新药Pemigatinib培米加替尼合成检索总结报告

新药Pemigatinib（培米加替尼）合成检索总结报告一、Pemigatinib（培米加替尼）简介2020年3月，Pemigatinib（培米加替尼）的2期关键性注册临床研究完成中国首例患者给药。该项研究的目的是评估Pemigatinib（培米加替尼）在既往至少接受过一线系统治疗、成纤维细胞生长因子受体2（FGFR2）基因融合或重排的中国晚期胆管癌患者中的有效性和安全性。2019年11月，美国食品药品监督管理局（FDA）正式受理Incyte递交的Pemigatinib（培米加替尼）用于治疗复发的FGFR2基因融合或重排的局部晚期胆管癌的NDA，并授予其优先审评资格。根据美国处方药使用者费用法案，预计Pemigatinib在美国获批的日期为2020年5月30日。Pemigatinib（培米加替尼）分子结构式如下：英文名称：Pemigatinib中文名称：培米加替尼本文主要对Pemigatinib（培米加替尼）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。二、Pemigatinib（培米加替尼）合成路线1Pemigatinib（培米加替尼）中间体13其他合成方法三、Pemigatinib（培米加替尼）合成检索总结报告（一）Pemigatinib（培米加替尼）中间体3的合成合成方法实验步骤参考文献操作方法一4-chloro-1-(phenylsufonyl)-1H-pyrrolo[2,3-bJpyridine-5-carbaldehyde4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde1(1.08g,6.00mmol)andcesiumcarbonate(3.91g,12.0mmol)weredissolvedinN,N-dimethyl-formamide(10mL),lightyellowsuspension.Themixturewasstirredatroomtemperaturefor20min,thenbenzenesulfonylchloride2(1.53mL,12.0mmol)wasaddeddropwise.Aftercompletionoftheaddition,white-pinkishsuspensionwasobtained.Themixturewasstirredatroomtemperaturefor2hatwhichtimeLC-MSindicatedtheWO2014/7951;(2014);(A2)English2

reactioncompletedtothedesiredproduct.Thereactionmixturewasdilutedwithwater.Thesolidwascollectedviafiltrationandwashedwithwaterthendriedtogivewhitesolid3(1.92g,quant.),whichwasusedinthenextstepwithoutfurtherpurification.操作方法Toa500LreactorwaschargedN,N-dimethylformamide(108L)and4-chloro-lH-pyrrolo[2,3-b]pyridine-5-carbal-dehyde1(10.8Kg,59.8mol)andcooledto0-5°C.Totheresultingthickslurrywaschargedcesiumcarbonate(39Kg,120mol)at0-5°C.Theslurrywasstirredat0°Cforabout20minandthemixturechangedtoanambercoloredthinslurry.Tothethinslurryatbelow10°Cwasaddedbenzenesulfonylchloride2(11.6Kg,65.8mol,1.1eq.)drop-wisethroughanadditionfunnel.Theresultingslurrywasstirredfor1hatbelow10°CandHPLCindicatedthereactionwascomplete.Extendedagitationatroomtemperatureovernighthadlittleimpactonreactionmixtureprofile.Tothismixturewasaddedwater(160L)andtheslurrywasstirredfor1h.Thesolidwascollectedbyfiltration(slow).Thefiltercakewaswashedwithwateranddriedinovenundervacuumtogive4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2.3-6]pyridine-5-carbaldehyde3asalightbrownsolid(17.8Kg,93%yield).WO2019/213544;(2019);(A2)English操作方法ToaslurryofCs2CO3(36.1g,110.8mmol)inDMF(100mL)isadded10.00g(55.4mmol)ofthestartingaldehyde1andstirredfor15min.Benzenesulfonylchloride2(14.1mL,111mmol)isaddeddropwiseandstirredfor2hatroomtemperature.Thereactionmixtureisdilutedwithwater(800mL),off-whiteprecipitateisfiltered,washedwithwateranddriedinvacuumovenat60°C.togivethedesiredproduct3.US2010/48552;(2010);(A1)English（二）Pemigatinib（培米加替尼）中间体4的合成合成方法实验步骤参考文献Toa1000Lreactorwerechargedtoluene(270L),4-chloro-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-5-carbaldehyde3(27Kg,84.2mmol).TsOH.H2O(217g,1.26mol,0.015eq.),and1,2-ethanediol(73.7Kg,1187mol,14.1eq.).Themixturewasstirredandheatedtorefluxtoremovewater(someethyleneglycolwasalsoremovedasthe3

操作方法一reactionprogresses)for9h(LCMSshowedreactioncomplete).Afterovernightstirringatroomtemperature,themixturewasdilutedwithethylacetate(135L)andwashedwithsaturatedNaHCO3solution.Thelayerswereseparatedandtheorganiclayerwaswashedwith10%aq.NaClsolutionandconcentrated.Heptane(108L)wasaddedandslurrywasformed.Thesolidwascollectedbyfiltration.Thesolidwasdissolvedindichloromethane(108L)andfilteredinordertoremovethemechanicalimpurities.Thefiltratewasconcentrated,thendissolvedin67.5L(2.5V)ofhotethylacetateandstirredfor2h.Themixturewasallowedtocoolasthesolidformed.Thesolidwascollectedbyfiltrationtogive4-chloro-5-(13-dioxolan-2-yl)-1-(phenylsulfonyl)-pyrrolo[2.3-6]pyridine4asanoff-whitesolid(22Kg,70%yield)WO2019/213544;(2019);(A2)English操作方法Amixtureofaldehyde3(8.88g,27.7mmol),ethyleneglycol(2.00mL,35.8mmol),andTsOH.H2O(200mg)intoluene(250mL)isrefluxedwithaDean-Starktrapovernight.ThereactionmixtureiswashedwithasolutionofNaHCO3,concentratedandpurifiedthroughaplugofsilicagel,eluenthexanes-EtOAc2:1.US2010/48552;(2010);(A1)English(三Qo◎4)Pemigatinib(培米力1口替尼）中间体7RoI0°裾〒气6Cl6-7，的合成o-yD%7CloJ合成方法实验步骤参考文献操作方法一Toal-Lflaskwasadded4-chloro-5-(l,3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine4(50.0g,137mmol)andtetrahydrofuran(THF,266g,300mL)underN2.Tothismixtureat-70°Cwasadded2.0MlithiumdiisopropylamideinTHF/heptane/ethylbenzene(77.4g,95mL,190mmol,1.4eq.).Themixturewasstirredat-70°Cfor1h.TothemixturewasaddedN-formylmorpholine5(29.7g,258mmol,1.9eq.)inTHF(22.2g,25mL)dropwise.Thereactionwasdonein30minafteraddition.LC/MSshowedthatthedesiredproduct6,wasformedcleanly.Thereactionwasquenchedwithaceticacid(16.4g,15.6mL,274mmol,2.0eq.)andthedryicecoolingwasremoved.Tothemixturewasaddedmorpholine(33.7g,33.5mL,387mmol,2.83eq.)followedbyaceticacid(74.0g,70mL,1231mmol,andWO2019/213544;(2019);(A2)English

9.0eq.)at0°C(internaltemperaturerosefrom0°Cto18°C)andstirredovernight.Sodiumtriacetoxyborohydride(52.50g,247.7mmol,1.8eq.)wasaddedandthereactionmixturetemperaturerosefrom20°Cto32°C.Themixturewasstirredatroomtemperaturefor30min.HPLC&LC/MSindicatedthereactionwascomplete.Water(100g,100mL)wasaddedfollowedby2.0Msodiumcarbonate(Na2cO3)inwater(236g,200mL,400mmol,2.9eq.)slowly(offgas).Themixturewasstirredforabout30min.Theorganiclayerwasseparatedandwater(250g,250mL)andheptane(308g,450mL)wereadded.Theresultingslurrywasstirredfor1handthesolidwascollectedbyfiltration.Thewetcakewaswashedwithheptanetwice(75.00mLx2,51.3gx2)beforebeingdriedinovenat50°Covernighttogivethedesiredproduct,4-((4-chloro-5-(13-dioxolan-2-yl)-1-(phenylsul-fonyl)-1//-pyrrolo[2.3-6]pyridin-2-yl)methyl)morpholine7asalightbrownsolid(52.00g,81.8%yield).Pemigatinib（培米加替尼）中间体8的合成合成方法实验步骤参考文献操作方法一Toa2Lreactorwithathermocouple,anadditionfunnel,andamechanicalstirrerwascharged4-((4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1//-pyrrolo[2,3-6]pyridin-2-yl)methyl)morpholine7(20.00g,43.1mmol)anddichloromethane(265g,200mL)atroomtemperature.Theresultingmixturewasstirredatroomtemperature(internaltemperaturewas19.5°C)toachieveasolution.Totheresultingsolutionwasaddedanaqueoushydrochloricacidsolution(0.5M,240g,200.0ml,100mmol,2.32eq.)atroomtemperaturein7min.Afterover23hagitationsatroomtemperature,thebilayerreactionmixtureturnedintoathickcolorlesssuspension.WhenHPLCshowedthereactionwascomplete,theslurrywascooledto0-5°Candaqueoussodiumhydroxidesolution(1N,104g,100mL,100mmol,and2.32eq.)wasaddedinabout10mintoadjustthepHofthereactionmixtureto10-11.Heptane(164g,240mL)wasaddedandthereactionmixtureandthemixturewerestirredWO2019/213544;(2019);(A2)English

atroomtemperaturefor1h.Thesolidwascollectedbyfiltrationandthewetcakewaswashedwithwater(2x40mL),heptane(2x40ml)beforebeingdriedinovenat50°Cundervacuumtoaffordthedesiredproduct8asalightbrownsolid(16.9g,93%yield).Pemigatinib（培米加替尼）中间体10的合成合成方法实验步骤参考文献操作方法一Toa2-Lreactorequippedwithathermocouple,anitrogeninletandmechanicalstirrerwerechargedN-dimethylformamide(450mL,425g),4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-l//-pyrrolo[2.3-6]pyridine-5-carbaldehyde8(30.0g,71.45mmol)and2,6-difluoro-3,5-dimethoxyanihne9(14.2g,75.0mmol).Tothissuspension(internaltemperature20°C)wasaddedchlorotrimethylsilane(19.4g,22.7mL,179mmol)dropwisein10minatroomtemperature(internaltemperature20-23°C).Thesuspensionchangedintoasolutionin5minafterthechlorotrimethylsilaneaddition.Thesolutionwasstirredatroomtemperaturefor1.5hbeforecooledto0-50Cwithice-bath.Borane-THFcomplexinTHF(1.0M,71.4mL,71.4mmol,64.2g,1.0eq.)wasaddeddropwiseviaadditionalfunnelover30minwhilemaintainingtemperatureat0-5°C.Afteraddition,themixturewasstirredfor4h.Water(150g,150mL)wasaddedunderice-bathcoolingin20min,followedbyslowadditionofammoniumhydroxidesolution(28%,15.3g,17ml,252mmol,3.53eq.)topH9-10whilemaintainingthetemperaturebelow10°C.Morewater(250mL,250g)wasaddedthroughtheadditionalfunnel.Theslurrywasstirredfor30minandthesolidswerecollectedbyfiltration.Thewetcakewaswashedwithwater(90gx2,90mlx2)andheptane(61.6gx2,90mlx2).Theproduct10assuctiondriedovernighttogivethedesiredproduct10(41.6g,96%yield).WO2019/213544;(2019);(A2)English（六）Pemigatinib（培米加替尼）中间体12的合成

合成方法实验步骤参考文献操作方法一Toa2-L,3-neckroundbottomflaskfittedwithathermocouple,anitrogenbubblerinlet,andamagneticstirwerecharged/V-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline10(67.0g,113mmol)andacetonitrile(670ml,527g).Thesuspensionwascooledto0-5°C.Tothemixturewaschargedethylisocyanate11(17.7mL,15.9g,224mmol,1.98eq.)over30sec.Thetemperaturestayedunchangedat0.7°Cafterthecharge.Methanesulfonicacid(16.1mL,23.9g,248mmol,2.2eq.)waschargeddropwiseover35minwhilemaintainingthetemperaturebelow2°C.Themixturewaswarmedtoroomtemperatureandstirredovernight.At24hafteradditionshowedthattheproductwas93.7%,unreactedSMwas0.73%andthemajorimpurity(bis-isocyanateadduct)was1.3%.Themixturewascooledwithanice-bathandquenchedwithsodiumhydroxide(NaOH)solution(1.0M,235mL,244g,235mmol,2.08eq.)over20minandthensaturatedaqueoussodiumbicarbonate(NaHCOs)solution(1.07M,85mL,91g,0.091mol,0.80eq.)over10min.Water(550mL,550g)wasaddedandtheliquidbecameonephase.Themixturewasstirredfor2handthesolidswerecollectedbyfiltration,washedwithwater(165mL,165g)togive12(70.3g,93.7%yield).WO2019/213544;(2019);(A2)English（七）Pemigatinib（培米加替尼）中间体13的合成方法

合成方法实验步骤参考文献操作方法一Toa2000mLflaskequippedwithathermalcouple,anitrogeninlet,andamechanicalstirrerwerechargeddryl-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-1//-pyrroloI2.3-6|pyridin-5-yl)methyl)-1-(2.6-dinuoro-3.5-dimethoyphenyl)-3-ethylurea12(30.0g,45.2mmol,KF=0.ll%)andtetrahydrofuran(1200mL,1063g).Tothissuspensionatroomtemperaturewascharged1.0MlithiumhexamethyldisilazideinTHF(62.3mL,55.5g,62.3mmol,1.38eq).Themixtureturnedintoasolutionafterthebaseaddition.Thereactionmixturewasstirredfor2handHPLCshowsthestartingmaterialwasnotdetectable.Tothismixturewasadded1.0Mhydrochloricacid(18.1mL,18.1g.18.1mmol,0.4eq.).Thesolutionwasconcentratedto600mLandwater(1200mL,1200g)wasadded.Slurrywasformedafterwateraddition.Theslurrywasstirredfor30minatroomtemperatureandthesolidwascollectedbyfiltration.Thewetcakewaswashedwithwatertwice(60mLx2,(0746)60gx2)anddriedat500Covernighttogive3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one13asalightbrownsolid(26.58g,as-isyield93.7%).WO2019/213544;(2019);(A2)English（八）Pemigatinib（培米加替尼）中间体13的合成方法①Pemigatinib（培米加替尼）中间体15的合成合成方法实验步骤参考文献操作方法一Amixtureof4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde14(7.0g,37mmol),2,6-difluoro-3,5-dimethoxyaniline9(9.1g,48mmol)and[(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid(2g,7mmol)inxylenes(250mL)washeatedtorefluxwithazeotropicremovalofwaterusingDean-Starkfor2daysatwhichtimeLC-MSshowedthereactionwascomplete.Themixturewascooledtoroomtemperatureandthesolventwasremovedunderreducedpressure.Theresiduewasdissolvedintetrahydrofuran(500mL)andthen2.0MlithiumtetrahydroaluminateinTHF(37mL,74mmol)wasaddedWO2014/7951(2014);(A2)English8

slowlyandtheresultingmixturewasstirredat50°Cfor3hthencooledtoroomtemperature.Thereactionwasquenchedbyadditionofwater,15%aqueousNaOHandwater.ThemixturewasfilteredandwashedwithTHF.ThefiltratewasconcentratedandtheresiduewaswashedwithCH2cl2andthenfilteredtogetthepureproduct15(82%).②Pemigatinib（培米加替尼）中间体16的合成合成方法实验步骤参考文献操作方法一Asolutionoftriphosgene(5.5g,18mmol)intetrahydrofuran(30mL)wasaddedslowlytoamixtureof5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-iH15pyrrolo[2,3-b]pyridin-4-amine15(5.6g,15mmol)intetrahydrofuran(100mL)at0°Candthenthemixturewasstirredatroomtemperaturefor6h.Themixturewascooledto0°Candthen1.0Msodiumhydroxideinwater(100mL,100mmol)wasaddedslowly.Thereactionmixturewasstirredatroomtemperatureovernightandtheformedprecipitatewascollectedviafiltration,washedwithwater,andthendriedtoprovidethefirstbatchofthepurifieddesiredproduct.Theorganiclayerinthefiltratewasseparatedandtheaqueouslayerwasextractedwithmethylenechloride.Thecombinedorganiclayerwasconcentratedandtheresiduewastrituratedwithmethylenechloridethenfilteredanddriedtoprovideanotherbatchoftheproduct16(total5.5g,92%).WO2014/7951(2014);(A2)English③Pemigatinib（培米加替尼）中间体17的合成

合成方法实验步骤参考文献操作方法一Toasolutionof3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-i,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido-[4,3-d]pyrimidin-2-one16(900mg,2.32mmol)inN,N-dimethylformamide(20mL)cooledto0°Cwasaddedsodiumhydride(185mg,4.63mmol,60wt%inmineraloil).Theresultingmixturewasstirredat00Cfor30mmthenbenzenesulfonylchloride2(0.444mL,3.48mmol)wasadded.Thereactionmixturewasstirredat0°Cfor1.5hatwhichtimeLC-MSshowedthereactioncompletedtothedesiredproduct.ThereactionwasquenchedwithsaturatedNH4clsolutionanddilutedwithwater.Thewhiteprecipitatewascollectedviafiltrationthenwashedwithwaterandhexanes,driedtoaffordthedesiredproduct17(1.2g,98%)asawhitesolidwhichwasusedinthenextstepwithoutfurtherpurification.WO2014/7951(2014);(A2)English④Pemigatinib（培米加替尼）中间体18的合成合成方法实验步骤参考文献操作方法一Toasolutionof3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-,3,4,7-tetrahydro2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one17(1.75g,3.31mmol)intetrahydrofuran(80mL)at-780Cwasaddedfreshlypreparedlithiumdiisopropylamide(1Mintetrahydrofuran(THF),3.48mL,3.48mmol).Theresultingmixturewasstirredat-780Cfor30minthenN,N-dimethyl-formamide(1.4mL,18mmol)wasaddedslowly.Thereactionmixturewasstirredat-780Cfor30mmthenquenchedwithwaterandextractedwithEtOAc.Theorganicextractswerecombinedthenwashedwithwaterandbrine.TheorganiclayerwasdriedoverNa2sO4andconcentrated.Theresiduewaspurifiedbyflashchromatographyelutedwith0to20%EtOAcinDCMtogivethedesiredproduct18asawhitesolid(1.68g,91%).WO2014/7951(2014);(A2)English10⑤Pemigatinib（培米加替尼）中间体13的合成合成方法实验步骤参考文献操作方法一Toasolution3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-eth-yl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2’:5,6]py-d]pyrimidine-8-carbaldehyde18(1.73g,3.11mmol)indichloromethane(50mL)wasaddedmorpholine(0.95mL,11mmol),followedbyaceticacid(2mL,30mmol).Theresultingyellowsolutionwasstirredatroomtemperatureovernightthensodiumtriacetoxyborohydride(2.3g,11mmol)wasadded.Themixturewasstirredatroomtemperaturefor3hatwhichtimeLC-MSshowedthereactionwenttocompletiontothedesiredproduct.ThereactionwasquenchedwithsaturatedNaHCO3thenextractedwithethylacetate(EtOAc).Theorganicextractswerecombinedthenwashedwithwaterandbrine.TheorganiclayerwasdriedoverNa2sO4andconcentrated.Theresiduewaspurifiedbyflashchromatographyelutedwith0to40%EtOAcinDCMtogivethedesiredproduct13asayellowsolid(1.85g,95%).WO2014/7951(2014);(A2)English（九）Pemigatinib（培米加替尼）19的合成合成方法实验步骤参考文献Toastirrings