盐酸右旋咪唑消旋化及拆分工艺研究
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摘要
本论文所研究的盐酸左旋咪唑,又名驱虫净,是咪唑的一个衍生物。它是盐酸四咪唑的左旋体,是一种广谱抗线虫药。盐酸四咪唑与盐酸左旋咪唑从化学特性上看,都是6—苯基2、3、5、6—四氢咪唑并(2,1—b)噻唑的盐酸盐,具有相同的化学结构。所不同的是四咪唑为外消旋体,左旋咪唑是四咪唑经过化学方法处理后拆分而成的左旋体。在一般条件下,两者的理化性质相同,但生理生化作用却大不一样。四咪唑的原料成本要比左旋咪唑低50%,其临床驱虫效果也要比左旋咪唑小50%。左旋咪唑的疗效是消旋体的两倍,毒性低一半。
传统消旋工艺采用以二甲基亚砜作为溶剂在加热的碱性条件下进行消旋,但由于该工艺中大量使用了价格昂贵、难以回收且污染环境的有机溶剂二甲基亚砜,使得生产厂家经济效益低下,同时面临严重的环保问题。针对这些问题,本以盐酸右旋四咪唑游离碱为研究对象,以乙醇水溶液代替二甲基亚砜溶媒,确定了新的消旋化工艺路线,通过单因素和正交化试验找到了该工艺路线的最佳工艺条件。同时还在查阅文献的基础上积极探索出了一条新的拆分工艺路线。这是该课题的主要的创新点之一。
试验结果表明:
1、以乙醇水溶液作为溶剂在碱性条件下进行减压回流消旋化工艺试验的最佳工艺条件为:(20g盐酸右旋咪唑游离碱,70℃反应温度,0.07MPa减压回流):消旋时间为1.5h,氢氧化钠加入量3g,乙醇与水的体积比为1:3,溶剂的加入体积为40ml。这种新方法工艺简单、反应条件温和,所需的反映物价廉易得且对环境污染小,具有良好的环保意义和积极的技术进步意义。
2、在研究盐酸右旋咪唑外消旋物拆分工艺中,确定了成盐后温度和成盐终点的pH值作为影响因素进行试验。最佳工艺条件为:温度5℃,pH值为3。
Levamisole hydrochloride, the ramification of imidazole, is a broad-spectrum medicine against wireworm. Compare to its racemate (DL-Tetramisole) , levamisole hydrochloride has more validity and less toxicity. In general, it can be got by disconnecting from DL-Tetramisole . Its dextrorotatory substant is an antidepressant which does not have the helminthic effect.Based on consulting the domestic and international reference documents, two totally different processes are discussed in my paper and a reasonable process is determined by the comparison of process available . In the first one , Our experiment team use ethanol liquor as solvent and achieve the process of racemization of dextrorotatory imidazole in sodium hydroxide environment. And monofactor method and multifactor orthogonalizing design method are applized to get the optimum processing conditions in this racemization process. And then a new split technics, which can not be found in any documentation, is searched after: Through controlling the pH cost and temperature of reaction of the solution, the split process can be easily obtained.
Meanwhile, we got the optimum processing conditions. This is exactly one of the innovations in my paper.The following have been obtained through lots of experiments.1. The optimum processing conditions by using ethanol liquor as the solvent in this racemization process:( dextromisole hydrochloride 20g, reaction temperature 70°C, pressure 0.07MPa) racemization time 1.5 hours;volume of ethanol liquor 40 ml;the mass of sodium hydroxide 3.0 grams;proportion of ethanol and water 3:1.2. The optimum processing of the new split technics has been obtained based on a large number experiments, which the optimum processing conditions is: reaction temperature 5°C,pH costs 3.
传统消旋工艺采用以二甲基亚砜作为溶剂在加热的碱性条件下进行消旋,但由于该工艺中大量使用了价格昂贵、难以回收且污染环境的有机溶剂二甲基亚砜,使得生产厂家经济效益低下,同时面临严重的环保问题。针对这些问题,本以盐酸右旋四咪唑游离碱为研究对象,以乙醇水溶液代替二甲基亚砜溶媒,确定了新的消旋化工艺路线,通过单因素和正交化试验找到了该工艺路线的最佳工艺条件。同时还在查阅文献的基础上积极探索出了一条新的拆分工艺路线。这是该课题的主要的创新点之一。
试验结果表明:
1、以乙醇水溶液作为溶剂在碱性条件下进行减压回流消旋化工艺试验的最佳工艺条件为:(20g盐酸右旋咪唑游离碱,70℃反应温度,0.07MPa减压回流):消旋时间为1.5h,氢氧化钠加入量3g,乙醇与水的体积比为1:3,溶剂的加入体积为40ml。这种新方法工艺简单、反应条件温和,所需的反映物价廉易得且对环境污染小,具有良好的环保意义和积极的技术进步意义。
2、在研究盐酸右旋咪唑外消旋物拆分工艺中,确定了成盐后温度和成盐终点的pH值作为影响因素进行试验。最佳工艺条件为:温度5℃,pH值为3。
Levamisole hydrochloride, the ramification of imidazole, is a broad-spectrum medicine against wireworm. Compare to its racemate (DL-Tetramisole) , levamisole hydrochloride has more validity and less toxicity. In general, it can be got by disconnecting from DL-Tetramisole . Its dextrorotatory substant is an antidepressant which does not have the helminthic effect.Based on consulting the domestic and international reference documents, two totally different processes are discussed in my paper and a reasonable process is determined by the comparison of process available . In the first one , Our experiment team use ethanol liquor as solvent and achieve the process of racemization of dextrorotatory imidazole in sodium hydroxide environment. And monofactor method and multifactor orthogonalizing design method are applized to get the optimum processing conditions in this racemization process. And then a new split technics, which can not be found in any documentation, is searched after: Through controlling the pH cost and temperature of reaction of the solution, the split process can be easily obtained.
Meanwhile, we got the optimum processing conditions. This is exactly one of the innovations in my paper.The following have been obtained through lots of experiments.1. The optimum processing conditions by using ethanol liquor as the solvent in this racemization process:( dextromisole hydrochloride 20g, reaction temperature 70°C, pressure 0.07MPa) racemization time 1.5 hours;volume of ethanol liquor 40 ml;the mass of sodium hydroxide 3.0 grams;proportion of ethanol and water 3:1.2. The optimum processing of the new split technics has been obtained based on a large number experiments, which the optimum processing conditions is: reaction temperature 5°C,pH costs 3.
引文
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[4] 田志伟.偏振光及其应用(第二版)[M].上海:上海科学技术出版社,1965:46-48.
[5] 兰斯别尔格著,王鼎昌译.光学(上册)[M].北京:人民教育出版社,1961:293-323.
[6] Yaozhong Jiang, Song Xue, Kaibai Yu, Zhi Li. Asymmetric hydroformylation catalyzed by rhodium (1) complexes of novel chiral spiro ligands Journal of Organometallic Chemistry[J]. 1999, 586(2):159-165.
[7] Ching-Wen Lin, Chi-Ching Lin, Yue-Ming Li. A highly efficient and stereospecific borane reduction of spiro [4, 4] nonane-i, 6-dione catalyzed by a chiral oxazaborolidinc [J]. Tetrahedmn Letters, 2000,41(22):4425-4429.
[8] H B Kagan, J D Morrison(Editor) "Chiral Ligand for Asymmetric Catalysis: Asymmetric Synthesis"Vol 5, Academic Press, New York, 1985, chapt 1.
[9] 尹玉英,刘春蕴.有机化合物分子旋光性的螺旋理论[M].北京:化学出版社,2000:3-5.
[10] Ching-Wen Lin, Chi-Ching Lin, Yue-Ming Li. A highly efficient and stereospecific borane reduction of spiro [4, 4] nonane-i, 6-dione catalyzed by a chiral oxazaborolidinc [J]. Tetrahedmn Letters, 2000, 41(22):4425-4429.
[11] Cahn R S, C. Ingold and V. Prelog, Angew. Chem., Intern. Ed., 5,385(1966).
[12] Cahn R S, Ingold C K, prelog V. Experientia,1956,12(2): 81-94.
[13] hsuno S, Nakano M, Miyasaki K, et al. Enantioselective reduction of ketones and oxime ethem with magenta pre-pared from borane and chiral amino alcohols[J]. J. Chem. Soc. Perldn Trans. 1985, 12(10): 2039-2044.
[14] 方百盈,冯大炎.L-氨基酸消旋化作用的探讨[J].化学研究与应用.1997(1):40-44.
[15] 尹玉英,刘春蕴.螺旋理论和旋光性—旋光机理和对几个问题的解疑[J].石油化工高等学校学报,1996,9(2):13-15.
[16] 尹玉英,刘春蕴.导致旋光性根本原因的探讨[J].化学研究与应用,1977,9(5):537-541.
[17] 尹玉英,刘春蕴.螺旋结构导致旋光性[J].石油化工高等学校学报,1998,11(1):6-11.
[18] 舒天霖,孙毓庆编著.偏振光及其在药学上的应用[M].北京:人民卫生出版社,1983:61-63.
[19] 尹玉英,刘春蕴.有机化合物分子旋光性的螺旋理论[M].北京:化学出版社,2000:169-171.
[20] Gutsche C D,Pasto D J. Fundamantals of Organic Chemistry. New Jersey, Englewood Cliffs: Prentice Hall, Inc. 1975: 494-542.
[21] 尹玉英,刘春蕴.测定条件对旋光度的影响[J].中国科学院研究生学报,1997,14(1):23-26.
[22] Izumi Y, Tai A. Stereo-Differentiating Reactions. Japan: Kodansha Ltd,1977,67.
[23] Horsman G, Emeis C A.Low Temperature Optical Rotatory Dispersion. Tetrahedren Lett. 1965,33(3):3037-3039.
[24] Cai L S, Mahmoud H,Han Y. Bionudear verts mononuclear copper complexes as catalysts for asymmetric cyelopropanation of styrene[J]. Tetrahedron: Asymmetry, 1999, 10(3): 411-427.
[25] 冯海嶷.有机化学[M].北京:高等教育出版社,1983:19-20.
[26] Rippert A J. New axially chiral bis(dihydrocxazoles)as llghands in stereoselective transition-metalcatalysis[J]. Helv. Chim. Acta, 1998, 81(4): 676-687.
[27] HOFFMANN LA ROCHE. A process for the manufacture of 3-(3, 4-dihydroxyphenyl)serlne. GB 1445049,1976-11-10.
[28] Huneck S, Porzel A. Synthese and spektroskopische Eigenschaften der stereoisomerenEster aus L-und D-N-Benzoylalanin und L-and D-N-Benzoylalaninol [J]. Z. Natuoeorsch. 1994, 49(4): 569—575.
[29] Ivanova T M, Arkhipova S F,Kugalova-Shemyakina G P.Akad.Nauk. SSSR Ser.Khim Vol. 7. 1973: 1521-1526.
[30] Peter Etta, Horz, Fdsdrich, et. al. [J]. Geochim. Acta 1997, 61(18): 102-113.
[31] Raeymaekers A H M,Roevens L F C. Janssen P A J. Tetrahedron Letters. 1967,16: 1467-1470.
[32] E. L. Eliel. Stereochemistry of Carbon Compounds,1962,Chapter 4: 43-78.
[33] A. F Holleman,Org. Syn., Coll. Vol. 1,1944: 497. E. H.. Rodd,Chem of Carbon Compounds,2B,1168(1952).
[34] H Bruckner, J Justus, J Kirschbaum. Saccharide induced racemization of amino acid in the course of the Maillard reaction[J]. Amino acids 2001, 21: 429-433.
[35] Yamada Y, Hongo C, Yoshioka R.. Method for the racemization of optically active amino acid[J]. J Org Chem. 1983, 48: 843-846.
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