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Synthesis_3

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Synthesis_3Synthe

    Synthesis

Availableonlineatwww.sciencedirect.com

    ;?:三二,ScienceDirect

    ;ChineseChemicalLetters19(2008)166-168

    ;CHINESE

    ;CHEMICAL

    ;LETTER5

    ;vcvgv~.elsevier.com/loeate/celet

    ;SynthesisofureaacetatesaspotentialPPARcd~/dualagonists

    ;ChangYanZhao,v,ChangQingShi,v,YuanWeiChen,

    ;KeyLaboratoryofAsymmetricSynthesis&ChirotechnologyofSichuanProvinceandUnionLaboratoryofAsymmetricSynthesis,Chengdu

    ;InstituteofOrganicChemistry,ChineseAcademyofSciences,Che.gd.61OO41.China ;GraduateSchoolofChineseAcademyofSciences,Beijing100049,China ;Received28September2007

    ;InthequestfornovelPPARed~/dualagonistsasputativedrugsforthetreatmentoftype2diabetesanddyslipidemia,we

    ;designedandsynthesizedaseriesof

    ;.

    ;umaacetatesaspotentialPPARod~/dualagonists.Thestructureofthetargetcompounds, ;intermediateswerecharactefizedbyHNMR,HRMS.

    ;?

    2007YuanWeiChen.PublishedbyElsevierB.VonbehalfofChineseChemicalSociety.Allfightsreserved.

    ;Keywords:Oxazole;PPARagonist;Type2diabetes;Urea;Ammonolysis;Synthesis ;Thenuclearreceptorperoxisomeproliferatoractivatedreceptors(PPARs)areligand-activatedanscriptionfactors

    ;tllatgovernlipidandglucosehomeostasisplayingacentralroleincardiovasculardisease,obesityanddiabetes1.

    ;TherearethreeP

    ARsubtypeswhichdesignatedPPARa.PPAR~/andPPAR8.Thefibrateclassofhypolipidemic

    ;drugsactthroughPPARa2

    andthethiazolidinedioneclassofantidiabeticagentsactthroughPPAR~/3.

    ;Synchronizedtherapieswhichconcurrentlycontroldiabetesandinhibitprogressionofcardiovascularcomplications

    ;maybeafascinatingtherapeuticoptioninthetreatmentofdiabetes.Therefore,PIARdualagonistsareunder

    ;developmenttopreventdiabeticcardiovascularcomplications.AnumberofP]?

    dualagonistshaveappearedin

;theliterature4

    andsomeofthemarecurrentlyinclinicaldevelopment.ThecompoundsofPI,ARdualagonists

    ;haveafewessentialpharmacophoreelements.Thesecompriseofanacidicgrouplinkedtoacentralttatringanda

    ;largelipophilicsubstructure

    .InordertosearchformorepotentPPddualagonists,tostudythestructIre 5

    ;activityrelationshipofthemandeventuallytodevelopantidiabeticagents,anovelseries

    ofureaacetateswere

    ;designedandsynthesizedasScheme1.

    ;Thestartingmaterialthiophene3..carboxamidecondensatedwithethyl4..bromo..3--oxopentanoatetoprovideethyl

    ;2(5-methyl-2(thiophen3

    y1)oxazol-4-y1)acetate.whichcanbeeasilypurifiedbvcolumnchromatography. ;Reductionofester2byLiAmdillrI’

    producedthecorrespondingalcoholinhighyield.Subsequentmesylationof ;thealcoholprovidedthemethylsulfonate3quantitively.The4(2(5methyl2

    phen3y1)oxazol4.y1)ethoxy) Ohio

    ;benzahyde4wasobtainedbythecouplingofmethylsulf-onate3witll4

    hydroxylbenzaldehydeinCH3CNinthe

    ;presenceofpotassiumcarbonate.Then,aldehyde5reactedwithglycinemethylesterhydrochlorideandsodium

    ;cyanoborohydrideinmethanoltoaffordaminoester6in90%Yields.Withthecompound6inhand.aseriesof

    ;Correspondingauthor.

    ;E,mailaddress:chenyw@cioc.ac.CDfYWChen).

    ;1001-8417/$seefrontmatter?

    2007YuanWeiChen.PublishedbyElsevierB.VoilbehalfofChineseChemicalSociety.Allfightsreserved.

    ;doi:lO.10160.celet.2007.12.013

    ;疆一

    ;

    ;O

    ;a

    ;NH2—...’

    ;CEZhaoeta1./ChineseChemicalLetters19(2008)166-168

    ;2

    ;5

    ;HO

    ;b

    ;——-——

    ;C02Et

    ;e

    ;——-——

;3

    ;C02CH3

    ;Ar

    ;6

    ;O

    ;167

    ;8a.k

    ;f

     ;——-——

    ;abcde

    ;Fc.c.c?

    ;ghk

    ;H

    ;Scheme1.Reagentsandconditions:(a)ethyl4-bromo?3?oxopentanoate,toluene,reflux,4h,51%;(b)TFIF,LAH,0.C,2h,>90%;(c)MeSO2C1,

    ;Et3N,CH2C12,25.C,2h,>98%;(d)4-hydroxybenzaldehyde,K2CO3,CH3CN,80.C,24h,95%;(e)glycinemethylesterhydrochloride,

    ;anhydrousMgS04,methanol,0.C,0.5h;NaCNBH3,70.C,8h,90%;(f)R-PhNHCH3,tnphosgene,Et3N,CH3CN,0-25.C,12h,20--60%;(g)

    ;LiOH?H20,THF/I-I20(1:1),25.C,3h,>95%.

    ;substitutedN-methylbenzenamineswereusedforthesynthesisureidoesters7.N-Methylbenzenamineswas

    ;carbonylatedwitIltriphosgeneinthepresenceofMethylamine,followedbyadditionofa

    minoesters6insitutogive

    ;thedesiredureidoesters7.Ureidoesters7werehydrolyzedtoprovidethetargetcompound8quantitatively.

    ;Inconclusion,wehavesynthesizedaseriesofureaacetates8ingoodyieldsviaoxazoleformation,coupling

    ;reaction,carbonylationandhydrolysis.Thesecompoundscontainawiderangeofsubstitutionpatternsandwerefully

    ;characterized.Moreover,weusedN-methY1benzenamineswhichreactwithaminoester6toprovideureaesters7,this

    ;successfullypreventedtheammonolysisofester6toproduceamide,seeRef.[6.Functio

    nalactivityassayofthese

    ;compoundsarecurrentlyinprogess.

    ;Acknowledgments

    ;Theauthorsthankthe100TalentsprogramofChineseAcademyofSciences,theChengduInstituteofOrganic

    ;Chemistry,andtheGraduateSchooloftheChineseAcademyofSciencesforfinancialsupportofthiswork.

    ;1]D.E.Moller,Nature414(2001)821.

    ;2]P_J.Brown,eta1.J.Med.Chem.42(1999)3785.

    ;

    3]J.M.Lehmann,L.B.Moore,TA.SimthOlive~W.O.W1lkison,M.Willson,S.A.Klie

wer,J.Bio1.Chem.270(1995)12953

    ;[4](a)B.R.Henke,J.Med.Chem.47(2004)4l18:

    ;(b)YLu,eta1.Bioorg.Med.Chem.Lett.16(2006)915;

    ;(c)EVDevasthale,eta1.Bioorg.Med.Chem.Lett.17(2007)2312.

    ;5]B.Kuhn,eta1.Bioorg.Med.Chem.Lett.16(2006)4016.

    ;H

    ;C

     ;4?

    ;NH

    ;

    ;l68C.YZhaoeta1./ChineseChemicalLetters19(2008)i66168

    ;[61Ammonolysisofaminoesterincarbonylationwasobservedinourexperiments,andthereactionproductischaracterizedasfollows

    ;ammonolysis

    ;?

    ;CH3OH

    ;+

    ;Br

    ;

    ;triphosgene

    ;Et3N

    ;Br

    ;N./~--CO2CH36=o,

    ;:

    ;o

    ;lHNMR(300Hz,CDCI3)8ppm):7.59(m,2H),7.34(m,2H),7.16(m,2H),6.83(m,2H),4.55(s,2H),3.87(s,2H),0.99(s,9H),0.2O(s,6H).;

    ;(8a)0HNMR(300Hz,CDCI8ppm):7.85(dd,1H,J=3.0,1.2Hz),7.56(dd,lH,J:5.0,1.2Hz),7.337.36(m,lH),7.14.7.2O(m,2H),6.88-

    ;6.97(m,2H),6.69-6.79(m,4H),4.14(t,2H,J=6.6Hz),4.08(s,2H),3.83(s,3H),3.69(s,2H),3.14(s,3H),2.92(t,2H,J=6.6Hz),2.33(s,

    ;3H);HRMS(ESI,m/z):Calcdfor[C28H29N3o6S+Na],558.1669found,55868;

    ;(8b)0HNMR(300Hz.CDC11,8ppm):7.87(dd,lH,J=3.0,1.2Hz),7.55(dd,lH,J=5.0,1.2Hz),7.32.-7-36(m,3H),7.2O7.29(m,2H),7.10L-

    ;7.15(m,lH),6.89(d,2H,J=8.6Hz),6.76(d,2H,J:8.6Hz),4.16(t,2H,J=6.6Hz),4.15(s,2H),3.75(s,2H),3.24(s,3H),2.94(t,2H,

    ;J=6.6Hz).2.33(s,3H):HRMS(ESI,m/z):Calcdfor[C27H27N305S+Na],528.1564found,528.1557;

    ;(8c)HNMR(3ooHz,CDCI3,8ppm):7.87(dd,1H,J=3.0,1.2Hz),7.56(dd,lH’J=5.0,1.2Hz),7.33-7.36(m,tH),7.21-7.29(m,lH),7.()(

    ;7.O3(m.2H),6.92’6.97(m,2H),6.76

    _6.79(m,3H),4.1(.17(m,4H),3.79(s,2H),3.22(s,3H),2.95(t,2H,J=6.6Hz),2.34(s,3H);HRMS

    ;(ESI,m/z):Calcdfor[C27H26FN3OsS+Na],546.1469found,546.1456;

    ;(8d)0HNMR(300Hz,CDC13,8ppm):7.86(dd,lH,J:3.0,1.0Hz),7.56(dd,IH,J:5.0,1.0Hz),7.347.36(m,lH),7.187.24(m,1H),6.90

    ;(d.2H,J=8.6Hz),6.74._6.79(m,4H),6.67(d,lH,J:7.9Hz),4.1_4.17(m,4H),3.99(q,2H,J=6.9Hz),3.78(s,2H),3.25(s,3H),2.94(t,

    ;2H.J=6.6Hz),2.34(s,3H),1.37(t,3H,J=6.9Hz);HRMS(ESI,m/z):Calcdfor[C29H3IN306S+Na],572.1826found,572.1837;

    ;(8e)HNMR(300Hz,CDCI3,8ppm):7.88(d,lH,J=2.7Hz),7.56(dd,1H,J=5.0,1.0Hz),7.337.4l(m,3H),7.1l(d,2H,J=8.6Hz),6.92

    ;(d,2H..,=8.6Hz),6.77(d,2H,J=8.6Hz),4.17(s,2H,J=6.6Hz),4.15(s,2H),3.77(s,2H),3.20(s,3H),2.96(t,2H,J=6.6Hz),2.34(s,

    ;3H);HRMS(ESI,m/z):Calcdf0r[C27H26BrN3o5S+Na],606.0669found,606.06911608.0672;

    ;(

    HNMR(300Hz.CDCl3,8ppm):7.87(dd,1H,J:3.0,I.1Hz),7.56(dd,lH’J=5.0,IllHz),7.34.7.37(m,lH),7.26-_7.29(m,2H),7.14.

    ;7.18(m.2H),6.90(d.2H,J:8.6Hz),6.77(d,2H,J=8.6Hz),4.16(s,2H,J:6.6Hz),4.13(s,2H),3.79(s,2H),3.2l(s,3H),2.95(t,2H,

    ;J=6.6Hz),2.34(s.3H);HRMS(ESl,m/z):Calcdfor

    C27H26CIN305S+Na],562.1174found,562.1163;

    ;(8g)’HNMR(300Hz,CDCI3,8ppm):7.86(dd,lH,J:3.0,I-lHz),7.56(dd,IH,J=5.0,1.1Hz),

    7.14(m,4H),6.86 7.34.7.35(m,IH),7.07

    ;(d.2H..,:8.6Hz),6.75(d,2H,.,=8.6Hz),4.16(t,2H,J=6.6Hz),4.08(s,2H),3.74(s,2H),3.23(s,3H),2.93(t,2H,J=6.6Hz),2.34(s,3H),

    ;2-28(s,3H);HRMS(ESI,m/z):CalcdforC28H29N3o5S,542.1720found,542.1735.HRMS(ESI,m/z):Calcdfor[C28H29N305S+Na],

    ;542.1720found,542.1735;.

    ;(8h

    HNMR(300Hz,CDCl3,8ppm):7.87(dd,1H,J=3.0,I.IHz),7.56(dd,IH,J=5.0,1.1Hz),7.34.7.37(m,lH)’7.17-7.22(m,2H),7.00

    ;(t.2H..,:8.0Hz),6.90(d,2H,J:8.6Hz),6.75-6.78(m,2H),4.16(t,2H,J=6.6Hz),4.10(s,2H),3.76(s,2H),3.20(s,3H),2.95(t,2H,

    ;J=6.6Hz).2.34(s,3H);HRMS(ESI,m/z):Calcdf0r[C27H26FN305S+Na],546.1469found,546.1456;

    ;(8i)HNMR(300Hz,CDC18ppm):7.89(dd,lH,J:3.0,1.1Hz),7.557.59(m,2H),7.347

    .38(m,3H),6.92(d,2H,J=8.6Hz),6.78(d,2H,

    ;.,:8.6Hz),4.O.18(m,4H),3.85(s,2H),3.23(s,3H),2.96(t,2H,J=6.6Hz),2.35(s,3H);HRMS(ESI,m/z):Calcdfor

    ;fC28H2sClF3N3o6S+Na],630.1048found,630.1048/632.10l4;

    ;(8})IHNMR(300Hz,CDCI3,6m):7.88(dd,1H,J=3.0,1.1Hz),7.56(dd,1H,J:5.0,1.1Hz),7.34_7.37(m,1H),7.2l7.26(m,2H),7-O6-

    ;7.14(m.2H),6.92(d,2H,J=8.6Hz),6.78(d,2H,J:8.6Hz),4.O84.18(m,4H),3.08(s,2H),

    3.24(s,3H),2.95(t,2H,J:6.6Hz),2?34(s,

    ;3H):HRMS(ESI,/z):CalcdforfC27H26CIN3o5S+Na],562.174found,562.163;

    ;(8k)IHNMR(300Hz,CDCI3,8ppm):7.89(dd,lH,J=3.0,1.0Hz),7.56(dd,lH,J:5.0,1.0Hz)

,7.337.37(m,3H),7.10(dd,lH,.,:8-6,

    ;2.6Hz).6.94(d,2H..,=8.6Hz),6.79(d,2H,J:8.6Hz),4.16(t,2H,J:6.6Hz),3.83(s,2H)’3.2l(s,3H),2.96(t,2H,.,=6.6Hz),2_35(s,

    ;3H1:HRMS(ESI,z1:Calcdf0r[C27H2s(=l2N3o5S+Na1,596.O784f0und.596.O765/597.0942/598.O82O.

    ;

    ;

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