CN111574322A - 一种二氟甲基芳烃类化合物的制备方法 - Google Patents
一种二氟甲基芳烃类化合物的制备方法 Download PDFInfo
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- CN111574322A CN111574322A CN202010523796.4A CN202010523796A CN111574322A CN 111574322 A CN111574322 A CN 111574322A CN 202010523796 A CN202010523796 A CN 202010523796A CN 111574322 A CN111574322 A CN 111574322A
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- China
- Prior art keywords
- silver
- difluoromethyl
- potassium
- sodium
- producing
- Prior art date
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- -1 difluoromethyl aromatic compound Chemical class 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000012074 organic phase Substances 0.000 claims abstract description 26
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 23
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 22
- 239000011737 fluorine Substances 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 14
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000004332 silver Substances 0.000 claims abstract description 12
- 229910052709 silver Inorganic materials 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000000758 substrate Substances 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 9
- 239000002585 base Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000010791 quenching Methods 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 34
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 34
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical group [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 17
- 235000011181 potassium carbonates Nutrition 0.000 claims description 17
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 239000000741 silica gel Substances 0.000 claims description 12
- 229910002027 silica gel Inorganic materials 0.000 claims description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000012363 selectfluor Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 235000021317 phosphate Nutrition 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 4
- 239000004299 sodium benzoate Substances 0.000 claims description 4
- 235000010234 sodium benzoate Nutrition 0.000 claims description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 229940050390 benzoate Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 2
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 150000004673 fluoride salts Chemical class 0.000 claims description 2
- 150000002222 fluorine compounds Chemical class 0.000 claims description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000004300 potassium benzoate Substances 0.000 claims description 2
- 235000010235 potassium benzoate Nutrition 0.000 claims description 2
- 229940103091 potassium benzoate Drugs 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- BLVWQJBQOLAQEZ-UHFFFAOYSA-M potassium;4-chlorobenzoate Chemical compound [K+].[O-]C(=O)C1=CC=C(Cl)C=C1 BLVWQJBQOLAQEZ-UHFFFAOYSA-M 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- 229940096017 silver fluoride Drugs 0.000 claims description 2
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims description 2
- 229910001923 silver oxide Inorganic materials 0.000 claims description 2
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 claims description 2
- 229910000367 silver sulfate Inorganic materials 0.000 claims description 2
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 235000013024 sodium fluoride Nutrition 0.000 claims description 2
- 239000011775 sodium fluoride Substances 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- GHMWZRWCBLXYBX-UHFFFAOYSA-M sodium;4-chlorobenzoate Chemical compound [Na+].[O-]C(=O)C1=CC=C(Cl)C=C1 GHMWZRWCBLXYBX-UHFFFAOYSA-M 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 4
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 4
- RUYZJEIKQYLEGZ-UHFFFAOYSA-N 1-fluoro-4-phenylbenzene Chemical group C1=CC(F)=CC=C1C1=CC=CC=C1 RUYZJEIKQYLEGZ-UHFFFAOYSA-N 0.000 description 3
- WTGWHMMQWMLFMZ-UHFFFAOYSA-N 2-(4-phenylphenyl)propanedioic acid Chemical compound C1=CC(C(C(O)=O)C(=O)O)=CC=C1C1=CC=CC=C1 WTGWHMMQWMLFMZ-UHFFFAOYSA-N 0.000 description 3
- BPLWLYWRZQYGSG-UHFFFAOYSA-N 4-(Difluoromethyl)biphenyl Chemical group C1=CC(C(F)F)=CC=C1C1=CC=CC=C1 BPLWLYWRZQYGSG-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 3
- STERQFIZWRUAIL-UHFFFAOYSA-N 1-(difluoromethyl)-2-propan-2-ylbenzene Chemical compound CC(C)C1=CC=CC=C1C(F)F STERQFIZWRUAIL-UHFFFAOYSA-N 0.000 description 2
- YNZBAHINXSRPNN-UHFFFAOYSA-N 1-(difluoromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(C(F)F)C=C1 YNZBAHINXSRPNN-UHFFFAOYSA-N 0.000 description 2
- OOLVDGPKGLYEEH-UHFFFAOYSA-N 1-(difluoromethyl)-4-phenoxybenzene Chemical compound FC(F)c1ccc(Oc2ccccc2)cc1 OOLVDGPKGLYEEH-UHFFFAOYSA-N 0.000 description 2
- ANQMTLKEAKYWEZ-UHFFFAOYSA-N 1-tert-butyl-4-(difluoromethyl)benzene Chemical compound CC(C)(C)C1=CC=C(C(F)F)C=C1 ANQMTLKEAKYWEZ-UHFFFAOYSA-N 0.000 description 2
- ATPPNMLQNZHDOG-UHFFFAOYSA-N 2-fluoro-2-phenylacetic acid Chemical compound OC(=O)C(F)C1=CC=CC=C1 ATPPNMLQNZHDOG-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- JDZLOJYSBBLXQD-UHFFFAOYSA-N difluoromethylbenzene Chemical compound FC(F)C1=CC=CC=C1 JDZLOJYSBBLXQD-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VTTGFHYJTHPIQB-UHFFFAOYSA-N 1-(difluoromethyl)-3-phenylbenzene Chemical group FC(F)C1=CC=CC(C=2C=CC=CC=2)=C1 VTTGFHYJTHPIQB-UHFFFAOYSA-N 0.000 description 1
- HKGWZPGNUJEGCT-UHFFFAOYSA-N 2-(4-methoxyphenyl)propanedioic acid Chemical compound COC1=CC=C(C(C(O)=O)C(O)=O)C=C1 HKGWZPGNUJEGCT-UHFFFAOYSA-N 0.000 description 1
- LKSCXJKSTWZKJL-UHFFFAOYSA-N 2-(4-phenoxyphenyl)propanedioic acid Chemical compound C1=CC(C(C(O)=O)C(=O)O)=CC=C1OC1=CC=CC=C1 LKSCXJKSTWZKJL-UHFFFAOYSA-N 0.000 description 1
- NANIJEVJJZEWBS-UHFFFAOYSA-N 2-(4-tert-butylphenyl)propanedioic acid Chemical compound CC(C)(C)C1=CC=C(C(C(O)=O)C(O)=O)C=C1 NANIJEVJJZEWBS-UHFFFAOYSA-N 0.000 description 1
- KAANENIVZBWMME-UHFFFAOYSA-N 2-(difluoromethyl)dibenzofuran Chemical compound FC(C1=CC2=C(OC3=C2C=CC=C3)C=C1)F KAANENIVZBWMME-UHFFFAOYSA-N 0.000 description 1
- HKDOPIKMUZUTSW-UHFFFAOYSA-N 2-dibenzofuran-2-ylpropanedioic acid Chemical compound C1=C(C=CC=2OC3=C(C21)C=CC=C3)C(C(=O)O)C(=O)O HKDOPIKMUZUTSW-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 241000353097 Molva molva Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 235000010678 Paulownia tomentosa Nutrition 0.000 description 1
- 240000002834 Paulownia tomentosa Species 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical compound OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
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Abstract
本发明公开了一种二氟甲基芳烃类化合物的制备方法,该方法包括以下步骤:(1)在氮气氛围下,将芳基单取代丙二酸底物、银催化剂、碱、选择性氟试剂依次加入反应管中,再加入溶剂,在对应温度下反应11~13h;其中,所述芳基单取代丙二酸底物、银催化剂、碱、选择性氟试剂的摩尔比为1:0.1~1:0.5~5:4~10;(2)使用3M的盐酸淬灭反应,将反应产物依次进行萃取、合并有机相、洗涤、干燥、旋干有机相以及纯化后,得到二氟甲基芳烃类化合物。本发明制备方法操作简单,原料简单廉价且易制备,条件温和,且具有良好的官能团兼容性,非常实用。
Description
技术领域
本发明属于有机氟化学技术领域,尤其涉及一种二氟甲基芳烃类化合物的制备方法。
背景技术
二氟甲基中存在两个氟原子以及一个氢原子,氟原子的吸电子效应使得该氢原子具有弱酸性,可以作为亲脂性氢键供体与生物大分子中的富电子体系形成氢键,有利于药物与受体的选择性结合,从而提高药物或先导化合物的活性;并且该结构片段在药物化学领域深受重视,常作为伯醇、硫醇、羟肟酸及酰胺基的生物电子等排体用于药物以及生物活性分子的设计中。
常规的制备二氟甲基芳烃类化合物的方法有:(1)通过芳香醛与二乙胺基三氟化硫(DAST)[1.F.S.Fawcett,C.W.Yullock,D.D.Coffman,J.Am.Chem.Soc.84,4275-4285(1962).],但是该方法不能够兼容羰基、羟基、羧基等基团,底物较为受限;(2)金属参与或催化下,官能化的芳烃与二氟甲基试剂进行偶联也是制备二氟甲基芳烃的一种方法[2.P.S.Fire,J.F.Harwig,J.Am.Chem.Soc.134,5524-5527(2012);3.Y.Gu,X.Leng,Q.L.Shen,Nat.Commun.5,5405-5411(2014);4.Z.Feng,Q.Q.Min,X.G.Zhang,Nat.Chem.9,918-923(2017)],但是该方法由于使用了金属,使得反应体系对于水和氧气较为敏感;(3)利用二氟甲基自由基对简单芳烃进行加成是制备二氟甲基芳烃最直接的方法[5.Y.Fujiwara,J.A.Dixon,P.S.Baran,J.Am.Chem.Soc.134,1494-1497(2012);6.T.T.Tung,S.B.Christensen,J.nielsen,Chem.Eur.J.23,18125-18128(2017)],但是该方法存在反应位点选择性问题,无法得到单一产物。
总而言之,虽然上述方法都可以得到二氟甲基芳烃类化合物,但是缺点也是明显的。此外,丙二酸衍生物制备偕二氟亚甲基的方法已经被报道[7.Z.Wang,C.Y.Guo,C.Yang,J.P.Chen,J.Am.Chem.Soc.141,5617-5622(2019)],但该反应原料主要局限于二取代的丙二酸衍生物,对于单取代的丙二酸衍生物制备二氟甲基化合物非常困难。
因此,鉴于二氟甲基芳烃类化合物在药物合成领域中的重要应用,开拓新的合成方法迫在眉睫。
发明内容
本发明的目的在于提供一种二氟甲基芳烃类化合物的制备方法,旨在解决上述背景技术中现有技术所存在的各种不足之处。
本发明是这样实现的,一种二氟甲基芳烃类化合物的制备方法,该方法包括以下步骤:
(1)在氮气氛围下,将芳基单取代丙二酸底物、银催化剂、碱、选择性氟试剂依次加入反应管中,再加入溶剂,在对应温度下反应11~13h;其中,所述芳基单取代丙二酸底物、银催化剂、碱、选择性氟试剂的摩尔比为1:0.1~1:0.5~5:4~10;
(2)使用3M的盐酸淬灭反应,将反应产物依次进行萃取、合并有机相、洗涤、干燥、旋干有机相以及纯化后,得到二氟甲基芳烃类化合物。
优选地,在步骤(1)中,所述芳基单取代丙二酸底物的芳基为苯环或杂环芳烃,其中,苯环上可含有如下一种到多种取代基:4-苯基、3-苯基、2-苯基、4-甲氧基、4-己氧基、4-苯氧基、4-叔丁基、4-丙酰胺基、4-(2-氧吡咯烷-1-基)、4-(苯基乙炔基)、4-溴基、4-苯甲酰基、4-(3-甲氧基-3-氧丙基)苯基、2-异丙基、3-溴-4-甲氧基、4-((1-乙氧基-2-甲基-1-氧丙烷-2-基)氧基);所述杂环芳烃包括二苯并[b,d]呋喃、萘环、11-氧代-6,11-二氢二苯并[b,e]氧杂环丁。
优选地,在步骤(1)中,所述银催化剂为硝酸银、氟化银、氧化银、醋酸银、硫酸银、三氟甲磺酸银、四氟硼酸银;
在步骤(1)中,所述碱包括无机碱、有机碱;所述无机碱包括磷酸盐类、碳酸盐类、氟化盐类,所述有机碱包括苯甲酸盐类、有机胺类、吡啶类。
优选地,在步骤(1)中,所述银催化剂为硝酸银;
在步骤(1)中,所述磷酸盐类包括磷酸钾、磷酸钠、磷酸二氢钾、磷酸二氢钠、磷酸氢二钾、磷酸氢二钠;
所述碳酸盐类包括碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠;所述氟化盐类包括氟化钾、氟化钠、氟化锂;
所述苯甲酸盐类包括苯甲酸钠、苯甲酸钾、对氯苯甲酸钠、对氯苯甲酸钾;
所述胺类包括三乙胺。
优选地,在步骤(1)中,所述碱为碳酸钾、磷酸氢二钾或苯甲酸钠。
优选地,在步骤(1)中,所述选择性氟试剂为Selectfluor、Selectfluor II。
优选地,在步骤(1)中,所述溶剂为有机溶剂和水按体积比1:1组成的混合溶剂,所述有机溶剂为乙腈、丙酮、卤代烃类、烷烃类、苯类中的至少一种;其中,
所述卤代烃类包括二氯甲烷,醚类如乙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚;
所述烷烃类包括正己烷、环己烷、正戊烷、环戊烷;
所述苯类包括苯、甲苯。
优选地,所述溶剂为正己烷和水按体积比1:1组成。
优选地,在步骤(2)中,所述萃取为用乙酸乙酯萃取,所述洗涤为用饱和食盐水洗涤,所述干燥为用无水硫酸钠干燥,所述纯化为用石油醚/乙酸乙酯=70~2:1的硅胶板纯化。
本发明克服现有技术的不足,提供一种二氟甲基芳烃类化合物的制备方法,通过芳基单取代丙二酸衍生物的一个羧酸与一价银结合成银盐,银盐再被选择性氟试剂Selectfluor氧化为二价银盐,生成的二价银盐氧化羧酸,并脱去一分子二氧化碳,得到α-羧基自由基,再与氟试剂反应得到α-氟代苯乙酸中间体;最后,上述α-氟代苯乙酸中间体再经历一次银催化脱羧氟化反应,最终得到二氟甲基芳烃类化合物。
相比于现有技术的缺点和不足,本发明具有以下有益效果:本发明制备方法操作简单,原料简单廉价且易制备,条件温和,且具有良好的官能团兼容性,非常实用。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1 4-(二氟甲基)-1,1'-联苯的合成
(1)将2-([1,1'-联苯]-4-基)丙二酸(51.2mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂Selectfluor(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,25℃下反应12h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=70:1)得到目标产物4-(二氟甲基)-1,1'-联苯32.7mg,呈白色固体,产率为80%。
1H NMR(400MHz,CDCl3):δ7.67(d,J=8.2Hz,2H),7.58(t,J=7.2Hz,4H),7.46(t,J=7.5Hz,2H),7.38(t,J=7.3Hz,1H),6.69(t,J=56.5Hz,1H).
19F NMR(376MHz,CDCl3):δ-110.22(d,J=56.5Hz,2F).
13C NMR(100MHz,CDCl3):δ143.8,140.3,133.3(t,J=22.5Hz),129.0,128.0,127.6,127.4,126.2(t,J=5.9Hz),114.9(t,J=238.5Hz).
实施例2 3-(二氟甲基)-1,1'-联苯的合成
(1)将2-([[1,1'-联苯]-3-基)丙二酸(51.2mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂Selectfluor II(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,在25℃下反应12h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=70:1)得到目标产物3-(二氟甲基)-1,1'-联苯24.5mg,呈白色固体,产率为60%。
1H NMR(400MHz,CDCl3):δ7.75–7.66(m,2H),7.63–7.57(m,2H),7.56–7.42(m,4H),7.42–7.34(m,1H),6.71(t,J=56.5Hz,1H).
19FNMR(376MHz,CDCl3):δ-110.44(d,J=56.4Hz,2F).
13C NMR(100MHz,CDCl3):δ142.0,140.3,135.0(t,J=22.2Hz),129.6,129.3,129.1,128.0,127.3,124.5(dd,J=10.9,5.7Hz),114.9(t,J=238.9Hz).
实施例3二氟甲基苯的合成
(1)将2-苯基丙二酸(36.0mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,25℃下反应12h;
(2)使用4-氟联苯作为内标,对反应体系通过19F NMR测定产率为66%,由于产物易挥发,通过19F NMR和GC/MS确定产物为二氟甲基苯。
实施例4 1-二氟甲基-4-甲氧基苯的合成
(1)将2-(4-甲氧基苯基)丙二酸(42.0mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,室温下反应12h;
(2)使用4-氟联苯作为内标,对反应体系通过19F NMR测定产率为90%,通过19FNMR和GC/MS确定产物为1-二氟甲基-4-甲氧基苯。
1H NMR(400MHz,CDCl3):δ7.45(d,J=8.6Hz,2H),6.96(d,J=8.7Hz,2H),6.61(t,J=56.7Hz,1H),3.84(s,3H).
19FNMR(376MHz,CDCl3):δ-108.00(d,J=56.8Hz,2F).
13C NMR(100MHz,CDCl3):δ161.5,127.2(t,J=5.8Hz),126.8(t,J=22.8Hz),115.1(t,J=236.1Hz),114.1,55.4,55.4.
实施例5 1-二氟甲基-4-苯氧基苯的合成
(1)将2-(4-苯氧基苯基)丙二酸(54.4mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,室温下反应12h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=50:1)得到目标产物1-二氟甲基-4-苯氧基苯29.5mg,呈白色固体,产率为67%。
1H NMR(400MHz,CDCl3):δ7.40(d,J=8.5Hz,2H),7.30(t,J=8.0Hz,2H),7.09(t,J=7.9Hz,1H),6.97(d,J=7.8Hz,4H),6.56(t,J=56.6Hz,1H).
19FNMR(376MHz,CDCl3):δ-108.82(d,J=56.6Hz,2F).
13C NMR(100MHz,CDCl3):δ159.7,156.3,130.1,129.0(t,J=22.7Hz),127.5(t,J=6.0Hz),124.3,119.8,118.4,114.7(t,J=237.9Hz).
实施例6 1-叔丁基-4-二氟甲基苯的合成
(1)将2-(4-(叔丁基)苯基)丙二酸(47.2mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,25℃下反应12h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,二氯甲烷萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,0℃下旋干有机相,粗产品经制备硅胶板纯化(石油醚)得到目标产物1-叔丁基-4-二氟甲基苯24.9mg,呈无色油状物,产率为67%。
1H NMR(400MHz,CDCl3):δ7.51(d,J=8.6Hz,2H),7.48(d,J=8.5Hz,2H),6.65(t,J=56.6Hz,1H),1.37(s,9H).
19FNMR(376MHz,CDCl3):δ-109.67(d,J=56.6Hz,2F).
13C NMR(100MHz,CDCl3):δ154.1,131.7(t,J=22.4Hz),125.8,125.5(t,J=5.9Hz),115.1(t,J=237.9Hz),35.0,31.3.
实施例7N-(4-(二氟甲基)苯基)丙酰胺的合成
(1)将2-(4-丙酰胺基苯基)丙二酸(50.2mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,25℃下反应12h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=2:1)得到目标产物N-(4-(二氟甲基)苯基)丙酰胺19.1mg,呈白色固体,产率为48%。
1H NMR(400MHz,CDCl3):δ7.62(d,J=8.3Hz,2H),7.45(d,J=8.4Hz,2H),7.39(br,1H),6.61(t,J=56.6Hz,1H),2.42(q,J=7.6Hz,2H),1.25(t,J=7.5Hz,3H).
19FNMR(376MHz,CDCl3):δ-109.50(d,J=56.6Hz,2F).
13C NMR(100MHz,CDCl3):δ196.1,139.9,137.9(t,J=22.5Hz),137.2,133.0,130.3(d,J=14.6Hz),128.6,125.7(t,J=5.9Hz),114.2(t,J=239.7Hz).
HRMS-ESI(m/z):calcd for C10H11F2ONa[(M+Na)+]222.0706,found2222.0705.
IR(cm-1):3752,3498,2919,2354,1670,1532,1414,1014,800.
实施例8 3-(4-(二氟甲基)苯基)丙酸甲酯的合成
(1)将2-(4-(3-甲氧基-3-氧丙基)苯基)丙二酸(53.2mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,25℃下反应12h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=50:1)得到目标产物3-(4-(二氟甲基)苯基)丙酸甲酯17.1mg,呈无色油状物,产率为40%。
1H NMR(400MHz,CDCl3):δ7.43(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),6.61(t,J=56.6Hz,1H),3.67(s,3H),2.99(t,J=7.7Hz,2H),2.64(t,J=7.7Hz,2H).
19FNMR(376MHz,CDCl3):δ-109.99(d,J=56.6Hz,2F).
13C NMR(100MHz,CDCl3):δ173.2,143.5,132.6(t,J=22.4Hz),128.8,125.9(t,J=6.0Hz),114.9(t,J=238.1Hz),51.8,35.7,30.8.
实施例9 1-二氟甲基-2-异丙基苯的合成
(1)将2-(2-异丙基苯基)丙二酸(44.4mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,25℃下反应12h;
(2)使用4-氟联苯作为内标,对反应体系通过19F NMR产率测定为64%,通过19FNMR和GC/MS确定产物为1-二氟甲基-2-异丙基苯。
1H NMR(400MHz,CDCl3):δ7.56-7.52(m,1H),7.50–7.40(m,2H),7.32-7.26(m,1H),6.88(t,J=55.5Hz),3.35-3.23(m,1H),1.30(d,J=6.8Hz,6H).
19FNMR(376MHz,CDCl3):δ-110.09(d,J=54.5Hz,2F).
13C NMR(100MHz,CDCl3):δ147.5(t,J=4.1Hz),131.1,131.0(t,J=21.3Hz),126.2,126.0,125.9(t,J=7.7Hz),114.2(t,J=237.6Hz),28.8,24.2.
实施例10 2-溴-4-(二氟甲基)-1-甲氧基苯的合成
(1)将2-(3-溴-4-甲氧基苯基)丙二酸(57.8mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,25℃下反应12h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=5:1)得到目标产物2-溴-4-(二氟甲基)-1-甲氧基苯36.0mg,呈无色油状物,产率为76%。
1H NMR(400MHz,CDCl3):δ7.70(s,1H),7.42(d,J=8.3Hz,1H),6.94(d,J=8.5Hz,1H),6.57(t,J=56.5Hz,1H),3.93(s,3H).
19FNMR(376MHz,CDCl3):δ-109.01(d,J=56.6Hz,2F).
13C NMR(100MHz,CDCl3):δ157.8,130.9(t,J=6.0Hz),128.1(t,J=23.2Hz),126.3(t,J=6.1Hz),114.0(t,J=237.4Hz),112.0,111.7,56.5.
HRMS-ESI(m/z):calcd for C8H7BrFO[(M-F)+]216.9664,found 216.9661.
IR(cm-1):3746,2928,2361,1610,1498,1367,1265,1209,1016,813,676.
实施例11 2-(二氟甲基)二苯并[b,d]呋喃的合成
(1)将2-(二苯并[b,d]呋喃-2-基)丙二酸(54.0mg,0.2mmol,1.0equiv.)、硝酸银(10.2mg,0.06mmol,0.3equiv.)、碳酸钾(82.9mg,0.6mmol,3.0equiv.)和选择性氟试剂(566.8mg,1.6mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,25℃下反应12h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=50:1)得到目标产物2-(二氟甲基)二苯并[b,d]呋喃28.4mg,呈白色固体,产率为65%。
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.96(d,J=7.8Hz,1H),7.64-7.56(m,3H),7.49(t,J=7.7Hz,1H),7.37(t,J=7.5Hz,1H),6.80(t,J=56.6Hz,1H).
19FNMR(376MHz,CDCl3):δ-107.63(d,J=56.6Hz,2F).
13C NMR(100MHz,CDCl3):δ157.4,156.8,129.3(t,J=22.6Hz),128.0,124.8(t,J=5.8Hz),123.7,123.3,121.0,118.5(t,J=6.3Hz),115.2(t,J=238.5Hz),112.1(d,J=8.6Hz).
实施例12
(1)将2-([1,1'-联苯]-4-基)丙二酸(51.2mg,0.2mmol,1.0equiv.)、硝酸银(3.4mg,0.02mmol,0.3equiv.)、碳酸钾(13.8mg,0.1mmol,3.0equiv.)和Selectfluor(283.4mg,0.8mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,30℃下反应11h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=2:1)得到目标产物4-(二氟甲基)-1,1'-联苯。
实施例13
(1)将2-([1,1'-联苯]-4-基)丙二酸(51.2mg,0.2mmol,1.0equiv.)、硝酸银(34mg,0.2mmol,0.3equiv.)、碳酸钾(138mg,1mmol,3.0equiv.)和Selectfluor(708.5mg,2mmol,8.0equiv.)加入到反应管中,将反应体系置换为氮气,加入正己烷/水=1:1共4mL,20℃下反应13h;
(2)往反应体系中加入3M盐酸2mL淬灭反应,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干有机相,粗产品经制备硅胶板纯化(石油醚/乙酸乙酯=2:1)得到目标产物4-(二氟甲基)-1,1'-联苯。
实施例14~24
实施例14~24与实施例1基本相同,差别之处在于如下表1所示:
表1实施例1与实施例14~24的差别比较
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (9)
1.一种二氟甲基芳烃类化合物的制备方法,其特征在于,该方法包括以下步骤:
(1)在氮气氛围下,将芳基单取代丙二酸底物、银催化剂、碱、选择性氟试剂依次加入反应管中,再加入溶剂,在对应温度下反应11~13h;其中,所述芳基单取代丙二酸底物、银催化剂、碱、选择性氟试剂的摩尔比为1:0.1~1:0.5~5:4~10;
(2)使用3M的盐酸淬灭反应,将反应产物依次进行萃取、合并有机相、洗涤、干燥、旋干有机相以及纯化后,得到二氟甲基芳烃类化合物。
2.如权利要求1所述的二氟甲基芳烃类化合物的制备方法,其特征在于,在步骤(1)中,所述芳基单取代丙二酸底物的芳基为苯环或杂环芳烃,其中,苯环上可含有如下一种到多种取代基:4-苯基、3-苯基、2-苯基、4-甲氧基、4-己氧基、4-苯氧基、4-叔丁基、4-丙酰胺基、4-(2-氧吡咯烷-1-基)、4-(苯基乙炔基)、4-溴基、4-苯甲酰基、4-(3-甲氧基-3-氧丙基)苯基、2-异丙基、3-溴-4-甲氧基、4-((1-乙氧基-2-甲基-1-氧丙烷-2-基)氧基);所述杂环芳烃包括二苯并[b,d]呋喃、萘环、11-氧代-6,11-二氢二苯并[b,e]氧杂环丁。
3.如权利要求1所述的二氟甲基芳烃类化合物的制备方法,其特征在于,在步骤(1)中,所述银催化剂为硝酸银、氟化银、氧化银、醋酸银、硫酸银、三氟甲磺酸银、四氟硼酸银;
在步骤(1)中,所述碱包括无机碱、有机碱;所述无机碱包括磷酸盐类、碳酸盐类、氟化盐类,所述有机碱包括苯甲酸盐类、有机胺类、吡啶类。
4.如权利要求3所述的二氟甲基芳烃类化合物的制备方法,其特征在于,在步骤(1)中,所述银催化剂为硝酸银;
在步骤(1)中,所述磷酸盐类包括磷酸钾、磷酸钠、磷酸二氢钾、磷酸二氢钠、磷酸氢二钾、磷酸氢二钠;
所述碳酸盐类包括碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠;所述氟化盐类包括氟化钾、氟化钠、氟化锂;
所述苯甲酸盐类包括苯甲酸钠、苯甲酸钾、对氯苯甲酸钠、对氯苯甲酸钾;
所述胺类包括三乙胺。
5.如权利要求4所述的二氟甲基芳烃类化合物的制备方法,其特征在于,在步骤(1)中,所述碱为碳酸钾、磷酸氢二钾或苯甲酸钠。
6.如权利要求1所述的二氟甲基芳烃类化合物的制备方法,其特征在于,在步骤(1)中,所述选择性氟试剂为Selectfluor、Selectfluor II。
7.如权利要求1所述的二氟甲基芳烃类化合物的制备方法,其特征在于,在步骤(1)中,所述溶剂为有机溶剂和水按体积比1:1组成的混合溶剂,所述有机溶剂为乙腈、丙酮、卤代烃类、烷烃类、苯类中的至少一种;其中,
所述卤代烃类包括二氯甲烷,醚类如乙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚;
所述烷烃类包括正己烷、环己烷、正戊烷、环戊烷;
所述苯类包括苯、甲苯。
8.如权利要求7所述的二氟甲基芳烃类化合物的制备方法,其特征在于,所述溶剂为正己烷和水按体积比1:1组成。
9.如权利要求1所述的二氟甲基芳烃类化合物的制备方法,其特征在于,在步骤(2)中,所述萃取为用乙酸乙酯萃取,所述洗涤为用饱和食盐水洗涤,所述干燥为用无水硫酸钠干燥,所述纯化为用石油醚/乙酸乙酯=70~2:1的硅胶板纯化。
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