肉桂酸合成文献.docx
- 文档编号:26111823
- 上传时间:2023-06-17
- 格式:DOCX
- 页数:9
- 大小:41.04KB
肉桂酸合成文献.docx
《肉桂酸合成文献.docx》由会员分享,可在线阅读,更多相关《肉桂酸合成文献.docx(9页珍藏版)》请在冰豆网上搜索。
肉桂酸合成文献
Supplementaryinformation.
StructureActivityRelationshipoftrans-Substituted-PropenoicAcidDerivativesontheNicotinicAcidReceptorHCA2(GPR109A).
J.P.D.vanVeldhoven,C.C.Blad,C.M.Artsen,C.Klopman,D.R.Wolfram,M.J.Abdelkadir,J.R.Lane,J.BrusseeandA.P.IJzerman
DivisionofMedicinalChemistry,Leiden/AmsterdamCenterforDrugResearch,LeidenUniversity,P.O.Box9502,2300RALeiden,TheNetherlands.
1.Chemistry.
Allreagentsusedwereobtainedfromcommercialsourcesandallsolventswereofanalyticalgrade.1Hand13CNMRspectrawererecordedonaBrukerAV400(1HNMR,400MHz;13CNMR,100MHz)spectrometerwithtetramethylsilaneasaninternalstandard.Chemicalshiftsarereportedinδ(ppm)andthefollowingabbreviationsareused:
s=singlet,d=doublet,dd=doubledoublet,t=triplet,m=multiplet,br=broad,ar=aromaticprotons,ph=phenylprotons.ElementalanalyseswereperformedbytheLeidenInstituteofChemistryandarewithin0.4%ofthetheoreticalvaluesunlessotherwisestatedorpuritywasconfirmedbyHPLCandHighResolutionMassSpectroscopy.HPLCwasperformedonaGilson306system(detectionat254nm)equippedwithananalyticalC18column(4.6mmx12.5cm,5µm)incombinationwithagradientofmixtureA:
1MeCN/9H2O,B:
9MeCN/1H2O.Highresolutionmassspectrawererecordedbydirectinjectiononamassspectrometer(ThermoFinniganLTQOrbitrap)equippedwithanelectrosprayionsourceinpositivemode(sourcevoltage3.5kV,sheathgasflow10,capillarytemperature250°C)withresolutionR=60000atm/z400(massrangem/z=150‐2000)anddioctylphthalate(m/z=391.2842)asa“lockmass”.ReactionswereroutinelymonitoredonTLCusingMercksilicagelF254plates.MicrowavereactionswereperformedinanEmrysOptimizer(BiotageAB,formerlyPersonalChemistry).Wattagewasautomaticallyadjustedsoastomaintainthedesiredtemperature.Theyieldsofallproductswerenotoptimized.Allthefinalproducts(Tables1and2)werepurifiedbycolumnchromatographyfollowedbyrecrystallization.
Compounds1-3,25-46,48,50,51,55and56wereobtainedfromcommercialsources.
1.1.Generalproceduresforthesynthesisofthemonosubstitutedfumarates.
Scheme1.Synthesisoffumaric/maleicacidesters:
(a)N-methylmorpholine,EDC*HCl,DMF;(b)DMF,microwave,180ºC.
1.1.1.MethodA1:
Toamixtureoffumaricacid(8mmol,1.0eq)andtheappropriatealcohol(8mmol,1eq.)inDMF(10mL)wasaddedN-methylmorpholine(8mmol,1eq.)andEDC*HCl(8mmol,1eq.)whilecooledonice.ThereactionmixturewasstirredovernightafterwhichtheDMFwasremovedinvacuo.A1MHClsolutionwasaddedandtheproductwasextracted3timeswithDCM.ThecombinedorganiclayersweredriedoverMgSO4andconcentratedtodryness.Thecrudeproductconsistingofthedi-ester,thetrans-andcisproductwaspurifiedbycolumnchromatographyonSiO2,elutingwithatetrahydrofuran/petroleumethersolventsystemandcrystallizationfrombenzene
1.1.2.MethodB2:
Aneatmixtureoffumaricacid(14mmol,1eq.)andthealcohol(14mmol,1eq.)washeatedinthemicrowaveat180oCfor40minutes.Tothereactionmixture100mLofdichloromethanewasaddedandthenondissolvedfumaricacidwasfilteredoff.Thefiltratewasconcentratedinvacuo,consistingofthediesterandthetransproduct,andpurifiedbycolumnchromatographyusingdichloromethaneanda2%methanol/dichloromethanemixture.Thecrystallineproductwasobtainedaftercrystallizationfrombenzene.
1.1.3.Propylfumarate(4)
MethodA,yield7%,100mg;whitesolid.1H-NMRδ(DMSO):
6.69(s,2H,acrylic-H),4.11(t,2H,J=6.8Hz,OCH2CH2CH3),1.66–1.61(m,2H,OCH2CH2CH3),0.90(t,3H,J=7.2Hz,OCH2CH2CH3).13C-NMRδ(DMSO):
165.8,164.7,134.6,132.7,66.4,21.5,10.2.Anal.CalcdforC7H10O4:
C,53.16;H,6.37.FoundC,52.95;H,6.67.
1.1.4.Isopropylfumarate(5)
MethodB,yield4%,170mg;whitesolid.1HNMR(DMSO):
13.15(sbr,1H,COOH),6.66(d,J=19.2Hz,2H,acrylic-H),4.99(sept,J=6.4Hz,1H,CH(CH3)2),1.24(d,J=6.4Hz,6H,CH(CH3)2).13C-NMRδ(DMSO):
165.7,164.1,134.4,133.0,68.6,21.5.Anal.CalcdforC7H10O4:
C,53.16;H,6.37.FoundC,53.60;H,6.57.
1.1.5.Butylfumarate(6)
MethodB,yield8%,87mg;whitesolid.1HNMR(CDCl3):
6.95(d,J=15.6Hz,1H,acrylic-H),6.85(d,1H,acrylic-H),4.22(t,J=6.8Hz,2H,CH2),1.71-1.64(m,2H,CH2),1.46-1.37(m,2H,CH2),0.95(t,J=7.6Hz,3H,CH3).13C-NMRδ(CDCl3):
170.3,164.9,135.9,132.7,65.6,30.6,19.2,13.7.Anal.CalcdforC8H12O4:
C,55.81;H,7.02.FoundC,55.52;H,7.28.
1.1.6.Pentylfumarate(7)
MethodB,yield7%,115mg.offwhitesolid.1HNMR(CDCl3):
10.93(sbr,1H,COOH),6.96(d,J=15.6Hz,1H,acrylic-H),6.85(d,J=16.0Hz,1H,acrylic-H),4.22(t,J=6.8Hz,2H,CH2),1.73-1.66(m,2H,CH2),1.39-1.35(m,4H,CH2),0.92(t,J=6.8Hz,3H,CH3).13C-NMRδ(CDCl3):
170.3,164.9,136.1,132.6,65.9,28.3,28.1,22.4,14.1.Anal.CalcdforC9H14O4*0.04C6H6:
C,58.72;H,7.58.FoundC,58.72;H,7.80.
1.1.7.Hexylfumarate(8)
MethodB,yield24%,190mg;offwhitesolid.1HNMR(CDCl3):
10.45(sbr,1H,COOH),6.95(d,J=15.6Hz,1H,acrylic-H),6.85(d,J=16.0Hz,1H,acrylic-H),4.22(t,J=6.8Hz,2H,CH2),1.72-1.66(m,2H,CH2),1.40-1.26(m,6H,CH2),0.90(t,J=6.8Hz,3H,CH3).13C-NMRδ(CDCl3):
169.9,164.8,136.1,132.5,65.9,31.5,28.6,25.7,22.7,14.1.Anal.CalcdforC10H16O4:
C,59.98;H,8.05.FoundC,60.37;H,8.07.
1.1.8.Cyclohexylfumarate(9)
MethodA,yield3%,72mg;whitesolid.1H-NMRδ(DMSO):
6.66(s,2H,acrylic-H),4.80–4.74(m,1H,OCHcyclohexyl),1.81–1.79(m,2H,CH2cyclohexyl),1.68–1.65(m,2H,CH2cyclohexyl),1.50–1.23(m,6H,CH2cyclohexyl).13C-NMRδ(DMSO):
165.8,164.0,134.6,133.1,73.2,30.9,24.9,23.1.Anal.CalcdforC10H14O4:
C,60.59;H,7.12.FoundC,60.99;H,7.16.HRMSMH+:
199.09645delta=0.2ppm.HPLCpurity99%.
1.1.9.Phenylfumarate(10)
MethodA,yield6%,160mg;whitesolid.1H-NMRδ(DMSO):
7.47–7.43(m,2H,Ar-H),7.31–7.28(m,1H,Ar-H),7.22–7.21(m,2H,Ar-H),6.90(s,2H,acrylic-H).13C-NMRδ(DMSO):
165.6,163.4,150.1,136.1,131.9,129.6,126.3,121.7.Anal.CalcdforC11H10O4:
C,62.50;H,4.20.FoundC,62.46;H,4.25.
1.1.10.Benzylfumarate(11)
MethodA,yield5%,90mg;whitesolid.1H-NMRδ(DMSO):
7.42–7.34(m,5H,Ar-H),6.74(s,2H,acrylic-H),5.23(s,2H,CH2Ar).13C-NMRδ(DMSO):
165.7,164.5,135.6,137.1,132.4,128.6,128.3,128.2,66.5.Anal.CalcdforC11H10O4:
C,64.08;H,4.89.FoundC,64.08;H,4.98.HRMSMH+:
207.06522delta=0.1ppm.HPLCpurity97%.
1.1.11.(rac)-α-methylbenzylfumarate(12)
MethodB,yield20%,534mg;whitesolid.1HNMRδ(DMSO)13.21(sbr,1H,COOH),7.38-7.29(m,5H,Ar-H),6.73(s,2H,acrylic-H),5.91(q,J=6.4Hz,1H,ArCHCH3).13C-NMRδ(DMSO):
165.7,163.8,141.2,134.9,132.7,128.5,127.9,125.9,72.9,22.1.Anal.CalcdforC12H12O4:
C,65.45;H,5.49.FoundC,65.85;H,5.51.
1.1.12.Phenylethylfumarate(13)
MethodA,yield17%,769mg;whitesolid.1HNMR(DMSO)13.22(sbr,1H,COOH),7.32-7.20(m,5H,Ar-H),6.66(s,2H,acrylic-H),4.36(t,J=6.8Hz,2H,ArCH2CH2O),2.94(t,J=6.8Hz,2H,ArCH2CH2O).13C-NMRδ(DMSO):
165.7,164.4,137.9,134.7,132.5,128.9,128.4,126.5,65.4,34.2.Anal.CalcdforC12H12O4:
C,65.45;H,5.49.FoundC,65.42;H,5.60.
1.1.13.Phenylpropylfumarate(14)
MethodB,yield6%,110mg;whitesolid.1HNMR(DMSO):
7.30-7.16(m,5H,Ar-H),6.69(s,2H,acrylic-H),4.14(t,J=6.4Hz,2H,CH2),2.67(t,J=7.6Hz,2H,CH2),1.97-1.90(m,2H,CH3).13C-NMRδ(DMSO):
165.8,164.6,141.1,132.6,128.4,128.3,125.9,64.3,31.4,29.6.Anal.CalcdforC13H14O4*0.06C6H6:
C,67.29;H,6.07.FoundC,67.28;H,6.25.
1.1.14.2-Bromobenzylfumarate(15)
MethodB,yield6%,66mg;whitesolid.1HNMR(CDCl3):
10.12(sbr,1H,COOH),7.60(d,J=7.6Hz,1H,Ar-H),7.43(d,J=6.8Hz,1H,Ar-H),7.34(t,J=7.2Hz,1H,Ar-H),7.22(t,J=6.8Hz,1H,Ar-H),7.01(d,J=15.6Hz,1H,acrylic-H),6.91(d,J=16.0Hz,1H,acrylic-H),5.34(s,2H,CH2).13C-NMRδ(CDCl3):
170.1,164.4,135.3,134.5,133.4,133.1,130.3,130.2,127.7,123.8,66.9.Anal.CalcdforC11H9BrO4:
C,46.34;H,3.18.FoundC,46.52;H,3.33.
1.1.15.2-Methoxybenzylfumarate(16)
MethodB,yield4%,34mg;whitesolid.1HNMR(CDCl3):
9.22(sbr,1H,COOH),7.33(s,2H,Ar-H),7.00-6.85(m,4H,acrylic-H+Ar-H),5.30(s,2H,CH2)3.85(s,3H,CH3).13C-NMRδ(CDCl3):
170.1,164.7,157.8,135.9,132.8,130.2,123.5,120.6,110.6,63.0,55.6.Anal.CalcdforC12H12O5:
C,61.02;H,5.12.FoundC,61.20;H,5.24.
1.1.16.3-Bromobenzylfumarate(17)
MethodB,yield10%,336mg;whitesolid.1HNMR(DMSO)13.25(sbr,1H,COOH),7.64(m,1H,Ar-H),7.54(d,J=7.6Hz,1H,Ar-H),7.42(d,J=7.6Hz,1H,Ar-H),7.37-7.33(m,1H,Ar-H),6.76(s,2H,acrylic-H),5.22(s,2H,CH2).13C-NMRδ(DMSO):
165.7,164.4,138.4,135.1,132.2,131.6,130.7,127.1,121.7,65.5.Anal.CalcdforC11H9BrO4:
C,46.34;H,3.18.FoundC,46.38;H,3.31.
1.1.17.3-Chlorobenzylfumarate(18)
MethodB,yield11%,119mg;whitesolid.1HNMR(CDCl3):
11.11(sbr,1H,COOH),7.38-7.14(m,4H,Ar-H),6.99(d,J=15.6Hz,1H,acrylic-H),6.89(d,J=15.6Hz,1H,acrylic-H),5.22(s,2H,CH2).13C-NMRδ(CDCl3):
170.2,164.4,137.1,135.4,134.7,133.4,130.1,128.9,128.5,126.5,66.5.Anal.CalcdforC11H9ClO4:
C,54.90;H,3.77.FoundC,55.21;H,3.69.
1.1.18.3-Fluorobenzylfumarate(19)
MethodB,yield11%,112mg;whitesolid.1HNMR(CDCl3):
10.05(sbr,1H,COOH),7.38-7.32(m,1H,Ar-H),7.15(d,J=7.6Hz,1H,Ar-H),7.10-7.02(m,2H,Ar-H),7.00(d,J=16.0Hz,1H,acrylic-H),6.89(d,J=15.6Hz,1H,acrylic-H),5.24(s,2H,CH2).13C-NMRδ(CDCl3)
- 配套讲稿:
如PPT文件的首页显示word图标,表示该PPT已包含配套word讲稿。双击word图标可打开word文档。
- 特殊限制:
部分文档作品中含有的国旗、国徽等图片,仅作为作品整体效果示例展示,禁止商用。设计者仅对作品中独创性部分享有著作权。
- 关 键 词:
- 肉桂 合成 文献