吲哚的合成060117概要.docx
- 文档编号:16976135
- 上传时间:2023-07-20
- 格式:DOCX
- 页数:11
- 大小:123.56KB
吲哚的合成060117概要.docx
《吲哚的合成060117概要.docx》由会员分享,可在线阅读,更多相关《吲哚的合成060117概要.docx(11页珍藏版)》请在冰点文库上搜索。
吲哚的合成060117概要
经典化学合成反应标准操作
吲哚的合成
编者:
柏祝
药明康德新药开发有限公司化学合成部
目录
2.Fischer吲哚合成2
2.1Fischer吲哚合成反应示例2
3.从硝基苯的衍生物出发合成吲哚3
3.1邻甲基硝基苯衍生物合成吲哚4
3.1.1邻甲基硝基苯衍生物合成吲哚示例4
3.2邻甲酰基硝基苯衍生物合成吲哚4
3.1.2邻甲酰基硝基苯衍生物合成吲哚示例5
3.3邻氰甲酰基硝基苯衍生物合成吲哚示例5
3.4邻乙烯基硝基苯衍生物合成吲哚示例6
3.5邻位有氢的硝基苯衍生物直接用乙烯格氏试剂合成吲哚(Bartoli反应)示例7
4.从苯胺的衍生物出发合成吲哚7
4.1苯胺经佛克烷基化再还原关环合成吲哚7
4.2N-羟基苯胺DMAP催化下与丙炔酸酯缩合合成3-羧酸吲哚衍生物9
4.3Nenitzescu吲哚合成9
5.2-叠氮基-3-芳基丙烯酸酯环合合成2-羧酸吲哚衍生物10
5.12-叠氮基-3-芳基丙烯酸酯环合合成2-羧酸吲哚衍生物示例11
1.Introduction
吲哚及其衍生物是一类非常有效的药物中间体。
已有不少相关综述报道其合成方法1。
我们将一些常用的合成方法简单的列举了出来,供大家在合成此类化合物的时候参考。
1(a)G.W.Gribble,Contemp.Org.Synth.,1994,145.(b)U.PindurandR.Adam,J.Heterocycl.Chem.,1988,25,1.(c)C.J.Moody,Synlett,1994,681.(d)R.J.Sundberg,Indoles,AcademicPress,SanDiego,CA,1996.(e)T.L.Gilchrist,J.Chem.Soc.,PerkinTrans.1,1999,2849.(f)G.W.Gribble,J.Chem.Soc.,PerkinTrans.1,2000,1045.
2.Fischer吲哚合成
Fischer吲哚合成法是一个常见的吲哚合成方法。
通过苯腙在酸催化下加热重排消除一分子氨得到2-取代或3-取代吲哚衍生物。
在实际操作中,常可以用醛或酮与等当量的苯肼在酸中加热回流得到苯腙,其在酸催化下立即进行重排、消除氨而得到吲哚化合物。
常用的催化剂有氯化锌、三氟化硼、多聚磷酸等,常用的酸有AcOH,HCl,三氟乙酸等。
其机理大致如下:
2.1Fischer吲哚合成反应示例
4-Bromophenylhydrazinehydrochloride1(21g)wassuspendedin150mLofaceticacid,andthemixturewasheatedtoreflux.Thenasolutionofcyclohexanone2(9.3mL)in10mLofaceticacidwasaddeddropwise.Aftertheaddition,themixturewasstirredunderrefluxforanother2h.Water(50mL)wasaddeddropwiseslowly,cooledtoroomtemperature,thesolidwasfiltered,washedwithwater,dried,palebrownsolid3(21.65g,91%)wasobtained.
Ref:
(a)B.Robinson,Chem.Rev.,1963,373.(b)B.Robinson,Chem.Rev.,1969,227.(c)H.Ishii,Accts.Chem.Res.,1981,233.(d)B.Robinson,TheFischerIndoleSynthesis,1982,923.(e)D.L.Hughes,Org.Prep.Proced.Int.,1993,607.(f)S.M.Hutchins,K.T.Chapman,TetrahedronLetters,1996,4869.(g)O.Miyataetal.,ibid.1999,3601.(h)S.Wagawetal.,J.Am.Chem.Soc.,1999,10251.
3.从硝基苯的衍生物出发合成吲哚
对于2,3位没有取代基的吲哚,一般工业上大多采用硝基苯的衍生物出发合成,邻甲基、邻甲酰基、邻氰乙基、邻乙烯基、及邻位有氢的硝基苯衍生物都可通过相应的方法得到吲哚。
3.1邻甲基硝基苯衍生物合成吲哚
该方法是目前最常用的,邻甲基硝基苯衍生物与DMF-DMA反应后得到相应的烯胺,然后硝基可通过多种方法还原后加成得到吲哚。
还原方法一般通过加氢,但当分子内有敏感官能团(比如:
Br,I都可或烯烃等)存在时可通过化学还原如:
NH2NH2-RaneyNi,铁粉,TiCl3,锌粉还原得到吲哚。
3.1.1邻甲基硝基苯衍生物合成吲哚示例
Toasolutionof4-methoxy-2-nitrotoluene1(17.9g,0.107mol)in200mLofdryDMFwasaddedDMFDMA(42mL,0.316mol)andpyrrolidine(10mL,0.12mmol).Themixturewasheatedat1050Cfor19hundernitrogen,thencooled,dilutedwithwaterandextractedwithether(8×50mL).Theetherlayerwasextractedwithwater(3×25mL),driedwithsodiumsulfate,andconcentratedtogiveadeepredoil2whichwasdissolverinethylacetate(150mL),andtothesolutionwasadded10%palladiumoncarbon(1.8g).Hydrogenationat50p.s.i.withshakingfor3handthenfiltrationthroughcelitegavealightbrownfiltrate.Thisfiltrateisevaporatedtopurpleoil,whichwaspurifiedbychromatographyonsilicagel(eluent:
DCM)togive6-methoxyindoleYield:
76%
Ref:
(a)Feldman,etal,Synthesis,1986,735.(b)Kline.T.B.etal,J.Med.Chem.,1982,908.(c)Schumacher,R.W.etal,Tetrahedron,1999,935.(d)bromidge,S.M.,etal,J.Med.Chem.,1998,1598.(e)Maehr,H.etal,J.Org.Chem.1984,1549.(f)Nicolaou,K.C.etal,J.Am.Chem.Soc.,2004,10162.
3.2邻甲酰基硝基苯衍生物合成吲哚
该邻甲酰基硝基苯衍生物与硝基甲烷反应后得到相应的不饱和硝化物再还原后得到吲哚。
3.1.2邻甲酰基硝基苯衍生物合成吲哚示例
Toasolutionof2-nitro-benzaldehyde1(3.14g,0.02mol)innitromethane(40mL)wasaddedammoniaacetate(0.9g,0.012mol)underN2protected.Thenitwasheatedtorefluxfor1.25h.Aftercooledtoroomtemperature,itwaspouredintowaterandstirredfor30min.ThenitwasextractedwithDCM(50mL×3),andthecombinedorganiclayerwaswashedwithbrine,driedoverNa2SO4andevaporatedundervacuum.Theresiduewaspurifiedbyflashcolumnchromatographytoyield1.2gpure2-(2-nitro-vinyl)-nitrobenzene2.Yield:
42%
Toasolutionof2-(2-nitro-vinyl)-nitrobenzene2(1.0g,0.005mol)inethanol(10mL),glacialacetateacid(10mL)andwater(3mL)wasaddedironpowder(5.7g,0.1mol)portionwise.Aftertheaddition,itwasheatedto50Cfor30min.Aftercooledtoroomtemperature,aq.NaHSO3wasaddedtoitandextractedwithether(50mL×3).Thecombinedorganiclayerwaswashedwithsaturatedaq.NaHCO3,driedoverNa2SO4andevaporatedundervacuum.Theresiduewaspurifiedbyflashcolumnchromatographytoyield0.45g1H-indole3.Yield:
75%
Ref:
(a)Sinhababu,AchintyaK.;Borchardt,RonaldT.,J.Am.Chem.Soc.,1985,7618,(b)He,Feng;Bo,Yunxin;Altom,JasonD.;Corey,E.J.;J.Am.Chem.Soc.,1999,6771.
3.3邻氰甲酰基硝基苯衍生物合成吲哚示例
Toasolutionof2-nitro-1-naphthyl-acetonitrile(33g,0.155mol)in630mLofethanolcontaining10%waterand6.3mLofpureaceticacidwasadded19gof10%palladium-on-carbon.Thenitwasstirredatr.t.under4barsofhydrogen.Afterthereactioncompleted,thecatalystwasfilteredandthefiltrationwasconcentratedunderreducedpressure.Thenresiduewasdissolvedin250mLofDCM,washedwith100mLof0.1NKOHsolutionandthendriedoverNa2SO4,evaporatedunderreducedpressuretogivethecrudeproduct,whichwaspurifiedbycolumnchromatographyusingcyclohexane/EA=4:
1aseluanttoyield13gof3H-benzo[e]indole.Yield:
50%
Ref:
(a)Makosza,M.etal.,Tetrahedron,1995,7263.(b)Bromidge,S.M.etal.,J.Med.Chem.,1998,1598.
3.4邻乙烯基硝基苯衍生物合成吲哚示例
Toasolutionof2-bromo-4-methylnitrobenzene1(1.00g,4.61mmol)andvinyltri-n-butyltin(1.61g,5.07mmol)intoluene(25mL)wasadded,underapositiveflowofargon,bis(dibenzylideneacetone)palladium(0)(265mg,0.46mmol)togetherwithtriphenylphosphine(498mg,1.90mmol).Thesolutionwasheatedatreflux(19h)whereuponaredsolutioncontainingablackprecipitatewasformed.Thereactionmixturewascooledtoambienttemperature,andthesolventwasremovedtogiveblackoil.Theoilwasdissolvedindichloromethane(50mL),washedwithNH4OH(10%,aq,3x30mL),anddried(MgSO4).Removalofsolventgaveyellowoilcontainingasmalleramountofblackviscousoil.Thecrudeproductwaspurifiedbychromatography(hexanes-EtOAc,19:
1)togive2-ethenyl-4-methylnitrobenzene(589mg,3.61mmol,78%)asyellowoil2.
Toanoven-dried,threadedACEglasspressuretubewasadded2-ethenyl-4-methylnitrobenzene2(152mg,0.93mmol),Pd(OAc)2(13mg,0.06mmol),triphenylphosphine(62mg,0.24mmol),and4mLofMeCN.Thetubewasfittedwithapressurehead,thesolutionwassaturatedwithCO(fourcyclesto4atmofCO),andthereactionmixturewasheatedto70°C(oilbathtemperature)underCO(4atm)untilallstartingmaterialwasconsumed(15h)asjudgedbyTLC.ThereactionmixturewasdilutedwithHCl(aq,10%,10mL)andextractedwithEt2O(3x10mL).ThecombinedorganicphaseswerewashedwithHCl(aq,10%,10mL)anddried(MgSO4),andthesolventwasremovedtogivethecrudeproduct.Thecrudeproductwaspurifiedbychromatography(hexanes-EtOAc,9:
1)togive5-methylindole3(62mg,0.47mmol,51%)asfaintyellowcrystals.
Ref:
Soederberg,B.etal,J.Org.Chem.,1997,5838
3.5邻位有氢的硝基苯衍生物直接用乙烯格氏试剂合成吲哚(Bartoli反应)示例
The2-nitrotoluene(685mg,5mmol)wasplacedinatwo–neckedroundbottomedflaskfittedwithagasinlet(argon)andrubberseptum.TheflaskwaspurgedseveraltimeswithargonbeforeaddingTHF(35–40ml)andcoolingtobetween–40and–45°C.TheGrignardreagent(3eq.)wasthenaddedrapidlyinoneportiontotheTHFsolutionandstirringcontinuedforafurther30minsto1hour(exactlengthoftimehadlittleeffectonyield).Saturatedammoniumchloridesolutionwasaddedtothereactionmixture(atca.–40°C)beforeallowingthemixturetowarmtoroomtemperature.Themixturewasthoroughlyextractedwithdiethylether(2x200ml),theetherextractscombinedandthoroughlywashedwithfurtherammoniumchloride(300ml),water(300ml)andbrine(300ml)beforedrying(MgSO4)andconcentratinginvacuotogiveadarkbrowngum,whichwaspurifiedbyflashcolumnchromatography(hexane:
ethylacetate9:
1)togive465mgof7-methyl-indole.Yield:
71%.
Ref:
(a)AdrianP.Dobbs,MartynVoyle,NeilWhittall,Synlett,1999,1594,(b)Curtin,M.Letal,J.Med.Chem.,1998,74.
4.从苯胺的衍生物出发合成吲哚
从苯胺的衍生物合成吲哚虽不常用,但还是有一些方法被报道。
4.1苯胺经佛克烷基化再还原关环合成吲哚
Toastirredsolutionofborontrichloride(645mg,5.5mmol)indrybenzene(6mL),asolutionof4-chloroaniline1(638mg,5mmol)indrybenzene(6mL)wasaddeddropwiseunderice-cooling.Totheresultingmixturecontaining4-chloroanilineborontrichloridecomplex,chloroacetonitrile(0.38mL,6mmol)andaluminumtrichloride(734mg,5.5mmol)wereaddedsuccessively.Themixturewasthenrefluxedfor6hundernitrogen,becomingasolutionoftwolayers.Theevolvedhydrogenchloridewasabsorbedthroughadryingtubecontainingsilicagelorcalciumchloridetoasurfaceofaqueoussodiumhydroxide.Aftercooling,ice2Nhydrochloricacidwasaddedandayellowprecipitatewasformed.Tohydrolyzetheketimineof2themixturewaswarmedat80Cunderstirring,untiltheprecipitatehaddissolved(ca.30min).Thecooledmixturewasextractedwithchloromethane(threetimes)andtheorganiclayerwaswashedwithwater,dried(MgS04),andconcentrated.Theneutralfractionobtained(744mg)wasrecrystallizedtoobtainpure2(674mg).Yield:
66%.Theacidiclayerwasmadealkalinewith2Nsodiumhydroxideandextractedwithdichloromethane.Washing,drying,andevaporationofthesolventgavethebasicfraction(170mg).Thin-layerchromatographicpurification(silicagel,chloroformcontaining10%methanol)gaverecovered1(103mg).
Toastirredsolutionof5-chloro-2-amino-α-chloroacetophenone2(204mg,lmmol)indioxane(5m
- 配套讲稿:
如PPT文件的首页显示word图标,表示该PPT已包含配套word讲稿。双击word图标可打开word文档。
- 特殊限制:
部分文档作品中含有的国旗、国徽等图片,仅作为作品整体效果示例展示,禁止商用。设计者仅对作品中独创性部分享有著作权。
- 关 键 词:
- 吲哚 合成 060117 概要