新药Gefapixant(吉法匹生)合成检索总结报告

PAGEPAGE1新药Gefapixant（吉法匹生）合成检索总结报告一、Gefapixant（吉法匹生）简介2020年3月17日，默沙东宣布了Gefapixant（吉法匹生）治疗难治性或病因不明慢性咳嗽的两项关键III期COUGH-1和COUGH-2研究的一线结果。COUGH-1研究第12周结果和COUGH-2研究第24周结果显示，Gefapixant（吉法匹生）45mg每日2次相比安慰剂能够显著降低每小时的咳嗽次数，但是两项研究中Gefapixant（吉法匹生）15mg每日2次均未能到达减少咳嗽次数的主要疗效终点。Gefapixant（吉法匹生）的疗效和安全性与II期研究的结果一致。两项研究将继续进行，以收集更多的证据。Gefapixant（吉法匹生）分子结构式如下:英文名称：Gefapixant中文名称：吉法匹生本文主要对Gefapixant（吉法匹生）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、Gefapixant（吉法匹生）合成路线三、Gefapixant（吉法匹生）合成检索总结报告(一)Gefapixant（吉法匹生）中间体3的合成方法一合成方法实验步骤参考文献操作方法一A12-15wt%solutionof2-isopropyl-4-methoxylphenol1(314.3g,12wt%,226.8mmol)wasconcentratedtogreaterthan50wt%2-isopropyl-4-methoxyphenol1intolueneundervacuumat40-50°C.Tothesolutionwasadded189mLofNMP,andthemixturewascooledto5°C.Sodiumhydroxide(27.2g,50wt%inwater,340mmol)andchloroacetonitrile2(36g,340mmol)wereaddedsequentiallytothemixturewhilemaintainingtheinternaltemperaturebelow10°C.Thereactionwasagedfor2handthendilutedwith150mLoftolueneand226mLofwaterwhilemaintainingthetemperaturebelow10°C.Themixturewaswarmedto20-25°C,thelayerswereseparated,andtheorganiclayerwaswashedwith75mLof20wt%NaCl(aq.).Theorganiclayerwasandfilteredtoprovide2-(2-isopropyl-4-methoxyphenoxy)acetonitrile3(56.8g,74.6wt%)asasolutionintoluene.ThefilterwaswashedwithNMPtoprovideadditional2-(2-isopropyl-4-methoxyphen-oxy)acetonitrile3(27.1g,5.0wt%)asasolutioninNMP.Thecombinedyieldwasabout94%.WO2019/209607;(2019);(A1)English.(二)Gefapixant（吉法匹生）中间体3的合成方法二合成方法实验步骤参考文献操作方法一Astirredslurryoftoluene-4-sulfonicacidcyanomethylester4(13.0g),potassiumcarbonate(13.0g)and2-isopropyl-4-methoxyphenol1(9.57g)in85mLof2-butanonewasheatedto55-60oC.for4days,thenheatedtoreluxfor18hours.Theresultantslurrywascooledandfilteredtoremovesolids.Thefiltratewasconcentratedunderreducedpressureandtheresiduewasredissolvedintoluene.Thetoluenesolutionwasextractedwith1NKOH,andtheorganicphasewasconcentratedunderreducedpressuretogive20.6gofa1:1(byweight)solutionof(2-Isopropyl-4-methoxy-phenoxy)-acetonitrile3intoluene,whichwasuseddirectlyinthenextstep.Aanliquot(0.967g)ofthissolutionwasconcentratedtodrynesstogive0.509gofcrude(2-Isopropyl-4-methoxy-phenoxy)-acetonitrile3.US2007/49758;(2007);(A1)English;US2008/207619;(2008);(A1)English;US2007/49534;(2007);(A1)English.操作方法二Astirredslurryoftoluene-4-sulfonicacidcyanomethylester4(13.0kg),potassiumcarbonate(13.0kg)and2-isopropyl-4-methoxyphenol1(9.57Kg)in79.7kgof2-butanonewasheatedto55-60oC.for4days,thenheatedtorefluxfor18hours.Theresultantslurrywascooledandfilteredtoremovesolids.Thefiltratewasconcentratedunderreducedpressureandtheresiduewasredissolvedintoluene.Thetoluenesolutionwasextractedwith1NKOH,andtheorganicphasewasconcentratedbydistillationtogive20.6gofa1:1(byweight)solutionof(2-Isopropyl-4-methoxy-phenoxy)-acetonitrileintoluene,whichwasuseddirectlyinthenextstep.Analiquot(96.7g)ofthissolutionwasconcentratedtodrynesstogive50.9gofcrude(2-Isopropyl-4-methoxy-phenoxy)-acetonitrile3,projectingtoayieldof10.9kginthebulksolutionUS2008/86004;(2008);(A1)English;US2007/49751;(2007);(A1)English.(三)Gefapixant（吉法匹生）中间体5的合成方法一合成方法实验步骤参考文献操作方法一Asolutionofpotassiumtert-butoxide(44.8g,0399mmol)inNMP(180mL)wascooledto-10°C.Asolutionof2-(2-isopropyl-4-methoxyphenoxy)acetonitrile3,thecyanoether,(59.3g,61.4wt%,177mmol)intolueneandethylformate(26.3g,355mmol)waschargedtothebasesolutionwhilemaintainingtheinternaltemperaturebetween-12°Cand-8°C.Aftera3hage,guanidinehydrochloride(136g,1420mmol)wasaddedtothemixtureandthereactionwasheatedto115°Cfor6h.Themixturewasallowedtocoolto90°C,dilutedwith200mLofwater,andageduntilthereactionmixturewashomogeneous(about30-45min).Afterallsolidsdissolved,vacuum(400mmHg)wasappliedtothereactortoremovetoluene.Vacuumwasdisconnectedandthesolutionwasallowedtocoolto85°C.5-(2-Isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamineseed(49.8mg)wascharged,thesolutionwasagedfor2h,200mLofwaterwasadded,andthebatchwasallowedtocoolto20°Cover6h.Theslurrywasagedfor10hat20°C,filtered,washedwith2:1water:NMP(3×100mL)andwater(3×100mL),anddriedundervacuumat50°Ctoprovidethetitlecompound5(42.2g,88%)asasolid.WO2019/209607;(2019);(A1)English.(四)Gefapixant（吉法匹生）中间体5的合成方法二合成方法实验步骤参考文献操作方法一A1:1(byweight)solutionoftolueneand(2-Isopropyl-4-methoxy-phenoxy)-acetonitrile3(10.6g)wasconcentratedunderreducedpressureandtheresiduewastreatedwith10.8goftert-butoxybis(dimethylamino)methane6(Bredrick'sReagent).Theresultingmixturewasdissolvedin22mLofDMFandthesolutionwasheatedto110oC.for2hours.TheDMFsolutionwascooledandtransferredonto14.7gofanilinehydrochloride.Theresultingmixturewasheatedto120oC.for22hours,thencooled,dilutedwith25mLtoluene,thenwith70mLofwater.Theorganiclayerwasseparated,washedwithwater,andconcentratedunderreducedpressure.Theresiduewastransferredinto25mLDMF,andtheDMFsolutionwastransferredonto6.01gofguanidinecarbonate.Theresultingmixturewasheatedto120oC.for3days,thencooled,dilutedwith10mLofEtOAc,thenreheatedto60oC.Water(75.1mL)wasaddedandtheresultantmixturewasallowedtocooltoambienttemperature.Theprecipitatedsolidwascollectedbyfiltration,rinsedwithisopropanolanddriedundervacuumat50degreestogive9.62gof5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine5,m.p.170-171oC.US2007/49758;(2007);(A1)English;US2008/207619;(2008);(A1)English;US2007/49534;(2007);(A1)English.操作方法二Anapproximately1:1(byweight)solutionof10.6kgof(2-Isopropyl-4-methoxy-phenoxy)-acetonitrile3intoluenewasconcentratedunderreducedpressureandtheresiduewastreatedwith10.8kgoftert-butoxybis(dimethylamino)methane6(Brederick'sReagent).Theresultingmixturewasdissolvedin20.2kgofDMFandthesolutionwasheatedto110oC.for2hours,atwhichpointHPLCanalysisshowedessentiallycompleteconversionto3,3-Bis-dimethylamino-2-(2-isopropyl-4-methoxy-phenoxy)-propionitrile7.TheDMFsolutionwascooledandtransferredonto14.7kgofanilinehydrochloride.Theresultingmixturewasheatedto120oC.for22hours,atwhichpointHPLCanalysisshowedgreaterthan97%conversionto2-(2-Isopropyl-4-methoxy-phenoxy)-3-phenylamino-acrylonitrile8.Themixturewascooled,dilutedwith21.5kgtoluene,thenwith72.2Lofwater.Theorganiclayerwasseparated,washedwithwater,andconcentratedbydistillation.Theconcentratewastransferredinto23.8kgDMF,andtheDMFsolutionwastransferredonto6.01kgofguanidinecarbonate.Theresultingmixturewasheatedto120oC.for3days,atwhichpointHPLCanalysisshowedgreaterthan95%conversionof2-(2-Isopropyl-4-methoxy-phenoxy)-3-phenylamino-acrylonitrileinto5-(2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine5.Thereactionmixturewascooled,dilutedwith7.8kgofEtOAc,thenreheatedto60oC.Water(75.1L)wasaddedandtheresultantmixturewasallowedtocooltoambienttemperature.Theprecipitatedsolidwascollectedbyfiltration,rinsedwithisopropanolanddriedundervacuumat50oCtogive9.62kgof5-(2-isopropyl-4-methoxy-phen-oxy)-pyrimidine-2,4-diamine5.US2007/49751;(2007);(A1)English.(五)Gefapixant（吉法匹生）9的合成合成方法实验步骤参考文献操作方法一Toasuspensionof5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine5,thediaminopyrimidine,(47.0g,171mmol)in141mLofacetonitrileat-10°Cwasaddedchlorosulfonicacid(63.1mL,942mmol)whilemaintainingtheinternaltemperaturebelow25°C.Thesolutionwasagedfor1hat2°Candthenheatedto45°Cfor12h.Thesolutionwasallowedtocool