NO762158L - - Google Patents
Info
- Publication number
- NO762158L NO762158L NO762158A NO762158A NO762158L NO 762158 L NO762158 L NO 762158L NO 762158 A NO762158 A NO 762158A NO 762158 A NO762158 A NO 762158A NO 762158 L NO762158 L NO 762158L
- Authority
- NO
- Norway
- Prior art keywords
- acid
- hydroxy
- mixture
- solution
- residue
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 description 91
- 239000000243 solution Substances 0.000 description 82
- -1 hydroxy, mercapto Chemical class 0.000 description 67
- 239000000203 mixture Substances 0.000 description 67
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 49
- 238000000034 method Methods 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 46
- 239000002253 acid Substances 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 150000003839 salts Chemical class 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 229910052739 hydrogen Inorganic materials 0.000 description 33
- 239000001257 hydrogen Substances 0.000 description 33
- 125000000217 alkyl group Chemical group 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- 239000000155 melt Substances 0.000 description 25
- 239000007858 starting material Substances 0.000 description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 19
- 125000003545 alkoxy group Chemical group 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- 239000000284 extract Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 150000002431 hydrogen Chemical class 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 235000011054 acetic acid Nutrition 0.000 description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 125000004423 acyloxy group Chemical group 0.000 description 13
- 150000007513 acids Chemical class 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000012280 lithium aluminium hydride Substances 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000004414 alkyl thio group Chemical group 0.000 description 9
- 238000009835 boiling Methods 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
- KQKFQBTWXOGINC-UHFFFAOYSA-N 4-phenylpiperidin-4-ol Chemical compound C=1C=CC=CC=1C1(O)CCNCC1 KQKFQBTWXOGINC-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 7
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 7
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 150000007522 mineralic acids Chemical class 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- 150000007524 organic acids Chemical class 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000011343 solid material Substances 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 241000282693 Cercopithecidae Species 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 150000003053 piperidines Chemical class 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- NPEFMXMRSFIHKN-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-3-yl)acetic acid Chemical compound C1=CC=C2OC(CC(=O)O)COC2=C1 NPEFMXMRSFIHKN-UHFFFAOYSA-N 0.000 description 4
- IZDQKYKYHYKLRG-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-3-yl)ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1OC2=CC=CC=C2OC1 IZDQKYKYHYKLRG-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 229940071870 hydroiodic acid Drugs 0.000 description 4
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical class OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 239000000052 vinegar Substances 0.000 description 4
- 235000021419 vinegar Nutrition 0.000 description 4
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 3
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940109275 cyclamate Drugs 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- SNVSNVQHFNKFEY-UHFFFAOYSA-N (2-ethoxy-2-methoxy-2-methylsulfanylethyl) thiohypofluorite Chemical compound COC(CSF)(SC)OCC SNVSNVQHFNKFEY-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- APQJHJROGNWTBL-UHFFFAOYSA-N 1-bromo-4-(4-hydroxy-4-phenylpiperidin-1-yl)butan-2-one;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(O)CCN(CCC(=O)CBr)CC1 APQJHJROGNWTBL-UHFFFAOYSA-N 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- YOZIPAXYZMHZRX-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-3-yl)acetaldehyde Chemical compound C1=CC=C2OC(CC=O)COC2=C1 YOZIPAXYZMHZRX-UHFFFAOYSA-N 0.000 description 2
- PWZFEIJALHLRKF-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-3-yl)acetonitrile Chemical compound C1=CC=C2OC(CC#N)COC2=C1 PWZFEIJALHLRKF-UHFFFAOYSA-N 0.000 description 2
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- SJNALLRHIVGIBI-UHFFFAOYSA-N allyl cyanide Chemical compound C=CCC#N SJNALLRHIVGIBI-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical class C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 150000002736 metal compounds Chemical class 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000003176 neuroleptic agent Substances 0.000 description 2
- 230000000701 neuroleptic effect Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 235000012976 tarts Nutrition 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- YUTFQTAITWWGFH-UHFFFAOYSA-N 1-(1-benzofuran-2-yl)ethanone Chemical compound C1=CC=C2OC(C(=O)C)=CC2=C1 YUTFQTAITWWGFH-UHFFFAOYSA-N 0.000 description 1
- QAWRUQMKWRUBJZ-UHFFFAOYSA-N 1-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-4-phenylpiperidin-4-ol Chemical compound C1CN(CC2OC3=CC=CC=C3OC2)CCC1(O)C1=CC=CC=C1 QAWRUQMKWRUBJZ-UHFFFAOYSA-N 0.000 description 1
- SKLNOSSRLFROHI-UHFFFAOYSA-N 1-[2-(1-benzofuran-2-yl)ethyl]-4-phenylpiperidin-4-ol Chemical compound C1CN(CCC=2OC3=CC=CC=C3C=2)CCC1(O)C1=CC=CC=C1 SKLNOSSRLFROHI-UHFFFAOYSA-N 0.000 description 1
- SBJGMUOIXKNSEK-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1,4-benzodioxin-3-yl)ethyl]-4-phenylpiperidin-4-ol Chemical compound C1CN(CCC2OC3=CC=CC=C3OC2)CCC1(O)C1=CC=CC=C1 SBJGMUOIXKNSEK-UHFFFAOYSA-N 0.000 description 1
- QDMKBDGBEZMNRY-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1,4-benzodioxin-3-yl)ethyl]piperidin-4-one Chemical compound C1CC(=O)CCN1CCC1OC2=CC=CC=C2OC1 QDMKBDGBEZMNRY-UHFFFAOYSA-N 0.000 description 1
- RWJYJUNHUZJEOT-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1-benzofuran-2-yl)ethyl]-4-phenylpiperidin-4-ol Chemical compound C1CN(CCC2OC3=CC=CC=C3C2)CCC1(O)C1=CC=CC=C1 RWJYJUNHUZJEOT-UHFFFAOYSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- LLSKXGRDUPMXLC-UHFFFAOYSA-N 1-phenylpiperidine Chemical compound C1CCCCN1C1=CC=CC=C1 LLSKXGRDUPMXLC-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- ZYIXXVCNAOYWQA-UHFFFAOYSA-N 2-(1-benzofuran-2-yl)acetic acid Chemical compound C1=CC=C2OC(CC(=O)O)=CC2=C1 ZYIXXVCNAOYWQA-UHFFFAOYSA-N 0.000 description 1
- XQSREKUOEGUHHZ-UHFFFAOYSA-N 2-(1-benzofuran-2-yl)ethanol Chemical compound C1=CC=C2OC(CCO)=CC2=C1 XQSREKUOEGUHHZ-UHFFFAOYSA-N 0.000 description 1
- UVDCEJJTNFWPSV-UHFFFAOYSA-N 2-(1-benzofuran-2-yl)ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1=CC2=CC=CC=C2O1 UVDCEJJTNFWPSV-UHFFFAOYSA-N 0.000 description 1
- SCDRFFVQCMNORR-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzoxathiin-2-yl)acetic acid Chemical compound C1=CC=C2OC(CC(=O)O)CSC2=C1 SCDRFFVQCMNORR-UHFFFAOYSA-N 0.000 description 1
- RNONDDBIDOOLOX-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzoxathiin-2-yl)acetonitrile Chemical compound C1=CC=C2OC(CC#N)CSC2=C1 RNONDDBIDOOLOX-UHFFFAOYSA-N 0.000 description 1
- HKJSLKIPAZEKGM-UHFFFAOYSA-N 2-(2,3-dihydro-1-benzofuran-2-yl)acetic acid Chemical compound C1=CC=C2OC(CC(=O)O)CC2=C1 HKJSLKIPAZEKGM-UHFFFAOYSA-N 0.000 description 1
- ZJMQZZXXIOGDIO-UHFFFAOYSA-N 2-(2,3-dihydro-1-benzofuran-2-yl)ethanol Chemical compound C1=CC=C2OC(CCO)CC2=C1 ZJMQZZXXIOGDIO-UHFFFAOYSA-N 0.000 description 1
- XHQRVJPQGSRKMK-UHFFFAOYSA-N 2-(2,3-dihydro-1-benzofuran-2-yl)ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1OC2=CC=CC=C2C1 XHQRVJPQGSRKMK-UHFFFAOYSA-N 0.000 description 1
- QQLNIFBCQNGXIQ-UHFFFAOYSA-N 2-(6-methyl-2,3-dihydro-1,4-benzodioxin-3-yl)acetic acid Chemical compound O1CC(CC(O)=O)OC2=CC(C)=CC=C21 QQLNIFBCQNGXIQ-UHFFFAOYSA-N 0.000 description 1
- PDPFIODCZGCNTK-UHFFFAOYSA-N 2-(6-methyl-2,3-dihydro-1,4-benzodioxin-3-yl)ethanol Chemical compound O1CC(CCO)OC2=CC(C)=CC=C21 PDPFIODCZGCNTK-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- XHYCSCBAALGUBR-UHFFFAOYSA-N 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-3-yl)ethanone Chemical compound C1=CC=C2OC(C(=O)CBr)COC2=C1 XHYCSCBAALGUBR-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- CGERYHYIVJQVLJ-UHFFFAOYSA-N 2-methylbutane Chemical group CC[C](C)C CGERYHYIVJQVLJ-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- VMKYTRPNOVFCGZ-UHFFFAOYSA-N 2-sulfanylphenol Chemical compound OC1=CC=CC=C1S VMKYTRPNOVFCGZ-UHFFFAOYSA-N 0.000 description 1
- MCHBWFDXJBLCAG-UHFFFAOYSA-N 3,4-dibromobutanenitrile Chemical compound BrCC(Br)CC#N MCHBWFDXJBLCAG-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UPMDYIZACLETKW-UHFFFAOYSA-N 4-(4-hydroxy-4-phenylpiperidin-1-yl)butan-2-one;hydrochloride Chemical compound Cl.C1CN(CCC(=O)C)CCC1(O)C1=CC=CC=C1 UPMDYIZACLETKW-UHFFFAOYSA-N 0.000 description 1
- RGFHJSYBDBNFMX-UHFFFAOYSA-N 4-(4-methoxyphenyl)piperidin-4-ol Chemical compound C1=CC(OC)=CC=C1C1(O)CCNCC1 RGFHJSYBDBNFMX-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- KJZBZOFESQSBCV-UHFFFAOYSA-N 4-benzylpiperidin-4-ol Chemical compound C=1C=CC=CC=1CC1(O)CCNCC1 KJZBZOFESQSBCV-UHFFFAOYSA-N 0.000 description 1
- GMBVQDPSOSICDP-UHFFFAOYSA-N 4-ethoxy-4-phenylpiperidine Chemical compound C=1C=CC=CC=1C1(OCC)CCNCC1 GMBVQDPSOSICDP-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- SETKGOFWOWUIIE-UHFFFAOYSA-N 4-phenylpiperidin-4-ol;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(O)CCNCC1 SETKGOFWOWUIIE-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-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
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 229930195725 Mannitol Natural products 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 241000786363 Rhampholeon spectrum Species 0.000 description 1
- 241000282695 Saimiri Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- WZUGLZFZLRQMEM-UHFFFAOYSA-N [1-[2-(2,3-dihydro-1,4-benzodioxin-3-yl)ethyl]-4-phenylpiperidin-4-yl] decanoate Chemical compound C1CN(CCC2OC3=CC=CC=C3OC2)CCC1(OC(=O)CCCCCCCCC)C1=CC=CC=C1 WZUGLZFZLRQMEM-UHFFFAOYSA-N 0.000 description 1
- RIUIXTCSZNGWNL-UHFFFAOYSA-N [2-[2-hydroxy-4-(4-hydroxy-4-phenylpiperidin-1-yl)butoxy]phenyl] acetate Chemical compound CC(=O)OC1=CC=CC=C1OCC(O)CCN1CCC(O)(C=2C=CC=CC=2)CC1 RIUIXTCSZNGWNL-UHFFFAOYSA-N 0.000 description 1
- UVMUORJXXBPSQE-UHFFFAOYSA-N [Na].COCCO[AlH2] Chemical compound [Na].COCCO[AlH2] UVMUORJXXBPSQE-UHFFFAOYSA-N 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 239000000159 acid neutralizing agent Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N beta-hydroxyethanesulfonic acid Natural products OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229950001002 cianidanol Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- IPIVAXLHTVNRBS-UHFFFAOYSA-N decanoyl chloride Chemical compound CCCCCCCCCC(Cl)=O IPIVAXLHTVNRBS-UHFFFAOYSA-N 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- YKWNUSJLICDQEO-UHFFFAOYSA-N ethoxyethane;propan-2-ol Chemical compound CC(C)O.CCOCC YKWNUSJLICDQEO-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000003350 kerosene Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical compound Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003151 propanoic acid esters Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte til fremstilling av nye 2-piperidinoålkyl-l,^-benzodioksaner. Process for the production of new 2-piperidinoalkyl-1,4-benzodioxanes.
Oppfinnelsen vedrører fremstillingen av nye 2-piperidinoalkyl-(1-benzofuraner eller 1,4-benzodioksaner) The invention relates to the production of new 2-piperidinoalkyl-(1-benzofurans or 1,4-benzodioxanes)
med den generelle formel I with the general formula I
hvori Ph betyr en 1,2-fenylenrest, som eventuelt er substituert med en til tre, like eller forskjellige substituenter valgt blant laverealkyl, hydroksy, merkapto, laverealkoksy, in which Ph means a 1,2-phenylene residue, which is optionally substituted with one to three, the same or different substituents selected from lower alkyl, hydroxy, mercapto, lower alkoxy,
laverealkylendioksy, benzyloksy, laverer»lkyltio, halogen, trifluormetyl, nitro eller aminb, X betyr oksygen eller svovel, m betyr de hele tall 0 eller 1 og n betyr de hele tall fra 1 til H, hvert av symbolene p og q betyr et helt tall fra 1 til 3, idet (p+q) er tallet 4, hvert av symbolene R-^ og betyr lower alkylenedioxy, benzyloxy, lower alkylthio, halogen, trifluoromethyl, nitro or amineb, X means oxygen or sulphur, m means the integers 0 or 1 and n means the integers from 1 to H, each of the symbols p and q means an integer numbers from 1 to 3, where (p+q) is the number 4, each of the symbols R-^ and means
hydrogen, laverealkyl eller HPh, betyr hydrogen, hydroksy, laverealkoksy, lavere eller høyere alkanoyloksy, R^betyr laverealkyl, HPh-laverealkyl, HPh eller naftyl, som eventuelt er substituert som Ph, furyl, tienyl, pyridyl, benzofuryl, benzotienyl, kinolyl eller isokinolyl, hvilke heterocykliske rester eventuelt er substituert som Ph samt S-oksyder eller syreaddisjonssalter, spesielt terapeutisk anvendbare syreaddisjonssalter av disse forbindelser. hydrogen, lower alkyl or HPh, means hydrogen, hydroxy, lower alkoxy, lower or higher alkanoyloxy, R^ means lower alkyl, HPh-lower alkyl, HPh or naphthyl, which is optionally substituted as Ph, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, quinolyl or isoquinolyl, which heterocyclic residues are optionally substituted as Ph as well as S-oxides or acid addition salts, especially therapeutically applicable acid addition salts of these compounds.
En 1,2-fenylenrest Ph er fortrinnsvis monosubstitu-ert, idet substituentene illustreres av følgende grupper: Laverealkyl, f.eks. metyl, etyl, n- eller i-propyl eller -bu-tylj hydroksy, merkapto; laverealkoksy, f.eks. metoksy, etoksy, n- eller i-propoksy eller -butoksy, laverealkylendioksy, f.eks. metylendioksy, 1,1- eller 1,2-etylendioksy, benzyloksy, laverealkyltio, f.eks. metyltio eller etyltio, halogen, f.eks. fluor, A 1,2-phenylene residue Ph is preferably monosubstituted, the substituents being illustrated by the following groups: Lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl hydroxy, mercapto; lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy, lower alkylenedioxy, e.g. methylenedioxy, 1,1- or 1,2-ethylenedioxy, benzyloxy, lower alkylthio, e.g. methylthio or ethylthio, halogen, e.g. fluoride,
klor eller brom, trifluormetyl, nitro eller amino.chlorine or bromine, trifluoromethyl, nitro or amino.
Av de nevnte hele tall er m fortrinnsvis 1, når formel I betyr 1,^-benzodioksaner eller 1,^-benzoksatianer eller null når formelen betyr 1-benzofuraner. Alkylengruppen<C>n<H>2n betyr fortrinnsvis metylen, 1,1- eller 1,2-etylen, 1,2-eller 1,3-propylen, 1,2-, 1,3- eller 1,4-butylen og hvert av symbolene p og q betyr fortrinnsvis tallet 2. Of the whole numbers mentioned, m is preferably 1, when formula I means 1,^-benzodioxanes or 1,^-benzoxathianes or zero when the formula means 1-benzofurans. The alkylene group <C>n<H>2n preferably means methylene, 1,1- or 1,2-ethylene, 1,2- or 1,3-propylene, 1,2-, 1,3- or 1,4-butylene and each of the symbols p and q preferably means the number 2.
Hvert av symbolene R-^og R2betyr fortrinnsvis hydrogen, men også laverealkyl, spesielt metyl, eller en annen overnevnte laverealkylrest. Et av disse symboler, spesielt R2kan også bety eventuelt substituert fenyl, idet substituentene er disse av en H-Ph-rest. Each of the symbols R 1 and R 2 preferably means hydrogen, but also lower alkyl, especially methyl, or another above-mentioned lower alkyl residue. One of these symbols, especially R2 can also mean optionally substituted phenyl, the substituents being those of an H-Ph residue.
Symbolet R^ betyr fortrinnsvis fri, foretreti-eller forestret hydroksy, som laverealkoksy, f.eks. en over-nevnt laverealkoksyrest, lavere eller høyere laverealkanoyl-oksy, f.eks. acetoksy, propionyloksy...eller pivalyloksy; okta-noyloksy, dekanoyloksy, undekanoyloksy, lauryloksy, myristoy.l-oksy, palmitoyloksy eller stearoyloksy; men også hydrogen. The symbol R 1 preferably means free, etherified or esterified hydroxy, such as lower alkoxy, e.g. an above-mentioned lower alkoxy residue, lower or higher lower alkanoyloxy, e.g. acetoxy, propionyloxy...or pivalyloxy; octa-noyloxy, decanoyloxy, undecanoyloxy, lauryloxy, myristoyloxy, palmitoyloxy or stearoyloxy; but also hydrogen.
En laverealkylgruppe. R^ er fortrinnsvis en se-kundær eller tertiær alkylgruppe med 3 til 7 karbonatomer, som 1- propyl, i- eller tert.-butyl, -pentyl^eller -heksyl. En aralkylgruppe R^ er fortrinnsvis en.HPh-CnH2n_gruppe, f.eks. benzyl, 1- eller 2-fenyletyl. Spesielt foretrukkede grupper Ril er fenylgrupper HPh, som allerede er nevnt ovenfor, men også 1- eller 2-naftylgrupper, som kan være substituert som angitt for HPh. Heterocykliske R^-grupper er fortrinnsvis usubstituert 2- eller 3~furyl eller -tienyl; 2-, 3- eller 4-pyridyl; 2- eller 3-(1-benzofury1 eller 1-benzotienyl); A lower alkyl group. R 1 is preferably a secondary or tertiary alkyl group with 3 to 7 carbon atoms, such as 1-propyl, i- or tert-butyl, -pentyl, or -hexyl. An aralkyl group R 1 is preferably a HPh-CnH 2n group, e.g. benzyl, 1- or 2-phenylethyl. Particularly preferred groups R1 are phenyl groups HPh, which have already been mentioned above, but also 1- or 2-naphthyl groups, which may be substituted as indicated for HPh. Heterocyclic R 1 groups are preferably unsubstituted 2- or 3-furyl or -thienyl; 2-, 3- or 4-pyridyl; 2- or 3-(1-benzofuryl or 1-benzothienyl);
2- , 3- eller 4-kinolyl eller 1-, 3- eller ^J-isokinolyl, idet disse grupper kan være substituert med en til tre laverealkyl, fortrinnsvis metylgrupper. 2-, 3- or 4-quinolyl or 1-, 3- or 4-isoquinolyl, these groups may be substituted with one to three lower alkyl, preferably methyl, groups.
Da det i forbindelsene med den generelle formel I minst er tilstede et nitrogenatom, kan de foreligge i form av syreaddisjonssalter, spesielt terapeutisk anvendbare syreaddisjonssalter, f.eks. slike, som'er avledet av de nedenfor Since at least one nitrogen atom is present in the compounds of the general formula I, they can be present in the form of acid addition salts, especially therapeutically applicable acid addition salts, e.g. such as are derived from those below
nevnte syrer. S-oksydene ifølge oppfinnelsen er slike forbindelser med formel I, hvori X betyr gruppen med formel SO. said acids. The S-oxides according to the invention are such compounds of formula I, in which X means the group of formula SO.
Med uttrykket "lavere" menes i overnevnte og følgende nevnte organiske rester eller forbindelser slike med maksimalt 7, fortrinnsvis 4, spesielt 1 eller 2 karbon atomer. Uttrykket "høyere" angir rester med 8 til 20, fortrinnsvis 10 til 16 karbonatomer. By the term "lower" is meant in the above and following mentioned organic residues or compounds such with a maximum of 7, preferably 4, especially 1 or 2 carbon atoms. The term "higher" denotes residues with 8 to 20, preferably 10 to 16, carbon atoms.
Forbindelsene ifølge oppfinnelsen viser verdifulle farmakologiske, f.eks. analgetiske og hovedsakelig neuroleptiske virkninger, idet de gunstigste egenskaper ligger langt fra de ekstrapyramidale bivirkninger (i avhengighet av dosen). Denne skarpe adskillelse av virkningstype er hittil ikke iakttatt ved andre neuroleptiske midler, f.eks. haloperidol. Disse egenskaper kan påvises i dyreforsøk, fortrinnsvis på pattedyr, f.eks. mus, rotter, hunder og spesielt aper som prøveobjekt. Forbindelsene ifølge oppfinnelsen kan admini-streres- dyrene enteralt, f.eks. oralt eller parenteralt, f.eks. subkutant, intraperitonealt eller intravenøst, f.eks., i form av gelatinkapsler, stivelsesholdige suspensjoner, vandige oppløsninger eller suspensjoner. Man anvender derved orale doser på omtrent 0,1 til 10 mg/kg/dag, fortrinnsvis omtrent 0,5 til 5 mg/kg/dag, spesielt 1 til 2,5 mg/kg/dag. De nevnte forbindelser, f.eks. 2-/_ 2-(4-hydroksy-4-fenylpiper.idino)-ety_l/-l, 4-benzodioksan, eller dets hydroklorid, forårsaker The compounds according to the invention show valuable pharmacological, e.g. analgesic and mainly neuroleptic effects, the most favorable properties being far from the extrapyramidal side effects (depending on the dose). This sharp separation of action type has not yet been observed with other neuroleptic agents, e.g. haloperidol. These properties can be demonstrated in animal experiments, preferably on mammals, e.g. mice, rats, dogs and especially monkeys as test subjects. The compounds according to the invention can be administered to the animals enterally, e.g. orally or parenterally, e.g. subcutaneously, intraperitoneally or intravenously, for example, in the form of gelatin capsules, starchy suspensions, aqueous solutions or suspensions. Oral doses of approximately 0.1 to 10 mg/kg/day, preferably approximately 0.5 to 5 mg/kg/day, especially 1 to 2.5 mg/kg/day, are thereby used. The aforementioned compounds, e.g. 2-/_ 2-(4-Hydroxy-4-phenylpiperidino)-ethyl_l/-l, 4-benzodioxane, or its hydrochloride, causes
i de overnevnte og orale doser, spesielt mellom ca. 0,5 ogin the above-mentioned and oral doses, especially between approx. 0.5 and
5 mg/kg/dag, en nedsettelse av vektarmbetjenings-refleksen på dødningehodeaper (squirrel monkeys).• Denne prøve gjennom-føres som følger: Aper utsettes i visse tidsintervaller for et elektrisk sjokk som gies gjennom foten. Dyrene kan unngå denne elektriske impuls, når de trykker på en knapp. Apene bringes ved trening til å trykke en knapp før inntreden av den elektriske utladning. Hvert knapptrykk forskyver det elektriske sjokk med 20 sekunder. Forsømmer apene i løpet av 20 sekunder å trykke på knappen, så undergår det korte (0,5 sekunder) elektriske sjokk hvert 20..sekund, inntil neste knapptrykk. Under kontrollbetingelsene trykker apen hevarmen med en forholdsvis jevn hastighet, således at de sjelden får mer enn 5 eller 6 sjokk i løpet av. en fire timers forsøks-periode. De nye forbindelser som undersøkes på deres neuroleptiske virkninger undertrykkes forsøksdyrenes opplærte betingede unngåelsesforholdsmåte. Blokkeringen av denne egen-skap åpenbarer seg i nedgang i evnen til å unngå elektrisk sjokk, idet forsøksdyrene undergår et vesentlig høyere antall sjokk. 5 mg/kg/day, a reduction of the weight arm operating reflex in squirrel monkeys.• This test is carried out as follows: Monkeys are exposed at certain time intervals to an electric shock that is given through the foot. The animals can avoid this electrical impulse when they press a button. The monkeys are trained to press a button before the onset of the electrical discharge. Each button press advances the electric shock by 20 seconds. If the monkeys neglect to press the button within 20 seconds, they will receive a short (0.5 second) electric shock every 20 seconds, until the next button press. Under the control conditions, the monkey presses the lever at a relatively steady rate, so that they rarely receive more than 5 or 6 shocks in the course of. a four-hour trial period. The new compounds that are being tested for their neuroleptic effects suppress the trained conditioned avoidance behavior of experimental animals. The blocking of this property manifests itself in a decrease in the ability to avoid electric shock, as the test animals undergo a significantly higher number of shocks.
Videre frembringer de nye forbindelser f.eks. Furthermore, they produce new compounds, e.g.
propionsyreesteren av den overnevnte dioksanforbindelse,the propionic acid ester of the above-mentioned dioxane compound,
ved en ovenfor nevnt oral dose, spesielt mellom omtrent 5 og 10. mg/kg/dag, analgetisk effekt på mus. Disse virkninger at an above-mentioned oral dose, especially between about 5 and 10 mg/kg/day, analgesic effect in mice. These effects
kan påvises ifølge hale-bortførings- eller fenylkinon-krummingsprøven. I førstnevnte prøve rettes det på halen hos hanrotter en varmestråle og det måles varigheten av be-strålingen. Sluttpunktet av dette tidsintervallet er det moment hvori dyret trekker halen bort fra strålingsområdet. Varmeirritasjonen anvendes aldri lenger enn 10 sekunder. Tidsverdien (kontrollverdien) bestemmes før medikasjon ved hvert dyr. Por bestemmelse av nærvær av.analgetiske virkninger beregnes gjennomsnittsverdien av kontrollverdiene og tre standardavvikningsverdier velges hertil. De etter medikasjon av dyrene oppnådde tidsverdier som ligger' over de ovenfor nevnte økede gjennomsnittsverdi viser nærvær av en analgetisk virkning. can be detected according to the tail abduction or phenylquinone curvature test. In the first test, a heat beam is directed at the tail of male rats and the duration of the radiation is measured. The end point of this time interval is the moment in which the animal pulls its tail away from the radiation area. The heat irritation is never used for longer than 10 seconds. The time value (control value) is determined before medication for each animal. For determining the presence of analgesic effects, the average value of the control values is calculated and three standard deviation values are selected for this. The time values obtained after medication of the animals which lie above the above-mentioned increased average value show the presence of an analgesic effect.
I krumningsprøvene injiserer man på hanmus intraperitonealt 2,5 mg/kg fenylkinon i 20 minutter etter den orale administrering av forbindelsene ifølge oppfinnelsen. Man be-stemmer antall mus, som etter 5-15 minutter etter injeksjonen krummer seg i smerte, idet de uforandrede forsøksdyr viser In the curvature tests, male mice are injected intraperitoneally with 2.5 mg/kg of phenylquinone for 20 minutes after the oral administration of the compounds according to the invention. One determines the number of mice which, after 5-15 minutes after the injection, curl up in pain, as the unchanged experimental animals show
nærvær av analgetisk virkning. *presence of analgesic effect. *
Forbindelsene ifølge oppfinnelsen kan følgelig anvendes som analgetiske og fortrinnsvis som neuroleptiske midler, f.eks. i behandling av aggressive tilstander, opp-hissethet,• angst og smerte hos dyr, fortrinnsvis pattedyr. Forbindelsene ifølge oppfinnelsen kan også anvendes som mellomprodukter .ved fremstilling av andre verdifulle, spesielt farmakologisk aktive forbindelser.. The compounds according to the invention can consequently be used as analgesics and preferably as neuroleptic agents, e.g. in the treatment of aggressive conditions, agitation, • anxiety and pain in animals, preferably mammals. The compounds according to the invention can also be used as intermediates in the production of other valuable, particularly pharmacologically active compounds.
Foretrukkede forbindelser er de med den generelle formel I, hvori Ph betyr en 1,2-fenylenrest, som eventuelt er substituert med en eller to substituenter, valgt blant' laverealkyl, hydroksy, merkapto, laverealkoksy, laverealkylendioksy, benzyloksy, laverealkyltio, halogen, trifluormetyl, nitro eller amino, X betyr.oksygen eller svovel, m betyr de hele tallene 0 eller 1, n betyr de hele tall fra 1 til ^, hvert av symbolene p og q betyr et helt tall fra 1 til 3, idet (p+q) er tallet 4, hvert av symbolene R-^og R2betyr hydrogen eller lavere alkyl, R-^betyr hydrogen, hydroksy, laverealkoksy, lavere eller høyere alkanoyloksy, R^betyr laverealkyl, HPh-CnH2n, HPh eller eventuelt med en eller to laverealkylrester substituert furyl, tienyl eller pyridyl samt terapeutisk anvendbare syreaddisjonssalter av disse forbindelser. Preferred compounds are those of the general formula I, in which Ph means a 1,2-phenylene residue, which is optionally substituted with one or two substituents, selected from lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, benzyloxy, lower alkylthio, halogen, trifluoromethyl , nitro or amino, X means oxygen or sulphur, m means the integers 0 or 1, n means the integers from 1 to ^, each of the symbols p and q means an integer from 1 to 3, where (p+ q) is the number 4, each of the symbols R-^ and R2 means hydrogen or lower alkyl, R-^ means hydrogen, hydroxy, lower alkoxy, lower or higher alkanoyloxy, R^ means lower alkyl, HPh-CnH2n, HPh or optionally with one or two lower alkyl radicals substituted furyl, thienyl or pyridyl as well as therapeutically usable acid addition salts of these compounds.
Foretrukket er videre forbindelser med den generelle formel I, hvori Ph betyr en 1,2-fenylenrest, Further compounds of the general formula I are preferred, in which Ph means a 1,2-phenylene residue,
som eventuelt er substituert med en eller to substituenter, valgt blant alkyl, alkoksy eller alkyltio med hver maksimalt 4 karbonatomer, halogen eller trifluormetyl, X betyr oksygen, m betyr hele tall 0 eller 1, n betyr de hele tall 2 til 4, hvert av symbolene p og q betyr tallet 2, hvert av symbolene R]_ °g ^2betvr hydrogen eller alkyl med maksimalt 4 karbonatomer, FUbetyr hydrogen, hydroksy, alkoksy med maksimalt 4 eller alkanoyloksy med maksimalt 16 karbonatomer, R^betyr sek. eller tert. alkyl med 3 til 7 karbonatomer, HPh-CH2, HPh, 2- eller 3-furyl eller -tienyl, 2-, 3- eller 4-pyridyl samt terapeutisk anvendbare syreaddisjonssalter av disse forbindelser. which is optionally substituted with one or two substituents, selected from alkyl, alkoxy or alkylthio with a maximum of 4 carbon atoms each, halogen or trifluoromethyl, X means oxygen, m means the whole number 0 or 1, n means the whole numbers 2 to 4, each of the symbols p and q mean the number 2, each of the symbols R]_ °g ^2betvr hydrogen or alkyl with a maximum of 4 carbon atoms, FU means hydrogen, hydroxy, alkoxy with a maximum of 4 or alkanoyloxy with a maximum of 16 carbon atoms, R^means sec. or tart. alkyl with 3 to 7 carbon atoms, HPh-CH2, HPh, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl as well as therapeutically usable acid addition salts of these compounds.
Spesielt å fremheve er forbindelser med den generelle formel II Of particular note are compounds of the general formula II
hvori R betyr hydrogen, alkyl, alkoksy eller alkyltio med hver maksimalt 4 karbonatomer, halogen eller trifluormetyl, in which R means hydrogen, alkyl, alkoxy or alkylthio each having a maximum of 4 carbon atoms, halogen or trifluoromethyl,
x betyr tallene"1 eller 2, y betyr de hele tall fra 2 til 4, R" betyr hydrogen, hydroksy, alkoksy med maksimalt H eller alkanoyloksy med maksimalt 16 karbonatomer, R' betyr sek. eller tert. alkyl med 3 til 7 karbonatomer, R^-benzyl, Rx~fenyl, 2- eller 3-furyl eller -tienyl, 2-, 3- eller 4-pyridyl samt terapeutisk anvendbare syreaddisjonssalter av disse forbindelser. x means the numbers "1 or 2, y means the whole numbers from 2 to 4, R" means hydrogen, hydroxy, alkoxy with a maximum of H or alkanoyloxy with a maximum of 16 carbon atoms, R' means sec. or tart. alkyl with 3 to 7 carbon atoms, R^-benzyl, Rx-phenyl, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl as well as therapeutically usable acid addition salts of these compounds.
Spesielt foretrukket er forbindelser med den generelle formel II, hvori.R betyr hydrogen, metyl, etyl, metoksy, etoksy, metyltio, etyltio, fluor, klor eller trifluormetyl, x betyr tallene 1 eller 2, y betyr tallene 2 eller 3, R" betyr hydrogen, hydroksy, metoksy, etoksy-eller alkanoyloksy med 2 til 12 karbonatomer, R' betyr, i-propyl, i-eller tert.-butyl, benzyl, Rx-fenyl, 2- eller 3-furyl eller -tienyl, 2-, 3- eller 4-pyridyl samt terapeutisk anvendbare syreaddisjonssalter av disse forbindelser. Particularly preferred are compounds of the general formula II, wherein R means hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluorine, chlorine or trifluoromethyl, x means the numbers 1 or 2, y means the numbers 2 or 3, R" means hydrogen, hydroxy, methoxy, ethoxy or alkanoyloxy with 2 to 12 carbon atoms, R' means i-propyl, i-or tert-butyl, benzyl, Rx-phenyl, 2- or 3-furyl or -thienyl, 2 -, 3- or 4-pyridyl as well as therapeutically applicable acid addition salts of these compounds.
Spesielt å fremheve er forbindelser méd den generelle formel II, hvori R betyr hydrogen, metyl, metoksy, fluor, klor eller trifluormetyl, hver gang i 7- eller 8-stilling, x betyr tallene 1 eller 2, y betyr tallene 2 eller 3, R" betyr hydroksy, metoksy eller alkanoyloksy med 3 til 10 karbonatomer, R' m- eller p-Rx-fenyl samt terapeutisk anvendbare syreaddisjonssalter av disse forbindelser. Of particular note are compounds with the general formula II, in which R means hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, each time in the 7- or 8-position, x means the numbers 1 or 2, y means the numbers 2 or 3, R" means hydroxy, methoxy or alkanoyloxy with 3 to 10 carbon atoms, R' m- or p-Rx-phenyl as well as therapeutically usable acid addition salts of these compounds.
Forbindelsene ifølge oppfinnelsen fremstilles etter i og for seg kjente metoder, f.eks. ved at The compounds according to the invention are produced according to methods known per se, e.g. by that
a) forbindelser med de generelle formler III og IV a) compounds of the general formulas III and IV
kondenseres, idet ett av symbolene Y og Z2betyr amino resp. is condensed, as one of the symbols Y and Z2 means amino or
imino og det andre betyr en reaksjonsdy&tig forestret hydroksygruppe. imino and the other means a reactive esterified hydroxy group.
En reaksjonsdyktig forestret hydroksygruppe er f.eks. en hydroksygruppe forestret med en sterk uorganisk eller organisk syre, fremfor alt en halogenhydrogensyre, f.eks. klorhydrogensyre, bromhydrogensyre eller jodhydrogensyre, svovelsyre eller en aromatisk sulfonsyre, f.eks. p-toluensulfonsyre eller p-brombenzensulfonsyre. Kondensa-sjonen gjennomføres fortrinnsvis i nærvær av basiske kondensasjonsmidler, f.eks. alkalimetall- eller jordalkalimetall-hydroksyder, -karbonater eller -hydrogenkarbonater, som . natrium-, kalium- eller kalsium-hydroksyd eller -karbonat, alkalimetallhydrider, -laverealkoksyder eller -laverealkano-later, som natriumhydrid, natriummetylat eller natriumacetat, eller av organiske tertiære nitrogenbaser, som trilaverealkyl-aminer eller pyridiner, f.eks. trietylamin eller lutidin. A reactive esterified hydroxy group is e.g. a hydroxy group esterified with a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid. The condensation is preferably carried out in the presence of basic condensation agents, e.g. alkali metal or alkaline earth metal hydroxides, carbonates or hydrogen carbonates, such as . sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, lower alkyl alkoxides or lower alkyl alkanoates, such as sodium hydride, sodium methylate or sodium acetate, or of organic tertiary nitrogen bases, such as trilower alkyl amines or pyridines, e.g. triethylamine or lutidine.
En ytterligere fremgangsmåte til fremstilling av de nye forbindelser består i at A further method for producing the new compounds consists in that
b) en forbindelse med den generelle formel Vb) a compound of the general formula V
reduseres, idet A betyr en gruppe med formel cn<H2>n-2~COj<C>n<H>2n-s ellerY'"CnH2n-l'idet Y' betyr en reaksjonsdyktig forestret hydroksygruppe, R^betyr hydrogen' eller R-^og R^danner sammen en ytterligere C,C-binding, R^ betyr R^eller HPh-laverealkanoyl, hvert av symbolene r og s betyr de hele tall 0 eller 2, idet (r+s) er tallene 2 eller 4. is reduced, with A meaning a group of formula cn<H2>n-2~COj<C>n<H>2n-s orY'"CnH2n-l'where Y' means a reactive esterified hydroxy group, R^means hydrogen' or R-^ and R^ together form a further C,C bond, R^ means R^ or HPh-lower alkanoyl, each of the symbols r and s means the whole numbers 0 or 2, with (r+s) being the numbers 2 or 4.
Gruppen Y' er fortrinnsvis en hydroksygruppe, forestret med en sterk uorganisk eller organisk syre, fremfor alt en halogenhydrogensyre, f.eks. klorhydrogensyre, bromhydrogensyre eller jodhydrogensyre, svovelsyre eller en aromatisk sulfonsyre, f.eks. p-toluensulfonsyre eller p-brom-benzensulf onsyre . Reduksjonen gjennomføres på i og for seg kjent måte, alt etter nærvær av en keto- og/eller amidkarbonyl-gruppe. Sistnevnte foretas fortrinnsvis med enkle eller komplekse lettmetallhydrider.som diboran eller alkalimetall-borhydrider, alkalimetallaluminiumhydrifler eller alkalimetall-alkoksyborhydrider, f.eks. litiumaluminiumhydrid og/ eller natrium-trimetoksyborhydrid. Reduksjonen av ketoner eller olefiner gjennomføres fortrinnsvis med katalytisk akti-vert eller naskerende hydrogen, som hydrogen i nærvær av palladium- eller platina-katalysatorer, eller med el-ektro-lyttisk frembragt hydrogen eller fortrinnsvis med cyanborhydrid. Endelig foretas den reduktive eliminering av Y' ved behandling av nevnte ester med de overnevnte hydrid-reduksjonsmidler, fortrinnsvis med litiumaluminiumhydrid. The group Y' is preferably a hydroxy group, esterified with a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid. The reduction is carried out in a manner known per se, depending on the presence of a keto and/or amide carbonyl group. The latter is preferably carried out with simple or complex light metal hydrides such as diborane or alkali metal borohydrides, alkali metal aluminum hydrides or alkali metal alkoxy borohydrides, e.g. lithium aluminum hydride and/or sodium trimethoxyborohydride. The reduction of ketones or olefins is preferably carried out with catalytically activated or nascent hydrogen, such as hydrogen in the presence of palladium or platinum catalysts, or with electrolytically produced hydrogen or preferably with cyanoborohydride. Finally, the reductive elimination of Y' is carried out by treating said ester with the above-mentioned hydride reducing agents, preferably with lithium aluminum hydride.
En ytterligere fremgangsmåte til fremstilling av de nye forbindelser består i at A further method for producing the new compounds consists in that
c) forbindelser med formel VI c) compounds of formula VI
kondenseres med R^-metallforbindelser. is condensed with R^ metal compounds.
De nevnte reagenser er fortrinnsvis litium-eller halogenmagnesium-(Grignard-)-forbindelser. Omsetningen gjennomføres på i og for seg kjent måte, fortrinnsvis i nærvær av polare oppløsningsmidler som åpenkjedede eller cykliske etere, f.eks. dietyleter, tetrahydrofuran eller dioksan. The reagents mentioned are preferably lithium or halomagnesium (Grignard) compounds. The reaction is carried out in a manner known per se, preferably in the presence of polar solvents such as open-chain or cyclic ethers, e.g. diethyl ether, tetrahydrofuran or dioxane.
En ytterligere fremgangsmåte til fremstilling av-de nye forbindelser består i A further method for producing the new compounds consists in
d) en ringslutning av en forbindels.e med formel VII. d) a cyclization of a compound of formula VII.
hvori Y betyr en reaksjonsdyktig forestret hydroksygruppe. wherein Y means a reactive esterified hydroxy group.
En reaksjonsdyktig forestret hydroksygruppe er f.eks. en hydroksygruppe forestret med en sterk uorganisk eller organisk syre, fremfor alt en halogenhydrogensyre, f.eks. klorhydrogensyre, bromhydrogensyre eller jodhydrogensyre, svovelsyre eller e.n aromatisk sulfonsyre, f.eks. p-toluensulfonsyre eller p-brombenzensulfonsyre. Ringslut-ningen gjennomføres fortrinnsvis i nærvær av basiske kondensasjonsmidler, f.eks. alkalimetall- eller jordalkalimetall-hydroksyder, -karbonater eller -hydrogenkarbonater, som natrium-, kalium- eller kalsiumhydroksyd eller -karbonat, alkalimetallhydrider, -laverealkoksyder eller -laverealkano-ater, som natriumhydrid, natriummetylat eller natriumacetat eller av organiske tertiære nitrogenbaser, som trilaverealkyl-aminer eller pyridiner, f.eks. trietylamin eller lutidin. A reactive esterified hydroxy group is e.g. a hydroxy group esterified with a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid. The ring closure is preferably carried out in the presence of basic condensation agents, e.g. alkali metal or alkaline earth metal hydroxides, carbonates or hydrogen carbonates, such as sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, lower alkoxides or lower alkanoates, such as sodium hydride, sodium methylate or sodium acetate or of organic tertiary nitrogen bases, such as trilower alkyl- amines or pyridines, e.g. triethylamine or lutidine.
Forbindelsene fremstillet ifølge oppfinnelsen kan på i og for. seg kjent måte overføres i hverandre. Således kan f. eks. dannede forbindelser, hvori R-^ betyr hydroksy, foretres eller forestres eller deres alkalimetall-, f.eks. litiumsalter omsettes med reaksjonsdyktige estere av lavere-alkanoler eller med reaksjonsdyktige alkansyrederivater, The compounds produced according to the invention can on i and for. in a known way are transferred into each other. Thus, e.g. compounds formed, in which R-^ means hydroxy, are etherified or esterified or their alkali metal, e.g. lithium salts are reacted with reactive esters of lower alkanols or with reactive alkanoic acid derivatives,
f.eks. deres halogenidér eller anhydrider. Dannede estere kan hydrolyseres etter i og for seg kjente metoder, fortrinnsvis med vandige alkalier. Videre kan dannede fenoler foretres med diazoalkaner. Dannede benzyletere kan også spaltes hydrogenolyttisk, f.eks. i nærvær av palladium- e.g. their halides or anhydrides. Formed esters can be hydrolysed according to methods known per se, preferably with aqueous alkalis. Furthermore, phenols formed can be etherified with diazoalkanes. Benzyl ethers formed can also be cleaved hydrogenolytically, e.g. in the presence of palladium-
eller platina-katalysatorer. Disse metoder kan også anvendes for dehalogeneringen av enrest Ph eller til reduksjon av en nitrogruppe av denne rest til aminogruppen. Nitreringen av en Ph-gruppe kan også gjennomføres på i og for seg kjent måte, f.eks. ved oppvarmning. av en dannet forbindelse med en blanding av rykende salpetersyre og svovelsyre eller eddiksy-reanhydrid eller dets nitrat i trifluoreddiksyre. Et jodatom i Ph-resten kan erstattes med trifluormetyl, f.eks. ved omsetning av et jodid med trifluormetyljodid i nærvær av kobberpulver. Dannede forbindelser kan oksyderes til sulfoksyder med vanlige milde oksydasjbnsmidler, f.eks. alkalimetallperjodater, or platinum catalysts. These methods can also be used for the dehalogenation of a Ph residue or for the reduction of a nitro group of this residue to the amino group. The nitration of a Ph group can also be carried out in a manner known per se, e.g. during heating. of a compound formed with a mixture of fuming nitric and sulfuric acids or acetic anhydride or its nitrate in trifluoroacetic acid. An iodine atom in the Ph residue can be replaced by trifluoromethyl, e.g. by reacting an iodide with trifluoromethyl iodide in the presence of copper powder. Formed compounds can be oxidized to sulfoxides with common mild oxidizing agents, e.g. alkali metal periodicates,
som natriumperjodat.as sodium periodate.
Alt etter fremgangsmåtebetingelsene får .man sluttstoffene i fri form eller i den likeledes av oppfinnelsen omfattede form av deres syreaddisjonssalter. Dannede salter kan på i og for seg kjent måte, f.eks. med sterkere base, som metall- eller ammoniumhydroksyd, et basisk salt eller ioneutvekslere, som alkalimetallhydroksyd eller -karbonat, overføres i den fri forbindelse. På den annen side kan de dannede frie baser med organiske eller uorganiske syrer danne salter. Til fremstilling av syreaddisjonssaltene anvendes spesielt syrer som., gir terapeutisk anvendbare salter. Slike syrer er f.eks. uorganiske syrer som sterke mineral-syrer, f.eks. halogenhydrogensyrer, som klorhydrogen-, brom-hydrogen- eller jodhydrogensyre, svovelsyre, fosforsyre, salpetersyre eller perklorsyre, organiske syrer, f.eks. ali-fatiske eller aromatiske karboksyIsyrer eller ■ sulfonsyrer, Depending on the process conditions, the final substances are obtained in free form or in the form of their acid addition salts, which is also covered by the invention. Formed salts can in a manner known per se, e.g. with a stronger base, such as metal or ammonium hydroxide, a basic salt or ion exchangers, such as alkali metal hydroxide or carbonate, are transferred in the free compound. On the other hand, the free bases formed with organic or inorganic acids can form salts. For the preparation of the acid addition salts, acids are used in particular which give therapeutically usable salts. Such acids are e.g. inorganic acids such as strong mineral acids, e.g. hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, organic acids, e.g. aliphatic or aromatic carboxylic acids or ■ sulphonic acids,
som maursyre, eddiksyre, propionsyre, ravsyre, glykolsyre, melkesyre, eplesyre, vinsyre, sitronsyre, maleinsyre, hydroksy-maleinsyre eller pyrodruesyre, fenyleddiksyre, benzosyre,p-aminobenzosyre, antranilsyre, p-hydroksybenzosyre, salicylsyre such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, hydroxy-maleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid
eller p-amino-salicylsyre, pamosyre, nikotinsyre., metansulfon-syre, etansulfonsyre, hydroksyetansulfonsyre, etylensulfon-syre, halogenbenzensulfonsyre, toluensulfonsyre, naftalin-sulfonsyrer, sulfanilsyre eller cykloheksansulfaminsyre eller askorbinsyre. or p-amino-salicylic acid, pamoic acid, nicotinic acid., methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalene sulfonic acids, sulfanilic acid or cyclohexanesulfamic acid or ascorbic acid.
Disse eller andre salter av de nye forbindelser, som f.eks. pikratene, kan også tjene til rensning av de dannede fri forbindelser, idet man overfører de fri forbindelser til saltene og adskiller disse og fra saltene igjen frigjør den fri forbindelse. These or other salts of the new compounds, such as e.g. the picrates, can also serve to purify the free compounds formed, as one transfers the free compounds to the salts and separates them and releases the free compound from the salts again.
På grunn av det snevre forhold mellom den nye forbindelse i fri form og i form av dens syreaddisjonssålt skal det i det foregående og følgende med fri forbindelse forstås hensiktsmessig eventuelt også de tilsvarende syre-addis jons salter. Due to the narrow relationship between the new compound in free form and in the form of its acid addition salt, in the foregoing and the following, free compound is to be understood as appropriate, possibly also the corresponding acid addition salts.
Utgangsstoffene med formlene III til VIII erThe starting materials with the formulas III to VIII are
nye, de kan imidlertid fremstilles etter kjente metoder, slik det f.eks. er omtalt i eksemplene. new, they can, however, be produced according to known methods, as e.g. are discussed in the examples.
Forbindelsene med formel III kan lett fremstilles ved reduksjon av en tilsvarende 1-benzofuran- eller 1,4-benzodioksan-2-yl-alkansyre med litiumaluminiumhydrid The compounds of formula III can be easily prepared by reduction of a corresponding 1-benzofuran- or 1,4-benzodioxan-2-yl-alkanoic acid with lithium aluminum hydride
eller natrium-2-metoksy-etoksy-aluminiu!hhydrid til tilsvarende alkohol og dens forestring med de overnevnte sterke syrer eller deres derivater. De dannede reaksjonsdyktige estere kan ved omsetning med ammoniakk i et organisk oppløs-ningsmiddel, f.eks. etanol eller benzen, fortrinnsvis under forhøyet trykk eller forhøyet temperatur overføres i de tilsvarende aminer. or sodium 2-methoxy-ethoxy-aluminium hydride to the corresponding alcohol and its esterification with the above-mentioned strong acids or their derivatives. The formed reactive esters can, by reaction with ammonia in an organic solvent, e.g. ethanol or benzene, preferably under elevated pressure or elevated temperature are transferred in the corresponding amines.
Forbindelser med formel V kan fåes av de tidligere nevnte syrer ved deres omdannelse i et halogenid, blandet anhydrid eller amid av imidazol, og omsetning av disse forbindelser med tilsvarende piperidiner. De umettede utgangsstoffer er fortrinnsvis enaminer, som fremstilles av de tilsvarende aldehyder og de tidligere nevnte piperidiner. Compounds of formula V can be obtained from the previously mentioned acids by converting them into a halide, mixed anhydride or amide of imidazole, and reacting these compounds with corresponding piperidines. The unsaturated starting materials are preferably enamines, which are prepared from the corresponding aldehydes and the previously mentioned piperidines.
De anvendte aldehyder kan fåes ved reduksjon av overnevnte syrehalogenider ifølge Rosenmund, eller syrenitriler med diisobutylaluminiumhydrid. ' Endelig kan de til utgangsstoffene med formel V svarende alkoholer, i hvilke utgangsstoffer A betyr gruppen med formel Y'"cnH2n-l f1,61713^1!63 ved kondensasjon av et 1-benzofuran- eller 1,4-benzodioksan-2-yl-alkylen- oksyd med de allerede nevnte piperidiner eller ved" omsetning av det -tilsvarende a-bromketon og reduksjon med natriumborhydrid. Disse alkoholer er omtalt i US-patent nr. ■ 3•914.238. De'kan omdannes i deres reaksjonsdyktige estere på i og for seg kjent måte, enten ved omsetning med syrene HY' under vannfrie betingelser, f.eks. i nærvær av svovelsyre, eller med halogenider eller anhydrider av de overnevnte syrer, f.eks. tosylklorid. The aldehydes used can be obtained by reduction of the above-mentioned acid halides according to Rosenmund, or acid nitriles with diisobutylaluminum hydride. ' Finally, they can to the starting substances of formula V correspond to alcohols, in which starting substances A means the group of formula Y'"cnH2n-l f1,61713^1!63 by condensation of a 1-benzofuran- or 1,4-benzodioxane-2- yl-alkylene-oxide with the already mentioned piperidines or by reaction of the -corresponding α-bromoketone and reduction with sodium borohydride. These alcohols are discussed in US Patent No. ■ 3•914,238. They can be converted into their reactive esters in a manner known per se, either by reaction with the acids HY' under anhydrous conditions, e.g. in the presence of sulfuric acid, or with halides or anhydrides of the above-mentioned acids, e.g. tosyl chloride.
Utgangsstoffene med formel VI kan fremstilles analogt fremgangsmåte a), dvs. ved omsetning av tilsvarende piperidoner med de i denne fremgangsmåte nevnte reaksjonsdyktige estere. The starting substances with formula VI can be prepared analogously to method a), i.e. by reacting corresponding piperidones with the reactive esters mentioned in this method.
Endelig kan utgangsstoffene med formel VII fåes ved Mannich-reaksjon av de overnevnte piperidiner med tilsvarende aldehyder og/eller ketoner ved bromering av de dannede piperidinoalkanoner, kondensasjon av de dannede a-bromketoner med monoacety1-pyrokatekin, reduksjon av' det keto-niske kondensasjonsprodukt med natriumborhydrid til den tilsvarende alkohol og dens forestring som angitt i fremgangsmåte Finally, the starting substances with formula VII can be obtained by Mannich reaction of the above-mentioned piperidines with corresponding aldehydes and/or ketones by bromination of the formed piperidinoalkanones, condensation of the formed α-bromoketones with monoacetyl-pyrocatechin, reduction of the ketonic condensation product with sodium borohydride to the corresponding alcohol and its esterification as indicated in the procedure
a), a),
Utgangsstoffer og sluttprodukter med formel IStarting materials and end products with formula I
til VII, som er isomerblandinger, kan d%les i de enkelte isomere etter i og for seg kjente metoder, f.eks. ved fraksjonert destillering, krystallisasjon og/eller kromatografi. Racemiske produkter kan oppdeles i de optiske antipoder, f.eks. ved adskillelse av deres diastereoisomere salter, f.eks. ved fraksjonert krystallisasjon av d- eller 6-tar'trater eller, a-metylbenzylammoniumsalter. to VII, which are mixtures of isomers, can be resolved into the individual isomers according to methods known per se, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can be divided into the optical antipodes, e.g. by separation of their diastereoisomeric salts, e.g. by fractional crystallization of d- or 6-tartrates or, a-methylbenzylammonium salts.
De overnevnte reaksjoner gjennomføres etter i og for seg kjente metoder i nærvær eller fravær av fortynnings- . midler, fortrinnsvis i slike, som er inerte overfor reagensene og oppløser disse, katalysatorer, kondensasjons- og nøytrali-sasjonsmidler og/eller i en inert atmosfære, under avkjøling, ved værelsestemperatur eller ved forhøyede temperaturer, fortrinnsvis ved det anvendte oppløsningsmiddels - kokepunkt ved. normalt eller forhøyet trykk. The above-mentioned reactions are carried out according to methods known per se in the presence or absence of diluents. agents, preferably in such, which are inert towards the reagents and dissolve them, catalysts, condensation and neutralization agents and/or in an inert atmosphere, under cooling, at room temperature or at elevated temperatures, preferably at the solvent used - boiling point at. normal or elevated pressure.
Oppfinnelsen vedrører likeledes modifikasjoner av foreliggende fremgangsmåte ifølge hvilke ett på et eller annet trinn av fremgangsmåten oppnåelige mellomprodukt anvendes som utgangsmaterial og de gjenblivende fremgangsmåtetrinn gjennom- føres eller fremgangsmåten avbrytes på ett eller annet trinn eller ifølge hvilke et utgangsmaterial dannes under reaksjonsbetingelsene, eller hvori et utgangsstoff anvendes i form av et S-oksyd, et salt eller en optisk ren antipode. The invention also relates to modifications of the present method according to which an intermediate product obtainable at one or other step of the method is used as starting material and the remaining method steps are carried out or the method is interrupted at one or another step or according to which a starting material is formed under the reaction conditions, or in which a starting material is used in the form of an S-oxide, a salt or an optically pure antipode.
Ved fremgangsmåten ifølge oppfinnelsen anvendes fortrinnsvis slike utgangssto-fer som hører til de innled-ningsvis som spesielt verdifulle omtalte forbindelser, spesielt slike med formel II. In the method according to the invention, such starting materials are preferably used which belong to the compounds mentioned at the outset as particularly valuable, especially those with formula II.
De farmakologisk anvendbare forbindelser fremstillet ifølge oppfinnelsen kan f.eks. anvendes til fremstilling av farmasøytiske preparater som inneholder én virk-som mengde av det aktive stoff sammen eller i blanding med bærestoffer, som egner seg til enteral eller parenteral administrering. Fortrinnsvis anvender man tabletter eller gelatinkapsler, som inneholder det virksomme stoff sammen med fortynningsmidlet, f.eks. laktose, dekstrose, rørsukker, mannitol, sorbitol, cellulose og/eller glycin og smøremidler, f.eks. kiseljord, talkum, stearinsyre eller salter herav, som magnesium- eller kalsiumstearat og/eller polyetylenglykol. Tabletter inneholder likeledes bindemidlet, f.eks. magnesium-aluminiumsilikat, stivelsespastaer, gelatin, tragant, metyl-cellulose, natriumkarboksymetylcellulose og/eller polyvinyl-pyrrolidon, og hvis ønsket, sprengmidlet, f.eks. stivelse, The pharmacologically usable compounds produced according to the invention can e.g. are used for the production of pharmaceutical preparations that contain one effective amount of the active substance together or in a mixture with carriers, which are suitable for enteral or parenteral administration. Tablets or gelatin capsules are preferably used, which contain the active substance together with the diluent, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and/or glycine and lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Tablets also contain the binder, e.g. magnesium aluminum silicate, starch pastes, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolidone, and if desired, the explosive, e.g. starch,
agar, alginsyre eller et salt herav, som natriumalginat, enzymer av bindemidlet og/eller bruseblandinger, eller adsprp-sjonsmidler, farvestoffer, smaksstoffer og søtningsstoffer. Injiserbare preparater er fortrinnsvis isotoniske vandige opp-løsninger eller suspensjoner og suppositorier i første rekke fettemulsjoner eller -suspensjoner. De farmakologiske prepa--rater kan være sterilisert og/eller inneholde hjelpestoffer, f.eks. konserverings-, stabiliserings-, fukte- og/eller emul-geringsmidler, oppløselighetsformidlere, salter til regulering av. det osmotiske trykk og/eller puffere. De foreliggende farmasøytiske preparater som hvis ønsket kan inneholde ytter-,ligere farmakologisk verdifulle stoffer fremstilles på i og for seg kjent måte, f.eks. ved hjelp av vanlige blande-, granulerings- eller drasjeringsfremgangsmåter og inneholder fra ca. 0, 1% til ca. 75%, spesielt fra ca. 1% til ca. 50% av det aktive stoff. agar, alginic acid or a salt thereof, such as sodium alginate, enzymes of the binder and/or fizzy mixtures, or adsorbents, colourings, flavorings and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions and suppositories primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifiers, solubility mediators, salts for regulation of. the osmotic pressure and/or buffers. The present pharmaceutical preparations which, if desired, can contain additional, pharmacologically valuable substances are prepared in a manner known per se, e.g. using usual mixing, granulating or coating methods and contains from approx. 0.1% to approx. 75%, especially from approx. 1% to approx. 50% of the active substance.
Oppfinnelsen skal■forklares nærmere ved hjelpThe invention must be ■explained in more detail with help
av noen eksempler. Når intet annet er angitt gjennomføres inndampningen av oppløsningsmidlet under nedsatt trykk. Eksempel 1. of some examples. When nothing else is specified, the evaporation of the solvent is carried out under reduced pressure. Example 1.
En blanding av 6,68 g 2-(2-tosyloksyetyl)-l,4-benzodioksan, 3,54 g 4-hydroksy-4-fenylpiperidin, 10 g vannfritt natriumkarbonat og 100 ml 4-metyl-2-pentanon kokes 48 timer under tilbakeløp. Blandingen filtreres, inndampes og residuet omkrystalliseres fra isopropanol. Man får 2-[_ 2- ( 4-hydroksy-4-fenylpiperidino)-etyl/-1,4-benzodioksan, som smelter ved l42°C. A mixture of 6.68 g of 2-(2-tosyloxyethyl)-1,4-benzodioxane, 3.54 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is boiled for 48 hours during reflux. The mixture is filtered, evaporated and the residue recrystallized from isopropanol. This gives 2-[_2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxane, which melts at 142°C.
Produktet suspenderes i 20 ml etanol, suspen-sjonen nøytraliseres med etanolisk klorhydrogen og den dannede utfelling omkrystalliseres fra etanol-dietyleter. Man får det tilsvarende hydroklorid som smelter, ved 203°C. The product is suspended in 20 ml of ethanol, the suspension is neutralized with ethanolic hydrogen chloride and the precipitate formed is recrystallized from ethanol-diethyl ether. You get the corresponding hydrochloride which melts at 203°C.
På analog måte fremstilles også 2-(4-hydroksy-4-fenylpiperidinometyl)-1,4-benzodioksan, som etter omkrystallisering fra metanol smelter ved 215-217°C. In an analogous manner, 2-(4-hydroxy-4-phenylpiperidinomethyl)-1,4-benzodioxane is also produced, which after recrystallization from methanol melts at 215-217°C.
Utgangsstoffet fremstilles som følger: En oppløs-ning av 16 g brom i 10 ml petroleter tilsettes, langsomt til en oppløsning av 6,7 g allylcyanid i 30 ml petroleter under omrøring og ved en temperatur på omtren<*>c -15°C. Oppløsnings-midlet avdampes og man får det oljeaktige 3,4-dibromsmørsyre-nitril i kvantitativt utbytte (J.A.C.S. 67, 400 (1945)). The starting material is prepared as follows: A solution of 16 g of bromine in 10 ml of petroleum ether is added slowly to a solution of 6.7 g of allyl cyanide in 30 ml of petroleum ether with stirring and at a temperature of approximately -15°C. The solvent is evaporated and the oily 3,4-dibromobutyric acid nitrile is obtained in quantitative yield (J.A.C.S. 67, 400 (1945)).
Den sistnevnte nitrilforbindelse oppdeles iThe latter nitrile compound is divided into
fem like deler (45,4 g). Første porsjon settes langsomt til en omrørt blanding av 85 g pyrokatekin og 50 g vannfritt kaliumkarbonat i 100 ml aceton under tilbakeløp. Den omrørte blanding blandes deretter med 50 g kaliumkarbonat og med den annen porsjon av nitrilforbindelsen langsomt. Derpå anvendes . de ytterligere tre deler av nitrilet, idet man til reaksjonsblandingen på forhånd hver gang setter .40 g kaliumkarbonat og en mengde aceton som letter omrøringen. Reaksjonsblandingen kokes deretter 20 timer under tilbakeløp, avkjøles, filtreres og filtratet inndampes. Residuet destilleres og fraksjonen som koker ved 105°C/0,15 mm Hg oppfanges. Man får 1,4-benzodioksan-2-yl-acetonitril (belgisk patent nr. 643.853). five equal parts (45.4 g). The first portion is slowly added to a stirred mixture of 85 g of pyrocatechin and 50 g of anhydrous potassium carbonate in 100 ml of acetone under reflux. The stirred mixture is then slowly mixed with 50 g of potassium carbonate and with the second portion of the nitrile compound. It is then used. the further three parts of the nitrile, each time adding .40 g of potassium carbonate and an amount of acetone to the reaction mixture in advance to facilitate stirring. The reaction mixture is then boiled for 20 hours under reflux, cooled, filtered and the filtrate evaporated. The residue is distilled and the fraction boiling at 105°C/0.15 mm Hg is collected. 1,4-benzodioxan-2-yl-acetonitrile is obtained (Belgian patent no. 643,853).
Reaksjonsblandingen filtreres, filtratet inndampes, residuet destilleres og fraksjonen som koker ved 105°C/ 0,5 mm Hg oppfanges. Man får 1,4-benzodioksan-2-yl-acetonitril The reaction mixture is filtered, the filtrate is evaporated, the residue is distilled and the fraction boiling at 105°C/ 0.5 mm Hg is collected. 1,4-benzodioxan-2-yl-acetonitrile is obtained
fcelgisk patent nr. 643.853)-'French Patent No. 643,853)-'
En blanding av 111 g av sistnevnte forbindelse, 6.3,5 ml svovelsyre, 160-ml eddiksyre og l60 ml vann kokes 48 timer under tilbakeløp. Blandingen helles på is, det dannede faste material adskilles og omkrystalliseres fra benzen-petroleter. Man får 1,4-benzodioksan-2-yl-eddiksyre, som smelter ved 100°C (belgisk patentnr. 613-211). A mixture of 111 g of the latter compound, 6.3.5 ml of sulfuric acid, 160 ml of acetic acid and 160 ml of water is boiled for 48 hours under reflux. The mixture is poured onto ice, the solid material formed is separated and recrystallized from benzene-petroleum ether. 1,4-benzodioxan-2-yl-acetic acid is obtained, which melts at 100°C (Belgian patent no. 613-211).
En oppløsning av 5,8 g av sistnevnte forbindelse i 100 ml benzen haes dråpevis under tilbakeløp i en nitrogenatmosfære til 16,5 ml av en 70#-ig benzenoppløsning av natrium-bis(2-metoksyetoksy)-aluminiumhydrid. Deretter kokes blandingen 4 timer under tilbakeløp, avkjøles og helles langsomt i 20 ml 25%-ig svovelsyre. Reaksjonsblandingen filtreres, oppløsningsmidlet avdampes, residuet opptas i metylenklorid. Oppløsningen vaskes flere ganger med mettet vandig natriumhydrogenkarbonatoppløsning, tørkes og inndampes. Man får det oljeaktige 2-(2-hydroksyetyl')-l, 4-benzodioksån. A solution of 5.8 g of the latter compound in 100 ml of benzene is added dropwise under reflux in a nitrogen atmosphere to 16.5 ml of a 70% benzene solution of sodium bis(2-methoxyethoxy)-aluminum hydride. The mixture is then boiled for 4 hours under reflux, cooled and slowly poured into 20 ml of 25% sulfuric acid. The reaction mixture is filtered, the solvent is evaporated, the residue is taken up in methylene chloride. The solution is washed several times with saturated aqueous sodium bicarbonate solution, dried and evaporated. The oily 2-(2-hydroxyethyl')-1,4-benzodioxane is obtained.
En blanding av 3,6 g av sistnevnte forbindelse, 5,7 g p-toluensulfonsyreklorid og 20 ml tørr pyridin omrøres under avkjøling i isbad i 2 timer. Reaksjonsblandingen blandes deretter med is, det dannede faste material adskilles og omkrystalliseres fra eddikester-petrolet.ef'. Man får 2-(2-tosyloksyety1)-1,4-benzodioksan, som smelter ved 82-83°C. A mixture of 3.6 g of the latter compound, 5.7 g of p-toluenesulfonic acid chloride and 20 ml of dry pyridine is stirred while cooling in an ice bath for 2 hours. The reaction mixture is then mixed with ice, the solid material formed is separated and recrystallized from the acetic ester-kerosene.ef'. 2-(2-tosyloxyethyl)-1,4-benzodioxane is obtained, which melts at 82-83°C.
Ifølge overnevnte metode fremstilles også ut-gangsstof f ene for forbindelsene med formel II, som er omtalt i eksempel 8, idet det gåes ut fra ekvivalente mengder av tilsvarende forbindelser.. Disse utgangsstoffers smeltepunkter er angitt i siste spalte i tabellen i eksempel 8. Eksempel 2. According to the above-mentioned method, the starting materials for the compounds of formula II, which are discussed in example 8, are also prepared, starting from equivalent amounts of corresponding compounds. The melting points of these starting materials are indicated in the last column of the table in example 8. Example 2.
En - oppløsning av 5,5 g l-/~2-(£-1,4-benzodioksan-2-yl)-acety_l7-4-hydroksy-4-fenylpiperidin i 50 ml tetrahydrofuran haes under avkjøling til en suspensjon av '1,2 g litiumaluminiumhydrid i 20 ml tetrahydrofuran under omrøring. Reak-sj onsblandingen omrøres natten over ved værelsestemperatur og spaltes med noen dråper eddikester, 1,2 ml vann,'1,2 ml av en 15$-ig vandig natriumhydroksydoppløsning og 3,6 ml vann. Bland ingen filtreres, filtratet inndampes og résiduet omkrystalliseres fra isopropanol. Man får £- 2- 1^ 2-(4-hydroksy-4-fenyl-piperidino)-etyl7-l,4-benzodioksan, som smelter ved l4l-l43°C. /~o7D= -44,8° (metanol). Dets hydroklorid smelter ved 225- A solution of 5.5 g of 1-[2-([alpha]-1,4-benzodioxan-2-yl)-acetyl-17-4-hydroxy-4-phenylpiperidine in 50 ml of tetrahydrofuran is heated under cooling to a suspension of '1 .2 g of lithium aluminum hydride in 20 ml of tetrahydrofuran with stirring. The reaction mixture is stirred overnight at room temperature and partitioned with a few drops of acetic acid, 1.2 ml of water, 1.2 ml of a 15% aqueous sodium hydroxide solution and 3.6 ml of water. The mixture is not filtered, the filtrate is evaporated and the residue is recrystallized from isopropanol. One obtains £-2-1^ 2-(4-hydroxy-4-phenyl-piperidino)-ethyl7-1,4-benzodioxane, which melts at 141-143°C. /~o7D= -44.8° (methanol). Its hydrochloride melts at 225-
227°C. a7D<=><->36,5° (metanol).227°C. a7D<=><->36.5° (methanol).
' På samme måte fåes også d-basen. Smeltepunkt l4l-l43°C. /~ci7D = +44,8° (metanol). Dets hydroklorid smelter ved 225-227°C.'/f"a7D= +36,5°C (metanol). ' The d-base is also obtained in the same way. Melting point l4l-l43°C. /~ci7D = +44.8° (methanol). Its hydrochloride melts at 225-227°C.'/f"a7D= +36.5°C (methanol).
Utgangsstoffet fremstilles som følger: Man oppløser 19,4 g 1,4-benzodioksan-2-yl-eddiksyre og 12,1 g d-a-metyl-benzylamin i 100 ml varm isopropanol. Man lar oppløsningen stå natten over, frafiltrerer det dannede salt og omkrystalliserer fem ganger fra isopropanol. Forsøkene viser at dette er tilstrekkelig for optisk 'adskillelse av The starting material is prepared as follows: 19.4 g of 1,4-benzodioxan-2-yl-acetic acid and 12.1 g of d-a-methyl-benzylamine are dissolved in 100 ml of hot isopropanol. The solution is allowed to stand overnight, the salt formed is filtered off and recrystallized five times from isopropanol. The experiments show that this is sufficient for optical separation of
de nevnte syrer. Syrene frigjøres med fortynnet klorhydrogensyre, blandingen ekstraheres med'dietyleter og ekstraktene inndampes. Man får d-1,4-benzodioksan-2-y 1-eddiksyre . J_ a/D= + 49° (etanol.). the aforementioned acids. The acids are released with dilute hydrochloric acid, the mixture is extracted with diethyl ether and the extracts are evaporated. One obtains d-1,4-benzodioxan-2-y 1-acetic acid. J_ a/D= + 49° (ethanol.).
På analog måte under anvendelse av -£-a-metylben-zylamin, får man den tilsvarende antipodiske syre. I_ a/^ = In an analogous manner using -£-α-methylbenzylamine, the corresponding antipodic acid is obtained. I_ a/^ =
-49° (etanol).-49° (ethanol).
En oppløsning av 3 g -£-1,4-benzodioksan-2-y1-eddiksyre i 20 ml tetrahydrofuran omrøres en time med '3 g karbonyldiimidazol. Man tilsetter en suspensjon av 4-hydroksy-4-fenylpiperidin i.20 ml tetrahydrofuran og omrører blandingen natten over. Deretter inndampes det og*residuet oppløses j i eddikester. Oppløsningen vaskes med fortynnet vandig klorhydrogensyre og vandig natriumhydroksydoppløsning, tørkes og inndampes. Man får l-/~ 2-( t- 1, 4-benzodioksan-2-yl)-acety_l/- ^l-hydroksy-^-f enylpiperidin. A solution of 3 g of -£-1,4-benzodioxan-2-yl-acetic acid in 20 ml of tetrahydrofuran is stirred for one hour with 3 g of carbonyldiimidazole. A suspension of 4-hydroxy-4-phenylpiperidine in 20 ml of tetrahydrofuran is added and the mixture is stirred overnight. It is then evaporated and the residue is dissolved in vinegar. The solution is washed with dilute aqueous hydrochloric acid and aqueous sodium hydroxide solution, dried and evaporated. One obtains 1-[2-(t-1,4-benzodioxan-2-yl)-acetyl-1/-1-hydroxy-2-phenylpiperidine.
Eksempel 3»Example 3»
En oppløsning av 5 g 1-/_~3-(1, 4-benzodioksan-2-yl)-propiony]./-4-hydroksy-il-fenylpiperidin i 50 ml tetrahydrofuran haes til den omrørte blanding av 2 g litiumaluminiumhydrid og 50 ml tetrahydrofuran ved værelsestemperatur og videreomrøres. 12 timer. Reaks j onsb landingen spaltes deretter med noen dråper eddikester, 2 ml vann, 4 ml av en 15%-ig vandig natriumhydroksydoppløsning og 4 ml vann. Blandingen filtreres, filtratet inndampes og residuet omkrystalliseres fra isopropanol. Man får 2-/_ 3- (4-hydroksy-4-fenylpiperidino)-propyl7-1,4-benzodioksan, som smelter ved 95~98<<>?C. Dets hydroklorid fremstilles som angitt ovenfor og omkrystalliseres fra isopropanol.. Smeltepunkt 155-157°C. A solution of 5 g of 1-/_~3-(1,4-benzodioxan-2-yl)-propiony]/-4-hydroxy-yl-phenylpiperidine in 50 ml of tetrahydrofuran is added to the stirred mixture of 2 g of lithium aluminum hydride and 50 ml of tetrahydrofuran at room temperature and continue stirring. 12 hours. The reaction mixture is then split with a few drops of acetic acid, 2 ml of water, 4 ml of a 15% aqueous sodium hydroxide solution and 4 ml of water. The mixture is filtered, the filtrate is evaporated and the residue is recrystallized from isopropanol. One obtains 2-/_ 3-(4-hydroxy-4-phenylpiperidino)-propyl7-1,4-benzodioxane, which melts at 95~98<<>?C. Its hydrochloride is prepared as indicated above and recrystallized from isopropanol. Melting point 155-157°C.
Utgangsstoffet fremstilles som følger: En blanding av 10 g 2-(2-tosyloksyetyl)-l,4-benzodioksan, 2,4 g natrium-cyanid, 4 ml vann og 20 ml etanol kokes 48 timer, under til-bakeløp. Reaksjonsblandingen inndampes, residuet opptas i vann og ekstraheres med dietyleter. Ekstraktet tørkes og inndampes. En blanding av 2,8 g svovelsyre, 7,2 ml vann og 7,2 ml eddiksyre blandes med 5 g av det dannede rå nitril, omrøres og kokes 48 timer under tilbakeløp. Blandingen helles i isvann, ekstraheres med dietyleter, ekstraktet vaskes med vann og reekstraheres med vandig riatriumhydrpgen-karbonatoppløsning. Den alkaliske oppløsning surgjøres med klorhydrogensyre og ekstraheres med dietyleter. Ekstraktet tørkes og inndampes. Man oppløser 2,5 g av den rå syre i 25 ml tetrahydrofuran og, blander den omrørte oppløsning i løpet av 30 minutter med 3 g karbonyldiimidazol. Man til- The starting material is prepared as follows: A mixture of 10 g of 2-(2-tosyloxyethyl)-1,4-benzodioxane, 2.4 g of sodium cyanide, 4 ml of water and 20 ml of ethanol is boiled for 48 hours under reflux. The reaction mixture is evaporated, the residue is taken up in water and extracted with diethyl ether. The extract is dried and evaporated. A mixture of 2.8 g of sulfuric acid, 7.2 ml of water and 7.2 ml of acetic acid is mixed with 5 g of the crude nitrile formed, stirred and refluxed for 48 hours. The mixture is poured into ice water, extracted with diethyl ether, the extract is washed with water and re-extracted with aqueous sodium hydrogen carbonate solution. The alkaline solution is acidified with hydrochloric acid and extracted with diethyl ether. The extract is dried and evaporated. Dissolve 2.5 g of the crude acid in 25 ml of tetrahydrofuran and mix the stirred solution with 3 g of carbonyldiimidazole over the course of 30 minutes. Man to-
setter 2,5 g ,4-hydroksy-4-fenylpiperidin og.omrører bland-add 2.5 g of ,4-hydroxy-4-phenylpiperidine and stir the mix-
ingen natten over. Reaksjonsblandingen inndampes, residuet oppløses i eddikester, oppløsningen vaskes med fortynnet vandig natriumhydroksydoppløsning og klorhydrogensyre, tørkes og inndampes. Man får l-/~3-(1, 4-benzodioksan-2-yl)-propiony_l7-4-hydroksy-4-fenylpiperidin. none overnight. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, the solution is washed with dilute aqueous sodium hydroxide solution and hydrochloric acid, dried and evaporated. 1-(1,4-benzodioxan-2-yl)-propionyl-17-4-hydroxy-4-phenylpiperidine is obtained.
Eksempel 4.Example 4.
En oppløsning av 1,9 g tiofSn i 25 ml tetrahydrofuran blandes i en nitrogenatmosfære under omrøring ved -75°C, dråpevis i 16 ml 1,6 N butyllitium i heksan. Etter 15 minutter tilsetter man dråpevis en oppløsning av 4 g 2-/~2-(4-oksopiperidino)-ety_l7-l, 4-benzodioksan i 25 ml tetrahydrofuran under omrøring og lar blandingen oppvarme til værelsestemperatur. Det blandes med 10 ml mettet, vandig ammoniumklorid. Det organiske sjikt adskilles, inndampes og residuet omkrystalliseres fra isopropanol. Man får 2-/_—2-(4-hydroksy-4-tienyl-2-piperidino)-etyl7-l,4-benzodioksan, som smelter ved 117-ll8°C. A solution of 1.9 g of thiofSn in 25 ml of tetrahydrofuran is mixed in a nitrogen atmosphere with stirring at -75°C, dropwise in 16 ml of 1.6 N butyllithium in hexane. After 15 minutes, a solution of 4 g of 2-[2-(4-oxopiperidino)-ethyl-17-1,4-benzodioxane in 25 ml of tetrahydrofuran is added dropwise while stirring and the mixture is allowed to warm to room temperature. It is mixed with 10 ml of saturated, aqueous ammonium chloride. The organic layer is separated, evaporated and the residue recrystallized from isopropanol. 2-(4-Hydroxy-4-thienyl-2-piperidino)-ethyl 7-1,4-benzodioxane is obtained, which melts at 117-118°C.
Utgangsstoffet fremstilles som følger: En blanding av 10 g 2-(2-tosyloksyetyl)-1,4-benzodioksan, 10 g 4-piperidonhydroklorid, 20 g vannfritt natriumkarbonat og 160 ml dimetylformamid omrøres sterkt ved værelsestemperatur i 48 timer. Reaksjonsblandingen filtreres, residuet vaskes med en liten mengde dimetylformamid og filtratet inndampes. Residuet opp-løses i eddikester, oppløsningen ekstraheres med klorhydrogensyre, ekstraktet gjøres basisk under avkjøling med 50%-ig vandig natriumhydroksydoppløsning og reekstraheres med metylenklorid. Det 'siste ekstrakt tørkes og. inndampes. Man får 2-/_ 2-(4-okso- piperidino)-ety JL/-1, 4-benzodioksan, som blir fast ved henstand. The starting material is prepared as follows: A mixture of 10 g of 2-(2-tosyloxyethyl)-1,4-benzodioxane, 10 g of 4-piperidone hydrochloride, 20 g of anhydrous sodium carbonate and 160 ml of dimethylformamide is stirred vigorously at room temperature for 48 hours. The reaction mixture is filtered, the residue is washed with a small amount of dimethylformamide and the filtrate is evaporated. The residue is dissolved in acetic acid, the solution is extracted with hydrochloric acid, the extract is made basic under cooling with a 50% aqueous sodium hydroxide solution and re-extracted with methylene chloride. The 'last extract is dried and. is evaporated. 2-[2-(4-oxo-piperidino)-ethyl]-1,4-benzodioxane is obtained, which becomes solid on standing.
Eksempel 5■ Example 5■
En blanding av 4,6 g 2-(2-t.oksyloksyetyl)-2, 3~ dihydrobenzofuran, 2,64 g 4-hydroksy-4-fenylpiperidin, 10 g vannfri natriumkarbonat og 100 ml 4-metyl-2-pentanon kokes 48 timer under tilbakeløp. Reaksjonsblandingen filtreres, inndampes og residuet omkrystalliseres fra isopropanol-petroleter. Man får 2-/~2-(4-hydroksy-4-fenylpiperidino)-etyl/-2,3-dihydrobenzofuran, som smelter ved 107°C. A mixture of 4.6 g of 2-(2-t.oxyloxyethyl)-2,3~ dihydrobenzofuran, 2.64 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is boiled 48 hours during reflux. The reaction mixture is filtered, evaporated and the residue is recrystallized from isopropanol-petroleum ether. 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-2,3-dihydrobenzofuran is obtained, which melts at 107°C.
Produktet suspenderes i etanol, nøytraliseres med etanolisk klorhydrogen og utfellingen omkrystalliseres fra etanol-dietyleter. Man får det tilsvarende hydroklorid, smeltepunkt l85-l87°C. The product is suspended in ethanol, neutralized with ethanolic hydrogen chloride and the precipitate recrystallized from ethanol-diethyl ether. The corresponding hydrochloride is obtained, melting point 185-187°C.
Utgangstetoffet fremstilles.som følger: En oppløs-ning av. 14,2 g 2-(2,3-dihydrobenzofuran-2-yl)-eddiksyre (Gazz.. Chim. Ital. 93, 52 (1963j_7 i 100 ml tetrahydrofuran haes dråpevis til en omrørt suspensjon av 4,55 g litiumaluminiumhydrid The starting substance is prepared as follows: A solution of 14.2 g of 2-(2,3-dihydrobenzofuran-2-yl)-acetic acid (Gazz.. Chim. Ital. 93, 52 (1963j_7) in 100 ml of tetrahydrofuran is added dropwise to a stirred suspension of 4.55 g of lithium aluminum hydride
i 200 ml tetrahydrofuran. Blandingen kokes 18 timer under til-bakeløp, avkjøles deretter i et isbad og spaltes ved tilsetning av 4,5 ml vann, 4,5 ml av en 15%- ig vandig natriumhydroksydopp-løsning og 14,6 ml vann. Blandingen filtreres, inndampes og in 200 ml of tetrahydrofuran. The mixture is refluxed for 18 hours, then cooled in an ice bath and decomposed by adding 4.5 ml of water, 4.5 ml of a 15% aqueous sodium hydroxide solution and 14.6 ml of water. The mixture is filtered, evaporated and
residuet opptas i eddikester. Oppløsningen vaskes med vandig natriumhydrogenkarbonatoppløsning, vann og mettet vandig natriumkloridoppløsning, tørkes og inndampes. Residuet destilleres i et kulerør ved l40°C/0,l mm Hg. Man får 2-(2-hydroksy-etyl)-2,3-dihydrobenzofuran. the residue is taken up in vinegar. The solution is washed with aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried and evaporated. The residue is distilled in a bubble tube at 140°C/0.1 mm Hg. 2-(2-hydroxyethyl)-2,3-dihydrobenzofuran is obtained.
En blanding av 10 g av sistnevnte forbindelse, 17,4 g p-toluensulfonsyreklorid og 30 ml pyridin avkjøles under 'omrøring 2 timer i et isbad. Blandingen blandes deretter med is, det dannede faste material frafiltreres og omkrystalliseres fra eddikester-petroleter. Man får 2-(2-tosyloksyetyl)-2,3-dihydrobenzofuran, som smelter ved 51-54°C. A mixture of 10 g of the latter compound, 17.4 g of p-toluenesulfonic acid chloride and 30 ml of pyridine is cooled with stirring for 2 hours in an ice bath. The mixture is then mixed with ice, the solid material formed is filtered off and recrystallized from ethyl acetate-petroleum ether. 2-(2-tosyloxyethyl)-2,3-dihydrobenzofuran is obtained, which melts at 51-54°C.
Eksempel 6.Example 6.
En blanding av '2 g 2-/_~2-( 4-hydroksy-4-f eny 1-piperidino)-etyl/-l,4-benzodioksan-hydroklorid, 4 ml propionsyreanhydrid og 4 ml pyridin kokes under omrøring 10 minutter under tilbakeløp. Reaksjonsblandingen. fortynnes med dietyleter, det halvfaste material frafiltreres, vaskes med dietyleter og omkrystalliseres fra isopropanol-dietyleter. Man får 2-/_ 2-(4-propionyloksy-4-fenylpiperidino)-etyl7-l,4-benzo dioksan-hydroklorid, som smelter under spaltning ved 170°C. A mixture of 2 g of 2-[2-(4-hydroxy-4-phenyl-1-piperidino)-ethyl]-1,4-benzodioxane hydrochloride, 4 ml of propionic anhydride and 4 ml of pyridine is boiled with stirring for 10 minutes during reflux. The reaction mixture. diluted with diethyl ether, the semi-solid material is filtered off, washed with diethyl ether and recrystallized from isopropanol-diethyl ether. 2-(4-propionyloxy-4-phenylpiperidino)-ethyl 7-1,4-benzo dioxane hydrochloride is obtained, which melts during decomposition at 170°C.
Eksempel 7-Example 7-
En oppløsning av 3 g 2-/_ 2-(4-hydroksy-4-fenyl-piperidino)-ety_l/-l,4-benzodioksan i 50 ml tetrahydrofuran blandes under omrøring med 8 ml 1,6 N butyllitium i heksan. Etter 3 timer tilsetter man en oppløsning av 2,4 g n-dekanoyl-klorid i 10 ml tetrahydrofuran, koker blandingen 48 timer under tilbakeløp og behandler den med 10 ml mettet vandig ammoniumkloridoppløsning. Den organiske fase adskilles, inndampes og residuet kromatograferes på silikagelplater. Man eluerer med kloroform-eddikester (4:1). Materialet samles ved Rcm= 4,5. Man får'det•analytisk rene 2-/~2-(4-n-dekanoy1-oksy-4-fenylpiperidino)-ety_l/-l, 4-benzodioksan som en lysegul olje. A solution of 3 g of 2-[2-(4-hydroxy-4-phenyl-piperidino)-ethyl]-1,4-benzodioxane in 50 ml of tetrahydrofuran is mixed with stirring with 8 ml of 1.6 N butyllithium in hexane. After 3 hours, a solution of 2.4 g of n-decanoyl chloride in 10 ml of tetrahydrofuran is added, the mixture is refluxed for 48 hours and treated with 10 ml of saturated aqueous ammonium chloride solution. The organic phase is separated, evaporated and the residue is chromatographed on silica gel plates. Elute with chloroform-acetic ester (4:1). The material is collected at Rcm= 4.5. Analytically pure 2-[2-(4-n-decanoyl-oxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxane is obtained as a pale yellow oil.
For fremstilling av injeksjoner med en langvarig virkning kan produktet oppløses i sesamolje. For the preparation of injections with a long-lasting effect, the product can be dissolved in sesame oil.
Eksempel 8.Example 8.
Ifølge de i foregående eksempler omtalte metoder fremstilles også følgende forbindelser med formel II, idet det gåes ut fra ekvivalente mengder tilsvarende utgangsstoffer. According to the methods mentioned in the preceding examples, the following compounds of formula II are also prepared, starting from equivalent amounts of corresponding starting substances.
I tabellen er y = 2, det angjeldende eksempel er angitt i spalte Ex og siste spalte angir smeltepunktet av det tilsvarende tosylat-utgangsstoff: In the table, y = 2, the relevant example is indicated in column Ex and the last column indicates the melting point of the corresponding tosylate starting material:
De i tabellen nevnte forbindelser er følgende: 1-3) 2-/_ 2-(4-hydroksy-4-/_ p-tolyl, p-metoksyfenyl eller p-f luorfenylV-piperidino)-ety_l/-l, 4-benzodioksan; 4) 7-klor-2-/_ 2-(4-hydroksy-4-f eny lpiperidino)-ety IV-1,4-benzodioksan; The compounds mentioned in the table are the following: 1-3) 2-/_ 2-(4-hydroxy-4-/_ p-tolyl, p-methoxyphenyl or p-fluorophenylV-piperidino)-ethyl_1/-1, 4-benzodioxane; 4) 7-chloro-2-(2-(4-hydroxy-4-phenylpiperidino)-ethyl IV-1,4-benzodioxane;
5-6) 2-/_ 2-(4-hydroksy-4-_/ benzyl eller p-klorfenyl/- 5-6) 2-/_ 2-(4-hydroxy-4-_/ benzyl or p-chlorophenyl/-
piperidino)-etyl/-l,r-benzodioksan; (piperidino)-ethyl N -l,r -benzodioxane;
7-11) 8-metyl-, 7-metyl-, 8-metoksy-, 6,7-diklor-7-11) 8-methyl-, 7-methyl-, 8-methoxy-, 6,7-dichloro-
eller 6, 7 , 8-triklor-2-_/~2-(4-hydroksy-4-f eny 1-piperidino.)-ety_l7-l, 4-benzodioksan; or 6,7,8-trichloro-2-[2-(4-hydroxy-4-phenyl-1-piperidino)-ethyl-17-1,4-benzodioxane;
12-16) 2-/~2-(4-hydroksy-4-7~t-butyl) 2-pyridyl, 3-pyridyl, 12-16) 2-[2-(4-hydroxy-4-7-t-butyl) 2-pyridyl, 3-pyridyl,
p-klor-m-trifluorfenyl eller l-benzotien-2-y 1/piperidino) -ety_l7-l, 4-benzodioksan; 17) 2-/_ 2-(4-fenylpipéridino)-ety_l7-lj 4-benzodioksan og 18) 2-/~2-(4-metoksy-4-fenylpiperidino)-etyl7-l,4-benzodioksan. p-chloro-m-trifluorophenyl or 1-benzothien-2-yl(piperidino)-ethyl-17-1,4-benzodioxane; 17) 2-[2-(4-phenylpiperidino)-ethyl-17-14-benzodioxane and 18) 2-[2-(4-methoxy-4-phenylpiperidino)-ethyl7-1,4-benzodioxane.
Fremstillingen av forskjellige nye utgangsstoffer illustreres som følger: The production of various new starting materials is illustrated as follows:
En suspensjon av 13,4 g litiumaluminiumhydridA suspension of 13.4 g of lithium aluminum hydride
i 200- ml tørr tetrahydrofuran blandes under omrøring og koking ved tilbakeløp dråpevis med en oppløsning av 48,6 g 2-(7-metyl-1,4-benzodioksan-2-yl)-eddiksyre i en minimal mengde, tetrahydrofuran. Blandingen kokes natten over under tilbakeløp, avkjøles og spaltes ved tilsetning av 13,4 ml vann, 13,4 ml av en 15#-ig vandig natriumhydroksydoppløsning og 40 ml vann. Reaksjonsblandingen filtreres, filtratet inndampes, residuet destilleres i en molekylardestillasjonsapparatur og oppfanges den ved 155-l65°C70,1 mm Hg kokende fraksjon som farveløs olje. Man får 2-(2-hydroksyety1)-7-mety1-1,4-benzodioksan. in 200 ml of dry tetrahydrofuran is mixed dropwise with stirring and boiling at reflux with a solution of 48.6 g of 2-(7-methyl-1,4-benzodioxan-2-yl)-acetic acid in a minimal amount of tetrahydrofuran. The mixture is refluxed overnight, cooled and decomposed by adding 13.4 ml of water, 13.4 ml of a 15# aqueous sodium hydroxide solution and 40 ml of water. The reaction mixture is filtered, the filtrate is evaporated, the residue is distilled in a molecular distillation apparatus and the fraction boiling at 155-165°C70.1 mm Hg is collected as a colorless oil. 2-(2-Hydroxyethyl)-7-methyl-1,4-benzodioxane is obtained.
En Grignard-reagens som er fremstillet av 3,6 g magnesium og 18,9 g benzylbromid i 50 ml dietyleter blandes med en oppløsning av 18,4 g 1-benzy1-4-piperidon i 100 ml dietyleter og blandingen kokes 1 time under tilbakeløp. Blandingen spaltes med 30 ml mettet, vandig ammoniumkloridoppløsning, den eteriske oppløsning adskilles, tørkes og inndampes. Man får en tykk olje. Man hydrerer 26 g av denne olje over 3 g 10$-ig palladium-på-kull-katalysator i en blanding av 120 ml etanol og 120 ml eddiksyre, ved 3 atmosfærer og 50°C, inntil opptak av en molekvivalent. hydrogen. Blandingen filtreres, filtratet inndampes, residuet behandles med ammoniumhydroksyd og ekstraheres med metylenklorid. A Grignard reagent prepared from 3.6 g of magnesium and 18.9 g of benzyl bromide in 50 ml of diethyl ether is mixed with a solution of 18.4 g of 1-benzyl1-4-piperidone in 100 ml of diethyl ether and the mixture is refluxed for 1 hour . The mixture is split with 30 ml of saturated aqueous ammonium chloride solution, the ethereal solution is separated, dried and evaporated. You get a thick oil. 26 g of this oil are hydrated over 3 g of 10$-ig palladium-on-charcoal catalyst in a mixture of 120 ml of ethanol and 120 ml of acetic acid, at 3 atmospheres and 50°C, until uptake of a molar equivalent. hydrogen. The mixture is filtered, the filtrate is evaporated, the residue is treated with ammonium hydroxide and extracted with methylene chloride.
Ekstraktet tørkes og inndampes. Man får 4-benzyl-4-hydroksy-piperidin,- som er tilstrekkelig rent for den videre omsetning. The extract is dried and evaporated. 4-benzyl-4-hydroxy-piperidine is obtained, which is sufficiently pure for the further reaction.
På analog måte fremstilles 4-hydroksy-4-(4-metoksyfenyl)-piperidin, som etter omkrystallisering fra isopropanol-petroleter smelter ved 121-123°C. In an analogous manner, 4-hydroxy-4-(4-methoxyphenyl)-piperidine is prepared, which after recrystallization from isopropanol-petroleum ether melts at 121-123°C.
En oppløsning av 11,64 g 2-(1,4-benzodioksan-2-yl)-eddiksyre i 60 ml tetrahydrofuran blandes under omrøring med 12 g.1,1-karbonyldiimidazol. Etter opphør av karbondioksyd-utvikling blandes reaksjonsblandingen med 10,6 g 4-hydroksy-4-fenylpiperidin og omrøres natten over ved værelsestemperatur. Blandingen inndampes, residuet opptas i eddikester, oppløsningen vaskes med vann, normal klorhydrogensyre og vann, tørkes og inndampes. Man får !-/_ 2-(1, 4-benzodioksan-2-y 1)-acetyl_/-4-hydroksy-4-fenylpiperidin. A solution of 11.64 g of 2-(1,4-benzodioxan-2-yl)-acetic acid in 60 ml of tetrahydrofuran is mixed with stirring with 12 g of 1,1-carbonyldiimidazole. After carbon dioxide evolution has ceased, the reaction mixture is mixed with 10.6 g of 4-hydroxy-4-phenylpiperidine and stirred overnight at room temperature. The mixture is evaporated, the residue is taken up in ethyl acetate, the solution is washed with water, normal hydrochloric acid and water, dried and evaporated. 1-/_ 2-(1,4-benzodioxan-2-yl)-acetyl_/-4-hydroxy-4-phenylpiperidine is obtained.
Eksempel £)• Example £)•
En oppløsning av 20 g 2- 1_ 2-(4-hydroksy-4-fenyl-piperidino)-l-tosyloksyetyl./-l, 4-benzodioksan i 500 ml tetrahydrofuran blandes med 7 g litiumaluminiumhydrid og blandingen kokes under tilbakeløp, under omrøring i 6.timer. Blandingen behandles deretter under omrøring med 2 ml eddikester, 7 ml vann, 7 ml av en 15$-ig vandig natriumhydroksydoppløsning og 22 ml vann. Det uorganiske residuet frafiltreres, filtratet inndampesresiduet behandles med etanolisk klorhydrogen og omkrystalliseres fra etanol-dietyleter. Mån får 2- 1_ 2-(4-hydroksy-4-f eny lpiperidino) -ety 1,7-1, 4-benzodioksan-hydroklorid, som smelter ved 203°C. A solution of 20 g of 2-1_ 2-(4-hydroxy-4-phenyl-piperidino)-1-tosyloxyethyl./-1,4-benzodioxane in 500 ml of tetrahydrofuran is mixed with 7 g of lithium aluminum hydride and the mixture is refluxed, with stirring in 6 hours. The mixture is then treated with stirring with 2 ml of acetic acid, 7 ml of water, 7 ml of a 15% aqueous sodium hydroxide solution and 22 ml of water. The inorganic residue is filtered off, the filtrate evaporated residue is treated with ethanolic hydrogen chloride and recrystallized from ethanol-diethyl ether. Moon obtains 2-1_ 2-(4-hydroxy-4-phenylpiperidino)-ethyl 1,7-1,4-benzodioxane hydrochloride, which melts at 203°C.
Utgangsstoffet fremstilles som følger:, En oppløs-ning av 42 g 2-(2-bromacetyl)-l,4-benzodioksan i 360 ml metanol, blandes under omrøring og avkjøling ved en temperatur under 10°C, med 12 g natriumborhydrid. Etter 5 timer avkjøles blandingen'til 0°C, blandes med 13,2 g natriumhydroksyd i 150 ml metanol og holdes natten over ved -15°C. Blandingen helles deretter på is og ekstraheres med dietyleter, ekstraktet vaskes med mettet vandig natriumkloridoppløsning,■tørkes og inndampes. Man får 1,4-benzodioksan-2-y1-etylenoksyd. The starting material is prepared as follows: A solution of 42 g of 2-(2-bromoacetyl)-1,4-benzodioxane in 360 ml of methanol is mixed with 12 g of sodium borohydride while stirring and cooling at a temperature below 10°C. After 5 hours, the mixture is cooled to 0°C, mixed with 13.2 g of sodium hydroxide in 150 ml of methanol and kept overnight at -15°C. The mixture is then poured onto ice and extracted with diethyl ether, the extract is washed with saturated aqueous sodium chloride solution, dried and evaporated. 1,4-benzodioxan-2-y1-ethylene oxide is obtained.
En blanding av 7,1 g av sistnevnte forbindelse og 3,54 g 4-hydroksy-4-fenylpiperidin i 75 ml isopropanol kokes 5 timer under tilbakeløp og inndampes. Residuet oppløses i eddikester og oppløsningen ekstraheres med vandig metansulfon-syre. Det substituerte piperidin fordeler seg mellom det vandige og det organiske sjikt. Etter inndampning av det organiske sjikt får man et gummiaktig residu, som langsomt kry-stalliserer. Etter omkrystallisering fra isopropanol får man 2-[_ 2-(4-hydroksy-4-fenylpiperidino)-l-hydroksyety_l/-l,4-benzodioksan-metansulfonat, som smelter ved 208-210°C. A mixture of 7.1 g of the latter compound and 3.54 g of 4-hydroxy-4-phenylpiperidine in 75 ml of isopropanol is boiled for 5 hours under reflux and evaporated. The residue is dissolved in ethyl acetate and the solution is extracted with aqueous methanesulfonic acid. The substituted piperidine is distributed between the aqueous and the organic layers. After evaporation of the organic layer, a gummy residue is obtained, which slowly crystallizes. After recrystallization from isopropanol, 2-[_2-(4-hydroxy-4-phenylpiperidino)-1-hydroxyethyl-1/-1,4-benzodioxane-methanesulfonate is obtained, which melts at 208-210°C.
Det vandige ekstrakt gjøres basisk med ammoniumhydroksyd og ekstraheres med metylenklorid, den organiske fase tørkes og inndampes. Residuet omkrystalliseres fra isopropanol-petroleter. Man får den tilsvarende fri base, som smelter ved 95°C. The aqueous extract is made basic with ammonium hydroxide and extracted with methylene chloride, the organic phase is dried and evaporated. The residue is recrystallized from isopropanol-petroleum ether. The corresponding free base is obtained, which melts at 95°C.
En oppløsning av 20 g av sistnevnte forbindelseA solution of 20 g of the latter compound
i 80 ml pyridin, blandes under omrøring og avkjøling i et isbad, med 11,-8 gtoluensulf ony lklorid. Man lar reaks j onsbland-ingen stå 3 timer i isbad, heller den på 200 g isvann og dekan- in 80 ml of pyridine, mixed with stirring and cooling in an ice bath, with 11.8 g of toluenesulfonyl chloride. The reaction mixture is allowed to stand for 3 hours in an ice bath, poured into 200 g of ice water and decanted
terer den vandige, fase fra rått faste material. Residuet vaskes flere ganger med vann, filtreres og tørkes. Man får 2-/_ 2-(4-hydroksy-4-f enyl-piperidino)-l-tosyloksyety_l/-l t ~4-benzodioksan. teres the aqueous phase from raw solid material. The residue is washed several times with water, filtered and dried. 2-(4-Hydroxy-4-phenyl-piperidino)-1-tosyloxyethyl-1-4-benzodioxane is obtained.
Eksempel 10.Example 10.
En oppløsning av 10 g 1,4-benzodioksan-2-yl-acetaldehyd og 12,7 g 4-hydroksy-4-fenylpiperidin i 300 ml metanol blandes med 8 ml 4,5 N etanolisk klorhydrogen. Under disse betingelser får man in situ 2-_ 12- (4-hydroksy-4-fenyl-piperidino )-viriyl7-l,4-benzodioksan. Etter en time blander man reaksjonsblandingen under omrøring ved værelsestemperatur dråpevis med en oppløsning av 2,4 g natriumcyanborhydrid i 30 ml metanol. Etter en time gjøres oppløsningen sterkt basisk med vandig natriumhydroksydoppløsning, konsentreres til et lite volum og fortynnes med vann. Blandingen ekstraheres med eddikester, ekstraktet tørkes og inndampes. Residuet behandles med etanolisk klorhydrogen og den dari'nederutfelling omkrystalliseres fra etanol-dietyleter. Man får 2-/~2-(4-hydroksy-4-fenylpiperidino)-etyl7-l,4-benzodioksan-hydroklorid, som smelter ved ■203°C. A solution of 10 g of 1,4-benzodioxan-2-yl-acetaldehyde and 12.7 g of 4-hydroxy-4-phenylpiperidine in 300 ml of methanol is mixed with 8 ml of 4.5 N ethanolic hydrogen chloride. Under these conditions, 2-_12-(4-hydroxy-4-phenyl-piperidino)-viriyl7-1,4-benzodioxane is obtained in situ. After one hour, the reaction mixture is mixed dropwise with stirring at room temperature with a solution of 2.4 g of sodium cyanoborohydride in 30 ml of methanol. After one hour, the solution is made strongly basic with aqueous sodium hydroxide solution, concentrated to a small volume and diluted with water. The mixture is extracted with vinegar, the extract is dried and evaporated. The residue is treated with ethanolic hydrogen chloride and the resulting precipitate is recrystallized from ethanol-diethyl ether. 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl-7-1,4-benzodioxane hydrochloride is obtained, which melts at ■203°C.
Utgangsstoffet fremstilles som følger: En oppløs-ning av 20 g 1,4-benzodioksan-2-yl-aceto«iitril i 200. ml benzen i blandes under omrøring dråpevis ved 10 o C, med 71 ml av en 1,6 N oppløsning av diisobutylaluminiumhydrid i benzen. Etter 6 timer, i blandes reaksjonsblandingen først med 50 ml metanol og deretter med 200 ml vann. Det organiske sjikt adskilles, tørkes og inndampes. Man får 1,4-benzodioksan-2-yl-acetaldehyd. The starting material is prepared as follows: A solution of 20 g of 1,4-benzodioxan-2-yl-acetotritrile in 200 ml of benzene is mixed dropwise with stirring at 10 o C with 71 ml of a 1.6 N solution of diisobutylaluminum hydride in benzene. After 6 hours, the reaction mixture is first mixed with 50 ml of methanol and then with 200 ml of water. The organic layer is separated, dried and evaporated. 1,4-benzodioxan-2-yl-acetaldehyde is obtained.
Eksempel 11.Example 11.
En oppløsning av 7 g natriummetylat i 200 ml metanol blandes med 20 g l-/_ 4-(2-acetoksy f enoksy )-3-tosyl-oksybuty_l/-4-hydroksy-4-fenylpiperidin, blandingen kokes under tilbakeløp 6 timer og inndampes til et lite volum. Reaksjonsblandingen fortynnes med vann, ekstraheres med metylenklorid, ekstraktet tørkes og inndampes. Residuet behandles med etanolisk klorhydrogen og residuet omkrystalliseres flere ganger fra etanol-dietyleter. Man får 2-/~2-(4-hydroksy-4-feny lpiperidino)'-etyl7-l,4-benzodioksan-hydroklorid, som smelter ved 203°C. A solution of 7 g of sodium methylate in 200 ml of methanol is mixed with 20 g of l-/_ 4-(2-acetoxyphenoxy)-3-tosyl-oxybutyl_l/-4-hydroxy-4-phenylpiperidine, the mixture is refluxed for 6 hours and evaporated to a small volume. The reaction mixture is diluted with water, extracted with methylene chloride, the extract is dried and evaporated. The residue is treated with ethanolic hydrogen chloride and the residue is recrystallized several times from ethanol-diethyl ether. This gives 2-[2-(4-hydroxy-4-phenylpiperidino)'-ethyl-7-1,4-benzodioxane hydrochloride, which melts at 203°C.
Utgangsstoffet fremstilles som følger: En oppløs-ning av 20 g 4-hydroksy-4-fenylpiperidin-hydroklorid, 10 ml aceton, 5j6 g paraformaldehyd og 100 ml nitrometan kokes 12 timer under tilbakeløp. Reaksjonsblandingen fortynnes med 500 ml cykloheksan og utfellingen adskilles. Man får 4-(4-hydroksy-4-fenylpiperidino)-2-butanon-hydroklorid. The starting material is prepared as follows: A solution of 20 g of 4-hydroxy-4-phenylpiperidine hydrochloride, 10 ml of acetone, 5.6 g of paraformaldehyde and 100 ml of nitromethane is boiled for 12 hours under reflux. The reaction mixture is diluted with 500 ml of cyclohexane and the precipitate is separated. 4-(4-hydroxy-4-phenylpiperidino)-2-butanone hydrochloride is obtained.
En suspensjon av 20 g av sistnevnte forbindelseA suspension of 20 g of the latter compound
i 100 ml eddiksyre blandes under sterk omrøring med 3,7 ml brom i 25 ml eddiksyre dråpevis, idet man holder temperaturen ved 25°C. Etter en time forsvinner bromfarven fullstendig. Deretter avdestilleres halvparten av eddiksyren. Konsentratet fortynnes med dietyleter og den dannede utfelling fraskilles. Man får l-brom-4-(4-hydroksy-4-fenyl-piperidino)-2-butanon-hydroklorid . in 100 ml of acetic acid is mixed with vigorous stirring with 3.7 ml of bromine in 25 ml of acetic acid dropwise, keeping the temperature at 25°C. After an hour, the bromine color disappears completely. Half of the acetic acid is then distilled off. The concentrate is diluted with diethyl ether and the precipitate formed is separated. 1-Bromo-4-(4-hydroxy-4-phenyl-piperidino)-2-butanone hydrochloride is obtained.
En med is avkjølet suspensjon av 10 g 56#-ig natriumhydrid i mineralolje og 100 ml dimetylformamid blandes under omrøring langsomt i rekkefølge, med 16 g o-acetylpyro-katekin og 20 g l-brom-4-(4-hydroksy-4-fenylpiperidino)-2- - butanon-hydroklorid. Reaksjonsblandingen omrøres 12 timer ved 5°C og blandes deretter med 2 g natriumborhydrid. Man lar blandingens temperatur øke til værelsestemperatur, heller den etter 1 time på is og ekstraherer den med metylenklorid. Ekstraktet tørkes og inndampes. Man får 1-(2-acetoksyfenoksy)-4-(4-hydroksy-4-fenylpiperidino)-2-butanol som en olje. Man oppløser 20 g herav i 70 ml pyridin, avkjøler oppløsningen i et isbad og blander den under omrøring porsjonsvis med 10 g p-toluensulfonsyreklorid. Etter 3 timer fortynnes blandingen med 500 ml isvann, det dannede faste material adskilles, vaskes flere ganger med vann og tørkes over fosforpentoksyd. Man får !-/_ 4 - (2-acetoksyfenoksy) -3~ tosy loksybuty l7-4-hydroksy- 4- f eny 1-piperidin. An ice-cooled suspension of 10 g of 56#-ig sodium hydride in mineral oil and 100 ml of dimethylformamide is mixed with stirring slowly in sequence, with 16 g of o-acetylpyro-catechin and 20 g of 1-bromo-4-(4-hydroxy-4- phenylpiperidino)-2- - butanone hydrochloride. The reaction mixture is stirred for 12 hours at 5°C and then mixed with 2 g of sodium borohydride. The temperature of the mixture is allowed to rise to room temperature, after 1 hour it is poured onto ice and extracted with methylene chloride. The extract is dried and evaporated. 1-(2-acetoxyphenoxy)-4-(4-hydroxy-4-phenylpiperidino)-2-butanol is obtained as an oil. Dissolve 20 g of this in 70 ml of pyridine, cool the solution in an ice bath and mix it with stirring in portions with 10 g of p-toluenesulphonic acid chloride. After 3 hours, the mixture is diluted with 500 ml of ice water, the solid material formed is separated, washed several times with water and dried over phosphorus pentoxide. !-/_ 4 - (2-acetoxyphenoxy)-3-tosyloxybutyl 17-4-hydroxy-4-phenyl 1-piperidine is obtained.
Eksempel 12.Example 12.
En oppløsning av 5 g 2-/_ 2-(4-fenyl-l,2,5,6-tetrahydropyridyl-1)-ety1/-1,4-benzodioksan-hydroklorid i 100 ml eddiksyre-vånn (9:1) blandes med 0,5 g 10%-ig palladium-p-kull-katalysator og blandingen hydreres ved 3 atmosfærer inntil opptak av den ekvivalente hydrogenmengde. Blandingen filtreres, filtratet inndampes og residuet opptas i vann. Blandingen gjøres basisk med ammoniumhydroksyd, ekstraheres med metylenklorid, ekstraktet tørkes og inndampes. Residuet opptas i isopropanol og oppløsningen surgjøres med etanolisk klorhydrogen. Man får 2-7 2-(4-fenylpiperidino)-etyl/-l,4-benzodioksan-hydroklorid, som smelter ved 224-225°C. Produktet er identisk med forbindelse nr. 17 fra eksempel 8. A solution of 5 g of 2-[2-(4-phenyl-1,2,5,6-tetrahydropyridyl-1)-ethyl]-1,4-benzodioxane hydrochloride in 100 ml of acetic acid-water (9:1) is mixed with 0.5 g of 10% palladium-p-charcoal catalyst and the mixture is hydrogenated at 3 atmospheres until uptake of the equivalent amount of hydrogen. The mixture is filtered, the filtrate is evaporated and the residue is taken up in water. The mixture is made basic with ammonium hydroxide, extracted with methylene chloride, the extract is dried and evaporated. The residue is taken up in isopropanol and the solution acidified with ethanolic hydrogen chloride. 2-7 2-(4-phenylpiperidino)-ethyl/-1,4-benzodioxane hydrochloride is obtained, which melts at 224-225°C. The product is identical to compound No. 17 from Example 8.
Utgangsstoffet fremstilles ifølge den metodeThe starting material is produced according to that method
som er angitt i eksempel 1. Smeltepunkt 200-201°C.which is indicated in example 1. Melting point 200-201°C.
Eksempel 13.Example 13.
En oppløsning av 5 g 2- 1_ 2-(4-benzoylpiperidino)-ety_l/-l, 4-benzodioksan-hydrobromid i 100 ml 90%-ig vandig eddiksyre blandes med 1 g 10#-ig palladium-på-kull-katalysator og blandingen hydreres ved 3 atmosfærer og 50°C til opptak av to molekvivalenter hydrogen. Reaksjonsblandingen filtreres deretter, filtratet inndampes og residuet opptas i vann. Blandingen gjøres basisk med ammoniumhydroksyd og ekstraheres med metylenklorid. Ekstraktet tørkes, inndampes, residuet nøytraliseres med etanolisk klorhydrogen og det faste material adskilles. Man får 2- f~ 2-( 4-benzy lpiperidino)-etyl_7-l, 4-benzodioksan-hydroklorid, som i I.R.-spektrum viser bånd ved 2447 og 748 cm"<1>. A solution of 5 g of 2-1_ 2-(4-benzoylpiperidino)-ethyl_l/-l,4-benzodioxane hydrobromide in 100 ml of 90% aqueous acetic acid is mixed with 1 g of 10# palladium-on-charcoal catalyst and the mixture is hydrogenated at 3 atmospheres and 50°C to absorb two molar equivalents of hydrogen. The reaction mixture is then filtered, the filtrate is evaporated and the residue is taken up in water. The mixture is made basic with ammonium hydroxide and extracted with methylene chloride. The extract is dried, evaporated, the residue is neutralized with ethanolic hydrogen chloride and the solid material is separated. 2-f~ 2-(4-benzyl piperidino)-ethyl_7-1,4-benzodioxane hydrochloride is obtained, which in the I.R. spectrum shows bands at 2447 and 748 cm"<1>.
Utgangsstoffet fremstilles analogt den i eksempel omtalte metode. Smeltepunkt 193-195°C. The starting material is prepared analogously to the method mentioned in the example. Melting point 193-195°C.
På analog'måte vil man ved hydrering av 2- 1_ 2-(4-p-fluorbenzoyImetylpiperidino)-etyl/-l,4-benzodioksan-hydroklorid (smeltepunkt 165-166°C)' få 2-<T>2-(4-p-fluorfenyletyl-piperidino)-ety_l/-l,4-benzodioksan-hydro'klorid, som i I.R.--1 '■ spektrum viser bånd ved 2485 og 695 cm .. Eksempel 14. In an analogous way, by hydrogenating 2-1_ 2-(4-p-fluorobenzoylmethylpiperidino)-ethyl/-1,4-benzodioxane hydrochloride (melting point 165-166°C) you get 2-<T>2-( 4-p-Fluorophenylethyl-piperidino)-ethyl_l/-l,4-benzodioxane hydrochloride, which in the I.R.--1 '■ spectrum shows bands at 2485 and 695 cm .. Example 14.
Fremstilling av 10.000 tabletter med et innholdProduction of 10,000 tablets with a content
på hver 5 mg av det aktive stoff:on every 5 mg of the active substance:
Bestanddeler:Ingredients:
F remgangsmåte: Samtlige pulverformede bestanddeler siktes med en sikt av 0,6 mm'maskevidde, Deretter blandes det virksomme stoff med melkesukker, talkum, magnesium-stearat og med halvparten av stivelsen i en egnet blander. Den andre halvparten av stivesen suspenderes i 40 ml vann og suspen- sjonen haes til en kokende oppløsning av ■ polyetylenglykol i 150 ml vann. Den dannede pasta haes til pulvrene og granu-leres , eventuelt under tilsetning av en ytterligere vann-mengde. Granulatet tørkes natten over ved 35°C, drives gjennom en sikt av 1,2 mm maskevidde og presses til tabletter med 6,4 mm diamete.r, som har en bruddrille. Method: All powdered ingredients are sieved with a sieve of 0.6 mm mesh size. The active substance is then mixed with milk sugar, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension is brought to a boiling solution of ■ polyethylene glycol in 150 ml of water. The resulting paste is ground into powders and granulated, possibly with the addition of a further amount of water. The granulate is dried overnight at 35°C, passed through a sieve of 1.2 mm mesh and pressed into tablets of 6.4 mm diameter, which have a breaking drill.
Fremstilling av 10.000 kapsler med et innhold på hver 2,5 mg av det aktive stoff: Production of 10,000 capsules each containing 2.5 mg of the active substance:
Bestanddeler:Components:
Fremgangsmåte: Samtlige pulverformede bestanddeler siktes med en sikt av 0,6 mm maskevidde. Deretter homo-geniseres det virksomme stoff, først med talkum og deretter med melkesukker i en egnet blander. Gelatinkapsler nr. 3 avfylles med hver gang 200 mg av den dannede blanding i en fyllmaskin. Procedure: All powdered components are sieved with a sieve of 0.6 mm mesh size. The active substance is then homogenized, first with talc and then with milk sugar in a suitable mixer. Gelatin capsules No. 3 are filled each time with 200 mg of the resulting mixture in a filling machine.
På analog måte fremstilles tabletter og hårde gelatinkapsler med andre, i eksemplene, omtalte forbindelser.. Eksempel 15. In an analogous way, tablets and hard gelatin capsules are prepared with other compounds mentioned in the examples. Example 15.
En blanding av 2,2 g 2-/_ 2- (4-hydroksy-4-pyridyl-2-piperidino)-ety]L/-l, 4-benzpdioksan-hydroklorid, 4 ml pyridin og 4 ml propionsyreanhydrid kokes under omrøring 20 minutter under tilbakeløp. Reaksjonsblandingen fortynnes med dietyleter og den dannede utfelling omkrystalliseres fra isopropanol. Man får 2-/_ 2-(4-propionyloksy-4-pyridy 1-2-piperidino)-etyJL/- 1,4-benzodioksan-hydroklorid, som smelter ved 125-130°C under spaltning. A mixture of 2.2 g of 2-(4-hydroxy-4-pyridyl-2-piperidino)-ethyl]L/-l, 4-benzpdioxane hydrochloride, 4 ml of pyridine and 4 ml of propionic anhydride is boiled with stirring 20 minutes during reflux. The reaction mixture is diluted with diethyl ether and the precipitate formed is recrystallized from isopropanol. 2-[2-(4-propionyloxy-4-pyridy 1-2-piperidino)-ethyl]-1,4-benzodioxane hydrochloride is obtained, which melts at 125-130°C during decomposition.
Eksempel 16.Example 16.
En oppløsning av 4 g 2-/~2-(4-hydroksy-4-fenyl-piperidino)-etyl7-l,4-benzodioksan i 50 ml vannfritt tetrahydrofuran blandes under omrøring ved 0°C med 1,6 N n-butyllitium i heksan. Man lar blandingen oppvarme til værelsestemperatur, spalter den under omrøring med 1,5 ml pivaloylklorid i 10 ml tetrahydrofuran og koker den 24 timer under tilbakeløp. Etter avkjøling blandes reaksjonsblandingen med 10 ml mettet vandig ammoniumkloridoppløsning og deretter med 200 nil dietyleter. Det organiske sjikt adskilles, vaskes med vann, tørkes, inndampes og residuet oppløses i isopropanol. Oppløsningen surgjøres med 6 N etanolisk klorhydrogen og utfellingen fraskilles. Man får 2- 1_ 2-(4-pivaloyloksy-4-fenylpiperidino)-etyl/-l,4-benzodioksan-hydroklorid som smelter under spaltning ved 195-200°C. A solution of 4 g of 2-[2-(4-hydroxy-4-phenyl-piperidino)-ethyl7-1,4-benzodioxane in 50 ml of anhydrous tetrahydrofuran is mixed with stirring at 0°C with 1.6 N n-butyllithium in hexane. The mixture is allowed to warm to room temperature, split while stirring with 1.5 ml of pivaloyl chloride in 10 ml of tetrahydrofuran and boiled for 24 hours under reflux. After cooling, the reaction mixture is mixed with 10 ml of saturated aqueous ammonium chloride solution and then with 200 nil of diethyl ether. The organic layer is separated, washed with water, dried, evaporated and the residue dissolved in isopropanol. The solution is acidified with 6 N ethanolic hydrogen chloride and the precipitate is separated. 2-1_ 2-(4-pivaloyloxy-4-phenylpiperidino)-ethyl/-1,4-benzodioxane hydrochloride is obtained which melts during cleavage at 195-200°C.
Eksempel 17.Example 17.
En^blanding av 1,44 g litiumaluminiumhydrid iA mixture of 1.44 g of lithium aluminum hydride i
150 ml vannfritt tetrahydrofuran blandes under omrøring med en oppløsning av 14 g l-_/ 2-(1,4-benzoksatian-2-yl)-acety_l/- 4-hydroksy-4-fenyl-piperidin i 140 ml tetrahydrofuran. Reaksjonsblandingen omrøres natten over ved værelsestemperatur, blandes med 1,4 ml vann, 2,9 ml 15%- ig vandig natriumhydroksyd-oppløsning ' og 2,9 ml vann, filtreres og filtratet inndampes. Residuet opptas i 10 ml varm isopropanol, oppløsningen behandles med 4,5 g cykloheksansulfaminsyre. Etter avkjøling utkrystalliserer 2- l_ 2- (4-hydroksy-4-fenylpiperidino).-etyl7-l,4-benzoksa-tian-cyklamat. Smeltepunkt 17.6°C. 150 ml of anhydrous tetrahydrofuran are mixed with stirring with a solution of 14 g of 1-_/2-(1,4-benzoxathian-2-yl)-acetyl_1/-4-hydroxy-4-phenyl-piperidine in 140 ml of tetrahydrofuran. The reaction mixture is stirred overnight at room temperature, mixed with 1.4 ml of water, 2.9 ml of 15% aqueous sodium hydroxide solution and 2.9 ml of water, filtered and the filtrate evaporated. The residue is taken up in 10 ml of hot isopropanol, the solution is treated with 4.5 g of cyclohexanesulfamic acid. After cooling, 2-1_ 2-(4-hydroxy-4-phenylpiperidino)-ethyl 7-1,4-benzoxathiane-cyclamate crystallizes out. Melting point 17.6°C.
Utgangsstoffet fremstilles som følger: En oppløs-ning av 21 g 2-hydroksy-tiofenol i 290 ml aceton blandes dråpevis under omrøring og koking under tilbakeløp, med 12,5 g 3,4-dibrom-butyronitril og også med små porsjoner.av 15,8 g vannfri kaliumkarbonat. Etter 30 minutter gjentas den parallelle tilsetning av de nevnte mengder av dibromforbindelsen og av kaliumkarbonatet. Etter ytterligere 30 minutter gjentas den nevnte tilsetning for tredje gang. Reaksjonsblandingen kokes deretter 20 timer under tilbakeløp, avkjøles og filtreres. De som residuum dannede salter vaskes med aceton og filtratet inndampes. Residuet destilleres og den fraksjon som koker ved l85°C/0,5 mm Hg oppfanges. Man får 2-(1,4-benzoksatian-2-yl)-acetonitril. The starting material is prepared as follows: A solution of 21 g of 2-hydroxythiophenol in 290 ml of acetone is mixed dropwise with stirring and boiling under reflux, with 12.5 g of 3,4-dibromobutyronitrile and also with small portions of 15 .8 g anhydrous potassium carbonate. After 30 minutes, the parallel addition of the mentioned quantities of the dibromine compound and of the potassium carbonate is repeated. After a further 30 minutes, the aforementioned addition is repeated for a third time. The reaction mixture is then refluxed for 20 hours, cooled and filtered. The salts formed as a residue are washed with acetone and the filtrate is evaporated. The residue is distilled and the fraction boiling at 185°C/0.5 mm Hg is collected. 2-(1,4-Benzoxathian-2-yl)-acetonitrile is obtained.
En blanding av 50 g av sistnevnte forbindelse,A mixture of 50 g of the latter compound,
74 ml vann, 74 ml eddiksyre og 28,6 g svovelsyre kokes 48 timer 74 ml of water, 74 ml of acetic acid and 28.6 g of sulfuric acid are boiled for 48 hours
under tilbakeløp. Etter avkjøling ekstraheres reaksjonsblandingen. tre ganger med hver gang 150 ml benzen. Ekstraktet vaskes med vandig natriumhydrogenkarbonatoppløsning og den vandige fase surgjøres med klorhydrogensyre. Blandingen ekstraheres med dietyleter. Ekstraktet tørkes og inndampes. Man får 2-(1,4-benzoksatian-2-yl)-eddiksyre. during reflux. After cooling, the reaction mixture is extracted. three times with each time 150 ml of benzene. The extract is washed with aqueous sodium bicarbonate solution and the aqueous phase is acidified with hydrochloric acid. The mixture is extracted with diethyl ether. The extract is dried and evaporated. 2-(1,4-Benzoxathian-2-yl)-acetic acid is obtained.
En oppløsning av 10 g av sistnevnte forbindelseA solution of 10 g of the latter compound
i 45 ml vannfri tetrahydrofuran blandes under omrøring med 9,2 g karbonyldiimidazol og etter. 30 minutter med 10,1 g 4-hydroksy-4- in 45 ml of anhydrous tetrahydrofuran is mixed with stirring with 9.2 g of carbonyldiimidazole and then. 30 minutes with 10.1 g of 4-hydroxy-4-
f eny lpiperidin og omrøringen fortsetter i 24 timer. Reaksj.ons-blandingen inndampes, residuet opptas i eddikester og opplas-tningen vaskes med vann, surgjøres med klorhydrogensyre, tørkes og inndampes. Man får 2-(1, 4-benzoksatian-2-yl)-acetyl/- 4-hydroksy-4-fenylpiperidin. f phenylpiperidine and stirring is continued for 24 hours. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and the mixture is washed with water, acidified with hydrochloric acid, dried and evaporated. 2-(1,4-Benzoxathian-2-yl)-acetyl/-4-hydroxy-4-phenylpiperidine is obtained.
På analog måte fremstilles også 2-/~2-(4-fenyl-piperidino)-etyl/-l,4-benzoksatian-cyklamat. Smeltepunkt146-148°C. 2-[2-(4-phenyl-piperidino)-ethyl]-1,4-benzoxathane cyclamate is also prepared in an analogous manner. Melting point 146-148°C.
Eksempel 18.Example 18.
En oppløsning av 3,55 g 2-/_ 2-(4-hydroksy-4-fenylpiperidino)-ety_l/-l, 4-benzoksatian i 10 ml dioksan og 10 ml metanol haes dråpevis tiii en omrørt oppløsning av 2,67 g A solution of 3.55 g of 2-/_ 2-(4-hydroxy-4-phenylpiperidino)-ethyl_/-1,4-benzoxathane in 10 ml of dioxane and 10 ml of methanol is added dropwise to a stirred solution of 2.67 g
natrium-metaperjodat i 20 ml vann. Reaksjonsblandingen omrøressodium metaperiodate in 20 ml of water. The reaction mixture is stirred
2 timer ved værelsestemperatur, inndampes og residuet opptas 2 hours at room temperature, evaporate and absorb the residue
i'metylenklorid. Oppløsningen tørkes, inndampes og man oppløser 2,3 g av residuet i en minimal etanolmehgde. Oppløsningen blandes med en oppløsning av 1,45 g cykloheksan-sulfami.nsyre i etanol og den dannede utfelling fraskilles. Man får det tilsvarende S-oksyd-cyklamat, som smelter ved 158-l60°C. i'methylene chloride. The solution is dried, evaporated and 2.3 g of the residue is dissolved in a minimal amount of ethanol. The solution is mixed with a solution of 1.45 g of cyclohexane-sulfamic acid in ethanol and the precipitate formed is separated. The corresponding S-oxide cyclamate is obtained, which melts at 158-160°C.
Eksempel 19.Example 19.
En oppløsning av 4 ,9 g 2-(1,4-benzodioksan-2-yl)-acety_l/-4-etoksy-4-fenylpiperidin -i 50 ml tetrahydrofuran haes til den omrørte blanding av 0,7 g litiumaluminiumhydrid A solution of 4.9 g of 2-(1,4-benzodioxan-2-yl)-acetyl-1/-4-ethoxy-4-phenylpiperidine in 50 ml of tetrahydrofuran is added to the stirred mixture of 0.7 g of lithium aluminum hydride
i og 100 ml tetrahydrofuran ved værelsestemperatur. Reaksjons- s blandingen omrøres natten over og blandes deretter med noen dråper eddikester, 0,7 ml vann, 1,4 ml av en 15%- ig vandig in and 100 ml of tetrahydrofuran at room temperature. The reaction mixture is stirred overnight and then mixed with a few drops of acetic acid, 0.7 ml of water, 1.4 ml of a 15% aqueous
natriumhydroksydoppløsning og 2,1 ml vann. Blandingen filtreres, filtratet inndampes og man oppløser 5 g av residuet i en minimal etanolmengde. Oppløsningen forenes med oppløsningen av 1,7 g maleinsyre i etanol. Blandingen avkjøles, filtreres og residuet omkrystalliseres fra etanol. Man får 2- l_ 2-(4-etoksy-4-fenylpiperidino)-ety_l/-l,4-benzodioksan-maleat, som smelter ved l60-l62°C. sodium hydroxide solution and 2.1 ml of water. The mixture is filtered, the filtrate is evaporated and 5 g of the residue is dissolved in a minimal amount of ethanol. The solution is combined with the solution of 1.7 g of maleic acid in ethanol. The mixture is cooled, filtered and the residue recrystallized from ethanol. 2-1-2-(4-ethoxy-4-phenylpiperidino)-ethyl-1/-1,4-benzodioxane maleate is obtained, which melts at 160-162°C.
Utgangsstoffet fremstilles som følger: En oppløs-ning av 3,3 g 1,4-benzodioksan-2-yl-eddiksyre i 30 ml tetrahydrofuran blandes under omrøring først med 3,1 g l,l'-karbonyldiimidazol og etter 30 minutter med 3,5 g 4-etoksy-4-fenyl-piperidin i 30 ml tetrahydrofuran. Blandingen omrøres 18 timer ved værelsestemperatur, inndampes og residuet opptas i eddikester. Oppløsningen vaskes med vann, normal klorhydrogensyre og med mettet vandig natriumkloridoppløsning, tørkes og inndampes. Man får 2-(1, 4-benzodioksan-2-yl)-acety_l/-4-etoksy-4-fenylpiperidin. The starting material is prepared as follows: A solution of 3.3 g of 1,4-benzodioxan-2-yl-acetic acid in 30 ml of tetrahydrofuran is mixed with stirring first with 3.1 g of 1,1'-carbonyldiimidazole and after 30 minutes with 3, 5 g of 4-ethoxy-4-phenyl-piperidine in 30 ml of tetrahydrofuran. The mixture is stirred for 18 hours at room temperature, evaporated and the residue taken up in vinegar. The solution is washed with water, normal hydrochloric acid and with saturated aqueous sodium chloride solution, dried and evaporated. 2-(1,4-benzodioxan-2-yl)-acetyl-1H-4-ethoxy-4-phenylpiperidine is obtained.
Eksempel 20.Example 20.
En blanding av 5 g 2-_/—2-(^l-hydroksy-^-fenyl-piperidino)-etyl7-benzof uran, 100 ml eddiksyre og 1 g 10$-ig platina-på-kull-katalysator hydreres ved værelsestemperatur og 3 atmosfærer til opptak av den teoretiske hydrogenmengde. Reaksjonsblandingen filtreres, filtratet inndampes,- residuet opptas i vann, blandingen gjøres basisk med '2 N vandig natrium-hydroksydoppløsning og ekstraheres méd metylenklorid. Ekstraktet tørkes, inndampes og residuet opptas i etanol. Opp-løsningen nøytraliseres med etanolisk klorhydrogen og den dannede utfelling omkrystalliseres fra etanol-dietyleter. Man får 2- l_ 2-(4-hydroksy-4-fenylpiperidino)-etyl/-2,3-dihydrobenzofuran-hydroklorid, som smelter ved l85-l87°C. Produktet er identisk med produktet fra eksempel 5. A mixture of 5 g of 2-_/-2-(^1-hydroxy-^-phenyl-piperidino)-ethyl-7-benzofuran, 100 ml of acetic acid and 1 g of 10$-ig platinum-on-charcoal catalyst is hydrated at room temperature and 3 atmospheres to absorb the theoretical amount of hydrogen. The reaction mixture is filtered, the filtrate is evaporated, the residue is taken up in water, the mixture is made basic with 2 N aqueous sodium hydroxide solution and extracted with methylene chloride. The extract is dried, evaporated and the residue taken up in ethanol. The solution is neutralized with ethanolic hydrogen chloride and the precipitate formed is recrystallized from ethanol-diethyl ether. 2-1_ 2-(4-hydroxy-4-phenylpiperidino)-ethyl/-2,3-dihydrobenzofuran hydrochloride is obtained, which melts at 185-187°C. The product is identical to the product from example 5.
Utgangsstoffet fremstilles som følger: "En blanding av 16 g 2-acety1-benzofuran, 4,8 g svovel og 13,2 ml morfolin kokes 8 timer under tilbakeløp. Deretter blandes reaksjonsblandingen med l60 ml 10%-ig etanolisk natriumhydroksyd og viderekokes 6 timer under tilbakeløp. Blandingen konsentreres til et lite volum, surgjøres med klorhydrogensyre, : ekstraheres med dietyleter og ekstraktet inndampes. Residuet destilleres og fraksjonen som koker ved l45°C70,l mm Hg oppfanges. Man får benzofuran-2-yl-eddiksyre. The starting material is prepared as follows: "A mixture of 16 g of 2-acetyl-benzofuran, 4.8 g of sulfur and 13.2 ml of morpholine is refluxed for 8 hours. The reaction mixture is then mixed with 160 ml of 10% ethanolic sodium hydroxide and further boiled for 6 hours under reflux. The mixture is concentrated to a small volume, acidified with hydrochloric acid, : extracted with diethyl ether and the extract evaporated. The residue is distilled and the fraction boiling at 145°C70.1 mm Hg is collected. Benzofuran-2-yl-acetic acid is obtained.
En oppløsning av 10,5 g av sistnevnte forbindelse i 50 ml tetrahydrofuran haes til den omrørte og under tilbake-løp kokende blanding av 3,4 g litiumaluminiumhydrid i 50 ml tetrahydrofuran. Blandingen kokes 12 timer under tilbakeløp, avkjøles i is og spaltes med 3,4 ml av en 15%-ig vandig natrium-hydroksydoppløsning og 10,2 ml vann.'De uorganiske .salter frafiltreres, vaskes med dietyleter, filtratet tørkes og inndampes. Man får 2-(2-hydroksyetyl)-benzofuran. A solution of 10.5 g of the latter compound in 50 ml of tetrahydrofuran is added to the stirred and refluxing mixture of 3.4 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. The mixture is refluxed for 12 hours, cooled in ice and split with 3.4 ml of a 15% aqueous sodium hydroxide solution and 10.2 ml of water. The inorganic salts are filtered off, washed with diethyl ether, the filtrate is dried and evaporated. 2-(2-Hydroxyethyl)-benzofuran is obtained.
En oppløsning av 3,25 g av sistnevnte forbindelse i 10 ml pyridin blandes under omrøring ved 5°C med 5,7 g p~toluensulfonsyreklorid. Etter 2 timer helles blandingen på is, det faste 'material adskilles og omkrystalliseres fra eddikesterr petroleter. Man får 2-(2-tosyloksyetyl)-benzofuran. A solution of 3.25 g of the latter compound in 10 ml of pyridine is mixed with stirring at 5°C with 5.7 g of p-toluenesulfonic acid chloride. After 2 hours, the mixture is poured onto ice, the solid material is separated and recrystallized from ethyl acetate. 2-(2-tosyloxyethyl)-benzofuran is obtained.
En blanding av 4,55 g av sistnevnte forbindelse, 2,64 g 4-hydroksy-4-fenylpiperidin og 10 g natriumkarbonat i 100 ml 4-mety1-2-pentanon omrøres og kokes 2 dager under til-bakeløp. Reaksjonsblandingen filtreres deretter, filtratet inndampes, residuet oppløses i varm isopropanol, behandles med aktivkull og filtreres. Etter avkjøling utkrystalliserer 2-/_ 2-(4-hydroksy-4-fenylpiperidino)-etyl/-benzofuran. A mixture of 4.55 g of the latter compound, 2.64 g of 4-hydroxy-4-phenylpiperidine and 10 g of sodium carbonate in 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 2 days. The reaction mixture is then filtered, the filtrate is evaporated, the residue is dissolved in hot isopropanol, treated with activated carbon and filtered. After cooling, 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-benzofuran crystallizes out.
Smeltepunkt 195-197°CMelting point 195-197°C
Patentkrav:Patent claims:
1.. Fremgangsmåte til fremstilling av nye 2-piperi-dinoalkyl-(1-benzofuraner eller 1,4-benzodioksaner) med den generelle formel I 1.. Process for the production of new 2-piperidinoalkyl-(1-benzofurans or 1,4-benzodioxanes) of the general formula I
hvori Ph betyr en 1,2-fenylenrest, som eventuelt er substituert med 1 til 3, like eller forskjellige substituenter, valgt blant laverealkyl, hydroksy, merkapto, laverealkoksy, laverealkylendioksy, benzyloksy, laverealkyltio, halogen, trifluormetyl, nitro eller amino, X betyr oksygen eller svovel, m betyr de hele tall 0 eller 1 og n betyr de hele tall fra 1 til 4, hvert av symbolene p og q betyr et helt tall fra 1 i til 3, idet (p+q) er tallet 4, hvert av symbolene R-^ og R2betyr hydrogen, laverealkyl eller HPh, R-^ betyr hydrogen, wherein Ph means a 1,2-phenylene residue, which is optionally substituted with 1 to 3, the same or different substituents, selected from lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, benzyloxy, lower alkylthio, halogen, trifluoromethyl, nitro or amino, X means oxygen or sulphur, m means the whole numbers 0 or 1 and n means the whole numbers from 1 to 4, each of the symbols p and q means a whole number from 1 i to 3, (p+q) being the number 4, each of the symbols R-^ and R2 means hydrogen, lower alkyl or HPh, R-^ means hydrogen,
hydroksy, laverealkoksy, lavere eller høyere alkanoyloksy,hydroxy, lower alkoxy, lower or higher alkanoyloxy,
Rj| betyr laverealkyl, HPh-laverealkyl, HPh eller naftyl,Rj| means lower alkyl, HPh-lower alkyl, HPh or naphthyl,
som eventuelt er substituert som Ph, furyl, tienyl, pyridyl, benzofuryl, benzotienyl, kinolyl eller isokinolyl, hvilke heterocykliske rester eventuelt er substituert som Ph, samt S-oksyder og syreaddisjonssalter av disse forbindelser,karakterisert vedat which is optionally substituted as Ph, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, quinolyl or isoquinolyl, which heterocyclic residues are optionally substituted as Ph, as well as S-oxides and acid addition salts of these compounds, characterized in that
a) forbindelser med den generelle formel III og IVa) compounds of the general formula III and IV
hvori ett av symbolene Y og Z2betyr amino resp. imino og det andre betyr en reaksjonsdyktig forestret hydroksygruppe eller in which one of the symbols Y and Z2 means amino or imino and the other means a reactive esterified hydroxy group or
b) en forbindelse med den generelle formel Vb) a compound of the general formula V
reduseres, is reduced,
hvori A betyr en gru-pe med formel CnH2n_2-CO*in which A means a group with formula CnH2n_2-CO*
cn<H>2n-s eller Y'~CnH2n-]'idet Y' betyr en reaksjonsdyktig forestret hydroksygruppe, Rcbetyr hydrogen eller R-^og R^sammen danner en ytterligere C,C-binding, R^ betyr R^eller HPh-laverealkanoyl, hvert av symbolene r og s betyr de hele i tall 0 eller 2, idet (r+s) er tallet 2 eller 4, eller cn<H>2n-s or Y'~CnH2n-]'where Y' means a reactive esterified hydroxy group, Rc means hydrogen or R-^and R^together form a further C,C bond, R^ means R^or HPh -low-alkanoyl, each of the symbols r and s means the whole in the number 0 or 2, (r+s) being the number 2 or 4, or
c) forbindelse med VIc) connection with VI
kondenseres med R^-metallforbindelser, eller d) en forbindelse med formel VII hvori Y betyr en reaksjonsdyktig forestret hydroksygruppe, ringsluttes, og hvis ønskelig, omdannes en dannet forbindelse i en annen forbindelse ifølge oppfinnelsen og/eller, hvis ønskelig, .oksyderes en dannet forbindelse til S-oksydet og/eller hvis ønskelig, overføres en dannet fri forbindelse i et syreaddi-sj onssalt eller et dannet syreaddisjonssalt i den fri forbindelse eller, i et annet syreaddisjonssalt, og/eller hvis ønskelig, oppdeles en dannet blanding av isomere eller racemater i de enkelte isomere eller racemater og/eller hvis ønskelig, oppspaltes dannede racemater i de optiske antipoder. 2. Fremgangsmåte ifølge krav la),karakterisert vedat det anvendes utgangsstoffer, hvori Y eller Z betyr en med en sterk uorganisk eller organisk syre forestret hydroksygruppe. | 3. Fremgangsmåte ifølge et av kravene la) og 2,karakterisert vedat reaksjonen gjennomføres i i nærvær av basiske kondensasjonsmidler. 4. Fremgangsmåte ifølge krav lb),,karakterisert vedat reaksjonen gjennomføres med enkle hydrider eller komplekse' lettmetallhydrider, katalytisk akti-vert, naskerende eller elktrolyttisk frembragt hydrogen. 5- Fremgangsmåte ifølge krav lc),karakterisert vedat reaksjonen gjennomføres'med en Rjj-litium- eller en R^-halogenmagnesium-f orbindelse. 6. Fremgangsmåte ifølge krav ld),karakterisert vedat det anvendes utgangsstoffer, is condensed with R^ metal compounds, or d) a compound of formula VII in which Y means a reactive esterified hydroxy group, is ring-closed, and if desired, a compound formed is converted into another compound according to the invention and/or, if desired, a formed compound is oxidized compound to the S-oxide and/or if desired, a formed free compound is transferred in an acid addition salt or a formed acid addition salt in the free compound or, in another acid addition salt, and/or if desired, a formed mixture of isomers is separated or racemates into the individual isomers or racemates and/or if desired, the racemates formed are resolved into the optical antipodes. 2. Process according to claim la), characterized in that starting substances are used, in which Y or Z means a hydroxy group esterified with a strong inorganic or organic acid. | 3. Method according to one of claims la) and 2, characterized in that the reaction is carried out in the presence of basic condensation agents. 4. Method according to claim lb), characterized in that the reaction is carried out with simple hydrides or complex light metal hydrides, catalytically activated, nascent or electrolytically produced hydrogen. 5- Method according to claim 1c), characterized in that the reaction is carried out with an Rjj-lithium or an Rj-halogenmagnesium compound. 6. Method according to claim ld), characterized in that starting substances are used,
hvori Y betyr en med en sterk uorganisk eller organisk syre forestret hydroksygruppe. wherein Y means a hydroxy group esterified with a strong inorganic or organic acid.
7- Fremgangsmåte ifølge et av kravene ld) og 6,karakterisert vedat reaksjonen gjennomføres 7- Method according to one of claims ld) and 6, characterized in that the reaction is carried out
i nærvær av basiske kondensasjonsmidler.in the presence of basic condensing agents.
8. Fremgangsmåte ifølge et av kravene 1 til 7,karakterisert vedat en dannet forbindelse med 8. Method according to one of claims 1 to 7, characterized in that a formed compound with
formel I, hvori R^betyr hydroksy eller deres alkalimetall-salter omsettes med reaksjonsdyktige estere av lavere alka-noler eller med reaksjonsdyktige alkansyrederivater og derved, fremstiller en tilsvarende foretret eller forestret forbindelse. 9. Fremgangsmåte ifølge et av kravene 1 til 8,karakterisert vedat én dannet ester hydrolyseres. 10. Fremgangsmåte ifølge et, av 'kravene 1 til 9,karakterisert vedat en dannet forbindelse som har en fenolisk hydroksygruppe foretres med diazolavere-alkaner. 11. • Fremgangsmåte ifølge' et av kravene 1 til 9,karakterisert vedaten dannet forbindelse, som har en b.enzyloksy-1,2-fenylengruppe, hydrogenolyseres. 12. Fremgangsmåte ifølge et av kravene 1 til 10,karakterisert vedat"en dannet forbindelse som har en halogen-1,2-fenylengruppe, dehalogeneres. 13- Fremgangsmåte ifølge et av kravene 1 til 10,karakterisert vedat i en dannet forbindelse, som har en nitro-1,2-fenylengruppe, reduseres nitrogruppen til aminogruppen. 14. Fremgangsmåte ifølge et av kravene 1 til 10,karakterisert vedat det i en dannet forbindelse nitreres 1,2-fenylengruppen Ph. 15. Fremgangsmåte ifølge et av kravene 1 til 10,karakterisertvéd at man i en dannet forbindelse, som i en 1,2-fenylenresten Ph har et jodatom, erstattes denne med en trifluormetylgruppe. 16. Fremgangsmåte ifølge et av kravene 1 til 15,karakterisert vedat en dannet forbindelse med formel I oksyderes med milde oksydasjonsmidler til sulfoksyd. formula I, in which R^ denotes hydroxy or their alkali metal salts are reacted with reactive esters of lower alkanols or with reactive alkanoic acid derivatives and thereby produce a corresponding etherified or esterified compound. 9. Method according to one of claims 1 to 8, characterized in that one formed ester is hydrolysed. 10. Method according to one of claims 1 to 9, characterized in that a compound formed which has a phenolic hydroxy group is etherified with diazole lower alkanes. 11. • Process according to one of claims 1 to 9, characterized in that the compound formed, which has a b.enzyloxy-1,2-phenylene group, is hydrogenolysed. 12. Method according to one of claims 1 to 10, characterized in that "the compound formed which has a halogen-1,2-phenylene group is dehalogenated. 13- Method according to one of claims 1 to 10, characterized in that in a compound formed, which has a nitro-1,2-phenylene group, the nitro group is reduced to the amino group. 14. Method according to one of claims 1 to 10, characterized in that in a formed compound the 1,2-phenylene group is nitrated Ph. 15. Method according to one of claims 1 to 10 ,characterized by the fact that in a formed compound, which in a 1,2-phenylene residue Ph has an iodine atom, this is replaced by a trifluoromethyl group. 16. Method according to one of claims 1 to 15, characterized by the fact that a formed compound of formula I is oxidized with mild oxidizing agents to sulfoxide.
17* Fremgangsmåte ifølge et av kravene 1 til 16,karakterisert vedat det anvendes et på ønskelig fremgangsmåtetrinn dannet mellomprodukt som utgangsmateriale og de gjenblivende fremgangsmåtetrinn gjennomføres eller fremgangsmåten avbrytes på ett eller annet trinn, eller et utgangs-stof f dannes under reaksjonsbetingelsene eller anvendes i form av et S-oksyd, et salt eller en optisk ren antipode. 17* Process according to one of the claims 1 to 16, characterized in that an intermediate product formed in a desired process step is used as starting material and the remaining process steps are carried out or the process is interrupted at one or the other step, or a starting substance f is formed under the reaction conditions or used in the form of an S-oxide, a salt or an optically pure antipode.
l8. Fremgangsmåte ifølge et av kravene 1 til 15 og 17, l8. Method according to one of claims 1 to 15 and 17,
karakterisert vedat det fremstilles forbindelser med den i krav 1 viste formel I, hvori Ph betyr en 1,2-fenylenrest, som eventuelt er substituert med en eller to substituenter, valgt blant laverealkyl, hydroksy, merkapto, characterized in that compounds are prepared with the formula I shown in claim 1, in which Ph means a 1,2-phenylene residue, which is optionally substituted with one or two substituents, selected from lower alkyl, hydroxy, mercapto,
laverealkoksy, laverealkylendioksy, benzyloksy, laverealkyltio, halogen, trifluormetyl, nitro eller amino, X betyr oksygen eller svovel, m betyr de hele tall 0 eller 1,-n betyr de hele tall fra 1 til 4, hvert av symbolene p og q betyr et helt tall fra 1 til 3, idet (p+q) er tallet 4, hvert av symbolene R-^og R2betyr hydrogen eller laverealkyl, R-^betyr hydrogen, hydroksy, laverealkoksy, lavere eller høyere alkanoyloksy, R^betyr laverealkyl, HPn~CnH2n, HPh eller eventuelt med en eller to laverealkylrester substituert furyl, tienyl eller pyridyl, lower alkoxy, lower alkylenedioxy, benzyloxy, lower alkylthio, halogen, trifluoromethyl, nitro or amino, X means oxygen or sulphur, m means the whole numbers 0 or 1, -n means the whole numbers from 1 to 4, each of the symbols p and q means a whole number from 1 to 3, where (p+q) is the number 4, each of the symbols R-^ and R2 means hydrogen or lower alkyl, R-^ means hydrogen, hydroxy, lower alkoxy, lower or higher alkanoyloxy, R^ means lower alkyl, HPn ~CnH2n, HPh or optionally with one or two lower alkyl residues substituted furyl, thienyl or pyridyl,
samt deres syreaddisjonssalter.as well as their acid addition salts.
19« . Fremgangsmåte ifølge et av kravene 1 til 10, 12, 15 og 17,karakterisert vedat det fremstilles 19«. Method according to one of claims 1 to 10, 12, 15 and 17, characterized in that it is produced
forbindelser med den i krav 1 angitte generelle formel I,compounds with the general formula I specified in claim 1,
hvori Ph betyr en 1,2-fenylenrest, som eventuelt er substituert med.en eller to substituenter, valgt blant alkyl,' alkoksy, eller alkyltio med hver maksimalt 4 karbonatomer, halogen eller trif luormetyl, X betyr oksygen, m betyr de hele.^.tall 0 eller 1, n betyr de hele tall fra 2 til 4, hvert av symbolene in which Ph means a 1,2-phenylene residue, which is optionally substituted with one or two substituents, selected from among alkyl, ' alkoxy, or alkylthio with a maximum of 4 carbon atoms each, halogen or trifluoromethyl, X means oxygen, m means all of them. ^.number 0 or 1, n means the whole numbers from 2 to 4, each of the symbols
i p og q betyr tallet 2, hvert av symbolene R-^ og R2betyr hydrogen eller alkyl med maksimalt 4 karbonatomer,' R^ betyr ! in p and q the number means 2, each of the symbols R-^ and R2 means hydrogen or alkyl with a maximum of 4 carbon atoms,' R^ means !
■hydrogen, alkoksy med maksimalt 4 eller alkanoyloksy med maksimalt 16 karbonatomer, R^betyr sekundært eller tertiært alkyl med 3 til 7 karbonatomer, HPh-CH"2, HPh,. 2- eller 3-furyl eller -tienyl, 2-, 3_ eller 4-pyridyl samt deres syreaddisjonssalter. 20. Fremgangsmåte ifølge et av kravene 1 til 10, 12, 15 og 17,karakterisert vedat det fremstilles forbindelser med den generelle formel II ■hydrogen, alkoxy with a maximum of 4 or alkanoyloxy with a maximum of 16 carbon atoms, R^means secondary or tertiary alkyl with 3 to 7 carbon atoms, HPh-CH"2, HPh,. 2- or 3-furyl or -thienyl, 2-, 3_ or 4-pyridyl and their acid addition salts 20. Process according to one of claims 1 to 10, 12, 15 and 17, characterized in that compounds of the general formula II are prepared
hvori R betyr hydrogen, alkyl, alkoksy eller alkyltio med hver maksimalt 4 karbonatomer, halogen.eller trifluormetyl, x betyr tallene' 1 eller 2, y betyr de hele tall fra 2 til 4, R" betyr hydrogen,•hydroksy, alkoksy med maksimalt 4 eller in which R means hydrogen, alkyl, alkoxy or alkylthio with a maximum of 4 carbon atoms each, halogen or trifluoromethyl, x means the numbers' 1 or 2, y means the whole numbers from 2 to 4, R" means hydrogen,•hydroxy, alkoxy with a maximum 4 or
alkanoyloksy med maksimalt 16 karbonatomer. R' betyr sekundært eller tertiært alkyl med 3 til 7 karbonatomer, Rx~benzyl, R -A.-fenyl, 2- eller 3-furyl eller -tienyl, 2-, 3- eller 4-pyridyl samt deres syreaddisjonssalter. 21. Fremgangsmåte ifølge et av kravene 1 til 10, 12, 15 og 17,karakterisert ved- at det fremstilles forbindelser med den i krav 20 viste generelle formel II, hvori R betyr hydrogen, metyl, etyl, metoksy, etoksy, metyltio, etyltio, fluor, klor eller trifluormetyl, x betyr tallene 1 eller 2, y betyr tallene 2 eller 3, R" betyr hydrogen, hydroksy, metoksy, etoksy eller alkanoyloksy med 2 til 12 karbonatomer, R' betyr i-propyl, i- eller, tert.-butyl, benzyl, Rx~fenyl, 2- eller 3-furyl eller -tienyl, 2-, 3~eller 4-pyridyl samt deres syreaddisjonssalter. 22.. Fremgangsmåte ifølge et av kravene 1 til 10, 12, 15 og 17,karakterisert vedat det fremstilles forbindelser med den i krav 20 angitte generelle formel II, hvori R betyr hydrogen, metyl, metoksy, fluor, klor eller trifluormetyl, hver i 7- eller 8-stilling, x betyr tallene 1 eller 2, y betyr tallene 2 eller 3, R" betyr hydroksy, metoksy eller alkanoyloksy med 3. til 10 karbonatomer, R' betyr m-eller p-Rx~fenyl samt deres syreaddisjonssalter. 23- , Fremgangsmåte ifølge et av kravene 1 til 7, 9, 12 og 17,karakterisert vedat det fremstilles . 2-</_>2-(4-h<y>droks<y->4-fenylpi<p>eridino)-ety<l>7-l,4-benzodioksan og dets syreaddisjonssalter. alkanoyloxy with a maximum of 16 carbon atoms. R' means secondary or tertiary alkyl with 3 to 7 carbon atoms, Rx~benzyl, R -A.-phenyl, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl and their acid addition salts. 21. Method according to one of claims 1 to 10, 12, 15 and 17, characterized in that compounds are prepared with the general formula II shown in claim 20, in which R means hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio , fluorine, chlorine or trifluoromethyl, x means the numbers 1 or 2, y means the numbers 2 or 3, R" means hydrogen, hydroxy, methoxy, ethoxy or alkanoyloxy with 2 to 12 carbon atoms, R' means i-propyl, i- or, tert-butyl, benzyl, Rx-phenyl, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl and their acid addition salts. 22.. Method according to one of claims 1 to 10, 12, 15 and 17, characterized in that compounds are prepared with the general formula II specified in claim 20, in which R means hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, each in the 7- or 8-position, x means the numbers 1 or 2, y means the numbers 2 or 3, R" means hydroxy, methoxy or alkanoyloxy with 3 to 10 carbon atoms, R' means m-or p-Rx~phenyl and their acid addition salts r. 23-, Method according to one of claims 1 to 7, 9, 12 and 17, characterized in that it is produced. 2-</_>2-(4-H<y>drox<y->4-phenylpyr<p>eridino)-ethyl<l>7-1,4-benzodioxane and its acid addition salts.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/589,118 US4039676A (en) | 1975-06-23 | 1975-06-23 | 2-piperidinoalkyl-1,4-benzodioxans |
Publications (1)
Publication Number | Publication Date |
---|---|
NO762158L true NO762158L (en) | 1976-12-27 |
Family
ID=24356671
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO762158A NO762158L (en) | 1975-06-23 | 1976-06-22 |
Country Status (13)
Country | Link |
---|---|
CS (1) | CS198190B2 (en) |
DD (1) | DD126408A5 (en) |
DK (1) | DK278976A (en) |
ES (4) | ES449069A1 (en) |
FI (1) | FI761818A (en) |
GR (1) | GR60557B (en) |
HU (1) | HU174277B (en) |
IE (1) | IE43244B1 (en) |
IL (1) | IL49863A0 (en) |
NO (1) | NO762158L (en) |
NZ (1) | NZ181241A (en) |
PT (1) | PT65229B (en) |
ZA (2) | ZA762264B (en) |
-
1976
- 1976-04-14 ZA ZA762264A patent/ZA762264B/en unknown
- 1976-06-16 PT PT6522976A patent/PT65229B/en unknown
- 1976-06-21 ES ES449069A patent/ES449069A1/en not_active Expired
- 1976-06-21 GR GR51055A patent/GR60557B/en unknown
- 1976-06-22 FI FI761818A patent/FI761818A/fi not_active Application Discontinuation
- 1976-06-22 CS CS411376A patent/CS198190B2/en unknown
- 1976-06-22 IE IE134376A patent/IE43244B1/en unknown
- 1976-06-22 DK DK278976A patent/DK278976A/en unknown
- 1976-06-22 ZA ZA00763705A patent/ZA763705B/en unknown
- 1976-06-22 NZ NZ18124176A patent/NZ181241A/en unknown
- 1976-06-22 DD DD19350376A patent/DD126408A5/xx unknown
- 1976-06-22 IL IL49863A patent/IL49863A0/en unknown
- 1976-06-22 NO NO762158A patent/NO762158L/no unknown
- 1976-06-22 HU HU76CI1670A patent/HU174277B/en unknown
-
1977
- 1977-07-13 ES ES460694A patent/ES460694A1/en not_active Expired
- 1977-07-13 ES ES460696A patent/ES460696A1/en not_active Expired
- 1977-07-13 ES ES460695A patent/ES460695A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
PT65229A (en) | 1976-07-01 |
PT65229B (en) | 1977-11-23 |
CS198190B2 (en) | 1980-05-30 |
FI761818A (en) | 1976-12-24 |
ZA762264B (en) | 1977-04-27 |
IE43244L (en) | 1976-12-23 |
ES460695A1 (en) | 1978-05-01 |
IL49863A0 (en) | 1976-08-31 |
DD126408A5 (en) | 1977-07-13 |
ES460694A1 (en) | 1978-05-16 |
ZA763705B (en) | 1978-02-22 |
ES449069A1 (en) | 1977-11-16 |
GR60557B (en) | 1978-06-22 |
NZ181241A (en) | 1978-04-03 |
HU174277B (en) | 1979-12-28 |
DK278976A (en) | 1976-12-24 |
IE43244B1 (en) | 1981-01-14 |
ES460696A1 (en) | 1978-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4104396A (en) | 2-Piperidinoalkyl-1,4-benzodioxans | |
NL192451C (en) | Process for the preparation of phthalan derivatives and process for the preparation of pharmaceutical preparations containing a phthalan derivative. | |
JPS5833876B2 (en) | Chikansareta 1 3- Dihydrospiro (isobenzofuran) Kagobutsunoseiho | |
NO853609L (en) | Carbonyl compounds. | |
NO803453L (en) | PROCEDURE FOR THE PREPARATION OF PIPERIDYLBENZIMIDAZOLONE DERIVATIVES | |
EP0004358B1 (en) | N-oxacyclylalkyl piperidines, process for their preparation, pharmaceutical compositions containing these compounds | |
CA1045139A (en) | Process for the preparation of tetrahydropyridine and piperidine derivatives | |
US4171359A (en) | Benz-tetrasubstituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines | |
US3262938A (en) | Carbocyclic substituted piperidyl dioxolanes | |
NO134055B (en) | ||
US4129655A (en) | Neuroleptic 2-piperidinoalkyl-1,4-benzodioxans | |
Openshaw et al. | 276. The synthesis of emetine and related compounds. Part IV. A new synthesis of 3-substituted 1, 2, 3, 4, 6, 7-hexahydro-9, 10-dimethoxy-2-oxo-11bH-benzo [a] quinolizines | |
NO762158L (en) | ||
CA1102807A (en) | Piperidylidene derivatives of benzo-fused xanthenes, thioxanthenes and dibenzoxepins | |
CA1087190A (en) | Substituted 4-phenyl-piperidines | |
US4600719A (en) | Tetrahydropyridine and piperidine derivatives | |
NO864455L (en) | HEXSAHYDRO- (1) -BENZO- (PYRANO AND TIOPYRANO) (4,3-C) -PYRIDINES. | |
NO121212B (en) | ||
US4684731A (en) | Phenyl-quinolizidines | |
DE2318273C3 (en) | Basically substituted 13-benzodioxole derivatives and their pharmacologically acceptable salts, as well as medicaments containing these compounds | |
DK142987B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF 4- (7-BROMO-5-METHOXY-2-BENZOPHYRANYL) -PIPERIDINE OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. | |
US4443453A (en) | Quinoline derivatives, pharmaceutical compositions containing such compounds, and methods for treating cardiovascular conditions with them | |
DK152843B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF N-SUBSTITUTED 4- (3-TRIFLUORMETHYLPHENYL) -1,2,3,6-TETRAHYDROPYRIDINES AND PHARMACEUTICAL ACCEPTABLE SALTS THEREOF | |
US4113729A (en) | 3-Phenoxymorphinans and derivatives thereof | |
EP0035820B1 (en) | Novel quinoline derivatives, pharmaceutical compositions containing such compounds, and method for the preparation of these compounds |