氧氟沙星的合成改进_图文

1、中国抗生紊杂志2003年6月第28卷第6期.341.氧氟沙星的合成改进文章壤号:1001.8689(200306.034103王训道1谭翎燕1王斌2(i郑州大学化工学院.郑州450002;2昆山双鹤药业有限责任公司研究所,江苏昆山215315摘要:采用2,3,4一三氟硝基苯为原料和2-羟甲基2一甲基一1.3-二氧五环缩合,水解得醚酮.收率90%.再经雷尼镩氧化,7-氧亚甲基丙=酸二乙酯(EMME缩A,再经硫酸、乙酐环台,加水水解得羧酸物,收率75%。羧酸物与N一甲基哌啸缩舍、精制得氧氟沙星,收率85“,总收率57.4oA.关键词:氧氟沙星;23t4-三氟硝基苯2-羟甲基一2甲基一】,3-二氧五

2、环合成f改进中圈分类号:R914.5文献标识码:A氧氟沙星是第三代氟喹诺酮类广谱抗菌药.主要用于治疗呼吸系统、消化系统、泌尿系统、胃肠道及五官科等的感染。因其疗效好、副作用小而在I临床上得到了广泛的应用。国内氧氟沙星的生产工艺主要以路线a为主,即以2,3,4一三氟硝基苯(2为起始原料,经碱水解.与一氯丙酮缩合得醚酮(5,收率7578%i再经雷尼镍还原,与乙氧亚甲基丙=酸二乙酯(EMME缩台;再以多聚磷酸乙酯(PPE或多聚磷酸为环台剂进行环台,以盐酸、冰乙酸进行水解,得羧酸物(9,收率75%左右;9与N一甲基哌嚷缩合、精制,得氧氟沙星,收率85%,总收率50%左右。作者针对现工艺中醚酮(5的合成

3、收率较低,参考有关文献【l”,以路线b合成氧氟沙星,即以2与2一羟甲基一2一甲基一1,3一二氧j略缱a五环(3缩台、水解得s,收率90%,并将路线a中价格较贵的环台剂PPE改为浓硫酸和乙酐”;并在冰浴冷却下向环合后的反应液加入适量水,然后再开始水解,从而革除了盐酸和冰乙酸,总收率较路线a提高7%左右。l实验1.1主要试剂及原料主要合成原料均为工业品,霄尼镍(ReyNi及2一羟甲基一2一甲基一1,3一二氧五环由昆山双鹤药业有限责任公司提供。1.2氧氟沙星的合成2一(2,2一亚乙二氧基丙氧基一3,4一二氟硝基苯(4的制备将0.282mol(5092,3,4-三氟硝基苯、甲詈:鼍:礓亍礅FF举慨+。

4、苍旦;毪02夕/性5一,按bSOI(CH3CObO8收辅日期2002-11-25融九芸杖等杖。04Z笨250ml投入反应瓶,冷至OC以下,加人研细的1.5tool(849KOH,于一50C滴加0.4237mol(509 2羟甲基一2一甲基一1,3一二氧五环,约30rain滴毕,再于一j0(、反应3h,反应毕。过滤,滤饼用甲苯(50ml×3洗涤,合并洗涤液及滤液,用水(200m×3洗涤, 509无水硫酸钠干燥,将干燥后的甲苯液减压蒸馏至干,得4,淡黄色油状物74.69,收率96“。无须精制,直接用于下步反应。将吸干的粗品投入反应瓶,加入去离子水600ml,活一r#炭129,搅

5、拌升温至6070C,用浓盐酸调pH至1,6070C保温搅拌1h.趁热过滤,滤饼用70C去离了水】00ml洗涤。合并洗涤液和滤液于6570C,用氧氟沙星的台成改进王训道等质量分数为40%/的氢氧化钠溶液调pH至7,冷至20C以下,过滤,滤饼用去离子水(200m×3洗涤,抽干,于90C下烘干,得成品氧氟沙星(t,类白色粉末, 54,妇,收率85%。2结论(1采用2,3,4-三氟硝基苯为原料和2羟甲基一2一甲基l,3一二氧五环缩台、水解得醚酮(5收率90%。经ReyNi氢化,乙氧亚甲基丙二酸二乙酯(EMME缩台,再经硫酸、乙酐环合,加水水解得羧酸物(9,收率7j%。9与N一甲基哌嗪缩合、精

6、制得氧氟沙星,收率8j%,总收率57.4%。(2采用本工艺氧氟沙星总收率这57.4%,较目前国内氧氟沙星的生产工艺路线a提高7%左右。(3产品氧氟沙星经双鹤药业有限责任公司质量部门检验,其中氧氟沙星含量99.0%,有关物质含量0.2%,质量完全符合中国药典2000版的要求。参考文献1Yang Y S.JiR Y.Hu z J,“a1.A new practicaroutetostereo specific synthesis of(s(o/oxaeinJj Acta Phanna Sin,1998,33(11:8282Hayakawa Isao,Atarashi Shohgo,Yokohama

7、 Shuichi.eta1.Synthesis and antibacterial activities of optically active ofloxaeinJ.Antimicrob Agents Chemother.1986,29(1: 1633Hokuriku Pharmaceutical Co.,Ltd10-Substituted piper-azino一9一f/uoro-7-OXO一2.3-dihydro一7Hpyrido1,2,3-dr一l, 4-benzoxazine一6-carhoxylic acid derivativesP.P6*A2.19850413(CA1985.1

8、03:1235224Daiichi Seiyaku Co.t Ltd.Oxazines LP:.JP60078986A2.19850504(CA1985,103.1234915Daiichi Seiyaku Co.。Ltd.Pyrido1,2.3-de一1,4-benzoxazine derivatives as bactericidesI.JP6(1034968A2, l985一0222(CA1985.10363706Daiichi Seiyaku Co.Ltd Pyrld。benzoxadme derivativesP.JP59216890A2-19841.206(CA1985.102:2

9、20885 7Wang E H.Zhou S Q.Peng S x.Synthesis of ofioxaeinJ.Chin J Pharma,1991,22(9:38583Zheng M.Qu J K.Sutfurlc acid and acetic anhydride as a cyclizing agent for preparation of ofloxacin intermediate J.J Shenyang Pharma Univ.1998,15(4:285中国抗生素杂志2003年6月第28卷第6期.343.A modified synthetic route of ofloxa

10、cinWang Xunqiul,Tan Lingyan2and Wang Bin2(1College of Chemical Engineering,ZhengzhouUniversity,Zhengzhou450002;2Devetopment Department,Kunshan DoubleCrane Pharmaceutical Co.,Ltd.Kunshan215315ABSTRACT A modified synthetic route of ofloxacin(1waspresented.2,3,4-trifIuoroni“.obenzene as starting materi

11、al,reacted with2-hydroxymethyl2methyl一1,3-dioxane and then hydrolyzed to give2-acetonyloxo3,t-difluoronitrobenzene(swith a yield of90%.Catalyzed by ReyNi,(5was hydrogcnatedIn Eive7,8-dlfluoro2,3-dihydro一3一methyl一4H一1,4-benzoxazine(6,6was condensed with EMME,thcn after cyclizationin the presence of c

12、oncentrated sulfuric acid and acetic anhydride,water was addeddropwise under coolinz andthen hydrolyzed by refluxing togive(±一9,10一difluoro一3一methyl一7一OXO一2.3-dihydro一7Hpyrido Cl,2,3-de一1,4一benzoxazine一6carboxylic acid(9with a yield of75%.(8was reacted with Nmethylpiperazine inDMSO to give(

13、7;一9-fluoro3一methyl一10一(4-methyl一1一piperazinyl一7一OXO一2,3一dihydro一7Hpyrido1,2,3-de3-1,4一benzoxazine6-carboxylic acid(1of85%yield.And the overatl yield of ofloxacin(1was57%.KEY WORDS Ofloxacin;2,3,4-trifluoronitrobenzene;2-hydroxymethyl一2-methylI,3-dioxanel Synthesis (上接第340页Study oil the sisomiein ex

14、traction with macroporous carboxylic acid type ion exchange resinsZhang Xing,Ruan Qi,Ye Changshen and (College of Chemistry and Chemical Engineering Huang Shihuang,Shi HanyingFuzhou University.Fuzfiou350002JABSTRACT The exchange capacity and dcsorption profiles of sisomicin in some macroporouscarbox

15、ylicacid type ionexchange resins and the conventional sulfonic acid type ion exchange resin were compared.粤Primary experiments were conducted in three kinds of carboxylie acid type ion exchange resins(Resin I.II, III,and Resin1was selected for furlher study,and compared the specific characteristics

16、with the sulfonic acid type resin732Results showed that the staticexchange capacity of ResinI to sisomicin was18.1×107Hg/ml,which was 80%higher than that of sulfonic acid type resin732.The optimum pH for adsorption of sisomicin was around 75;Dynamic exchange capacity of Resin1was further increased by13.8%than static exchange capacitv, In dynamic exchange of extraction and desorption of sisomicin,the total recovery rale Was82.6%,and itwas8%higher than using the sulfonic acid type resin732.The elution of sisomicin Was performed hvuse of 5%aqueous