NO845278L - SUBSTITUTED IMIDAZOLS. - Google Patents
SUBSTITUTED IMIDAZOLS.Info
- Publication number
- NO845278L NO845278L NO845278A NO845278A NO845278L NO 845278 L NO845278 L NO 845278L NO 845278 A NO845278 A NO 845278A NO 845278 A NO845278 A NO 845278A NO 845278 L NO845278 L NO 845278L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- compound
- residue
- phenyl
- methyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 117
- 150000003839 salts Chemical class 0.000 claims description 54
- -1 1-[-(3-methoxy-phenyl)-ethyl]-2-methyl-imidazole Chemical compound 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 239000007858 starting material Substances 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- CILDGVODBJAMGO-UHFFFAOYSA-N 2-methyl-1-(1-phenylethyl)imidazole Chemical compound C1=CN=C(C)N1C(C)C1=CC=CC=C1 CILDGVODBJAMGO-UHFFFAOYSA-N 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 5
- 150000001450 anions Chemical class 0.000 claims description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
- GHRIIVLOPKZOSX-UHFFFAOYSA-N 1-[1-(2,3-dimethoxyphenyl)ethyl]-2-methylimidazole Chemical compound COC1=CC=CC(C(C)N2C(=NC=C2)C)=C1OC GHRIIVLOPKZOSX-UHFFFAOYSA-N 0.000 claims description 2
- BQKOTSFOFCIBBI-UHFFFAOYSA-N 1-[1-(2,3-dimethylphenyl)ethyl]-2-methylimidazole Chemical compound C1=CN=C(C)N1C(C)C1=CC=CC(C)=C1C BQKOTSFOFCIBBI-UHFFFAOYSA-N 0.000 claims description 2
- MBVSJGYRZOVPLT-UHFFFAOYSA-N 1-[1-(2,6-dimethoxyphenyl)ethyl]-2-methylimidazole Chemical compound COC1=CC=CC(OC)=C1C(C)N1C(C)=NC=C1 MBVSJGYRZOVPLT-UHFFFAOYSA-N 0.000 claims description 2
- ZMPUEZSKKQYTIH-UHFFFAOYSA-N 1-[1-(2,6-dimethylphenyl)ethyl]-2-methylimidazole Chemical compound C1=CN=C(C)N1C(C)C1=C(C)C=CC=C1C ZMPUEZSKKQYTIH-UHFFFAOYSA-N 0.000 claims description 2
- PDCKEFKFQGVGRN-UHFFFAOYSA-N 1-[1-(2-ethylphenyl)ethyl]-2-methylimidazole Chemical compound CCC1=CC=CC=C1C(C)N1C(C)=NC=C1 PDCKEFKFQGVGRN-UHFFFAOYSA-N 0.000 claims description 2
- XEMAHKDYQSYSJZ-UHFFFAOYSA-N 1-[1-(2-methoxyphenyl)ethyl]-2-methylimidazole Chemical compound COC1=CC=CC=C1C(C)N1C(C)=NC=C1 XEMAHKDYQSYSJZ-UHFFFAOYSA-N 0.000 claims description 2
- VYZUVHXMYUUWCL-UHFFFAOYSA-N 2-methyl-1-(1-phenylpropyl)imidazole Chemical compound C1=CN=C(C)N1C(CC)C1=CC=CC=C1 VYZUVHXMYUUWCL-UHFFFAOYSA-N 0.000 claims description 2
- VUSYGDCECFZYRZ-UHFFFAOYSA-N 2-methyl-1-[1-(2,4,6-trimethylphenyl)ethyl]imidazole Chemical compound C1=CN=C(C)N1C(C)C1=C(C)C=C(C)C=C1C VUSYGDCECFZYRZ-UHFFFAOYSA-N 0.000 claims description 2
- JULVGTZEGOFPSR-UHFFFAOYSA-N 2-methyl-1-[1-(2-methylphenyl)ethyl]imidazole Chemical compound C1=CN=C(C)N1C(C)C1=CC=CC=C1C JULVGTZEGOFPSR-UHFFFAOYSA-N 0.000 claims description 2
- AKAJCYZGUXNBJC-UHFFFAOYSA-N 2-methyl-1-[1-(3-methylphenyl)ethyl]imidazole Chemical compound C1=CN=C(C)N1C(C)C1=CC=CC(C)=C1 AKAJCYZGUXNBJC-UHFFFAOYSA-N 0.000 claims description 2
- QUDYEMXSFYTKNP-UHFFFAOYSA-N 2-methyl-1-[1-(4-methylphenyl)ethyl]imidazole Chemical compound C1=CN=C(C)N1C(C)C1=CC=C(C)C=C1 QUDYEMXSFYTKNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- ZIBMBPFYMHCCEY-UHFFFAOYSA-N 1-[1-(4-methoxyphenyl)ethyl]-2-methylimidazole Chemical compound C1=CC(OC)=CC=C1C(C)N1C(C)=NC=C1 ZIBMBPFYMHCCEY-UHFFFAOYSA-N 0.000 claims 1
- 125000005037 alkyl phenyl group Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 65
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- 239000000155 melt Substances 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- 239000013543 active substance Substances 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 18
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 230000002378 acidificating effect Effects 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 14
- 229910052736 halogen Inorganic materials 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000002367 halogens Chemical class 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 150000007513 acids Chemical class 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 239000000825 pharmaceutical preparation Substances 0.000 description 9
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 229910052744 lithium Inorganic materials 0.000 description 7
- 239000000052 vinegar Substances 0.000 description 7
- 235000021419 vinegar Nutrition 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 230000001476 alcoholic effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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 4
- 102000010909 Monoamine Oxidase Human genes 0.000 description 4
- 108010062431 Monoamine oxidase Proteins 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- DNHQUGRUHBFDFT-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)ethanol Chemical compound CC(O)C1=CC=C(C)C=C1C DNHQUGRUHBFDFT-UHFFFAOYSA-N 0.000 description 3
- ZLKAKOOPZYTDOD-UHFFFAOYSA-N 2-methyl-1-(1-phenylethyl)imidazole;hydrochloride Chemical compound Cl.C1=CN=C(C)N1C(C)C1=CC=CC=C1 ZLKAKOOPZYTDOD-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 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
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- YKWNUSJLICDQEO-UHFFFAOYSA-N ethoxyethane;propan-2-ol Chemical compound CC(C)O.CCOCC YKWNUSJLICDQEO-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- PPLYZPAMMOECNS-UHFFFAOYSA-N n'-(1-phenylethyl)ethane-1,2-diamine Chemical compound NCCNC(C)C1=CC=CC=C1 PPLYZPAMMOECNS-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 229920001592 potato starch Polymers 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- XABRUGLLZWCSPM-UHFFFAOYSA-N 1-(2,6-dimethoxyphenyl)ethanol Chemical compound COC1=CC=CC(OC)=C1C(C)O XABRUGLLZWCSPM-UHFFFAOYSA-N 0.000 description 2
- JESIHYIJKKUWIS-UHFFFAOYSA-N 1-(4-Methylphenyl)ethanol Chemical compound CC(O)C1=CC=C(C)C=C1 JESIHYIJKKUWIS-UHFFFAOYSA-N 0.000 description 2
- CRJFHXYELTYDSG-UHFFFAOYSA-N 1-(4-nitrophenyl)ethanol Chemical compound CC(O)C1=CC=C([N+]([O-])=O)C=C1 CRJFHXYELTYDSG-UHFFFAOYSA-N 0.000 description 2
- HBIXOIOMBMDWQG-UHFFFAOYSA-N 2,2-dimethoxy-n-(1-phenylethyl)ethanamine Chemical compound COC(OC)CNC(C)C1=CC=CC=C1 HBIXOIOMBMDWQG-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- XALRZLLUQUXZMB-UHFFFAOYSA-N 2-(2-methylimidazol-1-yl)-2-phenylethanol;hydrochloride Chemical compound Cl.CC1=NC=CN1C(CO)C1=CC=CC=C1 XALRZLLUQUXZMB-UHFFFAOYSA-N 0.000 description 2
- WLHXOSIQSJQAMB-UHFFFAOYSA-N 2-[1-(2-methylimidazol-1-yl)ethyl]phenol Chemical compound C1=CN=C(C)N1C(C)C1=CC=CC=C1O WLHXOSIQSJQAMB-UHFFFAOYSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- PPQNDCSTOHZQEH-UHFFFAOYSA-N bis(benzotriazol-1-yl) carbonate Chemical compound N1=NC2=CC=CC=C2N1OC(=O)ON1C2=CC=CC=C2N=N1 PPQNDCSTOHZQEH-UHFFFAOYSA-N 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical compound [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
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- 235000010487 tragacanth Nutrition 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
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- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- CPRPKIMXLHBUGA-UHFFFAOYSA-N triethyltin Chemical group CC[Sn](CC)CC CPRPKIMXLHBUGA-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, ***e
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Description
Oppfinnelsen vedrører fremgangsmåter til fremstilling av substituerte imidazoler med den generelle formel The invention relates to methods for the preparation of substituted imidazoles with the general formula
eller deres salter, hvori Ph betyr usubstituert eller med laverealkyl eller laverealkoksy substituert fenyl og R, or their salts, wherein Ph means unsubstituted or lower alkyl or lower alkoxy substituted phenyl and R,
og R 2 resp. betyr laverealkyl. Det omtales deres anvendelse og farmasøytiske preparater, inneholdende en forbindelse med formel I eller et farmasøytisk anvendbart salt herav. and R 2 resp. means lower alkyl. Their use and pharmaceutical preparations containing a compound of formula I or a pharmaceutically usable salt thereof are discussed.
Med laverealkyl eller laverealkoksy substituert fenyl har spesielt en eller flere, f.eks. to, videre tre, i første linje i orto- og/eller meta-stilling bundet, laverealkyl- With lower alkyl or lower alkoxy substituted phenyl in particular has one or more, e.g. two, further three, in the first line in the ortho- and/or meta-position bonded, lower alkyl-
eller laverealkoksyrester.or lower carboxylic acid residues.
Ovenfor og i det følgende er det med "lavere" betegnedeAbove and in the following, "lower" is denoted
rester eller forbindelser fortrinnsvis å forstå slike som inneholder til og med 7, fremforalt til og med 4 karbonatomer. residues or compounds preferably to be understood as containing up to and including 7, preferably up to and including 4 carbon atoms.
De anvendte generelle begreper har følgende betydninger: Laverealkyl er f.eks. metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl, sek-butyl, tert.-butyl og omfatter videre tilsvarende pentyl-, heksyl- eller heptylrester. Laverealkoksy er f.eks. metoksy, etoksy, n-propyloksy, isopropyloksy, pentyloksy, isobutyloksy og tert-butyloksy. The general terms used have the following meanings: Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and further includes corresponding pentyl, hexyl or heptyl residues. Low-area coke is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, pentyloxy, isobutyloxy and tert-butyloxy.
Salter av forbindelser med formel I er deres syreaddisjonssalter, fortrinnsvis farmasøytisk anvendbare syreaddisjonssalter. Disse dannes eksempelvis med sterke uorganiske syrer, som mineralsyre, f.eks. svovelsyre, en fosforsyre eller en halogenhydrogensyre, med sterke organiske karboksyl- Salts of compounds of formula I are their acid addition salts, preferably pharmaceutically usable acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acid, e.g. sulfuric acid, a phosphoric acid or a halohydrogen acid, with strong organic carboxyl
syrer, som laverealkankarboksylsyrer, f.eks. eddiksyre, som acids, such as lower alkanecarboxylic acids, e.g. acetic acid, which
eventuelt umettede dikarboksylsyrer, f.eks. malon-, malein-eller fumarsyre, eller som hydroksykarboksylsyre, f.eks. vin- eller sitronsyre, eller med sulfonsyrer, som lavere-alkan- eller eventuelt substituerte benzensulfonsyrer, optionally unsaturated dicarboxylic acids, e.g. malonic, maleic or fumaric acid, or as hydroxycarboxylic acid, e.g. tartaric or citric acid, or with sulfonic acids, such as lower-alkane or optionally substituted benzenesulfonic acids,
f.eks. metan- eller p-toluen-sulfonsyre. Omfattet er videre for farmasøytiske anvendelser uegnede salter, da disse eksempelvis kan anvendes for isolering resp. rensning av frie forbindelser ifølge oppfinnelsen samt deres farmasøytisk anvendbare salter. e.g. methanoic or p-toluenesulfonic acid. Also covered are salts unsuitable for pharmaceutical applications, as these can, for example, be used for isolation or purification of free compounds according to the invention as well as their pharmaceutically usable salts.
Forbindelsene ifølge oppfinnelsen har f.eks. verdifulle farmakologiske egenskaper. Spesielt har de den evne selektivt og reversibelt å hemme monoaminooksidase (MAO) The compounds according to the invention have e.g. valuable pharmacological properties. In particular, they have the ability to selectively and reversibly inhibit monoamine oxidase (MAO)
av typen A. Disse egenskaper kan påvises såvel i rottelever som også i rotte-hjerne, hvor resp. avbygningen av serotonin hemmes selektivt. Bestemmelsene av MAO-aktiviteten i rottelever resp. i rottehjerner gjennomføres analogt metodikken av R.J. Wurtman et al., Biochem. Pharmacol. 12, 1439 (1963), idet MAO-hemningen er å fastslå fra en dose på ca. 1 mg/kg etter peroral applikasjon av det virksomme stoff. of type A. These properties can be demonstrated both in rat liver and in rat brain, where resp. the breakdown of serotonin is selectively inhibited. The determinations of the MAO activity in rat liver resp. in rat brains, the methodology of R.J. is carried out analogously. Wurtman et al., Biochem. Pharmacol. 12, 1439 (1963), the MAO inhibition being determined from a dose of approx. 1 mg/kg after oral application of the active substance.
Tilsvarende dan forbindelsene ifølge oppfinnelsen anvendes til profylaktisk og terapeutisk behandling av depressive tilstander. Correspondingly, the compounds according to the invention are used for prophylactic and therapeutic treatment of depressive conditions.
En ytterligere gjenstand for oppfinnelsen er således den profylaktiske og terapeutiske behandling av menneskelig og dyrisk legeme samt anvendelsen av forbindelsen ifølge oppfinnelsen til behandling av depressive tilstander. A further object of the invention is thus the prophylactic and therapeutic treatment of the human and animal body as well as the use of the compound according to the invention for the treatment of depressive conditions.
Oppfinnelsen vedrører eksempelvis forbindelser med formel I eller deres salter, hvori Ph betyr usubstituert eller en-eller flere ganger f.eks. to ganger, med laverealkyl, spesielt med til og med 4 C-atomer substituert fenyl og R^og R^betyr resp. laverealkyl, spesielt med til og med 4 C-atomer. The invention relates, for example, to compounds of formula I or their salts, in which Ph means unsubstituted or one or more times e.g. twice, with lower alkyl, especially with up to 4 C atoms substituted phenyl and R^ and R^ mean resp. lower alkyl, especially with up to 4 C atoms.
Oppfinnelsen vedrører eksempelvis forbindelser med formel I eller deres salter, hvori Ph betyr en- eller flere ganger, f.eks. to ganger, med laverealkoksy, spesielt med til og med 4 C-atomer som metoksy substituert fenyl, og R, og R£betyr resp. laverealkyl, spesielt med til og med 4 C-atomer, som metyl. The invention relates, for example, to compounds of formula I or their salts, in which Ph means one or more times, e.g. twice, with lower alkoxy, especially with up to 4 C atoms such as methoxy substituted phenyl, and R, and R£ means resp. lower alkyl, especially with up to 4 C atoms, such as methyl.
Oppfinnelsen vedrører spesielt forbindelser med formel I eller deres salter, hvori Ph betyr usubstituert eller i stilling 2 eller 3 enkelt med laverealkyl eller laverealkoksy resp. med til og med 4 C-atomer, som metyl eller metoksy, eller i stilling 2 og 6 to ganger med laverealkyl med til og med 4 C-atomer, som metyl, substituert fenyl og R^og R^betyr resp. laverealkyl med til og med 4 C-atomer, som metyl. The invention relates in particular to compounds of formula I or their salts, in which Ph means unsubstituted or in position 2 or 3 single with lower alkyl or lower alkoxy resp. with up to and including 4 C atoms, such as methyl or methoxy, or in positions 2 and 6 twice with lower alkyl with up to and including 4 C atoms, such as methyl, substituted phenyl and R^ and R^ mean resp. lower alkyl with up to 4 C atoms, such as methyl.
Oppfinnelsen vedrører spesielt forbindelser med formel I eller deres salter, hvori Ph betyr usubstituert fenyl og R^ og R^resp. betyr laverealkyl med til og med 4 C-atomer, som metyl. The invention relates in particular to compounds of formula I or their salts, in which Ph means unsubstituted phenyl and R^ and R^ respectively. means lower alkyl of up to 4 C atoms, such as methyl.
Oppfinnelsen vedrører spesielt de i eksemplene nevnte nye forbindelser og deres salter. The invention relates in particular to the new compounds mentioned in the examples and their salts.
Fremgangsmåten til fremstilling av forbindelsene med formel I og deres salter erkarakterisert vedat The process for preparing the compounds of formula I and their salts is characterized thereby
a) en forbindelse med formela) a compound with formula
hvori betyr reaksjonsdyktig forestret hydroksy, omsettes in which means reactive esterified hydroxy, is converted
med en forbindelse med formelwith a compound of formula
hvori X_ betyr hydrogen eller en metallisk rest, eller wherein X_ means hydrogen or a metallic residue, or
b) i en forbindelse med formelb) in a connection with formula
Ph - CH- Het (III) Ph - CH - Het (III)
hvori Het betyr en til 2-R2-imidazol-l-yl overførbar rest, overføres Het til 2-R2-imidazol-l-yl, eller wherein Het means a 2-R2-imidazol-1-yl transferable residue, Het is transferred to 2-R2-imidazol-1-yl, or
c) i en forbindelse med formelc) in a connection with formula
hvori A betyr en til -CH(R^)- overførbar gruppering og wherein A means a group transferable to -CH(R^)- and
resten R^ betyr en til R2overførbar rest eller betyr R2, eller hvori A betyr grupperingen -CH(R^)- og betyr en til R^overførbar rest, overføres A til - CH(R1)- og/eller the residue R^ means a residue transferable to R2 or means R2, or in which A means the group -CH(R^)- and means a residue transferable to R^, A is transferred to - CH(R1)- and/or
R2overføres til R2, ellerR2 is transferred to R2, or
d) en forbindelse med formeld) a compound of formula
hvori A 0 betyr anionet av en protonsyre, reduseres til en tilsvarende forbindelse med formel I, eller wherein A 0 means the anion of a protonic acid, is reduced to a corresponding compound of formula I, or
e) en forbindelse med formele) a compound of formula
hvori betyr en med cyklisering til 2-R2-imidazol-l-yl wherein means a with cyclization to 2-R2-imidazol-1-yl
overførbar gruppe, cykliseres, ellertransferable group, cyclized, or
f) en forbindelse med formelf) a compound of formula
omsettes med en forbindelse med formel R°-Xo, (Vllb), hvori en av restene X^og X^ betyr reaksjonsdyktig forestret hydroksy og den andre betyr en metallisk rest, Xj. betyr restene R^og R°Betyr resten R^>eller hvori en av restene X,, og Xg betyr reaks jonsdyktig forestret hydroksy og den annen betyr en metallisk rest, X^ betyr resten R^og R betyr resten R^, eller g) for fremstilling av forbindelser med formel I eller deres salter, hvori Ph betyr med laverealkoksy i substituert fenyl, overføres i en forbindelse med formel is reacted with a compound of formula R°-Xo, (Vllb), in which one of the residues X^ and X^ means reactive esterified hydroxy and the other means a metallic residue, Xj. means the residues R^ and R° means the residue R^>or in which one of the residues X,, and Xg means reactive ionizable esterified hydroxy and the other means a metallic residue, X^ means the residue R^ and R means the residue R^, or g ) for the preparation of compounds of formula I or their salts, in which Ph means with lower alkoxy in substituted phenyl, is transferred in a compound of formula
hvori Ph<1>betyr en til Ph overførbar rest overføres Ph<1> in which Ph<1> means a residue transferable to Ph is transferred Ph<1>
til Ph,to Ph.
idet de i fremgangsmåtevariant a) til g) anførte utgangsforbindelser eventuelt kan foreligge også i saltform, og hvis ønsket, overføres en ifølge oppfinnelsen oppnådd forbindelse med formel I til en annen forbindelse med formel I og/eller hvis ønsket overføres et dannet salt til den frie forbindelse med formel I eller til et annet salt og/ eller hvis ønsket overføres en ifølge oppfinnelsen oppnådd fri forbindelse med formel I til et salt og/eller hvis ønsket oppdeles en oppnådd isomerblanding i de enkelte komponenter. in that the starting compounds listed in process variant a) to g) can optionally also be present in salt form, and if desired, a compound of formula I obtained according to the invention is transferred to another compound of formula I and/or if desired, a formed salt is transferred to the free compound of formula I or to another salt and/or if desired, a free compound of formula I obtained according to the invention is transferred to a salt and/or if desired, an isomer mixture obtained is divided into the individual components.
De ovenfor og i det følgende i variantene a) til g) omtalte omsetninger gjennomføres på i og for seg kjent måte, f.eks. The transactions mentioned above and below in variants a) to g) are carried out in a manner known per se, e.g.
i fravær eller vanligvis i nærvær av et egnet oppløsnings-eller fo-tynningsmiddel eller en blanding herav, idet man alt etter behov arbeider under avkjøling ved værelsetemperatur eller under oppvarming, f.eks. i et temperaturområde fra in the absence or usually in the presence of a suitable solvent or base thinner or a mixture thereof, working according to need under cooling at room temperature or under heating, e.g. in a temperature range from
ca. -10°C til ca. 250°C, fortrinnsvis på ca. 20° til ca. 150°C, og hvis nødvendig i et lukket kar under trykk, i en inertgass-atmosfære og/eller under vannfrie betingelser. about. -10°C to approx. 250°C, preferably at approx. 20° to approx. 150°C, and if necessary in a closed vessel under pressure, in an inert gas atmosphere and/or under anhydrous conditions.
Det ovenfor og i det følgende oppførte utgangsmaterial medThe above and in the following listed starting material with
. formlene Ila og Hb, III, IV, V, VI, Vila og Vllb samt VIII, som ble utviklet for fremstilling av forbindelser med formel I er delvis kjent eller kan fremstilles likeledes etter i og for seg kjente metoder, f.eks. analogt de ovenfor og nedenfor omtalte fremgangsmåtevarianter. . the formulas Ila and Hb, III, IV, V, VI, Vila and Vllb as well as VIII, which were developed for the preparation of compounds of formula I are partially known or can be prepared likewise according to methods known per se, e.g. analogously to the method variants discussed above and below.
Variant a)Variant a)
Reaksjonsdyktig forestret hydroksy betyr spesielt med enReactive esterified hydroxy means especially with a
sterk uorganisk syre eller organisk sulfonsyre forestret hydroksy, eksempelvis halogen, som klor, brom eller jod, strong inorganic acid or organic sulphonic acid esterified hydroxy, for example halogen, such as chlorine, bromine or iodine,
I sulfonyloksy, som hydroksysulfonyloksy, halogensulfonyloksy, f.eks. fluorsulfonyloksy, eventuelt, f.eks. med halogen substituert laverealkansulfonyloksy, f.eks. metan- eller trifluormetan-sulfonyloksy, cykloalkansulfonyloksy, f.eks. cykloheksansulfonyloksy, eller ventuelt f.eks. med laverealkyl eller halogen, substituert benzensulfonyloksy, f.eks. p-bromfenyl- eller p-toluensulfonyloksy. In sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, e.g. fluorosulfonyloxy, optionally, e.g. with halogen substituted lower alkanesulfonyloxy, e.g. methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or optionally e.g. with lower alkyl or halogen, substituted benzenesulfonyloxy, e.g. p-bromophenyl or p-toluenesulfonyloxy.
En metallisk rest er eksempelvis en alkalimetall-, spesielt litiumrest, videre en kobber-I- eller fra litiumcuprater avledet litium-kobber(I)-rest. A metallic residue is, for example, an alkali metal, especially lithium residue, further a copper-I or lithium-copper(I) residue derived from lithium cuprates.
Omsetningen gjennomføres spesielt i nærvær av et kondensa-sjonsmiddel, som en egnet base. The reaction is carried out in particular in the presence of a condensation agent, such as a suitable base.
Som baser kommer det eksempelvis på tale alkalimetall-hydroksyder, -hydrider, -amider, -alkanolater, -karbonater, -trifenylmetylider, -dilaverealkylamider, -aminoalkyl-amider eller -laverealkylsilylamider, naftalinaminer, laverealkylaminer, basiske heterocykler, ammoniumhydroksyd samt karbocykliske aminer. Eksempelvis skal det nevnes natriumhydroksyd, -hydrid, -amid, kalium-tert-butylat, -karbonat, litium-trifenylmetylid, -diisopropylamid, kalium-3-(aminopropyl)-amid, -bis-(trimetylsilyl)-amid, dimetylaminonaftalin, di- eller trietylamin, pyridin, benzyl-trimetyl-ammoniumhydroksyd, 1,5-diaza-bicyklo [4,3,0]non-5-en (DBN) samt 1,8-diaza-bicyklo[5,4,0]undec-7-en (DBU). Examples of bases include alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, dilower alkyl amides, amino alkyl amides or lower alkyl silyl amides, naphthalene amines, lower alkyl amines, basic heterocycles, ammonium hydroxide and carbocyclic amines. Examples include sodium hydroxide, -hydride, -amide, potassium tert-butylate, -carbonate, lithium triphenylmethylide, -diisopropylamide, potassium 3-(aminopropyl)-amide, -bis-(trimethylsilyl)-amide, dimethylaminonaphthalene, di - or triethylamine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diaza-bicyclo[4,3,0]non-5-ene (DBN) and 1,8-diaza-bicyclo[5,4,0]undec -7-en (DBU).
Betyr X^hydrogen, er tilsetningen av ekstrabase ikke nødvendig, når den som base virkende forbindelse med formel Ilb anvendes i overskudd. Omsetningen av forbindelser med formel Ilb, når X^betyr en metallisk rest, foregår fortrinnsvis uten basetilsetning. If X represents hydrogen, the addition of extra base is not necessary, when the base-acting compound of formula IIb is used in excess. The reaction of compounds of formula IIb, when X represents a metallic residue, preferably takes place without base addition.
Fortrinnsvis gjennomføres omsetningen med slike forbindelser med formel Ilb hvori X ? betyr hydrogen. Preferably, the reaction is carried out with such compounds of formula IIb in which X ? means hydrogen.
Variant b)Variant b)
En i 2-R2-imidazol-l-yl overførbar rest Het kan f.eks. være 3-R2-pyrazol-l-yl. A 2-R2-imidazol-1-yl transferable residue Het can e.g. be 3-R2-pyrazol-1-yl.
Dets overføring til 2-R2-imidazol-l-yl kan eksempelvis foregå ved fotoisomerisering, f.eks. ved bestråling, som med en høytrykks kvikksølvlampe. Its transfer to 2-R2-imidazol-1-yl can for example take place by photoisomerisation, e.g. by irradiation, as with a high-pressure mercury lamp.
En til 2-R2-imidazol-l-yl overførbar rest Het kan likeledes bety 2-R2-imidazolin-l-yl, spesielt 2-R2-imidazol-2-in-l-yl, som f.eks. ved dehydrogenering kan overføres til 2-R2~imidazol-l-yl. A 2-R2-imidazol-1-yl transferable residue Het can also mean 2-R2-imidazolin-1-yl, especially 2-R2-imidazol-2-yn-1-yl, as e.g. by dehydrogenation can be transferred to 2-R2~imidazol-1-yl.
For dehydrogeneringen anvender man egnede dehydrogeneringsmidler, eksempelvis bigruppeelementer, fortrinnsvis slike fra det periodiske systems VIII bigruppe, f.eks. palladium, Raney-nikkel eller platina, eller tilsvarende edelmetall-derivater, f.eks. platinaoksyd eller ruthenium-trifenyl-fosfid-klorid, idet midlene kan være trukket opp av egnede bærematerialer som kull. Ytterligere foretrukkede dehydrogeneringsmidler er eksempelvis chinoner, som p-benzochinon, f.eks. tetraklor-p-benzochinon eller 2,3-diklor-5,6-dicyano-p-benzochinon, samt fenantren-9,10-chinon. Videre kan det anvendes N-halogensuccinimid, som N-klor-succinimid, manganforbindelser, som bariummanganat eller mangandioksyd og svovel- samt selenderivater, som svovel, selen, selendioksyd eller difenylselenium-bis-trifluoracetat. For the dehydrogenation, suitable dehydrogenating agents are used, for example subgroup elements, preferably those from subgroup VIII of the periodic table, e.g. palladium, Raney nickel or platinum, or similar precious metal derivatives, e.g. platinum oxide or ruthenium triphenyl phosphide chloride, the agents can be drawn up by suitable carrier materials such as coal. Further preferred dehydrogenating agents are, for example, quinones, such as p-benzoquinone, e.g. tetrachloro-p-benzoquinone or 2,3-dichloro-5,6-dicyano-p-benzoquinone, as well as phenanthrene-9,10-quinone. Furthermore, N-halogensuccinimide, such as N-chlorosuccinimide, manganese compounds, such as barium manganate or manganese dioxide and sulfur and selenium derivatives, such as sulphur, selenium, selenium dioxide or diphenylselenium bis-trifluoroacetate, can be used.
Variant c)Variant c)
Et til grupperingen -CH(R^)-overførbar strukturelement A betyr eksempelvis grupperingen -C(R^)(Zq)-, idet R| enten betyr resten Ri . som har en til i hydrogen overførbar rest Z-,L og Zq betyr hydrogen, eller R^ betyr R^og Zq er en til hydrogen overførbar rest Z^, eller idet R| og Zq sammen danner laverealkenyliden eller en tautomer form. Likeledes er til R2overførbare rester R2med en i hydrogen overførbar rest Z^ substituert laverealkylrester. A structural element A transferable to the grouping -CH(R^) means, for example, the grouping -C(R^)(Zq)-, where R| either the remainder means Ri. which has one more hydrogen-transferable residue Z-, L and Zq means hydrogen, or R^ means R^ and Zq is a hydrogen-transferable residue Z^, or where R| and Zq together form the lower alkenylidene or a tautomeric form. Similarly, to R 2 transferable residues R 2 with a hydrogen transferable residue Z 2 are substituted lower alkyl residues.
kan f.eks. ved reduksjon overføres til hydrogen og betyr følgelig eksempelvis hydroksy, foretret hydroksy, som laverealkoksy, halogen, sulfonyloksy, som eventuelt f.eks. can e.g. by reduction is transferred to hydrogen and consequently means, for example, hydroxy, etherified hydroxy, such as lower alkoxy, halogen, sulfonyloxy, which may e.g.
med halogen substituert laverealkansulfonyloksy, cyklo-laverealkansulfonyloksy eller eventuelt, f.eks. med laverealkyl eller halogen, substituert benzensulfonyloksy, with halogen-substituted lower alkanesulfonyloxy, cyclo-lower alkanesulfonyloxy or optionally, e.g. with lower alkyl or halogen, substituted benzenesulfonyloxy,
merkapto eller foretret merkapto, som laverealkyltio.mercapto or etherified mercapto, such as lower alkylthio.
Den reduktive overføring av A til grupperingen -CH(R^)- resp. fra R^ til R2foregår på i og for seg kjent måte, f.eks. ved hjelp av et reduksjonsmiddel, eksempelvis ved hydrogenering i nærvær av en hydrogeneringskatalysator ved reduksjon med hydridoverførende reagens eller ved reduksjon med et metallisk reduksjonssystem av metall og protonavspaltende middel. The reductive transfer of A to the group -CH(R^)- resp. from R^ to R2 takes place in a manner known per se, e.g. by means of a reducing agent, for example by hydrogenation in the presence of a hydrogenation catalyst by reduction with a hydride-transferring reagent or by reduction with a metallic reduction system of metal and proton-releasing agent.
Som hydrogeneringskatalysatorer kommer det f.eks. på tale elementer fra det VIII. bigruppe i det periodiske system eller deres derivater, som palladium, platina, platinaoksyder, rutenium, rhodium, tris-(trifenylfosfin)-rhodium(I)halogenid, f.eks. -klorid, eller Raney-nikkel, som eventuelt er trukket opp på et bærematerial, som aktivkull, alkalimetallkarbonat resp. -sulfat eller en kiselgel. Som hydrid-overførende reagenser kommer det eksempelvis på tale egnede lettmetall-hydrider, spesielt alkalimetallaluminiumhydrider resp. -borhydrider, som litiumaluminiumhydrid, litiumtrietyl-borhydrid, natriumborhydrid, natriumcyanborhydrid eller tinnhydrider som trietyl- eller tributyltinnhydrid, eller diboran. Metallbestanddelene av det metalliske reduksjonssystem er eksempelvis et uedlet metall, som alkali- eller jordalkalimetall, f.eks. litium, natrium, kalium, magnesium eller kalsium, eller overgangsmetaller, f.eks. sink, tinn eller jern eller titan, mens som protonavspaltende middel f.eks. kommer på tale protonsyrer, som salt- eller eddiksyre, laverealkanoler, som etanol og/eller aminer resp. ammoniakk. Slike systemer er eksempelvis natrium/ammoniakk, sink/salt- eller eddiksyre eller sink/etanol. As hydrogenation catalysts, there are e.g. speaking of elements from the VIII. subgroup of the periodic table or their derivatives, such as palladium, platinum, platinum oxides, ruthenium, rhodium, tris-(triphenylphosphine)-rhodium(I) halide, e.g. -chloride, or Raney nickel, which is possibly drawn up on a carrier material, such as activated carbon, alkali metal carbonate or -sulphate or a silica gel. Suitable hydride-transferring reagents include, for example, suitable light metal hydrides, especially alkali metal aluminum hydrides or -borohydrides, such as lithium aluminum hydride, lithium triethyl borohydride, sodium borohydride, sodium cyanoborohydride or tin hydrides such as triethyl or tributyltin hydride, or diborane. The metal components of the metallic reduction system are, for example, a base metal, such as alkali or alkaline earth metal, e.g. lithium, sodium, potassium, magnesium or calcium, or transition metals, e.g. zinc, tin or iron or titanium, while as a proton splitting agent e.g. come into question protonic acids, such as hydrochloric or acetic acid, lower alkanols, such as ethanol and/or amines or ammonia. Such systems are, for example, sodium/ammonia, zinc/hydrochloric or acetic acid or zinc/ethanol.
I en foretrukket utførelsesform av denne fremgangsmåte reduseres eksempelvis hydroksy eller eventuelt foretret merkapto ved hjelp av katalyttisk hydrogenering, f.eks. i nærvær av Raney-nikkel, og halogen eller sulfonyloksyd, f.eks. med hydrid-overfarende reagenser, ved hjelp av tributyltinnhydrid, litiumaluminiumhydrid eller natrium-cyanoborhydrid eller natrium/ammoniakk. In a preferred embodiment of this method, for example, hydroxy or optionally etherified mercapto is reduced by means of catalytic hydrogenation, e.g. in the presence of Raney nickel, and halogen or sulfonyl oxide, e.g. with hydride transfer reagents, using tributyltin hydride, lithium aluminum hydride or sodium cyanoborohydride or sodium/ammonia.
Hydroksy kan videre ved behandling med fosfor (rød) og jodhydrogen resp. jod erstattes med hydrogen. Hydroxy can further by treatment with phosphorus (red) and hydrogen iodide resp. iodine is replaced by hydrogen.
Fortrinnsvis erstattes i benzylisk stilling befinnendePreferably substituted in the benzylic position
med hydrogen erstattbare rester Z^ med hydrogen.hydrogen-replaceable residues Z^ with hydrogen.
Z1kan videre bety karboksy. Dekarboksyleringen av tilsvarende forbindelser med formel IV kan vanligvis gjennom-føres ved forhøyede temperaturer, eksempelvis fra en temperatur på ca. 50°C, spesielt i et temperaturområde på Z1 can further mean carboxy. The decarboxylation of corresponding compounds of formula IV can usually be carried out at elevated temperatures, for example from a temperature of approx. 50°C, especially in a temperature range of
ca. 100°C til ca. 300°C.Dekarboksyleringen kan eksempelvis understøttes ved nærvær av baser, som høytkokende nitrogenbase, f.eks. collidin og/eller i nærvær av edel-metaller, som kobber eller kobberbronse. about. 100°C to approx. 300°C. The decarboxylation can, for example, be supported by the presence of bases, such as high-boiling nitrogen base, e.g. collidin and/or in the presence of noble metals, such as copper or copper bronze.
I første rekke går man ut fra slike forbindelser medIn the first place, one starts from such connections with
formel IV, som bare har en til hydrogen overførbar rest Z . formula IV, which has only one hydrogen transferable residue Z .
Variant d)Variant d)
Reduksjonen av iminiumsaltene med formel V til de tertiære aminer med formel I foregår eksempelvis ved hjelp av et reduksjonsmiddel, f.eks. et slikt av de i variant c) oppførte typer. Eksempelvis for egnede muligheter av reduksjonen skal det nevnes katalyttiske hydrogenering, behandling med et hydrid-overførende reagens, f.eks. natriumborhydrid, eller anvendelse av det metalliske reduksjonssystem sink/saltsyre. The reduction of the iminium salts of formula V to the tertiary amines of formula I takes place, for example, with the aid of a reducing agent, e.g. one of the types listed in variant c). Examples of suitable options for the reduction include catalytic hydrogenation, treatment with a hydride-transferring reagent, e.g. sodium borohydride, or use of the metallic reduction system zinc/hydrochloric acid.
Som reduksjonsmiddel kan det videre anvendes maursyre. Formic acid can also be used as a reducing agent.
Variant e)Variant e)
En ved hjelp av cyklisering til 2-R2-imidazol-l-yl over-førbar gruppering X^betyr eksempelvis gruppen med formel A transferable grouping X^ by means of cyclization to 2-R2-imidazol-1-yl means, for example, the group of formula
Cykliseringen av gruppen Via foregår eksempelvis ved vanlig behandling av tilsvarende forbindelser med formel VII The cyclization of the group Via takes place, for example, by usual treatment of corresponding compounds of formula VII
med et surt middel, spesielt et mineralsyreanhydrid, som et fosforoksyhalogenid, f. eks. -klorid eller fosforpenta-halogenid, f.eks. -klorid. Spesielt egnet er systemet trifenylfosfin/heksakloretan/trietylamin. I første rekke går man frem analogt den av W. Steglich et al., Liebigs Ann. Chem. 1978, 1916-1927 omtalte måte. with an acidic agent, especially a mineral anhydride, such as a phosphorus oxyhalide, e.g. -chloride or phosphorus pentahalide, e.g. -chloride. The system triphenylphosphine/hexachloroethane/triethylamine is particularly suitable. In the first instance, one proceeds analogously to that of W. Steglich et al., Liebig's Ann. Chem. 1978, 1916-1927 mentioned manner.
X^ kan videre bety en gruppe med formelX^ can further mean a group with formula
1idet formylgruppen også kan foreligge i acetalisert form, eksempelvis som med en alkohol som laverealkanol resp. laverealkandiol, acetalisert formyl. 1 since the formyl group can also be present in acetalized form, for example with an alcohol such as lower alkanol or lower alkanediol, acetalized formyl.
Cykliseringen kan eksempelvis foregå i nærvær av et surtThe cyclization can, for example, take place in the presence of an acid
i middel, eksempelvis en protonsyre, som en mineralsyre, f.eks. in medium, for example a protonic acid, such as a mineral acid, e.g.
halogenhydrogen-, svovel- eller polyfosforsyre, en sulfonsyre, f.eks. trifluormetan- eller p-toluensulfonsyre, eller en sterk karboksylsyre, f.eks. eventuelt substituert laverealkankarboksylsyre, f.eks. iseddik eller trifluoreddiksyre. Videre , egner det seg eksempelvis de ovennevnte mineralsyreanhydrider. hydrohalic, sulfuric or polyphosphoric acid, a sulphonic acid, e.g. trifluoromethane or p-toluenesulfonic acid, or a strong carboxylic acid, e.g. optionally substituted lower alkanecarboxylic acid, e.g. glacial acetic acid or trifluoroacetic acid. Furthermore, the above-mentioned mineral anhydrides are suitable, for example.
Variant f)Variant f)
Reaksjonsdyktig forestret hydroksy X^resp. X,, resp. X^har eksempelvis de i variant a) for X^angitte betydning, mens en metallisk rest X^resp. X^resp. X^f.eks. betyr et alkalimetall- som litium-, natrium- eller kaliumrest, en magnesiumhalogenid- som -bromidrest, en kobber- eller litiumkobberrest som avleder seg fra litium-kuprater. Reactive esterified hydroxy X^resp. X,, resp. X^, for example, has the meaning given in variant a) for X^, while a metallic residue X^resp. X^resp. X^eg means an alkali metal such as lithium, sodium or potassium residue, a magnesium halide such as bromide residue, a copper or lithium copper residue derived from lithium cuprates.
I en modifikasjon av fremgangsmåten kan man eksempelvis gå ut fra en forbindelse med formel Vila, hvori X^ og X^ resp. betyr hydrogen, og behandle disse med en sterk base som butyllitium, og omsetter den således oppnådde forbindelse med formel Vila, hvori X^og X,, hver betyr en metallisk rest som litium, med minst 2 mol av en forbindelse med formel Vllb. Derved kan man i første rekke in situ få en forbindelse In a modification of the method, one can for example start from a compound of formula Vila, in which X^ and X^ resp. means hydrogen, and treat these with a strong base such as butyllithium, and react the thus obtained compound of formula VIIa, in which X^ and X,, each means a metallic residue such as lithium, with at least 2 moles of a compound of formula VIIb. Thereby, a connection can primarily be obtained in situ
med formel Vila, hvori en av restene X^og X^betyr en metallisk rest og den andre betyr R^resp. R2, som under reaksjonsbetingelsene direkte viderereagerer til den tilsvarende forbindelse med formel I. with formula Vila, in which one of the residues X^ and X^ means a metallic residue and the other means R^resp. R2, which under the reaction conditions directly further reacts to the corresponding compound of formula I.
Fortrinnsvis gjennomføres denne omsetning i første rekkePreferably, this turnover is carried out in the first place
ved lave temperaturer, f.eks. i et temperaturområde fraat low temperatures, e.g. in a temperature range from
-78°C til værelsetemperatur.-78°C to room temperature.
Variant g)Variant g)
Ph' betyr eksempelvis med hydroksy substituert fenyl.Ph' means, for example, hydroxy substituted phenyl.
Slike forbindelser med formel VIII kan ved foretring medSuch compounds of formula VIII can by etherification with
et laverealkyleringsmiddel overføres i forbindelser med formel I. Til de laverealkyleringsmidler hører eksempelvis laverealkanoler eller reaksjonsdyktige estere herav, som tilsvarende halogen-, som klor-, brom- eller jod-, sulfonyloksy-, som hydroksysulfonyloksy-, halogensulfonyloksy-, f.eks. fluorsulfonyloksy-, eventuelt f.eks. med halogen substituert laverealkansulfonyloksy-, f.eks. a lower alkylating agent is transferred into compounds of formula I. The lower alkylating agents include, for example, lower alkanols or reactive esters thereof, such as corresponding halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halogensulfonyloxy, e.g. fluorosulfonyloxy-, possibly e.g. with halogen substituted lower alkanesulfonyloxy-, e.g.
metan- eller trifluormetansulfonyloksy-, cykloalkan3ulfonyl-, f.eks. cykloheksansulfonyloksy-, eller eventuelt f.eks. methane- or trifluoromethanesulfonyloxy-, cycloalkane3sulfonyl-, e.g. cyclohexanesulfonyloxy-, or optionally e.g.
med laverealkyl eller halogen substituert benzensulfonyl-oksyderivater, f.eks. p-bromfenyl- eller p-toluensulfonyloksy-derivater. Likeledes kommer det som laverealkyleringsmidler f.eks. i betraktning dilaverealkylsulfat, diazolaverealkan, trilaverealkylsulfonium-, trilaverealkyl-selenium-, trilaverealkyloksosulfonium- eller trilavere-alkylanilinium-hydroksyd, videre pentalaverealkoksyfosfin. with lower alkyl or halogen substituted benzenesulfonyloxy derivatives, e.g. p-bromophenyl or p-toluenesulfonyloxy derivatives. Likewise, it comes as lower alkylating agents, e.g. in consideration dilaverealkyl sulfate, diazolaveralkane, trilaverealkylsulfonium, trilaverealkylselenium, trilaverealkyloxosulfonium or trilaverealkylanilinium hydroxide, further pentalavereal oxyphosphine.
Ved anvendelsen av reaksjonsdyktige estere av laverealkanoler eller dilaverealkylsulfater som laverealkyleringsmidler foregår foretringen spesielt i nærvær av en av de ovennevnte baser, mens omsetning med diazolaverealkan eventuelt gjennomføres i nærvær av en Lewis-syre. Lewis-syrer er eksempelvis halogenider av bor, aluminium, Tinn(II), antimon(III), arsen(III), sølv(I), sink(II) og jern(III). When using reactive esters of lower alkanols or dilower alkyl sulfates as lower alkylating agents, the etherification takes place in particular in the presence of one of the above-mentioned bases, while reaction with diazole alkane is optionally carried out in the presence of a Lewis acid. Lewis acids are, for example, halides of boron, aluminium, tin(II), antimony(III), arsenic(III), silver(I), zinc(II) and iron(III).
Foretringen ved hjelp aven laverealkanol gjennomføres eksempelvis i nærvær av en sterk syre eller under vann- The esterification using lower alkanol is carried out, for example, in the presence of a strong acid or under water
frie betingelser, et dehydratiseringsmiddel.free conditions, a dehydrating agent.
Som sterke syrer skal det spesielt nevnes sterke protonsyrer, eksempelvis mineralsyrer, som halogenhydrogen- As strong acids, special mention should be made of strong protonic acids, for example mineral acids, such as halogen hydrogen-
syrer, svovel- eller en fosforsyre, sterke karboksylsyrer som en eventuelt f.eks. med halogen substituert laverealkankarboksylsyre resp. benzosyre, f.eks. iseddik eller trifluoreddiksyre, eller sulfonsyrer, som eventuelt f.eks. med halogen, substituerte laverealkansulfonsyrer eller eventuelt, f.eks. med halogen eller laverealkyl substituert benzolsulfonsyre, f.eks. p-toluensulfonsyre. acids, sulfuric or a phosphoric acid, strong carboxylic acids such as a possibly e.g. with halogen-substituted lower alkanecarboxylic acid resp. benzoic acid, e.g. glacial acetic acid or trifluoroacetic acid, or sulphonic acids, which may e.g. with halogen, substituted lower alkanesulfonic acids or optionally, e.g. with halogen or lower alkyl substituted benzenesulfonic acid, e.g. p-toluenesulfonic acid.
Egnede dehydratiseringsmidler er eksempelvis karbodiimider, f.eks. N,N'-dilaverealkyl- eller N,N'-dicykloalkyl-karbo-diimid, som N,N'-dietyl-, N,N'-diisopropyl- eller N ,N' - dicykloheksyl-karbodiimider, fortrinnsvis under tilsetning av N-hydroksysuccinimid eller eventuelt, f.eks. med halogen, laverealkyl eller laverealkoksy, substituert 1-hydroksy-benzotriazol eller N-hydroksy-5-norbornen-2,3-dikarboksamid, N,N'-diimidazolkarbonyl, en egnet fosforyl- resp. fosfin-forbindelse, f.eks. dietylfosfonylcyanid, difenyl-fosfonylazid eller trifenylfosfin-disulfid, et 1-laverealkyl-2-halogen-pyridinium-halogenid, f.eks. l-metyl-2-klor-pyridiniumiodid, et egnet 1,2-dihydrokinolin, f.eks. N-etoksykarbonyl-2-etoksy-l,2-dihydrokinolin eller 1,1'-(karbonyldioksy)-dibenzotriazol. Suitable dehydrating agents are, for example, carbodiimides, e.g. N,N'-dilower alkyl or N,N'-dicycloalkyl carbodiimide, such as N,N'-diethyl, N,N'-diisopropyl or N,N'-dicyclohexyl carbodiimides, preferably with the addition of N -hydroxysuccinimide or optionally, e.g. with halogen, lower alkyl or lower alkoxy, substituted 1-hydroxy-benzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide, N,N'-diimidazole carbonyl, a suitable phosphoryl- or phosphine compound, e.g. diethylphosphonyl cyanide, diphenylphosphonyl azide or triphenylphosphine disulfide, a 1-lower alkyl-2-halo-pyridinium halide, e.g. 1-methyl-2-chloro-pyridinium iodide, a suitable 1,2-dihydroquinoline, e.g. N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or 1,1'-(carbonyldioxy)-dibenzotriazole.
Ph<1>betyr eksempelvis likeledes en diazoniumgruppering -N A av fenyl, idet A betyr et anion av en sterk protonsyre. Ph<1> also means, for example, a diazonium grouping -N A of phenyl, where A means an anion of a strong protonic acid.
For overføring av slike forbindelser med formel VIII i tilsvarende forbindelser med formel I substitueres diazonium-0 0 For the transfer of such compounds of formula VIII into corresponding compounds of formula I, diazonium-O 0 is substituted
grupperingen -N2 A med laverealkoksy, spesielt ved behandling med en laverealkanol. the grouping -N2 A with lower alkoxy, especially when treated with a lower alkanol.
I en fordelaktig modifikasjon av denne fremgangsmåtevariant kan forbindelsene med formel VIII dannes in situ og viderereagere under reaksjonsbetingelsene uten isolering til forbindelsene med formel I. Derved går man i første rekke ut fra en forbindelse med formel VIII, hvori Ph' In an advantageous modification of this process variant, the compounds of formula VIII can be formed in situ and react further under the reaction conditions without isolation to the compounds of formula I. Thereby, one starts primarily from a compound of formula VIII, in which Ph'
betyr en aminogruppeholdig fenyl, diazoterer denne med nitritter, som alkalimetallnitriter, eller nitrolaverealkaner i nærvær av protonsyrer, f.eks. slike av ovennevnte type, means a phenyl containing an amino group, diazotizes this with nitrites, such as alkali metal nitrites, or nitrolower alkanes in the presence of protonic acids, e.g. those of the above type,
og omsetter de in situ dannede forbindelser med formel VIIIand reacts the in situ formed compounds of formula VIII
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hvori Ph<1>betyr eri diazoniumgruppering N,>A holdig fenyl, uten deres isolering med en laverealkanol. Fortrinnsvis velges for denne omsetning en reaksjonstemperatur på ca. wherein Ph<1>means eri diazonium grouping N,>A containing phenyl, without their isolation with a lower alkanol. A reaction temperature of approx.
-10° til ca. 40°C.-10° to approx. 40°C.
Oppfinnelsen vedrører fremforalt de utførelseseksemplene omtalt ved fremstillingsfremgangsmåter. The invention relates above all to the examples of execution mentioned in manufacturing methods.
En forbindelse ifølge oppfinnelsen kan etter i og for seg kjente metoder overføres i en annen forbindelse ifølge oppfinnelsen. A compound according to the invention can be transferred into another compound according to the invention by methods known per se.
Således kan det eksempelvis i fenylringen Ph innføres en laverealkylrest, idet eksempelvis det alkyleres med en reaksjonsdyktig ester av laverealkanol i nærvær av en Lewis-syre (Friedel-Crafts-alkylering). Thus, for example, a lower alkyl residue can be introduced into the phenyl ring Ph, as, for example, it is alkylated with a reactive ester of a lower alkanol in the presence of a Lewis acid (Friedel-Crafts alkylation).
Fremstillingen av de i variantene a) til g) omtalte utgangsmaterialer foregår under anvendelse av i og for seg kjente metoder. The production of the starting materials mentioned in variants a) to g) takes place using methods known per se.
Således kan eksempelvis utgangsmaterialene med formel III fremstilles ved omsetning av forbindelser med formel Ila med forbindelser med formel X2-Het (Illa) analogt den i variant a) omtalte fremgangsmåte. Thus, for example, the starting materials of formula III can be prepared by reacting compounds of formula IIa with compounds of formula X2-Het (IIa) analogously to the method described in variant a).
Likeledes kan man komme til utgangsforbindelser med formel IV, Vila resp. VIII f.eks. ved omsetning av Likewise, one can get to output connections with formula IV, Vila resp. VIII e.g. by turnover of
forbindelser med formel Ph-A-X1(IVa) og (Ilb) [fører til forbindelser med formel IV] resp. Ph-CH(X4)-X1(VIIc) og compounds of formula Ph-A-X1(IVa) and (Ilb) [leads to compounds of formula IV] resp. Ph-CH(X4)-X1(VIIc) and
(Vlld) [fører til forbindelser med formel Vila] samt Ph'-CH(R1)-X1(Illa) og (Ilb) [fører til forbindelser med formel VIII]. Forbindelser med formel VI, hvori X^betyr grupperingen med formel Via, er eksempelvis oppnåelig ved syrekatalysert reaksjon av forbindelsene med formel med forbindelser med formel Forbindelser med formel VI, hvori X^betyr grupperingen med formel Vlb resp. Vlb' er eksempelvis tilgjengelig ved kondensasjon av forbindelser med formel hvori Xg betyr en avspaltbar gruppe som laverealkoksy eller amino, og forbindelser med formel idet den sekundære aminogruppe også i tillegg kan ha en acylrest som laverealkanoyl, f.eks. acetyl. En ytterligere variant ved fremstilling av en forbindelse med formel VI, hvori X^betyr grupperingen med formel Vlb resp. Vlb', består f.eks. i omsetning av en forbindelse med formel Vid med en forbindelse med formel Vie og kondensasjon av den således oppnåelige forbindelse med formel med et monohalogenacetaldehyd eller spesielt et acetal herav. Likeledes kan man omsette forbindelser med formel (Vlld) [leading to compounds of formula Vila] as well as Ph'-CH(R1)-X1(Illa) and (Ilb) [leading to compounds of formula VIII]. Compounds of formula VI, in which X^ means the grouping of formula Via, can for example be obtained by acid-catalyzed reaction of the compounds of formula with compounds of formula Compounds of formula VI, in which X^ means the grouping of formula Vlb resp. Vlb' is, for example, available by condensation of compounds of formula in which Xg means a cleavable group such as lower alkoxy or amino, and compounds of formula where the secondary amino group can also additionally have an acyl residue such as lower alkanoyl, e.g. acetyl. A further variant in the preparation of a compound of formula VI, in which X represents the grouping of formula Vlb or Vlb', consists of e.g. in reaction of a compound of formula Vid with a compound of formula Vie and condensation of the thus obtainable compound of formula with a monohalogenacetaldehyde or especially an acetal thereof. Similarly, compounds can be converted by formula
med et acetal av aminoacetaldehyd. with an acetal of aminoacetaldehyde.
En forbindelse med formel VI, hvori X^betyr grupperingen Vlb resp. Vlb' kan spesielt dannes in situ og viderereagere under reaksjonsbetingelsene direkte til den tilsvarende forbindelse med formel I. A compound of formula VI, in which X represents the grouping Vlb or Vlb' can in particular be formed in situ and further react under the reaction conditions directly to the corresponding compound of formula I.
Salter av forbindelser med formel (I) kan fremstilles på i og for seg kjente måte. Således får man eksempelvis syre-addis jonssalter av forbindelser med formel (I) ved behandling med en syre eller et egnet ioneutvekslingsreagens. Salter kan på vanlig måte overføres til de frie forbindelser, syreaddisjonssalter f.eks. ved behandling med et egnet basisk middel. Salts of compounds of formula (I) can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of formula (I) are obtained by treatment with an acid or a suitable ion exchange reagent. Salts can be transferred in the usual way to the free compounds, acid addition salts, e.g. by treatment with a suitable basic agent.
Alt etter fremgangsmåte res<p>. reaksjonsbetingelser kan forbindelsene ifølge oppfinnelsen med saltdannende, spesielt basiske, egenskaper fåes i fri form eller i form av salter. Depending on the procedure res<p>. reaction conditions, the compounds according to the invention with salt-forming, especially basic, properties can be obtained in free form or in the form of salts.
På grunn av det snevre forhold mellom de nye forbindelserBecause of the narrow relationship between the new connections
i fri form og i form av deres salter er det i det foregående og følgende med fri forbindelse eller deres salter også eventuelt å forstå de tilsvarende salter resp. de frie forbindelser. in free form and in the form of their salts, in the foregoing and the following, free compounds or their salts also possibly mean the corresponding salts or the free connections.
De nye forbindelser inbefattende deres salter av saltdannende forbindelser kan også fåes i form av deres hydrater eller andre som inneslutter til krystallisering anvendte oppløsningsmidler. The new compounds including their salts of salt-forming compounds can also be obtained in the form of their hydrates or others which contain solvents used for crystallization.
De nye forbindelser kan alt etter valg av utgangsstofferThe new compounds can depend on the choice of starting materials
og arbeidsmåter foreligge i form av en av de mulige isomere eller som blandinger av disse, f.eks. alt etter antallet av asymmetriske karbonatomer som rene optiske isomere, som antipoder eller som isomerblandinger, som racemater, diastereomerblandinger eller racematblandinger. and working methods exist in the form of one of the possible isomers or as mixtures of these, e.g. depending on the number of asymmetric carbon atoms as pure optical isomers, as antipodes or as mixtures of isomers, as racemates, diastereomer mixtures or racemate mixtures.
Dannede diastereomerblandinger og racematblandinger kan oppdeles på grunn av de fysikalsk-kjemiske forskjeller av bestanddelen på kjent måte i de rene isomere,diasteromere eller racemater, eksempelvis ved fraksjonert krystallisering . Formed diastereomer mixtures and racemate mixtures can be divided due to the physico-chemical differences of the component in a known manner into the pure isomers, diastereomers or racemates, for example by fractional crystallization.
Dannede racemater lar seg videre etter kjente metoder oppdele i de optiske antipoder, eksempelvis ved omkrystal lisering fra et optisk aktivt oppløsningsmiddel, kromato-grafi på chirale adsorbentier ved hjelp av egnede mikro-organismer, under spaltning med spesifikke, immobiliserte enzymer, over dannelsene av innslutningsforbindelser, f.eks. under anvendelse av chirale kroneetere, idet bare en enantiomer komplekseres, eller ved overføring i diastereomere salter, f.eks. ved omsetning av et basisk sluttstoff-racemat med en optisk aktiv syre, som karboksylsyre, f.eks. vin- eller eplesyre, eller sulfonsyre, f.eks. kamfer-sulfonsyre, og oppdeling av den på denne måte dannede diastereomerblanding, f.eks. på grunn av deres forskjellige oppløseligheter, i de diastereomere, hvorav den ønskede enantiomere kan frigjøres ved innvirkning av egnede midler. Fortrinnsvis isolerer man den mest virksomme enantiomer. Formed racemates can be further divided into the optical antipodes according to known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents with the help of suitable micro-organisms, during cleavage with specific, immobilized enzymes, over the formation of inclusion compounds , e.g. using chiral crown ethers, with only one enantiomer being complexed, or by transfer into diastereomeric salts, e.g. by reacting a basic end product racemate with an optically active acid, such as carboxylic acid, e.g. tartaric or malic acid, or sulphonic acid, e.g. camphor-sulfonic acid, and splitting the diastereomer mixture formed in this way, e.g. due to their different solubilities, in the diastereomers, of which the desired enantiomer can be liberated by the action of suitable agents. Preferably, the most active enantiomer is isolated.
Oppfinnelsen vedrører også de utførelsesformer av fremgangsmåten ifølge hvilke man går ut fra en på et eller annet trinn av fremgangsmåten som mellomprodukt dannet forbindelse og gjennomfører de manglende trinn, eller anvender et utgangsstoff i form av et derivat resp. salt, og/eller dets-racemat resp. antipoder eller spesielt dannede under reaksjonsbetingelsene. The invention also relates to the embodiments of the method according to which one starts from one or the other step of the method as an intermediate formed compound and carries out the missing steps, or uses a starting substance in the form of a derivative resp. salt, and/or its race food resp. antipodes or specially formed under the reaction conditions.
Ved fremgangsmåten ifølge oppfinnelsen anvendes fortrinnsvis slike utgangsstoffer, som fører til de innledningsvis som spesielt fordelaktig omtalte forbindelser. Nye utgangsstoffer som ble utviklet spesielt for fremstilling av forbindelsene ifølge oppfinnelsen, deres anvendelse og fremgangsmåter til deres fremstilling omfattes likeledes av oppfinnelsen, idet de variable , R2og Ph har de for de despektive foretrukne forbindelsesgrupper med formel I angitte betydninger. In the method according to the invention, such starting materials are preferably used, which lead to the compounds mentioned at the outset as particularly advantageous. New starting materials that were developed specifically for the production of the compounds according to the invention, their use and methods for their production are also covered by the invention, as the variables , R 2 and Ph have the meanings indicated for the derogatory preferred compound groups with formula I.
Forbindelsen med formel (I) eller farmasøytisk anvendbare salter herav anvendes spesielt som farmakologiske, i første rekke antidepressivt virksomme, virksomme stoffer. Derved kan man anvende dem fortrinnsvis i form av farma-søytisk anvendbare tilberedninger, i en fremgangsmåte til profylaktisk og/eller terapeutisk behandling av den dyriske eller menneskelige kropp, spesielt som antidepressiva til behandling av depressjoner. The compound of formula (I) or pharmaceutically usable salts thereof are used in particular as pharmacological, primarily antidepressant active, active substances. Thereby, they can be used preferably in the form of pharmaceutical preparations, in a method for prophylactic and/or therapeutic treatment of the animal or human body, especially as antidepressants for the treatment of depression.
Farmasøytiske preparater inneholder forbindelsene fremstilt ifølge oppfinnelsen eller farmasøytisk anvendbare salter herav som virksomme stoffer. Pharmaceutical preparations contain the compounds produced according to the invention or pharmaceutically usable salts thereof as active substances.
De farmasøytiske preparater som inneholder forbindelsene fremstilt ifølge oppfinnelsen eller farmasøytisk anvndbare salter herav, dreier det seg om slike til enteral, som oral videre rektal og parenteral administrering på varmblods-dyr, samt mennesker, idet det farmakologisk virksomme stoff er inneholdt alene eller sammen med farmasøytisk anvendbart bærematerial. Den daglige dosering av det virksomme stoff, avhenger av alderen og den individuelle tilstand, samt applikasjonsmåte. The pharmaceutical preparations containing the compounds produced according to the invention or pharmaceutically usable salts thereof, are those for enteral, as oral further rectal and parenteral administration on warm-blooded animals, as well as humans, as the pharmacologically active substance is contained alone or together with pharmaceutical applicable carrier material. The daily dosage of the active substance depends on the age and the individual condition, as well as the method of application.
De virksomme stoffer kan videre bringes på huden fra transdermale terapeutiske systemer (TTS), som tjener til kontrollert perkutan virksomme stofftilførsler for en systemisk behandling, eksempelvis i form av et klebeplaster av avrundet form med en størrelse på ca. 2 til 50 cm 2. The active substances can also be brought to the skin from transdermal therapeutic systems (TTS), which serve for controlled percutaneous active substance supplies for a systemic treatment, for example in the form of an adhesive patch of rounded shape with a size of approx. 2 to 50 cm 2.
Den virksomme stoffavgivning kan eksempelvis foregå overThe active substance release can, for example, take place above
et tidsrom på ca. 24 timer inntil en uke.a period of approx. 24 hours up to a week.
Ikke transdermalsystemer er bygget flerelags og består f.eks. utenifra og innad av en ugjennomtrengelig dekkfolie, et virksomt stoffreservoar, et adhesiv- eller klebeskikt samt en avtrekningsfolie som skal fjernes før applikasjonen. Ved de tilsvarende matrix- eller monolittsystemer er det virksomme stoff fordelt i et polymerskikt, hvorfra det frigjøres ved diffusjon. Videre kan også membrankontrollerte systemer anvendes, hvor det mellom det virksomme stoffreservoar og huden befinner seg en semipermeabel eller mikroporøs kontrollmembran som bestemmer diffusjonshastig-heten. For doseringen er mengden av pr. tidsenhet opptatte virksomme stoff f.eks. avhengig av størrelsen av kontaktflaten mellom virksomt stoffreservoar og huden. Non-transdermal systems are multi-layered and consist, for example, of from the outside and inside of an impermeable cover foil, an active substance reservoir, an adhesive or adhesive layer and a pull-off foil that must be removed before application. In the corresponding matrix or monolith systems, the active substance is distributed in a polymer layer, from which it is released by diffusion. Furthermore, membrane-controlled systems can also be used, where between the active substance reservoir and the skin there is a semi-permeable or microporous control membrane that determines the diffusion rate. For the dosage, the amount of per time unit occupied active substance, e.g. depending on the size of the contact surface between the active substance reservoir and the skin.
De nye farmasøytiske preparater inneholder f.eks. fra ca.The new pharmaceutical preparations contain e.g. from approx.
10% til ca. 80%, fortrinnsvis fra ca. 20% til ca. 60% av det virksomme stoff. Farmasøytiske preparater til enteral resp. parenteral administrering er f.eks. slike i dosis-enhetsformer, som drageer, tabletter, kapsler eller suppositorier, videre ampuller. Disse fremstilles på i og for seg kjent måte, f.eks. ved hjelp av konvensjonelle blande-, granulerings-, dragerings-, oppløsning- eller lyofiliseringsfremgangsmåter. Således kan man få farma-søytiske preparater til oral anvendelse, idet man kombinerer det virksomme stoff med faste bærestoffer, eventuelt granulerer en dannet blanding og forarbeider blandingen resp. granulatet hvis nødvendig, eller ønskelig, etter tilsetning av egnede hjelpestoffer, til tabletter eller drage-kj erner. 10% to approx. 80%, preferably from approx. 20% to approx. 60% of the active substance. Pharmaceutical preparations for enteral resp. parenteral administration is e.g. such in dosage unit forms, such as dragees, tablets, capsules or suppositories, further ampoules. These are produced in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, possibly granulating a formed mixture and processing the mixture or the granulate if necessary, or desired, after the addition of suitable excipients, into tablets or dragon's cores.
Egnede bærestoffer er spesielt fyllstoffer, som sukker, f.eks. laktose, saccharose, mannit eller sorbit, cellulosepreparater og/eller kalsiumfosfat, f.eks. trikalsium-fosfat eller kalsiumhydrogenfosfat, videre bindemidler, som stivelsesklister under anvendelse av f.eks. mais-, hvete-, ris- eller potetstivelse, gelatiner, tragant, metylcellulose og/eller polyvinylpyrrolidon, hvis ønsket, sprengmidler som de ovennevnte stivelser, videre karboksymetylstivelse, tverrbundet polyvinylpyrrolidon, Agar, alginsyre eller et salt herav, som natriumalginat, Hjelpemidler er i første rekke flyte-, regulerings- og smøremidler, f.eks. kiselsyre talkum stearinsyre eller salter herav,.som magnesium- eller kalsiumstearat og/eller polyetylenglykol. Drage-kjerner utstyres med egnede, eventuelt mavesaft-resistente overtrekk, idet man anvender blant annet konsentrerte sukker-oppløsninger, som eventuelt inneholder gummi-arabikum, talkum polyvinylpyrrolidon, polyetylenglykol og/eller titandioksyd, lakkoppløsninger i egnede organiske oppløsningsmidler eller oppløsningsmiddelblandinger eller, for fremstilling av mavesaft-resistente overtrekk, oppløsninger av egnede cellulosepreparater, som acetylcelluloseftalat eller hydroksypropylmetylcelluloseftalat. Til tablettene eller dragé-overtrekkene kan det settes farvestoffer eller pigmenter, f.eks. til identifisering eller karakterisering av forskjellige virksomme stoffdoser. Suitable carriers are especially fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch pastes using e.g. corn, wheat, rice or potato starch, gelatins, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, explosives such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, Agar, alginic acid or a salt thereof, such as sodium alginate, Excipients are in first range of flow, regulation and lubricants, e.g. silicic acid talc stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Dragon cores are equipped with suitable, possibly gastric juice-resistant coatings, using, among other things, concentrated sugar solutions, which possibly contain gum arabic, talc polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments can be added to the tablets or dragé coatings, e.g. for the identification or characterization of different active substance doses.
Ytterligere oralt anvendbare farmasøytiske preparater er stikk-kapsler av gelatin, samt myke, lukkede kapsler av gelatin og et mykningsmiddel, som glycerol eller sorbitol. Stikkapslene kan inneholde det virksomme stoff i form av Further orally usable pharmaceutical preparations are capsules made of gelatin, as well as soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active substance in the form of
et granulat, f.eks. i blanding med fyllstoffer, som laktose, bindemidler, som stivelser og/eller glidemidler, som talkum eller magnesiumstearat, og eventuelt stabilisatorer. I myke kapsler er det virksomme stoff fortrinnsvis oppløst i egnede væsker, som fete oljer, parafinolje eller flytende polyetylenglykoler, eller suspendert, a granule, e.g. in a mixture with fillers, such as lactose, binders, such as starches and/or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active substance is preferably dissolved in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, or suspended,
idet det likeledes kan være tilsatt stabilisatorer.since stabilizers may also be added.
Som rektalt anvendbare farmasøytiske preparater kommerAs rectally applicable pharmaceutical preparations come
det f.eks. i betraktning suppositorier som består av en kombinasjon av det virksomme stoff med en suppositorie-grunnmasse. Som suppositorie grunnmasse egner det seg f.eks. naturlige eller syntetiske triglycerider, parafinhydrokarboner, polyetylenglykoler eller høyere alkanoler. it e.g. considering suppositories which consist of a combination of the active substance with a suppository base. As a suppository base material, it is suitable e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
Videre kan det også anvendes gelatin-rektalkapsler som inneholder en kombinasjon av det virksomme stoff med en grunnmasse stoff. Som grunnmasse stoffer kommer det f.eks. på tale flytende triglycerider, polyetylenglykoler eller parafinhydrokarboner. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with a base mass of substance. As a base mass of substances, there are e.g. namely liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
Til parenteral administrering egner det seg i første rekke vandige oppløsninger av et virksomt stoff i vannoppløselig form, f.eks. et vannoppløselig salt, videre suspensjoner av det virksomme stoff som tilsvarende oljeaktig injeksjonssuspensjoner, idet man anvender egnede lipofile oppløs-ningsmidler eller bærere, som fete oljer, f.eks. sesamolje eller syntetiske fettsyreestere, f.eks. etyloleat eller triglycerider, eller vandige injeksjonssuspensjoner, som inneholder viskositetsøkende stoffer, f.eks. natrium-karboksymetylcellulose, sorbit og/eller dekstran, og eventuelt også stabilisatorer. For parenteral administration, aqueous solutions of an active substance in water-soluble form are primarily suitable, e.g. a water-soluble salt, further suspensions of the active substance as corresponding oily injection suspensions, using suitable lipophilic solvents or carriers, such as fatty oils, e.g. sesame oil or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also stabilizers.
Doseringen av det virksomme stoff avhenger av varmblods-typen, alderen og den individuelle tilstand, samt applika-sjonsmåten. I mormaltilfelle er det for et ca. 75 kg tungt individ ved oral applikasjon å foreslå en omtrentlig dagsdose på ca. 100 til ca. 500 mg, spesielt 200 til ca. The dosage of the active substance depends on the warm-blooded type, age and individual condition, as well as the method of application. In the normal case, it is for an approx. 75 kg individual by oral application to suggest an approximate daily dose of approx. 100 to approx. 500 mg, especially 200 to approx.
300 mg, fortrinnsvis i flere like deldoser.300 mg, preferably in several equal partial doses.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eksempler hvor temperaturen er angitt i Celsiusgrader. The invention will be explained in more detail with the help of some examples where the temperature is indicated in degrees Celsius.
Eksempel 1Example 1
24,4 g (0,2 mol) 1-fenyl-etanol og 27,6 g (0,24 mol) metansulfoklorid oppløses i 250 ml toluen og ved 10°C inndryppes i løpet av 30 minutter en oppløsning av 28,2 g (0,28 mol) trietylamin i 50 ml toluen under omrøring. Reaksjonsblandingen omrøres 12 timer ved værelsetemperatur 24.4 g (0.2 mol) of 1-phenyl ethanol and 27.6 g (0.24 mol) of methanesulfochloride are dissolved in 250 ml of toluene and at 10°C a solution of 28.2 g is added dropwise over the course of 30 minutes (0.28 mol) of triethylamine in 50 ml of toluene with stirring. The reaction mixture is stirred for 12 hours at room temperature
og deretter frafiltreres det utfelte trietylamin-hydroklorid. Residuumet utvaskes med toluen og de forenede filtrater inndampes i vannstrålevakuum til tørrhet. Den dannede olje tildryppes under omrøring ved 95°C i løpet av 15 minutter til en oppløsning av 50 g (0,6 mol) 2-metylimidazol og holdes 6 timer ved 100°C. Reaksjonsblandingen blandes med 200 ml eter og 200 ml vann, den organiske fase adskilles og utvaskes 3 ganger med vann. De organiske faser utrystes 3 ganger med hver gang 100 ml saltsyre 2 n, de vandige, sure faser gjøres alkalisk med konsentrert natronlut og utrystes igjen med eter. De organiske faser tørkes over magnesiumsulfat og oppløsningsmidlet fjernes under vannstrålevakuum. and then the precipitated triethylamine hydrochloride is filtered off. The residue is washed out with toluene and the combined filtrates are evaporated in a water jet vacuum to dryness. The oil formed is added dropwise with stirring at 95°C during 15 minutes to a solution of 50 g (0.6 mol) 2-methylimidazole and kept at 100°C for 6 hours. The reaction mixture is mixed with 200 ml of ether and 200 ml of water, the organic phase is separated and washed out 3 times with water. The organic phases are shaken 3 times with each time 100 ml of hydrochloric acid 2 n, the aqueous, acidic phases are made alkaline with concentrated caustic soda and shaken again with ether. The organic phases are dried over magnesium sulfate and the solvent is removed under a water jet vacuum.
Den som råprodukt dannede olje destilleres i høyvakuum ved 120°C (13,3 Pa) og gir etter omkrystallisering fra cykloheksan ren 1-(1-fenyl-etyl)-2-metyl-imidazol, som smelter ved 84-85°C. 22,8 g (0,12 mol) av den dannede base oppløses i 100 ml eddiksyreetylester og gjøres sur med alkalisk saltsyre (pH-vl) . Etter tilsetning av 25 ml eter frafUtreres den dannede utfelling, vaskes med eter og tørkes i vakuum ved 60°C. Det dannede rene 1-(1-fenyletyl)-2-metyl-imidazol-hydroklorid smelter ved 229-229,5°C. The oil formed as a crude product is distilled in high vacuum at 120°C (13.3 Pa) and after recrystallization from cyclohexane gives pure 1-(1-phenyl-ethyl)-2-methyl-imidazole, which melts at 84-85°C. 22.8 g (0.12 mol) of the formed base are dissolved in 100 ml of acetic acid ethyl ester and made acidic with alkaline hydrochloric acid (pH-vl). After adding 25 ml of ether, the formed precipitate is filtered off, washed with ether and dried in a vacuum at 60°C. The pure 1-(1-phenylethyl)-2-methyl-imidazole hydrochloride formed melts at 229-229.5°C.
Eksempel 2Example 2
På analog måte som omtalt i eksempel 1 fåes av 40,8 6 gIn an analogous way as discussed in example 1, 6 g is obtained from 40.8
(0,3 mol) 1-(p-metyl-fenyl)-etanol og 73,9 g (0,9 mol) 2-metylimidazol oljeaktig 1-[1-(p-metyl-fenyl)-etyl]-2-metyl-imidazol. Det herav fremstilte hydroklorid smelter ved 237-238°C. (0.3 mol) 1-(p-methyl-phenyl)-ethanol and 73.9 g (0.9 mol) 2-methylimidazole oily 1-[1-(p-methyl-phenyl)-ethyl]-2- methyl imidazole. The hydrochloride produced from this melts at 237-238°C.
Eksempel 3Example 3
På analog måte som omtalt i eksempel 1 fåes av 30,1 gIn an analogous way as described in example 1, 30.1 g is obtained
(0,2 mol) 1-(2,4-dimetylfenyl)-etanol og 4 9,3 g (0,6 mol) 2-metylimidazol 21,3 g oljeaktig 1-[1-(2,4-dimetyl-fenyl)-etyl]-2-metyl-imidazol som råprodukt. Det analogt fremstilte hydroklorid smelter ved 238-239°C. (0.2 mol) 1-(2,4-dimethylphenyl)-ethanol and 4 9.3 g (0.6 mol) 2-methylimidazole 21.3 g oily 1-[1-(2,4-dimethyl-phenyl) )-ethyl]-2-methyl-imidazole as crude product. The analogously prepared hydrochloride melts at 238-239°C.
Det som utgangsmaterial nødvendige 1-(2,4-dimetyl-fenyl)-etanol fremstilles som følger: 44,5 g (0,3 mol) 2,4-dimetylacetofenon oppløses i 200 ml isopropanol og ved 60°C under omrøring inndryppes en iskold oppløsning av 5,7 g (0,15 mol) natriumborhydrid i 50 ml vann langsomt. Reaksjonsblandingen oppvarmes 4 timer ved tilbakeløpstemperatur, avkjøles og blandes med 200 ml 1-molar natriumdihydrogenfosfatoppløsning. Isopropanolen fjernes best mulig på vannstrålevakuum og residuumet utrystes med eter. De organiske faser utvaskes med salt-lake, tørkes over magnesiumsulfat og oppløsningsmidlet fjernes under vannstrålevakuum. Det dannede residuum destilleres i vannstrålevakuum og gir 1-(2,4-dimetyl-fenyl)-etanol av kokepunkt (1866,5 Pa) 120°C [Ishizaka, Chem. Ber. 47, 2461, Kp14= 124-125°]. The 1-(2,4-dimethyl-phenyl)-ethanol required as starting material is prepared as follows: 44.5 g (0.3 mol) of 2,4-dimethylacetophenone is dissolved in 200 ml of isopropanol and at 60°C with stirring a ice-cold solution of 5.7 g (0.15 mol) sodium borohydride in 50 ml of water slowly. The reaction mixture is heated for 4 hours at reflux temperature, cooled and mixed with 200 ml of 1-molar sodium dihydrogen phosphate solution. The isopropanol is best removed using a water jet vacuum and the residue is shaken out with ether. The organic phases are washed out with brine, dried over magnesium sulfate and the solvent is removed under a water jet vacuum. The residue formed is distilled in a water jet vacuum and gives 1-(2,4-dimethyl-phenyl)-ethanol of boiling point (1866.5 Pa) 120°C [Ishizaka, Chem. Pray. 47, 2461, Kp14= 124-125°].
Eksempel 4Example 4
På analog måte som omtalt i eksempel 1 fåes av 27,3 gIn an analogous way as described in example 1, 27.3 g is obtained
(0,2 mol) 1-[(2-metyl-fenyl)-etyl]-etanol og 49,3 g (0,6 mol) 2-metylimidazol oljeaktig 1-[1-(2-metyl-fenyl)-etyl]-2-metyl-imidazol som råprodukt. Hydrokloridet smelter ved 237-238°C. (0.2 mol) 1-[(2-methyl-phenyl)-ethyl]-ethanol and 49.3 g (0.6 mol) 2-methylimidazole oily 1-[1-(2-methyl-phenyl)-ethyl ]-2-methyl-imidazole as crude product. The hydrochloride melts at 237-238°C.
Det som utgangsmaterial nødvendige 1-(2-metyl-fenyl)-The starting material required 1-(2-methyl-phenyl)-
etanol fremstilles analogt eksempel 3 (V. Auwers et al., Chem. Ber. 58, 46, Kp2Q= 107-108°C) ethanol is prepared analogously to example 3 (V. Auwers et al., Chem. Ber. 58, 46, Kp2Q= 107-108°C)
Eksempel 5Example 5
25 g (0,113 mol) 1-(1-fenyl-etenyliden-l-yl)-2-metyl-imidazolhydroklorid has i 200 ml mettet pottaske-oppløsning og utrystes med hver gang 100 ml eter 3 ganger. De organiske ekstrakter tørkes over magnesiumsulfat og inndampes under vakuum til tørrhet. Det dannede residuum oppløses i 500 ml metanol og hydrogeneres under tilsetning av 1 g 5% palladiumkull ved værelsetemperatur og normaltrykk. Katalysatoren frafUtreres, utvaskes med metanol og de forenede metanoliske oppløsninger inndampes til tørrhet under vakuum. Det dannede oljeaktige residuum krystalliseres fra cykloheksan og gir rent 1-(1-fenyl-etyl)-2-metylimidazol av smp. 84-85°C. 25 g (0.113 mol) of 1-(1-phenyl-ethenylidene-1-yl)-2-methyl-imidazole hydrochloride is dissolved in 200 ml of saturated pot ash solution and shaken out with 100 ml of ether each time 3 times. The organic extracts are dried over magnesium sulfate and evaporated under vacuum to dryness. The residue formed is dissolved in 500 ml of methanol and hydrogenated with the addition of 1 g of 5% palladium charcoal at room temperature and normal pressure. The catalyst is filtered off, washed out with methanol and the combined methanolic solutions are evaporated to dryness under vacuum. The oily residue formed is crystallized from cyclohexane and gives pure 1-(1-phenyl-ethyl)-2-methylimidazole of m.p. 84-85°C.
Utgangsmaterialet fåes som følger:The starting material is obtained as follows:
a) 130 g (0,68 mol) a-klor-fenylacetylklorid dryppes ved 20-30°C til 500 ml etanol og omrøres 3 timer ved 30-40°C. a) 130 g (0.68 mol) α-chloro-phenylacetyl chloride is added dropwise at 20-30°C to 500 ml of ethanol and stirred for 3 hours at 30-40°C.
Oppløsningsmidlet fjernes under' vakuum og gir rått 2-klor-2-fenyl-eddiksyreetylester. Det dannede produkt (137 g) oppløses i 2 1 toluen og oppløsningen blandes med 170 g (2,07 mol) 2-metylimidazol. Reaksjonsblandingen holdes under omrøring i 12 timer ved 100°C. Den dannede reaksjons-blanding utrystes 4 ganger med 500 ml vann, de vandige faser ettervaskes med litt toluen og de forenede organiske faser tørkes over magnesiumsulfat. Etter fjerning av oppløsnings-midlet i vakuum fåes rått oljeaktig 2-fenyl-2-(2-metylimidazol-l-yl)-eddiksyreetylester. Forbindelsen destilleres ved 145<W>C (26,66 Pa). Det rene hydroklorid smelter ved 157-159°C. The solvent is removed under vacuum to give crude 2-chloro-2-phenyl-acetic acid ethyl ester. The product formed (137 g) is dissolved in 2 1 of toluene and the solution is mixed with 170 g (2.07 mol) of 2-methylimidazole. The reaction mixture is kept under stirring for 12 hours at 100°C. The resulting reaction mixture is shaken 4 times with 500 ml of water, the aqueous phases are washed with a little toluene and the combined organic phases are dried over magnesium sulphate. After removal of the solvent in vacuo, crude oily 2-phenyl-2-(2-methylimidazol-1-yl)-acetic acid ethyl ester is obtained. The compound is distilled at 145<W>C (26.66 Pa). The pure hydrochloride melts at 157-159°C.
b) 142,9 g (0,585 mol) 2-fenyl-2-(2-metyl-imidazol-l-yl)-eddiksyreetylester oppløses i 1,5 1 isopropanol og under b) 142.9 g (0.585 mol) 2-phenyl-2-(2-methyl-imidazol-1-yl)-acetic acid ethyl ester is dissolved in 1.5 1 isopropanol and under
omrøring tildryppes ved 5°C en oppløsning av 23 g (0,6 mol) natriumborhydrid i 150 ml vann i løpet av 30 minutter. Blandingen omrøres uten avkjøling i 6 timer idet blandingens temperatur når 45-50°C. Blandingen gjøres sur kaldt med en blanding av konsentrert saltsyre og vann (1:1) (pH = 1-2) stirring, a solution of 23 g (0.6 mol) of sodium borohydride in 150 ml of water is added dropwise at 5°C over the course of 30 minutes. The mixture is stirred without cooling for 6 hours as the temperature of the mixture reaches 45-50°C. The mixture is made acidic cold with a mixture of concentrated hydrochloric acid and water (1:1) (pH = 1-2)
og oppløsningsmidlet fjernes best mulig i vakuum. Residuumet blandes koldt med mettet pottaskeoppløsning inntil alkalisk reaksjon og utrystes 3 ganger, hver gang med 300 ml eter. and the solvent is best removed under vacuum. The residue is mixed cold with saturated pot ash solution until an alkaline reaction and shaken 3 times, each time with 300 ml of ether.
De forenede organiske faser tørkes over magnesiumsulfat og oppløsningsmidlet fjernes i vakuum. Det dannede oljeaktige residuum krystalliseres fra. eter/cykloheksan og gir ren 2-fenyl-2-(2-metyl-imidazol-l-yl)-etanol-(1) av smp. 114-116°C. The combined organic phases are dried over magnesium sulphate and the solvent is removed in vacuo. The oily residue formed is crystallized from. ether/cyclohexane and gives pure 2-phenyl-2-(2-methyl-imidazol-1-yl)-ethanol-(1) of m.p. 114-116°C.
105,3 g av den dannede base oppløses i 300 ml etanol og blandes med alkoholisk saltsyre til sur reaksjon. Etter tilsetning av 200 ml eddikester og ca. 200 ml eter frafUtreres det utfelte produkt, vaskes med eddikester og tørkes i vakuum ved 60°C. Det rene 2-fenyl-2-(2-metylimidazol-l-yl ) -etan-ol-hydroklorid smelter ved 144-146°C. 105.3 g of the formed base are dissolved in 300 ml of ethanol and mixed with alcoholic hydrochloric acid to an acidic reaction. After adding 200 ml of vinegar and approx. The precipitated product is filtered from 200 ml of ether, washed with vinegar and dried in a vacuum at 60°C. The pure 2-phenyl-2-(2-methylimidazol-1-yl)-ethan-ol hydrochloride melts at 144-146°C.
115 g (0,481 mol) 2-fenyl-2-(2-metyl-imidazol-l-yl)-etanol-hydroklorid oppløses ill kloroform og kokes under tilbake-løp med 120 g (1 mol) tionylklorid i 10 timer. Reaksjonsblandingen inndampes i vakuum til tørrhet og råproduktet videreanvendes direkte. 120,4 g av det rå 1-[2-(l-klor-2-fenyl-etyl)]-2-metyl-imidazol-hydroklorid oppløses ill 115 g (0.481 mol) of 2-phenyl-2-(2-methyl-imidazol-1-yl)-ethanol hydrochloride are dissolved in chloroform and refluxed with 120 g (1 mol) of thionyl chloride for 10 hours. The reaction mixture is evaporated in vacuo to dryness and the crude product is used directly. 120.4 g of the crude 1-[2-(1-chloro-2-phenyl-ethyl)]-2-methyl-imidazole hydrochloride are dissolved in
kloroform og omrøres med 152 g (1,0 mol) 1,8-diaza-bicyklo [5,4,0]-undec-7-en i 12 timer ved værelsetemperåtur. chloroform and stirred with 152 g (1.0 mol) of 1,8-diaza-bicyclo [5,4,0]-undec-7-ene for 12 hours at room temperature.
Reaksjonsblandingen befris for oppløsningsmiddel i vakuumThe reaction mixture is freed of solvent in vacuo
og blandes med av hver 500 ml cykloheksan og vann. Den vandige fase adskilles og den organiske fase vaskes 3 ganger med hver gang 100 ml vann. Den organiske fase tørkes over magnesiumsulfat og oppløsningsmidlet fjernes i vakuum. and mixed with 500 ml each of cyclohexane and water. The aqueous phase is separated and the organic phase is washed 3 times with 100 ml of water each time. The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo.
Det rå 1-(1-fenyl-etenyliden-l-yl)-2-metyl-imidazol fåesThe crude 1-(1-phenyl-ethenylidene-1-yl)-2-methyl-imidazole is obtained
som olje. Basen har et kokepunkt på kp. 130°C (6,66 Pa).like oil. The base has a boiling point of kp. 130°C (6.66 Pa).
82 g av den rå base oppløses i 200 ml eddikester og blandes med ca. 7n alkoholisk saltsyre til sur reaksjon. Etter tilsetning av 50 ml eter frafiltreres det utfelte produkt, vaskes med eter og tørkes i vakuum ved 60°C. Dissolve 82 g of the raw base in 200 ml of vinegar and mix with approx. 7n alcoholic hydrochloric acid to acid reaction. After adding 50 ml of ether, the precipitated product is filtered off, washed with ether and dried in vacuum at 60°C.
Det rene 1-(1-fenyl-etenyliden-l-yl)-2-metyl-imidazol-hydroklorid smelter ved 258-260°C. The pure 1-(1-phenyl-ethenylidene-1-yl)-2-methyl-imidazole hydrochloride melts at 258-260°C.
Eksempel 6Example 6
8,6 g (0,05 mol) 1-(1-fenyl-l-etyl)-imidazol oppløses i 80 ml abs. tetrahydrofuran og ved -70°C tildryppes 30 ml (2 mol) n-butyl-litiumoppløsning i heksan. Blandingen omrøres 30 minutter ved -70°C og deretter tildryppes 7,1 g (0,05 mol) metyljodid i 20 ml tetrahydrofuran. Kjølingen fjernes, blandingen bringes langsomt til værelsetemperatur og hensettes 2 timer ved denne temperatur. Til opparbeidelse tilsettes 25 ml 2 n natronlut og tetrahydrofuranet fjernes best mulig i vakuum. Residuumet utrystes med eter, de organiske faser tørkes over magnesiumsulfat og oppløsnings-midlet fjernes i vakuum. Det dannede oljeaktige residuum oppløses i eddikester, blandes med eterisk saltsyre til sur reaksjon og det utfelte produkt frafiltreres. Etter omkrystallisering fra isopropanol/eter smelter det rene 1-(1-fenyl-etyl)-2-metyl-imidazol-hydroklorid ved 228-229°C. 8.6 g (0.05 mol) of 1-(1-phenyl-1-ethyl)-imidazole is dissolved in 80 ml of abs. tetrahydrofuran and at -70°C 30 ml (2 mol) of n-butyl lithium solution in hexane are added dropwise. The mixture is stirred for 30 minutes at -70°C and then 7.1 g (0.05 mol) of methyl iodide in 20 ml of tetrahydrofuran are added dropwise. The cooling is removed, the mixture is slowly brought to room temperature and allowed to stand for 2 hours at this temperature. For work-up, 25 ml of 2 N caustic soda is added and the tetrahydrofuran is removed as best as possible under vacuum. The residue is shaken off with ether, the organic phases are dried over magnesium sulphate and the solvent is removed in vacuo. The oily residue formed is dissolved in vinegar, mixed with ethereal hydrochloric acid to form an acidic reaction and the precipitated product is filtered off. After recrystallization from isopropanol/ether, the pure 1-(1-phenyl-ethyl)-2-methyl-imidazole hydrochloride melts at 228-229°C.
Eksempel 7Example 7
På analog måte som angitt i eksempel 1 fåes av 13,6 gIn an analogous way as stated in example 1, 13.6 g is obtained
(0,1 mol) 1-[1-(3-metyl-fenyl)-etyl]-etanol og 24,6 g (0,3 mol)(0.1 mol) 1-[1-(3-methyl-phenyl)-ethyl]-ethanol and 24.6 g (0.3 mol)
2-metylimidazol oljeaktig 1-[1-(3-metyl-fenyl)-etyl]-2-metylimidazol som råprodukt. Hydrokloridet smelter ved 228-230°C. 2-Methylimidazole oily 1-[1-(3-methyl-phenyl)-ethyl]-2-methylimidazole as crude product. The hydrochloride melts at 228-230°C.
Eksempel 8Example 8
På analog måte som omtalt i eksempel 1 fåes av 13,6 gIn an analogous way as discussed in example 1, 13.6 g is obtained
(0,1 mol) 1-fenyl-propanol-(1) og 25 g (0,3 mol) 2-metylimidazol rått 1-[1-(fenyl)-propyl]-2-metyl-imidazol som olje. Hydrokloridet smelter ved 177-179°C. (0.1 mol) 1-phenyl-propanol-(1) and 25 g (0.3 mol) 2-methylimidazole crude 1-[1-(phenyl)-propyl]-2-methyl-imidazole as an oil. The hydrochloride melts at 177-179°C.
Eksempel 9Example 9
På analog måte som omtalt i eksempel 1, fåes av 15,0 gIn an analogous way as discussed in example 1, 15.0 g is obtained
(0,1 mol) 1-(2-etyl-fenyl)-etanol og 25 g (0,3 mol) 2-metylimidazol rått, oljeaktig 1-[1-(2-etyl-fenyl)-etyl]-2-metyl-imidazol. Hydrokloridet smelter ved 211-213°C. (0.1 mol) 1-(2-ethyl-phenyl)-ethanol and 25 g (0.3 mol) 2-methylimidazole crude, oily 1-[1-(2-ethyl-phenyl)-ethyl]-2- methyl imidazole. The hydrochloride melts at 211-213°C.
Eksempel 10Example 10
På analog måte som omtalt i eksempel 1, fåes av 15,0 gIn an analogous way as described in example 1, 15.0 g is obtained
(0,1 mol) 1-(2,6-dimetyl-fenyl)-etanol og 25 g (0,3 mol) 2-metylimidazol krystallinsk 1-[1-(2,6-dimetyl-fenyl)-etyl] - 2-metyl-imidazol med smp. 100-103°C. Hydrokloridet smelter ved 265-267°C. (0.1 mol) 1-(2,6-dimethyl-phenyl)-ethanol and 25 g (0.3 mol) 2-methylimidazole crystalline 1-[1-(2,6-dimethyl-phenyl)-ethyl] - 2-methyl-imidazole with m.p. 100-103°C. The hydrochloride melts at 265-267°C.
Eksempel 11Example 11
18,8 g (0,1 mol) 1-[1-(fenyl)-etyl]-2-metyl-4,5-dihydro-imidazol oppløses i 4000 ml metylenklorid og under omrøring og fuktighetsutelukkelse tilsettes 282 g (1,1 mol) bariummanganat. Blandingen omrøres 24 timer under tilbakeløp. Deretter tilsettes 20 g magnesiumsulfat, faste deler frafiltreres og residuumet utvaskes med metylenklorid. De organiske filtrater inndampes i vakuum til tørrhet og den dannede olje oppløses i eddikester. Etter tilsetning av eterisk saltsyre til sur reaksjon frafiltreres det utfelte hydroklorid og omkrystalliseres fra isopropanol-eter. Det rene 1- [1- (fenyl)-etyl] --2-metyl-imidazol-hydroklorid smelter ved 228-229°C. 18.8 g (0.1 mol) of 1-[1-(phenyl)-ethyl]-2-methyl-4,5-dihydro-imidazole are dissolved in 4000 ml of methylene chloride and, while stirring and exclusion of moisture, 282 g (1.1 moles) of barium manganate. The mixture is stirred for 24 hours under reflux. Then 20 g of magnesium sulphate are added, solid parts are filtered off and the residue is washed out with methylene chloride. The organic filtrates are evaporated in vacuo to dryness and the oil formed is dissolved in acetic acid. After adding ethereal hydrochloric acid to an acidic reaction, the precipitated hydrochloride is filtered off and recrystallized from isopropanol ether. The pure 1-[1-(phenyl)-ethyl]-2-methyl-imidazole hydrochloride melts at 228-229°C.
Utgangsproduktet fremstilles som følger:The starting product is produced as follows:
a) N-[ 1-( fenyl)- etyl]- aminoetyl- amina) N-[1-(phenyl)-ethyl]-aminoethyl-amine
30 g (0,25 mol) acetofenon oppløses i 300 ml metanol og 30 g (0.25 mol) of acetophenone are dissolved in 300 ml of methanol and
hydrogeneres etter tilsetning av 30 g (0,5 mol) etylen-diamin og 1,0 g platin-kull med hydrogen ved 20°C og normaltrykk i løpet av 22 timer. Den dannede oppløsning filreres fra katalysatoren, oppløsningsmidlet fjernes i vakuum og residuumet destilleres under vannstrålevakuum. Det som olje dannede N-[1-(fenyl)-etyl]-aminoetylamin is hydrogenated after adding 30 g (0.5 mol) ethylene diamine and 1.0 g platinum charcoal with hydrogen at 20°C and normal pressure during 22 hours. The solution formed is filtered from the catalyst, the solvent is removed in vacuo and the residue is distilled under a water jet vacuum. It gave N-[1-(phenyl)-ethyl]-aminoethylamine as an oil
koker ved 115-118°C (1466,5 Pa).boils at 115-118°C (1466.5 Pa).
b) 16,4 g (0,1 mol) N-[1-(fenyl)-etyl]-aminoetylamin opp-løses i 100 ml etanol og ved 0°C innføres 16,0 g (0,1 mol) b) Dissolve 16.4 g (0.1 mol) of N-[1-(phenyl)-ethyl]-aminoethylamine in 100 ml of ethanol and at 0°C introduce 16.0 g (0.1 mol)
acetamidsyre-etylester-hydroklorid. Blandingen omrøres 3 timer ved 0°C og oppløsningsmidlet fjernes i vakuum. acetamic acid ethyl ester hydrochloride. The mixture is stirred for 3 hours at 0°C and the solvent is removed in vacuo.
Det dannede olje utrystes med vann og eter, det eteriske ekstrakt tørkes over magnesiumsulfat og oppløsningsmidlet fjernes under vakuum. Residuumet oppløses i eddikester og blandes med oksalsyre til sur reaksjon. Etter tilsetning av noe eter frafiltreres det utfelte produkt og omkrystalliseres fra isopropanol-eter. Det rene 1-[1-(fenyl)-etyl]-2-metyl-4,5-dihydroimidazol-oksalat smelter ved 80-84°C. The oil formed is shaken off with water and ether, the ethereal extract is dried over magnesium sulphate and the solvent is removed under vacuum. The residue is dissolved in vinegar and mixed with oxalic acid for an acidic reaction. After adding some ether, the precipitated product is filtered off and recrystallized from isopropanol-ether. The pure 1-[1-(phenyl)-ethyl]-2-methyl-4,5-dihydroimidazole oxalate melts at 80-84°C.
For ytterligere omsetning overføres 29 g av oksalatet medFor further conversion, 29 g of the oxalate is transferred with
1 n kalilut og eter til den frie base. Det fåes ren base, som koker ved 130°C (1,33Pa). 1 n potassium chloride and ether to the free base. Pure base is obtained, which boils at 130°C (1.33Pa).
Eksempel 12Example 12
5,0 g (0,0409 mol) R-(+)-1-fenyletanol ([a]<22>= + 39,5°C)5.0 g (0.0409 mol) R-(+)-1-phenylethanol ([a]<22>= + 39.5°C)
og 5,2 g (0,055 mol) metansulfoklorid oppløses i 100 ml eter og avkjøles til 0°C og ved denne temperatur inndryppes en oppløsning av 5,1 g(0,060 mol) trietylamin i 50 ml eter. Blandingen omrøres 1 time ved 0°C og frafiltrerer fra utfelt utfelling. Filtratet inndampes mest mulig skånende på vannstrålevakuum, residuumet oppløses i 20 ml toluen og ved 90°C dryppes til en oppløsning ay 8,2 g (0,1 mol) and 5.2 g (0.055 mol) of methanesulfochloride are dissolved in 100 ml of ether and cooled to 0°C and at this temperature a solution of 5.1 g (0.060 mol) of triethylamine in 50 ml of ether is added dropwise. The mixture is stirred for 1 hour at 0°C and filtered off from the deposited precipitate. The filtrate is evaporated as gently as possible on a water jet vacuum, the residue is dissolved in 20 ml of toluene and at 90°C dripped to a solution ay 8.2 g (0.1 mol)
2-metylimidazol. Blandingen oppvarmes i 1 time ved 90°C.2-methylimidazole. The mixture is heated for 1 hour at 90°C.
For opparbeidelse fortynnes blandingen med eter og utrystes med vann og deretter med 3 ganger 50 ml 2N saltsyre. Saltsyreekstraktene gjøres alkalisk med konsentrert natronlut og uttrekkes med eter. De dannede eteriske oppløsninger tørkes over magnesiumsulfat og inndampes til tørrhet. For work-up, the mixture is diluted with ether and shaken with water and then with 3 times 50 ml of 2N hydrochloric acid. The hydrochloric acid extracts are made alkaline with concentrated caustic soda and extracted with ether. The ethereal solutions formed are dried over magnesium sulfate and evaporated to dryness.
Det gjenblivende residuum krystalliseres 2 ganger fra cykloheksan og gir rent venstredreiende 1-(1-fenyletyl)-2-metyl-imidazol av smp. 113-115°C [a]p° = -15° - 1°. The remaining residue is crystallized twice from cyclohexane and gives pure levorotatory 1-(1-phenylethyl)-2-methyl-imidazole of m.p. 113-115°C [a]p° = -15° - 1°.
(Enantiomerrenhet ca. 95% ifølge NMR). Hydrokloridet smelter ved 243-244°C. (Enantiomer purity approx. 95% according to NMR). The hydrochloride melts at 243-244°C.
Eksempel 13Example 13
På samme måte som omtalt i eksempel 11 fåes av 5,0 g S(-)-l-fenyletanol ([a]^° = -41,3°) høyredreiende 1-[1-(fenyl)-etyl]-2-metyl-imidazol av smp. 113-115 [a]D<20>In the same way as discussed in example 11, 5.0 g of S(-)-1-phenylethanol ([a]^° = -41.3°) dextrorotatory 1-[1-(phenyl)-ethyl]-2- methyl-imidazole of m.p. 113-115 [a]D<20>
+15° N ( - 1°). Hydrokloridet smelter ved 243-244°C.+15°N (-1°). The hydrochloride melts at 243-244°C.
Eksempel 14Example 14
På analog måte som omtalt i eksempel 1, fåes av 20,2 gIn an analogous way as discussed in example 1, 20.2 g is obtained
(0,1 mol) 1-(3-metoksyfenyl)-etanol og 25 g (0,3 mol) 2-metylimidazol 1-[1-(3-metoksy-fenyl)-etyl]-2-metyl- (0.1 mol) 1-(3-methoxyphenyl)-ethanol and 25 g (0.3 mol) 2-methylimidazole 1-[1-(3-methoxy-phenyl)-ethyl]-2-methyl-
imidazol som olje. Hydrokloridet smelter ved 197-199°C. imidazole as oil. The hydrochloride melts at 197-199°C.
Eksempel 15Example 15
6,0 g(0,0297 mol) 1-[1-(2-hydroksy-fenyl)-etyl]-2-metylimidazol og 25 ml heksametanol suspenderes i 25 ml tetrahydrofuran og ved 20°C tilsettes under omrøring porsjonsvis 1,3 g (0,030 mol) natriumhydridsuspensjon (55%). Blandingen omrøres 2 timer ved 20°C. Deretter inndryppes en oppløsning av 4,25 g (0,030 mol) metyljodid i 25 ml heksametapol og blandingen holdes 1 time ved 45°C. 6.0 g (0.0297 mol) of 1-[1-(2-hydroxy-phenyl)-ethyl]-2-methylimidazole and 25 ml of hexamethanol are suspended in 25 ml of tetrahydrofuran and at 20°C, while stirring, 1.3 g (0.030 mol) sodium hydride suspension (55%). The mixture is stirred for 2 hours at 20°C. A solution of 4.25 g (0.030 mol) of methyl iodide in 25 ml of hexametapol is then dripped in and the mixture is kept for 1 hour at 45°C.
Reaksjonsblandingen helles på 200 ml isvann og utrystes med metylenklorid. De organiske faser adskilles, vaskes med vann og tørkes over magnesiumsulfat. Etter fjerning av oppløsningsmidlet fåes det rå 1-[1-(2-metoksy-fenyl)-etyl]-2-metyl-imidazol som olje.Hydrokloridet smelter ved 201-203°C. The reaction mixture is poured into 200 ml of ice water and shaken with methylene chloride. The organic phases are separated, washed with water and dried over magnesium sulphate. After removal of the solvent, crude 1-[1-(2-methoxy-phenyl)-ethyl]-2-methyl-imidazole is obtained as an oil. The hydrochloride melts at 201-203°C.
Det som utgangsprodukt nødvendige 1-[1-(2-metoksyfenyl)-etyl-2-metyl-imidazol kan fåes som følger: 20,0 g (0,1 mol) a-metylen-1-(2-hydroksybenzyl)-2-metylimidazol oppløses i 500 ml etanol og etter tilsetning av 1 g Pd-kull hydrogeneres ved normaltrykk og værelsetemperatur. Deretter frafiltreres fra katalysatoren, oppløsnings-midlet fjernes best mulig i vakuum og residuumet blandes med fumarsyre til svakt sur reaksjon. Etter tilsetning av eddikester frafiltreres det utfelte produkt, omkrystalliseres fra alkohol-eddikester og tørkes. Det rene 1- [1-(2-hydroksyfenyl)-etyl]-2-metylimidazol smelter ved 148-150°C. The 1-[1-(2-methoxyphenyl)-ethyl-2-methyl-imidazole required as starting product can be obtained as follows: 20.0 g (0.1 mol) α-methylene-1-(2-hydroxybenzyl)-2 -methylimidazole is dissolved in 500 ml of ethanol and, after adding 1 g of Pd charcoal, hydrogenated at normal pressure and room temperature. It is then filtered off from the catalyst, the solvent is removed as best as possible under vacuum and the residue is mixed with fumaric acid to a slightly acidic reaction. After adding acetic acid, the precipitated product is filtered off, recrystallized from alcohol-acetic acid and dried. The pure 1-[1-(2-hydroxyphenyl)-ethyl]-2-methylimidazole melts at 148-150°C.
For videre omsetning spaltes 10 g (0,03 mol) av fumaratet med 2 n natronlut og eter til den frie base. Det fåes fri base som omsettes som omtalt. For further reaction, 10 g (0.03 mol) of the fumarate are cleaved with 2 N caustic soda and ether to the free base. A free base is obtained which is converted as described.
Eksempel 16Example 16
På analog måte som omtalt i eksempel 1 fåes fra 18,2 gIn an analogous way as described in example 1, 18.2 g is obtained
(0,1 mol) 1-(2,3-dimetoksy-fenyl)-etanol og 25 g (0,3 mol) 2- metylimidazol råprodukt. Den frie base kromatograferes med metylenklorid/1-5% metanol på silikagel og gir rent 1- [1-(2,3-dimetoksyfenyl)-etyl]-2-metyl-imidazol av smp. 122-124°C. Hydrokloridet smelter ved 175-178°C. (0.1 mol) 1-(2,3-dimethoxy-phenyl)-ethanol and 25 g (0.3 mol) 2-methylimidazole crude product. The free base is chromatographed with methylene chloride/1-5% methanol on silica gel and gives pure 1-[1-(2,3-dimethoxyphenyl)-ethyl]-2-methyl-imidazole of m.p. 122-124°C. The hydrochloride melts at 175-178°C.
Eksempel 17Example 17
På analog måte som omtalt i eksempel 1 fåes av 16,4 gIn an analogous way as discussed in example 1, 16.4 g is obtained
(0,1 mol) 1-(2,4,6-trimetylfenyl)-etanol og 25 g (0,3 mol) 2- metylimidazol 7,9 g rent 1-[1-(2,4,6-trimetylfenyl)-etyl]-2-metyl-imidazol av smp. 129-131°C. Hydrokloridet smelter ved 267°C under spaltning. (0.1 mol) 1-(2,4,6-trimethylphenyl)-ethanol and 25 g (0.3 mol) 2-methylimidazole 7.9 g pure 1-[1-(2,4,6-trimethylphenyl) -ethyl]-2-methyl-imidazole of m.p. 129-131°C. The hydrochloride melts at 267°C during decomposition.
Eksempel 18Example 18
På analog måte som omtalt i eksempel 1, fåes av 9,1 gIn an analogous way as discussed in example 1, 9.1 g is obtained
(0,05 mol) 1-(2,6-dimetoksyfenyl)-etanol og 12,5 g (0,15 mol) 2-metylimidazol 3,7 g rått 1-[1-(2,6-dimetoksyfenyl)-etyl]-2-metyl-imidazol som gir rent hydroklorid av smp. 214-216°C. (0.05 mol) 1-(2,6-dimethoxyphenyl)-ethanol and 12.5 g (0.15 mol) 2-methylimidazole 3.7 g crude 1-[1-(2,6-dimethoxyphenyl)-ethyl ]-2-methyl-imidazole which gives pure hydrochloride of m.p. 214-216°C.
Utgangsproduktet kan fremstilles som følger:The starting product can be produced as follows:
16,6 g (0,1 mol) 2,6-dimetoksybenzaldehyd oppløses i 200 ml abs. tetrahydrofuran og 60 ml av en 2,58 molar metylmagnesium-jodid-oppløsning i tetrahydrofuran tildryppes ved 10°C. Reaksjonsblandingen holdes 2 timer ved værelsetemperatur og blandes deretter med en oppløsning av 30 g ammoniumklorid i 200 ml vann. Den dannede blanding utrystes med eter, de organiske faser vaskes med saltoppløsning og tørkes over magnesiumsulfat. Etter fjerning av oppløsningsmidlet krystalliseres residuumet fra isopropyleter/petroleter. 16.6 g (0.1 mol) of 2,6-dimethoxybenzaldehyde are dissolved in 200 ml of abs. tetrahydrofuran and 60 ml of a 2.58 molar methyl magnesium iodide solution in tetrahydrofuran are added dropwise at 10°C. The reaction mixture is kept for 2 hours at room temperature and is then mixed with a solution of 30 g of ammonium chloride in 200 ml of water. The resulting mixture is shaken with ether, the organic phases are washed with saline and dried over magnesium sulphate. After removal of the solvent, the residue is crystallized from isopropyl ether/petroleum ether.
Det dannede 1-(2,6-dimetoksyfenyl)-etanol smelter ved 56-58°C. The 1-(2,6-dimethoxyphenyl)-ethanol formed melts at 56-58°C.
Eksempel 19Example 19
Analogt som angitt i eksempel 1 fåes av 3 g (0,02 mol) 1- (2,3-dimetylfenyl)-etanol og 4,92 g (0,06 mol) 2-metylimidazol 1,95 g oljeaktig 1-[1-(2,3-dimetyl-fenyl)-etyl]-2- metyl-imidazol. Av 1,92 g av den rå base fremstilles med eterisk saltsyre det rene 1-[1-(2,3-dimetylfenyl)-etyl]-2-metyl-imidazol-hydroklorid med smp. 244-246°C. Analogous to that stated in example 1, 3 g (0.02 mol) of 1-(2,3-dimethylphenyl)-ethanol and 4.92 g (0.06 mol) of 2-methylimidazole yield 1.95 g of oily 1-[1 -(2,3-dimethyl-phenyl)-ethyl]-2-methyl-imidazole. From 1.92 g of the crude base, the pure 1-[1-(2,3-dimethylphenyl)-ethyl]-2-methyl-imidazole hydrochloride with m.p. 244-246°C.
Eksempel 20Example 20
9,25 g (0,05 mol) 1-fenyl-etylbromid oppløses med 20,5 g (0,25 mol) 2-metylimidazol i 100 ml toluen og oppvarmes under omrøring 8 timer ved 100°C. Reaksjonsblandingen av-kjøles, blandes med 2n saltsyre til sur reaksjon og den sure vandige fase adskilles. Toluenoppløsningen utrystes 3 ganger med hver gang 50 ml 1 n saltsyre og de forenede sure, vandige faser gjøres alkalisk med natronlut. Den dannede blanding utrystes med eter, den eteriske oppløsning 9.25 g (0.05 mol) of 1-phenyl-ethyl bromide are dissolved with 20.5 g (0.25 mol) of 2-methylimidazole in 100 ml of toluene and heated with stirring for 8 hours at 100°C. The reaction mixture is cooled, mixed with 2N hydrochloric acid to an acidic reaction and the acidic aqueous phase is separated. The toluene solution is shaken 3 times with each time 50 ml of 1 N hydrochloric acid and the combined acidic, aqueous phases are made alkaline with caustic soda. The resulting mixture is shaken with ether, the ethereal solution
tørkes over magnesiumsulfat og oppløsningsmidlet fjernes i vakuum. Det dannede residuum oppløses i eddikester og blandes med eterisk saltsyre til sur reaksjon. Etter ytterligere tilsetning av eter frafiltreres det utfelte produkt, vaskes med eter og omkrystalliseres fra cykloheksan. Det rene 1-(1-fenyletyl)-2-metyl-imidazol smelter ved 84-85°C. is dried over magnesium sulfate and the solvent is removed in vacuo. The residue formed is dissolved in acetic acid and mixed with ethereal hydrochloric acid for an acidic reaction. After further addition of ether, the precipitated product is filtered off, washed with ether and recrystallized from cyclohexane. The pure 1-(1-phenylethyl)-2-methyl-imidazole melts at 84-85°C.
Som angitt i eksempel 1 fremstilles fra basen hydrokloridet. Det rene 1-(1-fenyl-etyl)-2-metyl-imidazohydroklorid As indicated in example 1, the hydrochloride is prepared from the base. The pure 1-(1-phenyl-ethyl)-2-methyl-imidazo hydrochloride
smelter ved 229-229,5°C.melts at 229-229.5°C.
Eksempel 21Example 21
23,02 g (0,11 mol) N-(1-fenyl-etyl)-2-amino-acetaldehyd-dimetylacetal blandes med 10,9 g (0,1 mol) acetiminometyleter-hydroklorid, oppløses i 200 ml metanol og hensettes 4 dager ved værelsetemperatur. Reaksjonsblandingen befris for oppløsningsmiddel i vakuum, det oljeaktige residuum oppløses i 250 ml vann og settes til 500 ml kons. saltsyre. Blandingen inndampes ved 100°C til tørrhet og det dannede residuum gjøres alkalisk med en mettet pottaskeoppløsning. Den dannede blanding utrystes 3 ganger med 500 ml eter, de eteriske faser tørkes over magnesium-sulf at og oppløsningsmidlet fjernes i vakuum. Det oljeaktige residuum destilleres i høyvakuum (6,66 Pa), kokepunkt = 115-120°C. Det dannede produkt oppløses i eddikester og blandes med eterisk saltsyre til sur reaksjon. Det utfelte produkt frafiltreres og omkrystalliseres fra isopropanol/eter. Det rene 1-(2-fenyl-etyl)-2-metylimidazol-hydroklorid smelter ved 228-229°C. 23.02 g (0.11 mol) of N-(1-phenyl-ethyl)-2-amino-acetaldehyde-dimethylacetal are mixed with 10.9 g (0.1 mol) of acetiminomethyl ether hydrochloride, dissolved in 200 ml of methanol and set aside 4 days at room temperature. The reaction mixture is freed of solvent in vacuo, the oily residue is dissolved in 250 ml of water and added to 500 ml of conc. hydrochloric acid. The mixture is evaporated at 100°C to dryness and the residue formed is made alkaline with a saturated pot ash solution. The resulting mixture is shaken 3 times with 500 ml of ether, the ethereal phases are dried over magnesium sulphate and the solvent is removed in vacuo. The oily residue is distilled under high vacuum (6.66 Pa), boiling point = 115-120°C. The product formed is dissolved in acetic acid and mixed with ethereal hydrochloric acid for an acidic reaction. The precipitated product is filtered off and recrystallized from isopropanol/ether. The pure 1-(2-phenyl-ethyl)-2-methylimidazole hydrochloride melts at 228-229°C.
Utgangsmaterialet kan fåes som følger:The starting material can be obtained as follows:
a) 60,1 g (0,5 mol) acetofenon oppløses i 1000 ml metanol med 56,78 g (0,54 mol) 2-aminoacetaldehyd-dimetylacetal a) 60.1 g (0.5 mol) acetophenone is dissolved in 1000 ml methanol with 56.78 g (0.54 mol) 2-aminoacetaldehyde-dimethyl acetal
og hydrogeneres etter tilsetning av 10 g palladium-kull ved værelsetemperatur og normaltrykk katalyttisk. Etter foretatt and hydrogenated catalytically after adding 10 g of palladium charcoal at room temperature and normal pressure. After made
hydrogenopptak frafiltreres katalysatoren og oppløsningsmid-let fjernes i vakuum. Det dannede residuum destilleres i høyvakuum ved 60-65°C (7,99Pa) og gir rent N-(1-fenyl-etyl )-2-aminoacetaldehyd-dimetylacetal. b) 82 g (2 mol) acetonitril oppløses i 65 g (2 mol) metanol og tilsettes 500 ml 4 n eterisk saltsyre. Reaksjonsblandingen hensettes ved værelsetemperatur og frafiltreres fra utfelt produkt. Det dannede produkt vaskes med eter og tørkes i vakuum ved værelsetemperatur. Det dannede acetiminometyleter-hydroklorid smelter ved 97°C. hydrogen uptake, the catalyst is filtered off and the solvent is removed under vacuum. The residue formed is distilled in high vacuum at 60-65°C (7.99Pa) and gives pure N-(1-phenyl-ethyl)-2-aminoacetaldehyde-dimethyl acetal. b) Dissolve 82 g (2 mol) acetonitrile in 65 g (2 mol) methanol and add 500 ml 4 N ethereal hydrochloric acid. The reaction mixture is left at room temperature and filtered from the precipitated product. The product formed is washed with ether and dried in vacuum at room temperature. The formed acetiminomethyl ether hydrochloride melts at 97°C.
Eksempel 22Example 22
9,1 g (0,05 mol) 1-[2-metoksybenzyl]-imidazol oppløses i 90 ml tetrahydrofuran og ved -78°Ctildryppes 7,1 g (0,11 mol, tilsvarende 55,4 ml 2-molar oppløsning) butyllitium i 9.1 g (0.05 mol) of 1-[2-methoxybenzyl]-imidazole is dissolved in 90 ml of tetrahydrofuran and at -78°C 7.1 g (0.11 mol, corresponding to 55.4 ml of a 2-molar solution) are added dropwise. butyllithium i
50 ml tetrahydrofuran. Blandingen omrøres 2 timer ved50 ml tetrahydrofuran. The mixture is stirred for 2 hours at
-78°C og deretter inndryppes 17,0 g (0,12 mol) metyljodid oppløst i 20 ml tetrahydrofuran. Reaksjonsblandingen oppvarmes til værelsetemperatur og omrøres 30 timer ved denne temperatur. Deretter inndryppes langsomt 50 ml vann og tetrahydrofuranet fjernes best mulig i vakuum. -78°C and then 17.0 g (0.12 mol) of methyl iodide dissolved in 20 ml of tetrahydrofuran are added dropwise. The reaction mixture is heated to room temperature and stirred for 30 hours at this temperature. Then 50 ml of water is slowly dripped in and the tetrahydrofuran is removed as best as possible under vacuum.
Etter tilsetning av 2n natronlut til sterkt alkaliskAfter adding 2n caustic soda to strongly alkaline
reaksjon utrystes residuumet met eter. De organiske faser tørkes over magnesiumsulfat og oppløsningsmidlet fjernes under vakuum. Det dannede oljeaktige residuum opp-løses i eddikester og blandes med eterisk saltsyre til sur reaksjon. Det utfelte produkt frafiltreres og omkrystalliseres fra isopropanol-eter. Det rene l-[l-(2-metoksy-fenyl)-etyl]-2-metyl-imidazol-hydroklorid smelter ved 201-203°C. reaction, the residue is removed with ether. The organic phases are dried over magnesium sulphate and the solvent is removed under vacuum. The oily residue formed is dissolved in vinegar and mixed with ethereal hydrochloric acid for an acidic reaction. The precipitated product is filtered off and recrystallized from isopropanol ether. The pure 1-[1-(2-methoxy-phenyl)-ethyl]-2-methyl-imidazole hydrochloride melts at 201-203°C.
Utgangsmaterialet kan fåes som følger:The starting material can be obtained as follows:
Analogt det som er omtalt i eksempel 1 fåes av 13,8 gAnalogous to what is discussed in example 1, 13.8 g is obtained
(0,1 mol) 2-metoksy-benzylalkohol og 34 g (0,5 mol)(0.1 mol) 2-methoxy-benzyl alcohol and 34 g (0.5 mol)
imidazol 9,78 g rent oljeaktig 2-metoksybenzylimidazol.imidazole 9.78 g pure oily 2-methoxybenzylimidazole.
Det dannede produkt destilleres i høyvakuum ved 120-130°C (1,33 Pa). The product formed is distilled in high vacuum at 120-130°C (1.33 Pa).
Eksempel 23Example 23
4,0 g (20 mmol) 1-[1-(4-aminofenyl)-etyl]-2-metyl-4.0 g (20 mmol) 1-[1-(4-aminophenyl)-ethyl]-2-methyl-
imidazol oppløses i 100 ml metanol, blandes med 6 mlimidazole is dissolved in 100 ml of methanol, mixed with 6 ml
(60 mmol) kons. saltsyre og ved 0°C inndryppes 2,68 g(60 mmol) conc. hydrochloric acid and at 0°C drop in 2.68 g
(26 mmol) tert.-butylnitrit. Blandingen omrøres 30(26 mmol) tert-butyl nitrite. The mixture is stirred for 30
minutter ved 0°C, deretter oppvarmes langsomt i løpet av 1 time til tilbakeløp og holdes 30 minutter ved denne temperatur. Reaksjonsblandingen inndampes i vannstrålevakuum, blandes med 2n natronlut til alkalisk reaksjon, fortynnes med saltoppløsning og utrystes med eter. De eteriske ekstrakter tørkes over magnesiumsulfat og oppløsningsmidlet fjernes i vakuum og residuumet blandes med alkoholisk saltsyre til sur reaksjon. Etter tilsetning av eddikester frafiltreres det utfelte produkt og tørkes. Etter omkrystallisering fra alkohol/eddikester fåes det rene 1-[1-(4-metoksy-fenyl)-etyl]-2-metyl-imidazol-hydroklorid av smp. 200-202°C. minutes at 0°C, then slowly heated over 1 hour to reflux and kept at this temperature for 30 minutes. The reaction mixture is evaporated in a water jet vacuum, mixed with 2N caustic soda for an alkaline reaction, diluted with salt solution and shaken out with ether. The ethereal extracts are dried over magnesium sulphate and the solvent is removed in vacuo and the residue is mixed with alcoholic hydrochloric acid for an acidic reaction. After adding vinegar, the precipitated product is filtered off and dried. After recrystallization from alcohol/acetic ester, pure 1-[1-(4-methoxy-phenyl)-ethyl]-2-methyl-imidazole hydrochloride of m.p. 200-202°C.
Utgangsmaterialet kan fåes som følger:The starting material can be obtained as follows:
16,5 g (0,1 mol) p-nitroacetofenon oppløses i 160 ml metanol og langsomt under avkjøling innføres 3,7 g (0,1 mol) natriumborhydrid. Etter avsluttet tilsetning oppvarmes blandingen langsomt til 60°C og holdes til avslutning av gassutviklingen ved denne temperatur. Etter foretatt avkjøling tilsettes ca. 150 ml 1 molar natriumdihydrogen-fosfatoppløsning og metanolen fjernes best mulig i vakuum. Residuumet utrystes med eter, de organiske faser tørkes 16.5 g (0.1 mol) of p-nitroacetophenone are dissolved in 160 ml of methanol and slowly, while cooling, 3.7 g (0.1 mol) of sodium borohydride are introduced. After the addition has been completed, the mixture is slowly heated to 60°C and kept at this temperature until gas evolution ends. After cooling, add approx. 150 ml of 1 molar sodium dihydrogen phosphate solution and the methanol are best removed in a vacuum. The residue is shaken out with ether, the organic phases are dried
over magnesiumsulfat og oppløsningsmidlet fjernes i vakuum. Det dannede 1-[p-nitrofenyl]-etanol videreanvendes som rå olje. over magnesium sulfate and the solvent is removed in vacuo. The 1-[p-nitrophenyl]-ethanol formed is further used as crude oil.
Av 16 g (0,096 mol) 1-(p-nitrofenyl)-etanol og 23,6 gOf 16 g (0.096 mol) 1-(p-nitrophenyl)-ethanol and 23.6 g
(0,29 mol) 2-metylimidazol fåes som omtalt i eksempel 1 rent (0.29 mol) 2-methylimidazole is obtained as described in example 1 pure
1-[1-(4-nitrofenyl)-etyl]-2-metyl-imidazol av smp. 78-79°C. 1-[1-(4-nitrophenyl)-ethyl]-2-methyl-imidazole of m.p. 78-79°C.
(omkrystallisering fra diisopropyleter-petroleter).(recrystallization from diisopropyl ether-petroleum ether).
14,0 g (0,06 mol) 1-[-(4-nitrofenyl)-etyl]-2-metyl-imidazol i 150 ml etanol, 2 g Raney-nikkel tilsettes og hydrogeneres med hydrogen ved normaltrykk og 20°C i løpet av 15 timer katalyttisk. 14.0 g (0.06 mol) 1-[-(4-nitrophenyl)-ethyl]-2-methyl-imidazole in 150 ml of ethanol, 2 g of Raney nickel are added and hydrogenated with hydrogen at normal pressure and 20°C in during 15 hours catalytically.
Deretter frafiltreres katalysatoren, oppløsningsmidlet fjernes i vakuum og residuumet krystalliseres fra eddikester. Det rene 1-[1-(4-aminofenyl)-etyl]-2-metyl-imidazol The catalyst is then filtered off, the solvent is removed in vacuo and the residue is crystallized from acetic acid. The pure 1-[1-(4-aminophenyl)-ethyl]-2-methyl-imidazole
smelter ved 149-151°C.Dihydrokloridet (fra alkohol-eddikester med alkoholisk saltsyre) smelter ved 165-167°C. melts at 149-151°C. The dihydrochloride (from alcohol-acetic ester with alcoholic hydrochloric acid) melts at 165-167°C.
Eksempel 24Example 24
På analog måte som omtalt i eksempel 23, kan det av 20,1 g (0,1 mol) 1-[1-(2-aminofenyl)-etyl]-2-metyl-imidazol fåes det rene 1-[1-(2-metoksyfen^l)-etyl]-2-meetyl-imidazol-hydroklorid av smp. 201-203 C. In an analogous manner to that described in example 23, the pure 1-[1-( 2-Methoxyphene(1)-ethyl]-2-methyl-imidazole hydrochloride of m.p. 201-203C.
Dihydrokloridet (fra alkohol-eddikester med alkoholisk saltsyre) smelter ved 165-167°C. The dihydrochloride (from alcohol-acetic ester with alcoholic hydrochloric acid) melts at 165-167°C.
Eksempel 25Example 25
Tabletter, inneholdende 0,020 g 1-(1-fenyl-etyl)-2-metyl-imidazol, fremstilles f.eks. som følger: Tablets, containing 0.020 g of 1-(1-phenyl-ethyl)-2-methyl-imidazole, are prepared, e.g. as follows:
En blanding av det virksomme stoff, laktosen og 194,70 g potetstivelse fuktes med en etanolisk oppløsning av stearin-syren og granuleres gjennom en sikt. Etter tørkning blander man den.resterende potetstivelse, talkum, magnesiumstearat og den kolloidale silisiumdioksyd og presser blandingen til tabletter på hver 0,1 g vekt, som hvis ønsket kan være utstyrt med bruddanvisning til finere tilpassing av doseringen. A mixture of the active substance, the lactose and 194.70 g of potato starch is moistened with an ethanolic solution of the stearic acid and granulated through a sieve. After drying, the remaining potato starch, talc, magnesium stearate and the colloidal silicon dioxide are mixed and the mixture is pressed into tablets of 0.1 g weight each, which, if desired, can be equipped with break instructions for finer adjustment of the dosage.
Eksempel 26Example 26
Kapsler inneholdende 0,025 g 1-(1-fenyl-etyl)-2-metylimidazol, kan fremstilles som følger: Capsules containing 0.025 g of 1-(1-phenyl-ethyl)-2-methylimidazole can be prepared as follows:
Sammensetning (for 1000 kapsler):Composition (for 1000 capsules):
Man blander det virksomme stoff med laktosen, fukter blandingen jevnt med en vandig oppløsning av gelatin og granulerer den gjennom en sikt med en maskevidde på 1,2-1,5 mm. Granulatet blander man med den tørkede maisstivelse og talk og fyller porsjoner på 300 mg i hårdgelatinkapsler (størrelse 1). The active substance is mixed with the lactose, the mixture is moistened evenly with an aqueous solution of gelatin and granulated through a sieve with a mesh size of 1.2-1.5 mm. The granulate is mixed with the dried corn starch and talc and portions of 300 mg are filled into hard gelatin capsules (size 1).
Claims (11)
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JP (1) | JPS60158176A (en) |
AU (1) | AU569135B2 (en) |
CA (1) | CA1233828A (en) |
DD (1) | DD228249A5 (en) |
DK (1) | DK614384A (en) |
ES (6) | ES8800166A1 (en) |
FI (1) | FI845140L (en) |
GR (1) | GR82625B (en) |
HU (1) | HU193916B (en) |
IL (1) | IL73955A (en) |
NO (1) | NO845278L (en) |
NZ (1) | NZ210722A (en) |
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EP0200947B1 (en) | 1985-04-26 | 1990-09-12 | F. Hoffmann-La Roche Ag | 1,3-disubstituted imidazolium salts |
DE3628545A1 (en) * | 1985-09-23 | 1987-04-23 | Hoechst Ag | ARYLMETHYLAZOLES AND THEIR SALTS, METHOD FOR THE PRODUCTION THEREOF, MEANS CONTAINING THEM AND THEIR USE |
JPS62103068A (en) * | 1985-09-23 | 1987-05-13 | ヘキスト・アクチエンゲゼルシヤフト | Arylmethylazoles and salts and manufacture of them |
US4749713A (en) * | 1986-03-07 | 1988-06-07 | Ciba-Geigy Corporation | Alpha-heterocycle substituted tolunitriles |
US4978672A (en) * | 1986-03-07 | 1990-12-18 | Ciba-Geigy Corporation | Alpha-heterocyclc substituted tolunitriles |
US4937250A (en) * | 1988-03-07 | 1990-06-26 | Ciba-Geigy Corporation | Alpha-heterocycle substituted tolunitriles |
DE3707151A1 (en) * | 1987-03-06 | 1988-09-15 | Hoechst Ag | 1- (1-ARYL-2-HYDROXY-ETHYL) -IMIDAZOLES AND THE SALTS THEREOF, METHOD FOR THE PRODUCTION THEREOF, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND THEIR USE |
DE3812483A1 (en) * | 1987-06-27 | 1989-01-05 | Bayer Ag | (AZOLYL VINYL) PHENOL ALKENYL ETHER |
JPH03130266A (en) * | 1989-07-28 | 1991-06-04 | Hodogaya Chem Co Ltd | Substituted phenylalkylimidazole derivative |
DE3931554A1 (en) * | 1989-09-22 | 1991-04-04 | Hoechst Ag | (+) - (2-HYDROXY-2-ADAMANTYL) -1-IMIDAZOLYL-3-TOLYL-METHANE AND THEIR SALTS, METHODS FOR THE PRODUCTION THEREOF, AND THEIR MEDICAMENTS CONTAINING THEM AND THEIR USE |
JP3938651B2 (en) * | 2000-04-13 | 2007-06-27 | セントラル硝子株式会社 | Process for producing optically active α-methyl-bis-3,5- (trifluoromethyl) benzylamine |
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IE40911B1 (en) * | 1974-04-11 | 1979-09-12 | Schering Ag | Imidazole derivatives and process for their manufacture |
DE2546064A1 (en) * | 1975-10-10 | 1977-04-21 | Schering Ag | (1)-Benzyl-(1,2,4)-triazole derivs. - with antimycotic activity |
EP0003732B1 (en) * | 1978-02-01 | 1983-10-19 | The Wellcome Foundation Limited | Imidazole derivatives and salts thereof, their synthesis, and pharmaceutical formulations thereof |
US4532331A (en) * | 1983-04-12 | 1985-07-30 | Smithkline Beckman Corporation | 1-Benzyl-2-aminomethyl imidazole derivatives |
US4581370A (en) * | 1983-07-12 | 1986-04-08 | Schering A.G. | Antiarrhythmic imidazoliums |
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- 1984-12-27 IL IL73955A patent/IL73955A/en unknown
- 1984-12-28 ES ES539204A patent/ES8800166A1/en not_active Expired
- 1984-12-28 DD DD84272059A patent/DD228249A5/en unknown
- 1984-12-28 JP JP59275046A patent/JPS60158176A/en active Pending
- 1984-12-28 ZA ZA8410105A patent/ZA8410105B/en unknown
- 1984-12-28 CA CA000471118A patent/CA1233828A/en not_active Expired
- 1984-12-28 NO NO845278A patent/NO845278L/en unknown
- 1984-12-28 HU HU844868A patent/HU193916B/en unknown
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- 1984-12-31 GR GR82625A patent/GR82625B/en unknown
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1985
- 1985-01-04 NZ NZ210722A patent/NZ210722A/en unknown
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- 1986-02-28 ES ES552559A patent/ES8705397A1/en not_active Expired
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FI845140L (en) | 1985-07-01 |
EP0149976A2 (en) | 1985-07-31 |
PT79761B (en) | 1986-12-10 |
PT79761A (en) | 1985-01-01 |
NZ210722A (en) | 1987-06-30 |
DD228249A5 (en) | 1985-10-09 |
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DK614384A (en) | 1985-07-01 |
JPS60158176A (en) | 1985-08-19 |
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FI845140A0 (en) | 1984-12-27 |
ES552555A0 (en) | 1987-05-01 |
ES8705397A1 (en) | 1987-05-01 |
IL73955A (en) | 1988-09-30 |
GR82625B (en) | 1985-05-07 |
EP0149976A3 (en) | 1986-12-10 |
DK614384D0 (en) | 1984-12-20 |
ES8705394A1 (en) | 1987-05-01 |
ES552558A0 (en) | 1987-05-01 |
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HU193916B (en) | 1987-12-28 |
HUT36463A (en) | 1985-09-30 |
ZA8410105B (en) | 1985-08-28 |
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