NO124111B - - Google Patents
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- NO124111B NO124111B NO1212/68A NO121268A NO124111B NO 124111 B NO124111 B NO 124111B NO 1212/68 A NO1212/68 A NO 1212/68A NO 121268 A NO121268 A NO 121268A NO 124111 B NO124111 B NO 124111B
- Authority
- NO
- Norway
- Prior art keywords
- solution
- mixture
- ether
- formula
- acid
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 10
- -1 hydroperoxide compound Chemical class 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 150000001491 aromatic compounds Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 150000007514 bases Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 239000000243 solution Substances 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 53
- 239000000203 mixture Substances 0.000 description 47
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- 238000002844 melting Methods 0.000 description 36
- 230000008018 melting Effects 0.000 description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000002244 precipitate Substances 0.000 description 27
- 238000004458 analytical method Methods 0.000 description 22
- 238000001953 recrystallisation Methods 0.000 description 22
- 238000010521 absorption reaction Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000000354 decomposition reaction Methods 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000010992 reflux Methods 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 150000002978 peroxides Chemical class 0.000 description 9
- 239000008096 xylene Substances 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- DKUKKXXCBPICGC-UHFFFAOYSA-N [2-(4,5-dihydro-1h-imidazol-2-yl)phenyl]-phenylmethanone Chemical compound C=1C=CC=C(C=2NCCN=2)C=1C(=O)C1=CC=CC=C1 DKUKKXXCBPICGC-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- REFMUVZBSRUILL-UHFFFAOYSA-N 2-(4-chlorobenzoyl)benzaldehyde Chemical compound C1=CC(Cl)=CC=C1C(=O)C1=CC=CC=C1C=O REFMUVZBSRUILL-UHFFFAOYSA-N 0.000 description 4
- PHBKQTTUKZXPHG-UHFFFAOYSA-N 5-hydroperoxy-5-phenyl-2,3-dihydroimidazo[2,1-a]isoindole Chemical compound N12CCN=C2C2=CC=CC=C2C1(OO)C1=CC=CC=C1 PHBKQTTUKZXPHG-UHFFFAOYSA-N 0.000 description 4
- WAUSCHXBFNDDSK-UHFFFAOYSA-N 5-phenyl-3,5-dihydro-2h-imidazo[2,1-a]isoindole;sulfuric acid Chemical compound OS(O)(=O)=O.C12=CC=CC=C2C2=NCCN2C1C1=CC=CC=C1 WAUSCHXBFNDDSK-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- YHWQUWUHLPRUID-UHFFFAOYSA-N (2-chlorophenyl)-[2-(4,5-dihydro-1h-imidazol-2-yl)phenyl]methanone Chemical compound ClC1=CC=CC=C1C(=O)C1=CC=CC=C1C1=NCCN1 YHWQUWUHLPRUID-UHFFFAOYSA-N 0.000 description 3
- WKQOOBZACKJBQB-UHFFFAOYSA-N (2-chlorophenyl)-[2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=CC=C1C(O)C1=CC=CC=C1Cl WKQOOBZACKJBQB-UHFFFAOYSA-N 0.000 description 3
- UMTVPIGVAJASSU-UHFFFAOYSA-N 2-(4-bromobenzoyl)benzaldehyde Chemical compound C1=CC(Br)=CC=C1C(=O)C1=CC=CC=C1C=O UMTVPIGVAJASSU-UHFFFAOYSA-N 0.000 description 3
- XADYAGFTKHRPNE-UHFFFAOYSA-N 2-(4-methoxybenzoyl)benzaldehyde Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1C=O XADYAGFTKHRPNE-UHFFFAOYSA-N 0.000 description 3
- HIHTVTATSKDEQF-UHFFFAOYSA-N 2-benzoylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C(=O)C1=CC=CC=C1 HIHTVTATSKDEQF-UHFFFAOYSA-N 0.000 description 3
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 3
- OUDUVJXYNXZDIM-UHFFFAOYSA-N 5-phenyl-3,5-dihydro-2h-imidazo[2,1-a]isoindole Chemical compound C12=CC=CC=C2C2=NCCN2C1C1=CC=CC=C1 OUDUVJXYNXZDIM-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000002775 capsule 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
- 150000004985 diamines Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical class O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 3
- 239000003368 psychostimulant agent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- NHZJEVSTGFERMD-UHFFFAOYSA-N (4-bromophenyl)-[2-(4,5-dihydro-1h-imidazol-2-yl)phenyl]methanone Chemical compound C1=CC(Br)=CC=C1C(=O)C1=CC=CC=C1C1=NCCN1 NHZJEVSTGFERMD-UHFFFAOYSA-N 0.000 description 2
- PNIZNQBBRNKJNE-UHFFFAOYSA-N (4-chlorophenyl)-[2-(4,5-dihydro-1h-imidazol-2-yl)phenyl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1=CC=CC=C1C1=NCCN1 PNIZNQBBRNKJNE-UHFFFAOYSA-N 0.000 description 2
- YTSWAXSUNMFKBE-UHFFFAOYSA-N 2-(2-chlorobenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1Cl YTSWAXSUNMFKBE-UHFFFAOYSA-N 0.000 description 2
- WSMRDQYRUQAEKX-UHFFFAOYSA-N 2-benzoyl-4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(C(=O)C=2C=CC=CC=2)=C1 WSMRDQYRUQAEKX-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- VHOLDVWNAVAZQQ-UHFFFAOYSA-N 9b-phenyl-2,3-dihydro-1h-imidazo[2,1-a]isoindol-5-one Chemical compound C12=CC=CC=C2C(=O)N2CCNC21C1=CC=CC=C1 VHOLDVWNAVAZQQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000004992 fission Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000009965 odorless effect Effects 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- JNAKRUICNFHBRK-UHFFFAOYSA-N (2-chlorophenyl)-[2-(4,5-dihydro-1h-imidazol-2-yl)phenyl]methanone;hydrochloride Chemical compound Cl.ClC1=CC=CC=C1C(=O)C1=CC=CC=C1C1=NCCN1 JNAKRUICNFHBRK-UHFFFAOYSA-N 0.000 description 1
- DLYQDBJPCWSEOG-UHFFFAOYSA-N (4-chlorophenyl)-[2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=CC=C1C(O)C1=CC=C(Cl)C=C1 DLYQDBJPCWSEOG-UHFFFAOYSA-N 0.000 description 1
- MCZXMWARUTZVDK-UHFFFAOYSA-N 1,2,3,9b-tetrahydroimidazo[1,2-b]isoindol-5-one;hydrochloride Chemical compound Cl.C12=CC=CC=C2C(=O)N2C1NCC2 MCZXMWARUTZVDK-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KORKIRUGUNPQML-UHFFFAOYSA-N 2-(2-aminobenzoyl)benzoic acid Chemical compound NC1=CC=CC=C1C(=O)C1=CC=CC=C1C(O)=O KORKIRUGUNPQML-UHFFFAOYSA-N 0.000 description 1
- NONNFIAFWRSPPY-UHFFFAOYSA-N 2-(4-bromobenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(Br)C=C1 NONNFIAFWRSPPY-UHFFFAOYSA-N 0.000 description 1
- SQFMIHCARVMICF-UHFFFAOYSA-N 3-phenyl-3h-2-benzofuran-1-one Chemical compound C12=CC=CC=C2C(=O)OC1C1=CC=CC=C1 SQFMIHCARVMICF-UHFFFAOYSA-N 0.000 description 1
- XETVOTQWKUDCJG-UHFFFAOYSA-N 5-(2-chlorophenyl)-5-hydroperoxy-2,3-dihydroimidazo[2,1-a]isoindole Chemical group N12CCN=C2C2=CC=CC=C2C1(OO)C1=CC=CC=C1Cl XETVOTQWKUDCJG-UHFFFAOYSA-N 0.000 description 1
- RAZRHYOBZPAGEG-UHFFFAOYSA-N 5-(4-bromophenyl)-2,3-dihydroimidazo[1,2-b]isoindol-5-ol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Br)C=C1 RAZRHYOBZPAGEG-UHFFFAOYSA-N 0.000 description 1
- RTGSWQKZPNQRPV-UHFFFAOYSA-N 5-(4-chlorophenyl)-5-hydroperoxy-2,3-dihydroimidazo[2,1-a]isoindole;hydrochloride Chemical compound Cl.N12CCN=C2C2=CC=CC=C2C1(OO)C1=CC=C(Cl)C=C1 RTGSWQKZPNQRPV-UHFFFAOYSA-N 0.000 description 1
- HQICEQOCYAITRP-UHFFFAOYSA-N 5-(4-methoxyphenyl)-2,3-dihydroimidazo[1,2-b]isoindol-5-ol Chemical compound C1=CC(OC)=CC=C1C1(O)C2=CC=CC=C2C2=NCCN21 HQICEQOCYAITRP-UHFFFAOYSA-N 0.000 description 1
- AYCFVKGYERYDRT-UHFFFAOYSA-N 5-phenyl-2,3-dihydroimidazo[1,2-b]isoindol-5-ol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=CC=C1 AYCFVKGYERYDRT-UHFFFAOYSA-N 0.000 description 1
- TXMKWLMXNSUAPQ-UHFFFAOYSA-N 7-chloro-5-phenyl-2,3-dihydroimidazo[1,2-b]isoindol-5-ol Chemical compound N12CCN=C2C2=CC=C(Cl)C=C2C1(O)C1=CC=CC=C1 TXMKWLMXNSUAPQ-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010065369 Burnout syndrome Diseases 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
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- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
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- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 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
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- C07D233/20—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 substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/22—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Structures Of Non-Positive Displacement Pumps (AREA)
Description
Fremgangsmåte for fremstilling av aromatiske forbindelser. Process for the production of aromatic compounds.
Nærværende oppfinnelse vedrorer en ny, spesiell fremgangsmåte for fremstilling av aromatiske forbindelser med den generelle formel I hvor B betyr en alkylengruppe med 2-4 karbon-at omer , The present invention relates to a new, special method for producing aromatic compounds with the general formula I where B means an alkylene group with 2-4 carbon atoms,
hydrogen eller halogen og hydrogen or halogen and
R 3 og R^ hydrogen, halogen, lavere alkyl, lavere alkoksy eller trifluormetyl. R 3 and R 3 are hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl.
Forbindelser med formel I kan ved protonvandring gå over til forbindelser med formel II Compounds of formula I can change to compounds of formula II by proton migration
hvor R^, R^, R^ og B har foran angitte betydning. where R^, R^, R^ and B have the meanings indicated above.
Nærværende oppfinnelse vedrorer begge tautomere isomerer og The present invention relates to both tautomeric isomers and
blandinger derav. mixtures thereof.
Nærværende oppfinnelse omfatter også fremstillingen av syreaddisjonssalter av de nevnte forbindelser. The present invention also includes the production of acid addition salts of the aforementioned compounds.
Ved en foretrukken utforelsesform betyr B etylen. In a preferred embodiment, B means ethylene.
Det i denne beskrivelse anvendte uttrykk "lavere alkyl" vedrorer rettkjedete og forgrenete hydrokarboner med 1-6 kar-bonatomer, som metyl, etyl, propyl, isopropyl, butyl, sek.-butyl, tert.-butyl og lignende. Uttrykket "lavere alkoksy" vedrorer lavere alkyletergrupper, hvor alkylgruppen har foran angitte betydning. Uttrykket "halogen" omfatter alle fire halogener, dvs. klor, brom, jod og fluor. The term "lower alkyl" used in this description refers to straight-chain and branched hydrocarbons with 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and the like. The term "lower alkoxy" refers to lower alkyl ether groups, where the alkyl group has the above meaning. The term "halogen" includes all four halogens, ie chlorine, bromine, iodine and fluorine.
Egnede salter av forbindelser med formlene I og II er slike med ikke-toksiske, organiske og uorganiske syrer. Egnede organiske syrer er f.eks. maleinsyre, fumarsyre, askorbinsyre, vinsyre, salicylsyre, ravsyre, sitronsyre og lignende. Egnede uorganiske syrer er f.eks. halogenhydrogensyre, som klorhydro-gensyre og bromhydrogensyre, svovelsyre, sulfaminsyre, fosfor-syre og lignende. Syreaddisjonssaltene fremstilles etter kjente metoder, som enhver fagmann er fortrolig med. Suitable salts of compounds of formulas I and II are those with non-toxic organic and inorganic acids. Suitable organic acids are e.g. maleic acid, fumaric acid, ascorbic acid, tartaric acid, salicylic acid, succinic acid, citric acid and the like. Suitable inorganic acids are e.g. hydrohalic acid, such as hydrochloric acid and hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and the like. The acid addition salts are produced according to known methods, with which every person skilled in the art is familiar.
Forbindelser med formlene I og II kan ifolge oppfinnelsen fremstilles slik at man behandler en forbindelse med formel III hvor B, R^, R, og R^ har foran angitte betydning, med et oksydasjonsmiddel og reduserer en eventuelt oppnådd hydroperoksyforbindelse med formel X Compounds with the formulas I and II can, according to the invention, be prepared by treating a compound with the formula III where B, R^, R, and R^ have the meanings given above, with an oxidizing agent and reducing a possibly obtained hydroperoxy compound with the formula X
hvor B, R^, R, og R^ har foran angitte betydning, og, hvis onsket, overforer en oppnådd basisk forbindelse til et syreaddisjonssalt. wherein B, R^, R, and R^ have the above meanings, and, if desired, converts an obtained basic compound into an acid addition salt.
Fremgangsmåten ifolge oppfinnelsen til fremstilling av forbindelser med formlene I og II, såvel som fremstillingen av utgangsproduktene er anskueliggjort i det folgende reaksjons-skj erna: The process according to the invention for the production of compounds with the formulas I and II, as well as the production of the starting products, is illustrated in the following reaction scheme:
hvor R^, R^, R^ og B har foran angitte betydning. where R^, R^, R^ and B have the meanings indicated above.
Diolene med formel V er kjente forbindelser eller kan oppnås analogt fremstillingen av kjente forbindelser. Disse diol-utgangsmaterialer kan lett overfores ved oksydasjon på i og for seg kjent måte, f.eks. med selendioksyd og lignende som oksydasjonsmiddel eller med et annet oksydasjonssystem, som f.eks. kromtrioksyd i pyridin, til dikarbonyl-forbindelser med formel IV. The diols of formula V are known compounds or can be obtained analogously to the preparation of known compounds. These diol starting materials can be easily transferred by oxidation in a manner known per se, e.g. with selenium dioxide and the like as oxidizing agent or with another oxidation system, such as e.g. chromium trioxide in pyridine, to dicarbonyl compounds of formula IV.
Behandlingen med oksydasjonsmidlet gjennomfores vanligvis i et organisk opplosningsmiddel, som f.eks. dimetylformamid, dime-tylsulfoksyd, hydrokarboner, som benzen, toluen, alkanoler, som lavere alkanoler, f.eks. metanol, etanol og lignende, eddiksyre og lignende. Fortrinnsvis anvender man okede temperaturer, beste temperaturer mellom romtemperatur og 150°C. The treatment with the oxidizing agent is usually carried out in an organic solvent, such as e.g. dimethylformamide, dimethyl sulfoxide, hydrocarbons, such as benzene, toluene, alkanols, such as lower alkanols, e.g. methanol, ethanol and the like, acetic acid and the like. Better temperatures are preferably used, best temperatures between room temperature and 150°C.
Mellomproduktene med formel IV er nye forbindelser. De kan lett kondenseres med diaminer med formel XII The intermediates of formula IV are new compounds. They can be readily condensed with diamines of formula XII
hvor B har foran angitte betydning, where B has the above meaning,
ved blanding av komponentene eller ved reaksjon i nærvær av et organisk opplosningsmiddel, som benzen, toluen, alkanoler, som lavere alkanoler og lignende. Kondensasjonen gjennomfores vanligvis ved romtemperatur eller over, fortrinnsvis ved temperaturer mellom 20 og 150°C. I en annen utforelsesform kan dog også diaminet med formel XII anvendes som salt, idet reaksjonen gjennomfores ved oppvarmning for reaksjonsblandingen til smelte. by mixing the components or by reaction in the presence of an organic solvent, such as benzene, toluene, alkanols, such as lower alkanols and the like. The condensation is usually carried out at or above room temperature, preferably at temperatures between 20 and 150°C. In another embodiment, however, the diamine of formula XII can also be used as a salt, the reaction being carried out by heating the reaction mixture to melt.
Ifolge den foran angitte alternative utforelsesform kan forbindelser med formel III også fremstilles ved cyklisering av et fthalimidin med formel VI. Cykliseringen oppnås enkelt ved behandling med en Lewis-syre, som titantetraklorid, bortriflu-orid og lignende. Oksydasjonen og reduksjonen av forbindelser med formel III kan gjennomfores ifolge de foran angitte metoder. Reaksjonen med en Lewis-syre gjennomfores fortrinnsvis i nærvær av et inert organisk opplosningsmiddel, som hydrokarboner, f.eks. toluen, xylen og lignende, og ved okede temperaturer, fortrinnsvis inntil tilbakeloptemperaturen for opplosningsmid-let. Et egnet temperaturområde for cykliseringen av fthalimi-dinet er en temperatur mellom 50 til 200°C. Fthalimidmellom-produktene med formel VI fremstilles ved kondensasjon av et 3-fenyl-fthalid med formel VII med et diamin med formel XII. 3-fenyl-fthaiidene med formel VII og diamidene med formel XII er kjente forbindelser eller analoge av kjente -forbindelser, som lett kan fremstilles analogt disse kjente forbindelser. According to the above alternative embodiment, compounds of formula III can also be prepared by cyclization of a phthalimidine of formula VI. The cyclization is easily achieved by treatment with a Lewis acid, such as titanium tetrachloride, boron trifluoride and the like. The oxidation and reduction of compounds of formula III can be carried out according to the methods indicated above. The reaction with a Lewis acid is preferably carried out in the presence of an inert organic solvent, such as hydrocarbons, e.g. toluene, xylene and the like, and at elevated temperatures, preferably up to the reflux temperature for the solvent. A suitable temperature range for the cyclization of the phthalimidine is a temperature between 50 to 200°C. The phthalimide intermediates of formula VI are prepared by condensation of a 3-phenyl phthalide of formula VII with a diamine of formula XII. The 3-phenylphthaiides of formula VII and the diamides of formula XII are known compounds or analogues of known compounds, which can easily be prepared analogously to these known compounds.
Fremstillingen av forbindelser med formel VI katalyseres av salter av organiske baser, som pyridin, trialkylamin, kinolin, etylendiamin og lignende med syrer, som av en organisk syre, The production of compounds of formula VI is catalyzed by salts of organic bases, such as pyridine, trialkylamine, quinoline, ethylenediamine and the like with acids, such as by an organic acid,
en mineralsyre, f.eks. svovelsyre, halogenhydrogensyre, fos-forsyre, perklorsyre og lignende eller en Lewis-syre, som sinkklorid, aluminiumklorid og lignende. Egnede katalysatorer for denne reaksjon er saltene av etylendiamin og pyridin, som f.eks. pyridinhydroklorid og lignende. Det er foretrukket å gjennomfore reaksjonen med et overskudd av etylendiamin-rea-gensen som opplosningsmiddel. Det kan dog også anvendes inerte organiske opplosningsmidler, som alkoholer, f.eks. metanol, etanol og lignende, hydrokarboner, som benzen, toluen og lignende, eter, som tetrahydrofuran, dioksan og lignende. Reaksjonen gjennomfores ved okede temperaturer, fortrinnsvis ved en temperatur på over 100°C. Spesielt egnede temperaturer er temperaturer mellom 180 og 250°C. a mineral acid, e.g. sulfuric acid, hydrohalic acid, phosphoric acid, perchloric acid and the like or a Lewis acid such as zinc chloride, aluminum chloride and the like. Suitable catalysts for this reaction are the salts of ethylenediamine and pyridine, which e.g. pyridine hydrochloride and the like. It is preferred to carry out the reaction with an excess of the ethylenediamine reagent as solvent. However, inert organic solvents can also be used, such as alcohols, e.g. methanol, ethanol and the like, hydrocarbons such as benzene, toluene and the like, ether such as tetrahydrofuran, dioxane and the like. The reaction is carried out at elevated temperatures, preferably at a temperature of over 100°C. Particularly suitable temperatures are temperatures between 180 and 250°C.
Ifolge en annen utforelsesform kan forbindelser med formel VI fremstilles ved katalytisk hydrering av et 1,2,3,9b-tetrahydro-9b-fenyl-5H-imidazo[2,l-a]isoindol-5-on. According to another embodiment, compounds of formula VI can be prepared by catalytic hydrogenation of a 1,2,3,9b-tetrahydro-9b-phenyl-5H-imidazo[2,1-a]isoindol-5-one.
Ifolge en ytterligere utforelsesform kan forbindelser med formel III fremstilles fra tilsvarende diazacykloalkenylisoindo-ler med formel VIII ved reaksjon med en tilsvarende fenyl-organometallisk forbindelse med formel XI hvor R. og R^ har foran angitte betydning, og Z betyr Ni, MgZr, MgJ eller MgCl. According to a further embodiment, compounds of formula III can be prepared from corresponding diazacycloalkenyl isoindoles of formula VIII by reaction with a corresponding phenyl-organometallic compound of formula XI where R. and R.sub.3 have the above meaning, and Z means Ni, MgZr, MgJ or MgCl.
Reaksjonen med en fenyl-litium-forbindelse med formel XI gjennomfores vanligvis i nærvær av et inert organisk opplosningsmiddel og ved romtemperatur. Det kan dog også anvendes lavere eller hoyere temperaturer, fortrinnsvis i et område fra 10 til 100°C. Egnede opplosningsmidler er f.eks. hydrokarboner, som benzen, toluen, xylen og lignende, etere og lignende eller blandinger av slike opplosningsmidler. The reaction with a phenyl-lithium compound of formula XI is usually carried out in the presence of an inert organic solvent and at room temperature. However, lower or higher temperatures can also be used, preferably in a range from 10 to 100°C. Suitable solvents are e.g. hydrocarbons, such as benzene, toluene, xylene and the like, ethers and the like or mixtures of such solvents.
Diazacykloalkenylisoindolonene med formel VIII er nye forbindelser. De kan lett fremstilles ved kondensasjon av et fthal-aldehyd-derivat med formel IX med et alkylendiamin med formel XII. Kondensasjonen gjennomfores vanligvis i nærvær av et inert organisk opplosningsmiddel og fortrinnsvis ved oket temperatur. Egnede temperaturer er temperaturer mellom 20 og 100°C eller kokepunktet for reaksjonsblandingen. Som opplosningsmidler kan alle vanlige organiske opplosningsmidler, som alkoholer, hydrokarboner, etere og lignende anvendes. The diazacycloalkenylisoindolones of formula VIII are new compounds. They can be readily prepared by condensation of a phthalaldehyde derivative of formula IX with an alkylenediamine of formula XII. The condensation is usually carried out in the presence of an inert organic solvent and preferably at an elevated temperature. Suitable temperatures are temperatures between 20 and 100°C or the boiling point of the reaction mixture. As solvents, all common organic solvents, such as alcohols, hydrocarbons, ethers and the like can be used.
Fthalaldehydsyre-derivatene med formel IX er kjente forbindelser og analoge av kjente forbindelser, som kan fremstilles analogt disse. The phthalaldehyde acid derivatives of formula IX are known compounds and analogues of known compounds, which can be prepared analogously to these.
De således oppnådde forbindelser med formel III behover ikke å isoleres og kan lett oksyderes, f.eks. ved behandling med et oksydasjonsmiddel, som hydrogenperoksyd eller gassformig oksy-gen ved romtemperatur til peroksyder med formel X. Disse peroksyder kan lett reduseres til de tilsvarende forbindelser med formel I. Oksydasjonen gjennomfores vanligvis i et organisk opplosningsmiddel, som alkohol, dimetylformamid og lignende ved romtemperatur. Det kan dog også anvendes hoyere og The thus obtained compounds of formula III do not need to be isolated and can be easily oxidized, e.g. by treatment with an oxidizing agent, such as hydrogen peroxide or gaseous oxygen at room temperature to peroxides of formula X. These peroxides can be easily reduced to the corresponding compounds of formula I. The oxidation is usually carried out in an organic solvent, such as alcohol, dimethylformamide and the like at room temperature . However, it can also be used higher and
lavere temperaturer som f.eks. mellom 20 og 100°C. lower temperatures such as between 20 and 100°C.
Da peroksydene med formel X lett reduseres, inneholder reaksjonsblandingen etter behandlingen av en forbindelse med formel III med oksydasjonsmidlet såvel sluttprodukter med formel I sammen med peroksyd-mellomproduktet med formel X. Fullsten-dig reduksjon av peroksydet kan finne sted uten dets fras~kil-lelse fra reaksjonsblandingen; i en foretrukken utforelsesform behandles oksydasjonsproduktet direkte med et reduksjons-middel. Hvis onsket, kan peroksydet med formel X også skilles fra reaksjonsblandingen etter vanlige metoder, f.eks. kromato-grafisk eller ved fraksjonert krystallisasjon og lignende. As the peroxides of formula X are easily reduced, the reaction mixture after the treatment of a compound of formula III with the oxidizing agent contains both end products of formula I together with the peroxide intermediate of formula X. Complete reduction of the peroxide can take place without its release from the reaction mixture; in a preferred embodiment, the oxidation product is treated directly with a reducing agent. If desired, the peroxide of formula X can also be separated from the reaction mixture by conventional methods, e.g. chromatographically or by fractional crystallization and the like.
Reduksjonen av peroksydet kan oppnås med vanlig reduksjons-middel, som anvendes til reduksjon av peroksyder, som f.eks. natriumsulfitt, trialkylfosfitt og lignende. Reaksjonen gjennomfores fortrinnsvis i nærvær av et organisk opplosningsmiddel, som en alkohol, f.eks. metanol, etanol og lignende, dimetylformamid og lignende eller i tilfelle et salt av peroksydet anvendes, et vandig opplosningsmiddel, som f.eks. et vandig alkoholisk opplosningsmiddel. Fortrinnsvis arbeider man ved romtemperatur eller over, egnede temperaturer er f.eks. mellom 20 og 100°C. The reduction of the peroxide can be achieved with a common reducing agent, which is used to reduce peroxides, such as e.g. sodium sulphite, trialkyl phosphite and the like. The reaction is preferably carried out in the presence of an organic solvent, such as an alcohol, e.g. methanol, ethanol and the like, dimethylformamide and the like or in case a salt of the peroxide is used, an aqueous solvent, such as e.g. an aqueous alcoholic solvent. Preferably you work at room temperature or above, suitable temperatures are e.g. between 20 and 100°C.
Som allerede fremfort, kan hydroksylprotonet i en forbindelse med formel I være underkastet en protonvandring, idet tilsvarende isomere sluttprodukter med formel II oppstår. I opplosning er det erholdte sluttprodukt etter oksydasjon og reduksjon av et mellomprodukt med formel III vanligvis en blanding av de tautomere former I og II. Den relative mengde av de isomere former er avhengig av faktorer som opplosningsmiddelsystemet, mediets pH og det spesielle produkt, dvs. betydningen av B, R1, R3 og R4 i formlene I og II. F.eks. inneholder i en opplosning av kloroform det oppnådde produkt etter oksydasjon og reduksjon av 2,3-dihydro-5-fenyl-5H-imidazo[2,l-a]isoindol en blanding av isomerer 2,3-dihydro-5-hydroksy-5-fenyl-5H-imidazo [2,l-a]isoindol og 2-(2-benzoylfenyl)-2-imidazolin i forholdet 1:1. Syreaddisjonssaltene som isoleres etter vanlige metoder fra reaksjonsproduktet ved oksydasjon og reduksjon av 2,3-dihydro-5-fenyl-5H-imidazo[2,l-a]isoindol har vanligvis struk-turen med formel II. As already stated, the hydroxyl proton in a compound of formula I can be subjected to a proton migration, with corresponding isomeric end products of formula II occurring. In solution, the final product obtained after oxidation and reduction of an intermediate with formula III is usually a mixture of the tautomeric forms I and II. The relative amount of the isomeric forms depends on factors such as the solvent system, the pH of the medium and the particular product, i.e. the meaning of B, R1, R3 and R4 in formulas I and II. E.g. contains in a solution of chloroform the product obtained after oxidation and reduction of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole a mixture of isomers 2,3-dihydro-5-hydroxy-5-phenyl -5H-imidazo [2,1-a]isoindole and 2-(2-benzoylphenyl)-2-imidazoline in a 1:1 ratio. The acid addition salts which are isolated by usual methods from the reaction product by oxidation and reduction of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole usually have the structure of formula II.
Forbindelser med formlene I og II og deres farmasøytisk anvendbare syreaddisjonssalter har psykostimulerende virkning. Etter f.eks. oral administrasjon på dyr,som mus, forårsaker de en direkte stimulerende langvarig virkning. Eksempler på forbindelser med formlene I og II, som ble provet og i provene ble funnet som hoyaktive hva angår psykostimulerende virkning, er f.eks. Compounds of formulas I and II and their pharmaceutically usable acid addition salts have psychostimulant action. After e.g. oral administration to animals, such as mice, they cause a direct stimulating long-lasting effect. Examples of compounds with the formulas I and II, which were tested and found in the samples to be highly active in terms of psychostimulant effects, are e.g.
2-(2-benzoylfenyl)-2-imidazolin52-(2-benzoylphenyl)-2-imidazoline5
5-(4-klorfenyl)- 2,3-dihydro-5-hydroksy-5H-imidazo [2,l-a]isoindol5 2,3-dihydro-5-hydroksy-5-(4-metoksyfenyl)-5H-imidazol2,l-a]isoindol5 5-(4-chlorophenyl)- 2,3-dihydro-5-hydroxy-5H-imidazo [2,1-a]isoindole5 2,3-dihydro-5-hydroxy-5-(4-methoxyphenyl)-5H-imidazole2,1-a ]isoindole5
2,3,4,5-tetrahydro-7-hydroksy-7-fenyl-7H-diaze-pino[2,l-a]isoindol. 2,3,4,5-tetrahydro-7-hydroxy-7-phenyl-7H-diaze-pino[2,1-a]isoindole.
Forbindelser med formlene I og II egner seg derfor som psyko-stimulantier til behandling av depresjoner, f.eks. i tilfelle enkle depresjoner eller ved kronisk nervos utmattelse. Compounds with formulas I and II are therefore suitable as psycho-stimulants for the treatment of depression, e.g. in case of simple depressions or chronic nervous exhaustion.
Dessuten egner forbindelser med formel II seg som analgetika. Furthermore, compounds of formula II are suitable as analgesics.
I tillegg viser de antiinflammatorisk, antiodem og muskelre-lakserende virkning. F.eks. viser 2-(2-benzoylfenyl)-2-imidazolin i standardprbver for analgetisk virkning utpreget aktivitet. Forbindelser med formel II er videre virksomme som appetitthemmere. Dessuten viser de kardiovaskulære egenskaper . In addition, they show anti-inflammatory, anti-oedema and muscle-relaxing effects. E.g. 2-(2-benzoylphenyl)-2-imidazoline shows pronounced activity in standard tests for analgesic effect. Compounds of formula II are also effective as appetite suppressants. In addition, they show cardiovascular properties.
Forbindelser med formel II er dessuten virksomme fungicider. Det ble f.eks. funnet at de in vitro er virksomme overfor Candida albicans, Microsporum audouini og Trichophyton menta-grophytes. Disse forbindelser kan derfor anvendes som fungicider til behandling av patogene sykdommer, som er blitt frem-kalt gjennom denne organisme. F.eks. kan man anvende dem til behandling av infektose soppsykdommer, som f.eks. Moniliasis og Dermatomycosis. Til behandling av soppinfeksjoner kan forbindelser med formel II eller farmasoytisk anvendbare salter derav anvendes i et vanlig bæremateriale for maksimal administrasjon. Compounds of formula II are also effective fungicides. It was e.g. found that they are active in vitro against Candida albicans, Microsporum audouini and Trichophyton menta-grophytes. These compounds can therefore be used as fungicides for the treatment of pathogenic diseases, which have been caused by this organism. E.g. can they be used to treat infectious fungal diseases, such as Moniliasis and Dermatomycosis. For the treatment of fungal infections, compounds of formula II or pharmaceutically usable salts thereof can be used in a conventional carrier material for maximum administration.
De nye sluttproduktene er for det meste hvite, luktelose krystaller med smeltepunkter omkring 200°C. De har basiske egenskaper og kan lett fremstilles i form av deres syreaddisjonssalter. Disse salter er karakteristiske hvite luktelose krystaller, som er oppløselige i vann og under normale betin-gelser viser god stabilitet. The new end products are mostly white, odorless crystals with melting points around 200°C. They have basic properties and can be easily prepared in the form of their acid addition salts. These salts are characteristic white odorless crystals, which are soluble in water and under normal conditions show good stability.
Sluttproduktene ved fremgangsmåten ifolge oppfinnelsen og fortrinnsvis deres syreaddisjonssalter kan administreres enteralt eller parenteralt i form av farmasøytiske preparater. Parenterale administrasjonsformer inneholder vanligvis mindre aktiv-substans enn preparater til enteral, dvs. til oral anvendelse. Til oral administrasjon fremstilles fortrinnsvis tabletter, kapsler og lignende. Denne orale administrasjonsform kan enten bevirke en øyeblikkelig eller en langvarig frisetning av aktivsubstansen. I almindelighet anvender man for deres fremstilling farmasoytisk anvendbare folgematerialer i en mengde av 60 - 98 vekts-% av preparatet for den orale dosering. The end products of the method according to the invention and preferably their acid addition salts can be administered enterally or parenterally in the form of pharmaceutical preparations. Parenteral forms of administration usually contain less active substance than preparations for enteral, i.e. for oral use. For oral administration, tablets, capsules and the like are preferably prepared. This oral form of administration can either cause an immediate or a prolonged release of the active substance. In general, for their production, pharmaceutically usable secondary materials are used in an amount of 60 - 98% by weight of the preparation for the oral dosage.
For parenteral administrasjon av forbindelser kan disse bringes i egnede parenterale doseringsformer med et flytende fortynn-ingsmiddel, f.eks. destillert vann. I almindelighet bringes de ifolge oppfinnelsen fremstillbare forbindelser med vanlige inerte folge-stoffer til den enterale og parenterale administrasjon egnede doseringsformer etter vanlige metoder. Egnede doseringsformer er f.eks. tabletter, kapsler, oppløsninger, emulsjoner og suspensjoner. Egnede bærematerialer er flytende og faste uorganiske og organiske stoffer, som vann, gelatin, laktose, stivelse, magnesiumstearat, talkum, vegetabilske oljer, gummi arabicum, polyalkylenglykoler, vaselin og lignende. Dessuten kan de inneholde konserveringsmiddel, stabi-liseringsmiddel, fuktnings- eller emulgermiddel, salter til forandring av det osmotiske trykk, puffer og lignende. Hvis onsket, kan de også inneholde ennå andre terapeutisk verdifullé stoffer. For parenteral administration of compounds, these can be brought into suitable parenteral dosage forms with a liquid diluent, e.g. distilled water. In general, the compounds which can be prepared according to the invention are brought into dosage forms suitable for enteral and parenteral administration with usual inert secondary substances according to usual methods. Suitable dosage forms are e.g. tablets, capsules, solutions, emulsions and suspensions. Suitable carrier materials are liquid and solid inorganic and organic substances, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols, petroleum jelly and the like. In addition, they may contain preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure, buffers and the like. If desired, they can also contain other therapeutically valuable substances.
Ved en foretrukken oral doseringsform, dvs. tabletter eller kapsler, administreres preparatet under normale omstendigheter tre eller fire ganger daglig. Den parenterale administrasjon finner normalt sted en eller to ganger daglig. Den effektive dosering avhenger dog av de undertiden gitte omstendigheter. Det er derfor også klart at mengden av aktivsubstansen og bære-materialene kan varieres i tilsvarende bredde. In a preferred oral dosage form, i.e. tablets or capsules, the preparation is administered under normal circumstances three or four times a day. The parenteral administration normally takes place once or twice a day. However, the effective dosage depends on the sometimes given circumstances. It is therefore also clear that the amount of the active substance and carrier materials can be varied to a corresponding width.
De folgende eksempler anskueliggjor fremgangsmåten ifolge oppfinnelsen. Alle smeltepunkter er angitt i Celsiusgrader. Smeltepunkter, ved hvilke spaltning inntrer, kan variere med 10° avhengig av oppvarmningen. The following examples illustrate the method according to the invention. All melting points are given in degrees Celsius. Melting points, at which decomposition occurs, can vary by 10° depending on the heating.
EKSEMPEL 1 EXAMPLE 1
Til 1 ml etylendiamin tilsettes 1 g 2-(p-klorbenzoyl)-benzalde-hyd i små porsjoner. Det inntrer en eksoterm reaksjon. Man oppnår et gult bunnfall som opploses i metylenklorid. Eter og petroleter tilfores og opplosningen rystes i luft ved 25°. To 1 ml of ethylenediamine, 1 g of 2-(p-chlorobenzoyl)-benzaldehyde is added in small portions. An exothermic reaction occurs. A yellow precipitate is obtained which dissolves in methylene chloride. Ether and petroleum ether are added and the solution is shaken in air at 25°.
Man oppnår et krystallint bunnfall, som etter omkrystallisasjon fra en blanding av metylenklorid og metanol gir "hvite nåler av 2-[2'-(4-klorbenzoyl)fenyl]-2-imidazolin med smeltepunkt 178 - 180° (spaltning). UV max. (2-propanol) ved 223 mu ( £. = 21,250), 268 mp ( £ = 4,300), 275 mu ( £ = 4,320), infleksjon ved 290 mu ( £ = 2,200), infrarod-absorpsjon (KBr) ved 1660 cm<-1>. A crystalline precipitate is obtained, which after recrystallization from a mixture of methylene chloride and methanol gives "white needles of 2-[2'-(4-chlorobenzoyl)phenyl]-2-imidazoline with melting point 178 - 180° (decomposition). UV max .(2-propanol) at 223 mu ( £ = 21,250), 268 mp ( £ = 4,300), 275 mu ( £ = 4,320), inflection at 290 mu ( £ = 2,200), infrared absorption (KBr) at 1660 cm<-1>.
Analyse: Analysis:
Beregnet for C16H13C1N20: C, 67,49; H, 4,60 Calcd for C16H13C1N2O: C, 67.49; H, 4.60
Funnet: C, 67,38; H, 4,56. Found: C, 67.38; H, 4.56.
Det således oppnådde 2-[2'-(4-klorbenzoyl)fenyl]-2-imidazolin kan danne isomert 5-(4-klorfenyl)-2,3-dihydro-5-hydroksy-5H-imidazo[2,l-a]isoindol. The thus obtained 2-[2'-(4-chlorobenzoyl)phenyl]-2-imidazoline can form isomeric 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole .
Hydrokloridet oppnår man ved tilsetning av en opplosning av hydrogenklorid i eter til en suspensjon av 5-(4-klorfenyl)-2,3-dihydro-5-hydroksy-5H-imidazo[2,l-a]isoindol. Etter 30 minutters omroring oppnår man et krystallint bunnfall, som omkrystalliseres fra en blanding av kloroform og eter og gir hvite prismer med smeltepunkt 168 - 171° (spaltning). UV infleksjon (2-propanol) ved 220 mu ( £ = 22,000), max. ved 252 mu ( i, = 12,900), 266 mu ( £. = 13,000); infrarod-absorpsjon (KBr) ved 1670 cm"^. The hydrochloride is obtained by adding a solution of hydrogen chloride in ether to a suspension of 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole. After 30 minutes of stirring, a crystalline precipitate is obtained, which is recrystallized from a mixture of chloroform and ether and gives white prisms with a melting point of 168 - 171° (decomposition). UV inflection (2-propanol) at 220 mu ( £ = 22,000), max. at 252 mu ( i, = 12,900), 266 mu ( £. = 13,000); infrared absorption (KBr) at 1670 cm"^.
Analyse: Analysis:
Beregnet for C16H13<C>1N20.HC1: Cl, 22,08 Calculated for C16H13<C>1N20.HC1: Cl, 22.08
Funnets Cl, 22,18 Found's Cl, 22,18
Det som utgangsmateriale anvendte 2-(p-klorbenzoyl)-benzalde-hyd kan fremstilles på folgende måte: The 2-(p-chlorobenzoyl)-benzaldehyde used as starting material can be prepared in the following way:
En opplosning av 18,6 g 4'-klor-2-hydroksymetylbenzhydrol i A solution of 18.6 g of 4'-chloro-2-hydroxymethylbenzhydrol i
100 ml eddiksyre og 10,4 g selendioksyd oppvarmes i 2 timer ved tilbakelop. Blandingen helles på is, innstilles alkalisk og ekstraheres med eter. Etter konsentrasjon av eteropplos-ningen og tilsetning av petroleter oppnår man svakt gule prismer, som etter omkrystallisasjon fra en blanding av eter og petroleter gir 2-(p-klorbenzoyl)-benzaldehyd med smeltepunkt 112 - 113°. UV infleksjon (2-propanol) ved 225 mu = 17,500) og max. ved 259 mu ( £, = 22,500), infrarod-absorpsjon (CHCl.,) 100 ml of acetic acid and 10.4 g of selenium dioxide are heated for 2 hours at reflux. The mixture is poured onto ice, made alkaline and extracted with ether. After concentration of the ether solution and addition of petroleum ether, slightly yellow prisms are obtained, which after recrystallization from a mixture of ether and petroleum ether give 2-(p-chlorobenzoyl)-benzaldehyde with a melting point of 112 - 113°. UV inflection (2-propanol) at 225 mu = 17,500) and max. at 259 mu ( £, = 22,500), infra-red absorption (CHCl.,)
-1 -1 -1 -1
ved 1670 cm og 1705 cm at 1670 cm and 1705 cm
Analyse: Analysis:
Beregnet for C14HgC102: C, 68,72; H, 3,71 Calculated for C14HgC102: C, 68.72; H, 3.71
Funnet: C, 69,12; H, 3,50. Found: C, 69.12; H, 3.50.
EKSEMPEL 2 EXAMPLE 2
Til 4 ml etylendiamin tilsettes 2 g 2-(p-anisoyl)-benzaldehyd 2 g of 2-(p-anisoyl)-benzaldehyde are added to 4 ml of ethylenediamine
i små porsjoner. Opplosningen omrores i 10 minutter, helles i isvann og ekstraheres med metylenklorid. Metylenkloridopplosningen inndampes, resten opploses i etanol og en luftstrbm ledes gjennom opplosningen i 18 timer. Man oppnår et krystallint bunnfall, som etter omkrystallisasjon fra en blanding av kloroform og eter gir hvite prismer av 2-[2<1->(4-anisoyl)-fenyl]-2-imidazolin med smeltepunkt 171 - 174° (spaltning). UV max. in small portions. The solution is stirred for 10 minutes, poured into ice water and extracted with methylene chloride. The methylene chloride solution is evaporated, the residue is dissolved in ethanol and a stream of air is passed through the solution for 18 hours. A crystalline precipitate is obtained, which after recrystallization from a mixture of chloroform and ether gives white prisms of 2-[2<1->(4-anisoyl)-phenyl]-2-imidazoline with melting point 171 - 174° (decomposition). UV max.
(2-propanol) ved 227 mu ( £ = 20,200), 277 mu ( t = 8,800), (2-propanol) at 227 mu ( £ = 20.200), 277 mu ( t = 8.800),
282 mu ( £, = 8,750), infleksjon ved 292 rau ( £. = 7,200); in- 282 mu ( £, = 8,750), inflection at 292 rau ( £. = 7,200); in-
_ i _ i
frarod-absorpsjon (KBr) ved 1660 cm frarod absorption (KBr) at 1660 cm
Analyse: Analysis:
Beregnet for <C>17H16N2°2: C> 12, Q$\ H? 5>755 N> 9j" Funnet: C, 73,07; H, 5,71; N, 9,83. Calculated for <C>17H16N2°2: C> 12, Q$\ H? 5>755 N> 9j" Found: C, 73.07; H, 5.71; N, 9.83.
Det således oppnådde 2-[2'-(4-anisoyl)fenylj-2-imidazolin kan danne isomert 2,3-dihydro-5-hydroksy-5-(4-metoksy-fenyl)-5H-imidazo[2,l-a]isoindol. The thus obtained 2-[2'-(4-anisoyl)phenylj-2-imidazoline can form isomeric 2,3-dihydro-5-hydroxy-5-(4-methoxy-phenyl)-5H-imidazo[2,1-a] isoindole.
Det som utgangsmateriale anvendte 2-(p-anisoyl)-benzaldehyd It used 2-(p-anisoyl)-benzaldehyde as starting material
kan fremstilles på fblgende måte: can be produced in the following way:
En opplosning av 26 g 4'-metoksy-2-hydroksymetylbenzhydrol i A solution of 26 g of 4'-methoxy-2-hydroxymethylbenzhydrol in
140 ml eddiksyre og 40,5 g selendioksyd oppvarmes i 2 timer under tilbakelop. Blandingen filtreres, og filtratet innstil- 140 ml of acetic acid and 40.5 g of selenium dioxide are heated for 2 hours under reflux. The mixture is filtered, and the filtrate
les basisk. Ved henstand skiller det seg ut en olje, som et- read basic. When allowed to stand, an oil separates, which
ter omkrystallisasjon fra en blanding av metylenklorid og petroleter gir grå-hvite små blader av 2-(p-anisoyl)-benzaldehyd med smeltepunkt 90 - 91°. UV max. (2-propanol) ved 221 mu (£ = 21,600), 258 mu = 12,400) og 292 mu ( £ = 17,000); infrarod-absorpsjon (CHCl^) ved 1660 cm-"1" og ved 1700 cm-"'". ter recrystallization from a mixture of methylene chloride and petroleum ether gives gray-white small leaves of 2-(p-anisoyl)-benzaldehyde with a melting point of 90 - 91°. UV max. (2-propanol) at 221 mu (£ = 21,600), 258 mu = 12,400) and 292 mu (£ = 17,000); infrared absorption (CHCl^) at 1660 cm-"1" and at 1700 cm-"'".
Analyse: Analysis:
Beregnet for ci5Hi2°3: C' 74»995 H» 5,03 Calculated for c15H12°3: C' 74»995 H» 5.03
Funnet: C, 75,27; H, 5,26. Found: C, 75.27; H, 5.26.
EKSEMPEL 3 EXAMPLE 3
Til 2 ml etylendiamin tilfores 0,9 g 2-benzoyl-4-klorbenzalde- To 2 ml of ethylenediamine is added 0.9 g of 2-benzoyl-4-chlorobenzalde-
hyd i små porsjoner. Opplosningen omrores i 10 minutter, hel- hyd in small portions. The solution is stirred for 10 minutes, completely
les i isvann, idet man oppnår et gult bunnfall. Dette bunn- read in ice water, obtaining a yellow precipitate. This bottom-
fall opploses i eter og rystes med luft i 45 minutter. Man oppnår et hvitt bunnfall, som etter omkrystallisasjon fra en blanding av metylenklorid og metanol gir 2-[4'-klor-2'-benzoyl-fenylj-2-imidazolin med smeltepunkt 200 - 202° (spaltning). drop is dissolved in ether and shaken with air for 45 minutes. A white precipitate is obtained, which after recrystallization from a mixture of methylene chloride and methanol gives 2-[4'-chloro-2'-benzoyl-phenylj-2-imidazoline with melting point 200 - 202° (decomposition).
UV max. (2-propanol) ved 242 mu ( £ = 17,500), 278 mu (£ = 3,800), 286 mu = 3,300), infleksjoner ved 270 mu (£ = 3,450), UV max. (2-propanol) at 242 mu (£ = 17,500), 278 mu (£ = 3,800), 286 mu = 3,300), inflections at 270 mu (£ = 3,450),
295 mu ( £ = 2,400); infrarod-absorpsjon (KBr) ved 1665 cm<->''". 295 mu (£=2,400); infrared absorption (KBr) at 1665 cm<->''".
Analyse: Analysis:
Beregnet for C16H13C1N20: C, 67,49; H, 4,60 Calcd for C16H13C1N2O: C, 67.49; H, 4.60
Funnet: C, 67,42; H, 4,90. Found: C, 67.42; H, 4.90.
Det således fremstilte 2-[4'-klor-2<1->benzoylfenyl]-2-imidazo- The thus prepared 2-[4'-chloro-2<1->benzoylphenyl]-2-imidazo-
lin kan danne isomert 7-klor-2,3-dihydro-5-hydroksy-5-fenyl-5H-imidazo[2,l-a]isoindol. lin can form isomeric 7-chloro-2,3-dihydro-5-hydroxy-5-phenyl-5H-imidazo[2,1-a]isoindole.
Det som utgangsmateriale anvendte 2-benzoyl-4-klor-benzaldehyd It used 2-benzoyl-4-chloro-benzaldehyde as starting material
kan fremstilles på folgende måte: can be produced in the following way:
En opplosning av 9,3 g 5-klor-2-hydroksymetylbenzhydrol i 50 A solution of 9.3 g of 5-chloro-2-hydroxymethylbenzhydrol in 50
ml eddiksyre og 5,2 g selendioksyd oppvarmes i 3 timer ved tilbakelop. Blandingen filtreres, avkjoles, helles på is, innstilles alkalisk og ekstraheres med eter. Etter konsen-treringen under tilsetning av petroleter oppnår man prismer av 2-benzoyl-4-klorbenzaldehyd, som etter omkrystallisasjon fra en blanding av eter og petroleter smelter ved 82 - 84°. UV max. (2-propanol) ved 230 mu (£ = 19,500), og 257 mu ml of acetic acid and 5.2 g of selenium dioxide are heated for 3 hours at reflux. The mixture is filtered, cooled, poured onto ice, made alkaline and extracted with ether. After concentration with the addition of petroleum ether, prisms of 2-benzoyl-4-chlorobenzaldehyde are obtained, which after recrystallization from a mixture of ether and petroleum ether melt at 82 - 84°. UV max. (2-propanol) at 230 mu (£ = 19,500), and 257 mu
(£ = 23,500), infrarod-absorpsjon (CHC1.J ved 1675 cm"1 og (£ = 23,500), infrared absorption (CHC1.J at 1675 cm"1 and
-1 -1
1705 cm . 1705 cm.
Analyse: Analysis:
Beregnet for C14HgCl02: C, 68,72-, H, 3,71 Calculated for C14HgCl02: C, 68.72-, H, 3.71
Funnet: C, 69,05; H, 3,87. Found: C, 69.05; H, 3.87.
EKSEMPEL 4 EXAMPLE 4
En opplosning av 6 g 2-(4-brombenzoyl)-benzaldehyd og 6,6 ml A solution of 6 g of 2-(4-bromobenzoyl)-benzaldehyde and 6.6 ml
etylendiamin i 50 ml toluen oppvarmes i 18 timer til tilbakelop. I lopet av denne tid utskiller det seg 0,5 ml av en vandig fase i vannav ski Heren. Blandingen inndampes i vakuum, og den tilbakeblivende orange olje opploses i en blanding av ethylenediamine in 50 ml of toluene is heated to reflux for 18 hours. In the course of this time, 0.5 ml of an aqueous phase separates out in the water nav ski Heren. The mixture is evaporated in vacuo, and the remaining orange oil is dissolved in a mixture of
15 ml etanol, 15 ml metylenklorid og 1,5 ml av en 30 %'ig vandig opplosning av hydrogenperoksyd. Ebter 18 timers omroring ved 25° oppnår man et hvitt bunnfall, som etter omkrystallisasjon fra metanol gir hvite nåler av 2-[2-(4-brombenzoyl)-fenyl]-2-imidazolin med sme ltepunkt 187 - 189u (spaltning). UV max. (2-propanol) ved 227 mu (£ = 22,800), 259 mu 15 ml of ethanol, 15 ml of methylene chloride and 1.5 ml of a 30% aqueous solution of hydrogen peroxide. After 18 hours of stirring at 25°, a white precipitate is obtained, which after recrystallization from methanol gives white needles of 2-[2-(4-bromobenzoyl)-phenyl]-2-imidazoline with melting point 187 - 189u (decomposition). UV max. (2-propanol) at 227 mu (£ = 22,800), 259 mu
(£ = 4,700), 275 mu (£ = 4,800), infleksjon ved 292 mu (£ = 4,700), 275 mu (£ = 4,800), inflection at 292 mu
(£ = 2,300); infrarod-absorpsjon (KBr) ved 1660 cm<-1>. (£ = 2,300); infrared absorption (KBr) at 1660 cm<-1>.
Analyse: Analysis:
Beregnet for C16H13<B>rN20: C, 58,37; H, 3,98 Calcd for C16H13<B>rN2O: C, 58.37; H, 3.98
Funnet: C, 58,27; H, 3,75. Found: C, 58.27; H, 3.75.
Det således erholdte 2-[2-(4-brombenzoyl)fenyl]-2-imidazolin kan isomert danne 5-(4-bromfenyl)-2,3-dihydro-5-hydroksy-5H-imidazo[2,1-a]isoindol. The thus obtained 2-[2-(4-bromobenzoyl)phenyl]-2-imidazoline can isomerically form 5-(4-bromophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a] isoindole.
Hydrokloridet fremstilles ved tilsetning av eterisk hydrogenklorid til en opplosning av 5r(4-bromfenyl)-2,3-dihydro-5-hydroksy-5H-imidazo[2,l-a}isoindol i en blanding av metylenklorid og metanol. Bunnfallet omkrystalliseres fra en blanding av etanol og eter, idet man oppnår hvite prismer med smeltepunkt 155 - 158° (spaltning). UV infleksjon (2-propanol) ved 223 mu ( £ = 20,000), max. ved 251 mu ( £. = 12,2000) og 271 mu (£ = 13,300); infrarod-absorpsjon (KBr) ved 1660 cm<-1>. The hydrochloride is prepared by adding ethereal hydrogen chloride to a solution of 5r(4-bromophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a}isoindole in a mixture of methylene chloride and methanol. The precipitate is recrystallized from a mixture of ethanol and ether, obtaining white prisms with a melting point of 155 - 158° (decomposition). UV inflection (2-propanol) at 223 mu ( £ = 20,000), max. at 251 mu (£. = 12,2000) and 271 mu (£ = 13,300); infrared absorption (KBr) at 1660 cm<-1>.
Analyse: Analysis:
Beregnet for C16H13BrN20 HCl: Cl, 9,70 Calculated for C 16 H 13 BrN 2 O HCl: Cl, 9.70
Funnet: Cl, 9,82. Found: Cl, 9.82.
Det som utgangsmateriale anvendte 2-(4-brombenzoyl)-benzalde-hyd kan fremstilles som folger: The 2-(4-bromobenzoyl)-benzaldehyde used as starting material can be prepared as follows:
Til en omrort opplosning av 8,2 g litiumaluminiumhydrid i To a stirred solution of 8.2 g of lithium aluminum hydride i
180 ml tetrahydrofuran tilsettes 40 g 2-(4-brombenzoyl)-benzo-syre i lopet av 30 minutter. Reaksjonsblandingen las stå i 2 timer ved 25°, avkjoles derpå og tilsettes 40 ml av en mettet natriumsulfatopplosning langsomt. Blandingen filtreres, og filtratet inndampes. Den erholdte oljelignende rest opploses i 32 ml eddiksyre og 96 ml xylen. Denne opplosning tilsettes til en blanding av 17,1 g selendioksyd i 60 ml eddiksyre og 120 ml xylen og oppvarmes i 17 timer under tilbakelop. I lopet av denne tid oppsamler det seg 22 ml av en vandig fase i vannavskiHeren. Opplosningen filtreres, vaskes med natriumhydroksyd og inndampes. Etter tilsetning av petroleter oppnår man hvite prismer av 2-(4-brombenzoyl)-benzaldehyd med smeltepunkt 103 - 109°. Etter omkrystallisasjon fra en blanding av eter og petroleter stiger smeltepunktet til 110 - 113°. UV infleksjon (2-propanol) ved 225 mu ( £ = 17,500) og max. ved 261 mu ( £ = 22,200); infrarod-absorpsjon (CHC1-) ved 1675 cm<-1>180 ml of tetrahydrofuran are added to 40 g of 2-(4-bromobenzoyl)-benzoic acid over the course of 30 minutes. The reaction mixture is allowed to stand for 2 hours at 25°, then cooled and 40 ml of a saturated sodium sulphate solution is added slowly. The mixture is filtered, and the filtrate is evaporated. The obtained oil-like residue is dissolved in 32 ml of acetic acid and 96 ml of xylene. This solution is added to a mixture of 17.1 g of selenium dioxide in 60 ml of acetic acid and 120 ml of xylene and heated for 17 hours under reflux. During this time, 22 ml of an aqueous phase collects in the water skimmer. The solution is filtered, washed with sodium hydroxide and evaporated. After adding petroleum ether, white prisms of 2-(4-bromobenzoyl)-benzaldehyde with a melting point of 103 - 109° are obtained. After recrystallization from a mixture of ether and petroleum ether, the melting point rises to 110 - 113°. UV inflection (2-propanol) at 225 mu ( £ = 17,500) and max. at 261 mu (£ = 22,200); infrared absorption (CHC1-) at 1675 cm<-1>
_1 J _1 J
og 1705 cm and 1705 cm
Analyse: Analysis:
Beregnet for C^HgBrO^ C, 58,16; H, 3,14 Calculated for C^HgBrO^ C, 58.16; H, 3.14
Funnet: C, 57,86; H, 3,41. Found: C, 57.86; H, 3.41.
EKSEMPEL 5 EXAMPLE 5
En opplosning av 10,5 g 2-benzoylbenzaldehyd og 28,5 ml 1,4-diaminobutan i lOO ml toluen oppvarmes i 18 timer under tilbakelop. I lopet av denne tid utskiller det seg 2,5 ml av en vandig fase i vannavskiHeren. Opplosningen utsettes i 60 timer i luft, inndampes og fortynnes med 300 ml karbontetra-klorid. Man oppnår et krystallint bunnfall, som suspenderes i 40 ml etanol. En opplosning av 1,9 g oksalsyre i 40 ml metanol tilfores, og opplosningen inndampes og fortynnes så med eter. Man oppnår et bunnfall, som etter omkrystallisasjon fra en blanding av metanol og eter gir det oksalsure salt som hvite prismer med smeltepunkt på ca. 200° (spaltning). Dette salt suspenderes i en blanding av vandig natriumkarbonatopp-losning og metylenklorid. Metylenkloridopplosningen inndampes og resten omkrystalliseres fra en blanding av kloroform og eter, idet man oppnår hvite nåler av 2,3,4,5-tetrahydro-7-hydroksy-7-fenyl-7H-diazepino[2,l-a]isoindol med smeltepunkt 216 - 220° (spaltning). UV max. (2-propanol) ved 258 mu (£ = 5,000), 265 mu (£ = 5,100), 273 mu = 4,800), infleksjoner ved 230 mu ( £. = 15,000, 290 mu (£ = 2,400); infrarod-absorpsjon (KBr) ved 1650 cm A solution of 10.5 g of 2-benzoylbenzaldehyde and 28.5 ml of 1,4-diaminobutane in 100 ml of toluene is heated for 18 hours under reflux. In the course of this time, 2.5 ml of an aqueous phase separates out in the water separator. The solution is exposed for 60 hours in air, evaporated and diluted with 300 ml of carbon tetrachloride. A crystalline precipitate is obtained, which is suspended in 40 ml of ethanol. A solution of 1.9 g of oxalic acid in 40 ml of methanol is added, and the solution is evaporated and then diluted with ether. A precipitate is obtained, which after recrystallization from a mixture of methanol and ether gives the oxalic acid salt as white prisms with a melting point of approx. 200° (cleavage). This salt is suspended in a mixture of aqueous sodium carbonate solution and methylene chloride. The methylene chloride solution is evaporated and the residue recrystallized from a mixture of chloroform and ether, obtaining white needles of 2,3,4,5-tetrahydro-7-hydroxy-7-phenyl-7H-diazepino[2,1-a]isoindole with melting point 216 - 220° (cleavage). UV max. (2-propanol) at 258 mu (£ = 5,000), 265 mu (£ = 5,100), 273 mu = 4,800), inflections at 230 mu ( £. = 15,000, 290 mu (£ = 2,400); infrared absorption ( KBr) at 1650 cm
Analyse: Analysis:
Beregnet for <C>18<H>18<N>2<0:> C, 77,67; H, 6,52; 0, 5,75 Funnet: C, 77,64; H, 6,75; 0, 5,64. Calculated for <C>18<H>18<N>2<0:> C, 77.67; H, 6.52; 0, 5.75 Found: C, 77.64; H, 6.75; 0, 5.64.
EKSEMPEL 6 EXAMPLE 6
I en 2 liter trehalset-rundkolbe med mekanisk omrorer, dråpe-trakt og vannavskiller oppvarmes en blanding av 41,7 g In a 2 liter three-necked round flask with a mechanical stirrer, dropping funnel and water separator, heat a mixture of 41.7 g
(0,376 mol) selendioksyd i 150 ml eddiksyre og 300 ml xylen i 15 minutter under tilbakelop. Til den kokende blanding tilsettes dråpevis i lopet av 1 time en opplosning av 74,4 g (0.376 mol) of selenium dioxide in 150 ml of acetic acid and 300 ml of xylene for 15 minutes under reflux. A solution of 74.4 g is added dropwise over the course of 1 hour to the boiling mixture
(0,3 mol) 2-klor-2'-hydroksymetylbenzhydrol i 85 ml eddiksyre og 250 ml xylen. Vannavski Heren kjoles i lopet av denne tid for å fremskynde utskillingen av den vandige fase. I lopet av 5 timer utskiller det seg 60 ml vandig fase. Reaksjonsblandingen oppvarmes totalt i 22 timer under tilbakelop, avkjoles og filtreres. Filtratet tilsettes til 800 ml is og vann, inn- (0.3 mol) of 2-chloro-2'-hydroxymethylbenzhydrol in 85 ml of acetic acid and 250 ml of xylene. Vannavski Heren is dressed during this time to speed up the separation of the aqueous phase. In the course of 5 hours, 60 ml of aqueous phase separates. The reaction mixture is heated for a total of 22 hours under reflux, cooled and filtered. The filtrate is added to 800 ml of ice and water, in-
stilles alkalisk med 50 %'ig natriumhydroksydopplosning, og blandingen ekstraheres med 600 ml eter. Ekstraktene vaskes med vann, torkes over vannfritt natriumsulfat og inndampes, idet man oppnår en orange ikke-krystalliserende olje. Den gasskromatografiske analyse viser nærværet av to forbindelser. is made alkaline with 50% sodium hydroxide solution, and the mixture is extracted with 600 ml of ether. The extracts are washed with water, dried over anhydrous sodium sulfate and evaporated, obtaining an orange non-crystallizing oil. The gas chromatographic analysis shows the presence of two compounds.
45,4 g av denne olje, 5 2,5 g (0,875 mol) etylendiamin og 400 ml benzen oppvarmes i 5 timer i en rundkolbe med en vannavskiller under tilbakelop. Det utskiller seg omtrent 6 ml av en vandig fase. Reaksjonsblandingen avkjoles, vaskes tre ganger med mettet vandig saltopplosning og torkes over vannfritt natrium-sulf at. Gjennom benzenopplosningen gjennomledes luft i 15 timer, idet det danner seg bare en liten mengde bunnfall. 45.4 g of this oil, 2.5 g (0.875 mol) of ethylenediamine and 400 ml of benzene are heated for 5 hours in a round bottom flask with a water separator under reflux. Approximately 6 ml of an aqueous phase separates. The reaction mixture is cooled, washed three times with saturated aqueous salt solution and dried over anhydrous sodium sulfate. Air is passed through the benzene solution for 15 hours, with only a small amount of sediment forming.
Benzenen fjernes i vakuum, og resten opploses i 150 ml etanol og 40 ml (0,350 mol) 30 %'ig hydrogenperoksyd. Etter 3 timers omroring fjernes etanolen i vakuum og 300 ml benzen tilsettes. Den vandige fase skilles fra, og benzenopplosningen torkes over vannfritt natriumsulfat og konsentreres i vakuum, idet man oppnår en svak gul olje. Etter tilsetning av 150 ml eter utskiller det seg et krystallinsk bunnfall. Blandingen filtreres, idet man oppnår et svakt gult bunnfall med smeltepunkt 164 - 167° (spaltning). Eterfiltratene omrores ved romtemperatur, og utsettes for luft i 2 dager. Det erholdte bunnfall filtreres, idet man oppnår ytterligere svak gul substans. Tynnskiktskromatografi av de to forente substanser viser nærværet av et hovedprodukt Rf 0,41 og en ytterligere komponent Rf 0,67. Den siste komponent er 2,3-dihydro-5-hydroperoksy-5-(o-klorfenyl)-5H-imidazo[2,l-a]isoindol, da det gule bunnfallet jod utfelles fra en mettet metanolisk natriumjodidopp-losning. The benzene is removed in vacuo, and the residue is dissolved in 150 ml of ethanol and 40 ml (0.350 mol) of 30% hydrogen peroxide. After stirring for 3 hours, the ethanol is removed in vacuo and 300 ml of benzene is added. The aqueous phase is separated, and the benzene solution is dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining a pale yellow oil. After adding 150 ml of ether, a crystalline precipitate separates. The mixture is filtered, obtaining a faint yellow precipitate with a melting point of 164 - 167° (decomposition). The ether filtrates are stirred at room temperature and exposed to air for 2 days. The resulting precipitate is filtered, obtaining a further faint yellow substance. Thin layer chromatography of the two combined substances shows the presence of a main product Rf 0.41 and a further component Rf 0.67. The last component is 2,3-dihydro-5-hydroperoxy-5-(o-chlorophenyl)-5H-imidazo[2,1-a]isoindole, as the yellow precipitate iodine is precipitated from a saturated methanolic sodium iodide solution.
Til en suspensjon av den gule substans i 60 ml kokende metanol tilsettes en opplosning av 4,28 g (0,017 mol) Na^O^ . 7H20 i 30 ml vann i lopet av 5 minutter. Reaksjonsblandingen oppvarmes ennå i 15 minutter under tilbakelop, avkjoles og filtreres. Det filtrerte bunnfall vaskes tre ganger med 20 ml vann og torkes. Etter omkrystallisasjon fra metanol/kloroform oppnår man fargelose prismer av 2-[2-(2-klorbenzoyl)fenyl]-2-imidazo-lin med smeltepunkt 180 - 181° (spaltning). A solution of 4.28 g (0.017 mol) Na^O^ is added to a suspension of the yellow substance in 60 ml of boiling methanol. 7H20 in 30 ml of water over the course of 5 minutes. The reaction mixture is further heated for 15 minutes under reflux, cooled and filtered. The filtered precipitate is washed three times with 20 ml of water and dried. After recrystallization from methanol/chloroform, colorless prisms of 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline with melting point 180 - 181° (decomposition) are obtained.
Analyse: Analysis:
Beregnet for C16<H>13<C>1N20: C, 67,49; H, 4,60; N, 9,84 Funnet: C, 67,15; H, 4,56; N, 9,66. Calculated for C16<H>13<C>1N2O: C, 67.49; H, 4.60; N, 9.84 Found: C, 67.15; H, 4.56; N, 9.66.
Det således erholdte 2-[2-(2-klorbenzoyl)fenyl]-2-imidazolin kan danne isomert 2,3-dihydro-5-hydroksy-5-(2-klorfenyl)-5H-imidazo£2,l-a]isoindol. The thus obtained 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline can form isomeric 2,3-dihydro-5-hydroxy-5-(2-chlorophenyl)-5H-imidazo£2,1-a]isoindole.
Til en varm opplosning av 6,0 g (21,2 mmol) 2-[2-(2-klorben-zoyl ) f enyl]- 2-imidazolin i 25 ml 6-n metanolisk saltsyre og 35 ml metanol tilsettes 200 ml eter, og opplosningen avkjoles. Etter filtrering oppnår man 2-[2-(2-klorbenzoyl)-fenyl]-2-imidazolin-hydroklorid med smeltepunkt 178 - 180° (spaltning). Fortynning av moderlutene med 200 ml eter og så kjoling og filtrering gir et ytterligere utbytte av hydroklorid. Etter omkrystallisasjon av metanol/eter oppnår man fargelose prismer med smeltepunkt 178 - 180° (spaltning). To a hot solution of 6.0 g (21.2 mmol) of 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline in 25 ml of 6-n methanolic hydrochloric acid and 35 ml of methanol, 200 ml of ether is added , and the solution is cooled. After filtration, 2-[2-(2-chlorobenzoyl)-phenyl]-2-imidazoline hydrochloride with melting point 178 - 180° (decomposition) is obtained. Dilution of the mother liquors with 200 ml of ether and then cooling and filtration gives a further yield of hydrochloride. After recrystallization from methanol/ether, colorless prisms with a melting point of 178 - 180° (decomposition) are obtained.
Analyse: Analysis:
Beregnet for <C>16<H>14<C>12<N>2<0>^ Cl, 2 2,08 Calculated for <C>16<H>14<C>12<N>2<0>^ Cl, 2 2.08
Funnet: Cl, 22,00. Found: Cl, 22.00.
Det som utgangsmateriale anvendte 2-klor-2'-hydroksymetyl-benzhydrol kan fremstilles på folgende måte: Til 250 ml konsentrert svovelsyre tilsettes under omroring og lett avkjoling 37,5 g (0,545 mol) natriumnitrit. Dertil til-foyer man 120,5 g (0,50 mol) 2-(2-aminobenzoyl)benzosyre i slike porsjoner at temperaturen i reaksjonsblandingen blir mellom 30 og 40°. Etter avsluttet tilsetning omrores reaksjonsblandingen i 1 time og helles så i 1 liter is og vann. Filtratet tilsettes hurtig til en omrbrt opplosning av 55 g (0,555 mol) kobberklorid, 150 g natriumklorid, 250 ml konsentrert saltsyre og 300 ml vann. Det gummilignende bunnfall ekstraheres med kloroform og ekstraktene vaskes to ganger med vann, torkes over vannfritt natriumsulfat og inndampes i vakuum, idet man oppnår en rod olje, som krystalliserer ved kloring. Omkrystallisasjon fra 200 ml etylacetat gir 2-(2-klorbenzoyl)-benzosyre som rosa bunnfall. En prove omkrystalliseres tre ganger fra etylacetat, idet man oppnår fargelose prismer med dobbeltsmeltepunkt 112 - 116° og 124 - 126°. The 2-chloro-2'-hydroxymethyl-benzhydrol used as starting material can be prepared in the following way: 37.5 g (0.545 mol) of sodium nitrite are added to 250 ml of concentrated sulfuric acid with stirring and slight cooling. To this is added 120.5 g (0.50 mol) of 2-(2-aminobenzoyl)benzoic acid in such portions that the temperature of the reaction mixture is between 30 and 40°. After the addition is complete, the reaction mixture is stirred for 1 hour and then poured into 1 liter of ice and water. The filtrate is quickly added to a stirred solution of 55 g (0.555 mol) copper chloride, 150 g sodium chloride, 250 ml concentrated hydrochloric acid and 300 ml water. The gum-like precipitate is extracted with chloroform and the extracts are washed twice with water, dried over anhydrous sodium sulfate and evaporated in vacuo, obtaining a red oil, which crystallizes upon chlorination. Recrystallization from 200 ml of ethyl acetate gives 2-(2-chlorobenzoyl)-benzoic acid as a pink precipitate. A sample is recrystallized three times from ethyl acetate, obtaining colorless prisms with double melting points 112 - 116° and 124 - 126°.
Til en omrort suspensjon av 22,8 g (0,60 mol) litiumaluminiumhydrid i 700 ml tort tetrahydrofuran tilsettes 104 g (0,40 mol) 2-(2-klorbenzoyl)benzoesyre i slike porsjoner at reaksjonsblandingen beholder en temperatur mellom 15 og 30° med isavkjoling. Etter avsluttet tilsetning omrores reaksjonsblandingen i 1 time. Etter tilsetning av 400 ml eter tilsettes langsomt 80 ml vann under isavkjoling. Blandingen filtreres gjennom en vid glass-sintertrakt, som inneholder et lag av Celit som filterhjelpe-middel. De filtrerte bunnfall vaskes med tetrahydrofuran, og de forente filtrater inndampes i vakuum, idet man oppnår en gul olje, som krystalliserer ved kloring. Dette materiale omkrystalliseres fra 150 ml isopropyleter og gir svakt gul 2-klor-2'-hydroksymetyl-benzhydrol med smeltepunkt 85 - 87°. En prove omkrystalliseres tre ganger fra isopropyleter og gir fargelose prismer med smeltepunkt 86 - 87°. To a stirred suspension of 22.8 g (0.60 mol) of lithium aluminum hydride in 700 ml of dry tetrahydrofuran, 104 g (0.40 mol) of 2-(2-chlorobenzoyl)benzoic acid are added in such portions that the reaction mixture maintains a temperature between 15 and 30 ° with ice cooling. After the addition is complete, the reaction mixture is stirred for 1 hour. After adding 400 ml of ether, slowly add 80 ml of water under ice cooling. The mixture is filtered through a wide glass sinter funnel, which contains a layer of Celite as a filter aid. The filtered precipitates are washed with tetrahydrofuran, and the combined filtrates are evaporated in vacuo, obtaining a yellow oil, which crystallizes upon chlorination. This material is recrystallized from 150 ml of isopropyl ether and gives slightly yellow 2-chloro-2'-hydroxymethyl-benzhydrol with a melting point of 85 - 87°. A sample is recrystallized three times from isopropyl ether and gives colorless prisms with a melting point of 86 - 87°.
EKSEMPEL 7 EXAMPLE 7
En opplosning av 7,5 g fthalaldehydsyre i 30 ml etanol og 34 A solution of 7.5 g of phthalaldehyde acid in 30 ml of ethanol and 34
ml etylendiamin oppvarmes i 16 timer under tilbakelop. Opplosningen inndampes i vakuum, og resten opploses i metylenklorid. Opplosningen vaskes med vann, torkes og inndampes. Resten destilleres i et lite kuleror ved 0,3 ml og en badtem-peratur på 150 - 180°. Man oppnår en fargelos olje, som opploses i metanol og etter tilsetning av eterisk saltsyre gir hvite prismer av 1,2,3,9b-tetrahydro-5H-imidazo[2,l-a]isoindol-5-on-hydroklorid med smeltepunkt 222 - 224° (spaltning). ml of ethylenediamine is heated for 16 hours under reflux. The solution is evaporated in vacuo, and the residue is dissolved in methylene chloride. The solution is washed with water, dried and evaporated. The residue is distilled in a small still at 0.3 ml and a bath temperature of 150 - 180°. A colorless oil is obtained, which dissolves in methanol and after addition of ethereal hydrochloric acid gives white prisms of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one hydrochloride with melting point 222 - 224 ° (cleavage).
Dette salt behandles med vandig kaliumkarbonatopplosning. This salt is treated with aqueous potassium carbonate solution.
Etter ekstraksjon med metylenklorid oppnår man en olje av hvilken 9 g opploses i en blanding av 25 ml benzen og IO ml eter. Til denne opplosning tilsettes 5,5 ml av en 2-n opp-lbsning av fenyllitium i en blanding av benzen og eter (7 : 3). Opplosningen omrores i 1 time ved 25° og helles så i isvann og ekstraheres med etylacetat. Opplosningen inndampes, og resten utsettes for luft i 48 timer. Etter tilsetning av metylenklorid oppnår man krystaller, som opploses i metanol. Etter tilsetning av eterisk saltsyre oppnår man hvite prismer, som etter omkrystallisering fra en blanding av metanol og eter gir krystaller av 2-(2-benzoylfenyl)-2-imidazolin-hydroklorid med smeltepunkt 173 - 175° (spaltning). After extraction with methylene chloride, an oil is obtained, 9 g of which is dissolved in a mixture of 25 ml of benzene and 10 ml of ether. To this solution is added 5.5 ml of a 2-n solution of phenyllithium in a mixture of benzene and ether (7:3). The solution is stirred for 1 hour at 25° and then poured into ice water and extracted with ethyl acetate. The solution is evaporated, and the residue is exposed to air for 48 hours. After addition of methylene chloride, crystals are obtained, which are dissolved in methanol. After the addition of ethereal hydrochloric acid, white prisms are obtained, which after recrystallization from a mixture of methanol and ether give crystals of 2-(2-benzoylphenyl)-2-imidazoline hydrochloride with a melting point of 173 - 175° (decomposition).
EKSEMPEL 8 EXAMPLE 8
Den fra 16,6 g 2,3-dihydro-5-fenyl-5H-imidazo[2,l-a]isoindol-sulfat frisatte base opploses i 50 ml etanol og 11 ml av en 30 %'ig vandig opplosning av hydrogenperoksyd tilsettes dertil. Blandingen omrores i 40 timer ved 25°. Man oppnår et krystallint bunnfall, som bringes på en kolonne med 250 g silicagel. Etter eluering med en blanding av 1 vol.del metanol og 1 vol. The base released from 16.6 g of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole sulfate is dissolved in 50 ml of ethanol and 11 ml of a 30% aqueous solution of hydrogen peroxide is added thereto. The mixture is stirred for 40 hours at 25°. A crystalline precipitate is obtained, which is applied to a column with 250 g of silica gel. After elution with a mixture of 1 vol. part methanol and 1 vol.
del kloroform oppnår man fraksjoner, som etter konsentrasjon gir et krystallint bunnfall. Etter omkrystallisasjon fra en blanding av metanol og kloroform oppnår man 2,3-dihydro-5-hydroperoksy-5-fenyl-5H-imidazo[2,l-a]isoindol som hvite prismer med smeltepunkt 167 - 168° (spaltning). UV infleksjoner (2-propanol) ved 232 mu (£ = 14,000) og 290 mu { £' = 2,600), max. ved 269 mu ( £' = 4,000) og 275 mu ( c = 4,400) , infrarod-absorpsjon (KBr) ved 1665 cm<-1>. part chloroform, fractions are obtained, which after concentration give a crystalline precipitate. After recrystallization from a mixture of methanol and chloroform, 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole is obtained as white prisms with a melting point of 167 - 168° (decomposition). UV inflections (2-propanol) at 232 mu (£ = 14,000) and 290 mu { £' = 2,600), max. at 269 mu ( £' = 4,000) and 275 mu ( c = 4,400), infrared absorption (KBr) at 1665 cm<-1>.
Analyse: Analysis:
Beregnet for c16Hi4N2°2: C' 72'16"'H' 5?3o5 N? IO,52 Funnet: C, 72,09; H., 5,39; N, 10,22. Calculated for c16Hi4N2°2: C' 72'16"'H' 5?3o5 N? IO.52 Found: C, 72.09; H., 5.39; N, 10.22.
Hydrokloridet av 2,3-dihydro-5-hydroperoksy-5-fenyl-5H-imidazo [2,l-a]isoindol fremstilles med metanolisk saltsyre. Etter omkrystallisasjon av en blanding av metanol og eter oppnås hvite små plater med smeltepunkt 158 - 159° (spaltning). UV The hydrochloride of 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole is prepared with methanolic hydrochloric acid. After recrystallization from a mixture of methanol and ether, white small plates with a melting point of 158 - 159° (decomposition) are obtained. UV
max. (2-propanol) ved 245 mu = 14,800) og 278 mu (£ = 5,200); infrarod-absorpsjon (KBr) ved 1680 cm max. (2-propanol) at 245 mu = 14.800) and 278 mu (£ = 5.200); infrared absorption (KBr) at 1680 cm
Analyse: Analysis:
Beregnet for <C>16H14N202.HC1: C, 63,47; H, 4,99; Cl, 11,71 Funnet: C, 63,63; H, 4,83; Cl, 11,79. Calculated for <C>16H14N2O2.HCl: C, 63.47; H, 4.99; Cl, 11.71 Found: C, 63.63; H, 4.83; Cl, 11.79.
En opplosning av 0,7 g natriumsulfitheptahydrat i 3 ml vann tilsettes til 0,5 g 2,3-dihydro-5-hydroperoksy-5-fenyl-5H-imidazo[2,l-a]isoindol i 7 ml dimetylformamid. Opplosningen oppvarmes i 15 minutter til 100°. Etter avkjolingen og til-setningen av 20 ml vann oppnår man 2-(2-benzoylfenyl)-2-imi-dazolin. A solution of 0.7 g of sodium sulfite heptahydrate in 3 ml of water is added to 0.5 g of 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole in 7 ml of dimethylformamide. The solution is heated for 15 minutes to 100°. After cooling and the addition of 20 ml of water, 2-(2-benzoylphenyl)-2-imidazoline is obtained.
Det som utgangsmateriale anvendte 2,3-dihydro-5-fenyl-SH-imidazo^jlajisoindol-sulf at kan fremstilles etter folgende to metoder: a) En blanding av 1 g selendioksyd og 1 g 2-hydroksy-metyl-benzhydrol i 5 ml eddiksyre oppvarmes i 4 1/2 time til tilbakelop. Opplosningen avkjoles, selenet filtreres fra og filtratet helles i isvann og innstilles alkalisk med natriumhydroksyd. Ekstraksjonen med eter gir en gul olje, hvilken tilsettes petroleter. Man oppnår hvite prismer av o-benzoylbenzaldehyd med smeltepunkt 64 - 67°. UV max. (2-propanol) ved 226/7 mu The 2,3-dihydro-5-phenyl-SH-imidazo^jlaisoindole-sulphate used as starting material can be prepared by the following two methods: a) A mixture of 1 g of selenium dioxide and 1 g of 2-hydroxy-methyl-benzhydrol in 5 ml acetic acid is heated for 4 1/2 hours to reflux. The solution is cooled, the selenium is filtered off and the filtrate is poured into ice water and made alkaline with sodium hydroxide. The extraction with ether gives a yellow oil, to which petroleum ether is added. White prisms of o-benzoylbenzaldehyde with a melting point of 64 - 67° are obtained. UV max. (2-propanol) at 226/7 mu
( t 15,750) og 251/2 mu ( C = 18,500), infleksjon ved 294 mu ( .£. 2,600); infrarod-absorpsjon (CHC13) ved 1665 cm-1 og ( t 15.750) and 251/2 mu ( C = 18.500), inflection at 294 mu ( .£. 2.600); infrared absorption (CHC13) at 1665 cm-1 and
1705 cm<-1>. 1705 cm<-1>.
Analyse: Analysis:
Beregnet for c14<H>l0<0>2<:> c, 79,98; H, 4,79 Calculated for c14<H>10<0>2<:> c, 79.98; H, 4.79
Funnet: C, 80,00; H, 4,68. Found: C, 80.00; H, 4.68.
En opplosning av 21 g o-benzoylbenzaldehyd i 250 ml toluen og A solution of 21 g of o-benzoylbenzaldehyde in 250 ml of toluene and
34 ml etylendiamin oppvarmes i 24 timer under tilbakelop. I lopet av denne tid skiller det seg ut 11,5 ml av en vandig fase i en vannavskiller. Reaksjonsblandingen konsentreres i vakuum til en orange olje, som opploses i etylacetat og vaskes to ganger med vann. Opplosningen torkes og inndampes, opploses i 200 ml etylacetat og en opplosning av 5,3 ml konsentrert svovelsyre tilsettes i 100 ml etanol. Man oppnår et krystallint bunnfall, som etter omkrystallisasjon fra en blanding av metanol og etylacetat gir hvite prismer av 2,3-dihydro-5-fenyl-5H-imidazo[2,l-a]isoindol-sulfat med smeltepunkt 226 - 229° 34 ml of ethylenediamine is heated for 24 hours under reflux. During this time, 11.5 ml of an aqueous phase separates out in a water separator. The reaction mixture is concentrated in vacuo to an orange oil, which is dissolved in ethyl acetate and washed twice with water. The solution is dried and evaporated, dissolved in 200 ml of ethyl acetate and a solution of 5.3 ml of concentrated sulfuric acid is added in 100 ml of ethanol. A crystalline precipitate is obtained, which after recrystallization from a mixture of methanol and ethyl acetate gives white prisms of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole sulfate with a melting point of 226 - 229°
(spaltning). UV max. (2-propanol) ved 240 mu ( £ = 15,000) og 276 mp ( <S = 5,400); infrarod-absorpsjon (KBr) 1660 cm<-1>. (fission). UV max. (2-propanol) at 240 mu ( £ = 15,000) and 276 mp ( <S = 5,400); infrared absorption (KBr) 1660 cm<-1>.
Analyse: Analysis:
Beregnet for C16<H>14<N>2<*H>2<S>°4<:> C' 57 '82' H' 4'85' N' 8>43 Funnet: C, 57,61; H, 4,81; N, 8,73. Calculated for C16<H>14<N>2<*H>2<S>°4<:> C' 57 '82' H' 4'85' N' 8>43 Found: C, 57.61; H, 4.81; N, 8.73.
Hydrokloridet av 2,3-dihydro-5-fenyl-5H-imidazo[2,l-a]isoindol oppnår man fra den tilsvarende base med vandig l-n saltsyre. Etter omkrystallisasjon av en blanding av metanol og toluen oppnår man hvite prismer med smeltepunkt 2 26 - 2 28° (spaltning) Nmr peaks (DMS0) ved £> 3,6 - 4,6 (4H, multiplet), ved 6 6,13 (1H, singlet), ved 6 7,3 - 7,9 (9H, multiplet). The hydrochloride of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole is obtained from the corresponding base with aqueous 1-n hydrochloric acid. After recrystallization from a mixture of methanol and toluene, white prisms are obtained with melting point 2 26 - 2 28° (cleavage) Nmr peaks (DMS0) at £> 3.6 - 4.6 (4H, multiplet), at 6 6.13 (1H, singlet), at 6 7.3 - 7.9 (9H, multiplet).
b) En opplosning av 25 g (0,1 mol) 1,2,3,9b-tetrahydro-9b-fenyl-5H-imidazo[2,l-a]isoindol-5-on i 150 ml eddiksyre, som b) A solution of 25 g (0.1 mol) of 1,2,3,9b-tetrahydro-9b-phenyl-5H-imidazo[2,1-a]isoindol-5-one in 150 ml of acetic acid, which
inneholder 2,5 g hydrogenklorid, rystes under en atmosfære hydrogen ved 25° og med 0,5 g platinoksyd som katalysator. contains 2.5 g of hydrogen chloride, is shaken under an atmosphere of hydrogen at 25° and with 0.5 g of platinum oxide as catalyst.
I lopet av 7 timer absorberes 3000 ml hydrogen (teoretisk ca. 2500 ml) og opptagelsen synker betraktelig. Opplosningen helles i isvann, innstilles basisk med ammoniakk og ekstraheres med metylenklorid. Den organiske fase torkes og inndampes. Resten krystalliseres fra eter og omkrystalliseres fra en blanding av metylenklorid og petroleter og gir hvite prismer av 2-(2-aminoetyl)-3-fenylfthalimidin med smeltepunkt 90 - 93 . Yco<Cl>3 = 1685 Cm_1 X maxr°P £ 247 6>°°0> 279 m^ t = 1,900. In the course of 7 hours, 3,000 ml of hydrogen is absorbed (theoretically approx. 2,500 ml) and the absorption drops considerably. The solution is poured into ice water, made basic with ammonia and extracted with methylene chloride. The organic phase is dried and evaporated. The residue is crystallized from ether and recrystallized from a mixture of methylene chloride and petroleum ether and gives white prisms of 2-(2-aminoethyl)-3-phenylphthalimidine with a melting point of 90 - 93 . Yco<Cl>3 = 1685 Cm_1 X maxr°P £ 247 6>°°0> 279 m^ t = 1.900.
Analyse: Analysis:
Beregnet for ci6<H>i6<N>2<0:> c • > 76,16; H, 6,39 Calculated for ci6<H>i6<N>2<0:> c • > 76.16; H, 6.39
Funnet: C, 75,81; H, 6,32. Found: C, 75.81; H, 6.32.
En opplosning av 1,2 ml titantetraklorid i 30 ml xylen tilsettes ved 25° til en omrort opplosning av 2,5 g 2-(2-amino-etyl)-3-fenylfthalimidin i 150 ml xylen. Blandingen oppvarmes i 18 timer under tilbakelop, avkjoles og vaskes med en vandig opplosning av natriumkarbonat. Xylenopplosningen ekstraheres med 2-n saltsyre. De sure ekstrakter helles på is og innstil- A solution of 1.2 ml of titanium tetrachloride in 30 ml of xylene is added at 25° to a stirred solution of 2.5 g of 2-(2-amino-ethyl)-3-phenylphthalimidine in 150 ml of xylene. The mixture is heated for 18 hours under reflux, cooled and washed with an aqueous solution of sodium carbonate. The xylene solution is extracted with 2-n hydrochloric acid. The acidic extracts are poured onto ice and set
les alkalisk med natriumhydroksyd. Opplosningen ekstraheres med etylacetat, og ekstraktet inndampes. Etter tilsetning av en opplosning av svovelsyre i en blanding av etanol og tetrahydrofuran og ytterligere fortynning med etylacetat oppnår man et krystallint bunnfall. Etter omkrystallisasjon fra en blan- read alkaline with sodium hydroxide. The solution is extracted with ethyl acetate, and the extract is evaporated. After addition of a solution of sulfuric acid in a mixture of ethanol and tetrahydrofuran and further dilution with ethyl acetate, a crystalline precipitate is obtained. After recrystallization from a mix-
ding av metanol og etylacetat oppnår man hvite prismer av 2,3-dihydro-5-fenyl-5H-imidazo[2,l-a]isoindolsulfat med smelte- of methanol and ethyl acetate, white prisms of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole sulfate are obtained with melting
punkt 225 - 228° (spaltning). point 225 - 228° (cleavage).
EKSEMPEL 9 EXAMPLE 9
En opplosning.av 0,1 g 2,3-dihydro-5-hydroperoksy-5-fenyl-5H-imidazo[2,l-a]isoindol og 0,33 g trietylfosfit i 20 ml etanol holdes i 5 minutter på et dampbad og deretter i 18 timer ved 25°. Opplosningen inndampes i vakuum og etter tilsetning av vann oppnår man 2-(2-benzoylfenyl)-2-imidazolin. A solution of 0.1 g of 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole and 0.33 g of triethyl phosphite in 20 ml of ethanol is kept for 5 minutes on a steam bath and then for 18 hours at 25°. The solution is evaporated in vacuo and after addition of water, 2-(2-benzoylphenyl)-2-imidazoline is obtained.
EKSEMPEL 10 EXAMPLE 10
1 g 2-(p-klorbenzoyl)-benzaldehyd blandes godt med 0,9 g etylen-diamintoluensulfonat og oppvarmes i et metallbad (badtempera- 1 g of 2-(p-chlorobenzoyl)-benzaldehyde is mixed well with 0.9 g of ethylene diamine toluene sulphonate and heated in a metal bath (bath temperature
tur 120 - 125°) i 1 minutt. Etter avkjølingen oppnår man det morkt gule glassaktige materiale, som etter tilsetning av metylenklorid, etylacetat og petroleter gir et krystallint bunnfall, som behandles med iskald vandig natriumhydroksydopplosning. Blandingen ekstraheres med eter, og ekstraktet ut- turn 120 - 125°) for 1 minute. After cooling, the dark yellow glassy material is obtained, which after addition of methylene chloride, ethyl acetate and petroleum ether gives a crystalline precipitate, which is treated with ice-cold aqueous sodium hydroxide solution. The mixture is extracted with ether, and the extract
settes for luft i 18 timer ved 25°. Man oppnår et krystallint bunnfall, som suspenderes i metylenklorid. Etter tilsetning av eterisk saltsyre oppnår man et krystallint materiale som etter omkrystallisasjon fra en blanding av metanol og eter gir hvite prismer av 5-(p-klorfenyl)-2,3-dihydro-5-hydroperoksy-5H-imidazo£2,l-aJisoindol-hydroklorid med smeltepunkt 175 - 177° exposed to air for 18 hours at 25°. A crystalline precipitate is obtained, which is suspended in methylene chloride. After addition of ethereal hydrochloric acid, a crystalline material is obtained which, after recrystallization from a mixture of methanol and ether, gives white prisms of 5-(p-chlorophenyl)-2,3-dihydro-5-hydroperoxy-5H-imidazo£2,1- aJisoindole hydrochloride with melting point 175 - 177°
(spaltning). UV infleksjon (2-propanol) ved 223 mu ( £, = 21,800) og 279 mu = 5,600), max. ved 243 mu (£ = 15,500); infrarod-absorpsjon (KBr) ved 1670 cm<-1>. (fission). UV inflection (2-propanol) at 223 mu ( £, = 21.800) and 279 mu = 5.600), max. at 243 mu (£ = 15,500); infrared absorption (KBr) at 1670 cm<-1>.
Analyse: Analysis:
Beregnet for ci6Hi3C1N2°2 HC1: Calculated for ci6Hi3C1N2°2 HC1:
C, 56,99; H, 4,18; Cl, 21,03; N, 8,31 Funnet: C, 57,14; H, 4,15; Cl, 21,02; N, 8,30. C, 56.99; H, 4.18; Cl, 21.03; N, 8.31 Found: C, 57.14; H, 4.15; Cl, 21.02; N, 8.30.
Det således oppnådde 5-(p-klorfenyl)-2,3-dihydro-5-hydroper-oksy-5H-imidazo[2,l-a]isoindol-hydroklorid kan analogt eksempel 8, siste avsnitt, reduseres til 5-(p-klorfenyl)-2,3-di-hydro-5-hydroksy-5H-imidazo[2,l-a]isoindol, smeltepunkt 178 - 180° (spaltning). The thus obtained 5-(p-chlorophenyl)-2,3-dihydro-5-hydroperoxy-5H-imidazo[2,1-a]isoindole hydrochloride can be reduced analogously to example 8, last section, to 5-(p-chlorophenyl )-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole, melting point 178 - 180° (decomposition).
EKSEMPEL 11 EXAMPLE 11
Til en suspensjon av 8,5 g 2,3-dihydro-5-fenyl-5H-imidazo [2,l-a]isoindol-sulfat i vann tilsettes 50 ml av en l-n vandig natriumhydroksydopplosning. Etter ekstraksjon med metylenklorid og konsentrering oppnår man en orange-farget olje, som opploses i en blanding av 30 ml metylenklorid og 30 ml etanol. Til denne opplosning tilsettes 2,3 ml av en 30 %'ig hydrogen-peroksydopplosning. Etter 18 timers omroring ved 25° oppnår man et bunnfall, som etter omkrystallisasjon fra metanol gir hvite prismer av 2-(2-benzoylfenyl)-2-imidazolin med smeltepunkt 194 - 196° (spaltning). UV infleksjoner (2-propanol) ved 225 mu ( £ = 15,500) og 290 mu ( £ = 2,250), max. ved 269 mu (£ = 4,100) og 276 mu ( £ = 4, 250); infrarod-absorpsjon (KBr) 1660 cm<-1>. To a suspension of 8.5 g of 2,3-dihydro-5-phenyl-5H-imidazo [2,1-a]isoindole sulfate in water is added 50 ml of a 1-n aqueous sodium hydroxide solution. After extraction with methylene chloride and concentration, an orange-coloured oil is obtained, which is dissolved in a mixture of 30 ml methylene chloride and 30 ml ethanol. 2.3 ml of a 30% hydrogen peroxide solution is added to this solution. After 18 hours of stirring at 25°, a precipitate is obtained, which after recrystallization from methanol gives white prisms of 2-(2-benzoylphenyl)-2-imidazoline with melting point 194 - 196° (decomposition). UV inflections (2-propanol) at 225 mu ( £ = 15,500) and 290 mu ( £ = 2,250), max. at 269 mu (£ = 4,100) and 276 mu (£ = 4,250); infrared absorption (KBr) 1660 cm<-1>.
Analyse: Analysis:
Beregnet for C16H14N20: c> 76,78; H, 5,64; N, 11,19 Funnet: C, 76,42; H, 5,79; N, 11,13. Calculated for C16H14N20: c > 76.78; H, 5.64; N, 11.19 Found: C, 76.42; H, 5.79; N, 11,13.
Det således erholdte 2-(2-benzoyifenyl)-2-imidazolin kan danne isomert 2,3-dihydro-5-hydroksy-5-feny1-5H-imidazo[2,l-aJisoin-dol. The 2-(2-benzoylphenyl)-2-imidazoline thus obtained can form isomeric 2,3-dihydro-5-hydroxy-5-phenyl-5H-imidazo[2,1-aJisoindol.
Hydrokloridet fremstilles ved tilsetning av en opplosning av hydrogenklorid i metanol til en suspensjon av 2-(2-benzoyl-fenyl)-2-imidazolin i metanol. Etter tilsetning av eter oppnår man et krystallint bunnfall, som etter omkrystallisasjon fra en blanding av metanol og eter gir hvite prismer med smeltepunkt 173 - 176° (spaltning). UV max. (2-propanol) ved 252 mp (£ = 13,600)5 infrarod-absorpsjon (KBr) ved 1665 cm-"''. The hydrochloride is prepared by adding a solution of hydrogen chloride in methanol to a suspension of 2-(2-benzoyl-phenyl)-2-imidazoline in methanol. After adding ether, a crystalline precipitate is obtained, which after recrystallization from a mixture of methanol and ether gives white prisms with a melting point of 173 - 176° (decomposition). UV max. (2-propanol) at 252 mp (£ = 13,600)5 infrared absorption (KBr) at 1665 cm-"''.
Analyse: Analysis:
Beregnet for C16H14<N>2<0><H>C1: cl>12,36 Calculated for C16H14<N>2<0><H>C1: cl>12.36
Funnet: Cl, 12,22. Found: Cl, 12.22.
Hydrobromidet fremstilles ved tilsetning av en vandig opplosning av bromhydrogensyre til en suspensjon av 2-(2-benzoyl-fenyl)-2-imidazolin i etanol. Etter tilsetning av eter oppnår man et bunnfall, som etter omkrystallisasjon fra en blanding av etanol og eter gir hvite små plater med smeltepunkt 193 - 194° (spaltning). The hydrobromide is prepared by adding an aqueous solution of hydrobromic acid to a suspension of 2-(2-benzoyl-phenyl)-2-imidazoline in ethanol. After adding ether, a precipitate is obtained, which after recrystallization from a mixture of ethanol and ether gives white small plates with a melting point of 193 - 194° (decomposition).
Analyse: Analysis:
Beregnet for C16H14N20 • HBr: Br, 24,13 Calculated for C16H14N20 • HBr: Br, 24.13
Funnet: Br, 24,15. Found: Br, 24.15.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62696567A | 1967-03-30 | 1967-03-30 | |
US639315A US3888846A (en) | 1967-03-30 | 1967-05-18 | Process for 2(2-(1,3-diazacycloalk-2-enyl))benzophenone derivatives and 1,3-diazacycloalkenyl(2,1-a)isoindole derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
NO124111B true NO124111B (en) | 1972-03-06 |
Family
ID=27090306
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO1212/68A NO124111B (en) | 1967-03-30 | 1968-03-29 | |
NO03752/71*[A NO127238B (en) | 1967-03-30 | 1971-10-12 | |
NO03755/71*[A NO127351B (en) | 1967-03-30 | 1971-10-12 | |
NO03753/71*[A NO127239B (en) | 1967-03-30 | 1971-10-12 | |
NO03754/71*[A NO127350B (en) | 1967-03-30 | 1971-10-12 |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO03752/71*[A NO127238B (en) | 1967-03-30 | 1971-10-12 | |
NO03755/71*[A NO127351B (en) | 1967-03-30 | 1971-10-12 | |
NO03753/71*[A NO127239B (en) | 1967-03-30 | 1971-10-12 | |
NO03754/71*[A NO127350B (en) | 1967-03-30 | 1971-10-12 |
Country Status (8)
Country | Link |
---|---|
JP (2) | JPS4843360B1 (en) |
ES (1) | ES352173A1 (en) |
IE (1) | IE31999B1 (en) |
IL (1) | IL29651A (en) |
MY (1) | MY7300459A (en) |
NO (5) | NO124111B (en) |
SE (1) | SE346318B (en) |
YU (1) | YU33929B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS50125392U (en) * | 1974-03-30 | 1975-10-14 |
-
1968
- 1968-03-18 IL IL29651A patent/IL29651A/en unknown
- 1968-03-27 SE SE4081/68A patent/SE346318B/xx unknown
- 1968-03-29 IE IE366/68A patent/IE31999B1/en unknown
- 1968-03-29 YU YU717/68A patent/YU33929B/en unknown
- 1968-03-29 NO NO1212/68A patent/NO124111B/no unknown
-
1969
- 1969-05-19 ES ES352173A patent/ES352173A1/en not_active Expired
-
1970
- 1970-08-03 JP JP45067352A patent/JPS4843360B1/ja active Pending
-
1971
- 1971-10-12 NO NO03752/71*[A patent/NO127238B/no unknown
- 1971-10-12 NO NO03755/71*[A patent/NO127351B/no unknown
- 1971-10-12 NO NO03753/71*[A patent/NO127239B/no unknown
- 1971-10-12 NO NO03754/71*[A patent/NO127350B/no unknown
-
1973
- 1973-02-09 JP JP48016353A patent/JPS5017479B1/ja active Pending
- 1973-12-30 MY MY459/73A patent/MY7300459A/en unknown
Also Published As
Publication number | Publication date |
---|---|
ES352173A1 (en) | 1969-10-01 |
NO127238B (en) | 1973-05-28 |
NO127351B (en) | 1973-06-12 |
YU71768A (en) | 1978-02-28 |
NO127239B (en) | 1973-05-28 |
YU33929B (en) | 1978-09-08 |
IE31999L (en) | 1968-09-30 |
IL29651A (en) | 1972-07-26 |
SE346318B (en) | 1972-07-03 |
JPS4843360B1 (en) | 1973-12-18 |
IE31999B1 (en) | 1973-03-07 |
JPS5017479B1 (en) | 1975-06-20 |
NO127350B (en) | 1973-06-12 |
MY7300459A (en) | 1973-12-31 |
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