CN1239490C - 制备西酞普兰的中间体的方法 - Google Patents
制备西酞普兰的中间体的方法 Download PDFInfo
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- CN1239490C CN1239490C CNB2004100018711A CN200410001871A CN1239490C CN 1239490 C CN1239490 C CN 1239490C CN B2004100018711 A CNB2004100018711 A CN B2004100018711A CN 200410001871 A CN200410001871 A CN 200410001871A CN 1239490 C CN1239490 C CN 1239490C
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- China
- Prior art keywords
- formula
- compound
- acid
- alkyl
- citalopram
- 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.)
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- 150000002900 organolithium compounds Chemical class 0.000 claims description 3
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910015243 LiMg Inorganic materials 0.000 claims 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims 1
- 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 abstract description 24
- 229960001653 citalopram Drugs 0.000 abstract description 24
- 239000007818 Grignard reagent Substances 0.000 abstract description 4
- 150000004795 grignard reagents Chemical class 0.000 abstract description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 3
- QTWUWCFGWYYRRL-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2C(=O)OCC2=C1 QTWUWCFGWYYRRL-UHFFFAOYSA-N 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- -1 4-fluorophenyl magnesium halide Chemical class 0.000 description 31
- 125000000217 alkyl group Chemical group 0.000 description 23
- 125000003118 aryl group Chemical group 0.000 description 18
- 125000001072 heteroaryl group Chemical group 0.000 description 16
- 125000003282 alkyl amino group Chemical group 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000012024 dehydrating agents Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 230000001430 anti-depressive effect Effects 0.000 description 5
- 239000000935 antidepressant agent Substances 0.000 description 5
- 229940005513 antidepressants Drugs 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 150000003456 sulfonamides Chemical class 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- GECQEQCYCDJXJC-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carboxylic acid Chemical compound O1CC2=CC(C(O)=O)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 GECQEQCYCDJXJC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 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
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 125000001979 organolithium group Chemical group 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- IUXHPSPHPKXTPA-ONEGZZNKSA-N (e)-1-bromobut-1-ene Chemical compound CC\C=C\Br IUXHPSPHPKXTPA-ONEGZZNKSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- YXCRMKYHFFMNPT-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound C1=CC(F)=CC=C1C1C2=CC=C(C#N)C=C2CO1 YXCRMKYHFFMNPT-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- IWYHZMPXXYOJPU-UHFFFAOYSA-M CN(C)CCCC1(OCc2cc([Mg]Br)ccc12)c1ccc(F)cc1 Chemical compound CN(C)CCCC1(OCc2cc([Mg]Br)ccc12)c1ccc(F)cc1 IWYHZMPXXYOJPU-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical class OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- GWFKSQSXNUNYAC-AATRIKPKSA-N [(e)-hex-1-enyl]boronic acid Chemical compound CCCC\C=C\B(O)O GWFKSQSXNUNYAC-AATRIKPKSA-N 0.000 description 1
- ALIGTYPNWJPIKT-UHFFFAOYSA-M [Cl-].FC1=CC=C([Mg+])C=C1 Chemical compound [Cl-].FC1=CC=C([Mg+])C=C1 ALIGTYPNWJPIKT-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- VYEYJCBEXFTGBN-UHFFFAOYSA-N acetic acid;1,3-dimethyl-7h-purine-2,6-dione Chemical class CC(O)=O.O=C1N(C)C(=O)N(C)C2=C1NC=N2 VYEYJCBEXFTGBN-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000005910 alkyl carbonate group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
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Abstract
公开了一种制备西酞普兰的方法，包括将式VIII化合物转化为其中Z是卤素的式IV化合物，随后将式IV化合物转化为西酞普兰。还公开了制备式IV化合物的方法。
Description
本申请为2001年8月17日提交的中国专利申请01133947.0的分案申请。
技术领域
本发明涉及制备公知的抗抑郁药西酞普兰1-[3-(二甲基氨基)丙基]-1-(4-氟苯基)-1，3-二氢-5-异苯并呋喃甲腈的方法，制备在西酞普兰的制备中使用的中间体的方法和将所述的中间体转化为西酞普兰的方法。
背景技术
西酞普兰是公知的抗抑郁药，已经面市数年，其结构式如下：
式I
它为选择性的、中枢活性的5-羟色胺(5-羟基色胺；5-HT)再摄取抑制剂，因此具有抗抑郁活性。在一些出版物中已经报道了该化合物的抗抑郁活性，例如J.Hyttel Prog.Neuro-Psychopharmacol.& Biol.Psychiat.1982，6，277-295和A.Gravem Acta Psychiatr.Scand.1987，75，478-486。在EP-A-474580中进一步公开了在治疗痴呆和脑血管疾病方面的作用。
在与US 4136193相应的DE 2657013中首次公开了西酞普兰。该专利公开描述了一种制备西酞普兰的方法并略述了可用于制备西酞普兰的另一种方法。
根据所描述的方法，在作为缩合剂的甲基亚硫酰基甲基化物存在下，相应的1-(4-氟苯基)-1，3-二氢-5-异苯并呋喃甲腈与3-(N，N-二甲基氨基)丙基氯反应。起始原料通过相应的5-溴衍生物与氰化亚铜反应制备。
根据仅简要描述的方法，通过在脱水剂存在下使式II化合物进行闭环反应
以及然后用氰化亚铜交换5-溴基团得到西酞普兰。式II的起始原料通过两个连续的格氏反应，即，分别用4-氟苯基氯化镁和N，N-二甲基氨基丙基氯化镁，由5-溴-2-苯并[c]呋喃酮得到。
在US 4650884中描述了制备西酞普兰的新的、令人惊奇的方法和中间体，根据该方法，将式III中间体
用浓硫酸脱水进行闭环反应以得到西酞普兰。式III中间体通过两个连续的格氏反应，即，分别用4-氟苯基卤化镁和N，N-二甲基氨基丙基卤化镁，由5-氰基-2-苯并[c]呋喃酮得到。
在国际申请WO98019511、WO98019512和WO98019513中公开了其它方法。WO98019512和WO98019513涉及的方法中5-氨基、5-烷氧基羰基或5-(仲氨基羰基)-2-苯并[c]呋喃酮进行两个连续的格氏反应，闭环反应，以及将得到的1，3-二氢异苯并呋喃衍生物转化成相应的5-氰基化合物，即，西酞普兰。国际专利申请WO98019511公开了制备西酞普兰的方法，其中(4-取代-2-羟基甲基苯基-(4-氟苯基)甲醇化合物进行闭环反应，得到的5-取代的1-(4-氟苯基)-1，3-二氢异苯并呋喃转化为相应的5-氰基衍生物，用(3-二甲基氨基)丙基卤化物将该化合物烷基化，得到西酞普兰。
最后，在US4943590中公开了制备西酞普兰的单个对映体的方法，其中还指出式III中间体的闭环反应可经不稳定的酯用碱进行。
现已惊奇地发现，西酞普兰可使用方便的起始原料用新的、有利的、安全的方法制备。
发明内容
因此，本发明涉及新的制备式I的西酞普兰的方法，
式I
包括：
将式VIII化合物转化为式IV化合物，
式VIII
其中Z是卤素，
随后将式IV化合物转化为西酞普兰。
特别地，本发明涉及这样一种方法，其中包括：
i)将式IV化合物与脱水剂和式H2N-SO2-R的磺酰胺反应，其中R是：
a)任选被取代的NH2，或C1-6烷氧基，
b)任选被卤素，C1-4烷基，氰基，羟基，C1-4烷氧基，三氟甲基，硝基，氨基，C1-4烷基氨基或二-C1-4烷基氨基取代的芳氧基或杂芳氧基，或
c)任选被卤素，C1-4烷基，氰基，羟基，C1-4烷氧基，三氟甲基，硝基，氨基，C1-4烷基氨基或二-C1-4烷基氨基取代的芳基或杂芳基；
或
ii)将式IV化合物转化为相应的式V酰胺
式V
其中R1和R2独立地是氢，C1-6烷基，被一个或多个选自下列的取代基取代的C1-6烷基：芳基和杂芳基，羟基，C1-6烷氧基，芳氧基，杂芳氧基，芳基-C1-6-烷氧基，或三取代的甲硅烷基，其中三取代的甲硅烷基中取代基独立地是C1-6烷基，芳基，杂芳基或芳基-C1-6-烷基，然后将式V酰胺与脱水剂反应，
从而得到碱形式的西酞普兰或其药学上可接受的盐。
将式IV的5-羧基衍生物转化为式V的酰胺的反应可以通过式VI的活化酸衍生物进行：
其中R3是卤素，C1-6烷氧基，芳氧基，杂芳氧基，芳基-C1-6-烷氧基，杂芳基-C1-6-烷氧基，烷基碳酸酯，芳基碳酸酯，烷基氨甲酸酯，芳基氨甲酸酯，烷基硫代碳酸酯，芳基硫代碳酸酯，烷基硫代氨甲酸酯，芳基硫代氨甲酸酯，烷基酰氧基，芳基酰氧基，取代的或未取代的芳基或取代的或未取代的杂芳基。
在另一方面，本发明涉及制备式IV中间体的方法，包括将其中Z是卤素的式VIII化合物转化为式IV化合物。
在另一方面，本发明涉及制备式VII中间体的方法，
式VII
其中X选自卤素，CN，OR5或SR6，其中R5和R6独立地选自C1-6烷基，芳基，杂芳基或苄基，这些C1-6烷基，芳基，杂芳基或苄基是未取代的或被下列基团取代的：卤素，C1-4-烷基，氰基，羟基，C1-4烷氧基，三氟甲基，硝基，氨基，C1-4烷基氨基或二-C1-4-烷基氨基，NR7R8，其中，R7和R8独立地选自氢，C1-6烷基，芳基，杂芳基或苄基，这些C1-6烷基，芳基，杂芳基或苄基是未取代的或被卤素，C1-6-烷基，氰基，羟基，C1-4烷氧基，三氟甲基，硝基，氨基，C1-4烷基氨基或二-C1-4烷基氨基取代的；
Y是O，S或NR9，其中R9选自氢，C1-6烷基，芳基，杂芳基或苄基，这些C1-6烷基，芳基，杂芳基或苄基是未取代的或被卤素，C1-4-烷基，氰基，羟基，C1-4烷氧基，三氟甲基，硝基，氨基，C1-4烷基氨基或二-C1-4烷基氨基取代的；
该方法包括：将式VIII化合物转化为式VII化合物，
其中Z是卤素。
在另一方面，本发明涉及抗抑郁药物组合物，含有用本发明方法制备的碱形式的西酞普兰或其任何适当的盐。
在整个说明书和权利要求中，术语“脱水剂”指任何适用的脱水剂，本领域技术人员可容易地确定最佳的试剂。适合的脱水剂的例子是SOCl2，POCl3，PCl5，SOBr2，POBr3，PBr5，SOI2，POI3，PI5，P4O10，草酰氯，羰基二咪唑和Vilsmeier试剂。优选使用含氯的试剂，最优选SOCl2或POCl3。Vilsmerier试剂通过混合N，N-二甲基甲酰胺(DMF)和脱水剂形成，例如DMF/SOCl2和DMF/POCl3。
在整个说明书和权利要求中，C1-6烷基指支化的或未支化的有1-6个碳原子的烷基，诸如甲基，乙基，1-丙基，2-丙基，1-丁基，2-丁基，2-甲基-2-丙基，2，2-二甲基-1-乙基和2-甲基-1-丙基。类似地，C1-4烷基指有1-4个碳原子的这样的基团，C1-6烷氧基，C1-4烷氧基和C1-4烷基氨基指其中烷基部分如所定义的这样的基团。
卤素指氟，氯，溴或碘。
在本发明的方法i)中，一种可能的但非限制性的反应机理是式IV的5-羧基化合物与脱水剂反应以形成相应的活化的衍生物，其随后与磺酰胺H2N-SO2-R反应，从而形成西酞普兰。在后一反应中，催化量的酸可能是必需的。
在该方法中使用的磺酰胺H2N-SO2-R优选是硫酰胺H2N-SO2-NH2。
在该方法中使用的任选被取代的NH2优选是叔丁胺。
在本发明方法中与脱水剂的反应可不使用溶剂或在适合的诸如环丁砜或乙腈之类的溶剂中进行。当在ii)的脱水反应中使用溶剂时，可能需要催化量的N，N-二甲基甲酰胺。
在本发明的一个优选实施方案中，制备西酞普兰和/或式IV或式VII化合物的方法包括：
a)将式VIII的5-卤代类似物
式VIII
其中Z是卤素，
与Mg或有机锂化合物例如正丁基锂反应，或与有机金属配合物反应，所述的有机金属配合物由Mg和/或Mn和/或Li和烷基或芳基组成，随后与CO2，CS2或式IX的化合物反应，
其中A和X独立地选自卤素，CN，OR5或SR6，其中R5和R6独立地选自C1-6烷基，芳基，杂芳基或苄基，这些C1-6烷基，芳基，杂芳基或苄基是未取代的或被下列基团取代的：卤素，C1-4-烷基，氰基，羟基，C1-4烷氧基，三氟甲基，硝基，氨基，C1-4烷基氨基或二-C1-4烷基氨基，NR7R8，其中，R7和R8独立地选自氢，C1-6烷基，芳基，杂芳基或苄基，这些C1-6烷基，芳基，杂芳基或苄基是未取代的或被卤素，C1-4-烷基，氰基，羟基，C1-4烷氧基，三氟甲基，硝基，氨基，C1-4烷基氨基或二-C1-4烷基氨基取代的；Y是O，S或NR9，其中R9选自氢，C1-6烷基，芳基，杂芳基或苄基，这些C1-6烷基，芳基，杂芳基或苄基是未取代的或被卤素，C1-4-烷基，氰基，羟基，C1-4烷氧基，三氟甲基，硝基，氨基，C1-4烷基氨基或二-C1-4烷基氨基取代的；
并在制备西酞普兰或式IV化合物的方法中，随后与水，氢氧化物如氢氧化钠，或酸的水溶液反应；
b)将式VIII化合物
其中Z是Br或I，
在金属催化剂如镍或钯基催化剂存在下与任选被取代的乙烯基或炔属基团偶联，然后将乙烯基或炔属基团氧化成羧基，得到式IV化合物；
在方法a)中，有机金属配合物的例子是式(R4)3MgLi的三烷基镁化物(magnesate)，式(R4)3MnLi的三烷基锰化物(magnesate)和式(R4)3MnMgBr的混合的镁和锰配合物，其中R4表示可以相同或不同的C1-6烷基或芳基。由格氏试剂R4MgX(X是卤素)和有机锂例如正丁基锂可就地制备三烷基镁化物。从MnCl2和有机锂例如正丁基锂可就地生成三烷基锰化物。由格氏试剂R4MgX和MnCl2可制备(R4)3MnMgBr。如US4136193所述可得到起始的式VIII的5-溴代化合物。
在方法a)中，式IX起始原料的例子是氯甲酸乙酯，氯甲酸苯酯，氯甲酸苄基酯，氯甲酸乙烯基酯，氯甲酸异丁酯，硫代氯甲酸乙酯，氰基甲酸甲酯，羰基二咪唑和碳酸二乙酯。可从市场购买或用文献中的方法制备式IX起始原料。
在方法b)中，镍基催化剂可以是任何适合的起催化剂作用的含Ni(0)或Ni(II)的配合物，诸如Ni(PPh3)3和(σ-芳基)-Ni(PPh3)2Cl，而钯基催化剂可以是任何适合的含Pd(0)或Pd(II)的催化剂，诸如Pd(PPh3)4，Pd(dba)3和Pd(PPh)2Cl2。氧化剂可以是任何适合的试剂，诸如在钌催化剂存在下的过氧化物。其中B是三氟甲磺酸酯基团的起始化合物可如WO 0013648所述得到。与式VIII化合物偶联的乙烯基或炔属基团的例子包括丙烯酸甲酯，1-溴丁-1-烯，丙炔，三甲基(丙-1-烯基)锡烷，E-1-己烯基硼酸和三氟甲基磺酸丙-1-烯基酯。
式I化合物可以游离碱的形式使用，或作为其药学上可接受的酸加成盐使用。作为酸加成盐，可使用与有机或无机酸形成的盐。这样的有机盐的例子是与马来酸，富马酸，苯甲酸，抗坏血酸，琥珀酸，草酸，二亚甲基水杨酸，甲磺酸，乙二磺酸，乙酸，丙酸，酒石酸，水杨酸，柠檬酸，葡糖酸，乳酸，苹果酸，扁桃酸，肉桂酸，柠康酸，天门冬氨酸，硬脂酸，棕榈酸，衣康酸，乙醇酸，对氨基苯甲酸，谷氨酸，苯磺酸和茶碱乙酸的盐，以及其8-卤代茶碱例如8-溴代茶碱。这样的无机盐的例子是与盐酸，氢溴酸，硫酸，氨基磺酸，磷酸和硝酸的盐。
所述化合物的酸加成盐可以用本领域已知的方法制备。所述碱与计算量的酸在可与水混溶的溶剂诸如丙酮或乙醇中反应，然后通过浓缩和冷却分离盐；或者所述碱与过量的酸在不与水混溶的的溶剂诸如乙醚，乙酸乙酯或二氯甲烷中反应，自动分离出盐。
本发明的药物组合物可用任何适合的方法以任何适合的剂型给药，例如以片剂，胶囊，粉剂或糖浆口服，或非肠道给予常用的无菌注射液。
本发明的药物制剂可用本领域的常规方法制备。例如，将活性成分和常规的辅剂和/或稀释剂混合，然后在常规压片机上将混合物压片，这样可以制备片剂。辅剂或稀释剂的例子包括：玉米淀粉，土豆淀粉，滑石，硬脂酸镁，明胶，乳糖，树胶等。可使用任何其它的辅剂或添加剂如着色剂，芳香剂，防腐剂等，前提条件是它们与活性成分相容。
将活性成分和可能的添加剂溶于一部分注射用溶剂，优选无菌水，将溶液调节到所需的体积，灭菌并灌装到适合的安瓿或小瓶中，这样可以制备注射液。可加入任何本领域常用的适合的添加剂，诸如紧张剂，防腐剂，抗氧化剂等。
具体实施方式
通过下列实施例进一步详细说明本发明，但不应认为这些实施例对本发明的范围有所限制。
实施例1
5-羧基-1-(4-氟苯基)-1-(3-二甲基氨基丙基)-1，3-二氢-异苯并呋喃
方法a)-Mg
将1-(4-氟苯基)-1-(3-二甲基氨基丙基)-1，3-二氢-异苯并呋喃-5-基溴化镁在无水THF(90ml)中的溶液(从5-溴-1-(4-氟苯基)-1-(3-二甲基氨基丙基)-1，3-二氢-异苯并呋喃(9g，0.024mol)和镁(0.73g，0.03mol)用常规方法制备)加入干固体CO2(50g)中。加完以后，将混合物置于室温下16小时。
真空下除去挥发性物质，用水(100g)溶解残留物。通过加入盐酸(水溶液，4N)将pH调节到5.5。用甲苯(100ml)萃取水相。
真空下除去甲苯，得到油状标题化合物。产量6g。
方法a)-正丁基锂
向5-溴-1-(4-氟苯基)-1-(3-二甲基氨基丙基)-1，3-二氢-异苯并呋喃(9g，0.024mol)在叔丁基甲基醚(150ml)中的溶液中在-78℃至-65℃下加入正丁基锂(在己烷中1.6M，40ml)。用2小时将溶液的温度升至-30℃。将反应混合物加入干固体CO2(50g)中。加完以后，将混合物置于室温下16小时。真空下除去挥发性物质，用水(100g)溶解残留物。通过加入盐酸(水溶液，4N)将pH调节到5.5。用甲苯(100ml)萃取水相。真空下除去甲苯，得到油状标题化合物。产量7.5g。
方法a)-三烷基镁化物
向异丙基氯化镁(8.0ml，在乙醚中2M)在THF(25ml)中的溶液中在0℃加入正丁基锂(20ml，在己烷中1.6M)。得到的混合物在0℃搅拌1小时，然后冷却到-78℃，加入5-溴-1-(4-氟苯基)-1-(3-二甲基氨基丙基)-1，3-二氢-异苯并呋喃(5.0g，13mmol)在THF(25ml)中的溶液。用1小时将混合物温热至-10℃，然后再冷却到-78℃，加入CO2(5.7g，130mmol)。将混合物温热至室温，然后蒸发。用离子交换色谱处理残留物(Dowex-50，酸型)，用1M NH3洗脱，得到粘稠油状产物。
实施例2
5-氰基-1-(4-氟苯基)-1-(3-二甲基氨基丙基)-1，3-二氢-异苯并呋喃(西酞普兰，游离碱)
将5-羧基-1-(4-氟苯基)-1-(3-二甲基氨基丙基)-1，3-二氢-异苯并呋喃(5g，0.015mol)和硫酰胺(1.65g，0.017mol)溶于环丁砜(15ml)中。在室温下加入亚硫酰氯(2.25g，0.019mol)，将反应混合物的温度升至130℃保持2小时。将反应混合物冷却到75℃，加入水(25ml)。温度在75℃保持15分钟，然后将反应混合物冷却到室温。用氨水将pH调节到9，然后加入正庚烷(75ml)。温度升至70℃，分离热的正庚烷层，冷却得到结晶的标题化合物。产量3.77g。纯度(HPLC峰面积)＞97％。
Claims (2)
1.一种制备式IV的化合物的方法，
式IV
包括通过下列步骤将式VIII化合物转化为式IV化合物，
式VIII
其中Z是卤素，
所述步骤是：
i)将式VIII化合物
式VIII
其中Z是卤素，
与Mg或有机锂化合物或与LiMg(i-Pr)(n-Bu)2反应得到第一中间体；
ii)随后将所述的第一中间体与CO2反应，生成第二中间体；
iii)然后将所述的第二中间体与一种酸的水溶液反应。
2.根据权利要求1的方法，其特征在于，有机锂化合物是n-BuLi。
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| DK213290D0 (da) | 1990-09-06 | 1990-09-06 | Lundbeck & Co As H | Treatment of cerebrovascular disorders |
| DE19626659A1 (de) | 1996-07-03 | 1998-01-08 | Basf Ag | Verfahren zur Herstellung von Phthaliden |
| DE19627697A1 (de) | 1996-07-10 | 1998-01-15 | Basf Ag | Verfahren zur Herstellung von Phthaliden |
| ZA9711376B (en) | 1996-12-20 | 1998-07-21 | Lundbeck & Co As H | Indole or dihydroindole derivatives |
| JP3526581B2 (ja) | 1997-07-08 | 2004-05-17 | ハー・ルンドベック・アクティーゼルスカブ | シタロプラムの製造方法 |
| UA62985C2 (en) * | 1997-11-10 | 2004-01-15 | Lunnbeck As H | A method for the preparation of citalopram |
| AU738359B2 (en) * | 1997-11-11 | 2001-09-13 | H. Lundbeck A/S | Method for the preparation of citalopram |
| WO2000023431A1 (en) | 1998-10-20 | 2000-04-27 | H. Lundbeck A/S | Method for the preparation of citalopram |
| AU764161B2 (en) | 1998-12-23 | 2003-08-14 | H. Lundbeck A/S | Method for the preparation of 5-cyanophthalide |
| AR022329A1 (es) | 1999-01-29 | 2002-09-04 | Lundbeck & Co As H | Metodo para la preparacion de 5-cianoftalida |
| HU227473B1 (en) | 1999-04-14 | 2011-07-28 | Lundbeck & Co As H | Method for preparation of citalopram |
| ITMI991581A1 (it) | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
| ITMI991579A1 (it) * | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
| GB2360281B (en) | 1999-10-25 | 2002-01-16 | Lundbeck & Co As H | Method for the preparation of citalopram |
| US6310222B1 (en) | 1999-11-01 | 2001-10-30 | Sumika Fine Chemicals Co., Ltd. | Production method of 5-phthalancarbonitrile compound, intermediate therefor and production method of the intermediate |
| FR2805812A1 (fr) | 2000-02-24 | 2001-09-07 | Lundbeck & Co As H | Procede de preparation du citalopram |
| IES20010143A2 (en) | 2000-02-24 | 2001-07-25 | Lundbeck & Co As H | Method for the preparation of citalopram |
| GB0005477D0 (en) * | 2000-03-07 | 2000-04-26 | Resolution Chemicals Limited | Process for the preparation of citalopram |
| CA2354877C (en) | 2000-08-18 | 2006-05-02 | H. Lundbeck A/S | Method for the preparation of citalopram |
| ES2228824T3 (es) | 2000-12-22 | 2005-04-16 | H. Lundbeck A/S | Metodo de preparacion de citalopram puro. |
| DE60100016T2 (de) | 2000-12-28 | 2003-04-17 | H. Lundbeck A/S, Valby | Verfahren zur herstellung von reinem citalopram |
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