CN101516845A - 2,5-双(2,2,2-三氟乙氧基)-n-(2-哌啶基甲基)-苯甲酰胺及其盐的制备方法 - Google Patents
2,5-双(2,2,2-三氟乙氧基)-n-(2-哌啶基甲基)-苯甲酰胺及其盐的制备方法 Download PDFInfo
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- CN101516845A CN101516845A CNA2007800358537A CN200780035853A CN101516845A CN 101516845 A CN101516845 A CN 101516845A CN A2007800358537 A CNA2007800358537 A CN A2007800358537A CN 200780035853 A CN200780035853 A CN 200780035853A CN 101516845 A CN101516845 A CN 101516845A
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- trifluoro ethoxy
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- benzamide
- pyridine
- toluene
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- 238000000034 method Methods 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000003839 salts Chemical class 0.000 title claims abstract description 17
- 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 title abstract description 9
- 230000008569 process Effects 0.000 title abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 67
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000010949 copper Substances 0.000 claims abstract description 6
- 229910052802 copper Inorganic materials 0.000 claims abstract description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 39
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 26
- -1 2-piperidyl Chemical group 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 10
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000010 aprotic solvent Substances 0.000 claims description 8
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 7
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- JYLNVJYYQQXNEK-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(CN)C1=CC=C(Cl)C=C1 JYLNVJYYQQXNEK-UHFFFAOYSA-N 0.000 claims description 6
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 5
- 239000012286 potassium permanganate Substances 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 4
- VCJZTATVUDMNLU-UHFFFAOYSA-N dibromomethylbenzene Chemical compound BrC(Br)C1=CC=CC=C1 VCJZTATVUDMNLU-UHFFFAOYSA-N 0.000 claims description 4
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 4
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims description 3
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 9
- 229960003670 flecainide acetate Drugs 0.000 abstract description 8
- 239000003054 catalyst Substances 0.000 abstract description 4
- QKEZTJYRBHOKHH-UHFFFAOYSA-N 1,4-dibromo-2-methylbenzene Chemical compound CC1=CC(Br)=CC=C1Br QKEZTJYRBHOKHH-UHFFFAOYSA-N 0.000 abstract 2
- 239000007858 starting material Substances 0.000 abstract 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- HNVXZKNHBRXZSH-UHFFFAOYSA-N 2-(2,2,2-trifluoroethoxy)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OCC(F)(F)F HNVXZKNHBRXZSH-UHFFFAOYSA-N 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical class CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 3
- 229910052728 basic metal Inorganic materials 0.000 description 3
- 150000003818 basic metals Chemical class 0.000 description 3
- 229960000449 flecainide Drugs 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- RHPBLLCTOLJFPH-UHFFFAOYSA-N piperidin-2-ylmethanamine Chemical class NCC1CCCCN1 RHPBLLCTOLJFPH-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RBZMSGOBSOCYHR-UHFFFAOYSA-N 1,4-bis(bromomethyl)benzene Chemical compound BrCC1=CC=C(CBr)C=C1 RBZMSGOBSOCYHR-UHFFFAOYSA-N 0.000 description 2
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 2
- DEMDYEJUAMZMSJ-UHFFFAOYSA-N 2,2,2-trifluoroethoxymethylbenzene Chemical compound FC(F)(F)COCC1=CC=CC=C1 DEMDYEJUAMZMSJ-UHFFFAOYSA-N 0.000 description 2
- RBCPJQQJBAQSOU-UHFFFAOYSA-N 2-bromo-5-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1Br RBCPJQQJBAQSOU-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical class 0.000 description 2
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 125000005587 carbonate group Chemical group 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- AMWRITDGCCNYAT-UHFFFAOYSA-L manganese oxide Inorganic materials [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 2
- PPNAOCWZXJOHFK-UHFFFAOYSA-N manganese(2+);oxygen(2-) Chemical class [O-2].[Mn+2] PPNAOCWZXJOHFK-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- DEUJSGDXBNTQMY-UHFFFAOYSA-N 1,2,2-trifluoroethanol Chemical compound OC(F)C(F)F DEUJSGDXBNTQMY-UHFFFAOYSA-N 0.000 description 1
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 1
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- FGERXQWKKIVFQG-UHFFFAOYSA-N 5-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Cl FGERXQWKKIVFQG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- 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
- 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
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/09—Preparation of ethers by dehydration of compounds containing hydroxy groups
-
- 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
- C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
- C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
本发明提供制备2,5-双(2,2,2-三氟乙氧基)-N-(2-哌啶基甲基)苯甲酰胺、其药学可接受盐及其重要中间体的方法,该方法涉及1,4-二卤代甲苯作为起始原料。该方法涉及通过将1,4-二溴甲苯与2,2,2-三氟乙醇在碱和含铜催化剂的存在下反应,以高产率制备起始原料2,5-双(2,2,2-三氟乙氧基)甲苯的技术。
Description
技术领域
[0001]本发明涉及制备2,5-双(2,2,2-三氟乙氧基)-N-(2-哌啶基甲基)苯甲酰胺(国际非专有名称-“氟卡胺(Flecainide)”)及其盐,特别是其药学可接受盐的改进方法。
背景技术
[0002]氟卡胺碱、其药学可接受盐,特别是其盐酸盐形式(hydrochloride form),在US-A-3900481中有一般性的说明。
[0003]如US-A-4005209所述,氟卡胺在人类治疗中用作抗心率不齐剂的活性成分。
[0004]现有技术有许多合成该化合物的方法的记载,例如:
[0005]US-B-4024175描述了从1,4-二溴代苯起始制备氟卡胺,其通过与三氟乙氧基化合物和乙酰化剂的反应转化为2,5-双(2,2,2-三氟乙氧基)苯乙酮,其随后得到氟卡胺。
[0006]GB-A-2045760中公开了一种从2,5-双(2,2,2-三氟乙氧基)苯甲酸起始制备氟卡胺的方法。2,5-双(2,2,2-三氟乙氧基)苯甲酸通过多步法制备,包括通过每摩尔二溴苯与8当量2,2,2-三氟乙醇的反应,将1,4-二溴苯转化为1,4-双(2,2,2-三氟乙氧基)苯,然后乙酰化1,4-双(2,2,2-三氟乙氧基)苯以形成2,5-双(2,2,2-三氟乙氧基)苯乙酮。随后将2,5-双(2,2,2-三氟乙氧基)苯乙酮氧化为相应的2,5-双(2,2,2-三氟乙氧基)苯甲酸。
[0007]随后,2,5-双(2,2,2-三氟乙氧基)苯甲酸在一步中转化成其酰氯,并与2-(氨基甲基)哌啶反应以形成氟卡胺。或者,酰氯可以与2-(氨基甲基)吡啶反应,然后将吡啶环催化氢化,以形成氟卡胺。
[0008]使用1,4-二溴苯形成1,4-双(2,2,2-三氟乙氧基)苯的缺点在于,该方法需要8当量2,2,2-三氟乙醇的反应而理论上只需要2当量。然而,使用的2,2,2-三氟乙醇少于8当量会导致向1,4-双(2,2,2-三氟乙氧基)苯的转化不完全,使起始原料和1-溴-4-(2,2,2-三氟乙氧基)苯成为主要杂质。
[0009]一步法的另一个缺点在于,酰氯非选择性地与2-(氨基甲基)哌啶的两个氮原子反应,导致形成两个酰化异构体的混合物。这是在现在商业上优选通过吡啶中间体的两步法的主要原因。另一个缺点是由于酰氯中间体是液体,其不能长期保存而必须在其制备后立刻使用。
[0010]用于获得2,5-双(2,2,2-三氟乙氧基)苯甲酸的多步法还有其它缺点。
[0011]2,5-双(2,2,2-三氟乙氧基)苯甲酸也可以从1-溴-4-氟苯(参见WO-A-02066413)或从2-溴-5-氯苯甲酸(参见WO-A-9902498)制备。
[0012]为了从2-溴-5-氯苯甲酸制备2,5-双(2,2,2-三氟乙氧基)苯甲酸,使用氢化钠结合N,N-二甲基甲酰胺。然而,已知使用氢化钠结合N,N-二甲基甲酰胺可导致爆炸(参见BUCKLEY,J..“Report on thermal reaction(热反应报告)”,“Chem.Eng.News”出版,1982,vol.60,no.28,p.5.,POND,DAVID,“Sodium hydride and DMF(氢化钠和DMF)”,“Chem.Eng.News”出版,1982,vol.60,no.37,p.5,43)。这是WO-A-9902498公开的方法的主要缺点。此外,使用1-溴-4-氟苯作为起始原料相对昂贵。
[0013]WO-A-02066413中公开的方法是多步法,包括获得2,5-双(2,2,2-三氟乙氧基)苯基乙醛酸烷基酯作为中间产物,其被氧化以形成2,5-双(2,2,2-三氟-乙氧基)苯甲酸。然而,此方法由于高成本仅具有有限的商业应用。
[0014]WO-A-9902498中公开的方法从2,5-双(2,2,2-三氟乙氧基)苯甲酸的氰基甲酯起始,其选择性地与2-(氨基甲基)哌啶反应以提供氟卡胺。
[0015]WO-A-02066413中公开的方法从2,5-双(2,2,2-三氟乙氧基)苯起始,其转化为2,5-双(2,2,2-三氟乙氧基)苯甲酰氯,然后与2,2,2-三氟乙醇在合适碱的存在下反应以产生2,5-双(2,2,2-三氟乙氧基)苯甲酸酯。最后,2,5-双(2,2,2-三氟乙氧基)苯甲酸酯与2-(氨基甲基)吡啶反应以形成2,5-双(2,2,2-三氟乙氧基)吡啶基苯甲酰胺,其随后还原以形成氟卡胺。
[0016]用于制备2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基-甲基)苯甲酰胺的现有技术方法具有一些缺点,它们已经通过本发明克服,即:
1.以前通过以下方式实现在芳香环上引入三氟乙氧基取代基
·通过采用高成本的磺酸酯离去基团,例如三氟甲磺酸酯或全氟丁磺酸酯,或者
·通过在甲基甲酰胺中在NaH的存在下用2,2,2-三氟乙醇处理1,4-二溴苯或5-溴-2-氯苯甲酸;
2.三氟乙氧基取代的芳香体系的衍生化以产生2,5-双(三氟乙氧基)苯甲酸或其衍生物,所述衍生化通过Friedel-Crafts酰基化,随后氯化进行;以及
3.2,5-双(2,2,2-三氟乙氧基)苯甲酸转化为2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基-甲基)苯甲酰胺以前需要制备酰氯或三氯苯乙酮,处理这些中间体意味着不必要的挑战。
发明内容
技术问题
[0017]本发明的目的在于克服现有技术上述缺点。特别是,本发明的目的在于提供一种新的商业方法以制备氟卡胺醋酸盐(acetate salt)或其盐,特别是其药学可接受盐,该方法从商购的式I表示的二卤代甲苯起始,其中X1和X2各自为F、Cl、Br或I。
技术方案
[0018]通过本发明的方法实现上述目的,所述方法包括下列从2,5-二溴甲苯起始顺序组合的四个步骤:
1.以三氟乙氧基取代2,5-二溴甲苯的芳香族溴取代基,由此制备2,5-双(三氟乙氧基)甲苯或2-溴-5-三氟乙氧基甲苯与5-溴-2-三氟乙氧基甲苯中的任何中间取代产物,
2.氧化2,5-双(三氟乙氧基)甲苯以制备2,5-双(三氟乙氧基)苯甲酸,
3.利用氯甲酸酯原位活化2,5-双(三氟乙氧基)苯甲酸,以2-(氨基甲基)吡啶取代离去的碳酸酯基(carbonate group),和
4.氢化2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基-甲基)苯甲酰胺以获得醋酸氟卡胺(Flecainide acetate)。
优点
[0019]下面的反应流程1概述了本发明制备醋酸氟卡胺的方法。该方法包括以下优点:
1.分别使用低毒性的、更环保的材料和溶剂;
2.使用金属钠代替氢化钠并与N,N-二甲基甲酰胺组合作为更安全的工业生产方法;
3.以高产率生产所需的终产物;
4.适应大规模生产,不需要专门的设备。
[0020]反应流程1
[0021]
[0022]因此,本发明的主题是制备式VI化合物及其盐,特别是其药学可接受盐的方法:
其中,R是2-哌啶基或2-吡啶基,所述方法包括以下步骤:
[0023]a)从式I的化合物制备式II的化合物
其中X1和X2各自为F、Cl、Br和I,
通过式I的2,5-二卤代甲苯与强碱和2,2,2-三氟乙醇在非质子溶剂中以及催化剂的存在下反应形成式II的2,5-双(2,2,2-三氟乙氧基)甲苯,
[0024]b)氧化化合物II以获得式III的2,5-双(2,2,2-三氟乙氧基)苯甲酸;
[0025]c)利用羧酸酯活化式III的苯甲酸,其后,将式III的苯甲酸的混合酸酐与式RCH2NH2的胺反应(其中R是2-吡啶基),以获得式IV的化合物;
[0026]d)将式IV的化合物转化为盐,特别是转化为其药学可接受盐,以获得式V的化合物。
[0027]本发明的主题还有制备关键的中间体2,5-双(2,2,2-三氟乙氧基)苯甲酸的方法,该方法从式I的起始原料起始,其中X1和X2各自为F、CI、B和I。
[0028]式I的起始原料与2,2,2-三氟乙醇在碱和合适的催化剂(如铜催化剂)的存在下反应,获得高产率(如92%)的式II化合物。
[0029]
[0030]利用高锰酸盐化合物(如高锰酸钠或高锰酸钾)氧化式II的化合物以获得式III的化合物,其为制备式V的化合物醋酸氟卡胺的关键中间体。
[0031]利用羧酸酯活化式III的化合物,然后与2-(氨基甲基)吡啶的伯氨基反应后获得式IV的化合物。
[0032]本发明的另一主题是用于制备式V的化合物醋酸氟卡胺的中间体2,5-二溴甲苯的制备和用途。
[0033]在含有钯碳和铂碳的合适溶剂(如水)中,式IV化合物的多相催化氢化在脂肪族羧酸(如冰醋酸)溶液中进行,获得式V的化合物醋酸氟卡胺。
具体实施方式
[0034]如上所示,本发明方法涉及通过在强碱和含铜催化剂的存在下使2,5-二卤代甲苯(I)与2,2,2-三氟乙醇反应,从而最初制备2,5-双(2,2,2-三氟乙氧基)甲苯(II)。2,2,2-三氟乙醇以约2至10倍摩尔的量过量于2,5-二卤代甲苯进行反应,用三氟乙氧基取代2,5-二卤代甲苯的芳香族卤素取代基。
[0035]可促使反应的碱包括碱金属,如金属钠。反应中使用含铜物质作为催化剂,如硫酸铜(II)。为了进行反应,N,N-二甲基甲酰胺能够用作非质子溶剂。进行反应的最佳方式是在约85-105℃下进行。
[0036]根据一个特别优选的实施方式,2,5-二溴甲苯(I)(其中X1和X2是Br)与2,2,2-三氟乙醇钠(通过2,2,2-三氟乙醇与钠反应制得)在约85-105℃下在含有CuSO4的N,N-二甲基甲酰胺中反应。
[0037]然后2,5-双(2,2,2-三氟乙氧基)甲苯(II)在合适的氧化剂存在下被氧化成2,5-双(2,2,2-三氟乙氧基)苯甲酸(III)。作为氧化剂,可以使用高锰酸钾和高锰酸钠。
[0038]2,5-双(2,2,2-三氟乙氧基)苯甲酸(III)通过氯甲酸乙酯被活化,然后与2-(氨基甲基)吡啶的伯氨基反应获得2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基甲基)苯甲酰胺(IV)。
[0039]2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基甲基)苯甲酰胺(IV)在合适溶剂(如水)中于钯碳或铂碳存在条件下被氢化。还原可以在4-6大气压下的氢气氛中进行。反应可以进行至多约3小时。残余滤液与合适的碱(如NaOH)反应生成氟卡胺游离碱。氟卡胺游离碱然后转化为醋酸氟卡胺(V)。该游离碱由此与冰醋酸反应形成醋酸酯。反应可以在31℃下进行。
[0040]通过参照下面的非限定性实例,本发明将更详细地得到说明。
[0041]实施例1
[0042]制备2,5-双(2,2,2-三氟乙氧基)甲苯(II)
[0043]将2,2,2-三氟乙醇(55.0g,0.550mol)加入到装有回流冷凝管的玻璃容器中的二噁烷(125ml)中。将金属钠(11.5g,0.500mol)分批(2-3克/批)加入到溶液中,导致温度从22℃升高至90℃。溶液在85-105℃下搅拌直到钠完全溶解,然后加入N,N-二甲基甲酰胺(100ml),2,5-二溴甲苯(I)(42.5g,0.170mol)和无水硫酸铜(II)(2.9g,0.018mol)。反应混合物在95-100℃下搅拌4小时,然后冷却至25-30℃,将其倒入900ml冷(5-10℃)40%乙醇水溶液中。
[0044]加入浓盐酸(-25ml,0.300mol),直到pH=1-2。结晶悬浮物在-5-0℃下搅拌1小时,过滤固体白色沉淀,然后用50ml水洗涤反应容器和过滤器上的产物滤饼。中间体2,5-双(2,2,2-三氟乙氧基)甲苯(II)在室温常压下干燥5小时,然后在22-24℃减压干燥4小时。获得白色或灰白色粉末状2,5-双(2,2,2-三氟乙氧基)甲苯(45.5g,92%),其熔点为37℃-42℃。
[0045]实施例2
[0046]制备2,5-双(2,2,2-三氟乙氧基)苯甲酸(III)
[0047]将2,5-双(2,2,2-三氟乙氧基)甲苯(II)(220g,0.986mol)在18-23℃下加入到磁力搅拌下的吡啶(1550ml)中。反应混合物在回流下搅拌。然后,将10%NaOH水溶液(20ml,0.050mol)和硫酸铜(II)(0.27g,0.0017mol)加入到反应混合物中。
[0048]反应混合物在81℃下加热1小时,在此温度下,于6.5小时内分批加入40%高锰酸钠水溶液(2290g,6.45mol)。加入高锰酸钠水溶液后,反应混合物在83-93℃下搅拌75分钟。在80-95℃下通过过滤分离锰氧化物沉淀,用5升热水(80℃)洗涤过滤器上的锰氧化物。50分钟后合并的滤液被冷却至9℃。
[0049]过滤结晶悬浮物得到未反应的2,5-双(2,2,2-三氟乙氧基)甲苯(II)湿滤饼,然后将其除去。
[0050]将活性碳(20.0g)与反应混合物滤液混合,搅拌75分钟;通过过滤分离碳沉淀,用浓HCl酸化液体相使pH=1-2。过滤结晶溶液,用200ml水洗涤过滤器上的产物滤饼。
[0051]中间体2,5-双(2,2,2-三氟乙氧基)苯甲酸(III)在减压下干燥18小。获得灰白色粉末状2,5-双(2,2,2-三氟乙氧基)苯甲酸(210.2g,81.6%),其熔点为121℃-125℃。
[0052]实施例3
[0053]在1升圆底烧瓶中混合吡啶(310ml)、水(175ml)和2,5-双(2,2,2-三氟乙氧基)甲苯(44.4g,0.154mol),用氢氧化钠将pH调节为11-12。
[0054]将混合物加热至85℃,用分成6份(各34克)的高锰酸钾(共204克,1.29mol)处理。高锰酸盐的加入速度使温度维持在90-100℃。将反应混合物的温度维持在85-95℃1小时,进行热过滤。用水洗涤锰氧化物沉淀,将洗涤液与吡啶-水滤液合并,然后冷却至5-10℃,过滤以除去未反应的起始原料。
[0055]通过浓盐酸将滤液酸化使pH=1-2,且通过过滤移出白色沉淀,从而分离出产物。用水在过滤器上进行洗涤并减压干燥后,获得37.2g(0.116mol,75.2%)白色粉末状2,5-双(2,2,2-三氟乙氧基)苯甲酸,其熔点为121℃-125℃。
[0056]实施例4
[0057]制备2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基-甲基)苯甲酰胺(IV)
[0058]在装有温度计、滴液漏斗和氯化钙干燥管的4升的3颈圆底烧瓶中混合2,5-双(2,2,2-三氟乙氧基)苯甲酸(III)(100g,0.314mol)、三乙胺(50.2ml)和醋酸乙酯(630ml)。搅拌并冷却反应混合物至5-10℃。氯甲酸乙酯(33.0ml,0.345mol)的醋酸乙酯(315ml)溶液滴加到反应混合物中。然后,反应混合物在5-10℃下搅拌30分钟。2-(氨基甲基)吡啶(36.0ml,0.350mol)的醋酸乙酯(315ml)溶液滴加到混合物中。反应混合物在15-25℃下搅拌1小时。加入水(600ml),分离出水层并用醋酸乙酯(300ml)进行萃取。真空下浓缩有机层,使体积为原来体积的三分之二,加入己烷(750ml)。所得悬浮液在5-10℃下搅拌1小时。
[0059]通过过滤分离沉淀,用己烷(250ml)洗涤。获得116.4g(91.7%)2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基-甲基)苯甲酰胺(IV),其熔点为101℃-106℃。
[0060]实施例5
[0061]制备醋酸2,5-双(2,2,2-三氟乙氧基)-N-(2-哌啶基甲基)苯甲酰胺(V)
[0062]在10升高压釜中混合2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基-甲基)苯甲酰胺(1205g,2.88mol)、冰醋酸(4000ml)、含水量为61%的5%铂碳(105.5g)和含水量为60%的10%钯碳(28.7g)。
[0063]将含有反应混合物的高压釜加热至70℃,在0.39×106Pa氢气压下快速搅拌20-30分钟。5分钟后压力升高至0.59×106Pa。在69-72℃下3个小时内氢气吸收停止,但氢化反应仍继续2个小时。过滤反应混合物,以除去催化剂。
[0064]通过减压蒸馏除去约60%的溶剂。将水(35L)加入到蒸馏残余物中,然后用NaOH水溶液处理混合物,使pH=13-14。过滤固体白色沉淀,减压下进行干燥,然后将其溶解在醋酸乙酯(12L)中。将溶液加热至73℃达5分钟,进行过滤,在31℃下向滤液加入冰醋酸(175ml)。
[0065]通过过滤分离沉淀,然后用醋酸乙酯(500ml)洗涤。20℃下减压干燥湿滤饼14小时,获得醋酸2,5-双(2,2,2-三氟乙氧基)-N-(2-哌啶基甲基)苯甲酰胺白色固体(1173g,86%),其熔点为146-152℃。
权利要求书(按照条约第19条的修改)
1.制备式VI的化合物或其药学可接受的盐的方法:
其中,R是2-哌啶基,所述方法包括以下步骤:
a)式(I)的2,5-二卤代甲苯与碱金属和2,2,2-三氟乙醇在非质子溶剂中以及催化剂的存在下反应形成式(II)的2,5-双(2,2,2-三氟乙氧基)甲苯,
其中X1和X2为卤素,
b)氧化式(II)的2,5-双(2,2,2-三氟乙氧基)甲苯以获得式(III)的2,5-双(2,2,2-三氟乙氧基)苯甲酸;
c)利用碳酸酯活化式(III)的2,5-双(2,2,2-三氟乙氧基)苯甲酸,将苯甲酸的混合酸酐与其中R1是2-吡啶基的式R1CH2NH2的胺反应以获得式(IV)的2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基甲基)苯甲酰胺;
d)将式(IV)的2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基甲基)苯甲酰胺转化为其药学可接受盐,以获得式V的醋酸2,5-双(2,2,2-三氟乙氧基)-N-(哌啶基甲基)苯甲酰胺
2.如权利要求1所述的方法,金属钠作为碱金属、铜型催化剂为硫酸铜,步骤a)在合适的非质子溶剂中进行。
3.如权利要求2所述的方法,其中N,N-二甲基甲酰胺用作步骤a)中的合适的非质子溶剂。
4.如权利要求1所述的方法,以高锰酸钾和高锰酸钠作为步骤b)中的氧化剂。
5.如权利要求1所述的方法,以氯甲酸乙酯作为步骤c)中的碳酸酯。
6.如权利要求1所述的方法,以2-(氨基甲基)吡啶作为步骤c)中的胺,在碳酸酯中获得2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基-甲基)-苯甲酰胺。
7.如权利要求1所述的方法,其中R是2-哌啶基,在步骤d)中获得醋酸2,5-双(2,2,2-三氟乙氧基)-N-(2-哌啶基甲基)苯甲酰胺。
8.如权利要求1所述的方法,其中式1中X1和X2是Cl、Br、J和Cl。
9.如权利要求8所述的方法,其中式1中X1和X2是Br。
Claims (10)
1.制备式VI的化合物或其药学可接受的盐的方法:
其中,R是2-哌啶基或2-吡啶基,所述方法包括以下步骤:
a)式(I)的2,5-二卤代甲苯与强碱和2,2,2-三氟乙醇在非质子溶剂中以及催化剂的存在下反应形成式(II)的2,5-双(2,2,2-三氟乙氧基)甲苯,
其中X1和X2为卤素,
b)氧化式(II)的2,5-双(2,2,2-三氟乙氧基)甲苯以获得式(III)的2,5-双(2,2,2-三氟乙氧基)苯甲酸;
c)利用碳酸酯活化式(III)的2,5-双(2,2,2-三氟乙氧基)苯甲酸,将苯甲酸的混合酸酐与其中R是2-吡啶基的式RCH2NH2的胺反应以获得式(IV)的2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基甲基)苯甲酰胺;
d)将式(IV)的2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基甲基)苯甲酰胺转化为其药学可接受盐,以获得式V的醋酸2,5-双(2,2,2-三氟乙氧基)-N-(哌啶基甲基)苯甲酰胺
2.如权利要求1所述的方法,以金属钠作为强碱、以铜型催化剂如硫酸铜作为催化剂,步骤a)在合适的非质子溶剂中进行。
3.如权利要求2所述的方法,其中N,N-二甲基甲酰胺用作步骤a)中的合适的非质子溶剂。
4.如权利要求1所述的方法,以高锰酸钾或高锰酸钠作为步骤b)中的氧化剂。
5.如权利要求1所述的方法,以氯甲酸乙酯作为步骤c)中的碳酸酯。
6.如权利要求1所述的方法,以2-(氨基甲基)吡啶作为步骤c)中的胺,在碳酸酯中获得2,5-双(2,2,2-三氟乙氧基)-N-(吡啶-2-基-甲基)-苯甲酰胺。
7.如权利要求1所述的方法,其中R是2-吡啶基,在步骤d)中获得醋酸2,5-双(2,2,2-三氟乙氧基)-N-(2-哌啶基甲基)苯甲酰胺。
8.如权利要求1所述的方法,其中式1中X1和X2是Cl、Br、J和Cl。
9.如权利要求8所述的方法,其中式1中X1和X2是Br。
10.如权利要求1所述的方法,其中式I为2,5-二溴甲苯。
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EP06123547.9 | 2006-11-06 | ||
EP06123547A EP1918280A1 (en) | 2006-11-06 | 2006-11-06 | Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide and salts thereof |
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CNA2007800358109A Pending CN101516817A (zh) | 2006-11-06 | 2007-11-02 | 制备三氟乙氧基甲苯的方法 |
CNA2007800358537A Pending CN101516845A (zh) | 2006-11-06 | 2007-11-02 | 2,5-双(2,2,2-三氟乙氧基)-n-(2-哌啶基甲基)-苯甲酰胺及其盐的制备方法 |
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US (2) | US20100056794A1 (zh) |
EP (3) | EP1918280A1 (zh) |
JP (2) | JP2010508330A (zh) |
KR (2) | KR20090064456A (zh) |
CN (2) | CN101516817A (zh) |
AT (1) | ATE514670T1 (zh) |
AU (2) | AU2007316690A1 (zh) |
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CA (2) | CA2660358A1 (zh) |
EA (2) | EA200900357A1 (zh) |
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CN102977003A (zh) * | 2012-11-28 | 2013-03-20 | 郑州大明药物科技有限公司 | 醋酸氟卡胺的制备方法 |
CN111018694A (zh) * | 2019-12-12 | 2020-04-17 | 贵州省欣紫鸿药用辅料有限公司 | 一种氟卡尼的生产方法 |
CN115368786B (zh) * | 2022-08-15 | 2023-05-09 | 江阴市华昌不锈钢管有限公司 | 一种超级奥氏体耐高温、耐腐蚀不锈钢焊管的制备工艺 |
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US3900481A (en) * | 1974-04-01 | 1975-08-19 | Riker Laboratories Inc | Derivatives of pyrrolidine and piperidine |
US4617396A (en) * | 1979-03-19 | 1986-10-14 | Riker Laboratories, Inc. | Process for the preparation of derivatives of piperidine |
IL120715A (en) * | 1997-04-21 | 2000-07-16 | Finetech Ltd | Process for the preparation of (2,2,2,-trifluoroethoxy)benzoic acids |
DE10025700A1 (de) * | 2000-05-26 | 2001-11-29 | Merck Patent Gmbh | Verfahren zur Herstellung von trifluorethoxysubstituierten Benzoesäuren |
US6458957B1 (en) * | 2000-07-12 | 2002-10-01 | Geneva Pharmaceuticals, Inc. | α,α-dibromo-α-chloro-acetophenones as synthons |
ITMI20011772A1 (it) * | 2001-08-10 | 2003-02-10 | A M S A Anonima Materie Sint E | Processo per la preparazione della 2,5-bis-(2,2,2-trifluoroetossi)-n-(2-piperidilmetil)-benzamide(flecainide) |
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 |
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US20100056794A1 (en) | 2010-03-04 |
MX2009004647A (es) | 2009-05-20 |
CA2660364A1 (en) | 2008-05-15 |
JP2010508330A (ja) | 2010-03-18 |
MX2009004648A (es) | 2009-05-21 |
EP2079674A1 (en) | 2009-07-22 |
WO2008055851A8 (en) | 2009-04-09 |
EP2079692A1 (en) | 2009-07-22 |
BRPI0714991A2 (pt) | 2013-07-30 |
KR20090064456A (ko) | 2009-06-18 |
CN101516817A (zh) | 2009-08-26 |
US20100063292A1 (en) | 2010-03-11 |
WO2008055851A1 (en) | 2008-05-15 |
KR20090055638A (ko) | 2009-06-02 |
EP2079674B1 (en) | 2011-06-29 |
WO2008055849A1 (en) | 2008-05-15 |
CA2660358A1 (en) | 2008-05-15 |
ZA200902183B (en) | 2010-07-28 |
EA200900356A1 (ru) | 2009-10-30 |
BRPI0714989A2 (pt) | 2013-07-30 |
ZA200902184B (en) | 2010-03-31 |
EP1918280A1 (en) | 2008-05-07 |
JP2010508331A (ja) | 2010-03-18 |
ATE514670T1 (de) | 2011-07-15 |
AU2007316690A1 (en) | 2008-05-15 |
EA200900357A1 (ru) | 2009-10-30 |
AU2007316692A1 (en) | 2008-05-15 |
PL2079674T3 (pl) | 2011-11-30 |
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