DOC

One-pot

By Maria Grant,2014-07-24 00:50
15 views 0
One-potOne,Pot,one,pot

    One-pot

Availableonlineatwww.sciencedirect.com

    ;?:,scienceDirect

    ;ChineseChemicalLetters19(2008)91_917

    ;CHINE5E

    ;CHEMICAL

    ;LETTERS

    ;www.elsevi~r.corallocate]cclet

    ;Onepotsynthesisof2(1acyloxypenty1)benzoicacids

    ;ZhenLiMin,YiHuaZhang,

    ;YiShengLai,SiXunPeng

    ;CenterofDrugDiscovery,ChinaPharmaceuticalUniversity,Nanjing210009,China ;Received24March2008

    ;Abstract

    ;Aone.potsynthesisof2-(1-acyloxypcnty1)benzoicacidsby

    ’ingthecarboxylatelalkoxidedianionwithacylatingreagents

    ;followingGrignardadditionwithn.BuMgBrto2-formylbenzoicacidwasdescribed.Comparedwithroutinesyntheticmethod,this

    ;novelprocedurehastheadvantageofconvenientoperationandhigheryields. ;?

    2008YiHuaZbang.PublishedbyElsevierB.VonbehalfofChineseChemicalSociety.Allrightsreserved.

    ;Keywords:One-potsynthesis;3-n-Butyl?1(3H)-isobenzofuranone;2-(1-Hydroxypenty1)benzoicacid;2-(1?Acyloxyponty1)?benzoicacids

    ;3-n.Buty1.1(3H).isobenzofuranone(2)hasbeenreportedtoexhibitsignificantbiologicalactivitiessuchas

    ;improvingmicrocirculation,decreasingbraininfarctvolume,regulatingenergymetabolism,inhibitingplatelet

    ;aggregationandreducingthrombusformation1.Aringopeningderivativeof2,2

    (1-hydroxypenty1)benzoicacid

    ;(3),possessespotencysimilarto2

    2.Inoureffortstosearchfornovelcardiovasculardrugsmorepotentthan2, ;compound2.(1.acetoxypenty1)benzoicacid(4a)wasfirstsynthesized,sinceitcouldrelease3whichcouldfurther

    ;undergoringclosuretoform2viatheactionofenzymesinvivo

    2.Moreimportantly,4aInightbesubstitutedfor2as

    ;aleadcompoundfornewdrugdiscoverybasedontheprincipleofprodrug. ;Tothebestofourknowledge,thesynthesisofcompoundslike4ahasneverbeenreportedbefore.Weatfirst

    ;designedthesyntheticrouteoutlinedinScheme1.AdditionofGrignardreagent,lBuMg

Brto2-formylbenzoicacid

    ;(1)gavelactone(2).Saponificationof2foHowcdbyacidificationafforded2(1

    hydroxypenty1)benzoicacid(3).

    ;However,compound3wasfoundtobeveryunstabletoheat,andveryeasytobelactonizedto2atroomtemperature.

    ;Tominimizethislactonization.thereactionof3anditsworknpshouldbehandledbelow0.C.atmentof3tIl

    ;acetylchlorideproducod4a,whichshouldalsobecarefullycarriedoutatlowtemperature.Despitethis,thetotalyield

    ;Of4afrom1wasonly38%.

    ;Inordertoimprovethesynthesisof4a.wetriedtheothersyntheticapproach.Sincereactionofn-BuMgBrwitIl1

    ;wouldproducereactiveintermediate5,acarboxylate/alkoxidedianionwhichcouldbetrappedbyanacetylating

    ;reagent

    3,theacetylatingreagentwasaddeddirectlyafterG-riguardadditionwascompletedtoavoidlactonizationof

    ;3.FinallythereactionwasquenchedbydilutedHClsolutiontogiveacrudeproduct,whichwaspurifiedbycolumn

    ;chromatographyandrecrystallizedfromhexanetoproduce4ainagoodyield(Scheme2).Thus,asimpleandefficient

    ;one-potreactionforthesynthesisof4awasdeveloped.

    ;Correspondingauthor.

    ;E-mailaddress:zylItgd@sohu.corn(YH.Zhang)

    ;1001?8417/5-seefrontmawr

    2008YiHuaZhang.PublishedbyElsevierB.VonbehalfofChille~ChemicalSociety.Allrightsreserved.

    ;doi:10.1016/j.cclet.2008.05.020

    ;墨一

    ;

    ;916

    ;O

    ;O

    ;ZLMineta1./ChineseChemicalLetters19(2oo8J915-917

    ;OH

    ;OO

    ;1234a

    ;Scheme1.(a)nBuMgBr,Et2O,5%HC1,0.Ctort,3h,76%;0a)(i)2mol/LNaOH,CH3OH]lq20,50.C,2h;(ii)5%HCl,10to0.C,O?5h,90%

    ;(c)CH3COC1,Et3N,DMAP,CH2C12,10to0.C,10h,55%.

    ;O

    ;O

    ;H

    ;OH

;5

    ;O6

    ;]OoR

    ;O

    ;74a-4f

    ;Scheme2.(e)(i)n-BuMgBr,EhO,0.Ctort,3h;(n)acylatingreagents,rt,4h;(iii)10%HC1,rt

    75% ,1h,57

    ;1Iablel

    ;1Iable2

    ;o

    ;O

    ;

    ;zLMineta1./ChineseChemicalLetters19(2oos)9159l7917

    ;ESI-MS,HNMR,IRandelementalanalysis

    5.Itwasfoundthatthestereoandelectriceffectsofacylatingreagents

    ;hadconsiderableinfluenceontheyieldsofproducts.Forexample,C1CH2C:OC1withsmallersterichindranceand

    attractingpropertygave4binthehighestyield,while4;strongerelectron

    CH3OPhCOC1,insharpcontrast,gavethe

    ;lowestyield.

    ;Insummary,asimpleandefficientprocedureforthepreparationof2f1

    acyloxypenty1)benzoicacidsviaaone-pot

    ;reactionwasdescribed,thisstraightforwardmethodhastheadvantageofconvenientoperationandgoodyields,and

    ;mightbehelpfultosearchformorepotentcompoundsderivedfrom2.

    ;[1(a)C.H.Yah,YP.Feng,J.Zhang,ActaPharmaco1.Sin.19(2)(1998)49; ;Co)x.z.Zhu,X.YLi,J.Liu,Eur.J.Pharmaco1.500(2OO4)221.

    ;[2YZhang,L.Wang,L.YZhang,X.L.Wang,DrugDev.Res.63(2004)174.

    ;[3EC.Engelhardt,Y.J.Shi.C_J.Cowden,eta1.J.Org.Chen1.71(2)(2OO6)480. ;f4

    Generalproceduresforthesynthesisofcompounds44f:Asuspensionofn-BtdVlgBr(22retoo1)inEt20(30mL)wasaddedportionwisetoa

    ;solutionof1(1.5g,10retoo1)inEt20(50mL)withstirringbelow-10to0.C,themixturewasthenstirredatloomtemperaturefor5h.

    ;acylatingreagent(30retoo1)inEt20wasaddeddropwisetothemixture.whichwasSti!Te,dfor4h.AfterEt20wasremoved,10%HClsolution

    ;(40mE)andTHF(20mE)wereadded.andthemixturewasStiH’edfor1h.TI-IFwasevapora

    tedinvacuum,thenthesolutionwasextractedwith

    ;Et20,andtheorganiclayerwascollected,dried,concentrated.1]heresiduewaspurifiedbycolumnchromatographyonsilicagelelutedwith

    ;petroleUlTIether/EtOAc/HAc(V=10:1:0.2-_4:1:0.2)togivethetidecompoundasawhitesolid,whichwascrystallizedfromhcxane.

    ;5-Ihedataof44f_4a:H?(30o?

    z,CDC13,6ppm):0.90(t,3H,J=13.8Hz),1.27-1.46(m,4H),1.751.89(m,2H),2.11(s,3H),

6.63

    ;(q,1H,J=12.6I-Iz),7.32._7.40(m,1H),7.55-7.59(m,2H),8.06(d,1H,J=8.1I-Iz),10.78Cor,1H};IR(KBr,v):1411,1579,1689,1735,2956

    ;and3447cm~1;ESI-MS:m/z523[2M+N;Ana1.Calcd.forCl4HlE04:C67.18,H7.25:Fou

    z, nd:C67.02,H7.28;4b:H?(30o?

    ;CDC13,6ppm):0.913H,J=13.8Hz),1_321.41(m,4hO,1.861.91(m,2H),4.11(s,2H

    ),6.78(q,IH,J=12.6I-Iz),7.3&-7.42(m,IH),

    ;7.56-7.622H),8.08(d,IH,J=8.1I-Iz),10.891H);IRliar,v):1412,1691,1734,2958and3450cm-1;BsI-Ms:ra/z283C1MH+1,

    ;285r7CIMH+1;Ana1.Caled.forC14H17C104:C59.o5,H6.02;Found:C59.21,H6.01;4e:H?(30o?z,CDC13,6ppm):0.9o3H’

    ;J=14.1Hz),1.26_1.47(m,4H),1.851

    (m,2H),2.78(t,2H,J=10.5I-Iz),3.72(t,2H,J=10.1I-Iz),6.65(q,IH,J=12.4Hz),7.31_7.35(m, ;IH),7.53-7.59(m,2H),8.05(d,IH,J=8.1Hz),10.78(br’11-1);IR(KBr,v):1415,1576,1686

    ,1731,2959and3445cm-1;ESI-MS:ra/z341

    ;[TYBrMH+1,343rBrM—H+1;Ana1.Caled.forC15Hl981”O4:C52.49,H5.58;Found:C52.61.H5.49;4d:HNM(30o?z,CDCl3,

    ;6ppm):0.923H,J=14.4Hz),1.39_-1.54(m,4h0,2.05(q’2H,J=21.6Hz),6.99(t,1H,J=12.5Hz),7.38-7.41(t,1H,J=14.7Hz),7.55-

    ;7.62(m,2H),8.1(d,1H,J=8.1I-Iz),8.25-8_31(m,4H),10.92(br,1H);IR(KBr,v):1415,1689,1736,2959and3451cm-1:BSI-MS:ra/z712

    ;

    2MH+1;Ana1.Calcd.forCI9HI9NO6:C63.86,H5.36,N3.92;Found:C63.65,H5.42,N3.84;4e:H?(30o?z’CDC13,6ppm):0.91

    ;(t,3H,J=13.9Hz),1.291.46(m,4H),1.96__2.O4(m,2hO,6.73(q,1H,J=12.8Hz),7.33-7.53(m,6H),7.95-7.99(m,2H),8.05(d,1H,

    ;J=8.1Hz),10.81br,1H);IR(Kar,v):1416,1684,1735,2955and3448cm-1;EsI.MS:ra/z6232MH+1;Ana1.Calcd.forCl[2d04:c

    ;73.o6,H6.45;Found:C72.87,H6.51;H?(30o?

    z’CDC13,ppm):0.89(t,3H,J=13.8Hz),1.23__1.41(m,4hO,1.94-2.03(m,2hO,

    ;3.73(s,3H),6.61(q,1H,J=12.4Hz),6.91-6.94(m,2H),7.31_7.38(m,1H),7.53.7.58(m,2H),7.84-7.88(m,2H),8.06(d,lH,J=8.1I-Iz),

    ;10.58br,1}D;IR(KBr,:1415,1685,1733,2951and3443cm-1;BsI-MS:ra/z6832MH+1;Ana1.Caled.forC2oH2205:C70.16,H6.48;

    ;Fotmd:C70.31.H6.42.

    ;

    ;

Report this document

For any questions or suggestions please email
cust-service@docsford.com