,A Rostagno and C M PRodrigues. Tauroursodeoxycholic acid prevents E22Q Alzheimer's Aβ toxicity in human cerebral endothelial cells[J].Cellular and Molecular Life Sciences. 2009,66:1094-1104
[92]Florian Schulz Ingo Just, and Harald Genth. Prevention of Clostridium sordellii Lethal Toxin-Induced Apoptotic Cell Death by Tauroursodeoxycholic Acid[J]. Biochemistry.2009, 48:9002-9010
[93]Brian C.Oveson,Takeshi Iwase,Sean F Hackett,Sun Young Lee,Shinichi Usui,Thomas W Sedlak,Solomon H Snyder,Peter A Campochiaro and Jennifer U Sung. Constituents of bile,bilirubin and TUDCA,protect against oxidative stress-induced retinal degeneration [J]. Journal of Neurochemistry.2011,116:144-153
[94]Ozcan U,Yilmaz E,Ozcan L,Furuhashi M,Vaillancourt E,Smith RO,Gorgun CZ,Hotamisligil GS.Chemical chaperoncs reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes[J]. Science.2006,313:1137-1140
[95]Asli F Ceylan-Isik,Nair Sreejayan,Jun Ren. Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction[J].Journal of Molecular and Cellular Cardiology.2011, (50):107-116
[96]Sancia Gaetani. A sideway glance:a new role for endoplasmic reticulum chemical chaperones as leptin sensitizers[J].Genes Nutr.2009(4):157-159
[97]Michael J Bull,Gottfried H Kellermann,Kelly L Olson.Methods for reducing cravings and impulses associated with addictive and compulsive behaviors[P].2011, US20110098265A1
[98]傅贤波,林三仁,范竹平,邱德凯.牛磺熊去氧胆酸溶解胆囊胆固醇结石有效性和安全 性——随机、双盲、安慰剂对照、多中心临床研究[J].中国微创外科杂志.2007,7(12)：1159-1163
[99]A Larghi,A Crosignani,P M Battezzati,G DE Valle.M Allocca,P Invernizzi,M Zuin,M Podda. Ursodeoxycholic and tauroursodeoxycholic acids for the treatment of primary billiary cirrhosis:a pilot crossover study[J].Aliment Pharmacol Ther.1997,11:409-414
[100]Pietro Invernizzi,Kenneth D. R. Setchell.Andrea Crosignani. Differences in the Metabolism and Disposition of Ursodeoxycholic Acid and of its Taurine-Conjugated Species in Patients With Primary Biliary Cirrhosis[J]. HEPATOLOGY.1999,29(2):320-327
[101]Ulrich Baumgartner,Jorgen Scholmerich,Markus Sellinger,Martina Reinhardt,Gunter Ruf,and Eduard-Heinrich Farthmann. Different Protective Effects of Tauroursodeoxycholate, Ursodeoxycholate, and 23-Methyl-Ursodeoxycholate Against Taurolithocholate-Induced Cholestasis[J]. Digestive Diseases and Sciences.1996,41(2):250-255
[102]Loria P,Bozzoli M,Angelico M,Bertolotti M,Carubbi F,Concari M.Baiocchi L,Nistri A,Della Guardia P,et al. Effect of taurohyodeoxycholic acid on biliary lipid secretion in man: Preliminary report[J]. Italian Journal of Gastroenterology.1996,28(7):391-392
[103]Balandraud-PieriNathalie,QueneauPierre-Edouard,Caroli-BoscFrancois-Xavier, Bertault-Peres Pierre,Montet Anne-Marie,Durand Alain,Montet Jean-Claude. Effects of tauroursodeoxycholate solutions on cyclosporin A bioavailability in rats[J].Drug Metabolism and Disposition.1997,25(8):912-916
[104]Sawada. Producing conjugated ursodeoxycholic acids[P].EP0119040A1.1984
[105]章贵荣,韩成光,万平,陈峰.一种牛磺熊去氧胆酸的禽胆制取法[P].2002,CN1357551A
[106]Parentl Massimo.Procedimentd per la sintesi di acido ursodesossicolico coniugato con la taurina[P].1983,IT1167038
[107]Parentl Massimo. Process for the preparation of taurousodesoxycholic acid[P]. 2007, EP1985622A1
[108]Reiner Alberto.Ursodeoxycholic acid derivatives and their inorganic and organic salts having therapeutic activity,and process for preparing the same[P].1987,EP0272462A1
[109]1990,EP400695;1993, US5260462
[110]Parentl Massimo. Process for the preparation of taurousodesoxycholic acid[P]. 2007,EP1985622A1
[111]卓超,冯炜,吴达俊,熊志刚.牛磺熊去氧胆酸的合成[J].合成化学.2002,10(5)：444-446
[112]Aroso Roberto,Rossetti Vittorio.Process for the preparation of taurocholic acids[P]. 1993,EP629634
[113]Parentl Massimo. Process for the preparation of taurousodesoxycholic acid[P]. 2008,WO2008128844A1.2007,EP1985622A1
[114]Bonaldi Antonio.Process for the preparation of taurine-conjugated bile acids[P]. 1993,EP0582891A2
[115]Arosio Roberto.Process for the preparation of taurocholic acid[P].1994,EP0629634A2. 1996,US5508453
[116]荣国斌.华东理工大学出版社.大学有机化学(第二版)[M].2000：441
[117]朱强,石朝周,孙汉清.牛黄胆酸钠的合成及其药理作用[J].中国药学杂志.1997,32(4)：236-238
[118]B Dayal,K R Rapole,G Salen,S Shefer,G S Tint,S R Wilson.Microwave-induced rapid synthesis of bile acid conjugate[J].Synlett.1995:861-862
[119]Bishambar Dayal, Jalpa Bhojawala.Keshava R Rapole, Birendra N Pramanik, Norman H Ertel,Sarah Shefer,Gerald Salen. Chemical Synthesis, structural analysis,and decomposition of N-nitroso bile acid conjugates[J].Bioorganic&Medicinal Chemistry.1996,4(6):885-890
[120]邓勇,沈怡,严忠勤,钟裕国.一种胆酸偶联物的制备方法[P].2008,CN101307088A
[121]王海龙,吴成龙,邓勇.牛磺熊去氧胆酸的合成[J].中国工业医药杂志.2009,40(2)：88-89
[122]邓勇,沈怡,王海龙,吴成龙.胆酸类偶合物、其制备方法和用途[P].2010,CN201010139549.0
[123]邓勇,王海龙,沈怡,钟裕国.用于制备胆酸偶联物的化合物、其制备方法和用途[P]2009,CN101503454
[124]Morteza Montazerozohori,Shiva Joohari,Bahador Karami and Nasrin Haghighat.Fast and Highly Efficient Solid State Oxidation of Thiols[J].Molecules.2007,12:694-702
[125]Abd El-Wareth and A O Sarhan. On Acidification of Thiols to Produce the Corresponding Disulfides[J].Heteroatom Chemistry.2000,11(6):399-402
[126]于韬,张珂良,王晖,赵燕芳,宫平.盐酸头孢唑兰的合成[J].中国药物化学杂志.2006,16(2)：91-92
[127]李爱军,周雪琴,李巍,刘东志.头孢地嗪钠的合成研究[J].中国抗生素杂志.2005,30(6)：332-335
[128]唐双强,刘建辉,张会欣,孙凤卿.头孢噻肟酸的合成工艺研究[J].河北化工.2007,30(7)：27-28
[129]黄君强.头孢地尼侧链酸及其活性硫酯的工艺研究[D].河北科技大学.2008
[130]Seema Kanwar and S. D. Sharma. Use of 2,2'-Dibenzothiazolyl Disulfide-Triphenylphosphine and Lawesson's Reagent in the Cyclization of β-Amino Acids[J]. Bull.Chem.Soc.Jpn.2006,79(11):1748-1752
[131]A. Armstrong. N,N'-Carbonyldiimidazole[J].Encyclopedia of Reagents for Organic Synthesis.2001, DOI:10.1002/047084289X.rc024
[132]朱强,石朝周,孙汉清.牛黄胆酸钠的合成及其药理作用[J].中国药学杂 志.1997,32(4)：236-238
[134]Rotenoids. XX, Masateru Miyano. Total Synthesis of Rotenone[J]. Journal of the American Chemical Society.1965,87(17):3958-3962
[135]Roger Adams, L. H. Ulich. The use of oxalyl chloride and bromide for producing acid chlorides, acid bromides or acid anhydrides[J]. J.Am. Chem. Soc.1920,42 (3):599-611
[136]余龙江.生物制药工厂工艺设计[M].化学工业出版社.2008;张衍.制药工程工艺设计[M].化学工业出版社.2006;赵临襄.化学制药工艺学[M].中国医药科技出版社.2003