奥硝唑的合成

●644●中国医药工业杂志Chinese Journal of Pharmaceuticals 2004, 35(11)奥硝唑的合成张峻松1.2，张广明'，贾春晓’，毛多斌2(1.郑州大学化学系，河南郑州450052; 2.郑州轻工业学院食品生物工程系，河南郑州450002)摘要:用2-甲基-s-硝基咪唑、环氧氯丙烷和少量浓硫酸在甲酸中于0~5C反应10h得到奥硝唑，收率51%。关键词:奧硝唑;抗菌剂;合成中图分类号: R978.69文献标识码: A文章编号: 1001-8255 (2004) 11-0644-01奥硝唑(ornidazole, 1)， 化学名为a- (氯甲基)-酸作用下开环后得到，但原料不易得";，<2) 用2和.2-甲基-5-硝基-1H-咪唑-1-乙醇，是继甲硝唑环氧氯丙烷(3)在AIC3作用下反应得到，收率45.5%，(metronidazole)、替硝唑(tinidazole)后，于1977年但反应需严格无水2: (3) 用2和3在甲酸中反应得由瑞士罗氏公司首次在德国上市的抗厌氧菌和抗到，收率42%，但反应时间长达72h，且甲酸用量滴虫药物，已在意大利、法国、瑞士等多个国家上大，不利于放大生产[3]。本文对第三法进行了改进，市11.21。加入少量浓硫酸作为催化剂，同时增强了反应体系1主要有以下合成路线: (1)用2-甲基-5-硝基的酸度,有利于原料的溶解，甲酸用量可减半，并确咪唑(2)和二(3-氯-2-羟丙基)硫酸酯反应，在浓盐定了最佳反应条件为0~5"C反应10h，收率51%。CH,H2C -CHCH2C1HCOOHL O2NCHH2SO4CH2CHCH2C1Of水(10ml)，用浓氨水调至pH 3~4后冷至0C，析实验部分出未反应的2(.5g)。滤液用浓氨水调至pH7~8后奥硝唑(1)加入硫酸铵至饱和，用苯萃取(25mlX5)，合并苯100ml圆底烧瓶中加入甲酸(35m1)和浓硫酸层后用10mol/L硫酸(15ml X 3)萃取，合并酸液后(1ml)，搅拌下加入2(6.3g, 0.05mol)， 于0~5°C加入硫酸铵饱和，用氨水调至pH 7~8，得黄色油滴加3(23.0g，0.25mol)， 滴毕继续室温搅拌反应状物，加少量1晶种后析晶，过滤，滤饼用水洗涤10h。减压回收甲酸和过量的3。剩余物中加入冰后干燥，得到1粗品(6.9g)，再用甲苯重结晶得淡收稿日期: 2004-07-06黄色粉末状固体1(5.6g，51%，如扣除未反应的2作者简介:张峻松(1971)， 男，讲师，博士研究生，专业方向:计为71%)，mp 76~77C (文献51: 77~78C)。药物合成。IR、'HNMR和MS确证结构。Tel: 0371-3670231E-mail: zhangjunsong@ zili.edu.cn(下转第660页)啪啪响响Synthesis of EdaravoneTAO Qiong-Hua', WANG Shao-Jie2李HAρ 7hi-nian3。a. Hainan Tongyong tongmeng Pharmaceutical Co.Ltd, Haikou 570310中国煤化Inerin, ShenyangPharnaceutical University, Shenyang 110016; 3. Yantai LuyirYHCNMHG46002)ABSTRACT: Edaravone, a free radical scavenger, was synthesized by condensation of ethyl acetoacetate withphenylhydrazine in presence of NaHSO3 in water at pH 6 for 2h in a yield of 83%.Key Words: edaravone; acute cerebral infarction; free radical scavenger; synthesis方方数据中国医药工业杂志Chinese Journal of Pharmaceuticals 2004, 35(11)球的包封率代替。参考文献:3.2所得微囊能基本满足临床长效缓释的要求，但1] 袁静.榄香烯_ -种新型的抗肿瘤药[J].中国野生植对于累积释放率偏低、能否达到有效治疗浓度等物资源, 1997, 16(3): 8-11.问题还需进一步研究。通过成膜反应中的参数可制[2谭清和,龚振夏,江坚榄香烯腔内注射治疗癌性胸水20例疗效观察[J].南通医学院学报, 1997, 17(2): 202-203.得不同膜强度的海藻酸钙-壳聚糖微囊，以控制微囊释药性能，从而实现针对不同应用情况的控释效[3]许春明，魏金芝,谭清和,等新型胸腔置管引流术治疗恶性胸腔积液[J].河南肿瘤学杂志, 2002, 15(1): 47-48.果[4]。[4刘群, 薛伟明,于炜婷,等海藻酸钠-壳聚糖微囊膜强度3.3乳化- 内部凝胶化技术是- -种新的微囊制备技的研究[J].高等学校化学学报, 2002, 23(7): 1417-1420.术，比传统制备方法易于扩大生产,生产效率较高。[5]沈正荣, 朱家蕙,吴兰亭,等5-氟尿嘧啶聚乳酸微球制备本文为脂溶性小分子药物微囊载体的制备工艺和释及体内外释药特性的研究[].中国医药工业杂志, 1995, 26放性能研究提供帮助，使1微囊化缓释载体在肿瘤(7): 306- 309.治疗上的应用成为可能。Preparation of β-Elemene Calcium Alginate- Chitosan MicrocapsulesLI Sheng', XU You-Wei, REN Dong- Wen', ZHENG Jian -Hua', MA Xiao Jun'*(1. Laboratory of Biomedical Material Engineering, Dalian Instiute of Chemical Physics, Graduate School of the Chinese Academy ofSciences, Chinese Academy of Sciences, Dalian 116023; 2. College of Pharmnaceutical, Dalian Medical University Dalian 116027)ABSTRACT: β-Elemene calcium alginate gel microspheres were prepared by emulsification-internal gelatificationtechnology, and then microspberes reacted with chitosan solution to obtain β elemene calcium alginate chitosan microcapsules.The shape, diameter and size distribution of the microcapsules were investigated using confocal laser scanning microscopeand laser difaction particle size analyzer, respectively. In vitro drug release property was examined using gas chromatography.The results showed that β elemene microcapsules were spherical with uniform membrane thickness and diameters of normaldistribution. The in viro release property of B-elemene from microcapsules was ftted to the Higuchi kinetics equation.Key Words: β-elemene; calcium alginate-chitosan microcapsules; emulsion-intermal gelatification(上接第644页)nitroimidazole[P]. CS: 211414, 1984-03-15. (CA 1984, 101:[1] Hoffmannia F, Roche C. Imidazole derivatives[P]. NL:151850g)6606853, 1965-05-19. (CA 1968. 68 21933a)[3Hoffer M, Grunberg E. Synthesis and antiprotozoal activityJakubcova J, David L, Rybar A, et al. Process for the prepara-of 1-(3 chloro 2-hydroxypropyI) subsited nitroimidazoles[].tion of 1- (3-chloro-2-hydroxypropyl) -2- methy1-5-J Med Chem, 1974, 17 (9): 1019-1020.Preparation of OmnidazoleZHANG Jun-Song]l2, ZHANG Guang-Ming', JIA Chun-Xiao', MAO Duo-Bin2(1. Dept. of Chemistry, Zhengzhou Unive中国煤化工2. Depl. of Food and Bioengineering, Zhengzhou Insitiunt二002)YHCNMHGABSTRACT: Omidazole was prepared from 2-methyl-5-nitroimidazole and epichlorohydrin in formic acid with con-centrated sulfuric acid as catalyst at 0~5C for 10h in a yield of 51%.Key Words: omnidazole; antibacterial agent; synthesis