CN112759551B - 2, 5-substituent 1H-imidazole-4-carboxylate compound and synthetic purification method thereof - Google Patents
2, 5-substituent 1H-imidazole-4-carboxylate compound and synthetic purification method thereof Download PDFInfo
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- 238000000746 purification Methods 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 12
- -1 enamine compound Chemical class 0.000 claims abstract description 58
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 41
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011630 iodine Substances 0.000 claims abstract description 5
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 5
- 239000007800 oxidant agent Substances 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 110
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 85
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 80
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 76
- 239000012074 organic phase Substances 0.000 claims description 74
- 239000003208 petroleum Substances 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 40
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 39
- 239000001632 sodium acetate Substances 0.000 claims description 39
- 235000017281 sodium acetate Nutrition 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 38
- 238000010898 silica gel chromatography Methods 0.000 claims description 37
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims description 37
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 36
- 238000010992 reflux Methods 0.000 claims description 34
- 238000000605 extraction Methods 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 238000001308 synthesis method Methods 0.000 claims description 9
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 235000010290 biphenyl Nutrition 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
- 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
- 150000002367 halogens Chemical group 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
- 239000002994 raw material Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 claims 2
- GTZZAXOPIHHUQI-UHFFFAOYSA-N 4H-imidazole-4-carboxylic acid Chemical compound N=1C=NC(C=1)C(=O)O GTZZAXOPIHHUQI-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 35
- 238000005481 NMR spectroscopy Methods 0.000 description 35
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 239000000047 product Substances 0.000 description 35
- 238000001914 filtration Methods 0.000 description 32
- 238000001035 drying Methods 0.000 description 29
- 239000007787 solid Substances 0.000 description 24
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 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
- 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 2
- 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 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
- 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 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
- 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 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
- 230000007547 defect Effects 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
- 238000003818 flash chromatography Methods 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
- 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 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 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
- 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
- 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000000543 intermediate 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
- 238000002156 mixing Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 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
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- 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, wherein iodine is used as an oxidant to promote the oxidation cyclization reaction of an enamine compound, 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 acid 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-carboxylate compound and a synthesis and purification method thereof.
Background
Imidazole compounds are special five-membered nitrogen heterocyclic compounds, and are widely applied in the medicine field, ligand chemistry and material science due to the special heterocyclic skeleton (org. Lett.2020,22, 1980-1984). 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 a new corner in coordination chemistry and is widely used to construct the Metal Organic Framework (MOF) of interest (org. Lett.2019,21, 9874-9877). Prior to this, transition metal catalyzed and transition metal free catalyzed processes have been greatly advanced, with no transition metal participating reactions being environmentally friendly (org. Lett.2019,21, 9874-9877). However, the current imidazole synthesis method still has the defects that most reactions still need participation of transition metals and complex composite substrates are needed for the substrates, and the synthesis cost is high, so that it is not enough to find an efficient, simple and low-cost synthesis method.
Disclosure of Invention
In view of the defects existing in the prior art, the inventor establishes a simple and practical preparation method of 2, 5-substituent-1H-imidazole-4-carboxylic acid ester through a large number of experiments, and synthesizes a series of compounds 2, 5-substituent-1H-imidazole-4-carboxylic acid ester with novel structures.
Based on the experimental results of the inventor, the first aim of the invention is to provide a series of 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compounds, the structural general formula is as follows:
wherein R is 1 =aryl or trifluoromethyl, R 2 ＝C 1 -C 7 Alkyl, phenyl, C 1 -C 6 Alkoxy, phenoxy, benzyl or benzyloxy, R 3 =ester group or benzoyl group.
Further preferred are 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compounds as described above wherein R 1 The aryl is phenyl, biphenyl or heterocyclic aryl containing substituent groups. The phenyl containing substituent groups 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.
Further preferred are 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compounds as described above wherein R 2 Selected from one of the following: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy.
Further preferred is the esterification of 2, 5-substituent-1H-imidazole-4-carboxylic acid as described aboveCompounds, wherein R 3 Is an ester group, the ester group is-CO 2 R, r=methyl or ethyl.
In addition, a second object of the present invention is to provide a method for synthesizing the above 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound, which uses enamine ester or enamine ketone compound and azido trimethylsilane as raw materials, uses iodine as oxidant, adds mixed alkali, and reflux-reacts in solvent to obtain crude product, the reaction formula is as follows:
the mixed alkali consists of potassium carbonate and sodium acetate, wherein: the molar ratio of enamine ester or enamine ketone to azido trimethyl silane to iodine to potassium carbonate to sodium acetate is 1 (2.5-3.5) (0.8-1.2), preferably 1:3:3:3:1.
Further preferably, the synthesis method of the 2, 5-substituent-1H-imidazole-4-carboxylic acid 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 method for purifying the crude 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound, which comprises the following steps: taking the crude product of the 2, 5-diphenyl 1H-imidazole-4-carboxylate obtained by the synthesis method, and mixing according to the following steps of (4.5-5.5): (9-11): 1, adding water, petroleum ether and ethyl acetate into the mixture in a volume ratio for extraction, combining organic phases after 2 to 4 times of extraction to obtain an extract, purifying the extract by silica gel column chromatography, wherein the volume ratio of eluent is (2.8 to 3.2): 1 petroleum ether-ethyl acetate.
Further preferably, the above purification method is carried out according to 5:10: adding water, petroleum ether and ethyl acetate into the mixture according to the volume ratio of 1 for extraction, merging organic phases after 2-4 times of extraction to obtain an extract, and purifying the extract by silica gel column chromatography, wherein the volume ratio of eluent is 3:1 petroleum ether-ethyl acetate.
Compared with the prior art, the method creatively uses iodine as an oxidant to promote the oxidation cyclization reaction of the enamine compound, so that the operation for preparing the 2, 5-substituent-1H-imidazole-4-carboxylate is simple, the preparation cost is greatly reduced, the relative yield and purity are higher, the environmental pollution is less, the ideal effect is obtained, and the method is one of the most direct and efficient methods for synthesizing the 2, 5-substituent-1H-imidazole-4-carboxylate reported at present. In addition, the 2, 5-substituent-1H-imidazole-4-carboxylate 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 the technical solutions of the present invention are further described, but the scope of the present invention is not limited to these examples. All changes and equivalents that do not depart from the gist of the invention are intended to be within the scope of the invention.
Example 1: the synthesis of 2, 5-diphenyl-1H-imidazole-4-carboxylic acid methyl ester (2 a) has the following structural formula:
0.3mmol of enamine ester (1 a), 0.9mmol of azidometrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate are added to 6mL of N, N-dimethylformamide, the mixture is refluxed for 12h, after the reaction is finished, 110mL of organic phase (PE: EA=10:1, PE is petroleum ether, EA is ethyl acetate) is added in three times (5:3:3), 50mL of water is added, the organic phases are combined after three times of extraction, the extract is obtained, anhydrous sodium sulfate is dried, the mixture is filtered, the mixture is concentrated under reduced pressure, and the crude product is subjected to flash silica gel column chromatography (V) Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 71mg of product, calculated as 85% yield.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):δ7.92-7.95(m,2H),7.84-7.86(m,2H),7.36-7.45(m,6H),3.84(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 17 H 15 N 2 O 2 [M+H] + 279.1128,found:279.1131。
Example 2: the synthesis of 2-phenyl-5- (p-tolyl) -1H-imidazole-4-carboxylic acid methyl ester (2 b) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 b), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 61mg of product, calculated as 70%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 17 N 2 O 2 [M+H] + 293.1285,found:293.1291。
Example 3 Synthesis of 2-phenyl-5- (m-tolyl) -1H-imidazole-4-carboxylic acid methyl ester (2 c) having the following structural formula:
0.3mmol of enamine ester (1 c), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate are added to 6mL of N, N-dimethylformamide and refluxedAfter the reaction was completed for 12h, 110mL (PE: ea=10:1) of the organic phase was added in total for three times (5:3:3), 50mL of water was added, the organic phases were combined after three times of extraction, the extract was obtained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 60mg of product, calculated as 68%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 17 N 2 O 2 [M+H] + 293.1285,found:293.1281。
Example 4: the synthesis of 2-phenyl-5- (o-tolyl) -1H-imidazole-4-carboxylic acid methyl ester (2 d) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 d), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 33mg of product, calculated as 38%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 17 N 2 O 2 [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 (2 e) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 e), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 73mg of product, calculated as 80%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 19 H 19 N 2 O 2 [M+H] + 307.1441,found:307.1452。
Example 6: the synthesis of 2-phenyl-5- (p-methoxyphenyl) -1H-imidazole-4-carboxylic acid methyl ester (2 f) has the following specific structural formula:
0.3mmol of enamine ester (1 f), 0.9mmol of azido trimethylsilane, 0.9mmol of iodine, 0.9mol of carbonAdding potassium acetate and 0.3mmol sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in total for three times (5:3:3) after the reaction, extracting for three times with 50mL of water, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash column chromatography (V) on the crude product Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 62mg of product, calculated as 67%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ.HRMS(ESI-TOF):m/z calcd for C 18 H 17 N 2 O 3 [M+H] + 309.1233,found:309.1240。
Example 7: synthesis of methyl 2-phenyl-5- (m-methoxyphenyl) -1H-imidazole-4-carboxylate (2 g) with the following structural formula:
0.3mmol of enamine ester (1 g), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate are added to 6mL of N, N-dimethylformamide, the mixture is refluxed for 12h, after the reaction is finished, 110mL of organic phase (PE: EA=10:1) is added in three times (5:3:3), 50mL of water is added, the organic phases are combined after three times of extraction, the extract is obtained, dried over anhydrous sodium sulfate, concentrated under reduced pressure after filtration, and the crude product is subjected to flash silica gel column chromatography (V) Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 53mg of product, calculated as 57%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 17 N 2 O 3 [M+H] + 309.1233,found:309.1241。
Example 8: the synthesis of 2-phenyl-5- (3, 4-dimethoxy phenyl) -1H-imidazole-4-carboxylic acid methyl ester (2H) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 h), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 82mg of product, calculated as 81%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 19 H 19 N 2 O 4 [M+H] + 339.1339,found:339.1356。
Example 9: the synthesis of 2-phenyl-5- (p-fluorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2 i) has the following specific structural formula:
0.3mmol of enamine ester (1 i), 0.9mmol of azido trimethylsilane, 0.9mmol of iodine,0.9mol of potassium carbonate and 0.3mmol of sodium acetate are added into 6mL of N, N-dimethylformamide, reflux is carried out for 12h, after the reaction is finished, 110mL of an organic phase (PE: EA=10:1) is added in three times (5:3:3) in total, 50mL of water is added, the organic phases are combined after three times of extraction, an extract is obtained, anhydrous sodium sulfate is dried, filtered, reduced pressure is carried out, and the crude product is subjected to flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 54mg of product, calculated to yield 61%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):δ7.92-7.96(m,4H),7.43-7.49(m,3H),7.08-7.13(m,2H),7.87(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 17 H 14 FN 2 O 2 [M+H] + 297.1033,found:297.1052。
Example 10: the synthesis of 2-phenyl-5- (p-chlorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2 j) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 j), 0.9mmol of azido-trimethylsilane, 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 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 70mg of product, calculated as 75%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):δ7.93-7.95(m,4H),7.43-7.47(m,3H),7.37-7.40(m,2H),3.87(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ134.6,130.6,130.1,129.0,128.6,128.2,125.9,52.HRMS(ESI-TOF):m/z calcd for C 17 H 14 ClN 2 O 2 [M+H] + 313.0738,found:313.0747。
Example 11: the synthesis of 2-phenyl-5- (m-chlorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2 k) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 k), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 64mg of product, calculated as 68%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 17 H 14 ClN 2 O 2 [M+H] + 313.0738,found:313.0742。
Example 12: synthesis of methyl 2-phenyl-5- (p-bromophenyl) -1H-imidazole-4-carboxylate (2 l) has the following structural formula:
0.3mmol of enamine ester (1 l), 0.9mmol of azido trimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and0.3mmol of sodium acetate is added into 6mL of N, N-dimethylformamide, reflux is carried out for 12h, after the reaction is finished, 110mL of an organic phase (PE: EA=10:1) is added in three times (5:3:3) in total, 50mL of water is added, the organic phases are combined after three times of extraction, an extract is obtained, anhydrous sodium sulfate is dried, and after filtration, decompression concentration is carried out, and the crude product is subjected to flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 74mg of product, calculated as 69%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 17 H 13 NaBrN 2 O 2 [M+Na] + 379.0052,found:379.0059。
Example 13: the synthesis of 2-phenyl-5- (p-trifluoromethylphenyl) -1H-imidazole-4-carboxylic acid methyl ester (2 m) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 m), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 77mg of the product, calculated as 74% yield.
The main physicochemical properties are as follows:
white solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ160.6,147.9,130.5,130.3,130.2,129.6,129.1,128.4,126.2,126.0,125.5,124.9(J C-F ＝3.81Hz),122.8,52.1.HRMS(ESI-TOF):m/z calcd for C 18 H 14 F 3 N 2 O 2 [M+H] + 347.1001,found:347.1004。
Example 14: the synthesis of 2-phenyl-5- (thiophen-2-yl) -1H-imidazole-4-carboxylic acid methyl ester (2 n) has the following specific structural formula:
adding 0.3mmol of enamine ester (1N), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 57mg of product, calculated as 67%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 15 H 13 N 2 O 2 S[M+H] + 285.0692,found:285.0712。
Example 15: the synthesis of 2-phenyl-5- (thiophen-3-yl) -1H-imidazole-4-carboxylic acid methyl ester (2 o) has the following specific structural formula:
0.3mmol of enamine ester (1 o), 0.9mmol of azideThe preparation method comprises the steps of adding methyltrimethylsilane, 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 110mL of an organic phase (PE: EA=10:1) into the mixture three times (5:3:3) after the reaction is finished, extracting 50mL of water three times, combining the organic phases to obtain an extract, drying the extract by anhydrous sodium sulfate, filtering, concentrating the extract under reduced pressure, and performing flash silica gel column chromatography on the crude product (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 63mg of product, calculated as 74% yield.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 15 H 13 N 2 O 2 S[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 (2 p) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 p), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 72mg of product, calculated as 68%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 23 H 19 N 2 O 2 [M+H] + 355.1441,found:355.1454。
Example 17: the synthesis of 5- (naphthalene-4-yl) -2-phenyl-1H-imidazole-4-carboxylic acid methyl ester (2 q) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 q), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 47mg of product, calculated as 48% yield.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 21 H 17 N 2 O 2 [M+H] + 329.1284,found:329.1293。
Example 18: the synthesis of 2, 5-diphenyl-1H-imidazole-4-carboxylic acid ethyl ester (2 r) has the following structural formula:
adding 0.3mmol of enamine ester (1 r), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 70mg of product, calculated as 80%.
The main physicochemical properties are as follows:
white solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 17 N 2 O 2 [M+H] + 293.1284,found:293.1289。
Example 19: the synthesis of 5- (4-nitrophenyl) -2-phenyl-1H-imidazole-4-carboxylic acid ethyl ester (2 s) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 s), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 35mg of product, calculated as 35% yield.
The main physicochemical properties are as follows:
yellow solid. H NMR (400 MHz, 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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 16 N 3 O 4 [M+H] + 338.1135,found:338.1142。
Example 20: the synthesis of 2-phenyl-5- (trifluoromethyl) -1H-imidazole-4-carboxylic acid ethyl ester (2 t) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 t), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 56mg of product, calculated as 58% yield.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 22 H 17 N 2 O[M+H] + 325.1341,found:308.1394。
Example 21: the synthesis of (2, 5-diphenyl-1H-imidazol-4-yl) (phenyl) methanone (2 u) has the following specific structural formula:
adding 0.3mmol of enamine ester (1 u), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 56mg of product, calculated as 58% yield.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 22 H 17 N 2 O[M+H] + 325.1341,found:308.1394。
Example 22: the synthesis of 2-phenylchromium [3,4-d ] imidazole-4 (1H) -ketone (2 v) has the following structural formula:
adding 0.3mmol of enamine ester (1V), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography on the crude product (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 67mg of product, calculated as 85% yield.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,DMSO-d 6 ):δ13.81(b,1H),8.07-8.17(m,3H),7.38-7.55(m,6H). 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):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 C 16 H 10 N 2 O 2 [M+H] + 263.0815,found:263.0811。
Example 23: the synthesis of 2-methyl-5-phenyl-1H-4-carboxylic acid methyl ester (4 a) has the following specific structural formula:
adding 0.3mmol of enamine ester (3 a), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 33mg of product, calculated as 51%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ10.27(b,1H),7.66-7.68(m,2H),7.29-7.33(m,3H),3.74(s,3H),2.25(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 12 H 13 N 2 O 2 [M+H] + 217.0971,found:217.0967。
Example 24: the synthesis of 2-ethyl-5-phenyl-1H-4-carboxylic acid methyl ester (4 b) has the following structural formula:
adding 0.3mmol of enamine ester (3 b), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 35mg of product, calculated as 51%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 13 H 15 N 2 O 2 [M+H] + 231.1128,found:231.1127。
Example 25: the synthesis of 2-propyl-5-phenyl-1H-4-carboxylic acid methyl ester (4 c) has the following structural formula:
adding 0.3mmol of enamine ester (3 c), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 30mg of product, calculated as 41%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 14 H 17 N 2 O 2 [M+H] + 245.1284,found:245.1232。
Example 26: the synthesis of 2-n-butyl-5-phenyl-1H-4-carboxylic acid methyl ester (4 d) has the following specific structural formula:
adding 0.3mmol of enamine ester (3 d), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 35mg of product, calculated as 45%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 15 H 19 N 2 O 2 [M+H] + 259.1441,found:259.1388。
Example 27: the synthesis of 2-amyl-5-phenyl-1H-4-carboxylic acid methyl ester (4 e) has the following specific structural formula:
adding 0.3mmol of enamine ester (3 e), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 29mg of product, calculated as 36%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 16 H 21 N 2 O 2 [M+H] + 273.1597,found:273.1600。
Example 28: the synthesis of 2-hexyl-5-phenyl-1H-4-carboxylic acid methyl ester (4 f) has the following specific structural formula:
adding 0.3mmol of enamine ester (3 f), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 37mg of product, calculated as 43%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 17 H 23 N 2 O 2 [M+H] + 287.1754,found:287.1757。
Example 29: synthesis of methyl 2-heptyl-5-phenyl-1H-4-carboxylate (4 g) having the following structural formula:
0.3mmol of enamine ester (3 g), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate are added to 6mL of N, N-dimethylformamide, the mixture is refluxed for 12h, after the reaction is finished, 110mL of organic phase (PE: EA=10:1) is added in three times (5:3:3), 50mL of water is added, the organic phases are combined after three times of extraction, the extract is obtained, dried over anhydrous sodium sulfate, concentrated under reduced pressure after filtration, and the crude product is subjected to flash silica gel column chromatography (V) Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 36mg of product, calculated as 40%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 25 N 2 O 2 [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 (3 h), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 44mg of product, calculated as 50% yield.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 17 N 2 O 2 [M+H] + 293.1284,found:293.1279。
Example 31: the synthesis of 2- (methoxymethyl) -5-phenyl-1H-4-carboxylic acid methyl ester (4 i) has the following structural formula:
adding 0.3mmol of enamine ester (3 i), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 31mg of product, calculated as 42%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ7.74-7.77(m,2H),7.34-7.40(m,3H),4.56(s,2H),3.81(s,3H),3.42(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 13 H 15 N 2 O 3 [M+H] + 247.1077,found:247.1072。
Example 32: synthesis of methyl 2- ((benzyloxy) methyl) -5-phenyl-1H-4-carboxylate (4 j) has the following specific structural formula:
adding 0.3mmol of enamine ester (3 j), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 67mg of product, calculated as 69%.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ7.73-7.76(m,2H),7.29-7.40(m,8H),4.63(s,2H),4.57(s,2H),3.81(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 19 H 19 N 2 O 3 [M+H] + 323.1390,found:323.1379。
Example 33: the synthesis of 2- (phenoxymethyl) -5-phenyl-1H-4-carboxylic acid methyl ester (4 k) has the following structural formula:
adding 0.3mmol of enamine ester (3 k), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 53mg of product, calculated as 57%.
The main physicochemical properties are as follows:
yellow solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 18 H 17 N 2 O 3 [M+H] + 309.1233,found:309.1227。
Example 34: synthesis of methyl 2-azidomethyl-5-phenyl-1H-4-carboxylate (4 l) with the following structural formula:
adding 0.3mmol of enamine ester (3 l), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 9mg of product, calculated as 13% yield.
The main physicochemical properties are as follows:
as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ87.69-7.72(m,2H),7.34-7.39(m,3H),4.41(s,2H),3.79(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 12 H 12 N 5 O 2 [M+H] + 258.0985,found:258.0973。
Example 35: the synthesis of 2-phenyl-5- (trifluoromethyl) -1H-4-carboxylic acid methyl ester (4 m) has the following structural formula:
adding 0.3mmol of enamine ester (3 m), 0.9mmol of azido-trimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate to 6mL of N, N-dimethylformamide, refluxing for 12h, adding 110mL of organic phase (PE: EA=10:1) in three times (5:3:3) after the reaction is finished, extracting with 50mL of water for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V Acetic acid ethyl ester ∶V Petroleum ether =3:1), purification gave 71mg of product, calculated as 83%.
The main physicochemical properties are as follows:
white solid. 1 H NMR(400MHz,CDCl 3 ):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). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):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 C 13 H 12 F 3 N 2 O 2 [M+H] + 285.0845,found:285.0847。
The chemical structures of the enamine esters used as starting materials in examples 1 to 35 above were as follows:
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Claims (5)
1.2, 5-substituent-1HThe synthesis method of the imidazole-4-carboxylic ester compound is characterized in that enamine ester or enamine ketone compound and azido trimethylsilane are used as raw materials, iodine is used as an oxidant, mixed alkali is added, reflux reaction is carried out in a solvent to obtain a crude product, the mixed alkali consists of potassium carbonate and sodium acetate, and the molar use ratio of enamine ester or enamine ketone to azido trimethylsilane, iodine, potassium carbonate and sodium acetate is 1 (2.5-3.5) (0.8-1.2);
the reaction formula of the synthesis method is as follows:
；
wherein:
R 1 aryl or trifluoromethyl, wherein the aryl is phenyl, biphenyl or heterocyclic aryl containing substituents; the phenyl containing substituent groups is phenyl containing one or more substituent groups, and the substituent groups are alkyl, alkoxy, halogenated alkyl, nitro and halogen substituent groups; the biphenyl is 4-biphenyl; the heterocyclic aryl is 2-thienyl or 3-thienyl;
R 2 =C 1 -C 7 alkyl, phenyl, C 1 -C 6 Alkoxy, phenoxy, benzyl or benzyloxy;
R 3 =ester group or benzoyl group, the ester group being-CO 2 R, r=methyl or ethyl.
2. 2, 5-substituent-1 according to claim 1HThe synthesis method of the imidazole-4-carboxylate compound is characterized in that R 2 Selected from one of the following: methyl group, ethyl group,propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy.
3.2, 5-substituent-1 according to claim 1HThe synthesis method of the imidazole-4-carboxylate compound is characterized in that the solvent isN,NDimethylformamide, reflux reaction time is 6-12h.
4. 2, 5-substituent-1 according to claim 1H-a process for the synthesis of imidazole-4-carboxylic acid esters, characterized in that it further comprises a purification step: crude product was taken as (4.5-5.5): (9-11): 1, adding water, petroleum ether and ethyl acetate into the mixture in a volume ratio for extraction, combining organic phases after 2 to 4 times of extraction to obtain an extract, purifying the extract by silica gel column chromatography, wherein the volume ratio of eluent is (2.8 to 3.2): 1 petroleum ether-ethyl acetate.
5. The 2, 5-substituent-1 of claim 4H-imidazole-4-carboxylic acid ester compound synthesis method according to 5:10: adding water, petroleum ether and ethyl acetate into the mixture according to the volume ratio of 1 for extraction, merging organic phases after 2-4 times of extraction to obtain an extract, and purifying the extract by silica gel column chromatography, wherein the volume ratio of eluent is 3:1 petroleum ether-ethyl acetate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (4)
| Title |
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| A Domino Azidation/C−H Amination Approach toward Trifluoromethyl Substituted Imidazoles;Haichao Ma et al.;J. Org. Chem.;第82卷;第11841-11847页 * |
| CAS号36783-90-1等.STN REGISTRY.2019,第1-3页. * |
| Hypervalent iodane mediated reactions of N-acetyl enamines for the synthesis of oxazoles and imidazoles;Kang Xu et al.;Org. Biomol. Chem.;第17卷;第8977-8981页 * |
| 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. .2016,第81卷第5606−5622页. * |
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