多种缩合条件在合成核苷中的应用

多种缩合条件在合成核苷中的应用近些年来，核苷由于其有很好的生物活性和化学治疗特性在抗病毒及抗癌方面常作为潜药被报道出来，这使得在近年来化学合成核苷变得盛行起来。许多新的核苷类药物不断的被合成出来，本文主要报道多种缩合条件在核苷的C-N键偶联方面的应用,具体有以下几种方法：1.Toapre-cooled(0oC)solutionofcompound1(0.479mol),Base(0.719mol)in6000mLCH3CNwereaddedDBU(0.985mol)at0oCandstirredfor30mins,ThenfollowedbyTMSOTf(1.916mol)dropwise.Themixturewasstirredat70oCfor8hrs.TLCshowedreactionwascompleted.ThesolutionwaspouredintoamixtureofEtOAcandNaHCO3solution.ThesolutionwasextractedwithEtOAcandwashedwithbrine,thendriedwithNa2SO4.Thesolventwasremovedandtheresiduewaspurifiedbycolumn.2Toapre-cooled(0oC)solutionofcompound1(1mmol)andBase(1.5mmol)in30mLCH3CNwereaddedBSA(2mmol)at0oCandstirredfor10mins,ThenfollowedbyTMSOTf(3mmol)dropwise.Themixturewasstirredat70oCfor8hrs.TLCshowedreactionwascompleted.ThesolutionwaspouredintoamixtureofEtOAcandNaHCO3solution.ThesolutionwasextractedwithEtOAcandwashedwithbrine,thendriedwithNa2SO4.Thesolventwasremovedandtheresiduewaspurifiedbycolumn.3.Toasolutionofcompound1(1mmol)andTEA(3mmol)inanhydrousDCM(4mL)isstirredat30oCfor10min.ThenthemixtureisaddeddropwiseofMs2O(1.3mmol,dissolvedin1mLDCM)for10min.Thereactionisstirredat40oCfor2.5h.ThenthemixtureisaddedDCM(50mL),washedwithH2O（50mL）,brine(50mL).Theorganiclayerisdried,evaporatedtodynesstoafftodthecrudeproduct.ToaflaskchargedwithBase(1.48mmol)areaddedNaH(1.48mmol)andACN(4mL),stirringfor10mins.Crudecompound2(0.74mmol)dissolvedinACN(2mL)isaddedandthereactionisheatedto50oCfor15h.ThemixtureisadjustedtoPH=7.0by1NHClandevaporatedtoundervacuum.EtOAc(50mL)isaddedtotheresiduesolutionanditiswashedwith1NHCl(8mL),brine(10mL),dried,evaporatedtodrynessandpurifiedbycolumntoaffordthedesiredproduct.4.Toamixtureofcompound1(1mmol)andNaH(5mmol)inacetonitrile(15mL)previouslystirredfor0.5hatroomtemperatureisaddedcompound2(1mmol),andthemixtureisstirredatroomtemperaturefor18h.ThesolventisremovedanddilutedwithEtOAc(60mL),washedwithwater,brinedried,andconcentratedtogivethecrudeproduct.Thecrudeproductispurifiedbycolumntogivethepureproduct.5.Toasolutionofcompound1(2.14mol)inanhydrousTHF(1.3Lx4)wasaddeddropwise1MsolutionofLiAl(OBu-t)3HinTHF(600mLx4,2.4mol)at-60oCfor30mins.Thereactionmixturewasstirredfor2-3hrsatthesametemperature.ThereactionwascompletedforcheckedbyTLC.SaturatedNH4Clsolution(750mLx2)wasaddedandalargelotofthesolidwasprecipitated,filteredthesolidandwashedthecakewithEtOAc(300mlx4),combinedthesolutionandevaporatedtodryness.Theresiduewasdissolvedin2LEtOAc,washedwithbrine(3x500ml),water(500mlx2),driedwithMgSO4,filteredandevaporatedthesolventtotogive800gofcrudecompound2asatransparentoil,whichwasusedfornextstepreactionwithoutfurtherpurification.Toasolutionofcompound2(2.13mol),Base(3.07mol)andPh3P(40gx20,3.05mol)inanhydrousTHF(1.4Lx20)undernitrogenatmospherestirredfor15minsatr.t,thenDEAD(40mLx20)wasaddeddropwise.Afteraddition,thereactionmixturewasstirredatroomtemperatureovernight.ReactionwascompletedforcheckingbyTLCandLCMS.Filteredsomeoftheinsolublerawmaterial,washedwithEtOAc,combinedtheorganicphaseandconcentratedunderreducepressure.Theresiduewaspurifiedbycolumntogivethreepartsofthecrudeproduct6.OR3R2OHMDS,NH4SO4,TMSOTf,BaseBaseOR3R2BaseR4OR4O12Inaglass-linedreactorchargedwith1,4-dioxane(28.3L)wereaddedunderstirring3(1.9kg,9.0mol),ammoniumsulfate(20g,0.15mol,finelygrounded),andHMDS(1.32kg,8.2mol).Themixturewasheatedgentlyto96-99oCandkeptatrefluxfor3h(CAUTION!foaming).1,4-Dioxane(9L)wasdistilledoffafterwhichthemixturewascooledto22-25oC.Tothemixturewasaddeddiisopropylether(19L)and6(1.0kg,4.3mol)followedbyslowadditionoftrimethylsilyltrifluoromethanesulfonate(1.0kg,4.5mol).Afterstirringfor20hat20oC,amixtureofmethanol(0.8L)andtriethylamine(0.8L)wasaddedatsucharatethatthetemperaturedidnotexceed25oC.Themixturewascooledto15oCandthenfilteredthroughaglass-sinteredfunnel.Thefiltratewasconcentratedtoathickoilatreducedpressure(10mbar)androomtemperature.Ethylacetate(20L)wasadded,andtheresultingsolutionwaswashedwithaqueousaceticacid(10%,8L)andaqueouspotassiumcarbonate(10%,8L).Silicagel60(0.0350.070mm)(3kg)wasaddedtotheorganicphase,andthemixturewasconcentratedtodrynessinaneva-porator.Theresiduewaspurifiedwithchromatography(silicagel60,n-hexaneethylacetate,2:3)whichgave0.728kg(41%)ofthepureβ-anomeraswhitecrystals:7Astirredsuspensionofuracil(1.1g,9.7mmol)andammoniumsulfate(40mg)in1,1,1,3,3,3-hexamethyldisilazane(40mL)washeatedatrefluxunderargonuntilaclearsolutionformed(about1h).Theclearsolutionwasevaporatedundervacuumtoremovetheexcess1,1,1,3,3,3-hexamethyldisilazaneandfurtherdriedunderhighvacuum(0.1mmHg)for1h.Thecrudebis(trimethylsilyl)uracilobtainedwasdissolvedindryacetonitrile(40mL)andtransferredviacannulatoatwo-neckedround-bottomflask(equippedwithawatercondenser)containingdifluoromethylribofuranose4(2g,3.24mmol).UnderanargonatmosphereSnCl4(1.14mL,9.72mmol)wasaddedinoneportionwithvigorousstirringandexclusionofmoisture.Theresultinghomogeneouslightyellowsolutionwasstirredunderrefluxfor2days.WhenTLCindicatedthat4wascompletelyconsumed,thereactionwasquenchedcarefullybytheadditionof50mLofsaturatedaqueoussodiumbicarbonat