CN105111139B - 一种医药中间体二芳基取代吡啶衍生物的合成方法 - Google Patents
一种医药中间体二芳基取代吡啶衍生物的合成方法 Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 37
- 150000003222 pyridines Chemical class 0.000 title claims abstract description 14
- 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 9
- 239000003814 drug Substances 0.000 title abstract description 7
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 239000003513 alkali Substances 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 17
- 239000003446 ligand Substances 0.000 claims abstract description 13
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
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- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- KXIBSBLPGLHJNY-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;nickel Chemical compound [Ni].CC1=CC=C(S(O)(=O)=O)C=C1 KXIBSBLPGLHJNY-UHFFFAOYSA-N 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 11
- 150000002941 palladium compounds Chemical class 0.000 claims description 11
- UFMZWBIQTDUYBN-UHFFFAOYSA-N cobalt dinitrate Chemical compound [Co+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O UFMZWBIQTDUYBN-UHFFFAOYSA-N 0.000 claims description 10
- 229910001981 cobalt nitrate Inorganic materials 0.000 claims description 10
- 150000002816 nickel compounds Chemical class 0.000 claims description 9
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 2
- 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 claims description 2
- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
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- RRHPTXZOMDSKRS-PHFPKPIQSA-L (1z,5z)-cycloocta-1,5-diene;dichloropalladium Chemical compound Cl[Pd]Cl.C\1C\C=C/CC\C=C/1 RRHPTXZOMDSKRS-PHFPKPIQSA-L 0.000 description 7
- 101150003085 Pdcl gene Proteins 0.000 description 7
- 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 7
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000006254 arylation reaction Methods 0.000 description 2
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- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002153 concerted effect Effects 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 2
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 2
- 150000003003 phosphines Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 239000002585 base Substances 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 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
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 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
- 229910052759 nickel Inorganic materials 0.000 description 1
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(ii) nitrate Chemical compound [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005887 phenylation reaction Methods 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 150000003839 salts Chemical class 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
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
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
- C07D213/24—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
-
- 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
- C07D213/127—Preparation from compounds containing pyridine rings
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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
- C07D213/24—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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- 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
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
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- Chemical & Material Sciences (AREA)
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及一种下式(III)所示二芳基取代吡啶衍生物的合成方法，所述方法包括：在有机溶剂中，于催化剂、膦配体、碱和促进剂的存在下，下式(I)化合物和下式(II)化合物发生反应，从而得到所述(III)化合物，其中，R1为H或C1‑C6烷基；R2为C1‑C6烷基、C1‑C6烷氧基、氰基或卤素；X为卤素。该方法通过催化剂、配体、碱、促进剂和有机溶剂等的综合选择与协同，从而可以高产率得到目的产物，在有机化学合成领域尤其是医药中间体合成领域具有良好的应用前景和广泛的工业化生产潜力。
Description
技术领域
本发明涉及一种吡啶类衍生物的合成方法，更具体地涉及一种2,6-二芳基取代吡啶衍生物的合成方法，属于有机合成领域尤其是医药中间体合成领域。
背景技术
在有机化学领域中，吡啶类化合物是天然化合物、药物活性分子的重要结构单元，其还可以作为有机配体、功能材料来应用，可谓用途广泛、需求量大。
正是由于吡啶类化合物的如此重要的作用和应用潜力，因此，研究吡啶及其衍生物的合成方法自然成为科学家们的关注焦点。
一般来讲，吡啶衍生物常常通过交叉偶联反应来实现制备，如采用吡啶金属化物等原料，但这些原料却常常需要预先的制备，从而使得制备工艺复杂化。此外，吡啶金属化物的稳定性并不十分好，且合成存在难度，应用受到限制。
为了改进吡啶类化合物的合成方法，人们进行了大量的研究。目前，已经有多篇文献报道了吡啶类衍生物的合成方法，作为示例性如下：
Kamil Godula等(“Site-Specific Phenylation of Pyridine Catalyzed byPhosphido-Bridged Ruthenium Dimer Complexes:A Prototype for C-H Arylation ofElectron-Deficient Heteroarenes”,J.Am.Chem.Soc.,2005,127,3548-3649)报道了一种吡啶与芳基碘的偶联反应，其反应式如下：
Louis-Charlers等(“A Solution to the 2-Pyridyl Organometallic Cross-Coupling Problem:Regioselective Catalytic Direct Arylation of Pyridine N-Oxides”,J.Am.Soc.Chem.,2005,127,18020-18021)报道了一种吡啶氮氧化物的直接芳基化反应，其反应式如下所示：
如上所述，目前现有技术中已经存在多种吡啶类化合物的合成方法，但对于新型的合成方法仍存在继续研究的必要。
为了拓展底物的应用范围以及为医药领域提供廉价的医药中间体化合物，本发明人经过刻苦的钻研，在调研大量文献资料的基础上，提出了一种二芳基取代吡啶衍生物的合成方法，该方法通过反应体系的优化组合，实现了目标产物的高收率制备，表现出广泛的市场前景。
发明内容
为了克服上述所指出的诸多缺陷，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)所示二芳基取代吡啶衍生物的合成方法，所述方法包括：在有机溶剂中，于催化剂、膦配体、碱和促进剂的存在下，下式(I)化合物和下式(II)化合物发生反应，从而得到所述(III)化合物，
其中，R1为H或C1-C6烷基；
R2为C1-C6烷基、C1-C6烷氧基、氰基或卤素；
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烷氧基的含义是指上述定义的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，所述卤素的含义是指卤族元素，例如可为F、Cl、Br或I。
在本发明的所述合成方法中，所述催化剂为有机钯化合物与镍化合物的混合物；其中，有机钯化合物与镍化合物的摩尔比为1:2-3，例如可为1:2、1:2.5或1:3。
其中，所述有机钯化合物为Pd(PhCN)2Cl2(二(氰苯基)氯化钯)、Pd(O2CCF3)2(三氟乙酸钯)、Pd(OAc)2(乙酸钯)、Pd(acac)2(乙酰丙酮钯)、PdCl2(cod)(1,5-环辛二烯氯化钯)中的任意一种，最优选为PdCl2(cod)。
在本发明的所述合成方法中，所述镍化合物为NiCl2(氯化镍)、Ni(NO3)2(硝酸镍)或对甲苯磺酸镍中的任意一种或其水合盐，最优选为对甲苯磺酸镍。
在本发明的所述合成方法中，所述膦配体为下式L1-L3中的任意一种，
最优选为L1。
在本发明的所述合成方法中，所述碱为二甲氨基吡啶(DMPA)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)、三甲胺、二异丙基胺、三乙醇胺、叔丁醇钾、碳酸钾、碳酸氢钠等中的任意一种，最优选为DMPA。
在本发明的所述合成方法中，所述促进剂为二茂铁与硝酸钴的混合物，其中二茂铁与酸钴的摩尔比为1:4。
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)、乙醇、二甲基亚砜(DMSO)、乙腈、N-甲基吡咯烷酮(NMP)、正丙醇、苯、甲苯、1,4-二氧六环等中的任意一种，最优选为1,4-二氧六环。
其中，有机溶剂的用量并没有特别的限定，本领域技术人员可进行合适的选择和确定，这都是常规技术手段，在此不再进行详细陈述。
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1:2-3，例如可为1:2、1:2.5或1:3。
在本发明的所述合成方法中，所述式(I)化合物与催化剂的摩尔比为1:0.05-0.09，即所述式(I)化合物的摩尔用量与构成所述催化剂的有机钯化合物与镍化合物的两种组分的总摩尔用量的比为1:0.05-0.09，非限定性地例如可为1:0.05、1:0.07或1:0.09。
在本发明的所述合成方法中，所述式(I)化合物与膦配体的摩尔比为1:0.1-0.15，例如可为1:0.1、1:0.12、1:0.14或1:0.15。
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1:0.5-0.8，例如可为1:0.5、1:0.6、1:0.7或1:0.8。
在本发明的所述合成方法中，所述式(I)化合物与促进剂的摩尔比为1:0.1-0.2，即所述式(I)化合物的摩尔用量与构成所述促进剂的二茂铁与硝酸钴的两种组分的总摩尔用量的比为1:0.1-0.2，非限定性地例如可为1:0.1、1:0.15或1:0.2。
在本发明的所述合成方法中，反应温度为60-80℃，例如可为60℃、70℃或80℃。
在本发明的所述合成方法中，反应时间为7-10小时，例如可为7小时、8小时、9小时或10小时。
在本发明的所述合成方法中，反应结束后的后处理可如下：反应结束后，过滤得到滤液，向滤液中加入质量百分浓度为10％的盐酸水溶液，将pH值调节为6-7，然后用乙酸乙酯充分振荡萃取2-3次，合并有机相，减压蒸馏浓缩，残留物过200-300目硅胶柱色谱进行分离(以体积比为1:2的乙酸乙酯和氯仿的混合液进行洗脱)，从而得到所述式(III)化合物。
综上所述，本发明提供了一种二芳基取代吡啶衍生物的合成方法，该方法通过催化剂、配体、碱、促进剂和有机溶剂等的综合选择与协同，从而可以高产率得到目的产物，在有机化学合成领域尤其是医药中间体合成领域具有良好的应用前景和广泛的工业化生产潜力。
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
向适量有机溶剂1,4-二氧六环中，加入100mmol上式(I)化合物、200mmol上式(II)化合物、5mmol催化剂(为1.6mmol PdCl2(cod)与3.4mmol对甲苯磺酸镍的混合物)、10mmol膦配体L1、50mmol碱DMPA和10mmol促进剂(为2mmol二茂铁与8mmol硝酸钴的混合物)，然后升温至60℃，并在该温度下充分搅拌反应10小时。
反应结束后，过滤得到滤液，向滤液中加入质量百分浓度为10％的盐酸水溶液，将pH值调节为6-7，然后用乙酸乙酯充分振荡萃取2-3次，合并有机相，减压蒸馏浓缩，残留物过200-300目硅胶柱色谱进行分离(以体积比为1:2的乙酸乙酯和氯仿的混合液进行洗脱)，从而得到所述式(III)化合物，产率为97.1％。
1H NMR(CDCl3,400MHz):δ8.18-8.07(m,4H),7.76(m,1H),7.57(d,J＝7.8Hz,2H),7.07-6.95(m,4H),3.86(s,6H)。
HRMS(ESI)([M+H]+):292.13。
实施例2
向适量有机溶剂1,4-二氧六环中，加入100mmol上式(I)化合物、250mmol上式(II)化合物、7mmol催化剂(为2mmol PdCl2(cod)与5mmol对甲苯磺酸镍的混合物)、12mmol膦配体L1、60mmol碱DMPA和15mmol促进剂(为3mmol二茂铁与12mmol硝酸钴的混合物)，然后升温至70℃，并在该温度下充分搅拌反应8小时。
反应结束后，过滤得到滤液，向滤液中加入质量百分浓度为10％的盐酸水溶液，将pH值调节为6-7，然后用乙酸乙酯充分振荡萃取2-3次，合并有机相，减压蒸馏浓缩，残留物过200-300目硅胶柱色谱进行分离(以体积比为1:2的乙酸乙酯和氯仿的混合液进行洗脱)，从而得到所述式(III)化合物，产率为97.3％。
1H NMR(CDCl3,400MHz):δ7.86-7.81(m,4H),7.78(d,J＝1.8Hz,2H)。
HRMS(ESI)([M+H]+):282.10。
实施例3
向适量有机溶剂1,4-二氧六环中，加入100mmol上式(I)化合物、300mmol上式(II)化合物、9mmol催化剂(为2.25mmol PdCl2(cod)与6.75mmol对甲苯磺酸镍的混合物)、15mmol膦配体L1、80mmol碱DMPA和20mmol促进剂(为4mmol二茂铁与16mmol硝酸钴的混合物)，然后升温至80℃，并在该温度下充分搅拌反应7小时。
反应结束后，过滤得到滤液，向滤液中加入质量百分浓度为10％的盐酸水溶液，将pH值调节为6-7，然后用乙酸乙酯充分振荡萃取2-3次，合并有机相，减压蒸馏浓缩，残留物过200-300目硅胶柱色谱进行分离(以体积比为1:2的乙酸乙酯和氯仿的混合液进行洗脱)，从而得到所述式(III)化合物，产率为96.9％。
1H NMR(CDCl3,400MHz):δ7.78(t,J＝7.8Hz,1H),7.437.39(m,2H),7.34(d,J＝7.8Hz,2H),7.23(m,6H),2.43(s,6H)。
HRMS(ESI)([M+H]+):260.14。
实施例4
向适量有机溶剂1,4-二氧六环中，加入100mmol上式(I)化合物、220mmol上式(II)化合物、6mmol催化剂(为2mmol PdCl2(cod)与4mmol对甲苯磺酸镍的混合物)、14mmol膦配体L1、60mmol碱DMPA和13mmol促进剂(为2.6mmol二茂铁与10.4mmol硝酸钴的混合物)，然后升温至65℃，并在该温度下充分搅拌反应9小时。
反应结束后，过滤得到滤液，向滤液中加入质量百分浓度为10％的盐酸水溶液，将pH值调节为6-7，然后用乙酸乙酯充分振荡萃取2-3次，合并有机相，减压蒸馏浓缩，残留物过200-300目硅胶柱色谱进行分离(以体积比为1:2的乙酸乙酯和氯仿的混合液进行洗脱)，从而得到所述式(III)化合物，产率为97.4％。
1H NMR(CDCl3,400MHz):δ8.08-7.98(m,2H),7.67-7.55(m,4H),7.18-7.09(m,4H),2.39(s,3H)。
HRMS(ESI)([M+H]+):282.11。
实施例5-36：催化剂的考察
实施例5-8：除将催化剂中的PdCl2(cod)替换为Pd(PhCN)2Cl2外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例5-8。
实施例9-12：除将催化剂中的PdCl2(cod)替换为Pd(O2CCF3)2外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例9-12。
实施例13-16：除将催化剂中的PdCl2(cod)替换为Pd(OAc)2外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例13-16。
实施例17-20：除将催化剂中的PdCl2(cod)替换为Pd(acac)2外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例17-20。
实施例21-24：除将催化剂中的对甲苯磺酸镍替换为NiCl2外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例21-24。
实施例25-28：除将催化剂中的对甲苯磺酸镍替换为Ni(NO3)2外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例25-28。
实施例29-32：除将催化剂换为用量为原来两种组分总用量的单一组分PdCl2(cod)外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例29-32。
实施例33-36：除将催化剂换为用量为原来两种组分总用量的单一组分对甲苯磺酸镍外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例33-36。
结果见下表1。
表1
注：其中“--”表示不存在。
由表1数据可见，在有机钯化合物和镍化合物中，PdCl2(cod)与对甲苯磺酸镍分别具有最好的催化效果。同时也可以看出，当单独采用PdCl2(cod)或对甲苯磺酸镍时，产率均有明显降低(其中的，当单独使用PdCl2(cod)时，其产率与其它有机钯化合物相差不大，这证明其它有机钯化合物与对甲苯磺酸镍之间并没有发挥协同催化作用)。由此证明了，只有同时使用PdCl2(cod)与对甲苯磺酸镍的混合物时，两者之间发挥了独特的协同催化效果，从而取得了最为优异的产物产率。
实施例37-44：膦配体的考察
实施例37-40：除将其中的膦配体L1替换为L2外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例37-40。
实施例41-44：除将其中的膦配体L1替换为L3外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例41-44。
结果见下表2。
表2
由此可见，在配体L1-L3中，L1具有最好的效果。
实施例45-51：碱的考察
除使用如下的碱外，其它操作均相同，从而重复进行了实施例1-4，所使用的碱、实施例对应关系和产物产率见下表3。
表3
由此可见，当在所有的碱中，DMPA具有最好的效果，其它碱均导致产率有显著降低。
实施例52-63：促进剂的考察
实施例52-55：除将促进剂换为用量为原来两种组分总用量的单一组分二茂铁外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例52-55。
实施例56-59：除将促进剂换为用量为原来两种组分总用量的单一组分硝酸钴外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例56-59。
实施例60-63：除省略掉促进剂外，其它操作均相同，从而重复进行了实施例1-4，顺次得到实施例60-63。
结果见下表4。
表4
注：“--”表示不存在。
由表4数据可见，当单独使用二茂铁或硝酸钴，以及不使用任何促进剂时，产率相差不大(但比实施例1-4有显著降低)，这证明当同时使用二茂铁和硝酸钴作为促进剂时，能够发挥意想不到的促进效果。
实施例64-：有机溶剂的考察
除使用如下的有机溶剂外，其它操作均相同，从而重复进行了实施例1-4，所使用的有机溶剂、实施例对应关系和产物产率见下表5。
表5
由此可见，在所有的有机溶剂中，1,4-二氧六环具有最好的效果。
综合上述，本发明提出了一种二芳基取代吡啶衍生物的合成方法，该方法通过催化剂、配体、碱、促进剂和有机溶剂等的综合选择与协同，从而可以高产率得到目的产物，在有机化学合成领域尤其是医药中间体合成领域具有良好的应用前景和广泛的工业化生产潜力。
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 (6)
1.一种下式(III)所示二芳基取代吡啶衍生物的合成方法，所述方法包括：在有机溶剂中，于催化剂、膦配体、碱和促进剂的存在下，下式(I)化合物和下式(II)化合物发生反应，从而得到所述(III)化合物，
其中，R1为H或C1-C6烷基；
R2为C1-C6烷基、C1-C6烷氧基、氰基或卤素；
X为卤素；
所述催化剂为有机钯化合物与镍化合物的混合物；其中，有机钯化合物与镍化合物的摩尔比为1:2-3；
所述有机钯化合物为1,5-环辛二烯氯化钯，所述镍化合物为对甲苯磺酸镍；
所述膦配体为下式L1，
所述碱为二甲氨基吡啶；
所述促进剂为二茂铁与硝酸钴的混合物，其中二茂铁与酸钴的摩尔比为1:4；
所述有机溶剂为1,4-二氧六环。
2.如权利要求1所述的合成方法，其特征在于：所述式(I)化合物与式(II)化合物的摩尔比为1:2-3。
3.如权利要求1所述的合成方法，其特征在于：所述式(I)化合物的摩尔用量与构成所述催化剂的有机钯化合物与镍化合物的两种组分的总摩尔用量的比为1:0.05-0.09。
4.如权利要求1所述的合成方法，其特征在于：所述式(I)化合物与膦配体的摩尔比为1:0.1-0.15。
5.如权利要求1所述的合成方法，其特征在于：所述式(I)化合物与碱的摩尔比为1:0.5-0.8。
6.如权利要求1-5任一项所述的合成方法，其特征在于：所述式(I)化合物与促进剂的摩尔比为1:0.1-0.2。
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