CN103145542B - Method for producing difluorobenzene derivative - Google Patents
Method for producing difluorobenzene derivative Download PDFInfo
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- CN103145542B CN103145542B CN201310004873.5A CN201310004873A CN103145542B CN 103145542 B CN103145542 B CN 103145542B CN 201310004873 A CN201310004873 A CN 201310004873A CN 103145542 B CN103145542 B CN 103145542B
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- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical class FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 title abstract description 16
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 125000002769 thiazolinyl group Chemical group 0.000 abstract description 27
- 238000000034 method Methods 0.000 abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 69
- 125000004432 carbon atom Chemical group C* 0.000 description 61
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- 239000002904 solvent Substances 0.000 description 45
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 42
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 239000001301 oxygen Substances 0.000 description 31
- 229910052760 oxygen Inorganic materials 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 229920002554 vinyl polymer Polymers 0.000 description 26
- -1 2,3-difluorophenyl Chemical class 0.000 description 22
- 235000002639 sodium chloride Nutrition 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 125000000217 alkyl group Chemical group 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- 230000006837 decompression Effects 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 238000004949 mass spectrometry Methods 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- 239000004973 liquid crystal related substance Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000003513 alkali Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 125000003545 alkoxy group Chemical group 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 150000001336 alkenes Chemical class 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 10
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 10
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002798 polar solvent Substances 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- 239000007810 chemical reaction solvent Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 5
- QLKNTHXMJDKIQM-UHFFFAOYSA-N [2-(methoxymethyl)phenyl]-diphenylphosphane Chemical class COCC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QLKNTHXMJDKIQM-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- RPEPGIOVXBBUMJ-UHFFFAOYSA-N 2,3-difluorophenol Chemical compound OC1=CC=CC(F)=C1F RPEPGIOVXBBUMJ-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 3
- 125000006017 1-propenyl group Chemical group 0.000 description 3
- 125000006042 4-hexenyl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 3
- 150000001639 boron compounds Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000005595 deprotonation Effects 0.000 description 3
- 238000010537 deprotonation reaction Methods 0.000 description 3
- 229940117389 dichlorobenzene Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- LIIBOJGBDQRXAY-UHFFFAOYSA-N methoxymethylphosphane Chemical compound COCP LIIBOJGBDQRXAY-UHFFFAOYSA-N 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 3
- 235000019798 tripotassium phosphate Nutrition 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 0 CCC1(CCC(C*)*CC=C)OCCO1 Chemical compound CCC1(CCC(C*)*CC=C)OCCO1 0.000 description 1
- JSDUOUVZQRZOOY-UHFFFAOYSA-N CCCC1OCCO1 Chemical compound CCCC1OCCO1 JSDUOUVZQRZOOY-UHFFFAOYSA-N 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDSSEOIBFVTMNM-UHFFFAOYSA-N [K].[K].[K].P(O)(O)(O)=O Chemical compound [K].[K].[K].P(O)(O)(O)=O KDSSEOIBFVTMNM-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000007697 cis-trans-isomerization reaction Methods 0.000 description 1
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 230000005685 electric field effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229910001463 metal phosphate Inorganic materials 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- AZFQCTBZOPUVOW-UHFFFAOYSA-N methyl(triphenyl)phosphanium Chemical class C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 AZFQCTBZOPUVOW-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Liquid Crystal Substances (AREA)
Abstract
The invention provides a method for producing difluorobenzene derivative, and relates to an efficiently producing method of the difluorobenzene derivative containing thiazolinyl on a side chain and an intermediate usable for the production method. Especially, the invention provides a compound represented by a general formulae (3).
Description
The present invention is to be the divisional application that March 30, application number in 2007 are 201010105726.3, denomination of invention is " preparation method of difluoro bezene derivative " applying date.
Technical field
The present invention relates to a kind of preparation method of difluoro bezene derivative and prepare intermediate.
Background technology
Liquid crystal display device, due to advantages such as it is low voltage operated, slim demonstrations, is nowadays widely used.The display mode of liquid crystal display device had TN(twisted-nematic in the past), STN(supertwist is to row), or the active-matrix (active-matrix) (TFT: thin film transistor) that forms on substrate of TN etc., they are all that to utilize dielectric constant anisotropy value be positive liquid-crystal composition.But it is that its visual angle is narrower that these display modes have a shortcoming, the raising requiring along with liquid crystal board maximization in recent years, improves this problem and becomes larger problem.
As its solution, vertical orientation mode, IPS(In Plane Switching transverse electric field effect in recent years) etc. display mode start to be practical.Vertical orientation mode is utilize liquid crystal molecule vertical orientated to improve the method at visual angle, use be that dielectric constant anisotropy value is negative liquid-crystal composition.IPS in addition, is to use transverse electric field conversion liquid crystal molecule to improve the method at visual angle in the horizontal direction of relative glass substrate, use be the liquid-crystal composition that dielectric constant anisotropy value is negative or positive.So, in the vertical orientation mode of effective display mode at visual angle and IPS, all to need dielectric constant anisotropy value be negative liquid crystalline cpd and liquid-crystal composition can improve, and urgent hope can be achieved.
Be the liquid crystalline cpd using in negative liquid-crystal composition as dielectric constant anisotropy value, can enumerate 2,3-difluorophenyl derivative (with reference to patent documentation 1).But only disclosing side chain in patent documentation 1 is amino compound, the compound that openly side chain is not thiazolinyl completely, its preparation method is not known yet.In addition, there is the compound of alkoxyl group on 1 and 4 of known phenyl ring because therefore chemically unstable does not use (with reference to non-patent literature 1) as liquid crystal material, therefore the exploitation of this compounds process for production thereof is not carried out.
Patent documentation 1: special public table 2-503568 communique
Non-patent literature 1: field, natural pond, " trend of liquid crystal material ", monthly magazine デ イ ス プ レ イ, in March, 1998, the 4th volume, No. 3 (page 5)
Summary of the invention
The invention provides and on side chain, have the used intermediate of preparing in the effective preparation method of the difluoro bezene derivative of thiazolinyl and this preparation method.
The inventor attentively studies for solving above-mentioned problem, found that the method by compound shown in formula (1) being converted to compound shown in formula (2), can effectively prepare the difluoro bezene derivative on side chain with thiazolinyl, thereby complete the present invention.
The present invention relates to,
The compound represented by formula (1) reacts compound shown in the formula of obtaining (2) with the phenates being made by 2,3-difluorophenol;
After compound oxidation shown in this formula (2), obtain compound shown in formula (13);
The phenates being made by compound shown in this formula (13) reacts with compound shown in formula (7), obtains compound shown in formula (16);
After compound deprotection shown in this formula (16), obtain compound shown in formula (17);
In compound and methoxymethyl phosphine shown in this formula (17), after reactant salt, hydrolyzable obtains compound shown in formula (18);
In compound and alkylphosphines shown in this formula (18), reactant salt obtains the preparation method of compound shown in formula (9),
And,
Compound shown in formula (1) obtains compound shown in formula (2) with the phenates reaction being made by 2,3-difluorophenol;
After compound deprotection shown in this formula (2), obtain compound shown in formula (3);
In compound and methoxymethyl phosphine shown in this formula (3), after reactant salt, hydrolyzable obtains compound shown in formula (4);
In compound and alkylphosphines shown in this formula (4), reactant salt obtains compound shown in formula (5);
After compound oxidation shown in this formula (5), obtain compound shown in formula (6);
The phenates being made by compound shown in this formula (6) reacts with compound shown in formula (7), obtains the preparation method of compound shown in formula (9).
R
4X
2 (7)
Wherein,
In formula (1), (2), (13), (16), R
1and R
2represent independently methyl, ethyl or propyl group separately, or, R
1and R
2expression-CH
2cH
2-,-CH
2cH
2cH
2-or-CH
2c (CH
3)
2cH
2-;
In formula (1), X
1represent chlorine, bromine, iodine, phenylsulfonyloxy, tolysulfonyl oxygen base, methanesulfonyloxy group or trifluoromethane sulfonyloxy;
In formula (5), (6), (9), R
3represent the alkyl of hydrogen atom or carbonatoms 1 to 5;
In formula (7), X
2represent chlorine, bromine, iodine, phenylsulfonyloxy, tolysulfonyl oxygen base, methanesulfonyloxy group or trifluoromethane sulfonyloxy;
In formula (7), (9), (16), (17), (18), R
4represent thiazolinyl or the expression (8) of carbonatoms 2 to 12;
In formula (8), R
5for the alkyl of carbonatoms 1 to 12, the thiazolinyl of carbonatoms 2 to 12, the alkoxyl group of carbonatoms 1 to 12, the alkene oxygen base of carbonatoms 2 to 12.
Further, the invention provides the used intermediate of preparing in preparation process of the present invention, by compound shown in formula (2), (3), (4), (5), (6), (13), (16), (17) and (18).
Preparation method of the present invention, as the preparation method of difluoro bezene derivative of great use.In addition, preparation method of the present invention is owing to having introduced side chain R in final step
3or R
4, can extremely easily synthesize and only have R
3or R
4compound group shown in different formulas (9).
Embodiment
In preparation method of the present invention, 2,3-difluorophenol and alkali effect generate phenates, then react compound shown in the formula of obtaining (2) with compound shown in formula (1), the alkali using can be enumerated metal hydride, metal carbonate, metal phosphate, metal hydroxides, metal carboxylate, metal amide and metal etc., wherein preferred as alkali hydride, alkali metal phosphate, alkali metal phosphate, alkaline carbonate, alkali metal hydroxide, alkali metal amide, basic metal; Further preferred as alkali phosphoric acid salt, alkalimetal hydride, alkaline carbonate.The preferred lithium hydride of alkalimetal hydride, sodium hydride, potassium hydride KH, alkali metal phosphate preferably phosphoric acid tripotassium, the preferred sodium carbonate of alkaline carbonate, sodium bicarbonate, cesium carbonate, salt of wormwood, saleratus.
As reaction solvent, if be applicable to reaction carry out any all can, but preferably use ether solvent, chlorine kind solvent, varsol, aromatic series kind solvent, polar solvent etc.As ether solvent, can enumerate Isosorbide-5-Nitrae-bis-
alkane, 1,3-bis-
alkane, tetrahydrofuran (THF), Anaesthetie Ether, t-butyl methyl ether etc., can enumerate methylene dichloride, 1 as chlorine kind solvent, 2-ethylene dichloride, four salinization carbon etc., can enumerate amylene, hexene, tetrahydrobenzene, heptane, octane etc. as varsol, can enumerate benzene,toluene,xylene, trimethylbenzene, chlorobenzene, dichlorobenzene etc. as aromatic series kind solvent, polar solvent can be enumerated the example preferably such as DMF, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), tetramethylene sulfone.Wherein be more preferably the polar solvent of ether solvent, the DMF etc. of tetrahydrofuran (THF), Anaesthetie Ether etc.In addition, each solvent of front note can be used alone, also can 2 kinds or above mixing use.
Though temperature of reaction can be carried out in the zero pour from solvent in reflow temperature range, preferably 0 DEG C to 150 DEG C, further preferably 30 DEG C to 120 DEG C.In addition, the phenates of generation can react with compound shown in formula (1) after flash liberation, also can not separate and react, but consider under not separating, to react better from the difficulty or ease of operation.
Shown in formula (2) or formula (16), the deprotection of compound preferably carries out under acidic conditions.The acid using, can enumerate the protonic acid of formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tosic acid etc., the Lewis acid of boron trifluoride element etc. etc., but preferably use formic acid.
Reaction solvent, any as long as the carrying out that is applicable to reacting can be used, preferably use ether solvent, chlorine kind solvent, ketones solvent, varsol, aromatic series kind solvent, polar solvent etc., also can under solvent-free, react.Ether solvent, can enumerate Isosorbide-5-Nitrae-bis-
alkane, 1,3-bis-
alkane, tetrahydrofuran (THF), Anaesthetie Ether, t-butyl methyl ether etc., chlorine kind solvent has methylene dichloride, 1,2-ethylene dichloride, chloroform, four salinization carbon etc., ketones solvent can be enumerated acetone, 2-butanone etc., varsol can be enumerated amylene, hexene, tetrahydrobenzene, heptane, octane etc., aromatic series kind solvent can be enumerated benzene,toluene,xylene, trimethylbenzene, chlorobenzene, dichlorobenzene etc., and polar solvent can be enumerated the example preferably such as acetonitrile, dimethyl sulfoxide (DMSO).Wherein, be more preferably the varsol of amylene, hexene, tetrahydrobenzene, heptane, octane etc., the aromatic series kind solvent of benzene,toluene,xylene etc. etc.In addition, each solvent of front note can be used alone, also can 2 kinds or above solvent use.
Though temperature of reaction can be carried out in the zero pour from solvent in reflow temperature range, preferably 0 DEG C to 100 DEG C, further preferably 30 DEG C to 60 DEG C.
In compound and methoxymethyl phosphine shown in formula (3) or formula (17), hydrolyzable after reactant salt, can obtain compound shown in formula (4) from formula (3), can obtain compound shown in formula (18) from formula (17).Methoxymethyl phosphine inner salt can make from phosphonium salt, phosphoric acid ester etc., preferably makes from methoxymethyl triphenylphosphine salt.
While using methoxymethyl triphenylphosphine salt to prepare inner salt and alkali effect, the preferred potassium tert.-butoxide of alkali of use, n-Butyl Lithium, phenyl lithium, sodium hydride etc., be more preferably potassium tert.-butoxide.Reaction solvent preferably uses ether solvent, aromatic series kind solvent, polar solvent etc.Ether solvent can be enumerated Isosorbide-5-Nitrae-bis-
alkane, 1,3-bis-
alkane, tetrahydrofuran (THF), Anaesthetie Ether, t-butyl methyl ether etc., aromatic series kind solvent can be enumerated benzene,toluene,xylene, trimethylbenzene etc., and polar solvent can be enumerated DMF etc.Wherein be more preferably tetrahydrofuran (THF), toluene.In addition, each solvent of front note can be used alone, also can 2 kinds or above solvent use.
Temperature of reaction is carried out in can be from the zero pour of solvent to reflow temperature range, but preferably-40 DEG C to 30 DEG C, further preferably-20 DEG C to 20 DEG C.The inner salt obtaining preferably reacts with compound shown in formula (3) under unseparated situation.In addition, shown in methoxymethyl triphenylphosphine salt, formula (3), in the mixture of compound, also can add alkali.
Hydrolyzable can be carried out under acid catalyst.The acid using, can enumerate dilute hydrochloric acid, aqueous sulfuric acid etc.Reaction solvent, any as long as the carrying out that is applicable to reacting can be used, preferably use ether solvent, varsol, aromatic series kind solvent etc., also can under solvent-free, react.Ether solvent, can enumerate Isosorbide-5-Nitrae-bis-
alkane, 1,3-bis-
alkane, tetrahydrofuran (THF), Anaesthetie Ether, t-butyl methyl ether etc., varsol can be enumerated amylene, hexene, tetrahydrobenzene, heptane, octane etc., and aromatic series kind solvent can be enumerated benzene,toluene,xylene, trimethylbenzene, chlorobenzene, dichlorobenzene etc.Wherein, be more preferably tetrahydrofuran (THF).In addition, each solvent of front note can be used alone, also can 2 kinds or above solvent use.
Temperature of reaction is carried out in can be from the zero pour of solvent to reflow temperature range, preferably 0 DEG C to 80 DEG C.
Compound shown in the formula (4) so obtaining or formula (18), what obtain for cyclohexene ring is cis and trans mixture, but uses preferably trans as the intermediate of liquid crystalline cpd.For the cyclohexene ring of the combination formyloxy side of compound shown in formula (4) or formula (18), by making its cis-trans isomerization with alkali effect, thereby make trans surplus.The preferred sodium hydroxide of alkali, the potassium hydroxide etc. that now use, reaction solvent particular methanol, ethanol, tetrahydrofuran (THF) etc., preferably-40 DEG C to 20 DEG C of temperature of reaction, further preferred-20 DEG C to 10 DEG C.
Reactant salt in compound and alkylphosphines shown in formula (4) or formula (18), can obtain formula (5) from formula (4), obtains compound shown in ultimate aim product formula (9) from formula (18).In this reaction, alkylphosphines inner salt can make from phosphonium salt, phosphoric acid ester etc., preferably makes from alkyl triphenylphosphine salt.
In the time using alkyl triphenylphosphine salt to make inner salt and alkali effect, the preferred potassium tert.-butoxide of alkali of use, n-Butyl Lithium, phenyl lithium, sodium hydride etc., be more preferably potassium tert.-butoxide.Reaction solvent preferably uses ether solvent, aromatic series kind solvent, polar solvent etc.Ether solvent, can enumerate Isosorbide-5-Nitrae-bis-
alkane, 1,3-bis-
alkane, tetrahydrofuran (THF), Anaesthetie Ether, t-butyl methyl ether etc., aromatic series kind solvent can be enumerated benzene,toluene,xylene, trimethylbenzene etc., and polar solvent can be enumerated DMF etc., is wherein more preferably tetrahydrofuran (THF), toluene.In addition, each solvent of front note can use separately, also can 2 kinds or above solvent use.Temperature of reaction is carried out in can be from the zero pour of solvent to reflow temperature range, preferably from-40 DEG C to 30 DEG C, and further preferably-20 DEG C to 20 DEG C.The inner salt of gained preferably reacts with compound shown in formula (4) under unseparated situation.In addition, shown in alkyl triphenylphosphine salt, formula (4), in the mixture of compound, also can add alkali.Alkyl triphenylphosphine salt is preferably used methyl triphenyl phosphonium salt.
The oxidation of compound shown in formula (2) or formula (5), reacts and obtains boron compound with trialkyl borate after can utilizing the de-proton of organometallic reagent, then with oxygenant effect.Reaction solvent, as long as carrying out of being applicable to reacting is any all passable, can enumerate ether solvent, varsol etc.As ether solvent, can enumerate Isosorbide-5-Nitrae-bis-
alkane, 1,3-bis-
alkane, tetrahydrofuran (THF), Anaesthetie Ether, t-butyl methyl ether etc., varsol can be enumerated amylene, hexene, tetrahydrobenzene, heptane, octane etc., wherein preferred tetrahydrofuran (THF).Organometallic reagent can be enumerated n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, lithium methide, lithium diisopropylamide etc., from the viewpoint of obtaining and operate the preferred n-Butyl Lithium of difficulty or ease, s-butyl lithium, because effective deprotonation is more preferably s-butyl lithium.In addition, when deprotonation, also can add the potassium tert.-butoxide as additive, the alkali such as tetramethylethylened together with above-mentioned organometallic reagent.Preferably-100 DEG C to-20 DEG C of temperature of reaction when deprotonation, further preferred-78 DEG C to-40 DEG C.
Trialkyl borate, preferably uses trimethyl borate.Preferably-100 DEG C to-20 DEG C of temperature of reaction when boronation, further preferred-78 DEG C to-40 DEG C.The boron compound obtaining can flash liberation, also can not separate directly and oxidant reaction.In addition, after the boron compound hydrolyzable obtaining, change into after boronic acid compounds also passable with oxidant reaction again.
Oxygenant, preferably uses hydrogen peroxide, peracetic acid or peroxyformic acid.Preferably-78 DEG C to 70 DEG C of temperature of reaction, further preferably 0 DEG C to 50 DEG C.In addition, during with oxidant reaction, solvent comprises water also has no relations.
Shown in formula (1), formula (2), formula (13) and formula (16), in compound, carbonyl utilizes R
1and R
2protect.R
1and R
2independent is separately methyl, ethyl or propyl group, or, R
1and R
2expression-CH
2cH
2-,-CH
2cH
2cH
2-or-CH
2c (CH
3)
2cH
2-, work as R
1and R
2for-CH
2cH
2-,-CH
2cH
2cH
2-or-CH
2c (CH
3)
2cH
2in-time, the concrete formula that formula (1) is recorded is as follows.
In formula (1), preferably R
1and R
2be methyl, or R
1and R
2for-CH
2cH
2-or-CH
2cH
2cH
2-.X
1and X
2for chlorine, bromine, iodine, phenylsulfonyloxy, tolysulfonyl oxygen base, methanesulfonyloxy group or trifluoromethane sulfonyloxy, preferably bromine or methanesulfonyloxy group.R
4for the thiazolinyl of carbonatoms 2 to 12, preferably 3-butenyl and 4-pentenyl.R
5for the alkyl of carbonatoms 1 to 12, the thiazolinyl of carbonatoms 2 to 12, the alkoxyl group of carbonatoms 1 to 12, the alkene oxygen base of carbonatoms 2 to 12, the preferably alkyl of carbonatoms 1 to 12 or the thiazolinyl of carbonatoms 2 to 12, the alkyl of further preferred carbonatoms 1 to 7.
The present invention is further specifically preferably as follows described compound suc as formula the intermediate of preparing of (2).
Wherein compound shown in further preferred formula (2a), formula (2b) or formula (2d).
R in formula (5)
3for the alkyl of hydrogen atom or carbonatoms 1 to 5, preferably hydrogen atom or methyl, more preferably hydrogen atom.
R in formula (6)
3for the alkyl of hydrogen atom or carbonatoms 1 to 5, preferably hydrogen atom or methyl, more preferably hydrogen atom.
The present invention suc as formula (13) prepare intermediate be further specifically preferably as follows shown in compound.
Wherein compound shown in further preferred formula (13a), formula (13b) or formula (13d).
The present invention's intermediate of preparing as the formula (16) is further preferably as follows formula (16a) to compound shown in formula (16l).
In formula, R
6for the thiazolinyl of carbonatoms 2 to 12.
Formula (16a) arrives in formula (16f), R
6concrete is preferably 3-butenyl, 3-pentenyl, 4-pentenyl or 4-hexenyl, further preferred 3-butenyl or 4-pentenyl.
In formula, R
5for the alkyl of carbonatoms 1 to 12, thiazolinyl, the alkoxyl group of carbonatoms 1 to 12 or the alkene oxygen base of carbonatoms 2 to 12 of carbonatoms 2 to 12.
Formula (16g) arrives in formula (16l), R
5be preferably the alkyl of carbonatoms 1 to 7, thiazolinyl, the alkoxyl group of carbonatoms 1 to 7 or the alkene oxygen base of carbonatoms 2 to 7 of carbonatoms 2 to 7, the alkyl of further preferred carbonatoms 1 to 5, thiazolinyl, the alkoxyl group of carbonatoms 1 to 5 or the alkene oxygen base of carbonatoms 2 to 5 of carbonatoms 2 to 5, the particularly preferably thiazolinyl of the alkyl of carbonatoms 1 to 5 or carbonatoms 2 to 5.Thiazolinyl preferred vinyl, 1-propenyl, 3-butenyl or 3-pentenyl, particularly preferably vinyl.
The present invention's intermediate of preparing as the formula (17) is further specifically preferably as follows compound shown in formula (17a) and formula (17b).
In formula, R
6for the thiazolinyl of carbonatoms 2 to 12, R
5for the alkyl of carbonatoms 1 to 12, thiazolinyl, the alkoxyl group of carbonatoms 1 to 12 or the alkene oxygen base of carbonatoms 2 to 12 of carbonatoms 2 to 12.
In formula (17a), R
6concrete is preferably 3-butenyl, 3-pentenyl, 4-pentenyl or 4-hexenyl, further preferred 3-butenyl or 4-pentenyl.
In formula (17b), R
5be preferably the alkyl of carbonatoms 1 to 7, thiazolinyl, the alkoxyl group of carbonatoms 1 to 7 or the alkene oxygen base of carbonatoms 2 to 7 of carbonatoms 2 to 7, the more preferably alkoxyl group of the thiazolinyl of the alkyl of carbonatoms 1 to 5, carbonatoms 2 to 5, carbonatoms 1 to 5 or the alkene oxygen base of carbonatoms 2 to 5, is particularly preferably the alkyl of carbonatoms 1 to 5 or the thiazolinyl of carbonatoms 2 to 5.Thiazolinyl preferred vinyl, 1-propenyl, 3-butenyl or 3-pentenyl, particularly preferably vinyl.
The present invention as the formula (18) prepare compound shown in the concrete formula that is preferably as follows (18a) of intermediate and formula (18b).
In formula, R
6for thiazolinyl, the R of carbonatoms 2 to 12
5for the alkyl of carbonatoms 1 to 12, thiazolinyl, the alkoxyl group of carbonatoms 1 to 12 or the alkene oxygen base of carbonatoms 2 to 12 of carbonatoms 2 to 12.
In formula (17a), R
6concrete is preferably 3-butenyl, 3-pentenyl, 4-pentenyl or 4-hexenyl, more preferably 3-butenyl or 4-pentenyl.
In formula (17b), R
5be preferably thiazolinyl, the alkoxyl group of carbonatoms 1 to 7 or the alkene oxygen base of carbonatoms 2 to 7 of alkyl, the carbonatoms 2 to 7 of carbonatoms 1 to 7, the more preferably alkyl, thiazolinyl, the alkoxyl group of carbonatoms 1 to 5 or the alkene oxygen base of carbonatoms 2 to 5 of carbonatoms 2 to 5 of carbonatoms 1 to 5, the particularly preferably thiazolinyl of the alkyl of carbonatoms 1 to 5 or carbonatoms 2 to 5.Thiazolinyl preferred vinyl, 1-propenyl, 3-butenyl or 3-pentenyl, particularly preferably vinyl.
Embodiment
Below, enumerate embodiment and be described in further detail the present invention, but the present invention is not restricted to these embodiment.The structure of compound, can utilize nucleus magnetic resonance (NMR), and mass spectroscopy (MS) etc. is confirmed.
Utilize following abbreviation to describe compound.
THF: tetrahydrofuran (THF)
DMF:N, dinethylformamide
Me: methyl
Et: ethyl
Bu: butyl
Ph: phenyl
Ms: methane sulfonyl
Reference example
Initial substance of the present invention is compound shown in formula (1), can utilize for example following method preparation.
In formula, R
1and R
2for representing the meaning identical with formula (1), Ms is methane sulfonyl.
Embodiment 1:4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2, synthetic 1 of the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (If)
1-1:3-[4, oneself-4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-1,2-difluorobenzene (Ia) synthetic
Methanesulfonic (4, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo) methyl, 2,3-methylene fluoride sulfonic acid (4, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo) methyl esters 122.9g, 2,3-difluorophenol 49.5g, Tripotassium phosphate 235.4g and DMF 690mL mix, 3 stirrings hour at 80 DEG C.Filter reaction mixture, solid ingredient utilizes DMF to clean, and filters.Merging filtrate adds frozen water, and solid is separated out in leaching, in the mixed solvent of acetic acid ethyl, hexene, toluene, dissolves.Packed in column chromatography, desolventizing is heated up in a steamer in decompression, the refining 3-[4 that obtains 111.6g of residue recrystallize, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-1,2-difluorobenzene (Ia).Compound (Ia), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:366(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.3–2.0(m,19H),3.8–4.0(m,6H),6.4–6.6(m,2H),6.8–7.0(m,1H)
1-2:4-[4, oneself-4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-2,3-difluorophenol (Ig) synthetic
By the 3-[4 of 90g, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-1,2-difluorobenzene (Ia) is dissolved in the THF of 540mL.At Nei Wen-60 DEG C, add secondary BuLi(1.0M tetrahydrobenzene solution) 260mL, stirs 2 hours.At Nei Wen-60 DEG C, add trimethyl borate 29g, be warming up to 20 DEG C.Add 15% hydrogen peroxide 72mL, at 35 DEG C, stir 5 hours.After adding 10% aqueous solution of sodium bisulfite, utilize 10% hydrochloric acid neutralization, divide and get after organic layer, with 400mL methylbenzene extraction water layer, merge organic layer and utilize 10% salt solution 250mL and water 250mL to clean, utilize anhydrous sodium sulfate drying.Desolventizing is heated up in a steamer in decompression, the refining 4-[4 that obtains of residue recrystallize, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-2,3-difluorophenol (Ib) 87.9g.Compound (Ib), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:382(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.3–2.2(m,19H),3.8–4.0(m,6H),4.0–6.0(s,1H),6.3–6.5(m,2H)
1-3:4-[4, oneself-4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ih) synthetic
By bromo-5-1-amylene, 4-[4, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-2,3-difluorophenol (Ig), Tripotassium phosphate and DMF mix, and stir 2 hours at 130 DEG C.Add water, with methylbenzene extraction, after water and saturated aqueous common salt are cleaned organic layer, desolventizing is heated up in a steamer in decompression.Residue utilizes column chromatography and recrystallize to refine, and obtains 4-[4, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ih).Compound (Ih), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:450(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.3–2.2(m,23H),3.8–4.0(m,8H),4.9–5.1(m,2H),5.6–5.8(m,1H),6.3–6.5(m,2H)
1-4:4-(dicyclo oneself-4-ketone-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ii) synthetic
4-[4, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-2, in the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ih), add toluene and formic acid, at 50 DEG C, stir 2 hours.Be cooled to after room temperature, add moisture and get organic layer, utilize methylbenzene extraction water layer.After merging organic layer and utilizing water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt to clean, utilize decompression after anhydrous magnesium sulfate drying to heat up in a steamer desolventizing.Residue recrystallize is refining obtains 4-(dicyclo oneself-4-ketone-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ii).Compound (Ii), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:406(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.6–2.0(m,19H),2.0–2.4(m,4H),3.8–4.0(m,4H),4.9–5.1(m,2H),5.6–5.8(m,1H),6.3–6.5(m,2H)
1-5:4-(anti-, trans-4-formyloxy dicyclo oneself-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ij) synthetic
4-(dicyclo oneself-4-ketone-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ii) and methoxymethyl triphenylphosphine muriate are scattered in THF, the THF solution that adds potassium tert.-butoxide at 0～5 DEG C of interior temperature, stirs 2 hours.After adding water, desolventizing is heated up in a steamer in decompression, adds hexene filtering separation solid ingredient in residue.Filtrate is utilized 50% methanol aqueous solution, and water and saturated aqueous common salt are cleaned, and use anhydrous magnesium sulfate drying.Desolventizing is heated up in a steamer in decompression, adds 10% hydrochloric acid and THF in residue, adds and refluxes 1 hour.Divide and get organic layer, utilize methylbenzene extraction water layer.Merge organic layer and utilize saturated aqueous common salt to clean, with reducing pressure and heat up in a steamer desolventizing after anhydrous sodium sulfate drying.In residue, add triethylamine, THF and methyl alcohol.Then add therein 30% aqueous sodium hydroxide solution, at 5 DEG C, stir 3 hours.After adding water, with 10% hydrochloric acid neutralization, add THF and toluene.Divide and get organic layer, heat up in a steamer desolventizing with decompression after anhydrous magnesium sulfate drying, obtain 4-(anti-, own-the 4 '-yl of trans-4-formyloxy dicyclo) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ij).Compound (Ij), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:420(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.3–2.0(m,23H),2.2–2.4(m,1H),3.8–4.0(m,4H),4.9–5.1(m,2H),5.6–5.8(m,1H),6.4–6.6(m,2H),9.6–9.8(m,1H)
1-6:4-(anti-, trans-4-vinyl dicyclo oneself-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (If) synthetic
Methyl triphenyl phosphine bromide is scattered in THF, adds below potassium tert.-butoxide at 0 DEG C, stirs 30 points of stirrings.Splash into 4-(anti-, own-the 4 '-yl of trans-4-formyloxy dicyclo) methoxyl group-2, the THF solution of the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (Ij), stirs 1 hour.After adding acetone and water, desolventizing is heated up in a steamer in decompression, adds hexene leaching solid ingredient in residue.Filtrate utilizes 50% methanol aqueous solution, water and saturated aqueous common salt to clean, and uses anhydrous magnesium sulfate drying.Desolventizing is heated up in a steamer in decompression, and residue utilizes column chromatography and recrystallize to refine, and obtains 4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (If).Compound (If), as the component parts of liquid-crystal composition of great use.
Embodiment 2:4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2, synthetic 2 of the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (If)
2-1: adopt with the synthetic 3-[4 of the same method of 1-1 in embodiment 1, own-the 4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-1,2-difluorobenzene (Ia).
2-2:3-(dicyclo oneself-4-ketone-4 '-yl) methoxyl group-1,2-difluorobenzene (Ib) synthetic
3-[4, oneself-4 '-yl of 4-(ethylidene dioxy) dicyclo] methoxyl group-1,2-difluorobenzene (Ia) 111g is dissolved in toluene 330mL, stirs 2 hours after adding formic acid 270mL at 50 DEG C.Be cooled to after room temperature, the 200mL that adds water divides and gets organic layer, extracts water layer with toluene 300mL.After merging organic layer, utilize water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt to clean, with reducing pressure and heat up in a steamer desolventizing after anhydrous magnesium sulfate drying.Residue recrystallize is refining obtains 3-(dicyclo oneself-4-ketone-4 '-yl) methoxyl group-1,2-difluorobenzene (Ib) 95g.Compound (Ib), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:322(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.6–2.0(m,15H),2.0–2.4(m,4H),3.8–4.0(m,2H),6.4–6.6(m,2H),6.8–7.0(m,1H)
2-3:3-(anti-, trans-4-formyloxy dicyclo oneself-4 '-yl) methoxyl group-1,2-difluorobenzene (Ic) synthetic
3-(dicyclo oneself-4-ketone-4 '-yl) methoxyl group-1,2-difluorobenzene (Ib) 95g and methoxymethyl triphenylphosphine muriate 132g are scattered in THF650mL, at 0～5 DEG C of interior temperature, add the THF(180mL of potassium tert.-butoxide 44g) solution, stirs 2 hours.Desolventizing is heated up in a steamer in the decompression after 25mL that adds water, and adds hexene 700mL leaching solid ingredient in residue.Filtrate is utilized 50% methanol aqueous solution, and water and saturated aqueous common salt are cleaned, and use anhydrous magnesium sulfate drying.Desolventizing is heated up in a steamer in decompression, adds 10% hydrochloric acid 300mL and THF 400mL, reflux 1 hour in residue.Divide and get organic layer, utilize toluene 300mL to extract water layer.After merging organic layer, utilize saturated aqueous common salt to clean, with reducing pressure and heat up in a steamer desolventizing after anhydrous sodium sulfate drying.In residue, add triethylamine 8mL, THF 250mL and methyl alcohol 400mL.Wherein add again 30% aqueous sodium hydroxide solution 20mL, at 5 DEG C, stir 3 hours.Add water after 600mL with 10% hydrochloric acid neutralization, add THF 300mL and toluene 700mL.Divide and get organic layer, heat up in a steamer desolventizing with decompression after anhydrous magnesium sulfate drying, obtain 3-(anti-, own-the 4 '-yl of trans-4-formyloxy dicyclo) methoxyl group-1,2-difluorobenzene (Ic) 99g.Compound (Ic), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:336(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.3–2.0(m,19H),2.2–2.4(m,1H),3.8–4.0(m,2H),6.4–6.6(m,2H),6.8–7.0(m,1H),9.6–9.8(m,1H)
2-4:3-(anti-, trans-4-vinyl dicyclo oneself-4 '-yl) methoxyl group-1,2-difluorobenzene (Id) synthetic
Methyl triphenyl phosphine bromide 136g is scattered in THF340mL, adds below potassium tert.-butoxide 46g at 0 DEG C, stirs 30 points.Drip 3-(anti-, own-the 4 '-yl of trans-4-formyloxy dicyclo) methoxyl group-1, the THF(200mL of 2-difluorobenzene (Ic) 99g) solution, stirs 1 hour.After adding acetone 15mL and water 15mL, desolventizing is heated up in a steamer in decompression, adds hexene 500mL leaching solid ingredient in residue.Filtrate utilizes 50% methanol aqueous solution, water and saturated aqueous common salt to clean, and uses anhydrous magnesium sulfate drying.Desolventizing is heated up in a steamer in decompression, and residue utilizes column chromatography and recrystallize to refine, and obtains 3-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-1,2-difluorobenzene (Id) 81g.Compound (Id), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:334(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.3–2.2(m,20H),3.8–4.0(m,2H),4.8–5.0(m,2H),5.7–5.9(m,1H),6.4–6.6(m,2H),6.8–7.0(m,1H)
2-5:4-(anti-, trans-4-vinyl dicyclo oneself-4 '-yl) methoxyl group-2,3-difluorophenol (Ie) synthetic
3-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-1,2-difluorobenzene (Id) 39g is dissolved in THF 320mL.At Nei Wen-60 DEG C, add secondary BuLi(0.95M tetrahydrobenzene solution) 196mL, stirs 2 hours.At Nei Wen-60 DEG C, add the THF(42mL of trimethyl borate 21g) solution, be warming up to 0 DEG C.The 7.2mL that adds water adds 30% hydrogen peroxide 34mL after stirring 10 points, stirs 5 hours at 35 DEG C.Add after 10% aqueous solution of sodium bisulfite with 10% hydrochloric acid neutralization, point get organic layer.Utilize 120mL methylbenzene extraction water layer, after merging organic layer, utilize 10% salt solution to clean, utilize anhydrous sodium sulfate drying.Desolventizing is heated up in a steamer in decompression, refining 4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2,3-difluorophenol (Ie) 36g of obtaining of residue recrystallize.Compound (Ie), prepares intermediate of great use as liquid crystalline cpd.
MS m/z:350(M
+)
1H-NMR(60MHz,CDCl
3)
δ:1.3–2.2(m,20H),3.8–4.0(m,2H),4.8–5.0(m,2H),5.7–5.9(m,1H),6.3–6.5(m,2H),4.0–6.0(s,1H)
2-6:4-(anti-, trans-4-vinyl dicyclo oneself-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (If) synthetic
The bromo-1-amylene of 5-, 4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2,3-difluorophenol (Ie), Tripotassium phosphate and DMF mix, and stir 2 hours at 130 DEG C.Add water, utilize methylbenzene extraction, after organic layer utilizes water and saturated aqueous common salt to clean, desolventizing is heated up in a steamer in decompression.Residue utilizes column chromatography and recrystallize to refine, and obtains 4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2, the fluoro-1-of 3-bis-(4-amylene oxygen) benzene (If).Compound (If), as the formation portion material of liquid-crystal composition of great use.
Phase inversion temperature: C 75.6 N 195.2 I
MS m/z:418(M
+)
1H-NMR(400MHz,CDCl
3)
δ:0.95–1.15(m,10H),1.65–2.00(m,12H),2.20–2.30(m,2H),3.76(d,J=6.4Hz,2H),3.98(t,J=6.8Hz,2H),4.87(d,J=10.0Hz,1H),4.95(d,J=17.2Hz,1H),5.00(d,J=10.4Hz,1H),5.05(d,J=17.2Hz,1H),5.77(ddd,J=17.2Hz,J=10.4Hz,J=6.4Hz,1H),5.84(ddt,J=16.8Hz,J=13.6Hz,J=6.8Hz,1H),6.55–6.65(m,2H)
Embodiment 3:4-(anti-, trans-4-vinyl dicyclo oneself-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(3-butylene oxygen) benzene (IIf) synthetic
In embodiment 1 or 2, replace the bromo-1-amylene of 5-to use the bromo-1-butylene of 4-, carry out same reaction, obtain 4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2, the fluoro-1-of 3-bis-(3-butylene oxygen) benzene (IIf).
Phase inversion temperature C 64.5 N 119.5 I
MS m/z:404(M
+),55(100)
1H-NMR(400MHz,CDCl
3)
δ:0.95-1.15(m,10H),1.65-2.00(m,10H),2.50–2.60(m,2H),3.76(d,J=6.4Hz,2H),4.03(t,J=6.8Hz,2H),4.80–5.30(m,4H),5.79(ddd,J=17.2Hz,J=10.4Hz,J=6.4Hz,1H),5.83–5.95(m,1H),6.55–6.70(m,2H)
Embodiment 4:4-(anti-, trans-4-vinyl dicyclo oneself-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(trans-4-ethyl cyclohexyl) anisole (IIIf) synthetic
In embodiment 1 or 2, replace the bromo-1-amylene of 5-to use trans-4-(ethyl cyclohexyl) monobromethane, carry out same reaction, obtain 4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2, the fluoro-1-of 3-bis-(trans-4-ethyl cyclohexyl) anisole (IIIf).
Phase inversion temperature C 94.1 N 197.5 I
MS m/z:474(M
+),146(100)
1H-NMR(400MHz,CDCl
3)
δ:0.88(t,J=7.2Hz,3H),0.90–1.30(m,17H),1.65–2.00(m,15H),3.70–3.80(m,4H),4.80–5.00(m,2H),5.77(ddd,J=16.8Hz,J=10.4Hz,J=6.4Hz,1H),6.59(d,J=5.6Hz,2H)
Embodiment 5:4-(anti-, trans-4-vinyl dicyclo oneself-4 '-yl) methoxyl group-2, the fluoro-1-of 3-bis-(trans-4-vinyl cyclohexyl) anisole (IVf) synthetic
In embodiment 1 or 2, replace the bromo-1-amylene of 5-to use the trans-4-of methanesulfonic (vinyl cyclohexyl) methyl, carry out same reaction, obtain 4-(anti-, own-the 4 '-yl of trans-4-vinyl dicyclo) methoxyl group-2, the fluoro-1-of 3-bis-(trans-4-vinyl cyclohexyl) anisole (IVf).
Phase inversion temperature C 86.5 N 205.8 I
MS m/z:472(M
+),146(100)
1H-NMR(400MHz,CDCl
3)
δ:0.95–1.25(m,14H),1.65–2.00(m,16H),3.77(t,J=7.2Hz,4H),4.85–5.05(m,4H),5.70–5.85(m,2H),6.60(d,J=5.6Hz,2H)
Industrial utilizability
The inventive method as the preparation method of liquid crystalline cpd of great use.Compound of the present invention is prepared intermediate also of great use as liquid crystalline cpd in addition.
Claims (2)
1. suc as formula a compound shown in (3),
2. suc as formula a compound shown in (4),
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