NO118676B - - Google Patents
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- Publication number
- NO118676B NO118676B NO16711967A NO16711967A NO118676B NO 118676 B NO118676 B NO 118676B NO 16711967 A NO16711967 A NO 16711967A NO 16711967 A NO16711967 A NO 16711967A NO 118676 B NO118676 B NO 118676B
- Authority
- NO
- Norway
- Prior art keywords
- solution
- ether
- tropyl
- acid
- chloroform
- Prior art date
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- 239000002253 acid Substances 0.000 claims description 11
- -1 tropinone oxime Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 claims description 4
- QQXLDOJGLXJCSE-KNVOCYPGSA-N Tropinone Natural products C1C(=O)C[C@H]2CC[C@@H]1N2C QQXLDOJGLXJCSE-KNVOCYPGSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 150000003813 tropane derivatives Chemical class 0.000 claims description 4
- 230000004217 heart function Effects 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 1
- 239000000243 solution Substances 0.000 description 109
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 76
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 65
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- 238000001953 recrystallisation Methods 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- 238000001816 cooling Methods 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 14
- 150000001540 azides Chemical class 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 239000000155 melt Substances 0.000 description 10
- HJGMRAKQWLKWMH-IEESLHIDSA-N (1r,5s)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine Chemical class C1C(N)C[C@@]2([H])CC[C@]1([H])N2C HJGMRAKQWLKWMH-IEESLHIDSA-N 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 7
- 235000010288 sodium nitrite Nutrition 0.000 description 7
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 6
- 239000004202 carbamide Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 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 5
- 125000001743 benzylic group Chemical group 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- JCSVKHMIPDZUEM-UHFFFAOYSA-N 2,2-diphenylpropanedioyl dichloride Chemical compound C=1C=CC=CC=1C(C(Cl)=O)(C(=O)Cl)C1=CC=CC=C1 JCSVKHMIPDZUEM-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 4
- 239000012259 ether extract Substances 0.000 description 4
- ITUXLWJCQXAREP-FDNDLASISA-N (1S,5R)-6-methoxy-8-methyl-8-azabicyclo[3.2.1]octan-3-amine Chemical compound COC1[C@H]2CC(C[C@@H](C1)N2C)N ITUXLWJCQXAREP-FDNDLASISA-N 0.000 description 3
- XSXYESVZDBAKKT-UHFFFAOYSA-N 2-hydroxybenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1O XSXYESVZDBAKKT-UHFFFAOYSA-N 0.000 description 3
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229960000581 salicylamide Drugs 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 2
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 2
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- FHPZUVVXVRYZAS-SFYZADRCSA-N (1r,5s)-8-methyl-8-azabicyclo[3.2.1]octan-5-amine Chemical compound C1CC[C@@]2(N)CC[C@]1([H])N2C FHPZUVVXVRYZAS-SFYZADRCSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- DVIHKVWYFXLBEM-UHFFFAOYSA-N 2-hydroxybenzoyl chloride Chemical compound OC1=CC=CC=C1C(Cl)=O DVIHKVWYFXLBEM-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012675 alcoholic extract Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000003440 anti-fibrillation Effects 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- UKXSKSHDVLQNKG-UHFFFAOYSA-N benzilic acid Chemical compound C=1C=CC=CC=1C(O)(C(=O)O)C1=CC=CC=C1 UKXSKSHDVLQNKG-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000002090 nicotinolytic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 208000008510 paroxysmal tachycardia Diseases 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- 150000007519 polyprotic acids Polymers 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- FMBOFMNHMFFBBD-UHFFFAOYSA-N pyridine-3-carbohydrazide;dihydrochloride Chemical compound Cl.Cl.NNC(=O)C1=CC=CN=C1 FMBOFMNHMFFBBD-UHFFFAOYSA-N 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Classifications
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04D—NON-POSITIVE-DISPLACEMENT PUMPS
- F04D29/00—Details, component parts, or accessories
- F04D29/26—Rotors specially for elastic fluids
- F04D29/28—Rotors specially for elastic fluids for centrifugal or helico-centrifugal pumps for radial-flow or helico-centrifugal pumps
- F04D29/281—Rotors specially for elastic fluids for centrifugal or helico-centrifugal pumps for radial-flow or helico-centrifugal pumps for fans or blowers
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F24—HEATING; RANGES; VENTILATING
- F24F—AIR-CONDITIONING; AIR-HUMIDIFICATION; VENTILATION; USE OF AIR CURRENTS FOR SCREENING
- F24F7/00—Ventilation
- F24F7/02—Roof ventilation
- F24F7/025—Roof ventilation with forced air circulation by means of a built-in ventilator
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Combustion & Propulsion (AREA)
- Structures Of Non-Positive Displacement Pumps (AREA)
- Ventilation (AREA)
- Air-Flow Control Members (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Fremgangsmåte for fremstilling av syreamidlignende tropanderivater. Process for the production of acid amide-like tropane derivatives.
Det har vist seg at det er mulig å It has been shown that it is possible to
komme frem til syreamidlignende deriva- arrive at acid amide-like deriva-
ter av tropanrekken med den alminnelige formel ter of the tropane series with the general formula
når et tropinonoksim med den alminnelige formel when a tropinone oxime with the general formula
hvor Ri har samme betydning som ovenfor, på i og for seg kjent måte reduseres til tilsvarende 3-amino-tropanderivat, og det primære amin som oppnås på denne måten omsettes med et derivat av en organisk en- eller fler-basisk syre med den alminnelige formel R2( Y) U, hvor R2 og n har samme betydning som ovenfor, og Y står for klor eller for N3, resten av kvelstoffvannstoffsyren. where Ri has the same meaning as above, is reduced in a manner known per se to the corresponding 3-aminotropane derivative, and the primary amine obtained in this way is reacted with a derivative of an organic mono- or polybasic acid with the usual formula R2(Y) U, where R2 and n have the same meaning as above, and Y stands for chlorine or for N3, the rest of the nitrogen hydrogen acid.
Fremgangsmåten kan utføres slik at et tropinonoksim reduseres katalytisk eller med natrium i en alifatisk alkohol til det tilsvarende 3-amino-tropanderivat, og dette omsettes med et syreklorid eller et syre-amid i et indifferent oppløsningsmiddel i kulde, ved romtemperaturer eller ved for-høyet temperatur, med eller uten tilsetting av et middel som binder halogenvann-stoff, f. eks. en tertiær organisk base. Re-aksjonsproduktet blir på kjent måte isolert fra reaksjonsblandingen, f. eks. ved å filtreres av eller ved inndamping av reak-sjonsoppløsningen og ekstrahering av resten med et passende oppløsningsmiddel. Rensingen foregår ved omkrystallisering, eventuelt etter fraksjonering i vakuum. Det kan dog også være nødvendig å overføre råproduktet til et salt av en passende syre og omkrystallisere dette. The method can be carried out so that a tropinone oxime is reduced catalytically or with sodium in an aliphatic alcohol to the corresponding 3-aminotropane derivative, and this is reacted with an acid chloride or an acid amide in an indifferent solvent in the cold, at room temperatures or at elevated temperature, with or without the addition of an agent that binds halogen water-substance, e.g. a tertiary organic base. The reaction product is isolated from the reaction mixture in a known manner, e.g. by filtering off or by evaporating the reaction solution and extracting the residue with a suitable solvent. The purification takes place by recrystallization, possibly after fractionation in a vacuum. However, it may also be necessary to transfer the crude product to a salt of a suitable acid and recrystallize this.
De syreamidlignende tropanderivater som oppnås i henhold til foreliggende opp-finnelse er ved romtemperatur faste, kry-stalliserte baser som sammen med syrer danner bestandige salter. Mange av dem utmerker seg ved terapeutisk verdifulle farmakodynamiske egenskaper, idet de vir-ker nikotinolytisk og utøver en spesielt antifibrillatorisk virkning som regulerer rytmen for hjertefunksjonen. Ved lav tok-sisitet har de en stor terapeutisk bredde. De skal brukes i terapien for å bekjempe forstyrrelser av hjertefunksjonen, f. eks. paroksysmal takykardi med forkammer-flimring, men tjener også profylaktisk til å forhindre at det opptrer slike forstyrrelser. Anvendelsen foregår parenteralt eller per os, fortrinsvis per os, i en enkeltdosis på ca. 5—10 mg. Noen av de forbindelser som er fremstillet i henhold til oppfinnel-sen tjener også som mellomprodukter for fremstilling av legemidler. The acid amide-like tropane derivatives obtained according to the present invention are at room temperature solid, crystallized bases which, together with acids, form stable salts. Many of them are distinguished by therapeutically valuable pharmacodynamic properties, as they have a nicotinolytic effect and exert a particularly antifibrillator effect that regulates the rhythm of heart function. With low toxicity, they have a wide therapeutic range. They are to be used in therapy to combat disturbances of heart function, e.g. paroxysmal tachycardia with atrial fibrillation, but also serves prophylactically to prevent such disturbances from occurring. The application takes place parenterally or per os, preferably per os, in a single dose of approx. 5-10 mg. Some of the compounds produced according to the invention also serve as intermediates for the production of pharmaceuticals.
Eksempel i: Example in:
beusilsyre- tropyl- 3- umicl. beusylic acid- tropyl- 3- umicl.
10 g tropinonoksim oppløst i 100 cm<:1 >alkohol og 8 cm<3> iseddik blir hydrert ved romtemperatur i 18 timer i nærvær av Ra-neynikkel ved 60 atm overtrykk. Katalysatoren filtreres av, oppløsningen dampes inn, resten oppløses i 20 cm'<1> vann og blandes under kjøling med 15 g kaliumhydroksyd. Den alkaliske oppløsning blir ekstrahert fullstendig med eter, og resten av den inndampede eterekstrakt blir destillert ved 12 mm. Den fraksjon som går over ved 10 g of tropinone oxime dissolved in 100 cm<:1 >alcohol and 8 cm<3> glacial acetic acid are hydrated at room temperature for 18 hours in the presence of Raney nickel at 60 atm overpressure. The catalyst is filtered off, the solution is evaporated, the residue is dissolved in 20 cm'<1> of water and mixed with 15 g of potassium hydroxide while cooling. The alkaline solution is extracted completely with ether, and the remainder of the evaporated ether extract is distilled at 12 mm. The fraction that goes over wood
88—97° er 3-aminotropan som inneholder 20—30 pst. 3-amino-ip-tropan. Den blir be-arbeidet uten ytterligere rensing. 88-97° is 3-aminotropane containing 20-30 per cent 3-amino-ip-tropane. It is be-worked without further purification.
6,9 g bensilsyrehydrazid oppløses i for-tynnet saltsyre og en vandig oppløsning av 2,3 g natriumnitrit blir tilsatt dråpevis under sterk kjøling og sterk rysting. Det smussige azid som oppnås blir vasket med isvann og tørket i eterisk oppløsning over natriumsulfat. Den eteriske oppløsning av azidet blir dråpevis under kjøling blandet med 4 g av den blanding av 3-aminotropan og 3-amino-\|j-tropan som er fremstillet slik som angitt ovenfor og blandingen får stå i 18 timer ved 0°. Resten av oppløsnin-gen som er inndampet i vakuum blir opptatt i kloroform og rystet med natriumkar-bonatoppløsning. Kloroformomslaget blir tørket over kaliumkarbonat, inndampet i vakuum og resten oppløst i metanol. Ved oppblanding med eter krystalliserer bensilsyre-tropyl-3-amid ut og oppnås etter flere gangers omkrystallisering i små staver med smp. 201—202°. 6.9 g of benzylic hydrazide are dissolved in dilute hydrochloric acid and an aqueous solution of 2.3 g of sodium nitrite is added dropwise under vigorous cooling and vigorous shaking. The dirty azide obtained is washed with ice water and dried in ethereal solution over sodium sulfate. The ethereal solution of the azide is mixed dropwise under cooling with 4 g of the mixture of 3-aminotropane and 3-amino-1|j-tropane which has been prepared as indicated above and the mixture is allowed to stand for 18 hours at 0°. The rest of the solution which has been evaporated in vacuo is taken up in chloroform and shaken with sodium carbonate solution. The chloroform coating is dried over potassium carbonate, evaporated in vacuo and the residue dissolved in methanol. When mixed with ether, benzylic acid-tropyl-3-amide crystallizes out and is obtained after several times of recrystallization in small sticks with m.p. 201—202°.
Hydrokloridet blir behandlet med metanolisk klorvannstoff. Stavformede prismer med spaltingspunkt 225—230° etter to gangers omkrystallisering fra etanol-eter. The hydrochloride is treated with methanolic hydrogen chloride. Rod-shaped prisms with cleavage point 225-230° after recrystallization twice from ethanol-ether.
Eksempel 2: Example 2:
nikotinsyre- tropyl- 3- amid. nicotinic acid-tropyl-3-amide.
7,5 g nikotinsyre-hydrazid-di-hydroklorid oppløses i 20 cm8 vann, og en opp-løsning av 5 g natriumnitrit i 10 cm<:t> vann blir tilsatt dråpevis ved 0° under kraftig omrøring. Oppløsningen blir gjort alkalisk med kaliumkarbonat og ekstrahert tre ganger med eter og to ganger med eddikester. De .forenede eter- og eddikester-uttrekk som er tørket over kaliumkarbonat blandes dråpevis og under kjøling med 5 g 3-aminotropan (råprodukt som inneholder 20 7.5 g of nicotinic acid hydrazide dihydrochloride are dissolved in 20 cm8 of water, and a solution of 5 g of sodium nitrite in 10 cm<:t> of water is added dropwise at 0° with vigorous stirring. The solution is made alkaline with potassium carbonate and extracted three times with ether and twice with acetic acid. The combined ether and acetate extracts which have been dried over potassium carbonate are mixed dropwise and under cooling with 5 g of 3-aminotropane (crude product containing 20
—30 pst. 3-amino-v|)-tropan, fremstillet som —30 per cent of 3-amino-v|)-tropane, prepared as
i eksempel 1), og blandingen får stå i 20 timer ved romtemperatur. Resten av opp-løsningen som er inndampet i vakuum blir opptatt i kloroform og rystet med natrium-karbonatoppløsning. Kloroformlaget tørkes over kaliumkarbonet, inndampes i vakuum, og resten oppløses i aceton, og eter tilsettes langsomt. Etter å ha stått i lengre tid krystalliserer nikotinsyretropyl-3-amidet ut og oppnås etter omkrystallisering fra aceton i form av sterkt hygroskopiske kry-staller. Destilleringen av dette produkt ved 170—180° ved 0,02 mm Hg gir et destillat som straks stivner i prismer med smp. 122 —123°. in example 1), and the mixture is allowed to stand for 20 hours at room temperature. The remainder of the solution which has been evaporated in vacuo is taken up in chloroform and shaken with sodium carbonate solution. The chloroform layer is dried over potassium carbonate, evaporated in vacuo, and the residue is dissolved in acetone, and ether is added slowly. After standing for a longer time, the nicotinic acid tropyl-3-amide crystallizes out and is obtained after recrystallization from acetone in the form of highly hygroscopic crystals. The distillation of this product at 170-180° at 0.02 mm Hg gives a distillate which immediately solidifies in prisms with m.p. 122 -123°.
For å fremstille hydrokloridet blir ami-det oppløst i litt metanol, blandet med metanolisk klorvannstoff til kongosur reaksjon og tilsatt eter, hvorpå nikotinsyretro-pyl-3-amid-di-hydroklorid krystalliserer ut og oppnås i form av hygroskopiske små staver etter omkrystallisering fra metanol-eter. Smp etter tørking ved 110° i høy-vakuum 230—250° (sp). To prepare the hydrochloride, the amide is dissolved in a little methanol, mixed with methanolic hydrogen chloride for a Congolese reaction and ether is added, after which nicotinic acid-retro-pyl-3-amide dihydrochloride crystallizes out and is obtained in the form of hygroscopic small rods after recrystallization from methanol -ether. M.p. after drying at 110° in high-vacuum 230-250° (sp).
Eksempel 3: Example 3:
salisylsyre- tropyl- 3- amid. salicylic acid-tropyl-3-amide.
7,1 g salisylsyre-hydrazid oppløses i 21 cm:; 2-n. saltsyre, og en oppløsning av 3,5 g natriumnitrit i 5 cm<3> vann tilsettes dråpevis under kjøling og kraftig røring. "Det azid som oppnås blir gnidd ut, vasket med isvann og tørket i eddikesteroppløsning over natriumsulfat. Oppløsningen av azidet i eddikester blir blandet dråpevis med 6,5 g 3-amino-tropan (råprodukt som inneholder 20—30 pst. 3-amino-i|)-tropan, fremstillet slik som i eksempel 1), blandingen får stå i 20 timer ved 4°, og oppnådd olje blir dekantert av. Denne blir oppløst i metanol og blandet med metanolisk klorvannstoff til kongosur reaksjon. Etter tilsetting av eter krystalliserer salisylsyre-tropyl-3-amid-hydroklorid ut. Inndampingsresten av eddikesteroppløsningen gir med metanolisk klorvannstoff ennå en fraksjon av det samme hydroklorid. De forenede hydroklorider blir oppløst i den fem-dobbelte mengde mettet natriumkarbonat-oppløsning. Etter kort tid krystalliserer salisylsyre-tropyl-3-amid ut som etter omkrystallisering fra metanol-aceton og fra etanol smelter ved 188—189°. 7.1 g of salicylic acid hydrazide is dissolved in 21 cm:; 2-n. hydrochloric acid, and a solution of 3.5 g of sodium nitrite in 5 cm<3> of water is added dropwise while cooling and vigorous stirring. "The azide that is obtained is rubbed out, washed with ice water and dried in acetic ester solution over sodium sulfate. The solution of the azide in acetic ester is mixed dropwise with 6.5 g of 3-amino-tropane (raw product containing 20-30 percent 3-amino- i|)-tropane, prepared as in example 1), the mixture is allowed to stand for 20 hours at 4°, and the resulting oil is decanted off. This is dissolved in methanol and mixed with methanolic hydrogen chloride for a Congo acid reaction. After the addition of ether, crystallizes salicylic acid-tropyl-3-amide hydrochloride out. Evaporation of the residue of the acetic ester solution gives with methanolic hydrogen chloride another fraction of the same hydrochloride. The combined hydrochlorides are dissolved in five times the amount of saturated sodium carbonate solution. After a short time salicylic acid-tropyl- 3-amide out which after recrystallization from methanol-acetone and from ethanol melts at 188-189°.
Fra den frie base oppnås med matanol-isk klorvannstoff hydrokloridet, lange nåler med smp 245—251° etter omkrystallisering fra metanol-eter. From the free base, the hydrochloride is obtained with methanolic hydrogen chloride, long needles with m.p. 245-251° after recrystallization from methanol-ether.
Eksempel 4: N- tropyl- 3- uretan ( N- tropyl- 3- karbamin- syre- etylester). Example 4: N-tropyl-3-urethane (N-tropyl-3-carbamine- acid ethyl ester).
Til en oppløsning av 5 g 3-amino-tropan (råprodukt som inneholder 20—30 pst. 3-amino-v|)-tropan, fremstillet som i eksempel 1) og 5 cm<:i> trietyl-amin i 30 cm<8> bensol blir det dråpevis satt 5 cm'<1> klorkullsyre-etylester under iskjøling og kraftig omrø-ring. Etter at blandingen har stått i 15 timer ved romtemperatur tilsettes litt mettet kaliumkarbonat-oppløsning for å opp-løse hydrokloridet, bensollaget skilles ut, og det vandige lag rystes ut tre ganger med kloroform. De forenede bensol- og kloroform-ekstrakter blir dampet inn etter tørk-ing over natriumsulfat, og den gule oljelignende rest blir destillert ved 12 mm Hg. Den svakt gulfarvede olje som går over ved 140—170° overføres med metanolisk klorvannstoff til hydrokloridet som ved utko-king med aceton befris for vedhengende smussige substanser. Etter en gangs omkrystallisering fra etanoleter og to ganger fra etanolaceton oppnås tropyl-3-uretan-hydroklorid i form av hygroskopiske nåler med smp 211—214°. To a solution of 5 g of 3-amino-tropane (crude product containing 20-30% of 3-amino-v|)-tropane, prepared as in example 1) and 5 cm<:i> of triethylamine in 30 cm< 8> benzol, 5 cm'<1> of chlorocarbonic acid ethyl ester is added dropwise under ice-cooling and vigorous stirring. After the mixture has stood for 15 hours at room temperature, a little saturated potassium carbonate solution is added to dissolve the hydrochloride, the benzol layer is separated, and the aqueous layer is shaken out three times with chloroform. The combined benzol and chloroform extracts are evaporated after drying over sodium sulfate, and the yellow oil-like residue is distilled at 12 mm Hg. The faintly yellow-coloured oil which changes at 140-170° is transferred with methanolic hydrogen chloride to the hydrochloride, which is freed from adhering dirty substances by boiling with acetone. After recrystallization once from ethanol ether and twice from ethanol acetone, tropyl-3-urethane hydrochloride is obtained in the form of hygroscopic needles with mp 211-214°.
Eksempel 5: Example 5:
di- tropyl- 3- urinstoff. di- tropyl- 3-urea.
En oppløsning av 6 g 3-amino-tropan (råprodukt som inneholder 20—30 pst. 3-amino-i|)-tropan, fremstillet som i eksempel 1) i 25 cm:! bensol blir under omrøring i løpet av to timer ved 50° dråpevis blandet med 12 cm3 av en oppløsning av 20 pst. fosgen i bensol, og blandingen får stå i 12 timer ved romtemperatur. Det bunnfall som oppnås blir filtrert av, oppløst i litt vann og oppløsningen mettet med kaliumkarbonat og ekstrahert flere ganger med kloroform. Kloroformoppløsningen som er tørket over kaliumkarbonat etterlater etter inndamping en brun oljelignende rest som oppløses i aceton. Etter å ha stått lenge krystalliserer di-tropyl-3-urinstoff ut, som etter rensing ved fraksjonert krystallise-ring fra metanol-eter smelter ved 220— 230° under spalting. A solution of 6 g of 3-amino-tropane (crude product containing 20-30 percent 3-amino-i|)-tropane, prepared as in example 1) in 25 cm:! benzol is mixed dropwise with 12 cm3 of a solution of 20% phosgene in benzol with stirring during two hours at 50°, and the mixture is allowed to stand for 12 hours at room temperature. The precipitate obtained is filtered off, dissolved in a little water and the solution saturated with potassium carbonate and extracted several times with chloroform. The chloroform solution dried over potassium carbonate leaves after evaporation a brown oil-like residue which dissolves in acetone. After standing for a long time, ditropyl-3-urea crystallizes out, which, after purification by fractional crystallization from methanol-ether, melts at 220-230° during cleavage.
Fra den frie base blir det med metanolisk klorvannstoff oppnådd di-tropyl-3-urinstoff-di-hydroklorid som etter to gangers omkrystallisering har et smp på over 300°. From the free base, di-tropyl-3-urea dihydrochloride is obtained with methanolic hydrogen chloride, which after recrystallization twice has a m.p. of over 300°.
Eksempel 6: Example 6:
nikotinsyre-\\ >- tropyl- 3- amid. nicotinic acid-\\ >- tropyl- 3- amide.
Til en oppløsning av 2,2 g 3-amino-i|>-tropan [R. Willståtter og W. Muller, Ber. 31, 1202 (1898)] i 10 cm;! bensol blir det under iskjøling og kraftig omrøring dråpevis satt en oppløsning av 2,5 g nikotinsyreklorid i 10 cm<3> bensol. Det danner seg straks et fargeløst bunnfall som langsomt rødgarges. Blandingen får stå i 20 minutter ved romtemperatur, det hygroskopiske bunnfall suges bort, oppløses i vann, oppløsningen mettes med natriumbikarbonat og ekstraheres med kloroform. Kloroformoppløsningen etterlater etter tørking over natriumsulfat ved inndamping i vakuum som rest nikotinsyre-i|)-tropyl-3-amid som etter omkrystallisering fra metanol-eter oppnås i nåler med smp. 195—196°. To a solution of 2.2 g of 3-amino-1>-tropane [R. Willstätter and W. Muller, Ber. 31, 1202 (1898)] in 10 cm;! benzol, a solution of 2.5 g of nicotinic acid chloride in 10 cm<3> of benzol is added dropwise under ice-cooling and vigorous stirring. A colorless precipitate immediately forms which slowly turns red. The mixture is allowed to stand for 20 minutes at room temperature, the hygroscopic precipitate is sucked off, dissolved in water, the solution is saturated with sodium bicarbonate and extracted with chloroform. The chloroform solution, after drying over sodium sulfate by evaporation in vacuum, leaves as a residue nicotinic acid i|)-tropyl-3-amide which, after recrystallization from methanol-ether, is obtained in needles with m.p. 195-196°.
Nikotinsyre-i|j-tropyl-3-amid-di-hydro~ klorid blir fremstillet fra den frie base med metanolisk saltsyre og krystalliserer ut vannfritt fra metanol-eter. Det er hygro-skopisk og danner derunder et monohydrat. Nicotinic acid i|j-tropyl-3-amide dihydrochloride is prepared from the free base with methanolic hydrochloric acid and crystallizes out anhydrously from methanol-ether. It is hygroscopic and forms a monohydrate underneath.
Eksempel 7: Example 7:
Salisylsyre-\\)- tropyl- 3- amid. Salicylic acid-\\)-tropyl-3-amide.
a) Til en oppløsning av 5 g salisylsyre-klorid i 20 cm3 bensol blir det ved 0° under a) For a solution of 5 g of salicylic acid chloride in 20 cm3 of benzol, at 0° below
kraftig omrøring dråpevis satt en oppløs-ning av 4 g 3-amino-ip-tropan i 20 cm3 bensol og blandingen omrøres først i 2 timer ved romtemperatur, derpå i ytterligere 2 timer ved ved 80°. Det utfelles straks et gult smussig bunnfall som etterhvert blir fargeløst og ved oppvarming kornet. Det oppløses i litt vann, og oppløsningen mettes med natriumbikarbonat hvorunder det skiller seg ut fargeløse nåler. Da disse bare lar seg krystallisere ut fra vann og bare med store tap, blir de overført med metanolisk klorvannstoff til hydrokloridet som krystalliserer ut fra metanol-eter i nåler med sp. 258—264°. with vigorous stirring, a solution of 4 g of 3-amino-ip-tropane in 20 cm3 of benzene is added dropwise and the mixture is first stirred for 2 hours at room temperature, then for a further 2 hours at 80°. A yellow, dirty precipitate is immediately precipitated which eventually becomes colorless and grainy when heated. It is dissolved in a little water, and the solution is saturated with sodium bicarbonate, during which colorless needles stand out. As these can only be crystallized from water and only with great losses, they are transferred with methanolic hydrogen chloride to the hydrochloride which crystallizes from methanol-ether in needles with sp. 258—264°.
b) 5 g salisylsyre-hydrazid oppløses i 15 cm<3> 2-n. saltsyre, og under kjøling og kraftig rysting blir en oppløsning av 2,8 g natriumnitrit i litt vann satt til dråpevis. Det azid som oppnås blir gnidd ut, vasket med isvann og kortvarig tørket i eddikesteropp-løsning over natriumsulfat. Oppløsningen av azidet i eddikester blir dråpevis blandet med 4,5 g 3-amino-i|)-tropan. Det skiller seg straks ut en gul olje som etter en stund be-gynner å krystallisere. Blandingen får stå i to dager ved 0°, det utskilte produkt opp- b) Dissolve 5 g of salicylic acid hydrazide in 15 cm<3> 2-n. hydrochloric acid, and while cooling and vigorous shaking, a solution of 2.8 g of sodium nitrite in a little water is added dropwise. The azide obtained is rubbed out, washed with ice water and briefly dried in acetic ester solution over sodium sulphate. The solution of the azide in acetic ester is mixed dropwise with 4.5 g of 3-amino-1)-tropane. A yellow oil immediately separates, which after a while begins to crystallize. The mixture is allowed to stand for two days at 0°, the separated product
løses i metanol etter en gangs omkrystallisering fra etanol, og ved tilsetting av eterisk klorvannstoff fremstilles salisylsyre-ajj-tropyl-3-amid-hydroklorid som etter omkrystallisering fra etanol-eter smelter under spalting ved 255—264°. is dissolved in methanol after a single recrystallization from ethanol, and by the addition of ethereal hydrogen chloride, salicylic acid ajj-tropyl-3-amide hydrochloride is prepared which, after recrystallization from ethanol-ether, melts with decomposition at 255-264°.
Eksempel 8. Example 8.
Bensilsyre-\\)- tropyl- 3- aviid. Benzylic acid-\\)- tropyl- 3- aviid.
3 g bensilsyre-hydrazid oppslemmes i 6 cm3 vann, det tilsettes så meget 2-n. saltsyre at nettopp alt oppløses, og ved 0° under kraftig rysting blir en oppløsning av 1 g natriumnitrit i 3 cm<3> vann tilsatt dråpevis. Det smussige azid som oppnås blir vasket med isvann og tørket i eterisk opp-løsning over natriumsulfat. Den eteriske oppløsning av azidet blandes dråpevis under kjøling med 1,87 g 3-amino-\|)-tropan. Det skiller seg ut et smussig bunnfall som blir krystallinsk hvis det står lenge. Blandingen får stå natten over ved romtemperatur, bunnfallet suges fra, oppløses i kloroform, og kloroformoppløsningen rystes ut med 2-n. natriumkarbonatoppløsning. Etter at kloroformoppløsningen er tørket over natrium-sulfat etterlater den etter inndamping en rest som ved omkrystallisering fra metanol-eter gir bensilsyre-i|j-tropyl-3-amid i terninger med smp. 210—211°. 3 g of benzylic hydrazide are suspended in 6 cm3 of water, so much 2-n is added. hydrochloric acid that just about everything dissolves, and at 0° under vigorous shaking a solution of 1 g of sodium nitrite in 3 cm<3> of water is added dropwise. The dirty azide that is obtained is washed with ice water and dried in ethereal solution over sodium sulfate. The ethereal solution of the azide is mixed dropwise under cooling with 1.87 g of 3-amino-β-tropane. A dirty precipitate separates, which becomes crystalline if it stands for a long time. The mixture is allowed to stand overnight at room temperature, the precipitate is sucked off, dissolved in chloroform, and the chloroform solution is shaken out with 2-n. sodium carbonate solution. After the chloroform solution has been dried over sodium sulphate, it leaves after evaporation a residue which, on recrystallization from methanol-ether, yields benzylic acid i|j-tropyl-3-amide in cubes with m.p. 210—211°.
Hydrokloridet krystalliserer fra metanol i nåler med smp. 250—252°. The hydrochloride crystallizes from methanol in needles with m.p. 250-252°.
Eksempel 9: Example 9:
Malonsyre- di-\\!- tropyl- 3- a?nid. Malonic acid- di-\\!- tropyl- 3- a?nide.
Til en oppløsning av 4 g 3-amino-i|>-tropan i 25 cm- bensol, blir det under is-kjøling og kraftig omrøring dråpevis satt en oppløsning av 2,2 g malonylklorid i 15 cm3 bensol, omrøring foretas ved romtemperatur i en time og ved 60° i tre timer, og det utfeldte bunnfall filtreres av. Dets opp-løsning i litt vann blir mettet med kaliumkarbonat og ekstrahert med kloroform. Etter tørking over natriumsulfat etterlater kloroformoppløsningen ved inndamping en rest som etter ekstrahering med aceton omkrystalliseres fra kloroform-eter. To gangers omkrystallisering fra metanol-eter gir analyserent malonsyre-di-i|>-tropyl-3-amid med spp. 258—264°. A solution of 2.2 g of malonyl chloride in 15 cm3 of benzene is added dropwise under ice-cooling and vigorous stirring to a solution of 4 g of 3-amino-i|>-tropane in 25 cm3 of benzene, stirring is carried out at room temperature in one hour and at 60° for three hours, and the precipitate precipitated is filtered off. Its solution in a little water is saturated with potassium carbonate and extracted with chloroform. After drying over sodium sulfate, the chloroform solution leaves a residue on evaporation which, after extraction with acetone, is recrystallized from chloroform-ether. Twice recrystallization from methanol-ether yields analytically pure malonic acid-di-isotropyl-3-amide with mp 258-264°.
Den frie base gir med metanolisk klorvannstoff di-hydrokloridet som omkrystalliseres fra metanol-aceton og rent metanol. Det spaltes over 250° og er sterkt hygro-skopisk. The free base yields with methanolic hydrogen chloride the dihydrochloride, which is recrystallized from methanol-acetone and pure methanol. It decomposes above 250° and is highly hygroscopic.
Eksempel 10: N-\\ i- tropyl~ 3- uretan. (N-i|)-tropyl-3-karbaminsyre-etylester). Til en oppløsning av 2,8 g 3-amino-a|j-tropan og 2,8 cm:! trietylamin i 15 cm<:i> bensol blir det under iskjøling og kraftig om-røring dråpevis satt 2,5 cm<:i> klorkullstoff-syre-etylester. Etter at blandingen har stått i 24 timer ved romtemperatur oppvarmes den kortvarig på vannbad, og det fargeløse bunnfall som er dannet blir filtrert av. Filtratet etterlater etter inndamping en olje som langsomt krystalliserer og som etter destillering under 12 mm ved 150 —160° og to gangers omkrystallisering fra heksan gir N-i|;-tropyl-3-uretan i lange nåler med smp. 93—94°. Example 10: N-\\ i- tropyl~ 3-urethane. (N-i|)-tropyl-3-carbamic acid ethyl ester). To a solution of 2.8 g of 3-amino-α|j-tropane and 2.8 cm:! of triethylamine in 15 cm<:i> of benzene, 2.5 cm<:i> of carbonic acid ethyl ester is added dropwise under ice-cooling and vigorous stirring. After the mixture has stood for 24 hours at room temperature, it is briefly heated in a water bath, and the colorless precipitate that forms is filtered off. The filtrate leaves after evaporation an oil which slowly crystallizes and which, after distillation below 12 mm at 150 —160° and twice recrystallization from hexane, gives N-i|;-tropyl-3-urethane in long needles with m.p. 93-94°.
Den frie base danner et hydroklorid som krystalliserer fra metanol-eter i prismer med smp. 240—241°. The free base forms a hydrochloride which crystallizes from methanol-ether in prisms with m.p. 240-241°.
Eksempel 11: Example 11:
di-\\ >- tropyl- urinstoff. di-\\ >- tropyl- urea.
En oppløsning av 5 g 3-amino-i|j-tropan i 20 cm'! bensol blandes ved 50° dråpevis med 10 cm:! av en oppløsning av 20 pst. fosgen i bensol, etter to timer settes ytterligere 5 cm<:i> fosgenoppløsning til, og det røres om i ytterligere to timer. Det fargeløse bunnfall blir filtret av, og dets oppløsning i litt vann blir mettet med kaliumkarbonat. Pro-duktet som delvis allerede skiller seg ut krystallinsk opptas i kloroform, og oppløs-ningen inndampes etter tørking over kaliumkarbonat. Resten blir omkrystallisert fra aceton, så fra metylenklorid-eter og en-delig fra aceton. Di-i|>-tropyl-3-urinstoff smelter under spalting ved 200—210°. A solution of 5 g of 3-amino-i|j-tropane in 20 cm'! benzol is mixed at 50° dropwise with 10 cm:! of a solution of 20 per cent phosgene in benzol, after two hours a further 5 cm<:i> of phosgene solution is added, and it is stirred for a further two hours. The colorless precipitate is filtered off, and its solution in a little water is saturated with potassium carbonate. The product, which partly already separates out crystalline, is taken up in chloroform, and the solution is evaporated after drying over potassium carbonate. The residue is recrystallized from acetone, then from methylene chloride-ether and finally from acetone. Di-i|>-tropyl-3-urea melts during cleavage at 200—210°.
Fra den frie base fremstilles med metanolisk klorvannstoff di-\|>-tropyl-urinstoff-di-hydrokloridet som etter to gangers omkrystallisering fra metanol-eter har et smp. på over 330°. From the free base, the di-\|>-tropyl-urea dihydrochloride is prepared with methanolic hydrogen chloride which, after recrystallization twice from methanol-ether, has a m.p. of over 330°.
Eksempel 12: Example 12:
\\)- tropyl- 3- dimetyl- urinstoff. \\)- tropyl- 3- dimethyl- urea.
En oppløsning av 2,5 g dimetyl-karba-myl-klorid og 3 cm" trietylamin i 20 cm<:i >bensol blir under omrøring og kjøling blandet med en oppløsning av 3 g 3-amino-i|>-tropan i 20 cm<3> bensol, og blandingen røres om i ytterligere en time ved romtemperatur og 3 timer ved 80°. Det foretas avfiltrering i varme fra det fargeløse bunnfall, og resten av det inndampede filtrat destilleres under 0,03 mm Hg. Den fraksjon som går over ved A solution of 2.5 g of dimethylcarbamyl chloride and 3 cm" of triethylamine in 20 cm<:i>benzene is mixed with stirring and cooling with a solution of 3 g of 3-amino-i|>-tropane in 20 cm<3> benzol, and the mixture is stirred for a further hour at room temperature and 3 hours at 80°. The colorless precipitate is filtered off in heat, and the remainder of the evaporated filtrate is distilled below 0.03 mm Hg. The fraction which goes over wood
130—140° blir omkrystallisert fra metylenklorid-eter. Smp. 142—145°. Den rest som er uoppløselig i bensol blir ekstrahert med etanol, resten av den alkoholekstrakt som er inndampet i vakuum oppløses i vann og oppløsningen ekstraheres med kloroform etter å være gjort alkalisk med natronlut. Inndampingsresten av kloroformoppløsnin-gen som er tørket over natriumsulfat gir etter omkrystallisering fra metylenklorid-eter et produkt med smp. 140—144°. De to fraksjoner forenes og gir etter omkrystalli-seringen fra metylenklorid-eter-i|)-tropyl-3-dimetyl-urinstoff i kvadratiske små plater med smp. 145—146°. 130-140° is recrystallized from methylene chloride-ether. Temp. 142-145°. The residue which is insoluble in benzol is extracted with ethanol, the residue of the alcoholic extract which has been evaporated in vacuo is dissolved in water and the solution is extracted with chloroform after being made alkaline with caustic soda. The evaporation residue of the chloroform solution which has been dried over sodium sulphate gives, after recrystallization from methylene chloride ether, a product with m.p. 140-144°. The two fractions are combined and after the recrystallization from methylene chloride-ether-1|)-tropyl-3-dimethyl-urea in square small plates with m.p. 145-146°.
Den frie base gir med metanolisk klorvannstoff i|> tropyl-dimetyl-urinstoff-hydroklorid som etter to gangers omkrystallisering fra kloroform-aceton smelter ved ca. 100° under avgivelse av 1 mol krystallvann, men deretter igjen størkner. Substansen som er tørket i høyvakuum ved 75° smelter under spalting ved 224°. Det opptar i luften raskt 1 mol krystallvann. The free base yields with methanolic hydrogen chloride i|> tropyl-dimethyl-urea hydrochloride which, after recrystallization twice from chloroform-acetone, melts at approx. 100° during the release of 1 mol of crystal water, but then solidifies again. The substance which is dried in high vacuum at 75° melts during cleavage at 224°. It quickly absorbs 1 mol of crystal water in the air.
Eksempel 13: 6- etoksy-\\ i- tropyl- 3- nikotinsyre- amid. Example 13: 6-ethoxy-\\ i-tropyl-3-nicotinic acid-amide.
En oppløsning av 300 g 6-etoksy-tropinon-hydroklorid (A. Stoll, E. Jucker og A. Lindenmann, Heiv. 37, 495 (1954)) og 918 g kaliumhydroksyd i 1680 cm3 vann blandes under kjøling med 193 g hydroksylamin-hydroklorid i 672 cm:! vann. Etter å ha stått i tre dager ved romtemperatur blir en kraftig kulldioksydstrøm blåst inn i blandingen under kjøling inntil den er bikarboriat-alkalisk. Kloroformoppløsningen av den olje som fremkommer blir tørket over mag-nesiumsulfat og inndampet i vakuum. Opp-løsningen av den viskose blekkbrune rest i litt etanol blir under iskjøling blandet med etanolisk klorvannstoff inntil kongosur reaksjon, hvorpå etter tilsetting av litt eter 6-etoksy-tropinonoksim-hydroklorid krystalliserer ut, som etter omkrystallisering fra den firedobbelte mengde etanol har et smp. 190—191°. A solution of 300 g of 6-ethoxytropinone hydrochloride (A. Stoll, E. Jucker and A. Lindenmann, Heiv. 37, 495 (1954)) and 918 g of potassium hydroxide in 1680 cm3 of water is mixed under cooling with 193 g of hydroxylamine- hydrochloride in 672 cm:! water. After standing for three days at room temperature, a strong current of carbon dioxide is blown into the mixture while cooling until it is bicarbonate-alkaline. The chloroform solution of the resulting oil is dried over magnesium sulphate and evaporated in vacuo. The solution of the viscous ink-brown residue in a little ethanol is mixed with ethanolic hydrogen chloride under ice-cooling until a Congolese reaction, whereupon after the addition of a little ether 6-ethoxy-tropinone oxime hydrochloride crystallizes out, which after recrystallization from the quadruple amount of ethanol has a m.p. 190-191°.
Det frie oksim er en svakt gul seig olje. The free oxime is a pale yellow viscous oil.
I en oppløsning av 25 g 6-etoksy-tropinon-oksim i 250 cm3 amylalkohol blir det ved 140° langsomt ført inn 36 g natrium i små stykker. Når vannstoffutviklingen blir langsommere, tilsettes ytterligere 250 cm<3> amylalkohol. Etter 3 timer er alt natrium opp-løst hvoretter det hele avkjøles, 500 cm<3 >vann tilsettes, og det hele gjøres surt (kon-gorødt) med kons. saltsyre. Den vandige fase blir skilt fra og amylalkoholet rystet ut to ganger til, hver gang med 50 cm<:l> 2-n. saltsyre. Inndampingsresten av den vandige ekstrakt oppløses i litt vann, fast kaliumhydroksyd tilsettes inntil sterk alkalisk reaksjon og den olje som fremkommer destilleres med vanndamp. Destillatet blir nøy-tralisert med saltsyre, inndampet i vakuum og oppløsningen av resten i litt vann overmettet med kaliumhydroksyd. Derpå ekstraheres med eter, eterekstrakten som er tør-ket over kaliumhydroksyd blir inndampet og resten fraksjonert ved 12 mm Hg. Den hovedfraksjon som går over mellom 115— 135° blir destillert ennå en gang, hvorunder 6-etoksy-3-amino-i|)-tropan går over mellom 124 og 128° under 12 mm Hg. Into a solution of 25 g of 6-ethoxy-tropinone oxime in 250 cm3 of amyl alcohol, 36 g of sodium are slowly introduced in small pieces at 140°. When the evolution of hydrogen becomes slower, a further 250 cm<3> of amyl alcohol are added. After 3 hours, all the sodium has dissolved, after which it is all cooled, 500 cm<3> of water is added, and the whole is made acidic (congo red) with conc. hydrochloric acid. The aqueous phase is separated and the amyl alcohol shaken out twice more, each time with 50 cm<:l> 2-n. hydrochloric acid. The evaporation residue of the aqueous extract is dissolved in a little water, solid potassium hydroxide is added until a strong alkaline reaction occurs and the resulting oil is distilled with steam. The distillate is neutralized with hydrochloric acid, evaporated in vacuo and the solution of the residue in a little water supersaturated with potassium hydroxide. It is then extracted with ether, the ether extract which has been dried over potassium hydroxide is evaporated and the residue fractionated at 12 mm Hg. The main fraction passing between 115-135° is distilled once more, during which 6-ethoxy-3-amino-1)-tropane passes between 124 and 128° under 12 mm Hg.
Dihydrokloridet krystalliserer fra alkohol-aceton i sterkt hygroskopiske nåler som straks flyter bort i luften. Det oljelignende dihydroklorid krystalliseres så igjen ved riving som hydrat. The dihydrochloride crystallizes from alcohol-acetone in highly hygroscopic needles which immediately float away in the air. The oil-like dihydrochloride is then crystallized again by trituration as a hydrate.
Til en oppløsning av 5 g nikotinsyreklorid i 20 cm<3> abs alkohol settes det dråpevis ved 0° en oppløsning av 4 g 6-etoksy-3-amino-i|»-tropan i 20 cm:! bensol. Etter kort tid skiller det seg ut en olje som etterhvert blir fast. Etter å ha stått i 20 timer ved romtemperatur blir bunnfallet suget av, dets oppløsning i1 litt vann gjort alkalisk med kaliumkarbonat og rystet ut tre ganger med kloroform. Etter tørking over natriumsulfat etterlater oppløsningen ved inndamping en rest som fraksjoneres ved høy vakuum. Den fraksjon som går over ved 170—180° under 0,05 mm Hg, en fargeløs olje, gir ved kry-stallisering fra fuktig eter 6-etoksy-t|)-tropyl-3-nikotinsyre-amid-dihydrat i prismer som etter to gangers omkrystallisering fra aceton-eter smelter ved ca. 80° under avgivelse av vann. To a solution of 5 g of nicotinic acid chloride in 20 cm<3> abs alcohol is added dropwise at 0° a solution of 4 g of 6-ethoxy-3-amino-i|»-tropane in 20 cm:! benzol. After a short time, an oil separates, which eventually solidifies. After standing for 20 hours at room temperature, the precipitate is suctioned off, its solution in a little water made alkaline with potassium carbonate and shaken out three times with chloroform. After drying over sodium sulfate, the solution leaves a residue on evaporation which is fractionated at high vacuum. The fraction which passes at 170-180° below 0.05 mm Hg, a colorless oil, gives on crystallization from moist ether 6-ethoxy-t|)-tropyl-3-nicotinic acid amide dihydrate in prisms which after recrystallization twice from acetone-ether melts at approx. 80° while dispensing water.
For fremstilling av monohydroklorid blir basen blandet med den beregnede mengde metanolisk saltsyre og inndampet. Resten blir omkrystallisert fra aceton og to ganger fra etanol-eter og gir 6-etoksy-ip-tropyl-3-nikotinsyre-amid-hydroklorid i små staver med spp 228—231°. For the production of monohydrochloride, the base is mixed with the calculated amount of methanolic hydrochloric acid and evaporated. The residue is recrystallized from acetone and twice from ethanol-ether to give 6-ethoxy-ip-tropyl-3-nicotinic acid amide hydrochloride in small sticks with spp 228-231°.
Eksempel 14: 6- etoksy-\\ >- tropyl- 3- salisylsyre- amid. ■ Example 14: 6-ethoxy-\\>-tropyl-3-salicylic acid-amide. ■
3 g salisylsyre-hydrazid oppløses i 10 cm'<;> 2-n. saltsyre, og under kjøling og kraftig omrøring blir det dryppet inn en opp-løsning av 1,4 g natriumnitrit i 3 cm'<!> vann. Det azid som fremkommer blir gnidd ut, vasket med isvann og tørket i edikkester-oppløsning over natriumsulfat. Oppløsnin-gen av azidet i eddikester blandes under kjøling dråpevis med 3,6 g 6-etoksy-3-amino-i|j-tropan (fremstillet som i eks- 3 g of salicylic acid hydrazide are dissolved in 10 cm'<;> 2-n. hydrochloric acid, and while cooling and vigorous stirring, a solution of 1.4 g of sodium nitrite in 3 cm'<!> of water is added drop by drop. The resulting azide is rubbed out, washed with ice water and dried in acetic ester solution over sodium sulphate. The solution of the azide in acetic acid is mixed dropwise with 3.6 g of 6-ethoxy-3-amino-i|j-tropane (prepared as in ex-
empel 13). Allerede etter kort tid skiller det seg ut en olje. Blandingen får stå i 20 timer ved romtemperatur, den rystes ut med litt mettet natrium-bikarbonatoppløsning og edikkesterlaget, som er tørket over natrium-sulfat, blir inndampet. Resten blir destillert i høyvakuum (kulerør). Den fraksjon som går over under 0,02 mm Hg ved 150—190° blir med metanolisk klorvannstoff overført til hydroklorid som krystalliserer fra aceton-eter i hygroskopiske nåler som er forenet til bunter. Når 6-etoksy-i|j-ti opyl-3-salisylsyre-amid-hydroklorid har ligget utsatt for fuktig luft krystalliserer det fra aceton-eter i hygroskopiske nåler som er forenet til bunter. Når 6-etoksy-i|>-tropyl-3-salisylsyre-amid-hydroklorid har ligget utsatt for fuktig luft krystalliserer det fra aceton-eter som hydrat som under avgivelse av vann smelter ved 105—108°. example 13). Already after a short time, an oil separates. The mixture is allowed to stand for 20 hours at room temperature, it is shaken out with a little saturated sodium bicarbonate solution and the acetic ester layer, which has been dried over sodium sulphate, is evaporated. The remainder is distilled in a high vacuum (bubble tube). The fraction which passes below 0.02 mm Hg at 150—190° is transferred with methanolic hydrogen chloride to hydrochloride which crystallizes from acetone-ether in hygroscopic needles which are united into bundles. When 6-ethoxy-i|j-ti opyl-3-salicylic acid amide hydrochloride has been exposed to moist air it crystallizes from acetone-ether in hygroscopic needles which are united into bundles. When 6-ethoxy-i|>-tropyl-3-salicylic acid amide hydrochloride has been exposed to moist air it crystallizes from acetone-ether as a hydrate which melts at 105-108° on giving off water.
Eksempel 15: Example 15:
6- etoksy-\\)- tropyl- bensilsyre- amid. 6- ethoxy-\\)- tropyl- benzylic acid- amide.
5 g bensilsyrehydrazid oppslemmes i 6 cm3 vann, hvoretter det tilsettes så meget 2-n. saltsyre at nettopp alt oppløses, og ved 0° under sterk rysting dryppes det inn en oppløsning av 1,5 g natriumnitrit i 3 cm<;1 >vann. Det smussige azid som oppnås blir vasket med isvann og tørket i edikkester-oppløsning over natriumsulfat. Oppløsnin-gen av azidet i edikkester blir under kjøling dråpevis blandet med 3,8 g 6-etoksy-3-amino-\|j-tropan (fremstillet som i eksempel 13), blandingen får stå i 20 timer ved 4°, 5 g of benzylic hydrazide is suspended in 6 cm3 of water, after which as much 2-n is added. hydrochloric acid that just about everything dissolves, and at 0° under vigorous shaking, a solution of 1.5 g of sodium nitrite in 3 cm<;1 >of water is dripped in. The dirty azide obtained is washed with ice water and dried in ethyl acetate solution over sodium sulfate. The solution of the azide in ethyl acetate is mixed dropwise with 3.8 g of 6-ethoxy-3-amino-β-tropane (prepared as in example 13) while cooling, the mixture is allowed to stand for 20 hours at 4°,
og eddikesteren dekanteres av fra utskilt olje. Etter inndampingen i vakuum blir det tilbake en rest som i kloroformopp-løsning rystes ut med mettet kalium-karbonatoppløsning. Etter å være tør-ket over natriumsulfat etterlater klo-roformoppløsningen ved inndamping en krystallinsk rest som først kokes ut med eter og derpå omkrystalliseres fra aceton-eter. To ganger omkrystallisering fra aceton-eter gir 6-etoksy-i|)-tropyl-3-bensilsyre-amid i flate, rettvinklede plater med smp. 164—166°. and the acetic ester is decanted off from the separated oil. After evaporation in vacuum, a residue remains which is shaken out in chloroform solution with saturated potassium carbonate solution. After being dried over sodium sulphate, the chloroform solution leaves a crystalline residue on evaporation which is first boiled out with ether and then recrystallized from acetone-ether. Twice recrystallization from acetone-ether gives 6-ethoxy-i|)-tropyl-3-benzylic acid amide in flat, right-angled plates of m.p. 164—166°.
For å fremstille hydrokloridet blir den frie base oppløst i metanol og oppløsningen To prepare the hydrochloride, the free base is dissolved in methanol and the solution
blandet med så meget metanolisk klorvannstoff at den reagerer kongosurt. Resten av mixed with so much methanolic hydrogen chloride that it reacts Congo acid. The rest of
oppløsningen som er inndampet til tørr til-stand krystalliserer fra aceton-eter. Ved omkrystallisering fra metanol-eter oppnås hydrokloridet i fine nåler med smp. 214— 216°. the solution evaporated to dryness crystallizes from acetone-ether. By recrystallization from methanol-ether, the hydrochloride is obtained in fine needles with m.p. 214— 216°.
Eksempel 16: N-( 6- eloksy-\\ t- tropyl- 3)- urelan.. Example 16: N-(6-eloxy-\\t-tropyl-3)-urelan..
(6-etoksy-i|i-tropyl-3-karbaminsyre-etyl-ester) (6-ethoxy-i|i-tropyl-3-carbamic acid ethyl ester)
En oppløsning av 3,7 g 6-etoksy-3-amino-\|>-tropan og 2,5 cm'<1> trietylamin i 30 cm<3> bensol blandes under omrøring ved 0° dråpevis med 2,5 cm<3> klorkullstoffsyre-etyl-ester, blandingen får stå 20 timer ved romtemperatur og blir rystet ut med litt mettet kaliumkarbonatoppløsning. Kaliumkar-bonatoppløsningen blir så trukket ut ennå to ganger med kloroform. De forenete or-ganiske ekstrakter blir tørket over natriumsulfat og dampet inn. Fra resten destillerer N-(6-etoksy-t|}-tropyl-3)-uretan over under 12 mm Hg ved 175—195° som farve-løs, viskøs olje som etter lengre henstand krystalliserer i nåler og, etter omkrystallisering fra heksan smelter ved 73—74°. Den frie base gir med metanolisk klorvannstoff hydrokloridet som etter tre gangers omkrystallisering fra aceton oppnås i kvadratiske, flate, hygroskopiske små plater. A solution of 3.7 g of 6-ethoxy-3-amino-\|>-tropane and 2.5 cm'<1> of triethylamine in 30 cm<3> of benzene is mixed with stirring at 0° dropwise with 2.5 cm< 3> carbonic acid ethyl ester, the mixture is allowed to stand for 20 hours at room temperature and is shaken out with a slightly saturated potassium carbonate solution. The potassium carbonate solution is then extracted twice more with chloroform. The combined organic extracts are dried over sodium sulfate and evaporated. From the residue, N-(6-ethoxy-t|}-tropyl-3)-urethane distils above below 12 mm Hg at 175—195° as a colorless, viscous oil which, after prolonged standing, crystallizes in needles and, after recrystallization from hexane melts at 73-74°. The free base yields with methanolic hydrogen chloride the hydrochloride which, after three recrystallizations from acetone, is obtained in square, flat, hygroscopic small plates.
Eksempel 17: Malonsyre- bis-( 6- metoksy- pseudotropyl-3- amid.) Example 17: Malonic acid bis-(6-methoxy-pseudotropyl-3-amide.)
Oppløsningen av 2,5 g kaliumhydroksyd og 1,18 g 6-metoksy-tropinon-hydroklorid A. Stoll, E. Jucker og A. Lindenmann, Heiv. 37, 495, 1954) i 5 cm3 vann blandes med en opp-løsning av 1 g hydroksylamin-hydroklorid i 2 cm<3> vann, og blandingen får stå i 48 timer ved romtemperatur. Derpå blir det le-det inn kulldioksyd, og oppløsningen som er mettet med kaliumkarbonat blir ekstrahert med ialt 80 cm<3> kloroform. De forente kloroformuttrekk som er tørket over natriumsulfat gir ved inndamping en oljelignende rest som bringes til å krystallisere som hydroklorid. 6-metoksy-tropinon-oksim-hydroklorid har etter omkrystallisering fra metanol/eter smp 216—218°. The solution of 2.5 g of potassium hydroxide and 1.18 g of 6-methoxytropinone hydrochloride A. Stoll, E. Jucker and A. Lindenmann, Heiv. 37, 495, 1954) in 5 cm3 of water is mixed with a solution of 1 g of hydroxylamine hydrochloride in 2 cm<3> of water, and the mixture is allowed to stand for 48 hours at room temperature. Carbon dioxide is then introduced, and the solution which is saturated with potassium carbonate is extracted with a total of 80 cm<3> of chloroform. The combined chloroform extracts, which are dried over sodium sulphate, yield on evaporation an oil-like residue which is caused to crystallize as hydrochloride. 6-Methoxy-tropinone-oxime hydrochloride has, after recrystallization from methanol/ether, mp 216-218°.
I en oppløsning av 33 g 6-metoksy-tropinon-oksim i 400 cm<3> amylalkohol blir det ved 140° langsomt ført inn 60 g natrium i små stykker. Når vannstoffutviklingen blir langsommere tilsettes ytterligere 400 cm3 amylalkohol. Etter 3 timer er alt natrium oppløst, hvoretter det hele avkjøles, 500 cm3 vann settes til og det hele gjøres surt med kons. saltsyre (kongorødt). Den vandige fase skilles fra, og amylalko-holen rystes ut ennå to ganger hver gang med 100 cm<3> 2-n. saltsyre. Inndampingsresten av de vandige sure ekstrakter opp-løses i litt vann, fast kaliumhydroksyd tilsettes inntil sterk alkalisk reaksjon oppnås, og den olje som oppnås destilleres med vanndamp. Destillatet blir nøytralisert med saltsyre, inndampet i vakuum, og oppløs-ningen av resten i litt vann overmettet med kaliumhydroksyd. Derpå foretas ekstrahering med eter, eterekstrakten blir etter å være tørket over kaliumhydroksyd inndampet og resten fraksjonert ved 12 mm Hg. Ved 117—122° destillerer 6-metoksy-3-amino-pseudo-tropan som f arveløs olje. Into a solution of 33 g of 6-methoxytropinone oxime in 400 cm<3> of amyl alcohol, 60 g of sodium are introduced slowly at 140° in small pieces. When the evolution of hydrogen becomes slower, a further 400 cm3 of amyl alcohol is added. After 3 hours, all the sodium has dissolved, after which the whole is cooled, 500 cm3 of water is added and the whole is made acidic with conc. hydrochloric acid (Congo red). The aqueous phase is separated, and the amyl alcohol mixture is shaken out twice more each time with 100 cm<3> 2-n. hydrochloric acid. The evaporation residue of the aqueous acidic extracts is dissolved in a little water, solid potassium hydroxide is added until a strong alkaline reaction is achieved, and the oil obtained is distilled with steam. The distillate is neutralized with hydrochloric acid, evaporated in vacuo, and the solution of the residue in a little water supersaturated with potassium hydroxide. Extraction is then carried out with ether, the ether extract is evaporated after being dried over potassium hydroxide and the residue fractionated at 12 mm Hg. At 117-122°, 6-methoxy-3-amino-pseudo-tropane distils as a colorless oil.
Dihydrokloridet krystalliserer fra etanol/eter i nåler som straks smelter i luften. The dihydrochloride crystallizes from ethanol/ether in needles which immediately melt in the air.
For karakterisering kan N-(6-metoksy-tropyl-3) -N'-f enyl-tiourinstof f fremstilles med fenylisotiocyanat. Det krystalliserer fra eddikester i nåler med smp. 183°. For characterization, N-(6-methoxytropyl-3)-N'-phenylthiourea can be prepared with phenylisothiocyanate. It crystallizes from acetic acid in needles of m.p. 183°.
Til en oppløsning av 3,4 g metoksy-3-amino-pseudo-tropan i 15 cm<3> abs kloroform blir det ved romtemperatur under kraftig omrøring satt en oppløsning av 1,4 g malonyldiklorid i 10 cm<3> abs kloroform. Etter 3 timer tilsettes langsomt 3 cm3 trietyl-amin og oppløsningen får stå under omrø-ring i ytterligere 3 timer. Oppløsningen blir rystet ut med kalium-karbonatoppløsning, tørket over natriumsulfat og inndampet. Fra oppløsningen av den gule rest i eter avsetter det seg etter noen tid malonsyre-bis- (6-metoksy-pseudo-tropyl-3-amid) som etter to gangers omkrystallisering har smp 195—201°. To a solution of 3.4 g of methoxy-3-amino-pseudo-tropane in 15 cm<3> abs of chloroform, a solution of 1.4 g of malonyl dichloride in 10 cm<3> abs of chloroform is added at room temperature with vigorous stirring. After 3 hours, 3 cm3 of triethylamine is slowly added and the solution is allowed to stand under stirring for a further 3 hours. The solution is shaken out with potassium carbonate solution, dried over sodium sulphate and evaporated. From the solution of the yellow residue in ether, malonic acid-bis-(6-methoxy-pseudo-tropyl-3-amide) is deposited after some time, which after recrystallization twice has a melting point of 195-201°.
Eksempel 18: bensosyre- 6- metoksy- tropyl- 3- amid. Example 18: benzoic acid-6-methoxy-tropyl-3-amide.
En oppløsning av 15 g 6-metoksy-tropinon-oksim-hydroklorid (fremstillet som i eksempel 17, første avsnitt) i 100 cm3 metanol i nærvær av Raney-nikkel blir rystet ut med vannstoff ved romtemperatur og 50 atm overtrykk i 15 timer. Når oppløsnin-gen er filtrert av fra katalysatoren blir den blandet med metanolisk klorvannstoff inntil kongosur reaksjon og inndampet i vakuum. Resten blir kokt opp med abs etanol, hvorunder 6-metoksy-3-amino-tropan-dihydroklorid skiller seg ut som farveløst pulver. Etter to gangers omkrystallisering fra metanol/aceton har det et spaltingspunkt på ca. 260°. A solution of 15 g of 6-methoxytropinone oxime hydrochloride (prepared as in Example 17, first paragraph) in 100 cm 3 of methanol in the presence of Raney nickel is shaken out with hydrogen at room temperature and 50 atm overpressure for 15 hours. When the solution has been filtered off from the catalyst, it is mixed with methanolic hydrogen chloride until a Congolese reaction and evaporated in a vacuum. The residue is boiled up with absolute ethanol, during which 6-methoxy-3-aminotropane dihydrochloride separates as a colorless powder. After recrystallization twice from methanol/acetone, it has a cleavage point of approx. 260°.
Moderlutene inneholder det meget sterkt hygroskopiske 6-metoksy-3-amino-pseudotropan-dihydroklorid. The mother liquors contain the highly hygroscopic 6-methoxy-3-amino-pseudotropane dihydrochloride.
Oppløsningen av 6 metoksy-3-amino-dihydroklorid i litt vann blandes med kaliumhydroksyd og ekstraheres fullstendig r med eter. Inndampingsresten av eterekstrakten som er tørket over kaliumhydroksyd blir destillert under et trykk på 12 mm Hg, hvorunder 6-metoksy-3-amino-tropan går over som farveløs olje ved 114—115°. The solution of 6-methoxy-3-amino-dihydrochloride in a little water is mixed with potassium hydroxide and extracted completely with ether. The evaporation residue of the ether extract which has been dried over potassium hydroxide is distilled under a pressure of 12 mm Hg, under which 6-methoxy-3-amino-tropane passes as a colorless oil at 114-115°.
Til en oppløsning av 1 g 6-metoksy-3-amino-tropan i 10 cm;i abs kloroform settes det langsomt og dråpevis under om-røring en oppløsning av 0,7 g bensoylklorid i 5 cm:! abs. kloroform hvorunder blandingen oppvarmes svakt. Deretter tilsettes 0,85 cm<3> trietylamin og reaksjonsblandingen får stå i fire timer under omrøring. Oppløsningen blir rystet ut med 2-n. na-triumkarbonatoppløsning, tørket over natriumsulfat og dampet inn, hvorunder resten krystalliserer fullstendig. Bensosyre-6-metoksy-tropyl-3-amid krystalliserer fra aceton/eter eller eddikester/eter i nåler med smp. 135—136°. To a solution of 1 g of 6-methoxy-3-aminotropane in 10 cm in abs chloroform, a solution of 0.7 g of benzoyl chloride in 5 cm is added slowly and dropwise with stirring. abs. chloroform during which the mixture is gently heated. Then 0.85 cm<3> of triethylamine is added and the reaction mixture is allowed to stand for four hours with stirring. The solution is shaken out with 2-n. sodium carbonate solution, dried over sodium sulfate and evaporated, during which the residue crystallizes completely. Benzoic acid 6-methoxy-tropyl-3-amide crystallizes from acetone/ether or acetic ester/ether in needles with m.p. 135-136°.
Eksempel 19: difenylmalonyl- bis-( tropyl- 3- amid). Example 19: diphenylmalonyl-bis-(tropyl-3-amide).
En oppløsning av 2,77 g av den blanding som er fremstillet i eksempel 1 av 3-amino-tropan og 3-amino-pseudotropan i 20 cm<3> kloroform blandes under omrøring ved romtemperatur dråpevis med oppløs-ningen av 2,77 g difenyl-malonyl-diklorid i 10 cm<3> kloroform, etter 4 timer tilsettes 2,7 cm3 trietylamin og blandingen får stå under omrøring i 12 timer ved romtemperatur. Derpå blir oppløsningen rystet ut to ganger med kalium-karbonatoppløsning, tørket over natriumsulfat og dampet inn. Resten blir oppløst i heksan og kromato-grafert i en søyle fra 120 g aluminiumok-syd. Fra de fraksjoner som er eluert med bensin og kloroform krystalliserer fra heksan difenylmalonyl-bis-(tropyl-3-amid) i fine små staver som etter to gangers omkrystallisering fra heksan og fra eter har smp 136—138°. A solution of 2.77 g of the mixture prepared in example 1 of 3-aminotropane and 3-amino-pseudotropane in 20 cm<3> chloroform is mixed dropwise with stirring at room temperature with the solution of 2.77 g diphenyl-malonyl dichloride in 10 cm<3> chloroform, after 4 hours 2.7 cm3 of triethylamine is added and the mixture is allowed to stand under stirring for 12 hours at room temperature. The solution is then shaken out twice with potassium carbonate solution, dried over sodium sulphate and evaporated. The residue is dissolved in hexane and chromatographed in a column of 120 g aluminum oxide. From the fractions eluted with gasoline and chloroform, diphenylmalonyl-bis-(tropyl-3-amide) crystallizes from hexane in fine small rods which, after recrystallization twice from hexane and from ether, have a melting point of 136-138°.
Eksempel 20: difenylmalonyl- bis-( pseudotropyl- 3- amid). Example 20: diphenylmalonyl-bis-(pseudotropyl-3-amide).
En oppløsning av 2,45 g 3-amino-pseudotropan og 2,5 cm<3> trietylamin i 20 cm3 abs kloroform blir under omrøring blandet dråpevis med en oppløsning av 2,5 g difenylmalonyl-diklorid, og blandingen får stå i 20 timer under stadig omrøring. Den oppløsning som filtreres av fra små mengder oppnådd 3-amino-pseudotropan-hydroklorid blir vasket med mettet natri-umkarbonatoppløsning, tørket over natriumsulfat og dampet inn. Fra oppløsningen av resten i heksan krystalliserer etter lengre henstand difenylmalonyl-bis-(pseudotropyl-3-amid) i nåler som er forenet til bunter som etter omkrystallisering fra heksan/eter og ren eter har smp 136—137°. A solution of 2.45 g of 3-amino-pseudotropane and 2.5 cm<3> of triethylamine in 20 cm3 of abs chloroform is mixed dropwise with a solution of 2.5 g of diphenylmalonyl dichloride while stirring, and the mixture is allowed to stand for 20 hours with constant stirring. The solution filtered off from small amounts of 3-amino-pseudotropane hydrochloride obtained is washed with saturated sodium carbonate solution, dried over sodium sulfate and evaporated. From the solution of the residue in hexane, after a longer period of time, diphenylmalonyl-bis-(pseudotropyl-3-amide) crystallizes in needles which are united into bundles which, after recrystallization from hexane/ether and pure ether, have a melting point of 136-137°.
Eksempel 21: difenylmalonyl- bis-( 6- metoksy- tropyl- 3- amid). Example 21: diphenylmalonyl-bis-(6-methoxy-tropyl-3- amide).
En oppløsning av 2,4 g 6-metoksy-3-. amino-tropan (fremstillet som i eksempel 18) i 20 cm<3> abs kloroform blir ved romtemperatur dråpevis blandet under omrø-ring med en oppløsning av 2,0 g difenylmalonyldiklorid i 20 cm<8> abs kloroform, etter 2 timer tilsettes i 2 cm<3> trietylamin og blandingen får stå under omrøring i 15 timer. Oppløsningen blir rystet ut to ganger med mettet natriumkarbonatoppløs-ning, tørket over natriumsulfat og dampet inn. Fra oppløsningen av resten i eter krystalliserer difenylmalonyl-bis- (6-metoksy-tropyl-3-amid) i rettvinklete små plater som etter omkrystallisering fra heksan og eter smelter ved 139—142°. A solution of 2.4 g of 6-methoxy-3-. aminotropane (prepared as in example 18) in 20 cm<3> abs chloroform is mixed dropwise at room temperature with stirring with a solution of 2.0 g of diphenylmalonyl dichloride in 20 cm<8> abs chloroform, after 2 hours is added in 2 cm<3> of triethylamine and the mixture is allowed to stand under stirring for 15 hours. The solution is shaken out twice with saturated sodium carbonate solution, dried over sodium sulfate and evaporated. From the solution of the residue in ether, diphenylmalonyl-bis-(6-methoxy-tropyl-3-amide) crystallizes in right-angled small plates which, after recrystallization from hexane and ether, melt at 139-142°.
Eksempel 22: difenylmalonyl- bis-( 6- metoksy- pseudo tropyl- 3- amid). Example 22: diphenylmalonyl-bis-(6-methoxy-pseudo tropyl-3-amide).
En oppløsning av 2,4 g 6-metoksy-3-amino-pseudotropan i 20 cm3 abs kloroform ved romtemperatur under omrøring blandet dråpevis med en oppløsning av 2,0 g difenylmalonyldiklorid i 20 cm<8> abs kloroform. Etter to timer tilsettes 2 cm<3> tretyl-amin, og blandingen får stå under omrø-ring i 15 timer. Oppløsningen blir rystet ut to ganger med mettet natriumkarbonat-oppløsning, tørket over natriumsulfat og dampet inn. Fra oppløsningen av resten i heksan krystalliserer difenyl-malonyl-bis-(6-metoksy-pseudotropyl-3-amid) i farve-løse nåler som etter flere gangers omkrystallisering fra heksan eller isopropyleter smelter skarpt mellom 90 og 105°. A solution of 2.4 g of 6-methoxy-3-amino-pseudotropane in 20 cm3 of abs chloroform at room temperature with stirring is mixed dropwise with a solution of 2.0 g of diphenylmalonyl dichloride in 20 cm<8> abs of chloroform. After two hours, 2 cm<3> of tretylamine is added, and the mixture is allowed to stand under stirring for 15 hours. The solution is shaken out twice with saturated sodium carbonate solution, dried over sodium sulfate and evaporated. From the solution of the residue in hexane, diphenyl-malonyl-bis-(6-methoxy-pseudotropyl-3-amide) crystallizes in colorless needles which, after several times of recrystallization from hexane or isopropyl ether, melt sharply between 90 and 105°.
Eksempel 23: p- nitrobensosyre- 6- metoksy- tropyl-3- amid. Example 23: p-nitrobenzoic acid 6-methoxy-tropyl-3-amide.
Til en oppløsning av 2,7 g 6-metoksy-3-aminotropan (fremstillet som i eksempel To a solution of 2.7 g of 6-methoxy-3-aminotropane (prepared as in example
18) i 20 cm<3> abs kloroform settes dråpevis oppløsningen av 3,6 g p-nitrobensoylklorid i 20 cm'<1> kloroform, 2,4 cm<3> trietylamin tilsettes og blandingen får stå i tre timer under omrøring ved romtemperatur. Kloroformlaget blir rystet ut med natriumkar-bonatoppløsning og dampet inn. Resten gir 18) in 20 cm<3> abs chloroform, the solution of 3.6 g p-nitrobenzoyl chloride in 20 cm'<1> chloroform is added dropwise, 2.4 cm<3> triethylamine is added and the mixture is allowed to stand for three hours with stirring at room temperature . The chloroform layer is shaken out with sodium carbonate solution and evaporated. The rest gives
ved omkrystallisering fra bensol p-nitrobensosyre-6-metoksy-tropyl-3-amid i form by recrystallization from benzene p-nitrobenzoic acid-6-methoxy-tropyl-3-amide in the form
av et svakt gult pulver som etter videre of a faint yellow powder which after further
omkrystallisering, en gang fra bensol i nær- recrystallization, once from benzol in near-
vær av benkull og tre ganger fra aceton smelter ved 164—165°. weather of bone charcoal and three times from acetone melts at 164—165°.
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GB956166A GB1141198A (en) | 1966-03-04 | 1966-03-04 | Improvements in or relating to impellers, especially for ventilators |
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FR (1) | FR1513039A (en) |
GB (1) | GB1141198A (en) |
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WO1998019070A1 (en) * | 1996-10-28 | 1998-05-07 | Elta Fans Ltd. | Fan rotor |
KR100574860B1 (en) * | 2004-02-25 | 2006-04-27 | 엘지전자 주식회사 | The fan structure of air-conditioner inner door unit |
KR100590333B1 (en) * | 2004-03-05 | 2006-06-19 | 엘지전자 주식회사 | The fan structure of air-conditioner inner door unit |
EP2246191B1 (en) * | 2008-02-28 | 2018-08-15 | Universal Can Corporation | Printing plate cylinder, printing apparatus, and method for producing printing plate cylinder |
DE102012207727B4 (en) * | 2012-05-09 | 2019-04-18 | Man Energy Solutions Se | centrifugal compressors |
FR3033591B1 (en) * | 2015-03-09 | 2019-09-06 | Ecofit | REACTION TYPE VENTILATION TURBINE |
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DE1628421A1 (en) | 1971-09-09 |
DE1941757U (en) | 1966-07-07 |
DE1628421B2 (en) | 1979-02-01 |
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