ES2234797T3 - Procedimiento para la preparacion de citalopram partiendo de 5-formilftalida. - Google Patents
Procedimiento para la preparacion de citalopram partiendo de 5-formilftalida.Info
- Publication number
- ES2234797T3 ES2234797T3 ES01830517T ES01830517T ES2234797T3 ES 2234797 T3 ES2234797 T3 ES 2234797T3 ES 01830517 T ES01830517 T ES 01830517T ES 01830517 T ES01830517 T ES 01830517T ES 2234797 T3 ES2234797 T3 ES 2234797T3
- Authority
- ES
- Spain
- Prior art keywords
- formula
- procedure
- group
- citalopram
- triphenylmethyl
- 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 - Lifetime
Links
- 229960001653 citalopram Drugs 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- WSEQXVZVJXJVFP-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 title description 2
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims abstract description 48
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 150000002923 oximes Chemical class 0.000 claims abstract description 28
- -1 4-fluorophenylmagnesium halide Chemical class 0.000 claims abstract description 22
- 125000003118 aryl group Chemical group 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 18
- 150000002009 diols Chemical class 0.000 claims abstract description 17
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 15
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 14
- 150000004820 halides Chemical class 0.000 claims abstract description 13
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- VLQBZZYXIIHJIP-UHFFFAOYSA-N CN(C)CCC[Mg] Chemical compound CN(C)CCC[Mg] VLQBZZYXIIHJIP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000002576 ketones Chemical class 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 230000008030 elimination Effects 0.000 claims abstract description 5
- 238000003379 elimination reaction Methods 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 125000002560 nitrile group Chemical group 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 3
- 230000001351 cycling effect Effects 0.000 claims abstract description 3
- 150000002825 nitriles Chemical class 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 239000000543 intermediate Substances 0.000 claims description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 9
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- NOYCNNBKNIAAHS-UHFFFAOYSA-N FC1=CC=C([Mg])C=C1 Chemical compound FC1=CC=C([Mg])C=C1 NOYCNNBKNIAAHS-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 150000001649 bromium compounds Chemical group 0.000 claims 1
- 150000001805 chlorine compounds Chemical group 0.000 claims 1
- DBSGLQIKLWDTTD-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carbaldehyde Chemical compound O=CC1=CC=C2C(=O)OCC2=C1 DBSGLQIKLWDTTD-UHFFFAOYSA-N 0.000 abstract description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 239000012071 phase Substances 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000008367 deionised water Substances 0.000 description 14
- 229910021641 deionized water Inorganic materials 0.000 description 14
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 235000019256 formaldehyde Nutrition 0.000 description 5
- NZFHJBSDSXDUAO-UHFFFAOYSA-N o-tritylhydroxylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(ON)C1=CC=CC=C1 NZFHJBSDSXDUAO-UHFFFAOYSA-N 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 150000002680 magnesium Chemical class 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- ORWKVZNEPHTCQE-UHFFFAOYSA-N acetic formic anhydride Chemical compound CC(=O)OC=O ORWKVZNEPHTCQE-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 150000002443 hydroxylamines Chemical class 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- HKJJZYHKYHMFBY-UHFFFAOYSA-N (4-fluorophenyl)-[2-(hydroxymethyl)-4-(trityloxyiminomethyl)phenyl]methanone Chemical compound C=1C=C(C(=O)C=2C=CC(F)=CC=2)C(CO)=CC=1C=NOC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 HKJJZYHKYHMFBY-UHFFFAOYSA-N 0.000 description 2
- VTWKXBJHBHYJBI-SOFGYWHQSA-N (ne)-n-benzylidenehydroxylamine Chemical compound O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 description 2
- GRNCGIVYWGYYLT-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbaldehyde Chemical compound O1CC2=CC(C=O)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 GRNCGIVYWGYYLT-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- SSQVKKGZFIVXEX-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carbonyl chloride Chemical compound ClC(=O)C1=CC=C2C(=O)OCC2=C1 SSQVKKGZFIVXEX-UHFFFAOYSA-N 0.000 description 2
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 2
- GEFFUPMLASDXTR-UHFFFAOYSA-N 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-(trityloxyiminomethyl)phenyl]butan-1-ol Chemical compound C=1C=C(C=NOC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C(CO)C=1C(O)(CCCN(C)C)C1=CC=C(F)C=C1 GEFFUPMLASDXTR-UHFFFAOYSA-N 0.000 description 2
- IUSPXLCLQIZFHL-UHFFFAOYSA-N 5-bromo-3h-2-benzofuran-1-one Chemical compound BrC1=CC=C2C(=O)OCC2=C1 IUSPXLCLQIZFHL-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- WVBFIDZABNOPOS-UHFFFAOYSA-N (4-fluorophenyl)-[2-(hydroxymethyl)-4-(phenylmethoxyiminomethyl)phenyl]methanone Chemical compound C(C1=CC=CC=C1)ON=CC1=CC(=C(C=C1)C(C1=CC=C(C=C1)F)=O)CO WVBFIDZABNOPOS-UHFFFAOYSA-N 0.000 description 1
- WIHMBLDNRMIGDW-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;hydron;bromide Chemical compound [Br-].O1CC2=CC(C#N)=CC=C2C1(CCC[NH+](C)C)C1=CC=C(F)C=C1 WIHMBLDNRMIGDW-UHFFFAOYSA-N 0.000 description 1
- XEEGWTLAFIZLSF-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carbonitrile Chemical compound N#CC1=CC=C2C(=O)OCC2=C1 XEEGWTLAFIZLSF-UHFFFAOYSA-N 0.000 description 1
- OFYLHQMBVCAUSM-UHFFFAOYSA-N 2-tert-butyl-2-methyloxolane Chemical compound CC(C)(C)C1(C)CCCO1 OFYLHQMBVCAUSM-UHFFFAOYSA-N 0.000 description 1
- WOLPGGGWZDXCNM-UHFFFAOYSA-N 3-[5-bromo-1-(4-fluorophenyl)-3h-2-benzofuran-1-yl]-n,n-dimethylpropan-1-amine Chemical compound O1CC2=CC(Br)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WOLPGGGWZDXCNM-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KEEXQDLFNVUTBZ-UHFFFAOYSA-N C=1C=C(C=NOCC=2C=CC=CC=2)C=C(CO)C=1C(O)(CCCN(C)C)C1=CC=C(F)C=C1 Chemical compound C=1C=C(C=NOCC=2C=CC=CC=2)C=C(CO)C=1C(O)(CCCN(C)C)C1=CC=C(F)C=C1 KEEXQDLFNVUTBZ-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- NDYLAABPGFMVIY-UHFFFAOYSA-M [Cl-].CN(C)CCC[Mg+] Chemical compound [Cl-].CN(C)CCC[Mg+] NDYLAABPGFMVIY-UHFFFAOYSA-M 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 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 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229960000584 citalopram hydrobromide Drugs 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- VHARROAGRCLEDM-UHFFFAOYSA-N o-benzhydrylhydroxylamine Chemical compound C=1C=CC=CC=1C(ON)C1=CC=CC=C1 VHARROAGRCLEDM-UHFFFAOYSA-N 0.000 description 1
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01830517A EP1281707B1 (en) | 2001-08-02 | 2001-08-02 | Process for the preparation of 5-subtituted isobenzofurans |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2234797T3 true ES2234797T3 (es) | 2005-07-01 |
Family
ID=8184643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES01830517T Expired - Lifetime ES2234797T3 (es) | 2001-08-02 | 2001-08-02 | Procedimiento para la preparacion de citalopram partiendo de 5-formilftalida. |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US7166729B2 (enExample) |
| EP (1) | EP1281707B1 (enExample) |
| JP (1) | JP2005501056A (enExample) |
| KR (1) | KR20040043176A (enExample) |
| CN (1) | CN1298713C (enExample) |
| AR (1) | AR036212A1 (enExample) |
| AT (1) | ATE286037T1 (enExample) |
| AU (1) | AU2002325385B2 (enExample) |
| BG (1) | BG108554A (enExample) |
| BR (1) | BR0211858A (enExample) |
| CA (1) | CA2456004A1 (enExample) |
| DE (1) | DE60108105T2 (enExample) |
| DK (1) | DK1281707T3 (enExample) |
| ES (1) | ES2234797T3 (enExample) |
| HU (1) | HUP0401166A3 (enExample) |
| MX (1) | MXPA04001030A (enExample) |
| PL (1) | PL368320A1 (enExample) |
| PT (1) | PT1281707E (enExample) |
| RO (1) | RO122147B1 (enExample) |
| TW (1) | TWI225055B (enExample) |
| WO (1) | WO2003011846A2 (enExample) |
| ZA (1) | ZA200400841B (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IS7239A (is) * | 2001-12-14 | 2004-04-29 | H. Lundbeck A/S | Aðferð til framleiðslu á essítalóprami |
| AU2003263155A1 (en) * | 2002-09-20 | 2004-04-08 | H. Lundbeck A/S | Method for manufacture of dihydroisobenzofuran derivatives |
| GB0601286D0 (en) * | 2006-01-23 | 2006-03-01 | Sandoz Ag | Asymmetric synthesis |
| CA2932121A1 (en) | 2007-11-30 | 2009-06-11 | Newlink Genetics Corporation | Ido inhibitors |
| CN106632182A (zh) * | 2016-12-07 | 2017-05-10 | 万全万特制药（厦门）有限公司 | 草酸艾司西酞普兰脱甲基杂质的制备方法 |
| DE112019006382T8 (de) * | 2018-12-22 | 2021-12-09 | Malladi Drugs And Pharmaceuticals Ltd. | NEUES VERFAHREN ZUR HERSTELLUNG VONR-PHENYLACETYLCARBINOL UND β-AMINOALKOHOLEN |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8419963D0 (en) * | 1984-08-06 | 1984-09-12 | Lundbeck & Co As H | Intermediate compound and method |
| GB8814057D0 (en) * | 1988-06-14 | 1988-07-20 | Lundbeck & Co As H | New enantiomers & their isolation |
| SK283309B6 (sk) * | 1997-07-08 | 2003-05-02 | H. Lundbeck A/S | Spôsob výroby citalopramu a medziprodukty |
| EP1173431B2 (en) * | 1999-04-14 | 2009-08-26 | H. Lundbeck A/S | Method for the preparation of citalopram |
| ITMI991486A1 (it) * | 1999-07-06 | 2001-01-06 | Vis Farmaceutici S P A | Processo per la sintesi di citalopram |
| IES20010143A2 (en) * | 2000-02-24 | 2001-07-25 | Lundbeck & Co As H | Method for the preparation of citalopram |
| IT1319686B1 (it) * | 2000-12-12 | 2003-10-23 | C D Farmasint S R L | Procedimento di preparazione di citalopram. |
-
2001
- 2001-08-02 ES ES01830517T patent/ES2234797T3/es not_active Expired - Lifetime
- 2001-08-02 EP EP01830517A patent/EP1281707B1/en not_active Expired - Lifetime
- 2001-08-02 PT PT01830517T patent/PT1281707E/pt unknown
- 2001-08-02 AT AT01830517T patent/ATE286037T1/de not_active IP Right Cessation
- 2001-08-02 DK DK01830517T patent/DK1281707T3/da active
- 2001-08-02 DE DE60108105T patent/DE60108105T2/de not_active Expired - Fee Related
-
2002
- 2002-07-29 JP JP2003517038A patent/JP2005501056A/ja active Pending
- 2002-07-29 CA CA002456004A patent/CA2456004A1/en not_active Abandoned
- 2002-07-29 WO PCT/EP2002/008550 patent/WO2003011846A2/en not_active Ceased
- 2002-07-29 RO ROA200400084A patent/RO122147B1/ro unknown
- 2002-07-29 BR BR0211858-0A patent/BR0211858A/pt not_active IP Right Cessation
- 2002-07-29 MX MXPA04001030A patent/MXPA04001030A/es active IP Right Grant
- 2002-07-29 CN CNB028183231A patent/CN1298713C/zh not_active Expired - Fee Related
- 2002-07-29 PL PL02368320A patent/PL368320A1/xx not_active Application Discontinuation
- 2002-07-29 HU HU0401166A patent/HUP0401166A3/hu unknown
- 2002-07-29 AU AU2002325385A patent/AU2002325385B2/en not_active Ceased
- 2002-07-29 KR KR10-2004-7001616A patent/KR20040043176A/ko not_active Ceased
- 2002-07-31 TW TW091117176A patent/TWI225055B/zh active
- 2002-08-02 AR ARP020102955A patent/AR036212A1/es unknown
-
2004
- 2004-01-30 BG BG108554A patent/BG108554A/bg unknown
- 2004-01-31 US US10/776,625 patent/US7166729B2/en not_active Expired - Fee Related
- 2004-02-02 ZA ZA200400841A patent/ZA200400841B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2002325385B2 (en) | 2007-07-05 |
| ATE286037T1 (de) | 2005-01-15 |
| US7166729B2 (en) | 2007-01-23 |
| HK1070357A1 (zh) | 2005-06-17 |
| CN1298713C (zh) | 2007-02-07 |
| DE60108105D1 (de) | 2005-02-03 |
| HUP0401166A2 (hu) | 2004-09-28 |
| MXPA04001030A (es) | 2004-12-03 |
| DK1281707T3 (da) | 2005-05-02 |
| KR20040043176A (ko) | 2004-05-22 |
| RO122147B1 (ro) | 2009-01-30 |
| PL368320A1 (en) | 2005-03-21 |
| BG108554A (bg) | 2005-03-31 |
| EP1281707A1 (en) | 2003-02-05 |
| WO2003011846A3 (en) | 2003-11-27 |
| HUP0401166A3 (en) | 2007-05-29 |
| ZA200400841B (en) | 2005-02-02 |
| CA2456004A1 (en) | 2003-02-13 |
| EP1281707B1 (en) | 2004-12-29 |
| WO2003011846B1 (en) | 2003-12-24 |
| AR036212A1 (es) | 2004-08-18 |
| TWI225055B (en) | 2004-12-11 |
| BR0211858A (pt) | 2004-09-21 |
| WO2003011846A2 (en) | 2003-02-13 |
| PT1281707E (pt) | 2005-04-29 |
| US20040230065A1 (en) | 2004-11-18 |
| CN1555370A (zh) | 2004-12-15 |
| AU2002325385B8 (en) | 2003-02-17 |
| DE60108105T2 (de) | 2005-12-08 |
| JP2005501056A (ja) | 2005-01-13 |
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