NO134157B - - Google Patents
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- Publication number
- NO134157B NO134157B NO16769367A NO16769367A NO134157B NO 134157 B NO134157 B NO 134157B NO 16769367 A NO16769367 A NO 16769367A NO 16769367 A NO16769367 A NO 16769367A NO 134157 B NO134157 B NO 134157B
- Authority
- NO
- Norway
- Prior art keywords
- aza
- mixture
- acid
- phenethyl
- dibenzo
- Prior art date
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- -1 substituents halogen Chemical class 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 62
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000000034 method Methods 0.000 description 26
- 150000002576 ketones Chemical class 0.000 description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- 238000010438 heat treatment Methods 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 229960000583 acetic acid Drugs 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 229920000137 polyphosphoric acid Polymers 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 150000001204 N-oxides Chemical class 0.000 description 10
- 150000002596 lactones Chemical class 0.000 description 10
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 10
- 238000007363 ring formation reaction Methods 0.000 description 10
- FIBVUGPJCPOSJB-UHFFFAOYSA-N 2-(2-phenylethyl)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1CCC1=CC=CC=C1 FIBVUGPJCPOSJB-UHFFFAOYSA-N 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- 238000006356 dehydrogenation reaction Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- JENIILKCEYGCJV-UHFFFAOYSA-N 3-(2-phenylethyl)pyridine-2-carbonitrile Chemical compound N#CC1=NC=CC=C1CCC1=CC=CC=C1 JENIILKCEYGCJV-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HMWBPQZTSAICMS-UHFFFAOYSA-N 3-(2-phenylethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=C1CCC1=CC=CC=C1 HMWBPQZTSAICMS-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- LDPMSPVUGCVFHB-UHFFFAOYSA-N 2-(2-phenylethenyl)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1C=CC1=CC=CC=C1 LDPMSPVUGCVFHB-UHFFFAOYSA-N 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 150000003997 cyclic ketones Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- DXKCYWXEHAMAQW-UHFFFAOYSA-N 3-(2-phenylethyl)pyridine Chemical compound C=1C=CC=CC=1CCC1=CC=CN=C1 DXKCYWXEHAMAQW-UHFFFAOYSA-N 0.000 description 4
- DJJPOVQKVDBHFG-UHFFFAOYSA-N 3-(2-phenylethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1CCC1=CC=CC=C1 DJJPOVQKVDBHFG-UHFFFAOYSA-N 0.000 description 4
- OXIDANFQRMCKEW-UHFFFAOYSA-N 4-(2-phenylethyl)pyridine-3-carboxylic acid Chemical class OC(=O)C1=CN=CC=C1CCC1=CC=CC=C1 OXIDANFQRMCKEW-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000005644 Wolff-Kishner reduction reaction Methods 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- ZDXGKCWPISPQIQ-UHFFFAOYSA-N ethyl 4-methylpyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=CC=C1C ZDXGKCWPISPQIQ-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 239000011664 nicotinic acid Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- QSVZFWGNHWNVDJ-UHFFFAOYSA-N 3-(2-phenylethyl)pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1CCC1=CC=CC=C1 QSVZFWGNHWNVDJ-UHFFFAOYSA-N 0.000 description 3
- AWLFVFGRSPUANH-UHFFFAOYSA-N 4-methyl-3-(2-phenylethyl)pyridine Chemical compound CC1=CC=NC=C1CCC1=CC=CC=C1 AWLFVFGRSPUANH-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 3
- LOBURDZWGMSKIG-UHFFFAOYSA-N benzo[1,2]cyclohepta[3,4-a]pyridin-11-one Chemical compound C1=CC2=CN=CC=C2C(=O)C2=CC=CC=C21 LOBURDZWGMSKIG-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- QFWPJPIVLCBXFJ-UHFFFAOYSA-N glymidine Chemical compound N1=CC(OCCOC)=CN=C1NS(=O)(=O)C1=CC=CC=C1 QFWPJPIVLCBXFJ-UHFFFAOYSA-N 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DWQYMLYCTCRYHL-UHFFFAOYSA-N 1-(4-methylpyridin-3-yl)-2-phenylethanone Chemical compound CC1=CC=NC=C1C(=O)CC1=CC=CC=C1 DWQYMLYCTCRYHL-UHFFFAOYSA-N 0.000 description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 2
- GVEQCFMNUYFHOE-UHFFFAOYSA-N 2-phenyl-1-pyridin-3-ylethanone Chemical compound C=1C=CN=CC=1C(=O)CC1=CC=CC=C1 GVEQCFMNUYFHOE-UHFFFAOYSA-N 0.000 description 2
- OTJNZCAGDNFIMV-UHFFFAOYSA-N 4-(2-phenylethenyl)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC=C1C=CC1=CC=CC=C1 OTJNZCAGDNFIMV-UHFFFAOYSA-N 0.000 description 2
- FBZVBNFRUXEOHE-UHFFFAOYSA-N 5,6-dihydrobenzo[1,2]cyclohepta[3,4-a]pyridin-11-one Chemical compound C1CC2=CN=CC=C2C(=O)C2=CC=CC=C21 FBZVBNFRUXEOHE-UHFFFAOYSA-N 0.000 description 2
- PDPKDRIXAIQZAV-UHFFFAOYSA-N 5,6-dihydrobenzo[1,2]cyclohepta[3,4-b]pyridin-11-one Chemical compound C1CC2=CC=CN=C2C(=O)C2=CC=CC=C21 PDPKDRIXAIQZAV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- HOCIEUJADYTZNL-UHFFFAOYSA-N benzo[1,2]cyclohepta[3,4-b]pyridin-11-one Chemical compound C1=CC2=NC=CC=C2C(=O)C2=CC=CC=C21 HOCIEUJADYTZNL-UHFFFAOYSA-N 0.000 description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 229960001238 methylnicotinate Drugs 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QPDZAAFAAADIRA-UHFFFAOYSA-N 1-oxido-3-(2-phenylethyl)pyridin-1-ium Chemical compound [O-][N+]1=CC=CC(CCC=2C=CC=CC=2)=C1 QPDZAAFAAADIRA-UHFFFAOYSA-N 0.000 description 1
- NIJWAAUHTPDGOM-UHFFFAOYSA-N 2-(2-phenylethyl)pyridine Chemical compound C=1C=CC=CC=1CCC1=CC=CC=N1 NIJWAAUHTPDGOM-UHFFFAOYSA-N 0.000 description 1
- LGJWRMLKCCVIBL-UHFFFAOYSA-N 2-bromo-3-(2-phenylethyl)pyridine Chemical compound BrC1=NC=CC=C1CCC1=CC=CC=C1 LGJWRMLKCCVIBL-UHFFFAOYSA-N 0.000 description 1
- WMKYKQWKLILFBM-UHFFFAOYSA-N 2h-pyridine-1-carboxylic acid Chemical class OC(=O)N1CC=CC=C1 WMKYKQWKLILFBM-UHFFFAOYSA-N 0.000 description 1
- SWHRHZCHAQSEHY-UHFFFAOYSA-N 3-(2-phenylethenyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1C=CC1=CC=CC=C1 SWHRHZCHAQSEHY-UHFFFAOYSA-N 0.000 description 1
- AGIAYOIJHFTOSV-UHFFFAOYSA-N 3-(2-phenylethyl)-1h-pyridin-2-one Chemical compound O=C1NC=CC=C1CCC1=CC=CC=C1 AGIAYOIJHFTOSV-UHFFFAOYSA-N 0.000 description 1
- KERIVOPTFMHQMZ-UHFFFAOYSA-N 3-(2-phenylethyl)pyridin-4-amine hydrochloride Chemical compound Cl.C1(=CC=CC=C1)CCC=1C=NC=CC1N KERIVOPTFMHQMZ-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
- MRHMJGLJPOGNFH-UHFFFAOYSA-N 3-oxo-2-phenyl-3-pyridin-3-ylpropanenitrile Chemical compound C=1C=CN=CC=1C(=O)C(C#N)C1=CC=CC=C1 MRHMJGLJPOGNFH-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- PSHZPPBCBVTVAC-UHFFFAOYSA-N 5,6-dihydrobenzo[1,2]cyclohepta[3,4-a]pyridin-11-one Chemical compound C1CC2=CC=NC=C2C(=O)C2=CC=CC=C21 PSHZPPBCBVTVAC-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- VSXAGIHWDDTIQP-UHFFFAOYSA-N 6,11-dihydro-5h-benzo[1,2]cyclohepta[3,4-b]pyridine Chemical compound C1CC2=CC=CN=C2CC2=CC=CC=C12 VSXAGIHWDDTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 101000856746 Bos taurus Cytochrome c oxidase subunit 7A1, mitochondrial Proteins 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 description 1
- 101100062121 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cyc-1 gene Proteins 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 101000650578 Salmonella phage P22 Regulatory protein C3 Proteins 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 101001040920 Triticum aestivum Alpha-amylase inhibitor 0.28 Proteins 0.000 description 1
- RMPCPFLMKUEWKH-UHFFFAOYSA-N [3-(2-phenylethyl)pyridin-2-yl] acetate Chemical compound C(C)(=O)OC1=NC=CC=C1CCC1=CC=CC=C1 RMPCPFLMKUEWKH-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- JGDFBJMWFLXCLJ-UHFFFAOYSA-N copper chromite Chemical compound [Cu]=O.[Cu]=O.O=[Cr]O[Cr]=O JGDFBJMWFLXCLJ-UHFFFAOYSA-N 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 150000008508 dibenzocycloheptenes Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- SWGLFOANRWDGLW-UHFFFAOYSA-N ethyl 4-(2-phenylethenyl)pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=CC=C1C=CC1=CC=CC=C1 SWGLFOANRWDGLW-UHFFFAOYSA-N 0.000 description 1
- 229940064982 ethylnicotinate Drugs 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012144 step-by-step procedure Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Description
Foreliggende oppfinnelse angår nye aza-dibenzo-[a,dj-cyclohepten-forbindelser for anvendelse som utgangsmaterialer ved fremstilling av terapeutisk virksomme 5-substituerte aza-dibenzo-[a,d]-cycloheptener. The present invention relates to new aza-dibenzo-[a,dj-cycloheptene compounds for use as starting materials in the production of therapeutically effective 5-substituted aza-dibenzo-[a,d]-cycloheptenes.
De nye forbindelser ifølge-oppfinnelsen bar den generelle formel: The new compounds according to the invention had the general formula:
hvor den stiplede linje betegner en fakultativ dobbeltbinding, where the dashed line denotes a facultative double bond,
A betegner hydrogen eller én eller flere av substituentene halogen (fortrinnsvis klor eller brom), lavere alkyl (fortrinnsvis methyl eller ethyl), trifluormethyl, lavere alkoxy (fortrinnsvis methoxy eller ethoxy), hydroxy eller lavere alkanoyloxy bundet i stillingene 6, 7, 8 og/eller 9 (fortrinnsvis 7 og/eller 8), og A denotes hydrogen or one or more of the substituents halogen (preferably chlorine or bromine), lower alkyl (preferably methyl or ethyl), trifluoromethyl, lower alkoxy (preferably methoxy or ethoxy), hydroxy or lower alkanoyloxy bound in positions 6, 7, 8 and /or 9 (preferably 7 and/or 8), and
Q betegner (H,H) eller O.Q denotes (H,H) or O.
Omfattet av formelen II er de respektive 1-aza-, 2-aza-, 3-aza- og -analoge, som alle faller innenfor den for B gitte definisjon. ,..." Included in formula II are the respective 1-aza-, 2-aza-, 3-aza- and -analogs, all of which fall within the definition given for B. ,..."
Den nomenklatur.som her er anvendt, er stort sett basert på den nomenklatur som er godkjent av Chemical Abstracts for dibenzo-cycloheptener. Identifiseringen av stillingene i det tricycliske system illustreres ved den følgende formel for 4~aza-lO,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-on, som er et av de foretrukne produkter i henhold til oppfinnelsen; The nomenclature used here is largely based on the nomenclature approved by Chemical Abstracts for dibenzo-cycloheptenes. The identification of the positions in the tricyclic system is illustrated by the following formula for 4~aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one, which is one of the preferred products according to the invention ;
For å lette identifiseringen er de av forbindelsene som har en 5-keto-substituent i den nedenstående av og til betegnet som "forbindelser av formel IIA", mens de som ikke er substituert i 5-stillingen [dvs. hvor Q i formel II er (H,H)], er betegnet som "forbindelser av formel IIB". For ease of identification, those of the compounds which have a 5-keto substituent in the following are occasionally designated as "compounds of formula IIA", while those which are unsubstituted in the 5-position [i.e. where Q in formula II is (H,H)], are designated as "compounds of formula IIB".
Aza-dibenzo-[a,d]-cyclohepten-forbindelsene med formel II ifølge oppfinnelsen anvendes som utgangsmaterialer ved fremstilling av terapeutisk aktive 5-substituerte aza-dibenzo-[a,d]-cyclohepten med den generelle formel: The aza-dibenzo-[a,d]-cycloheptene compounds of formula II according to the invention are used as starting materials in the production of therapeutically active 5-substituted aza-dibenzo-[a,d]-cycloheptene of the general formula:
og de i farmasøytisk henseende aksepterbare syreaddisjonssalter av disse, hvor A og B har den ovenfor angitte betydning og Z betegner en av gruppene^. • >f ..-..«.-I-.v'<;>• ■ -.^W hvor W er hydrogen eller hydroxyl, U er 3-piperidyl, N-lavere-alkyl-3-piperidyl, 4-piperidyl, N-lavere-alkyl-4-piperidyl eller og V er 3-piperidyliden, N-lavere-alkyl-3-piperidyliden, 4-piperidyliden, N-lavere-alkyl-4-piperidyliden eller and the pharmaceutically acceptable acid addition salts thereof, where A and B have the above meaning and Z denotes one of the groups ^. • >f ..-..«.-I-.v'<;>• ■ -.^W where W is hydrogen or hydroxyl, U is 3-piperidyl, N-lower-alkyl-3-piperidyl, 4- piperidyl, N-lower-alkyl-4-piperidyl or and V is 3-piperidylidene, N-lower-alkyl-3-piperidylidene, 4-piperidylidene, N-lower-alkyl-4-piperidylidene or
idet R^og R uavhengig av hverandre kan være hydrogen, in that R^ and R independently of each other can be hydrogen,
lavere alkyl eller en gruppe som sammen med nit rogenatornet til hvilket de er bundet, danner en eventuelt lavere-alkyl-subst i - tuert 5- eller 6-leddet heterocyclisk ring hvor et av leddene kan være.et oxygenatom eller et - ytterligere nitrogenatom, og X og Y er hydrocarbonradikaler med fra 2 til 9 carbonatomer, ved fremgangsmåten beskrevet i patent nr. 120.935. lower alkyl or a group which, together with the nitrogen atom to which they are attached, forms an optionally lower-alkyl-substituted 5- or 6-membered heterocyclic ring where one of the members can be an oxygen atom or an additional nitrogen atom, and X and Y are hydrocarbon radicals having from 2 to 9 carbon atoms, by the method described in patent no. 120,935.
Fremstillingen av foreliggende forbindelser med formel II er også beskrevet i patent 120.935. The preparation of the present compounds of formula II is also described in patent 120,935.
Forbindelsene av formel IIAkan fremstilles efter mange for-skjellige fremgangsmåter, blant hvilke der foretrekkes den intra-molekylære Friedel-Crafts-cyclisering av en ortho-styry1- eller ortho-fenethyl-pyridin-carboxylsyre (VIII) efter følgende reaksjonsskjema: The compounds of formula IIA can be prepared according to many different methods, among which the intra-molecular Friedel-Crafts cyclization of an ortho-styryl- or ortho-phenethyl-pyridine-carboxylic acid (VIII) according to the following reaction scheme is preferred:
I dette reaksjonsskjema har A, B og den stiplede linje de ovenfor angitte betydninger. Cycliseringen av den ortho-subst i - tuerte pyridin-carboxylsyre (VIII) utføres fortrinnsvis ved at den oppvarmes med polyfosforsyre ved en temperatur i området fra 100 til l6o°C, hvorved cycliseringen finner sted med dannelse av ketonet, IIA. Det er således åpenbart at den isomer som dannes, bestemmes av valget,av pyridin-carboxylsyre. Går man eksempelvis ut fra en forbindelse VIIIA, som 3-styryl-picolinsyre eller 3-fenethyl-2-picolinsyre, dannes der et 4~aza-keton (IIAd): In this reaction scheme, A, B and the dashed line have the meanings given above. The cyclization of the ortho-substituted pyridine carboxylic acid (VIII) is preferably carried out by heating it with polyphosphoric acid at a temperature in the range from 100 to 160°C, whereby the cyclization takes place with formation of the ketone, IIA. It is thus obvious that the isomer formed is determined by the choice of pyridine carboxylic acid. For example, starting from a compound VIIIA, such as 3-styryl-picolinic acid or 3-phenethyl-2-picolinic acid, a 4~aza-ketone (IIAd) is formed:
Ved på tilsvarende måte å-gå ut f ra - 4.-styryl - eller 4-f enethyl -nicot insyrene (VIIIB),. fåes dertil sva rende 3-aza_ ketoner (IIAc). Fra 3-styryl- eller 3-fenethyl-isonicotiasyrene (VIIIC) fåes 2-aza-ketoner (IIAb) og fra 2-styryl- eller 2-fen--ethyl-nicot insyrene (VIIID) fåes 1 -aza-ketoner '(IIAa ) . By starting in a similar way from - 4.-styryl - or 4-phenethyl -nicotinic acids (VIIIB). corresponding 3-aza_ketones (IIAc) are obtained. From the 3-styryl or 3-phenethyl-isonicotia acids (VIIIC) 2-aza-ketones (IIAb) are obtained and from the 2-styryl- or 2-phen--ethyl-nicotinic acids (VIIID) 1-aza-ketones are obtained '( IIAa ).
Cycliser ingen som er illustrert ovenfor, utføres på Jf rie pyridin-carboxylsyrer (VIII). Alternative og ekvivalente fremgangsmåter vil være åpenbare for en fagmann på området. således kan der i stedet for syren anvendes et funksjonelt derivat av" denne, som en tilsvarende ester, et amid, et nitril eller et isomert lacton, eller carboxylsyren kan først overføres til et syrehalogenid, f.eks. klorid, ved hjelp av et kloreringsmiddel såsom thionylklorid, f osfort riklorid eller oxalylklorid ired på-følgende behandling f.eks. med en Friede1-Crafts-kat a lysa tor som. aluminiumklorid, hvorved cyclisering finner sted med derav følg-ende dannelse av den respektive forbindelse som omfattes av den generelle formel IIA. Cycliseringen utføres vanligvis ved kon-vensjonelle metoder for utførelse av en Friedel-Crafts-reaksjon, nemlig ved at blandingen oppvarmes i et inert oppløsningsimiddel som carbondisulfid, petrolether, benzen og lignende og isolering av det cycliserte produkt fra dette. Cyclizations illustrated above are carried out on Jf rie pyridine carboxylic acids (VIII). Alternative and equivalent methods will be apparent to one skilled in the art. thus, instead of the acid, a functional derivative of this can be used, such as a corresponding ester, an amide, a nitrile or an isomeric lactone, or the carboxylic acid can first be transferred to an acid halide, e.g. chloride, by means of a chlorinating agent such as thionyl chloride, phosphoric chloride or oxalyl chloride followed by subsequent treatment, for example with a Friede1-Crafts cat lysator such as aluminum chloride, whereby cyclization takes place with consequent formation of the respective compound which is covered by the general formula IIA The cyclization is usually carried out by conventional methods for carrying out a Friedel-Crafts reaction, namely by heating the mixture in an inert solvent such as carbon disulphide, petroleum ether, benzene and the like and isolating the cyclized product therefrom.
Andre derivater av pyridin-carboxylsyrene (VIII), som visse lactoner som det er gitt eksempler på nedenfor, kan likeledes anvendes som ut gangsmaterialer i den cycliseringsprosess som . Other derivatives of the pyridine-carboxylic acids (VIII), such as certain lactones of which examples are given below, can likewise be used as starting materials in the cyclization process which .
leder til mellomproduktene IIA. leading to the intermediates IIA.
Fenethyl-pyridin-carboxylsyre-utgangsmaterialene med den generelle formel VIII kan lett fremstilles ut fra de tilsvarende" e styryi-pyridin-carboxylsyrer efter kjente metoder som ved kata-' lytisk hydrogenering eller ved uavhengige synteser, som det vil bli beskrevet lenger, f remme .- Som det skal vises , f r em st i. Iles'"de cycliske ketoner (IIA),som har en umettethet mellom sti 1lingene.IO og 11, av og til fortrinnsvis fra 10|ll-dihydro-analogen2 ved. dehydrogenering med seléndioxyd eller efter andre metoder som gir det samme resultat , 'som ved behandling med N-brom-succinimid eller ved bromering under innvirkning av sollys, med påfølgende de-hydrohalogenering ved hjelp av triethylamin, alkoholisk kaliumhydroxyd eller andre' kjente dehydrohalogeneringsmidler. The phenethyl-pyridine-carboxylic acid starting materials with the general formula VIII can be easily prepared from the corresponding styryl-pyridine-carboxylic acids according to known methods such as by catalytic hydrogenation or by independent syntheses, which will be described further on .- As will be shown, primarily i. Iles'" the cyclic ketones (IIA), which have an unsaturation between the sti 1lings. 10 and 11, occasionally preferably from the 10|11-dihydro-analogue2 by. dehydrogenation with selenium dioxide or by other methods which give the same result, 'such as by treatment with N-bromosuccinimide or by bromination under the influence of sunlight, with subsequent dehydrohalogenation using triethylamine, alcoholic potassium hydroxide or other' known dehydrohalogenation agents.
<å>Benzen kan strengt tatt ikke kalles "inert" i en Friedel-Crafts-reaksjon. Det kan imidlertid her betraktes som praktisk talt inert. <å>Benzene cannot strictly speaking be called "inert" in a Friedel-Crafts reaction. However, it can be considered here as practically inert.
Spesielt fremstilles 1-aza-ketonene (IIAa) fortrinnsvis på en av de mulige måter som er vist i det følgende reaksjonsskjema: In particular, the 1-aza-ketones (IIAa) are preferably prepared in one of the possible ways shown in the following reaction scheme:
I det foregående reaks jonsskjema^ utføres omsetningen mellom X og en 2-methyl-nicotinsyreester (IX) som ethylT2-methy1 - nicotinat, ved oppvarmning med tilbakeløpskjøling.i eddiksyreanhydrid, hvorved der fåes et lacton (XI). Lactonet (XI) kan overføres direkte til det tilsvarende cycliske keton (IIAaa) ved oppvarmning med polyfosforsyre.- Det kan også'; som vist ', overføres indirekte til det cycliske keton via en 2-styryl-nicotinsyre . VIIIDa. Ved behandling av lactonet (XI) med'fosfor og jod i vann (eller med 57%-ig vandig jodsyre og fosfor) eller ved reduksjon av 2-styryl-nicotinsyren (VIIIDa) fåes den tilsvarende 2-fenethyl-nicotinsyre (VIIIDb) . ' Denne sistnevnte overf øres ' ved oppvarmning med polyfosforsyre til den 10,11-dihydro-analoge (IIAaØ) og IIAaa. In the preceding reaction scheme^, the reaction between X and a 2-methyl-nicotinic acid ester (IX) is carried out as ethylT2-methyl-nicotinate, by heating with reflux in acetic anhydride, whereby a lactone (XI) is obtained. The lactone (XI) can be transferred directly to the corresponding cyclic ketone (IIAaa) by heating with polyphosphoric acid.- It can also'; as shown', is indirectly transferred to the cyclic ketone via a 2-styryl-nicotinic acid. VIII Then. By treating the lactone (XI) with phosphorus and iodine in water (or with 57% aqueous iodic acid and phosphorus) or by reducing the 2-styryl-nicotinic acid (VIIIDa) the corresponding 2-phenethyl-nicotinic acid (VIIIDb) is obtained. ' This latter is transferred ' by heating with polyphosphoric acid to the 10,11-dihydro analogue (IIAaØ) and IIAaa.
Ved den ovenfor beskrevne reaksjon er den kjemiske omdann-else av IX til XI kjent på området for A = H, men den er vist her for å gi et grunnlag for fremstillingen av de cycliske ketoner (IIAaa) og deres 10,11-dihydro-analoge (IIAa(3) hvor A har .andre betydninger enn hydrogen. In the reaction described above, the chemical conversion of IX to XI is known in the area of A = H, but it is shown here to provide a basis for the preparation of the cyclic ketones (IIAaa) and their 10,11-dihydro- analogous (IIAa(3) where A has meanings other than hydrogen.
2-aza-ketonene (IIAb) fremstilles fortrinnsvis i de følg-ende trinn: The 2-aza-ketones (IIAb) are preferably prepared in the following steps:
I denne serie av reaksjoner, kondenseres en 4-methyl-nicotinsyreester (XII) som ethy1-4-methyl-nicontinat med et fenyl- ' ' ' acetonitril (XIII), hvorved det tilsvarende ketonitril (XIV) dannes. Fortrinnsvis anvendes der en basisk katalysator "som et alkalimetallalkoxyd, f .eks. natriumethoxyd i ethanol. Imidlertid kan også andre kondensasjonsmidler anvendes, som natriumamid eller nat riumhydroxyd i et oppløsningsmiddel som' benzen eller toluen. Omdannelsen til ketonet, XV, utføres ved oppvarmning av XIV med en sterk mineralsyre, fortrinnsvis konsentrert hydrobrom-syre. (Alternativt kan dette trinn utføres ved at XIV oppvarmes med konsentrert svovelsyre, hvorved forbindelsen omdannes til det tilsvarende syreamid. Dette kan. hydrolyseres, og produktet kan deca rboxy ler es ved tilsetning av vann til reaks jonsblandi ngen .. under fortsatt oppvarmning.) Reduksjon av ketonet (XV) utføres fortrinnsvis ved den velkjente Wolff-Kishner-reaksjon som omfatter oppvarmning av XV med hydrazinhydrat i et høytkokende polart opp-løsningsmiddel som trimethylenglycol i nærvær av alkali, s;om natriumhydroxyd eller kaliumhydroxyd. I stedet for Wolff-Kishner-reduksjonen kan man også anvende kobberkromitt i dioxan ved en temperatur på ca. l6o°C og et hydrogentrykk på ca. 100 atmosfærer. Ved denne reduksjon fåes et 3-fenethyl-4-methylpyridin, XVI. Denne sistnevnte forbindelse overføres f.eks. ved oxydasjon med selendioxyd i pyridin, til den tilsvarende 3-f enethyl-isonicot :.nsyre (VHICb) , som ved oppvarmning med polyfosforsyre undergår cyciiser-ing til det cycliske keton IIAb(3. In this series of reactions, a 4-methyl-nicotinic acid ester (XII) is condensed as ethyl 1-4-methyl-nicotinate with a phenyl- ' ' ' acetonitrile (XIII), whereby the corresponding ketonitrile (XIV) is formed. Preferably, a basic catalyst is used, such as an alkali metal alkoxide, e.g. sodium ethoxide in ethanol. However, other condensation agents can also be used, such as sodium amide or sodium hydroxide in a solvent such as benzene or toluene. The conversion to the ketone, XV, is carried out by heating XIV with a strong mineral acid, preferably concentrated hydrobromic acid. (Alternatively, this step can be carried out by heating XIV with concentrated sulfuric acid, whereby the compound is converted to the corresponding acid amide. This can be hydrolyzed, and the product can be decarboxylated by the addition of water to reaction ion mixture .. with continued heating.) Reduction of the ketone (XV) is preferably carried out by the well-known Wolff-Kishner reaction which comprises heating XV with hydrazine hydrate in a high-boiling polar solvent such as trimethylene glycol in the presence of alkali, s; about sodium hydroxide or potassium hydroxide Instead of the Wolff-Kishner reduction, copper can also be used rchromite in dioxane at a temperature of approx. l6o°C and a hydrogen pressure of approx. 100 atmospheres. This reduction gives a 3-phenethyl-4-methylpyridine, XVI. This latter connection is transferred e.g. by oxidation with selenium dioxyd in pyridine, to the corresponding 3-phenethyl-isonicotic acid (VHICb), which undergoes cyclization to the cyclic ketone IIAb (3.
Det vil sees at man ved anvendelse av et para-substituert f eny lacetonit r il (XIII) til sist vil få et cyclisk ke^o^^^IAbS^^^.-. «mj-med nevnte substituent i 7-stillingen. Med et meta-subst ituert/v. fenylacetonitril (CIII) fåes der en blanding av ketoner (EIAbB), idet det ene har substituenten i 6-stillingen og det andre har • substituenten i 8-stillingen. Disse kan separeres,enten i' dette.. sluttrinn, eller de isomere mellomprodukter kan separeres i et hvilket som helst trinn i serien av reaksjoner efter kjente fremgangsmåter, som ved fraksjonert destillasjon, fraksjonert krystallisasjon, søylekromatografer ing og lignende. It will be seen that by using a para-substituted f eny lacetonite r il (XIII) you will finally get a cyclic ke^o^^^IAbS^^^.-. «mj-with said substituent in the 7-position. With a meta-subst ituated/v. phenylacetonitrile (CIII), a mixture of ketones (EIAbB) is obtained, one having the substituent in the 6-position and the other having the • substituent in the 8-position. These can be separated, either in this final step, or the isomeric intermediates can be separated in any step in the series of reactions according to known methods, such as by fractional distillation, fractional crystallization, column chromatography and the like.
Den 10,11-dehydro-analoge (IIAba) av IIAbp fremstilles fortrinnsvis ut fra sistnevnte ved dehydrogeriering, enten ved hjelp av selendioxyd i pyridin eller ved behandling.avIIAbS med N-brom-succinimid med påfølgende'dehydrobromering av det således erholdte brom-mellomprodukt. The 10,11-dehydro analogue (IIAba) of IIAbp is preferably prepared from the latter by dehydrogenation, either with the help of selenium dioxide in pyridine or by treatment of IIAbS with N-bromosuccinimide followed by dehydrobromination of the bromine intermediate thus obtained .
Ved fremstilling av 3-aza-ketonene (IIAc) foretrekkes den følgende serie av reaksjoner: In the preparation of the 3-aza-ketones (IIAc), the following series of reactions is preferred:
I denne serie av reaksjoner omsettes en 4-methyl-nicotinsyreester (XII) som ethyl-4-methyl-nicotinat, nemlig det samme utgangsmateriale som ble anvendt i den ovenfor beskrevne fore- In this series of reactions, a 4-methyl-nicotinic acid ester (XII) is reacted as ethyl-4-methyl-nicotinate, namely the same starting material that was used in the above-described preparation
trukne fremgangsmåte for fremstilling av forbindelser av 2-aza-drawn process for the preparation of compounds of 2-aza-
rekken, med X ved oppvarmning i eddiksyreanhydrid med tilbake-løpsk jøling_, hvorved fåes en 4-styryl-nicotinsyreester (VIIIBa'). series, with X by heating in acetic anhydride with refluxing_, whereby a 4-styryl-nicotinic acid ester (VIIIBa') is obtained.
Ved reduksjon av esteren (VIIIBa'), fortrinnsvis katalytisk somIn the reduction of the ester (VIIIBa'), preferably catalytically as
med palladium og hydrogen, med påfølgende hydrolyse av ester-with palladium and hydrogen, with subsequent hydrolysis of ester-
gruppen, fåes en 4-fenethyl-nicotinsyre (VIIIBb) som ved oppvarm-group, a 4-phenethyl-nicotinic acid (VIIIBb) is obtained which, when heated
ning med polyfosforsyre cycliseres til det tilsvarende 3_aza-ning with polyphosphoric acid is cyclized to the corresponding 3_aza-
keton (IIAc(3). De 10,11-dehydro-ana loge (IIAca) av IIAcp frem-ketone (IIAc(3). The 10,11-dehydro analogues (IIAca) of IIAcp pre-
stilles enten ved dehydrogenering av selve ketonet (IIAcp) som tidligere beskrevet, eller ved hydrolyse av VIIIBa' til den til- v> • svarende frie carboxylsyre (VIIIBa) med påfølgende oppvarmning V is produced either by dehydrogenation of the ketone itself (IIAcp) as previously described, or by hydrolysis of VIIIBa' to the corresponding free carboxylic acid (VIIIBa) with subsequent heating V
av sistnevnte med polyfosforsyre. Dersom cycliseringen utføres ved forhøyede temperaturer i området rundt 190°C, fåes hovedsake- of the latter with polyphosphoric acid. If the cyclization is carried out at elevated temperatures in the region of around 190°C, the main
lig IIAca. Ved lavere temperaturer dannes et lacton, nemlig den 4-aralkyl-isomere av XI som et biprodukt. Når dette lacton opp- equal to IIAca. At lower temperatures, a lactone, namely the 4-aralkyl isomer of XI, is formed as a by-product. When this lactone up-
varmes med polyfosforsyre efter den fremgangsmåte som er be-heated with polyphosphoric acid according to the procedure
skrevet for 1-aza-rekken, omdannes det i sin tur til det cycliske :.. keton (IIAca) . written for the 1-aza series, it is in turn converted into the cyclic :.. ketone (IIAca) .
For fremstilling av 4-aza-ketonene (IIAd) foretrekkes derFor the preparation of the 4-aza-ketones (IIAd) there is preferred
anvendt den følgende serie av reaksjoner: applied the following series of reactions:
I dette reaksjonsskjema overføres en nicotinsyreester (XVII), fortrinnsvis ethy1-nicotinat, til et 3-fenethyl-pyridin (XX) efter den samme serie av reaksjoner som beskrevet for de respektive homo-forbindelser ved fremstilling av 2-aza-rekken. Kondensasjonen av XVII med.et fenylacetonitril (XIII) utføres fortrinnsvis i ethanol i nærvær av natriumethoxyd eller andre kondensasjonsmidler som de som er anvendt i den ovenfor beskrevne kondensasjon "XII + XIII »XIV". I stedet for Wolff-Kishner-reduksjonen kan der også anvendes kobberkromitt i dioxan ved ca. l6o°C under et hydrogentrykk på ca. 100 atmosfærer. Fenethyl-pyridinet (XX) over-.føres til dets N-oxyd (XXI) ved hjelp av en peroxysyre, som hydrogenperoxyd og eddiksyre. Ved omsetning av XXI med dimethylsulfat og derefter med vandig natriumcyanid-oppløsning fåes et 2-cyano-3~fenethyl-pyridin (XXII). Nitrilet (XXII) kan cycliseres direkte til det tilsvarende 4-aza-keton (IladB) ved oppvarmning med polyfosforsyre, eller det kan først hydrolyseres til den tilsvarende carboxylsyre (Vlllab) som derefter cycliseres. De 10,11-dehydro-analoge (IIAda) av IIAd(3 kan fremstilles ved direkte dehydrogenering av sistnevnte, f.eks. med selendioxyd i pyridin, eller ved en hvilken som helst av de fremgangsmåter som er angitt i de efterfølgende eksempler. In this reaction scheme, a nicotinic acid ester (XVII), preferably ethyl 1-nicotinate, is transferred to a 3-phenethyl-pyridine (XX) following the same series of reactions as described for the respective homo-compounds in the preparation of the 2-aza series. The condensation of XVII with a phenylacetonitrile (XIII) is preferably carried out in ethanol in the presence of sodium ethoxide or other condensation agents such as those used in the above-described condensation "XII + XIII »XIV". Instead of the Wolff-Kishner reduction, copper chromite in dioxane can also be used at approx. l6o°C under a hydrogen pressure of approx. 100 atmospheres. The phenethyl pyridine (XX) is converted to its N-oxide (XXI) by means of a peroxyacid, such as hydrogen peroxide and acetic acid. By reacting XXI with dimethylsulphate and then with aqueous sodium cyanide solution, a 2-cyano-3-phenethyl-pyridine (XXII) is obtained. The nitrile (XXII) can be cyclized directly to the corresponding 4-aza-ketone (IladB) by heating with polyphosphoric acid, or it can first be hydrolyzed to the corresponding carboxylic acid (VIllab) which is then cyclized. The 10,11-dehydro analogues (IIAda) of IIAd(3) can be prepared by direct dehydrogenation of the latter, e.g. with selenium dioxide in pyridine, or by any of the methods indicated in the following examples.
N-oxydene XXI er særlig verdifulle ved fremstilling av 4-aza-ketonene (IIAd) fordi der også kan utføres ytterligere andre omdannelser som til slutt fører til sådanne ketoner (IIAd). Spesielt fåes der ved omsetning av et N-oxyd (XXI) med eddiksyreanhydrid det tilsvarende 2-acetoxy-3-fenethyl-pyridin, som kan hydrolyseres til dens 2-fri-hydroxy-analoge ved hjelp av vandig mineralsyre, f.eks. saltsyre. Hydroxygruppen kan derefter er-stattes med brom (ved hjelp av fosforoxybromid), hvorved man får det respektive 2-brom-3-f enethyl-pyr idin. Ved omsetning av dette The N-oxides XXI are particularly valuable in the preparation of the 4-aza-ketones (IIAd) because further other conversions can also be carried out which ultimately lead to such ketones (IIAd). In particular, by reacting an N-oxide (XXI) with acetic anhydride, the corresponding 2-acetoxy-3-phenethyl-pyridine is obtained, which can be hydrolysed to its 2-free-hydroxy analogue by means of aqueous mineral acid, e.g. hydrochloric acid. The hydroxy group can then be replaced with bromine (using phosphorus oxybromide), whereby the respective 2-bromo-3-phenethyl-pyridine is obtained. When selling this
sistnevnte mellomprodukt med "butyllithium og derefter med carbon-dioxyd fåes carboxylsyren (VIIIAb) som derefter kan cycliseres the latter intermediate with "butyllithium and then with carbon dioxide gives the carboxylic acid (VIIIAb) which can then be cyclized
til 11 Ad 3 .. to 11 Ad 3 ..
Det vil være åpenbart for f agmannen på området at der er . • r" utallige varianter av de ovenfor beskrevne reaks joner som vil ., V'-':'. ' -føre til dannelse a-v fenethyl- og styry 1-py ridin-carboxylsyrer. It will be obvious to the person skilled in the art that there is . • r" innumerable variants of the reactions described above which will ., V'-':'. ' -lead to the formation of a-v phenethyl- and styry 1-pyridin-carboxylic acids.
Alle disse reaksjoner ansees i kjemisk henseende å være ekvivalente med dem som er illustrert ovenfor. Eksempelvis kan reak-sjonsskjemaet som viser fremstillingen av et 2-aza-keton (IIAb), tilpasses for fremstilling av. et 4-aza-keton (IIAd) ganske enkelt ved at der anvendes en 2-methyl-nicotinsyreesterf.som ethyl-2- : methylnicotinat som utgangsmateriale. Den nære analogi mellom fremgangsmåtene for fremstilling av 1-aza-ketonene (IIAaj og 3- 1 ■ aza-ketonene (IIAc) vil også lett sees.... All these reactions are considered to be chemically equivalent to those illustrated above. For example, the reaction scheme showing the production of a 2-aza ketone (IIAb) can be adapted for the production of a 4-aza-ketone (IIAd) simply by using a 2-methyl-nicotinic acid ester such as ethyl-2-:methylnicotinate as starting material. The close analogy between the methods for the preparation of the 1-aza-ketones (IIAaj and the 3- 1 ■ aza-ketones (IIAc) will also be readily seen....
Fremstillingen av aza-dibenzo-cycloheptenene (IIB) [hvor Q i formel II er (H,H)] kan utføres efter hvilken som helst av de kjente fremgangsmåter for overføring av en ketogruppe til en methylengruppe. Wolff-Kishner-reduksjonsmetoden, hvor et keton (IIA) oppvarmes med hydrazin og etc alkali som kaliumhydroxyd,fer den foretrukne fremgangsmåte'.På^den annen side kan' ket o-gruppen i forbindelsene med formel IIA først reduseres til en hydroxy-gruppe, hvorefter den således erholdte carbinol i sin tur ytterligere reduseres til den tilsvarende forbindelse IIB.. Det første trinn i denne serie kan utføres f .eks. ved at ketonet (IIA) ouir settes med lithium-aluminiumhydrid under anvendelse av zinkstøv i ammoniakk, eller ved katalytisk reduksjon under anvendelse av platinaoxyd eller Raney-nikkel. De således erholdte cartainoler kan derefter overføres til methylenforbindelsene (IIB) ved at de kloreres med thionylklorid med påfølgende erstatning av kloratomet med hydrogen, f.eks. ved å oppvarme klor-mellomproduktet med til-bakeløpskjøling i nærvær av zinkstøv, kaliumjodid og eddiksyre, eller carbinolene kan reduseres direkte, f.eks. med jod og fosfor i iseddik. Også andre metoder kan selvfølgelig anvendes. I de tilfeller hvor aza -dibenzo-cyclohepten-5-on-mellomproduktet (IIA) inneholder halogen- eller trifluormethyl-substituenter i benzenoid-delen, er det særlig å foretrekke at. man anvender-,-;,,, - •Wolf f -Kishner-reduksjonen „,, „-»'»•♦.. ■ The production of the aza-dibenzo-cycloheptenes (IIB) [where Q in formula II is (H,H)] can be carried out according to any of the known methods for transferring a keto group to a methylene group. The Wolff-Kishner reduction method, where a ketone (IIA) is heated with hydrazine and etc alkali such as potassium hydroxide, is the preferred method'. On the other hand, the ketone o group in the compounds of formula IIA can first be reduced to a hydroxy group , after which the carbinol thus obtained is in turn further reduced to the corresponding compound IIB.. The first step in this series can be carried out e.g. by adding the ketone (IIA) ouir with lithium aluminum hydride using zinc dust in ammonia, or by catalytic reduction using platinum oxide or Raney nickel. The cartainols thus obtained can then be transferred to the methylene compounds (IIB) by chlorinating them with thionyl chloride with subsequent replacement of the chlorine atom with hydrogen, e.g. by heating the chlorine intermediate with reflux in the presence of zinc dust, potassium iodide and acetic acid, or the carbinols can be reduced directly, e.g. with iodine and phosphorus in glacial acetic acid. Other methods can of course also be used. In those cases where the aza-dibenzo-cyclohepten-5-one intermediate (IIA) contains halogen or trifluoromethyl substituents in the benzenoid part, it is particularly preferable that. one applies-,-;,,, - •Wolf f -Kishner reduction „,, „-»'»•♦.. ■
De nedenstående eksempler 1-4 illustrerer fremstillingen av ketoner med formel IIA. Alle disse eksempler fører t:Ll aza-dibenzo-cycloheptenoner som er usubstituerte på benzenringen. For å fremstille ketoner med en substituent i én eller, fleire, av 6-, 7-j 8_ og 9-stUlingene, er det som ovenfor névnt, bare å anvende den passende substituerte reaktant . 'I eksemplene 1 og" 3 er det anvendt benzaldehyd som_reaktant,.mens det i eksemplene 2 og 4 er anvendt fenylacetonitril..Dersom disse reaktanter er substituerte, vil. substituenten.bii fdrt méd til det respektive aza-diberizo-cycloheptenon, idet^stillingen vil være avhengig av. still--a "'ingen ; i" den' opprinnelige reaktant. Eksempelvis fører en para- substituent i den opprinnelige reaktant..til, et 7-subst ituert sza-dibenzo-cycloheptenon, mens en ortho,-subst ituent kommer til syne i 9-stillingen og en meta-substituent. fører^.til en blanding bestående av et 6-subst ituert' og et 8-subst ituert aza-dibenzo-cycloheptenon. • (For separering av en blanding av 6- og ^-substituerte aza-dibenzo-cycloheptenoner anvendes"' fort r innsv is spyle-kromatografering, hvor blandingen adsorberes på a 1uminiumoxyd og elueres med blandinger av benzen og hexan i 'varierende mengdefor-hold. Sammenslåing av eluater som er påvist like ved analyse i det infrarøde eller det ult rafiolette.område eller- ved t ynnskikts-kromatogrnfering, gir de respektiveisomere'adskilt fra-hverandre. Den opprinnelige reaktant, nemlig benza1dehydet oller feny1acetonitr i let , kan således ha en o-, m- eller p-substituent , som methyl , kl orj brom, trifluormethyl , methoxy og lignende, og en sådan substituent vil være tilstede i den tilsvarende stilling i det erholdte aza-dibenzo-cycloheptanon. De substituerte, opprinnelige reaktanter, som p-k 1 orf eny lacet onit r i 1 oller p-t r.i - f1uormethylbenza1dehyd. er enten kjente forbindelser oller kan lott fremstilles efter fremgangsmåter som vil være kjent for en fagmann på området. The examples 1-4 below illustrate the preparation of ketones of formula IIA. All these examples lead to t:Ll aza-dibenzo-cycloheptenones which are unsubstituted on the benzene ring. To prepare ketones with a substituent in one or, more, of the 6-, 7-, 8- and 9-stUlings, it is, as mentioned above, only to use the suitably substituted reactant. In examples 1 and 3, benzaldehyde is used as reactant, while in examples 2 and 4 phenylacetonitrile is used. If these reactants are substituted, the substituent will be added to the respective aza-diberizo-cycloheptenone, as the position will depend on. still--a "'none ; in the original reactant. For example, a para-substituent in the original reactant leads to a 7-substituted sza-dibenzo-cycloheptenone, while an ortho-substituent appears in the 9-position and a meta- substituent. leads^.to a mixture consisting of a 6-substituted' and an 8-substituted aza-dibenzo-cycloheptenone. • (For separation of a mixture of 6- and ^-substituted aza-dibenzo-cycloheptenones use rapid flash chromatography, where the mixture is adsorbed on aluminum oxide and eluted with mixtures of benzene and hexane in varying amounts. Combining eluates that have been detected by analysis in the infrared or ultraviolet range or by t thin-layer chromatography gives the respective isomers separated from each other. The original reactant, namely benzaldehyde or phenylacetonitrile, can thus have an o-, m- or p-substituent, such as methyl, chlorine, bromine, trifluoromethyl, methoxy and similar, and such a substituent will v honor present in the corresponding position in the obtained aza-dibenzo-cycloheptanone. The substituted, original reactants, such as p-k 1 orf eny lacet onit r i 1 oller p-t r.i - fluoromethylbenza1dehyde. are either known compounds or lots can be prepared according to methods that will be known to a person skilled in the field.
Eksempel 1 Example 1
1-aza-10 ,11 -di hydro-5H-dibenzo-|a,d j-cyclohepten-5-on on 1 -aza - 5H -di bonzo -| a , d ] - cyc 1 ohept o n- 5-on 1-aza-10 ,11 -di hydro-5H-dibenzo-|a,d j-cyclohepten-5-one on 1 -aza - 5H -di bonzo -| a , d ] - cyc 1 ohept o n- 5-one
A . 2 - ((' - hydruxy -[ - f eny 1 ) - et hy 1 - nico t in sy re - 1 act on - hydr ■ iK 1 o r i d A. 2 - ((' - hydruxy -[ - f eny 1 ) - et hy 1 - nico t in sy re - 1 act on - hydr ■ iK 1 o r i d
Omrør og oppvarm med tilbakeløpskjøling en blanding av 6.5 g et hy 1-2-mothy 1-nicot inat , 57 g. benza 1 dehyd og 37"il eddiksyre-" anhydrid i 20 timer. Avkjøl så og hell blandingen over i 2,G n saltsyre. ' Frafiltrer det faste stoff efter krysta 11 ise ring og omkryst a 1 1 i ser det fra ethanol. Det fåes 13,5 g 2 - (('. -hydroxy-B - f eny 1 )-et hy 1-nicot insy re-lact on-hydroklor id , smp. 1^3 lh,~) °C. Stir and reflux a mixture of 6.5 g of ethyl 1-2-mothy 1-nicotinate, 57 g of benza 1 dehyde and 37 µl of acetic anhydride for 20 hours. Then cool and pour the mixture into 2.G n hydrochloric acid. Filter off the solid after crystallization and recrystallize it from ethanol. 13.5 g of 2 - (('. -hydroxy-B - f eny 1 )-et hy 1-nicotin insy re-lact on-hydrochlor id , mp. 1^3 lh,~) °C are obtained.
-v-..-w-..
B. 2- styry 1- nicotinsyreB. 2- styry 1- nicotinic acid
Bland 60 g rødt fosfor, 20 g jod.i 1,5 liter iseddik og til-sett porsjonsvis til den således erholdte bla ndihg '176 g'2.-(^-' hydroxy -(?.-feny 1) -et hyl -nicot insyre - lacton -hy drok lor id':, "'Oppvarm i Mix 60 g of red phosphorus, 20 g of iodine in 1.5 liters of glacial acetic acid and add in portions to the mixture thus obtained. -nicot insyre - lactone -hy drok lor id':, "'Heat i
• '. '•■< .>.<,"-• '. '•■< .>.<,"-
20 timer og filtrer den varmé oppløsning gjennom, en-trakt av 20 hours and filter the warm solution through, one-funnel off
sintret glass. Hell filtratet over"'i vahn"'og: f ilt rer utfelninaen efter den nødvendige tid for dens .dannelse :"og.; koaguler i ng . Opp-løs den filtrerte utfeining i 2 liter varm, 'fortynnet ( IO - 15~) sintered glass. Pour the filtrate into a vessel and: filter the precipitate after the necessary time for its formation: and coagulate in ng. Dissolve the filtered precipitate in 2 liters of warm, diluted (10 - 15~ )
vandig ammoniakk, filtrer påny, og nøytraliser filtratet med eddiksyre. Avkjøl og fraskill den utfelte..2-styryl-nicotinsyre ved filtrering og omkrystalliser fra ethanol.. Smp.: 219 - 221°C; utbytte: 130 g. aqueous ammonia, filter again, and neutralize the filtrate with acetic acid. Cool and separate the precipitated..2-styryl-nicotinic acid by filtration and recrystallize from ethanol.. Mp.: 219 - 221°C; yield: 130 g.
C. 2-fenethyl- nicotinsyreC. 2-phenethyl-nicotinic acid
(1) I et (Parr) hydrogeneringsapparat av rystetypen blandes(1) In a (Parr) shaker-type hydrogenator, mix
22 g 2-styryl-nicotinsyre, 2CO ml ethanol og 20 ml av en 25%-ig 22 g of 2-styryl-nicotinic acid, 20 ml of ethanol and 20 ml of a 25%
vandig oppløsning av natriumhydroxyd. Blandingen hydrogeneres ved et hydrogentrykk på ca. 3>6 atmosfærer under anvendelse av en friskt tilberedt Raney-nikkel-katalysator. Efter at den teo-retiske mengde hydrogen er blitt absorbert (1 mol pr. mol syre), vanligvis efter omtrent 30 - 60 minutter, filtreres blandingen, aqueous solution of sodium hydroxide. The mixture is hydrogenated at a hydrogen pressure of approx. 3>6 atmospheres using a freshly prepared Raney nickel catalyst. After the theoretical amount of hydrogen has been absorbed (1 mole per mole of acid), usually after about 30 - 60 minutes, the mixture is filtered,
og filtratet konsentreres ved oppvarmning på et dampbad. Resi-and the filtrate is concentrated by heating on a steam bath. Resi-
duet oppløses i vann. Efter surgjøring frafiltreres den urene fenethyl-nicotinsyre. Efter omkrystallisering fra benzen-hexan er smeltepunktet 162 - l63°C. (2) Alternativt kan 2-fenethyl-nicotinsyre fremstilles på følg-ende måte: 100 g av laconet fra dette eksempels del A oppvarmes med 1 liter 57%-ig jodsyre med tilsetning av 60 g rødt fosfor over et tidsrom på 2 timer. Blandingen oppvarmes med tilbakeløps-kjøling i 18 timer og filtreres varm. Det meste av den overskyt-ende jodsyre fjernes ved konsentrering, og den gjenværende opp-løsning nøytraliseres med vandig ammoniakk, hvorved 2-fenethyl-nicotinsyreTitfelles. the dove dissolves in water. After acidification, the impure phenethyl-nicotinic acid is filtered off. After recrystallization from benzene-hexane, the melting point is 162 - 163°C. (2) Alternatively, 2-phenethyl-nicotinic acid can be prepared in the following way: 100 g of the lacone from part A of this example is heated with 1 liter of 57% iodic acid with the addition of 60 g of red phosphorus over a period of 2 hours. The mixture is heated with reflux cooling for 18 hours and filtered hot. Most of the excess iodic acid is removed by concentration, and the remaining solution is neutralized with aqueous ammonia, whereby 2-phenethyl-nicotinic acid is formed.
D. l-aza-10,ll-dihydro-5H-dibenzo-[a,dJ-cyclohepten-5-onD. 1-aza-10,11-dihydro-5H-dibenzo-[a,dJ-cyclohepten-5-one
50 g 2-fenethyl-nicotinsyre og 5CO. g polyfosforsyre blandes " og oppvarmes ved l6o - l65°C i 5 - 6 timer under omrøring. Blandingen kjøles derefter, helles over i isvann, nøytraliser.es med vandig ammoniakk og ekstraheres med ether .Etherekstrakten vaskes med 10%-ig natriumhydroxydoppløsning. Etherskiktet tørres og konsentreres til et residuum som ved krystallisasjon fra hexan gir det ønskede keton. Smeltepunkt 62 - 64°C. 50 g of 2-phenethyl-nicotinic acid and 5CO. g of polyphosphoric acid are mixed and heated at 160 - 165°C for 5 - 6 hours with stirring. The mixture is then cooled, poured into ice water, neutralized with aqueous ammonia and extracted with ether. The ether extract is washed with 10% sodium hydroxide solution. The ether layer dried and concentrated to a residue as by crystallization from hexane gives the desired ketone. Melting point 62 - 64°C.
E. 1-aza-5H-dibenzo-[a,d]-cyclohepten-5-onE. 1-aza-5H-dibenzo-[a,d]-cyclohepten-5-one
(1) 20av ketonet fra dette eksempels del D oppløses i 150 ml eddiksyre, hvorefter der tilsettes 40 ml 30%-ig hydrogenperoxyd. Blandingen oppvarmes i 24 timer på et vannbad som hoLdes ved 65 - 70°C og helles derefter over i isvann. Blandingen nøytraliseres med konsentrert natriumhydroxydoppløsning pg får krystallisere. Efter filtrering, o m k r y s t a 11 i s e r i n g - f r a ;i f or ,t y n "ne i ^ethanol og lufttørring fåes N-oxydet av ketoneV f ra' deis DV'• ; (1) 20 of the ketone from part D of this example is dissolved in 150 ml of acetic acid, after which 40 ml of 30% hydrogen peroxide is added. The mixture is heated for 24 hours in a water bath maintained at 65 - 70°C and then poured into ice water. The mixture is neutralized with concentrated sodium hydroxide solution and allowed to crystallize. After filtration, o m k r y s t a 11 i s e r i n g - f r a ;i f or,t y n "ne in ^ethanol and air drying, the N-oxide of ketone V f ra' deis DV'• is obtained;
(2) Til 100 ml eddiksyreanhydrid som oppvarmes med tilbakeløps-kjøling, tilsettes 15 g av det ;under punkt^'( 1) f remst ilte N-oxyd. Blandingen oppvarmes med tilbakeløpskjøling iv10 timer og helles derefter over i vann. Blandingen får ^stå i flere timer (for å hydrolysere eventuelt over skudd, a v" anhydrid) og nøytraliseres derefter med nat riumbicarbonat. Blandingen ekstraheres med kloroform," og klorof ormekst rakten inndampes t il- tørrhet .'•' Residuet be-handles med 100 ml 48%-ig bromsyre," hvoretter 100 ml eddiksyre tilsettes, og blandingen oppvarmes med tilbakeløpskjøling i 6 t imer . "■'"<->•"<->'<!>' (2) To 100 ml of acetic anhydride which is heated with reflux cooling, add 15 g of the oxygenated N-oxide obtained under point (1). The mixture is heated with reflux for 10 hours and then poured into water. The mixture is allowed to stand for several hours (to hydrolyze any excess, with anhydride) and is then neutralized with sodium bicarbonate. The mixture is extracted with chloroform, and the chloroform extract is evaporated to dryness. The residue is treated with 100 ml of 48% bromic acid," after which 100 ml of acetic acid is added, and the mixture is heated with reflux for 6 hours. "■'"<->•"<->'<!>'
Efter konsentrering i vakuum oppløses residuet i vann. Oppløs-ningen gjøres alkalisk med vandig ammoniakk. Blandingen ekstraheres med ether. Etherekstrakten konsentreres til et residuum, som ved krystallisasjon fra petrolether gir 1-aza-5H-dibenzo-[a,d]-cyclohepten-5-on med smeltepunkt 95 - 96°C. After concentration in vacuum, the residue is dissolved in water. The solution is made alkaline with aqueous ammonia. The mixture is extracted with ether. The ether extract is concentrated to a residue, which upon crystallization from petroleum ether gives 1-aza-5H-dibenzo-[a,d]-cyclohepten-5-one with melting point 95 - 96°C.
Eksempel 2 Example 2
2-aza-10,11-dihydro-5H-dibenzo-[a,dJ-cyclohepten-5-on og 2 - aza - 5H - dibenzo - f a , d \ - cyclonepten - 5 - on 2-aza-10,11-dihydro-5H-dibenzo-[a,dJ-cyclohepten-5-one and 2-aza-5H-dibenzo-fa,d\-cyclonepten-5-one
A. 3~fenethyl-isonicotinsyre via a-(4-methyl-nicotinyl)-fenylacetonitril; benzyl-(4-methyl-3-pyridyl)-keton og 3_fenethyl-4- methyl- pyridin A. 3-phenethyl-isonicotinic acid via α-(4-methyl-nicotinyl)-phenylacetonitrile; benzyl-(4-methyl-3-pyridyl)-ketone and 3_phenethyl-4- methyl- pyridine
.Fortrinnsvis fremstilles 3_fenethyl-isonicotinsyre på følg-ende måt e: ' '■•"."' (1). 3-fenethyl-4-methylrpyridin'fremstilles først analogt med den fremgangsmåte som er beskrevet'i det nedenstående eksempel 4, del A (1 - 3), med utgangspunkt i ethyl-4-methyl-nicotinat, via a-(4-methy 1-nicot inoy1)-fenylacetonitril og benzyl-(4-methyl-3-pyridyl)-keton. «....,•-<,•-• •-».». _-. „.■■ , -« (2) En blanding av 8,6.g av^det.således erholdte'3-fenethyl-4-methy1-pyrid in, 50 ml tørt pyridin og;12,g'pulverformig selendioxyd oppvarmes derefter med tilbakeløpskjøling i\3 timer, for-tynnes med CHC1„ og filtreres. Filt ratet •' inndampes , 'res iduet oppløses i fortynnet vandig ammoniakk, og.oppløsningen ekstraheres med ether. Det gjenværende vandige.skikt.surgjøres derefter med eddiksyre, og utfelningen filtreres pg.|Omkrystalliseres fra isopropylether. Det erholdes 3,9 g av' det ønskede produkt. Smeltepunkt: 99 - 101°C. Preferably, 3-phenethyl-isonicotinic acid is produced in the following manner: (1). 3-phenethyl-4-methylpyridine' is first prepared analogously to the method described' in the following example 4, part A (1 - 3), starting from ethyl-4-methyl-nicotinate, via α-(4-methyl 1-nicotinyl)-phenylacetonitrile and benzyl-(4-methyl-3-pyridyl)-ketone. «....,•-<,•-• •-».». _-. (2) A mixture of 8.6 g of the thus obtained 3-phenethyl-4-methylpyridine, 50 ml of dry pyridine and 12 g of powdered selenium dioxide is then heated with reflux for 3 hours, dilute with CHCl 2 and filter. The filtrate is evaporated, the residue is dissolved in dilute aqueous ammonia, and the solution is extracted with ether. The remaining aqueous layer is then acidified with acetic acid, and the precipitate is filtered off and recrystallized from isopropyl ether. 3.9 g of the desired product is obtained. Melting point: 99 - 101°C.
B. Alternativ fremgangsmåte for fremstilling av 3-fenéthyl-isonicot insyre B. Alternative method for the production of 3-phenethyl-isonicotinic acid
Alternativt kan 3-fenethyl-isonicotinsyre fremstilles efterAlternatively, 3-phenethyl-isonicotinic acid can be produced after
den følgende trinnvise fremgangsmåte:the following step-by-step procedure:
(1) En oppløsning av 24,2 g 3~styryl-4-nitro-pyridin-N-oxyd i 250 ml iseddik reduseres i et Parr-hydrogeneringsapparat i nærvær av IO g 5%-ig palladium på carbon som.katalysator, ved 55 - 6o°C (1) A solution of 24.2 g of 3~styryl-4-nitro-pyridine-N-oxide in 250 ml of glacial acetic acid is reduced in a Parr hydrogenation apparatus in the presence of 10 g of 5% palladium on carbon as a catalyst, by 55 - 6o°C
og omtrent 3-6 atmosfærers trykk. Reduksjonen tar vanligvis om-and approximately 3-6 atmospheres of pressure. The reduction usually involves
trent 6 timer. Derefter filtreres blandingen, filtratet konsentreres i vakuum på et dampbad, og residuet oppløses i 150 ml 20%-ig saltsyre. Den sure oppløsning konsentreres til tørrhet, trained 6 hours. The mixture is then filtered, the filtrate is concentrated in vacuo on a steam bath, and the residue is dissolved in 150 ml of 20% hydrochloric acid. The acidic solution is concentrated to dryness,
og det urene 3-fenethyl-4-amino-pyridinklorid som herved oppnåesand the impure 3-phenethyl-4-amino-pyridine chloride which is thereby obtained
som residuum, anvendes direkte i fremgangsmåten som er beskrevet i punkt (2) nedenfor. as residue, is used directly in the method described in point (2) below.
(2) (a) Det under punkt (1) erholdte produkt oppløses i 100 ml 10%-ig saltsyre, og oppløsningen kjøles til O - 5°C. Derefter tilsettes langsomt en oppløsning inneholdende 6,9 g natriumnitritt i 50 ml vann, mens temperaturen holdes ved 0 - 5°C. Den således dannede diazoniumsaltoppløsning omrøres i ytterligere en halv time. I mellomtiden fremstilles en oppløsning av 0„3 mol cuprocyanid efter de retningslinjer som er gitt i "Organic Synthesis" (2) (a) The product obtained under point (1) is dissolved in 100 ml of 10% hydrochloric acid, and the solution is cooled to 0 - 5°C. A solution containing 6.9 g of sodium nitrite in 50 ml of water is then added slowly, while the temperature is kept at 0 - 5°C. The diazonium salt solution thus formed is stirred for a further half an hour. Meanwhile, a solution of 0.3 mol cuprocyanide is prepared according to the guidelines given in "Organic Synthesis"
Vol. 1, s. 500. Oppløsningen kjøles langsomt til 0°C, hvorefterVol. 1, p. 500. The solution is cooled slowly to 0°C, after which
den tilsettes til den ovennevnte, avkjølte diazoniumsaltoppløs-it is added to the above cooled diazonium salt soln.
ning. Blandingen får oppvarmes til romtemperatur og omrøres i nothing. The mixture is allowed to warm to room temperature and stirred in
ytterligere 1 time. Derefter gjøres oppløsningen alkalisk ved forsiktig tilsetning av 50%-ig vandig natriumhydroxydoppløsning, another 1 hour. The solution is then made alkaline by the careful addition of 50% aqueous sodium hydroxide solution,
mens den kjøles grundig i et bad av is og salt. Det erholdte 3-fenethyl-4-cyano-pyridin ekstraheres med kloroform. Kloroform-ekstrakten vaskes, og kloroformen fordampes. while it is cooled thoroughly in a bath of ice and salt. The 3-phenethyl-4-cyano-pyridine obtained is extracted with chloroform. The chloroform extract is washed and the chloroform is evaporated.
(b) Alternativt kan diazoniumsaltoppløsningen fra det ovenstå-(b) Alternatively, the diazonium salt solution from the above may
ende underpunkt (a) først overføres til 3-fenethyl-4-hydroxy-end subsection (a) is first transferred to 3-phenethyl-4-hydroxy-
pyridin ved oppvarmning med 25%-ig vandig svovelsyre med tilbake-løpskjøling, hvorefter det sistnevnte overføres til dets 4-brom-analoge ved oppvarmning i en glassbelagt autoklav i 6 timer ved l6o - l65°C med tre ganger dets vekt av fosforoxybromid. 4-brom-analogen isoleres ved at man heller reaksjonsblandingen over i isvann, nøytraliserer med natriumcarbonat, ekstraherer med kloro- pyridine by heating with 25% aqueous sulfuric acid with reflux, after which the latter is transferred to its 4-bromo analogue by heating in a glass-lined autoclave for 6 hours at l6o - l65°C with three times its weight of phosphorus oxybromide. The 4-bromo analogue is isolated by pouring the reaction mixture into ice water, neutralizing with sodium carbonate, extracting with chloro-
form og avdestillerer oppløsningsmidlet fra ekstrakten. Den så-form and distills the solvent from the extract. The so-
ledes erholdte 4-bromforbindelse omdannes ytterligere at man opp- the resulting 4-bromo compound is further converted that one up-
løser den i fire ganger dens vekt av vannfritt pyridin, tilsetter en ekvivalent mengde cuprocyanid, oppvarmer forsiktig til HO - 111°C inntil den første eksoterme. reaksjon.; er , over., og til slutt oppvarmer under vakuum under anvendelse a v..\eir~'fedt emperåtur på 200 - 220°C, idet 3-fenethyl-4-cyano-pyridinet avdestilleres efter hvert som det dannes. v ...... dissolve it in four times its weight of anhydrous pyridine, add an equivalent amount of cuprocyanide, heat gently to HO - 111°C until the first exotherm. reaction.; is , over., and finally heating under vacuum using a v..\eir~'fat emperature of 200 - 220°C, the 3-phenethyl-4-cyano-pyridine being distilled off as it is formed. w ......
(c) En annen alternativ fremgangsmåte til fremstilling av 3-fenethyl-4-cyano-pyridin er beskrevet'i underavsnitt (a) i del At 5) i eksempel 4« -•■-,-(3) En oppløsning inneholdende' 20,8. 9 3-fenethyl-4-cyano - (c) Another alternative method for the preparation of 3-phenethyl-4-cyano-pyridine is described' in subsection (a) of part At 5) of example 4« -•■-,-(3) A solution containing' 20 ,8. 9 3-phenethyl-4-cyano -
pyridin, 40 g kaliumhydroxyd, 60 ml vann og 150 ml ethanol oppvarmes med tilbakeløpskjøling og under omrøring i 24 timer eller inntil utviklingen av ammoniakk er opphørt. Blandingen inndampes til halvt volum, og den gjenværende del helles over i vann. Den resulterende oppløsning kjøles og ekstraheres med ether. Den vandige oppløsning nøytraliseres forsiktig med eddiksyre for å utkrystallisere 3_fenethyl-isonicotinsyren, som derefter filtreres og omkryst alliseres fra ethanol. pyridine, 40 g of potassium hydroxide, 60 ml of water and 150 ml of ethanol are heated under reflux and with stirring for 24 hours or until the evolution of ammonia has ceased. The mixture is evaporated to half the volume, and the remaining part is poured into water. The resulting solution is cooled and extracted with ether. The aqueous solution is carefully neutralized with acetic acid to crystallize the 3-phenethyl-isonicotinic acid, which is then filtered and recrystallized from ethanol.
C. 2-aza-IO,11-dihydro-5H-dibenzo-[a,d j-cyclonepten-5-onC. 2-aza-10,11-dihydro-5H-dibenzo-[a,d j-cyclonepten-5-one
(1) Fortrinnsvis fremstilles 2-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-on ved oppvarmning av 3_fenethyl-isonicotinsyre med polyfosforsyre analogt med den fremgangsmåte som er beskrevet i del D av eksempel 1. (2) Alternativt tilsettes der til 20,8 g 3-fenethyl-isonicotinsyre 50 ml renset thionylklorid. Blandingen oppvarmes på et dampbad i en halv time. * Overskuddet.av thionylklorid fjernes i ...*«''••• '••.• - -i-:.*; -S. 'f« •'• vakuum, og residuet oppslemmes i 2,0 liter vannfri petrolether (kokeområdet 60 -.90°C).Under.kraftig.omrøring tilsettes lang somt 2o.'g vannf rie aluminiumkloridgranuler': v* Den ■ result e rende oppløsning omrøres 1 4 t imer„ ved romtemperat ur , hvoref t er . oppløs - ,. ningen helles over i en blanding av 2 kg is'og '25 ml konsentrert «;'' '.••'- ' . ■•-.,•■>.«•--• ' '.'.-;•.. saltsyre. Pet roletheren fraskilles og hives.'» Den vandige', opp—rT * ■ ' ■ . • ••'". ' ♦.">«. •* 4V v ;<"". »>'» løsning gjøres alkalisk med 50%-ig vandig nat riumhydroxydoppløs - .. • ning mens den holdes kjølt".•'til: 5; - lb C Produktet , 2-aza-10,11-dihydro-5H-dibe nzo-[ a , d J -cyclohept en-5 -on'; .""eks t rahe r es med kloroform, og kloroformen fjernes.. Efter triturering med iskald petrolether omkrystalliserés residuet; f ra-~erif''blanding''av benzen og hexan. """' (1) Preferably, 2-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one is prepared by heating 3_phenethyl-isonicotinic acid with polyphosphoric acid analogously to the method described in part D of example 1. (2) Alternatively, 50 ml of purified thionyl chloride is added to 20.8 g of 3-phenethyl-isonicotinic acid. The mixture is heated on a steam bath for half an hour. * The excess.of thionyl chloride is removed in ...*«''••• '••.• - -i-:.*; -S. 'f« •'• vacuum, and the residue is suspended in 2.0 liters of anhydrous petroleum ether (boiling range 60 - 90°C). as 2o.'g anhydrous aluminum chloride granules': v* The resulting solution is stirred for 1 4 hours at room temperature, after which dissolve - ,. the mixture is poured into a mixture of 2 kg of ice and 25 ml of concentrated '.••'- ' . ■•-.,•■>.«•--• ' '.'.-;•.. hydrochloric acid. The pet rolether is separated and lifted.'" The aqueous', up—rT * ■ ' ■ . • ••'". ' ♦.">«. •* 4V v ;<"". »>'» solution is made alkaline with 50% aqueous sodium hydroxide solution - .. • ning while kept refrigerated".•'to: 5; - lb C The product , 2-aza-10,11-dihydro-5H-dibe nzo-[ a , d J -cyclohept en-5-one'; .""ex t rahe r es with chloroform, and the chloroform is removed.. After trituration with ice-cold petroleum ether, the residue is recrystallized; from ra-~erif''mixture'' of benzene and hexane. """'
D. 2-aza-5H-dibenzo-[a,d]-cyclohepten-5-onD. 2-aza-5H-dibenzo-[a,d]-cyclohepten-5-one
(1) Fortrinnsvis fremstilles 2-aza-5H-dibenzo-[a,d]-cyclohepten-5-on ved dehydrogenering av dets 10,11-dihydro-analoge (kan fremstilles som beskrevet i del C av dette eksempel) analogt med den fremgangsmåte som er beskrevet i del C, avsnitt (1) av eksempel 4-(2) Alternativt kan den nevnte dehydrogenering utføres på følg-ende måte: En oppløsning av 19,7 g 2-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-on i 150 ml tørt carbontetraklorid tilsettes langsomt og under kraftig omrøring til en suspensjon av 17,8 g N-brom-succinimid i 500 ml carbontetraklorid inneholdende 0,1 g benzoylperoxyd. Efter at den første eksoterme reaksjon er over, oppvarmes blandingen med tilbakeløpskjøling og under omrøring i ytterligere 3 timer. Det herved dannede succinimid fjernes ved filtrering, og carbontetrakloridoppløsningen konsentreres til tørrhet. 300 ml triethylamin tilsettes til residuet, og blandingen oppvarmes på et dampbad i 18 - 20 timer. Efter filtrering konsentreres filtratet til et residuum, som helles over i vann. Den erholdte blanding ekstraheres så med kloroform, og 2-aza-5H-dibenzo-[a,d]-cyclohepten-5-on isoleres fra ekstrakten og renses ved omkryst allisering fra fortynnet ethanol. (1) Preferably, 2-aza-5H-dibenzo-[a,d]-cyclohepten-5-one is prepared by dehydrogenation of its 10,11-dihydro analogue (can be prepared as described in part C of this example) analogously to the method described in part C, section (1) of example 4-(2) Alternatively, the aforementioned dehydrogenation can be carried out in the following manner: A solution of 19.7 g of 2-aza-10,11-dihydro-5H- dibenzo-[a,d]-cyclohepten-5-one in 150 ml of dry carbon tetrachloride is added slowly and with vigorous stirring to a suspension of 17.8 g of N-bromosuccinimide in 500 ml of carbon tetrachloride containing 0.1 g of benzoyl peroxide. After the first exothermic reaction is over, the mixture is heated under reflux and with stirring for a further 3 hours. The succinimide thus formed is removed by filtration, and the carbon tetrachloride solution is concentrated to dryness. 300 ml of triethylamine is added to the residue, and the mixture is heated on a steam bath for 18 - 20 hours. After filtration, the filtrate is concentrated to a residue, which is poured into water. The resulting mixture is then extracted with chloroform, and 2-aza-5H-dibenzo-[a,d]-cyclohepten-5-one is isolated from the extract and purified by cross-alization from dilute ethanol.
Eksempel 3Example 3
3-aza-IO,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-on og 3~ aza-5H-dibenzo-[a,d]-cyclohepten-5-on 3-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one and 3~ aza-5H-dibenzo-[a,d]-cyclohepten-5-one
A. Ethyl- 4- styryl- nicotinatA. Ethyl-4-styryl-nicotinate
En blanding av 165 g ethyl-4-methyl-nicotinat, 106 g benzaldehyd og 1 liter eddiksyreanhydrid oppvarmes med tilbakeløps-kjøling i 4 timer. Blandingen helles over på is, filtreres og omkrystalliserés fra benzen, hvorved esteren erholdes. A mixture of 165 g of ethyl-4-methyl-nicotinate, 106 g of benzaldehyde and 1 liter of acetic anhydride is heated with reflux cooling for 4 hours. The mixture is poured onto ice, filtered and recrystallized from benzene, whereby the ester is obtained.
B. 4~ fenethyl- nicotinsyreB. 4~ phenethyl-nicotinic acid
(1) En blanding av 50 g av esteren fra dette eksempels del A, 50 g kaliumhydroxyd, 50 ml vann og 200 ml ethanol oppvarmes med tilbakeløpskjøling i 6 timer. Blandingen konsentreres for å fjerne oppløsningsmidlene, og residuet oppløses i 200 ml vann. Efter nøytralisering med eddiksyre får blandingen stå å utkrystallisere. Efter filtrering og tørring hydrogeneres 22 g av den således erholdte 4-styryl-nicotinsyre på tilsvarende måte som beskrevet i del C av eksempel 1. (2) Alternativt oppløses .20,2 g av esteren fra.det te eksempels del A i 200 ml ethanol med påfølgende hydrogenering under omtrent 3,6 atmosfærers hydrogentrykk ved .romtemperatur^i nærvær av en katalysator bestående a v•" 5 g' 5%-ig|. pa 1 ladium-, på;'-ca rbon. -. Det således erholdte ethyl-4-fenethyl-nicotinat forsåpes på kjent måte. C. ' 3-aza-IO , 11-dihydro-5H-dibenzo-[a', d]-cyclohepten-5-on 80 g 4-fenethyl-nicotinsyre og 1 kg polyfosforsyre blandes, hvorefter man følger en fremgangsmåte analog med den som er beskrevet Ti del D av eksempel. 1.....Ved. omkrystallisering fra benzen-petrolether, fåes et smeltepunkt ■ på. 66--'67°C . (1) A mixture of 50 g of the ester from part A of this example, 50 g of potassium hydroxide, 50 ml of water and 200 ml of ethanol is heated under reflux for 6 hours. The mixture is concentrated to remove the solvents, and the residue is dissolved in 200 ml of water. After neutralization with acetic acid, the mixture is allowed to crystallize. After filtration and drying, 22 g of the thus obtained 4-styryl-nicotinic acid is hydrogenated in a similar manner as described in part C of example 1. (2) Alternatively, 20.2 g of the ester from part A of that example is dissolved in 200 ml ethanol with subsequent hydrogenation under approximately 3.6 atmospheres of hydrogen pressure at room temperature in the presence of a catalyst consisting of v•" 5 g' 5%-ig|. pa 1 ladium-, on;'-ca rbon. -. The thus obtained ethyl 4-phenethyl nicotinate is saponified in a known manner. C. ' 3-aza-10 , 11-dihydro-5H-dibenzo-[a', d]-cyclohepten-5-one 80 g 4-phenethyl-nicotinic acid and 1 kg of polyphosphoric acid is mixed, after which a procedure analogous to that described in part D of example 1.....By recrystallization from benzene-petroleum ether, a melting point ■ of 66--'67°C is obtained.
D. 3-aza-5H-dibenzo-f a ,d]-cyclohepten-5-onD. 3-aza-5H-dibenzo-f a,d]-cyclohepten-5-one
(1) 5Q g 4-styryl-nicotinsyre (forbindelsen som er omtalt under (1) 5Q g of 4-styryl-nicotinic acid (the compound discussed under
punkt (1) i del B av dette eksempel, før hydrogeneringstrinnet) blandes med 1 kg polyfosforsyre, hvorefter man følger den fremgangsmåte som er beskrevet i del A av eksempel 1. Ved omkrystallisering fra benzen-hexan fåes et smeltepunkt på 157 - 158°C. point (1) in part B of this example, before the hydrogenation step) is mixed with 1 kg of polyphosphoric acid, after which the procedure described in part A of example 1 is followed. By recrystallization from benzene-hexane, a melting point of 157 - 158°C is obtained .
(2) Alternativt kan 3-aza-5H-dibenzo-[a,dJ-cyclohepten-5-on (2) Alternatively, 3-aza-5H-dibenzo-[a,dJ-cyclohepten-5-one can
fremstilles ved dehydrogenering av den tilsvarende 10,11-dihydro-forbindelse (produktet fra del C av denne fremstilling) på tilsvarende måte som beskrevet i avsnitt (2) av del D av eksempel 2. is prepared by dehydrogenation of the corresponding 10,11-dihydro-compound (the product from part C of this preparation) in a similar way as described in section (2) of part D of example 2.
Eksempel 4Example 4
4-aza-10,11-dihydro-5-dibenzo-ja,d]-cyclohepten-5-on og 4-aza-5H-■ dibenzp-[a,d ]-cyclohepten-5-on 4-aza-10,11-dihydro-5-dibenzo-ja,d]-cyclohepten-5-one and 4-aza-5H-■ dibenzp-[a,d]-cyclohepten-5-one
A. 2-cyano-3-fenethyl-pyridin via a-nicotinoyl-fenylacetonitril, A. 2-cyano-3-phenethyl-pyridine via α-nicotinoyl-phenylacetonitrile,
benzyl-(3-pyridyl)-keton, 3-fenet hyl-pyridin og 3-fenethyl-pyridin- N- oxyd benzyl-(3-pyridyl)-ketone, 3-phenethyl-pyridine and 3-phenethyl-pyridine-N-oxide
(1) •• ;Til en oppløsning av 34 g metallisk natrium i 500 ml(1) •• ;To a solution of 34 g of metallic sodium in 500 ml
absolutt ethanol som oppvarmes mod(tilbakeløp, tildryppes en blanding av 266 g ethy 1 nicot ina t og . 133 • ~ <3 f enylacetonit r il . Efter 4 timer helles blandingen over på is og ekstraheres'-'med ether. absolute ethanol, which is heated at reflux, is added dropwise to a mixture of 266 g of ethyl nicotinate and 133 g of phenylacetonitrile. After 4 hours, the mixture is poured onto ice and extracted with ether.
Den vandige fase nøytraliseres med eddiksyre, og produktet får'-utkrystallisere. Det utkrystalliserte produkt f rafiltreres, The aqueous phase is neutralized with acetic acid, and the product is allowed to crystallize. The crystallized product is filtered,
vaskes med vann og tørres i luft. Det således erholdte a-nicotinoyl-fenylacetonitril (smeltepunkt 137 - l'4l°C) anvendes i washed with water and dried in air. The a-nicotinoyl-phenylacetonitrile thus obtained (melting point 137 - 1'41°C) is used in
neste trinn (2) uten ytterligere rensning.next step (2) without further purification.
(2) Nitrilet erholdt under punkt (1) oppvarmes med tilbakeløp i 16 timer med 1 ,4 liter konsentrert bromsy re V; '-'Blandingen helles over på is og får krystallisere. Hydrobromidet frafiltreres, oppslemmes i vann og nøytraliseres med natriumcarbonatoppløsning. Efter krystallisering, frafilt rering og tørring i luft erholdes 126 g benzyl-(3-pyridyl)-keton med smeltepunkt 53 - 56°C. (3) 26 g av ketonet erholdt under punkt (2) blandes med 11 g natriumhydroxyd, 11 ml 85%-ig hydrazinhydrat og.175 ml diethylen-glycol. Blandingen anbringes i et destillasjonsapparat og oppvarmes ved 235 - 240°C i 3 - 4 timer, slik at destillasjonen blir fullstendig. Efter kjøling ekstraheres blandingen og destillatet med benzen. De sammenslåtte benzenekstrakter vaskes med vann og destilleres i vakuum. Fraksjonen som koker ved 120 - 128°C, taes vare på. Utbytte: 21 g. (4) En blanding av 18393-fenethyl-pyridin (produktet erholdt under punkt (3), 120 ml 30%-ig hydrogenperoxyd og 300 ml iseddik oppvarmes i 20 - 24 timer ved 60 - 65°C. Blandingen helles derefter over i isvann, og pH-verdien innstilles på 8 - 9 med vandig ammoniakk. Utfelningen frafiltreres og oppløses i hexart. Det erholdes 150 - 15893-fenethyl-pyridin-N-oxyd med smeltepunkt 82 - 89°C. (5) (a) 2-cyano-3-fenethyl-pyridin fremstilles fortrinnsvis fra det under punkt (4) erholdte N-oxyd på følgende måte: 75,6 g dimethylsulfat tildryppes under omrøring til 118,893-i'enethyl-pyridin-N-oxyd. Blandingen oppvarmes ved 85°C i 3 timer, kjøles og oppløses i 180 ml vann. Den vandige oppløsning tilsettes dråpevis til en omrørt oppløsning av 88,2 g natriumcyanid i 250 ml vann. Dette utføres under nitrogenatmosfære, mens reak-sjonstemperaturen holdes i området 0 - 5°C. Efter omrøring i 6 timer ved 0°C får blandingen oppvarmes til romtemperatur ved å stå natten over. Blandingen ekstraheres med kloroform og destilleres i vakuum efter vask med vann. Den fraksjon som koker ved 160 - l67°C ved 0,8 torr, oppsamles. (En høyerekokende fraksjon som koker ved 190 - 195°C/l,5 torr, utgjøres av den 4-cyano-isomere, som kan anvendes som et mellomprodukt ved fremstillingen av 2-aza-ketonet, se del B av eksempel 2). (b) Alternativt tilsettes 9893~fenethyl-pyridin-N-oxyd til 1 liter eddiksyreanhydrid, og blandingen oppvarmes med tilbake-løpskjøling i 20 timer. Overskuddet av oppløsningsmidler avdestilleres, og residuet helles over i vann. Blandingen nøy-traliseres med base, og produktet ekstraheres med kloroform. (2) The nitrile obtained under point (1) is heated under reflux for 16 hours with 1.4 liters of concentrated bromic acid re V; '-'The mixture is poured over ice and allowed to crystallize. The hydrobromide is filtered off, suspended in water and neutralized with sodium carbonate solution. After crystallization, filtration and drying in air, 126 g of benzyl-(3-pyridyl) ketone with a melting point of 53 - 56°C are obtained. (3) 26 g of the ketone obtained under point (2) are mixed with 11 g of sodium hydroxide, 11 ml of 85% hydrazine hydrate and 175 ml of diethylene glycol. The mixture is placed in a distillation apparatus and heated at 235 - 240°C for 3 - 4 hours, so that the distillation is complete. After cooling, the mixture and the distillate are extracted with benzene. The combined benzene extracts are washed with water and distilled in vacuo. The fraction that boils at 120 - 128°C is taken care of. Yield: 21 g. (4) A mixture of 18393-phenethyl-pyridine (the product obtained under point (3), 120 ml of 30% hydrogen peroxide and 300 ml of glacial acetic acid is heated for 20 - 24 hours at 60 - 65°C. The mixture is then poured into ice water, and the pH value is adjusted to 8 - 9 with aqueous ammonia. The precipitate is filtered off and dissolved in hexart. 150 - 15893-phenethyl-pyridine-N-oxide with a melting point of 82 - 89°C is obtained. (5) (a) 2-cyano-3-phenethyl-pyridine is preferably prepared from the N-oxide obtained under point (4) in the following way: 75.6 g of dimethyl sulphate is added dropwise while stirring to 118.893-l'enethyl-pyridine-N-oxide. The mixture is heated at 85°C for 3 hours, cooled and dissolved in 180 ml of water. The aqueous solution is added dropwise to a stirred solution of 88.2 g of sodium cyanide in 250 ml of water. This is carried out under a nitrogen atmosphere, while maintaining the reaction temperature in the range 0 - 5°C. After stirring for 6 hours at 0°C, the mixture is allowed to warm to room temperature by standing overnight. The mixture extracts es with chloroform and distilled in vacuum after washing with water. The fraction boiling at 160 - 167°C at 0.8 torr is collected. (A higher-boiling fraction that boils at 190 - 195°C/l.5 torr is made up of the 4-cyano-isomer, which can be used as an intermediate in the preparation of the 2-aza-ketone, see part B of example 2). (b) Alternatively, 9893~phenethyl-pyridine-N-oxide is added to 1 liter of acetic anhydride, and the mixture is heated under reflux for 20 hours. The excess of solvents is distilled off, and the residue is poured into water. The mixture is neutralized with base, and the product is extracted with chloroform.
Kloroformen avdestilleres, 200 ml 20%-ig natriumhydroxydoppløs-ning' tilsettes til residuet, og den resulterende oppløsning oppvarmes med tilbakeløpskjøling .i; 6 timer.' Blandingen kjøles og nøytraliseres med eddiksyre og får stå til utfelning. Det således erholdte 2-hydroxy-3-fenethyl-pyridin overføres'til dets 2-brom-a na loge og til slutt til;, dets 2-cyano-analoge på;;-t il svarende måte som i det annet og tredje trinn av den fremgangsmåte The chloroform is distilled off, 200 ml of 20% sodium hydroxide solution is added to the residue, and the resulting solution is heated under reflux. 6 hours.' The mixture is cooled and neutralized with acetic acid and left to precipitate. The 2-hydroxy-3-phenethyl-pyridine thus obtained is transferred to its 2-bromo-analogue and finally to its 2-cyano-analogue in the same way as in the second and third steps of that procedure
som' er beskrevet i underavsnitt (b) av del B(2) av eksempel 2. which' is described in subsection (b) of Part B(2) of Example 2.
B. 4-aza- 10, 11- dihydro- 5H- dibenzo-[ a, d]- cyclohepten- 5- onB. 4-aza- 10, 11- dihydro- 5H- dibenzo-[ a, d]- cyclohepten- 5- one
(1) 99 g 2-cyano-3-fenethyl-pyridin og 5 kg'polyfosforsyre om-" røres og' oppvarmes ved' 180°C i 20 24 t imer'.' ^Blandingen helles over på is ,'.nøyt ral iseres med 50%-ig vandig natriumhydroxydopp- løsning og ekstraheres med kloroform. Efter konsentrer ing til et residuum, med påfølgende triturering, med hexan og filtrering, erholdes det ønskede keton. Smeltepunkt 68 - 73°C. (2) Alternativt kan cyclisering utføres i to trinn på følgende måte : (a) En blanding inneholdende 25 g 2-cyano-3-fenethyl-pyridin, 25 g kaliumhydroxyd (oppløst i 50 ml vann) og 100 ml ethanol oppvarmes i 24 timer ved tilbakeløpstemperatur. Derefter går man frem analogt med den fremgangsmåte som er beskrevet i del B(3) av eksempel 2, hvorved der fåes 3~fenethyl-picolinsyre. (b) En blanding av 20 g 3-fenethy1-picolinsyre og 200 g polyfosforsyre oppvarmes i 6 timer ved 105 - 110°C. Videre går man frem på tilsvarende måte som beskrevet i del D av eksempel 1. (1) 99 g of 2-cyano-3-phenethyl-pyridine and 5 kg of polyphosphoric acid are stirred and heated at 180°C for 24 hours. ^The mixture is poured over ice, then neutralized with 50% aqueous sodium hydroxide solution solution and extracted with chloroform. After concentration to a residue, with subsequent trituration, with hexane and filtration, the desired ketone is obtained. Melting point 68 - 73°C. (2) Alternatively, cyclization can be carried out in two steps as follows: (a) A mixture containing 25 g of 2-cyano-3-phenethyl-pyridine, 25 g of potassium hydroxide (dissolved in 50 ml of water) and 100 ml of ethanol is heated for 24 hours at reflux temperature. You then proceed analogously to the method described in part B(3) of example 2, whereby 3-phenethyl-picolinic acid is obtained. (b) A mixture of 20 g of 3-phenethyl-picolinic acid and 200 g of polyphosphoric acid is heated for 6 hours at 105 - 110°C. You then proceed in a similar way as described in part D of example 1.
C. 4-aza-5H-dibenzo-I a ,d ]-cyclohepten-5-onC. 4-aza-5H-dibenzo-1α,d]-cyclohepten-5-one
(1) En blanding av 15 g av det som beskrevet i del B av denne (1) A mixture of 15 g of that described in Part B hereof
fremstilling erholdte keton, 15.g selendioxyd og 6o ml pyridin oppvarmes med tilbakeløpskjøling i;4.timer.under nitrogenatmosfaere. Blandingen kjøles , og ut f einingen'f raf ilt reres og vaskes med.ethanol. Filtratet og vaskevæsken slåes sammen og konsentreres i vakuum til et residuum. Res iduet. t ilset tes , vann , og ; ■ "• den resulterende blanding gjøres alka lisk med vandig i ammoniakk ,' .'. hvorefter den ekstraheres med kloroform. Kloroformdppløsningen vaskes med vann og konsentreres t i 1 - et. • res iduum .'Ved kryst al-lisasjon fra isopropylether eller,benzen-hexan faes det ønskede produkt med smeltepunkt 118 - H9°C... '■■ ' (2) Alternativt kan dehydrogenering utføres på følgende måte: Til en oppløsning av 50 g 4-aza-10,ll-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-on i 150 ml vannfritt cymen tilsettes 30 g av en katalysator bestående av 5% palladium på kull, og blandingen oppvarmes med tilbakeløpskjøling i 24 timer. " Den resulterende blanding kjøles, og palladiumet og kullet frafiltreres. Filtratet helles over i 250 ml 10%-ig saltsyre. Cymen-skiktet fraskilles og hives. Den gjenværende sure oppløsning nøytraliseres med vandig ammoniakk, og den resulterende olje ekstraheres med kloroform. Kloroformen fjernes, og produktet omkrystalliserés fra fortynnet ethanol. preparation of the ketone obtained, 15 g of selenium dioxyde and 60 ml of pyridine are heated with reflux for 4 hours under nitrogen atmospheres. The mixture is cooled, and the solution is filtered and washed with ethanol. The filtrate and washing liquid are combined and concentrated in vacuo to a residue. Res iduet. t ilset tea , water , and ; ■ "• the resulting mixture is made alkaline with aqueous ammonia,' .'. after which it is extracted with chloroform. The chloroform solution is washed with water and concentrated to 1 - et. • residue .'By crystallization from isopropyl ether or,benzene -hexane gives the desired product with melting point 118 - H9°C... '■■ ' (2) Alternatively, dehydrogenation can be carried out in the following way: To a solution of 50 g of 4-aza-10,11-dihydro-5H-dibenzo -[a,d]-cyclohepten-5-one in 150 ml of anhydrous cymene is added 30 g of a catalyst consisting of 5% palladium on charcoal, and the mixture is heated under reflux for 24 hours. " The resulting mixture is cooled, and the palladium and charcoal is filtered out. The filtrate is poured into 250 ml of 10% hydrochloric acid. The cymen layer is separated and lifted. The remaining acidic solution is neutralized with aqueous ammonia, and the resulting oil is extracted with chloroform. The chloroform is removed, and the product is recrystallized from dilute ethanol.
Eksempel 5Example 5
4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene
En blanding av 40 g 4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-on, 50 g kaliumhydroxyd, lOO g hydrazinhydrat og 350 ml trimethylenglycol oppvarmes med tilbakeløpskjøling i 24 timer. Blandingen konsentreres i vakuum til 30% av det opprinnelige volum, og residuet helles over i isvann. Det ekstraheres med ether, hvorefter etheroppløsningen vaskes med vann og konsentreres til et residuum som krystalliseres fra vandig methanoi. A mixture of 40 g of 4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one, 50 g of potassium hydroxide, 100 g of hydrazine hydrate and 350 ml of trimethylene glycol is heated under reflux for 24 hours. The mixture is concentrated in vacuo to 30% of the original volume, and the residue is poured into ice water. It is extracted with ether, after which the ether solution is washed with water and concentrated to a residue which is crystallized from aqueous methanol.
På tilsvarende måte kan man ved å anvende et hvilket som helst -av ketonene fra eksempler 1 - 4 og substitusjonsproduktene derav, og ved å omsette disse ketoner som beskrevet i eksempel 5, fremstille de tilsvarende aza-dibenzo-cycloheptener. In a similar way, by using any of the ketones from examples 1 - 4 and the substitution products thereof, and by reacting these ketones as described in example 5, the corresponding aza-dibenzo-cycloheptenes can be prepared.
Claims (3)
Priority Applications (1)
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NO16769367A NO134157C (en) | 1963-04-24 | 1967-04-12 |
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US27523763A | 1963-04-24 | 1963-04-24 | |
US330263A US3326924A (en) | 1963-04-24 | 1963-12-13 | Novel aza-dibenzo[a, d]-cycloheptene derivatives |
US330244A US3366635A (en) | 1963-04-24 | 1963-12-13 | Aza-5h-dibenzo-[a,d]-(cycloheptenes and cycloheptene-5-ones) and the corresponding 10, 11-dihydro derivatives thereof |
NO152953A NO120935B (en) | 1963-04-24 | 1964-04-23 | |
US42010164A | 1964-12-21 | 1964-12-21 | |
US580169A US3357986A (en) | 1963-04-24 | 1966-09-19 | 1, 2, 3 or 4, aza,-[5-piperdyl or hydrocarbyl amino]-10, 11 dihydro-5h-dibenzo-[a, d]-cycloheptene |
NO16769367A NO134157C (en) | 1963-04-24 | 1967-04-12 |
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