CN116813670A - Large-steric-hindrance C-C coupled palladium ligand and synthesis method thereof - Google Patents
Large-steric-hindrance C-C coupled palladium ligand and synthesis method thereof Download PDFInfo
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 110
- 239000003446 ligand Substances 0.000 title claims abstract description 85
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 47
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 39
- 230000008569 process Effects 0.000 claims abstract description 28
- 239000000126 substance Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 185
- 238000006243 chemical reaction Methods 0.000 claims description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 75
- 239000007787 solid Substances 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 43
- 239000012300 argon atmosphere Substances 0.000 claims description 35
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 34
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 30
- 238000003786 synthesis reaction Methods 0.000 claims description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 28
- 230000015572 biosynthetic process Effects 0.000 claims description 26
- 238000001816 cooling Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 25
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 22
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 18
- 229910052786 argon Inorganic materials 0.000 claims description 17
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 17
- 239000012414 tert-butyl nitrite Substances 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 14
- DOWCWUCBOQRQJE-UHFFFAOYSA-N ditert-butylphosphane;hydrochloride Chemical compound Cl.CC(C)(C)PC(C)(C)C DOWCWUCBOQRQJE-UHFFFAOYSA-N 0.000 claims description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 14
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims description 14
- -1 hexamethylpiperidine lithium Chemical compound 0.000 claims description 13
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 229940125904 compound 1 Drugs 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 12
- 239000012295 chemical reaction liquid Substances 0.000 claims description 11
- 238000006138 lithiation reaction Methods 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 11
- 238000005086 pumping Methods 0.000 claims description 11
- XINXXEPJKIRVNV-UHFFFAOYSA-N 1,2-dichloro-N,N,N',N'-tetramethylethane-1,2-diamine Chemical compound ClC(C(N(C)C)Cl)N(C)C XINXXEPJKIRVNV-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 10
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 10
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 9
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 238000004321 preservation Methods 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- 238000006555 catalytic reaction Methods 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 238000004537 pulping Methods 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 claims description 6
- 238000005580 one pot reaction Methods 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000005658 halogenation reaction Methods 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 238000006193 diazotization reaction Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- PKZCRWFNSBIBEW-UHFFFAOYSA-N 2-n,2-n,2-trimethylpropane-1,2-diamine Chemical compound CN(C)C(C)(C)CN PKZCRWFNSBIBEW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 3
- 239000002689 soil Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 8
- 230000008859 change Effects 0.000 abstract description 3
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 abstract description 3
- 230000035515 penetration Effects 0.000 abstract description 3
- 125000001624 naphthyl group Chemical group 0.000 abstract description 2
- 230000000087 stabilizing effect Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 5
- 239000004327 boric acid Substances 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- HYCYKHYFIWHGEX-UHFFFAOYSA-N (2-phenylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C1=CC=CC=C1 HYCYKHYFIWHGEX-UHFFFAOYSA-N 0.000 description 1
- HEAUFJZALFKPBA-JPQUDPSNSA-N (3s)-3-[[(2s,3r)-2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-(1h-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]-3-hydroxybutanoyl]amino]-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[2-[[(2s)-1-[[(2s)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-JPQUDPSNSA-N 0.000 description 1
- QHCORZJIOKCRMT-UHFFFAOYSA-N 1,2,2,3,3,4-hexamethylpiperidine Chemical compound CC1CCN(C)C(C)(C)C1(C)C QHCORZJIOKCRMT-UHFFFAOYSA-N 0.000 description 1
- KTADSLDAUJLZGL-UHFFFAOYSA-N 1-bromo-2-phenylbenzene Chemical group BrC1=CC=CC=C1C1=CC=CC=C1 KTADSLDAUJLZGL-UHFFFAOYSA-N 0.000 description 1
- MYMYVYZLMUEVED-UHFFFAOYSA-N 2-bromo-1,3-dimethylbenzene Chemical compound CC1=CC=CC(C)=C1Br MYMYVYZLMUEVED-UHFFFAOYSA-N 0.000 description 1
- APSMUYYLXZULMS-UHFFFAOYSA-N 2-bromonaphthalene Chemical compound C1=CC=CC2=CC(Br)=CC=C21 APSMUYYLXZULMS-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 101800000399 Neurokinin A Proteins 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- ZAZKJZBWRNNLDS-UHFFFAOYSA-N methyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC ZAZKJZBWRNNLDS-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a large steric hindrance C-C coupled palladium ligand and a synthesis method, wherein naphthyl is used as a main group for stabilizing the ligand, and the group provides a large plane rigid configuration in the use process of the ligand, and simultaneously provides large pi electrons for complex molecules to stabilize the complex; in addition, a configuration of pyridofuran is adopted, and O is introduced to the N coordination point ortho position of the traditional N-P bidentate ligand through a furan functional group to regulate the chemical environment of the N coordination point in the molecule, so that the traditional N-P bidentate ligand is modified into a tridentate ligand, and the change can effectively increase the penetration capacity of Pd active center in the actual ligand use, thereby improving the catalytic activity.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a large-steric-hindrance C-C coupled palladium ligand and a synthesis method.
Background
The carbon-carbon coupling reaction is an important component of the current organic chemical synthesis, especially the directional coupling synthesis process by taking metallic palladium as a catalyst, and the efficiency and environmental friendliness of the reaction are widely studied and accepted. The use and selection of palladium ligands when using palladium as the catalytic active site has a critical impact on the specific reaction results and is now a popular direction of palladium catalytic research.
The synthesis process of the aromatic compound is a very important method for synthesizing medicines and materials at present through the C-C coupling process, and the classical name synthesis reaction at present mainly comprises a Suzuki reaction, a Heck reaction, a Sonogashira reaction and the like aiming at the reactions.
From the wide application of palladium catalysis and the supply and popularization of the current market ligand, the number of the current commercial metal palladium ligands is relatively small, part of the current commercial metal palladium ligands are also poor in stability, the compatibility of the use process to a large-steric-hindrance substrate is very low, the large-steric-hindrance catalytic docking reaction is difficult to realize, and halogen or boric acid is easy to fall in the process. At present, the research on OLED materials is mainly carried out on the stacking and organic arrangement and combination process of aromatic condensed rings and heterocycles. When substituents with larger steric hindrance at the ortho-position are frequently encountered in the development process of the material, the catalyst Pd (PPh 3 ) 4 Or Xphos-Pd 2 (dba) 3 ,Sphos-Pd 2 (dba) 3 ，X-Antphos-Pd 2 (dba) 3 The coupling process of C-C is not well realized, or the conversion rate of the butt joint process is very low, so that the problems of halogen or boric acid are easy to generate, for example, the coupling of 2, 6-dimethylbenzeneboronic acid and 2, 6-dimethylbromobenzene is realized, the coupling and butt joint of C-C are difficult to realize under the influence of the substitution of ortho methyl, and 2,2', 6' -tetramethylbiphenyl is difficult to obtain; the same is true of the coupling process of 2-biphenylboronic acid and 2-bromonaphthalene. Therefore, developing a ligand compatible with large steric hindrance is significant for smoothly synthesizing the compound.
The existing catalyst ligand mature in the market is difficult to realize a C-C coupling process with larger steric hindrance or electron donating groups at the ortho position of an aromatic benzene ring, and although partial literature reports on a catalyst related to synthesis, the structure and the synthesis process are complex, so that the market popularization is difficult to realize. In order to practically solve the above problems, it is necessary to design a novel ligand for solving such docking problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a large steric hindrance C-C coupled palladium ligand and a synthesis method thereof.
In order to solve the technical problems, the technical scheme of the invention is as follows: a method for synthesizing a large steric hindrance C-C coupled palladium ligand comprises the following steps:
step 1: the 2-anisole is subjected to hydrogen removal and lithiation by n-butyl lithium, then reacts with tributyl borate, and is subjected to acidolysis to obtain a compound B, namely 2-anisole: n-butyllithium: the molar ratio of tributyl borate is 1:1.1 to 1.2:1.2 to 1.3, the structural formula of the compound B is
Step 2: the compound B and bromobenzene are subjected to Suzuki reaction to prepare a compound C, wherein the compound B is as follows: the molar ratio of bromobenzene is 1:1 to 1.1, the structure of the compound C is
Step 3: the compound C is subjected to halogenation reaction to obtain a compound D, and the structural formula of the compound D is
Step 4: the 2-amino-5-methylpyridine is protected by di-tert-butyl dicarbonate to obtain a compound F, 2-amino-5-methylpyridine: the mole ratio of di-tert-butyl dicarbonate is 1:1.1 to 1.2, the structural formula of the compound F is
Step 5: the compound F is selectively subjected to hydrogen drawing and lithiation to the 3 position of a pyridine ring in the presence of N, N-tetramethyl ethylenediamine, then reacts with triisopropyl borate, and is subjected to acidolysis to obtain a compound G, wherein the compound F is prepared by the steps of: n, N-tetramethyl ethylenediamine: the mole ratio of the triisopropyl borate is 1:1.2 to 1.3:1.2 to 1.25, the structural formula of the compound G is
Step 6: compound D and compound G undergo a Suzuki reaction to form compound H, compound D: the molar ratio of compound G is 1:1 to 1.05, the structural formula of the compound H is
Step 7: amino group and tert-butyl nitrite of the compound H undergo diazotization reaction process under the catalysis of copper acetate and intramolecular ether linkage to form a compound J, and the compound H: copper acetate: the molar ratio of the tert-butyl nitrite is 1:0.01 to 0.1:1.2 to 1.5, the structural formula of the compound J is
Step 8: the compound J reacts with hexamethylpiperidine lithium, the pyridine ring substituent methyl hydrogen is removed by lithiation, and then the compound J reacts with di-tert-butyl phosphine chloride to obtain a compound K, wherein the compound J is as follows: lithium hexamethylpiperidine: the mole ratio of the di-tert-butyl phosphine chloride is 1:1.1 to 1.2:1.2 to 1.25, and the structural formula of the compound K is
Preferably, the step 1 specifically includes: dissolving the compound A2-anisole in a THF solvent, dripping 2.5mol/L of n-butyllithium at the temperature of between 20 ℃ below zero and 10 ℃ below zero in an argon atmosphere, carrying out heat preservation and hydrogen extraction reaction for 2 hours to 3 hours, cooling to the temperature of between 85 ℃ below zero and 80 ℃ below zero, dripping tributyl borate, naturally heating to the internal temperature of higher than 10 ℃ below zero after the completion of the reaction, concentrating under reduced pressure, acidifying with hydrochloric acid, and crystallizing PE to obtain a white solid compound B.
Preferably, the step 2 specifically includes: sequentially adding compound B, bromobenzene, potassium carbonate, toluene, ethanol, water and Pd (PPh) 3 ) 4 Reflux reaction is carried out for 6-8 h at 70-75 ℃ in an argon atmosphere by a one-pot method until the compound B is completely reacted, the reaction liquid is washed with water and separated, then the organic phase is evaporated to dryness under reduced pressure, and then the white solid compound C is obtained by methanol crystallization, wherein the compound B is: bromobenzene: potassium carbonate: pd (PPh) 3 ) 4 The molar ratio of (2) is 1:1 to 1.1:1.5 to 2: 0.005-0.01, compoundingThe dosage ratio of the substance B to toluene, ethanol and water is 100g: 600-615 ml: 200-210 ml: 200-210 ml.
Preferably, the step 3 specifically includes: under the protection of argon, adding a compound C and DMF (dimethyl formamide) into a reaction bottle, taking N-bromosuccinimide as a brominating reagent, adding N-bromosuccinimide in batches at the temperature of 0-10 ℃, pouring the reaction liquid into a large amount of water after the completion of tracking reaction, filtering out a solid, pulping and dispersing the solid by using ethanol to obtain a white-like solid compound D, wherein the compound C is prepared by the steps of: the molar ratio of N-bromosuccinimide is 1:1 to 1.1, the dosage ratio of the compound C to the DMF is 100g: 510-520 ml.
Preferably, the step 4 specifically includes: adding a compound E, 4-dimethylaminopyridine and methylene dichloride into a three-mouth bottle under the argon atmosphere, maintaining the internal temperature at 15-25 ℃, and dripping Boc 2 And (3) carrying out heat preservation reaction on the DCM solution of O for 24 hours until the raw materials are basically complete, concentrating the solvent and low boiling point substances under reduced pressure to obtain a crude product, and pulping, dispersing and filtering by using PE to obtain a compound F, wherein the compound E is: DMAP: boc 2 The mol ratio of O is 1:1-1.05: 1.1 to 1.2, the dosage ratio of the compound E to the DCM is 10g: 92-95 ml.
Preferably, the step 5 specifically includes: dissolving a compound F in THF, adding N, N-tetramethyl ethylenediamine, cooling to-80 ℃ to-75 ℃ under argon atmosphere, dripping 2.5mol/L of N-BuLi, stirring and reacting for 1-2 h, continuously cooling to-95 ℃ to-85 ℃, dripping triisopropyl borate, then heating to room temperature, concentrating a reaction solution after the reaction is completed, dissociating an ammonium chloride aqueous solution, dispersing and crystallizing PE to obtain a soil gray solid compound G, and obtaining the compound F: n, N-tetramethyl ethylenediamine: n-BuLi: the mole ratio of the triisopropyl borate is 1:1.2 to 1.3:1.1 to 1.2:1.2 to 1.25, the dosage ratio of the compound F to the THF is 10g:100ml.
Preferably, the step 6 specifically includes: sequentially adding a compound D, a compound G, potassium carbonate, dioxane and water into a three-mouth bottle, replacing a system with argon, and adding a catalyst Pd (PPh) 3 ) 4 After the reaction is carried out for 12 hours at 75 ℃ to 80 ℃ by a one-pot method and the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure, toluene is added to dissolve the concentrated dry matter, and then deionized water is used for washingDrying, filtering the organic phase to remove the drying agent after the drying is finished, and concentrating and drying under reduced pressure to obtain a compound H, a compound D: compound G: potassium carbonate: pd (PPh) 3 ) 4 The molar ratio of (2) is 1:1 to 1.05:1.5 to 2: 0.005-0.01, the dosage ratio of the compound D to dioxane and water is 10g:100ml: 16-18 ml.
Preferably, the step 7 specifically includes: dissolving a compound H in a three-mouth bottle by THF, heating to an internal temperature of 55-60 ℃, stopping heating, adding copper acetate, carefully dripping a THF solution dissolved with tert-butyl nitrite into the system, keeping the system warm for 1-2 hours after dripping, directly concentrating the reaction solution under reduced pressure, adding toluene, refluxing, dissolving, clearing, passing the solution through a silica gel column, collecting a product column liquid, concentrating under reduced pressure until solid is separated out, cooling to a temperature of below 20 ℃, filtering, pumping, drying to obtain a yellowish solid powder compound J, and obtaining the compound H: copper acetate: the molar ratio of the tert-butyl nitrite is 1:0.01 to 0.1:1.2 to 1.5, the dosage ratio of the compound H to the THF is 10g: 78-80 ml, the dosage ratio of tert-butyl nitrite to THF is 10g: 24-26 ml.
Preferably, the step 8 specifically includes: dissolving a compound J in THF (tetrahydrofuran) under the argon atmosphere, cooling to minus 50 ℃ to minus 60 ℃, then dripping a hexamethylpiperidine lithium solution, preserving heat for 2 to 3 hours at minus 55 ℃ to minus 50 ℃ until the system turns dark brown, dripping a di-tert-butyl phosphine chloride solution at an internal temperature of minus 90 ℃ to minus 80 ℃, naturally heating to the internal temperature of 0 ℃ after the completion of the reaction, directly concentrating reaction liquid under negative pressure, adding n-heptane, refluxing and dissolving a concentrated dry matter under the argon atmosphere, cooling to the internal temperature of 20 ℃ to 30 ℃, quickly passing through diatomite under the argon atmosphere, removing insoluble salts, collecting filtrate, concentrating under reduced pressure to a few solvents, stirring, cooling to 0 ℃ to 5 ℃ under the protection of argon, precipitating white solid, filtering and pumping to dryness under the protection of inert gas to obtain a white to yellowish waxy solid compound K, wherein the compound J: lithium hexamethylpiperidine: the mole ratio of the di-tert-butyl phosphine chloride is 1:1.1 to 1.2:1.2 to 1.25, the dosage ratio of the compound J to the THF is 10g: 96-100 ml.
Preferably, a highly sterically hindered C-C coupled palladiumThe ligand is a tridentate N-P-O ligand, and the structural formula is as follows:the tridentate N-P-O ligand synthesized by the method of synthesizing a highly sterically hindered C-C coupled palladium ligand as defined in any one of claims 1 to 9, said tridentate N-P-O ligand being used in the synthesis of catalysts compoud1 and compoud 2;
the structural formula of the compound1 is as follows:the structural formula of the compound2 is:the synthesis process of the compound1 or the compound2 is as follows: THF is measured and put into a three-mouth bottle, palladium acetate or dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium is weighed and dissolved in the three-mouth bottle after the system is replaced by argon, the temperature is raised to 45-55 ℃, the three-tooth ligand of N-P-O is dissolved in the THF under the argon atmosphere after the three-mouth bottle is fully stirred to be dissolved and cleared, the solution of the three-tooth ligand of N-P-O and palladium acetate or dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium are slowly dripped into the system, the molar ratio of the three-tooth ligand of N-P-O to palladium acetate or dichloro (N, N ', N' -tetramethyl ethylenediamine) palladium is 1:0.4-0.6, the dripping speed is controlled to be 0.5-1 h, the reaction is continuously stirred for 3-4 h until the reaction is complete after the dripping is completed, then the reaction system is reduced in pressure until most of solids are separated out, then N-heptane is added, the protection of the argon atmosphere, the three-tooth ligand is continuously stirred and crystallized for 2-3 h at room temperature, the solution is filtered, and pumped to be dried, and the light red solid compound powder or dark red solid compound powder is obtained.
Compared with the prior art, the invention has the advantages that:
(1) The ligand of the invention uses naphthyl as the main group for stabilizing the ligand, and the group provides a large plane rigid configuration in the using process of the ligand, and simultaneously provides large pi electrons for the complex molecules to stabilize the complex; in addition, a pyridofuran configuration is adopted, and O is introduced to the N coordination point ortho position of the traditional N-P bidentate ligand through a furan functional group to regulate the chemical environment of the N coordination point in the molecule, so that the traditional N-P bidentate ligand is modified into a tridentate ligand, and the change can effectively increase the penetration capacity of Pd active center in the actual ligand use, so that the catalytic activity is improved;
(2) The ligand of the invention needs to be used in combination with palladium acetate or dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium in the practical application process, the use process is convenient, the ligand has good compatibility to the large steric hindrance coupling catalysis effect, and the conversion rate is obviously better than that of the traditional ligand when the ligand is used in the large steric hindrance C-C coupling process;
(3) The invention discloses a large steric hindrance C-C coupled palladium ligand which is solid at room temperature, insensitive to oxygen in air at room temperature, easy to store and transport and convenient to use;
(4) The raw materials used in the ligand preparation process are commercialized, the sources are wide, the synthesis process is realized by adopting a conventional reaction process, and the large-scale preparation and popularization are expected to be good.
Drawings
FIG. 1, nuclear magnetic spectrum of a large steric hindrance C-C coupled palladium ligand of the present invention.
Detailed Description
The invention will now be described with reference to the following examples, which are given by way of illustration of the invention, but are not intended to limit the scope of the invention, using conventional commercial products as raw materials, solvents and catalysts.
The invention discloses a synthesis method of a large steric hindrance C-C coupled palladium ligand, which comprises the following steps:
step 1: the 2-anisole is subjected to hydrogen removal and lithiation by n-butyl lithium, then reacts with tributyl borate, and is subjected to acidolysis to obtain a compound B, namely 2-anisole: n-butyllithium: the molar ratio of tributyl borate is 1:1.1 to 1.2:1.2 to 1.3, the structural formula of the compound B is
Step 2: the compound B and bromobenzene are subjected to Suzuki reaction to prepare a compound C, wherein the compound B is as follows: the molar ratio of bromobenzene is 1:1 to 1.1, the structure of the compound C is
Step 3: the compound C is subjected to halogenation reaction to obtain a compound D, and the structural formula of the compound D is
Step 4: the 2-amino-5-methylpyridine is protected by di-tert-butyl dicarbonate to obtain a compound F, 2-amino-5-methylpyridine: the mole ratio of di-tert-butyl dicarbonate is 1:1.1 to 1.2, the structural formula of the compound F is
Step 5: the compound F is selectively subjected to hydrogen drawing and lithiation to the 3 position of a pyridine ring in the presence of N, N-tetramethyl ethylenediamine, then reacts with triisopropyl borate, and is subjected to acidolysis to obtain a compound G, wherein the compound F is prepared by the steps of: n, N-tetramethyl ethylenediamine: the mole ratio of the triisopropyl borate is 1:1.2 to 1.3:1.2 to 1.25, the structural formula of the compound G is
Step 6: compound D and compound G undergo a Suzuki reaction to form compound H, compound D: the molar ratio of compound G is 1:1 to 1.05, the structural formula of the compound H is
Step 7: amino group and tert-butyl nitrite of the compound H undergo diazotization reaction process under the catalysis of copper acetate and intramolecular ether linkage to form a compound J, and the compound H: copper acetate: the molar ratio of the tert-butyl nitrite is 1:0.01 to 0.1:1.2 to 1.5, the structural formula of the compound J is
Step 8: the compound J reacts with hexamethylpiperidine lithium, the pyridine ring substituent methyl hydrogen is removed by lithiation, and then the compound J reacts with di-tert-butyl phosphine chloride to obtain a compound K, wherein the compound J is as follows: lithium hexamethylpiperidine: the mole ratio of the di-tert-butyl phosphine chloride is 1:1.1 to 1.2:1.2 to 1.25, compoundingThe structural formula of the substance K is
Preferably, the step 1 specifically includes: dissolving the compound A2-anisole in a THF solvent, dripping 2.5mol/L of n-butyllithium at the temperature of between 20 ℃ below zero and 10 ℃ below zero in an argon atmosphere, carrying out heat preservation and hydrogen extraction reaction for 2 hours to 3 hours, cooling to the temperature of between 85 ℃ below zero and 80 ℃ below zero, dripping tributyl borate, naturally heating to the internal temperature of higher than 10 ℃ below zero after the completion of the reaction, concentrating under reduced pressure, acidifying with hydrochloric acid, and crystallizing PE to obtain a white solid compound B.
Preferably, the step 2 specifically includes: sequentially adding compound B, bromobenzene, potassium carbonate, toluene, ethanol, water and Pd (PPh) 3 ) 4 Reflux reaction is carried out for 6-8 h at 70-75 ℃ in an argon atmosphere by a one-pot method until the compound B is completely reacted, the reaction liquid is washed with water and separated, then the organic phase is evaporated to dryness under reduced pressure, and then the white solid compound C is obtained by methanol crystallization, wherein the compound B is: bromobenzene: potassium carbonate: pd (PPh) 3 ) 4 The molar ratio of (2) is 1:1 to 1.1:1.5 to 2: 0.005-0.01, the dosage ratio of the compound B to toluene, ethanol and water is 100g: 600-615 ml: 200-210 ml: 200-210 ml.
Preferably, the step 3 specifically includes: under the protection of argon, adding a compound C and DMF (dimethyl formamide) into a reaction bottle, taking N-bromosuccinimide as a brominating reagent, adding N-bromosuccinimide in batches at the temperature of 0-10 ℃, pouring the reaction liquid into a large amount of water after the completion of tracking reaction, filtering out a solid, pulping and dispersing the solid by using ethanol to obtain a white-like solid compound D, wherein the compound C is prepared by the steps of: the molar ratio of N-bromosuccinimide is 1:1 to 1.1, the dosage ratio of the compound C to the DMF is 100g: 510-520 ml.
Preferably, the step 4 specifically includes: adding a compound E, 4-dimethylaminopyridine and methylene dichloride into a three-mouth bottle under the argon atmosphere, maintaining the internal temperature at 15-25 ℃, and dripping Boc 2 And (3) carrying out heat preservation reaction on the DCM solution of O for 24 hours until the raw materials are basically complete, concentrating the solvent and low boiling point substances under reduced pressure to obtain a crude product, and pulping, dispersing and filtering by using PE to obtain a compound F, wherein the compound E is: DMAP: boc 2 O (O)The molar ratio is 1:1-1.05: 1.1 to 1.2, the dosage ratio of the compound E to the DCM is 10g: 92-95 ml.
Preferably, the step 5 specifically includes: dissolving a compound F in THF, adding N, N-tetramethyl ethylenediamine, cooling to-80 ℃ to-75 ℃ under argon atmosphere, dripping 2.5mol/L of N-BuLi, stirring and reacting for 1-2 h, continuously cooling to-95 ℃ to-85 ℃, dripping triisopropyl borate, then heating to room temperature, concentrating a reaction solution after the reaction is completed, dissociating an ammonium chloride aqueous solution, dispersing and crystallizing PE to obtain a soil gray solid compound G, and obtaining the compound F: n, N-tetramethyl ethylenediamine: n-BuLi: the mole ratio of the triisopropyl borate is 1:1.2 to 1.3:1.1 to 1.2:1.2 to 1.25, the dosage ratio of the compound F to the THF is 10g:100ml.
Preferably, the step 6 specifically includes: sequentially adding a compound D, a compound G, potassium carbonate, dioxane and water into a three-mouth bottle, replacing a system with argon, and adding a catalyst Pd (PPh) 3 ) 4 After the reaction is carried out for 12 hours at 75-80 ℃ by a one-pot method, the reaction of the raw material D is completed, the reaction liquid is concentrated to dryness under reduced pressure, toluene is added to dissolve the concentrated dry matter, then deionized water is used for washing, drying is carried out, after the completion, the organic phase is filtered to remove the drying agent, and the compound H and the compound D are obtained by concentrating under reduced pressure: compound G: potassium carbonate: pd (PPh) 3 ) 4 The molar ratio of (2) is 1:1 to 1.05:1.5 to 2: 0.005-0.01, the dosage ratio of the compound D to dioxane and water is 10g:100ml: 16-18 ml.
Preferably, the step 7 specifically includes: dissolving a compound H in a three-mouth bottle by THF, heating to an internal temperature of 55-60 ℃, stopping heating, adding copper acetate, carefully dripping a THF solution dissolved with tert-butyl nitrite into the system, keeping the system warm for 1-2 hours after dripping, directly concentrating the reaction solution under reduced pressure, adding toluene, refluxing, dissolving, clearing, passing the solution through a silica gel column, collecting a product column liquid, concentrating under reduced pressure until solid is separated out, cooling to a temperature of below 20 ℃, filtering, pumping, drying to obtain a yellowish solid powder compound J, and obtaining the compound H: copper acetate: the molar ratio of the tert-butyl nitrite is 1:0.01 to 0.1:1.2 to 1.5, the dosage ratio of the compound H to the THF is 10g: 78-80 ml, the dosage ratio of tert-butyl nitrite to THF is 10g: 24-26 ml.
Preferably, the step 8 specifically includes: dissolving a compound J in THF (tetrahydrofuran) under the argon atmosphere, cooling to minus 50 ℃ to minus 60 ℃, then dripping a hexamethylpiperidine lithium solution, preserving heat for 2 to 3 hours at minus 55 ℃ to minus 50 ℃ until the system turns dark brown, dripping a di-tert-butyl phosphine chloride solution at an internal temperature of minus 90 ℃ to minus 80 ℃, naturally heating to the internal temperature of 0 ℃ after the completion of the reaction, directly concentrating reaction liquid under negative pressure, adding n-heptane, refluxing and dissolving a concentrated dry matter under the argon atmosphere, cooling to the internal temperature of 20 ℃ to 30 ℃, quickly passing through diatomite under the argon atmosphere, removing insoluble salts, collecting filtrate, concentrating under reduced pressure to a few solvents, stirring, cooling to 0 ℃ to 5 ℃ under the protection of argon, precipitating white solid, filtering and pumping to dryness under the protection of inert gas to obtain a white to yellowish waxy solid compound K, wherein the compound J: lithium hexamethylpiperidine: the mole ratio of the di-tert-butyl phosphine chloride is 1:1.1 to 1.2:1.2 to 1.25, the dosage ratio of the compound J to the THF is 10g: 96-100 ml.
Preferably, the large steric hindrance C-C coupled palladium ligand is a tridentate N-P-O ligand, and the structural formula is as follows:the tridentate N-P-O ligand synthesized by the method of synthesizing a highly sterically hindered C-C coupled palladium ligand as defined in any one of claims 1 to 9, said tridentate N-P-O ligand being used in the synthesis of catalysts compoud1 and compoud 2;
the structural formula of the compound1 is as follows:the structural formula of the compound2 is:the synthesis process of the compound1 or the compound2 is as follows: THF is measured and put into a three-mouth bottle, after the system is replaced by argon, palladium acetate or dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium is measured and dissolved in the three-mouth bottle, the temperature is raised to 45 ℃ to 55 ℃, and after the three-mouth bottle is fully stirred to dissolve and clear, the tridentate ligand of N-P-O is dissolved in the argon atmosphereSlowly dripping solution of THF into the system, wherein the molar ratio of the tridentate ligand of N-P-O to palladium acetate or dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium is 1:0.4-0.6, the dripping speed is controlled to be 0.5-1 h, after the reaction dripping is finished, stirring and reacting for 3-4 h until the reaction is complete, concentrating the reaction system under reduced pressure at 30-40 ℃ until most of the solid in the system is separated out, then adding N-heptane and argon atmosphere for protection, stirring and crystallizing for 2-3 h at room temperature, filtering, pumping to dryness, leaching with N-heptane, and pumping to obtain light brown red solid powder compound1 or dark black red solid powder compound 2.
Example 1
Compound a (2-naphthyridine ether) is a commercially available conventional intermediate with a GC detection purity of greater than 99.5%.
Compound B synthesis process: dissolving compound A (158.2, 1.0 mol) in 1.5LTHF solvent, dripping n-BuLi (2.5 mol/L) 0.48L at-20-10 ℃ under argon atmosphere, cooling to-85-80 ℃ after heat preservation and hydrogen extraction reaction for 2-3 h, and dripping B (C) 4 H 9 ) 3 (288 g,1.25 mol) and naturally heating to an internal temperature higher than-10 ℃ after completion of the reaction. The reaction solution was concentrated under reduced pressure, acidified with hydrochloric acid, and PE crystallized to give a white solid, the major content of which was more than 98% by LC detection, yielding 157g (yield 78%).
Synthesis of Compound C: in a 3L three-necked flask, 147.8g of B, 157g of bromobenzene, 138g of potassium carbonate, 900mL of toluene, 300mL of ethanol, 300mL of water, 300mL of Pd (PPh 3 ) 4 3.5g, reflux reacting for 6-8 h under argon atmosphere until the reaction of B is complete; the reaction solution is washed with water to separate the solution, then the organic phase is evaporated under reduced pressure, and then the white solid 131g (yield 93%) is obtained by crystallization of methanol, GC content>98％.
Synthesis of Compound D: under the protection of argon, C117 g and DMF 600mL are added into a 2L bottle, NBS 98g is added in batches at the temperature of 0-10 ℃, after the completion of the follow-up reaction, the reaction solution is poured into a large amount of water, the solid is filtered out, and then the white solid is obtained by pulping and dispersing with ethanol (yield 88%).
Compound F synthesis: E54g,DMAP 12g,DCM 500mL is added into a 2L three-mouth bottle under argon atmosphere, and the inside is maintainedAt 15-25 deg.C, 164g Boc is added dropwise 2 O in DCM, the reaction was carried out for 24h under heat preservation until the starting materials were substantially complete, then the solvent and the low boilers were concentrated under reduced pressure to give a semisolid, and then the semisolid was slurried with PE, dispersed and filtered to give compound F, which was 70.5g (yield 73%).
Compound G synthesis: 50g of compound F is dissolved in 500mL of THF, 39g of N, N-tetramethyl ethylenediamine is added, the temperature is reduced to minus 80 ℃ to minus 75 ℃ under the argon atmosphere, 115mL of N-BuLi (2.5 mol/L) is dripped, the temperature is continuously reduced to minus 85 ℃ to minus 80 ℃ after stirring reaction for 1h, 65g of triisopropyl borate is dripped, then the temperature is increased to room temperature, and the reaction preparation is completed; the reaction solution was concentrated, the aqueous ammonium chloride solution was dissociated, and PE was dispersed and crystallized to give a grayish solid, 21.2g (yield 53%) in weight, 95% in major LC content, and 152% in molecular weight by LC-MS detection.
Compound H synthesis: 30.0g of compound D, 16.7g of compound G, 20.7g of potassium carbonate, 300mL of dioxane and 50mL of water are sequentially added into a 500mL three-necked flask, and after the system is replaced by argon, catalyst Pd (PPh) 3 ) 4 1.2g, heating to 72-75 ℃ and preserving heat for reaction for 12h until the reaction of the raw material D is complete. Concentrating the reaction solution under reduced pressure, adding 500mL of toluene to dissolve the concentrated dry matter, and adding 200mL of deionized water for three times each time, and then adding anhydrous sodium sulfate for drying; and after the completion, the organic phase is filtered to remove the drying agent, the filtrate is decompressed and concentrated to obtain a crude product of the compound H, the weight of the crude product is 38g, the LC detection content is 91%, and the crude product can be fed into the next step without purification.
Compound J synthesis: dissolving 38g of a crude product of a compound H in 300mL of THF in a 500mL three-port bottle, heating to 55-57 ℃ until the internal temperature is reached, stopping heating, adding 0.35g of copper acetate, then carefully dripping a 50mL of HF solution dissolved with 20.6g of tert-butyl nitrite into the system, releasing heat and deflating the system, and then preserving heat for 1 hour after the dripping is finished to finish the reaction; the reaction solution is directly concentrated to dryness under reduced pressure, 500mL of toluene is added, the solution is dissolved and cleared after reflux, the solution passes through a silica gel column, the column liquid is collected, the reduced pressure concentration is carried out until the volume of the solution is about 60mL, then solid is separated out, the temperature is reduced to be lower than 20 ℃, the filtration is carried out, the drying is carried out, 19.5g (yield: 63%) of yellowish solid powder is obtained after the filtration and drying, LC purity is 97%, LC-MS detection is carried out, and molecular weight is 309.1.
Compound K synthesis: and (3) dissolving 15.5g of compound J in 150mL of THF under argon atmosphere, cooling to-55 ℃ to-50 ℃, then dropwise adding 55mmol of hexamethylpiperidine lithium salt solution, keeping the temperature between-55 ℃ and-50 ℃ for 2 hours until the system turns dark brown, cooling the internal temperature to-90 ℃ to-80 ℃, then dropwise adding 55mmol of di-tert-butyl phosphine chloride solution, and naturally heating to the internal temperature to 0 ℃ after the completion of the reaction. Directly concentrating the reaction solution under negative pressure, adding 1.2L of n-heptane, refluxing under argon atmosphere to dissolve the concentrated dry matter, cooling to an internal temperature of 20-30 ℃, rapidly passing through diatomite under argon atmosphere to remove insoluble salts, collecting filtrate, concentrating under reduced pressure to the left of about 100mL, stirring under argon protection, cooling to 0-5 ℃, and precipitating white-like solid; filtering and pumping to obtain white to yellowish waxy solid under the protection of inert gas, wherein the weight of the waxy solid is 16.3g (yield is 72%), and the LC main content is 98.5%; LC-MS, molecular weight 453.1.
As shown in FIG. 1, a nuclear magnetic resonance spectrum of the compound K of this example was obtained.
The procedure for the preparation of the catalysts compound1 and compound2 by using compound K was carried out using the following method:
the synthesis process comprises the following steps: compound1: 400mL of THF is measured in a 1L three-mouth bottle, after the system is replaced by argon, 2.0g of palladium acetate is weighed and dissolved in the three-mouth bottle, the temperature is raised to 45-55 ℃, and the three-mouth bottle is fully stirred to be dissolved to form orange solution; then, under the argon atmosphere, slowly dripping a solution of 4.5g of compound K dissolved in 90mL of THF into the system, wherein the dripping is controlled to be completed within 0.5-1 h; the system gradually changes from orange to light red, and a little solid particles are gradually separated out; after the dripping is finished, stirring and reacting for 3-4 hours until the reaction is complete; concentrating the reaction system under reduced pressure at 30-40 ℃ to remove most THF until about 50mL of the system is left, wherein most solid is separated out, adding 200mL of n-heptane, protecting in argon atmosphere, continuing stirring and crystallizing at room temperature for 2h, filtering, pumping to dry, eluting with 50mL of n-heptane, pumping to obtain light brown red solid powder, and weighing 4.67g (yield 83%); the compound is subjected to LC-MS qualitative analysis, and the detection molecular weight is 631-633, so that the compound meets the expectations.
The Compound2 synthesis process is consistent with the Compound1 synthesis process, the source of palladium is replaced by dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium, the reaction process and the treatment flow are similar, the color of the obtained Compound2 is dark red, the yield is 87%, and the molecular weight is 675-677 according with expectations when detected by LC-MS.
The structure of the synthesized palladium complex is schematically shown as follows:
the catalysts compound1 and compound2 are compared with conventional catalytic ligands in the following synthesis process as shown in table 1 below:
reaction process:
TABLE 1 catalytic Effect of the catalysts
Reaction conditions: anaerobic conditions; the catalyst amount is 1% molar equivalent; boric acid substrate equivalent to bromo substrate equivalent 1.2:1, koh equivalent 2.0; as can be seen from Table 1, the reaction temperature is 83-85 ℃, the concentration of the product obtained by the reaction of the catalyst compound1 and the catalyst compound2 can reach 88.6%, the concentration of boric acid removing substances is obviously superior to other catalysts, and the concentration of boric acid removing substances is 1.3-9.1%, and is obviously lower than other catalysts.
In the above, the following substitutions may be made:
in the synthesis process of the compound K, the di-tert-butyl phosphine chloride is replaced by diphenyl phosphine chloride, so that the ligand structure can be changed, and the actual application may have similar effects.
In the synthesis of the compound C, bromobenzene is replaced by similar fluorobromobenzene, bromobiphenyl and the like, and the obtained product can have similar effects.
The source of palladium is replaced by palladium acetate or dichlorotetramethyl ethylenediamine palladium with other similar sources of palladium.
The synthetic reaction route of the large steric hindrance ligand of the invention is as follows:
the method comprises the steps of carrying out hydrogen removal lithiation on 2-anisole through N-butyl lithium, then carrying out acidolysis on the compound B after reacting with tributyl borate to obtain a compound B, carrying out Suzuki reaction on the compound B and bromobenzene to obtain a compound C, carrying out halogenation on the compound C to obtain a compound D, carrying out selective first hydrogen removal lithiation on the compound F to a pyridine ring 3 position in the presence of N, N-tetramethyl ethylenediamine, then carrying out acidolysis on the compound F and triisopropyl borate to obtain a compound G, carrying out Suzuki reaction on the compound D and the compound G to generate a compound H, carrying out diazotization reaction on amino of the compound H and tert-butyl nitrite under the catalysis of copper acetate to obtain a compound J, carrying out lithium removal on the compound J and hexamethyl piperidine to obtain a compound K, carrying out halogenation the compound K and palladium acetate or dichloro (N, N ', N' -tetramethyl ethylenediamine) palladium to synthesize a compound G, carrying out a compound I, and a stable ligand in a large-plane by using the ligand as a main ligand, and simultaneously providing a stable ligand, wherein the ligand is provided with a large-scale coordination structure; in addition, a configuration of pyridofuran is adopted, and O is introduced to the N coordination point ortho position of the traditional N-P bidentate ligand through a furan functional group to regulate the chemical environment of the N coordination point in the molecule, so that the traditional N-P bidentate ligand is modified into a tridentate ligand, and the change can effectively increase the penetration capacity of Pd active center in the actual ligand use, thereby improving the catalytic activity.
The ligand of the invention needs to be used in combination with palladium acetate or dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium in the practical application process, has convenient use process, has good compatibility on the large steric hindrance coupling catalysis effect, and has the conversion rate obviously superior to that of the traditional ligand in the large steric hindrance C-C coupling process.
The invention discloses a large steric hindrance C-C coupled palladium ligand which is solid at room temperature, insensitive to oxygen in air at room temperature, easy to store and transport and convenient to use.
The raw materials used in the ligand preparation process are commercialized, the sources are wide, the synthesis process is realized by adopting a conventional reaction process, and the large-scale preparation and popularization are expected to be good.
While the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes may be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.
Many other changes and modifications may be made without departing from the spirit and scope of the invention. It is to be understood that the invention is not to be limited to the specific embodiments, but only by the scope of the appended claims.
Claims (10)
1. A method for synthesizing a large steric hindrance C-C coupled palladium ligand, which is characterized by comprising the following steps:
step 1: the 2-anisole is subjected to hydrogen removal and lithiation by n-butyl lithium, then reacts with tributyl borate, and is subjected to acidolysis to obtain a compound B, namely 2-anisole: n-butyllithium: the molar ratio of tributyl borate is 1:1.1 to 1.2:1.2 to 1.3, the structural formula of the compound B is
Step 2: the compound B and bromobenzene are subjected to Suzuki reaction to prepare a compound C, wherein the compound B is as follows: the molar ratio of bromobenzene is 1:1 to 1.1, the structure of the compound C is
Step 3: the compound C is subjected to halogenation reaction to obtain a compound D, and the structural formula of the compound D is
Step 4: the 2-amino-5-methylpyridine is protected by di-tert-butyl dicarbonate to obtain a compound F, 2-amino-5-methylpyridine: the mole ratio of di-tert-butyl dicarbonate is 1:1.1 to 1.2, the structural formula of the compound F is
Step 5: the compound F is selectively subjected to hydrogen drawing and lithiation to the 3 position of a pyridine ring in the presence of N, N-tetramethyl ethylenediamine, then reacts with triisopropyl borate, and is subjected to acidolysis to obtain a compound G, wherein the compound F is prepared by the steps of: n, N-tetramethyl ethylenediamine: the mole ratio of the triisopropyl borate is 1:1.2 to 1.3:1.2 to 1.25, the structural formula of the compound G is
Step 6: compound D and compound G undergo a Suzuki reaction to form compound H, compound D: the molar ratio of compound G is 1:1 to 1.05, the structural formula of the compound H is
Step 7: amino group and tert-butyl nitrite of the compound H undergo diazotization reaction process under the catalysis of copper acetate and intramolecular ether linkage to form a compound J, and the compound H: copper acetate: the molar ratio of the tert-butyl nitrite is 1:0.01 to 0.1:1.2 to 1.5, the structural formula of the compound J is
Step 8: the compound J reacts with hexamethylpiperidine lithium, the pyridine ring substituent methyl hydrogen is removed by lithiation, and then the compound J reacts with di-tert-butyl phosphine chloride to obtain a compound K, wherein the compound J is as follows: lithium hexamethylpiperidine: the mole ratio of the di-tert-butyl phosphine chloride is 1:1.1 to 1.2:1.2 to 1.25, and the structural formula of the compound K is
2. The method for synthesizing a large steric hindrance C-C coupled palladium ligand according to claim 1, wherein the step 1 specifically comprises: dissolving the compound A2-anisole in a THF solvent, dripping 2.5mol/L of n-butyllithium at the temperature of between 20 ℃ below zero and 10 ℃ below zero in an argon atmosphere, carrying out heat preservation and hydrogen extraction reaction for 2 hours to 3 hours, cooling to the temperature of between 85 ℃ below zero and 80 ℃ below zero, dripping tributyl borate, naturally heating to the internal temperature of higher than 10 ℃ below zero after the completion of the reaction, concentrating under reduced pressure, acidifying with hydrochloric acid, and crystallizing PE to obtain a white solid compound B.
3. The method for synthesizing a large steric hindrance C-C coupled palladium ligand according to claim 1, wherein the step 2 specifically comprises: sequentially adding compound B, bromobenzene, potassium carbonate, toluene, ethanol, water and Pd (PPh) 3 ) 4 Reflux reaction is carried out for 6-8 h at 70-75 ℃ in an argon atmosphere by a one-pot method until the compound B is completely reacted, the reaction liquid is washed with water and separated, then the organic phase is evaporated to dryness under reduced pressure, and then the white solid compound C is obtained by methanol crystallization, wherein the compound B is: bromobenzene: potassium carbonate: pd (PPh) 3 ) 4 The molar ratio of (2) is 1:1 to 1.1:1.5 to 2: 0.005-0.01, the dosage ratio of the compound B to toluene, ethanol and water is 100g: 600-615 ml: 200-210 ml: 200-210 ml.
4. The method for synthesizing a highly hindered C-C coupled palladium ligand according to claim 1, wherein the step 3 specifically comprises: under the protection of argon, adding a compound C and DMF (dimethyl formamide) into a reaction bottle, taking N-bromosuccinimide as a brominating reagent, adding N-bromosuccinimide in batches at the temperature of 0-10 ℃, pouring the reaction liquid into a large amount of water after the completion of tracking reaction, filtering out a solid, pulping and dispersing the solid by using ethanol to obtain a white-like solid compound D, wherein the compound C is prepared by the steps of: the molar ratio of N-bromosuccinimide is 1:1 to 1.1, the dosage ratio of the compound C to the DMF is 100g: 510-520 ml.
5. The method for synthesizing a highly hindered C-C coupled palladium ligand according to claim 1, wherein the step 4 specifically comprises: adding a compound E, 4-dimethylaminopyridine and methylene dichloride into a three-mouth bottle under the argon atmosphere, maintaining the internal temperature at 15-25 ℃, and dripping Boc 2 And (3) carrying out heat preservation reaction on the DCM solution of O for 24 hours until the raw materials are basically complete, concentrating the solvent and low boiling point substances under reduced pressure to obtain a crude product, and pulping, dispersing and filtering by using PE to obtain a compound F, wherein the compound E is: DMAP: boc 2 The mol ratio of O is 1:1-1.05: 1.1 to 1.2, the dosage ratio of the compound E to the DCM is 10g: 92-95 ml.
6. The method for synthesizing a highly hindered C-C coupled palladium ligand according to claim 1, wherein the step 5 specifically comprises: dissolving a compound F in THF, adding N, N-tetramethyl ethylenediamine, cooling to-80 ℃ to-75 ℃ under argon atmosphere, dripping 2.5mol/L of N-BuLi, stirring and reacting for 1-2 h, continuously cooling to-95 ℃ to-85 ℃, dripping triisopropyl borate, then heating to room temperature, concentrating a reaction solution after the reaction is completed, dissociating an ammonium chloride aqueous solution, dispersing and crystallizing PE to obtain a soil gray solid compound G, and obtaining the compound F: n, N-tetramethyl ethylenediamine: n-BuLi: the mole ratio of the triisopropyl borate is 1:1.2 to 1.3:1.1 to 1.2:1.2 to 1.25, the dosage ratio of the compound F to the THF is 10g:100ml.
7. The method for synthesizing a highly hindered C-C coupled palladium ligand according to claim 1, wherein the step 6 specifically comprises: sequentially adding a compound D, a compound G, potassium carbonate, dioxane and water into a three-mouth bottle, replacing a system with argon, and adding a catalyst Pd (PPh) 3 ) 4 After the reaction is carried out for 12 hours at 75-80 ℃ by a one-pot method, the reaction of the raw material D is completed, the reaction liquid is concentrated to dryness under reduced pressure, toluene is added to dissolve the concentrated dry matter, then deionized water is used for washing, drying is carried out, after the completion, the organic phase is filtered to remove the drying agent, and the compound H and the compound D are obtained by concentrating under reduced pressure: compound G: potassium carbonate: pd (PPh) 3 ) 4 The molar ratio of (2) is 1:1 to 1.05:1.5 to 2: 0.005-0.01, compound D and dioxyThe dosage ratio of hexacyclic ring and water is 10g:100ml: 16-18 ml.
8. The method for synthesizing a highly hindered C-C coupled palladium ligand according to claim 1, wherein the step 7 specifically comprises: dissolving a compound H in a three-mouth bottle by THF, heating to an internal temperature of 55-60 ℃, stopping heating, adding copper acetate, carefully dripping a THF solution dissolved with tert-butyl nitrite into the system, keeping the system warm for 1-2 hours after dripping, directly concentrating the reaction solution under reduced pressure, adding toluene, refluxing, dissolving, clearing, passing the solution through a silica gel column, collecting a product column liquid, concentrating under reduced pressure until solid is separated out, cooling to a temperature of below 20 ℃, filtering, pumping, drying to obtain a yellowish solid powder compound J, and obtaining the compound H: copper acetate: the molar ratio of the tert-butyl nitrite is 1:0.01 to 0.1:1.2 to 1.5, the dosage ratio of the compound H to the THF is 10g: 78-80 ml, the dosage ratio of tert-butyl nitrite to THF is 10g: 24-26 ml.
9. The method for synthesizing a highly hindered C-C coupled palladium ligand according to claim 1, wherein the step 8 is specifically: dissolving a compound J in THF (tetrahydrofuran) under the argon atmosphere, cooling to minus 50 ℃ to minus 60 ℃, then dripping a hexamethylpiperidine lithium solution, preserving heat for 2 to 3 hours at minus 55 ℃ to minus 50 ℃ until the system turns dark brown, dripping a di-tert-butyl phosphine chloride solution at an internal temperature of minus 90 ℃ to minus 80 ℃, naturally heating to the internal temperature of 0 ℃ after the completion of the reaction, directly concentrating reaction liquid under negative pressure, adding n-heptane, refluxing and dissolving a concentrated dry matter under the argon atmosphere, cooling to the internal temperature of 20 ℃ to 30 ℃, quickly passing through diatomite under the argon atmosphere, removing insoluble salts, collecting filtrate, concentrating under reduced pressure to a few solvents, stirring, cooling to 0 ℃ to 5 ℃ under the protection of argon, precipitating white solid, filtering and pumping to dryness under the protection of inert gas to obtain a white to yellowish waxy solid compound K, wherein the compound J: lithium hexamethylpiperidine: the mole ratio of the di-tert-butyl phosphine chloride is 1:1.1 to 1.2:1.2 to 1.25, the dosage ratio of the compound J to the THF is 10g: 96-100 ml.
10. A large steric hindrance C-C coupled palladium ligand, wherein the ligand is a tridentate N-P-O ligand having the structural formula:the tridentate N-P-O ligand synthesized by the method of synthesizing a highly sterically hindered C-C coupled palladium ligand as defined in any one of claims 1 to 9, said tridentate N-P-O ligand being used in the synthesis of catalysts compoud1 and compoud 2;
the structural formula of the compound1 is as follows:
the structural formula of the compound2 is:the synthesis process of the compound1 or the compound2 is as follows: THF is measured and put into a three-mouth bottle, palladium acetate or dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium is weighed and dissolved in the three-mouth bottle after the system is replaced by argon, the temperature is raised to 45-55 ℃, the three-tooth ligand of N-P-O is dissolved in the THF under the argon atmosphere after the three-mouth bottle is fully stirred to be dissolved and cleared, the solution of the three-tooth ligand of N-P-O and palladium acetate or dichloro (N, N, N ', N' -tetramethyl ethylenediamine) palladium are slowly dripped into the system, the molar ratio of the three-tooth ligand of N-P-O to palladium acetate or dichloro (N, N ', N' -tetramethyl ethylenediamine) palladium is 1:0.4-0.6, the dripping speed is controlled to be 0.5-1 h, the reaction is continuously stirred for 3-4 h until the reaction is complete after the dripping is completed, then the reaction system is reduced in pressure until most of solids are separated out, then N-heptane is added, the protection of the argon atmosphere, the three-tooth ligand is continuously stirred and crystallized for 2-3 h at room temperature, the solution is filtered, and pumped to be dried, and the light red solid compound powder or dark red solid compound powder is obtained. />
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