JPH01125344A - Production of 2, 5-bis (2, 2, 2-trifluoroethoxy)benzoate - Google Patents
Production of 2, 5-bis (2, 2, 2-trifluoroethoxy)benzoateInfo
- Publication number
- JPH01125344A JPH01125344A JP63135370A JP13537088A JPH01125344A JP H01125344 A JPH01125344 A JP H01125344A JP 63135370 A JP63135370 A JP 63135370A JP 13537088 A JP13537088 A JP 13537088A JP H01125344 A JPH01125344 A JP H01125344A
- Authority
- JP
- Japan
- Prior art keywords
- bis
- trifluoroethoxy
- mixture
- benzene
- compd
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims 2
- YPGYLCZBZKRYQJ-UHFFFAOYSA-M 2,5-bis(2,2,2-trifluoroethoxy)benzoate Chemical compound [O-]C(=O)C1=CC(OCC(F)(F)F)=CC=C1OCC(F)(F)F YPGYLCZBZKRYQJ-UHFFFAOYSA-M 0.000 title 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims abstract description 12
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 alkali metal 2,2,2-trifluoroethoxide Chemical class 0.000 claims abstract description 4
- 239000011968 lewis acid catalyst Substances 0.000 claims abstract description 4
- ZHUBFESHPMGIDZ-UHFFFAOYSA-N 1,4-bis(2,2,2-trifluoroethoxy)benzene Chemical compound FC(F)(F)COC1=CC=C(OCC(F)(F)F)C=C1 ZHUBFESHPMGIDZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- CUKRFIGOPWVJGQ-UHFFFAOYSA-N 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]ethanone Chemical compound CC(=O)C1=CC(OCC(F)(F)F)=CC=C1OCC(F)(F)F CUKRFIGOPWVJGQ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 3
- YPGYLCZBZKRYQJ-UHFFFAOYSA-N 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid Chemical compound OC(=O)C1=CC(OCC(F)(F)F)=CC=C1OCC(F)(F)F YPGYLCZBZKRYQJ-UHFFFAOYSA-N 0.000 claims abstract 2
- 230000000397 acetylating effect Effects 0.000 claims abstract 2
- 239000002798 polar solvent Substances 0.000 claims abstract 2
- 150000002500 ions Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 3
- MFWASTQSJSBGNG-UHFFFAOYSA-N 2,2,2-trifluoroethoxybenzene Chemical compound FC(F)(F)COC1=CC=CC=C1 MFWASTQSJSBGNG-UHFFFAOYSA-N 0.000 claims 1
- WMADYFXBXCQPHL-UHFFFAOYSA-N 2,3-bis(2,2,2-trifluoroethoxy)benzoic acid Chemical compound OC(=O)C1=CC=CC(OCC(F)(F)F)=C1OCC(F)(F)F WMADYFXBXCQPHL-UHFFFAOYSA-N 0.000 claims 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims 1
- DJBNUMBKLMJRSA-UHFFFAOYSA-N Flecainide Chemical compound FC(F)(F)COC1=CC=C(OCC(F)(F)F)C(C(=O)NCC2NCCCC2)=C1 DJBNUMBKLMJRSA-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003416 antiarrhythmic agent Substances 0.000 abstract description 3
- 229960000449 flecainide Drugs 0.000 abstract description 3
- 239000012345 acetylating agent Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 abstract 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 abstract 1
- 230000002152 alkylating effect Effects 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 238000005660 chlorination reaction Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- OAMHTTBNEJBIKA-UHFFFAOYSA-N 2,2,2-trichloro-1-phenylethanone Chemical compound ClC(Cl)(Cl)C(=O)C1=CC=CC=C1 OAMHTTBNEJBIKA-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 4
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000008062 acetophenones Chemical class 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- RKXNZRPQSOPPRN-UHFFFAOYSA-N flecainide acetate Chemical compound CC(O)=O.FC(F)(F)COC1=CC=C(OCC(F)(F)F)C(C(=O)NCC2NCCCC2)=C1 RKXNZRPQSOPPRN-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 229910001504 inorganic chloride Inorganic materials 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- RHPBLLCTOLJFPH-UHFFFAOYSA-N piperidin-2-ylmethanamine Chemical compound NCC1CCCCN1 RHPBLLCTOLJFPH-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CERJZAHSUZVMCH-UHFFFAOYSA-N 2,2-dichloro-1-phenylethanone Chemical compound ClC(Cl)C(=O)C1=CC=CC=C1 CERJZAHSUZVMCH-UHFFFAOYSA-N 0.000 description 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- GWESVXSMPKAFAS-UHFFFAOYSA-N Isopropylcyclohexane Natural products CC(C)C1CCCCC1 GWESVXSMPKAFAS-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- JYVSZCNTYXUUGH-UHFFFAOYSA-N acetic acid;benzamide Chemical compound CC(O)=O.NC(=O)C1=CC=CC=C1 JYVSZCNTYXUUGH-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical group CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 1
- 229940076286 cupric acetate Drugs 0.000 description 1
- 229960003670 flecainide acetate Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
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Abstract
Description
【発明の詳細な説明】
本発明は抗不整脈剤2.5−ビス(2,2,2=トリフ
ルオロエトキシ)−N−(2−ピペリジルメチル)ヘン
ザミド〔フレカイニド(flecainide))及び
その塩のブロモ−又はヒドロキシ−置換ベンゼンからの
改良された製造における中間体化合物2.5−ビス(2
,2,2−)リフルオロエトキシ)安息香酸の製造方法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the antiarrhythmic agent 2,5-bis(2,2,2=trifluoroethoxy)-N-(2-piperidylmethyl)henzamide (flecainide) and its salts. Intermediate compound 2.5-bis(2
, 2,2-)rifluoroethoxy)benzoic acid.
抗不整脈性化合物即ちフレカイニド及びその塩並びにそ
の製造方法は米国特許第3900481号明細書に記載
されている。該化合物の化学構造は下式の通りである;
本発明方法は上記の従前技術の方法に比し種々の実用上
の諸利益例えば出発物質が比較的に廉価であること、単
位操作の実施が容易であること及び所望製品の収率が比
較的に高いことにもとづき好適な方法である。Antiarrhythmic compounds, flecainide and its salts, and methods for their preparation are described in US Pat. No. 3,900,481. The chemical structure of the compound is: This is the preferred method due to its ease and relatively high yield of the desired product.
詳細には本発明は下記の諸工程を包含する:(1)式
〔但しX(複〕は同じであってOH及びBrから選ばれ
る〕
の化合物を適宜の下式
%式%
〔但しAは−5O2CF3又はアルカリ金属である〕
のアルキル化剤と反応させて式
の化合物をつくり、
(2) この化合物をルイス酸(Lewis aci
d )触媒の存在下にアセチル化して式
の1mアセトフェノンをつくり、
(31(al 該置換アセトフェノンをクロル化して
下式の対応するα、αジクロロアセトフェノンをっ(す
、そして
fbl 緩衝用塩基を加えて更にクロル化することに
より式
のα、α、α−トリクロロアセトフェノンをつくり、又
は別法として
(c) 該置換アセトフェノンを次亜塩素酸塩と反応
させて式
の対応する安息香酸化合物をつ(す、そして((fl
この酸化合物を無機性塩化物と反応させて式
の酸塩化物をつくり、次に
(4)上記工程3(b)又は3(d)の生成物を夫々2
−(アミノメチル)ヒペリジンと反応させることによリ
ー工程で所望の製品をつくるか、或は2−(アミノメチ
ル)ピリジンと反応させてから還元することにより所望
製品をつくるか、もしくは任意に遊離塩基としての所望
製品をつくる。Specifically, the present invention includes the following steps: (1) A compound of the formula [wherein -5O2CF3 or an alkali metal] to form a compound of the formula;
d) acetylate in the presence of a catalyst to form a 1m acetophenone of the formula (31(al), chlorinate the substituted acetophenone to form the corresponding α,α dichloroacetophenone of the formula (31(al), and add fbl a buffer base. and further chlorination to produce the α,α,α-trichloroacetophenone of the formula, or alternatively (c) reacting the substituted acetophenone with hypochlorite to form the corresponding benzoic acid compound of the formula ( So, and ((fl
This acid compound is reacted with an inorganic chloride to form an acid chloride of formula, and then (4) the product of step 3(b) or 3(d) above is converted into 2
- (aminomethyl)hyperidine to form the desired product in a Lee step, or reaction with 2-(aminomethyl)pyridine followed by reduction to form the desired product, or optionally free Create the desired product as a base.
上記の諸工程(11,(11−+21 ; (31(a
) ; (3Hc) ; (1)、 (21及び[31
fc) ; (31(b) ; (31(al及びf3
Hb)、並びに(4)の諸工程を含む諸方法は下式の中
間化合物類:〔但しBは−CH3+ CHCj2 z
及びCC7!3から選ばれる〕の製造に関する包括的発
明の別の特徴的諸態様を構成する。The above steps (11, (11-+21; (31(a)
) ; (3Hc) ; (1), (21 and [31
fc); (31(b); (31(al and f3
Hb), and methods including the steps (4) are intermediate compounds of the following formula: [where B is -CH3+ CHCj2 z
and CC7!3] constitutes another characteristic aspect of the generic invention.
本発明の包括的方法の反応順序を下式に示す:本性の第
1工程においてXがOHである場合にはAは好ましくは
−S O2CF 3であって反応体(複)は溶媒例えば
アセトン又はN、N−ジメチルホルムアミド中で、塩基
例えばアルカリ金属炭酸塩、好ましくは例えば炭酸カリ
又は炭酸ソーダの如き弱塩基の存在下に、−緒に加熱さ
れる。The reaction sequence of the generic process of the invention is shown below: In the essential first step, when X is OH, A is preferably -S O2CF3 and the reactants are a solvent such as acetone or The mixture is heated in N,N-dimethylformamide in the presence of a base such as an alkali metal carbonate, preferably a weak base such as potassium carbonate or soda carbonate.
上記のXがBrである場合には、1.4−ジブロモベン
ゼン(1)と、2,2.2−)リフルオロエトキシドイ
オンとを、強度に極性の混合溶媒中で、この溶液の還流
温度未満の温度の下に、第1銅イオン又は第2銅イオン
の存在下に反応させることにより好収率で所望生成物(
I[)をつくる。When the above X is Br, 1,4-dibromobenzene (1) and 2,2,2-)lifluoroethoxide ion are mixed in a strongly polar mixed solvent, and the solution is refluxed. The desired product (
Create I[).
2.2.2−)リフルオロエトキシドイオンを得るには
対応アルコールを強塩基例えばカセイソーダ又は好適に
は水素化ナトリウムと反応させる。2.2.2-) To obtain the refluoroethoxide ion, the corresponding alcohol is reacted with a strong base, such as caustic soda or preferably sodium hydride.
好適な混合溶媒にはジメチルスルホキシド、N。Suitable mixed solvents include dimethyl sulfoxide, N.
N−ジメチルアセタミド及び好適物としてN、 N−ジ
メチルホルムアミドの夫々と約10〜50%、好ましく
は約20%の2.2.2−)リフルオロエタノールとの
混合物が包括される。第1銅イ第ンは例えばハロゲン化
第1銅例えばヨウ化第1銅又は臭化第1銅によって供給
される。第2銅イオンは例えば臭化第2銅、硫酸第2銅
又は酢酸第2銅によって供給される。Included are N-dimethylacetamide and, suitably, mixtures of each of N,N-dimethylformamide with about 10-50%, preferably about 20%, of 2.2.2-) refluoroethanol. Cuprous ions are provided, for example, by cuprous halides such as cuprous iodide or cuprous bromide. Cupric ions are provided, for example, by cupric bromide, cupric sulfate or cupric acetate.
工程(2)においては1,4−ビス(2,2,2−トリ
フルオロエトキシ)−ベンゼン(■) 〔このものは工
程(1)で生成される〕を穏和な条件下にルイス酸触媒
例えば塩化スズ、塩化第2鉄又は好ましくは塩化アルミ
ニウムの存在下でアセチル化剤例えば塩化アセチル又は
無水酢酸と反応させることによってアセチル化する。こ
のアセチル化を適宜の不反応性溶媒例えばクロル化炭化
水素例えばジクロロメタン、トリクロロエチレン又は1
.2−ジクロロエタン、ジエチルエーテル、テトラヒド
ロフラン及び類似物中で行う。この反応により所望のア
セトフェノン(I[[)が高収率で提供されることは予
測外のことである。In step (2), 1,4-bis(2,2,2-trifluoroethoxy)-benzene (■) [which is produced in step (1)] is heated under mild conditions with a Lewis acid catalyst such as Acetylation is carried out by reaction with an acetylating agent such as acetyl chloride or acetic anhydride in the presence of tin chloride, ferric chloride or preferably aluminum chloride. This acetylation is carried out using a suitable non-reactive solvent such as a chlorinated hydrocarbon such as dichloromethane, trichloroethylene or
.. Worked in 2-dichloroethane, diethyl ether, tetrahydrofuran and the like. It is unexpected that this reaction provides the desired acetophenone (I[[) in high yield.
工程+31 (a)の反応は適宜の溶媒例えば酢酸エチ
ル、塩素化炭化水素中で、又は好ましくは酢酸溶液中で
の中間体(III)の単純なりロル化である。この反応
を中等度の温度好ましくは50〜60℃で行う。Step +31 The reaction of (a) is a simple chlorination of intermediate (III) in a suitable solvent such as ethyl acetate, a chlorinated hydrocarbon or preferably in an acetic acid solution. The reaction is carried out at a moderate temperature, preferably 50-60°C.
所望により生成物(IV)を単離し得る。或は工程+3
1 (b)におけるようにクロル化を行い、該クロル化
を継続しながら緩衝剤例えば酢酸ナトリウムの如き酢酸
塩を添加して温度を僅かに、例えば80〜100℃にま
で上昇させることにより中間体(V)を得る。Product (IV) can be isolated if desired. Or process +3
The intermediate can be prepared by carrying out the chlorination as in 1(b) and, while continuing the chlorination, adding a buffer, e.g. an acetate salt such as sodium acetate, and raising the temperature slightly, e.g. (V) is obtained.
工程(31(c)の反応は、アルカリ金属水酸化物又は
アルカリ土金属水酸化物(例えばカセイソーダ、カセイ
カリ或は水酸化カルシウム)の冷溶液に塩酸を飽和させ
てp)17としたもの(対応する次亜塩素酸塩を形成)
に対しアセトフェノン(I)を添加することにより最も
便利に遂行される。この反応は反応混合物を加温するこ
とによって促進される。所望の2.5−ビス(2,2,
2−1−リフルオロエトキシ)安息香酸(VI)が著し
い高収率で得られる。The reaction of step (31(c)) consists of saturating a cold solution of an alkali metal hydroxide or alkaline earth metal hydroxide (e.g. caustic soda, caustic potash or calcium hydroxide) with hydrochloric acid to give p) 17 (corresponding (forms hypochlorite)
This is most conveniently accomplished by adding acetophenone (I) to the reaction mixture. This reaction is accelerated by warming the reaction mixture. desired 2.5-bis(2,2,
2-1-Lifluoroethoxy)benzoic acid (VI) is obtained in significantly higher yields.
工程(31fdlにおいて上記の酸を対応するアシルク
ロリドに転化させるがこの転化は適宜の不反応性溶媒例
えばベンゼン又はトルエン或はハロゲン化炭化水素の存
在下又は不在下に無機性塩化物例えば塩化チオニル、三
塩化リン又は五塩化リン(好ましくは三塩化リン)と核
酸との還流下の反応による。Step (31fdl) converts the acid described above to the corresponding acyl chloride, which is carried out using an inorganic chloride such as thionyl chloride, in the presence or absence of a suitable non-reactive solvent such as benzene or toluene or a halogenated hydrocarbon. By reaction of phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride) with a nucleic acid under reflux.
工程(4)の方法は飽和ジアミン2−(アミノエチル)
ピペリジンから直接的に、又は非還元ジアミン2−(ア
ミノエチル)ピリジンから間接的に遂行され得る。即ち
2−アミノメチルピペリジンをトリクロロアセトフェノ
ン〔工程(31fb)の生成物〕と反応させることがで
きるし、或は化合物2−アミノメチルピリジンをトリク
ロロアセトフェノン〔工程(3) (blの生成物(■
)〕と反応させることができる。いずれの場合にも外部
から加熱することな(不反応性溶媒例えばトルエン、ベ
ンゼン、イソプロピルアルコール、シクロヘキサン及び
類似物中で該反応は容易に進行する。非還元ジアミンを
トルエンとシクロヘキサンとの混合物中で反応させると
反応は特に容易にしかも高収率で進行する。The method of step (4) is to use saturated diamine 2-(aminoethyl)
It can be accomplished directly from piperidine or indirectly from the non-reduced diamine 2-(aminoethyl)pyridine. That is, 2-aminomethylpiperidine can be reacted with trichloroacetophenone [product of step (31fb)], or the compound 2-aminomethylpyridine can be reacted with trichloroacetophenone [product of step (3) (bl) (■
)]. The reaction proceeds readily in non-reactive solvents such as toluene, benzene, isopropyl alcohol, cyclohexane and the like, in both cases without external heating. When allowed to react, the reaction proceeds particularly easily and in high yields.
工程(31fdlの生成物である酸塩化物(■)を出発
物質として最終工程の方法を遂行する際にこの方法は2
−(アミノメチル)ピペリジンから直接的に、又は2−
(アミノメチル)ピリジンから間接的にも遂行される。Step (2) When carrying out the final step method using the acid chloride (■), which is the product of 31fdl, as a starting material,
-(aminomethyl)piperidine directly or 2-
It is also accomplished indirectly from (aminomethyl)pyridine.
酸塩化物〔工程(31fdlの生成物〕を不反応性溶媒
例えばグリム(glyme ) 、ベンゼン、トルエン
又はジエチルエーテル(好ましくはグリム)中で加熱し
て反応させる。或は別法として2−アミノメチルピリジ
ンと酸塩化物〔工程(3)(d+の生成物〕とを不反応
性溶媒例えばトルエン又はベンゼンの存在下に反応させ
ることができる。The acid chloride [product of 31 fdl] is reacted by heating in a non-reactive solvent such as glyme, benzene, toluene or diethyl ether (preferably glyme). Alternatively, 2-aminomethyl Pyridine and the acid chloride [step (3) (product of d+)] can be reacted in the presence of a non-reactive solvent such as toluene or benzene.
この混合物を酸受容体(例えばトリエチルアミンの如き
第3級アミン)の存在下で還流温度に加熱する。化合物
(V)又は(■)のいずれかと2−(アミノメチル)ピ
リジンとの反応から得られた付加物を酸化白金又は(好
ましくは)炭素上白金の存在下に接触的に水素化するこ
とにより所望製品■へ還元する。この反応に使用される
溶媒はメタノール又は低級アルカン酸例えば(そして好
ましくは)氷酢酸であって好適温度範囲は15〜30℃
である。酢酸使用の際に得られる製品はフレカイニドア
セテートである。This mixture is heated to reflux temperature in the presence of an acid acceptor (eg, a tertiary amine such as triethylamine). By catalytically hydrogenating the adduct obtained from the reaction of either compound (V) or (■) with 2-(aminomethyl)pyridine in the presence of platinum oxide or (preferably) platinum on carbon. Return to desired product ■. The solvent used in this reaction is methanol or a lower alkanoic acid such as (and preferably) glacial acetic acid, and the preferred temperature range is 15-30°C.
It is. The product obtained when acetic acid is used is flecainide acetate.
下記の諸例は本発明の諸方法と該方法における中間体製
品類の製法とを例示するが上記の本発明の範囲の限定を
企図するものではない。The following examples illustrate the methods of the invention and the preparation of intermediate products therein, but are not intended to limit the scope of the invention described above.
■−1(参考例)
工程(1)ノ 法: A = S Oz CF 3
、 X = OHアセトン1.02 A中の2.42モ
ル(334,4g)炭酸カリ、2.2モル(510,6
g)の2. 2. 2−トリフルオロエチルトリフルオ
ロメタンスルホネートに対し1.11のアセトン中1.
0モル(110g)のヒドロキノンを2時間以上かけて
徐々に添加した。次に反応物を還流下に24時間加熱し
てから反応混合物を蒸発し、残留物に対し21のクロロ
ホルムと21の水とを加えた。クロロホルム層を分別し
、水層を17+のクロロホルムで2回洗い、クロロホル
ム溶液を合併してこれを11の水で洗った。クロロホル
ム溶液を硫酸マグネシウム上で乾燥してから真空下に濃
縮した。残留物にヘキサンを加えて固体生成物を濾過に
より集めヘキサンで洗った。濃縮残留物から追加の物質
を集めた。1.4−ビス(2,2,2−1−リフルオロ
エトキシ)ベンゼン(融点75〜77°C)の241g
、収率88%、が得られた。■-1 (Reference example) Process (1) Method: A = S Oz CF 3
, X = 2.42 mol (334,4 g) potassium carbonate in OH acetone 1.02 A, 2.2 mol (510,6
g) 2. 2. 1.1 in acetone for 2-trifluoroethyl trifluoromethanesulfonate.
0 mole (110 g) of hydroquinone was added slowly over 2 hours. The reaction was then heated under reflux for 24 hours before the reaction mixture was evaporated and 21 parts of chloroform and 21 parts of water were added to the residue. The chloroform layer was separated, the aqueous layer was washed twice with 17+ chloroform, and the chloroform solution was combined and washed with 11+ water. The chloroform solution was dried over magnesium sulfate and then concentrated under vacuum. Hexane was added to the residue and the solid product was collected by filtration and washed with hexane. Additional material was collected from the concentrated residue. 1.241 g of 4-bis(2,2,2-1-lifluoroethoxy)benzene (melting point 75-77°C)
A yield of 88% was obtained.
N、N−ジメチルホルムアミド40m7!中の0.20
モル(9,6g)(7350%水素化ナトリウムに対し
40m1の2.2.2−)リフルオロエタノールを加え
てから0.034モル(8,0g)の1゜4−ジブロモ
ベンゼンと0.006モル(1,0g)のヨウ化第1銅
とを加えた。この混合物をその還流温度に4時間加熱し
てから約25°Cにまで冷却して濾過した。残留物をN
、N−ジメチルホルムアミドで洗った。溶液を水中へ注
ぎ沈殿を濾別した。生成物をジエチルエーテルに熔かし
て濾過し、濾液を蒸発して生成させた固形残留物をヘキ
サンで洗って乾燥した。生成物は1,4−ビス(2゜2
.2−)リフルオロエトキシ)ベンゼン(融点77〜7
9℃)の7.3g(80%)である。N,N-dimethylformamide 40m7! 0.20 inside
mol (9.6 g) (40 ml of 2.2.2- to 7350% sodium hydride) is added, then 0.034 mol (8.0 g) of 1°4-dibromobenzene and 0.006 moles (1.0 g) of cuprous iodide were added. The mixture was heated to its reflux temperature for 4 hours, then cooled to about 25°C and filtered. The residue is N
, N-dimethylformamide. The solution was poured into water and the precipitate was filtered off. The product was dissolved in diethyl ether and filtered, and the filtrate was evaporated to form a solid residue, which was washed with hexane and dried. The product is 1,4-bis(2゜2
.. 2-)Lifluoroethoxy)benzene (melting point 77-7
7.3g (80%) of 9°C).
使用成分の条件と比率とを変更すると共に触媒として臭
化第2銅を用いて上記の反応を次のようにして百行した
: 40mj2のN、 N−ジメチルホルムアミド中の
4.8gの水素ナトリウム混合物に対し20mj!
(27,4g)の2.2.2−)リフルオロエタノール
を加えた。この混合物に0.034モル(8,Og)の
1,4−ジブロモベンゼンと1.0gの臭化第2銅とを
加えた。反応混合物を約100℃に2時間加熱してから
氷水で急冷した。The above reaction was carried out using cupric bromide as a catalyst, varying the conditions and proportions of the components used, as follows: 4.8 g of sodium hydrogen in 40 mj2 of N, N-dimethylformamide. 20 mj for the mixture!
(27.4 g) of 2.2.2-)lifluoroethanol was added. To this mixture was added 0.034 moles (8,0g) of 1,4-dibromobenzene and 1.0 g of cupric bromide. The reaction mixture was heated to about 100° C. for 2 hours and then quenched with ice water.
塩酸で酸性化して濾過すると9.2g(99%)の白色
固体の1,4−ビス(2,2,2−)リフルオロエトキ
シ)−ベンゼンを生成した。化学構造を赤外線スペクト
ル分析により確認した。Acidification with hydrochloric acid and filtration produced 9.2 g (99%) of 1,4-bis(2,2,2-)lifluoroethoxy)-benzene as a white solid. The chemical structure was confirmed by infrared spectroscopy.
例3
工程(2)ニアセチル化剤として無水酢 使用ジクロロ
メタン648mA中の2.43モル(324g)の塩化
アルミニウムの混合物に対し880mAのジクロロメタ
ン中の0.88モル(274g)の1.4−ビス(2,
2,2−)リフルオロエトキシ)ベンゼンと0.97モ
ル(92ml)の無水酢酸との溶液を3時間以上かけて
温度約O′Cに保ちながら加えた。次に反応混合物を還
流温度にまで加熱して還流下に5時間攪拌した。反応の
進行状態を薄層クロマトグラフィ使用によって追跡した
。Example 3 Step (2) Anhydrous vinegar as niacetylating agent used A mixture of 2.43 moles (324 g) of aluminum chloride in 648 mA of dichloromethane and 0.88 moles (274 g) of 1,4-bis( 2,
A solution of 2,2-)lifluoroethoxy)benzene and 0.97 mol (92 ml) of acetic anhydride was added over 3 hours while maintaining the temperature at about O'C. The reaction mixture was then heated to reflux temperature and stirred under reflux for 5 hours. The progress of the reaction was followed using thin layer chromatography.
反応混合物を水浴及び氷の中に置き10%塩酸を徐々に
加えて塩化アルミニウム錯体を分解した。The reaction mixture was placed in a water bath and ice, and 10% hydrochloric acid was gradually added to decompose the aluminum chloride complex.
反応混合物の温度を25℃以上に上昇させないようにし
た。有機相を分別し21の10%塩酸で一回洗い、次に
21の水で洗った。水相を合併し数リットルのジクロロ
メタンでこれを抽出した。有機相を硫酸マグネシウム上
で乾燥してから蒸発して湿潤残留物を得た。この残留物
にヘキサンを加えて得られた固体を濾過により集めヘキ
サンで洗った。乾燥すると250gの淡黄色結晶状の2
゜5−ビス(2,2,2−)リフルオロエトキシ)アセ
トフェノンが得られた。融点84〜86℃、収率90%
である。The temperature of the reaction mixture was not allowed to rise above 25°C. The organic phase was separated and washed once with 21 portions of 10% hydrochloric acid and then with 21 portions of water. The aqueous phases were combined and extracted with several liters of dichloromethane. The organic phase was dried over magnesium sulfate and then evaporated to give a wet residue. Hexane was added to this residue, and the resulting solid was collected by filtration and washed with hexane. When dried, 250g of pale yellow crystalline 2
5-bis(2,2,2-)lifluoroethoxy)acetophenone was obtained. Melting point 84-86℃, yield 90%
It is.
例4
と8.8+2のジクロロメタンとの0℃での混合物に対
し1.3/のジクロロメタン中の3.267 gの1゜
4へビス(2,2,2−1リフルオロエトキシ)ベンゼ
ン及び1.399kg (13,7干ル)の無水酢酸の
溶液を漸次に加えた。反応温度を5〜10℃に維持しな
がら混合物を約16時間撹拌した。次に反応混合物をそ
の還流温度にまで加熱して還流下に4時間保持した。次
に8.76 kgの10%塩酸を使用して該反応混合物
を酸性化した。この混合物に氷を加えて温度を20℃以
下に保持した。有機層を分別し水層をジクロロメタンで
数回抽出した。有機層を乾燥してから蒸発して得られた
残留物をヘキサンで細砕すると黄色固体生成物を与えた
。この生成物の2回にわたる収得物の全収量は3.08
8kgの2,5−ビス(2,2,2−トリフルオロエト
キシ)アセトフェノン(融点84〜88℃、収率82%
)であった。Example 4 3.267 g of 1°4 hebis(2,2,2-1-lifluoroethoxy)benzene in 1.3/dichloromethane and 1° A solution of .399 kg (13.7 liters) of acetic anhydride was added gradually. The mixture was stirred for about 16 hours while maintaining the reaction temperature at 5-10°C. The reaction mixture was then heated to its reflux temperature and kept under reflux for 4 hours. The reaction mixture was then acidified using 8.76 kg of 10% hydrochloric acid. Ice was added to the mixture to maintain the temperature below 20°C. The organic layer was separated and the aqueous layer was extracted several times with dichloromethane. The organic layer was dried and the resulting residue was triturated with hexane to give a yellow solid product. The total yield of this product over two harvests was 3.08
8 kg of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (melting point 84-88°C, yield 82%)
)Met.
塩化アルミニウムの0.022モル(2,8g)と1.
2−ジクロロエタンの100m6と混合物に対し、0.
020モル(5,6g)の1,4−ビス(2,2,2−
)リフルオロエトキシ)ベンゼンと0.022モル(1
,7g)の塩化アセチルとの1゜2−ジクロロエタン(
20mA’)中溶液を25℃で滴下して加えた。4時間
攪拌の後に反応混合物を氷水及び塩酸で洗い有機層を乾
燥した。蒸発して得られた残留物をヘキサンから再結す
ると4.1g(71%)の希黄色針状の2,5−ビス(
2゜2、 2−)リフルオロエトキシ)アセトフェノン
(赤外線スペクトル分析により確証)を与えた。0.022 mol (2.8 g) of aluminum chloride and 1.
For 100 m6 of 2-dichloroethane and a mixture, 0.
020 moles (5,6 g) of 1,4-bis(2,2,2-
) trifluoroethoxy) benzene and 0.022 mol (1
, 7 g) of acetyl chloride in 1°2-dichloroethane (
The solution in 20 mA') was added dropwise at 25°C. After stirring for 4 hours, the reaction mixture was washed with ice water and hydrochloric acid, and the organic layer was dried. The residue obtained by evaporation was recrystallized from hexane to yield 4.1 g (71%) of pale yellow needles of 2,5-bis(
2°2,2-)lifluoroethoxy)acetophenone (corroborated by infrared spectroscopy) was given.
■−エ(参考例)
工程(31(al
酢酸150m#中の0.25モル(79,1g)の2.
5−ビス(2,2,2−)リフルオロエトキシ)アセト
フェノンの混合物を50℃に加熱し、この溶液中へ塩素
ガスを泡沸させて導入し温度を漸次に55℃にまで増加
させた。塩素添加速度を調整して55〜60℃の温度を
維持するようにした。約75分の後に温度は減少し始め
た(これはもはや塩素化が行われていないことを示す)
。塩素の全添加量は35.5 gであった。得られた生
成物は2.5−ビス(2,2,2−)リフルオロエトキ
シ)−α、α−ジクロロアセトフェノンである。(1)-E (Reference Example) Step (31) 0.25 mol (79.1 g) of 2.
A mixture of 5-bis(2,2,2-)lifluoroethoxy)acetophenone was heated to 50°C, chlorine gas was bubbled into the solution and the temperature was gradually increased to 55°C. The chlorine addition rate was adjusted to maintain a temperature of 55-60°C. After about 75 minutes the temperature began to decrease (indicating that chlorination was no longer occurring)
. The total amount of chlorine added was 35.5 g. The product obtained is 2,5-bis(2,2,2-)lifluoroethoxy)-α,α-dichloroacetophenone.
例 7(参考例)
工程(9)剋
前記の例6の生成物(単離せず又は純化せず)に対し0
.35モル(28,7g)の酢酸ナトリウムを加えた。Example 7 (Reference Example) Step (9) 0 for the product of Example 6 above (not isolated or purified)
.. 35 mol (28.7 g) of sodium acetate were added.
温度は約80℃にまで上昇し、この溶液を85℃にまで
加熱した。塩素添加を継続して温度を100℃にまで上
昇させる。約20分の後に理論量の塩素が消費され、こ
の混合物を氷と水との混合物中へ注入した。生成沈殿を
濾過によって集め、水ですすぎ、ジクロロメタン中に溶
かして乾燥した。蒸発して得られた残留物をヘキサン使
用下に微細化して白色固体を得た。収量94g(90%
)の2.5−ビス(2,2,2−)リフルオロエトキシ
)α、α、α−トリクロロアセトフェノン(融点45〜
48°C)が得られた。The temperature rose to about 80°C and the solution was heated to 85°C. Continue adding chlorine and increase the temperature to 100°C. After about 20 minutes the theoretical amount of chlorine was consumed and the mixture was poured into a mixture of ice and water. The resulting precipitate was collected by filtration, rinsed with water, dissolved in dichloromethane and dried. The residue obtained by evaporation was micronized using hexane to obtain a white solid. Yield 94g (90%
) of 2,5-bis(2,2,2-)trifluoroethoxy)α,α,α-trichloroacetophenone (melting point 45~
48°C) was obtained.
水600mI!中の7.3モル(292g)のカセイソ
ーダ溶液に対し氷を加えて全量1.75ρにした。この
溶液の中へ塩素ガスをリドマスに対し中性となるまで通
人する一方において温度を10℃以下に維持した。20
0mj2の水に溶解させた2、19モル(87,6g)
のカセイソーダを加えた。Water 600mI! Ice was added to 7.3 mol (292 g) of caustic soda solution in the solution to make the total amount 1.75 ρ. Chlorine gas was passed into the solution until it became neutral to lidomas, while the temperature was maintained below 10°C. 20
2,19 moles (87,6 g) dissolved in 0 mj2 water
of caustic soda was added.
合併した溶液を50℃に加温し、0.73モル(230
g)の2,5−ビス(2,2,2−)リフルオロエトキ
シ)アセトフェノンを徐々に加えた。反応混合物を攪拌
しながら発熱約75℃となり始めるまで加熱し、その後
に冷却によって約80℃に保持した。約80〜90℃に
約16時間部合物を攪拌し、その間に薄層クロマトグラ
フィにより反応程度を検した。次に250m1lの水の
中の75gの重亜硫酸ナトリウムの添加により過剰の次
亜塩素酸塩を破壊し混合物を約25℃に冷却し10%塩
酸を用いて注意深く酸性化した。濾過によって黄色固体
生成物を集め水洗して乾燥した。収率94.5%で2.
5−ビス(2,2,2−)リフルオロエトキシ)安息香
酸(融点120〜122℃)が得られた。The combined solution was warmed to 50°C and 0.73 mol (230
g) 2,5-bis(2,2,2-)lifluoroethoxy)acetophenone was slowly added. The reaction mixture was heated with stirring until an exotherm of about 75°C began, and then maintained at about 80°C by cooling. The mixture was stirred at about 80-90° C. for about 16 hours, during which time the extent of reaction was monitored by thin layer chromatography. The excess hypochlorite was then destroyed by the addition of 75 g of sodium bisulfite in 250 ml of water, and the mixture was cooled to about 25° C. and carefully acidified with 10% hydrochloric acid. A yellow solid product was collected by filtration, washed with water and dried. 2 with a yield of 94.5%.
5-bis(2,2,2-)lifluoroethoxy)benzoic acid (melting point 120-122°C) was obtained.
例9
工程(31fdl
ベンゼン657mj!中の0.688モル(219g)
の2.5−ビス(2,2,2−)リフルオロエトキシ)
安息香酸の溶液に対し、1.376M(100mlりの
塩化チオニルを1時間以上かけて約60℃に加熱しなが
ら徐々に加えた。次にこの混合物を約8時間還流加熱し
てから蒸発すると所望生成物2,5−ビス(2,2,2
−)リフルオロエトキシ)安息香酸塩化物が残留物とし
て得られた。化学構造を赤外線スペクトル分析によって
確証した。Example 9 Process (0.688 mol (219 g) in 31 fdl benzene 657 mj!
2,5-bis(2,2,2-)lifluoroethoxy)
To a solution of benzoic acid, 100 ml of 1.376 M thionyl chloride was slowly added over 1 hour while heating to about 60°C. The mixture was then heated to reflux for about 8 hours and then evaporated to give the desired amount. Product 2,5-bis(2,2,2
-)trifluoroethoxy)benzoic acid chloride was obtained as a residue. The chemical structure was confirmed by infrared spectrum analysis.
例 10 (参考例)
トルエン60mf中の0.05モル(21,0g)の2
.5−ビス(2,2,2−)リフルオロエトキシ)−α
、α、α−トリクロロアセトフェノンの溶液に対し50
1のシクロヘキサン及び10m1.のトルエン中の0.
055モル(6,0g)の2=アミノメチルピリジンの
溶液を滴下して加えた。Example 10 (Reference example) 0.05 mol (21.0 g) of 2 in 60 mf of toluene
.. 5-bis(2,2,2-)lifluoroethoxy)-α
, α, 50 for a solution of α-trichloroacetophenone
1 of cyclohexane and 10 ml of cyclohexane. of toluene.
A solution of 0.055 mol (6.0 g) of 2=aminomethylpyridine was added dropwise.
この反応は発熱的であって沈殿が直ちに生成した。The reaction was exothermic and a precipitate formed immediately.
トルエンとシクロヘキサンとを追加して攪拌可能な混合
物稠度に至らせ約25℃で2時間攪拌を続けた。次に生
成固体を濾別してトルエンとシクロヘキサンとの混合物
で洗い、乾燥すると白色固体即ち2,5−ビス(2,2
,2−)リフルオロエ)キシ) −N −(2−ピリジ
ルメチル)ベンザミド(融点104〜106℃)の17
.8g(収率89%)が得られた。Additional toluene and cyclohexane were added to reach a stirrable mixture consistency and stirring continued for 2 hours at about 25°C. The resulting solid is then filtered off, washed with a mixture of toluene and cyclohexane, and dried to produce a white solid, i.e. 2,5-bis(2,2
,2-)lifluoroe)oxy)-N-(2-pyridylmethyl)benzamide (melting point 104-106°C) 17
.. 8 g (yield 89%) was obtained.
三種混合物即ち0.33モル(134,7g)の2゜5
−ビス(2,2,2−トリフルオロエトキシ)−N−(
2−ピリジルメチル)ベンザミド、1.347Nの氷酢
酸及び13.5 gの炭素上5%白金の混合物をパル装
置(Parr apparatus )中で約13.6
kg(約30ポンド)の水素圧下に室温で還元した。反
応は6〜7時間で完結した。反応混合物を濾過して触媒
をイソプロピルアルコールで洗った。溶液と洗液とを蒸
発して残留物を得た。この残留物にヘキサンを加えて得
られた白色固体を集めアセトンとへキサンとの混合物か
ら再結した。2°5 of a ternary mixture i.e. 0.33 mol (134.7 g)
-bis(2,2,2-trifluoroethoxy)-N-(
A mixture of 2-pyridylmethyl)benzamide, 1.347 N glacial acetic acid, and 13.5 g of 5% platinum on carbon was added in a Parr apparatus to about 13.6 g of 5% platinum on carbon.
kg (approximately 30 pounds) of hydrogen pressure at room temperature. The reaction was completed in 6-7 hours. The reaction mixture was filtered and the catalyst was washed with isopropyl alcohol. Evaporation of the solution and washings gave a residue. Hexane was added to this residue, and the resulting white solid was collected and reconsolidated from a mixture of acetone and hexane.
収率71%で2,5−ビス(2,2,2−トリフルオロ
エトキシ)−N−(2−ピペリジルメチル)−ベンザミ
ドアセテート(融点150〜152℃)が得られた。残
留液体を濃縮して収率18%の生成物(融点148〜1
50℃)が第2収得物として追加的に得られた。2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide acetate (melting point 150-152°C) was obtained in a yield of 71%. The residual liquid was concentrated to give a yield of 18% (melting point 148-1
50° C.) was additionally obtained as a second crop.
例 11 (参考例)
イソプロピルアルコール50m1中の0.01モル(4
,19g)の2,5−ビス(2,2,2−)リフルオロ
エトキシ)−α、α、α−トリクロロアセトフェノンの
溶液に対し0.01モル(1,2g)の2−アミノメチ
ルピペリジンを加えた。30分間以上経過で混合物は次
第に固化した。この混合物を約16時間静置してから0
.01Mの酢酸と5ml1のイソプロピルアルコールを
加え、この溶液を加温してすべての固体を溶解させた。Example 11 (Reference example) 0.01 mol (4
, 19 g) of 2,5-bis(2,2,2-)lifluoroethoxy)-α,α,α-trichloroacetophenone to a solution of 0.01 mol (1,2 g) of 2-aminomethylpiperidine. added. The mixture gradually solidified over 30 minutes. Let this mixture stand for about 16 hours, then
.. 01M acetic acid and 5ml of isopropyl alcohol were added and the solution was warmed to dissolve all solids.
冷却すると3.0gの白色固体が得られた。濾液を蒸発
し残留物をイソプロピルアルコールから再結すると白色
固体としての追加の生成物を与えた。赤外スペクトル及
び核磁気共鳴スペクトルからこの生成物は2.5−ビス
(2,2,2−トリフルオロエトキシ)−N−(2−ピ
ペリジルメチル)ベンザミドアセテートである。Upon cooling, 3.0 g of white solid was obtained. Evaporation of the filtrate and recondensation of the residue from isopropyl alcohol gave additional product as a white solid. The product is 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate from infrared and nuclear magnetic resonance spectra.
2−アミノメチルピリジン0.77モル(83,3g)
、トリエチルアミン0.77モル(106,7mj2)
及びベンゼン300mlから成る混合物に対し472m
4のベンゼン中の0.70モル(236g)の2.5−
ビス(2,2,2−)リフルオロエトキシ)安息香酸塩
化物を1時間以上かけて添加した。2-aminomethylpyridine 0.77 mol (83.3 g)
, triethylamine 0.77 mol (106,7mj2)
and 472 m for a mixture consisting of 300 ml of benzene.
0.70 mol (236 g) of 2.5- in benzene of 4
Bis(2,2,2-)lifluoroethoxy)benzoic acid chloride was added over 1 hour.
この反応混合物を25℃で約16時間攪拌し、1時間還
流させ、次に21!の水で2回洗浄した。The reaction mixture was stirred at 25° C. for about 16 hours, refluxed for 1 hour, then 21! Washed twice with water.
27!のベンゼンで水相を洗い有機相を合併して硫酸マ
グネシウム上で乾燥してから真空下に蒸発した。ベンゼ
ンとヘキサンとの混合物からの再結は240g(86%
)の灰白色の2,5−ビス(2゜2.2−1リフルオロ
エトキシ)−N−(2−ピリジルメチル)ベンザミド(
融点100〜102℃)を与えた。27! The aqueous phase was washed with 500 ml of benzene and the organic phases were combined, dried over magnesium sulfate and evaporated under vacuum. Reconsolidation from a mixture of benzene and hexane was 240g (86%
) of gray-white 2,5-bis(2゜2.2-1lifluoroethoxy)-N-(2-pyridylmethyl)benzamide (
melting point 100-102°C).
2.5−ビス(2,2,2−トリフルオロエトキシ)
−N−(2−ピリジルメチル)ベンザミド0.33モル
(134,7g)、氷酢酸1.34711及び炭素上5
%白金13.5 gの混合物をパル装置巾約4.5kg
(約10ポンド)の水素圧で室温下に還元した。反応は
6〜7時間で完結した。反応混合物を濾過して触媒をイ
ソプロピルアルコールで洗った。溶液と洗液とを蒸発し
て残留物を得た。この残留物にヘキサンを加えて得られ
た白色固体を集めアセトンとヘキサンとの混液から再結
した。2.5-bis(2,2,2-trifluoroethoxy)
-N-(2-pyridylmethyl)benzamide 0.33 mol (134,7 g), glacial acetic acid 1.34711 and 5 on carbon
A mixture of 13.5 g of platinum was put into a Pal device with a width of approximately 4.5 kg.
(approximately 10 pounds) of hydrogen pressure to room temperature. The reaction was completed in 6-7 hours. The reaction mixture was filtered and the catalyst was washed with isopropyl alcohol. Evaporation of the solution and washings gave a residue. Hexane was added to this residue, and the resulting white solid was collected and reconsolidated from a mixture of acetone and hexane.
収率71%で2.5−ビス(2,2,2−)リフルオロ
エトキシ) −N−(2−ピペリジルメチル)ベンザミ
ドアセテート(融点150〜152℃)が得られた。残
留液の濃縮により収率18%で追加の生成物(融点14
8〜150°C)が第2収得物として得られた。2.5-bis(2,2,2-)lifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate (melting point 150-152°C) was obtained in a yield of 71%. Concentration of the residue yielded additional product in 18% yield (melting point 14
8-150°C) was obtained as the second crop.
Claims (1)
2,2−トリフルオロエタノールを含有する強度に極性
の溶媒中で、1,4−ジブロモベンゼンとアルカリ金属
2,2,2−トリフルオロエトキシドとを接触させて1
,4−ビス(2,2,2−トリフルオロエトキシ)ベン
ゼンをつくり、 (b)該1,4−ビス(2,2,2−トリフルオロエト
キシ)ベンゼンをルイス酸触媒の存在下にアセチル化剤
で処理して2,5−ビス(2,2,2−トリフルオロエ
トキシ)アセトフェノンをつくり、 (c)該2,5−ビス(2,2,2−トリフルオロエト
キシ)アセトフェノンを次亜塩素酸塩と反応させること
によって2,5−ビス(2,2,2−トリフルオロエト
キシ)安息香酸を生成させることを特徴とする該2,5
−ビス(2,2,2−トリフルオロエトキシ)安息香酸
の製造方法。[Claims] The following steps include (a) in the presence of cuprous ions or cupric ions, 2,
1,4-dibromobenzene and an alkali metal 2,2,2-trifluoroethoxide are contacted in a strongly polar solvent containing 2,2-trifluoroethanol.
, 4-bis(2,2,2-trifluoroethoxy)benzene, and (b) acetylating the 1,4-bis(2,2,2-trifluoroethoxy)benzene in the presence of a Lewis acid catalyst. (c) treating the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with hypochlorite; The 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is produced by reacting with an acid salt.
- A method for producing bis(2,2,2-trifluoroethoxy)benzoic acid.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2133179A | 1979-03-19 | 1979-03-19 | |
US2133279A | 1979-03-19 | 1979-03-19 | |
US21331 | 1979-03-19 | ||
US21332 | 1979-03-19 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3467180A Division JPS55143967A (en) | 1979-03-19 | 1980-03-18 | Manufacture of 2*55bis*2*2*22trifluoroethoxy** nn*22piperidylmethyl*benzamide |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH01125344A true JPH01125344A (en) | 1989-05-17 |
JPH0339498B2 JPH0339498B2 (en) | 1991-06-14 |
Family
ID=26694559
Family Applications (8)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP63135366A Granted JPH01125339A (en) | 1979-03-19 | 1988-06-01 | Production of 1, 4-bis (2, 2, 2- trifluoroethoxy)benzene |
JP63135367A Granted JPH01125341A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)acetophenone and its production |
JP63135369A Granted JPH01125343A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)-alpha, aplha, alpha-trichloroacetophenone and its production |
JP63135363A Granted JPH01104045A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
JP63135365A Granted JPH01104044A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
JP63135364A Granted JPH01104043A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
JP63135370A Granted JPH01125344A (en) | 1979-03-19 | 1988-06-01 | Production of 2, 5-bis (2, 2, 2-trifluoroethoxy)benzoate |
JP63135368A Granted JPH01125342A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)-alpha, alpha-dichloroacetophenone and its production |
Family Applications Before (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP63135366A Granted JPH01125339A (en) | 1979-03-19 | 1988-06-01 | Production of 1, 4-bis (2, 2, 2- trifluoroethoxy)benzene |
JP63135367A Granted JPH01125341A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)acetophenone and its production |
JP63135369A Granted JPH01125343A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)-alpha, aplha, alpha-trichloroacetophenone and its production |
JP63135363A Granted JPH01104045A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
JP63135365A Granted JPH01104044A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
JP63135364A Granted JPH01104043A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP63135368A Granted JPH01125342A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)-alpha, alpha-dichloroacetophenone and its production |
Country Status (14)
Country | Link |
---|---|
JP (8) | JPH01125339A (en) |
CA (1) | CA1137486A (en) |
CH (1) | CH643829A5 (en) |
DE (1) | DE3010195A1 (en) |
DK (3) | DK167062B1 (en) |
ES (1) | ES489629A0 (en) |
FR (7) | FR2454438A1 (en) |
GB (2) | GB2045760B (en) |
IE (1) | IE49558B1 (en) |
IL (1) | IL59623A (en) |
IT (1) | IT1195262B (en) |
NL (1) | NL191486C (en) |
PT (1) | PT70967A (en) |
SE (5) | SE447992B (en) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2519975A1 (en) * | 1982-01-21 | 1983-07-22 | Rhone Poulenc Spec Chim | PROCESS FOR PREPARING TRIFLUOROMETHOXY OR TRIFLUOROMETHYLTHIOPHENYLCETONES |
FR2519980A1 (en) * | 1982-01-21 | 1983-07-22 | Rhone Poulenc Spec Chim | PROCESS FOR THE SULFONYLATION OF HALOGENO OR TRIHALOGENOMETHYLBENZENES |
FR2519979A1 (en) * | 1982-01-21 | 1983-07-22 | Rhone Poulenc Spec Chim | PROCESS FOR THE PREPARATION OF TRIFLUOROMETHOXY OR TRIFLUOROMETHYLTHIOPHENYLSULFONES |
FR2519974A1 (en) * | 1982-01-21 | 1983-07-22 | Rhone Poulenc Spec Chim | PROCESS FOR THE ACYLATION OF HALOGENO OR TRIHALOGENOMETHYLBENZENES |
FR2525588A1 (en) * | 1982-04-22 | 1983-10-28 | Rhone Poulenc Spec Chim | PROCESS FOR PREPARING PHENYLCETONES FROM HALOGENO OR TRIHALOGENOMETHYLBENZENES AND ALIPHATIC OR AROMATIC TRIHALOGENOMETHYL COMPOUNDS |
EP0175188A1 (en) * | 1984-09-11 | 1986-03-26 | Nihon Tokushu Noyaku Seizo K.K. | Carbamoylimidazole derivatives |
US4675448A (en) * | 1985-02-13 | 1987-06-23 | Ethyl Corporation | Chlorination process |
FR2579591B1 (en) * | 1985-03-29 | 1988-10-14 | Rhone Poulenc Spec Chim | PROCESS FOR THE PREPARATION OF PENTAFLUOROETHOXY AND PENTAFLUOROETHYLTHIOBENZENIQUE DERIVATIVES |
FR2579594B1 (en) * | 1985-03-29 | 1987-06-05 | Rhone Poulenc Spec Chim | PROCESS FOR THE PREPARATION OF TRIFLUOROETHOXY OR TRIFLUOROETHYLTHIOBENZENES |
NZ219913A (en) * | 1986-04-25 | 1990-08-28 | Riker Laboratories Inc | Various flecainide derivatives and antibodies raised thereto |
EP0242847B1 (en) * | 1986-04-25 | 1993-06-02 | Abbott Laboratories | Tracers for use in flecainide fluorescence polarization immunoassay |
DE3644798A1 (en) * | 1986-12-31 | 1988-07-14 | Hoechst Ag | NEW NITROHALOALCOXYBENZOLS, METHOD FOR THEIR PRODUCTION AND THEIR USE |
FR2640262B1 (en) * | 1988-12-14 | 1991-05-31 | Rhone Poulenc Chimie | PROCESS FOR THE PREPARATION OF TRIFLUOROETHOXYLATED ARYLIC KETONES |
IL121288A (en) * | 1997-07-11 | 2000-10-31 | Finetech Ltd | Process and a novel intermediate for the preparation of flecainide |
US6316627B1 (en) * | 1997-04-21 | 2001-11-13 | Fine Tech Ltd. | Process for the preparation of flecainide |
IL120715A (en) | 1997-04-21 | 2000-07-16 | Finetech Ltd | Process for the preparation of (2,2,2,-trifluoroethoxy)benzoic acids |
US7196197B2 (en) | 2003-09-17 | 2007-03-27 | Apotex Pharmachem Inc. | Process for the preparation of Flecainide, its pharmaceutically acceptable salts and important intermediates thereof |
JP4894226B2 (en) * | 2005-10-31 | 2012-03-14 | Dic株式会社 | Method for producing fluorine-containing liquid crystal compound having hydroquinone skeleton |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3539642A (en) * | 1967-07-19 | 1970-11-10 | Geigy Chem Corp | 2-phenyl-2-(1-naphthyl)acetamides |
US3772304A (en) * | 1969-10-30 | 1973-11-13 | Hoffmann La Roche | 4-hydroxy-isoquinolines and processes for their preparation |
US3655728A (en) | 1970-07-22 | 1972-04-11 | Riker Laboratories Inc | N-(2 - dialkylaminoalkylene)-esters of fluoroalkoxy-substituted aryl carboxylic acid and salts thereof |
US3719687A (en) * | 1970-07-22 | 1973-03-06 | Riker Laboratories Inc | N-(2-dialkylaminoalkylene)amides of 1,1-dihydroperfluoroalkoxy-substituted aryl acids and salts thereof |
US3967949A (en) * | 1973-06-18 | 1976-07-06 | Eli Lilly And Company | Fluoroalkoxyphenyl-substituted nitrogen heterocycles as plant stunting agents |
US4169108A (en) * | 1973-08-16 | 1979-09-25 | Sterling Drug Inc. | 5(OR 6)-[(Substituted-amino)alkyl]-2,3-naphthalenediols |
US4013670A (en) * | 1974-04-01 | 1977-03-22 | Riker Laboratories, Inc. | Derivatives of pyrrolidine and piperidine |
US3900481A (en) | 1974-04-01 | 1975-08-19 | Riker Laboratories Inc | Derivatives of pyrrolidine and piperidine |
US4005209A (en) * | 1974-04-01 | 1977-01-25 | Riker Laboratories, Inc. | Antiarrhythmic method utilizing fluoroalkoxy-N-piperidyl and pyridyl benzamides |
IL49803A (en) * | 1975-06-28 | 1979-11-30 | Fisons Ltd | Preparation of pyrogallol |
DE2616478C2 (en) * | 1976-04-14 | 1986-05-22 | Brickl, Rolf, Dr., 7951 Warthausen | Medicines, biocides and cosmetics containing fluoroacylresorcins |
JPS6023656B2 (en) * | 1976-09-02 | 1985-06-08 | 川研フアインケミカル株式会社 | Method for producing alkoxy aromatic compounds |
US4071524A (en) * | 1976-11-08 | 1978-01-31 | Riker Laboratories, Inc. | Derivatives of urea |
US4097481A (en) * | 1976-11-08 | 1978-06-27 | Riker Laboratories, Inc. | Tertiary amide derivatives of pyrrolidine and piperidine |
-
0
- GB GB8214964A patent/GB2097000B/en not_active Expired
-
1980
- 1980-03-04 CA CA000346919A patent/CA1137486A/en not_active Expired
- 1980-03-14 DK DK112180A patent/DK167062B1/en not_active IP Right Cessation
- 1980-03-14 IL IL59623A patent/IL59623A/en unknown
- 1980-03-14 SE SE8002003A patent/SE447992B/en not_active IP Right Cessation
- 1980-03-16 NL NL8001551A patent/NL191486C/en not_active IP Right Cessation
- 1980-03-17 DE DE19803010195 patent/DE3010195A1/en active Granted
- 1980-03-17 ES ES489629A patent/ES489629A0/en active Granted
- 1980-03-18 CH CH212880A patent/CH643829A5/en not_active IP Right Cessation
- 1980-03-18 IT IT20746/80A patent/IT1195262B/en active Protection Beyond IP Right Term
- 1980-03-18 GB GB8009041A patent/GB2045760B/en not_active Expired
- 1980-03-18 IE IE549/80A patent/IE49558B1/en not_active IP Right Cessation
- 1980-03-18 PT PT70967A patent/PT70967A/en active IP Right Revival
- 1980-03-18 FR FR8006019A patent/FR2454438A1/en active Granted
-
1981
- 1981-01-07 FR FR8100141A patent/FR2468570A1/en active Granted
- 1981-01-07 FR FR8100144A patent/FR2468590A1/en active Granted
- 1981-01-07 FR FR8100143A patent/FR2468576A1/en active Granted
- 1981-01-07 FR FR8100140A patent/FR2468569A1/en active Granted
- 1981-01-07 FR FR8100145A patent/FR2468591A1/en active Granted
- 1981-01-07 FR FR8100142A patent/FR2468571A1/en active Granted
-
1984
- 1984-03-21 SE SE8401555A patent/SE463260B/en not_active IP Right Cessation
- 1984-03-21 SE SE8401554A patent/SE447993B/en not_active IP Right Cessation
-
1988
- 1988-06-01 JP JP63135366A patent/JPH01125339A/en active Granted
- 1988-06-01 JP JP63135367A patent/JPH01125341A/en active Granted
- 1988-06-01 JP JP63135369A patent/JPH01125343A/en active Granted
- 1988-06-01 JP JP63135363A patent/JPH01104045A/en active Granted
- 1988-06-01 JP JP63135365A patent/JPH01104044A/en active Granted
- 1988-06-01 JP JP63135364A patent/JPH01104043A/en active Granted
- 1988-06-01 JP JP63135370A patent/JPH01125344A/en active Granted
- 1988-06-01 JP JP63135368A patent/JPH01125342A/en active Granted
-
1989
- 1989-04-27 SE SE8901533A patent/SE463419B/en not_active IP Right Cessation
- 1989-04-27 SE SE8901532A patent/SE463418B/en not_active IP Right Cessation
-
1990
- 1990-05-17 DK DK122290A patent/DK164857C/en not_active IP Right Cessation
-
1991
- 1991-04-30 DK DK079891A patent/DK79891A/en unknown
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