CN108947887A - 一种二芳基取代二羰基化合物的合成方法 - Google Patents
一种二芳基取代二羰基化合物的合成方法 Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 29
- -1 dicarbonyl compound Chemical class 0.000 title claims abstract description 16
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000008367 deionised water Substances 0.000 claims abstract description 13
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 13
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical class Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000012074 organic phase Substances 0.000 claims abstract description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000010949 copper Substances 0.000 claims abstract description 12
- 229910052802 copper Inorganic materials 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 9
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 claims abstract description 8
- IFPHDUVGLXEIOQ-UHFFFAOYSA-N ortho-iodosylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I=O IFPHDUVGLXEIOQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- YNHJECZULSZAQK-UHFFFAOYSA-N tetraphenylporphyrin Chemical compound C1=CC(C(=C2C=CC(N2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3N2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 YNHJECZULSZAQK-UHFFFAOYSA-N 0.000 claims abstract description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 7
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 238000010791 quenching Methods 0.000 claims abstract description 7
- 230000000171 quenching effect Effects 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims description 14
- 239000002131 composite material Substances 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 12
- 230000001590 oxidative effect Effects 0.000 claims description 12
- 239000012752 auxiliary agent Substances 0.000 claims description 10
- 238000000926 separation method Methods 0.000 claims description 7
- 150000003927 aminopyridines Chemical class 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- QAMFBRUWYYMMGJ-UHFFFAOYSA-N hexafluoroacetylacetone Chemical compound FC(F)(F)C(=O)CC(=O)C(F)(F)F QAMFBRUWYYMMGJ-UHFFFAOYSA-N 0.000 abstract description 10
- DXRFZHILMCWCNG-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N(C)C)=CC=C21 DXRFZHILMCWCNG-UHFFFAOYSA-N 0.000 abstract description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 18
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 12
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 12
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 229910052759 nickel Inorganic materials 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- DQDCGTUHSVXZIS-UHFFFAOYSA-N iodobenzene;2,2,2-trifluoroacetic acid Chemical group OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.IC1=CC=CC=C1 DQDCGTUHSVXZIS-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- YOCBOYPGZVFUCQ-UHFFFAOYSA-L nickel(2+);tricyclohexylphosphane;dichloride Chemical compound Cl[Ni]Cl.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 YOCBOYPGZVFUCQ-UHFFFAOYSA-L 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- QCWPXJXDPFRUGF-UHFFFAOYSA-N N1C=2C=C(N=3)C=CC=3C=C(N3)C=CC3=CC(=N3)C=CC3=CC1=CC=2C1=CC=CC=C1 Chemical compound N1C=2C=C(N=3)C=CC=3C=C(N3)C=CC3=CC(=N3)C=CC3=CC1=CC=2C1=CC=CC=C1 QCWPXJXDPFRUGF-UHFFFAOYSA-N 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- KDJHHFWQUAOVNB-UHFFFAOYSA-L dichloronickel tricyclohexylphosphane Chemical compound Cl[Ni]Cl.C1CCC(CC1)P(C1CCCCC1)C1CCCCC1 KDJHHFWQUAOVNB-UHFFFAOYSA-L 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical class C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002816 nickel compounds Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
- B01J31/223—At least two oxygen atoms present in one at least bidentate or bridging ligand
- B01J31/2234—Beta-dicarbonyl ligands, e.g. acetylacetonates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
- B01J31/2414—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/19—Catalysts containing parts with different compositions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/847—Nickel
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
本发明涉及下式(III)二芳基取代二羰基化合物的合成方法,反应式为:
Description
本申请是申请日为2016年10月14日、申请号为201610895883.6、发明名称为“一种二芳基取代二羰基化合物的合成方法”的分案申请。
技术领域
本发明涉及一种二羰基化合物的合成方法,更特别地涉及一种二芳基取代二羰基化合物的合成方法,属于有机化学合成技术领域。
背景技术
羰基结构是有机化学合成中非常重要的一类活性基团,其可以通过多种反应而进行基团的拓展和改变,从而在有机化学合成中具有重要的地位。例如,二羰基类化合物就是一类功能性很强的结构单元,其在在药物设计和官能团修饰中十分重要。
因此,开发二羰基类化合物的合成方法日益受到科学工作者的关注与重视,人们对其进行了大量的研究,并取得了一定的成果。迄今为止,现有技术中已经报道了多种有关二羰基类化合物的合成方法,例如:
Li Jin-Heng等(“Copper-Catalyzed CH Oxidation/Cross-Coupling of a-Amino Carbonyl Compounds”,Angew.Chem.Int.Ed.,2012,51,3453-3457)报道了一种铜催化的吲哚类化合物的直接羰基化反应方法,其反应式如下:
Wu Anxin等(“Direct Regioselective Oxidative Cross-Coupling of Indoleswith Methyl Ketones:A Novel Route to C3-Dicarbonylati on of Indoles”,OrganicLetters,2015,17,134-137)报道了一种吲哚化合物与甲基酮类化合物反应制备二羰基吲哚化合物的方法,其反应式如下:
如上所述,现有技术中公开了二羰基类化合物的多种合成方法。然而,现有的这些方法却仍存在着一些缺陷,尤其是产物产率较低,这影响了该类化合物的大规模应用。
本发明提供了一种二芳基取代二羰基化合物的合成方法,所述方法通过特定的底物选择和独特的综合反应体系,从而实现了二芳基取代二羰基化合物的高产率合成,具有良好的应用前景和工业化生产潜力。
发明内容
为了克服现有技术中产物产率过低的缺陷,以及研究二芳基取代二羰基化合物的新型合成方法,本发明人进行了深入的研究和探索,在付出了足够的创造性劳动后,从而完成了本发明。
具体而言,本发明的技术方案和内容涉及一种下式(III)所示二芳基取代二羰基化合物的合成方法,所述方法包括:在有机溶剂中,并在双组分复合催化剂、氧化剂、碱和助剂存在下,下式(I)化合物和式(II)化合物在70-100℃下反应6-9小时,反应完毕后用去离子水淬灭反应,过滤,用去离子水充分洗涤滤液,再用乙酸乙酯萃取有机相2-3次,合并有机相并用无水硫酸钠干燥,最后减压蒸馏,将所得粘稠残余物经300-400目硅胶柱色谱分离,即得所述式(III)化合物,
其中,R1、R2各自独立地选自H、C1-C6烷基、C1-C6烷氧基或卤素;
X为卤素。
在本发明的所述合成方法中,所述C1-C6烷基的含义是指具有1-6个碳原子的直链或支链烷基,非限定性地例如可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基或正己基等。
在本发明的所述合成方法中,所述C1-C6烷氧基的含义是指具有上述含义的C1-C6烷基与氧原子相连后得到的基团。
在本发明的所述合成方法中,所述卤素为卤族元素,例如可为F、Cl、Br或I。
在本发明的所述合成方法中,所述双组分复合催化剂为摩尔比1:1的有机镍化合物与六氟乙酰丙酮铜的混合物。
其中,所述有机镍化合物为二(三环己基膦)氯化镍(NiCl2(PCy3)2)、双(1,5-环辛二烯)镍(Ni(COD)2)、1,3-双(二苯基膦丙烷)二氯化镍((DPPP)NiCl2)或1,2-双(二苯基膦)乙烷氯化镍((DPPE)NiCl2)中的任意一种,最优选为1,3-双(二苯基膦丙烷)二氯化镍((DPPP)NiCl2)。
在本发明的所述合成方法中,所述氧化剂为双(三氟乙酸)碘苯(PhI(TFA)2)、叔丁基过氧化氢(TBHP)、间氯过氧苯甲酸或2-碘酰基苯甲酸(IBX)中的任意一种,最优选为2-碘酰基苯甲酸(IBX)。
在本发明的所述合成方法中,所述碱为吡啶、NaOH、叔丁醇钾、1,4-二氮杂二环[2.2.2]辛烷(DABCO)、二异丙基氨基锂(LDA)或二甲氨基吡啶(DMPA)中的任意一种,最优选为二甲氨基吡啶(DMPA)。
在本发明的所述合成方法中,所述助剂为四苯基卟啉。
在本发明的所述合成方法中,所述有机溶剂为N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、甲苯、苯、乙腈、1,4-二氧六环、聚乙二醇200(PEG-200)或N-甲基吡咯烷酮(NMP)中的任意一种或任意多种的混合物,最优选为体积比3:1的二甲基亚砜(DMSO)与乙腈的混合物。
其中,所述有机溶剂的用量并没有严格的限定,本领域技术人员可根据实际情况进行合适的选择与确定,例如其用量大小以方便反应进行和后处理即可,在此不再进行详细描述。
在本发明的所述合成方法中,反应结束和减压蒸馏后得到的稠残余物经300-400目硅胶柱色谱分离,便可得到所述式(III)化合物;其中,硅胶柱色谱分离时的洗脱溶剂为体积比1:2的丙酮与氯仿的混合物。
在本发明的所述合成方法中,所述式(I)化合物与式(II)化合物的摩尔比为1:1.2-1.8,例如可为1:1.2、1:1.5或1:1.8。
在本发明的所述合成方法中,所述式(I)化合物与双组分复合催化剂(以两种组分的总摩尔数计)的摩尔比为1:0.1-0.2,例如可为1:0.1、1:0.15或1:0.2。
在本发明的所述合成方法中,所述式(I)化合物与氧化剂的摩尔比为1:2-2.5,例如可为1:2、1:2.2、1:2.4或1:2.5。
在本发明的所述合成方法中,所述式(I)化合物与碱的摩尔比为1:1-1.5,例如可为1:1、1:1.2、1:1.4或1:1.5。
在本发明的所述合成方法中,所述式(I)化合物与助剂的摩尔比为1:0.14-0.18,例如可为1:0.14、1:0.16或1:0.18。
在本发明的所述合成方法中,上述使用的所有物料都可以通过多种商业渠道而购买得到,再此不再进行详细描述。
综上所述,本发明提供了一种二芳基取代二羰基化合物的合成方法,所述方法通过特定的底物选择、独特的综合反应体系如催化剂、氧化剂、碱和助剂以及有机溶剂的综合协同和相互促进,从而实现了二芳基取代二羰基化合物的高产率合成,具有良好的应用前景和工业化生产潜力。
具体实施方式
下面通过具体的实施例对本发明进行详细说明,但这些例举性实施方式的用途和目的仅用来例举本发明,并非对本发明的实际保护范围构成任何形式的任何限定,更非将本发明的保护范围局限于此。
实施例1
向室温下的合适用量的有机溶剂(为体积比3:1的二甲基亚砜(DMSO)与乙腈的混合物)中,加入100mmol上式(I)化合物、120mmol上式(II)化合物、20mmol双组分复合催化剂(由10mmol 1,3-双(二苯基膦丙烷)二氯化镍和10mmol六氟乙酰丙酮铜组成)、200mmol氧化剂2-碘酰基苯甲酸(IBX)、150mmol碱二甲氨基吡啶(DMPA)和14mmol助剂四苯基卟啉,然后边搅拌边加热升温至70℃,并在该温度下搅拌反应9小时;
反应完毕后用去离子水淬灭反应,过滤,用去离子水充分洗涤滤液,再用乙酸乙酯萃取有机相2-3次,合并有机相并用无水硫酸钠干燥,最后减压蒸馏,将所得粘稠残余物经300-400目硅胶柱色谱分离,其中洗脱溶剂为体积比1:2的丙酮与氯仿的混合物,即得上式(III)化合物,产率为96.2%。
1H NMR(CDCl3,400MHz):δ8.32(d,J=8.1Hz,1H),8.09(d,J=7.3Hz,2H),7.72(s,1H),7.63(t,J=7.4Hz,1H),7.47(t,J=7.7Hz,2H),7.23(d,J=8.1Hz,1H),7.14(s,1H),3.75(s,3H),2.50(s,3H)。
实施例2
向室温下的合适用量的有机溶剂(为体积比3:1的二甲基亚砜(DMSO)与乙腈的混合物)中,加入100mmol上式(I)化合物、180mmol上式(II)化合物、10mmol双组分复合催化剂(由5mmol 1,3-双(二苯基膦丙烷)二氯化镍和5mmol六氟乙酰丙酮铜组成)、250mmol氧化剂2-碘酰基苯甲酸(IBX)、100mmol碱二甲氨基吡啶(DMPA)和18mmol助剂四苯基卟啉,然后边搅拌边加热升温至100℃,并在该温度下搅拌反应6小时;
反应完毕后用去离子水淬灭反应,过滤,用去离子水充分洗涤滤液,再用乙酸乙酯萃取有机相2-3次,合并有机相并用无水硫酸钠干燥,最后减压蒸馏,将所得粘稠残余物经300-400目硅胶柱色谱分离,其中洗脱溶剂为体积比1:2的丙酮与氯仿的混合物,即得上式(III)化合物,产率为95.8%。
1H NMR(d6-DMSO,400MHz):δ8.36(s,1H),8.33(s,1H),7.97(d,J=7.5Hz,2H),7.75(t,J=7.4Hz,1H),7.64(dd,J=15.4,8.1Hz,3H),7.55(dd,J=8.7,1.4Hz,1H),3.85(s,3H)。
实施例3
向室温下的合适用量的有机溶剂(为体积比3:1的二甲基亚砜(DMSO)与乙腈的混合物)中,加入100mmol上式(I)化合物、150mmol上式(II)化合物、16mmol双组分复合催化剂(由8mmol 1,3-双(二苯基膦丙烷)二氯化镍和8mmol六氟乙酰丙酮铜组成)、225mmol氧化剂2-碘酰基苯甲酸(IBX)、125mmol碱二甲氨基吡啶(DMPA)和16mmol助剂四苯基卟啉,然后边搅拌边加热升温至80℃,并在该温度下搅拌反应8小时;
反应完毕后用去离子水淬灭反应,过滤,用去离子水充分洗涤滤液,再用乙酸乙酯萃取有机相2-3次,合并有机相并用无水硫酸钠干燥,最后减压蒸馏,将所得粘稠残余物经300-400目硅胶柱色谱分离,其中洗脱溶剂为体积比1:2的丙酮与氯仿的混合物,即得上式(III)化合物,产率为95.5%。
1H NMR(CDCl3,400MHz):δ8.44(d,J=4.5Hz,1H),8.08(d,J=8.6Hz,2H),7.75(s,1H),7.37(s,3H),6.97(d,J=8.7Hz,2H),3.85(s,3H),3.77(s,3H)。
实施例4
向室温下的合适用量的有机溶剂(为体积比3:1的二甲基亚砜(DMSO)与乙腈的混合物)中,加入100mmol上式(I)化合物、130mmol上式(II)化合物、12mmol双组分复合催化剂(由6mmol 1,3-双(二苯基膦丙烷)二氯化镍和6mmol六氟乙酰丙酮铜组成)、240mmol氧化剂2-碘酰基苯甲酸(IBX)、110mmol碱二甲氨基吡啶(DMPA)和17mmol助剂四苯基卟啉,然后边搅拌边加热升温至90℃,并在该温度下搅拌反应7小时;
反应完毕后用去离子水淬灭反应,过滤,用去离子水充分洗涤滤液,再用乙酸乙酯萃取有机相2-3次,合并有机相并用无水硫酸钠干燥,最后减压蒸馏,将所得粘稠残余物经300-400目硅胶柱色谱分离,其中洗脱溶剂为体积比1:2的丙酮与氯仿的混合物,即得上式(III)化合物,产率为96.5%。
1H NMR(CDCl3,400MHz):δ8.45-8.37(m,1H),8.06(s,1H),7.79(d,J=6.8Hz,1H),7.45(d,J=7.0Hz,1H),7.42-7.35(m,5H),3.85(s,3H)。
实施例5-24:催化剂的考察
1、分别将实施例1-4中的双组分复合催化剂中的(DPPP)NiCl2替换为二(三环己基膦)氯化镍(NiCl2(PCy3)2),其它操作均相同,从而顺次得到实施例5-8。
2、分别将实施例1-4中的双组分复合催化剂中的(DPPP)NiCl2替换为双(1,5-环辛二烯)镍(Ni(COD)2),其它操作均相同,从而顺次得到实施例9-12。
3、分别将实施例1-4中的双组分复合催化剂中的(DPPP)NiCl2替换为1,2-双(二苯基膦)乙烷氯化镍((DPPE)NiCl2),其它操作均相同,从而顺次得到实施例13-16。
4、分别将实施例1-4中的双组分复合催化剂替换为用量为原来两种组分总用量的单一组分(DPPP)NiCl2,其它操作均相同,从而顺次得到实施例17-20。
5、分别将实施例1-4中的双组分复合催化剂替换为用量为原来两种组分总用量的单一组分六氟乙酰丙酮铜,其它操作均相同,从而顺次得到实施例21-24。
结果见下表1。
表1
由此可见:1、当单独使用(DPPP)NiCl2或六氟乙酰丙酮铜时,产物产率有显著的降低,尤其是六氟乙酰丙酮铜仅能取得17.2-20.5%的产率。2、当将(DPPP)NiCl2替换为其它镍化合物时,产率仍有明显的降低(即便是使用非常类似的(DPPE)NiCl2也降低明显)。3、但令人意想不到的是,当使用(DPPP)NiCl2与六氟乙酰丙酮铜的混合物时,能够取得优异的技术效果(见实施例1-4),这证明两者之间能够相互促进和协同,取得了优异的协同催化效果。
实施例25-36:氧化剂的考察
1、分别将实施例1-4中的IBX替换为双(三氟乙酸)碘苯(PhI(TFA)2),其它操作均相同,从而顺次得到实施例25-28。
2、分别将实施例1-4中的IBX替换为叔丁基过氧化氢(TBHP),其它操作均相同,从而顺次得到实施例29-32。
3、分别将实施例1-4中的IBX替换为间氯过氧苯甲酸,其它操作均相同,从而顺次得到实施例33-36。
结果见下表2。
表2
由此可见,在氧化剂中,2-碘酰基苯甲酸(IBX)具有最好的效果,而其它氧化剂均导致产率有明显的降低(在进行色谱分析时,发现生成了大量的单羰基化合物,即氧化不完全)。
实施例37-56:碱的考察
1、分别将实施例1-4中的DMPA替换为吡啶,其它操作均相同,从而顺次得到实施例37-40。
2、分别将实施例1-4中的DMPA替换为NaOH,其它操作均相同,从而顺次得到实施例41-44。
3、分别将实施例1-4中的DMPA替换为叔丁醇钾,其它操作均相同,从而顺次得到实施例45-48。
4、分别将实施例1-4中的DMPA替换为1,4-二氮杂二环[2.2.2]辛烷(DABCO),其它操作均相同,从而顺次得到实施例49-52。
5、分别将实施例1-4中的DMPA替换为二异丙基氨基锂(LDA),其它操作均相同,从而顺次得到实施例53-56。
结果见下表3。
表3
由此可见:碱的种类能够不可预测地影响最终的反应结果,而在所有的碱中,DMPA具有最好的效果,其它碱均导致产率有显著的降低,尤其是叔丁醇钾和NaOH降低最明显。
实施例57-60:助剂的考察
当将实施例1-4中的四苯基卟啉省略时(其它均不变),再次操作了实施例1-4,得到实施例57-60,发现其产率为88.5-90.1%,相比于实施例1-4有很明显的降低,这证明四苯基卟啉的存在,可以在一定程度上改善反应效果。其原因应该是产生了共螯合效果,从而促进了催化效果。
实施例61-68:有机溶剂的考察
如下表4中所示,分别将实施例1-4中的混合有机溶剂替换为单一溶剂,其它操作均相同,从而得到了实施例61-68,具体的单一溶剂和对应关系同样见下表4中。
表4
由此可见:当采用单一溶剂时,产物产率有显著的降低,尤其是NMP、1,4-二氧六环有较显著的降低。这证明溶剂效应对于该反应的影响较大。
综上所述,本发明提供了一种二芳基取代二羰基化合物的合成方法,所述方法通过特定的底物选择、独特的综合反应体系如催化剂、氧化剂、碱和助剂以及有机溶剂的综合协同和相互促进,从而实现了二芳基取代二羰基化合物的高产率合成,具有良好的应用前景和工业化生产潜力。
应当理解,这些实施例的用途仅用于说明本发明而非意欲限制本发明的保护范围。此外,也应理解,在阅读了本发明的技术内容之后,本领域技术人员可以对本发明作各种改动、修改和/或变型,所有的这些等价形式同样落于本申请所附权利要求书所限定的保护范围之内。
Claims (1)
1.一种下式(III)二芳基取代二羰基化合物的合成方法,反应式为:
具体为:向室温下的合适用量的有机溶剂中,加入100mmol上式(I)化合物、150mmol上式(II)化合物、16mmol双组分复合催化剂、225mmol氧化剂2-碘酰基苯甲酸、125mmol碱二甲氨基吡啶和16mmol助剂四苯基卟啉,然后边搅拌边加热升温至80℃,并在该温度下搅拌反应8小时;
反应完毕后用去离子水淬灭反应,过滤,用去离子水充分洗涤滤液,再用乙酸乙酯萃取有机相2-3次,合并有机相并用无水硫酸钠干燥,最后减压蒸馏,将所得粘稠残余物经300-400目硅胶柱色谱分离,其中洗脱溶剂为体积比1:2的丙酮与氯仿的混合物,即得所述式(III)化合物,产率为95.5%;
所述有机溶剂为体积比3:1的二甲基亚砜与乙腈的混合物;
所述双组分复合催化剂由8mmol 1,3-双(二苯基膦丙烷)二氯化镍和8mmol六氟乙酰丙酮铜组成。
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