奧硝唑的合成

●644●中國醫藥工業(yè)雜志Chinese Journal of Pharmaceuticals 2004, 35(11)奧硝唑的合成張峻松1.2，張廣明'，賈春曉’，毛多斌2(1.鄭州大學(xué)化學(xué)系，河南鄭州450052; 2.鄭州輕工業(yè)學(xué)院食品生物工程系，河南鄭州450002)摘要:用2-甲基-s-硝基咪唑、環(huán)氧氯丙烷和少量濃硫酸在甲酸中于0~5C反應10h得到奧硝唑，收率51%。關(guān)鍵詞:奧硝唑;抗菌劑;合成中圖分類(lèi)號: R978.69文獻標識碼: A文章編號: 1001-8255 (2004) 11-0644-01奧硝唑(ornidazole, 1)， 化學(xué)名為a- (氯甲基)-酸作用下開(kāi)環(huán)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，是繼甲硝唑環(huán)氧氯丙烷(3)在A(yíng)IC3作用下反應得到，收率45.5%，(metronidazole)、替硝唑(tinidazole)后，于1977年但反應需嚴格無(wú)水2: (3) 用2和3在甲酸中反應得由瑞士羅氏公司首次在德國上市的抗厭氧菌和抗到，收率42%，但反應時(shí)間長(cháng)達72h，且甲酸用量滴蟲(chóng)藥物，已在意大利、法國、瑞士等多個(gè)國家上大，不利于放大生產(chǎn)[3]。本文對第三法進(jìn)行了改進(jìn)，市11.21。加入少量濃硫酸作為催化劑，同時(shí)增強了反應體系1主要有以下合成路線(xiàn): (1)用2-甲基-5-硝基的酸度,有利于原料的溶解，甲酸用量可減半，并確咪唑(2)和二(3-氯-2-羥丙基)硫酸酯反應，在濃鹽定了最佳反應條件為0~5"C反應10h，收率51%。CH,H2C -CHCH2C1HCOOHL O2NCHH2SO4CH2CHCH2C1Of水(10ml)，用濃氨水調至pH 3~4后冷至0C，析實(shí)驗部分出未反應的2(.5g)。濾液用濃氨水調至pH7~8后奧硝唑(1)加入硫酸銨至飽和，用苯萃取(25mlX5)，合并苯100ml圓底燒瓶中加入甲酸(35m1)和濃硫酸層后用10mol/L硫酸(15ml X 3)萃取，合并酸液后(1ml)，攪拌下加入2(6.3g, 0.05mol)， 于0~5°C加入硫酸銨飽和，用氨水調至pH 7~8，得黃色油滴加3(23.0g，0.25mol)， 滴畢繼續室溫攪拌反應狀物，加少量1晶種后析晶，過(guò)濾，濾餅用水洗滌10h。減壓回收甲酸和過(guò)量的3。剩余物中加入冰后干燥，得到1粗品(6.9g)，再用甲苯重結晶得淡收稿日期: 2004-07-06黃色粉末狀固體1(5.6g，51%，如扣除未反應的2作者簡(jiǎn)介:張峻松(1971)， 男，講師，博士研究生，專(zhuān)業(yè)方向:計為71%)，mp 76~77C (文獻51: 77~78C)。藥物合成。IR、'HNMR和MS確證結構。Tel: 0371-3670231E-mail: zhangjunsong@ zili.edu.cn(下轉第660頁(yè))啪啪響響Synthesis of EdaravoneTAO Qiong-Hua', WANG Shao-Jie2李HAρ 7hi-nian3。a. Hainan Tongyong tongmeng Pharmaceutical Co.Ltd, Haikou 570310中國煤化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方方數據中國醫藥工業(yè)雜志Chinese Journal of Pharmaceuticals 2004, 35(11)球的包封率代替。參考文獻:3.2所得微囊能基本滿(mǎn)足臨床長(cháng)效緩釋的要求，但1] 袁靜.欖香烯_ -種新型的抗腫瘤藥[J].中國野生植對于累積釋放率偏低、能否達到有效治療濃度等物資源, 1997, 16(3): 8-11.問(wèn)題還需進(jìn)一步研究。通過(guò)成膜反應中的參數可制[2譚清和,龔振夏,江堅欖香烯腔內注射治療癌性胸水20例療效觀(guān)察[J].南通醫學(xué)院學(xué)報, 1997, 17(2): 202-203.得不同膜強度的海藻酸鈣-殼聚糖微囊，以控制微囊釋藥性能，從而實(shí)現針對不同應用情況的控釋效[3]許春明，魏金芝,譚清和,等新型胸腔置管引流術(shù)治療惡性胸腔積液[J].河南腫瘤學(xué)雜志, 2002, 15(1): 47-48.果[4]。[4劉群, 薛偉明,于煒婷,等海藻酸鈉-殼聚糖微囊膜強度3.3乳化- 內部凝膠化技術(shù)是- -種新的微囊制備技的研究[J].高等學(xué)?；瘜W(xué)學(xué)報, 2002, 23(7): 1417-1420.術(shù)，比傳統制備方法易于擴大生產(chǎn),生產(chǎn)效率較高。[5]沈正榮, 朱家蕙,吳蘭亭,等5-氟尿嘧啶聚乳酸微球制備本文為脂溶性小分子藥物微囊載體的制備工藝和釋及體內外釋藥特性的研究[].中國醫藥工業(yè)雜志, 1995, 26放性能研究提供幫助，使1微囊化緩釋載體在腫瘤(7): 306- 309.治療上的應用成為可能。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頁(yè))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中國煤化工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