药物remdesivir(伦地西韦、瑞德西韦)合成检索总结报告

#药物remdesivir（伦地西韦、瑞德西韦）合成检索总结报告一、remdesivir（伦地西韦、瑞德西韦）简介瑞德西韦也叫伦地西韦，英文名称为remdesivir，它是一种抗病毒药物，已经用于抗埃博拉病毒和其他疾病。瑞德西韦（伦地西韦/remdesivir）分子结构式如下：HC?t)HHC?t)HCAS：1809249-37-3二、remdesivir（伦地西韦、瑞德西韦）合成路线（一）remdesivir（伦地西韦、瑞德西韦）合成路线1PHdBhII合成路线设计一（二）remdesivir（伦地西韦、瑞德西韦）合成路线二

合成路线设计二三、remdesivir（伦地西韦、瑞德西韦）合成检索总结报告（一）remdesivir（伦地西韦、瑞德西韦）合成路线一检索总结1、remdesivir（伦地西韦、瑞德西韦）中间体2的合成序号1+实验步骤参考文献CN104628681;(2017);(B)Chinese12g(73.1mmol)riboseglucoside(orgaloside)1wasplacedina250mLeggplantflask,160mLofanalyticallypureDMFwasadded,andafteradding17gofNaHunderanicebath,38mLofBnBrwasslowlyaddeddropwise,andslowlywarmeduptoroomtemperatureforovernight.TLCtracedthereactiontoanend.Thereactionwasextractedslowlywiththeadditionofmethanol,thenextractedwithEA,washedwithwater,andCrudeproductcolumnchromatographicseparation(PE:EA=9L51)ltoobatincompound(2R,4S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-CN104628681;(2017);(B)Chinese2Sodiumhydride(0.75g,18.3mmol)wasaddedtoasolutionofcompound1(1g,6.1mmol)indrytetrahydrofuran(15ml)at0°C.ThenBnBr(2.2ml,18.3mmol)wasaddeddropwiseover10minutes.Icebathwasremovedafterstirringfor0.5hat0°C.Thereactionmixturewasstirredat25°Covernight.Themixturewasfilteredbyusingdiatomite.Thefiltratewasconcentratedinvacuo.Theresiduewaspurifiedbychromatographyonsilicagel(petroleumether/ethylacetate=15:1)toobtaincompound2asacolorlesssyrupin84%yield.WO2018/53706;(2018);(A1)English3Compound1(150g,0.914mol)wasdissolvedindryN,N-dimethylformarnide(DMF,1.5L),undernitrogen,inathreeneckedflaskequippedwithamechanicalstirrerandanadditionfunnel.Thesolutionwascooledto0°Cinanicebath.NaH(220g,60%dispersioninmineraloil,5.48mole,6eq.)wasaddedinsmallportionstakingcaretocontrolthereactionandavoidoverheating.WhenalltheNaHhadbeenadded,additionofbenzylbromide(650mL,5.48mole,6eq.)wasinitiateddrop-wiseviatheadditionfunnel.Whenallthebenzylbromidehadbeenaddedthereactionwasallowedtocometoroomtemperatureandstirredfor5hrs.Thereactionwasthenheatedto60°Candstirredatthistemperatureovernight.Thereactionwasquenchedwithmethanol,concentratedinvacua,andpartitionedbetweenetherandwater.Theetherlayerwaswashedoncewith10%citricacidsolution,oncewithsaturatedsodiumbicarbonatesolutionandoncewithbrine.Theetherlayerwasdriedoveranhydroussodiumsulfate,andconcentratedtoapale,yellowsyrup.Thissyrupwasdissolvedin5%ethylacetateinhexaneandappliedtoasilicagelplugina2Lsinteredglassfunnel.5%ethylacetateinhexanewasusedtoelutethedesiredproductin2Lfractions.Thetargetfractionswereconcentratedunderreducedpressuretogivecompound2(300g)in75%yield.WO2005/27962;(2005);(A1)English4Toasolutionof1(20.0g,121.8mmol)inDMF(200mL)wasaddedNaH(17.1g,426.4mmol)at0°C.Themixturewasstirredat0°Cfor1h.TheresultingsolutionwastreatedwithTBAI(4.50g,12.2mmol)andBnBr(72.93g,426.4mmol,50.7mL).Themixturewasstirredat25°Cfor11h.Themixturewasdilutedwithwater(200mL)andquenchedwithsaturatedNHqClsolution(100mL).TheresultingsolutionwasextractedwithEA(200mL).ThecombinedorganiclayerswerewashedWO2018/31818;(2018);(A2)English

twicewithbrine(200mL)anddriedoveranhydrousNa2SO4.Afterconcentratingunderreducedpressure,theresiduewasappliedontoasilicagelcolumnwithPE/EA(25:1to5:1)togivecompound2((2R,3R,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-methoxytetrahydrofuran,37.20g,70%)aslightyellowoil.2、remdesivir（伦地西韦、瑞德西韦）中间体3的合成序号实验步骤参考文献1Toastirredsolutionof2(4.34g,10mmol)in26mLofglacialaceticacidcontainingSrCl2・6H2O(0.27g,1mmol)heatedat70°Cwasadded5mLof5Mhydrochloricacid.Thestirringwascontinuedat70°CuntilreactioncompletedasindicatedbyTLCanalysis(typicallywithin2-3h).Thereactionmixturewaspouredinto300mLofice-waterwhilestirringimmediatelyafterthereactioncompleted,andtheresultingmixturewasextractedwiththree100mLportionsofdichloromethane.Thecombinedextractswerewashedsuccessivelywithsaturatedsodiumbicarbonateandbrine,driedoveranhydroussodiumsulfateandevaporatedonarotaryevaporatortoaffordanoilyresidue,whichwaspurifiedbycolumnchromatographytoyieldthepure3asananomericmixture.Colorlessoil,3.66g,87%.SyntheticCommunications;vol.45;nb.12;(2015);p.1457-14702Thecompound2(3.5g,8.0mmol)wasweighedintoa100mLeggplantflask,28mLof1,4-dioxanewasaddedtodissolveit,and28mLof4NHClwasadded.Thetemperaturewasrefluxedfor3hours.AftercompletionofthereactiontrackedbyTLC,thereactionmixturewasextractedwithEA,washedwithwater,andthenwashedwithsaturatedNaHCO3solutionandsaturatedNaClsolution.Thecrudeproductwaschromatographedunderreducedpressure(PE:EA=5:1f3.5:1)too(3S,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol3(2.9g,6.9mmol,86%).CN106167475;(2016);ChineseCN104628681;(2017);ChinesebtainToasolutionofproductfrom2(114g,262.35mmol)indioxane(250mL)wasadded4NHCl(250mL)and

3heatedatrefluxfor4h.Thereactionmixturewasallowedtoattainroomtemperatureanddilutedwithethylacetate(1.5L).Theaqueouslayerwasseparatedandextractedwithethylacetate(3x1L).Theorganiclayerswerecombined,washedwithwater(2x500mL),saturatedaqueousNaHCO3(250mL),water(500mL),andbrine(250mL),anddriedoverMgSO4andfiltered.Thefiltratewasconcentratedundervacuumtofurnishcrudeproduct.Thecrudeproductwaspurifiedbyflashchromatography(silicagel1.5kg,elutingwithethylacetateinhexanes0to30%)tofurnishstartingmaterial(9.9g,)and85.3g(45%)ofdesiredproduct(mixtureofisomers)asanoil.WO2006/50161;(2006);(A2)English41mol/LH2SO4(3ml)wasaddedtoasolutionofcompound2(7g,16.1mmol)inAcOH(150ml).Thenthereactionmixturewasheatedto100°Cfor5h.Aftercoolingto25°C,themixturewasconcentratedinvacuo.Theresiduewaspurifiedbychromatographyonsilicagel((petroleumether/ethylacetate=8:1)toobtaincompound3asacolorlesssyrupin45%yield.WO2018/53706;(2018);(A1)English5Dissolvethecrude2,3,5-O-tribenzyl-D-arabino-furanoside2to400mLina80%byweightaqueoussolutionofaceticacid,dioxane(400mL)and1NH2SO4(400mL)wereadded,andthereactionwascarriedoutatabout95°C.Untilthematerialdisappearsalmostcompletely,dioxaneandaceticacidaredistilledoff,water(500mL)isadded,andthemixtureisextractedthreetimeswithethylacetate.Andtheorganicphasewasadjustedtoabout8withasaturatedaqueoussolutionofsodiumbicarbonate,theorganicphasewasseparated,andtheaqueousphasewasextractedoncewithethylacetate.Theorganicphaseswerecombinedanddriedoveranhydrousmagnesiumsulfate.Thesolventwasevaporatedunderreducedpressureandthecrudeproductwaspassedthroughacolumntogive353gofthehemiacetal2,3,5-O-tricarboxylicacid.Benzyl-D-arabinofuranoseisdirectlysubjectedtothenextstepreaction.CN105085357;(2018);(B)Chinese3、remdesivir（伦地西韦、瑞德西韦）中间体4的合成

序号实验步骤参考文献1Thecompound3(1.00g,1.0eq)wasdissolvedin10mLofdriedCH2C12,andtheresultingmixturewasstirredinanice-waterbath,followedbyadditionofCs2CO3(3.0eq).Thesuspensionwasstirredatthistemperature,andICl(1.5eq)dissolvedin2mLofCH2Cl2wasaddeddropwise.Afteraddition,thereactionmixturewasstirredatroomtemperatureuntilthereactioncompletedasindicatedbyTLCanalysis,whichwasconductedat0.5-hintervals.Thereactionmixturewassubjectedtoaqueousworkupdescribedpreviouslytoyieldthepurecarbonylcompounds4.SyntheticCommunications;vol.45;nb.12;(2015);p.1457-14702Compound3wasdissolvedinanhydrousDMSO(30mL)andplacedundernitrogen.Aceticanhydride(20mL)wasadded,andthemixturewasstirredfor48hatroomtemperature.WhenthereactionwascompletebyLC/MS,itwaspouredonto500mLicewaterandstirredfor20min.Theaqueouslayerwasextractedwithethylacetate(3x200mL).Theorganicextractswerecombinedandwashedwithwater(3x200mL).TheaqueouslayerswerediscardedandtheorganicwasdriedoveranhydrousMgSO4andevaporatedtodryness.TheresiduewastakenupinDCMandloadedontoasilicagelcolumn.Thefinalproduct30bwaspurifiedbyelutionwith25%EtOAc/hexanes;96%yield.WO2010/93608;(2010);(A1)English;WO2011/35250;(2011);(A1)English;WO2012/12776;(2012);(A1)English;US2017/71964;(2017);(A1)English3Adding1equivalentofasolutionofthecompound3tothereactionvessel,0.01equivalentofTEMPO,0.01equivalentofsodiumbromide,Thetemperaturewasloweredto0°C,and1.5equivalentsofa10%byweightaqueoussolutionofsodiumhypochloritewasaddeddropwise.Afterlh,thereactioniscompleted,0.5equivalentofsodiumhydrogensulfiteisadded,stirred,andthephasesareseparated.Theaqueousphaseisextractedwithasecondorganicsolvent,andthesecondorganicsolventisdichloromethane.Theorganicphaseswerecombined,washedthreetimeswithwaterandconcentratedtodrynesswithoutliquid.AddingathirdCN108285438;(2018);(A)Chinese

organicsolventforcrystallization,thethirdorganicsolventisanhydrousethanol,andslowlycoolingto20C,3gofbenzylriboselactonecrystalsweieaddedasseedcrystals,andthesolidwasprecipitatedandstirredovernight,andslowlycooledCtfo01hour,andttemperaturewascontrolledCatfor°hour.Thehemixturewascentrifuged,rinsedwithethanolanrit0°driedunderreducedpressureinanoveCi:aor42)°hourstoconstantweighttoobtainawhitecryswasabenzylriboselactonetalwhichOxalylchloride(41.3mmol,3.5mL)indryDCM(150mL)wastreatedatC-60°hDMSO(6.3mL)inDCM(110mL).After20minasolutionof2,3,4,6-tetra-0-benzyl-d-glucopyrfenb8e5mmol,10.0g)inDCM(100mL)andDMSO(1.4mL)wasadded4slowlykeepingthetemperaturebelow—50°Tetrahedror;vol.70;mixturewasstirredfor1h,and3N;h611-lEmmol,nb.10;2(I14);p.188015.5mL)wasaddedover10min.Themixturewas1888warmedtortover1h.Thenthemixturewaswashedwithwater(25c0mL),brine(50^L)andorganiclayerwaisdriedoverMgSRThesolventwasremovedunderdiminishedpressureandtheresidue(9.91g,95%)wasuseddirectlyinthenextstep.Analyticalsampobtainedbyflashchromatography(hexane2：1).lewas(3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)metrahydrofuran-2-ol(15.0g)wascombinedwithMTBEhyl)tet(60.0mL),KBr(424.5mg),aqueqHP0K4solution(2.5M,14.3mL),andTEMPO(56mg).Thismixture5wascooledtoaboutC.1AqueousbleachsolutionWO2O17/184668;2017);(7.9%wt.)wasslowlychargedinportionsuntilc(A1leEeglishconsumptionofstartingmaterialasindicatedthroughastarch/iodidetest.Thelayerswereseparated.andtheaqueouslayerwasextractedwithMTBE.Thecombinedorganicphasewasdriedover^gSUdconcentratedunderreducedpressuretoyieldtheproductasasolid.4、remdesivir（伦地西韦、瑞德西韦）中间体6的合成

h2n序号实验步骤参考文献17-Bromo-pyrrolo[2,l-f]triazine-4-ylamine5(2.78gm,equiv13.2mmol)wassuspendedinanhydrousTHF(70mL).Underinertatmosphere,1,1,4,4-tetramethyl-1,4-dichlorodisilyethylene(2.83gm,equiv,13.2mmol)wasaddedalongwithsodiumhydride(1.05gm,26.3mmol,2.2equiv)wasaddedandthemixturewasstirredfor20minatroomtemperature.Thereactionwasthencooledto-78°Cbeforen-BuLi(27.4mL,43.89mmol,1.6MinHexanes)slowlyover5min.Thereactionwasallowedtostirforafurther15minbeforelactone4(dissolvedin3mLwasaddeddropwise).WhenthereactionwascompletebyLCMS,thereactionwasquenchedwithaceticacid.ThereactionwasconcentratedinvacuobeforebeingdilutedinEtOAcandwashingwithwater,saturatedNH4Clandbrine.TheorganiclayersweredriedoverMgSO4,filteredandconcentratedinvacuo.Thematerialwaspurifiedbysilicachromatography(0-50%EtOAc/Hexanes)provideda3:1mixtureof5anomers.4.38gm(y.60%)ofawhitesolid6wasobtained.TetrahedronLetters,vol.53;nb.5;(2012);p.484-4862Toasolutionof7-bromopyrrolo[2,l-f][l,2,4]triazin-4-amine5(2g,9.39mmol,2.98equiv)inanhydrousTHF(200mL)underinertatmosphere,wasadded1,1,4,4-tetramethyl-1,4-dichlorodisilyethylene(2.2g,9.46mmol,1.1equiv)alongwithsodiumhydride(754mg,18.92mmol,2.2equiv)andthemixturewasstirredfor20minatroomtemperature.Thereactionwasthencooledto-78°Cbeforenbutyllithium(11.4mL,28.38mmol,2.5Minhexanes)wasaddedslowlyover10min.Thereactionwasallowedtostirforafurther15minbefore(3R,4R,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]oxolan-2-one4(3.6g,8.60mmol,1.00equiv)(dissolvedin5mLTHF)wasaddeddropwise.Theresultingsolutionwasstirredfor1hatWO2019/53696;(2019);(A1)English

-78°C,thenquenchedbytheadditionof200mLsat.ammoniumchloride(aq.).Theresultingsolutionwasextractedwithofethylacetate(200mLx3)andtheorganiclayerscombined,driedoversodiumsulfateandconcentratedunderreducedpressure.Thecrudeproductwaspurifiedbyreversephaseflashchromatography(ACN/H2O).Thisresultedin2g(42%)ofthetitlecompound6asayellowsolid.3Weigh300gramsof4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine5(1.4mol)dissolvedinsolvent,Undertheprotectionofinertgas,Add375ml(2.95mol)oftrimethylchlorosilane,lowerthetemperatureto-70°C,add2250ml(3.6mol)ofn-butyllithiumdropwise,aftertheadditionofn-butyllithium,Weigh620g(1.5mol)of2,3,5-tribenzyloxy-D-ribose-l,4-lactone4insolventaandaddittothereactionsolution.TLCmonitorstheprogressofthereaction.Afterthereaction,itisquenchedwithaceticacidAfterquenching,itwasconcentratedandwashedunderreducedpressure,andseparatedbycolumnchromatographytoobtainintermediateI,about225g.Theyieldofthisintermediate6was29.2%.CN110776512;(2020);(A)Chinese4Thebromopyrazole5(0.5g,2.4mmol)wassuspendedinanhydrousTHF(10mL)underN2(g).ThesuspensionwasstirredandTMSCl(0.67mL,5.28mmol)wasadded.Themixturewasstirredfor20min.atRTandthencooledto-78°C.afterwhichtimeasolutionofn-BuLi(6mL,1.6Ninhexanes,9.6mmol)wasaddedslowly.Thereactionmixturewasstirredfor10min.at-78°C.andthenthelactone4(1g,2.4mmol)wasaddedviasyringe.WhenthereactionwascompleteasmeasuredbyLCMS,AcOHwasaddedtoquenchthereaction.ThemixturewasconcentratedunderreducedpressureandtheresiduedissolvedinamixtureofCH2Cl2andH2O(100mL,1:1).TheorganiclayerwasseparatedandwashedwithH2O(50mL).TheorganiclayerwasthendriedoveranhydrousMgSO4,filteredandconcentratedunderreducedpressure.Theresiduewassubjectedtosilicagelchromatographyelutingwith0-50%EtOAcinhexanestoprovidetheproduct6asa1:1mixtureofanomers(345mg,26%yield).US2017/71964;(2017);(A1)Englishn-Butyllithium(2.5Minhexanes,34.4mL,86.0mmol)wasaddedrapidlytoasuspensionof7-iodopyrrolo[1,2-f][1,2,4]triazin-4-amine5(6.84g,26.3mmol)and1,2-bis(chlorodimethylsilyl)ethane(5.66g,26.3mmol)

5inTHF(200mL)at-78°C.underanargonatmosphere.Overthecourseoftheadditiontheinternaltemperatureofthereactionmixtureroseto-40.5°C.,andthereactionmixturebecameaclearbrownsolution.After15min,asolutionof(3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)dihydrofuran-2(3H)-one4intetrahydrofuran(40mL)precooledto-78°C.,wasaddedrapidlyviacannula.After1h,thereactionmixturewasquenchedwithaceticacid(15mL),andtheresultingmixturewasallowedtowarmtoRT.Theresultingmixturewasdilutedwithethylacetate(800mL)andwaswashedwithsaturatedaqueoussodiumbicarbonatesolution(500mL)andbrine(500mL).Theorganiclayerwasdriedoveranhydroussodiumsulfate,andwasconcentratedunderreducedpressure.ThecruderesiduewaspurifiedviaSiO2columnchromatography(220gSiO2Combi-flashHPGoldColumn,0-100%ethylacetate/hexanes)toaffordintermediate6.US2015/133395;(2015);(Al)English5、remdesivir（伦地西韦、瑞德西韦）中间体7的合成序号实验步骤参考文献1Thehydroxynucleoside6(l.lg,2.0mmol)wasdissolvedinanhydrousCH2Cl2(40mL)andthesolutioncooledwithstirringto0°CunderN2(g).TMSCN(0.931mL,7mmol)wasaddedandthemixturestirredforafurther10min.TMSOTf(1.63mL,9.0mmol)wasslowlyaddedtothereactionandthemixturestirredfor1h.ThereactionmixturewasthendilutedwithCH2Cl2(120mL)andaqueousNaHCO3(120mL)wasaddedtoquenchthereaction.Thereactionmixturewasstirredforafurther10minandtheorganiclayerseparated.TheaqueouslayerwasextractedwithCH2Cl2(150mL)andthecombinedorganicextractsdriedoveranhydrousMgSO4,filteredandconcentratedunderreducedpressure.TheresiduewasdissolvedinaminimalamountWO2012/12776;(2012);(A1)English;US2017/71964;(2017);(A1)English

ofCH2C12andsubjectedtosilicagelchromatographyelutingwithagradientof0-75%EtOAcandhexanestoprovidethetribenzylcyanonucleosideasamixtureofanomers.(0.9g,80%)2Toasolutionof(3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol6(2.2g,3.98mmol,1.00equiv)inDCM(80mL)underinertatmosphere,wasaddedtrimethylsilanecarbonitrile(1.86mL,3.50equiv)dropwiseat0°C.Theresultingsolutionwasstirredfor10mm.Tothiswasaddedtrimethylsilyltrifluoromethanesulfonate(3.26mL,4.50equiv)dropwiseat0°C.Theresultingsolutionwasstirredfor2hat0°C.thenquenchedbytheadditionof200mLofsat.sodiumbicarbonate(aq.).Theresultingsolutionwasextractedwith200mLofDCMandtheorganiclayerscombinedanddriedoveranhydroussodiumsulfateandconcentratedunderreducedpressure.Theresiduewaspurifiedonsilicagelcolumnwithethylacetate/petroleumether(1:10-2:1).Thisresultedin1.2g(54%)ofthetitlecompoundasayellowsolid7.WO2019/53696;(2019);(A1)English3Thehydroxynucleoside(1.1g,2.0mmol)wasdissolvedinanhydrousCH2Cl2(40mL)andthesolutioncooledwithstirringtoabout-78°CunderN2(g).TMSCN(0.931mL,7mmol)wasaddedandthemixturestirredforafurther10min.TMSOTf(1.63mL,9.0mmol)wasslowlyaddedtothereactionandthemixturestirredfor1h.ThereactionmixturewasthendilutedwithCH2Cl2(120mL)andaqueousNaHCO3(120mL)wasaddedtoquenchthereaction.Thereactionmixturewasstirredforafurther10minandtheorganiclayerseparated.TheaqueouslayerwasextractedwithCH2Cl2(150mL)andthecombinedorganicextractsdriedoveranhydrousMgSO4,filteredandconcentratedunderreducedpressure.TheresiduewasdissolvedinaminimalamountofCH2Cl2andsubjectedtosilicagelchromatographyelutingwithagradientof0-75%EtOAcandhexanestoprovidethetribenzylcyanonucleoside7asamixtureofanomers.WO2016/69826;(2016);(A1)English6、remdesivir（伦地西韦、瑞德西韦）中间体8的合成

h2n序号实验步骤参考文献1Toasolutionof(3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][l,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile7(1g,1.78mmol,1.00equiv)inDCM(5mL)underinertatmosphere,wasaddedasolutionofborontrichloride(1MinDCM,8mL,3.4eq)dropwiseat0°C.Theresultingsolutionwasstirredfor1hat0°C,thenquenchedbytheadditionofpotassiumcarbonateinmethanol.Afterfiltration,theresultingsolutionwasconcentratedunderreducedpressure.Thecrudeproductwaspurifiedbyreversephaseflashchromatography(ACN/H2O).Thisresultedin207mg(40%)ofthetitlecompound8asawhitesolid.WO2019/53696;(2019);(A1)English2Thetribenzylcyanonucleoside7(48.8g,86.9mmol,1.0equiv.)wasdissolvedinanhydrousCH2Cl2(244mL)andcooledtoabout-20°C.AsolutionofBCl3(1MinCH2Cl2,295mL,295mmol,3.4equiv.)wasaddeddropwise,maintainingtheinternaltemperaturebelowabout-15°C.Followingaddition,thereactionmixturewasstirredfor1hatabout-20°C.MeOH(340ml)wasaddeddropwise,maintainingtheinternaltemperaturebelow-15°C.Theresultingsolutionwasdistilledtoabout250ml,thenrefilledwithabout250mlMeOH.Theresultingsolutionwasagaindistilledtoabout250ml,thenrefilledwithabout250mlMeOH,andfinallydistilledtoabout125ml.Water(125ml)wasadded,followedbyK2CO3solution(20wt%inwater,125ml).ThepHwaschecked,andfoundtobe~3.K2CO3solutionwasadded(20wt%inwater,50ml),andthepHwasfoundtobe〜8.Theresultingslurrywasstirredovernight,thenfilteredandwashedwithwater(50ml)andMeOH(50ml).Thewetproductcakewasdriedovernightatabout40°Covernight.WO2016/69826;(2016);(A1)English

3Asolutionofcompound7(100mg,0.18mmol)indryDCMwascooledto-20°CandthenBCl3(1M,1.07mL,1.07mmol)wasaddedat-20°C.Themixturedwasthenslowlyallowedtoreachroomtemperatureandstirredfor2.5h.Aftercompletion,thereactionwasquenchedwithMeOHfollowedbyslowaddionoftriethylamineat0°C.Theresultingmixturewasthenevaporatedinvacuotogiveacrudeproduct,whichwaspurifiedfirstbysilicachromatographyandthenHPLCtoprovidecompounds8(15mg,30%)BioorganicandMedicinalChemstryLetters;vol.29;nb.12;(2019);p.1450-14534Thetribenzylcyanonucleoside7(70mg,0.124mmol)wasdissolvedinanhydrousCH2Cl2(2mL)andcooledto-78°CunderN2(g).AsolutionofBCl3(INinCH2Cl2,0.506mL,0.506mmol)wasaddedandthereactionmixturestirredfor1h.at-78°C.WhenthereactionwascompletebyLC/MS,MeOHwasaddedtoquenchthereaction.ThereactionmixturewasallowedtowarmtoroomRTandthesolventremovedunderreducedpressure.TheresiduewassubjectedtoCI8reversephaseHPLC,elutingfor5minwithH2O(0.1%TFA),followedbyagradientof0-70%MeCNinH20(0.1%TFA)over35min,toelutethea-anomer(20mg,37%),andp-anomer1(20mg,37%).WO2012/12776;(2012);(A1)English7、remdesivir（伦地西韦、瑞德西韦）中间体9的合成序号实验步骤参考文献1Toa2Lthree-neckedreactionflaskfittedwithamechanicalstirrerwasaddedphenyldichlorophosphate(41.2ml,276.4mmol)andCH2Cl2(300ml).Thesolutionwascooledto~0°C.withice/H2OunderN2-atmosphere.Theaminefromstepa(95.5g,276.4mmol)andCH2Cl2(100ml)wasaddedandtheslurrywascooledwithice/H2O/NaClkeepingtheinnertemperatureoftheflaskwasto~-12°C.After45min,triethylamine(848ml,608.2mmol)inCH2Cl2(200ml)wasaddedslowlyover65minutes.AftertheadditiontheUS201引143835;(2013);(A1)English

temperatureisslowlyraisedto20°C.After3h,thereactionmixturewascooledto~0°C.withice/H2Oand4-nitrophenol(38.5g,276.4mmol)wasaddedinoneportionfollowedbyadropwiseadditionoftriethylamine(38.5ml,276.4mmol)inCH2C12(150ml)over~60min.Thereactionmixtureisleftstirringovernight,thenfiltered,washedwithiso-hexaneandconcentrated.THF(350ml)wasaddedtotheresidueandtheslurrywasstirredatroomtemperaturefor~1.5h,thenputinat~5°C.for~1handfiltered.TheprecipitatewasfilteredoutandwashedwithTHF/iso-hexane50/50.Thefiltrateisevaporatedwhichgave200gofaviscoussyrup.ThesyrupwaspurifiedbyflashchromatographyusingYMC-gel,columnsize90*150mm.Eluent:EtOAc/l-hexane:25/75-35/65,whichgave95.3grofyellowishsyrup.theaffordedsyrupwassubjectedtofurtherpurificationbyflashchromatographyonsilica,whichgavethetitlecompound9(77.0g,62%)2Dissolvedphenyldichlorophosphate(1.5mL,10mmol)in30mLanhydrousDCMandstirredunderN2(g)inanicebath.AddedaminoesterHClsalt,(S)-2-ethylbutyl2-aminopropanoatehydrochloride,(preparedaccordingtoEur.J.Med.Chem.2009,44,3765-3770,2.1g,10mmol)inoneportion.AddedTEA(3mL,22mmol)dropwise.Stirredfor1hat0°C.Addedp-nitrophenol(1.4g,10mmol)inoneportionandTEA(1.5mL,11mmol).Thereactionmixturewasthenstirredatroomtemperaturefor16h.DilutedwithDCMandwashedwithsaturatedNaHCO3(aq).DriedorganicoveranhydrousNa2SO4andconcentratedunderreducedpressure.Purifiedwithsilicagelcolumn(0-15%EtOAcinhexanes)toaffordintermediate9.US2015/133395;(2015);(A1)English3AslurryofL-alanine-2-ethylbutylesterhydrochloride(20.08g,95.8mmol)andisopropylacetate(174g)wascooledwithstirringtoabout-20°C).Phenyldichlorophosphate(20.37g,96.5mmol)wasadded,followedbyslowadditionoftriethylamine(20.97g,207.2mmol)andthemixturewasstirredatabout-20°Cforabout1h.4-Nitrophenol(13.23g,95.1mmol)wasadded,followedbyslowadditionoftriethylamine(10.01g,98.8mmol)andthereactionmixturewasstirredforabout1.5h.Thereactionmixturewaswarmedtoabout0°Cand0.5MHCl(140g)wasadded.Theorganiclayerwasseparatedandwashedwith5%Na2CO3(2xWO2016/69826;(2016);(A1)English

100g)and10%NaCl(2x100g).Theorganiclayerwasthenconcentratedtoabout80mLvolumeandisopropylacetate(4g)wasadded,followedbyn-heptane(110g).Productseedcrystals(0.100g)wereaddedfollowedbyasecondportionofn-heptane(110g)andthemixturewascooledtoabout0°C.1,8-Diazabicycloundec-7-ene(1.49g,9.79mmol)wasaddedandthemixturewasstirredatabout0°Cforabout21h.Theresultantsolidswerefilteredandwashedfirstwithn-heptane(61g)andthenwithH2O(2x100g).ThesolidswerestirredwithH2O(200g)forabout1.5h,filtered,andrinsedwith0(3x100g),thenn-heptane(61g).Theobtainedsolidsweredriedundervacuumatabout40°Cforabout19htoprovide2-ethylbutyl((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate9.8、remdesivir（伦地西韦、瑞德西韦）中间体10的合成序号实验步骤参考文献1L-Alanine2-ethylbutylesterhydrochloride(5.0g,23.84mmol)wascombinedwithmethylenechloride(40mL),cooledtoabout-78°C,andphenyldichlorophosphate(3.65mL,23.84mmol)wasadded.Triethylamine(6.6mL,47.68mmol)wasaddedoverabout60minatabout-78°Candtheresultingmixturewasstirredatambienttemperaturefor3h.Thereactionmixturewascooledtoabout0°Candpentafluorophenol(4.4g,23.84mmol)wasadded.Triethylamine(3.3mL,23.84mmol)wasaddedoverabout60min.Themixturewasstirredforabout3hatambienttemperatureandconcentratedunderreducedpressure.TheresiduewasdissolvedinEtOAc,washedwithanaqueoussodiumcarbonatesolutionseveraltimes,andconcentratedunderreducedpressure.TheresiduewaspurifiedbysilicagelcolumnchromatographyusingagradientofEtOAcandhexanes(0to30%).Productcontainingfractionswereconcentratedunderreducedpressuretogive(2S)-2-ethylWO2016/69826;(2016);(A1)English;US2017/71964;(2017);(A1)English;WO2017/184668;(2017);(A1)English

butyl2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoateasasolid10.9、remdesivir（伦地西韦、瑞德西韦）的合成方法序号实验步骤参考文献11.50gofanucleosidecompound8,200mLoftetrahydrofuranand2.55gofactivephosphate10,cooledto0°Cinanicebath,Slowlyadd10mLoftert-butylmagnesiumchloridesolution(1.0Mtetrahydrofuransolution)understirring.Afterthedropwiseadditionwascompleted,thetemperaturewasraisedto40°C,andthereactionwasperformedatthetemperaturefor2hours.Afterthereactionwascompleted,thereactionsolutionwasconcentratedunderreducedpressure,andtheconcentratedsolutionwasaddedto200mLofdichloromethane.Itwaswashedtwicewith50mLofasaturatedsodiumchloridesolution,andtheorganicphasewasdriedoveranhydroussodiumsulfate.Itwasconcentratedunderreducedpressure,andtheconcentratedresiduewasseparatedbysilicagelcolumnchromatographyusingamixedsolutionofethylacetate/petroleumether=2/1asaneluent.1.04gofproduct11wasobtainedwithacalculatedyieldof33.5%.CN110613726;(2019);(A)2Thenucleoside8(29mg,0.1mmol)andthephosphonamide10(60mg,0.12mmol)andN,N-dimethylformamide(2mL)werecombinedatambienttemperature.Tert-Butylmagnesiumchloride(1MinTHF,0.15mL)wasslowlyadded.Afteraboutlh,thereactionwasdilutedwithethylacetate,washedwithaqueouscitricacidsolution(5%wt.),aqueoussaturatedNaHCO3solutionandsaturatedbrinesolution.TheorganicphasewasdriedoverNa2SO4andconcentratedunderreducedpressure.TheresiduewaspurifiedbysilicagelcolumnchromatographyusingagradientofmethanolandCH2Cl2(0to5%).Productcontainingfractionswereconcentratedunderreducedpressuretoprovidetheproduct11.WO2016/69826;(2016);(A1)English;US2017/71964;(2017);(A1)English;WO2017/184668;(2017);(A1)English

11HSNH(5'%HO10、remdesivir（伦地西韦、瑞德西韦）的合成方法二11HSNH(5'%HO序号实验步骤参考文献1(2S)-2-ethylbutyl2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate9(1.08g,2.4mmol)wasdissolvedinanhydrousDMF(9mL)andstirredunderanitrogenatmosphereatRT.(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile8(350mg,1.2mmol)wasaddedtothereactionmixtureinoneportion.Asolutionoft-butylmagnesiumchlorideinTHF(1M,1.8mL,1.8mmol)wasthenaddedtothereactiondropwiseover10minutes.Thereactionwasstirredfor2h,atwhichpointthereactionmixturewasdilutedwithethylacetate(50mL)andwashedwithsaturatedaqueoussodiumbicarbonatesolution(3x15mL)followedbysaturatedaqueoussodiumchloridesolution(15mL).Theorganiclayerwasdriedoveranhydroussodiumsulfateandconcentratedunderreducedpressure.Theresultingoilwaspurifiedwithsilicagelcolumnchromatography(0-10%MeOHinDCM)toafford(2S)-2-ethylbutyl2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate11(311mg,43%,1:0.4diastereomericmixtureatphosphorus)asawhitesolid.US2017/71964;(2017);(A1)English;WO2017/184668;(2017);(A1)English2(2S)-2-ethylbutyl2-(((4-nitrophenoxy)(phenoxy)phoAhoiyl)amino)propanoate9(1.08g,2.4mmol)wasdissolvedinanhydrousDMF(9mL)andstirredunderanitrogenatmosphereatRT.(2R,3R,4S,5R)-