NO317981B1 - Fremgangsmate for fremstilling av (R)-<alfa>-(2,3-dimetoksyfenyl)-1-[2-(4-fluorofenyl)etyl]-4-piperidinmetanol, mellomprodukter for bruk ved fremstilling av denne forbindelse og fremgangsmpter for fremstilling av noen av disse mellomprodukter - Google Patents
Fremgangsmate for fremstilling av (R)-<alfa>-(2,3-dimetoksyfenyl)-1-[2-(4-fluorofenyl)etyl]-4-piperidinmetanol, mellomprodukter for bruk ved fremstilling av denne forbindelse og fremgangsmpter for fremstilling av noen av disse mellomprodukter Download PDFInfo
- Publication number
- NO317981B1 NO317981B1 NO20004545A NO20004545A NO317981B1 NO 317981 B1 NO317981 B1 NO 317981B1 NO 20004545 A NO20004545 A NO 20004545A NO 20004545 A NO20004545 A NO 20004545A NO 317981 B1 NO317981 B1 NO 317981B1
- Authority
- NO
- Norway
- Prior art keywords
- dimethoxyphenyl
- fluorophenyl
- ethyl
- compound
- approx
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 169
- 238000000034 method Methods 0.000 title claims description 77
- 238000002360 preparation method Methods 0.000 title claims description 14
- 239000000543 intermediate Substances 0.000 title description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 593
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 357
- 239000000203 mixture Substances 0.000 claims description 231
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 230
- HXTGXYRHXAGCFP-OAQYLSRUSA-N (r)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol Chemical compound COC1=CC=CC([C@H](O)C2CCN(CCC=3C=CC(F)=CC=3)CC2)=C1OC HXTGXYRHXAGCFP-OAQYLSRUSA-N 0.000 claims description 177
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 164
- HXTGXYRHXAGCFP-UHFFFAOYSA-N volinanserin Chemical compound COC1=CC=CC(C(O)C2CCN(CCC=3C=CC(F)=CC=3)CC2)=C1OC HXTGXYRHXAGCFP-UHFFFAOYSA-N 0.000 claims description 161
- 150000003892 tartrate salts Chemical class 0.000 claims description 157
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 142
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 116
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 95
- 239000011975 tartaric acid Substances 0.000 claims description 81
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 80
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 80
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 77
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 76
- 239000002904 solvent Substances 0.000 claims description 75
- 235000002906 tartaric acid Nutrition 0.000 claims description 71
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 37
- JXRNNYSLIUEYHF-UHFFFAOYSA-N (2,3-dimethoxyphenyl)-pyridin-4-ylmethanone Chemical compound COC1=CC=CC(C(=O)C=2C=CN=CC=2)=C1OC JXRNNYSLIUEYHF-UHFFFAOYSA-N 0.000 claims description 34
- 239000003054 catalyst Substances 0.000 claims description 29
- -1 4-fluorophenylethyl Chemical group 0.000 claims description 28
- LZRHDSQWBVFQMC-CYBMUJFWSA-N (r)-(2,3-dimethoxyphenyl)-piperidin-4-ylmethanol Chemical compound COC1=CC=CC([C@H](O)C2CCNCC2)=C1OC LZRHDSQWBVFQMC-CYBMUJFWSA-N 0.000 claims description 25
- PYEKAUZGWYTWEY-UHFFFAOYSA-N 1-[2-(4-fluorophenyl)acetyl]piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1C(=O)CC1=CC=C(F)C=C1 PYEKAUZGWYTWEY-UHFFFAOYSA-N 0.000 claims description 24
- IRFMPRSXHIYMRM-UHFFFAOYSA-N (2,3-dimethoxyphenyl)-pyridin-4-ylmethanol Chemical compound COC1=CC=CC(C(O)C=2C=CN=CC=2)=C1OC IRFMPRSXHIYMRM-UHFFFAOYSA-N 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 22
- 239000003638 chemical reducing agent Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 claims description 17
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- YKCDBPGWURPFNX-UHFFFAOYSA-M lithium;1-[2-(4-fluorophenyl)acetyl]piperidine-4-carboxylate Chemical compound [Li+].C1CC(C(=O)[O-])CCN1C(=O)CC1=CC=C(F)C=C1 YKCDBPGWURPFNX-UHFFFAOYSA-M 0.000 claims description 11
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 9
- 239000002168 alkylating agent Substances 0.000 claims description 8
- 229940100198 alkylating agent Drugs 0.000 claims description 8
- 230000007071 enzymatic hydrolysis Effects 0.000 claims description 8
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 239000004367 Lipase Substances 0.000 claims description 6
- 102000004882 Lipase Human genes 0.000 claims description 6
- 108090001060 Lipase Proteins 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 235000019421 lipase Nutrition 0.000 claims description 6
- 150000004820 halides Chemical group 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 4
- LZRHDSQWBVFQMC-ZDUSSCGKSA-N (s)-(2,3-dimethoxyphenyl)-piperidin-4-ylmethanol Chemical compound COC1=CC=CC([C@@H](O)C2CCNCC2)=C1OC LZRHDSQWBVFQMC-ZDUSSCGKSA-N 0.000 claims description 4
- 241000179532 [Candida] cylindracea Species 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 238000010956 selective crystallization Methods 0.000 claims description 4
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- 239000010948 rhodium Substances 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 435
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 222
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 198
- 229910001868 water Inorganic materials 0.000 description 192
- 238000006243 chemical reaction Methods 0.000 description 152
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 144
- 239000011541 reaction mixture Substances 0.000 description 138
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
- 239000002002 slurry Substances 0.000 description 96
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 91
- 229960004592 isopropanol Drugs 0.000 description 88
- 239000012071 phase Substances 0.000 description 85
- 238000001914 filtration Methods 0.000 description 79
- 238000010992 reflux Methods 0.000 description 72
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 70
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 69
- 239000012074 organic phase Substances 0.000 description 68
- 239000007787 solid Substances 0.000 description 68
- 239000000463 material Substances 0.000 description 67
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 66
- CCIUQRKCMXXTOI-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methoxybenzoyl)butanedioic acid Chemical class C1=CC(OC)=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=C(OC)C=C1 CCIUQRKCMXXTOI-UHFFFAOYSA-N 0.000 description 65
- 239000000706 filtrate Substances 0.000 description 65
- 239000011521 glass Substances 0.000 description 62
- 239000008346 aqueous phase Substances 0.000 description 61
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- ASGQPSLNQQAJOW-UHFFFAOYSA-N tert-butyl 4-(2,3-dimethoxybenzoyl)piperidine-1-carboxylate Chemical compound COC1=CC=CC(C(=O)C2CCN(CC2)C(=O)OC(C)(C)C)=C1OC ASGQPSLNQQAJOW-UHFFFAOYSA-N 0.000 description 57
- 238000004128 high performance liquid chromatography Methods 0.000 description 55
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 52
- RKLBYZHXXUDLPI-UHFFFAOYSA-N tert-butyl 4-(methoxymethylcarbamoyl)piperidine-1-carboxylate Chemical compound COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 RKLBYZHXXUDLPI-UHFFFAOYSA-N 0.000 description 51
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 49
- LZRHDSQWBVFQMC-UHFFFAOYSA-N (2,3-dimethoxyphenyl)-piperidin-4-ylmethanol Chemical compound COC1=CC=CC(C(O)C2CCNCC2)=C1OC LZRHDSQWBVFQMC-UHFFFAOYSA-N 0.000 description 45
- HXTGXYRHXAGCFP-NRFANRHFSA-N (s)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol Chemical compound COC1=CC=CC([C@@H](O)C2CCN(CCC=3C=CC(F)=CC=3)CC2)=C1OC HXTGXYRHXAGCFP-NRFANRHFSA-N 0.000 description 45
- 238000000605 extraction Methods 0.000 description 45
- 238000003756 stirring Methods 0.000 description 45
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 42
- 239000013078 crystal Substances 0.000 description 42
- 239000000047 product Substances 0.000 description 41
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 40
- 238000004458 analytical method Methods 0.000 description 38
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 37
- 238000002425 crystallisation Methods 0.000 description 34
- 230000008025 crystallization Effects 0.000 description 34
- 239000012452 mother liquor Substances 0.000 description 34
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 33
- 238000001816 cooling Methods 0.000 description 33
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- 238000004821 distillation Methods 0.000 description 32
- 238000001953 recrystallisation Methods 0.000 description 31
- 239000003921 oil Substances 0.000 description 30
- 235000019198 oils Nutrition 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- GSMJQUNLZPMNPH-UHFFFAOYSA-N (2,3-dimethoxyphenyl)-piperidin-4-ylmethanone Chemical compound COC1=CC=CC(C(=O)C2CCNCC2)=C1OC GSMJQUNLZPMNPH-UHFFFAOYSA-N 0.000 description 26
- 229910000027 potassium carbonate Inorganic materials 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- 229960000583 acetic acid Drugs 0.000 description 25
- 238000002955 isolation Methods 0.000 description 25
- 239000002585 base Substances 0.000 description 24
- 150000008064 anhydrides Chemical class 0.000 description 23
- 235000019441 ethanol Nutrition 0.000 description 23
- 229960004756 ethanol Drugs 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 21
- 239000012065 filter cake Substances 0.000 description 21
- 239000012299 nitrogen atmosphere Substances 0.000 description 21
- 238000001035 drying Methods 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 18
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 18
- 239000007788 liquid Substances 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000000376 reactant Substances 0.000 description 17
- 239000008096 xylene Substances 0.000 description 17
- 150000003738 xylenes Chemical class 0.000 description 17
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 16
- 238000004296 chiral HPLC Methods 0.000 description 16
- 239000012258 stirred mixture Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
- 239000012456 homogeneous solution Substances 0.000 description 15
- BZFGKBQHQJVAHS-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1 BZFGKBQHQJVAHS-UHFFFAOYSA-N 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 239000001301 oxygen Substances 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 13
- 238000011084 recovery Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- HYBADYSRHQQTPG-UHFFFAOYSA-N n-(methoxymethyl)pyridine-4-carboxamide Chemical compound COCNC(=O)C1=CC=NC=C1 HYBADYSRHQQTPG-UHFFFAOYSA-N 0.000 description 11
- 230000003287 optical effect Effects 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000009835 boiling Methods 0.000 description 10
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 10
- 239000007789 gas Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 10
- SIOJFYRPBYGHOO-UHFFFAOYSA-N 2-(4-fluorophenyl)acetyl chloride Chemical compound FC1=CC=C(CC(Cl)=O)C=C1 SIOJFYRPBYGHOO-UHFFFAOYSA-N 0.000 description 9
- ZHZOHYWBWSRTME-UHFFFAOYSA-N 2-ethyl-1-[2-(4-fluorophenyl)ethanethioyl]piperidine-4-carboxylic acid Chemical compound C(C)C1N(CCC(C1)C(=O)O)C(CC1=CC=C(C=C1)F)=S ZHZOHYWBWSRTME-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000002178 crystalline material Substances 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 238000000023 Kugelrohr distillation Methods 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229910000085 borane Inorganic materials 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Natural products OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 8
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- 238000005292 vacuum distillation Methods 0.000 description 8
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 7
- 229910004298 SiO 2 Inorganic materials 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
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- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- UMFCIIBZHQXRCJ-NSCUHMNNSA-N trans-anol Chemical compound C\C=C\C1=CC=C(O)C=C1 UMFCIIBZHQXRCJ-NSCUHMNNSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D211/20—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 singly bound oxygen or sulphur atoms
- C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
- C07D211/34—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Otolaryngology (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Psychiatry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Nutrition Science (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicinal Preparation (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4225198A | 1998-03-13 | 1998-03-13 | |
| US25071899A | 1999-02-16 | 1999-02-16 | |
| PCT/US1999/005332 WO1999046245A2 (en) | 1998-03-13 | 1999-03-11 | PROCESSES FOR THE PREPARATION OF (R)-α- (2,3-DIMETHOXYPHENYL)-1-[2-(4-FLUOROPHENYL)ETHYL]-4-PIPERIDINEMETHANOL |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20004545D0 NO20004545D0 (no) | 2000-09-12 |
| NO20004545L NO20004545L (no) | 2000-11-13 |
| NO317981B1 true NO317981B1 (no) | 2005-01-17 |
Family
ID=26719032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20004545A NO317981B1 (no) | 1998-03-13 | 2000-09-12 | Fremgangsmate for fremstilling av (R)-<alfa>-(2,3-dimetoksyfenyl)-1-[2-(4-fluorofenyl)etyl]-4-piperidinmetanol, mellomprodukter for bruk ved fremstilling av denne forbindelse og fremgangsmpter for fremstilling av noen av disse mellomprodukter |
Country Status (25)
| Country | Link |
|---|---|
| EP (3) | EP1192134B1 (de) |
| JP (2) | JP4511723B2 (de) |
| KR (7) | KR100591640B1 (de) |
| CN (1) | CN100436415C (de) |
| AR (1) | AR015540A1 (de) |
| AT (1) | ATE373639T1 (de) |
| AU (1) | AU755436B2 (de) |
| BR (1) | BR9909260A (de) |
| CA (1) | CA2322501C (de) |
| CY (1) | CY1107104T1 (de) |
| DE (1) | DE69937162T2 (de) |
| DK (1) | DK1192134T3 (de) |
| DZ (1) | DZ2742A1 (de) |
| EG (1) | EG24052A (de) |
| ES (1) | ES2294838T3 (de) |
| HK (1) | HK1042484B (de) |
| HU (1) | HUP0400889A3 (de) |
| IL (3) | IL138307A0 (de) |
| MA (1) | MA25515A1 (de) |
| NO (1) | NO317981B1 (de) |
| NZ (1) | NZ506807A (de) |
| PT (1) | PT1192134E (de) |
| TN (1) | TNSN99035A1 (de) |
| TW (1) | TWI249526B (de) |
| WO (1) | WO1999046245A2 (de) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6713627B2 (en) * | 1998-03-13 | 2004-03-30 | Aventis Pharmaceuticals Inc. | Processes for the preparation of (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol |
| DE19934432A1 (de) | 1999-07-22 | 2001-02-01 | Merck Patent Gmbh | Indolderivate |
| WO2002072069A1 (en) * | 2001-03-12 | 2002-09-19 | Novo Nordisk A/S | Novel tablets and capsules and a process for its preparation |
| DE102004010132A1 (de) | 2004-02-27 | 2005-09-15 | Merck Patent Gmbh | Piperidinderivate |
| KR101442862B1 (ko) * | 2006-12-07 | 2014-09-22 | 다이이찌 산쿄 가부시키가이샤 | 만니톨 또는 유당을 함유하는 고형 제제 |
| US8964338B2 (en) | 2012-01-11 | 2015-02-24 | Emerson Climate Technologies, Inc. | System and method for compressor motor protection |
| WO2014144446A1 (en) | 2013-03-15 | 2014-09-18 | Emerson Electric Co. | Hvac system remote monitoring and diagnosis |
| CN112358398A (zh) * | 2020-11-19 | 2021-02-12 | 山东新华制药股份有限公司 | D-(+)-二对甲苯甲酰酒石酸的回收制备方法 |
| CN116082705B (zh) * | 2022-12-05 | 2023-09-12 | 苏州易昇光学材料股份有限公司 | 一种抗黄变自修复凝胶 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4260623A (en) * | 1979-11-26 | 1981-04-07 | Warner-Lambert Company | Hexahydro-1-arylspiro(3H-oxazolo(3,4-A)pyridine-3,4'-piperidene) antidepressants, pharmaceutical compositions thereof and method of use thereof |
| US5169096A (en) * | 1985-07-02 | 1992-12-08 | Merrell Dow Pharmaceuticals Inc. | N-aralkyl-piperidine-methanol derivatives |
| CA1280421C (en) * | 1985-07-02 | 1991-02-19 | Albert A. Carr | 1,4-disubstituted piperidinyl derivatives |
| DE69105501T2 (de) * | 1990-06-01 | 1995-04-13 | Merrell Dow Pharma | (+)-alpha-(2,3 dimethoxyphenyl)-1-[2-(fluorophenyl)ethyl]-4-piperidinmethanol. |
| WO1991018603A1 (en) * | 1990-06-07 | 1991-12-12 | Merrell Dow Pharmaceuticals Inc. | 1-pyperidinyl alkanoylarylsulfonamide derivatives |
| US5477029A (en) * | 1994-01-28 | 1995-12-19 | Skutt Ceramic Products, Inc. | Kiln with hinged control panel |
| US5618824A (en) * | 1994-03-09 | 1997-04-08 | Merrell Pharmaceuticals Inc. | Treatment of obsessive-compulsive disorders with 5-HT2 antagonists |
| EP0796619A1 (de) * | 1996-03-21 | 1997-09-24 | Merrell Pharmaceuticals Inc. | Verwendung von (+)-alpha-(2,3-dimethoxyphenyl)-1-(2-(4-Fluorophenyl)ethyl)-4-Piperidinmethanol zur Behandlung von Depressionen und bipolaren Erkrankungen |
-
1999
- 1999-03-09 TW TW088103619A patent/TWI249526B/zh not_active IP Right Cessation
- 1999-03-10 EG EG23399A patent/EG24052A/xx active
- 1999-03-10 MA MA25491A patent/MA25515A1/fr unknown
- 1999-03-10 DZ DZ990043A patent/DZ2742A1/xx active
- 1999-03-11 EP EP99911318A patent/EP1192134B1/de not_active Expired - Lifetime
- 1999-03-11 KR KR1020057024568A patent/KR100591640B1/ko not_active IP Right Cessation
- 1999-03-11 PT PT99911318T patent/PT1192134E/pt unknown
- 1999-03-11 IL IL13830799A patent/IL138307A0/xx active IP Right Grant
- 1999-03-11 WO PCT/US1999/005332 patent/WO1999046245A2/en active IP Right Grant
- 1999-03-11 BR BR9909260-3A patent/BR9909260A/pt not_active Application Discontinuation
- 1999-03-11 EP EP06016487A patent/EP1736469A3/de not_active Withdrawn
- 1999-03-11 EP EP06016486A patent/EP1734037A3/de not_active Ceased
- 1999-03-11 AU AU29988/99A patent/AU755436B2/en not_active Ceased
- 1999-03-11 KR KR1020057024567A patent/KR100591643B1/ko not_active IP Right Cessation
- 1999-03-11 NZ NZ506807A patent/NZ506807A/xx unknown
- 1999-03-11 AT AT99911318T patent/ATE373639T1/de not_active IP Right Cessation
- 1999-03-11 ES ES99911318T patent/ES2294838T3/es not_active Expired - Lifetime
- 1999-03-11 CA CA002322501A patent/CA2322501C/en not_active Expired - Fee Related
- 1999-03-11 KR KR1020057024573A patent/KR100591641B1/ko not_active IP Right Cessation
- 1999-03-11 CN CNB998060224A patent/CN100436415C/zh not_active Expired - Fee Related
- 1999-03-11 DE DE69937162T patent/DE69937162T2/de not_active Expired - Lifetime
- 1999-03-11 TN TNTNSN99035A patent/TNSN99035A1/fr unknown
- 1999-03-11 HU HU0400889A patent/HUP0400889A3/hu unknown
- 1999-03-11 JP JP2000535626A patent/JP4511723B2/ja not_active Expired - Fee Related
- 1999-03-11 KR KR1020057024569A patent/KR100586327B1/ko not_active IP Right Cessation
- 1999-03-11 KR KR1020057024572A patent/KR100591997B1/ko not_active IP Right Cessation
- 1999-03-11 KR KR1020007010103A patent/KR100591642B1/ko not_active IP Right Cessation
- 1999-03-11 AR ARP990101039A patent/AR015540A1/es unknown
- 1999-03-11 KR KR1020057024570A patent/KR100586328B1/ko not_active IP Right Cessation
- 1999-03-11 DK DK99911318T patent/DK1192134T3/da active
-
2000
- 2000-09-06 IL IL138307A patent/IL138307A/en not_active IP Right Cessation
- 2000-09-12 NO NO20004545A patent/NO317981B1/no not_active IP Right Cessation
-
2002
- 2002-05-08 HK HK02103493.4A patent/HK1042484B/zh not_active IP Right Cessation
-
2006
- 2006-05-29 IL IL175983A patent/IL175983A0/en unknown
-
2007
- 2007-12-19 CY CY20071101617T patent/CY1107104T1/el unknown
-
2009
- 2009-12-28 JP JP2009296809A patent/JP2010143925A/ja not_active Abandoned
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| MM1K | Lapsed by not paying the annual fees |