CN114560837A - Chromone compound and preparation method and application thereof - Google Patents
Chromone compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN114560837A CN114560837A CN202210121098.0A CN202210121098A CN114560837A CN 114560837 A CN114560837 A CN 114560837A CN 202210121098 A CN202210121098 A CN 202210121098A CN 114560837 A CN114560837 A CN 114560837A
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- CN
- China
- Prior art keywords
- formula
- reaction
- ethyl acetate
- chromone
- group
- Prior art date
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- -1 Chromone compound Chemical class 0.000 title claims abstract description 169
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 114
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims description 48
- SMQUZDBALVYZAC-UHFFFAOYSA-N ortho-hydroxybenzaldehyde Natural products OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 37
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 25
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 24
- 239000010948 rhodium Substances 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000003172 aldehyde group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000004185 ester group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 150000004777 chromones Chemical class 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052741 iridium Inorganic materials 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052723 transition metal Inorganic materials 0.000 claims description 5
- 150000003624 transition metals Chemical class 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 239000003963 antioxidant agent Substances 0.000 claims 1
- 230000003078 antioxidant effect Effects 0.000 claims 1
- 235000006708 antioxidants Nutrition 0.000 claims 1
- 150000002390 heteroarenes Chemical class 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 365
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 108
- 239000012074 organic phase Substances 0.000 description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
- 238000004440 column chromatography Methods 0.000 description 43
- 238000003786 synthesis reaction Methods 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 42
- 238000010791 quenching Methods 0.000 description 42
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 41
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- 238000012512 characterization method Methods 0.000 description 39
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 39
- 239000012071 phase Substances 0.000 description 37
- NEUPUPPESCHLPS-UHFFFAOYSA-N 2-(2,2-difluoroethenyl)-4-methylbenzenesulfonic acid Chemical compound Cc1ccc(c(C=C(F)F)c1)S(O)(=O)=O NEUPUPPESCHLPS-UHFFFAOYSA-N 0.000 description 26
- LGVUAXNPXVXCCW-UHFFFAOYSA-M cesium;2,2-dimethylpropanoate Chemical compound [Cs+].CC(C)(C)C([O-])=O LGVUAXNPXVXCCW-UHFFFAOYSA-M 0.000 description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 description 21
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 20
- 239000000920 calcium hydroxide Substances 0.000 description 20
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 20
- 238000004293 19F NMR spectroscopy Methods 0.000 description 18
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 18
- 238000001035 drying Methods 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- IPPQNXSAJZOTJZ-UHFFFAOYSA-N 3-methylsalicylaldehyde Chemical compound CC1=CC=CC(C=O)=C1O IPPQNXSAJZOTJZ-UHFFFAOYSA-N 0.000 description 7
- FZHSPPYCNDYIKD-UHFFFAOYSA-N 5-methoxysalicylaldehyde Chemical compound COC1=CC=C(O)C(C=O)=C1 FZHSPPYCNDYIKD-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- YZVFSQQHQPPKNX-UHFFFAOYSA-N 1,3-thiazole-5-carboxylic acid Chemical compound OC(=O)C1=CN=CS1 YZVFSQQHQPPKNX-UHFFFAOYSA-N 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- IDPIOFMWCNXVBA-UHFFFAOYSA-N 2-(2,2,2-trifluoroethoxy)chromen-4-one Chemical compound FC(COC=1OC2=C(C(C1)=O)C=CC=C2)(F)F IDPIOFMWCNXVBA-UHFFFAOYSA-N 0.000 description 4
- JODRRPJMQDFCBJ-UHFFFAOYSA-N 2-Hydroxy-4-methylbenzaldehyde Chemical compound CC1=CC=C(C=O)C(O)=C1 JODRRPJMQDFCBJ-UHFFFAOYSA-N 0.000 description 4
- NTCCNERMXRIPTR-UHFFFAOYSA-N 2-hydroxy-1-naphthaldehyde Chemical compound C1=CC=CC2=C(C=O)C(O)=CC=C21 NTCCNERMXRIPTR-UHFFFAOYSA-N 0.000 description 4
- ILEIUTCVWLYZOM-UHFFFAOYSA-N 2-hydroxy-5-methylbenzaldehyde Chemical compound CC1=CC=C(O)C(C=O)=C1 ILEIUTCVWLYZOM-UHFFFAOYSA-N 0.000 description 4
- IHFRMUGEILMHNU-UHFFFAOYSA-N 2-hydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC=C([N+]([O-])=O)C=C1C=O IHFRMUGEILMHNU-UHFFFAOYSA-N 0.000 description 4
- ROILLNJICXGZQQ-UHFFFAOYSA-N 3-tert-butyl-2-hydroxybenzaldehyde Chemical compound CC(C)(C)C1=CC=CC(C=O)=C1O ROILLNJICXGZQQ-UHFFFAOYSA-N 0.000 description 4
- QNZWAJZEJAOVPN-UHFFFAOYSA-N 4-chloro-2-hydroxybenzaldehyde Chemical compound OC1=CC(Cl)=CC=C1C=O QNZWAJZEJAOVPN-UHFFFAOYSA-N 0.000 description 4
- MKKSTJKBKNCMRV-UHFFFAOYSA-N 5-bromo-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(Br)C=C1C=O MKKSTJKBKNCMRV-UHFFFAOYSA-N 0.000 description 4
- FUGKCSRLAQKUHG-UHFFFAOYSA-N 5-chloro-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(Cl)C=C1C=O FUGKCSRLAQKUHG-UHFFFAOYSA-N 0.000 description 4
- FDUBQNUDZOGOFE-UHFFFAOYSA-N 5-fluoro-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(F)C=C1C=O FDUBQNUDZOGOFE-UHFFFAOYSA-N 0.000 description 4
- BGGDEYLNSNKIGJ-UHFFFAOYSA-N CC1=C(C(C(F)F)O)C2=CC(C)=CC=C2N1 Chemical compound CC1=C(C(C(F)F)O)C2=CC(C)=CC=C2N1 BGGDEYLNSNKIGJ-UHFFFAOYSA-N 0.000 description 4
- JBYBJRNVSDFUMS-UHFFFAOYSA-N OC(C(F)F)C1=CNC2=C1C(C=O)=CC=C2 Chemical compound OC(C(F)F)C1=CNC2=C1C(C=O)=CC=C2 JBYBJRNVSDFUMS-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- LBZHVONZEAUDNM-UHFFFAOYSA-N benzo[h]chromen-4-one Chemical compound C1=CC=CC2=CC=C3C(=O)C=COC3=C21 LBZHVONZEAUDNM-UHFFFAOYSA-N 0.000 description 4
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 4
- 125000004438 haloalkoxy group Chemical group 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OITQDWKMIPXGFL-UHFFFAOYSA-N 1-hydroxy-2-naphthaldehyde Chemical compound C1=CC=C2C(O)=C(C=O)C=CC2=C1 OITQDWKMIPXGFL-UHFFFAOYSA-N 0.000 description 3
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 3
- ABPAKMJTQTVEDR-UHFFFAOYSA-N 2-(trifluoromethyl)chromen-4-one Chemical compound C1=CC=C2OC(C(F)(F)F)=CC(=O)C2=C1 ABPAKMJTQTVEDR-UHFFFAOYSA-N 0.000 description 3
- WQUZBERVMUEJTD-UHFFFAOYSA-N 2-hydroxy-5-(trifluoromethoxy)benzaldehyde Chemical compound OC1=CC=C(OC(F)(F)F)C=C1C=O WQUZBERVMUEJTD-UHFFFAOYSA-N 0.000 description 3
- DCYKYFMFAFQHSE-UHFFFAOYSA-N 3-(3-formyl-4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CC1=CC=C(O)C(C=O)=C1 DCYKYFMFAFQHSE-UHFFFAOYSA-N 0.000 description 3
- HAGUMWGXABFJMN-UHFFFAOYSA-N 3-methyl-2-nitrobenzaldehyde Chemical compound CC1=CC=CC(C=O)=C1[N+]([O-])=O HAGUMWGXABFJMN-UHFFFAOYSA-N 0.000 description 3
- XFVZSRRZZNLWBW-UHFFFAOYSA-N 4-(Diethylamino)salicylaldehyde Chemical compound CCN(CC)C1=CC=C(C=O)C(O)=C1 XFVZSRRZZNLWBW-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- ZVCQQLGWGRTXGC-UHFFFAOYSA-N 5-tert-butyl-2-hydroxybenzaldehyde Chemical compound CC(C)(C)C1=CC=C(O)C(C=O)=C1 ZVCQQLGWGRTXGC-UHFFFAOYSA-N 0.000 description 3
- WQNTWZJPCLUXQC-UHFFFAOYSA-N 5-tert-butyl-2-hydroxybenzene-1,3-dicarbaldehyde Chemical compound CC(C)(C)C1=CC(C=O)=C(O)C(C=O)=C1 WQNTWZJPCLUXQC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- JEUUNKOFKDUVMN-UHFFFAOYSA-N benzo[f]chromen-1-one Chemical compound C1=CC=CC2=C3C(=O)C=COC3=CC=C21 JEUUNKOFKDUVMN-UHFFFAOYSA-N 0.000 description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- ADSJCWKOKYOJSZ-UHFFFAOYSA-N methyl 3-formyl-4-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(O)C(C=O)=C1 ADSJCWKOKYOJSZ-UHFFFAOYSA-N 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- IGKCQDUYZULGBM-UHFFFAOYSA-N 2,2,2-trifluoroethyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCC(F)(F)F)C=C1 IGKCQDUYZULGBM-UHFFFAOYSA-N 0.000 description 2
- QQKOGOQVUNOPMS-UHFFFAOYSA-N 2-hydroxy-4-methyl-3-nitrobenzaldehyde Chemical compound Cc1ccc(C=O)c(O)c1[N+]([O-])=O QQKOGOQVUNOPMS-UHFFFAOYSA-N 0.000 description 2
- VVPNFGSOEZZIAM-UHFFFAOYSA-N 6-(trifluoromethoxy)chromen-4-one Chemical compound O1C=CC(=O)C2=CC(OC(F)(F)F)=CC=C21 VVPNFGSOEZZIAM-UHFFFAOYSA-N 0.000 description 2
- XVNBWGGBXOJIDR-UHFFFAOYSA-N 6-bromochromen-4-one Chemical compound O1C=CC(=O)C2=CC(Br)=CC=C21 XVNBWGGBXOJIDR-UHFFFAOYSA-N 0.000 description 2
- VFZQATFTQAZCMO-UHFFFAOYSA-N 6-chlorochromen-4-one Chemical compound O1C=CC(=O)C2=CC(Cl)=CC=C21 VFZQATFTQAZCMO-UHFFFAOYSA-N 0.000 description 2
- WHIGSYZUTMYUAX-UHFFFAOYSA-N 6-fluorochromen-4-one Chemical compound O1C=CC(=O)C2=CC(F)=CC=C21 WHIGSYZUTMYUAX-UHFFFAOYSA-N 0.000 description 2
- HTXQVFXXVXOLCF-UHFFFAOYSA-N 6-methylchromen-4-one Chemical compound O1C=CC(=O)C2=CC(C)=CC=C21 HTXQVFXXVXOLCF-UHFFFAOYSA-N 0.000 description 2
- ORWADBVBOPTYQT-UHFFFAOYSA-N 6-nitrochromen-4-one Chemical compound O1C=CC(=O)C2=CC([N+](=O)[O-])=CC=C21 ORWADBVBOPTYQT-UHFFFAOYSA-N 0.000 description 2
- AEWCNPOKYFDMMA-UHFFFAOYSA-N 6-tert-butylchromen-4-one Chemical compound O1C=CC(=O)C2=CC(C(C)(C)C)=CC=C21 AEWCNPOKYFDMMA-UHFFFAOYSA-N 0.000 description 2
- JQQABSXUHNBEPB-UHFFFAOYSA-N 7-chlorochromen-4-one Chemical compound O1C=CC(=O)C=2C1=CC(Cl)=CC=2 JQQABSXUHNBEPB-UHFFFAOYSA-N 0.000 description 2
- MOISBGWJJHJRIH-UHFFFAOYSA-N 7-methylchromen-4-one Chemical compound O1C=CC(=O)C=2C1=CC(C)=CC=2 MOISBGWJJHJRIH-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- DLBDWKDOHINUIM-UHFFFAOYSA-N 8-methylchromen-4-one Chemical compound O1C=CC(=O)C2=C1C(C)=CC=C2 DLBDWKDOHINUIM-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 229910020323 ClF3 Inorganic materials 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 229910021640 Iridium dichloride Inorganic materials 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical group CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OSVXSBDYLRYLIG-UHFFFAOYSA-N chlorine dioxide Inorganic materials O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004490 chloroalkoxy group Chemical group 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- NJRGQNNSIAFIJC-UHFFFAOYSA-N ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(C=2C=C(C=O)C(O)=CC=2)=N1 NJRGQNNSIAFIJC-UHFFFAOYSA-N 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical group CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical group CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical group COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical group CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000002004 n-butylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical group CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- 125000006308 propyl amino group Chemical group 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 238000009489 vacuum treatment Methods 0.000 description 2
- YBEWLMKRCGNUIO-TWGQIWQCSA-N (5z)-5-[(5-methylfuran-2-yl)methylidene]furan-2-one Chemical compound O1C(C)=CC=C1\C=C/1C=CC(=O)O\1 YBEWLMKRCGNUIO-TWGQIWQCSA-N 0.000 description 1
- LSRYDXKYMCAGFS-UHFFFAOYSA-N 1h-naphthalene Chemical compound C1=CC=C2C=C[CH]CC2=C1 LSRYDXKYMCAGFS-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- DFZIJAGHWXOSDA-UHFFFAOYSA-N 2-methoxychromen-4-one Chemical compound C1=CC=C2OC(OC)=CC(=O)C2=C1 DFZIJAGHWXOSDA-UHFFFAOYSA-N 0.000 description 1
- HLPOZWDHUWSENJ-UHFFFAOYSA-N 5,6,8-trifluoro-7-methoxychromen-2-one Chemical compound C1=CC(=O)OC2=C(F)C(OC)=C(F)C(F)=C21 HLPOZWDHUWSENJ-UHFFFAOYSA-N 0.000 description 1
- JZYCZVLVWUCHTP-UHFFFAOYSA-N 7-methoxy-2-oxochromene-6-carbaldehyde Chemical compound O1C(=O)C=CC2=C1C=C(OC)C(C=O)=C2 JZYCZVLVWUCHTP-UHFFFAOYSA-N 0.000 description 1
- 229910014263 BrF3 Inorganic materials 0.000 description 1
- SYYIKKOIQGETCJ-UHFFFAOYSA-N CC1=C(C(=C(C1(C)[Rh+2])C)C)C Chemical compound CC1=C(C(=C(C1(C)[Rh+2])C)C)C SYYIKKOIQGETCJ-UHFFFAOYSA-N 0.000 description 1
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- SISAYUDTHCIGLM-UHFFFAOYSA-N bromine dioxide Inorganic materials O=Br=O SISAYUDTHCIGLM-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- VRMFZTBAWYVGGB-UHFFFAOYSA-N cyclopenta[c]pyran-7-carbaldehyde Chemical compound C1=COC=C2C(C=O)=CC=C21 VRMFZTBAWYVGGB-UHFFFAOYSA-N 0.000 description 1
- UGWROJUCIPQAPL-UHFFFAOYSA-L dichloroiridium(1+) Chemical compound Cl[Ir+]Cl UGWROJUCIPQAPL-UHFFFAOYSA-L 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- MBAKFIZHTUAVJN-UHFFFAOYSA-I hexafluoroantimony(1-);hydron Chemical compound F.F[Sb](F)(F)(F)F MBAKFIZHTUAVJN-UHFFFAOYSA-I 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- WGDGLHDMXWBFIU-UHFFFAOYSA-N methyl 2-[2-oxo-4-(trifluoromethyl)chromen-7-yl]oxyacetate Chemical compound FC(F)(F)C1=CC(=O)OC2=CC(OCC(=O)OC)=CC=C21 WGDGLHDMXWBFIU-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- WFMNHCSATCWAAQ-UHFFFAOYSA-M potassium;2,2-dimethylpropanoate Chemical compound [K+].CC(C)(C)C([O-])=O WFMNHCSATCWAAQ-UHFFFAOYSA-M 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- SJRDNQOIQZOVQD-UHFFFAOYSA-M sodium;2,2-dimethylpropanoate Chemical compound [Na+].CC(C)(C)C([O-])=O SJRDNQOIQZOVQD-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/54—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 substituted in the carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- C07D491/12—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 three hetero rings
- C07D491/16—Peri-condensed systems
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Abstract
The invention discloses a chromone compound and a preparation method and application thereof. The method has the advantages of environmental protection, low price and the like; the reaction condition is mild, the operation is simple and the yield is high; the post-treatment of the reaction is simple and convenient and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a chromone compound and a preparation method and application thereof.
Background
Chromone is a special oxygen-containing benzo heterocyclic compound, exists in natural products, and has remarkable biological properties such as oxidation resistance, anti-inflammation, cancer resistance and the like. At present, salicylaldehyde is widely applied to synthesis of a chromone framework, an alkynyl ligand used in the synthesis is high in cost and has certain dangerous raw materials, and efficient construction of the chromone framework is still a challenge to be realized by selecting an alkynyl equivalent synthon which is simple, easy to obtain and low in cost.
In view of the above, it would be desirable to provide a process for the preparation of chromone analogs that is cost effective.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides the chromone compound, and the medicine prepared from the chromone compound has good metabolic stability.
The invention also provides a preparation method of the chromone compound, and the preparation method is low in cost.
The invention also provides application of the chromone compound.
Specifically, the first aspect of the present invention provides a chromone compound, wherein the structural formula is shown in the following formula (iii):
in the formula, R1And R2Independently selected from hydrogen, alkyl, alkoxy, halogen atom, nitro, ester group, aldehyde group, amino, alkenyl, carboxyl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
x is selected from O atom, N atom or S atom;
R1and R2Cyclization or non-cyclization;
R1and the C atom in the benzene ring of the salicylaldehyde compound shown in the formula (III) forms a ring or does not form a ring;
R2and the C atom in the benzene ring of the salicylaldehyde compound shown in the formula (III) forms a ring or does not form a ring;
R3selected from hydrogen or alkoxy.
According to one technical scheme of the chromone compound, the invention at least has the following beneficial effects:
The chromone compound takes chromone as a parent nucleus structure, and the substituent is introduced into the chromone parent nucleus, so that the metabolic stability and the fat solubility of the chromone compound are improved through the introduction of the substituent.
According to some embodiments of the invention, the alkyl is C1～C20The alkyl group of (1).
According to some embodiments of the invention, the alkyl group comprises C1～C10Alkyl group of (1).
According to some embodiments of the invention, the alkyl group comprises C1～C8Alkyl group of (1).
According to some embodiments of the invention, the alkyl group comprises at least one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
According to some embodiments of the invention, the alkoxy group comprises C1～C10Alkoxy group of (2).
According to some embodiments of the invention, the alkoxy group comprises at least one of methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
According to some embodiments of the invention, the alkoxy further comprises haloalkoxy.
According to some embodiments of the invention, the haloalkoxy group comprises at least one of fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy.
According to some embodiments of the invention, the fluoroalkoxy group includes a trifluoroethoxy group or a trifluoromethoxy group.
According to some embodiments of the invention, the halogen atom comprises at least one of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
According to some embodiments of the invention, the ester group comprises C1～C10Ester group of (a).
According to some embodiments of the invention, the ester group comprises at least one of a methyl formate group, an ethyl formate group, a methyl acetate group, an ethyl acetate group and a propyl acetate group.
According to some embodiments of the invention, the aldehyde group comprises C1～C10An aldehyde group of (a).
According to some embodiments of the invention, the aldehyde group comprises at least one of a formaldehyde group, an aldehyde group, a propane group, a n-butane group, an iso-butane group.
According to some embodiments of the invention, the amine group comprises C1～C10The amine group of (1).
According to some embodiments of the invention, the amine group comprises at least one of a methylamino group, a diethylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a n-butylamino group, an isobutylamino group and a tert-butylamino group.
According to some embodiments of the invention, the alkenyl group comprises C1～C10Alkenyl groups of (a).
According to some embodiments of the invention, the alkenyl group comprises at least one of an ethenyl group, a propenyl group, and a butenyl group.
According to some embodiments of the invention, the carboxy group comprises C1～C10A carboxyl group of (2).
According to some embodiments of the invention, the substituted carboxy group comprises C1～C10Substituted carboxyl group of (1).
According to some embodiments of the invention, the aryl group is C1～C20Aryl group of (1).
According to some embodiments of the invention, the aryl group is C1～C15Aryl group of (1).
According to some embodiments of the invention, the aryl group comprises salicylaldehyde, phenyl or naphthyl.
According to some embodiments of the invention, the heteroaryl is C1～C15And a heterocyclic group containing at least one of N, O and S.
According to some embodiments of the invention, the heterocyclyl is C1～C10Nitrogen-containing heterocycles and oxygen-containing heterocycles.
According to some embodiments of the invention, the heterocyclyl is C1～C10The nitrogen-containing heterocyclic group of (1).
According to some embodiments of the invention, the chromonic compound comprises 3- (2, 2-difluoro-1-hydroxyethyl) -1H-indole-4-carbaldehyde, 1H-naphtho [2,1-b ] pyran-1-one, 4H-naphtho [1,2-b ] pyran-4-one, ethyl 4-methyl-2- (4-oxo-4H-chromen-6-yl) thiazole-5-carboxylate, 2- (2,2, 2-trifluoroethoxy) chromone, 6-fluoro-2- (2,2, 2-trifluoroethoxy) chromone, 6-chloro-2- (2,2, 2-trifluoroethoxy) chromone, 6-bromo-2- (2,2, 2-trifluoroethoxy) chromone, 6-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-methoxy-2- (2,2, 2-trifluoroethoxy) chromone, 6-tert-butyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-nitro-2- (2,2, 2-trifluoroethoxy) chromone, methyl 6-carboxylate-2- (2,2, 2-trifluoroethoxy) chromone, 7-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 7-chloro-2- (2,2, 2-trifluoroethoxy) chromone, 7-diethylamino-2- (2,2, 2-trifluoroethoxy) chromone, 2-trifluoromethyl-chromone, 2, 2-trifluoromethyl-ethoxy) chromone, 2, 2-trifluoromethyl-chromone, 2, 2-trifluoromethyl-ethoxy-chromone, 2, 2-trifluoromethyl-chromone, 2,2, 2-trifluoromethyl-trifluoro-ethoxy-chromone, and mixtures thereof, 8-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 8-tert-butyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-methyl-4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromene-8-carbaldehyde, 6-tert-butyl-4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromene-8-carbaldehyde, 3- (2,2, 2-trifluoroethoxy) -1H benzo [ f ] chromen-1-one, 1- (2, 5-dimethyl-1H-indol-3-yl) -2, 2-difluoroethan-1-ol, and mixtures thereof, At least one of 2- ((tert-butoxycarbonyl) amino) -3- (4-oxy-4H-chromen-6-yl) propionic acid and 4-methyl-2- (4-oxy-2- (2,2, 2-trifluoroethoxy) -4H-chromen-6-yl) thiazole-5-carboxylic acid.
The second aspect of the present invention provides a method for preparing chromone compounds according to the first aspect of the present invention, comprising the steps of:
mixing salicylaldehyde compounds shown in a formula (I) and fluorine-containing vinyl compounds shown in a formula (II) and then reacting to prepare chromone compounds shown in a formula (III);
in the formula, R1And R2Independently selected from hydrogen, alkyl, alkoxy, halogen atom, nitro, ester group, aldehyde group, amino, alkenyl, carboxyl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
x is selected from O atom, N atom or S atom;
R1and R2Cyclization or non-cyclization;
R1and the C atom in the benzene ring of the salicylaldehyde compound shown in the formula (I) forms a ring or does not form a ring;
R2and the C atom in the benzene ring of the salicylaldehyde compound shown in the formula (I) forms a ring or does not form a ring;
R3selected from hydrogen or alkoxy;
R4selected from hydrogen or fluorine;
r is selected from the group consisting of phenylsulfonyl, p-methylphenylsulfonyl, o-methylphenylsulfonyl, p-fluorophenylsulfonyl, o-fluorophenylsulfonyl, p-trifluoromethylphenylsulfonyl, o-trifluorophenylsulfonyl, phenyl and naphthyl;
the catalyst for the reaction is a transition metal catalyst.
According to one technical scheme of the preparation method provided by the invention, the preparation method at least has the following beneficial effects:
The fluorine-containing vinyl compound in the preparation raw materials is a fluorinated synthon, and the chromone framework is synthesized by the fluorine-containing vinyl compound, so that the construction method of the chromone framework is more convenient, efficient and environment-friendly. Meanwhile, the present invention provides various substituted chromone analogs in moderate to excellent yields based on hydrocarbon activation reactions catalyzed by transition metal catalysts. The preparation raw materials are simple and easy to obtain, environment-friendly and low in price; the reaction condition is mild, the operation is simple and the yield is high; the post-treatment of the reaction is simple and convenient and is suitable for industrial production.
According to some embodiments of the present invention, the salicylaldehyde compound represented by formula (I) includes salicylaldehyde, 5-chlorosalicylaldehyde, 5-bromosalicylaldehyde, 2-hydroxy-5-methylbenzaldehyde, 4-chloro-2-hydroxybenzaldehyde, 2-hydroxy-5-nitrobenzaldehyde, 2-hydroxy-4-methylbenzaldehyde, 2-hydroxy-3-methylbenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, methyl 3-formyl-4-hydroxybenzoate, 2-hydroxy-1-naphthaldehyde, 1-hydroxy-2-naphthaldehyde, 5- (tert-butyl) -2-hydroxybenzaldehyde, 3- (tert-butyl) -2-hydroxybenzaldehyde, methyl-ethyl-2-hydroxybenzoate, methyl-2-hydroxy-nitrobenzaldehyde, methyl-2-hydroxy-benzaldehyde, methyl-2-hydroxy-nitrobenzaldehyde, methyl-2-hydroxy-benzaldehyde, methyl-2-nitrobenzaldehyde, methyl-hydroxy-benzaldehyde, methyl-nitrobenzaldehyde, methyl-ethyl-methyl-hydroxy-benzaldehyde, methyl-2-nitrobenzaldehyde, methyl-hydroxy-benzaldehyde, methyl-ethyl-methyl-benzyl-ethyl-methyl-2-nitrobenzaldehyde, ethyl-methyl-benzyl, ethyl, At least one of 5- (tert-butyl) -2-hydroxyisophthalaldehyde, ethyl 2- (3-aldehyde-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate, 4-diethylamino-salicylaldehyde, 5- (trifluoromethoxy) salicylaldehyde, 5-fluoro-salicylaldehyde, and 2- ((tert-butoxycarbonyl) amino) -3- (3-formyl-4-hydroxyphenyl) propionic acid.
According to some embodiments of the present invention, the fluorine-containing vinyl compound represented by formula (II) includes at least one of 2-fluorovinyl 4-methylbenzenesulfonic acid or 2, 2-difluorovinyl 4-methylbenzenesulfonic acid.
According to the preparation method, the 2, 2-difluorovinyl 4-methylbenzenesulfonic acid or 2-fluorovinyl 4-methylbenzenesulfonic acid is used as a fluorinated synthon, and the reagent is used as an alkynyl equivalent synthon to synthesize the carbon hydrogen activation reaction of the chromone framework, so that the chromone framework is conveniently, efficiently and environmentally-friendly constructed.
According to some embodiments of the invention, the alkyl is C1～C20The alkyl group of (1).
According to some embodiments of the invention, the alkyl group comprises C1～C10The alkyl group of (1).
According to some embodiments of the invention, the alkyl group comprises C1～C8Alkyl group of (1).
According to some embodiments of the invention, the alkyl group comprises at least one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
According to some embodiments of the invention, the alkoxy group comprises C1～C10Alkoxy group of (2).
According to some embodiments of the invention, the alkoxy group comprises at least one of methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
According to some embodiments of the invention, the alkoxy group further comprises a haloalkoxy group.
According to some embodiments of the invention, the haloalkoxy group comprises at least one of fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy.
According to some embodiments of the invention, the fluoroalkoxy group includes a trifluoroethoxy group or a trifluoromethoxy group.
According to some embodiments of the invention, the halogen atom comprises at least one of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
According to some embodiments of the invention, the ester group comprises C1～C10Ester group of (2).
According to some embodiments of the invention, the ester group comprises at least one of a methyl formate group, an ethyl formate group, a methyl acetate group, an ethyl acetate group and a propyl acetate group.
According to some embodiments of the invention, the aldehyde group comprises C1～C10An aldehyde group of (a).
According to some embodiments of the invention, the aldehyde group comprises at least one of a formaldehyde group, an aldehyde group, a propane group, a n-butane group, an iso-butane group.
According to some embodiments of the invention, the amine group comprises C1～C10The amine group of (1).
According to some embodiments of the invention, the amine group comprises at least one of a methylamino group, a diethylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a n-butylamino group, an isobutylamino group and a tert-butylamino group.
According to some embodiments of the invention, the alkenyl comprises C1～C10The alkenyl group of (1).
According to some embodiments of the invention, the alkenyl group comprises at least one of ethenyl, propenyl, and butenyl.
According to some embodiments of the invention, the carboxy group comprises C1～C10A carboxyl group of (2).
According to some embodiments of the invention, the substituted carboxy group comprises C1～C10Substituted carboxyl groups of (2). According to some embodiments of the invention, the aryl group is C1～C20Aryl group of (1).
According to some embodiments of the invention, the aryl group is C1～C15Aryl group of (1).
According to some embodiments of the invention, the aryl group comprises salicylaldehyde, phenyl or naphthyl.
According to some embodiments of the invention, the heteroaryl refers to C1～C15And a heterocyclic ring containing at least one of N, O and S.
According to some embodiments of the invention, the heterocycle is C1～C10Nitrogen-containing heterocycles and oxygen-containing heterocycles.
According to some embodiments of the invention, the heterocycle is C1～C10The nitrogen-containing heterocycle of (1).
According to some embodiments of the invention, the chromonic compound comprises chromone, 6-chlorochromone, 6-bromochromone, 6-methylchromone, 7-chlorochromone, 6-nitrochromone, 7-methylchromone, 8-methylchromone, 3- (2, 2-difluoro-1-hydroxyethyl) -1H-indole-4-carbaldehyde, 6-carboxylic acid methyl ester chromone, 1H-naphtho [2,1-b ] pyran-1-one, 4H-naphtho [1,2-b ] pyran-4-one, 6-tert-butylchromone, 8-tert-butylchromone, 6- (tert-butyl) -8-carbaldehyde chromone, 4-methyl-2- (4-oxo-4H-chromen-6-yl) thiazole-5-carboxylic acid ethyl ester, 7-diethylaminochromone, 6-trifluoromethoxy chromone, 6-fluorochromone, 2- (2,2, 2-trifluoroethoxy) chromone, 6-fluoro-2- (2,2, 2-trifluoroethoxy) chromone, 6-chloro-2- (2,2, 2-trifluoroethoxy) chromone, 6-bromo-2- (2,2, 2-trifluoroethoxy) chromone, 6-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-methoxy-2- (2,2, 2-trifluoroethoxy) chromone, 6-tert-butyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-nitro-2- (2,2, 2-trifluoroethoxy) chromone, and mixtures thereof, Methyl 6-carboxylate-2- (2,2, 2-trifluoroethoxy) chromone, 7-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 7-chloro-2- (2,2, 2-trifluoroethoxy) chromone, 7-diethylamino-2- (2,2, 2-trifluoroethoxy) chromone, 8-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 8-tert-butyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-methyl-4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromene-8-carbaldehyde, 6-tert-butyl-4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromen-8-carbaldehyde, 3- (2,2, 2-trifluoroethoxy) -1H benzo [ f ] chromen-1-one, 1- (2, 5-dimethyl-1H-indol-3-yl) -2, 2-difluoroethan-1-ol, 2- ((tert-butoxycarbonyl) amino) -3- (4-oxy-4H-chromen-6-yl) propionic acid and 4-methyl-2- (4-oxy-2- (2,2, 2-trifluoroethoxy) -4H-chromen-6-yl) thiazole-5-carboxylic acid.
According to some embodiments of the present invention, the molar ratio of the salicylaldehyde compound represented by formula (I) to the fluorine-containing vinyl compound represented by formula (II) is 1:2 to 4.
According to some embodiments of the invention, the molar ratio of the salicylaldehyde compound represented by the formula (I) to the fluorine-containing vinyl compound represented by the formula (II) is 1: 2.
According to some embodiments of the invention, the transition metal catalyst is a trivalent iridium catalyst or a trivalent rhodium catalyst.
According to some embodiments of the invention, the trivalent iridium catalyst is [ Cp × IrCl ]2](Pentamethylcyclopentadienyl) iridium (III) dichloride, CAS number 12354-84-6).
According to some embodiments of the invention, the trivalent rhodium catalyst [ Cp × Rh (CH)3CN)3](SbF6)2](bis (hexafluoroantimonic acid) triethylenenitrile (pentamethylcyclopentadienyl) rhodium (III) with CAS number 125357-42-8 and [ Cp RhCl ]2]At least one of (pentamethylcyclopentadienyl) rhodium (III) dichloride dimer, CAS number: 212354-85-7).
According to some embodiments of the invention, the molar ratio of the salicylaldehyde compound represented by formula (I) to the catalyst is 1: 0.02 to 1.
According to some embodiments of the invention, the molar ratio of the salicylaldehyde compound represented by formula (I) to the catalyst is 1: 0.05 to 1.
According to some embodiments of the invention, the molar ratio of the salicylaldehyde compound represented by the formula (I) to the catalyst is 1: 0.05 to 0.15.
According to some embodiments of the invention, the molar ratio of salicylaldehyde compound represented by formula (I) to catalyst is 1: 0.05.
according to some embodiments of the invention, a base is added to the reaction.
According to some embodiments of the invention, the molar ratio of the base to the salicylaldehyde compound of formula (I) is 1:1 to 3.
According to some embodiments of the invention, the molar ratio of the base to the salicylaldehyde compound of formula (I) is 1: 1.5-3.
According to some embodiments of the invention, the base comprises a carbonate, pivalate, or hydroxide.
According to some embodiments of the invention, the carbonate comprises at least one of sodium carbonate, potassium carbonate, or cesium carbonate.
According to some embodiments of the invention, the pivalate salt comprises at least one of sodium pivalate, potassium pivalate, or cesium pivalate.
According to some embodiments of the invention, the hydroxide comprises at least one of sodium hydroxide, potassium hydroxide, cesium hydroxide, or calcium hydroxide.
According to some embodiments of the invention, the solvent of the reaction is at least one of trifluoroethanol, methanol, or hexafluoroisopropanol.
According to some embodiments of the present invention, when 2-fluorovinyl 4-methylbenzenesulfonic acid is used as a preparation raw material, the reaction solvent is hexafluoroisopropanol.
According to some embodiments of the present invention, when 2, 2-difluorovinyl 4-methylbenzenesulfonic acid is used as a starting material for the preparation, the reaction solvent is trifluoroethanol.
According to some embodiments of the invention, the molar ratio of the solvent to the salicylaldehyde compound of formula (I) is from 5mL/mmol to 15 mL/mmol.
According to some embodiments of the invention, the molar ratio of the solvent to the salicylaldehyde compound of formula (I) is 10 mL/mmol.
According to some embodiments of the invention, the reaction is a hydrocarbon activation reaction.
According to some embodiments of the invention, the temperature of the reaction is between 25 ℃ and 120 ℃.
According to some embodiments of the invention, the reaction time is between 3h and 12 h.
According to some embodiments of the invention, the reaction time is between 3h and 10 h.
According to some embodiments of the invention, the reaction time is 3 h.
According to some embodiments of the present invention, the reaction temperature is about 90 ℃ when starting from 2-fluorovinyl 4-methylbenzenesulfonic acid.
According to some embodiments of the present invention, the reaction time is about 10 hours when 2-fluorovinyl 4-methylbenzenesulfonic acid is used as a starting material for the preparation.
According to some embodiments of the present invention, the reaction temperature is about 80 ℃ when starting from 2, 2-difluorovinyl 4-methylbenzenesulfonic acid.
According to some embodiments of the present invention, 2-difluorovinyl 4-methylbenzenesulfonic acid is used as a starting material and the reaction time is about 3 hours.
According to some embodiments of the invention, after the reaction is completed, quenching, first washing, first extraction, second washing, second extraction, concentration and column chromatography are further included.
According to some embodiments of the invention, after the reaction is finished, pure water is added to quench the reaction, ethyl acetate is added to wash the reaction, the organic phase is obtained by layering, the aqueous phase is extracted with ethyl acetate again, the organic phases are combined, dried, the solvent is removed by distillation under reduced pressure, and the product is subjected to column chromatography.
The third aspect of the invention provides the application of the chromone compound in preparing any one of anti-inflammatory drugs, anti-oxidation drugs and anti-cancer drugs.
According to one technical scheme applied by the invention, the method at least has the following beneficial effects:
The chromone compound takes chromone as a parent nucleus structure, and the substituent is introduced into the chromone parent nucleus, so that the metabolic stability and the fat solubility of the chromone compound are improved through the introduction of the substituent.
According to some embodiments of the invention, the chromonic compound comprises 3- (2, 2-difluoro-1-hydroxyethyl) -1H-indole-4-carbaldehyde, 1H-naphtho [2,1-b ] pyran-1-one, 4H-naphtho [1,2-b ] pyran-4-one, ethyl 4-methyl-2- (4-oxo-4H-chromen-6-yl) thiazole-5-carboxylate, 2- (2,2, 2-trifluoroethoxy) chromone, 6-fluoro-2- (2,2, 2-trifluoroethoxy) chromone, 6-chloro-2- (2,2, 2-trifluoroethoxy) chromone, 6-bromo-2- (2,2, 2-trifluoroethoxy) chromone, 6-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-methoxy-2- (2,2, 2-trifluoroethoxy) chromone, 6-tert-butyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-nitro-2- (2,2, 2-trifluoroethoxy) chromone, 6-carboxylic acid methyl ester-2- (2,2, 2-trifluoroethoxy) chromone, 7-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 7-chloro-2- (2,2, 2-trifluoroethoxy) chromone, 7-diethylamino-2- (2,2, 2-trifluoroethoxy) chromone, 2-methoxy-2- (2,2, 2-trifluoroethoxy) chromone, 2-methoxy-chromone, and, 8-methyl-2- (2,2, 2-trifluoroethoxy) chromone, 8-tert-butyl-2- (2,2, 2-trifluoroethoxy) chromone, 6-methyl-4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromene-8-carbaldehyde, 6-tert-butyl-4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromene-8-carbaldehyde, 3- (2,2, 2-trifluoroethoxy) -1H benzo [ f ] chrome-1-one, 1- (2, 5-dimethyl-1H-indol-3-yl) -2, 2-difluoroethan-1-ol, and mixtures thereof, At least one of 2- ((tert-butoxycarbonyl) amino) -3- (4-oxy-4H-chromen-6-yl) propanoic acid and 4-methyl-2- (4-oxy-2- (2,2, 2-trifluoroethoxy) -4H-chromen-6-yl) thiazole-5-carboxylic acid.
Detailed Description
The idea of the invention and the resulting technical effects will be clearly and completely described below in connection with the embodiments, so that the objects, features and effects of the invention can be fully understood. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and other embodiments obtained by those skilled in the art without inventive efforts are within the protection scope of the present invention based on the embodiments of the present invention.
In the description of the present invention, reference to the description of "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples", etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available.
Specific examples of the present invention are described in detail below.
Unless otherwise specified, 5 mol% represents a catalyst ([ Cp × IrCl ] in the embodiment of the present invention2]、[Cp*Rh(CH3CN)3](SbF6)2]Or [ Cp + RhCl2]) The mol ratio of the salicylic aldehyde compound to the salicylic aldehyde compound is 1: 0.05.
in the embodiment of the present invention, 15 mol% represents a catalyst ([ Cp IrCl ]2]、[Cp*Rh(CH3CN)3](SbF6)2]Or [ Cp + RhCl2]) The mol ratio of the salicylic aldehyde compound to the salicylic aldehyde compound is 1: 0.15.
the preparation methods of the 2, 2-difluoroethylene 4-methylbenzenesulfonic acid and the 2-fluorovinyl 4-methylbenzenesulfonic acid mentioned in the embodiment of the invention are as follows:
a500 ml round bottom flask is taken, 19.0g (100mmol) of p-toluenesulfonyl chloride (CAS number: 98-59-9), 100g (1mol) of trifluoroethanol (CAS number: 75-89-8) and 200ml of dichloromethane are added, 28ml (200mmol) of triethylamine (CAS number: 121-44-8) are added dropwise at 0 ℃, the mixture is transferred to room temperature for reaction for 10 hours after 1 hour of reaction, dichloromethane and saturated sodium chloride solution are used for extraction after the reaction is finished, anhydrous sodium sulfate is added into an organic phase for drying, the solvent is removed by reduced pressure distillation, and then 25g of 2,2, 2-trifluoroethyl p-toluenesulfonate is obtained by column chromatography, wherein the yield is 98%.
Taking a 250ml round-bottom flask, adding 6g (24mmol) of 2,2, 2-trifluoroethyl p-toluenesulfonate and anhydrous tetrahydrofuran, carrying out vacuum treatment on the device, dropwise adding n-butyllithium (CAS number: 109-72-8) (2.5equiv) at-78 ℃, finishing dropwise adding within 20min, transferring to room temperature after reacting for 15min, adding 50ml of water for quenching, carrying out suction filtration on the reaction, extracting by using ethyl acetate and saturated sodium chloride solution after finishing reaction, adding anhydrous sodium sulfate into an organic phase for drying, carrying out reduced pressure distillation to remove a solvent, and carrying out column chromatography to obtain 4.2g of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid, wherein the yield is 75%.
Adding 4.68g (20mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid and 50ml of anhydrous ether into a 100ml round-bottom flask, carrying out vacuum treatment on the device, dropwise adding lithium aluminum hydride (CAS number: 16853-85-3) (2equiv) at-5 ℃, reacting for 15min, then transferring to room temperature for reaction for four hours, carrying out suction filtration after the reaction is finished, extracting by using ethyl acetate and saturated sodium chloride solution, adding anhydrous sodium sulfate into an organic phase for drying, distilling under reduced pressure to remove the solvent, and carrying out column chromatography to obtain 2.6g of 2-fluorovinyl 4-methylbenzenesulfonic acid with the yield of 60%.
The yield calculation method of the embodiment of the invention comprises the following steps: yield-product mass/(molecular weight)*The amount of material charged).
Example 1: synthesis of chromones
Adding 24.4mg (0.20mmol) of salicylaldehyde, 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid and [ Cp IrCl ] into a 15mL pressure-resistant tube2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and 2mL of hexafluoroisopropanol (CAS number: 920-66-1) were reacted at 90 ℃ for 3 hours. After the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, collecting organic phases by layering, extracting the aqueous phase with ethyl acetate for 2 times, wherein the dosage of ethyl acetate is 5mL each time, and combining the organic phases Adding anhydrous sodium sulfate, drying, distilling under reduced pressure to remove the solvent, and performing column chromatography to obtain the product with the yield of 83%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.20(dd,J＝8.0,1.5Hz,1H),7.85(d,J＝6.0Hz,1H),7.67(m,J＝8.7,7.2,1.7Hz,1H),7.47–7.43(m,1H),7.43–7.38(m,1H),6.34(d,J＝6.0Hz,1H).
13C NMR(126MHz,Chloroform-d)δ177.79,156.65,155.45,133.91,125.94,125.39,125.01,118.31,113.13.
ESI-MS:calculated for C9H6O2[M+H]-:147.0440,found:147.0440.
example 2: synthesis of 6-chlorochromone:
adding 31mg (0.20mmol) of 5-chlorosalicylaldehyde (CAS number: 635-93-8), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid and [ Cp IrCl ] into a 15mL pressure-resistant tube2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 86%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.14(d,J＝2.6Hz,1H),7.85(d,J＝6.0Hz,1H),7.59(dd,J＝8.9,2.6Hz,1H),7.41(d,J＝8.9Hz,1H),6.34(d,J＝6.0Hz,1H).
13C NMR(126MHz,Chloroform-d)δ176.53,155.61,154.91,134.14,131.34,125.85,125.32,120.08,113.02.
ESI-MS:calculated for C9H5ClO2[M+H]-:181.0050,found:181.0049.
example 3: synthesis of 6-bromochromone:
adding 40.2mg (0.20mmol) of 5-bromosalicylaldehyde (CAS number: 1761-61-1), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid and [ Cp IrCl ] into a 15mL pressure-resistant tube2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product with the yield of 81%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.31(d,J＝2.5Hz,1H),7.85(d,J＝6.0Hz,1H),7.74(dd,J＝8.9,2.5Hz,1H),7.35(d,J＝8.9Hz,1H),6.35(d,J＝6.0Hz,1H).
13C NMR(126MHz,Chloroform-d)δ176.37,155.61,155.36,136.89,128.55,126.23,120.31,118.84,113.14.
ESI-MS:calculated for C9H5BrO2[M+H]-:224.9545,found:224.9544.
example 4: synthesis of 6-methylchromone:
a15 mL pressure resistant tube was charged with 27.2mg (0.20mmol) of 2-hydroxy-5-methylbenzaldehyde (CAS number: 613-84-3), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol), and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. After the reaction is finished, 5mL of water is added to quench the reactionThen adding 10mL of ethyl acetate and 5mL of saturated saline solution for washing, collecting organic phases in a layered mode, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate for drying, removing a solvent by reduced pressure distillation, and carrying out column chromatography to obtain the product, wherein the yield is 76%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.98–7.96(m,1H),7.82(d,J＝6.0Hz,1H),7.46(dd,J＝8.6,1.9Hz,1H),7.34(d,J＝8.6Hz,1H),6.31(d,J＝6.0Hz,1H),2.43(s,3H).
13C NMR(126MHz,Chloroform-d)δ177.87,155.28,154.81,135.27,135.06,125.10,124.51,117.96,112.78,20.95.
ESI-MS:calculated for C10H8O2[M+H]-:161.0597,found:161.0596.
example 5: synthesis of 7-chlorochromone:
adding 31.3mg (0.20mmol) of 4-chloro-2-hydroxybenzaldehyde (CAS number: 2420-26-0), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid and [ Cp IrCl ] into a 15mL pressure-resistant pipe2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 74%.
The characterization data of the product are:1H NMR(500MHz,Chloroform-d)δ8.12(d,J＝8.6Hz,1H),7.82(d,J＝6.0Hz,1H),7.47(d,J＝1.9Hz,1H),7.36(dd,J＝8.6,1.9Hz,1H),6.33(d,J＝6.1Hz,1H).
13C NMR(126MHz,Chloroform-d)δ176.88,156.67,155.48,139.97,127.34,126.28,123.49,118.36,113.40.
ESI-MS:calculated for C9H5ClO2[M+H]-:181.0050,found:181.0050.
example 6: synthesis of 6-nitrochromone:
33.4mg (0.20mmol) of 2-hydroxy-5-nitrobenzaldehyde (CAS number: 97-51-8), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid and [ Cp IrCl ] were added to a 15mL pressure-resistant tube2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 68%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ9.07(d,J＝2.8Hz,1H),8.50(dd,J＝9.2,2.8Hz,1H),7.93(d,J＝6.1Hz,1H),7.63(d,J＝9.2Hz,1H),6.44(d,J＝6.1Hz,1H).
13C NMR(126MHz,Chloroform-d)δ176.05,159.41,155.83,144.91,128.27,125.02,122.73,120.20,113.69.
ESI-MS:calculated for C9H5NO4[M+H]-:192.0291,found:192.0290.
example 7: synthesis of 7-methylchromone:
a15 mL pressure-resistant tube was charged with 27.2mg (0.20mmol) of 2-hydroxy-4-methylbenzaldehyde (CAS number: 698-27-1), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl [ ]2]8mg(5mol％) Anhydrous potassium carbonate (41.4 mg, 0.3mmol) and hexafluoroisopropanol (2 mL) were reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 69%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.10(d,J＝8.1Hz,1H),7.83(d,J＝6.0Hz,1H),7.28–7.21(m,2H),6.32(d,J＝6.0Hz,1H),2.50(s,3H).
13C NMR(126MHz,Chloroform-d)δ177.67,156.66,155.11,145.18,126.79,125.55,122.62,117.89,112.91,21.83.
ESI-MS:calculated for C10H8O2[M+H]-:161.0597,found:161.0596.
example 8: synthesis of 8-methylchromone:
a15 mL pressure resistant tube was charged with 27.2mg (0.20mmol) of 2-hydroxy-3-methylbenzaldehyde (CAS No.: 90111-15-2), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 94%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.01(d,J＝7.2Hz,1H),7.88(d,J＝6.0Hz,1H),7.47(d,J＝7.2Hz,1H),7.25(d,J＝7.7Hz,1H),6.32(d,J＝6.0Hz,1H),2.44(s,3H).
13C NMR(126MHz,Chloroform-d)δ178.12,155.15,155.07,134.73,127.67,124.79,123.37,112.79,15.65.
ESI-MS:calculated for C10H8O2[M+H]-:161.0597,found:161.0596.
example 9: synthesis of 3- (2, 2-difluoro-1-hydroxyethyl) -1H-indole-4-carbaldehyde:
a15 mL pressure-resistant tube was charged with 30.4mg (0.20mmol) of 2-hydroxy-5-methoxybenzaldehyde (CAS number: 672-13-9), 86.4mg (0.40mmol) of 2-fluorovinyl-4-methylbenzenesulfonic acid, and [ Cp. IrCl [ ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product with the yield of 81%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.86(d,J＝6.0Hz,1H),7.57(d,J＝3.1Hz,1H),7.41(d,J＝9.1Hz,1H),7.27(dd,J＝9.1,3.1Hz,1H),6.34(d,J＝6.0Hz,1H),3.90(s,3H).
13C NMR(126MHz,Chloroform-d)δ177.72,157.07,155.21,151.52,125.58,124.07,119.76,112.24,104.87,56.06.
ESI-MS:calculated for C10H8O3[M+H]-:177.0546,found:177.0545.
example 10: synthesis of 6-Carboxylic acid methyl ester chromone:
taking 15mL of pressure-resistant pipe, adding 36mg (0.20mmol) of methyl 3-formyl-4-hydroxybenzoate (CAS number: 245889-99-9), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid and [ Cp IrCl [ ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 86%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.89(d,J＝2.1Hz,1H),8.33(dd,J＝8.8,2.2Hz,1H),7.89(d,J＝6.1Hz,1H),7.52(d,J＝8.8Hz,1H),6.40(d,J＝6.1Hz,1H),3.97(s,3H).
13C NMR(126MHz,Chloroform-d)δ177.12,165.83,159.03,155.57,134.54,128.45,127.42,124.61,118.81,113.59,52.61.
ESI-MS:calculated for C11H8O4[M+H]-:205.0495,found:205.0493.
example 11: synthesis of 1H-Naphthalene [2,1-b ] pyran-1-one:
a15 mL pressure-resistant tube was charged with 34.4mg (0.20mmol) of 2-hydroxy-1-naphthaldehyde (CAS number: 708-06-5), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. After the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and passing through a column layer The product was isolated in 70% yield.
The characterization data of the product are:
1H NMR(500MHz,DMSO-d6)δ0.03(d,J＝8.6Hz,1H),8.08(d,J＝9.0Hz,1H),7.92–7.87(m,2H),7.76(ddd,J＝8.5,7.0,1.4Hz,1H),7.62(ddd,J＝8.1,7.0,1.1Hz,1H),7.50(d,J＝9.0Hz,1H),6.52(d,J＝5.8Hz,1H).
13C NMR(126MHz,Chloroform-d)δ179.60,157.86,152.82,135.65,130.66,130.62,129.40,128.29,127.26,126.81,118.36,117.73,116.15.
ESI-MS:calculated for C13H8O2[M+H]-:197.0597,found:197.0596.
example 12: synthesis of 4H-naphtho [1,2-b ] pyran-4-one:
a15 mL pressure-resistant tube was charged with 34.4mg (0.20mmol) of 1-hydroxy-2-naphthaldehyde (CAS number: 574-96-9), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 92%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.48(d,J＝8.2Hz,1H),8.15(d,J＝8.7Hz,1H),8.06(d,J＝5.9Hz,1H),7.93(d,J＝7.7Hz,1H),7.78(d,J＝8.7Hz,1H),7.72(td,J＝8.1,7.6,1.4Hz,1H),7.68(td,J＝7.7,7.0,1.3Hz,1H),6.53(d,J＝5.9Hz,1H).
13C NMR(126MHz,Chloroform-d)δ177.64,154.70,154.18,136.01,129.52,128.27,127.34,125.57,124.15,122.48,121.36,120.87,114.50.
ESI-MS:calculated for C13H8O2[M+H]-:197.0597found：197.0596.
example 13: synthesis of 6-tert-butylchromone:
a15 mL pressure resistant tube was charged with 35.6mg (0.20mmol) of 5- (tert-butyl) -2-hydroxybenzaldehyde (CAS No.: 2725-53-3), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl [ ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 74%.
The characterization data of the product are:
1H NMR(400MHz,CDCl3)δ8.19(d,J＝2.5Hz,1H),7.84(d,J＝6.0Hz,1H),7.75(dd,1H),7.41(d,J＝8.8Hz,1H),6.34(d,J＝6.0Hz,1H),1.38(s,9H).
13C NMR(126MHz,Chloroform-d)δ178.18,155.31,154.85,148.70,131.86,124.33,121.64,117.92,112.94,35.00,31.43.
ESI-MS:calculated for C13H14O2[M+H]-:203.1066,found:203.1065.
example 14: synthesis of 8-tert-butylchromone:
a15 mL pressure resistant tube was charged with 35.6mg (0.20mmol) of 3- (tert-butyl) -2-hydroxybenzaldehyde (CAS number: 24623-65-2) and 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid、[Cp*IrCl2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 85%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.12(dd,J＝7.9,1.7Hz,1H),7.95(d,J＝5.9Hz,1H),7.65(dd,J＝7.6,1.6Hz,1H),7.33(t,J＝7.8Hz,1H),6.38(d,J＝5.9Hz,1H),1.49(s,9H).
13C NMR(126MHz,Chloroform-d)δ178.21,155.52,154.53,139.33,131.12,125.72,124.95,124.10,112.65,35.23,30.07.
ESI-MS:calculated for C13H14O2[M+H]-203.1066,found:203.1066.
example 15: synthesis of 6- (tert-butyl) -8-carbaldehyde chromone:
a15 mL pressure resistant tube was charged with 41.3mg (0.20mmol) of 5- (tert-butyl) -2-hydroxyisophthalaldehyde (CAS number: 84501-28-0), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl [ ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 80%.
The characterization data of the product are:
1H NMR(500MHz,CDCl3)δ10.64(s,1H),8.48(d,J＝2.6Hz,1H),8.30(d,J＝2.6Hz,1H),7.96(d,J＝6.0Hz,1H),6.44(d,J＝6.0Hz,1H),1.41(s,9H).
13C NMR(126MHz,Chloroform-d)δ187.46,176.84,155.26,155.01,148.91,131.42,128.70,125.13,124.88,113.66,35.21,31.29.
ESI-MS:calculated for C14H14O3[M+H]-:231.1015,found:231.1014.
example 16: synthesis of ethyl 4-methyl-2- (4-oxo-4H-chromium-6-yl) thiazole-5-carboxylate:
a15 mL pressure-resistant tube was charged with 58.3mg (0.20mmol) of ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate (CAS number: 161798-01-2), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp IrCl [ ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product with the yield of 30%.
The characterization data of the product are:
1H NMR(400MHz,CDCl3)δ8.70(d,J＝2.2Hz,1H),8.37(dd,J＝8.8,2.2Hz,1H),7.89(d,J＝6.0Hz,1H),7.55(d,J＝8.8Hz,1H),6.40(d,J＝6.0Hz,1H),4.37(q,J＝7.1Hz,2H),2.79(s,3H),1.40(t,J＝7.1Hz,3H).
13C NMR(126MHz,Chloroform-d)δ177.06,167.82,162.23,161.30,157.82,155.56,131.85,130.48,125.22,124.59,122.75,119.44,113.45,61.54,17.62,14.45.
ESI-MS:calculated for C16H14NO4S[M+H]-:317.0716,found:317.0711.
example 17: synthesis of 7-diethylaminochromone:
a15 mL pressure-resistant tube was charged with 38.6mg (0.20mmol) of 4-diethylaminosalicylaldehyde (CAS No.: 17754-90-4), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl [ ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 58%.
The characterization data of the product are:
1H NMR(500MHz,CDCl3)δ7.99(d,J＝9.1Hz,1H),7.66(d,J＝6.0Hz,1H),6.72(dd,J＝9.1,2.5Hz,1H),6.43(d,J＝2.5Hz,1H),6.18(d,J＝6.0Hz,1H),3.44(q,J＝7.1Hz,4H),1.23(t,J＝7.1Hz,6H).
13C NMR(126MHz,Chloroform-d)δ177.06,159.14,154.19,152.02,127.07,114.19,112.64,110.67,96.46,44.86,12.55.
ESI-MS:calculated for C13H15NO2[M+H]-:218.1175,found:218.1174.
example 18: synthesis of 6-trifluoromethoxy chromone:
a15 mL pressure-resistant tube was charged with 41.3mg (0.20mmol) of 5- (trifluoromethoxy) salicylaldehyde (CAS No.: 93249-62-8), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. IrCl ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol), and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 86%.
The characterization data of the product are:
1H NMR(500MHz,CDCl3)δ8.05(m,1H),7.89(d,J＝6.1Hz,1H),7.53(d,J＝1.3Hz,2H),6.38(d,J＝6.1Hz,1H).
13C NMR(126MHz,Chloroform-d)δ176.69,155.69,154.59,146.18,127.27,125.84,120.50(q,J＝258.3Hz),120.45,117.51,112.84.
ESI-MS:calculated for C10H5F3O3[M+H]-:231.0263found:231.0262.
example 19: synthesis of 6-fluorochromone:
a15 mL pressure-resistant tube was charged with 28mg (0.20mmol) of 5-fluorosalicylaldehyde (CAS number: 347-54-6), 86.4mg (0.40mmol) of 2-fluorovinyl 4- (trifluoromethyl) benzenesulfonic acid, and [ Cp. IrCl ]2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 3 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 87%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.87(d,J＝6.0Hz,1H),7.85(dd,J＝8.3,3.1Hz,1H),7.48(dd,J＝9.1,4.2Hz,1H),7.40(m,J＝9.2,7.6,3.1Hz,1H),6.34(d,J＝6.0Hz,1H).
13C NMR(126MHz,Chloroform-d)δ177.02(d,J＝2.0Hz),160.66,158.69,155.61,152.89,126.18(d,J＝7.3Hz),122.20(d,J＝25.4Hz),120.75–120.22(m),112.41,110.85(d,J＝23.7Hz).
ESI-MS:calculated for C9H5FO2[M+H]-:165.0346,found:165.0345.
example 20: synthesis of 2- ((tert-butoxycarbonyl) amino) -3- (4-oxy-4H-chromen-6-yl) propanoic acid:
a15 mL pressure resistant tube was charged with 61.8mg (0.20mmol) of 2- ((t-butoxycarbonyl) amino) -3- (3-formyl-4-hydroxyphenyl) propionic acid (CAS number: 71522-60-6), 86.4mg (0.40mmol) of 2-fluorovinyl 4-methylbenzenesulfonic acid, and [ Cp IrCl2]8mg (5 mol%), anhydrous potassium carbonate 41.4mg (0.3mmol) and hexafluoroisopropanol 2mL, and reacted at 90 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 15%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ10.98(s,1H),7.85(s,1H),7.71(d,J＝8.4Hz,1H),7.59(d,J＝10.9Hz,1H),7.39(s,1H),7.19(d,J＝7.5Hz,1H),6.30(d,J＝10.9Hz,1H),4.86(t,J＝7.0Hz,1H),3.30(dd,J＝12.4,7.0Hz,1H),1.44(s,9H).
13C NMR(126MHz,Chloroform-d)δ177.25,173.62,157.20,156.12,155.37,134.17,128.20,124.71,124.06,117.06,112.44,79.69,55.65,37.03,28.34.
ESI-MS:calculated for C17H19NO6[M+H]-:333.1212,found:333.1210.
example 21: synthesis of 2- (2,2, 2-trifluoroethoxy) chromone:
a15 mL pressure resistant tube was charged with salicylaldehyde (CAS number: 90-02-8)24.4mg (0.20mmol), 2-difluorovinyl 4-methylbenzenesulfonic acid 93.6mg (0.40mmol), and [ CpRh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate (CAS No.: 20442-70-0)93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and 2mL of trifluoroethanol (CAS No.: 75-89-8) were reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 68%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.18(dd,J＝8.2,1.6Hz,1H),7.68(ddd,J＝9.1,7.4,1.7Hz,1H),7.44(t,J＝7.5Hz,2H),5.71(s,1H),4.59(q,J＝7.7Hz,2H).
13C NMR(126MHz,Chloroform-d)δ179.01,165.01,153.58,133.88,126.16,126.05,125.69–118.76(m),122.99,117.33,89.56,65.12(q,J＝37.8Hz).
19F NMR(471MHz,Chloroform-d)δ-73.63–-73.77(m).
ESI-MS:calculated for C11H7F3O3[M+H]-:245.0420,found:245.0418.
example 22: synthesis of 6-fluoro-2- (2,2, 2-trifluoroethoxy) chromone:
adding 28mg (0.20mmol) of 5-fluorosalicylaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid and [ Cp Rh (CH) into a 15mL pressure-resistant tube3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 54%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.78(dd,J＝8.0,3.1Hz,1H),7.42(dd,J＝9.1,4.1Hz,1H),7.39–7.33(m,1H),5.70(s,1H),4.60(q,J＝7.6Hz,2H).
13C NMR(126MHz,Chloroform-d)δ178.0,165.2,160.1(d,J＝248.1Hz),149.5,124.3(d,J＝7.4Hz),122.2(q,J＝277.5Hz),121.7(d,J＝25.7Hz),119.3(d,J＝8.2Hz),111.3(d,J＝24.0Hz),89.1,65.2(q,J＝37.7Hz).
19F NMR(471MHz,CDCl3)δ-73.74,-114.34.
ESI-MS:calculated for C11H6F4O3[M+H]-:263.0325,found:263.0324.
example 23: synthesis of 6-chloro-2- (2,2, 2-trifluoroethoxy) chromone:
adding 31.3mg (0.20mmol) of 5-chlorosalicylaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid and [ Cp Rh (CH) into a 15mL pressure-resistant tube3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. After the reaction is finished, 5mL of water is added to quench the reaction, 10mL of ethyl acetate and 5mL of saturated saline are added to wash the reaction solution, the organic phase is collected by layering, the aqueous phase is extracted by ethyl acetate for 2 times, and each time, ethyl acetate is used The amount is 5mL, the organic phases are combined, anhydrous sodium sulfate is added for drying, the solvent is removed by reduced pressure distillation, and the product is obtained by column chromatography with the yield of 51%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.12(d,J＝2.4Hz,1H),7.61(dd,J＝8.8,2.5Hz,1H),7.38(d,J＝8.9Hz,1H),5.70(s,1H),4.59(q,J＝7.6Hz,2H).
13C NMR(126MHz,Chloroform-d)δ177.66,165.12,151.81,133.99,132.07,125.67,124.03,122.14(q,J＝277.7Hz),118.98,89.54,65.26(q,J＝37.8Hz).
19F NMR(471MHz,Chloroform-d)δ-73.59–-73.76(m).
ESI-MS:calculated for C11H6ClF3O3[M+H]-:279.0030,found:279.0029.
example 24: synthesis of 6-bromo-2- (2,2, 2-trifluoroethoxy) chromone:
adding 5-bromosalicylaldehyde 40mg (0.20mmol), 2-difluorovinyl 4-methylbenzenesulfonic acid 93.6mg (0.40mmol) and [ Cp Rh (CH) into a 15mL pressure-resistant tube3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 31%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.18(d,J＝2.5Hz,1H),7.67(dd,J＝8.8,2.5Hz,1H),7.25(d,J＝8.8Hz,1H),5.64(s,1H),4.54(q,J＝7.7Hz,2H).
13C NMR(126MHz,Chloroform-d)δ177.5,165.1,152.2,136.8,128.7,124.3,122.1(q,J＝277.9Hz),119.4,119.2,89.5,65.2(q,J＝37.9Hz).
19F NMR(471MHz,CDCl3)δ-73.69.
ESI-MS:calculated for C11H6BrF3O3[M+H]-:322.9525,found:322.9523.
example 25: synthesis of 6-methyl-2- (2,2, 2-trifluoroethoxy) chromone:
a15 mL pressure resistant tube was charged with 27.2mg (0.20mmol) of 2-hydroxy-5-methylbenzaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. multidot.Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate (93.6 mg) (0.40mmol), calcium hydroxide (14.8 mg) (0.20mmol), and trifluoroethanol (2 mL) were reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product with the yield of 48%.
The characterization data of the product are:
1H NMR(500MHz,CDCl3)δ7.84(s,1H),7.37(dd,J＝8.5,2.3Hz,1H),7.21(d,J＝8.5Hz,1H),5.60(s,1H),4.53(q,J＝7.8Hz,2H),2.35(s,3H).
13C NMR(126MHz,CDCl3)δ179.1,164.9,151.7,136.0,134.8,125.4,122.5,122.3(q,J＝277.8Hz),117.0,89.3,65.0(q,J＝37.6Hz),20.9.
19F NMR(471MHz,CDCl3)δ-73.78.
ESI-MS:calculated for C12H9F3O3[M+H]-:259.0576,found:259.0576.
example 26: synthesis of 6-methoxy-2- (2,2, 2-trifluoroethoxy) chromone:
a15 mL pressure resistant tube was charged with 30.4mg (0.20mmol) of 2-hydroxy-5-methoxybenzaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid, and [ Cp > Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 52%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.55(d,J＝3.1Hz,1H),7.35(d,J＝9.0Hz,1H),7.24(dd,J＝9.1,3.1Hz,1H),5.70(s,1H),4.59(q,J＝7.7Hz,2H),3.89(s,3H).
13C NMR(126MHz,Chloroform-d)δ178.96,164.87,157.57,148.07,123.65,123.34,126.07–118.81(m),118.61,105.85,89.12,65.05(q,J＝37.7Hz),56.11.
19F NMR(471MHz,Chloroform-d)δ-73.74(t,J＝7.7Hz).
ESI-MS:calculated for C12H9F3O4[M+H]-:275.0525,found:275.0522.
example 27: synthesis of 6-tert-butyl-2- (2,2, 2-trifluoroethoxy) chromone:
taking 15mL of pressure resistant pipe, adding 5- (tert-butyl)36mg (0.20mmol) of phenyl) -2-hydroxybenzaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl-4-methylbenzenesulfonic acid, [ Cp ] Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 43%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.14(d,J＝2.4Hz,1H),7.70(dd,J＝8.8,2.4Hz,1H),7.34(d,J＝8.8Hz,1H),5.68(s,1H),4.59(q,J＝7.7Hz,2H),1.36(s,9H).
13C NMR(126MHz,Chloroform-d)δ179.36,164.95,151.66,149.39,131.57,122.27(q,J＝277.8Hz),122.23,122.00,116.85,89.35,65.03(q,J＝37.6Hz),34.98,31.40.
19F NMR(471MHz,Chloroform-d)δ-73.68-73.81(m).
ESI-MS:calculated for C15H15F3O3[M+H]-:301.1046,found:301.1043.
example 28: synthesis of 6-nitro-2- (2,2, 2-trifluoroethoxy) chromone:
a15 mL pressure resistant tube was charged with 33.4mg (0.20mmol) of 2-hydroxy-5-nitrobenzaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl-4-methylbenzenesulfonic acid, and [ Cp > Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate (93.6 mg (0.40 mmol)), calcium hydroxide (14.8 mg (0.20mmol), and trifluoroethanol (2 mL) were reacted at 80 ℃ for 10 hours. After the reaction, 5mL of water was added to quench the reaction, and 10mL of ethyl acetate and 5mL of saturated food were addedWashing with saline, collecting organic phase by layers, extracting water phase with ethyl acetate for 2 times, wherein the amount of ethyl acetate is 5mL each time, combining organic phases, adding anhydrous sodium sulfate, drying, distilling under reduced pressure to remove solvent, and performing column chromatography to obtain the product with yield of 20%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.93(d,J＝2.8Hz,1H),8.44(dd,J＝9.1,2.8Hz,1H),7.55(d,J＝9.1Hz,1H),5.73(s,1H),4.59(q,J＝7.6Hz,2H).
13C NMR(126MHz,CDCl3)δ176.9,165.4,156.3,145.5,128.3,122.6,122.0(q,J＝277.9Hz),119.,89.8,65.6(q,J＝37.9Hz),27.2.
19F NMR(471MHz,CDCl3)δ-73.60.
ESI-MS:calculated for C11H6F3NO5[M+H]-:290.0270,found:290.0274.
example 29: synthesis of methyl 6-carboxylate-2- (2,2, 2-trifluoroethoxy) chromone:
a15 mL pressure resistant tube was charged with 36mg (0.20mmol) of methyl 3-formyl-4-hydroxybenzoate, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid, and [ Cp × Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate (93.6 mg) (0.40mmol), calcium hydroxide (14.8 mg) (0.20mmol), and trifluoroethanol (2 mL) were reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 46%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.81(d,J＝2.3Hz,1H),8.30(dd,J＝8.7,2.3Hz,1H),7.47(d,J＝8.7Hz,1H),5.72(s,1H),4.61(q,J＝7.6Hz,2H).
13C NMR(126MHz,Chloroform-d)δ178.01,165.5,165.1,155.8,134.5,128.2,128.0,122.6,122.0(q,J＝278.0Hz),117.7,89.6,65.2(q,J＝37.7Hz),52.5.
19F NMR(471MHz,CDCl3)δ-73.67.
ESI-MS:calculated for C13H9F3O5[M+H]-:303.0474,found:303.0472.
example 30: synthesis of 7-methyl-2- (2,2, 2-trifluoroethoxy) chromone:
a15 mL pressure resistant tube was charged with 27.2mg (0.20mmol) of 2-hydroxy-4-methylbenzaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl-4-methylbenzenesulfonic acid, and [ Cp > Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate (93.6 mg (0.40 mmol)), calcium hydroxide (14.8 mg (0.20mmol), and trifluoroethanol (2 mL) were reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 45%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.97(d,J＝8.1Hz,1H),7.17(d,J＝8.1Hz,1H),7.15(s,1H),5.62(s,1H),4.57(q,J＝7.8Hz,2H),2.43(s,3H).
13C NMR(126MHz,Chloroform-d)δ178.9,164.8,153.6,145.2,127.2,125.6,122.2(q,J＝276.3Hz),120.5,117.1,89.2,64.9(q,J＝37.7Hz),21.8.
ESI-MS:calculated for C12H9F3O3[M+H]-:259.0576,found:259.0576.
example 31: synthesis of 7-chloro-2- (2,2, 2-trifluoroethoxy) chromone:
31.3mg (0.20mmol) of 4-chloro-2-hydroxybenzaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid and [ Cp Rh (CH) were added to a 15mL pressure-resistant tube3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 52%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.09(d,J＝8.4Hz,1H),7.44(d,J＝1.9Hz,1H),7.39(dd,J＝8.5,1.9Hz,1H),5.69(s,1H),4.59(q,J＝7.7Hz,2H).
13C NMR(126MHz,Chloroform-d)δ178.0,165.0,153.6,139.9,127.3,126.8,122.1(d,J＝277.8Hz),121.5,117.6,89.6,65.3(q,J＝37.7Hz).
19F NMR(471MHz,CDCl3)δ-73.69.
ESI-MS:calculated for C11H6ClF3O3[M+H]-:279.0030,found:279.0030.
example 32: synthesis of 7-diethylamino-2- (2,2, 2-trifluoroethoxy) chromone:
taking a 15mL pressure resistant pipe, adding 38.6mg (0.20mmol) of 6-diethylamino salicylaldehyde,2, 2-Difluorovinyl 4-methylbenzenesulfonic acid 93.6mg (0.40mmol), [ Cp. multidot.Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 42%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.93(d,J＝9.0Hz,1H),6.70(dd,J＝9.1,2.4Hz,1H),6.43(d,J＝2.4Hz,1H),5.50(s,1H),4.51(q,J＝7.7Hz,2H),3.43(q,J＝7.1Hz,4H),1.22(t,J＝7.1Hz,6H).
13C NMR(126MHz,Chloroform-d)δ178.69,164.46,156.20,152.13,127.06,122.37(d,J＝277.6Hz),111.48,110.53,96.32,88.25,65.63–64.52(m),44.93,12.53.
19F NMR(471MHz,Chloroform-d)δ-73.75(t,J＝7.7Hz).
ESI-MS:calculated for C15H16F3NO3[M+H]-:316.1155,found:316.1153.
example 33: synthesis of 8-methyl-2- (2,2, 2-trifluoroethoxy) chromone:
a15 mL pressure resistant tube was charged with 27.2mg (0.20mmol) of 2-hydroxy-3-methylbenzaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. multidot.Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. After the reaction, 5mL of water was added to quench the reaction, and 10mL of ethyl acetate and 5mL of saturated brine were added Washing, collecting organic phase by layers, extracting water phase with ethyl acetate for 2 times, wherein the amount of ethyl acetate is 5mL each time, combining organic phases, adding anhydrous sodium sulfate for drying, distilling under reduced pressure to remove solvent, and performing column chromatography to obtain the product with yield of 50%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.91(m,1H),7.45–7.34(m,1H),7.26–7.16(m,1H),5.61(s,1H),4.54(q,J＝7.8Hz,2H),2.39(s,3H).
13C NMR(126MHz,Chloroform-d)δ179.4,164.8,152.0,134.9,126.8,125.4,123.6,122.8,122.3(q,J＝277.8Hz),89.23,65.0(q,J＝37.6Hz),15.45.
19F NMR(471MHz,CDCl3)δ-73.65.
ESI-MS:calculated for C12H9F3O3[M+H]-:259.0576,found:259.0575.
example 34: synthesis of 8-tert-butyl-2- (2,2, 2-trifluoroethoxy) chromone:
a15 mL pressure resistant tube was charged with 36mg (0.20mmol) of 3- (tert-butyl) -2-hydroxybenzaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid, and [ Cp. multidot.Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 45%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.07(dd,J＝7.9,1.7Hz,1H),7.65(dd,J＝7.7,1.7Hz,1H),7.34(t,J＝7.8Hz,1H),5.70(s,1H),4.57(q,J＝7.7Hz,2H),1.49(s,9H).
13C NMR(126MHz,Chloroform-d)δ179.5,165.0,152.5,138.6,131.4,125.5,124.3,123.6,122.2(q,J＝276.0Hz),88.8,65.5(q,J＝37.6Hz),35.1,30.2.
19F NMR(471MHz,CDCl3)δ-73.63.
ESI-MS:calculated for C15H15F3O3[M+H]-:301.1046,found:301.1046.
example 35: synthesis of 6-methyl-4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromene-8-carbaldehyde:
adding 32.8mg (0.20mmol) of 5-methyl-2-hydroxy-m-phthalaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid and [ Cp Rh (CH) into a 15mL pressure-resistant tube 3CN)3](SbF6)225mg (15 mol%), cesium pivalate (93.6 mg (0.40 mmol)), calcium hydroxide (14.8 mg (0.20mmol), and trifluoroethanol (2 mL) were reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product with the yield of 30%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ10.44(s,1H),8.25–8.22(d,2H),7.98(d,J＝2.0Hz,1H),5.78(s,1H),4.73(q,J＝7.7Hz,2H),2.52(s,3H).
13C NMR(126MHz,Chloroform-d)δ187.29,177.79,164.74,151.26,136.31,136.25,132.16,124.53,123.54,125.64–118.86(m),90.14,65.25(q,J＝37.6Hz),20.89.
19F NMR(471MHz,Chloroform-d)δ-73.64–-73.75(m).
ESI-MS:calculated for C13H8F3O4[M+H]-:286.0447,found:286.0447.
example 36: synthesis of 6-tert-butyl-4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromen-8-carbaldehyde:
adding 32.8mg (0.20mmol) of 5- (tert-butyl) -2-hydroxy-m-phthalaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid and [ Cp Rh (CH) into a 15mL pressure-resistant tube3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 35%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ10.48(s,1H),7.80(d,J＝2.5Hz,1H),7.61(d,J＝2.3Hz,1H),4.76(s,1H),4.74(q,J＝8.3Hz,2H),1.31(s,9H).
13C NMR(126MHz,Chloroform-d)δ168.82,157.97,142.45,133.64,128.96,127.34,127.09,125.38,110.22,61.77,60.85(q,J＝37.2Hz),34.33,31.37.
19F NMR(471MHz,Chloroform-d)δ-73.54(t,J＝8.2Hz).
ESI-MS:calculated for C16H15F3O[M+H]-:313.1046,found:313.1043.
example 37: synthesis of 3- (2,2, 2-trifluoroethoxy) -1H-benzo [ f ] chromium-1-one:
taking 15mL of pressure resistant tube, adding 34.4mg (0.20mmol) of 2-hydroxy-1-naphthaldehyde, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid and [ CpRh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 86%.
The characterization data of the product are:
1H NMR(500MHz,DMSO-d6)δ9.91(d,J＝8.4Hz,1H),8.33(d,J＝9.0Hz,1H),8.10(d,J＝7.6Hz,1H),7.77(ddd,J＝8.5,6.9,1.5Hz,1H),7.73(d,J＝9.1Hz,1H),7.68(ddd,J＝8.1,6.9,1.3Hz,1H),6.10(s,1H),5.16(q,J＝8.6Hz,2H).
13C NMR(126MHz,DMSO-d6)δ180.2,163.5,154.2,135.5,130.7,129.6,129.0,128.6,126.6,125.8,123.0(q,J＝277.4Hz),117.2,114.8,90.8,65.0(q,J＝35.7Hz).
19F NMR(471MHz,DMSO)δ-72.59.
ESI-MS:calculated for C15H9F3O3[M+H]-:295.0576,found:295.0573.
example 38: synthesis of 1- (2, 5-dimethyl-1H-indol-3-yl) -2, 2-difluoroethan-1-ol:
taking 15mL of pressure-resistant pipe, adding 54.6mg (0.20mmol) of 9-aldehyde-8-hydroxy-1, 1, 7, 7-tetramethyl julolidine (CAS number: 115662-09-4), 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid, and,[Cp*Rh(CH3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. And after the reaction is finished, adding 5mL of water to quench the reaction, adding 10mL of ethyl acetate and 5mL of saturated saline solution to wash, layering and collecting an organic phase, extracting a water phase for 2 times by using ethyl acetate, wherein the dosage of ethyl acetate is 5mL each time, combining the organic phases, adding anhydrous sodium sulfate to dry, distilling under reduced pressure to remove a solvent, and performing column chromatography to obtain the product, wherein the yield is 39%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ7.84(s,1H),5.52(s,1H),4.47(q,J＝7.7Hz,2H),3.32–3.26(m,2H),3.24–3.19(m,2H),1.85–1.79(m,2H),1.76–1.72(m,2H),1.48(s,6H),1.31(s,6H).
13C NMR(126MHz,Chloroform-d)δ179.15,164.54,152.71,146.88,129.99,125.88–118.77(m),121.01,114.39,111.78,87.33,65.46(q,J＝37.5Hz),47.44,46.84,39.62,35.90,32.63,32.37,30.78,29.43.
19F NMR(471MHz,Chloroform-d)δ-73.61-73.72(m).
ESI-MS:calculated for C21H24F3NO3[M+H]-:396.1781,found:396.1779.
example 39: synthesis of 4-methyl-2- (4-oxo-2- (2,2, 2-trifluoroethoxy) -4H-chromium-6-yl) thiazole-5-carboxylic acid:
15mL of pressure-resistant tube was added with 58.2mg (0.20mmol) of ethyl 2- (3-aldehyde-4-aldehyde phenyl) -4-methylthiazole-5-carboxylate, 93.6mg (0.40mmol) of 2, 2-difluorovinyl 4-methylbenzenesulfonic acid, and [ Cp Rh (CH)3CN)3](SbF6)225mg (15 mol%), cesium pivalate 93.6mg (0.40mmol), calcium hydroxide 14.8mg (0.20mmol) and trifluoroethanol 2mL, and reacted at 80 ℃ for 10 hours. After the reaction is finished, 5mL of water is added for quenching reaction, and thenWashing with 10mL ethyl acetate and 5mL saturated saline solution, collecting organic phase by layering, extracting water phase with ethyl acetate for 2 times, wherein the amount of ethyl acetate is 5mL each time, combining organic phases, adding anhydrous sodium sulfate for drying, distilling under reduced pressure to remove solvent, and performing column chromatography to obtain the product with yield of 43%.
The characterization data of the product are:
1H NMR(500MHz,Chloroform-d)δ8.65(d,J＝2.2Hz,1H),8.35(dd,J＝8.8,2.3Hz,1H),7.51(d,J＝8.8Hz,1H),5.73(s,1H),4.61(q,J＝7.7Hz,2H),4.36(q,J＝7.1Hz,2H),2.78(s,3H),1.39(t,J＝7.1Hz,3H).
13C NMR(126MHz,Chloroform-d)δ178.13,167.55,165.12,162.21,161.33,154.67,131.84,131.20,124.72,123.37,125.62–118.77(m),122.96,118.40,89.82,65.30(q,J＝37.7Hz),61.57,17.62,14.45.
19F NMR(471MHz,Chloroform-d)δ-73.60-73.71(m).
ESI-MS:calculated for C18H14F3NO5S[M+H]-:414.0617,found:414.0615.
as can be seen from the above examples 1 to 39: the suitable substrates of the reaction mainly comprise alkyl, alkoxy, halogenated group, halogenated alkyl, phenyl, nitryl, heterocyclic substituent and diethylamino substituted salicylaldehyde compounds. The reaction is catalyzed by Rh (III) catalyst or Ir (III) catalyst to form five-membered ring metal species, olefin coordination and olefin insertion are carried out to form seven-membered ring metal species, reduction elimination is carried out, addition elimination reaction is carried out, and finally a chromone framework structure is generated. Compared with the synthesis of other chromone compounds, the method only needs to use the alkynyl equivalent synthon (and the fluorine-containing vinyl compound in the invention) which is simple and easy to obtain and has low cost as the preparation raw material. The reaction is applicable to various types of substrates, and the reaction functional group has good tolerance, so that the application range is wide; the reaction yield is high, and the partial reaction yield is up to more than 90%; the reaction process is fast (the reaction time is far shorter than 12h in the related technology), the operation is simple and safe, and the method has the potential of large-scale production.
While the embodiments of the present invention have been described in detail with reference to the specific embodiments, the present invention is not limited to the embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A chromonic compound, wherein: the structural formula is shown as the following formula (III):
in the formula (III), R1And R2Independently selected from hydrogen, alkyl, alkoxy, halogen atom, nitro, ester group, aldehyde group, amino, alkenyl, carboxyl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
x is selected from O atom, N atom or S atom;
R1and R2Cyclization or non-cyclization;
R1and the C atom in the benzene ring of the salicylaldehyde compound shown in the formula (III) forms a ring or does not form a ring;
R2and the C atom in the benzene ring of the salicylaldehyde compound shown in the formula (III) forms a ring or does not form a ring;
R3selected from hydrogen or alkoxy.
2. The chromonic compound of claim 1, wherein: the alkyl group is C1～C20Alkyl groups of (a); preferably, the alkoxy group comprises C 1～C10Alkoxy of (2); preferably, the ester group comprises C1～C10Ester group of (2).
3. The chromonic compound of claim 1, wherein: said aryl group is C1～C20Aryl of (a); preferably, the heteroaryl groupIs C1～C15And a heterocyclic group containing at least one of N, O and S.
4. A process for the preparation of the chromonic compound of any one of claims 1 to 3, wherein: the method comprises the following steps:
mixing salicylaldehyde compounds shown in a formula (I) and fluorine-containing vinyl compounds shown in a formula (II) and then reacting to prepare chromone compounds shown in a formula (III);
in the formulae (I) and (III), R1And R2Independently selected from hydrogen, alkyl, alkoxy, halogen atom, nitro, ester group, aldehyde group, amino, alkenyl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroarene;
x in the formula (I) and the formula (III) is selected from O atom, N atom or S atom;
r in the formulae (I) and (III)1And R2Cyclization or non-cyclization;
r in the formula (I)1And the C atom in the benzene ring of the salicylaldehyde compound shown in the formula (I) forms a ring or does not form a ring;
r in the formula (I)2And the C atom in the benzene ring of the salicylaldehyde compound shown in the formula (I) forms a ring or does not form a ring;
r in the formulae (III) and (II)3Selected from hydrogen or alkoxy;
R in the formula (II)4Selected from hydrogen or fluorine;
r in the formula (II) is selected from benzenesulfonyl, p-methylbenzenesulfonyl, o-methylbenzenesulfonyl, p-fluorobenzenesulfonyl, o-fluorobenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, o-trifluorobenzenesulfonyl, phenyl and naphthyl;
the catalyst for the reaction is a transition metal catalyst.
5. The method of manufacturing according to claim 4, characterized in that: the molar ratio of the salicylaldehyde compound shown in the formula (I) to the fluorine-containing vinyl compound shown in the formula (II) is 1: 2-4.
6. The method of claim 4, wherein: the transition metal catalyst is a trivalent iridium catalyst or a trivalent rhodium catalyst.
7. The method of claim 4, wherein: the solvent for the reaction is at least one of trifluoroethanol, methanol or hexafluoroisopropanol.
8. The method of claim 7, wherein: the volume mol ratio of the solvent of the reaction to the salicylaldehyde compound shown in the formula (I) is 5 mL/mmol-15 mL/mmol.
9. The method of claim 4, wherein: the reaction temperature is 25-120 ℃, and preferably, the reaction time is 3-12 h.
10. Use of a chromone compound according to any one of claims 1 to 3 in the manufacture of any one of an anti-inflammatory drug, an anti-oxidant drug and an anti-cancer drug.
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