氧氟沙星的合成改進(jìn)

1、中國(guó)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(jìn)文章壤號(hào):1001.8689(200306.034103王訓(xùn)道1譚翎燕1王斌2(i鄭州大學(xué)化工學(xué)院.鄭州450002;2昆山雙鶴藥業(yè)有限責(zé)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(huán)縮合,水解得醚酮.收率90%.再經(jīng)雷尼镩氧化,7-氧亞甲基丙=酸二乙酯(EMME縮A,再經(jīng)硫酸、乙酐環(huán)臺(tái),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(guān)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(huán)合成f改進(jìn)中圈分類(lèi)號(hào):R914.5文獻(xiàn)標(biāo)識(shí)碼:A氧氟沙星是第三代氟喹諾酮類(lèi)廣譜抗菌藥.主要用于治療呼吸系統(tǒng)、消化系統(tǒng)、泌尿系統(tǒng)、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(yīng)用。國(guó)內(nèi)氧氟沙星的生產(chǎn)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(jīng)堿水解.與一氯丙酮縮合得醚酮(5,收率7578%i再經(jīng)雷尼鎳還原,與乙氧亞甲基丙=酸二乙酯(EMME縮臺(tái);再以多聚磷酸乙酯(PPE或多聚磷酸為環(huán)臺(tái)劑進(jìn)行環(huán)臺(tái),以鹽酸、冰乙酸進(jìn)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(duì)現(xiàn)工藝中醚酮(5的合成

3、收率較低,參考有關(guān)文獻(xiàn)【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(huán)(3縮臺(tái)、水解得s,收率90%,并將路線a中價(jià)格較貴的環(huán)臺(tái)劑PPE改為濃硫酸和乙酐”;并在冰浴冷卻下向環(huán)合后的反應(yīng)液加入適量水,然后再開(kāi)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(shí)驗(yàn)1.1主要試劑及原料主要合成原料均為工業(yè)品,霄尼鎳(ReyNi及2一羥甲基一2一甲基一1,3一二氧五環(huán)由昆山雙鶴藥業(yè)有限責(zé)任公司提供。1.2氧氟沙星的合成2一(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FF舉慨+。

4、蒼旦;毪02夕/性5一,按bSOI(CH3CObO8收輔日期2002-11-25融九蕓杖等杖。04Z笨250ml投入反應(yīng)瓶,冷至OC以下,加人研細(xì)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(huán),約30rain滴畢,再于一j0(、反應(yīng)3h,反應(yīng)畢。過(guò)濾,濾餅用甲苯(50ml3洗滌,合并洗滌液及濾液,用水(200m3洗滌, 509無(wú)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,收率96“。無(wú)須精制,直接用于下步反應(yīng)。將吸干的粗品投入反應(yīng)瓶,加入去離子水600ml,活一r#炭129,攪拌升溫至6070C,用濃

5、鹽酸調(diào)pH至1,6070C保溫?cái)嚢?h.趁熱過(guò)濾,濾餅用70C去離了水】00ml洗滌。合并洗滌液和濾液于6570C,用氧氟沙星的臺(tái)成改進(jìn)王訓(xùn)道等質(zhì)量分?jǐn)?shù)為40%/的氫氧化鈉溶液調(diào)pH至7,冷至20C以下,過(guò)濾,濾餅用去離子水(200m3洗滌,抽干,于90C下烘干,得成品氧氟沙星(t,類(lèi)白色粉末, 54,婦,收率85%。2結(jié)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(huán)縮臺(tái)、水解得醚酮(5收率90%。經(jīng)ReyNi氫化,乙氧亞甲基丙二酸二乙酯(EMME縮臺(tái),再經(jīng)硫酸、乙酐環(huán)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

6、.4%。(2采用本工藝氧氟沙星總收率這57.4%,較目前國(guó)內(nèi)氧氟沙星的生產(chǎn)工藝路線a提高7%左右。(3產(chǎn)品氧氟沙星經(jīng)雙鶴藥業(yè)有限責(zé)任公司質(zhì)量部門(mén)檢驗(yàn),其中氧氟沙星含量99.0%,有關(guān)物質(zhì)含量0.2%,質(zhì)量完全符合中國(guó)藥典2000版的要求。參考文獻(xiàn)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.Synt

7、hesis 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(CA1985.103:1235224Daiichi

8、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(CA1985.102:220885 7Wang E H.Zh

9、ou 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中國(guó)抗生素雜志2003年6月第28卷第6期.343.A modified synthetic route of ofloxacinWang Xunqiul,Ta

10、n 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 material,reacted with2-h

11、ydroxymethyl2methyl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 concentrated sulfur

12、ic 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(一9-fluoro3一methyl一10一(4-meth

13、yl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頁(yè)Study oil the sisomiein extraction with macroporous carb

14、oxylic 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 macroporouscarboxylicacid type ionexchange resi

15、ns and the conventional 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 re

16、sin732Results showed that the staticexchange capacity of ResinI to sisomicin was18.1107Hg/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 a