JPS6357429B2 - - Google Patents
Info
- Publication number
- JPS6357429B2 JPS6357429B2 JP55034671A JP3467180A JPS6357429B2 JP S6357429 B2 JPS6357429 B2 JP S6357429B2 JP 55034671 A JP55034671 A JP 55034671A JP 3467180 A JP3467180 A JP 3467180A JP S6357429 B2 JPS6357429 B2 JP S6357429B2
- Authority
- JP
- Japan
- Prior art keywords
- trifluoroethoxy
- bis
- reaction
- mixture
- added
- 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.)
- Expired
Links
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 10
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 7
- 238000005660 chlorination reaction Methods 0.000 claims description 7
- 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 description 6
- 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 claims description 6
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 6
- 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 description 5
- 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 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 4
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000008062 acetophenones Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 159000000021 acetate salts Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229960000583 acetic acid Drugs 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
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 6
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 6
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- -1 hydroxy-substituted benzenes Chemical class 0.000 description 4
- YCKWLOJVFNPJAW-UHFFFAOYSA-N n-(pyridin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide Chemical compound FC(F)(F)COC1=CC=C(OCC(F)(F)F)C(C(=O)NCC=2N=CC=CC=2)=C1 YCKWLOJVFNPJAW-UHFFFAOYSA-N 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-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 3
- 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002329 infrared spectrum 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
- 239000000126 substance Substances 0.000 description 3
- MFWASTQSJSBGNG-UHFFFAOYSA-N 2,2,2-trifluoroethoxybenzene Chemical compound FC(F)(F)COC1=CC=CC=C1 MFWASTQSJSBGNG-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- UJJXIVQSEUDBLJ-UHFFFAOYSA-N 2,5-bis(2,2,2-trifluoroethoxy)benzoyl chloride Chemical compound FC(F)(F)COC1=CC=C(OCC(F)(F)F)C(C(Cl)=O)=C1 UJJXIVQSEUDBLJ-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
- 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
- 239000012345 acetylating agent Substances 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-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
- 229960000449 flecainide Drugs 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
- 229910001504 inorganic chloride Inorganic materials 0.000 description 2
- 239000011968 lewis acid catalyst Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material 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
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 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
- 238000007039 two-step reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- IEVJVQXLBZUEMH-UHFFFAOYSA-N 2-piperidin-2-ylethanamine Chemical compound NCCC1CCCCN1 IEVJVQXLBZUEMH-UHFFFAOYSA-N 0.000 description 1
- XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005711 Benzoic acid Substances 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
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 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
- 238000004566 IR spectroscopy Methods 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
- 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
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000000872 buffer 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper 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
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 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
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 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
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 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
- 238000010977 unit operation Methods 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- 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
Description
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）ベンザミド〔フレカイニド
（flecainide）〕及びその塩のブロモー又はヒドロ
キシ―置換ベンゼンからの改良された製造方法に
関する。又本発明は本方法において製造される或
種の中間体化合物類にも関連をもつ。
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。
詳細には本発明は下記の諸工程を包含する：
(1) 式
The present invention provides an antiarrhythmic agent 2,5-bis(2,2,2
-Trifluoroethoxy)-N-(2-piperidylmethyl)benzamide (flecainide) and its salts from bromo- or hydroxy-substituted benzenes. The invention also relates to certain intermediate compounds produced in the process. 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 as shown in the following formula; The process of the present invention offers various practical advantages over the prior art processes described above, such as relatively low starting materials, ease of carrying out unit operations, and relatively high yields of the desired product. This is a preferred method because of its high cost. Specifically, the present invention includes the following steps: (1) Formula
【式】
〔但し×（複）同じであつてOH及びBrから
選ばれる〕
の化合物を適宜の下式
CF3CH2O−Ａ
〔但しＡは−SO2CF3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 acid）触媒
の存在下にアセチル化して式
の置換アセトフエノンをつくり、
(3) (a) 該置換アセトフエノンをクロル化して下
式
の対応するα，α―ジクロロアセトフエノン
をつくり、そして
(b) 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エノンを
つくり、又は別法として
(c) 該置換アセトフエ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くり、そして
(d) 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
により一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。上記の諸工程(1)，(1)―(2)；(3)(a)；(3)(c)；
(1)，(2)及び(3)(c)；(3)(b)；(3)(a)及び(3)(b)；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，−CHC｜2及びCC｜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。
本発明の包括性方法の反応順序を下式に示す：
本法の第１工程においてＸがOHである場合に
はＡは好ましくは−SO2CF3であつて反応体（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、一緒に加熱される。
上記のＸがBrである場合には１，４―ジブロ
モベンゼン（）と、２，２，２―トリフルオロ
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末満の温度の下に、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（）をつくる。
２，２，２―ト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。
好適な混合溶媒にはジメチルスルホキシド、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―トリフルオロエタ
ノールとの混合物が包含される。第１銅イオンは
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銅によつて供給される。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
よつて供給される。
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
とによつてアセチル化する。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
所望のアセトフエノン（）が高収率で提供され
ることは予測外のことである。
工程(3)(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（）の単純なクロル化である。
この反応を中等度の温度好ましくは50〜60℃で行
う。
所望により生成物（）を単離し得る。或は工
程(3)(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（）
を得る。
工程(3)(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***液に塩
酸を飽和させてPH７としたもの（対応する次亜塩
素酸塩を形成）に対しアセトフエノン（）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つて促進され
る。所望の２，５―ビス（２，２，２―トリフル
オロエトキシ）安息香酸（）が著しい高収率で
得られる。
工程(3)(d)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）と該酸との還流下の反応に
よる。
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エノン〔工程(3)(b)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エノン
〔工程(3)(b)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
く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。
工程(3)(d)の生成物である酸塩化物（）を生発
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。酸塩化物〔工程(3)(d)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。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（）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）氷酢酸であつて好適温度範囲は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。
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。
例 １
工程(1)の方法：Ａ＝SO2CF3，Ｘ＝OH
アセトン1.02中の2.42モル（334.4ｇ）の炭酸
カリ、2.2モル（510.6ｇ）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1.1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２のクロロホルムと
２の水とを加えた。クロロホルム層を分別し、
水層を１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１の水で洗つた。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
て固体生成物を過により集めヘキサンで洗つ
た。濃縮残留物から追加の物質を集めた。１，４
―ビス（２，２，２―トリフルオロエトキシ）ベ
ンセン（融点75〜77℃）の241ｇ、収率88％、が
得られた。
例 ２
工程(1)：Ａ＝Na，Ｘ＝Br
Ｎ，Ｎ―ジメチルホルムアミド40ml中の0.20モ
ル（9.6ｇ）の50％水素化ナトリウムに対し40ml
の（２，２，２―ト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℃にまで冷却して過した。残留物
をＮ，Ｎ―ジメチルホルムアミドで洗つた。溶液
を水中へ注ぎ沈殿を別した。生成物をジエチル
エーテルに溶かして過し、液を蒸発して生成
させた固形残留物をヘキサンで洗つて乾燥した。
生成物は１，４―ビス（２，２，２―トリフルオ
ロエトキシ）ベンゼン（融点77〜79℃）の7.3ｇ
（80％）である。
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
にして再行した：40mlのＮ，Ｎ―ジメチルホルム
アミド中の4.8ｇの水素化ナトリウム混合物に対
し20ml（27.4ｇ）２，２，２―トリフルオロエタ
ノールを加えた。この混合物に0.034モル（8.0
ｇ）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。塩酸で酸性化し
て過すると9.2ｇ（99％）の白色固体の１，４
―ビス（２，２，２―トリフルオロエトキシ）―
ベンゼンを生成した。化学構造の赤外線スペクト
ル分析により確認した。
例 ３
工程(2)：アセチル化剤として無水酢酸使用
ジクロロメタン648ml中の2.43モル（324ｇ）の
塩化アルミニウムの混合物に対し880mlのジクロ
ロメタン中の0.88モル（274ｇ）の１，４―ビス
（２，２，２―ト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０℃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
時間撹拌した。反応の進行状態を薄層クロマトグ
ラフイ使用によつて追跡した。反応混合物を氷浴
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。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２の10％塩酸で一回洗い、次に２の水で
洗つた。水相を合併し数リツ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過
により集めヘキサンで洗つた。乾燥すると250ｇ
の淡黄色結晶状の２，５―ビス（２，２，２―ト
リフルオロエトキシ）アセトフエノンが得られ
た。融点84〜86℃、収率90％である。
例 ４
前掲例３の操作規模の拡大
塩化アルミニウムの４，367ｇ（32.75モル）と
8.8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３，267ｇの１，４
―ビス（２，２，２―トリフルオロエトキシ）ベ
ンゼン及び1.399Kg（13.7モル）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8.76Kg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3.088Kgの２，５
―ビス（２，２，２―トリフルオロエトキシ）ア
セトフエノン（融点84〜88℃、収率82％）であつ
た。
例 ５
工程(2)：アセチル化剤として塩化アセチル使用
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100mlと混合物に対し、
0.020モル（5.6ｇ）の１，４―ビス（２，２，２
―ト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（20ml）中溶液を25℃で滴下して加えた。４
時間撹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―トリフルオロエ
トキシ）アセトフエノン（赤外線スペクトル分析
により確証）を与えた。
例 ６
工程(3) (a)
酢酸150mlの0.25モル（79.1ｇ）の２，５―ビ
ス（２，２，２―トリフルオロエトキシ）アセト
フエノンの混合物を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35.5ｇ
であつた。得られた生成物は２，５―ビス（２，
２，２―トリフルオロエトキシ）―α，α―ジク
ロロアセトフエノンである。
例 ７
工程(3) (b)
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。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℃にまで上昇させた。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。生成沈殿を過によつて集め、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―トリフルオロエトキ
シ）α，α，α―トリクロロアセトフエノン（融
点45〜48℃）が得られた。
例８ （参考例）
工程(3) (c)
水600ml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1.75にした。この溶
液の中へ塩素ガスをリトマスに対し中性となるま
で通入する一方において温度を10℃以下に維持し
た。200ml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。合併した溶液を50℃に
加温し、0.73モル（230ｇ）の２，５―ビス（２，
２，２―トリフルオロエトキシ）アセトフエノン
を徐々に加えた。反応混合物を撹拌しながら発熱
約75℃となり始めるまで加熱し、その後に冷却に
よつて約80℃に保持した。約80〜90℃に約16時間
混合物を撹拌し、その間に薄層クロマトグラフイ
により反応程度を検した。次に250mlの水の中に
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。過によつて
淡黄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―トリフルオ
ロエトキシ）安息香酸（融点120〜122℃）が得ら
れた。
例９ （参考例）
工程(3) (d)
ベンゼン657ml中の0.688モル（219ｇ）の２，
５―ビス（２，２，２―トリフルオロエトキシ）
安息香酸の溶液に対し、1.375M（100ml）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―ト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つて確証した。
例10 （参考例）
工程(4)：中間体（）を出発物質として使用す
る２段反応の遂行
トルエン60ml中の0.05モル（21.0ｇ）の２，５
―ビス（２，２，２―トリフルオロエトキシ）―
α，α，α―トリクロロアセトフエノンの溶液に
対し50mlのシクロヘキサン及び10ml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。この反応は発熱的で
あつて沈殿が直ちに生成した。トルエンとシクロ
ヘキサンとを追加して撹拌可能な混合物稠度に至
らせ約25℃で２時間撹拌を続けた。次に生成固体
を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―ト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104〜
106℃）の17.8ｇ（収率89％）が得られた。
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、1.347
の氷酢酸及び13.5ｇの炭素上５％白金の混合物
をパル装置（Parr pparatus）中で約13.6Kg（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。反応混合物を過して触
媒をイソプロピルアルコールで洗つた。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
ヘキサンとの混合物から再結した。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〜
150℃）が第２収得物として追加的に得られた。
例 11
工程(4)：中間体（）を出発物質として使用す
る単一反応の遂行
イソプロピルアルコール50ml中の0.01モル
（4.19ｇ）の２，５―ビス（２，２，２―トリフ
ルオロエトキシ）―α，α，α―トリクロロアセ
トフエノンの溶液に対し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５ml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。冷却すると3.0ｇの白
色固体が得られた。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。
例12 （参考例）
工程(4)：中間体（）を出発物質として使用す
る２段反応の遂行
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（106.7ml）及びベン
ゼン300mlから成る混合物に対し472mlのベンゼン
中の0.70モル（236ｇ）の２，５―ビス（２，２，
２―ト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。
この反応混合物を25℃で約16時間撹拌し、１時
間還流させ、次に２の水で２回洗浄した。２
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240
ｇ（86％）の灰白色の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（融点100〜102℃）を与え
た。
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1.347及び炭素上５
％白金13.5ｇの混合物をパル装置中約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。反応混合物を過して触
媒をイソプロピルアルコールで洗つた。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。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。残留液の
濃縮により収率18％で追加の生成物（融点148〜
150℃）が第２収得物として得られた。[Formula] [provided that × (multiple) are the same and are selected from OH and Br] A compound of the following formula CF 3 CH 2 O-A [However, A is -SO 2 CF 3 or an alkali metal] By reacting with an alkylating agent, the formula (2) This compound is acetylated in the presence of a Lewis acid catalyst to obtain the formula (3) (a) The substituted acetophenone is chlorinated to form the following formula: (b) By further chlorination with the addition of a buffer base, the formula or (c) reacting the substituted acetophenone with hypochlorite to give the formula (d) react this acid compound with an inorganic chloride to form the formula (4) The product of step 3(b) or 3(d) above is converted into 2-
(aminomethyl)hyperidine to produce the desired product in one step, or in two steps.
-(Aminomethyl)pyridine and subsequent reduction to form the desired product, or optionally as the free base. The above steps (1), (1)-(2); (3)(a); (3)(c);
(1), (2) and (3)(c); (3)(b); (3)(a) and (3)(b); and
Methods including the steps (4) are intermediate compounds of the following formula: [where B is selected from -CH3 , -CHC| 2 and CC| 3 ] constitutes another characteristic aspect of the generic invention. The reaction sequence of the comprehensiveness method of the present invention is shown in the following formula: In the first step of the process, when X is OH, A is preferably -SO 2 CF 3 and the reactant(s).
is a base such as an alkali metal carbonate, in a solvent such as acetone or N,N-dimethylformamide,
They are preferably co-heated in the presence of a weak base such as, for example, potassium carbonate or soda carbonate. When the above-mentioned under the temperature of the first
The reaction in the presence of copper or cupric ions produces the desired product () in good yield.
To obtain the 2,2,2-trifluoroethoxide ion, the corresponding alcohol is reacted with a strong base, such as caustic soda or preferably sodium hydride.
Suitable mixed solvents include dimethyl sulfoxide, N,
N-dimethylacetamide and preferred N,N
-dimethylformamide and about 10 to 50%, preferably about 20%, of 2,2,2-trifluoroethanol. 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. In step (2), 1,4-bis(2,2,2-
Trifluoroethoxy)-benzene (), produced in step (1), is acetylated under mild conditions in the presence of a Lewis acid catalyst such as tin chloride, ferric chloride or preferably aluminum chloride. Acetylation, for example, by reaction with acetyl chloride or acetic anhydride. This acetylation is carried out using a suitable non-reactive solvent such as a chlorinated hydrocarbon such as dichloromethane, trichloroethylene or 1,2
- in dichloroethane, diethyl ether, tetrahydrofuran and the like. It is unexpected that this reaction provides the desired acetophenone () in high yield. The reaction of step (3)(a) is a simple chlorination of the intermediate () 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. The product () can be isolated if desired. Alternatively, chlorination is carried out as in step (3)(b), and while the chlorination is continued, a buffer such as an acetate such as sodium acetate is added to lower the temperature slightly, e.g.
Intermediate () by raising to 100℃
get. The reaction of step (3)(c) is carried out using an alkali metal hydroxide or alkaline earth metal hydroxide (e.g. caustic soda,
This is most conveniently accomplished by adding acetophenone () to a cold solution of caustic potash (or calcium hydroxide) saturated with hydrochloric acid to a pH of 7 (forming the corresponding hypochlorite). This reaction is accelerated by warming the reaction mixture. The desired 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid () is obtained in significantly high yields. In step (3)(d), the acid described above is converted to the corresponding acyl chloride, which is carried out using an inorganic chloride in the presence or absence of a suitable non-reactive solvent such as benzene or toluene or a halogenated hydrocarbon. For example, by reaction of the acid with thionyl chloride, phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride) under reflux. The method of step (4) can be carried out directly from the saturated diamine 2-(aminoethyl)piperidine or indirectly from the non-reduced diamine 2-(aminoethyl)pyridine. That is, 2-aminomethylpiperidine is converted into trichloroacetophenone [product of step (3)(b)].
Alternatively, the compound 2-aminomethylpyridine can be reacted with trichloroacetophenone [product of step (3)(b))]. In each case, the reaction proceeds readily in nonreactive solvents such as toluene, benzene, isopropyl alcohol, cyclohexane, and the like without external heating. The reaction proceeds particularly easily and in high yields when unreduced diamines are reacted in a mixture of toluene and cyclohexane. When carrying out the final step using the acid chloride (), which is the product of step (3)(d), as a generating material, this method can be carried out directly from 2-(aminomethyl)piperidine or from 2-( It is also accomplished indirectly from aminomethyl)pyridine. The acid chloride (product of step (3)(d)) is reacted by heating in a non-reactive solvent such as glyme, benzene, toluene or diethyl ether (preferably glyme). Alternatively, 2-aminomethylpyridine and the acid chloride (product of step (3)(d)) can be reacted in the presence of a non-reactive solvent such as toluene or benzene. This mixture is heated to reflux temperature in the presence of an acid acceptor (eg, a tertiary amine such as triethylamine). The desired product is produced by catalytic hydrogenation of the adduct obtained from the reaction of either compound () or () with 2-(aminomethyl)pyridine in the presence of platinum oxide or (preferably) platinum on carbon. Return to. 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 between 15 and
It is 30℃. The product obtained when acetic acid is used is flecainide acetate. 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. Example 1 Method of step (1): A = SO 2 CF 3 , 1.0 mole (110 g) of hydroquinone in 1.1 part of acetone to lomethane sulfonate was added slowly over 2 hours. The reaction was then heated under reflux for 24 hours, then the reaction mixture was evaporated and 2 parts of chloroform and 2 parts of water were added to the residue. Separate the chloroform layer,
The aqueous layer was washed twice with 1 part of chloroform, and the chloroform solution was combined and washed with 1 part of 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. 1,4
-241 g of -bis(2,2,2-trifluoroethoxy)benzene (melting point 75-77°C), yield 88%, was obtained. Example 2 Step (1): A=Na,
(2,2,2-trifluoroethanol) was added, followed by 0.034 moles (8.0 g) of 1,4-dibromobenzene and 0.006 moles (1.0 g) of cuprous iodide. Heated to reflux for 4 hours, then cooled to about 25°C and filtered. The residue was washed with N,N-dimethylformamide. The solution was poured into water to separate the precipitate. The product was dissolved in diethyl ether. The solid residue formed by evaporation was washed with hexane and dried.
The product is 7.3 g of 1,4-bis(2,2,2-trifluoroethoxy)benzene (melting point 77-79°C)
(80%). The above reaction was repeated with different conditions and proportions of the components used and using cupric bromide as a catalyst as follows: 4.8 g of sodium hydride in 40 ml of N,N-dimethylformamide. 20 ml (27.4 g) of 2,2,2-trifluoroethanol was added to the mixture. This mixture contains 0.034 mol (8.0
g) 1,4-dibromobenzene and 1.0 g of cupric bromide were added. The reaction mixture was heated to about 100° C. for 2 hours and then quenched with ice water. Acidification with hydrochloric acid yields 9.2 g (99%) of a white solid of 1,4
-Bis(2,2,2-trifluoroethoxy)-
produced benzene. The chemical structure was confirmed by infrared spectrum analysis. Example 3 Step (2): Using acetic anhydride as the acetylating agent A mixture of 2.43 mol (324 g) of aluminum chloride in 648 ml of dichloromethane to 0.88 mol (274 g) of 1,4-bis(2,2) in 880 ml of dichloromethane , 2-trifluoroethoxy)benzene and 0.97 mol (92 ml) of acetic anhydride was added over 3 hours while maintaining the temperature at about 0°C. The reaction mixture was then heated to reflux temperature and refluxed for 5
Stir for hours. The progress of the reaction was followed using thin layer chromatography. The reaction mixture was placed in an ice bath and ice, and 10% hydrochloric acid was gradually added to decompose the aluminum chloride complex. temperature of reaction mixture
The temperature was not allowed to rise above 25℃. The organic phase was separated and washed once with 10% hydrochloric acid (2) and then with water (2). 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. 250g when dried
A pale yellow crystalline 2,5-bis(2,2,2-trifluoroethoxy)acetophenone was obtained. Melting point: 84-86°C, yield: 90%. Example 4 Expansion of the operation scale of Example 3 above. 4,367 g (32.75 mol) of aluminum chloride and
3,267 g of 1,4 in 1.3 dichloromethane for a mixture at 0 °C with 8.8 g of dichloromethane
A solution of -bis(2,2,2-trifluoroethoxy)benzene and 1.399 Kg (13.7 moles) 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 8.76Kg 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 3.088 Kg of 2,5
-bis(2,2,2-trifluoroethoxy)acetophenone (melting point 84-88°C, yield 82%). Example 5 Step (2): Using acetyl chloride as the acetylating agent 0.022 mol (2.8 g) of aluminum chloride and 1,
For the mixture with 100 ml of 2-dichloroethane,
0.020 mol (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 (20 ml) was added dropwise at 25°C. 4
After stirring for an hour, 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-trifluoroethoxy)acetophenone (confirmed by infrared spectroscopy). gave. Example 6 Step (3) (a) A mixture of 0.25 mol (79.1 g) of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone in 150 ml of acetic acid is heated to 50°C, and chlorine is added to the solution. Gas was bubbled in and the temperature was gradually increased to 55°C. Adjust chlorine addition rate to 55-60
The temperature was maintained at ℃. After about 75 minutes the temperature began to decrease (indicating that chlorination was no longer occurring). Total amount of chlorine added is 35.5g
It was hot. The product obtained is 2,5-bis(2,
2,2-trifluoroethoxy)-α,α-dichloroacetophenone. Example 7 Step (3) (b) Product of Example 6 above (not isolated or purified)
0.35 mol (28.7 g) of sodium acetate was added to the solution. The temperature rose to about 80°C and the solution was heated to 85°C.
It was heated to ℃. Continue adding chlorine to raise the temperature.
The temperature was raised to 100℃. 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. A yield of 94 g (90%) of 2,5-bis(2,2,2-trifluoroethoxy)α,α,α-trichloroacetophenone (melting point 45-48°C) was obtained. Example 8 (Reference Example) Step (3) (c) Ice was added to a 7.3 mol (292 g) caustic soda solution in 600 ml of water to make a total volume of 1.75. Chlorine gas was passed into the solution until it became neutral to litmus while maintaining the temperature below 10°C. 2.19 moles (87.6 g) dissolved in 200 ml of water
of caustic soda was added. The combined solution was warmed to 50°C and 0.73 mol (230 g) of 2,5-bis(2,
2,2-trifluoroethoxy)acetophenone was added slowly. The reaction mixture was heated with stirring until it began to exotherm to about 75°C 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. Then into 250ml of water
The excess hypochlorite is destroyed by the addition of 75 g of sodium bisulfite and the mixture is cooled to approximately 25°C to reduce the 10%
Carefully acidified with hydrochloric acid. A pale yellow solid product was collected by filtration, washed with water and dried. yield
94.5% of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (melting point 120-122°C) was obtained. Example 9 (Reference example) Step (3) (d) 0.688 mol (219 g) of 2 in 657 ml of benzene,
5-bis(2,2,2-trifluoroethoxy)
To the benzoic acid solution, 1.375 M (100 ml) of thionyl chloride was gradually added over 1 hour while heating to about 60°C. The mixture was then heated at reflux for about 8 hours and then evaporated to yield the desired product 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride as a residue. The chemical structure was confirmed by infrared spectrum analysis. Example 10 (Reference example) Step (4): Performing a two-step reaction using intermediate () as starting material 0.05 mol (21.0 g) of 2,5 in 60 ml of toluene
-Bis(2,2,2-trifluoroethoxy)-
A solution of 0.055 mol (6.0 g) of 2-aminomethylpyridine in 50 ml of cyclohexane and 10 ml of toluene was added dropwise to the solution of α,α,α-trichloroacetophenone. The reaction was exothermic and a precipitate formed immediately. Additional toluene and cyclohexane were added to reach a stirrable mixture consistency and stirring continued for 2 hours at about 25°C. Next, the solid produced is separated, washed with a mixture of toluene and cyclohexane, and dried to produce a white solid, i.e., 2,5-bis(2,2,2-trifluoroethoxy)-N-
(2-pyridylmethyl)benzamide (melting point 104~
17.8 g (yield: 89%) of 106°C) was obtained. A ternary mixture i.e. 0.33 mol (134.7 g) of 2,5
-Bis(2,2,2-trifluoroethoxy)-
N-(2-pyridylmethyl)benzamide, 1.347
of glacial acetic acid and 13.5 g of 5% platinum on carbon in a Parr pparatus.
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. 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~
150° C.) was additionally obtained as a second crop. Example 11 Step (4): Carrying out a single reaction using intermediate () as starting material 0.01 mol (4.19 g) of 2,5-bis(2,2,2-trifluoroethoxy) in 50 ml of isopropyl alcohol -0.01 mol (1.2 g) of 2 for a solution of α,α,α-trichloroacetophenone
-Aminomethylpiperidine was added. The mixture gradually solidified over 30 minutes. This mixture is approx.
After standing for 16 hours, 0.01 M acetic acid and 5 ml of isopropyl alcohol were added and the solution was warmed to dissolve all solids. Upon cooling, 3.0 g of white solid was obtained. Evaporation of the liquid and recondensation of the residue from isopropyl alcohol gave additional product as a white solid. The infrared spectrum and nuclear magnetic resonance spectrum indicate that this product is 2,5-bis(2,2,2-trifluoroethoxy)-N-
(2-piperidylmethyl)benzamide acetate. Example 12 (Reference example) Step (4): Performing a two-step reaction using intermediate () as a starting material 0.77 mol (83.3 g) of 2-aminomethylpyridine,
0.70 moles (236 g) of 2,5-bis(2,2,
2-trifluoroethoxy)benzoic acid chloride 1
Added over time. The reaction mixture was stirred at 25° C. for about 16 hours, refluxed for 1 hour, then washed twice with 2 portions of water. 2
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 is 240
g (86%) of grayish-white 2,5-bis(2,2,2
-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide (melting point 100-102°C). 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide
0.33 mol (134.7 g), 1.347 glacial acetic acid and 5 on carbon
Approximately 4.5 kg (approx.
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. The solution and washings were evaporated to give a residue. Hexane was added to this residue, and the resulting white solid was collected and reconsolidated from a mixture of acetone and hexane. 2 with a yield of 71%,
5-bis(2,2,2-trifluoroethoxy)
-N-(2-piperidylmethyl)benzamide acetate (melting point 150-152°C) was obtained. Concentration of the residue yielded additional product (mp 148~) in 18% yield.
150°C) was obtained as the second crop.
Claims (1)
Brから選ばれる〕の化合物を式 CF3CH2O−Ａ 〔但しＡはＸがOHの時に−SO2CF3であり、
又はＸがBrの時にアルカリ金属である〕の適
宜のアルキル化剤と反応させて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) このものをルイス酸触媒の存在下にアセチル
化して２，５―ビス（２，２，２―トリフルオ
ロエトキシ）アセトフエノンをつくり、 (c) 該置換アセトフエノンをクロル化して２，５
―ビス（２，２，２―トリフルオロエトキシ）
―α，α―ジクロロアセトフエノンをつくり、 (d) 緩衝用塩基を加えて更にクロル化することに
より２，５―ビス（２，２，２―トリフルオロ
エトキシ）―α，α，α―トリクロロアセトフ
エノンをつくり、 (e) 上記工程(d)の生成物を２―（アミノメチル）
―ピペリジンと反応させることにより任意にア
セテート塩として回収され得る所望製品をつく
ることを特徴とする下式 を有する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）―ベンザミドの製造方法。 ２ 第１銅イオン又は第２銅イオンの存在下に、
２，２，２―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
ンと式 CF3CH2O−Ａ 〔但しＡはアルカリ金属である〕の適宜のアル
キル化剤とを反応させることによつて中間物質で
ある１，４―ビス（２，２，２―トリフルオロエ
トキシ）ベンゼンが製造される特許請求の範囲第
１項記載の方法。[Claims] 1. The following steps, namely formula (a) [However, X (plural) is the same and OH and
A compound with the formula CF 3 CH 2 O-A [where A is -SO 2 CF 3 when X is OH,
or an alkali metal when X is Br] to produce 1,4-bis(2,2,2-trifluoroethoxy)benzene; (c) chlorination of the substituted acetophenone to form 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;
-Bis(2,2,2-trifluoroethoxy)
-α,α-dichloroacetophenone is prepared, and (d) 2,5-bis(2,2,2-trifluoroethoxy)-α,α,α- is produced by adding a buffer base and further chlorination. Make trichloroacetophenone, (e) convert the product of step (d) above into 2-(aminomethyl)
- The following formula, characterized in that reaction with piperidine produces the desired product, which can optionally be recovered as the acetate salt. A method for producing 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide. 2 In the presence of cuprous ions or cupric ions,
1,4-dibromobenzene and a suitable alkylating agent of the formula CF 3 CH 2 O-A, where A is an alkali metal, in a strongly polar solvent containing 2,2,2-trifluoroethanol. 2. The method according to claim 1, wherein the intermediate 1,4-bis(2,2,2-trifluoroethoxy)benzene is produced by reacting with
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2133179A | 1979-03-19 | 1979-03-19 |
Related Child Applications (8)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63135370A Division JPH01125344A (en) | 1979-03-19 | 1988-06-01 | Production of 2, 5-bis (2, 2, 2-trifluoroethoxy)benzoate |
| JP63135365A Division JPH01104044A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
| JP63135366A Division JPH01125339A (en) | 1979-03-19 | 1988-06-01 | Production of 1, 4-bis (2, 2, 2- trifluoroethoxy)benzene |
| JP63135369A Division JPH01125343A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)-alpha, aplha, alpha-trichloroacetophenone and its production |
| JP63135364A Division JPH01104043A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
| JP63135363A Division JPH01104045A (en) | 1979-03-19 | 1988-06-01 | Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide |
| JP63135367A Division JPH01125341A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)acetophenone and its production |
| JP63135368A Division JPH01125342A (en) | 1979-03-19 | 1988-06-01 | 2, 5-bis (2, 2, 2-trifluoroethoxy)-alpha, alpha-dichloroacetophenone and its production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55143967A JPS55143967A (en) | 1980-11-10 |
| JPS6357429B2 true JPS6357429B2 (en) | 1988-11-11 |
Family
ID=21803605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3467180A Granted JPS55143967A (en) | 1979-03-19 | 1980-03-18 | Manufacture of 2*55bis*2*2*22trifluoroethoxy** nn*22piperidylmethyl*benzamide |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS55143967A (en) |
| BE (1) | BE882318A (en) |
| ZA (1) | ZA801565B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0653474U (en) * | 1992-12-24 | 1994-07-22 | 株式会社貝印刃物開発センター | Opening and closing structure of the lid for various small item storage cases |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50137975A (en) * | 1974-04-01 | 1975-11-01 |
-
1980
- 1980-03-18 ZA ZA00801565A patent/ZA801565B/en unknown
- 1980-03-18 JP JP3467180A patent/JPS55143967A/en active Granted
- 1980-03-19 BE BE0/199864A patent/BE882318A/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50137975A (en) * | 1974-04-01 | 1975-11-01 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55143967A (en) | 1980-11-10 |
| BE882318A (en) | 1980-09-19 |
| ZA801565B (en) | 1981-05-27 |
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