CN112759551A - 2, 5-substituent 1H-imidazole-4-carboxylic ester compound and synthesis and purification method thereof - Google Patents
2, 5-substituent 1H-imidazole-4-carboxylic ester compound and synthesis and purification method thereof Download PDFInfo
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- CN112759551A CN112759551A CN202110015268.2A CN202110015268A CN112759551A CN 112759551 A CN112759551 A CN 112759551A CN 202110015268 A CN202110015268 A CN 202110015268A CN 112759551 A CN112759551 A CN 112759551A
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- substituent
- imidazole
- ester compound
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 title claims description 15
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 title claims description 3
- 238000003786 synthesis reaction Methods 0.000 title abstract description 42
- 230000015572 biosynthetic process Effects 0.000 title abstract description 40
- 238000000746 purification Methods 0.000 title abstract description 6
- -1 enamine compounds Chemical class 0.000 claims abstract description 54
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 111
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 86
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 78
- 239000012074 organic phase Substances 0.000 claims description 75
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 45
- 239000003208 petroleum Substances 0.000 claims description 44
- 239000012043 crude product Substances 0.000 claims description 40
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 39
- 238000010898 silica gel chromatography Methods 0.000 claims description 39
- 239000001632 sodium acetate Substances 0.000 claims description 39
- 235000017281 sodium acetate Nutrition 0.000 claims description 39
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims description 39
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 37
- 238000010992 reflux Methods 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000011630 iodine Substances 0.000 abstract description 3
- 229910052740 iodine Inorganic materials 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000007243 oxidative cyclization reaction Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 134
- 239000000047 product Substances 0.000 description 35
- 238000004983 proton decoupled 13C NMR spectroscopy Methods 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
- 238000001914 filtration Methods 0.000 description 34
- 238000001035 drying Methods 0.000 description 33
- 239000007787 solid Substances 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- HHPQJNZZSMAEBH-UHFFFAOYSA-N C1(=CC=C(C=C1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C1(=CC=C(C=C1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1)C1=CC=CC=C1 HHPQJNZZSMAEBH-UHFFFAOYSA-N 0.000 description 2
- QCQSNCBRLZPCLH-UHFFFAOYSA-N C1(=CC=CC=C1)C=1NC(=C(N=1)C(=O)OC)C1=CSC=C1 Chemical compound C1(=CC=CC=C1)C=1NC(=C(N=1)C(=O)OC)C1=CSC=C1 QCQSNCBRLZPCLH-UHFFFAOYSA-N 0.000 description 2
- XQTYXCVCHUTWIM-UHFFFAOYSA-N C1(=CC=CC=C1)C=1NC(=C(N=1)C=1SC=CC=1)C(=O)OC Chemical compound C1(=CC=CC=C1)C=1NC(=C(N=1)C=1SC=CC=1)C(=O)OC XQTYXCVCHUTWIM-UHFFFAOYSA-N 0.000 description 2
- HDXMUIJHZIHFIR-UHFFFAOYSA-N C=1C=CC=CC=1C(=O)C=1NC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 Chemical compound C=1C=CC=CC=1C(=O)C=1NC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 HDXMUIJHZIHFIR-UHFFFAOYSA-N 0.000 description 2
- CQVIHGDCKVYNJE-UHFFFAOYSA-N CC=1C=C(C=CC=1C)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 Chemical compound CC=1C=C(C=CC=1C)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 CQVIHGDCKVYNJE-UHFFFAOYSA-N 0.000 description 2
- UAHKEUNUYCMFLK-UHFFFAOYSA-N COC1=CC=C(C=C1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 Chemical compound COC1=CC=C(C=C1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 UAHKEUNUYCMFLK-UHFFFAOYSA-N 0.000 description 2
- KYUWFIPHDALRKF-UHFFFAOYSA-N ClC1=CC=C(C=C1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 Chemical compound ClC1=CC=C(C=C1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 KYUWFIPHDALRKF-UHFFFAOYSA-N 0.000 description 2
- UHLGZEHCXSKXCE-UHFFFAOYSA-N ClC=1C=C(C=CC=1)C1=C(N=C(N1)C1=CC=CC=C1)C(=O)OC Chemical compound ClC=1C=C(C=CC=1)C1=C(N=C(N1)C1=CC=CC=C1)C(=O)OC UHLGZEHCXSKXCE-UHFFFAOYSA-N 0.000 description 2
- BPDDFRMYIQRZHQ-UHFFFAOYSA-N ethyl 2,4-diphenyl-1h-imidazole-5-carboxylate Chemical compound CCOC(=O)C=1NC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 BPDDFRMYIQRZHQ-UHFFFAOYSA-N 0.000 description 2
- QMGZSOBQSKHVAW-UHFFFAOYSA-N ethyl 2-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylate Chemical compound N1C(C(F)(F)F)=C(C(=O)OCC)N=C1C1=CC=CC=C1 QMGZSOBQSKHVAW-UHFFFAOYSA-N 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 239000012621 metal-organic framework Substances 0.000 description 2
- GXDHXPNIFLWKSS-UHFFFAOYSA-N methyl 2,4-diphenyl-1h-imidazole-5-carboxylate Chemical compound COC(=O)C=1NC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 GXDHXPNIFLWKSS-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- YIMMDWQJMUECHD-OWOJBTEDSA-N 1-isocyanato-4-[(e)-2-(4-isocyanatophenyl)ethenyl]benzene Chemical compound C1=CC(N=C=O)=CC=C1\C=C\C1=CC=C(N=C=O)C=C1 YIMMDWQJMUECHD-OWOJBTEDSA-N 0.000 description 1
- QWJSXZHGKMIVNB-UHFFFAOYSA-N BrC1=CC=C(C=C1)C1=C(N=C(N1)C1=CC=CC=C1)C(=O)OC Chemical compound BrC1=CC=C(C=C1)C1=C(N=C(N1)C1=CC=CC=C1)C(=O)OC QWJSXZHGKMIVNB-UHFFFAOYSA-N 0.000 description 1
- OKKLNBGNVNSGAU-UHFFFAOYSA-N C1(=CC=CC2=CC=CC=C12)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 Chemical compound C1(=CC=CC2=CC=CC=C12)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 OKKLNBGNVNSGAU-UHFFFAOYSA-N 0.000 description 1
- MBVCVINJGWJRBY-UHFFFAOYSA-N C1(=CC=CC=C1)C=1NC(=C(N=1)C(=O)OC)C1=C(C=CC=C1)C Chemical compound C1(=CC=CC=C1)C=1NC(=C(N=1)C(=O)OC)C1=C(C=CC=C1)C MBVCVINJGWJRBY-UHFFFAOYSA-N 0.000 description 1
- GKJDJJWHWHMXPN-UHFFFAOYSA-N C1(=CC=CC=C1)C=1NC(=C(N=1)C(=O)OC)C=1C=C(C=CC=1)C Chemical compound C1(=CC=CC=C1)C=1NC(=C(N=1)C(=O)OC)C=1C=C(C=CC=1)C GKJDJJWHWHMXPN-UHFFFAOYSA-N 0.000 description 1
- JHOFVYZNEDUPDD-UHFFFAOYSA-N C1(=CC=CC=C1)C=1NC(=C(N=1)C1=CC=C(C=C1)C(F)(F)F)C(=O)OC Chemical compound C1(=CC=CC=C1)C=1NC(=C(N=1)C1=CC=C(C=C1)C(F)(F)F)C(=O)OC JHOFVYZNEDUPDD-UHFFFAOYSA-N 0.000 description 1
- FLDLZEDETSUXRD-UHFFFAOYSA-N COC=1C=C(C=CC=1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 Chemical compound COC=1C=C(C=CC=1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 FLDLZEDETSUXRD-UHFFFAOYSA-N 0.000 description 1
- CBYQAWSWNPWZQS-UHFFFAOYSA-N COC=1C=C(C=CC=1OC)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 Chemical compound COC=1C=C(C=CC=1OC)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 CBYQAWSWNPWZQS-UHFFFAOYSA-N 0.000 description 1
- BDNKIKBBUFGUOA-UHFFFAOYSA-N FC1=CC=C(C=C1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 Chemical compound FC1=CC=C(C=C1)C=1N=C(NC=1C(=O)OC)C1=CC=CC=C1 BDNKIKBBUFGUOA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- YQBFSYYGTNQDHE-UHFFFAOYSA-N methyl 4-(4-methylphenyl)-2-phenyl-1H-imidazole-5-carboxylate Chemical compound C1(=CC=CC=C1)C=1NC(=C(N=1)C(=O)OC)C1=CC=C(C=C1)C YQBFSYYGTNQDHE-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a 2, 5-substituent-1H-imidazole-4-carboxylic ester compound and a synthesis and purification method thereof, and the method takes iodine as an oxidant to promote the oxidative cyclization reaction of enamine compounds, so that the operation for preparing the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound is simpler, the preparation cost is greatly low, the relative yield and purity are higher, and the environmental pollution is less. In addition, the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound provided by the invention has been widely applied in the fields of medicine, ligand chemistry and material science due to the special heterocyclic skeleton, and is a valuable synthetic intermediate and functional organic molecule.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a 2, 5-substituent-1H-imidazole-4-carboxylic ester compound and a synthesis and purification method thereof.
Background
Imidazole compounds are special five-membered nitrogen heterocyclic compounds, and have been widely used in the fields of medicine, ligand chemistry and material science due to their special heterocyclic skeletons (org. Lett.2020,22, 1980-. Imidazoles are valuable synthetic intermediates and are therefore commonly used in organic synthesis. The imidazole structure contains two nitrogen donor coordination sites, which makes it completely emergent in coordination chemistry and widely used for constructing target Metal Organic Frameworks (MOFs) (org. lett.2019,21, 9874-. Prior to this, transition metal catalyzed and transition metal-free catalyzed processes have been greatly developed, with the transition metal-free reactions being environmentally friendly (org. lett.2019,21, 9874-. However, the imidazole synthesis method at present has disadvantages, because most reactions still need the participation of transition metal and the substrate needs complex composite substrate, and the synthesis cost is high, so that the search for a high-efficiency, simple and low-cost synthesis method is urgent.
Disclosure of Invention
In view of the defects in the prior art, the inventor establishes a simple and practical preparation method of 2, 5-substituent-1H-imidazole-4-carboxylic ester through a large number of experiments, and synthesizes a series of compounds 2, 5-substituent-1H-imidazole-4-carboxylic ester with novel structures.
Based on the experimental results of the inventor, the first object of the invention is to provide a series of 2, 5-substituent-1H-imidazole-4-carboxylic ester compounds, which have the following structural general formula:
wherein R is1Aryl or trifluoromethyl, R2＝C1-C7Alkyl, phenyl, C1-C6Alkoxy, phenoxy, benzyl or benzyloxy, R3An ester group or a benzoyl group.
Further preferred are the 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compounds as described above, wherein R is1Is aryl, and the aryl is phenyl, biphenyl or heterocyclic aryl containing substituent groups. The phenyl containing the substituent group is phenyl containing one or more substituent groups, the biphenyl is 4-biphenyl, and the heterocyclic aryl is 2-thienyl or 3-thienyl. The substituent is alkyl, alkoxy, halogenated alkyl, nitro or halogen substituent.
It is further preferred that the first and second liquid crystal compositions,the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound as described above, wherein R is2Selected from one of the following: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy.
Further preferred are the 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compounds as described above, wherein R is3Is an ester group, the ester group is-CO2R, R ═ methyl or ethyl.
In addition, the second objective of the present invention is to provide a method for synthesizing the above 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound, the method comprises using enamine ester or enaminoketone compound and azidotrimethylsilane as raw materials, using iodine as oxidant, adding mixed base, and refluxing in a solvent to obtain a crude product, wherein the reaction formula is as follows:
the mixed alkali consists of potassium carbonate and sodium acetate, wherein: the molar ratio of enamine ester or enaminone, azidotrimethylsilane, iodine, potassium carbonate and sodium acetate is 1 (2.5-3.5): (2.5-3.5): (2.5-3.5): 0.8-1.2), preferably 1:3:3:3: 1.
Further preferably, the method for synthesizing the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound is as described above, wherein the solvent is N, N-dimethylformamide, and the reflux reaction time is 6-12H.
Furthermore, the invention also provides a purification method of a crude product of the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound, which comprises the following steps: taking the crude product of the 2, 5-diphenyl 1H-imidazole-4-carboxylic ester obtained by the synthesis method according to the ratio of (4.5-5.5): (9-11): adding water, petroleum ether and ethyl acetate into the mixture according to the volume ratio of 1 for extraction, extracting for 2-4 times, combining organic phases to obtain an extract, and purifying the extract by silica gel column chromatography, wherein the volume ratio of eluent is (2.8-3.2): 1 petroleum ether-ethyl acetate.
Further preferably, the purification method is performed according to the following ratio of 5: 10:1, adding water, petroleum ether and ethyl acetate for extraction, extracting for 2-4 times, combining organic phases to obtain an extract, purifying the extract by silica gel column chromatography, wherein the volume ratio of the eluent is 3:1 petroleum ether-ethyl acetate.
Compared with the prior art, the method creatively takes iodine as an oxidant to promote the oxidative cyclization reaction of the enamine compound, so that the preparation method of the 2, 5-substituent-1H-imidazole-4-carboxylic ester has the advantages of simple operation, greatly reduced preparation cost, higher relative yield and purity, less environmental pollution and more ideal effect, and is one of the most direct and efficient methods for synthesizing the 2, 5-substituent-1H-imidazole-4-carboxylic ester reported at present. In addition, the 2, 5-substituent-1H-imidazole-4-carboxylic ester provided by the invention is a series of compounds with novel structures and potential application values, and can be widely applied to the field of medicines, ligand chemistry and material science.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Example 1: the synthesis of 2, 5-diphenyl-1H-imidazole-4-carboxylic acid methyl ester (2a) has the following structural formula:
adding 0.3mmol of enamine ester (1a), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, after the reaction is finished, adding 110mL of organic phase (PE: EA is 10:1, PE is petroleum ether, EA is ethyl acetate) in three times (5:3:3), extracting for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to obtain 71mg of product by calculationThe yield thereof was found to be 85%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.92-7.95(m,2H),7.84-7.86(m,2H),7.36-7.45(m,6H),3.84(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.5,147.5,129.9,129.2,128.9,128.8,128.7,128.0,126.0,51.8.HRMS(ESI-TOF):m/z calcd for C17H15N2O2[M+H]+279.1128,found:279.1131。
Example 2: synthesis of methyl 2-phenyl-5- (p-tolyl) -1H-imidazole-4-carboxylate (2b), the structural formula of which is specifically as follows:
adding 0.3mmol of enamine ester (1b), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 61mg of product, calculated in 70% yield.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.92-7.95(m,2H),7.74-7.76(m,2H),7.40-7.45(m,3H),7.20-7.22(m,2H),3.84(s,3H),2.37(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.5,147.2,138.8,130.2,129.9,129.2,129.1,128.9,128.7,128.6,126.0,51.8,21.4.HRMS(ESI-TOF):m/z calcd for C18H17N2O2[M+H]+293.1285,found:293.1291。
Example 3 Synthesis of methyl 2-phenyl-5- (m-tolyl) -1H-imidazole-4-carboxylate (2c), the structural formula is specifically as follows:
adding 0.3mmol of enamine ester (1c), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 60mg of product, calculated yield 68%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.89-7.92(m,2H),7.50-7.53(m,2H),7.35-7.37(m,3H),7.19-7.23(m,1H),7.10-7.13(m,1H),3.76(s,3.H),2.3(m,3H).13C{1H}NMR(100MHz,CDCl3):δ162.1,147.5,137.5,131.4,129.8,129.7,129.5,128.8,128.7,127.7,126.5,126.1,51.7,21.4.HRMS(ESI-TOF):m/z calcd for C18H17N2O2[M+H]+293.1285,found:293.1281。
Example 4: synthesis of methyl 2-phenyl-5- (o-tolyl) -1H-imidazole-4-carboxylate (2d), the structural formula is specifically as follows:
adding 0.3mmol of enamine ester (1d), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum etherPurifying at ratio of 3:1 to obtainTo 33mg of product, the calculated yield is 38%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.87-7.89(m,2H),7.35-7.37(m,3H),7.14-7.2(m,3H),7.06-7.10(m,1H),3.65(m,3H),2.13(m,3H).13C{1H}NMR(100MHz,CDCl3):δ162.3,147.2,137.4,130.1,129.9,129.6,128.9,128.8,126.0,125.1,51.6,19.8.HRMS(ESI-TOF):m/z calcd for C18H17N2O2[M+H]+293.1285,found:293.1297。
Example 5: the synthesis of 2-phenyl-5- (3, 4-dimethylphenyl) -1H-imidazole-4-carboxylic acid methyl ester (2e) has the following specific structural formula:
adding 0.3mmol of enamine ester (1e), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 73mg of product, calculated yield 80%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.90-7.93(m,2H),7.50-7.55(m,2H),7.38-7.41(m,3H),7.11-7.13(m,1H),3.81(s,3H),2.25(s,6H).13C{1H}NMR(100MHz,CDCl3):δ161.7,147.2,137.4,136.2,130.2,129.7,129.2,128.8,126.7,126.0,51.7,19.7,19.6.HRMS(ESI-TOF):m/z calcd for C19H19N2O2[M+H]+307.1441,found:307.1452。
Example 6: the synthesis of 2-phenyl-5- (p-methoxyphenyl) -1H-imidazole-4-carboxylic acid methyl ester (2f) has the following structural formula:
adding 0.3mmol of enamine ester (1f), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to give 62mg of product, calculated yield 67%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.94-7.97(m,2H),7.84-7.87(m,2H),7.41-7.44(m,3H),6.93-6.95(m,2H),3.86(s,3H),3.83(s,3H).13C{1H}NMR(100MHz,CDCl3):δ.HRMS(ESI-TOF):m/z calcd for C18H17N2O3[M+H]+309.1233,found:309.1240。
Example 7: synthesis of methyl 2-phenyl-5- (m-methoxyphenyl) -1H-imidazole-4-carboxylate (2g), the structural formula is specifically as follows:
adding 0.3mmol of enamine ester (1g), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to obtain 53mg of product,the calculated yield was 57%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.93-7.96(m,2H),7.41-7.47(m,5H),7.28-7.32(m,1H),6.90-6.93(m,1H),3.84(s,3H),3.83(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.3,159.2,147.4,133.3,130.0,129.0,128.9,128.5,126.0,121.7,114.9,114.5,55.3,51.9.HRMS(ESI-TOF):m/z calcd for C18H17N2O3[M+H]+309.1233,found:309.1241。
Example 8: synthesis of methyl 2-phenyl-5- (3, 4-dimethoxyphenyl) -1H-imidazole-4-carboxylate (2H), the structural formula is specifically as follows:
adding 0.3mmol of enamine ester (1h), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 82mg of product, calculated in 81% yield.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.94-7.97(m,2H),7.51-7.57(m,2H),7.40-7.45(m,3H),6.88-6.90(m,1H),3.91(s,3H),3.89(s,3H),3.85(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.3,149.5,148.3,147.2,130.0,128.9,128.6,126.0,122.1,112.6,110.6,55.9,55.8,51.8.HRMS(ESI-TOF):m/z calcd for C19H19N2O4[M+H]+339.1339,found:339.1356。
Example 9: the synthesis of 2-phenyl-5- (p-fluorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2i) has the following specific structural formula:
adding 0.3mmol of enamine ester (1i), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 54mg of product, calculated yield 61%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.92-7.96(m,4H),7.43-7.49(m,3H),7.08-7.13(m,2H),7.87(s,3H).13C{1H}NMR(100MHz,CDCl3):δ164.3,161.8,147.5,131.3,131.2,130.1,129.0,128.4,126.0,115.1,114.8,51.9.HRMS(ESI-TOF):m/z calcd for C17H14FN2O2[M+H]+297.1033,found:297.1052。
Example 10: the synthesis of 2-phenyl-5- (p-chlorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2j) has the following structural formula:
adding 0.3mmol of enamine ester (1j), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 70mg of product, calculated in 75% yield.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.93-7.95(m,4H),7.43-7.47(m,3H),7.37-7.40(m,2H),3.87(s,3H).13C{1H}NMR(100MHz,CDCl3):δ134.6,130.6,130.1,129.0,128.6,128.2,125.9,52.HRMS(ESI-TOF):m/z calcd for C17H14ClN2O2[M+H]+313.0738,found:313.0747。
Example 11: the synthesis of 2-phenyl-5- (m-chlorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2k) has the following structural formula:
adding 0.3mmol of enamine ester (1k), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 64mg of product, calculated in 68% yield.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ10.20(b,1H),7.94-8.00(m,3H),7.86-7.90(m,1H),7.44-7.48(m,3H),7.33-7.35(m,2H),3.88(s,3H).13C{1H}NMR(100MHz,CDCl3):δ160.5,148.0,146.9,134.9,133.8,130.2,129.3,129.2,129.1,128.5,127.4,126.0,118.5,52.1.HRMS(ESI-TOF):m/z calcd for C17H14ClN2O2[M+H]+313.0738,found:313.0742。
Example 12: synthesis of methyl 2-phenyl-5- (p-bromophenyl) -1H-imidazole-4-carboxylate (2l) having the following specific structural formula:
adding 0.3mmol of enamine ester (1l), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 74mg of product, calculated yield 69%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.94-7.97(m,2H),7.84-7.86(m,2H),7.54-7.56(m,2H),7.45-7.49(m,3H),3.88(s,3H).13C{1H}NMR(100MHz,CDCl3):δ160.6,147.6,131.2,130.9,130.4,129.1,127.9,126.1,123.2,52.1.HRMS(ESI-TOF):m/z calcd for C17H13NaBrN2O2[M+Na]+379.0052,found:379.0059。
Example 13: the synthesis of 2-phenyl-5- (p-trifluoromethylphenyl) -1H-imidazole-4-carboxylic acid methyl ester (2m) has the following structural formula:
adding 0.3mmol of enamine ester (1m), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 77mg of product, calculated yield 74%.
The main physicochemical properties are as follows:
a white solid.1H NMR(400MHz,CDCl3):δ8.08-8.10(m,2H),7.95-7.97(m,2H),7.66-7.69(m,2H),7.45-7.49(m,3H),3.88(s,3H).13C{1H}NMR(100MHz,CDCl3):δ160.6,147.9,130.5,130.3,130.2,129.6,129.1,128.4,126.2,126.0,125.5,124.9(JC-F＝3.81Hz),122.8,52.1.HRMS(ESI-TOF):m/z calcd for C18H14F3N2O2[M+H]+347.1001,found:347.1004。
Example 14: the synthesis of 2-phenyl-5- (thiophene-2-yl) -1H-imidazole-4-carboxylic acid methyl ester (2n) has the following structural formula:
adding 0.3mmol of enamine ester (1N), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 57mg of product, calculated in 67% yield.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ10.47(b.1H),7.95-8.05(m,3H),7.36-7.40(m,4H),7.06-7.09(m,1H),3.90(m,3H).13C{1H}NMR(100MHz,CDCl3):δ160.6,148.1,142.5,136.3,130.1,128.9,128.5,128.3,127.5,127.1,126.2,116.8,52.0.HRMS(ESI-TOF):m/z calcd for C15H13N2O2S[M+H]+285.0692,found:285.0712。
Example 15: the synthesis of 2-phenyl-5- (thiophene-3-yl) -1H-imidazole-4-carboxylic acid methyl ester (2o) has the following structural formula:
adding 0.3mmol of enamine ester (1o), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 63mg of product, calculated yield 74%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ8.17-8.18(m,1H),7.92-7.94(m,2H),7.18-7.80(m,1H),7.41-7.45(m,3H),7.32-7.34(m,1H),3.90(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.0,147.3,130.0,128.9,128.8,128.6,128.4,127.9,126.0,125.9,124.8,51.9.HRMS(ESI-TOF):m/z calcd for C15H13N2O2S[M+H]+285.0692,found:285.0707。
Example 16: the synthesis of 5- ([1, 1' -biphenyl ] -4-yl) -2-phenyl-1H-imidazole-4-carboxylic acid methyl ester (2p) has the following specific structural formula:
adding 0.3mmol of enamine ester (1p), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, and reducing the volumeConcentrating under pressure, and performing rapid silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 72mg of product, calculated in 68% yield.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.97-8.01(m,4H),7.61-7.67(m,4H),7.42-7.47(m,5H),7.33-7.37(m,1H),3.89(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.2,147.4,141.5,140.7,130.7,130.2,129.7,129.0,128.9,128.8,128.3,127.5,127.3,127.1,126.7,126.1,52.0.HRMS(ESI-TOF):m/z calcd for C23H19N2O2[M+H]+355.1441,found:355.1454。
Example 17: synthesis of methyl 5- (naphthalen-4-yl) -2-phenyl-1H-imidazole-4-carboxylate (2q), the structural formula of which is specifically as follows:
adding 0.3mmol of enamine ester (1q), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 47mg of product, calculated yield 48%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.91-7.93(m,2H),7.85-7.89(m,2H),7.77(m,1H),7.52-7.53(m,1H),7.44-7.49(m,2H),7.38-7.43(m,4H),3.61(s,3H).13C{1H}NMR(100MHz,CDCl3):δ133.5,132.0,129.8,129.3,129.0,128.8,128.5,128.3,126.3,125.9,125.6,124.9,51.7.HRMS(ESI-TOF):m/z calcd for C21H17N2O2[M+H]+329.1284,found:329.1293。
Example 18: the synthesis of 2, 5-diphenyl-1H-imidazole-4-carboxylic acid ethyl ester (2r) has the following specific structural formula:
adding 0.3mmol of enamine ester (1r), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 70mg of product, calculated yield 80%.
The main physicochemical properties are as follows:
a white solid.1H NMR(400MHz,CDCl3):δ7.94-7.96(m,2H),7.83-7.85(m,2H),7.32-7.44(m,6H),4.27-4.34(m,2H),1.24-1.30(m,3H).13C{1H}NMR(100MHz,CDCl3):δ161.1,.147.6,132.3,129.8,129.4,128.9,128.6,127.8,126.1,61.0,14.2.HRMS(ESI-TOF):m/z calcd for C18H17N2O2[M+H]+293.1284,found:293.1289。
Example 19: the synthesis of 5- (4-nitrophenyl) -2-phenyl-1H-imidazole-4-carboxylic acid ethyl ester (2s) has the following specific structural formula:
0.3mmol of enamine ester (1s), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and after completion of the reaction, 110mL of organic phase (PE: EA. RTM.10: 1) and 50mL of water were added in three portions (5:3:3) in total, and the organic phases were combined after extraction for three timesDrying the extract with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 35mg of product, calculated yield 35%.
The main physicochemical properties are as follows:
yellow solid. H NMR (400MHz, CDCl)3):δ8.21-8.32(m,4H)7.96-7.98(m,2H),7.46-7.52(m,3H),4.39(q,J＝7.1Hz,2H),1.36(t,J＝7.1Hz,3H).13C{1H}NMR(100MHz,CDCl3):δ159.8,148.1,147.5,130.4,130.2,129.4,129.1,128.2,128.0,126.6,126.0,123.1,61.6,14.3.HRMS(ESI-TOF):m/z calcd for C18H16N3O4[M+H]+338.1135,found:338.1142。
Example 20: the synthesis of 2-phenyl-5- (trifluoromethyl) -1H-imidazole-4-carboxylic acid ethyl ester (2t) has the following structural formula:
adding 0.3mmol of enamine ester (1t), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to give 56mg of product, calculated yield 58%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ12.00(b,1H),8.19-8.21(m,2H),7.57-7.60(m,2H),7.29-7.42(m,3H),7.12-8.15(m,3H),7.05-7.09(m,5H).13C{1H}NMR(100MHz,CDCl3):δ187.7,150.8,149.9,137.2,133.7,132.3,130.1,129.9,129.6,128.8,128.0,127.9,127.8,127.6,126.7.HRMS(ESI-TOF):m/z calcd for C22H17N2O[M+H]+325.1341,found:308.1394。
Example 21: the synthesis of (2, 5-diphenyl-1H-imidazol-4-yl) (phenyl) methanone (2u) has the following structural formula:
adding 0.3mmol of enamine ester (1u), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to give 56mg of product, calculated yield 58%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ12.00(b,1H),8.19-8.21(m,2H),7.57-7.60(m,2H),7.29-7.42(m,3H),7.12-8.15(m,3H),7.05-7.09(m,5H).13C{1H}NMR(100MHz,CDCl3):δ187.7,150.8,149.9,137.2,133.7,132.3,130.1,129.9,129.6,128.8,128.0,127.9,127.8,127.6,126.7.HRMS(ESI-TOF):m/z calcd for C22H17N2O[M+H]+325.1341,found:308.1394。
Example 22: the synthesis of 2-phenylchromium [3,4-d ] imidazole-4 (1H) -ketone (2v) has the following structural formula:
0.3mmol of enamine ester (1v), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and after completion of the reaction, 110mL of organic phase (PE: EA ═ 3:3) were added in three portions in total10:1) and 50mL of water, extracting for three times, combining organic phases to obtain an extract, drying the extract by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on a crude productEthyl acetate∶VPetroleum ether3: 1) to yield 67mg of product, calculated in 85% yield.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,DMSO-d6):δ13.81(b,1H),8.07-8.17(m,3H),7.38-7.55(m,6H).13C{1H}NMR(100MHz,DMSO-d6):δ169.5,152.3,140.0,130.7,130.0,129.4,128.7,127.7,127.1,126.9,125.0,122.7,117.4.HRMS(ESI-TOF):m/z calcd for C16H10N2O2[M+H]+263.0815,found:263.0811。
Example 23: the synthesis of 2-methyl-5-phenyl-1H-4-carboxylic acid methyl ester (4a) has the following structural formula:
adding 0.3mmol of enamine ester (3a), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 33mg of product, calculated yield 51%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ10.27(b,1H),7.66-7.68(m,2H),7.29-7.33(m,3H),3.74(s,3H),2.25(s,3H).13C{1H}NMR(100MHz,CDCl3):δ162.2,146.3,142.8,131.2,129.1,128.6,128.0,121.3,51.6,13.6.HRMS(ESI-TOF):m/z calcd for C12H13N2O2[M+H]+217.0971,found:217.0967。
Example 24: the synthesis of 2-ethyl-5-phenyl-1H-4-carboxylic acid methyl ester (4b) has the following structural formula:
adding 0.3mmol of enamine ester (3b), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 35mg of product, calculated yield 51%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ7.72-7.74(m,2H),7.31-7.37(m,3H),3.78(s,3H),2.68-2.74(m,2H),1.27(t,J＝7.7Hz,3H).13C{1H}NMR(100MHz,CDCl3):δ161.8,151.4,131.9,129.1,128.5,127.5,120.2,51.6,21.7,12.3.HRMS(ESI-TOF):m/z calcd for C13H15N2O2[M+H]+231.1128,found:231.1127。
Example 25: the synthesis of 2-propyl-5-phenyl-1H-4-carboxylic acid methyl ester (4c) has the following structural formula:
adding 0.3mmol of enamine ester (3c), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, and drying with anhydrous sodium sulfateFiltering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 30mg of product, calculated in 41% yield.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ7.72-7.75(m,2H),7.31-7.37(m,3H),3.78(s,3H),2.60-2.64(m,2H),1.65-1.74(m,2H),0.90(t,J＝7.3Hz,3H).13C{1H}NMR(100MHz,CDCl3):δ161.9,150.4,131.9,129.1,128.5,127.9,51.6,30.3,21.9,13.7.HRMS(ESI-TOF):m/z calcd for C14H17N2O2[M+H]+245.1284,found:245.1232。
Example 26: the synthesis of 2-n-butyl-5-phenyl-1H-4-carboxylic acid methyl ester (4d) has the following structural formula:
adding 0.3mmol of enamine ester (3d), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 35mg of product, calculated yield 45%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ9.72(b,1H),7.68-7.70(m,2H),7.29-7.34(m,3H),3.75(s,3H),2.56-2.59(m,2H),1.53-1.61(m,2H),1.19-1.29(m,2H),0.81(t,J＝7.47Hz,3H).13C{1H}NMR(100MHz,CDCl3):δ162.1,150.6,143.3,131.6,129.1,128.5,127.9,120.8,51.6,30.4,28.0,22.3,13.7.HRMS(ESI-TOF):m/z calcd for C15H19N2O2[M+H]+259.1441,found:259.1388。
Example 27: synthesis of methyl 2-pentyl-5-phenyl-1H-4-carboxylate (4e), the structural formula of which is specifically as follows:
adding 0.3mmol of enamine ester (3e), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 29mg of product, calculated yield 36%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ7.72-7.74(m,2H),7.30-7.36(m,3H),3.77(s,3H),2.61-2.65(m,2H),1.62-1.69(m,2H),1.23-1.27(m,4H),0.82-0.85(m,3H).13C{1H}NMR(100MHz,CDCl3):δ161.9,150.6,131.9,129.1,128.5,127.9,51.6,31.4,28.4,28.0,22.3,13.9.HRMS(ESI-TOF):m/z calcd for C16H21N2O2[M+H]+273.1597,found:273.1600。
Example 28: synthesis of methyl 2-hexyl-5-phenyl-1H-4-carboxylate (4f), the structural formula is as follows:
0.3mmol of enamine ester (3f), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and after completion of the reaction, 110mL of organic phase (PE: EA. RTM.10: 1) and 50mL of water were added in three portions (5:3:3) in total, and the organic phase was combined after extraction three timesDrying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V)Ethyl acetate∶VPetroleum ether3: 1) to yield 37mg of product, calculated yield 43%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ7.70-7.73(m,2H),7.30-7.36(m,3H),3.77(s,3H),2.60(t,J＝7.9Hz,2H),1.58-1.66(m,2H),1.21-1.27(m,6H),0.82(t,J＝6.7Hz,3H).13C{1H}NMR(100MHz,CDCl3):δ162.0,150.6,131.8,129.9,129.1,128.5,128.2,127.9,51.6,31.4,29.0,28.4,28.3,22.5,14.0.HRMS(ESI-TOF):m/z calcd for C17H23N2O2[M+H]+287.1754,found:287.1757。
Example 29: synthesis of methyl 2-heptyl-5-phenyl-1H-4-carboxylate (4g), having the following specific structural formula:
adding 0.3mmol of enamine ester (3g), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 36mg of product, calculated yield 40%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ7.74-7.76(m,2H),7.33-7.39(m,3H),3.80(s,3H),2.65-2.69(m,2H),1.64-1.71(m,2H),1.21-1.28(m,8H),0.84(t,J＝6.7Hz,1H).13C{1H}NMR(100MHz,CDCl3):δ131.7,150.6,132.9,131.8,130.0,129.1,128.3,128.0,51.7,31.6,29.3,28.9,28.5,28.3,22.6,14.1.HRMS(ESI-TOF):m/z calcd for C18H25N2O2[M+H]+301.1910,found:301.1897。
Example 30: the synthesis of 2-benzyl-5-phenyl-1H-4-carboxylic acid methyl ester (4H) has the following structural formula:
adding 0.3mmol of enamine ester (3h), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 44mg of product, calculated yield 50%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ7.70-7.72(m,2H),7.31-7.37(m,3H),7.22-7.29(m,3H),7.15-7.18(m,2H),4.01(s,2H),3.74(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.8,148.6,136.1,131.5,129.3,129.1,128.9,128.8,128.6,128.0,127.9,127.2,51.6,34.8.HRMS(ESI-TOF):m/z calcd for C18H17N2O2[M+H]+293.1284,found:293.1279。
Example 31: synthesis of methyl 2- (methoxymethyl) -5-phenyl-1H-4-carboxylate (4i), the structural formula of which is specifically as follows:
0.3mmol of enamine ester (3i), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and reactedAdding organic phase 110mL (PE: EA is 10:1) and water 50mL in three times (5:3:3) for three times, extracting for three times, mixing organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 31mg of product, calculated yield 42%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ7.74-7.77(m,2H),7.34-7.40(m,3H),4.56(s,2H),3.81(s,3H),3.42(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.7,146.5,131.3,129.2,129.0,128.7,128.1,127.9,67.6,59.0,51.7.HRMS(ESI-TOF):m/z calcd for C13H15N2O3[M+H]+247.1077,found:247.1072。
Example 32: synthesis of methyl 2- ((benzyloxy) methyl) -5-phenyl-1H-4-carboxylate (4j), having the following specific structural formula:
adding 0.3mmol of enamine ester (3j), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 67mg of product, calculated in 69%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ7.73-7.76(m,2H),7.29-7.40(m,8H),4.63(s,2H),4.57(s,2H),3.81(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.6,146.5,136.9,129.4,129.1,128.7,128.6,128.2,128.1,127.7,73.4,65.3,51.7.HRMS(ESI-TOF):m/z calcd for C19H19N2O3[M+H]+323.1390,found:323.1379。
Example 33: synthesis of methyl 2- (phenoxymethyl) -5-phenyl-1H-4-carboxylate (4k), having the following specific structural formula:
adding 0.3mmol of enamine ester (3k), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 53mg of product, calculated yield 57%.
The main physicochemical properties are as follows:
yellow solid.1H NMR(400MHz,CDCl3):δ7.79-7.81(m,2H),7.38-7.44(m,3H),7.28-7.32(m,2H),5.22(s,2H),3.84(s,3H).13C{1H}NMR(100MHz,CDCl3):δ157.5,129.8,129.1,129.0,128.2,122.1,114.6,63.4,51.9.HRMS(ESI-TOF):m/z calcd for C18H17N2O3[M+H]+309.1233,found:309.1227。
Example 34: synthesis of methyl 2-azidomethyl-5-phenyl-1H-4-carboxylate (4l), the structural formula of which is specifically as follows:
0.3mmol of enamine ester (3l), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and after the reaction was completed, 110mL of organic phase (PE:EA 10:1), 50mL water, extracting for three times, combining organic phases to obtain an extract, drying the extract with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on a crude productEthyl acetate∶VPetroleum ether3: 1) to give 9mg of product, calculated yield 13%.
The main physicochemical properties are as follows:
yellow oil.1H NMR(400MHz,CDCl3):δ87.69-7.72(m,2H),7.34-7.39(m,3H),4.41(s,2H),3.79(s,3H).13C{1H}NMR(100MHz,CDCl3):δ161.8,143.8,130.9,129.1,128.9,128.8,128.1,120.0,51.8,47.5.HRMS(ESI-TOF):m/z calcd for C12H12N5O2[M+H]+258.0985,found:258.0973。
Example 35: synthesis of methyl 2-phenyl-5- (trifluoromethyl) -1H-4-carboxylate (4m), the structural formula is specifically as follows:
adding 0.3mmol of enamine ester (3m), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude productEthyl acetate∶VPetroleum ether3: 1) to yield 71mg of product, calculated yield 83%.
The main physicochemical properties are as follows:
a white solid.1H NMR(400MHz,CDCl3):δ7.94-7.97(m,2H),7.44-7.47(m,3H),4.41(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).13C{1H}NMR(100MHz,CDCl3):δ159.2,147.8,130.6,129.0,127.9,126.3,122.0,119.4,62.3,13.9.HRMS(ESI-TOF):m/z calcd for C13H12F3N2O2[M+H]+285.0845,found:285.0847。
The chemical structures of the enamine esters used as starting materials in examples 1 to 35 are as follows:
Claims (10)
1. a2, 5-substituent group 1H-imidazole-4-carboxylic ester compound has the following structural general formula:
wherein R is1Aryl or trifluoromethyl, R2＝C1-C7Alkyl, phenyl, C1-C6Alkoxy, phenoxy, benzyl or benzyloxy, R3An ester group or a benzoyl group.
2. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 1, wherein R is1Is aryl, and the aryl is phenyl, biphenyl or heterocyclic aryl containing substituent groups.
3. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound according to claim 2, wherein the phenyl group containing a substituent is a phenyl group containing one or more substituents, the biphenyl group is a 4-biphenyl group, and the heterocyclic aryl group is a 2-thienyl group or a 3-thienyl group.
4. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 3, wherein the substituent is alkyl, alkoxy, haloalkyl, nitro, or halo.
5. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 1, wherein R is2Selected from one of the following: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy.
6. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 1, wherein R is3Is an ester group, the ester group is-CO2R, R ═ methyl or ethyl.
7. A method for synthesizing 2, 5-substituent-1H-imidazole-4-carboxylic ester compounds according to any one of claims 1 to 6, which comprises the following steps of taking enamine esters or enaminones and azidotrimethylsilane as raw materials, adding mixed alkali into the raw materials, and carrying out reflux reaction in a solvent to obtain a crude product, wherein the reaction formula is as follows:
the mixed alkali consists of potassium carbonate and sodium acetate, and the molar usage ratio of the enamine ester or enaminone to the azidotrimethylsilane, iodine, the potassium carbonate and the sodium acetate is 1 (2.5-3.5) to (0.8-1.2).
8. The method for synthesizing the 2, 5-substituent-1H-imidazole-4-carboxylic ester compounds according to claim 7, wherein the solvent is N, N-dimethylformamide, and the reflux reaction time is 6-12H.
9. A method for purifying a crude product of a 2, 5-substituent-1H-imidazole-4-carboxylic ester compound is characterized by comprising the following steps: taking the crude product of the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound obtained by the synthesis method of claim 7, and carrying out the following steps (4.5-5.5): (9-11): adding water, petroleum ether and ethyl acetate into the mixture according to the volume ratio of 1 for extraction, extracting for 2-4 times, combining organic phases to obtain an extract, and purifying the extract by silica gel column chromatography, wherein the volume ratio of eluent is (2.8-3.2): 1 petroleum ether-ethyl acetate.
10. The method for purifying the crude 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 9, comprising the following steps of 5: 10:1, adding water, petroleum ether and ethyl acetate for extraction, extracting for 2-4 times, combining organic phases to obtain an extract, purifying the extract by silica gel column chromatography, wherein the volume ratio of the eluent is 3:1 petroleum ether-ethyl acetate.
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Citations (3)
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| CN104529809A (en) * | 2014-10-10 | 2015-04-22 | 浙江大学 | Preparation method polysubstituted imidazole derivatives |
| CN104844518A (en) * | 2015-04-08 | 2015-08-19 | 浙江大学 | Preparation method of 2,4,5-trisubstituted imidazole compound |
| CN109020860A (en) * | 2018-09-25 | 2018-12-18 | 宝鸡文理学院 | A kind of 2- aryl -3- ester group polysubstituted pyrrole class compound and its method for synthesizing and refining |
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| CN104529809A (en) * | 2014-10-10 | 2015-04-22 | 浙江大学 | Preparation method polysubstituted imidazole derivatives |
| CN104844518A (en) * | 2015-04-08 | 2015-08-19 | 浙江大学 | Preparation method of 2,4,5-trisubstituted imidazole compound |
| CN109020860A (en) * | 2018-09-25 | 2018-12-18 | 宝鸡文理学院 | A kind of 2- aryl -3- ester group polysubstituted pyrrole class compound and its method for synthesizing and refining |
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| "CAS号36783-90-1等", STN REGISTRY, pages 1 - 3 * |
| HAICHAO MA ET AL.: "A Domino Azidation/C−H Amination Approach toward Trifluoromethyl Substituted Imidazoles", J. ORG. CHEM., vol. 82, pages 11841 - 11847 * |
| KANG XU ET AL.: "Hypervalent iodane mediated reactions of N-acetyl enamines for the synthesis of oxazoles and imidazoles", ORG. BIOMOL. CHEM., vol. 17, pages 8977 - 8981 * |
| S. YUGANDAR ET AL.: "One-Pot Synthesis of 2, 4, 5-Trisubstituted Imidazoles via [2 + 2 + 1] Cycloannulation of 1, 3-Bishet(aryl)-monothio-1, 3-diketones, α-Substituted Methylamines and Sodium Nitrite through α-Nitrosation of Enaminones", J. ORG. CHEM., vol. 81, pages 5606, XP055795776, DOI: 10.1021/acs.joc.6b00938 * |
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