NO143785B - PROCEDURE FOR HEAT EXTRACTION OF ALUMINUM ALLOYS WITH HIGH STRENGTH - Google Patents
PROCEDURE FOR HEAT EXTRACTION OF ALUMINUM ALLOYS WITH HIGH STRENGTH Download PDFInfo
- Publication number
- NO143785B NO143785B NO782585A NO782585A NO143785B NO 143785 B NO143785 B NO 143785B NO 782585 A NO782585 A NO 782585A NO 782585 A NO782585 A NO 782585A NO 143785 B NO143785 B NO 143785B
- Authority
- NO
- Norway
- Prior art keywords
- compounds
- anhydride
- acid
- lower alkyl
- phenyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 238000000605 extraction Methods 0.000 title description 2
- 229910000838 Al alloy Inorganic materials 0.000 title 1
- -1 3,4-methylenedioxyphenyl Chemical group 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 4
- SSSYOIPHXANRMO-UHFFFAOYSA-N 4h-benzo[a]quinolizine Chemical class C1=CC=C2C3=CC=CCN3C=CC2=C1 SSSYOIPHXANRMO-UHFFFAOYSA-N 0.000 claims description 3
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 150000008064 anhydrides Chemical class 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 150000003951 lactams Chemical class 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical group O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- WEAXKMDHHDNXKM-UHFFFAOYSA-N 1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one Chemical class C1=CC=C2C3CCCC(=O)N3CCC2=C1 WEAXKMDHHDNXKM-UHFFFAOYSA-N 0.000 description 2
- DNWAYXNMUKHONN-UHFFFAOYSA-N 4-phenyloxane-2,6-dione Chemical compound C1C(=O)OC(=O)CC1C1=CC=CC=C1 DNWAYXNMUKHONN-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 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
- 239000008096 xylene Substances 0.000 description 2
- RHVCCFKUACIGSM-UHFFFAOYSA-N 2,3,4,6,7,11b-hexahydro-1h-benzo[a]quinolizine Chemical compound C1CC2=CC=CC=C2C2N1CCCC2 RHVCCFKUACIGSM-UHFFFAOYSA-N 0.000 description 1
- GIRXKOJKVUCAIB-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)acetamide Chemical compound NC(=O)CC1=CC=C2OCOC2=C1 GIRXKOJKVUCAIB-UHFFFAOYSA-N 0.000 description 1
- WSWPCNMLEVZGSM-UHFFFAOYSA-N 2-(2-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC=C1CCN WSWPCNMLEVZGSM-UHFFFAOYSA-N 0.000 description 1
- WJBMRZAHTUFBGE-UHFFFAOYSA-N 2-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC(CCN)=C1 WJBMRZAHTUFBGE-UHFFFAOYSA-N 0.000 description 1
- GMZAHGCTRHHQKR-UHFFFAOYSA-N 2-(4-chlorophenyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1h-benzo[a]quinolizine Chemical compound C1C2C=3C=C(OC)C(OC)=CC=3CCN2CCC1C1=CC=C(Cl)C=C1 GMZAHGCTRHHQKR-UHFFFAOYSA-N 0.000 description 1
- OQIMYLCOTAZDEZ-UHFFFAOYSA-N 2-(4-ethoxyphenyl)ethanamine Chemical compound CCOC1=CC=C(CCN)C=C1 OQIMYLCOTAZDEZ-UHFFFAOYSA-N 0.000 description 1
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical class COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 1
- FDGHDEZMPWGVQH-UHFFFAOYSA-N 3-(4-methylphenyl)pentanedioic acid Chemical compound CC1=CC=C(C(CC(O)=O)CC(O)=O)C=C1 FDGHDEZMPWGVQH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RZOKZOYSUCSPDF-UHFFFAOYSA-N 3-phenylpentanedioic acid Chemical compound OC(=O)CC(CC(O)=O)C1=CC=CC=C1 RZOKZOYSUCSPDF-UHFFFAOYSA-N 0.000 description 1
- UVYLEXYRTBDZNM-UHFFFAOYSA-N 4,4-diethyloxane-2,6-dione Chemical compound CCC1(CC)CC(=O)OC(=O)C1 UVYLEXYRTBDZNM-UHFFFAOYSA-N 0.000 description 1
- HIJQFTSZBHDYKW-UHFFFAOYSA-N 4,4-dimethyloxane-2,6-dione Chemical compound CC1(C)CC(=O)OC(=O)C1 HIJQFTSZBHDYKW-UHFFFAOYSA-N 0.000 description 1
- GUKUBPWCSDXSRK-UHFFFAOYSA-N 4-(3-chlorophenyl)oxane-2,6-dione Chemical compound ClC1=CC=CC(C2CC(=O)OC(=O)C2)=C1 GUKUBPWCSDXSRK-UHFFFAOYSA-N 0.000 description 1
- UVZKTNHKBFICNI-UHFFFAOYSA-N 4-(4-bromophenyl)oxane-2,6-dione Chemical compound C1=CC(Br)=CC=C1C1CC(=O)OC(=O)C1 UVZKTNHKBFICNI-UHFFFAOYSA-N 0.000 description 1
- BZPVATHCQGARAN-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-2,6-dione Chemical compound C1=CC(F)=CC=C1C1CC(=O)OC(=O)C1 BZPVATHCQGARAN-UHFFFAOYSA-N 0.000 description 1
- OPJADAOABCOMIC-UHFFFAOYSA-N 4-(4-methoxyphenyl)oxane-2,6-dione Chemical compound C1=CC(OC)=CC=C1C1CC(=O)OC(=O)C1 OPJADAOABCOMIC-UHFFFAOYSA-N 0.000 description 1
- IYPYPJZEUSLPNW-UHFFFAOYSA-N 4-(4-methylphenyl)oxane-2,6-dione Chemical compound C1=CC(C)=CC=C1C1CC(=O)OC(=O)C1 IYPYPJZEUSLPNW-UHFFFAOYSA-N 0.000 description 1
- PTGCUXZHDCRLEE-UHFFFAOYSA-N 4-(trifluoromethyl)oxane-2,6-dione Chemical compound FC(F)(F)C1CC(=O)OC(=O)C1 PTGCUXZHDCRLEE-UHFFFAOYSA-N 0.000 description 1
- GMZLJCJCIBNHIF-UHFFFAOYSA-N 4-benzyloxane-2,6-dione Chemical compound C1C(=O)OC(=O)CC1CC1=CC=CC=C1 GMZLJCJCIBNHIF-UHFFFAOYSA-N 0.000 description 1
- VSVZSLYJGKSCBI-UHFFFAOYSA-N 4-ethyl-4-methyloxane-2,6-dione Chemical compound CCC1(C)CC(=O)OC(=O)C1 VSVZSLYJGKSCBI-UHFFFAOYSA-N 0.000 description 1
- KACOZSYMGFIYND-UHFFFAOYSA-N 4-ethyl-4-phenyloxane-2,6-dione Chemical compound C=1C=CC=CC=1C1(CC)CC(=O)OC(=O)C1 KACOZSYMGFIYND-UHFFFAOYSA-N 0.000 description 1
- YIEQRBOBYGITMJ-UHFFFAOYSA-N 4-ethyloxane-2,6-dione Chemical compound CCC1CC(=O)OC(=O)C1 YIEQRBOBYGITMJ-UHFFFAOYSA-N 0.000 description 1
- LTPVSOCPYWDIFU-UHFFFAOYSA-N 4-methoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1 LTPVSOCPYWDIFU-UHFFFAOYSA-N 0.000 description 1
- CRQXSDWUENFLIJ-UHFFFAOYSA-N 4-methyl-4-phenyloxane-2,6-dione Chemical compound C=1C=CC=CC=1C1(C)CC(=O)OC(=O)C1 CRQXSDWUENFLIJ-UHFFFAOYSA-N 0.000 description 1
- MGICRVTUCPFQQZ-UHFFFAOYSA-N 4-methyloxane-2,6-dione Chemical compound CC1CC(=O)OC(=O)C1 MGICRVTUCPFQQZ-UHFFFAOYSA-N 0.000 description 1
- LNTKZYQUFRHQKA-UHFFFAOYSA-N 4-propyloxane-2,6-dione Chemical compound CCCC1CC(=O)OC(=O)C1 LNTKZYQUFRHQKA-UHFFFAOYSA-N 0.000 description 1
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 1
- 238000006407 Bischler-Napieralski reaction Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- MBYXEBXZARTUSS-QLWBXOBMSA-N Emetamine Natural products O(C)c1c(OC)cc2c(c(C[C@@H]3[C@H](CC)CN4[C@H](c5c(cc(OC)c(OC)c5)CC4)C3)ncc2)c1 MBYXEBXZARTUSS-QLWBXOBMSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- AUVVAXYIELKVAI-UHFFFAOYSA-N SJ000285215 Natural products N1CCC2=CC(OC)=C(OC)C=C2C1CC1CC2C3=CC(OC)=C(OC)C=C3CCN2CC1CC AUVVAXYIELKVAI-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- RKAOCDSWXMPAHH-UHFFFAOYSA-M [I-].C1=CC=C[N+]2=CC=C3C(=C12)C=CC=C3 Chemical compound [I-].C1=CC=C[N+]2=CC=C3C(=C12)C=CC=C3 RKAOCDSWXMPAHH-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000002908 adrenolytic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- AUVVAXYIELKVAI-CKBKHPSWSA-N emetine Chemical compound N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@@H]1CC AUVVAXYIELKVAI-CKBKHPSWSA-N 0.000 description 1
- 229960002694 emetine Drugs 0.000 description 1
- AUVVAXYIELKVAI-UWBTVBNJSA-N emetine Natural products N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@H]1CC AUVVAXYIELKVAI-UWBTVBNJSA-N 0.000 description 1
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000004800 hydroisoquinoline derivatives Chemical class 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 150000002669 lysines Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- RRIRDPSOCUCGBV-UHFFFAOYSA-N methylenedioxyphenethylamine Chemical compound NCCC1=CC=C2OCOC2=C1 RRIRDPSOCUCGBV-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B21—MECHANICAL METAL-WORKING WITHOUT ESSENTIALLY REMOVING MATERIAL; PUNCHING METAL
- B21C—MANUFACTURE OF METAL SHEETS, WIRE, RODS, TUBES OR PROFILES, OTHERWISE THAN BY ROLLING; AUXILIARY OPERATIONS USED IN CONNECTION WITH METAL-WORKING WITHOUT ESSENTIALLY REMOVING MATERIAL
- B21C23/00—Extruding metal; Impact extrusion
- B21C23/002—Extruding materials of special alloys so far as the composition of the alloy requires or permits special extruding methods of sequences
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22F—CHANGING THE PHYSICAL STRUCTURE OF NON-FERROUS METALS AND NON-FERROUS ALLOYS
- C22F1/00—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working
- C22F1/04—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working of aluminium or alloys based thereon
- C22F1/053—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working of aluminium or alloys based thereon of alloys with zinc as the next major constituent
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22F—CHANGING THE PHYSICAL STRUCTURE OF NON-FERROUS METALS AND NON-FERROUS ALLOYS
- C22F1/00—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working
- C22F1/04—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working of aluminium or alloys based thereon
- C22F1/057—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working of aluminium or alloys based thereon of alloys with copper as the next major constituent
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- Chemical & Material Sciences (AREA)
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- Crystallography & Structural Chemistry (AREA)
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- Metallurgy (AREA)
- Physics & Mathematics (AREA)
- Extrusion Of Metal (AREA)
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Description
Fremgangsmåte til fremstilling av terapeutisk aktive benzokinoliziner. Process for the preparation of therapeutically active benzoquinolizines.
Foreliggende oppfinnelse angår frem- The present invention relates to
stilling av terapeutisk aktive benzokinoli-zinderivater med den generelle formel position of therapeutically active benzoquinolizine derivatives of the general formula
hvori R, betyr lavere alkyl, trifluormetyl, wherein R, means lower alkyl, trifluoromethyl,
fenyl, halofenyl, (lavere alkyl)fenyl, (lave- phenyl, halophenyl, (lower alkyl)phenyl, (lower-
re alkoksy)fenyl, 3,4-metylendioksyfenyl re alkoxy)phenyl, 3,4-methylenedioxyphenyl
eller fenyl lavere alkyl, R., betyr hydrogen or phenyl lower alkyl, R., means hydrogen
eller lavere alkyl, R:l og R4 betyr hver hyd- or lower alkyl, R:1 and R4 each means hyd-
rogen eller lavere alkoksy og sammen er rogen or lower alkoxy and together are
R., og R4 metylendioksy samt deres syreaddisjonssalter og deres kvaternære ammoniumforbindelser. R., and R4 methylenedioxy as well as their acid addition salts and their quaternary ammonium compounds.
Det er kjent et stort antall benzokino- A large number of benzoquino-
liziner. Det kan nevnes forbindelser som lysines. Connections can be mentioned such as
fremstilles ifølge det østerrikske patent nr. manufactured according to the Austrian patent no.
195 928, som representeres med den gene- 195,928, which is represented by the gene-
relle formel real formula
hvori R5 og R(i er hydrogen, hydroksyl- el- in which R5 and R(i are hydrogen, hydroxyl- or
ler alkoksygrupper eller sammen en alkylendioksy-gruppe, og R- betyr en alkyl-, cykloalkyl-, alkenyl- eller aralkylgruppe. ler alkoxy groups or together an alkylenedioxy group, and R- means an alkyl, cycloalkyl, alkenyl or aralkyl group.
Videre kan det henvises til det bel- Furthermore, reference can be made to the bel-
giske patent nr. 554 816 som beskriver for- German patent no. 554 816 which describes the
bindelser med bonds with
hvori R- og R,, er som definert i det fore- in which R- and R,, are as defined in the preceding
gående og RH betyr en alkyl-, alkenyl- walking and RH means an alkyl-, alkenyl-
eller aralkyl-gruppe. Hvis RH betyr en alkyl- or aralkyl group. If RH means an alkyl-
gruppe, kan hydrokarbonkjeden være av- group, the hydrocarbon chain may be of-
brutt med et oksygenatom. broken with an oxygen atom.
Også forbindelsen ifølge det belgiske Also the connection according to the Belgian
patent nr. 565 824 kan nevnes, hvilke rep- patent no. 565 824 can be mentioned, which rep-
resenteres av formelen resented by the formula
hvori R9, R10 og Rn hver betyr et hydrogenatom, en alkoksy-gruppe eller en alkylendioksy-gruppe, hvis hvilke som helst to av disse radikaler tas sammen, R12 betyr et hydrogenatom eller en hydrokarbon-gruppe som er timettet i p-stilling, R,.( betyr et, hydrogenatom eller en karbalkoksy-gruppe., wherein R9, R10 and Rn each represents a hydrogen atom, an alkoxy group or an alkylenedioxy group, if any two of these radicals are taken together, R12 represents a hydrogen atom or a hydrocarbon group which is saturated in the p-position, R ,.( means a, hydrogen atom or a carboxyl group.,
Forbindelsen ifølge det belgiske patent • nr. 554 816 viser meget stor likhet med, forbindelsen ifølge det østerriske patent nr., 206 441, hvilket beskriver en fremgangs-' måte som er litt forskjellig fra den som er beskrevet i det nevnte belgiske patent. The compound according to Belgian Patent No. 554,816 shows a very close resemblance to the compound according to Austrian Patent No. 206,441, which describes a process which is slightly different from that described in the said Belgian patent.
Videre kan forbindelsen ifølge det franske patent nr. 1 210 144 nevnes. Disse forbindelser representeres av den generelle formel Furthermore, the compound according to the French patent no. 1,210,144 can be mentioned. These compounds are represented by the general formula
hvori Rl4 og Rl3 hver betyr et hydrogenatom, en alkoksygruppe eller sammen betyr en alkylendioksy-gruppe, R1(i betyr en alkyl-, alkoksyalkyl-, alkenyl- eller aralkyl-radikal, Rl7 er en etynyliden-, etenyliden-eller etylengruppe og R,8 er et hydrogenatom, en alkoksy-, alkyl- eller aryl-gruppe. Det franske patent nr. 1 221 027 beskriver forbindelser med formelen wherein Rl4 and Rl3 each represent a hydrogen atom, an alkoxy group or together represent an alkylenedioxy group, R1(i represents an alkyl, alkoxyalkyl, alkenyl or aralkyl radical, Rl7 is an ethynylidene, ethenylidene or ethylene group and R, 8 is a hydrogen atom, an alkoxy, alkyl or aryl group French Patent No. 1,221,027 describes compounds of the formula
hvori symbolene Rl9 og R20 respektive betyr en alkyl- eller arylgruppe og et hydrogenatom! eller en alkylgruppe. Hvis R2() betyr hydrogen kan R19 også være et hydrogenatom. in which the symbols R19 and R20 respectively mean an alkyl or aryl group and a hydrogen atom! or an alkyl group. If R2() means hydrogen, R19 can also be a hydrogen atom.
Benzenringen kan også ha substitu-enter. The benzene ring can also have substituents.
Flere av de forbindelser som er beskrevet ovenfor er ment som mellomprodukter ved fremstilling av emetin og lignende forbindelser. I andre tilfeller til-skrives forbindelsene også terapeutiske egenskaper. Several of the compounds described above are intended as intermediates in the production of emetine and similar compounds. In other cases, the compounds are also attributed with therapeutic properties.
Forbindelsene som fremstilles ifølge foreliggende oppfinnelse er farmakologisk aktive stoffer som har adrenolytisk og analgetisk aktivitet. Dertil har forbindelsene sedativ aktivitet og kan følgelig anvendes i stedet for kjente sedativer. Dess-uten har et antall av disse en vasodilatorisk effekt, mens noen forbindelser senker le-gemstemperaturen for prøvedyrene. The compounds produced according to the present invention are pharmacologically active substances that have adrenolytic and analgesic activity. In addition, the compounds have sedative activity and can therefore be used instead of known sedatives. In addition, a number of these have a vasodilatory effect, while some compounds lower the body temperature of the test animals.
Toksisiteten er lav. The toxicity is low.
For anvendelse som terapeutiske mid-ler anvendes forbindelsene enten som så-danne eller i form av deres syreaddisjonssalter, i de vanlige farmasøytiske former slik som tabletter, piller og kapsler. For use as therapeutic agents, the compounds are used either as such or in the form of their acid addition salts, in the usual pharmaceutical forms such as tablets, pills and capsules.
Blant de egnede syreaddisjonssalter som fremstilles ifølge foreliggende oppfinnelse kan nevnes de ikke-giftige syreaddisjonssalter, f. eks. saltene med uorga-niske syrer, slik som hydrohalogensyrer (f. eks. saltsyre og hydrobromsyre), svovel-syre, borsyre og fosforsyre, og organiske syrer, slik som eddiksyre, oksalsyre, male-insyre, fumarsyre, sitronsyre, melkesyre, vinsyre og pamoinsyre. Among the suitable acid addition salts which are prepared according to the present invention can be mentioned the non-toxic acid addition salts, e.g. the salts with inorganic acids, such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), sulfuric acid, boric acid and phosphoric acid, and organic acids, such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, lactic acid, tartaric acid and pamoic acid.
Forbindelsene som fåes ifølge foreliggende oppfinnelse fremstiles ved reduksjon av forbindelser med formelen The compounds obtained according to the present invention are produced by reduction of compounds with the formula
Denne reduksjon utføres fortrinnsvis ved hjelp av litiumaluminiumhydrid som reduksjonsmiddel. Reaksjonen utføres fortrinnsvis i-et oppløsningsmiddel. Etere slik som dietyletere og tetrahydrofuran er meget egnet hvis litiumaluminiumhydrid anvendes som reduksjonsmiddel. This reduction is preferably carried out using lithium aluminum hydride as reducing agent. The reaction is preferably carried out in a solvent. Ethers such as diethyl ether and tetrahydrofuran are very suitable if lithium aluminum hydride is used as the reducing agent.
Av primær betydning er egenskapene av forbindelsene 9,10-dimetoksy-2-(4'-halofenyl)-1,3,4,6,7,1 lb-heksahydro-2H-benzo [a] kinolizin og særlig 9,10-dimet-oksy-2-(4'-klorofenyl)-l,3,4,6,7,llb-heksahydro-2H-benzo [a] kinolizin som har meget god analgetisk aktivitet. Of primary importance are the properties of the compounds 9,10-dimethoxy-2-(4'-halophenyl)-1,3,4,6,7,1 lb-hexahydro-2H-benzo[a]quinolizine and especially 9,10- dimethoxy-2-(4'-chlorophenyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine which has very good analgesic activity.
Følgende eksempel kan tjene til å illustrere oppfinnelsen. Det er inkludert en fremgangsmåte til fremstilling av de forskjellige mellomprodukter som anvendes ved syntese av utgangsproduktene. The following example may serve to illustrate the invention. A method for the production of the various intermediate products used in the synthesis of the starting products is included.
Fremstilling av l, 3, 4, 6, 7, llb- heksahydro-2H- benzo [a] kinolizin. Preparation of 1,3,4,6,7,llb-hexahydro-2H-benzo[a]quinolizine.
Reduksjon av kinolizonene (laktamer) til de tilsvarende kinoliziner utføres vanligvis med litiumaluminiumhydrid, idet det anvendes minst y2 mol hydrid og ofte et overskudd pr. mol laktam. Reduction of the quinolizones (lactams) to the corresponding quinolysines is usually carried out with lithium aluminum hydride, using at least y2 mol of hydride and often an excess per moles of lactam.
Ved fremstillingen av laktamene, som beskrevet i det følgende, innføres et asym-metrisentrum med nitrogenatomet, således at det dannes to isomere. In the preparation of the lactams, as described below, an asymmetry center is introduced with the nitrogen atom, so that two isomers are formed.
Da de isomere laktamer noen ganger er vanskelige å skille fra hverandre, reduseres vanligvis en blanding av laktamene. Aminfraksj onen som dannes isoleres fra reaksjonsblandingen og underkastes frak-sjonert krystallisasjon for å utskille ami-nene. As the isomeric lactams are sometimes difficult to distinguish from each other, a mixture of the lactams is usually reduced. The amine fraction that is formed is isolated from the reaction mixture and subjected to fractional crystallization to separate the amines.
2,1 g av en blanding av isomere 1,3,4, 6,7,llb-heksahydro-9,10-dimetoksy-2-(4'-metylfenyl)-2H-benzo [a] kinolizin-4-oner, smelteområde 164-174°C, hovedsakelig be-stående av laktam med smelteområde 178— 181°C', oppløses i vannfri tetrahydrofuran og tilsettes 0,4 g litiumaluminiumhydrid i 50 ml tetrahydrofuran. Blandingen oppvarmes under tilbakeløpskjøling i 2 timer, hvoretter overskudd av litiumaluminiumhydrid spaltes- med litt vann. Aluminium-hydroksydet som dannes fjernes ved filtrering og vaskes med dietyleter. Tetrahydro-furanet fjernes ved destillasjon og resten behandles med vann og dietyleter. Den eteriske oppløsning tørkes og konsentreres. 2.1 g of a mixture of isomeric 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2-(4'-methylphenyl)-2H-benzo[a]quinolizin-4-ones, melting range 164-174°C, mainly consisting of lactam with melting range 178-181°C', is dissolved in anhydrous tetrahydrofuran and 0.4 g of lithium aluminum hydride in 50 ml of tetrahydrofuran is added. The mixture is heated under reflux for 2 hours, after which excess lithium aluminum hydride is decomposed with a little water. The aluminum hydroxide that is formed is removed by filtration and washed with diethyl ether. The tetrahydrofuran is removed by distillation and the residue is treated with water and diethyl ether. The ethereal solution is dried and concentrated.
Under dette trinn krystalliseres cis l,3,4,6,7,llb-heksahydro-9,10-dimetoksy-2-(4'-metylfenyl)-2H-benzo [a] kinolizin-base (1,2 g = 60 pst.) i form av lange nål-formede krystaller. During this step, cis 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2-(4'-methylphenyl)-2H-benzo[a]quinolizine base (1.2 g = 60 pst.) in the form of long needle-shaped crystals.
Etter krystallisasjon fra petroleter med kokeområde 60—80°C er smeltepunk-tet 117—118,5°C. Hydroklorid av basen fremstilt på vanlig måte i dietyleter blir krystallinsk ved behandling med aceton og smelter etter krystallisasjon fra en blanding av alkohol og etylacetat ved 245— 247°C. Saltet er lettere å"rense enn den fri base. Ved tilsetning av en eterisk hydto-klorsyreoppløsning til moderluten av cis-basen, kan transhydrokloridet isoleres. After crystallization from petroleum ether with a boiling range of 60-80°C, the melting point is 117-118.5°C. Hydrochloride of the base prepared in the usual way in diethyl ether becomes crystalline on treatment with acetone and melts after crystallization from a mixture of alcohol and ethyl acetate at 245-247°C. The salt is easier to purify than the free base. By adding an ethereal hydrochloric acid solution to the mother liquor of the cis-base, the trans-hydrochloride can be isolated.
Utbyttet er 40 pst. Dette salt kan krystalliseres fra etanol med litt vann, smeltepunkt: 264—266°C. The yield is 40 percent. This salt can be crystallized from ethanol with a little water, melting point: 264-266°C.
Basen som frigjøres fra dette salt smelter ved 65—66° C, etter krystallisasjonen fra petroleter. The base liberated from this salt melts at 65-66° C, after crystallization from petroleum ether.
Som regel er det relative nivå for smeltepunktene for kinoliziner som fremstilles ifølge foreliggende oppfinnelse, som angitt ovenfor. As a rule, the relative level of the melting points for quinolysines produced according to the present invention is as indicated above.
Den fri cis-base har et høyere smeltepunkt enn trans-basen, mens det omvendte synes å være tilfelle for hydrokloridet. The free cis base has a higher melting point than the trans base, while the reverse appears to be the case for the hydrochloride.
Noen ganger er de forskjeller som finnes for de rensede forbindelser så små at det ikke skal legges for stor vekt på denne regel, særlig når det inngår utilstrekkelig rensede reaksjonsprodukter. Det infrarøde spektrum gir informasjon med hensyn til romstrukturen for molekylet. Sometimes the differences found for the purified compounds are so small that too much emphasis should not be placed on this rule, especially when insufficiently purified reaction products are included. The infrared spectrum provides information regarding the spatial structure of the molecule.
Spektrene for cis- og transisomere av-viker tilstrekkelig til å tillate en utvetydig bestemmelse av cis- eller trans-konfigura-sjonen for forbindelsene som er på tale. Det er således blitt funnet at alle cis-forbindelser som fremstilles ifølge foreliggende oppfinnelse viser absorpsjons-maksima ved 2750 og 2805 cm—1„ mens trans-forbindelsene ikke viser disse mak-sima. The spectra for cis- and trans-isomers differ sufficiently to allow an unequivocal determination of the cis- or trans-configuration of the compounds in question. It has thus been found that all cis-compounds produced according to the present invention show absorption maxima at 2750 and 2805 cm-1", while the trans-compounds do not show these maxima.
Dette er i overensstemmelse med det som er funnet av Bohlman, Berichte 91, 2157 (1958). Følgende tabell viser en opp-summering av data ved et antall kinoliziner som fremstilles ifølge foreliggende oppfinnelse. Med hensyn til smeltepunktene for saltene, skal det bemerkes at saltene smelter under dekomponering. Fremstilling av kvaternære ammonium-derivater av 1, 3, 4, 6, 7 , llb- heksahydro- 2H-benzo [a] kinoliziner. This is in agreement with the finding of Bohlman, Berichte 91, 2157 (1958). The following table shows a summary of data for a number of quinolysines produced according to the present invention. With regard to the melting points of the salts, it should be noted that the salts melt during decomposition. Preparation of quaternary ammonium derivatives of 1, 3, 4, 6, 7, llb-hexahydro-2H-benzo [a] quinolizines.
Kinolizin-basene som fremstilles ifølge foreliggende oppfinnelse kan omdannes til kvaternære ammoniumforbindelser på vanlig måte, f. eks. oppløse 7,5 g i 1,3,4,6,7, 1 lb-heksahydro-9,10-dimetoksy-2- (4-klo-rofenyl)-2H-benzo [a] kinolizin-base i en blanding av aceton og metylalkohol. Overskudd av en oppløsning av metyljodid i aceton tilsettes dråpevis. Etter ett minutt begynner l,3,4,6;7,llb-heksahydro-9,10-di-Metojodidet krystalliseres fra en blanding benzo [a] kinoliziniumjodid å utkrystalli-sere. Utbyttet er 8,5 g, smeltepunkt 260°C. Metojodidet krystalliseres fra en blanding av metanol med en liten mengde vann. Utbyttet er 5 g, smeltepunkt 274—276°C. The quinolizine bases produced according to the present invention can be converted into quaternary ammonium compounds in the usual way, e.g. dissolve 7.5 g in 1,3,4,6,7,1 lb-hexahydro-9,10-dimethoxy-2-(4-chlorophenyl)-2H-benzo[a]quinolizine base in a mixture of acetone and methyl alcohol. Excess of a solution of methyl iodide in acetone is added dropwise. After one minute, the 1,3,4,6;7,11b-hexahydro-9,10-di-Methioiodide is crystallized from a mixture of benzo [a] quinolizinium iodide begins to crystallize. The yield is 8.5 g, melting point 260°C. The metho iodide is crystallized from a mixture of methanol with a small amount of water. The yield is 5 g, melting point 274-276°C.
l,3,4,6,7,llb-heksahydro-2H-benzo [a] kinolizin-4-oner anvendes som begynnende reaksjonsdeltaker i ovenstående reaksjon og kan fremstilles på følgende måte. 1,3,4,6,7,11b-hexahydro-2H-benzo [a]quinolizin-4-ones are used as starting reaction participants in the above reaction and can be prepared in the following way.
A. Fremstilling av glutarsyre- anhydrider substituert i 3- stilling. A. Preparation of glutaric anhydrides substituted in the 3-position.
Fremgangsmåten er i stor utstrekning analog med den som er beskrevet av W. F. Smith c. s. i J. Am. Chem. Soc. 72, 1877 The procedure is largely analogous to that described by W. F. Smith et al. in J. Am. Chem. Soc. 72, 1877
(1950). (1950).
120 g p-metylbenzaldehyd 260 g etylacetoacetat 50 ml etanol og 20 ml pyridin blandes. 120 g p-methylbenzaldehyde 260 g ethyl acetoacetate 50 ml ethanol and 20 ml pyridine are mixed.
Etter flere timers henstand er det ut-krystallisert 112 g dietyl-2,4-diacetyl-3-(4-metylfenyl) glutarat, med smeltepunkt 133-133,5°C. Hvis blandingen står i flere uker kan det fåes nok en porsjon av sam-me ester. After standing for several hours, 112 g of diethyl-2,4-diacetyl-3-(4-methylphenyl) glutarate, with a melting point of 133-133.5°C, have crystallized out. If the mixture stands for several weeks, another portion of the same ester can be obtained.
112 g dietyl-2,4-diacetyl-3-(4-metyl-fenyl) glutarat, oppløst i 1500 ml etanol, kokes med tilbakeløpskjøler med 1,8 kg av en 50 pst.-ig natriumhydroksyd-oppløsning i 1 time. 112 g of diethyl-2,4-diacetyl-3-(4-methyl-phenyl) glutarate, dissolved in 1500 ml of ethanol, is boiled with a reflux condenser with 1.8 kg of a 50% sodium hydroxide solution for 1 hour.
Etter fjernelse av alkoholen ved destillasjon og sur gjøring fåes krystallinsk 3-(4-metylfenyl)glutarsyre ved filtrering. Ekstrahering med eter og moderluten gir en videre mengde av produktet. Utbyttet er 56 g (82 pst.), smeltepunkt 164—166°C. After removal of the alcohol by distillation and acidification, crystalline 3-(4-methylphenyl)glutaric acid is obtained by filtration. Extraction with ether and the mother liquor gives a further quantity of the product. The yield is 56 g (82 per cent), melting point 164-166°C.
Anhydridet fåes fra syren ved kok-ning med tilbakeløpskjøler med en dob-belt så stor mengde eddiksyreanhydrid. Om det ønskes kan eddiksyren anvendes som oppløsningsmiddel. Tabellen i det føl-gende angir dataene for anhydridene, hvilke fremstilles på lignende måte, og erstat-ter de tilsvarende aldehyder. Det er sjel-den nødvendig å rense mellomproduktene som er nevnt ovenfor, og syntesene kan deretter gå uten avbrytelse for rensning. The anhydride is obtained from the acid by boiling with a reflux condenser with twice the amount of acetic anhydride. If desired, acetic acid can be used as a solvent. The table below gives the data for the anhydrides, which are prepared in a similar way, replacing the corresponding aldehydes. It is rarely necessary to purify the intermediates mentioned above, and the syntheses can then proceed without interruption for purification.
20;4 g 2-(3,4-metylendioksyfenyl)etyl-amin i 50 ml benzen settes langsomt til 23,5 g 3-fenylglutarsyreanhydrid i 250 ml benzen. Det finner sted en eksoterm reaksjon, hvoretter amidet straks begynner å krystallisere. Etter avkjøling av reaksjonsblandingen isoleres 40,7 g (92 pst.) 3-fenyl-glutarsyrehomopiperonylamid. Etter flere gangers omkrystallisasjon fra en aceton-vannblanding smelter forbindelsen ved 136,5—137,5°C. 20.4 g of 2-(3,4-methylenedioxyphenyl)ethylamine in 50 ml of benzene is slowly added to 23.5 g of 3-phenylglutaric anhydride in 250 ml of benzene. An exothermic reaction takes place, after which the amide immediately begins to crystallize. After cooling the reaction mixture, 40.7 g (92 percent) of 3-phenyl-glutaric acid homopiperonylamide is isolated. After several times of recrystallization from an acetone-water mixture, the compound melts at 136.5-137.5°C.
Egnede etylamlner som kan anvendes som opprinnelige reaksjonsdeltakere i denne fremgangsmåte omfatter: fenetylamin (lavere alkoksy}substituerte fenetylaminer (f. eks. p-metoksyfenetylamin, p-etoksy-fenetylamin, o-metoksyfenetylamin og m-metoksyfenetylamin); di (lavere alkoksy) fenetylaminer (f. eks. m, p-dimetoksyfen-etylamin) og m,p-metylendioksyfenetyl-amin. Suitable ethylamines which can be used as initial reactants in this process include: phenethylamine (lower alkoxy} substituted phenethylamines (e.g. p-methoxyphenethylamine, p-ethoxyphenethylamine, o-methoxyphenethylamine and m-methoxyphenethylamine); di(lower alkoxy)phenethylamines (eg m,p-dimethoxyphenethylamine) and m,p-methylenedioxyphenethylamine.
Egnede glutarsyreanhydrider som kan anvendes som opprinnelige reaksjonsdeltakere i fremgangsmåten omfatter: 3-substituert glutarsyreanhydrider, slik som 3-(lavere alkyl)-glutarsyreanhydrider (f. eks. 3-metylglutarsyreanhydrid, 3-etylglutar-syreanhydrid og 3-propylglutarsyreanhyd-rid); 3-trifluormetylglutarsyreanhydrid; 3-f enylglutarsyreanhydrid; 3- (halof enyl) - glutarsyreanhydrider (f. eks. 3-p-klorfenyl-j glutarsyreanhydrid, 3-p-bromfenylglutar-j syreanhydrid, 3-p-fluorfenylglutarsyrean-;hydrid, 3-o-klorfenylglutarsyreanhydrid og 3-m-klorf enylglutarsyreanhydrid); 3- (lavere alkylfenyl) glutarsyreanhydrider (f. eks. 3-p-metylfenylglutarsyreanhydrid); Suitable glutaric anhydrides that can be used as initial reaction participants in the method include: 3-substituted glutaric anhydrides, such as 3-(lower alkyl)-glutaric anhydrides (e.g. 3-methylglutaric anhydride, 3-ethylglutaric anhydride and 3-propylglutaric anhydride); 3-trifluoromethylglutaric anhydride; 3-phenylglutaric anhydride; 3-(halophenyl)-glutaric anhydrides (e.g. 3-p-chlorophenyl-j glutaric anhydride, 3-p-bromophenylglutaric anhydride, 3-p-fluorophenylglutaric anhydride, 3-o-chlorophenylglutaric anhydride and 3-m- chlorophenylglutaric anhydride); 3-(lower alkylphenyl)glutaric anhydrides (eg, 3-p-methylphenylglutaric anhydride);
3- (lavere alkoksyfenyl)glutarsyreanhydrider (f. eks. 3-p-metoksyfenylglutarsyrean-hydrid); 3,4-metylendioksyfenylglutarsyre-anhydrid; 3-(fenyl lavere alkyl)glutarsyreanhydrider (f. eks. 3-benzylglutarsyrean-hydrid og 3-fenetylglutarsyreanhydrid); 3-(lower alkoxyphenyl)glutaric anhydrides (eg 3-p-methoxyphenylglutaric anhydride); 3,4-methylenedioxyphenylglutaric anhydride; 3-(phenyl lower alkyl)glutaric anhydrides (eg, 3-benzylglutaric anhydride and 3-phenethylglutaric anhydride);
3,3-di (lavere alkyl) glutarsyreanhydrider (f. eks. 3,3-dimetylglutarsyreanhydrid, 3-metyl-3-etylglutarsyreanhydrid og 3,3-di-etylglutarsyreanhydrid); 3-(lavere alkyl)-3-fenylglutarsyreanhydrider (f. eks. 3-metyl-3-fenylglutarsyreanhydrid og 3-etyl-3-fenylglutarsyreanhydrid); 3-(lavere alkyl ) -3 - (halof enyl) glutarsyreanhydrider (f. eks. 3-etyl-3-p-klorf enylglutarsyreanhydrid); 3-(lavere alkyl)-3-(lavere alkylfenyl) glutarsyreanhydrider; 3-(lavere alkyl)-3-(lavere alkoksyfenyl) glutarsyreanhydrider; 3-(lavere alkyl)-3-(fenyl lavere alkyl) glutarsyreanhydrider. 3,3-di(lower alkyl)glutaric anhydrides (eg, 3,3-dimethylglutaric anhydride, 3-methyl-3-ethylglutaric anhydride, and 3,3-diethylglutaric anhydride); 3-(lower alkyl)-3-phenylglutaric anhydrides (eg, 3-methyl-3-phenylglutaric anhydride and 3-ethyl-3-phenylglutaric anhydride); 3-(lower alkyl)-3-(halophenyl)glutaric anhydrides (eg, 3-ethyl-3-p-chlorophenylglutaric anhydride); 3-(lower alkyl)-3-(lower alkylphenyl)glutaric anhydrides; 3-(Lower Alkyl)-3-(Lower Alkoxyphenyl) Glutaric Anhydrides; 3-(lower alkyl)-3-(phenyl lower alkyl) glutaric anhydrides.
Tabell III oppsummerer dataene for et antall lignende homoveratrylamider, og disse forbindelser er fremstilt ifølge frem-gangsmåter som er analoge med fremgangsmåten som er beskrevet ovenfor. Table III summarizes the data for a number of similar homoveratrylamides, and these compounds were prepared according to procedures analogous to the procedure described above.
For denne omdannelse kan det anvendes Bischler-Napieralski isokinolinsyntese som beskrevet i Org. Reactions VI, 74-150. Ringslutningen som utføres under innvirk-ning av et kondensasjonsmiddel, slik som friskt destillert fosforoksyklorid, skjer uten unntagelse først ved forestring av den fri karboksylgruppe, f. eks. med diazometan. For this conversion, Bischler-Napieralski isoquinoline synthesis can be used as described in Org. Reactions VI, 74-150. The cyclization, which is carried out under the influence of a condensing agent, such as freshly distilled phosphorus oxychloride, takes place without exception only when the free carboxyl group is esterified, e.g. with diazomethane.
En oppløsning av diazometan i eter settes langsomt til 19 g N-2-(3,4-dimetok-syf enyl) etyl-3- (4-metoksyf enyl) -glutar-syremonoamid i 50 ml dietyleter og 5 ml metanol. Nitrogen utvikles og den gule diazometanfarge forsvinner, mens den dannede ester oppløses i reaksjonsblandingen. Dietyleter fjernes under forminsket trykk og den oljelignende rest oppvarmes under tilbakeløpskjøling med 50 ml friskt destillert fosforoksyklorid og 50 ml vannfri benzen i 4'5 minutter, idet hydrogenklorid utvikles under prosessen. Etter fjernelse av benzen og overskudd av fosforoksyklorid ved destillasjon under forminsket trykk spaltes resterende fosforoksyklorid med metanol under avkjøling. A solution of diazomethane in ether is added slowly to 19 g of N-2-(3,4-dimethoxyphenyl)ethyl-3-(4-methoxyphenyl)-glutaric acid monoamide in 50 ml of diethyl ether and 5 ml of methanol. Nitrogen is evolved and the yellow diazomethane color disappears, while the formed ester dissolves in the reaction mixture. Diethyl ether is removed under reduced pressure and the oil-like residue is heated under reflux with 50 ml of freshly distilled phosphorus oxychloride and 50 ml of anhydrous benzene for 4-5 minutes, hydrogen chloride being evolved during the process. After removing benzene and excess phosphorus oxychloride by distillation under reduced pressure, the remaining phosphorus oxychloride is split with methanol while cooling.
Reaksjonsblandingen gjøres alkalisk og ekstraheres flere ganger med dietyleter. 5 g oksylsyre i dietyleter tilsettes den tørkede eteriske oppløsning. Utbyttet er 17,1 g metyl-4-(3,4-dihydro-6,7-dimetoksy isokinol-l-yl)-3-(4'-metoksyfenyl)-butyratoksilat (73,2 pst.), smeltepunkt 132—134° C. The reaction mixture is made alkaline and extracted several times with diethyl ether. 5 g of oxalic acid in diethyl ether are added to the dried ethereal solution. The yield is 17.1 g of methyl 4-(3,4-dihydro-6,7-dimethoxy isoquinol-1-yl)-3-(4'-methoxyphenyl)-butyrate oxylate (73.2 percent), melting point 132— 134°C.
På lignende måte kan følgende metyl-4- [3,4-dihydro- (R3, R4-substituert) isokinol-l-yl]-3-(R1,R2-substituerte)butyrater fåes. In a similar manner, the following methyl 4-[3,4-dihydro-(R3,R4-substituted)isoquinol-1-yl]-3-(R1,R2-substituted)butyrates can be obtained.
Noen ganger anvendes en svakt av-vikende fremgangsmåte, hvorved de (3-substituerte glutarsyreanhydrider som fremstilles ifølge trinn A først omdannes til monometylesterne ved behandling med metanol. Esterne krystalliserer fra meta-noloppløsningen ved avkjøling og kan isoleres ved filtrering. Sometimes a slightly deviating method is used, whereby the (3-substituted glutaric anhydrides produced according to step A are first converted to the monomethyl esters by treatment with methanol. The esters crystallize from the methanol solution on cooling and can be isolated by filtration.
Deretter omsettes disse monoestere med tionylklorid, slik at den tilsvarende rrionoacylklorid av monoesteren dannes. These monoesters are then reacted with thionyl chloride, so that the corresponding rionoacyl chloride of the monoester is formed.
Overskudd av tionylklorid avdestilleres, idet det etterlates en gul sirupaktig masse som deretter uten forutgående rensning omsettes med en ekvivalent mengde av den ønskede (3-aryletylamin i overskudd av pyridin. Reaksjonen utføres ved en tempe-ratur på 80—85° C. Benzen anvendes som oppløsningsmiddel. Etter avkjøling ekstraheres blandingen med vann. Benzenlaget tørkes med natriumsulfat og filtreres. Benzen avdestilleres og etterlater et fast resi-duum som kan renses ved omkrystallisasjon fra et egnet oppløsningsmiddel. En del av de nevnte forbindelser i ovenstående tabell er fremstilt ved hjelp av disse frem-gangsmåter. Excess thionyl chloride is distilled off, leaving behind a yellow syrupy mass which is then reacted without prior purification with an equivalent amount of the desired (3-arylethylamine in an excess of pyridine. The reaction is carried out at a temperature of 80-85° C. Benzene is used as a solvent. After cooling, the mixture is extracted with water. The benzene layer is dried with sodium sulfate and filtered. The benzene is distilled off, leaving a solid residue that can be purified by recrystallization from a suitable solvent. Some of the compounds mentioned in the above table are prepared using these procedures.
Da den siste fremgangsmåte er mindre omstendelig, idet tid og materialforbru-kende renseoperasjoner for det meste unn-gås, foretrekkes vanlig denne fremgangsmåte. D. Fremstilling av metyl- 4-[ l, 2, 3, 4- tetra-hydro-( R3, Rj- substituerte) isokinol- l- yl]'-3-( R j, R2- substituerte) butyrater. As the last method is less cumbersome, as time and material-consuming cleaning operations are mostly avoided, this method is usually preferred. D. Preparation of methyl 4-[1,2,3,4-tetrahydro-(R3,R1-substituted)isoquinol-1-yl]'-3-(R1,R2-substituted)butyrates.
Reaksjonsskjema IV Reaction scheme IV
Hydrering av de hydroisokinolinderi-vatene for hvilket formål platina har vist seg å være en verdifull katalysator, går vanligvis glatt, idet den teoretiske mengde hydrogen absorberes. Hydrogenation of the hydroisoquinoline derivatives for which purpose platinum has proved a valuable catalyst usually proceeds smoothly, the theoretical amount of hydrogen being absorbed.
Som et resultat av denne reaksjon dannes et annet asymmetrisk sentrum, således at det kan ventes to isomere. Det er ofte vanskelig å skille de to isomere, og de iboende problemer forsterkes da de er-holdte aminosyreestere har en tendens til spontant å omdannes til det tilsvarende laktam. På grunn av at disse laktamer, selv om det ikke dannes spontant, fåes under det neste trinn, blir tetrahydroisokino-linderivatene vanligvis ikke isolert, men underkastes direkte neste reaksjonstrinn. As a result of this reaction, another asymmetric center is formed, so that two isomers can be expected. It is often difficult to separate the two isomers, and the inherent problems are exacerbated as the amino acid esters present tend to spontaneously convert to the corresponding lactam. Because these lactams, although not formed spontaneously, are obtained during the next step, the tetrahydroisoquinoline derivatives are usually not isolated, but are submitted directly to the next reaction step.
I stedet for esterne kan også de tilsvarende syrer anvendes som utgangspro-dukter for reduksjon. Instead of the esters, the corresponding acids can also be used as starting products for reduction.
5,5 g metyl-4-(3,4-dihydro-6,7-mety-lendioksyisokinol-l-yl)-3-fenylbutyrat, som oksalsyresaltet, oppløst i 150 ml metanol med en del vann, rystes med hydrogen i nærvær av 25 mg platinaoksyd (Adams katalysator) 325 ml 'hydrogen absorberes i 5.5 g of methyl 4-(3,4-dihydro-6,7-methylenedioxyisoquinol-1-yl)-3-phenylbutyrate, as the oxalic acid salt, dissolved in 150 ml of methanol with a portion of water, shaken with hydrogen in the presence of 25 mg platinum oxide (Adam's catalyst) 325 ml 'hydrogen is absorbed in
.2y2 itime. Etter fjernelse av katalysatoren ved filtrering konsentreres oppløsningen av oksalatet under •før-minsket trykk. Be-handlingen av resten med aceton gir 2,7 g .2y2 itime. After removal of the catalyst by filtration, the solution of the oxalate is concentrated under pre-reduced pressure. Treatment of the residue with acetone yields 2.7 g
av -en isomer av -metyJ-4-(l,2,3;4-tetrahyd-ro-6,7-metylendioksyisokinol-l-yl)-3-fenylbutyrat, som dets oksalat. Den isomere kalles cc-isomere. Etter fordampning of -an isomer of -methyl-4-(1,2,3;4-tetrahydro-6,7-methylenedioxyisoquinol-1-yl)-3-phenylbutyrate, as its oxalate. The isomers are called cc isomers. After evaporation
av aceton og behandling av 'residuet med etylacetat, fåes 2,2 g krystallinsk.fHisomer-e. of acetone and treatment of the residue with ethyl acetate, 2.2 g of crystalline fHisomer-e are obtained.
E. Fremstilling . av 1, 3, 4, 6, 7', llb- heksa-hy dr o- 2H- benzo [a] kinolizin- 4- oner. E. Manufacturing . of 1, 3, 4, 6, 7', llb- hexa-hy dr o- 2H- benzo [a] quinolizin- 4-ones.
Reaksjonsskjema V Reaction scheme V
Ringslutningen av aminoesterne til laktamer (kinolizinoner) går noen ganger mindre glatt hvis man -anvender saltene av aminoesterne som utgangsmaterial. På den annen side 'byr frigjøring av aminoester fra saltet i noen tilfeller på vanske-ligheter, og det bør derfor finnes ut i prak-sis hvilket utgangsprodukt, enten den fri aminoester eller ,dens salt, som skal foretrekkes for reaksjon. 4,5 g metyl-4-( 1,2,3,4-tetrahydro-6,7-metylendioksy-isokinol-l-yl)-3-fenylbutyrat i form av dets oksalat oppvarmes under tilbakeløpskjøling i xylen i 1 time. Oksalsyre krystalliserer ved av-kjøling. The cyclization of the amino esters to lactams (quinolizinones) sometimes goes less smoothly if the salts of the amino esters are used as starting material. On the other hand, liberation of amino ester from the salt in some cases presents difficulties, and it should therefore be found out in practice which starting product, either the free amino ester or its salt, is to be preferred for reaction. 4.5 g of methyl 4-(1,2,3,4-tetrahydro-6,7-methylenedioxy-isoquinol-1-yl)-3-phenylbutyrate in the form of its oxalate is heated under reflux in xylene for 1 hour. Oxalic acid crystallizes on cooling.
Xylenet fordampes og residuet krystalliseres fra en metanoldietyleter-blanding. Det erholdtes to isomere former av produktet. En isomere av 1,3,4,6,7,1 lb-heksahydro-9,10-métylendioksy-2-fenyl-2H-benzo [a] kinolizin-4-on med smeltepunkt 162—163°C fåes i 1 g utbytte. Av den annen isomere som smelter ved 121—126°C fåes en mengde på 1,5 g. The xylene is evaporated and the residue crystallized from a methanol-diethyl ether mixture. Two isomeric forms of the product were obtained. An isomer of 1,3,4,6,7,1 lb-hexahydro-9,10-methylenedioxy-2-phenyl-2H-benzo [a]quinolizin-4-one with melting point 162-163°C is obtained in 1 g dividend. A quantity of 1.5 g is obtained from the second isomer which melts at 121-126°C.
I stedet for-esteren kan den tilsvarende syre anvendes som utgangsprodukt for ringslutningen. Instead of the ester, the corresponding acid can be used as starting product for the ring closure.
1,3,4,6,7,llb-heksahydro-2H-benzo [a] kinolizin-4-oner som er ført opp i følgende tabell kan fremstilles på lignende måte. 1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-4-ones listed in the following table can be prepared in a similar manner.
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US5785776A (en) * | 1996-06-06 | 1998-07-28 | Reynolds Metals Company | Method of improving the corrosion resistance of aluminum alloys and products therefrom |
CN102909229A (en) * | 2012-10-30 | 2013-02-06 | 浙江瑞金铜铝型材有限公司 | Forming process of 7003 aluminum alloy sections |
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LU80055A1 (en) | 1979-05-15 |
AU526176B2 (en) | 1982-12-23 |
AU3840578A (en) | 1980-01-31 |
BE869353A (en) | 1979-01-29 |
AR215941A1 (en) | 1979-11-15 |
CA1058109A (en) | 1979-07-10 |
NO782585L (en) | 1979-01-30 |
MX150361A (en) | 1984-04-25 |
JPS5613529B2 (en) | 1981-03-28 |
FR2398558A1 (en) | 1979-02-23 |
FR2398558B1 (en) | 1982-02-19 |
DE2860131D1 (en) | 1980-12-11 |
DK333178A (en) | 1979-01-30 |
CH627382A5 (en) | 1982-01-15 |
GR63648B (en) | 1979-11-28 |
IT1097393B (en) | 1985-08-31 |
IT7826049A0 (en) | 1978-07-25 |
NO143785C (en) | 1981-04-15 |
ATA548278A (en) | 1980-03-15 |
YU181478A (en) | 1982-06-30 |
IL55216A0 (en) | 1978-09-29 |
EP0000684A1 (en) | 1979-02-07 |
JPS5426269A (en) | 1979-02-27 |
IE47282B1 (en) | 1984-02-08 |
ES471988A1 (en) | 1979-02-16 |
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