新藥Etrasimod(艾曲莫德)合成檢索總結(jié)報(bào)告

PAGEPAGE1新藥Etrasimod（艾曲莫德）合成檢索總結(jié)報(bào)告一、Etrasimod（艾曲莫德）簡(jiǎn)介Etrasimod（艾曲莫德）對(duì)特定的免疫細(xì)胞類型提供系統(tǒng)性和局部效應(yīng)，并有可能治療多種免疫介導(dǎo)的炎癥疾病，包括潰瘍性結(jié)腸炎、克羅恩病、嗜酸性食管炎、特應(yīng)性皮炎和斑禿。近日，ArenaPharmaceuticals宣布其Etrasimod用于治療潰瘍性結(jié)腸炎的II期臨床試驗(yàn)取得積極頂線結(jié)果，與安慰劑相比每日口服2mgEtrasimod的患者在所有的主要、次要和臨床緩解終點(diǎn)上都表現(xiàn)出統(tǒng)計(jì)學(xué)上的顯著提高，并且安全性數(shù)據(jù)優(yōu)秀。Etrasimod（艾曲莫德）分子結(jié)構(gòu)式如下:英文名稱：Etrasimod中文名稱：艾曲莫德本文主要對(duì)Etrasimod（艾曲莫德）的合成路線、關(guān)鍵中間體的合成方法及實(shí)驗(yàn)操作方法進(jìn)行了文獻(xiàn)檢索并作出了總結(jié)。二、Etrasimod（艾曲莫德）合成路線(一)Etrasimod（艾曲莫德）中間體15的合成路線(二)Etrasimod（艾曲莫德）中間體7的合成路線一(三)Etrasimod（艾曲莫德）中間體7的合成路線二(四)Etrasimod（艾曲莫德）的合成路線（從7開始合成）三、Etrasimod（艾曲莫德）合成檢索總結(jié)報(bào)告(一)Etrasimod（艾曲莫德）中間體3的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Toasuspensionof(4-benzyloxyphenyl)hydrazinehydro-chloride2(379.5g,2.17mol)andethyl1-(2-ethoxy-2-oxoethyl)-2-oxocyclopentanecarboxylate1(2.17mol)inEtOH(2.0L),AcOH(131g,124mL,2.17mol)wasaddedandthemixturestirredat75°Cfor18hunderN2.ThefinedarkbrownsuspensionwasallowedtocoolandneutralizedwithsaturatedaqueousNaHCO3.Thesolventwasevaporatedunderreducedpressure,thebrownoilyresiduetakenupinEtOAc(2L),filteredandtheorganicswashedwithwater(3×500mL)andbrine(2×500mL).Thecombinedaqueouslayerswerere-extractedwithEtOAc.Thecombinedorganicsweredried(MgSO4)andthesolventwasevaporatedunderreducedpressuretoaffordethyl3-(2-ethoxy-2-oxoethyl)-7-benzyloxy-1,2,3,4-tetrahydrocyclopenta[b]indole-3-carboxylate3(71%)asathickdarkbrownoil.TetrahedronLetters;vol.56;nb.2;(2015);p.378-381.(二)Etrasimod（艾曲莫德）中間體4的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一A50wt%aqueoussolutionofNaOH(346g,4.32mol,4equiv.)wasslowlyaddedtoasolutionof3(1.08mol)inEtOH(2.0L)andtheresultingmixturewasstirredat60oCfor18hunderN2.Thebrownsuspensionwasneutralizedat0°Cwith6NHClandthesolventwasevaporated.ThebrownresiduewaspartitionedbetweenH2O(2L)andEtOAc(1L)andthelayersseparated.TheaqueouslayerwasfurtherwashedwithEtOAc(3×500mL)andthepHoftheaqueousphasewasadjustedto3-4with6NHCl.Theprecipitatewascollectedanddriedundervacuumatambienttemperatureovernighttogivethetitlecompound4(62%)asabrownsolid.TetrahedronLetters;vol.56;nb.2;(2015);p.378-381.(三)Etrasimod（艾曲莫德）中間體5的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Asolutionof4(0.66mol)inAcOH(1.0L)wasstirredat60°Cfor4.5hunderN2.Thedarkbrownsolutionwasconcentrated,theprecipitatecollectedundersuction,washedwithH2O(3×500mL)anddriedat40°Cundervacuumovernighttoafford2-(7-benzyloxy-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)aceticacid(88%)asabrownsolid.TetrahedronLetters;vol.56;nb.2;(2015);p.378-381.(四)Etrasimod（艾曲莫德）中間體6的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Toasolutionof5(1.02g,3.17mmol)inEtOH(10mL)andwater(0.5mL),ammoniumformate(1.20g,19.04mmol)andwetpalladium-on-carbon(10%wt,0.10g,0.094mmol)wereaddedunderN2.Thedarkpurplereactionmixturewasheatedto40°C.ConversionbyHPLCafterstirringfor4.5hat40°Cwasdeterminedtobe75%.Additionalammoniumformate(1.20g,19.04mmol)andwetpalladium-on-carbon(10%wt,0.10g,0.094mmol)wereadded.ReactioncompletionwasachievedafterstirringunderN2at40°Cforfurther5h.Thereactionmixturewasallowedtocool,filteredthroughceliteandthefiltercakewashedwithEtOH(3×3mL).Thecombinedfiltrateswereconcentrated,thegreenishresiduetakenupinH2OandthepHadjustedto2with6NHCl.TheaqueousmixturewasextractedwithEtOAc(10mL),thelayersseparatedandtheaqueouslayerbackextractedwithEtOAc(2×5mL).Thecombinedorganiclayersweredried(Na2SO4),filteredandconcentratedtogivethetitlecompound6(0.40g,55%)asapurplesolid.TetrahedronLetters;vol.56;nb.2;(2015);p.378-381.(五)Etrasimod（艾曲莫德）中間體7的合成方法一合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Dissolvethecompound6inethanol,addingconcentratedsulfuricacid(0.6equiv),andheatrefluxtogetthetargetproduct7.TetrahedronLetters;vol.56;nb.2;(2015);p.378-381.(六)Etrasimod（艾曲莫德）中間體7的合成方法二①Etrasimod（艾曲莫德）中間體9的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Toasuspensionof(4-methoxyphenyl)hydrazinehydro-chloride8(379.5g,2.17mol)andethyll-(2-ethoxy-2-oxo-ethyl)-2-oxocyclopentanecarboxylate1(526g,2.17mol)inEtOH(2.0L),AcOH(131g,124mL,2.17mol)wasaddedandthemixturewasstirredat75oCfor18hunderN2.ThefinedarkbrownsuspensionwasallowedtocoolandneutralizedwithsaturatedaqueousNaHCO3.Thesolventwasevaporatedunderreducedpressure.ThebrownoilyresiduewastakenupinEtOAc(2L),filteredandtheorganicswerewashedwithwater(3×500mL)andbrine(2×500mL).Thecombinedaqueouslayerswerere-extractedwithEtOAc.Thecombinedorganicsweredried(MgSO4)andthesolventwasevaporatedunderreducedpressuretogivethetitlecompound9(703.4g)asathickdarkbrownoil.TetrahedronLetters;vol.56;nb.2;(2015);p.378-381.;WO2010/11316;(2010);(A1)English②Etrasimod（艾曲莫德）中間體10的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一A50wt%aqueoussolutionofNaOH(346g,432mol,4equiv.)wasslowlyaddedtoasolutionofethyl3-(2-ethoxy-2-oxoethyl)-7-methoxy-l,2,3,4-tetrahydrocyclopenta[(3]mdole-3-carboxylate9(373g,108mol)inEtOH(2.0L)andtheresultingmixturewasstirredat60oCfor18hunderN2.Thebrownsuspensionwasneutralizedat0°Cwith6NHClandthesolventwasevaporated.ThebrownresiduewaspartitionedbetweenH2O(2L)andEtOAc(1L)andthelayersseparated.TheaqueouslayerwasfurtherwashedwithEtOAc(3×500mL)andthepHoftheaqueousphasewasadjustedto3-4with6NHCl.Theprecipitatewascollectedanddriedundervacuumatambienttemperatureovernighttogivethetitlecompound10(191.4g)asabrownsolid.WO2010/11316;(2010);(A1)English③Etrasimod（艾曲莫德）中間體11的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Asolutionof3-(carboxymethyl)-7-methoxy-l,2,3,4-tetrahydrocyclopenta[j8]mdole-3-carboxyhcacid10(191g,0.66mol)inAcOH(1.0L)wasstirredat60oCfor4.5hunderN2.Thedarkbrownsolutionwasconcentrated.Theprecipitatewascollected,washedwithH2O(3×500mL)anddryedat40oCundervacuumovernighttogivethetitlecompound11(126.4g)asabrownsolid.TetrahedronLetters;vol.56;nb.2;(2015);p.378-381.;WO2010/11316;(2010);(A1)English④Etrasimod（艾曲莫德）中間體7的合成（由11合成7）合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一ToasolutionofBBr3(115g,43.3mL,458mmol,3equiv)inCH2Cl2(70mL)asuspensionof2-(7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid11(37.44g,153mmol)inCH2Cl2(300mL)wasaddedslowlywhilemaintainingthereactiontemperaturebetween-5to0°C.Theresultingdarkbrownsuspensionwasstirredat-5to0°Cforanadditional1h.EtOH(187mL)wasaddeddropwisetothereactionmixturewhilemaintainingthetemperaturebetween0-10°C.Theresultingsolutionwasheatedat40°Cfor30min.ThesolutionwascooledandthepHadjustedto8byadding10NNaOH(142.9mL,1.43mol)slowlywhilemaintainingthetemperaturebetween0-3°C.Thesolventwasremovedunderreducedpressureuntilabout200mLofconcentrateremained.ThepHwasadjustedtoabout7withconcentratedHCl,thesuspensionfiltered,thesolidswashedwithH2O(3×200mL)anddriedundervacuumatambienttemperatureovernight.ThelightbrownmaterialwasdissolvedinEtOAc(200mL),andfilteredwashingthesolidswithEtOAc.ThecombinedorganicswerewashedwithsaturatedaqueousNaHCO3.(2×200mL),brine(200mL),dried(Na2SO4)andthesolventrotaryevaporatedtoaffordethyl2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[β]indol-3-yl)acetate7(35.2g,88.9%)asalightbrownsolidTetrahedronLetters;vol.56;nb.2;(2015);p.378-381.WO2010/11316;(2010);(A1)English(七)Etrasimod（艾曲莫德）中間體13的合成方法一合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Toasolutionof4-cyclopentyl-3-(trifluoromethyl)benzal-dehyde12(0.25g,1.032mmol)inethanol(2.5mL)wasaddedsodiumborohydride(0.047g,1.238mmol)andthemixturewasstirredinroomtemperaturefor2h.Themixturewasquenchedwithwater,acidifiedwith6NHCl,dilutedwithmorewaterandextractedwithCH2Cl2.TheCH2Cl2layerwaswashedwithwater,driedoverNa2SO4,filteredandconcentratedinvacuotogivethetitlecompound13(0.22g).WO2010/11316;(2010);(A1)English;WO2011/94008;(2011);(A1)English.(八)Etrasimod（艾曲莫德）中間體13的合成方法二合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Toasolutionofmethyl4-cyclopentyl-3-(trifluoromethyl)-benzoate14(8.16g,30.0mmol)in1,4-dioxane(200mL)wasaddedlithiumborohydridesolution(2Mintetrahydrofuran,30.0mL,59.9mmol).Themixturewasheatedunderrefluxfor2.5h.Themixturewasallowedtocooltoroomtemperatureandcarefullyquenchedwith1NaqueousHClsolutiontopH5.Theorganiclayerwasseparatedandtheaqueouslayerwasextractedwithethylacetate.Thecombinedorganiclayersweredriedoveranhydroussodiumsulfate,concentratedunderreducedpressureandpurifiedbysilicagelcolumnchromatograhytogivethetitlecompound13asacolorlessoil(1.21g).WO2011/94008;(2011);(A1)English;WO2010/11316;(2010);(A1)English(九)Etrasimod（艾曲莫德）中間體15的合成方法一合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一To(4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol13(110g,113mmol),thionylchloride(329mL,4.50mol,10eq)wasaddeddropwiseatsucharateastomaintaintheinternaltemperaturebetween10-25oC(cooledwithice-water).Theresultingmixturewasstirredat50oCfor3.5hfollowedby6hat25oC.Themixturewasconcentratedunderreducedpressureandtheresultingoilyresiduepouredintoice-water(450mL)undervigorousstirring.ThelayerswereseparatedandtheaqueousphaseextractedwithCH2Cl2(3×400mL).ThecombinedorganiclayerswerewashedwithsaturatedNaHCO3(400mL),brine(2×400mL),dried(Na2SO4),filteredoverfreshNa2SO4,andconcentratedinvacuotoafford4-(chloromethyl)-l-cyclopentyl-2-(trifluoro-methyl)benzene15asapaleyellowoil(113.3g,96%).WO2010/11316;(2010);(A1)English;WO2011/94008;(2011);(A1)English;OrganicProcessResearchandDevelopment;vol.19;nb.6;(2015);p.618-623.(十)Etrasimod（艾曲莫德）中間體15的合成方法二合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Toa100gallonglasslinedreactorequippedwithastirrerwasaddedconcentratedsulphuricacid(48.6L)andcooledtoaninternaltemperaturebetweenabout-5to-10°CunderanatmosphereofN2.Tothesulfuricacidwasaddedthionylchloride(26.99kg,2eq)ataratetomaintaintheinternaltemperaturebelow-5°C.Totheresultingmixture1,3,5-trioxane(15.3kg,1.5eq)wasaddedportionwiseataratetomaintaintheinternaltemperaturebelow-5°C.Aftertheadditionof1,3,5-trioxane,l-cyclopentyl-2-(trifluoro-methyl)benzene16(24.0kg)wasaddeddropwiseoveraperiodofapproximately2-3hours.Thereactionmixturewasstirredat0°Cforapproximately3-4hours,allowedtowarmtoroomtemperatureovernightandsubsequentlycooledtoaninternaltemperatureof0-5°C.Totheresultingmixturewasaddedwater(316L)dropwiseoveraperiodofapproximately5-6hours(Note:Veryexothermic).Afterthequenchwithwater,theresultingaqueousmixturewasextractedwithMTBE(243Land123L).ThecombinedorganicswerewashedwithsaturatedNaHCO3(100L),brine(100L),water(100L),brine(100L),anddried(MgSO4).Themixturewasfilteredthroughanin-line(1micron)filtercartridgefollowedbyanadditionalin-line(0.45micron)filtercartridgeintoacleandryreactor.Thesolventwasevaporatedundervacuum(jacket<30°C)andfurtherevaporatedundervacuumat35-40°C.Theresultingoilwasdistilledunderhighvacuumtoprovidethetitlecompound15asayellowliquid,24.8kg(83%),purityasdeterminedbyHPLCwas99.47%.WO2011/94008;(2011);(A1)English;WO2020/51378;(2020);(A1)English.操作方法二Ina1L,3-neckedreactionflaskfittedwithamechanicalstirrer,atemperatureprobe,anadditionfunnelandadrynitrogeninletwasplacedl-cyclopentyl-2-(trifluoromethyl)-benzene16(50g,233mmol).Thematerialwasstirredandcooledto-12oC(dryice/IPAbath).Concentratedsulfuricacid(100mL,1877mmol)wasaddeddropwisesothatthetemperaturewasmaintainedbetween-12°Cto-10oC.Themixturewascooledto-15oCand3-trioxane(27.3g,303mmol)wasaddedin3batches(9.1geachbatch)whilethetemperaturewasmaintainedatbetween-15oCto-10oC.Themixturewasstirredat-10oCandalmostimmediatelysulfurochloridicacid(28.1mL,420mmol)wasaddedslowlymaintainingthetemperatureatbetween-10°Cto-5oC.Themixturewasstirredfor20minat-5oCand3hbetween-2to-3oC.Thereactionmixturewasslowlypoured(withefficientstirring)intoice-water(1L).MTBE(700mL)wasaddedandthemixturewasstirredwell.Celite(300g)wasaddedandstirredwell.TheceliteslurrywasfilteredandthecelitebedwaswashedwithMTBE.TheaqueouslayerofthefiltratewasseparatedandextractedwithMTBE(1×700mL).ThecombinedMTBElayerwaswashedwithwater(1×500mL)followedbysaturatedNaHCO3(2×350mL).TheMTBElayerwasthenwashedwithwater(2×500mL),dried(Na2SO4)andfiltered.Thefiltratewasconcentrated(at38oC,bathtemperature;200Torr)togiveayellowoil.Theoilwastakenupinhexane(500mL)andfilteredthroughabedofsilica;thenthesilicabedwaswashedwithhexane.Thefiltratewasconcentratedunderreducedpressure(38oC,bathtemperature;at200Torr)togivethetitlecompound15asalightyellowoil(36.2g;89%puritybyLCat214nm).WO2010/11316;(2010);(A1)English(十一)Etrasimod（艾曲莫德）中間體17的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Toa50literglassreactorcontainingethyl2-(7-hydroxy-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate7(2.000kg,1.000equiv.)wasaddedcesiumcarbonate(3.266kg,1.300equiv.)andacetonitrile(15.720kg)undernitrogen.Totheresultingmixturewasadded4-(chloromethyl)-l-cyclopentyl-2-(trifluoromethyl)benzene15(2.228kg,1.100equiv.)overapproximatelyonehourwhilemaintainingthestirredreactorcontentsat40°C±5°C.Aftertheadditionof4-(chloromethyl)-l-cyclopentyl-2-(trifluoromethyl)benzenethereactorcontentswereheatedto65°C±5°Cwithstirringuntiltheconcentrationofethyl2-(7-hydroxy-l,2,3,4-tetrahy-drocyclopenta[b]indol-3-yl)acetate7inthereactionmixturewaslessthan2.0%areabyHPLC.Thereactionmixturewascooledto50°C±5°Candfilteredundernitrogenthroughafinefilterclothwithsuctiontoremovecesiumsalts(Note:ethyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetatemayprecipitatebelow30°C).Thefiltercakewaswashedwithfreshhot(50°C±5°C)acetonitrile(5.658kgdividedinapproximatelythreeequalportions).Thefiltrateswerereturnedtothereactor.Thecombinedfiltrateswereconcentratedbyvacuumdistillationwithajackettemperatureof60°C±l0°C.Tothereactorwasaddedethylalcohol(3.156kg)andonceagainconcentratedwithstirringbyvacuumdistillationwithajackettemperatureof60°C±10°C.Onceagain,ethylalcohol(3.156kg)wasaddedtothereactorandthecontentswereconcentratedbyvacuumdistillationwithajackettemperatureof60°C±10°Ctoareactorvolumeofapproximately14L.Thestirredreactorcontentswerecooledto0°C±5°Candthetemperaturemaintainedfor4hourstofacilitatethecrystallizationoftheproduct.Theresultingslurrywasfiltered.Thefiltercakewaswashedwithcold0°C±5°Cethylalcohol(2×3.156kg).Thefiltercakewasdriedundervacuumat35°C±5°Cuntiltheweightlossover>1hourwas<2%toprovide3.0943kg(81.0%yield)ofthetitlecompound17asasolid.WO2011/94008;(2011);(A1)English;WO2020/51378;(2020);(A1)English操作方法二Toasolutionofethyl2-(7-hydroxy-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetate7(50.0mg,0.193mmol)and4-(chloromethyl)-l-cyclopentyl-2-(trifluoromethyl)benzene15(152.0mg,0.578mmol)inDMF(3mL)wasaddedcesiumcarbonate(75.0mg,0.231mmol).Themixturewasstirredatroomtemperatureovernight,filteredthroughCelite,andconcentratedunderreducedpressure.TheresiduewaspurifiedbyHPLCtogivethetitlecompound17asalightpinkoil(38.7mg)WO2010/11316;(2010);(A1)English(十二)Etrasimod（艾曲莫德）18的合成合成方法實(shí)驗(yàn)步驟參考文獻(xiàn)操作方法一Toasolutionofrac-ethyl2-(7-(4-cyclopentyl-3-(trifluoro-methyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate17(20.00g,41.19mmol)inacetonitrile(185ml)ina500mLthree-neckRBFequippedwithmagneticstirbar,N2inlet,thermocouple,andcondenserwasaddedpotassiumphosphatebuffer(15ml,1.0M,pH=7.80)andfollowedbyadditionoflipaseB,Candidaantarctica,immobilizedrecombinantfromyeast(1.0g,5865U/g,5865U).Theresultantyellowsuspensionwasstirredatabout40°CunderN2for16hours.Tothemixture,1McitricacidwasaddedtoadjustthepHto3.96whichwasthenfilteredonaWhatmanfiltercup.ThesolidswerewashedwithACN(3×15mL).Thecombinedfiltrateandwashingswereconcentratedatabout30°Cundervacuumtogiveanorangeresidue,whichwaspartitionedbetweenEtOAc(60mL)andbrine(60mL).ThelayerswereseparatedandtheaqueouslayerwasextractedwithEtOAc(2×40mL).ThecombinedorganiclayerswerewashedwithH20(2×80mL),brine(2×80mL),driedoverNa2SO4,decanted,andconcentratedat30°Cundervacuumtogiveanorangeoil,whichwasdriedundervacuumatroomtemperatureovernighttogivealightorangeoil(22.203g)containing(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopentaindol-3-yl)aceticacid18.Thecrudewasassayedtobe41.41wt%(9.194g)with99.42%ee.WO2011/94008;(2011);(A1)English操作方法二A1.0Mbuffersolutionwaspreparedcontainingpotassiumphosphatemonobasic(29.1g,0.0335equiv.)inUSPpurifiedwater(213g)andpotassiumphosphatedibasic(368.2g,0.331equiv.)inUSPpurifiedwater(2.107g).Toa50literglassreactorwasaddedethyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate17(3.094kg,1.000equiv.),LipaseB,Candidaantarctica,immobilized(88.18g,293250units/kgofethylesterstartingmaterial)andacetonitrile(22.32kg).Tothestirredcontentsofthereactorwasaddedthepreviouslyprepared1.0Mpotassiumphosphatebuffer.Theresultingmixturewasstirredundernitrogenatatemperatureof40°C±5°Cuntilthe2-(7-(4-cyclopentyl-3-(trifluoro-methyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacidconcentrationwas>35%areaasdeterminedbyHPLC(Note:althoughthereactionusuallyiscompleteafterabout10hours,thereactionmixturemaybeheldat40°C±5°Covernight).Thestirredreactorcontentswerecooledto25