1、中國抗生紊雜志2003年6月第28卷第6期.341.氧氟沙星的合成改進文章壤號:1001.8689(200306.034103王訓道1譚翎燕1王斌2(i鄭州大學化工學院.鄭州450002;2昆山雙鶴藥業有限責任公司研究所,江蘇昆山215315摘要:采用2,3,4一三氟硝基苯為原料和2-羥甲基2一甲基一1.3-二氧五環縮合,水解得醚酮.收率90%.再經雷尼镩氧化,7-氧亞甲基丙=酸二乙酯(EMME縮A,再經硫酸、乙酐環臺,加水水解得羧酸物,收率75%。羧酸物與N一甲基哌嘯縮舍、精制得氧氟沙星,收率85“,總收率57.4oA.關鍵詞:氧氟沙星;23t4-三氟硝基苯2-羥甲基一2甲基一】,3-二氧五

2、環合成f改進中圈分類號:R914.5文獻標識碼:A氧氟沙星是第三代氟喹諾酮類廣譜抗菌藥.主要用于治療呼吸系統、消化系統、泌尿系統、胃腸道及五官科等的感染。因其療效好、副作用小而在I臨床上得到了廣泛的應用。國內氧氟沙星的生產工藝主要以路線a為主,即以2,3,4一三氟硝基苯(2為起始原料,經堿水解.與一氯丙酮縮合得醚酮(5,收率7578%i再經雷尼鎳還原,與乙氧亞甲基丙=酸二乙酯(EMME縮臺;再以多聚磷酸乙酯(PPE或多聚磷酸為環臺劑進行環臺,以鹽酸、冰乙酸進行水解,得羧酸物(9,收率75%左右;9與N一甲基哌嚷縮合、精制,得氧氟沙星,收率85%,總收率50%左右。作者針對現工藝中醚酮(5的合成

3、收率較低,參考有關文獻【l”,以路線b合成氧氟沙星,即以2與2一羥甲基一2一甲基一1,3一二氧j略繾a五環(3縮臺、水解得s,收率90%,并將路線a中價格較貴的環臺劑PPE改為濃硫酸和乙酐”;并在冰浴冷卻下向環合后的反應液加入適量水,然后再開始水解,從而革除了鹽酸和冰乙酸,總收率較路線a提高7%左右。l實驗1.1主要試劑及原料主要合成原料均為工業品,霄尼鎳(ReyNi及2一羥甲基一2一甲基一1,3一二氧五環由昆山雙鶴藥業有限責任公司提供。1.2氧氟沙星的合成1.2.12一(2,2一亞乙二氧基丙氧基一3,4一二氟硝基苯(4的制備將0.282mol(5092,3,4-三氟硝基苯、甲詈:鼉:礓亍礅F

4、F舉慨+。蒼旦;毪02夕/性5一,按bSOI(CH3CObO8收輔日期2002-11-25作者簡彳r;王訓遘,男.生于1969年.硼士.講師.主要從事分離工程和藥物及藥物中間體方面的研究融九蕓杖等杖。04Z笨250ml投入反應瓶,冷至OC以下,加人研細的1.5tool(849KOH,于一50C滴加0.4237mol(509 2羥甲基一2一甲基一1,3一二氧五環,約30rain滴畢,再于一j0(、反應3h,反應畢。過濾,濾餅用甲苯(50ml×3洗滌,合并洗滌液及濾液,用水(200m×3洗滌, 509無水硫酸鈉干燥,將干燥后的甲苯液減壓蒸餾至干,得4,淡黃色油狀物74.69,收

5、率96“。無須精制,直接用于下步反應。1.2.22丙酮氧基一3,4一二氟硝基苯(5的制備將0.1818mol(5094、濃鹽酸150ml和甲醇250ml投人反應瓶,于70C回流反應3h。反應畢,將甲醇減壓蒸餾至盡,冷至05C,過濾,濾餅用冷乙醇(10ml×3洗滌,得淡黃色針狀結晶,晾干,得5,39.59,收率94“, mp4446C(文獻1lImp4748.5C。1.2.39,10一二氟一3一甲基一7一氧一2,3二氫一7H一吡啶駢1,2,3de1,4苯駢口惡嗪一6撥酸(9的制備將0.2164mol(5095,無水乙醇500ml和ReyNi209,于4045C邐人氫氣,約6h通畢,過濾

6、出催化劑,用無水乙醇(50ml×3洗滌,合并洗液和濾液,減壓蒸餾乙醇至盡,得6,紅棕色粘稠液體.然后加入0.2407moi (529EMME,于140145C反應2h畢,冷至常溫,加入乙酐200ml,攪拌0.5h,并于3040C下滴加質量分數為98%的濃硫酸80ml,約lh滴畢,繼續于30 ,10(、反應3h。然后冰浴冷卻至0C以下,滴加去離子水250m1,控制內溫不超過30C,滴畢。升溫回流反應3h,玲至室溫,過濾,濾餅用水洗至中性,于90C烘干,得9,灰白色針狀結晶45.69,收率75%。rap>300C (文獻12mI】>300C。無須精制直接用于下步反應。1.2.

7、4(±一9氟一2,3二氫一3一甲基一10一(4一甲基一1一哌嗪基一7氧.7H吡啶駢C a,2,3-de1,4苯駢口惡嗪一6一羧酸(1,氧氟沙里的制備將0.1779moi(5099,500ml 二甲基亞砜和0.1779moi(i7.89N一甲基哌嗪, 0.2669mol(279三乙胺,于8085C反應8h,反應畢,冷至20C以下,過濾,濾餅用甲酵(50ml×3洗滌,再用去離子水(50mlx3洗滌,吸干。將吸干的粗品投入反應瓶,加入去離子水600ml,活一r#炭129,攪拌升溫至6070C,用濃鹽酸調pH至1,6070C保溫攪拌1h.趁熱過濾,濾餅用70C去離了水】00ml洗滌

8、。合并洗滌液和濾液于6570C,用氧氟沙星的臺成改進王訓道等質量分數為40%/的氫氧化鈉溶液調pH至7,冷至20C以下,過濾,濾餅用去離子水(200m×3洗滌,抽干,于90C下烘干,得成品氧氟沙星(t,類白色粉末, 54,婦,收率85%。2結論(1采用2,3,4-三氟硝基苯為原料和2羥甲基一2一甲基l,3一二氧五環縮臺、水解得醚酮(5收率90%。經ReyNi氫化,乙氧亞甲基丙二酸二乙酯(EMME縮臺,再經硫酸、乙酐環合,加水水解得羧酸物(9,收率7j%。9與N一甲基哌嗪縮合、精制得氧氟沙星,收率8j%,總收率57.4%。(2采用本工藝氧氟沙星總收率這57.4%,較目前國內氧氟沙星的生

9、產工藝路線a提高7%左右。(3產品氧氟沙星經雙鶴藥業有限責任公司質量部門檢驗,其中氧氟沙星含量99.0%,有關物質含量0.2%,質量完全符合中國藥典2000版的要求。參考文獻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 Shuichi.eta1.Synthesis and antibacterial activities o

10、f 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(CA1985.103:1235224Daiichi Seiyaku Co.t Ltd.Oxazines LP:.JP6007

11、8986A2.19850504(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(CA1985.102:220885 7Wang E H.Zhou S Q.Peng S x.Synthesis of ofioxae

12、inJ.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中國抗生素雜志2003年6月第28卷第6期.343.A modified synthetic route of ofloxacinWang Xunqiul,Tan Lingyan2and Wang Bin2(1College of

13、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 material,reacted with2-hydroxymethyl2methyl一1,3-dioxane and

14、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 concentrated sulfuric acid and acetic anhydride,water w

15、as 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(±一9-fluoro3一methyl一10一(4-methyl一1一piperazinyl一7一OXO一2

16、,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頁Study oil the sisomiein extraction with macroporous carboxylic acid type ion exc

17、hange 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 macroporouscarboxylicacid type ionexchange resins and the conventional

18、sulfonic acid type ion exchange resin were compared.粵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 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