NO135173B - - Google Patents
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- Publication number
- NO135173B NO135173B NO1450/71A NO145071A NO135173B NO 135173 B NO135173 B NO 135173B NO 1450/71 A NO1450/71 A NO 1450/71A NO 145071 A NO145071 A NO 145071A NO 135173 B NO135173 B NO 135173B
- Authority
- NO
- Norway
- Prior art keywords
- benzodiazepine
- phenyl
- chloro
- trifluoromethyl
- recrystallized
- Prior art date
Links
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- -1 nitro, amino Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 239000012965 benzophenone Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 229940049706 benzodiazepine Drugs 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229940024874 benzophenone Drugs 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical class NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 2
- OYOUQHVDCKOOAL-UHFFFAOYSA-N 7-Aminonitrazepam Chemical compound C12=CC(N)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 OYOUQHVDCKOOAL-UHFFFAOYSA-N 0.000 description 2
- PEACRWGRSQUWBX-UHFFFAOYSA-N 7-methoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(OC)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 PEACRWGRSQUWBX-UHFFFAOYSA-N 0.000 description 2
- 101100520142 Caenorhabditis elegans pin-2 gene Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 2
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-UHFFFAOYSA-N 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NTVANYIWXRUGQR-UHFFFAOYSA-N 5-(4-chlorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C1=CC(Cl)=CC=C1C1=NCC(=O)NC2=CC=CC=C12 NTVANYIWXRUGQR-UHFFFAOYSA-N 0.000 description 1
- IVUAAOBNUNMJQC-UHFFFAOYSA-N 5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical class C12=CC=CC=C2NC(=O)CN=C1C1=CC=CC=C1 IVUAAOBNUNMJQC-UHFFFAOYSA-N 0.000 description 1
- AOJRGBWRJGTLDT-UHFFFAOYSA-N 5-phenyl-8-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C=1C(C(F)(F)F)=CC=C2C=1NC(=O)CN=C2C1=CC=CC=C1 AOJRGBWRJGTLDT-UHFFFAOYSA-N 0.000 description 1
- LODQZIQLZDHYJG-UHFFFAOYSA-N 7,9-dichloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(Cl)=CC(Cl)=C2NC(=O)CN=C1C1=CC=CC=C1 LODQZIQLZDHYJG-UHFFFAOYSA-N 0.000 description 1
- JHTJXLGLYZQIGI-UHFFFAOYSA-N 7-Acetamidonitrazepam Chemical compound C12=CC(NC(=O)C)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 JHTJXLGLYZQIGI-UHFFFAOYSA-N 0.000 description 1
- KMADJPBGARDOAO-UHFFFAOYSA-N 7-bromo-5-(2-fluorophenyl)-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1CC(=O)N(C)C2=CC=C(Br)C=C2C=1C1=CC=CC=C1F KMADJPBGARDOAO-UHFFFAOYSA-N 0.000 description 1
- KVXRLJHLTJKYKB-UHFFFAOYSA-N 7-bromo-5-(4-methylphenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C1=CC(C)=CC=C1C1=NCC(=O)NC2=CC=C(Br)C=C12 KVXRLJHLTJKYKB-UHFFFAOYSA-N 0.000 description 1
- SRDIBKOFJZSMMA-UHFFFAOYSA-N 7-bromo-8-methoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C1=2C=C(Br)C(OC)=CC=2NC(=O)CN=C1C1=CC=CC=C1 SRDIBKOFJZSMMA-UHFFFAOYSA-N 0.000 description 1
- DOGMLEAYMUQBTO-UHFFFAOYSA-N 7-chloro-5-(2-hydroxyphenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound ClC=1C=CC2=C(C(=NCC(N2)=O)C2=C(C=CC=C2)O)C1 DOGMLEAYMUQBTO-UHFFFAOYSA-N 0.000 description 1
- VMRHOEBUTQIEKP-UHFFFAOYSA-N 7-chloro-5-(2-methoxyphenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound COC1=CC=CC=C1C1=NCC(=O)NC2=CC=C(Cl)C=C12 VMRHOEBUTQIEKP-UHFFFAOYSA-N 0.000 description 1
- PLSKGUKSIDTEPG-UHFFFAOYSA-N 7-chloro-5-(2-methoxyphenyl)-1-methyl-3H-1,4-benzodiazepin-2-one Chemical compound COC1=C(C=CC=C1)C1=NCC(=O)N(C)C2=CC=C(Cl)C=C12 PLSKGUKSIDTEPG-UHFFFAOYSA-N 0.000 description 1
- AOOWAUAQVUYDCR-UHFFFAOYSA-N 7-chloro-5-(2-methylphenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound CC1=CC=CC=C1C1=NCC(=O)NC2=CC=C(Cl)C=C12 AOOWAUAQVUYDCR-UHFFFAOYSA-N 0.000 description 1
- JPSGKFVCUQLFJS-UHFFFAOYSA-N 7-chloro-5-(3-methoxyphenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound COC1=CC=CC(C=2C3=CC(Cl)=CC=C3NC(=O)CN=2)=C1 JPSGKFVCUQLFJS-UHFFFAOYSA-N 0.000 description 1
- BWQOGLAANRWTBZ-UHFFFAOYSA-N 7-chloro-5-(4-methoxyphenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C1=CC(OC)=CC=C1C1=NCC(=O)NC2=CC=C(Cl)C=C12 BWQOGLAANRWTBZ-UHFFFAOYSA-N 0.000 description 1
- CWAPDOCJCFWNIE-UHFFFAOYSA-N 7-hydroxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(O)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 CWAPDOCJCFWNIE-UHFFFAOYSA-N 0.000 description 1
- ZZLQGKUTUGIQNL-UHFFFAOYSA-N 7-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(C)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 ZZLQGKUTUGIQNL-UHFFFAOYSA-N 0.000 description 1
- PSRFZVMHJDITLA-UHFFFAOYSA-N 7-methylsulfinyl-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC([S+]([O-])C)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 PSRFZVMHJDITLA-UHFFFAOYSA-N 0.000 description 1
- RXCDCVYRSFPGHQ-UHFFFAOYSA-N 7-methylsulfonyl-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(S(=O)(=O)C)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 RXCDCVYRSFPGHQ-UHFFFAOYSA-N 0.000 description 1
- ZQNMREXZDXVUPB-UHFFFAOYSA-N 8-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C=1C(Cl)=CC=C2C=1NC(=O)CN=C2C1=CC=CC=C1 ZQNMREXZDXVUPB-UHFFFAOYSA-N 0.000 description 1
- OGDLFFYXUKTNDD-UHFFFAOYSA-N 8-methoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C=1C(OC)=CC=C2C=1NC(=O)CN=C2C1=CC=CC=C1 OGDLFFYXUKTNDD-UHFFFAOYSA-N 0.000 description 1
- NOJVFPSKPFOJHX-UHFFFAOYSA-N 8-nitro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C=1C([N+](=O)[O-])=CC=C2C=1NC(=O)CN=C2C1=CC=CC=C1 NOJVFPSKPFOJHX-UHFFFAOYSA-N 0.000 description 1
- NUXRLDCCKDXYCK-UHFFFAOYSA-N 9-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound ClC1=CC=CC2=C1NC(=O)CN=C2C1=CC=CC=C1 NUXRLDCCKDXYCK-UHFFFAOYSA-N 0.000 description 1
- YYSSSENOSHKUEM-UHFFFAOYSA-N 9-nitro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound [O-][N+](=O)C1=CC=CC2=C1NC(=O)CN=C2C1=CC=CC=C1 YYSSSENOSHKUEM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- HVVKOBYMMJCFSX-UHFFFAOYSA-N [2-(phenylmethoxycarbonylamino)acetyl] 2-(phenylmethoxycarbonylamino)acetate Chemical compound C=1C=CC=CC=1COC(=O)NCC(=O)OC(=O)CNC(=O)OCC1=CC=CC=C1 HVVKOBYMMJCFSX-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- KVDNWGDSNIDQLB-UHFFFAOYSA-N benzyl n-[2-(2-benzoyl-4-chloroanilino)-2-oxoethyl]carbamate Chemical compound C=1C=CC=CC=1C(=O)C1=CC(Cl)=CC=C1NC(=O)CNC(=O)OCC1=CC=CC=C1 KVDNWGDSNIDQLB-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical class [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- VPAYQWRBBOGGPY-UHFFFAOYSA-N diclazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1Cl VPAYQWRBBOGGPY-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ZRKDDZBVSZLOFS-UHFFFAOYSA-N flubromazepam Chemical compound FC1=CC=CC=C1C1=NCC(=O)NC2=CC=C(Br)C=C12 ZRKDDZBVSZLOFS-UHFFFAOYSA-N 0.000 description 1
- ROYOYTLGDLIGBX-UHFFFAOYSA-N fludiazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F ROYOYTLGDLIGBX-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- GWUSZQUVEVMBPI-UHFFFAOYSA-N nimetazepam Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1 GWUSZQUVEVMBPI-UHFFFAOYSA-N 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- AKPLHCDWDRPJGD-UHFFFAOYSA-N nordazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 AKPLHCDWDRPJGD-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- UUBMOUNXQFMBQF-UHFFFAOYSA-N ro5-2904 Chemical compound C12=CC(C(F)(F)F)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 UUBMOUNXQFMBQF-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B35/00—Supplying, feeding, arranging or orientating articles to be packaged
- B65B35/30—Arranging and feeding articles in groups
- B65B35/50—Stacking one article, or group of articles, upon another before packaging
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B25/00—Packaging other articles presenting special problems
- B65B25/14—Packaging paper or like sheets, envelopes, or newspapers, in flat, folded, or rolled form
- B65B25/145—Packaging paper or like sheets, envelopes, or newspapers, in flat, folded, or rolled form packaging folded articles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65H—HANDLING THIN OR FILAMENTARY MATERIAL, e.g. SHEETS, WEBS, CABLES
- B65H31/00—Pile receivers
- B65H31/34—Apparatus for squaring-up piled articles
- B65H31/38—Apparatus for vibrating or knocking the pile during piling
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65H—HANDLING THIN OR FILAMENTARY MATERIAL, e.g. SHEETS, WEBS, CABLES
- B65H2701/00—Handled material; Storage means
- B65H2701/10—Handled articles or webs
- B65H2701/17—Nature of material
- B65H2701/176—Cardboard
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Making Paper Articles (AREA)
- Supplying Of Containers To The Packaging Station (AREA)
- Container Filling Or Packaging Operations (AREA)
- Attitude Control For Articles On Conveyors (AREA)
- Closing Of Containers (AREA)
- Pile Receivers (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Discharge By Other Means (AREA)
Description
Fremgangsmåte for fremstilling av hittil ukjente terapeutisk virksomme benzodiazepinderivater.
Nærværende oppfinnelse vedrører en
fremgangsmåte for fremstilling av 5-fe-nyl-3H-l,4-benzodiazepin-2(1H)-oner. Dis-se er verdifulle terapeutiske midler og kan finne anvendelse som anticonvulsiva, mus-kelrelaxantia og sedativa. De kan admini-streres oralt eller parenteralt i enhver van-lig farmasøytisk form, f. eks. som oppløs-ning, suspensjon, kapsel, tabletter, suppo-sitorier eller lignende.
De ifølge oppfinnelsen fremstillbare
forbindelser tilsvarer den generelle formel
hvor R, betyr hydrogen eller lavere alkyl og R, hydrogen, lavere alkyl, halogen, hydroxy, lavere alkoxy eller trifluormethyl og Ri| og R4 hydrogen, lavere alkyl, halogen, hydroxy, lavere alkoxy, trifluormethyl, ni-tro, amino, lavere alkanoylamino, lavere alkylthio, lavere alkylsulfinyl eller lavere alkylsulfonyl. Fremgangsmåten ifølge oppfinnelsen består i at man omsetter et keton med den generelle formel
hvor R,, R,, R,, og R4 har den samme be-tydning som ovenfor angitt,
med en halogenhydrogensyre, fortrinnsvis bromhydrogensyre, i nærvær av eddiksyre, bringer reaksjonsproduktet på en pH-verdi på minst 7 og isolerer det dannede benzodiazepin.
Behandlingen av et 2-carbobenzoxy-glycylamido-benzo-fenon med en halogenhydrogensyre i nærvær av eddiksyre bevir-ker den selektive spaltning av en av amid-bindingene i carbobenzoxy-glycylamido-kjeden, slik at en glycylamido-forbindelse med den generelle formel
oppstår.
Fortrinnsvis anvender man ved fremgangsmåten ifølge oppfinnelsen bromhydrogensyre som halogenhydrogensyre. An-dre halogenhydrogensyrer, som klorhydro-gensyre, kan imidlertid likeledes anvendes. Reaksjonen kan gjennomføres enten i van-dig eller i vannfritt medium, såvel som enten ved romtemperatur eller temperaturer over eller under romtemperaturen.
Den dannede glycylamido-forbindelse cycliserer etter at man har bragt pH-verdien på minst 7, dvs. minst til nøytralitet.
Cycliseringen inntrer allerede ved henstand ved romtemperatur. En oppvarmning begunstiger dog cycliseringen. De for høy-ning av pH-verdien egnede alkalier kan enten avlede seg fra sterke eller fra svake baser, f. eks. ammoniakk, alkalihydroxyder, som natriumhydroxyd eller kaliumhydr-oxyd. j ordalkalihydroxyder, som kalsium-hydroxyder og lignende.
5-fenyl-3H-l,4-benzodiazepin-2(lH)-oner kan utvinnes direkte fra 2-carboben-zoxyglycylamido-benzofenoner uten isole-ring av 2-glycylamido-benzofenon-mel-lomproduktet, idet det rå mellomprodukt, som inneholder sistnevnte forbindelse, inn-stilles alkalisk.
Utgangsmaterialene for fremgangsmåten ifølge oppfinnelsen dvs. forbindelsene med den foranstående formel II er nye. De kan oppnåes ved innføring av carbobenz-oxyglycyl-resten i de tilsvarende 2-amino-benzofenoner. Egnede midler for innføring av denne rest er forbindelser, som carbobenzoxyglycin, carbobenzoxy-glycinanhy-rlrid og carbobenzoxyglycylhalogenider. Denne reaksjon kan gjennomføres ved romtemperatur eller ved temperaturer over eller under romtemperatur. Fortrinnsvis om-detter man da carbobenzoxyglycin med et ?-aminobenzofenon i nærvær av et N,N'-rUsubstituert carbodiimid. Det som konden-sasionsmiddel anvendte N,N'-disubstituerte carbodiimid kan oppnåes på forskjellige måter. Hvis man anvender egnede substi-tuerte carbodiimider, f. eks. N,N'-dicyclo-hexylcarbodiimid, får man urinstoffderi-vater som biprodukter, som lett kan skilles fra reaksjonsproduktet. Reaksjonen kan gjennomføres f. eks. ved en temperatur mellom 0° og 50, fortrinnsvis ved romtemperatur eller en noe derover liggende temperatur. Fortrinnsvis anvender man et opp-løsningsmiddel for reaksjonen. Som sådant egner seg f. eks. organiske oppløsningcmid-ler, som methylenklorid, kloroform, dioxan, tetrahydrofuran, dimethylformamid, ace-tonitril og lignende eller også vann.
Omdannelsen av 2-amino-benzofenoner til 2-glycylamido-benzofenoner over
innføringen av en carbobenzoxyglycylrest og etterfølgende behandling med en halogenhydrogensyre i nærvær av eddiksyre er <p>n virkningsfull måte for denne overføring,
•om forløper med gode utbytter.
De følgende eksempler anskueliggjør fremgangsmåten ifølge oppfinnelsen. Alle temperaturer er angitt i Celsiusgrader.
Eksempel 1.
En oppløsning av 2,25 g (2-benzoyl-4-trifluormethyl-fenyl-carbamoylmethyl)-carbaminsyre-benzylester i 15 ml 20 pst. bromhydrogensyre i eddiksyre røres i 25
minutter ved romtemperatur. Det erholdte
2-glycylamido-5-trifluormethyl-benzofe-non isoleres ikke. Reaksjonsblandingen til-dettes 200 ml vannfri ether. Man tilsetter derpå vann og avkjøler reaksjonsblandingen i et isbad og innstiller svakt alkalisk med ammoniakk. Det organiske sjikt skilles fra, vaskes med vann, tørkes over natriumsulfat og konsentreres til tørrhet i vakuum. Resten oppvarmes under tilbakeløp i 3 ti-mer i 30 ml pyridin. Etter fjerning av opp-løsningsmidlet i vakuum omkrystalliseres resten fra hexan, hvorved man får 7-trifluormethyl-5-fenyl-3H-l,4-benzodiazepin-2(lH)-on.
Utgangsmaterialet kan fremstilles som følger: Se eksempel 1 i patent nr. 104 964.
Eksempel 2.
i3n oppløsning av 3,0 g (2-benzoyl-4-methoxy-fenylcarbamovlmethyl)-carbaminsyre-benzylester i 30 ml 20 pst. bromhydrogensyre i eddiksyre røres 30 minutter ved romtemperatur. Man tilsetter langsomt 175 ml vannfri ether, hvorpå et gummiaktig bunnfall skiller seg ut. Den ovenstående væske helles fra og resten fordeles mellom vann og ether. Det erholdte 2-glycylamido-5-methoxy-benzofenon isoleres ikke. Etter avkjøling i is nøytraliseres reaksionsblan-h i ngen med ammoniakk. Ethersjiktet skilles 'ra, tørkes over natriumsulfat og bringes
til tørrhet i vakuum. Resten krystalliserer ved henstand. Ved omkrystallisasjon fra benzol/hexan får man 7-methoxy-5-fenyl-3H-l,4-benzodiazepin-2(lH)-on.
Eksempel 3.
En oppløsning av 3,1 g (2-benzoyl-4-klor-fenylcarbamoylmethyl)-carbaminsyre-benzylester i 30 ml 20 pst. bromhydrogensyre i iseddik røres i 45 minutter ved romtemperatur. Etter tilsetning av 175 ml vannfri ether skiller et gummiaktig produkt seg ut. Etter noen minutter dekanteres etheroppløsningen. Det erholdte 5-klor-2-glycylamido-benzofenon isoleres ikke. Man tilsetter 155 ml ether til resten og etter av-kjøling i et isbad tilsettes 10 pst.'ig natron-lut inntil reaksjonsblandingen er alkalisk. Etheroppløsningen skilles fra, vaskes to ganger med vann og tørkes over natriumsulfat. Etter filtrering dampes etheropp-løsningen inn til tørrhet i vakuum. Resten av 7-klor-5-fenyl-3H-l,4-benzodiazepin-2 (lH)-on krystalliserer man fra benzol.
På analog måte som ovenfor beskrevet kan følgende sammensetninger fremstilles: 7-methyl-5-fenyl-3H-l,4-benzodiazepin-
2(lH)-on, omkrystallisert fra aceton, farveløse prismer, smp. 209—210°. 7,9-dimethyl-5-fenyl-3H-l,4-benzodiaze
pin-2(lH)-on, omkrystallisert fra aceton, smp. 210—211°. 7.9-diklor-5-fenyl-3H-l,4-benzodiazepin-2(lH)-on, omkrystallisert fra aceton, smp.
207—208°. 7-klor-5-(4-klorfenyl)-3H-l,4-benzodia
zepin-2(lH)-on, omkrystallisert fra alkohol, smp. 247—248°. 7- brom-5-(p-tolyl)-3H-l,4-benzodiazepin-2(lH)-on, omkrystallisert fra aceton, smp. 239—240°. 7,8-dimethyl-5-fenyl-3H-l,4-benzodiaze
pin-2(lH)-on, omkrystallisert fra methanol, farveløse prismer, smp. 255— 256°. 8- trifluormethyl-5-fenyl-3H-l,4-benzodiazepin-2(lH)-on, smp. 180—183°, omkrystallisasjon fra benzen, farveløse nåler, smp. 184—186°. 7-methylsulfonyl-5-fenyl-3H-l,4-benzo
diazepin-2 (1H) -on, omkrystallisasjon fra aceton-Skellysolve B, gule nåler, smp. 256—258°. 5- (p-klorf enyl) -3H-l,4-benzodiazepin-2(lH)-on, omkrystallisert fra ethanol, hvite plater, smp. 262—263°. 7-nitro-5-fenyl-3H-l,4-benzodiazepin-2
(lH)-on, omkrystallisert fra en blanding av 1000 ml alkohol og 50 ml me-
thylen klorid, hvite prismer, smp. 224 —225°.
7-klor-l-methyl-5-fenyl-3H-l,4-benzo
diazepin-2- (1H) -on, omkrystallisert fra ether, smp. 123—124°.
l-methyl-7-klor-5-(2-klorfenyl)-3H-l,4-
benzodiazepin-2(lH)-on, smp. 135— 138°.
l-methyl-7-klor-5-(o-tolyl)-3H-l,4-ben
zodiazepin-2(lH)-on, smp. 137—139°.
l-methyl-5-fenyl-3H-l,4-benzodiazepin-
2(lH)-on, hvite prismer, smp. 153,5 — 155,5°.
l-methyl-7-nitro-5-fenyl-3H-l,4-benzodiazepin-2(lH)-on, nåler, smp. 156— 157°.
7-klor-l-ethyl-5-fenyl-3H-l,4-benzodia
zepin-2(lH)-on, farveløse prismer, smp. 127—128°.
7-klor-5-(2-methoxyfenyl)-l-methyl-3H-
l,4-benzodiazepin-2(lH)-on, smp. 161— 162°.
7-klor-l-methyl-5-(2-fluorfenyl)-3H-'l,4-
benzodiazepin-2-on, olje som ikke kan bli frembragt til å krystallisere. 7- brom-l-methyl-5-(2-fluorfenyl)-3H-l,4-benzodiazepin-2-on, farveløse nåler, smp. 132—132,5°. 8- klor-5-fenyl-3H-l,4-benzodiazepin-2(lH)-on, omkrystallisasjon fra aceton, hexagonale prismer, smp. 214— 215°. 5 (4-trif luormethyl-f enyl) -3H-1,4-benzodiazepin-2 (1H) -on, omkrystallisasj on fra aceton-benzen, farveløse nåler, smp. 219—220°.
5-(3-trifluormethyl-fenyl)-3H-l,4-ben
zodiazepin-2- (1H) -on, omkrystallisert fra aceton-benzen, farveløs, flate nåler, smp. 204—205°. 9- klor-5-fenyl-3H-l,4-benzodiazepin-2 (lH)-on, omkrystallisert fra benzen-hexan, smp. 174,5—176,5°.
7-klor-5-(2-klorfenyl)-3H-l,4-benzodia
zepin-2(lH)-on, omkrystallisert fra methanol, smp. 199—201°. 7- klor-5- (o-tolyl) -3H-l,4-benzodiazepin-2(lH)-on, omkrystallisert fra ether, smp. 180—181°.
7,8-dimethyl-5-(2-klorfenyl)-3H-l,4-ben
zodiazepin-2 (1H) -on, omkrystallisasj on fra fortynnet alkohol, farveløse prismer, smp. 259—260°. 8- methoxy-5-fenyl-3H-l,4-benzodiazepin-2(lH)-on, omkrystallisert fra aceton-hexan, smp. 186—188°.
7-methoxy-5-fenyl-3H-l,4-benzodiazepin-
2(lH)-on, omkrystallisert fra benzen-hexan, smp. 217—218°.
7-hydroxy-5-fenyl-3H-l,4-benzodiazepin-
2(lH)-on, omkrystallisert fra acetoni-tril, smp. 289—291°.
7-klor-5-(2-fluorfenyl)-3H-l,4-benzodia
zepin-2(lH)-on, omkrystallisert fra en blanding av aceton og hexan, hvite nåler, smp. 205—206°.
7-klor-5- (3-f luorfenyl) -3H-l,4-benzodia
zepin-2(lH)-on, omkrystallisert fra aceton, hvite prismer, smp. 200—201°. 7- brom-5-(2-fluorfenyl)-3H-l,4-benzodiazepin-2(lH)-on, omkrystallisert fra aceon-petroleum ether, hvite nåler, smp. 187—188°. 8- nitro-5-fenyl-3H-l,4-benzodiazepin-2 (lH)-on, farveløse prismer smp. 252° (spaltning).
7-methylsulfinyl-5-fenyl-3H-l,4-benzo
diazepin-2(lH)-on, gule nåler, smp. 254° (spaltning).
2',7-bis-(trifluormethyl)-5-fenyl-3H-
l,4-benzodiazepin-2(1H)-on, farveløse plater, smp. 226—227°.
7-brom-8-methoxy-5-fenyl-3H-l,4-benzo
diazepin-2(lH)-on, smp. 260,5—261,5°.
7-klor-5-(2-methoxyfenyl)-3H-l,4-benzo
diazepin-2(lH)-on, smp. 205,5—206,5°.
7-klor-5- (2-hydroxyf enyl) -3H-l,4-benzo
diazepin-2(lH)-on, smp. 286—288°.
7-klor-5-(3-methoxyfenyl)-3H-l,4-benzo
diazepin-2(lH)-on, smp. 219—221°.
7-klor-5- (4-methoxyf enyl) -3H-1,4-benzo
diazepin-2(lH)-on, smp. 212—214°. 9- nitro-5-fenyl-3H-l,4-benzodiazepin-2
(lH)-on, gule nåler, smp. 144—145°.
7-amino-5-f enyl-3H-1,4-benzodiazepin-
2(lH)-on, fargeløse prismer fra ace-tonitril/ethanol (3 : 1), smeltepunkt 236—239° C. Acetylering av 7-amino-5-fenyl-3H-l,4-
benzodiazepin-2(lH)-on med acetan-hydrid i pyridin (1 time ved 40° C) gir: 7-acetamido-5-fenyl-3H-l,4-benzodiazepin-2(lH)-on, hvite nåler, smeltepunkt 278—279°.
Claims (2)
1. Fremgangsmåte for fremstilling av hittil ukjente terapeutisk virksomme ben-
zodiazepinderivater med den generelle formel
hvor Ri betyr hydrogen eller lavere alkyl og R2 hydrogen, lavere alkyl, halogen, hydroxy, lavere alkoxy og trifluormethyl og R3 og R-t hydrogen, lavere alkyl, halogen, hydroxy, lavere alkoxy, trifluormethyl, ni-tro, amino, lavere alkanoylamino, lavere alkylthio, lavere alkylsulfinyl eller lavere alkylsulfonyl,karakterisert ved at man omsetter et keton med den generelle formel hvor Ri, R2, R3 og R* har den samme be-tydning som ovenfor angitt, med en halogenhydrogensyre, fortrinnsvis bromhydrogensyre, i nærvær av eddiksyre, bringer re-aksj onsproduktet på en pH-verdi på minst 7 og isolerer det dannete benzodiazepin.
2. Fremgangsmåte ifølge påstand 1, karakterisert ved at man anvender 5-klor- eller 5-trifluormethyl-2-carbobenz-oxyglycylamido-benzofenon som utgangs-materiale.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO754276A NO754276L (no) | 1970-04-20 | 1975-12-16 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3006970A | 1970-04-20 | 1970-04-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO135173B true NO135173B (no) | 1976-11-15 |
| NO135173C NO135173C (no) | 1977-02-23 |
Family
ID=21852342
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1450/71A NO135173C (no) | 1970-04-20 | 1971-04-19 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US3656271A (no) |
| JP (1) | JPS5320914B2 (no) |
| AT (1) | AT327102B (no) |
| BE (1) | BE765957A (no) |
| CA (1) | CA948603A (no) |
| CH (2) | CH544028A (no) |
| DE (1) | DE2118998A1 (no) |
| FR (1) | FR2089885A5 (no) |
| GB (2) | GB1351182A (no) |
| LU (1) | LU63014A1 (no) |
| NL (1) | NL7105253A (no) |
| NO (1) | NO135173C (no) |
| SE (2) | SE384831B (no) |
| ZA (1) | ZA712478B (no) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE789625A (fr) * | 1971-11-12 | 1973-02-01 | Fmc Corp | Procede et appareil pour emballer des articles flexibles |
| US3805482A (en) * | 1971-12-29 | 1974-04-23 | Union Carbide Corp | Packaging machine |
| US3919827A (en) * | 1974-11-26 | 1975-11-18 | Union Carbide Corp | Method and apparatus for packaging large size bags in cartons |
| DE2908943A1 (de) * | 1979-03-07 | 1980-09-11 | Hans Lehmacher | Vorrichtung zum einbringen eines losen flachstapels in einen verpackungskarton |
| DE2939310A1 (de) * | 1979-09-28 | 1981-04-16 | Bielomatik Leuze Gmbh + Co, 7442 Neuffen | Verfahren und vorrichtung tum verpacken von blattstapeln |
| US4472923A (en) * | 1981-08-06 | 1984-09-25 | Mobil Oil Corporation | Carton loader |
| US4751807A (en) * | 1987-04-17 | 1988-06-21 | C. G. Bretting Manufacturing Co. | Automatic transfer system |
| US5375393A (en) * | 1993-04-07 | 1994-12-27 | Automated Solutions, Inc. | Bag folding system |
| IT1282482B1 (it) * | 1995-04-04 | 1998-03-23 | Tecnomeccanica Srl | Metodo per ripiegare a soffietto uno spezzone tubolare di carta-filtro a forma allungata contenente un prodotto da infusione. ivi disposto |
| US6322315B1 (en) | 1999-10-04 | 2001-11-27 | C.G. Bretting Manufacturing Company, Inc. | Web stacker and separator apparatus and method |
| US6254522B1 (en) | 1999-10-05 | 2001-07-03 | C. G. Bretting Manufacturing Co., Inc. | Separator finger apparatus |
| US6832886B2 (en) | 2001-07-27 | 2004-12-21 | C. G. Bretting Manufacturing Co., Inc. | Apparatus and method for stacking sheets discharged from a starwheel assembly |
| US7470102B2 (en) * | 2001-07-27 | 2008-12-30 | C.G. Bretting Manufacturing Co., Inc. | Apparatus and method for insertion of separating means into a forming stack of sheets discharged from a starwheel assembly |
| US6732492B2 (en) * | 2002-07-23 | 2004-05-11 | Potlatch Corporation | Methods of packaging paper products |
| US6912826B2 (en) * | 2002-10-07 | 2005-07-05 | Zoran Momich | Carrier loading cartoner |
| US6877740B2 (en) * | 2003-07-30 | 2005-04-12 | C.G. Bretting Manufacturing Company, Inc. | Starwheel feed apparatus and method |
| US7497064B2 (en) * | 2004-10-01 | 2009-03-03 | Zoran Momich | Vertical cartoner |
| US7073310B1 (en) * | 2004-12-27 | 2006-07-11 | Kimberly-Clark Worldwide, Inc. | Flexible carton loading apparatus |
| JP5948900B2 (ja) | 2012-01-26 | 2016-07-06 | ブラザー工業株式会社 | 記録媒体後処理装置、該記録媒体後処理装置を備えたプリンタユニット、記録媒体後処理方法及び記録媒体後処理プログラム |
| CN105452108B (zh) * | 2013-08-09 | 2017-06-13 | 户谷技研工业株式会社 | 片状产品包装装置 |
| CN108583957A (zh) * | 2018-06-25 | 2018-09-28 | 歆坤智能装备（昆山）有限公司 | 抓手及包装系统 |
| CN112590297B (zh) * | 2020-12-10 | 2022-06-07 | 合肥派腾智能设备科技有限公司 | 一种高效率纸箱开箱机及其工作方法 |
| CN115231075B (zh) * | 2022-08-09 | 2024-07-09 | 天长市天粤塑胶有限公司 | 编织袋加工用切断打包台 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3053024A (en) * | 1961-04-07 | 1962-09-11 | Wexler Joseph | Machine for folding and wrapping paper bundles |
| US3309834A (en) * | 1963-10-04 | 1967-03-21 | Brown Co | Dispensing carton suitable for plastic bags and the like |
| US3481099A (en) * | 1968-09-09 | 1969-12-02 | Colgate Palmolive Co | Packaging apparatus and method |
-
1970
- 1970-04-20 US US30069A patent/US3656271A/en not_active Expired - Lifetime
-
1971
- 1971-04-16 CA CA110,508A patent/CA948603A/en not_active Expired
- 1971-04-19 GB GB5287272A patent/GB1351182A/en not_active Expired
- 1971-04-19 GB GB996671*[A patent/GB1351181A/en not_active Expired
- 1971-04-19 NL NL7105253A patent/NL7105253A/xx unknown
- 1971-04-19 FR FR7113825A patent/FR2089885A5/fr not_active Expired
- 1971-04-19 NO NO1450/71A patent/NO135173C/no unknown
- 1971-04-19 BE BE765957A patent/BE765957A/xx unknown
- 1971-04-19 ZA ZA712478A patent/ZA712478B/xx unknown
- 1971-04-19 SE SE7105053A patent/SE384831B/xx unknown
- 1971-04-19 CH CH814673A patent/CH544028A/fr not_active IP Right Cessation
- 1971-04-19 AT AT332971A patent/AT327102B/de not_active IP Right Cessation
- 1971-04-19 LU LU63014D patent/LU63014A1/xx unknown
- 1971-04-19 CH CH565771A patent/CH542092A/fr not_active IP Right Cessation
- 1971-04-20 DE DE19712118998 patent/DE2118998A1/de active Pending
-
1974
- 1974-09-30 SE SE7412294A patent/SE7412294L/xx unknown
-
1975
- 1975-11-08 JP JP13461075A patent/JPS5320914B2/ja not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| BE765957A (fr) | 1971-10-19 |
| ZA712478B (en) | 1972-01-26 |
| SE384831B (sv) | 1976-05-24 |
| JPS5169874A (no) | 1976-06-16 |
| CH542092A (fr) | 1973-09-30 |
| JPS5320914B2 (no) | 1978-06-29 |
| SE7412294L (no) | 1974-09-30 |
| FR2089885A5 (no) | 1972-01-07 |
| CH544028A (fr) | 1973-12-28 |
| ATA332971A (de) | 1975-03-15 |
| CA948603A (en) | 1974-06-04 |
| AT327102B (de) | 1976-01-12 |
| US3656271A (en) | 1972-04-18 |
| NO135173C (no) | 1977-02-23 |
| GB1351181A (en) | 1974-04-24 |
| DE2118998A1 (de) | 1971-12-02 |
| NL7105253A (no) | 1971-10-22 |
| GB1351182A (en) | 1974-04-24 |
| LU63014A1 (no) | 1972-03-02 |
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