肉桂酸合成文献.docx

肉桂酸合成文献.docx

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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）