CN107216302A - A kind of fluorine can draw fixed synthetic method - Google Patents
A kind of fluorine can draw fixed synthetic method Download PDFInfo
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- CN107216302A CN107216302A CN201710565804.XA CN201710565804A CN107216302A CN 107216302 A CN107216302 A CN 107216302A CN 201710565804 A CN201710565804 A CN 201710565804A CN 107216302 A CN107216302 A CN 107216302A
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- 239000011737 fluorine Substances 0.000 title claims abstract description 20
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 20
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 title claims abstract 4
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 239000000126 substance Substances 0.000 claims abstract description 7
- 150000002576 ketones Chemical class 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 4
- 239000010703 silicon Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 77
- 239000002904 solvent Substances 0.000 claims description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 44
- 239000000243 solution Substances 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- -1 benzyloxymethyl Chemical group 0.000 claims description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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 14
- 239000007788 liquid Substances 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 230000004224 protection Effects 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- 150000001408 amides Chemical class 0.000 claims description 12
- 239000000377 silicon dioxide Substances 0.000 claims description 12
- 150000001340 alkali metals Chemical class 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 150000004678 hydrides Chemical class 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 7
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 claims description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 4
- BVWCFOXBDSMXEP-UHFFFAOYSA-N 1-(5-acetyl-2-methoxyphenyl)-3-methylbutan-1-one Chemical compound COC1=CC=C(C(C)=O)C=C1C(=O)CC(C)C BVWCFOXBDSMXEP-UHFFFAOYSA-N 0.000 claims description 4
- JVDWKJQBWSKJOJ-UHFFFAOYSA-N 1-bromo-3-methylbuta-1,3-diene Chemical compound CC(=C)C=CBr JVDWKJQBWSKJOJ-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000007848 Bronsted acid Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical class COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 3
- 125000005999 2-bromoethyl group Chemical group 0.000 claims description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- LVAFXZPABJCMJK-UHFFFAOYSA-N COClCC1=CC=CC=C1 Chemical compound COClCC1=CC=CC=C1 LVAFXZPABJCMJK-UHFFFAOYSA-N 0.000 claims description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 claims description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- QAWLNTIPTFOWKZ-UHFFFAOYSA-N bromomethoxymethylbenzene Chemical compound BrCOCC1=CC=CC=C1 QAWLNTIPTFOWKZ-UHFFFAOYSA-N 0.000 claims description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- AIDQCFHFXWPAFG-UHFFFAOYSA-N n-formylformamide Chemical compound O=CNC=O AIDQCFHFXWPAFG-UHFFFAOYSA-N 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 claims description 2
- ASUAYTHWZCLXAN-UHFFFAOYSA-N prenol Chemical compound CC(C)=CCO ASUAYTHWZCLXAN-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- FKDJWPNZLPRUPO-UHFFFAOYSA-N COBrCC1=CC=CC=C1 Chemical compound COBrCC1=CC=CC=C1 FKDJWPNZLPRUPO-UHFFFAOYSA-N 0.000 claims 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims 1
- WTCBONOLBHEDIL-UHFFFAOYSA-M Sodium iodate Chemical group [Na+].[O-]I(=O)=O WTCBONOLBHEDIL-UHFFFAOYSA-M 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 claims 1
- 150000003863 ammonium salts Chemical class 0.000 claims 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 239000012071 phase Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims 1
- 239000012266 salt solution Substances 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 2
- JCIDEANDDNSHQC-UHFFFAOYSA-N 4H-chromene Chemical class C1=CC=C2CC=COC2=C1 JCIDEANDDNSHQC-UHFFFAOYSA-N 0.000 abstract 1
- TZJALUIVHRYQQB-XLRXWWTNSA-N icariin Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-XLRXWWTNSA-N 0.000 abstract 1
- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000012805 post-processing Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 3
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 3
- 229910052901 montmorillonite Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- VCCRNZQBSJXYJD-UHFFFAOYSA-N galangin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=CC=C1 VCCRNZQBSJXYJD-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BIAAQBNMRITRDV-UHFFFAOYSA-N 1-(chloromethoxy)-2-methoxyethane Chemical compound COCCOCCl BIAAQBNMRITRDV-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical class CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- NWPRCRWQMGIBOT-UHFFFAOYSA-N 7-(2-hydroxyethyl)-1,3-dimethylpurine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CCO)C=N2 NWPRCRWQMGIBOT-UHFFFAOYSA-N 0.000 description 1
- 241001061225 Arcos Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 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
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 239000012675 alcoholic extract Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- CIPSYTVGZURWPT-UHFFFAOYSA-N galangin Natural products OC1=C(Oc2cc(O)c(O)cc2C1=O)c3ccccc3 CIPSYTVGZURWPT-UHFFFAOYSA-N 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical group [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- LHTVMBMETNGEAN-UHFFFAOYSA-N pent-1-en-1-ol Chemical compound CCCC=CO LHTVMBMETNGEAN-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- SUYJZKRQHBQNCA-UHFFFAOYSA-N pinobanksin Natural products O1C2=CC(O)=CC(O)=C2C(=O)C(O)C1C1=CC=CC=C1 SUYJZKRQHBQNCA-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000010458 rotten stone Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Fixed synthetic method can be drawn the invention provides a kind of fluorine, this method is included with 3,5, the ketone of 7 trihydroxy 2 (4 trifluoromethyl) 4H chromenes 4 is raw material, icariine is prepared, the advantage of the invention is that being used as catalyst using silicon cheap and easy to get during rearrangement reaction, pass through existing chemical conjunction method, the fluorine of acquisition can draw fixed impurity few, and purity can reach 98%, and yield can reach 50%.
Description
Technical field
Fixed synthetic method can be drawn the present invention relates to a kind of fluorine, belongs to the field of chemical synthesis.
Background technology
It is the brand-new effective monomer got on the basis of A Kela is fixed by structure optimization surely that fluorine, which can be drawn, and its structural formula is such as
Shown in following formula (A)：
In 2010《Biological organic and pharmaceutical chemistry magazine (Bioorganic＆Medicinal Chemistry
Letters 20(2010))》Disclosed in 5709-5712 pages entitled《7-O- aryl methyls galangin is used as new anti-third
Liver inhibitor holder (7-O-Arylmethylgalangin as a novel scaffold for anti-HCV
agents)》Article.Give that fluorine can draw fixed precursor compound in this article prepares reaction scheme, passes through following route
Compound 2- (4- trifluoromethyls) -3,5,7- trihydroxy -4H- benzopyran-4-ones are obtained.R in following structural formula1For
Trifluoromethyl (- CF3), the reaction scheme is as follows：
The reaction condition of step 1 is pyridine solvent, room temperature；Step 2 reaction is divided into two parts, and Part I is anti-for cyclization
Should, Part II is hydrogenation, and wherein the reagent of annulation is K2CO3With TBAB (Bu4NBr), hydrogenation
Reagent be carbon-palladium catalyst (Pd/C), reaction dissolvent be volume ratio 1：1 dichloromethane and methanol (CH2C12/MeOH)。
In the entitled " synthesis of polyhydroxy Benzofurantone compound and its antitumor of Application No. WO2013104263
The step 4 of embodiment 1 of the patent application document of effect ", which discloses fluorine, can draw fixed preparation method.This method is with 2- (4- fluoroforms
Base phenyl) -3,5,7- trihydroxy -4H- benzopyran-4-ones be raw material, the compound and cesium carbonate is soluble in water, in frozen water
Isoprenyl bromide is added dropwise under the conditions of bath.After adding, reaction system is reacted overnight at room temperature, uses salt acid for adjusting pH value, Ran Houyong
Ethyl acetate is extracted 2 times.Merge organic phase, after saturated nacl aqueous solution washing, use anhydrous sodium sulfate drying.After filtering and concentrating,
Crude product purified by silica gel column chromatography is purified, with ethyl acetate/petroleum ether (1:25) it is eluent, obtaining target compound fluorine can draw
It is fixed.
However, present inventor determines low yield in practice, it has been found that the fluorine obtained by prior art can be drawn, accessory substance
Separation is difficult.In addition, the operation of silica gel column chromatography causes efficiency low in large-scale industrial production and cost is too high.
Accordingly, it would be desirable on the basis of original document patent, do further exploratory development, it is desirably to obtain and is adapted on a large scale
Industrialized synthesis technique can draw fixed production to carry out fluorine.
The content of the invention
Fixed synthetic method can be drawn it is an object of the invention to provide a kind of fluorine.This method is with 3,5,7- trihydroxy -2- (4-
Trifluoromethyl) -4H- benzopyran-4-ones are initiation material, fluorine is prepared by four-step reaction can draw fixed.
Fixed method can be drawn the invention provides a kind of fluorine, this method comprises the following steps：
A. with Formulas ICompound is raw material, progress 3,7 phenolic hydroxyl group protections, obtains formula
IICompound；
B. by Formula IICompound and formula IIICompound is reacted, and is obtained
Formula IVCompound；
C. by formula IVCompound carries out rearrangement reaction, obtains Formula V
Compound
D. by Formula VCompound is deprotected, and obtains formula A
Compound, wherein, the catalyst of step C rearrangement reactions is siliceous catalyst.
Preferably, the protection group of described Formula II compound, formula IV compound and 3 of Formula V compound and 7 phenolic hydroxyl groups
PG be selected from methoxy, 2- methoxvethoxvmethvls, ethoxyethyl, THP trtrahydropyranyl, benzyloxymethyl, benzyl, to first
One or more in oxygen benzyl and trityl.
Preferably, described compound of formula I by with selected from bromomethyl methyl ether, chloromethyl methyl ether, 2- methoxy ethoxies
Chloromethanes, 2- bromoethyls ether, 2- chloroethyls ether, dihydropyran, benzyl bromo-methyl-ether, Benzyl chloromethyl ether, benzyl bromine, to first
Epoxide benzyl bromine, in methoxy-benzyl chlorine and trityl chloride one kind react, obtain Formula II compound.
Preferably, formula III compoundIn substituent X be selected from bromine, chlorine, hydroxyl, p-methyl benzenesulfonic acid ester group and
One or more in methanesulfonic acid ester group.
Most preferably, described formula III compound be selected from isoprenyl bromide, isopentene group chlorine, prenol, to toluene sulphur
One or more in sour iso-amylene alcohol ester and methanesulfonic acid iso-amylene alcohol ester.
Preferably, in described step A, reaction dissolvent in ether solvent, halogenated alkane and amide solvent one
Plant or several.
It is highly preferred that described ether solvent is selected from diethyl ether, tetrahydrofuran, 2- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxy six
One or more in ring, 1,2- dimethoxy-ethanes and 1,2- diethoxyethane；Described halogenated alkane solvents include two
Chloromethanes or chloroform；Described amide solvent includes 1-METHYLPYRROLIDONE, DMAC N,N' dimethyl acetamide and N, N- dimethyl methyl
One or more in acid amides.
Preferably, acid binding agent is also added into reaction dissolvent.
It is highly preferred that described acid binding agent is selected from organic amine, alkaline nitrogenous aromatic compound, hydride or carbonate,
Described organic amine is selected from N, N- diisopropylethylamine or triethylamine；Described alkaline nitrogenous aromatic compound be selected from pyridine or its
Derivative；Described hydride is sodium hydride；Described carbonate is potassium carbonate, and reaction temperature is 0-40 DEG C.
Preferably, in described step B, reaction dissolvent contains alkali and light prolongs a kind of and non-proton pole in reaction promoter
Property solvent, reaction temperature be -20-70 DEG C.
It is highly preferred that described aprotic polar solvent is selected from ethers, arene, ketone, amide solvent and halo
One or more in alkane solvent.
More preferably, described ether solvent is selected from diethyl ether, tetrahydrofuran, 2- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxy six
One or more in ring, 1,2- dimethoxy-ethanes and 1,2- diethoxyethane solvents；Described aromatic hydrocarbon solvent choosing
From toluene or xylene solvent；One kind in acetone, espeleton and methyl tert-butyl ketone solvent of described ketones solvent or
It is several；It is molten that described amide solvent is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide and 1-METHYLPYRROLIDONE
One or more in agent；Described halogenated alkane solvents are selected from dichloromethane or chloroform solvent.
Preferably, described alkali be selected from the carbonate of alkali metal, alkoxide, ammonia salt, organic amine salt, hydroxide, hydride,
One or more in lithium alkylide compound and nitrogenous organic base.
Most preferably, the carbonate of described alkali metal is selected from potassium carbonate or cesium carbonate；Alkali alcoholate is selected from methanol
Sodium or potassium tert-butoxide；The ammonia salt of alkali metal is selected from Sodamide or potassamide；The organic amine salt of alkali metal is selected from diisopropyl amido
Lithium, sodium hexamethyldisilazide or potassium hexamethyldisilazide；The hydroxide of alkali metal is potassium hydroxide or hydroxide
Sodium；The hydride of alkali metal is sodium hydride；Lithium alkylide compound is selected from n-BuLi or phenyl lithium；Described nitrogenous organic base is 1,
8- diazabicylos-bicyclic (5,4,0) -7- hendecenes.
Preferably, described light, which prolongs reaction promoter, includes one kind and azoformic acid two in triphenylphosphine and tributylphosphine
A kind of mix reagent of composition in isopropyl ester and diethyl azodiformate.
Preferably, catalyst is also added in stepb.
It is highly preferred that described catalyst is sodium iodide or TBAB.
Preferably, the reaction dissolvent of the step C is aprotic polar solvent, one kind in toluene and dimethylbenzene or
It is several.
It is highly preferred that described aprotic polar solvent is toluene.
Preferably, the one kind of described siliceous catalyst in comprising silica, florisil silica and montmorillonite
Or the catalyst of several compositions.
Most preferably, described siliceous catalyst is florisil silica.
Preferably, in described step D, reaction dissolvent is in water, carboxylic acid, acid amides, esters, alcohols and ether solvent
One or more.
It is highly preferred that described reaction dissolvent is selected from one or both of alcohols and ethers.
Most preferably, described reaction dissolvent is a kind of the mixed of the and isopropanol in tetrahydrofuran and 2- methyltetrahydrofurans
Bonding solvent.
Preferably, deprotecting regent is also added in step D.
It is highly preferred that described deprotecting regent includes de- alkyl ether protective agent.
It is highly preferred that described de- alkyl ether protective agent is Bronsted acid or lewis acid.
Most preferably, described Bronsted acid is sulfuric acid or hydrochloric acid.
Preferably, step E is also included between described step A and step B:Purified product II.
It is highly preferred that adding water and ethyl acetate, point liquid into step A reaction solution, organic phase is purified.
Preferably, recrystallisation solvent crystallization purifying is added into organic phase, described recrystallisation solvent is isopropanol.
It is highly preferred that being added in reaction solution also into step A in weak acid solution and unreacted acid binding agent.
Most preferably, described weak acid solution is ammonium chloride solution.
Preferably, step F is also included between described step B and step C:Purification reaction product IV.
It is highly preferred that ethyl acetate and water are added into reaction solution, point liquid.
It is highly preferred that by adding C into organic phase6-C9Straight chain organic alkane is crystallized, filtering, collects filter cake.
More preferably, also with the alkali in ammonium chloride solution neutralization reaction liquid.
Most preferably, described C6-C9Straight chain organic alkane is n-hexane or normal heptane.
Preferably, step G is also included between described step C and step D：By step C reacting liquid filtering, remove anti-
The silicon-containing catalyst in liquid is answered, filter cake, merging filtrate, purification are washed with methane chloride.
It is highly preferred that adding recrystallisation solvent into organic phase, crystallized.
Most preferably, acetonitrile or ethanol are added also into organic phase, concentration removes methane chloride, then adds second thereto
Nitrile or ethanol cool to -5 DEG C to 5 DEG C, crystallization is filtrated to get Formula V compound as recrystallisation solvent.
Preferably, step H is also included after described step D：Step D reaction solution is added into water, filter is collected in filtering
Cake, ethanol dissolving filter cake, purifying obtains formula A compounds.
Preferably, step I is also included after described step D:Added into step D reaction solution and contain ethyl acetate
Organic solvent and the aqueous solution point liquid, concentration, cooling concentration liquid obtains formula A compounds.
It is highly preferred that also including step J between described step D and step I:Carbonate or carbon are added into reaction solution
With unreacted deprotecting regent in the sour hydrogen salt aqueous solution.
Most preferably, in described step I, the organic solvent containing ethyl acetate includes ethyl acetate and selected from tetrahydrochysene
Any one in furans, ethanol, acetonitrile, the alkane of 1,4- dioxies six, diformamide and acetone solvent.
The beneficial effects of the present invention are can draw fixed synthetic method, the synthesis side the invention provides a kind of new fluorine
Method uses siliceous catalyst cheap and easy to get, is selected from the one or more in silica, florisil silica and montmorillonite,
Reaction temperature is 60-120 DEG C, compared with prior art, reacts more easy to operate, post-processing operation is more simple, weight in the present invention
The yield of row's reaction can reach about 50%.Test result indicates that, the fluorine obtained using the chemical synthesis process of invention
It can draw fixed, cost is relatively low, simple to operate, reliable, product is easy to purifying, the fluorine finally given can draw fixed output quota condition for raw material 3,
5,7- trihydroxy -2- (4- trifluoromethyls) -4H- benzopyran-4-ones, yield reaches more than 30%, and purity can reach
More than 98%.
Embodiment
Unless otherwise indicated, 3,5,7- trihydroxy -2- (4- trifluoromethyls) -4H- chromenes -4- herein
Ketone, i.e. compound of formula I, refer to the compound with following structural formula：
Unless otherwise indicated, " MOM " herein represents methoxy.
Unless otherwise indicated, " ether solvent " herein represents the solvent that structure is ethers, and ether is by an oxygen atom
Two alkyl or aryls of connection are formed, and the formula of ether is：R-O-R ', wherein R and R ' represent identical or different each other
Alkyl or aryl.
Unless otherwise indicated, " amide solvent " herein represents the solvent that structure is amides compound, amide-type
Compound all contains amido link, and chemical constitution isWherein R1, R2And R3Can be hydrogen, alkyl, aryl or ring-type alkane
Base.
Unless otherwise indicated, " aprotic polar solvent " herein is represented in molecule without proton, but has weaker receiving
Proton is inclined to the solvent of the formation bonding abilities different with degree.
Unless otherwise indicated, silica, florisil silica and montmorillonite are included in " siliceous catalyst " herein
In one or more of compositions catalyst, for example main component be silica catalyst silica gel or magnesia-silica gel
Also in the protection domain of catalyst of the present invention.
Unless otherwise indicated, herein " alcohols solvent " represents the solvent that structure is alcohols, be aliphatic hydrocarbon, alicyclic or
The compound that hydrogen atom in aromatic hydrocarbon side chain is optionally substituted by a hydroxyl group.
Unless otherwise indicated, term herein " light prolongs reaction " is also referred to as Mitsunobu reactions.In the present invention, it is different
The alcoholic extract hydroxyl group of pentenol prolongs reaction promoter as light：Such as one kind and azoformic acid diisopropyl in triphenylphosphine and tributylphosphine
In the presence of a kind of mix reagent of composition in ester and diethyl azodiformate, with formula (II) compound phenolic hydroxyl group of 5
Generation nucleophilic displacement of fluorine, so as to complete step B reaction, the light in the present invention prolongs reaction temperature for -20-30 DEG C.
Unless otherwise indicated, " PG " herein represents blocking group (protecting group).
Unless otherwise indicated, " acid binding agent " herein is represented in chemical reaction, is carried out with the acid in reaction system anti-
The reagent answered, is reacted by acid binding agent with acid, so as to promote whole chemical reaction to carry out.In whole course of reaction, tie up
Sour agent is consumed, and the acid binding agent in the present invention is the reagent with alkalescence.
Unless otherwise indicated, " florisil silica " herein is purchased from the organic company Arcos Organics companies of Ai Ke.
Unless otherwise indicated, reagent herein " TBAB " is purchased from Shanghai Shu Ya Pharmaceutical Technology Co., Ltd,
Article number B40912.
Unless otherwise indicated, reagent herein " the bromo- 3- methyl-2-butenes of 1- " praises the limited public affairs of occasion chemical industry purchased from Shanghai
Department.
Embodiment 1
Raw material 3,5,7- trihydroxies -2- (4- trifluoromethyls) -4H- benzopyran-4-ones in background technology according to carrying
The method of confession is prepared from.
1) preparation of Formula II a compounds (PG=MOM)
The methoxy protection of 3,7- phenolic hydroxyl groups is carried out with bromomethyl methyl ether
Reaction
First under nitrogen protection, 3,5,7- trihydroxy -2- (4- trifluoromethyls) -4H- benzene is added into reactor
And pyrans -4- ketone (compound of formula I, 500g) and tetrahydrofuran (3.5L), add acid binding agent N, N- diisopropyl under being stirred at 0 DEG C
Ethamine (480g).Control temperature to be less than 10 DEG C, bromomethyl methyl ether (MOMBr, 380g) is added dropwise.After completion of dropping, room temperature is warming up to
20 DEG C of stirring reactions 3 hours are complete until reaction.
Post processing
Reaction solution is not further processed, and is directly used as next step reaction.
2) preparation of formula IV a compounds (PG=MOM)
Reaction
Under nitrogen protection, react potassium hydroxide (116g) is added in the solution got one step up, iso-amylene is then added dropwise
Bromide (DMABr, 308g) simultaneously controls temperature at 30 DEG C.Completion of dropping, is heated to 40-50 DEG C, and stirring 10 hours to reaction terminates.
Post processing
Concentration of reaction solution, then adds ethyl acetate (3.5L), ammonium chloride solution (3.0L), point liquid.Organic phase is used successively
Aqueous ammonium chloride solution (3.0L), sodium-chloride water solution (2.5L) washing.Organic phase is concentrated, normal heptane is added at 60-70 DEG C
(5.0L), is subsequently cooled to 0-10 DEG C, crystallization filtering.Vacuum drying obtains formula IV a compound 572g, relative to Formula II a chemical combination
The mole of thing, the yield of formula IV a compounds is 78%.
In addition, present inventor have studied replaces sodium hydroxide using different alkali, and different solvents replaces four
Hydrogen furans carries out IIa (PG=MOM) and isoprenyl bromide reaction.Different alkali includes but is not limited to potassium carbonate, diisopropyl
Base amido lithium, sodium hexamethyldisilazide, potassium tert-butoxide, the carbon -7- alkene (DBU) of 1,8- diazabicylos 11, potassium hydroxide,
Diisopropylethylamine, solvent includes but is not limited to tetrahydrofuran, DMF, 1-METHYLPYRROLIDONE.
3) preparation of Formula V a compounds
Catalytically rearranging method
Reaction
Under nitrogen protection, formula IV a compounds (2g, 0.11mol), toluene (20mL), Fu Luoli are added into reaction bulb
Tripoli (100~200 mesh, 50% mass ratio).Reaction solution is heated to 85~95 DEG C, reacts 5-7 hours.
Post processing
Reaction solution is cooled to room temperature, and filtering, filter cake is washed with dichloromethane (10mL).Merging filtrate, concentration, column chromatography is pure
Change obtains 1g Formula V a compounds, relative to the mole of formula IV a compounds, and Formula V a compound yields are 50%.
In addition, present inventor have studied when under different catalysts conditions, IVa (PG=MOM methoxyl methyls) is carried out
The response situation of Claisen rearangement, is recited in following table：
4) fluorine can draw fixed preparation
Reaction
Under nitrogen protection, Formula V a compounds (50g), tetrahydrofuran (250mL) and sulfuric acid are sequentially added into reactor
Aqueous isopropanol (0.4M, 250mL).Reaction solution is heated to 50 DEG C, reacted 12 hours.
Post processing
Reaction solution is cooled to 30 DEG C, 8% potassium bicarbonate aqueous solution (250mL) is slowly added to and is concentrated into 250mL or so, so
After sequentially add ethyl acetate (500mL) and tetrahydrofuran (100mL), point liquid.Washed with 15% sodium-chloride water solution (250mL)
Wash organic phase.
Organic phase is concentrated into 150mL or so, adds ethyl acetate (300mL) and tetrahydrofuran (60mL), is concentrated into 150mL
Left and right, adds ethyl acetate (300mL) and tetrahydrofuran (60mL), is concentrated into 150mL or so.Acetonitrile is added at 65-75 DEG C
(550mL), is subsequently cooled to -5 to 5 DEG C.Formula A compound 25.5g are filtrated to get, with the molar amount of Formula V a compounds, yield
62%.
Embodiment 2
The methoxvethoxvmethvl protection of 3,7- phenolic hydroxyl groups
1) preparation of Formula II a compounds (PG=methoxvethoxvmethvls)
Reaction
Under nitrogen protection, 3,5,7- trihydroxy -2- (4- trifluoromethyls) -4H- benzo pyrroles are added into reactor
Mutter -4- ketone (compound of formula I, 2g), DMF (DMF) (12mL) and 2- methoxy ethoxies chloromethanes (1.7g)
(MEMCl) acid binding agent triethylamine (TEA) (1.8g), is added at 0 DEG C.Reaction is carried out 2 hours at room temperature.
Post processing
Water (20mL) is added into reaction solution, is then extracted twice with ethyl acetate (25mL), merges organic phase and concentrates,
Purified by silica gel column chromatography, obtain 1.37g yellow powder products, yield is 45%.
Embodiment 3
The preparation of formula IV a compounds (PG=MOM)
Prolong reaction synthesis IVa using lightCompound
Reaction
Under nitrogen protection, Formula II a compounds (20g), tetrahydrofuran (80mL), triphenylphosphine are added into reaction bulb
(25g) and isobutene alcohol (5.4g).- 4 DEG C are cooled to, diethyl azodiformate (16.3g) tetrahydrofuran is slowly added dropwise
After (5mL, 1mL/g) solution, completion of dropping, reaction is carried out 2 hours at 0 DEG C.
Post processing
Reaction solution is concentrated, is then purified that (eluant, eluent proportioning is petroleum ether by silica gel column chromatography：Ethyl acetate=
3:1) formula IV a compounds, are obtained, with Formula II a compound mole ratios, yield is 65%.
Following step be the same as Example 1.
Claims (18)
1. a kind of fluorine can draw fixed synthetic method, this method comprises the following steps：
A. with Formulas ICompound is raw material, progress 3,7 phenolic hydroxyl group protections, obtains Formula IICompound；
B. by Formula IICompound and formula IIICompound is reacted, and obtains formula IVCompound；
C. by formula IVCompound carries out rearrangement reaction, obtains Formula VChange
Compound；
D. by Formula VCompound is deprotected, and obtains formula A
Compound, it is characterised in that the catalyst of rearrangement reaction is siliceous catalyst in step C.
2. according to the method described in claim 1, it is characterised in that described Formula II compound, formula IV compound and Formula V chemical combination
The protection group PG of 3 of thing and 7 phenolic hydroxyl groups is selected from methoxy, 2- methoxvethoxvmethvls, ethoxyethyl, tetrahydrochysene pyrrole
Mutter base, benzyloxymethyl, benzyl, to the one or more in methoxybenzyl and trityl；Preferably, described Formulas I chemical combination
Thing by with selected from bromomethyl methyl ether, chloromethyl methyl ether, 2- methoxy ethoxies chloromethanes, 2- bromoethyls ether, 2- chloroethyls
Ether, dihydropyran, benzyl bromo-methyl-ether, Benzyl chloromethyl ether, benzyl bromine, to methoxybenzyl bromine, to methoxy-benzyl chlorine and three
A kind of reaction in benzyl chlorine, obtains Formula II compound.
3. according to the method described in claim 1, it is characterised in that described formula III compoundIn substituent X
One or more in bromine, chlorine, hydroxyl, p-methyl benzenesulfonic acid ester group and methanesulfonic acid ester group；Preferably, described formula III
Compound is selected from isoprenyl bromide, isopentene group chlorine, prenol, p-methyl benzenesulfonic acid iso-amylene alcohol ester and methanesulfonic acid iso-amylene alcohol ester
In one or more.
4. according to the method described in claim 1, it is characterised in that in described step A, reaction dissolvent is molten selected from ethers
One or more in agent, halogenated alkane and amide solvent；Preferably, described ether solvent be selected from diethyl ether, tetrahydrofuran,
One or more in 2- methyltetrahydrofurans, 1,4- dioxane, 1,2- dimethoxy-ethanes and 1,2- diethoxyethane；
Described halogenated alkane solvents include dichloromethane or chloroform；Described amide solvent includes 1-METHYLPYRROLIDONE, N, N- bis-
One or more in methylacetamide and DMF.
5. method according to claim 4, it is characterised in that acid binding agent is also added into reaction dissolvent；Preferably, it is described
Acid binding agent be selected from organic amine, alkaline nitrogenous aromatic compound, hydride or carbonate, described organic amine is selected from N, N- bis-
Wopropyl ethyl amine or triethylamine；Described alkaline nitrogenous aromatic compound is selected from pyridine or derivatives thereof；Described hydride is
Sodium hydride；Described carbonate is potassium carbonate, and reaction temperature is 0-40 DEG C.
6. according to the method described in claim 1, it is characterised in that in described step B, reaction dissolvent contains alkali and light prolongs
One kind and aprotic polar solvent in reaction promoter, reaction temperature are -20-70 DEG C；Preferably, described aprotonic polar is molten
One or more of the agent in ethers, arene, ketone, amide solvent and halogenated alkane solvents；It is highly preferred that described
Ether solvent be selected from diethyl ether, tetrahydrofuran, 2- methyltetrahydrofurans, 1,4- dioxane, 1,2- dimethoxy-ethanes and
One or more in 1,2- diethoxyethane solvents；Described aromatic hydrocarbon solvent is selected from toluene or xylene solvent；Institute
One or more of the ketones solvent stated in acetone, espeleton and methyl tert-butyl ketone solvent；Described amide solvent
One or more in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide and 1-METHYLPYRROLIDONE solvent；It is described
Halogenated alkane solvents be selected from dichloromethane or chloroform solvent.
7. method according to claim 6, described alkali be selected from the carbonate of alkali metal, alkoxide, ammonia salt, organic amine salt,
One or more in hydroxide, hydride, lithium alkylide compound and nitrogenous organic base；Preferably, the carbonic acid of the alkali metal
Salt is selected from potassium carbonate or cesium carbonate；Alkali alcoholate is selected from sodium methoxide or potassium tert-butoxide；The ammonia salt of alkali metal is selected from Sodamide
Or potassamide；The organic amine salt of alkali metal is selected from lithium diisopropyl amido, sodium hexamethyldisilazide or the silicon substrate of hexamethyl two
Amido potassium；The hydroxide of alkali metal is potassium hydroxide or sodium hydroxide；The hydride of alkali metal is sodium hydride；Described alkyl
Lithiumation thing is selected from n-BuLi or phenyl lithium；Described nitrogenous organic base is 1,8- diazabicylos-bicyclic (5,4,0) -7- ten
One alkene.
8. method according to claim 6, wherein described light prolongs reaction promoter including in triphenylphosphine and tributylphosphine
It is a kind of with diisopropyl azodiformate and diethyl azodiformate in a kind of composition mix reagent.
9. method according to claim 6, also adds catalyst in stepb；Preferably, described catalyst is iodate
Sodium or TBAB.
10. according to the method described in claim 1, it is characterised in that the reaction dissolvent of the step C is that aprotonic polar is molten
Agent, the one or more in toluene and dimethylbenzene；Preferably, described aprotic polar solvent is toluene.
11. according to the method described in claim 1, siliceous catalyst is selected from and includes silica, florisil silica and Meng Tuo
The catalyst of one or more of compositions in stone；Preferably, described siliceous catalyst is florisil silica.
12. according to the method described in claim 1, it is characterised in that in described step D, reaction dissolvent is selected from water, carboxylic
One or more in acid, acid amides, esters, alcohols and ether solvent；Preferably, described reaction dissolvent is selected from alcohols and ethers
One or both of；Most preferably, described reaction dissolvent be tetrahydrofuran and 2- methyltetrahydrofurans in it is a kind of with it is different
The mixed solvent of propyl alcohol.
13. method according to claim 12, it is characterised in that also add deprotecting regent in step D；Preferably,
Described deprotecting regent includes de- alkyl ether protective agent；It is highly preferred that described de- alkyl ether protective agent is Bronsted acid or road
Lewis acid；Most preferably, described Bronsted acid is sulfuric acid or hydrochloric acid.
14. the method according to claim 1,5 or 6, it is characterised in that also include between described step A and step B
Step E:Purification reaction product II；Preferably, water and ethyl acetate, point liquid are added into step A reaction solution, is purified organic
Phase；Preferably, recrystallisation solvent crystallization purifying is added into organic phase；Described recrystallisation solvent is isopropanol；It is highly preferred that also to
Added in reaction solution in step A in weak acid solution and unreacted acid binding agent；Most preferably, described weak acid solution is chlorination
Ammonium salt solution.
15. the method according to claim 6 or 10, it is characterised in that also include between described step B and step C
Step F:Purification reaction product IV；Preferably, ethyl acetate and water are added into reaction solution, point liquid；It is highly preferred that by having
C is added in machine phase6-C9Straight chain organic alkane is crystallized, filtering, collects filter cake；More preferably, ammonium chloride solution neutralization reaction is also used
Alkali in liquid；Most preferably, described C6-C9Straight chain organic alkane is n-hexane or normal heptane.
16. the method according to claim 10 or 12, it is characterised in that also include between described step C and step D
Step G：By step C reacting liquid filtering, the silicon-containing catalyst in reaction solution is removed, filter cake is washed with methane chloride, merged
Filtrate, purification；Preferably, recrystallisation solvent is added into organic phase, is crystallized；It is highly preferred that also adding second into organic phase
Nitrile or ethanol, concentration remove methane chloride, then add acetonitrile or ethanol thereto as recrystallisation solvent, cool to -5 DEG C to 5
DEG C, crystallization is filtrated to get Formula V compound.
17. the method according to claim 1 or 12, it is characterised in that also include step H after described step D：Will
Step D reaction solution adds water, and filter cake is collected in filtering, and ethanol dissolving filter cake, purifying obtains formula A compounds.
18. the method according to claim 1 or 12, it is characterised in that also include step I after described step D:To
Organic solvent and the aqueous solution containing ethyl acetate point liquid are added in step D reaction solution, concentration, cooling concentration liquid obtains formula A
Compound；Preferably, step J is also included between described step D and step I:Carbonate or carbonic acid are added into reaction solution
With unreacted deprotecting regent in the hydrogen salt aqueous solution；Most preferably, in described step I, the organic of ethyl acetate is contained
Solvent includes ethyl acetate and in tetrahydrofuran, ethanol, acetonitrile, the alkane of 1,4- dioxies six, diformamide and acetone solvent
Any one.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101205223A (en) * | 2006-12-18 | 2008-06-25 | 李毅林 | Total synthesis method of natural product barrenwort glycosides compounds |
| CN103204838A (en) * | 2012-01-13 | 2013-07-17 | 北京盛诺基医药科技有限公司 | Synthesis of polyhydroxybenzo pyrone compound and antineoplastic effect of the compound |
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| CN101205223A (en) * | 2006-12-18 | 2008-06-25 | 李毅林 | Total synthesis method of natural product barrenwort glycosides compounds |
| CN103204838A (en) * | 2012-01-13 | 2013-07-17 | 北京盛诺基医药科技有限公司 | Synthesis of polyhydroxybenzo pyrone compound and antineoplastic effect of the compound |
Non-Patent Citations (2)
| Title |
|---|
| QINGGANG MEI，等: "Synthesis of icariin from kaempferol through regioselective methylation and para-Claisen–Cope rearrangement", 《BEILSTEIN J.ORG.CHEM.》 * |
| WEN-ZHANG CHEN，等: "First total synthesis of natural products cajanolactone A and cajanonic acid A", 《CHINESE CHEMICAL LETTERS》 * |
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