藥物Macitentan(馬西替坦)合成檢索總結(jié)報(bào)告

Macitentan（馬西替坦）于2013年10月18日在美國上市。本文主要對Macitentan（馬西替坦）的合成路線、關(guān)鍵中間體的)20mlacetonitrilewasaddedto4-bromophenylaceticacid1(2g,9.3mmol)and1,8-diazabicyclo[5.4.0]undec-2-ene(1.7g,11.2mmol)wasaddedat0°C.Iodomethane(1.98g,14.0mmol)wasslowlydroppedtothemixtureandstirredfor2hoursatroomtemperature.Afterthereactioniscomplete,themixturewasextractedusingwater(100ml×2)anddichloromethane(100ml).Thetitlecompound2(1.7g,75%)wasobtainedbycolumnchromatography(ethylacetate/n-hexane,(2013);(A1)Toastirredsolutionof(4-bromophenyl)aceticacid1(1.5g,6.9mmol)inDMF(10mL),potassiumcarbonate(1.92g,14mmol)andmethyliodide(1.46g,10mmol)wasaddedat0°C.inaRBflask.ReactionmixturewaskeptatRTfor2h.ThenthereactionmixturewascooledtoRT,pouredintowaterandextractedwithethylacetate.Thecombinedextractswerewashedwithwaterandbrinesolution.TheorganiclayerwasdriedoveranhydrousNa2SO4andconcentratedinvacuum.Thecrudeproductobtainedwaspurifiedbycolumnchromatographytogetthetitlecompound2asayellowliquid(1g,yield:(2016);(A1)Toasolutionof4-Bromo-phenyl-aceticacid1(8.6g,40mmol)inDMF(80mL)isaddedK2CO3(6.16g,44mmol)followedbymethyliodide(2.8mL,45mmol).Theresultingmixtureisstirredfor2.5hours,thendilutedwithether,washedwithwaterandbrine,driedoverMgSO4andconcentratedtogive9.1gofthetitlecompound2asan(2003);(B1)Asolutionof4-bromophenylaceticacid1(10g,47mmol)inmethanol(194ml)andsulfuricacid(2.48ml,46.5mmol)washeatedtorefluxfor16hours.Reactionwasconcentrated,dilutedwithethylacetateandwashedwithsaturatedsodiumbicarbonateandbrine.Organicwasdriedoversodiumsulfate,filteredandconcentratedtogivemethyl2-(4-bromo-phenyl)acetate2(10.63g,100%)asacolorless(2010);(A1)Concentratedsulfuricacid(30ml)wasaddedtoasolution(4-bromophenyl)aceticacid1(101g,468mmol)inmethanol(1000ml)underice-cooling,andthemixturewasstirredatroomtemperaturefor2hours.Thereactionmixturewasconcentratedand,afterethylacetatewasaddedtotheresidue,themixturewassuccessivelywashedwithwater,saturatedaqueoussodiumhydrogencarbonatesolutionandsaturatedaqueousNaClsolution,anddriedoveranhydroussodiumsulfate.Theresidueobtainedbyevaporatingthesolventunderreducedpressurewaspurifiedbysilicagelcolumnchromatography(elutionsolvent:n-hexane/ethylacetate=5/1)toobtainmethyl(4-bromophenyl)acetate2(107g,yield:(2007);(A1))15.0g(65.5mmol)ofmethyl(4-bromophenyl)acetate2weredissolvedin300mlofTHF,andsodiumhydrideinmineraloil(60%)wasaddedatRT.ThemixturewasstirredatRTfor1h,afterwhich23.6g(262mmol)ofdimethylcarbonate3wereslowlyaddeddropwise.ThereactionwasthenstirredatRTfor3d.1Nhydrochloricacidwasthenadded,andthereactionmixturewasconcentrated.Theresiduewasdissolvedinethylacetateandwashedsuccessivelywith1Nhydrochloricacid,waterandsaturatedsodiumchloridesolution.Theorganicphasewasseparatedoff,driedovermagnesiumsulphateandfiltered,andthefiltratewasconcentrated.Theresidueobtainedwaschromatographedonsilicagel(0.04-0.063mm/230-400meshASTM)usingcyclohexane/ethylacetate4/1.AfterTLC,thefractionswerecombinedandconcentrated.Thisgave14.6g(77%oftheory)ofasolid(2016);(A1)3.8gofsodiumhydride(55%inparaffinoil)arewashedindrytolueneandthensuspendedin100mlofdrytoluene.At60°C.,asolutionof10gofmethyl(4-bromophenyl)acetate2and11mlofdimethylcarbonate3in10mloftolueneareaddeddropwisewithin30minutes.Thereactionmixtureisstirredforafurther31/2hoursat60°C.andtheprecipitateformedissuctionfiltered.Aftertheprecipitatehasbeenwashedwithtolueneitisaddedinbatchestoamixtureof100mlofsaturatedaqueouscommonsaltsolutionand25mlofglacialaceticacid.Themixtureisextractedwithdiethylether,theetherphaseisdriedandevaporateddown.Theresidue4istrituratedwithpetroleumether,(1996);(A)filteredanddried.Yield:7g(56%oftheory),MeltingAt40°C,asolutionofintermediate2(52g)inTHFmL)wascarefullyaddedoveraperiodof40mintosuspensionofNaH(15.6g)indryTHF(450mL).wascontinuedfor70minwithoutheatingandthedroppedto27°C.Theevolutionofgasstopped(2009);dimethylcarbonate3(76.42rnL)wasaddeddropwisethetemperatureofthemixturewasmaintainedat29-Stirringwascontinuedfor22hatrt.Themixturewasto-10°CandthencarefullyneutralizedtopH6-7with(2006);HClbeforebulkoftheTHFwasremovedinvacuo.residuewasdissolvedinEA(700mL),washed3times1Naq.HCl-solutionandoncewithbrine,driedMgSO4.MostoftheEAwasevaporatedbeforeHex(2012);added.Theproductcrystallisedovernightat4°C.crystalswerecollected,washedwithHexanddriedtotheexpectedproduct4aspaleyellowcrystals)Toastirredsolutionof100gdimethyl(4--malonate4(10,0.348mol)in400mlmethanol,30formamide(0.66mol)and30gsodiummethoxide(0.555mol)wereaddedat20-25°C.Thereactionmasswasheatedto70°Candmaintaineduntilcompletionofreaction(monitoredbyHPLC).Aftercompletionofthereaction,methanolwasdistilledofffromthereactionmassunderreducedpressureat70°Ctoobtainthesyrup.Thesyrupwascooledto25-30°Canddilutedwith2dm3water.ThepHofthesolutionwasadjustedto2-2.5usingconc.hydrochloricacidandmaintainedfor45min.TheobtainedsolidwasfilteredandwashedwithwateruntilthepHofthefiltratebecame7-7.5.Theproductwassuckdriedanddriedunderreducedpressureat100°Ctoobtaincrude5.Thecrudesolidwasdissolvedin500mlmethanolat60-65°Candmaintainedfor1h.Thereactionmasswascooledto25-30°Candmaintainedfor30min.Theobtainedsolidwasfiltered,washedwithmethanol,anddriedat50-55°Cunderreducedpressuretooffer5.Yield:70g(75.25%);puritybyMonatsheftefurChemie;vol.nb.3;(2018);99.5%;m.p.:176-Asolutionofintermediate4(11.73g)inMeOH(100mL)wasaddedat0°Ctoasolutionofsodium(2.83g)inMeOH(100mL).Themixturewasstirredfor18hatrtbeforeformamidinehydrochloride(4.10g)wasadded.Thesuspensionwasstirredatrtfor4h.Thesolventwasremovedandtheresiduewassuspendedin10%aq.citricacid(100mL)andstirredfor10min.Thewhiteprecipitatewascollected,washedwith10%aq.citricacid,water,evaporatedthreetimesfromcyclohexaneanddriedunderHVat40°Ctogive5-(4-bromophenyl)-pyrimidine-4,6-diol5asapalepowder(9.90(2009);(A1)(2006);(A2)(2012);(A1)Asolutionof2-(4-bromophenyl)malonicaciddimethylester4(100g)inmethanol(1500ml)wasaddedtopre-cooled25%sodiummethoxidesolutioninmethanol(240mL)at0-5°Coveraperiodof60minsundernitrogenatmosphereandstirredfor15mins.Formamidineacetate(47.1g)wasaddedat0-5°C.Thenreactionmasstemperaturewasraisedto25-30°Candstirredfor6hrsAqueoushydrochloricacid(2N,1000mL)wasaddedtothereactionmassat25-30°Cfor90mins,cooledto0-5°Candstirredfor30mins.ThepHofthereactionmasswasadjustedto4usingaqueoussodiumhydroxideat0-5°Candstirredfor15mins.Thesolidobtainedwasfiltered,washedwithwaterfollowedbyacetoneandsuckdried.Acetone(300mL)wasaddedtothewetcompoundandstirredfor1hrat25-35°C.Thereactionmasswasfiltered,washedwithacetoneanddriedat60-65°Cfor12hrstogetthetitlecompound5.Yield:80g;PuritybyHPLC:(2017);(A1))Astirredsolutionof100g5-(4-4,6-diol5(0.374mol)wasaddedto300cm3oxychloride.Thereactionmasswasheatedto90°Cmaintaineduntilcompletion(monitoredbyHPLC).Monatsheftecompletionofthereaction,thereactionmasswascooledChemie;vol.nb.3;(2018);solidwasfilteredandwashedwithwateruntilthepHoffiltratebecame6.5-7.0.Thematerialwasdriedreducedpressureat65°Ctoobtainthecrudesolid.Thecrudesolidwasfurtherrecrystallizedinmethanolandtheobtainedsolidwasfilteredanddriedtoprovide6.Yield:90g(79%);puritybyHPLC:99.7%;m.p.:100-Toasuspensionof5-5-(4-bromophenyl)-pyrimidine-4,6-diol5(9.90g)inPOCl3(130ml)wascarefullyaddedN,N-dimethylaniline(13.5ML).Themixturewasheatedto130°Cfor2h.Thedarkbrownsolutionwasevaporatedandtheresiduewaspouredintoice/water.Thesuspensionwasdilutedwith2NHClandwaterandstirredfor20min.Theprecipitatewascollectedandwashedwithwater.ThesolidmaterialwasdissolvedinEA,washedwith1Naq.HCIandbrine.TheorganicphasewasdriedoverMgSO4andevaporated.Thematerialwasfurtherpurifiedbycolumnchromatographyonsilicagelelutingwithhexane:EA95:5to1:1followedbycrystallisationfromhexane/EAAT-20°Ctogive4,6-dichloro-5-(4-bromophenyl)-pyrimidine6(8.3g)aspaleyellow(2004);(A1)(2009);(A1)(2006);(A2)(2012);(A1)Triethylamine(130mL)wasaddedtoamixtureof5-(4-bromophenyl)-pyrimidine-4,6-diol5(100g),phosphorylchloride(400mL)andacetonitrile(600mL)at25-35°Cundernitrogenatmosphereforaperiodof60mins.Thereactionmasswasheatedto80-85°Candstirredfor4hrs.Thereactionmasswasdistilledoffundervacuumatbelow75°Cfollowedbystrippedoffwithacetonitrile.Thereactionmasswascooledto10-15°C,water(500mL)wasaddedandstirredfor30mins.Aqueoushydrochloricacid(2N,500ml)wasaddedtothereactionmassat10-15°Candstirredfor30mins.Thesolidobtainedwasfiltered,washedwithwateranddriedundervacuumat40-45°Cfor6hrstogetthetitlecompound6.Yield:100g;puritybyHPLC:(2017);(A1))ToasolutionofN-propylsulfamide7(25.0gm,0.180mol)indimethylsulfoxide(250.0ml)wasaddedLithiumamide(7.6gm,0.33mol)undernitrogenatmosphereat15-25°C,followedbyadditionof5-(4-bromophenyl)-4,6-pyrimidine6(50.0gm,0.164mol).Thereactionmasswasstirredfor2hr.atroomtemperatureandtheprogressofreactionwasmonitoredbyHPLC.AfterreactioncompletionthisreactionmasswasdropwiseaddedtothesolutioncontainingLithiumamide(7.6gm,0.33mol)andethyleneglycol(250.0ml)at15-25°Cundernitrogenatmosphere.Aftertheadditionreactionmixturewasheatedto-110°C,maintainedfor18-24hoursandthereactionprogresswasmonitoredbyHPLC.Aftercompletionofreaction,resultingmasswascooledto25-30°Cand5%w/vcitricacidsolution(1000.0ml)wasaddedtothereactionmass.Theproductwasextractedtwicewithethylacetate(1000.0ml×2),furtherorganiclayerwaswashedtwicewith10%w/vbrinesolution(500.0ml×2).Organiclayerwasat55-60°Cunderreducedpressuretoproduce8asa(2016);(A1)Potassiumtert-butoxide(90gm,0.802mol)wasaddedintoareactionflaskcontainingasolutionofN-Propyl-sulfamide7(N-Propyl-sulfamide(82gm,0.593mol)inDMSO(250ml))andstirredthereactionmassatroomtemperaturefor30mintoobtainpotassiumsaltofN-propylsulfamide.5-(4-bromophenyl)-4,6-dichloropyrimidine6(100gm,0.329mol)wasaddedintothereactionmassandstirredthecontentsfor5-6hrsat25-30°C.DMwater(500ml)wasaddedtothereactionmassastirredsolution.Further10%citricacidsolution(500ml)wasaddedslowlyforanabout1-2hrstoobtainsolid.TheprecipitatedsolidwasfilteredandwashedwithDMwater(120ml)andsuckdriedthematerialfor30min.Theproductwasdriedundervacuumat50-55°Cfor10-12hrstoobtaintitleproduct8.Yield:137gm;Purity(ByHPLC):(2017);(A1))AsolutionofKOtBu(97.0g,0.86mol,3.5eq.)inEG(200mL,3.6mol,14.5eq.)wasaddeddropwisetoasolutionofthecompound8(100g,0.25mol)inethyleneglycol(200mL,3.6mol,14.5eq.)sothatT<40°C.Theresultingmixturewasstirredat100°Cfor15h.Uponcompletionofthereaction(LC-MScontrol),itwascooledto20°C.(1L)wasadded.A40%aq.solutionofcitricacidmonohydrate(300mL)wasaddeduntilpH4wasreached.Thelayerswereseparated.Theorg.phasewaswashedwithwater(750mL)andthelayerswereseparated.Water(750mL)wasaddedandthemixturewasstirredat50°Cfor5min.Thelayerswereseparated.Theorgphasewasconcentratedundervacuumat50°Cuntil200mLofMIBKwereremoved.Hept(650mL)wasaddeddropwiseat60-65°Cuntilturbiditywasobservedat60-65°C.Themixturewasseededwithananalyticallypuresampleofropane-1-sulfamideandstirredat60-65°Cfor30min.Itwasallowedtocoolto5°Cwithin3h.Itwasfilteredoff,rinsedwithacoldMIBK/Heptmixture(400mL,1:1)anddriedundervacuumat50°Ctoyieldthetitlecompound9asawhitesolid(80g;75%15);(A1)600mlofethyleneglycolwasaddedto39.5gmofsodiumhydroxidefollowedby100gofsulfamidecompound8maintainingtemperature27±2°C.Thereactionmasswasheatedat108±2°Candmaintainedfor6hours.Oncompletionofreaction(checkedbyTLC),reactionmasswascooledto27±2°Cand600mlofpurifiedwaterwaschargedfollowedbypHadjustmentto6.0to7.0with1NHCl.Solutionwasheatedto55±2°Candstirredfor30minutes,furthercooledto27±2°C,filteredanddried.Tothedriedmaterialwasadded400mlof5%methanolintolueneandat27±2°C,furtherchilledto3±2°C,filtered,washedwithweight:90(2017);(A1)Ethyleneglycol(700mL)wasaddedtoN-5-(4-bromophen-yl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide8(100g)undernitrogenatmosphereat25-30°C.Potassiumtert-butoxide(249g)wasaddedinlotstotheabovereactionmassat25-35°C,thenheatedto85-90°Candstirredfor6hrsatreflux.Thereactionmasswascooledto25-35°Candpotassiumtert-butoxide(55g)wasaddedinlotstothereactionmassat25-35°C.Thereactionmasswasheatedtorefluxandstirredfor4hrsatrefluxtemperature.Thereactionmasswascooledto25-35°Candwater(300ml)followedbyINaqueoushydrochloricacid(1500ml)wasaddedtoitandstirredforanhour.Thesolidobtainedwasfiltered,washedwithwaterandsuckdried.Methanol(300mL)wasaddedtotheabovesolidandheatedthe(2017);(A1)massto65-70°Cthenstirredfor10mins.Thereactionmasswascooledto25-30°Candstirredforanhour.Thesolidobtainedwasfiltered,washedwithchilledmethanolanddriedat50-55°Cundervacuumfor6hrstogetthetitlecompound9.Yield:91g;PuritybyHPLC:Potassiumtert-butoxide(560.0gm,4.991mol)wasaddedintoareactionflaskcontainingethyleneglycol(3.5lit)at10-15°Candstirredthesolutionfor30minat25-amide8(350.0gm,0.863mol)wasaddedslowlyintothereactionmassandthecontentswasheatedto100-105°Cfor12-14hrs.TheobtainedreactionmasswascooledtoroomtemperatureandthenDMwater(700ml)andmethanol(175.0ml)wasadded.Reactionmixturewascooledto15-20°Candadded20%Citricacidsolution(4.5lit)foraperiodofabout1hourto2hoursandthereactionmasswasmaintainedfor2-3hrsatroomtemperature.Filterthesolidandwashedwithwater(700.0ml),suckdriedthematerialfor30min.Theproductwasdriedundervacuumat50-55°Cfor20-24hrstoobtaintitleproduct9.Yield:236gm;(ByHPLC):(2017);(A1)Toastirredsolutionof1.0kgN-[5-(4-bromophenyl)-6-hydroxyethoxy)pyrimidin-4-yl]-N0-propylsulfamide(6,2.31mol)in4dm3THFand4dm3DMF,0.557kgtertbutoxide(6.95mol)wasaddedat25-30°C.Themasswasheatedto40-45°Candasolutionof0.5385-bromo-2-chloropyrimidine10(7,2.78mol)inamixture1dm3THFand1dm3DMFwasaddedat40-45°C.reactionmasswasmaintainedatthesametemperaturecompletionofthereaction(around1-2h,monitoredHPLC).Afterensuringthecompletionofthereaction,Monatsheftereactionmasswascooledto25-30°CandthereactionChemie;vol.quenchedwith10dm35%citricacidsolution.Thenb.3;(2018);reactionmasswasextractedwithethylacetate(10dm3).ethylacetatelayerwaswashedwith5%brinesolutiondm3)andconcentratedunderreducedpressuretoobtaintheresidue.Theresiduewasdissolvedin25dm3methanolandtheresultingsolutionwasheatedat60-65°Cfor30min.Thereactionmasswascooledto0-5°Candmaintainedfor60min.Theobtainedsolidwasfilteredandwashedwith1dm3methanoltoprovidecrude11.Then,thewetsolidwasdissolvedin25dm3methanolat60-65°C,maintainedfor30min,andthereactionmasscooledslowlyto0-5°Candmaintainedfor60min.Theobtainedsolidwasfiltered,washedwith1dm3methanol,suckdried,anddriedatpuritybyHPLCropane-1-sulfamide9(200g;0.46mol)and5-bromo-2-chloropyrimidine10(117g;0.60mol;1.3eq)weredissolvedintoluene(3L)andDMF(400mL).Thereactionmixturewaswarmedupto50°Candtoluene(approx.400mL)wasdistilledourunderreducedpressure.Themixturewascooledto0°CandtBuOK(156g,3eq,1.38mol)wasaddedportionwise.Itwasstirredat20°Cfor1h.Water(1L)wasaddedandthepHofthesolutionwasadjustedto3-5using33%aq.HCl.Themixturewasheatedto50°Candthelayerswereseparated.Theorg.phasewastreatedwithcharcoalat50°CandfilteredoverCelite.Thefiltercakewasrinsedwithtoluene.At50°C,water(1L)wasaddedtotheorg.layer.Thelayerswereseparated.Theorg.layerwasconcentratedunderreducedpressuretoatotalvolumeof1Landcooledto0°C.ThesolidobtainedwasfilteredoffItwasrinsedwithtolueneandMeOH.ThecrudematerialwassuspendedinEA(1L)andheatedto50°C.300mLofEAweredistilledoutandMeOH(400mL)wasadded.Thesuspensionwascooleddownto0°C.Thesolidwasfilteredoff,rinsedwithMeOHanddriedunderreducedpressuretoaffordthetitlecompoundasawhitesolid11(225g;83%(2014);(A1)15);(A1)ToasolutionofTHF(2000.0ml)andsodiumhydride(17.0gm,0.708mol),wasaddedN-5-(4-bromophenyl)-6-(-2-hydroxyethoxy)-4-pyrimidinyl-N-propylsulfamide9(100.0gm,0.23mol)at25-30°C.Stirredthecontentfor30minat25-30°C.DMF(400.0ml)and5-bromo-2-chloro-pyrimi-dine10(65.0gm;0.033mol)wasaddedtothereactionmassat25-30°C.Stirredandheatedreactionmassto60-65°Candmaintainthereactionmassat60-65°Cfor2-4hr.AftercompletionofreactionmonitoredbyHPLC,cooledreactionmassto25-30°Cand5%w/vcitricacidsolution(2500.0ml)wasadded.Thecompoundwasextractedtwicewithethylacetate(1500.0ml×2),followedbyorganiclayerwaswashedwith10%w/vbrinesolution(1500.0ml).Ethylacetatelayerwasconcentratedat55-60°CunderreducedpressuretoproduceN-[5-(4-bromophenyl)-6-[2-[(5-bromode11asacruderesidue.Obtainedresiduewasdissolvedat65-70°Cinmethanol(2400.0ml),stirredandmaintainedfor30min.Theresultingsolutionwasgraduallycooledtoroomtemperaturethencooledto0-5°Candmaintainedreactionmassat0-5°Cfor45-60min.Obtainedsolidwasfiltered,washedwithmethanol(100.0ml),suckdriedtoaffordcrudehoxy]-4-pyrimidinyl]-N-propylsulfamide[Macitentan]11.[Yield=121.5gm;Purity(HPLC)=99.68%].PurificationofMacitentan.Macitentancrude(121.5gm,0.202mol)wetsolidwasdissolvedat65-70°Cinmethanol(2400.0ml)anddecolorizedwithactivatedcharcoal.Theresultingsolutionwasgraduallycooledtoroomtemperaturethencooledto0-5°Candmaintainedfor45-60min.Obtainedsolidwasfiltered,washedwithmethanol(100.0ml),suckdriedanddriedundervacuumat55-60°CtoaffordhighlypureMacitentan.[Yield=111.5gm;Purity(HPLC)=(2016);(A1)AsolutionofN-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide9(100g)intetrahydrofuran(500mL)wasaddedtosodamide(18g)intetrahydrofuran(1500mL)at25-30°Coveraperiodof45minandstirredfor10min.5-bromo-2-chloropyrimidine10(44.5g)wasaddedtotheabovereactionmassat25-30°Candstirredfor10mins.Thereactionmasswasheatedto40-50°Candstirredfor2.5hrs.Thereactionmasswasthencooledto25-30°C;sodamide(18g)and5-bromo-2-chloropyrimidine(44.5g)wasaddedtoit.Thereactionmasswasheatedto40-50°Candstirredfor2.5hrs.Thenthereactionmasswascooledto25-30°CandpHwasadjustedto2.5withaqueoushydrochloricacidandstirredfor15mins.Thesolventfromthereactionmasswasdistilledoffundervacuumat45°C.Methylenechloride(1000mL)followedbywater(500mL)wasaddedtothereactionmassandstirredfor15mins.Theorganicandaqueouslayerswereseparatedandtheaqueouslayerextractedwithmethylenechloride.Organiclayerswerecombined,washedwithwater,5%sodiumbicarbonatefollowedbywaterandsodiumchloridesolution.The(2017);(A1)layerwasconcentratedcompletelyundervacuumatbelow45°C.Thenthereactionmasswascooledto25-30°C,methylenechloride(130mL)wasaddedandheatedto35-40°Cforcompletedissolution.Methanol(1000mL)wasaddedtothereactionmassat35-40°C,thenheatedto55-60°Candstirredfor45minatreflux.Thereactionmasswascooledto25-30°Candstirredforanhour.Thesolidobtainedwasfiltered,washedwithmethanolanddriedat50-55°Cfor6hrstogetthetitlecompound11.Yield:95g;PuritybyHPLC:Sodiumhydride(23.80gm,0.992mol)wasaddedintoareactionflaskcontainingsolutionofN-5-(4--6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide9(34.0gm,0.079mol)inToluene(680.0ml),at10-15°C.Theobtainedreactionmasswasstirredfor20-30minsat10-15pyrimidine10(62.0gm,0.321mol)inDMF(136.0ml))wasaddedslowlytothereactionmixtureat10-15°C.Thereactionmixturewasallowedtoroomtemperatureandstirredfor5-6hrs.10%citricacidsolution(1020.0ml)wasaddedat10-15°Candallowthereactionmixtureat25-30°CandfilterthereactionmassthroughCelitebed.Theorganiclayerwasseparatedandwashedwith10%NaClsolution(170ml).Theorganiclayerwasseparatedanddistilledoutundervacuumat60-65°Ctoobtainresidue.Methanol(68.0ml)wasaddedtotheresidueandstirredfor1hrat10-15°Ctoobtainsolid.Theprecipitatedsolidwasfilteredandwashedwithchilledmethanol(10ml)andsuckdriedfor30min.Thesolidwasdriedundervacuumat55-60°Cfor20-24hrstoobtain