杂环的酚羟基的卤代-060114

经典化学合成反应标准操作杂环的酚羟基或醚的烷氧基卤代反应编者：李金鹏药明康德新药开发有限公司化学合成部经典合成反应标准操作—杂环的酚羟基的卤代反应药明康德新药开发有限公司药明康德内部保密资料Page1of7目录1．前言………………………………………………………………22．氯代………………………………………………………………22.1杂环的酚羟基的用三氯氧磷氯代反应示例……………………………22.2杂环的酚羟基用三氯氧磷与五氯化磷混合处理氯代反应示例………32.3杂环的酚醚甲氧基用三氯氧磷氯代反应示例………………………33．溴代………………………………………………………………43.1杂环的酚羟基用POBr3溴代反应示例（一）………………………43.2杂环的酚羟基用POBr3溴代反应示例（二）……………………………43.3杂环的酚羟基用四丁基溴化胺法溴代反应示例………………………53.4杂环的甲氧基用PBr3溴代反应示例………………………………54．参考文献…………………………………………………………6经典合成反应标准操作—杂环的酚羟基的卤代反应药明康德新药开发有限公司药明康德内部保密资料Page2of71．前言杂环的酚羟基的通常较易被卤代，其也是杂环一种常见的官能团的转换方式之一，卤代反应常见的有氯代、溴代反应。另外，在存在吸电子基的杂环上，不仅酚羟基容易被卤代，而且烷氧基（甲氧基，乙氧基等）也很容易被卤代。因此其也是合成的一种策略。经常有文献首先将杂环卤代物用甲氧基取代后，利用甲氧基推电子效应完成一系列转化后，再将甲氧基卤代回来。2.氯代杂环的酚羟基的氯代一般用三氯氧磷1,2,3或三氯氧磷与五氯化磷混合4,5处理。使用五氯化磷的条件更强，用于难以发生的杂环的酚羟基的氯代反应。杂环烷氧基的氯代也可用三氯氧磷直接处理6.2.1杂环的酚羟基的用三氯氧磷氯代反应示例1NO2NIOHPOCl3NO2NICl122-Hydroxy-3-iodo-5-nitropyridine1(70.5g,0.27mol)wasaddedtoquinoline(16mL,0.133mol).Thereactionflaskwascooledto5degreeandphosphorylchloride(25mL,0.27mol)wasaddeddropwise.Themixturewasblanketedwithargonandheatedto120degreefor2h.Uponcompleteconsumptionoftheprecursor,asindicatedbyTLC,themixturewascooledtoroomtemperatureand100mLofH2Owasadded.Themixturewasthencooledto0degree,andtheresultingbrownsolidwasfiltered.Recrystallizationfromethanolgavesand-colorcrystals2(60g,0.21mol,78%yield).经典合成反应标准操作—杂环的酚羟基的卤代反应药明康德新药开发有限公司药明康德内部保密资料Page3of72.2杂环的酚羟基用三氯氧磷与五氯化磷混合处理氯代反应示例5NOHNClPCl5/POCl312Toasolutionof10.5gof1in16mLofphosphorusoxychloridewasheatedtorefluxandadded20gofphosphoruspentachlorideinsmallportionsoveraperiodof1.5hr.Theoilbathtemperaturewasthenraisedto165degreeandkepttherefor1hr.Thephosphorusoxychloridewasremovedunderreducedpressure,50goficethenadded,andthemixturemadestronglybasicbyaddingaconcentratedKOHsolution.Whenthiswassteamdistilled,acolorlessheavyoilwasobtained,whichwasseparatedbytwoextractionswith100-mLportionsofether.Theetherwasdriedandremoved,andtheresiduedistilled,givingacolorlessoil(4.0g,34%).2.3杂环的酚醚甲氧基用三氯氧磷氯代反应示例6NSBnONSBnClPOCl312Amixtureof1(10mmol)andphosphorylchloride(20mL)wasrefluxedfor0.5hr.Thentheexcessofphosphorylchloridewasevaporatedinvacuo.Theresiduewascarefullypouredontoice(30g)andneutralizedwithconc.ammoniaat0-5degree.Thesolidwasfilteredoff,washedwithwaterandair-dried.Theproductwaspurifiedbycrystallizedfromethanoltogive86-94%yields.经典合成反应标准操作—杂环的酚羟基的卤代反应药明康德新药开发有限公司药明康德内部保密资料Page4of73．溴代杂环的酚羟基的溴代常见的方法有用三溴氧磷7,8或四丁基溴化胺9。杂环烷氧基的溴代也可用三溴氧磷处理10.3.1杂环的酚羟基用POBr3溴代反应示例一7NNHOOHPOBr3NNBrBr12Astirredmixtureof1(0.8g,4.25mmol)andfreshlypreparedPOBr3(8.0g,28mmol)inanisole(8.0mL)washeatedat145degreefor2days.Aftercooling,thereactionmixturewaspouredintoicewater(300mL)andbasifiedwithsaturatedsodiumcarbonatesolutionuntilthePHwas8-9.ThemixturewasextractedwithCH2Cl2(3x300mL);thecombinedextractsweredriedoveranhydroussodiumsulfateandevaporatedinvacuo.Purificationoftheresiduebyflashchromatography(silicagel,1:1CH2Cl2:Et2O)andrecrystallizationfromethanolgavebromide2(0.831g,60%)ascolorless,fineneedles.3.2杂环的酚羟基用POBr3溴代反应示例二8NO2NIOHNO2NIBrPOBr3,quinoline12Phosphorusoxybromide(25.0g,87.2mmol)wasaddedtotoluene(55mL)atroomtemperature.Next,1(21.1g,79.3mmol)andquinoline(9.5mL)wereaddedconsecutivelytomechanicallystirredreactionmixtureto90-100degree.ThevigorousreactionwasmonitoredbyTLC(ethylacetate/hexane5:15).Afterreactioncompletion,thetoluenelayerwasseparated.Theremainingbrownishsolidwas经典合成反应标准操作—杂环的酚羟基的卤代反应药明康德新药开发有限公司药明康德内部保密资料Page5of7extractedwithboilingtoluene(3x260mL).Thecombinedtoluenesolutionswerewashedwith5%aqueousNaHCO3,driedoveranhydroussodiumsulfate,andconcentratedbyrotaryevaporation.Flashcolumnchromatography(95:5hexane/ethylacetate)workupgave2(21.1g,81.1%)asayellowsolid.3.3杂环的酚羟基用四丁基溴化胺法溴代反应示例9NBuCNOHNBuCNBr12P2O5,NH4Bu4Br1(177g,1.01mol),phosporuspentoxide(300g,1.06mol)andtetrabutylammoniumbromide(391g,1.21mol)wasmixedintoluene(2L)andheatedtorefluxfor4h.Themixturewascooledtoroomtemperatureandwater(1L)wasaddedcarefullywithstirringandcooling.Themixturewasstirredfor2handthenfilteredthroughapadofCelite,andthelayerswereseparated.Thetoluenelayerwaswashedwithbrineandconcentratedinvacuo.Theproductwaspassedthroughapadofsilicagel(50g)andelutedwithethylacetate:hexane(10:1)togive202g(84%yield)of2asaclearyellowoil.3.4杂环的甲氧基用PBr3溴代反应示例10NCOOMeONCOOMeBr12PBr3/DMFPhosphorustribromide(3mL)wasaddedtoasolutionof1(1.3g)inDMF(30mL)inanicebath.Thereactionwasfurtherstirredfor2hrat80degreeandthenpouredintoice-water.TheaqueousmixturewasmadealkalinewithNaOHandextracted经典合成反应标准操作—杂环的酚羟基的卤代反应药明康德新药开发有限公司药明康德内部保密资料Page6of7withCH2Cl2.Theextractwaswashedwithbrine,driedandevaporated.TheresiduewaschromatographedonsilicagelusingCH2Cl2–acetone(50:1)asaneluenttogiveproduct2(1.04g,65%).参考文献：1.J.Med.Chem.;45;13;2002;2841-2849.2.J.Org.Chem.;68;18;2003;6919-6927.3.J.Med.Chem.;43;22;2000;4288-4312.4.J.Amer.Chem.Soc.;70;1948;1494-1497.5.J.Amer.Chem.Soc.;70;1948;3712-3715.6.J.HerterocyclicChem.;30;6;1993;1623-1628.7.J.Org.Chem.;62;9;1997;2774-2781.8.J.Med.Chem.;47;10;2004;2453-2465.9.J.Org.Chem.;64;261999;9658-9667.10.Chem.Pharm.Bull.;38;11;1990;2919-2925.