CN108640945A - A kind of amides compound and the preparation method and application thereof - Google Patents
A kind of amides compound and the preparation method and application thereof Download PDFInfo
- Publication number
- CN108640945A CN108640945A CN201810596951.8A CN201810596951A CN108640945A CN 108640945 A CN108640945 A CN 108640945A CN 201810596951 A CN201810596951 A CN 201810596951A CN 108640945 A CN108640945 A CN 108640945A
- Authority
- CN
- China
- Prior art keywords
- aryl
- hydrogen
- compound
- base
- saturated aliphatic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 amides compound Chemical class 0.000 title claims abstract description 100
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 239000000758 substrate Substances 0.000 claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- 229920006395 saturated elastomer Polymers 0.000 claims description 36
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 229930195733 hydrocarbon Natural products 0.000 claims description 27
- 150000002430 hydrocarbons Chemical class 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 17
- 125000002252 acyl group Chemical group 0.000 claims description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 229910052709 silver Inorganic materials 0.000 claims description 13
- 239000004332 silver Substances 0.000 claims description 13
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052710 silicon Inorganic materials 0.000 claims description 12
- 239000010703 silicon Substances 0.000 claims description 12
- IAFFEFPJCKQBKK-UHFFFAOYSA-N 2,3-dichloro-1-methyl-4-propan-2-ylbenzene;ruthenium Chemical class [Ru].CC(C)C1=CC=C(C)C(Cl)=C1Cl IAFFEFPJCKQBKK-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 10
- 150000003949 imides Chemical class 0.000 claims description 10
- 150000002503 iridium Chemical class 0.000 claims description 10
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical group [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 9
- 229940071536 silver acetate Drugs 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 8
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 2
- 229910001923 silver oxide Inorganic materials 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 2
- 235000021081 unsaturated fats Nutrition 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 229910052787 antimony Inorganic materials 0.000 claims 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims 1
- 150000001408 amides Chemical class 0.000 abstract description 14
- 238000005905 alkynylation reaction Methods 0.000 abstract description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 48
- KZGWPHUWNWRTEP-UHFFFAOYSA-N ethynyl-tri(propan-2-yl)silane Chemical group CC(C)[Si](C#C)(C(C)C)C(C)C KZGWPHUWNWRTEP-UHFFFAOYSA-N 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 150000001345 alkine derivatives Chemical class 0.000 description 27
- 125000000304 alkynyl group Chemical group 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 description 9
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
- FRUWMYWEARDNTC-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-indole Chemical compound C1C=CC=C2NCCC21 FRUWMYWEARDNTC-UHFFFAOYSA-N 0.000 description 8
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 229960005206 pyrazinamide Drugs 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- UJVWPZIWWKDJNH-UHFFFAOYSA-N (4-acetamido-2-hydroxyphenyl)arsonic acid Chemical class CC(=O)NC1=CC=C([As](O)(O)=O)C(O)=C1 UJVWPZIWWKDJNH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 150000005171 halobenzenes Chemical group 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 125000005968 oxazolinyl group Chemical group 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 5
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000004802 cyanophenyl group Chemical group 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 4
- 230000005311 nuclear magnetism Effects 0.000 description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical group N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010499 C–H functionalization reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000009434 installation Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- YUSWFULMAAAFJQ-UHFFFAOYSA-N 1,3-oxazole quinoline Chemical class C1=COC=N1.N1=CC=CC2=CC=CC=C21 YUSWFULMAAAFJQ-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- WEIWBVGUSBRKNW-UHFFFAOYSA-N ditert-butyl(methyl)silicon Chemical compound CC(C)(C)[Si](C)C(C)(C)C WEIWBVGUSBRKNW-UHFFFAOYSA-N 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- CJQKFKQIFQGELD-UHFFFAOYSA-N propan-2-ylsilicon Chemical compound CC(C)[Si] CJQKFKQIFQGELD-UHFFFAOYSA-N 0.000 description 2
- 150000003214 pyranose derivatives Chemical class 0.000 description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- OZOMQRBLCMDCEG-VIZOYTHASA-N 1-[(e)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)NC(=O)C1 OZOMQRBLCMDCEG-VIZOYTHASA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- CLWRFNUKIFTVHQ-UHFFFAOYSA-N [N].C1=CC=NC=C1 Chemical group [N].C1=CC=NC=C1 CLWRFNUKIFTVHQ-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 150000008430 aromatic amides Chemical class 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000003426 co-catalyst Substances 0.000 description 1
- 238000010959 commercial synthesis reaction Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical class NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention relates to technical field of organic synthesis more particularly to a kind of amides compound and the preparation method and application thereof, and the invention discloses a kind of amides compound preparation methods to include the following steps：In the presence of atent solvent, under the action of catalyst, formula (II) compound is reacted with formula (III) compound, obtain formula (I) compound, this method substrate is simple and easy to get, without the additional common level-one for being oriented to base and assisting, the alkynylation reaction of the direct C-H bond of two level amide, step is few, it is easy to operate, it is efficient, selectivity is good, it is economic and environment-friendly, this method is wide in the extreme to the scope of application of substrate simultaneously, with good Atom economy, the amide compound that the preparation method obtains is completely new amides compound, and it is widely used, it is complicated to solve existing amides compound synthetic reaction, the technical issues of substrate narrow scope of application.
Description
Technical field
The present invention relates to technical field of organic synthesis more particularly to a kind of amides compound and preparation method thereof with answer
With.
Background technology
Alkynes is a kind of very universal functional group, is divided from common simple building block, to synthetic intermediate, biology
Son and natural products are all omnipresent.The generality of triple carbon-carbon bonds also excites the permanent research interest of such functional group, packet
Include laboratory and commercial synthesis.From the seventies in last century, the appearance reacted using the Sonogashira of palladium, copper concerted catalysis, alkynes
The synthetic method of hydrocarbon has obtained significant progress, and develops toward the direction of atom and step economy.As a kind of important
Alkynes, mebenil base aryl ethane act not only as key intermediate by Diels-Alder reactions come Fast back-projection algorithm complexity
Molecule, and the potential source biomolecule activity that has of the aryl amide containing alkynyl of heterocyclic substituted make this kind of compound by extensive
Concern.
In recent years, directly alkynylation reaction is realized using C-H bond as raw material, provide not only introducing and expand molecule
The new method of complexity also becomes the strong strategy for building complicated alkynes.However, currently in order to realizing region
Selectively directly utilize the alkynylation reaction of C-H bond, it usually needs specific substrate, or volume is installed in advance into molecule
Outer homing device.For example, Su is realized using polyfluoro substituted benzene as the oxidative coupling reaction of raw material and end alkynes, polyfluoro generation is built
Interior alkynes [Y.Wei, H.Zhao, J.Kan, W.Su, M.Hong, J.Am.Chem.Soc.2010,132,2522.].
Transition metal-catalyzed carbon-hydrogen bond activation is grown rapidly.Based on transition metal-catalyzed carbon-hydrogen bond activation and official
Energy dough reaction, can shorten reaction process, improve Atom economy, realize that conventional method is difficult to the target product prepared, pole
The development of the big synthetic methodology for having pushed drug molecule and natural products.Recently, the C-H bond based on trivalent rhodium catalysis is lived
Change the alkynes compound that strategy prepares multifunctional dough and has relevant report.2014, Loh, Li, Glorius et al. respectively
Independent development is with [RhCl2Cp*]2For catalyst, there is the additional aryl amide for being oriented to base substitution and can not remove or further
The nitrogen heterocyclic ring of conversion is reacted by the alkynyl reagent of carbon-hydrogen bond activation and high price iodine, realizes nitrogenous aryl, alkenyl
The synthesis of substituted alkynes.Yu and Chatani reports palladium chtalyst bidentate amide and is oriented to base, i.e., the volume in amide nitrogen atom respectively
Outer installation is oriented to the alkynylation reaction of the alkane C-H bond of the amide substrate realization of base.However, on the one hand, the reaction of above-mentioned document
Condition is harsher (substrate reactions scale is 0.1mmol, 120 DEG C, for 24 hours), and substrate needs to install additional homing device in advance
And be difficult conversion or elimination, and react and need the additional alkynyl reagent (Waser for preparing difficult and expensive high price iodine
Reagent), therefore, this catalyst system and catalyzing does not obviously have practicability and economic value also, limits further applying for this method；
On the other hand, relative to nitrogen-atoms, the flatness of oxygen atom is relatively poor, complexing of the oxygen atom to metal in amides compound
Effect is weaker, this is but also even if such compound and metallic catalyst have occurred if invertibity is coordinated subsequent functional group very
Hardly possible realizes that the alkynylation reaction facing challenges of C-H bond occur for high conversion, i.e., this kind of compound：Hardly possible coordination, legibility from.
Therefore, the synthetic method of traditional amides compound is often based on the coupling reaction of functional group's such as carbon-halogen bond, or
Promote the activity and regioselectivity of reaction to install the groups such as pyridine or quinoline in amide nitrogen atom in advance, these are additional
The group of installation is unworthy in synthesis, for follow-up practical application, also to be removed again at the end of reaction, traditional
Synthetic method multistep synthesizes, and reaction is complicated, and substrate narrow scope of application etc., this makes them be received very in terms of commercial Application
Big limitation.
Therefore, a kind of simple, efficient, economic, amides compound with industrial application value of research and development and its preparation
The technical issues of method is current urgent need to resolve.
Invention content
The purpose of the present invention is to provide a kind of amides compound and the preparation method and application thereof, this method substrate is simple
It is easy to get, it is efficient, selective good, economic and environment-friendly, while this method step is few, easy to operate, and also the scope of application of substrate is non-
Chang Guang has good Atom economy, has industrial application value.Its specific technical solution is as follows：
The present invention also provides a kind of amides compounds.
Preferably, amides compound has structure shown in formula (I)；
Wherein, in formula (I)For C6~C14 aryl, C4~C8 heterocycle or heteroaryl containing S, O；
R1Selected from hydrogen, C1~C4 saturated aliphatic hydrocarbons, C1~C4 unsaturated fatty hydrocarbons base, methoxyl group, acetoxyl group,
Aryl, benzyl, benzenesulfonyl ,-CR7C(O)2R8Or CR9R10OH；
R2、R3、R4、R5It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons
It is base, C1~C40 alkoxies, C1~C40 alkylthio groups, methylene-dioxy, halogenated C1~C40 saturated aliphatic hydrocarbons, halogenated
C1~C40 unsaturated fatty hydrocarbons base, halogenated C1~C40 alkoxies, halogen, nitro, cyano ,-CO2R7、-OC(O)R8、-P
(O)(R9)(R10)、-P(O)(OR11)(OR12)、-SO2NR13R14、-NR15R16、-C(O)NR17R18, C6~C14 aryl, C6~C14
Aryloxy group, C1~C10 alkoxies, C2~C9 heteroaryls or C2~C9 heterocycles；
R6Selected from C1~C40 saturated hydrocarbyls, C1~C40 unsaturated alkyls, silicon substrate, C6~C14 aryl, C2~C9 heterocycles
Base；
R7、R9It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base or virtue
Base；
R8、R10It is each independently selected from C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base or aryl；
R11、R12、R13、R14、R15、R16It is unsaturated to be each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40
Aliphatic alkyl, C6~C14 aryl, C2~C9 heteroaryls or C2~C9 heterocycles；
R17Selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base, C6~C14 aryl, C6
~C14 aryl sulfonyls, C1~C10 alkyl sulphonyls, C1~C10 acyl groups, C2~C9 heteroaryls or C2~C9 heterocycles；
R18Selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, the undersaturated aliphatic alkyls of C1~C40, C6~C14 aryl,
C6~C14 aryl sulfonyls, C1~C10 alkyl sulphonyls, C1~C10 acyl groups, C2~C9 heteroaryls.
It should be noted that R2、R3、R4、R5It can be independently selected from above-mentioned group, it can also R2、R3、R4、R5Middle phase
The two adjacent groups and carbon atom being connect with two adjacent groups collectively forms C3~C6 naphthenic base or C2~C9 is miscellaneous
Ring group, i.e. R2、R3、R4、R5Meet a kind of above-mentioned situation.
Preferably, R6Selected from the saturated or unsaturated alkyl of C1~C40, silicon substrate, C6~C14 aryl or C2~C9 heterocycles
Base.
It is highly preferred that R6Selected from silicon substrate or C1~C10 be full or unsaturated alkyl, wherein silicon substrate includes trimethyl silicon substrate, and three
Isopropyl silicon substrate or methyl di-t-butyl silicon substrate.
Preferably, C1~C40 saturated aliphatic hydrocarbons are selected from C1~C40 alkyl.
Preferably, C1~C40 unsaturated fatty hydrocarbons base is selected from C2~C40 alkenyls or C2~C40 alkynyls.
Preferably, C6~C14 aryl includes at least one first substituent group；
First substituent group is selected from hydrogen, halogen, C1~C40 alkyl, C1~C10 acyl groups, C1~C40 alkoxies, trifluoro
Methyl, C6~C14 aryl, C2~C9 heteroaryls, substituted amido, ester group, cyano or phosphono.
It is highly preferred that the first substituent group is selected from methyl, methoxyl group, trifluoromethyl, C6~C14 aryl, C2~C9 heteroaryls
Base ,-NR15R16、-CO2R7, cyano, halogen ,-P (O) (R11)(R12) or-P (O) (OR11)(OR12)。
It is highly preferred that the first substituent group is selected from halogen, 40 alkoxy of C1~C40 alkyl, C1~C10 acyl groups or C1~C.
Preferably, when C6~C14 aryl is free of the first substituent group, C6~C14 aryl is selected from phenyl or naphthyl.
It is highly preferred that when C6~C14 aryl contains the first substituent group, C6~C14 aryl is selected from phenyl, o-tolyl, adjacent first
Oxygen phenyl, o-trifluoromethyl phenyl, adjacent aryl phenyl, adjacent heteroaryl-phenyl, adjacent substituted amido phenyl, adjacent ester group phenyl, adjacent cyanogen
Base phenyl, adjacent halobenzene base, tolyl, m-methoxyphenyl, substituted amido phenyl, m-trifluoromethylphenyl, halobenzene base,
Between aryl phenyl, heteroaryl-phenyl, ester group phenyl, cyano-phenyl, p-methylphenyl, p-methoxyphenyl, to replace amine
Base phenyl, p-trifluoromethyl phenyl, to halobenzene base, to ester group phenyl, to cyano-phenyl, to aryl phenyl and to heteroaryl benzene
Base, 2,3- bi-methoxies phenyl, 1- naphthalenes, 2- naphthalenes or phosphono phenyl.
Preferably, the aryl, C2~C9 heteroaryls and C2~C9 heterocycles include at least one second
Substituent group；
Second substituent group is selected from halogen, C1~C40 alkyl, C1~C10 acyl groups or C1~C40 alkoxies.
Preferably, C2~C9 heteroaryls are selected from furyl, benzofuranyl, thienyl, benzothienyl, niacin
Base, isonicotinic acid base, pyrrole radicals, thiazolyl, oxazolyls, pyrazolyl, imidazole radicals, pyranose, pyridazinyl, pyrazinyl, pyrimidine radicals, pyrrole
Piperidinyl, quinolyl, isoquinolyl or carbazyl.
It is highly preferred that C2~C9 heteroaryls are chosen in particular from 2- furyls, 3- furyls, 2- benzofuranyls, 3- benzo furans
Mutter base, 2- thienyls, 3- thienyls, 2- benzothienyls, 3- benzothienyls, 2- indyls, 3- indyls, 2- pyrrole radicals,
3- pyrrole radicals, 5- thiazolyls, 4- pyrazolyls, 3- pyridyl groups, 4- pyridyl groups, 6- quinolyls, 5- isoquinolyls, 2- pyridyl groups, 2-
Quinolyl, 2- pyrazinyls, 2- pyrimidine radicals, 1- pyrazolyls or 2- thiazolyls.
Preferably, C2~C9 heterocycles are selected from tetrahydric quinoline group, N- acyl group tetrahydric quinoline group, oxazolinyls, substitution
Oxazolinyl, tetrahydro indole base, N- acyl groups tetrahydro indole base, pyrrolin base, tetrahydro pyridyl, tetrahydrofuran base, morpholinyl,
Piperazinyl, piperidyl, pyrrolinyl or imidazolinyl.
It is highly preferred that C2~C9 heterocycles be selected from 6- tetrahydric quinoline groups, N- acyl groups tetrahydric quinoline group, 5- tetrahydro indole bases,
N- acyl group tetrahydro indole base, oxazolinyls, substituted oxazole quinoline base, tetrahydric quinoline group, tetrahydro indole base or 2- oxazolinyls.
The present invention also provides a kind of preparation methods of amides compound, include the following steps：
In the presence of atent solvent, under the action of catalyst, formula (II) compound and formula (III) compound are carried out anti-
It answers, obtains formula (I) compound；
Wherein, X is selected from hydrogen, bromine or iodine, and when X is hydrogen, the reaction need to be added oxidant, in formula (II)Indicate C6
~C14 aryl or C4~C8 heterocycle or heteroaryl containing S, O；
R1Selected from hydrogen, C1~C4 saturated aliphatic hydrocarbons, C1~C4 unsaturated fatty hydrocarbons base, methoxyl group, acetoxyl group,
Aryl, benzyl, benzenesulfonyl ,-CR7C(O)2R8Or CR9R10OH；
R2、R3、R4、R5It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons
It is base, C1~C40 alkoxies, C1~C40 alkylthio groups, methylene-dioxy, halogenated C1~C40 saturated aliphatic hydrocarbons, halogenated
C1~C40 unsaturated fatty hydrocarbons base, halogenated C1~C40 alkoxies, halogen, nitro, cyano ,-CO2R7、-OC(O)R8、-P
(O)(R9)(R10)、-P(O)(OR11)(OR12)、-SO2NR13R14、-NR15R16、-C(O)NR17R18, C6~C14 aryl, C6~C14
Aryloxy group, C1~C10 alkoxies, C2~C9 heteroaryls or C2~C9 heterocycles；
R6Selected from C1~C40 saturated hydrocarbyls, C1~C40 unsaturated alkyls, silicon substrate, C6~C14 aryl, C2~C9 heterocycles
Base；
R7、R9It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base or virtue
Base；
R8、R10It is each independently selected from C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base or aryl；
R11、R12、R13、R14、R15、R16It is unsaturated to be each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40
Aliphatic alkyl, C6~C14 aryl, C2~C9 heteroaryls or C2~C9 heterocycles；
R17Selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base, C6~C14 aryl, C6
~C14 aryl sulfonyls, C1~C10 alkyl sulphonyls, C1~C10 acyl groups, C2~C9 heteroaryls or C2~C9 heterocycles；
R18Selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, the undersaturated aliphatic alkyls of C1~C40, C6~C14 aryl,
C6~C14 aryl sulfonyls, C1~C10 alkyl sulphonyls, C1~C10 acyl groups or C2~C9 heteroaryls.
It should be noted that R2、R3、R4、R5It can be independently selected from above-mentioned group, it can also R2、R3、R4、R5Middle phase
The two adjacent groups and carbon atom being connect with two adjacent groups collectively forms C3~C6 naphthenic base or C2~C9 is miscellaneous
Ring group, i.e. R2、R3、R4、R5Meet a kind of above-mentioned situation.
Preferably, X is hydrogen or bromine.
Preferably, R6Selected from the saturated or unsaturated alkyl of C1~C40, silicon substrate, C6~C14 aryl or C2~C9 heterocycles
Base.
It is highly preferred that R6Selected from silicon substrate or C1~C10 be full or unsaturated alkyl, wherein silicon substrate includes trimethyl silicon substrate, and three
Isopropyl silicon substrate or methyl di-t-butyl silicon substrate.
Preferably, C1~C40 saturated aliphatic hydrocarbons are selected from C1~C40 alkyl.
Preferably, C1~C40 unsaturated fatty hydrocarbons base is selected from C2~C40 alkenyls or C2~C40 alkynyls.
Preferably, C6~C14 aryl includes at least one first substituent group；
First substituent group is selected from hydrogen, halogen, C1~C40 alkyl, C1~C10 acyl groups, C1~C40 alkoxies, trifluoro
Methyl, C6~C14 aryl, C2~C9 heteroaryls, substituted amido, ester group, cyano or phosphono.
It is highly preferred that the first substituent group is selected from methyl, methoxyl group, trifluoromethyl, C6~C14 aryl, C2~C9 heteroaryls
Base ,-NR15R16、-CO2R7, cyano, halogen ,-P (O) (R11)(R12) or-P (O) (OR11)(OR12)。
It is highly preferred that the first substituent group is selected from halogen, 40 alkoxy of C1~C40 alkyl, C1~C10 acyl groups or C1~C.
Preferably, when C6~C14 aryl is free of the first substituent group, C6~C14 aryl is selected from phenyl or naphthyl.
It is highly preferred that when C6~C14 aryl contains the first substituent group, C6~C14 aryl is selected from phenyl, o-tolyl, adjacent first
Oxygen phenyl, o-trifluoromethyl phenyl, adjacent aryl phenyl, adjacent heteroaryl-phenyl, adjacent substituted amido phenyl, adjacent ester group phenyl, adjacent cyanogen
Base phenyl, adjacent halobenzene base, tolyl, m-methoxyphenyl, substituted amido phenyl, m-trifluoromethylphenyl, halobenzene base,
Between aryl phenyl, heteroaryl-phenyl, ester group phenyl, cyano-phenyl, p-methylphenyl, p-methoxyphenyl, to replace amine
Base phenyl, p-trifluoromethyl phenyl, to halobenzene base, to ester group phenyl, to cyano-phenyl, to aryl phenyl and to heteroaryl benzene
Base, 2,3- bi-methoxies phenyl, 1- naphthalenes, 2- naphthalenes or phosphono phenyl.
Preferably, the aryl, C2~C9 heteroaryls and C2~C9 heterocycles include at least one second
Substituent group；
Second substituent group is selected from halogen, C1~C40 alkyl, C1~C10 acyl groups or C1~C40 alkoxies.
Preferably, C2~C9 heteroaryls are selected from furyl, benzofuranyl, thienyl, benzothienyl, niacin
Base, isonicotinic acid base, pyrrole radicals, thiazolyl, oxazolyls, pyrazolyl, imidazole radicals, pyranose, pyridazinyl, pyrazinyl, pyrimidine radicals, pyrrole
Piperidinyl, quinolyl, isoquinolyl or carbazyl.
It is highly preferred that C2~C9 heteroaryls are chosen in particular from 2- furyls, 3- furyls, 2- benzofuranyls, 3- benzo furans
Mutter base, 2- thienyls, 3- thienyls, 2- benzothienyls, 3- benzothienyls, 2- indyls, 3- indyls, 2- pyrrole radicals,
3- pyrrole radicals, 5- thiazolyls, 4- pyrazolyls, 3- pyridyl groups, 4- pyridyl groups, 6- quinolyls, 5- isoquinolyls, 2- pyridyl groups, 2-
Quinolyl, 2- pyrazinyls, 2- pyrimidine radicals, 1- pyrazolyls or 2- thiazolyls.
Preferably, C2~C9 heterocycles are selected from tetrahydric quinoline group, N- acyl group tetrahydric quinoline group, oxazolinyls, substitution
Oxazolinyl, tetrahydro indole base, N- acyl groups tetrahydro indole base, pyrrolin base, tetrahydro pyridyl, tetrahydrofuran base, morpholinyl,
Piperazinyl, piperidyl, pyrrolinyl or imidazolinyl.
It is highly preferred that C2~C9 heterocycles be selected from 6- tetrahydric quinoline groups, N- acyl groups tetrahydric quinoline group, 5- tetrahydro indole bases,
N- acyl group tetrahydro indole base, oxazolinyls, substituted oxazole quinoline base, tetrahydric quinoline group, tetrahydro indole base or 2- oxazolinyls.
Preferably, the molar ratio of formula (II) compound and formula (III) compound is 1:10~10:1.
It is highly preferred that the molar ratio of formula (II) compound and formula (III) compound is 1:3~1:1.
Preferably, the atent solvent be selected from toluene, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, N, N '-dimethyl formamide,
N, N '-dimethyl acetamide, N-Methyl pyrrolidone, dimethyl sulfoxide, 1,2- dichloroethanes, ether, glycol dimethyl ether, second
Nitrile, dichloromethane or acetone；
The oxidant is selected from silver acetate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulphate, copper chloride or bromination
Copper.
The catalyst is selected from dichloro (pentamethylcyclopentadiene base) and closes iridium dimer, dichloro (p-Methylisopropylbenzene) ruthenium two
Aggressiveness, bis- (trifluoromethane sulfonyl group) acid imide silver or silver hexafluoroantimonate；
In the present invention, dichloro (pentamethylcyclopentadiene base) closes iridium dimer, dichloro (p-Methylisopropylbenzene) ruthenium dimer
For major catalyst, bis- (trifluoromethane sulfonyl group) acid imides are silver-colored or silver hexafluoroantimonate is as co-catalyst, and mainly as main reminder
The accelerating agent of agent ligand exchange.
It is highly preferred that atent solvent is 1,2- dichloroethanes, oxidant is silver acetate.
Preferably, the dosage of the catalyst is 0.1~20mol% of the dosage of formula (II) compound, more preferably
2.5mol%~17.5mol%.
It is highly preferred that the dosage of major catalyst is 1~5mol% of the dosage of formula (II) compound, most it is selected as
2.5mol%.
Preferably, the reaction temperature is 20~140 DEG C；
The reaction time is 0.1~40h.
It is highly preferred that reaction temperature be 80~120 DEG C, the reaction time be 12~for 24 hours, most preferably 120 DEG C, 12h.
The present invention also provides amide compounds made from above-mentioned amide compound or above-mentioned preparation method in pharmaceutical synthesis
And/or the application in material.
In conclusion the present invention has the following advantages：
1, the present invention reacts level-one or two level aromatic amides with alkynyl compounds, obtains the level-one containing alkynyl and two
Grade amides compound, substrate are simple and easy to get；
2, alkynylation reaction of the present invention without the additional common level-one for being oriented to base assistance, the direct C-H bond of two level amide,
The tedious steps such as removal, easy to operate after avoiding installation in advance and reacting, economic and environment-friendly, has industrial application value；
3, it is only 1mol%~5mol% that the present invention, which prepares the major catalyst dosage of amide compound, so that the compound is closed
At efficient；
4, there is preparation method of the present invention good chemo-selective, i.e., preparation method of the present invention to use transition metal-catalyzed
Strategy realize amide substrate regioselectivity aryl ortho position C-H bond alkynylation reaction, and amide hydrogen bound to nitrogen keep
It is constant；
5, preparation method of the present invention has extraordinary regioselectivity, that is, reacts the assistance in catalyst and amide
Under, react to regioselectivity on the ortho position C-H bond of amide aromatic ring, without obtain traditional electrophilic substitution reaction neighbour,
Between, to mixture；
6, the scope of application of preparation method substrate of the present invention is very wide, and not only level-one, two level amide can participate in well
The amide of synthetic reaction provided in an embodiment of the present invention, heterocyclic substituted can also participate in synthesis provided in an embodiment of the present invention instead
It answers, and this kind of pyridine groups containing strong coordination of niacinamide and Pyrazinamide incompatible in previous report, it can also
Preferably participate in the reaction；
7, preparation method of the present invention has good Atom economy, after the pre- function dough and the reaction that avoid substrate
The problems such as removing of phase；
8, amide compound of the present invention is completely new amides compound, can be as the simple organic of synthesis complicated molecule
Raw material, in the fields extensive use such as drug, material.
Description of the drawings
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
Some embodiments of invention without having to pay creative labor, may be used also for those of ordinary skill in the art
To obtain other attached drawings according to these attached drawings.
Fig. 1 is total for 2- ((triisopropylsilyl) acetylene) benzamide (3a) nuclear-magnetism provided in the embodiment of the present invention one
It shakes1H spectrograms；
Fig. 2 is total for 2- ((triisopropylsilyl) acetylene) benzamide (3a) nuclear-magnetism provided in the embodiment of the present invention one
It shakes13C spectrograms；
Fig. 3 is 4- acetyl group -2- ((triisopropylsilyl) acetylene) benzamide provided in the embodiment of the present invention two
The nuclear magnetic resonance of (3b)1H spectrograms；
Fig. 4 is 4- acetyl group -2- ((triisopropylsilyl) acetylene) benzamide provided in the embodiment of the present invention two
The nuclear magnetic resonance of (3b)13C spectrograms；
Fig. 5 is that the nuclear-magnetism of 3- ((triisopropylsilyl) acetylene) Pyrazinamide (3c) provided in the embodiment of the present invention three is total
It shakes1H spectrograms；
Fig. 6 is that the nuclear-magnetism of 3- ((triisopropylsilyl) acetylene) Pyrazinamide (3c) provided in the embodiment of the present invention three is total
It shakes13C spectrograms；
Fig. 7 is the core of 3- ((triisopropylsilyl) the acetylene) -2- naphthalenecarboxamides (3d) provided in the embodiment of the present invention four
Magnetic resonance1H spectrograms；
Fig. 8 is the core of 3- ((triisopropylsilyl) the acetylene) -2- naphthalenecarboxamides (3d) provided in the embodiment of the present invention four
Magnetic resonance13C spectrograms；
Fig. 9 is bis- ((triisopropylsilyl) acetylene) the benzene first of 4- acetylaminohydroxyphenylarsonic acids 2,6- provided in the embodiment of the present invention five
The nuclear magnetic resonance of amide (3e)1H spectrograms；
Figure 10 is bis- ((triisopropylsilyl) acetylene) the benzene first of 4- acetylaminohydroxyphenylarsonic acids 2,6- provided in the embodiment of the present invention five
The nuclear magnetic resonance of amide (3e)13C spectrograms；
Figure 11 is N- ((L) -1- benzyl -1- methyl formates base) -1- (2- ((three isopropyls provided in the embodiment of the present invention six
Base silicon substrate) acetylene) phenyl) and methyl-1-amide (3f) nuclear magnetic resonance1H spectrograms；
Figure 12 is N- ((L) -1- benzyl -1- methyl formates base) -1- (2- ((three isopropyls provided in the embodiment of the present invention six
Base silicon substrate) acetylene) phenyl) and methyl-1-amide (3f) nuclear magnetic resonance13C spectrograms；
Figure 13 is (S)-N- (1- the methyl ethanols) -2- ((triisopropylsilyl) acetylene) provided in the embodiment of the present invention seven
The nuclear magnetic resonance of benzamide (3g)1H spectrograms；
Figure 14 is (S)-N- (1- the methyl ethanols) -2- ((triisopropylsilyl) acetylene) provided in the embodiment of the present invention seven
The nuclear magnetic resonance of benzamide (3g)13C spectrograms.
Specific implementation mode
Below in conjunction with the embodiment of the present invention, technical scheme of the present invention is clearly and completely described, it is clear that institute
The embodiment of description is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Other embodiment obtained by those of ordinary skill in the art without making creative efforts belongs to guarantor of the present invention
The range of shield.
Raw material used in amides compound provided by the invention and the preparation method and application thereof and the cities reagent Jun Keyou
Field is bought.
Just a kind of amides compound provided by the present invention and the preparation method and application thereof is described further below.
The preparation of one 2- of embodiment ((triisopropylsilyl) acetylene) benzamide (3a)
Under nitrogen atmosphere, sequentially added in 15mL Schlenk reaction tubes arylsulfonamide compounds 1a (12.1mg,
0.10mmol), alkynyl bromine or alkynes 2 (20 μ L, 0.10mmol), dichloro (pentamethylcyclopentadiene base) conjunction iridium dimer (2.3mg,
0.0025mmol) or dichloro (p-Methylisopropylbenzene) ruthenium dimer (1.5mg, 0.0025mmol), bis- (trifluoromethane sulfonyl group)
Acid imide silver (4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36mmol),
(when reaction is using alkynes bromine, it is not necessarily to excess oxygen agent；When reaction directly uses terminal alkyne, then the acetic acid of 2 equivalents is needed
Silver), 1,2- dichloroethanes (DCE, 1mL) reacts 12 hours in 120 DEG C.It is cooled to room temperature after reaction, through suction filtered through kieselguhr
Afterwards, it is concentrated to give crude product.Silica gel plate prepared by crude product carries out thin layer chromatography separation, and selected solvent is petroleum ether and second
The volume ratio of acetoacetic ester is 10：1, obtain product 2- ((triisopropylsilyl) acetylene) benzamide (3a)：Yellow liquid, yield
93% (27.9mg).
2- ((triisopropylsilyl) acetylene) benzamide (3a) nuclear magnetic resonance hydrogen spectruming determining result is：1H NMR
(400MHz,CDCl3):δ8.18-8.16(m,1H),7.87(brs,1H),7.59-7.56(m,1H),7.46-7.43(m,2H),
5.84(brs,1H),1.16-1.14(m,21H)。
2- ((triisopropylsilyl) acetylene) benzamide (3a) carbon-13 nmr spectra measurement result is：13C NMR
(100MHz,CDCl3):δ167.9,134.7,134.5,131.4,130.9,129.4,120.6,106.1,99.6,19.0,
11.6。
The preparation of embodiment two 4- acetyl group -2- ((triisopropylsilyl) acetylene) benzamide (3b)
Under nitrogen atmosphere, sequentially added in 15mL Schlenk reaction tubes aryl amides 1b (16.4mg,
0.10mmol), alkynyl bromine or alkynes 2 (30 μ L, 0.15mmol), dichloro (pentamethylcyclopentadiene base) conjunction iridium dimer (2.3mg,
0.0025mmol) or dichloro (p-Methylisopropylbenzene) ruthenium dimer (1.5mg, 0.0025mmol), bis- (trifluoromethane sulfonyl group)
Acid imide silver (4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36mmol),
(when reaction is using alkynes bromine, it is not necessarily to excess oxygen agent；When reaction directly uses terminal alkyne, then the acetic acid of 2 equivalents is needed
Silver), 1,2- dichloroethanes (DCE, 1mL) reacts 12 hours in 120 DEG C.It is cooled to room temperature after reaction, through suction filtered through kieselguhr
Afterwards, it is concentrated to give crude product.Silica gel plate prepared by crude product carries out thin layer chromatography separation, and selected solvent is petroleum ether and second
The volume ratio of acetoacetic ester is 5：1, obtain product 4- acetyl group -2- ((triisopropylsilyl) acetylene) benzamide (3b)：White
Solid, yield 76% (26.1mg).
4- acetyl group -2- ((triisopropylsilyl) acetylene) benzamide (3b) nuclear magnetic resonance hydrogen spectruming determining result is：1H
NMR(400MHz,CDCl3) δ 8.24 (d, J=8.4Hz, 1H), 8.11 (s, 1H), 7.96 (d, J=8.4Hz, 1H), 7.83
(brs,1H),6.20(brs,1H),2.64(s,3H),1.17-1.14(m,21H)。
4- acetyl group -2- ((triisopropylsilyl) acetylene) benzamide (3b) carbon-13 nmr spectra measurement result is：13C
NMR(100MHz,CDCl3)δ195.7,165.9,137.7,136.7,133.0,130.0,127.3,119.9,103.5,99.7,
25.8,17.6,10.2。
The present embodiment can be compatible with the ketone carbonyl of high reaction activity, and the alkynyl conversion zone selectively occurs in
The ortho position C-H bond of aryl amide, without being reacted at the ortho position C-H bond of aryl ketones.
Three 3- of embodiment ((triisopropylsilyl) acetylene) Pyrazinamide (3c)
Under nitrogen atmosphere, sequentially added into 15mL Schlenk pipes aryl amides 1c (12.2mg,
0.10mmol), alkynes 2 (40 μ L, 0.40mmol), dichloro (pentamethylcyclopentadiene base) conjunction iridium dimer (2.3mg,
0.0025mmol) or dichloro (p-Methylisopropylbenzene) ruthenium dimer (1.5mg, 0.0025mmol), bis- (trifluoromethane sulfonyl group)
Acid imide silver (4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36mmol),
(when reaction is using alkynes bromine, it is not necessarily to excess oxygen agent；When reaction directly uses terminal alkyne, then the acetic acid of 2 equivalents is needed
Silver), 1,2- dichloroethanes (DCE, 1mL) reacts 16 hours in 120 DEG C.It is cooled to room temperature after reaction, through suction filtered through kieselguhr
Afterwards, silica gel plate prepared by the crude product being concentrated to give carries out thin layer chromatography separation, and selected solvent is petroleum ether and acetic acid second
The volume ratio of ester is 3：1, obtain product 3- ((triisopropylsilyl) acetylene) Pyrazinamide (3c)：Yellow solid, yield 67%
(20.2mg)。
3- ((triisopropylsilyl) acetylene) Pyrazinamide (3c) nuclear magnetic resonance hydrogen spectruming determining result is：1H NMR
(400MHz,CDCl3) δ 8.82 (s, 1H), 8.68 (d, J=4.8Hz, 1H), 7.98 (d, J=5.2Hz, 1H), 7.82 (brs,
1H),6.20(brs,1H),1.15-1.14(m,21H)。
3- ((triisopropylsilyl) acetylene) Pyrazinamide (3c) carbon-13 nmr spectra measurement result is：13C NMR
(100MHz,CDCl3)δ165.6,154.8,149.6,140.6,123.1,116.2,103.2,102.4,18.6,11.2。
In the present embodiment, due to pyridine nitrogen atom and the extremely strong coordination ability of metal so that previous metal catalytic it is straight
It is difficult suitable in pyridine derivate to connect the reaction of C-H bond function dough.It, can be directly with good medicine in the present embodiment
It is reacted at the ortho position C-H bond of active Pyrazinamide, and it is potential multifunctional by further converting to obtain to be introduced directly into alkynyl
The picolinamide derivatives of dough are expected to find value in drug molecule.
Example IV 3- ((triisopropylsilyl) acetylene) -2- naphthalenecarboxamides (3d)
Under nitrogen atmosphere, aryl amides 1d (17.1mg, 0.10mmol), alkynyl are added into 15mL reaction tubes
Bromine or alkynes 2 (30 μ L, 0.15mmol), dichloro (pentamethylcyclopentadiene base) close iridium dimer (2.3mg, 0.0025mmol), or
Person's dichloro (p-Methylisopropylbenzene) ruthenium dimer (1.5mg, 0.0025mmol), bis- (trifluoromethane sulfonyl group) acid imide silver
(6.0mg, 0.015mmol) or silver hexafluoroantimonate (5.3mg, 0.015mmol), sodium acetate (30mg, 0.36mmol), silver acetate
(20mg, 0.12mmol) (when reaction is using alkynes bromine, is not necessarily to excess oxygen agent；When reaction directly uses terminal alkyne, then
Need the silver acetate of 2 equivalents), 1,2- dichloroethanes (DCE, 1mL), mixing is reacted 12 hours in 100 DEG C.It is cold after reaction
But concentrated to obtain crude product after vacuum filtration to room temperature.Silica gel plate prepared by crude product carries out thin layer chromatography separation, institute
It is 20 to select the volume ratio that solvent is petroleum ether and ethyl acetate：1, obtain product 3- ((triisopropylsilyl) acetylene) -2- naphthalenes
Formamide (3d)：Yellow solid, yield 92% (30.3mg).
3- ((triisopropylsilyl) acetylene) -2- naphthalenecarboxamides (3d) nuclear magnetic resonance hydrogen spectruming determining result is：1H NMR
(400MHz,CDCl3) δ 8.73 (s, 1H), 8.10 (s, 1H), 8.04 (brs, 1H), 7.93 (d, J=7.6Hz, 1H), 7.81 (d,
J=7.6Hz, 1H), 7.56 (t, J=7.4Hz, 2H), 6.26 (brs, 1H), 1.17-1.14 (m, 21H).
3- ((triisopropylsilyl) acetylene) -2- naphthalenecarboxamides (3d) carbon-13 nmr spectra measurement result is：13C NMR
(100MHz,CDCl3)δ167.9,135.1,133.8,132.3,132.0,130.3,129.2,128.6,127.8,127.1,
116.7,106.2,98.0,18.7,11.3。
Bis- ((triisopropylsilyl) acetylene) benzamides (3e) of five 4- acetylaminohydroxyphenylarsonic acids 2,6- of embodiment
Under nitrogen atmosphere, aryl amides 1e (17.8mg, 0.10mmol), alkynyl are added into 15mL reaction tubes
Bromine or alkynes 2 (60 μ L, 0.30mmol), dichloro (pentamethylcyclopentadiene base) close iridium dimer (2.3mg, 0.0025mmol), or
Person's dichloro (p-Methylisopropylbenzene) ruthenium dimer (1.2mg, 0.0020mmol), bis- (trifluoromethane sulfonyl group) acid imide silver
(4.0mg, 0.010mmol) or silver hexafluoroantimonate (5.3mg, 0.015mmol), sodium acetate (30mg, 0.36mmol), silver acetate
(20mg, 0.12mmol) (when reaction is using alkynes bromine, is not necessarily to excess oxygen agent；When reaction directly uses terminal alkyne, then
Need the silver acetate of 2 equivalents), 1,2- dichloroethanes (DCE, 1mL), mixing is reacted 12 hours in 80 DEG C.It cools down after reaction
It is concentrated to obtain crude product after vacuum filtration to room temperature.Silica gel plate prepared by crude product carries out thin layer chromatography separation, selected
Solvent is that the volume ratio of petroleum ether and ethyl acetate is 3：1, obtain product 4- acetylaminohydroxyphenylarsonic acids 2, bis- ((the triisopropyl silicon of 6-
Base) acetylene) benzamide (3e)：Yellow liquid, yield 58% (31.2mg).
Bis- ((triisopropylsilyl) acetylene) benzamide (3e) the nuclear magnetic resonance hydrogen spectruming determining results of 4- acetylaminohydroxyphenylarsonic acids 2,6-
For：1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.29(s,1H),8.12(brs,1H),7.96(brs,1H),5.78
(brs,1H),2.21(s,3H),1.17-1.13(m,42H)。
Bis- ((triisopropylsilyl) acetylene) benzamide (3e) the carbon-13 nmr spectra measurement results of 4- acetylaminohydroxyphenylarsonic acids 2,6-
For：13C NMR(100MHz,CDCl3)δ168.7,166.7,141.5,134.8,128.9,123.8,105.9,102.0,
101.8,101.0,25.1,19.1,19.0,11.6,11.5。
The present embodiment can be compatible with the acetylamino of high reaction activity, and the alkynyl conversion zone selectively occurs
In the ortho position C-H bond of aryl amide, without being reacted at the ortho position C-H bond of arylaceto amino.This more demonstrates level-one
The coordination ability that amide is oriented to base is better than acetylamino, also illustrates the good regioselectivity of the conversion, this is also amino
The selective later stage derivatization of substituted benzamides bioactive molecule provides new strategy.
Six N- of embodiment ((L) -1- benzyl -1- methyl formates base) -1- (2- ((triisopropylsilyl) acetylene) phenyl) first
Base -1- amides (3f)
Under nitrogen atmosphere, aryl amides 1e (28.3mg, 0.10mmol), alkynyl are added into 15mL reaction tubes
Bromine or end alkynes 2 (30 μ L, 0.15mmol), dichloro (pentamethylcyclopentadiene base) close iridium dimer (2.3mg, 0.0025mmol)
Or dichloro (p-Methylisopropylbenzene) ruthenium dimer (1.5mg, 0.0025mmol), bis- (trifluoromethane sulfonyl group) acid imide silver
(4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36mmol) (work as reaction
When using alkynes bromine, it is not necessarily to excess oxygen agent；When reaction directly uses terminal alkyne, then the silver acetate of 2 equivalents is needed), 1,2-
Dichloroethanes (DCE, 1mL) reacts 12 hours in 120 DEG C.It is cooled to room temperature after reaction, after suction filtered through kieselguhr, concentration
Obtain crude product.Silica gel plate prepared by crude product carries out thin layer chromatography separation, and selected solvent is petroleum ether and ethyl acetate
Volume ratio be 10：1, obtain product N- ((L) -1- benzyl -1- methyl formates base) -1- (2- ((triisopropylsilyl) acetylene)
Phenyl) methyl-1-amide (3f)：White solid, yield 78% (36.1mg).
N- ((L)-1- benzyl-1- methyl formates base)-1- (2- ((triisopropylsilyl) acetylene) phenyl) methyl-1-amide
(3f) nuclear magnetic resonance hydrogen spectruming determining result is：1H NMR(400MHz,CDCl3) δ 7.90-7.85 (m, 1H), 7.70 (d, J=
7.2Hz, 1H), 7.58-7.55 (m, 1H), 7.39 (t, J=7.2Hz, 3.6Hz 2H), 7.25-7.21 (m, 2H), 7.18 (d, J
=7.2Hz, 2H), 5.02 (q, J=6.8Hz, 1H), 3.68 (s, 3H), 3.29 (dd, J=14.0,6.8Hz, 1H), 3.20 (dd,
J=13.6,6.4Hz, 1H), 1.15-1.13 (m, 21H).
N- ((L)-1- benzyl-1- methyl formates base)-1- (2- ((triisopropylsilyl) acetylene) phenyl) methyl-1-amide
(3f) carbon-13 nmr spectra measurement result is：13C NMR(100MHz,CDCl3)δ134.8,130.5,129.3,128.7,
128.5,127.0,54.5,38.13 18.70,11.3。
The present embodiment can be compatible with aryl amide derived from chiral amino acid esters, and obtain the alkynyl production of chiral holding
Object, and in view of the high activity of alkynyl, such as the product of high function dough can be obtained by the reaction by electrophilic, nucleophilic addition so that
The conversion has powerful practicability.
Seven (s)-N- of embodiment (1- methyl ethanols) -2- ((triisopropylsilyl) acetylene) benzamide (3g)
Under nitrogen atmosphere, aryl amides 1g (17.9mg, 0.10mmol), alkynyl are added into 15mL reaction tubes
Bromine or alkynyl hydrogen 2 (30 μ L, 0.15mmol), dichloro (pentamethylcyclopentadiene base) close iridium dimer (2.3mg, 0.0025mmol)
Or dichloro (p-Methylisopropylbenzene) ruthenium dimer (1.5mg, 0.0025mmol), bis- (trifluoromethane sulfonyl group) acid imide silver
(4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36mmol) (work as reaction
When using alkynes bromine, it is not necessarily to excess oxygen agent；When reaction directly uses terminal alkyne, then the silver acetate of 2 equivalents is needed), 1,2-
Dichloroethanes (DCE, 1mL) reacts 12 hours in 120 DEG C.It is cooled to room temperature after reaction, after suction filtered through kieselguhr, concentration
Obtain crude product.Silica gel plate prepared by crude product carries out thin layer chromatography separation, selected solvent or eluant, eluent be petroleum ether and
The volume ratio of ethyl acetate is 5：1, obtain product (S)-N- (1- methyl ethanols) -2- ((triisopropylsilyl) acetylene) benzoyl
Amine (3g)：White solid, yield 82% (29.4mg).
(S)-N- (1- methyl ethanols) -2- ((triisopropylsilyl) acetylene) benzamide (3g) nuclear magnetic resonance hydrogen spectruming determining
As a result it is：1H NMR(400MHz,CDCl3) δ 8.14 (brs, 1H), 8.09 (t, J=4.8Hz, 1H), 7.57-7.55 (m, 1H),
7.42 (t, J=4.4Hz, 2H), 4.05-4.01 (m, 1H), 3.59-3.53 (m, 1H), 3.43-3.36 (m, 1H), 1.21 (d, J
=6.4Hz, 2H), 1.14-1.13 (m, 21H).
(S)-N- (1- methyl ethanols) -2- ((triisopropylsilyl) acetylene) benzamide (3g) carbon-13 nmr spectra measures
As a result it is：13C NMR(100MHz,CDCl3)δ167.6,134.6,134.5,130.7,130.2,129.0,119.8,105.5,
99.1,67.9,48.2,20.9,18.7,11.2。
The present embodiment obtains the alkynyl of chiral holding in addition to that can be compatible with aryl amide derived from above-mentioned chiral amino acid esters
Change product, which can also be compatible with amide derived from biologically active amino alcohol.
Above example can be seen that the substrate in the embodiment of the present invention is simple and easy to get, and synthesis step is few, economic and environment-friendly,
And what can be simple and efficient prepares amide compound.
The above, the above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although with reference to before
Stating embodiment, invention is explained in detail, it will be understood by those of ordinary skill in the art that：It still can be to preceding
The technical solution recorded in each embodiment is stated to modify or equivalent replacement of some of the technical features；And these
Modification or replacement, the spirit and scope for various embodiments of the present invention technical solution that it does not separate the essence of the corresponding technical solution.
Claims (10)
1. a kind of amides compound, which is characterized in that have structure shown in formula (I)；
Wherein, in formula (I)Indicate C6~C14 aryl or C4~C8 heterocycle or heteroaryl containing S, O；
R1Selected from hydrogen, C1~C4 saturated aliphatic hydrocarbons, C1~C4 unsaturated fatty hydrocarbons base, methoxyl group, acetoxyl group, aryl,
Benzyl, benzenesulfonyl ,-CR7C(O)2R8Or CR9R10OH；
R2、R3、R4、R5It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base, C1
~C40 alkoxies, C1~C40 alkylthio groups, methylene-dioxy, halogenated C1~C40 saturated aliphatic hydrocarbons, halogenated C1~
C40 unsaturated fatty hydrocarbons base, halogenated C1~C40 alkoxies, halogen, nitro, cyano ,-CO2R7、-OC(O)R8、-P(O)
(R9)(R10)、-P(O)(OR11)(OR12)、-SO2NR13R14、-NR15R16、-C(O)NR17R18, C6~C14 aryl, C6~C14 virtue
Oxygroup, C1~C10 alkoxies, C2~C9 heteroaryls or C2~C9 heterocycles；
R6Selected from C1~C40 saturated hydrocarbyls, C1~C40 unsaturated alkyls, silicon substrate, C6~C14 aryl, C2~C9 heterocycles；
R7、R9It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base or aryl；
R8、R10It is each independently selected from C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base or aryl；
R11、R12、R13、R14、R15、R16It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fats
Race's alkyl, C6~C14 aryl, C2~C9 heteroaryls or C2~C9 heterocycles；
R17Selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base, C6~C14 aryl, C6~
C14 aryl sulfonyls, C1~C10 alkyl sulphonyls, C1~C10 acyl groups, C2~C9 heteroaryls or C2~C9 heterocycles；
R18Selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, the undersaturated aliphatic alkyls of C1~C40, C6~C14 aryl, C6~
C14 aryl sulfonyls, C1~C10 alkyl sulphonyls, C1~C10 acyl groups or C2~C9 heteroaryls.
2. amides compound according to claim 1, which is characterized in that C6~C14 aryl includes at least one
First substituent group；
Second substituent group be selected from hydrogen, halogen, C1~C40 alkyl, C1~C10 acyl groups, C1~C40 alkoxies, trifluoromethyl,
C6~C14 aryl, C2~C9 heteroaryls, substituted amido, ester group, cyano or phosphono.
3. amides compound according to claim 1, which is characterized in that the aryl, C2~C9 heteroaryls and
C2~C9 heterocycles include at least one second substituent group；
Second substituent group is selected from halogen, C1~C40 alkyl, C1~C10 acyl groups or C1~C40 alkoxies.
4. a kind of preparation method of amides compound, which is characterized in that include the following steps：
In the presence of atent solvent, under the action of catalyst, formula (II) compound is reacted with formula (III) compound,
Obtain formula (I) compound；
Wherein, X is selected from hydrogen, bromine or iodine, when X is hydrogen, reaction addition oxidant, in formula (II)Indicate C6~C14 virtues
Base or C4~C8 heterocycle or heteroaryl containing S, O；
R1Selected from hydrogen, C1~C4 saturated aliphatic hydrocarbons, C1~C4 unsaturated fatty hydrocarbons base, methoxyl group, acetoxyl group, aryl,
Benzyl, benzenesulfonyl ,-CR7C(O)2R8Or CR9R10OH；
R2、R3、R4、R5It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base, C1
~C40 alkoxies, C1~C40 alkylthio groups, methylene-dioxy, halogenated C1~C40 saturated aliphatic hydrocarbons, halogenated C1~
C40 unsaturated fatty hydrocarbons base, halogenated C1~C40 alkoxies, halogen, nitro, cyano ,-CO2R7、-OC(O)R8、-P(O)
(R9)(R10)、-P(O)(OR11)(OR12)、-SO2NR13R14、-NR15R16、-C(O)NR17R18, C6~C14 aryl, C6~C14 virtue
Oxygroup, C1~C10 alkoxies, C2~C9 heteroaryls or C2~C9 heterocycles；
R6Selected from C1~C40 saturated hydrocarbyls, C1~C40 unsaturated alkyls, silicon substrate, C6~C14 aryl, C2~C9 heterocycles；
R7、R9It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base or aryl；
R8、R10It is each independently selected from C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base or aryl；
R11、R12、R13、R14、R15、R16It is each independently selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fats
Race's alkyl, C6~C14 aryl, C2~C9 heteroaryls or C2~C9 heterocycles；
R17Selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, C1~C40 unsaturated fatty hydrocarbons base, C6~C14 aryl, C6~
C14 aryl sulfonyls, C1~C10 alkyl sulphonyls, C1~C10 acyl groups, C2~C9 heteroaryls or C2~C9 heterocycles；
R18Selected from hydrogen, C1~C40 saturated aliphatic hydrocarbons, the undersaturated aliphatic alkyls of C1~C40, C6~C14 aryl, C6~
C14 aryl sulfonyls, C1~C10 alkyl sulphonyls, C1~C10 acyl groups or C2~C9 heteroaryls.
5. preparation method according to claim 4, which is characterized in that formula (II) compound and formula (III) compound
Molar ratio be 1:10~10:1.
6. preparation method according to claim 4, which is characterized in that the atent solvent is selected from toluene, tetrahydrofuran, 1,
4- dioxane, N, N '-dimethyl formamide, N, N '-dimethyl acetamide, N-Methyl pyrrolidone, dimethyl sulfoxide, 1,2- bis-
Chloroethanes, ether, glycol dimethyl ether, acetonitrile, dichloromethane or acetone；
The oxidant is selected from silver acetate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulphate, copper chloride or copper bromide.
7. preparation method according to claim 4, which is characterized in that the catalyst is selected from dichloro (pentamethyl ring penta 2
Alkenyl) close iridium dimer, dichloro (p-Methylisopropylbenzene) ruthenium dimer, bis- (trifluoromethane sulfonyl group) acid imide silver or hexafluoro antimony
Sour silver.
8. preparation method according to claim 7, which is characterized in that the dosage of the catalyst is formula (II) compound
0.1~20mol% of dosage.
9. preparation method according to claim 4, which is characterized in that the reaction temperature is 20~140 DEG C；
The reaction time is 0.1~40h.
10. the preparation side described in amide compound or claim 4 to 9 any one described in claims 1 to 3 any one
Application of the amide compound made from method in pharmaceutical synthesis and/or material.
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| CN110305155A (en) * | 2019-07-23 | 2019-10-08 | 广东工业大学 | A kind of imine derivative and its preparation method and application containing alkynyl |
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