CA2493559A1 - Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol - Google Patents

Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol Download PDF

Info

Publication number: CA2493559A1
Authority: CA; Canada
Prior art keywords: dimethoxyphenyl; piperidinemethanol; ethyl; fluorophenyl; solution
Prior art date: 1998-03-13
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.): Abandoned

Application number

CA002493559A

Other languages

English (en)

Inventor

Alan G. Bina

Edward D. Daugs

Jonathan C. Evans

Hans-Wolfram Flemming

Gerard Guillamot

Robert A. Hawthorne

Thomas H. E. Hilpert

James E. Hitt

Chi-Hsin R. King

Johannes N. Koek

Frederick M. Laskovics

John R. Lefler

Alexey L. Margolin

Sharon K. Minish

Thomas T. Ortyl

Lian G. Rajewski

Maryin J. Sack

Paul F. Skultety

Sandra K. Stolz-Dunn

Alonzo L. Tigner

Ian A. Tomlinson

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Sanofi Aventis Deutschland GmbH

Aventis Pharmaceuticals Inc

Original Assignee

Individual

Priority date (The priority date 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 date listed.)

1998-03-13

Filing date

1999-03-11

Publication date

1999-09-16

1999-03-11 Application filed by Individual filed Critical Individual

1999-03-11 Priority claimed from CA002322501A external-priority patent/CA2322501C/fr

1999-09-16 Publication of CA2493559A1 publication Critical patent/CA2493559A1/fr

Status Abandoned legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 77
238000002360 preparation method Methods 0.000 title abstract description 9
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 160
ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 claims description 90
150000001875 compounds Chemical class 0.000 claims description 73
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 72
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
159000000002 lithium salts Chemical class 0.000 claims description 21
238000004519 manufacturing process Methods 0.000 claims description 19
239000003638 chemical reducing agent Substances 0.000 claims description 17
229910003002 lithium salt Inorganic materials 0.000 claims description 12
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 claims description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 131
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 603
239000000243 solution Substances 0.000 description 469
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 354
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 220
239000000203 mixture Substances 0.000 description 218
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 201
229910001868 water Inorganic materials 0.000 description 199
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 183
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 135
239000011541 reaction mixture Substances 0.000 description 135
150000003892 tartrate salts Chemical class 0.000 description 134
238000006243 chemical reaction Methods 0.000 description 132
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 description 127
239000002253 acid Substances 0.000 description 120
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 104
238000007792 addition Methods 0.000 description 104
239000002002 slurry Substances 0.000 description 103
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 100
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 93
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 92
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 89
150000003839 salts Chemical class 0.000 description 87
239000012071 phase Substances 0.000 description 85
238000001914 filtration Methods 0.000 description 84
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 83
239000002904 solvent Substances 0.000 description 80
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 79
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 75
238000010992 reflux Methods 0.000 description 75
239000007787 solid Substances 0.000 description 74
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 73
238000003756 stirring Methods 0.000 description 72
239000011975 tartaric acid Substances 0.000 description 71
235000002906 tartaric acid Nutrition 0.000 description 71
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 69
239000008346 aqueous phase Substances 0.000 description 69
239000012074 organic phase Substances 0.000 description 69
239000000463 material Substances 0.000 description 67
-1 4-fluorophenylethyl Chemical group 0.000 description 64
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 63
239000011521 glass Substances 0.000 description 62
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 59
239000000706 filtrate Substances 0.000 description 57
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 56
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 54
229910052757 nitrogen Inorganic materials 0.000 description 52
LZRHDSQWBVFQMC-UHFFFAOYSA-N (2,3-dimethoxyphenyl)-piperidin-4-ylmethanol Chemical compound COC1=CC=CC(C(O)C2CCNCC2)=C1OC LZRHDSQWBVFQMC-UHFFFAOYSA-N 0.000 description 48
239000000047 product Substances 0.000 description 46
239000013078 crystal Substances 0.000 description 45
150000002148 esters Chemical class 0.000 description 42
238000010268 HPLC based assay Methods 0.000 description 39
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 39
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 38
238000004821 distillation Methods 0.000 description 37
235000019439 ethyl acetate Nutrition 0.000 description 36
238000005481 NMR spectroscopy Methods 0.000 description 33
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 32
239000003921 oil Substances 0.000 description 32
235000019198 oils Nutrition 0.000 description 32
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 32
238000003556 assay Methods 0.000 description 31
238000002425 crystallisation Methods 0.000 description 31
230000008025 crystallization Effects 0.000 description 31
239000003054 catalyst Substances 0.000 description 30
238000001816 cooling Methods 0.000 description 29
238000001953 recrystallisation Methods 0.000 description 29
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 28
235000011181 potassium carbonates Nutrition 0.000 description 28
238000002955 isolation Methods 0.000 description 27
229910000027 potassium carbonate Inorganic materials 0.000 description 27
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
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
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 description 25
239000002585 base Substances 0.000 description 25
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 25
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 description 24
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 24
125000003118 aryl group Chemical group 0.000 description 23
235000019441 ethanol Nutrition 0.000 description 23
101150041968 CDC13 gene Proteins 0.000 description 22
OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 22
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
150000008064 anhydrides Chemical class 0.000 description 21
239000012267 brine Substances 0.000 description 21
239000002244 precipitate Substances 0.000 description 21
238000002390 rotary evaporation Methods 0.000 description 21
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 20
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
229960000583 acetic acid Drugs 0.000 description 19
239000003153 chemical reaction reagent Substances 0.000 description 19
238000001035 drying Methods 0.000 description 19
239000012065 filter cake Substances 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
SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 19
229910052943 magnesium sulfate Inorganic materials 0.000 description 19
239000008096 xylene Substances 0.000 description 19
150000003738 xylenes Chemical class 0.000 description 18
239000007864 aqueous solution Substances 0.000 description 17
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 16
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
238000004587 chromatography analysis Methods 0.000 description 15
239000012452 mother liquor Substances 0.000 description 15
QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 15
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 14
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 14
239000012456 homogeneous solution Substances 0.000 description 14
USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 14
239000010410 layer Substances 0.000 description 14
BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 14
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
238000004296 chiral HPLC Methods 0.000 description 13
239000000376 reactant Substances 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
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 12
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
229920006395 saturated elastomer Polymers 0.000 description 12
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
239000012258 stirred mixture Substances 0.000 description 12
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 description 11
RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 11
239000000284 extract Substances 0.000 description 11
239000007789 gas Substances 0.000 description 11
239000002609 medium Substances 0.000 description 11
230000003287 optical effect Effects 0.000 description 11
229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
238000000967 suction filtration Methods 0.000 description 11
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
238000004458 analytical method Methods 0.000 description 10
238000010899 nucleation Methods 0.000 description 10
IIKFXOLJMNWWCH-UHFFFAOYSA-N piperidine-1,4-dicarboxylic acid Chemical compound OC(=O)C1CCN(C(O)=O)CC1 IIKFXOLJMNWWCH-UHFFFAOYSA-N 0.000 description 10
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 10
238000011084 recovery Methods 0.000 description 10
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 10
239000000741 silica gel Substances 0.000 description 10
229910002027 silica gel Inorganic materials 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
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 9
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 9
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
238000004128 high performance liquid chromatography Methods 0.000 description 9
230000011514 reflex Effects 0.000 description 9
238000000926 separation method Methods 0.000 description 9
229910052938 sodium sulfate Inorganic materials 0.000 description 9
235000011152 sodium sulphate Nutrition 0.000 description 9
SIOJFYRPBYGHOO-UHFFFAOYSA-N 2-(4-fluorophenyl)acetyl chloride Chemical compound FC1=CC=C(CC(Cl)=O)C=C1 SIOJFYRPBYGHOO-UHFFFAOYSA-N 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 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
239000002178 crystalline material Substances 0.000 description 8
238000003818 flash chromatography Methods 0.000 description 8
238000010438 heat treatment Methods 0.000 description 8
238000000746 purification Methods 0.000 description 8
238000010791 quenching Methods 0.000 description 8
235000017557 sodium bicarbonate Nutrition 0.000 description 8
239000000725 suspension Substances 0.000 description 8
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 7
238000000023 Kugelrohr distillation Methods 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
229910000085 borane Inorganic materials 0.000 description 7
RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 7
HYBADYSRHQQTPG-UHFFFAOYSA-N n-(methoxymethyl)pyridine-4-carboxamide Chemical compound COCNC(=O)C1=CC=NC=C1 HYBADYSRHQQTPG-UHFFFAOYSA-N 0.000 description 7
230000006911 nucleation Effects 0.000 description 7
239000012044 organic layer Substances 0.000 description 7
239000000523 sample Substances 0.000 description 7
239000000377 silicon dioxide Substances 0.000 description 7
239000012279 sodium borohydride Substances 0.000 description 7
229910000033 sodium borohydride Inorganic materials 0.000 description 7
239000011780 sodium chloride Substances 0.000 description 7
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 6
LPFKSKZZFYKZJN-UHFFFAOYSA-N 4-(methoxymethylcarbamoyl)piperidine-1-carboxylic acid Chemical compound COCNC(=O)C1CCN(C(O)=O)CC1 LPFKSKZZFYKZJN-UHFFFAOYSA-N 0.000 description 6
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
238000013019 agitation Methods 0.000 description 6
239000002168 alkylating agent Substances 0.000 description 6
229940100198 alkylating agent Drugs 0.000 description 6
229910021529 ammonia Inorganic materials 0.000 description 6
125000001207 fluorophenyl group Chemical group 0.000 description 6
239000000543 intermediate Substances 0.000 description 6
239000012299 nitrogen atmosphere Substances 0.000 description 6
RJUAEBLXGFKZMS-UHFFFAOYSA-N piperidin-1-ylmethanol Chemical compound OCN1CCCCC1 RJUAEBLXGFKZMS-UHFFFAOYSA-N 0.000 description 6
GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 6
230000000171 quenching effect Effects 0.000 description 6
239000011347 resin Substances 0.000 description 6
229920005989 resin Polymers 0.000 description 6
238000005292 vacuum distillation Methods 0.000 description 6
QCMFUJYCRNASBU-UHFFFAOYSA-N 4-(2,3-dimethoxybenzoyl)piperidine-1-carboxylic acid Chemical compound COC1=CC=CC(C(=O)C2CCN(CC2)C(O)=O)=C1OC QCMFUJYCRNASBU-UHFFFAOYSA-N 0.000 description 5
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229920001155 polypropylene Polymers 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
238000005086 pumping Methods 0.000 description 1
239000002994 raw material Substances 0.000 description 1
239000013557 residual solvent Substances 0.000 description 1
230000000717 retained effect Effects 0.000 description 1
229910052703 rhodium Inorganic materials 0.000 description 1
239000010948 rhodium Substances 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000011343 solid material Substances 0.000 description 1
238000000935 solvent evaporation Methods 0.000 description 1
229910001220 stainless steel Inorganic materials 0.000 description 1
239000010935 stainless steel Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000012485 toluene extract Substances 0.000 description 1
238000010792 warming Methods 0.000 description 1
238000005303 weighing Methods 0.000 description 1

Landscapes

Hydrogenated Pyridines (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA002493559A 1998-03-13 1999-03-11 Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol Abandoned CA2493559A1 (fr)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
US4225198A	1998-03-13	1998-03-13
US09/042,251		1998-03-13
US25071899A	1999-02-16	1999-02-16
US09/250,718		1999-02-16
CA002322501A CA2322501C (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

Related Parent Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002322501A Division CA2322501C (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

Publications (1)

Publication Number	Publication Date
CA2493559A1 true CA2493559A1 (fr)	1999-09-16

Family

ID=34279252

Family Applications (4)

Application Number	Title	Priority Date	Filing Date
CA002493173A Abandoned CA2493173A1 (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
CA002493559A Abandoned CA2493559A1 (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
CA002492600A Abandoned CA2492600A1 (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1- [2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
CA002493546A Abandoned CA2493546A1 (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

Family Applications Before (1)

Application Number	Title	Priority Date	Filing Date
CA002493173A Abandoned CA2493173A1 (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

Family Applications After (2)

Application Number	Title	Priority Date	Filing Date
CA002492600A Abandoned CA2492600A1 (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1- [2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
CA002493546A Abandoned CA2493546A1 (fr)	1998-03-13	1999-03-11	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

Country Status (1)

Country	Link
CA (4)	CA2493173A1 (fr)

1999
- 1999-03-11 CA CA002493173A patent/CA2493173A1/fr not_active Abandoned
- 1999-03-11 CA CA002493559A patent/CA2493559A1/fr not_active Abandoned
- 1999-03-11 CA CA002492600A patent/CA2492600A1/fr not_active Abandoned
- 1999-03-11 CA CA002493546A patent/CA2493546A1/fr not_active Abandoned

Also Published As

Publication number	Publication date
CA2492600A1 (fr)	1999-09-16
CA2493173A1 (fr)	1999-09-16
CA2493546A1 (fr)	1999-09-16

Legal Events

Date	Code	Title	Description
2005-01-28	EEER	Examination request
2010-01-07	FZDE	Discontinued
2023-05-26	FZDE	Discontinued	Effective date: 20100107

Publication	Publication Date	Title
EP0223403B1 (fr)	1993-08-04	Dérivé de pipéridine, sa préparation et son utilisation comme médicament
JP2010143925A (ja)	2010-07-01	（Ｒ）−α−（２，３−ジメトキシフェニル）−１−［２−（４−フルオロフェニル）エチル］−４−ピペリジンメタノールの製造方法
US20090227798A1 (en)	2009-09-10	Novel processes for the preparation of (r)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
US20070265450A1 (en)	2007-11-15	Novel processes for the preparation of (r)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
CA2072520A1 (fr)	1992-12-28	Derives de 2-(1-piperidyl) ethanol, leur obtention et leurs applications therapeutiques
CA2493559A1 (fr)	1999-09-16	Procedes de preparation de (r)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
HK1100288A (en)	2007-09-14	Processes for the preparation of (r)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
HK1100289A (en)	2007-09-14	Processes for the preparation of (r)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
NZ523652A (en)	2004-04-30	4-(2,3-dimethoxybenzoyl)-pyridine or 4-((2,3-dimethoxyphenyl)-4-pyridine
MXPA00008938A (en)	2002-07-25	PROCESSES FOR THE PREPARATION OF (R)-&agr;- (2,3-DIMETHOXYPHENYL)- 1-[2-(4- FLUOROPHENYL)ETHYL]- 4-PIPERIDINEMETHANOL