CN109824472A - 一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法 - Google Patents
一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法 Download PDFInfo
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- CN109824472A CN109824472A CN201910189160.8A CN201910189160A CN109824472A CN 109824472 A CN109824472 A CN 109824472A CN 201910189160 A CN201910189160 A CN 201910189160A CN 109824472 A CN109824472 A CN 109824472A
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- Prior art keywords
- silver
- fluorocarboxylic
- alfa
- gem
- cdcl
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- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 58
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 58
- 238000000034 method Methods 0.000 title claims abstract description 39
- -1 malonate derivative form silver carboxylate Chemical class 0.000 claims abstract description 62
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 34
- 239000011737 fluorine Substances 0.000 claims abstract description 34
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 33
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000004332 silver Substances 0.000 claims abstract description 22
- 229910052709 silver Inorganic materials 0.000 claims abstract description 22
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 19
- 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 claims abstract description 17
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims abstract description 7
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 150000002690 malonic acid derivatives Chemical class 0.000 claims abstract description 5
- 230000001590 oxidative effect Effects 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical group [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 41
- 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 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 239000012363 selectfluor Substances 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 22
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 16
- 239000004299 sodium benzoate Substances 0.000 claims description 16
- 235000010234 sodium benzoate Nutrition 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 claims description 6
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 235000010233 benzoic acid Nutrition 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 238000013459 approach Methods 0.000 claims description 3
- 150000001555 benzenes Chemical class 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 150000001559 benzoic acids Chemical class 0.000 claims description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 3
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 150000003016 phosphoric acids Chemical class 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 239000004300 potassium benzoate Substances 0.000 claims description 3
- 235000010235 potassium benzoate Nutrition 0.000 claims description 3
- 229940103091 potassium benzoate Drugs 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 3
- 229940071536 silver acetate Drugs 0.000 claims description 3
- 229940096017 silver fluoride Drugs 0.000 claims description 3
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims description 3
- 229910001923 silver oxide Inorganic materials 0.000 claims description 3
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 claims description 3
- 229910000367 silver sulfate Inorganic materials 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- 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 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 claims 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 45
- 125000000524 functional group Chemical group 0.000 abstract description 6
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 150000001735 carboxylic acids Chemical class 0.000 abstract 2
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000002512 chemotherapy Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 168
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 28
- 238000004293 19F NMR spectroscopy Methods 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- 239000012043 crude product Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- 239000012230 colorless oil Substances 0.000 description 13
- JYVHOGDBFNJNMR-UHFFFAOYSA-N hexane;hydrate Chemical compound O.CCCCCC JYVHOGDBFNJNMR-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000000746 purification Methods 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- LTVOKYUPTHZZQH-UHFFFAOYSA-N difluoromethane Chemical group F[C]F LTVOKYUPTHZZQH-UHFFFAOYSA-N 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 4
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 3
- BQZQWFXMPIMKQT-UHFFFAOYSA-N 7,7-difluorotridecane Chemical compound C(CCCCC)C(F)(F)CCCCCC BQZQWFXMPIMKQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- FPUQBSFTPVDELK-UHFFFAOYSA-N (1-fluoro-3-phenylpropyl)benzene Chemical compound FC(CCc1ccccc1)c1ccccc1 FPUQBSFTPVDELK-UHFFFAOYSA-N 0.000 description 2
- ZPQAKYPOZRXKFA-UHFFFAOYSA-N 6-Undecanone Chemical compound CCCCCC(=O)CCCCC ZPQAKYPOZRXKFA-UHFFFAOYSA-N 0.000 description 2
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- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
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- 230000002708 enhancing effect Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 239000011775 sodium fluoride Substances 0.000 description 2
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- 238000010189 synthetic method Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- CVAGHOPBSLAOLN-UHFFFAOYSA-N 1-fluoro-2-methylbut-1-ene Chemical compound CCC(C)=CF CVAGHOPBSLAOLN-UHFFFAOYSA-N 0.000 description 1
- DPFKMKWXWWRIDL-UHFFFAOYSA-N 2,2-dihexylpropanedioic acid Chemical compound CCCCCCC(C(O)=O)(C(O)=O)CCCCCC DPFKMKWXWWRIDL-UHFFFAOYSA-N 0.000 description 1
- OGAFKQWRXQJXJD-UHFFFAOYSA-N 2-ethyl-2-methylpropanedioic acid Chemical compound CCC(C)(C(O)=O)C(O)=O OGAFKQWRXQJXJD-UHFFFAOYSA-N 0.000 description 1
- UTMLVTCVBGQSOG-UHFFFAOYSA-N 2-methyl-2-(4-phenylbutyl)propanedioic acid Chemical compound OC(=O)C(C(O)=O)(C)CCCCC1=CC=CC=C1 UTMLVTCVBGQSOG-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
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- 230000000975 bioactive effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
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Abstract
本发明公开了一种新颖的合成偕二氟烷烃和α‑氟代羧酸的方法,具体包括以下步骤:S1、丙二酸衍生物中的一个羧酸与一价银成盐形成羧酸银,然后在氟试剂的氧化作用下产生二价银盐,S2、生成的二价银盐再将羧酸氧化,脱去一分子CO2,形成α‑羧酸自由基,S3、在二氟的条件下,α‑氟代羧酸可以再发生脱羧氟化反应,最终拿到偕二氟化产物,该发明涉及有机氟化合物技术领域。该一种新颖的合成偕二氟烷烃和α‑氟代羧酸的方法,通过调节碱和溶剂,在一价银催化下,丙二酸衍生物R1C(COOH)2R2与氟化试剂反应,选择性生成偕二氟化合物R1CF2R2和α‑氟代羧酸R1CF(COOH)R2,反应操作简单,原料廉价且易制备,反应条件温和,且具有良好的化学选择性和官能团兼容性,非常实用。
Description
技术领域
本发明涉及有机氟化合物技术领域,具体为一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法。
背景技术
偕二氟亚甲基官能团因为其具有增强母体分子的代谢稳定性,增强邻近基团酸性等独特性能,所以将二氟亚甲基引入小分子中可以改变其物理化学性质,因此很多药物和具有生物活性化合物中含有偕二氟亚甲基官能团。尽管人们在芳基取代偕二氟类化学物的制备上获得很大进展,但是合成偕二氟烷烃类化合物的方法仍然很少。常规方法制备合成偕二氟烷烃有:酮的脱氧氟化[1.L.N.Markovskij,V.E.Pashinnik,A.V.Kirsanov,Synthesis 787-789(1973);2.W.J.Middleton,J.Org.Chem.40,574-578(1975);3.R.P.Singh,J.M.Shreeve,J.Org.Chem.68,6063-6065(2003)],这是亲核型氟化反应,反应的官能团兼容性很差,如羟基,羰基,卤代硅烷等都能发生相应的亲核取代或加成反应,导致它们在这样的反应体系中不能兼容。炔烃的氢氟化也可以得到偕二氟亚甲基产物[3.G.A.Olah,J.T.Welch,Y.D.Vankar,M.Nojima,I.Kerekes,J.A.Olah,J.Org.Chem.44,3872-3881(1979);4.O.E.Okoromoba,J.Han,G.B.Hammond,B.Xu,J.Am.Chem.Soc.136,14381-14384(2014).],同样属于亲核型氟化反应,这些反应的官能团兼容性也是明显较差的,并且要使用氢氟酸这种具有腐蚀性的危险试剂。偕二氟产物也可以通过光诱导活化烯烃的二氟烷基化反应得到[5.G.N.Chernov,V.V.Levin,V.A.Kokorekin,M.I.Struchkova,A.D.Dilman,Adv.Synth.Catal.359,3063-3067(2017);6.V.I.Supranovich,V.V.Levin,M.I.Struchkova,J.Hu,A.D.Dilman,Beilstein J.Org.Chem.14,1637-1641(2018)]。其中使用的原料α-碘代二氟亚甲基化合物不易获得的,并且反应的底物烯烃只局限于活化的烯烃(如a,β-不饱和酮和烯醇硅)。这些方法虽然都可以得到偕二氟亚甲基化合物,但是缺点也是明显的,比如苛刻的反应条件,差的官能团兼容性,起始原料不易获得,底物的使用范围有限等,以上缺点都限制了这些方法在合成上的广泛应用。
传统的α-氟代羧酸的合成方法也是存在类似的问题,一般的制备方法是通过相应酯的烯醇化物的亲电氟化反应,再水解得到α-氟代羧酸[7.S.Rozen,A.Hagooly,R.Harduf,J.Org.Chem.66,7464-7468(2001);8.S.Y.Lee,S.Neufeind,G.C.Fu,J.Am.Chem.Soc.136,8899-8902(2014)]。在这个过程中通常要使用强碱:比如双三甲基硅基胺基锂(LiHMDS),二异丙基氨基锂(LDA)等。使用强碱一般需要严格的无水无氧操作,并且剧烈的反应条件也限制反应的底物范围。
鉴于二氟亚甲基和α-氟代羧酸在药物合成领域的重要应用,开拓新的合成方法迫在眉睫。
尽管单羧酸的脱羧氟代的方法已经被报道[13.F.Yin,Z.Wang,Z.Li,C.Li,J.Am.Chem.Soc.134,10401-10404(2012).],但是,这类方法只能制备得到单氟取代烷烃类化合物。通过丙二酸衍生物的脱羧氟化来合成偕二氟烷烃类化合物和α-氟代羧酸是没有相关报道。
发明内容
(一)解决的技术问题
针对现有技术的不足,本发明提供了一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,解决了现有技术中存在的反应条件苛刻,官能团兼容性差,起始原料不易获得且底物范围局限的问题。
(二)技术方案
为实现以上目的,本发明通过以下技术方案予以实现:一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,具体包括以下步骤:
S1、丙二酸衍生物中的一个羧酸与一价银成盐形成羧酸银,然后在氟试剂的氧化作用下产生二价银盐,羧酸银也可以通过另一个途径到达二价银盐,即反应产生的含氮正离子自由基将羧酸银氧化;
S2、生成的二价银盐再将羧酸氧化,脱去一分子CO2,形成α-羧酸自由基,α-羧酸自由基和氟化试剂反应得到α-氟代羧酸,在单氟的条件下,α-氟代羧酸即为最终产物;
S3、在二氟的条件下,α-氟代羧酸可以再发生脱羧氟化反应,最终拿到偕二氟化产物。
优选的,所述R1为烃基或芳基,R2为烃基,适用的R1,R2为C1-C100的烃基,优选C1-C20,可含有如下一种到多种取代基、苯基、羰基、氰基、C2-C10酯基、磺酰基、酰胺键、醚键、羟基、炔基、卤素、邻苯二甲酰亚胺基、C1-C10烷氧基、苯基取代C1-4烷基、C3-C7的环烷基、苯基羰基、苯甲酰基、含N的四元、五元或六元杂环或者具有苯并基C1-6烃基、卤代、酯基、烷氧基的含N的四元、五元或六元杂环。
优选的,所述丙二酸、碱、银盐和氟代试剂的比例为1:1-10:0.1-0.5:2-8,合成R1CF2R2时推荐为:1:2-4:0.1-0.3:4-6,合成R1CF(COOH)R2时推荐为:1:2-4:0.1-0.3:2-4。
优选的,所述溶剂为有机溶剂和水组成的混合溶剂,有机溶剂包括乙腈,丙酮,卤代烃类如二氯甲烷,醚类如乙醚、叔丁基甲基醚、二异丙醚、环戊基甲基醚、四氢呋喃、乙二醇二甲醚等,烷烃类如正己烷、环己烷、正戊烷、正庚烷、环戊烷等,苯类如苯、甲苯等,其中一种或几种与水的混合物,合成R1CF2R2时乙腈、水、正己烷比例为1:0.5-5:2-5,合成R1CF(COOH)R2时环戊基甲基醚、水比例为1:0.5-5。
优选的,所述碱包括无机碱,磷酸类,如磷酸钾、磷酸钠、磷酸二氢钾、磷酸二氢钠、磷酸一氢钾、磷酸一氢钠等,碳酸类如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠等,氢氟酸类如氟化钾、氟化钠、氟化锂等,有机碱,苯甲酸类如苯甲酸钠、苯甲酸钾、对氯苯甲酸钠、对氯苯甲酸钾等,胺类如三乙胺,吡啶类,合成R1CF2R2时推荐为,苯甲酸钠和磷酸氢二钾,合成R1CF(COOH)R2时推荐为磷酸氢二钾。
优选的,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、四氟硼酸银等,推荐为硝酸银。
优选的,所述氟化试剂是Selectfluor或者Selectfluor II及其相应的六氟磷酸盐。
(三)有益效果
本发明提供了一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法。与现有技术相比具备以下有益效果:该一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,具体包括以下步骤:S1、丙二酸衍生物中的一个羧酸与一价银成盐形成羧酸银,然后在氟试剂的氧化作用下产生二价银盐,S2、生成的二价银盐再将羧酸氧化,脱去一分子CO2,形成α-羧酸自由基,α-羧酸自由基和氟化试剂反应得到α-氟代羧酸,S3、在二氟的条件下,α-氟代羧酸可以再发生脱羧氟化反应,拿到最终偕二氟化产物,通过调节碱和溶剂,在一价银盐催化下,丙二酸衍生物R1C(COOH)2R2与氟化试剂Selectfluor反应,选择性生成偕二氟化合物R1CF2R2和α-氟代羧酸R1CF(COOH)R2,反应操作简单,原料简单廉价且易制备,条件温和,且具有良好的化学选择性和官能团兼容性,非常实用。
附图说明
图1为本发明反应机理图;
图2为本发明银催化脱羧偕二氟亚甲基的选择性合成表格;
图3为本发明银催化脱羧α-氟代羧酸的选择性合成表格。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
请参阅图1-3,本发明实施例提供一种技术方案:一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,具体包括以下步骤:
S1、丙二酸衍生物1中的一个羧酸与一价银成盐形成羧酸银7,然后在氟试剂的氧化作用下产生二价银盐10,羧酸银7也可以通过另一个途径到达二价银盐10,即反应产生的含氮正离子自由基8将羧酸银7氧化;
S2、生成的二价银盐再将羧酸氧化,脱去一分子CO2,形成α-羧酸自由基11,α-羧酸自由基11和氟化试剂反应得到α-氟代羧酸3,在单氟的条件下,α-氟代羧酸3即为最终产物;
S3、在二氟的条件下,α-氟代羧酸3可以再发生脱羧氟化反应,依次生成12、13、14、2,最终拿到偕二氟化产物2。
本发明中,R1为烃基或芳基,R2为烃基,适用的R1,R2为C1-C100的烃基,优选C1-C20,可含有如下一种到多种取代基、苯基、羰基、氰基、C2-C10酯基、磺酰基、酰胺键、醚键、羟基、炔基、卤素、邻苯二甲酰亚胺基、C1-C10烷氧基、苯基取代C1-4烷基、C3-C7的环烷基、苯基羰基、苯甲酰基、含N的四元、五元或六元杂环或者具有苯并基C1-6烃基、卤代、酯基、烷氧基的含N的四元、五元或六元杂环。
本发明中,丙二酸、碱、银盐和氟代试剂的比例为1:1-10:0.1-0.5:2-8,合成R1CF2R2时推荐为:1:2-4:0.1-0.3:4-6,合成R1CF(COOH)R2时推荐为:1:2-4:0.1-0.3:2-4。
本发明中,溶剂为有机溶剂和水组成的混合溶剂,有机溶剂包括乙腈,丙酮,卤代烃类如二氯甲烷,醚类如乙醚、叔丁基甲基醚、二异丙醚、环戊基甲基醚、四氢呋喃、乙二醇二甲醚等,烷烃类如正己烷、环己烷、正戊烷、正庚烷、环戊烷等,苯类如苯、甲苯等,其中一种或几种与水的混合物,合成R1CF2R2时乙腈、水、正己烷比例为1:0.5-5:2-5,合成R1CF(COOH)R2时环戊基甲基醚、水比例为1:0.5-5。
本发明中,碱包括无机碱,磷酸类,如磷酸钾、磷酸钠、磷酸二氢钾、磷酸二氢钠、磷酸一氢钾、磷酸一氢钠等,碳酸类如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠等,氢氟酸类如氟化钾、氟化钠、氟化锂等,有机碱,苯甲酸类如苯甲酸钠、苯甲酸钾、对氯苯甲酸钠、对氯苯甲酸钾等,胺类如三乙胺,吡啶类,合成R1CF2R2时推荐为,苯甲酸钠和磷酸氢二钾,合成R1CF(COOH)R2时推荐为磷酸氢二钾。
本发明中,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、四氟硼酸银等,推荐为硝酸银。
本发明中,氟化试剂是Selectfluor或者Selectfluor II及其相应的六氟磷酸盐。
实施例1
1-氯-4-(3,3-二氟戊基)苯(2a)的合成
将2-(4-氯苯基)-2-乙基丙二酸(1a,54.1mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(72mg,0.5mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共3mL,设置反应温度55℃,搅拌12小时。将反应冷却至室温,向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=50/1)。得到产物1-氯-4-(3,3-二氟戊基)苯,呈无色油状,产率:26.2mg(60%)。1H NMR(400MHz,CDCl3):δ7.26(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),2.83–2.72(m,2H),2.18–2.01(m,2H),1.97–1.79(m,2H),1.03(t,J=7.5Hz,3H).19F NMR(376MHz,CDCl3):δ-100.8–-101.0(m,2F).13C NMR(100MHz,CDCl3):δ139.4,132.1,129.8,128.8,124.9(t,J=240.8Hz),37.9(t,J=25.6Hz),29.9(t,J=26.2Hz),28.0(t,J=5.1Hz),6.8(t,J=5.7Hz).HRMS-EI(m/z)计算值(calcd for)C11H13ClF2:218.0674,实测值(found):218.0676.IR(KBr):ν(cm-1)2983,2944,1493,1466,1378,1194,1095,928,810。
实施例2
2,2-二氟-1,3-二苯基丙烷(2b)的合成
将2,2-二苄基丙二酸(1b,56.8mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(72mg,0.5mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共3mL,设置反应温度55℃,搅拌12小时。将反应冷却至室温,向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=50/1)。得到产物2,2-二氟-1,3-二苯基丙烷,呈无色油状,产率:27.8mg(60%)。1H NMR(400MHz,CDCl3):δ7.36–7.16(m,10H),3.09(t,J=16.4Hz,4H).19F NMR(376MHz,CDCl3):δ-94.6–-94.8(m,2F).13CNMR(100MHz,CDCl3):δ133.3,130.6,128.5,127.5,123.2(t,J=243.7Hz),42.5(t,J=25.6Hz)。
实施例3
5,5-二氟己基苯(2c)的合成
将2-甲基-2-(4-苯基丁基)丙二酸(1c,50.1mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(100.8mg,0.7mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共5mL,设置反应温度室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=50/1)。得到产物5,5-二氟己基苯,呈无色油状,产率:28.5mg(72%)。1H NMR(400MHz,CDCl3):δ7.31–7.25(m,2H),7.21–7.15(m,3H),2.63(t,J=7.6Hz,2H),1.93–1.79(m,2H),1.71–1.62(m,2H),1.62–1.47(m,5H).19F NMR(376MHz,CDCl3):δ-90.1–-90.4(m,2F).13C NMR(100MHz,CDCl3):δ142.3,128.5,128.5,125.9,124.5(t,J=236Hz),37.9(t,J=25.3Hz),35.9,31.3,23.4(t,J=28.0Hz),22.6(t,J=4.6Hz).HRMS-EI(m/z)计算值(calcd for)C12H16F2[M+]198.1220,实测值(found)198.1225.IR(KBr):ν(cm-1)2932,2858,1455,1392,1241,1192,1136,747,699。
实施例4
7,7-二氟十三烷(2d)的合成
将2,2-二己基丙二酸(1d,54.5mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(100.8mg,0.7mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共5mL,设置反应温度室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物硅胶柱纯化(石油醚/乙酸乙酯=100/1)。得到产物7,7-二氟十三烷,呈无色油状,产率:24.0mg(55%)。1H NMR(400MHz,CDCl3):δ1.88–1.72(m,4H),1.50–1.39(m,4H),1.37–1.23(m,12H),0.89(t,J=6.7Hz,6H).19F NMR(376MHz,CDCl3):δ-97.3–-97.6(m,2F).13C NMR(100MHz,CDCl3):δ125.7(t,J=239.9Hz),36.5(t,J=25.5Hz),31.8,29.2,22.7,22.5(t,J=4.5Hz),14.2.HRMS-EI(m/z)计算值(calcd for)C13H25F[(M-HF)+]200.1940,实测值(found)200.1947.IR(KBr):ν(cm-1)2957,2931,2859,1467,1379,1165,1033,953。
实施例5
4-(1,1-二氟丙基)-1,1’-联苯(2e)
将2-[(4-苯基)-苯基]-2-乙基丙二酸(1e,56.9mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(72.0mg,0.5mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共3mL,设置反应温度55℃,搅拌6小时。冷却至室温,向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=50/1)。得到产物4-(1,1-二氟丙基)-1,1’-联苯,呈黄色油状,产率:37.0mg(80%)。1HNMR(400MHz,CDCl3):δ7.68–7.57(m,4H),7.54(d,J=8.2Hz,2H),7.46(t,J=7.5Hz,2H),7.41–7.34(m,1H),2.28–2.11(m,2H),1.02(t,J=7.5Hz,3H).19F NMR(376MHz,CDCl3):δ-97.1(t,J=16.3Hz,2F).13C NMR(100MHz,CDCl3):δ142.6(t,J=1.7Hz),140.4,136.3(t,J=27.0Hz),129.0,127.9,127.3,127.2,125.7(t,J=6.2Hz),123.6(t,J=241Hz),32.4(t,J=28.5Hz),7.05(t,J=5.1Hz).HRMS-EI(m/z)计算值(calcd for)C15H14F2[M+]232.1064,实测值(found)232.1063.IR(KBr):ν(cm-1)2984,2944,1489,1464,1266,1166,841,729,691。
实施例6
4-(1,1-二氟戊基)苯甲酸(2f)的合成
将2-丁基-2-(4-羧基苯基)丙二酸(1f,56.1mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),碳酸钾K2CO3(82.9mg,0.6mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入1,2-二氯乙烷/水=1/1共4mL,设置反应温度55℃,搅拌12小时。冷却至室温,向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=1/1)。得到产物4-(1,1-二氟戊基)苯甲酸,呈无色油状,产率:30.1mg(66%)。1H NMR(400MHz,CDCl3):δ8.17(d,J=8.2Hz,2H),7.58(d,J=8.3Hz,2H),2.24–2.02(m,2H),1.46–1.30(m,4H),0.89(t,J=7.0Hz,3H).19F NMR(376MHz,CDCl3):δ-96.1–-96.3(m,2F).13C NMR(100MHz,CDCl3):δ171.8,143.0(t,J=26.9Hz),130.6,130.5,125.4(t,J=6.1Hz),122.8(t,J=243.1Hz),38.9(t,J=26.8Hz),24.6(t,J=3.9Hz),22.5,13.9.HRMS-EI(m/z)计算值(calcd for)C12H14F2O2[M+]228.0962,实测值(found)228.0969.IR(KBr):ν(cm-1)2960,2921,1703,1427,1288,1241,1168,914,817。
实施例7
N-(3,3-二氟丁基)邻苯二甲酰亚胺(2g)的合成
将2-(2-邻苯二甲酰亚胺基)乙基-2-甲基丙二酸(1g,58.2mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),磷酸氢二钾K2HPO4(69.6mg,0.4mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共3mL,设置反应温度55℃,搅拌12小时。冷却至室温,向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=5/1)。得到产物N-(3,3-二氟丁基)邻苯二甲酰亚胺,呈白色固体状,熔点:87~88℃,产率:37.0mg(77%)。1H NMR(400MHz,CDCl3):δ7.89–7.81(m,2H),7.76–7.69(m,2H),3.92(t,J=8.0,2H),2.38–2.20(m,2H),1.68(t,J=18.5Hz,3H).19F NMR(376MHz,CDCl3):δ-90.9–-91.2(m,2F).13C NMR(100MHz,CDCl3):δ168.1,134.2,132.1,123.4,123.1(t,J=236.5Hz),36.1(t,J=25.5Hz),32.2(t,J=5.8Hz),23.5(t,J=27.3Hz).HRMS-ESI(m/z)计算值(calcd for)C12H12NO2F2[(M+H)+]240.0836,实测值(found)240.0833.IR(KBr):ν(cm-1)2956,1716,1447,1396,1240,1180,991,737,720。
实施例8
5,5-二氟十一酸乙酯(2h)的合成
将2-(4-乙氧基-4-氧代丁基)-2-己基丙二酸(1h,60.5mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(100.8mg,0.7mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共5mL,设置反应温度为室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经硅胶柱纯化(石油醚/乙酸乙酯=20/1)。得到产物5,5-二氟十一酸乙酯,呈无色油状,产率:27.7mg(55%)。1H NMR(400MHz,CDCl3):δ4.14(q,J=7.1Hz,2H),2.36(t,J=7.0Hz,2H),1.93–1.73(m,6H),1.50–1.40(m,2H),1.35–1.23(m,9H),0.89(t,J=6.7Hz,3H).19F NMR(376MHz,CDCl3):δ-97.7–-98.0(m,2F).13C NMR(100MHz,CDCl3):δ173.2,125.2(t,J=240.4Hz),60.5,36.5(t,J=25.2Hz),35.6(t,J=25.7Hz),33.8,31.7,29.2,22.6,22.4(t,J=4.6Hz),18.1(t,J=4.9Hz),14.4,14.2.HRMS-EI(m/z)计算值(calcd for)C13H24FO2[(M-F)+]231.1760,实测值(found)231.1767.IR(KBr):ν(cm-1)2959,2934,1738,1464,1376,1260,1188,1033,953,861,806。
实施例9
2,2-二氟丁基戊基酮(2i)的合成
将2-甲基-2-(3-羰基辛基)丙二酸(1i,48.9mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(100.8mg,0.7mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共5mL,设置反应温度为室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经硅胶柱纯化(石油醚/乙酸乙酯=50/1)。得到产物2,2-二氟丁基戊基酮,呈无色油状,产率:26.4mg(69%)。1H NMR(400MHz,CDCl3):δ2.63(t,J=7.6Hz,2H),2.43(t,J=7.5Hz,2H),2.22–2.07(m,2H),1.67–1.54(m,5H),1.37–1.21(m,4H),0.89(t,J=7.0Hz,3H).19F NMR(376MHz,CDCl3):δ-92.3–-92.6(m,2F).13C NMR(100MHz,CDCl3):δ209.4,123.8(t,J=237.8Hz),43.1,35.4(t,J=3.4Hz),31.8(t,J=25.6Hz),31.5,23.8(t,J=27.7Hz),23.7,22.6,14.1.HRMS-EI(m/z)计算值(calcd for)C10H18F2O[M+]192.1326,实测值(found)192.1322.IR(KBr):ν(cm-1)2958,2934,1718,1394,1299,1241,1129,1083,897。
实施例10
2-(2,2-二氟丁基)苯腈(2j)的合成
将2-(2-氰基苯基)-2-乙基丙二酸(1j,49.5mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(72.0mg,0.5mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共3mL,设置反应温度为55℃,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=10/1)。得到产物2-(2,2-二氟丁基)苯腈,呈黄色油状,产率:24.2mg(62%)。1H NMR(400MHz,CDCl3):δ7.67(dd,J=7.9,0.9Hz,1H),7.57(td,J=7.7,1.1Hz,1H),7.48(d,J=7.8Hz,1H),7.40(td,J=7.6,0.9Hz,1H),3.40(t,J=16.1Hz,2H),2.03–1.82(m,2H),1.08(t,J=7.6Hz,3H).19F NMR(376MHz,CDCl3):δ-99.1–-99.4(m,2F).13C NMR(100MHz,CDCl3):δ137.2,133.0,132.8,131.8,128.1,123.6(t,J=243.2Hz),118.1,114.4,40.9(t,J=26.5Hz),29.8(t,J=25.5Hz),6.5(t,J=5.4Hz).HRMS-ESI(m/z)计算值(calcd for)C11H12F2N[(M+H)+]196.0938,实测值(found)196.0938.IR(KBr):ν(cm-1)2986,2227,1466,1368,1198,1136,984,762。
实施例11
1-(2,2-二氟丙基)-4-(甲磺酰基)苯(2k)的合成
将2-甲基-2-(4-甲磺酰基)苯基丙二酸(1k,57.3mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(100.8mg,0.7mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共5mL,设置反应温度为室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=2/1)。得到产物1-(2,2-二氟丙基)-4-(甲磺酰基)苯,呈白色固体状,熔点:87~88℃,产率:39.8mg(85%)。1H NMR(400MHz,CDCl3):δ7.91(d,J=8.2Hz,2H),7.49(d,J=8.1Hz,2H),3.24(t,J=15.6Hz,2H),3.07(s,3H),1.59(t,J=18.3Hz,3H).19F NMR(376MHz,CDCl3):δ-89.2–-89.5(m,2F).13C NMR(100MHz,CDCl3):δ134.0(t,J=4.2Hz),139.8,131.4,127.6,122.7(t,J=240.1Hz),44.6,44.3(t,J=26.5Hz),23.3(t,J=27.3Hz).HRMS-ESI(m/z)计算值(calcd for)C10H13SO2F2[(M+H)+]235.0604,实测值(found)235.0603.IR(KBr):ν(cm-1)3010,2927,1410,1304,1234,1150,773,875。
实施例12
(4,4-二氟哌啶-1-基)苯基酮(2l)
将1-苯甲酰基哌啶-4,4-二羧酸(1l,55.5mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),磷酸氢二钾K2HPO4(104.4mg,0.6mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水=1/1共4mL,设置反应温度为55℃,搅拌12小时。冷却至室温,向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=5/1)。得到产物(4,4-二氟哌啶-1-基)(苯基)酮,呈白色固体状,熔点:69~71℃,产率:36.4mg(81%)。1HNMR(400MHz,CDCl3):δ7.50–7.35(m,5H),4.03–3.39(m,4H),2.17–1.83(m,4H).19F NMR(376MHz,CDCl3):δ-97.4–-98.0(m,2F).13C NMR(100MHz,CDCl3):δ170.7,135.3,130.2,128.7,127.0,121.6(t,J=242.3Hz),44.6,39.2,34.6,34.1。
实施例13
1-丁氧基-6,6-二氟庚烷(2m)的合成
将2-(5-丁氧基戊基)-2-甲基丙二酸(1m,52.1mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(100.8mg,0.7mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共5mL,设置反应温度为室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经硅胶柱纯化(石油醚/乙酸乙酯=30/1)。得到产物1-丁氧基-6,6-二氟庚烷,呈无色油状,产率:24.1mg(58%)。1H NMR(400MHz,CDCl3):δ3.40(t,J=6.7Hz,4H),1.93–1.74(m,2H),1.64–1.32(m,13H),0.92(t,J=7.4Hz,3H).19FNMR(376MHz,CDCl3):δ-90.1–-90.5(m,2F).13C NMR(100MHz,CDCl3):δ124.5(t,J=237.5Hz),70.8,70.7,38.1(t,J=25.4Hz),32.0,29.7,26.2,23.4(t,J=28.1Hz),22.8(t,J=4.6Hz),19.5,14.1.HRMS-EI(m/z)计算值(calcd for)C11H22F2O[M+]208.1639,实测值(found)208.1645.IR(KBr):ν(cm-1)2959,2937,1466,1392,1261,1112,911,805。
实施例14
1-(4-溴苯基)-4,4-二氟戊基-1-酮(2n)的合成
将2-[3-(4-溴苯基)-3-羰基丙基]-2-甲基丙二酸(1n,65.8mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(100.8mg,0.7mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共5mL,设置反应温度为室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经硅胶板纯化(石油醚/乙酸乙酯=10/1)。得到产物1-(4-溴苯基)-4,4-二氟戊基-1-酮,呈白色固体状,熔点:54~55℃,产率:40.8mg(74%)。1H NMR(400MHz,CDCl3):δ7.85(d,J=8.5Hz,2H),7.62(d,J=8.5Hz,2H),3.18(t,J=7.6Hz 2H),2.40–2.25(m,2H),1.67(t,J=18.4Hz,3H).19F NMR(376MHz,CDCl3):δ-92.3–-92.6(m,2F).13C NMR(100MHz,CDCl3):δ197.3,135.3,132.1,129.7,128.6,123.8(t,J=238.0Hz),32.1(t,J=25.4Hz),31.5(t,J=3.6Hz),24.0(t,J=27.6Hz).HRMS-ESI(m/z)计算值(calcd for)C11H12BrOF2[(M+H)+]277.0040,实测值(found)277.0034.IR(KBr):ν(cm-1)2950,1683,1394,1243,1208,1164,830,740。
实施例15
6,6-二氟-7-苯基庚-3-醇(2o)的合成
将2-苄基-2-(3-羟基戊基)丙二酸(1o,56.0mg,0.2mmol),硝酸银AgNO3(10.2mg,0.06mmol),苯甲酸钠PhCOONa(100.8mg,0.7mmol),选择性氟试剂Selectfluor(425.2mg,1.2mmol),加入反应管中,置换N2,加入乙腈/水/正己烷=1/1/3共5mL,设置反应温度为室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂,粗产物经硅胶板纯化(石油醚/乙酸乙酯=5/1),得到产物6,6-二氟-7-苯基庚-3-醇,呈无色油状,产率:16.0mg(35%)。1H NMR(400MHz,CDCl3):δ7.38–7.16(m,5H),3.50(tt,J=8.4,4.6Hz,1H),3.15(t,J=16.0Hz,2H),2.12–1.90(m,1H),1.89–1.65(m,2H),1.63–1.37(m,4H),0.93(t,J=7.4Hz,3H).19F NMR(376MHz,CDCl3):δ-96.6–-97.3(m,2F).13C NMR(100MHz,CDCl3):δ133.5,130.4,128.6,127.4,124.4(t,J=242.2Hz),72.8,43.4(t,J=26.2Hz),32.2(t,J=25.0Hz),30.5,29.2(t,J=3.7Hz),10.0.HRMS-ESI(m/z)计算值(calcd for)C13H18NaOF2[(M+Na)+]251.1223,实测值(found)251.1218。
以下是α-氟代羧酸的合成实例:
实施例16
4-(4-氯苯基)-2-乙基-2-氟丁酸甲酯(3a)的合成
将2-(4-氯苯基)-2-乙基丙二酸(1a,54.1mg,0.2mmol),硝酸银AgNO3(6.8mg,0.04mmol),磷酸氢二钾K2HPO4(139.4mg,0.8mmol),选择性氟试剂Selectfluor(141.7mg,0.4mmol),加入反应管中,置换N2,加入环戊基甲基醚/水=1/1共4mL,设置反应温度室温,搅拌12小时。向其中加入3M盐酸溶液2mL,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,旋干有机溶剂。剩余物溶解在二氯甲烷/甲醇=4/1溶液中,共5mL,加入三甲基硅基重氮甲烷0.6mL(2.0M的正己烷溶液),通过TLC监测所以酸都反应完全,加入乙酸处理过多的甲基硅基重氮甲烷,旋干有机溶剂,粗产物经制备硅胶板纯化(石油醚/乙酸乙酯=20/1)。得到产物4-(4-氯苯基)-2-乙基-2-氟丁酸甲酯,呈无色油状,产率:28.1mg(54%)。1HNMR(400MHz,CDCl3):δ7.24(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),3.76(s,3H),2.85–2.70(m,1H),2.57–2.45(m,1H),2.27–1.76(m,4H),0.95(t,J=7.5Hz,3H).19F NMR(376MHz,CDCl3):δ-168.3–-168.7(m,1F).13C NMR(100MHz,CDCl3):δ171.9(d,J=25.9Hz),139.4,132.0,129.9,128.7,97.8(d,J=188.7Hz),52.5,38.9(d,J=22.3Hz),30.8(d,J=22.9Hz),29.1(d,J=3.7Hz),7.7(d,J=4.3Hz).HRMS-ESI(m/z)计算值(calcd for)C13H17ClFO2[(M+H)+]259.0901,实测值(found)259.0901.IR(KBr):ν(cm-1)2954,1760,1734,1493,1243,1197,1176,1094,814。
此反应也可以直接分离得到相应的羧酸,在萃取浓缩之后,粗产物不需要甲酯化,直接通过制备硅胶板分离,得到4-(4-氯苯基)-2-乙基-2-氟丁酸,呈白色固体状,熔点:64~66℃。1H NMR(400MHz,CDCl3):δ7.19(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),2.85–2.70(m,1H),2.63–2.57(m,1H),2.34–1.78(m,4H),0.97(t,J=7.4Hz,3H).19F NMR(376MHz,CDCl3):δ-166.6–-167.8(m,1F).13C NMR(100MHz,CDCl3):δ177.1(d,J=27.5Hz),139.2,132.1,129.8,128.7,97.9(d,J=185.4Hz),38.7(d,J=22.2Hz),30.5(d,J=22.8Hz),29.1(d,J=2.7Hz),7.7(d,J=3.8Hz).HRMS-EI(m/z)计算值(calcd for)C12H13O2Cl[(M–HF)+]224.0604,实测值(found)224.0609.IR(KBr):ν(cm-1)2975,1728,1492,1275,1260,809,764,750。
实施例17
2-苄基-2氟-1-苯基丙酸甲酯(3b)的合成
方法同3a,反应在室温下进行。经过制备硅胶板纯化(石油醚/乙酸乙酯=20/1)得到3b,呈白色固体,熔点:37~39℃,产率:25.6mg(47%)。1H NMR(400MHz,CDCl3):δ7.33–7.17(m,10H),3.53(s,3H),3.33–3.05(m,4H).19F NMR(376MHz,CDCl3):δ-163.7–-163.9(m,1F).13C NMR(100MHz,CDCl3):δ171.0(d,J=25.3Hz),134.5,130.3,128.4,127.3,97.8(d,J=194.7Hz),52.3,43.4(d,J=21.5Hz).HRMS-ESI(m/z)计算值(calcd for)C17H18FO2[(M+H)+]273.1291,实测值(found)273.1289.IR(KBr):ν(cm-1)2952,1764,1736,1496,1236,1200,1086,749,700。
实施例18
2-氟-2-甲基-6-苯基己酸甲酯(3c)的合成
方法同3a的合成,经过制备硅胶板纯化(石油醚/乙酸乙酯=50/1)得到3c,呈黄色油状,产率:28.5mg(60%)。1H NMR(400MHz,CDCl3):δ7.31–7.23(m,2H),7.20–7.13(m,3H),3.77(s,3H),2.61(t,J=7.6Hz,2H),2.04–1.74(m,2H),1.68–1.48(m,6H),1.36–1.27(m,1H).19F NMR(376MHz,CDCl3):δ-156.2–-156.6(m,1F).13C NMR(100MHz,CDCl3):δ172.8(d,J=25.6Hz),142.3,128.5,128.4,125.9,95.4(d,J=184.7Hz),52.6,38.3(d,J=22.4Hz),35.8,31.4,23.8(d,J=24.3Hz),23.1(d,J=3.3Hz).HRMS-ESI(m/z)计算值(calcd for)C14H20FO2[(M+H)+]239.1447,实测值(found)239.1449.IR(KBr):ν(cm-1)2952,1762,1741,1497,1454,1197,1123,982,700。
实施例19
4-邻苯二甲酰亚胺基-2-氟-2-甲基-1-丁酸甲酯(3g)的合成
方法同3a的合成,经过制备硅胶板纯化(石油醚/乙酸乙酯=2/1)得到3g,呈白色固体状,熔点:87~89℃,产率:51.3mg(92%)。1H NMR(400MHz,CDCl3):δ7.85(dd,J=5.5,3.0Hz,2H),7.72(dd,J=5.5,3.1Hz,2H),3.93–3.69(m,5H),2.46–2.17(m,2H),1.63(d,J=21.4Hz,3H).19F NMR(376MHz,CDCl3):δ-157.8–-158.2(m,1F).13C NMR(100MHz,CDCl3):δ171.9(d,J=25.2Hz),168.1,134.1,132.2,123.4,93.9(d,J=186.0Hz),52.9,36.2(d,J=21.7Hz),33.0(d,J=4.7Hz),23.8(d,J=24.1Hz).HRMS-ESI(m/z)计算值(calcd for)C14H15FNO4[(M+H)+]280.0985,实测值(found)280.0984.IR(KBr):ν(cm-1)2955,1758,1740,1713,1400,1376,1190,750,721。
实施例20
2-氟-2-己基-1,6-己二酸-1-甲基-6-乙基二酯(3h)的合成
方法同3a的合成,经过硅胶柱纯化(石油醚/乙酸乙酯=30/1)得到3h,呈无色油状,产率:36.3mg(63%)。1H NMR(400MHz,CDCl3):δ4.13(q,J=7.1Hz,2H),3.79(s,3H),2.31(t,J=7.1Hz,2H),2.03–1.71(m,5H),1.66–1.37(m,2H),1.34–1.14(m,10H),0.87(t,J=6.7Hz,3H).19F NMR(376MHz,CDCl3):δ-166.0–-166.2(m,1F).13C NMR(100MHz,CDCl3):δ173.1,172.1(d,J=26.0Hz),97.7(d,J=187.9Hz),60.5,52.5,37.5(d,J=22.3Hz),36.8(d,J=22.3Hz),34.0,31.7,29.3,23.2(d,J=2.8Hz),22.6,19.0(d,J=3.4Hz),14.4,14.2.HRMS-ESI(m/z)计算值(calcd for)C15H28FO4[(M+H)+]291.1972,实测值(found)291.1967.IR(KBr):ν(cm-1)2956,2931,1763,1738,1459,1193,1032,860,818。
实施例21
2-氟-2-甲基-5-羰基癸酸甲酯(3i)的合成
方法同3a的合成,经过硅胶柱纯化(石油醚/乙酸乙酯=20/1)得到3i,呈无色油状,产率:36.4mg(78%)。1H NMR(400MHz,CDCl3):δ3.79(s,3H),2.65–2.55(m,1H),2.49–2.36(m,3H),2.32–2.02(m,2H),1.63–1.49(m,5H),1.36–1.18(m,4H),0.89(t,J=7.1Hz,3H).19F NMR(376MHz,CDCl3):δ-156.8–-157.3(m,1F).13C NMR(100MHz,CDCl3):δ209.4,172.2(d,J=25.8Hz),94.4(d,J=184.6Hz),52.7,43.0,36.4(d,J=2.9Hz),32.1(d,J=22.2Hz),31.5,23.9(d,J=24.1Hz),23.6,22.5,14.0.HRMS-ESI(m/z)计算值(calcd for)C12H22FO3[(M+H)+]233.1553,实测值(found)233.1549.IR(KBr):ν(cm-1)2957,2934,1760,1743,1717,1458,1379,1203,1123,895,806。
实施例22
2-(2-氰基苄基)-2-氟丁酸甲酯(3j)的合成
方法同3a的合成,经过制备硅胶板纯化(石油醚/乙酸乙酯=10/1)得到3j,呈黄色油状,产率:34.7mg(74%)。1H NMR(400MHz,CDCl3):δ7.64(dd,J=7.7,1.0Hz,1H),7.54(td,J=7.7,1.3Hz,1H),7.38(m,2H),3.74(s,3H),3.54–3.33(m,2H),2.22–1.81(m,2H),0.99(t,J=7.4Hz,3H).19F NMR(376MHz,CDCl3):δ-165.6–-166.0(m,1F).13C NMR(100MHz,CDCl3):δ170.8(d,J=26.4Hz),138.4,133.0,132.8,131.3,127.9,118.0,114.1,97.6(d,J=191.9Hz),52.6,41.1(d,J=21.5Hz),30.5(d,J=22.7Hz),7.7(d,J=4.0Hz).HRMS-ESI(m/z)计算值(calcd for)C13H15FNO2[(M+H)+]236.1087,实测值(found)236.1083.IR(KBr):ν(cm-1)2977,2955,2227,1760,1739,1600,1489,1247,1206,776。
实施例23
2-氟-2-甲基-3-[4-(甲基磺酰基)苯基]丙酸甲酯(3k)的合成
方法同3a的合成,经过制备硅胶板纯化(石油醚/乙酸乙酯=2/1)得到3k,呈白色固体状,熔点:41~43℃,产率:44.0mg(80%)。1H NMR(400MHz,CDCl3):δ7.88(d,J=8.4Hz,2H),7.43(d,J=8.0Hz,2H),3.73(s,3H),3.40–3.10(m,2H),3.06(s,3H),1.61(d,J=21.2Hz,3H).19F NMR(376MHz,CDCl3):δ-155.3–-155.6(m,1F).13C NMR(100MHz,CDCl3):δ171.6(d,J=25.1Hz),141.1,139.6,131.3,127.5,94.7(d,J=189.0Hz),52.8,44.6,43.9(d,J=21.8Hz),23.7(d,J=24.0Hz).HRMS-ESI(m/z)计算值(calcd for)C12H16FSO4[(M+H)+]275.0753,实测值(found)275.0747.IR(KBr):ν(cm-1)2956,1755,1739,1304,1276,1149,1116,764,750。
实施例24
1-苯甲酰基-4-氟哌啶-4-羧酸甲酯(3l)的合成
方法同3a的合成,经过制备硅胶板纯化(石油醚/乙酸乙酯=2/1)得到3l,呈白色固体状,产率:46.1mg(87%)。1H NMR(400MHz,CDCl3):δ7.47–7.35(m,5H),4.77–4.45(m,1H),3.82(s,3H),3.80–3.60(m,1H),3.50–3.05(m,2H),2.30–1.70(m,4H).19F NMR(376MHz,CDCl3):δ-167.5–-167.8(m,1F).13C NMR(100MHz,CDCl3):δ171.0(d,J=24.3Hz),170.6,135.5,130.0,128.7,126.9,92.1(d,J=187.0Hz),53.0,43.0,37.4,32.8,32.3.HRMS-ESI(m/z)计算值(calcd for)C14H17FNO3[(M+H)+]266.1192,实测值(found):266.1186.IR(KBr):ν(cm-1)2932,1743,1636,1434,1294,1110,1070,750,711。
实施例25
7-丁氧基-2-氟-2-甲基庚酸甲酯(3m)
方法同3a的合成,经过硅胶柱纯化(石油醚/乙酸乙酯=20/1)得到3m,呈无色油状,产率:39.8mg(80%)。1H NMR(400MHz,CDCl3):δ3.79(s,3H),3.43–3.35(m,4H),2.00–1.73(m,2H),1.61–1.45(m,8H),1.43–1.30(m,5H),0.92(t,J=7.4Hz,3H).19F NMR(376MHz,CDCl3):δ-156.3–-156.6(m,1F).13C NMR(100MHz,CDCl3):δ172.8(d,J=25.3Hz),95.3(d,J=184.6Hz),70.8,70.7,52.5,38.5(d,J=22.4Hz),32.0,29.7,26.2,23.8(d,J=24.3Hz),23.3(d,J=3.4Hz),19.5,14.1.HRMS-ESI(m/z)计算值(calcd for)C13H26FO3[(M+H)+]249.1866,实测值(found)249.1864.IR(KBr):ν(cm-1)2934,1764,1742,1459,1376,1195,1115,813。
实施例26
2-氟-2-甲基-5-(4-溴苯基)-5-羰基-1-戊酸甲酯(3n)
方法同3a的合成,经过硅胶柱纯化(石油醚/乙酸乙酯=10/1)得到3n,呈白色固体状,熔点:61~62℃,产率:49.5mg(78%)。1H NMR(400MHz,CDCl3):δ7.82(d,J=8.6Hz,2H),7.61(d,J=8.6Hz,2H),3.80(s,3H),3.23–3.12(m,1H),3.00–2.89(m,1H),2.51–2.19(m,2H),1.64(d,J=21.4Hz,3H).19F NMR(376MHz,CDCl3):δ-156.7–-157.0(m,1F).13C NMR(100MHz,CDCl3):δ197.4,172.1(d,J=25.7Hz),135.3,132.0,129.7,128.5,94.5(d,J=184.7Hz),52.8,32.5,32.3,24.0(d,J=24.0Hz).HRMS-ESI(m/z)计算值(calcd for)C13H15FO3Br[(M+H)+]317.0189,实测值(found)317.0189.IR(KBr):ν(cm-1)2954,1756,1689,1585,1448,1275,1207,825,790。
实施例27
2-苄基-2-氟-5-羟基庚酸甲酯的合成(3o)
方法同3a的合成,经过硅胶板纯化(石油醚/乙酸乙酯=2/1)得到3o,得到一对非对映异构体,呈无色油状,产率:41.8mg(78%)。1H NMR(400MHz,CDCl3):δ7.35–7.21(3H),7.21–7.15(2H),3.70–3.64(3H),3.53–3.40(1H),3.27–3.04(2H),2.30–1.76(2H),1.75–1.54(1H),1.52–1.38(3H),1.34–1.22(1H),0.96–0.87(3H).19F NMR(376MHz,CDCl3):δ-164.7–-165.4(1F)13C NMR(100MHz,CDCl3):δ171.8,171.7,171.6,171.4,134.5,130.3,130.2,128.4,127.3,99.0,98.7,97.1,96.8,73.0,72.8,52.5,43.9,43.8,43.7,43.5,30.6,30.5,30.5,30.3,10.0,10.0.HRMS-ESI(m/z)计算值(calcd for)C15H21NaFO3[(M+Na)+]291.1372,实测值(found)291.1368。
需要说明的是,在本文中,诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来,而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者设备所固有的要素。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (7)
1.一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,其特征在于:具体包括以下步骤:
S1、丙二酸衍生物(1)中的一个羧酸与一价银成盐形成羧酸银(7),然后在氟试剂的氧化作用下产生二价银盐(10),羧酸银(7)也可以通过另一个途径到达二价银盐(10),即反应产生的含氮正离子自由基(8)将羧酸银(7)氧化;
S2、生成的二价银盐再将羧酸氧化,脱去一分子CO2,形成α-羧酸自由基(11),α-羧酸自由基(11)和氟化试剂反应得到α-氟代羧酸(3),在单氟的条件下,α-氟代羧酸(3)即为最终产物;
S3、在二氟的条件下,α-氟代羧酸(3)可以再发生脱羧氟化反应,依次生成(12)、(13)、(14)、(2),最终拿到偕二氟化产物(2)。
2.根据权利要求1所述的一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,其特征在于:所述R1为烃基或芳基,R2为烃基,适用的R1,R2为C1-C100的烃基,优选C1-C20,可含有如下一种到多种取代基、苯基、羰基、氰基、C2-C10酯基、磺酰基、酰胺键、醚键、羟基、炔基、卤素、邻苯二甲酰亚胺基、C1-C10烷氧基、苯基取代C1-4烷基、C3-C7的环烷基、苯基羰基、苯甲酰基、含N的四元、五元或六元杂环或者具有苯并基C1-6烃基、卤代、酯基、烷氧基的含N的四元、五元或六元杂环。
3.根据权利要求1所述的一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,其特征在于:所述丙二酸、碱、银盐和氟代试剂的比例为1:1-10:0.1-0.5:2-8,合成R1CF2R2时推荐为:1:2-4:0.1-0.3:4-6,合成R1CF(COOH)R2时推荐为:1:2-4:0.1-0.3:2-4。
4.根据权利要求1所述的一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,其特征在于:所述溶剂为有机溶剂和水组成的混合溶剂,有机溶剂包括乙腈,丙酮,卤代烃类如二氯甲烷,醚类如乙醚、叔丁基甲基醚、二异丙醚、环戊基甲基醚、四氢呋喃、乙二醇二甲醚等,烷烃类如正己烷、环己烷、正戊烷、正庚烷、环戊烷等,苯类如苯、甲苯等,其中一种或几种与水的混合物,合成R1CF2R2时乙腈、水、正己烷比例为1:0.5-5:2-5,合成R1CF(COOH)R2时环戊基甲基醚、水比例为1:0.5-5。
5.根据权利要求1所述的一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,其特征在于:所述碱包括无机碱,磷酸类,如磷酸钾、磷酸钠、磷酸二氢钾、磷酸二氢钠、磷酸一氢钾、磷酸一氢钠等,碳酸类如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠等,氢氟酸类如氟化钾、氟化钠、氟化锂等,有机碱,苯甲酸类如苯甲酸钠、苯甲酸钾、对氯苯甲酸钠、对氯苯甲酸钾等,胺类如三乙胺,吡啶类,合成R1CF2R2时推荐为,苯甲酸钠和磷酸氢二钾,合成R1CF(COOH)R2时推荐为磷酸氢二钾。
6.根据权利要求1所述的一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,其特征在于: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、四氟硼酸银等,推荐为硝酸银。
7.根据权利要求1所述的一种新颖的合成偕二氟烷烃和α-氟代羧酸的方法,其特征在于:所述氟化试剂是Selectfluor或者Selectfluor II及其相应的六氟磷酸盐。
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