CN111499565B - 一种2,3,4,6-四取代吡啶类化合物的制备方法 - Google Patents
一种2,3,4,6-四取代吡啶类化合物的制备方法 Download PDFInfo
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- CN111499565B CN111499565B CN202010322777.5A CN202010322777A CN111499565B CN 111499565 B CN111499565 B CN 111499565B CN 202010322777 A CN202010322777 A CN 202010322777A CN 111499565 B CN111499565 B CN 111499565B
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- aryl
- heteroaryl
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- 10mmol
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- -1 2,3,4, 6-tetra-substituted pyridine compound Chemical class 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- 125000001424 substituent group Chemical group 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 17
- 150000001412 amines Chemical class 0.000 claims abstract description 13
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 8
- 238000006452 multicomponent reaction Methods 0.000 claims abstract description 8
- 238000005580 one pot reaction Methods 0.000 claims abstract description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 4
- 150000003863 ammonium salts Chemical group 0.000 claims abstract description 4
- 150000003141 primary amines Chemical class 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 31
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 23
- 239000005695 Ammonium acetate Substances 0.000 claims description 23
- 229940043376 ammonium acetate Drugs 0.000 claims description 23
- 235000019257 ammonium acetate Nutrition 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 21
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
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- 229910001385 heavy metal Inorganic materials 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 72
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- 239000000706 filtrate Substances 0.000 description 19
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- OTKCEEWUXHVZQI-UHFFFAOYSA-N 1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(=O)CC1=CC=CC=C1 OTKCEEWUXHVZQI-UHFFFAOYSA-N 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 18
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- 238000010791 quenching Methods 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
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- 238000000605 extraction Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 8
- YEKFSEYSPFEQAB-UHFFFAOYSA-N 6-(2-methoxyphenyl)-2,3,4-triphenylpyridine Chemical compound COC1=C(C=CC=C1)C1=CC(=C(C(=N1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 YEKFSEYSPFEQAB-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 230000000171 quenching effect Effects 0.000 description 7
- 150000008062 acetophenones Chemical class 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- WYIVZJJEFMSEFS-UHFFFAOYSA-N 2,3,4,6-tetraphenylpyridine Chemical compound C1=CC=CC=C1C(N=C1C=2C=CC=CC=2)=CC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 WYIVZJJEFMSEFS-UHFFFAOYSA-N 0.000 description 4
- AWZPHDZXMZDJEO-UHFFFAOYSA-N 2,3,4-triphenyl-6-pyridin-3-ylpyridine Chemical compound C1(=CC=CC=C1)C1=CC(=NC(=C1C1=CC=CC=C1)C1=CC=CC=C1)C=1C=NC=CC=1 AWZPHDZXMZDJEO-UHFFFAOYSA-N 0.000 description 4
- KPSGVWBKSYVEES-UHFFFAOYSA-N 3-(4,5,6-triphenylpyridin-2-yl)phenol Chemical compound C1(=CC=CC=C1)C1=CC(=NC(=C1C1=CC=CC=C1)C1=CC=CC=C1)C=1C=C(C=CC=1)O KPSGVWBKSYVEES-UHFFFAOYSA-N 0.000 description 4
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 4
- QMKXMPWXSNGSOP-UHFFFAOYSA-N 6-(2-bromophenyl)-2,3,4-triphenylpyridine Chemical compound BrC1=C(C=CC=C1)C1=CC(=C(C(=N1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 QMKXMPWXSNGSOP-UHFFFAOYSA-N 0.000 description 4
- JDYCXAITEPGBIG-UHFFFAOYSA-N 6-(3-bromophenyl)-2,3,4-triphenylpyridine Chemical compound BrC=1C=C(C=CC=1)C1=CC(=C(C(=N1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 JDYCXAITEPGBIG-UHFFFAOYSA-N 0.000 description 4
- ITWOFZBXUWBTSH-UHFFFAOYSA-N 6-(4-bromophenyl)-2,3,4-triphenylpyridine Chemical compound BrC1=CC=C(C=C1)C1=CC(=C(C(=N1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 ITWOFZBXUWBTSH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- AFRMPVBNHKPZLC-UHFFFAOYSA-N 2,3,4-triphenyl-6-pyridin-2-ylpyridine Chemical compound C1(=CC=CC=C1)C1=CC(=NC(=C1C1=CC=CC=C1)C1=CC=CC=C1)C1=NC=CC=C1 AFRMPVBNHKPZLC-UHFFFAOYSA-N 0.000 description 3
- SSQLIYYLBUFPED-UHFFFAOYSA-N 6-(2-methylphenyl)-2,3,4-triphenylpyridine Chemical compound C1(=CC=CC=C1)C1=NC(=CC(=C1C1=CC=CC=C1)C1=CC=CC=C1)C1=C(C=CC=C1)C SSQLIYYLBUFPED-UHFFFAOYSA-N 0.000 description 3
- FWRJLBUKIPKQIN-UHFFFAOYSA-N 6-(3-methoxyphenyl)-2,3,4-triphenylpyridine Chemical compound COC=1C=C(C=CC=1)C1=CC(=C(C(=N1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 FWRJLBUKIPKQIN-UHFFFAOYSA-N 0.000 description 3
- XANSRSBFXOZOPK-UHFFFAOYSA-N 6-(3-methylphenyl)-2,3,4-triphenylpyridine Chemical compound C1(=CC=CC=C1)C1=NC(=CC(=C1C1=CC=CC=C1)C1=CC=CC=C1)C=1C=C(C=CC=1)C XANSRSBFXOZOPK-UHFFFAOYSA-N 0.000 description 3
- PJLWRIWCOYSPDA-UHFFFAOYSA-N 6-(4-chlorophenyl)-2,3,4-triphenylpyridine Chemical compound ClC1=CC=C(C=C1)C1=CC(=C(C(=N1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 PJLWRIWCOYSPDA-UHFFFAOYSA-N 0.000 description 3
- SILOCCQYVATNCT-UHFFFAOYSA-N 6-(4-methylphenyl)-2,3,4-triphenylpyridine Chemical compound C1(=CC=CC=C1)C1=NC(=CC(=C1C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=C(C=C1)C SILOCCQYVATNCT-UHFFFAOYSA-N 0.000 description 3
- BSQQVGGJKQBYBF-UHFFFAOYSA-N 6-tert-butyl-2,3,4-triphenylpyridine Chemical compound C(C)(C)(C)C1=CC(=C(C(=N1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 BSQQVGGJKQBYBF-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 description 2
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 2
- LUJMEECXHPYQOF-UHFFFAOYSA-N 3-hydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1 LUJMEECXHPYQOF-UHFFFAOYSA-N 0.000 description 2
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- HGFOMMFDQAPBAR-UHFFFAOYSA-N 4-(4,5,6-triphenylpyridin-2-yl)phenol Chemical compound C1(=CC=CC=C1)C1=CC(=NC(=C1C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=C(C=C1)O HGFOMMFDQAPBAR-UHFFFAOYSA-N 0.000 description 2
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- CEAXNHHESYMDCD-UHFFFAOYSA-N 6-(4-methoxyphenyl)-2,3,4-triphenylpyridine Chemical compound COC1=CC=C(C=C1)C1=CC(=C(C(=N1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 CEAXNHHESYMDCD-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 229910017912 NH2OH Inorganic materials 0.000 description 2
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- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
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- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
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- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 2
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- 125000006413 ring segment Chemical group 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
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- JYAQYXOVOHJRCS-UHFFFAOYSA-N 1-(3-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(Br)=C1 JYAQYXOVOHJRCS-UHFFFAOYSA-N 0.000 description 1
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- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- YRNDGUSDBCARGC-UHFFFAOYSA-N 2-methoxyacetophenone Chemical compound COCC(=O)C1=CC=CC=C1 YRNDGUSDBCARGC-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
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- 206010012601 diabetes mellitus Diseases 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种2,3,4,6‑四取代吡啶类化合物的制备方法，包括如下步骤：将如式(II)所示的二芳基酮类化合物、如式(III)所示的芳醛类化合物、如式(IV)所示的酮类化合物和胺源混合，进行多组分反应，一锅法制得如式(I)所示的2,3,4,6‑四取代吡啶类化合物；所述的胺源为铵盐、氨水、伯胺或盐酸羟胺；R1和R2均为芳基，所述的芳基任选被1～5个取代基取代；R3为芳基或杂芳基，所述的芳基或杂芳基任选被1～5个取代基取代；R4为芳基、杂芳基或脂肪基，所述的芳基、杂芳基或脂肪基任选被1～5个取代基取代。本发明提供的制备方法原料价廉易得；革除金属催化剂的使用，从源头上避免医药化学品中重金属污染；底物适用性广，具有较好的应用价值和潜在的社会经济效益。
Description
技术领域
本发明属于医药化工中间体合成技术领域，具体涉及一种2,3,4,6-四取代吡啶类化合物的制备方法。
背景技术
多取代吡啶类化合物是一类重要的杂环类化合物，在许多天然产物、功能材料、电化学、农药、药物、有机催化以及各种有价值的配体中，吡啶骨架经常作为核心结构出现，如治疗糖尿病的罗格列酮、常用的抗组胺扑尔敏、治疗胃溃疡的奥美拉唑。因此，在现代杂环化学中，人们对这一骨架的构建进行了广泛的研究，建立了大量高效的区域选择性合成这类化合物的方法，特别是过渡金属催化的C-H官能化和环化反应。
尽管文献中对吡啶的合成进行了大量的研究和应用，但对2,3,4,6-四取代吡啶的合成却鲜有报道。目前关于2,3,4,6-四取代吡啶类化合物的合成方法主要有以下四类。
第一类是以氨基烯、醛类化合物和芳基碘化物为原料，在金属钯(Pd)的催化下，多组分反应制备2,3,4,6-四取代吡啶类化合物(Synthesis of MultisubstitutedPyridines.Org.Lett.2013,15,334-337)。该方法为无溶剂体系，且产物收率较高(63-90％)。
第二类是在碱促进下，一锅法由炔酮和胺类化合物在无金属条件下制备2,3,4,6-四取代吡啶类化合物(Base-Promotedβ-C(sp3)–H Functionalization of Enaminones:AnApproach to Polysubstituted Pyridines.J.Org.Chem.2015,80,6584-6589)。该方法具有较好的底物官能团适用性，收率最高可达82％，但原料炔烃酮、胺类化合物均难以采购，需要自行制备，因此底物普适性差。
第三类是以N-磺酰基酮亚胺和炔烃为原料，在Rh(III)和金属银(Ag)的催化下，发生环化反应，制备2,3,4,6-四取代吡啶类化合物(Highly Functionalized PyridinesSynthesis from N-Sulfonyl Ketimines and Alkynes Using the N–S Bond as anInternal Oxidant.Org.Lett.2014,16,1684-1687)。该方法是Rh(III)催化的C-H活化的第一个例子，是通过新的C-C/C-N键的形成，S-N/S-C(或S-O)键的断裂，以及在非常温和的条件下的脱硫来合成2,3,4,6-四取代吡啶类化合物。
第四类是利用金属铜(Cu)为催化剂，在碱性条件下催化肟类化合物和α,β不饱和酮亚胺发生环化反应，制备2,3,4,6-四取代吡啶类化合物(Synthesis of HighlySubstituted Pyridines through Copper-Catalyzed Condensation of Oximes andalpha,beta-Unsaturated Imines.Angew.Chem.Int.Ed.2017,56,8240-8244)。该方法反应条件温和，底物官能团适用性较高，区域选择性高。
以上四类方法均存在高度依赖金属催化剂、底物官能团适用性差等不足。随着人们对药物中的重金属残留问题的不断重视，开发一种非金属催化或无需使用催化剂、原料易得的2,3,4,6-四取代吡啶类化合物的制备方法意义重大。
发明内容
本发明所要解决的技术问题是：提供一种革除金属催化剂的2,3,4,6-四取代吡啶类化合物的制备方法，以芳醛、酮、二芳基酮和胺源为原料，高效制备2,3,4,6-四取代吡啶类化合物。
本发明解决上述技术问题所提供的技术方案为：
一种2,3,4,6-四取代吡啶类化合物的制备方法，包括如下步骤：
将如式(II)所示的二芳基酮类化合物、如式(III)所示的芳醛类化合物、如式(IV)所示的酮类化合物和胺源混合，进行多组分反应，一锅法制得如式(I)所示的2,3,4,6-四取代吡啶类化合物；所述的胺源为铵盐、氨水、伯胺或盐酸羟胺；
其中，式(I)、(II)、(III)和(IV)中，
R1和R2均为芳基，所述的芳基任选被1～5个取代基取代；
R3为芳基或杂芳基，所述的芳基或杂芳基任选被1～5个取代基取代；
R4为芳基、杂芳基或脂肪基，所述的芳基、杂芳基或脂肪基任选被1～5个取代基取代；
所述的R1、R2、R3、R4相同或不同。
本发明所述制备方法的推测反应机理如下所示(以胺源为醋酸铵为例)，酮(IV)和芳醛(III)缩合成查尔酮再与二芳基乙酮(II)反应，然后加氨环合、空气氧化，一锅法制备得到2，3，4，6-四取代吡啶类化合物，不经中间体的分离，无额外催化剂，操作简便，收率稳定。
优选地，所述的杂芳基为5～6元杂芳基，所述5～6元杂芳基包含1、2、3或4个独立选自-C(＝O)NH-、-NH-、-S(＝O)2NH-、-S(＝O)NH-、N、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-NHC(＝O)NH-、-NHC(＝S)NH-或-H2P(＝O)-NH-的杂原子或杂原子团。
进一步优选，所述的杂芳基为噻吩基、呋喃基、吡啶基或吡咯基。
优选地，所述的脂肪族为C1～8烷基。
优选地，所述的取代基分别独立地为H、F、Cl、Br、I、NO2、NH2、OH、C1～3烷基、C1～3烷氧基，所述的C1～3烷基或C1～3烷氧基任选被1、2或3个H、F、Cl、Br、I、NO2、NH2、OH取代。
进一步优选，所述的取代基为H、F、Cl、Br、I、NO2、NH2、OH、甲基、甲氧基、三氟甲基或三氟甲氧基。
优选地，所述的R1为
优选地，所述的R2为
优选地，所述的R3为
优选地，所述的R4为
优选地，所述的胺源为卤化铵、硝酸铵、醋酸铵、甲酸铵、苄胺、氨水或盐酸羟胺。进一步优选为醋酸铵。
优选地，所述的多组分反应的反应温度为40～150℃，反应时间为1～30小时。进一步优选地，反应温度为50～120℃，反应时间为15～25小时。
通过考察反应温度发现，本发明反应在110℃左右能很好地进行转化，得到最佳收率，因此，进一步优选反应温度为80～120℃；通过考察反应时间发现，此反应在22小时内得到最佳收率，延长反应时间对收率没有明显影响，而缩短反应时间则导致收率降低；因此，进一步优选反应时间15～25小时。在反应温度为80～120℃、反应时间为10～20小时条件下收率均在80％左右。
优选地，所述的多组分反应在无溶剂下进行或者在反应溶剂为DMF(N,N-二甲基甲酰胺)、DMSO(二甲基亚砜)、CH3CN(乙腈)、甲苯下进行。
所述的芳醛类化合物、酮类化合物、二芳基酮类化合物和胺源的摩尔比为1:1:1:1～4。进一步优选为1:1:1:2.8～3.2。
除非另有规定，术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。
术语“任选被取代的”是指可以被取代，也可以不被取代，并且取代基的种类和数目在化学上可以实现的基础上可以是任意的。
除非另有规定，当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“C1-8烷基”用于表示直链或支链的由1至8个碳原子组成的饱和碳氢基团。所述C1-8烷基包括C1-8、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C8、C7、C6和C5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-8烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基、庚基、辛基等。
除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，本发明术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自-C(＝O)NH-、-NH-、-S(＝O)2NH-、-S(＝O)NH-、N、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-NHC(＝O)NH-、-NHC(＝S)NH-或-H2P(＝O)-NH-的杂原子或杂原子团，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。
与现有技术相比，本发明具有如下有益效果：
1、本发明所述的制备方法无需使用催化剂，从源头上杜绝金属催化剂的使用，可避免医药化学品中重金属污染。
2、本发明所述的制备方法反应原子经济性高，可在空气下进行，且不需要额外氧化剂或添加剂，副产物为水，符合绿色化学理念。
3、本发明所述的制备方法原料廉价易得、结构多样；底物适用性广，对于含有不同官能团的芳醛类化合物、酮类化合物、二芳基酮类化合物，均有较佳的收率，最高可达88％，具有较好的应用价值和潜在的社会经济效益。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1：2,3,4,6-四苯基吡啶(Ia)的制备
将苯乙酮(1.2g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在100℃下搅拌反应20小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的2,3,4,6-四苯基吡啶(Ia)，白色固体3.3g，以苯乙酮计算收率：87％。
1H NMR(400MHz,CDCl3)δ8.18-8.15(m,2H),7.78(s,1H),7.49(t,J＝7.2Hz,2H),7.44-7.37(m,3H),7.24-7.19(m,6H),7.14-7.12(m,2H),7.09-7.04(m 3H),6.93-6.91(m,2H).13C NMR(101MHz,CDCl3)δ157.99,154.61,150.64,140.99,139.85,139.10,137.87,132.88,131.44,130.20,129.34,129.01,128.71,127.94,127.72,127.53,127.38,127.35,127.07,126.59,120.38.ESI-MS:m/z[M+H]+384。
实施例2：6-(2-溴苯基)-2,3,4-三苯基吡啶(Ib)的制备
将2-溴苯乙酮(1.99g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在120℃下搅拌反应19小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(2-溴苯基)-2,3,4-三苯基吡啶(Ib)，白色固体3.7g，以苯乙酮计算收率：81％。
1H NMR(400MHz,CDCl3)δ7.77(dd,J＝7.6,1.7Hz,1H),7.73–7.68(m,2H),7.46–7.41(m,1H),7.37–7.31(m,2H),7.28(d,J＝1.7Hz,1H),7.24–7.16(m,6H),7.16–7.12(m,2H),7.12–7.05(m,3H),6.98–6.92(m,2H).13C NMR(101MHz,CDCl3)δ158.03,156.61,156.58,149.64,140.97,140.70,139.43,137.61,133.45,133.04,131.87,131.47,130.13,129.77,129.46,127.96,127.78,127.63,127.45,127.40,126.73,124.70,122.06.HRMS(ESI):calcd.for C29H21BrN[M+H]+462.0852；found 462.0856。
实施例3：6-(2-氯苯基)-2,3,4-三苯基吡啶(Ic)的制备
将2-氯苯乙酮(1.54g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在110℃下搅拌反应18小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(2-氯苯基)-2,3,4-三苯基吡啶(Ic)，白色固体3.5g，以苯乙酮计算收率：83％。
1H NMR(400MHz,CDCl3)δ7.82(dd,J＝7.6,1.8Hz,1H),7.74(s,1H),7.50(dd,J＝7.8,1.4Hz,1H),7.39(td,J＝7.5,1.5Hz,1H),7.36-7.32(m,3H),7.23–7.16(m,6H),7.15–7.05(m,5H),6.96–6.92(m,2H).13C NMR(101MHz,CDCl3)δ158.15,155.16,149.67,140.72,139.44,138.99,137.61,133.04,132.38,131.93,131.44,130.20,130.09,129.60,129.45,127.93,127.76,127.60,127.42,127.38,127.08,126.70,124.79.HRMS(ESI):calcd.forC29H21ClN[M+H]+418.1357；found 418.1355。
实施例4：6-(2-甲氧基苯基)-2,3,4-三苯基吡啶(Id)的制备
将2-甲氧基苯乙酮(1.5g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在120℃下搅拌反应18小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(2-甲氧基苯基)-2,3,4-三苯基吡啶(Ic)，白色固体3.2g，以苯乙酮计算收率：77％。
1H NMR(400MHz,CDCl3)δ8.00(dd,J＝7.6,1.8Hz,1H),7.92(s,1H),7.41–7.31(m,3H),7.23–7.19(m,3H),7.18-7.16(m,3H),7.15–7.10(m,3H),7.09-7.06(m,3H),7.05–7.01(m,1H),6.96–6.90(m,2H),3.92(s,3H).13C NMR(101MHz,CDCl3)δ157.87,157.19,154.36,149.37,141.15,140.02,138.05,132.42,131.59,131.51,130.18,129.97,129.54,128.92,127.84,127.68,127.51,127.19,127.17,126.50,125.01,121.17,111.32,55.73.HRMS(ESI):calcd.for C30H24NO[M+H]+414.1852；found 414.1850。
实施例5：6-(2-甲基苯基)-2,3,4-三苯基吡啶(Ie)的制备
将2-甲基苯乙酮(1.34g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在100℃下搅拌反应15小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(2-甲基苯基)-2,3,4-三苯基吡啶(Ic)，白色固体3.5g，以苯乙酮计算收率：89％。
1H NMR(400MHz,CDCl3)δ7.61-7.58(m,1H),7.47(s,1H),7.35–7.27(m,5H),7.23–7.15(m,6H),7.15–7.04(m,5H),6.97–6.92(m,2H),2.58(s,3H).13C NMR(101MHz,CDCl3)δ158.50,157.65,150.01,140.94,140.14,139.64,137.83,136.20,132.24,131.51,130.92,130.12,129.94,129.40,128.31,127.91,127.72,127.52,127.35,127.26,126.59,125.92,123.95,20.84.HRMS(ESI):calcd.for C30H24N[M+H]+398.1903；found 398.1907。
实施例6：6-(3-溴苯基)-2,3,4-三苯基吡啶(If)的制备
将3-溴苯乙酮(1.99g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在100℃下搅拌反应15小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(3-溴苯基)-2,3,4-三苯基吡啶(If)，白色固体3.8g，以苯乙酮计算收率：82％。
1H NMR(400MHz,CDCl3)δ7.44–7.38(m,3H),7.20–7.15(m,5H),7.01-6.98(m,5H),6.95–6.86(m,6H),6.79–6.76(m,1H).13C NMR(101MHz,CDCl3)δ156.46,150.27,140.90,138.45,138.17,133.73,132.36,131.34,130.97,130.44,130.24,130.02,129.25,128.65,127.95,127.66,127.62,127.54,127.41,127.36,127.00,126.28,126.21.HRMS(ESI):calcd.for C29H21BrN[M+H]+462.0852；found 462.0850。
实施例7：6-(3-甲氧基苯基)-2,3,4-三苯基吡啶(Ig)的制备
将3-甲氧基苯乙酮(1.5g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在110℃下搅拌反应16小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(3-甲氧基苯基)-2,3,4-三苯基吡啶(Ig)，白色固体3.4g，以苯乙酮计算收率：83％。
1H NMR(400MHz,CDCl3)δ7.78–7.70(m,3H),7.43–7.34(m,3H),7.25–7.17(m,6H),7.17–7.11(m,2H),7.11–7.03(m,3H),7.00-6.96(m,1H),6.95–6.88(m,2H),3.90(s,3H).13CNMR(101MHz,CDCl3)δ160.05,157.91,155.38,150.91,150.63,140.94,139.82,137.85,133.02,131.42,130.22,129.69,129.34,127.93,127.72,127.50,127.36,126.60,121.60,120.52,119.53,114.82,112.47,55.43.HRMS(ESI):calcd.for C30H24NO[M+H]+414.1852；found 414.1853。
实施例8：6-(3-甲基苯基)-2,3,4-三苯基吡啶(Ih)的制备
将3-甲基苯乙酮(1.34g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在100℃下搅拌反应15小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(3-甲基苯基)-2,3,4-三苯基吡啶(Ih)，白色固体3.5g，以苯乙酮计算收率：88％。
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.94(d,J＝7.6Hz,1H),7.76(s,1H),7.41–7.33(m,3H),7.23–7.17(m,6H),7.15–7.11(m,2H),7.09–7.02(m,3H),6.93–6.89(m,2H),2.44(s,3H).13C NMR(101MHz,CDCl3)δ157.97,155.83,150.57,141.06,139.91,139.10,138.33,137.93,132.80,131.47,130.24,129.81,129.36,128.62,127.94,127.78,127.71,127.54,127.37,127.34,126.57,124.22,120.47,21.62.HRMS(ESI):calcd.for C30H24N[M+H]+398.1903；found 398.1906。
实施例9：6-(3-羟基苯基)-2,3,4-三苯基吡啶(Ii)的制备
将3-羟基苯乙酮(1.36g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在90℃下搅拌反应18小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(3-羟基苯基)-2,3,4-三苯基吡啶(Ii)，白色固体2.4g，以苯乙酮计算收率：61％。
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.72(dd,J＝2.6,1.6Hz,1H),7.67-7.64(m,1H),7.38–7.32(m,3H),7.24-7.20(m,6H),7.16–7.11(m,2H),7.10–7.02(m,3H),6.93-6.89(m,3H).13C NMR(101MHz,CDCl3)δ158.06,156.21,155.22,150.76,140.76,139.69,137.69,133.19,131.41,130.15,129.94,129.33,128.55,127.97,127.73,127.56,127.48,127.44,126.65,120.74,119.31,116.27,114.13.HRMS(ESI):calcd.for C29H22NO[M+H]+400.1696；found 400.1695。
实施例10：6-(4-溴苯基)-2,3,4-三苯基吡啶(Ij)的制备
将4-溴苯乙酮(1.99g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在100℃下搅拌反应18小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(4-溴苯基)-2,3,4-三苯基吡啶(Ij)，白色固体3.8g，以苯乙酮计算收率：83％。
1H NMR(400MHz,CDCl3)δ8.06(d,J＝8.8Hz,2H),7.75(s,1H),7.61(d,J＝8.8Hz,2H),7.38–7.33(m,2H),7.24-7.20(m,6H),7.15–7.03(m,5H),6.94–6.88(m,2H).13C NMR(101MHz,CDCl3)δ158.17,154.37,150.84,140.82,139.67,137.96,137.71,133.26,131.87,131.40,130.18,129.33,128.64,128.02,127.80,127.61,127.53,127.49,126.72,123.52,120.12.HRMS(ESI):calcd.for C29H21BrN[M+H]+462.0852；found 462.0851。
实施例11：6-(4-氯苯基)-2,3,4-三苯基吡啶(Ik)的制备
将4-氯苯乙酮(1.54g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在100℃下搅拌反应18小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(4-氯苯基)-2,3,4-三苯基吡啶(Ik)，白色固体3.6g，以苯乙酮计算收率：85％。
1H NMR(400MHz,CDCl3)δ8.12(d,J＝8.4Hz,2H),7.74(s,1H),7.45(d,J＝8.4Hz,2H),7.39–7.34(m,2H),7.24-7.20(m,6H),7.15–7.03(m,5H),6.94–6.88(m,2H).13C NMR(101MHz,CDCl3)δ158.12,154.32,150.81,140.82,139.67,137.70,137.50,135.12,133.18,131.39,130.15,129.30,128.89,128.32,127.99,127.77,127.58,127.50,127.46,126.69,120.12.HRMS(ESI):calcd.for C29H21ClN[M+H]+418.1357；found 418.1358。
实施例12：6-(4-甲氧基苯基)-2,3,4-三苯基吡啶(Il)的制备
将4-甲氧基苯乙酮(1.5g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在110℃下搅拌反应15小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(4-甲氧基苯基)-2,3,4-三苯基吡啶(Il)，白色固体3.5g，以苯乙酮计算收率：85％。
1H NMR(400MHz,CDCl3)δ8.13(d,J＝8.8Hz,2H),7.71(s,1H),7.41–7.33(m,2H),7.24–7.18(m,6H),7.16–7.10(m,2H),7.10–6.98(m,5H),6.94–6.88(m,2H),3.88(s,3H).13CNMR(101MHz,CDCl3)δ160.56,157.80,155.28,150.59,141.10,139.99,138.00,132.21,131.74,131.50,130.24,129.37,128.38,127.94,127.71,127.53,127.35,126.53,119.61,114.09,55.40.HRMS(ESI):calcd.for C30H24NO[M+H]+414.1852；found 414.1855。
实施例13：6-(4-甲基苯基)-2,3,4-三苯基吡啶(Im)的制备
将4-甲氧基苯乙酮(1.34g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在100℃下搅拌反应15小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(4-甲基苯基)-2,3,4-三苯基吡啶(Im)，白色固体3.5g，以苯乙酮计算收率：88％。
1H NMR(400MHz,CDCl3)δ8.07(d,J＝8.0Hz,2H),7.75(s,1H),7.40–7.35(m,2H),7.28(d,J＝7.9Hz,2H),7.23-7.19(m,6H),7.15–7.10(m,2H),7.08–6.99(m,3H),6.92-6.90(m,2H),2.41(s,3H).13C NMR(101MHz,CDCl3)δ157.86,155.61,150.55,141.08,139.95,139.00,137.98,136.31,132.57,131.47,130.23,129.44,129.36,127.91,127.70,127.50,127.33,127.30,126.94,126.53,120.01,21.35.HRMS(ESI):calcd.for C30H24N[M+H]+398.1903；found 398.1901。
实施例14：6-(4-羟基苯基)-2,3,4-三苯基吡啶(In)的制备
将4-羟基苯乙酮(1.36g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在110℃下搅拌反应16小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(4-羟基苯基)-2,3,4-三苯基吡啶(In)，白色固体3.2g，以苯乙酮计算收率：79％。
1H NMR(400MHz,CDCl3)δ8.01(d,J＝8.8Hz,2H),7.68(s,1H),7.36–7.34(m,2H),7.24–7.15(m,6H),7.14–7.08(m,2H),7.08–7.01(m,3H),6.93–6.88(m,2H),6.86(d,J＝8.8Hz,2H).13C NMR(101MHz,CDCl3)δ157.92,156.92,155.53,150.70,140.85,139.86,137.83,132.33,131.46,130.16,129.33,128.63,127.93,127.69,127.53,127.41,127.35,126.53,119.96,115.70.HRMS(ESI):calcd.for C29H22NO[M+H]+400.1696；found 400.1694。
实施例15：4,5,6-三苯基-2,2'-联吡啶(Io)的制备
将2-乙酰基吡啶(1.21g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在110℃下搅拌反应15小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的4,5,6-三苯基-2,2'-联吡啶(Io)，白色固体2.6g，以苯乙酮计算收率：68％。
1H NMR(400MHz,CDCl3)δ8.69(d,J＝4.8Hz,1H),8.61(d,J＝8.0Hz,1H),8.47(s,1H),7.82(td,J＝7.7,1.8Hz,1H),7.39(dd,J＝6.7,3.0Hz,2H),7.31(ddd,J＝7.5,4.8,1.2Hz,1H),7.24–7.18(m,6H),7.18–7.13(m,2H),7.10–7.04(m,3H),6.95–6.91(m,2H).13CNMR(101MHz,CDCl3)δ157.67,156.10,154.41,150.93,149.12,140.95,139.67,137.92,136.91,134.40,131.42,130.20,129.48,127.84,127.76,127.58,127.45,127.32,126.69,123.78,121.55,120.98.HRMS(ESI):calcd.for C28H21N2[M+H]+385.1699；found 385.1695。
实施例16：4,5,6-三苯基-2,3'-联吡啶(Ip)的制备
将3-乙酰基吡啶(1.21g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在110℃下搅拌反应16小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的4,5,6-三苯基-2,3'-联吡啶(Ip)，白色固体2.7g，以苯乙酮计算收率：71％。
1H NMR(400MHz,CDCl3)δ9.35(s,1H),8.66(d,J＝4.8Hz,1H),8.49(dt,J＝8.0,2.0Hz,1H),7.79(s,1H),7.60–7.32(m,4H),7.23-7.21(m,5H),7.17–7.02(m,5H),6.97–6.81(m,2H).13C NMR(101MHz,CDCl3)δ158.52,153.01,151.00,149.91,148.34,140.63,139.44,137.53,134.60,133.69,131.36,130.14,129.30,128.06,127.83,127.63,127.58,126.81,123.92,123.72,123.63,120.43.HRMS(ESI):calcd.for C28H21N2[M+H]+385.1699；found 385.1696。
实施例17：2,3,4-三苯基-6-(2-噻吩)吡啶(Iq)的制备
将2-乙酰基噻吩(1.26g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在110℃下搅拌反应15小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的2,3,4-三苯基-6-(2-噻吩)吡啶(Iq)，白色固体2.5g，以苯乙酮计算收率：63％。
1H NMR(400MHz,CDCl3)δ8.02(d,J＝2.8Hz,1H),7.77(dd,J＝5.1,1.2Hz,1H),7.63(s,1H),7.39-7.35(m,3H),7.23–7.16(m,6H),7.12-7.10(m,2H),7.08–6.99(m,3H),6.94–6.84(m,2H).13C NMR(101MHz,CDCl3)δ157.98,151.93,150.66,142.09,140.90,139.79,137.92,132.63,131.49,130.25,129.34,127.98,127.75,127.55,127.44,127.40,126.60,126.51,126.22,123.96,120.21.HRMS(ESI):calcd.for C27H20NS[M+H]+390.1311；found390.1316。
实施例18：6-(叔丁基)-2,3,4-三苯基吡啶(Ir)的制备
将频呐酮(1.00g,10mmol)、苯甲醛(1.06g,10mmol)、二苯乙酮(1.96g,10mmol)、乙酸铵(2.31g,30mmol)在90℃下搅拌反应15小时。反应结束后，加入水(15mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到所需的6-(叔丁基)-2,3,4-三苯基吡啶(Is)，白色固体2.6g，以苯乙酮计算收率：73％。
1H NMR(400MHz,CDCl3)δ7.34–7.30(m,3H),7.21–7.14(m,6H),7.09–.01(m,5H),6.89–6.85(m,2H),1.47(s,9H).13C NMR(101MHz,CDCl3)δ167.67,156.30,149.79,141.32,140.40,138.34,131.51,131.10,130.31,129.41,127.79,127.63,127.34,127.09,127.04,126.33,118.94,37.55,30.30.HRMS(ESI):calcd.for C27H26N[M+H]+364.2060；found364.2064。
实施例19-35：
将二苯乙酮衍生物(II)(10mmol)、苯甲醛衍生物(III)(10mmol)、苯乙酮衍生物(IV)(10mmol)和乙酸铵(30mmol)和对甲苯磺酸(860mg,5mmol)的DMF溶液(10mL)在120℃下搅拌反应16小时。反应结束后，加入水(20mL)淬灭，用乙酸乙酯萃取(3×8mL)，合并有机相并用无水硫酸钠干燥，过滤后将滤液减压旋干溶剂，经硅胶柱层析快速分离得到目标化合物(Ik-i’)，反应式如下式所示；原料选择及结果如表1所示。
表1
Claims (8)
1.一种2,3,4,6-四取代吡啶类化合物的制备方法，其特征在于，包括如下步骤：将如式II所示的二芳基酮类化合物、如式III所示的芳醛类化合物、如式IV所示的酮类化合物和胺源混合，进行多组分反应，一锅法制得如式I所示的2,3,4,6-四取代吡啶类化合物；所述的芳醛类化合物、酮类化合物、二芳基酮类化合物和胺源的摩尔比为1:1:1:1～4；
所述的多组分反应的反应温度为40～150℃，反应时间为1～30小时；
所述的胺源为铵盐、氨水、伯胺或盐酸羟胺；
其中，式I、II、III和IV中，
R1和R2均为芳基，所述的芳基任选被1～5个取代基取代；
R3为芳基或杂芳基，所述的芳基或杂芳基任选被1～5个取代基取代；
R4为芳基、杂芳基或脂肪基，所述的芳基、杂芳基或脂肪基任选被1～5个取代基取代；
所述的R1、R2、R3、R4相同或不同；
所述的多组分反应在无溶剂下进行或者在反应溶剂为DMF、DMSO、CH3CN、甲苯下进行。
2.根据权利要求1所述的制备方法，其特征在于，所述的杂芳基为5～6元杂芳基，所述5～6元杂芳基包含1、2、3或4个独立选自-NH-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-O-、-S-的杂原子或杂原子团。
3.根据权利要求1所述的制备方法，其特征在于，所述的杂芳基为5～6元杂芳基，所述5～6元杂芳基包含1、2、3或4个独立选自-C(＝O)NH-、-S(＝O)2NH-、-S(＝O)NH-、-C(＝O)O-、-NHC(＝O)NH-、-NHC(＝S)NH-或-H2P(＝O)-NH-的杂原子团。
4.根据权利要求1所述的制备方法，其特征在于，所述的杂芳基为噻吩基、呋喃基、吡啶基或吡咯基。
5.根据权利要求1所述的制备方法，其特征在于，所述的脂肪基为C1～8烷基。
6.根据权利要求1所述的制备方法，其特征在于，所述的取代基分别独立地为-H、-F、-Cl、-Br、-I、-NO2、-NH2、-OH、未被取代或被取代的C1～3烷基、未被取代或被取代的C1～3烷氧基，所述的C1～3烷基或C1～3烷氧基任选被1、2或3个-H、-F、-Cl、-Br、-I、-NO2、-NH2、-OH取代。
7.根据权利要求1所述的制备方法，其特征在于，所述的取代基为-H、-F、-Cl、-Br、-I、-NO2、-NH2、-OH、甲基、甲氧基、三氟甲基或三氟甲氧基。
8.根据权利要求1所述的制备方法，其特征在于，所述的铵盐为卤化铵、硝酸铵、醋酸铵或甲酸铵；所述的伯胺为苄胺。
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| Title |
|---|
| Diversity-Oriented Synthesis of Kro¨hnke Pyridines;Bo Jiang et al.;《J. Comb. Chem.》;20091231;第11卷;第846-850页 * |
| Synthesis of Highly Substituted Pyridines through Copper-Catalyzed Condensation of Oximes and a,b-Unsaturated Imines;WeiWen Tan et al.;《Angew.Chem. Int. Ed.》;20171231;第56卷;第8240-8244页 * |
| 无溶剂反应在杂环合成中的应用进展;余富朝 等;《有机化学》;20101231;第30卷;第1421-1430页 * |
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