TWI338690B - Improved process for the preparation of (ethoxymethyl)-tropane derivatives - Google Patents
Improved process for the preparation of (ethoxymethyl)-tropane derivatives Download PDFInfo
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- TWI338690B TWI338690B TW094102759A TW94102759A TWI338690B TW I338690 B TWI338690 B TW I338690B TW 094102759 A TW094102759 A TW 094102759A TW 94102759 A TW94102759 A TW 94102759A TW I338690 B TWI338690 B TW I338690B
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- 238000000034 method Methods 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title description 3
- OYQQNDQWHWJCNW-MNOVXSKESA-N (1S,5R)-1-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane Chemical class C(C)OC[C@]12CCC[C@H](CC1)N2C OYQQNDQWHWJCNW-MNOVXSKESA-N 0.000 title 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000003444 phase transfer catalyst Substances 0.000 claims description 10
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 3
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- ULGQIISCCLEOHQ-UHFFFAOYSA-N [Li].O=O Chemical compound [Li].O=O ULGQIISCCLEOHQ-UHFFFAOYSA-N 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- -1 2-(hydroxyindenyl)-decane derivative Chemical class 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 235000011118 potassium hydroxide Nutrition 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 229930004006 tropane Natural products 0.000 description 3
- 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
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- KQZPOUHEOZDZEO-CFCGPWAMSA-N [(1r,5r)-8-methyl-8-azabicyclo[3.2.1]octan-4-yl]methanol Chemical class C1CC(CO)[C@@]2([H])CC[C@]1([H])N2C KQZPOUHEOZDZEO-CFCGPWAMSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical compound C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical compound C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- KVGOXGQSTGQXDD-UHFFFAOYSA-N 1-decane-sulfonic-acid Chemical compound CCCCCCCCCCS(O)(=O)=O KVGOXGQSTGQXDD-UHFFFAOYSA-N 0.000 description 1
- OXQHJIGWZNIQDS-UHFFFAOYSA-N 2,2-dimethoxybutane Chemical compound CCC(C)(OC)OC OXQHJIGWZNIQDS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- CACLKHMNNVCSOB-UHFFFAOYSA-N C(C)[Ru](CC)(CC)CC Chemical compound C(C)[Ru](CC)(CC)CC CACLKHMNNVCSOB-UHFFFAOYSA-N 0.000 description 1
- YIJSHXLSWDIGBW-UHFFFAOYSA-N C(CCCCCCCCCCCCC)[Ru] Chemical compound C(CCCCCCCCCCCCC)[Ru] YIJSHXLSWDIGBW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical group CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZJIZTCFFWKIBJE-UHFFFAOYSA-L S(=O)(=O)([O-])[O-].C(CCC)[N+](CCCC)(CCCC)CCCC.[Ar].C(CCC)[N+](CCCC)(CCCC)CCCC Chemical compound S(=O)(=O)([O-])[O-].C(CCC)[N+](CCCC)(CCCC)CCCC.[Ar].C(CCC)[N+](CCCC)(CCCC)CCCC ZJIZTCFFWKIBJE-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- KSBFFOYIOAYXEH-UHFFFAOYSA-N benzoic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)CC(O)(C(O)=O)CC(O)=O KSBFFOYIOAYXEH-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-M ethyl sulfate Chemical compound CCOS([O-])(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N fumaric acid group Chemical class C(\C=C\C(=O)O)(=O)O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- ZUZLIXGTXQBUDC-UHFFFAOYSA-N methyltrioctylammonium Chemical compound CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC ZUZLIXGTXQBUDC-UHFFFAOYSA-N 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 208000016657 midbrain disease Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CLMFECCMAVQYQA-UHFFFAOYSA-N nonylcyclohexane Chemical compound CCCCCCCCCC1CCCCC1 CLMFECCMAVQYQA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- CBXWGGFGZDVPNV-UHFFFAOYSA-N so4-so4 Chemical compound OS(O)(=O)=O.OS(O)(=O)=O CBXWGGFGZDVPNV-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- HJHUXWBTVVFLQI-UHFFFAOYSA-N tributyl(methyl)azanium Chemical compound CCCC[N+](C)(CCCC)CCCC HJHUXWBTVVFLQI-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000003813 tropane derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
1338690 九、發明說明： 【發明所屬之技術領域】 —，- 本發明係關於一藉由2-(羥甲基）-托烷衍生物與溴乙烷在 一鹼及一相轉移觸媒之存在下反應製備2_(乙氧基甲基）·托 炫衍生物之改良方法。 【先前技術】 2-(乙氧基甲基）-托烧衍生物係治療多種中拖神經障礙 (例如’帕金森氏症（Parkinson、disease)或阿兹海默氏症 1 (Alzheimer's disease))之重要醫藥活性物質。 根據國際專利申請案第WO 97/30997號之教義，其可自 2-(甲笨績S莲基曱基）_托燒衍生物藉由與一乙醇鹽反應或藉 ' 由2_(羥甲基）·托烷衍生物與作為鹼之氫化鈉及硫酸二乙醋 反應來製備。出於安全原因，實際上在工業規模生產中不 可能使用氫化鈉。而且’乙氧基化實際上不可重現，·反應 時間長且活性物質係以一難以分離之固體以不甚滿意之產 率獲得 .J 【發明内容】 因此’本發明之潛在問題係提供一種可在較大工業規模 中以較佳產率製備2 -(乙氧基曱基）-托衍生物之方法同時避 免先前技術習知方法中存在之缺點。 【實施方式】 令人驚訝的是，人們已發現式（I)之2-(乙氧基甲基）_托院 衍生物或其醫藥物上可接受之鹽， 98422.doc 1338690
其中 R1表示氫或0^-6烧基，尤其係甲基；且 R2表示視情況經自素、三氟甲基或氰基單或多取代之笨 基’尤其係3,4-二氣苯基；
可藉由式（II)之2-(羥甲基）·托烷衍生物，
其中R1及R2皆如式⑴之定義， 與溴乙烷在一鹼'-相轉移觸媒及視情況-稀釋劑的存在 下反應以較佳產率及工業規模來製備。
) J ，不㉟日月係關於-用於製備式⑴之2_(乙氧基甲基） 托炫生物或_其醫藥上可接受之鹽之改良方法，其中係 在-鹼、-相轉移觸媒及視情況一稀釋劑之存在下使式(H) 之2-(羥尹基)_牦烷衍生物與漠乙烷反應且然後視 一 酸處理。 本發明方法之較佳實施例係以下方法，其中·· ⑷金屬氫氧化物（例如氫氧錢、氫氧化鈉或氣氧化 尤其係粉末狀氫氧化鉀）作為驗； 用相轉移觸媒（PTC)係四炫基録或四炫基鱗鹽，同時 98422.doc 該等烧基可相同或不同’例如四辛基鍵、曱基三辛基 敍、四曱基敍、四乙基敍、四己基錄、Aliquatl75(三 丁基甲基銨）或Aliquat 336(甲基三辛基銨）之鹽。較佳 ptc係一 化四炫基敍、硫酸四院基錢、硫酸氫四燒 基銨、硝酸四烧基錢或填酸四炫基錢，尤其硫酸氫四 烷基銨，最佳者係硫酸氫四-正-丁基銨。 上文及下文所用與相轉移觸媒相關之術語「烷基」包含 具1至8個（較佳2至6個’尤其4個）碳原子之直鏈及具支鏈燒 基。因此’應提及之較佳院基係乙基、正-丙基、異-丙基、 正-丁基、2-丁基、第三-丁基、正-戊基、2-戊基、新-戊基、 正-已基-及2-已基基團。最佳者係正-丁基基團。 3本發明方法之其他較佳實施例係以下方法，其中 (C) 所用稀釋劑係一芳烴（較佳為笨、甲苯或二曱苯，尤其 係甲笨）、或一視情況經_代之脂肪族烴（較佳為環己 烷、曱基環己烷、二氣甲烷、氣仿、四氣化碳或二氣 乙烧，尤其係二氣甲烧）或一驗（較佳為四氫咬喃 (THF)、二乙醚 '二異丙醚、第三_ 丁基曱基鍵（tbme) 或1，2-二曱氧乙烷⑴ME),尤其係l2_二甲氧乙烷广 (D) 該反應係在介於-iOt至+90°C之範圍之溫度下進行， 較佳自0°c至80°c ’尤其自20至65t ; (E) 對1當量式（II)之化合物使用〇 75至1〇〇當量溴乙烷，較 佳為1.5至5.5當量，尤其約4當量； (F) 1當量式（II)之化合物使用2 5至1〇〇當量鹼，較佳為3.8 至10.5當量’尤其7.5至8.5當量； 98422.doc (G) 1當量式（II)之化合物使用0.01至〇·5當量相轉移觸媒， 較佳為0.02至0.2當量，尤其〇·〇5至〇15當量； (Η)該反應結束後’向反應混合物中添加水，分相，有機 相用水洗滌’然後於減壓下蒸發，且殘餘物用酸處理 並分離所獲得之酸加成鹽； (I)所付式（I)之活性物質係用一無機或有機酸處理。所得 酸加成鹽係（例如）鹽酸鹽、氫溴酸鹽、磷酸鹽、硝酸 鹽、尚氣酸鹽、硫酸鹽、檸檬酸鹽、乳酸鹽、酒石酸 鹽、馬來酸鹽'富馬酸鹽、扁桃酸鹽、安息香酸鹽、 抗壞血酸鹽、肉桂酸鹽、笨磺酸鹽、曱烷磺酸鹽、硬 月曰酸鹽、號珀酸鹽、谷氨酸鹽、經基乙酸鹽、曱笨-對 -磺酸鹽、曱酸鹽、丙二酸鹽、萘_2_磺酸鹽、水揚酸鹽 及乙酸鹽。尤佳者係檸檬酸鹽。該等鹽係使用相應已 知生產方法來製備。 在一尤佳之實施例中，在5至60分鐘内在自20至35。(：之間 之溫度下，將4當量溴乙烷（視情況溶於氧基乙烷） 計量加入I當量式（II)之化合物、約2〇倍（以重量計）於门之 二甲氧基乙烷、約8當量KOH犮約〇. 1當量硫酸氫四·正_丁基 銨之此合物中，同時攪拌。添加結束後，於40至80°C之間 之溫度下將該混合物攪拌3〇至3〇〇分鐘，較佳約45至18〇分 鐘。然後添加水，並在給定溫度下將該混合物再攪拌3〇至 3〇〇分鐘，較佳約45至18〇分鐘，然後分離有機相。蒸發有 機相且殘餘物用酸（較佳為檸檬酸）處理。 分離並乾燥式⑴之化合物之酸加成鹽。 98422.doc 本發明之程序之其他有利態樣係本發明方法之高時空產 率及高產量及不經任何其他純化製程而獲得式⑴之純化合 物或其鹽。 下列實例係以實例方式闡述用於製備式（I)之化合物之方 法。該等應理解為以實例方式闈述可能之程序而非將本發 明限於其内容= 4^11(111，213 5)-2-乙氧基甲基]_(3,4_二氣笨基）托烧捧 檬酸鹽 在15分鐘内於20至31°C之間之溫度下，將14 6克（〇 134莫 耳）溴乙烷計量加入1〇克（0,0333莫耳）(1R，2R，3S)-2_羥甲基 -3·(3,4·二氯苯基）_托烷（根據w〇 97/3〇997製備）、μ %克粉 末狀（0.266莫耳ΚΟΗ)苛性鉀、1‘16克（0.00334莫耳）硫酸氫 四-正-丁基銨及200毫升DME之混合物f，同時攪拌。 添加結束後’將混合物於58與62°C之間之溫度下授拌1.5 小時。然後添加76毫升水’在此溫度下再將混合物攪拌1 小時’分離有機相。在減壓下用旋轉蒸發器蒸發有機相。 於55°C下將殘餘物用90毫升丙酮溶解、過濾並用1〇毫升丙 酮洗務。在40 °C下將所得溶液用6.4克（0.03 33莫耳）檸檬酸 與20毫升甲醇之混合物處理。將晶體懸浮液冷卻至2(Γ(：且 在1 5至20°C下攪拌1小時。分離所獲晶體並用33毫升丙酮洗 條。在真空乾燥櫥中於40。〇下乾燥後，獲得14 55克（理論值 的83.6%)標題化合物，其為黃色晶體，純度為99.4%以上。 tAi (111，211，3 3)-2-乙氧基甲基-3-(3,4-二氣笨基）-托烷檸 樣酸鹽 98422.doc •10- 於20至31°C之間之溫度下，將溶於20毫升1，2-二甲氧基 乙烷中之17_5克（0.161莫耳）溴乙烷在15分鐘内計量加入12 克（0.0400莫耳）(111，211，3 8)-2-羥甲基-3-(3,4-二氣苯基）-托烷 (根據WO 97/30997製備）、17.9克粉末狀（0.320莫耳KOH)苛 性鉀、1.39克（0.00409莫耳）硫酸氩四-正-丁基銨及22〇毫升 DME之混合物中，同時授拌。 添加結束後，將混合物於58與62t之間之溫度下授拌1.5 小時。然後添加76毫升水，在此溫度下將混合物再攪拌1 小時’分離有機相。在減壓下用旋轉蒸發器蒸發有機相。 將殘餘物在55°C下溶於108毫升丙酮中，過濾並用40毫升丙 _洗務。在40°C下將所得溶液用7.68克（0.0400莫耳）檸檬酸 與24毫升甲醇之混合物處理。將晶體懸浮液冷卻至2〇〇c並 在15至20C下授拌1小時。分離所得晶體並用至少go毫升丙 酮洗滌。在真空乾燥櫥中在4(TC下乾燥後，獲得17.44克（理 論值的83.85%)標題化合物，其為黃色結晶，純度為99 5〇/〇 以上。 對照實例1 (丨R，2R，3S)-2-乙氧基甲基·3_(3,4-二氣·苯基）_ 托烷檸檬酸鹽 (根據 WO 97/30997) 將氫化鈉（60%於油中）（4.6克，0.12莫耳）及硫酸乙酯（15.7 毫升’ 0.12莫耳）添加至（iR，2R，3S)_2_羥曱基_3_(3,4_二氣笨 基托烷（26.9克’ 〇.〇9莫耳）與THF(200毫升）之混合物中， 並加熱至30至40°C保持半小時。於室溫下將反應混合物攪 拌過夜’然後加熱至3〇至40°C保持半小時，傾倒至500毫升 98422.doc -11 -
Claims (1)
133869¾ 094102759號專利申請案 r 中文申請專利範圍替換本(99年8月）j 種用於製備式（I)之2-(乙氧基甲基托烷衍生物或—其 醫藥上可接受之鹽之方法，
(D 十、申請專利範圍： 其中 R1表示氫或C!6烷基；及 氟甲基或氰基單或多 R2表示笨基，其視情況經_素、三 取代； R,\ Η
該方法之特徵在於將式（11)之2 (經甲基）·托⑨衍生物， H 一 κ 八 (H) 其中R1及R2皆如式⑴之定義， 與漠乙烧在—給、 一相轉移觸媒及視情況一稀釋劑之: 在下反應’並然後視情況用-酸處理； 及其中該驗俾谐&丄— 自由氧氧化鋰、氫氧化鈉及氫氧化鉀 組成之群。 2·如請求項1之方法，其中 Rl表示曱基，且 R2表示3,4-二氣苯基。 3-如請求項1或2 々法’其特徵在於以粉末狀氫氧化鉀 98422-990803.doc ί358690 為驗。 4. 々π求項1或2之方法，其特徵在於以四烷基銨或四烷基 鎮鹽作為相轉移觸媒。. 5. 士 π求項4之方法，其特徵在於以硫酸氫四烷基銨作為相 轉移觸媒。 6. 如μ求項1或2之方法，其特徵在於以一芳烴、一視情況 鹵代脂肪族烴或一醚作為稀釋液。 7. 如印求項6之方法，其特徵在於以曱苯、二氣曱烷或 一甲氧乙坑作為稀釋劑。 8·如研求項1或2之方法，其特徵在於反應係在介於_1〇。匚至 + 90°C之範圍之溫度下進行。 9. 如凊求項1或2之方法，其特徵在於溴乙烷係在5至18〇分 * 鐘内叶量加入，並將所得反應混合物再攪拌3〇至18〇分 鐘。 10. 如明求項1或2之方法，其特徵在於將〇 75至1〇〇當量之溴 乙烷加入1當量式（Π)中。 11. 如硐求項1或2之方法，其特徵在於將25至1〇〇當童鹼加入 1當量式（II)中。 12. 如蜎求項1或2之方法，其特徵在於將〇 〇1至〇 5當量相轉 移觸媒加入1當量式（Π)中。 13. 如請求項1或2之方法，其特徵在於式（π)之化合物與溴乙 烷之反應結束後，添加水至所得反應混合物中，將各相 分離，將有機相用水洗滌，於低於環境壓力的壓力下蒸 發且將殘餘物用相應的酸處理而不經任何進一步純化。 98422-990803.doc
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| US7544802B2 (en) | 2009-06-09 |
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| CA2554125A1 (en) | 2005-08-11 |
| DE102004004965B4 (de) | 2006-01-05 |
| US20050171145A1 (en) | 2005-08-04 |
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| EP1713800A2 (de) | 2006-10-25 |
| PE20050770A1 (es) | 2005-11-10 |
| CN1910180A (zh) | 2007-02-07 |
| DE502005008535D1 (de) | 2009-12-31 |
| HK1097845A1 (zh) | 2007-07-06 |
| JP2007519660A (ja) | 2007-07-19 |
| ATE449095T1 (de) | 2009-12-15 |
| UY28730A1 (es) | 2005-09-30 |
| DE102004004965A1 (de) | 2005-09-01 |
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