NO134616B - - Google Patents
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- NO134616B NO134616B NO17100867A NO17100867A NO134616B NO 134616 B NO134616 B NO 134616B NO 17100867 A NO17100867 A NO 17100867A NO 17100867 A NO17100867 A NO 17100867A NO 134616 B NO134616 B NO 134616B
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- Norway
- Prior art keywords
- dibenzo
- methyl
- compounds
- hydroxy
- ether
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- -1 aminopropylidene Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052736 halogen Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- ZKDOQFPDSUOLGF-UHFFFAOYSA-N 1-bromo-3-chloro-2-methylpropane Chemical compound ClCC(C)CBr ZKDOQFPDSUOLGF-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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910000861 Mg alloy Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- OWXLRKWPEIAGAT-UHFFFAOYSA-N [Mg].[Cu] Chemical compound [Mg].[Cu] OWXLRKWPEIAGAT-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002908 adrenolytic effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- XOVAMNMHLZQZJL-UHFFFAOYSA-N n-benzyl-3-chloro-n-methylpropan-1-amine Chemical compound ClCCCN(C)CC1=CC=CC=C1 XOVAMNMHLZQZJL-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 238000010653 organometallic reaction Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Nærværende oppfinnelse vedrorer en analogifremgangsmåte for fremstilling av 5-(y-sekundæraminopropyliden)-dibenzoheptaen-forbindelser med den generelle formel The present invention relates to an analogous process for the preparation of 5-(γ-secondary aminopropylidene)-dibenzoheptaene compounds of the general formula
hvor den stiplede binding kan være hydrogenert, betyr en alkylrest med inntil 4 karbonatomer, fortrinnsvis metyl eller etyl, where the dotted bond may be hydrogenated, means an alkyl residue with up to 4 carbon atoms, preferably methyl or ethyl,
1*2 hydrogen eller halogen og1*2 hydrogen or halogen and
A en eventuelt med en alkylrest med inntil 4 A optionally with an alkyl residue with up to 4
karbonatomer substituert etylenrest,carbon atoms substituted ethylene residue,
og deres syreaddisjonssalter.and their acid addition salts.
Fremgangsmåten karakteriseres ved at man dehydratiserer en forbindelse med den generelle formel The method is characterized by dehydrating a compound with the general formula
hvor den stiplede binding kan være hydrogenert, og wherein the dotted bond may be hydrogenated, and
Rl'R2 °^ A 'nar f°ran angitte betydning,Rl'R2 °^ A 'when previously indicated meaning,
og overforer eventuelt de erholdte forbindelser til deres syreaddisjonssalter. and optionally transfer the obtained compounds to their acid addition salts.
De som utgangsstoffer nodvendige forbindelser med formel II lar seg f.eks. fremstille på folgende måte: a) Et eventuelt halogensubstituert dibenzo/~a,e7cyklohepta /~1, 57dien-5-on, henh. dibenzo/~a, e7cyklohepta/~l, 3, j>7trien-5-on omsettes ved hjelp av en metallorganisk reaksjon med et alkylbenzyl-aminoalkylhalogenid, og reaksjonsproduktet debenzyleres etter hydrogenolyse. Det forste trinn av denne reaksjon kan f.eks. forlope via magnesium-, litium- eller sink-organiske metallforbindelser. De med fordel anvendte magnesiumforbindelser av alkyl-benzyl-aminoalkyl-halogenider lar seg f.eks. oppnå ved direkte omsetning av spesielt aktivt magnesium, f.eks. i form av ehfint fordelt kobbermagnesium-legering med en eterisk opplosning av halogenidet. Det er derved hensiktsmessig å stimulere omsetningen ved tilsetning av et egnet alkylhalogenid, som f.eks. metyljodid eller etyl-bromid. Hydrolysen av det metallorganiske kompleks finner fortrinnsvis sted under praktisk talt noytrale betingelser, d.v.s. f.eks. ved hjelp av ammoniumklorid. Avspaltningen av benzylgruppen finner hensiktsmessig sted ved hydrogenolyse i nærvær av edelmetallkatalysatorer, fortrinnsvis i en lavere-alifatisk alkohol med palladiumkull, ved oket hydrogentrykk og oket temperatur. Ved denne behandling blir de i ring-skjelettet tilstedeværende flerdobbeltbindinger uangrepne. b) Ved omsetning av et eventuelt halogensubstituert dibenzo /~a, e7cyklohepta/~l, 57dien-5-on henh. dibenzo/~a, ej?cyklohepta /~1,3,57trien-5-on med en alkalimetallforbindelse med formel The compounds of formula II required as starting materials can e.g. prepared in the following way: a) An optionally halogen-substituted dibenzo/~a,e7cyclohepta/~1,57dien-5-one, acc. dibenzo/~a,e7cyclohepta/~l,3,j>7trien-5-one is reacted by means of an organometallic reaction with an alkylbenzyl-aminoalkyl halide, and the reaction product is debenzylated after hydrogenolysis. The first step of this reaction can e.g. proceed via magnesium, lithium or zinc organometallic compounds. The advantageously used magnesium compounds of alkyl-benzyl-aminoalkyl-halides allow e.g. achieved by direct conversion of particularly active magnesium, e.g. in the form of finely divided copper-magnesium alloy with an ethereal solution of the halide. It is therefore appropriate to stimulate the turnover by adding a suitable alkyl halide, such as e.g. methyl iodide or ethyl bromide. The hydrolysis of the organometallic complex preferably takes place under practically neutral conditions, i.e. e.g. using ammonium chloride. The removal of the benzyl group conveniently takes place by hydrogenolysis in the presence of noble metal catalysts, preferably in a lower aliphatic alcohol with palladium charcoal, at increased hydrogen pressure and increased temperature. With this treatment, the multiple bonds present in the ring skeleton remain unattacked. b) When reacting an optionally halogen-substituted dibenzo /~a,e7cyclohepta/~1,57dien-5-one acc. dibenzo/~a, ej?cyclohepta /~1,3,57trien-5-one with an alkali metal compound of the formula
hvor R^<1>betyr en alkylrest med inntil 4 karbonatomer, where R^<1>means an alkyl residue with up to 4 carbon atoms,
R^hydrogen eller en alkylrest med inntil 4 karbonatomer og R^hydrogen or an alkyl residue with up to 4 carbon atoms and
Me et alkalimetall,Me an alkali metal,
og etterfolgende hydrolyse når man til forbindelser med formel and subsequent hydrolysis leads to compounds of formula
hvor R1', R2og R^ har foran angitte betydning og den stiplede binding kan være hydrogenert. where R1', R2 and R^ have the above meaning and the dashed bond may be hydrogenated.
Denne omsetning gjennomfores med fordel via en natrium-, kalium- eller litium-forbindelse. Hensiktsmessig tilsetter man de tricykliske ketoner enten i fast, fint pulverisert form eller i et indifferent opplosningsmiddel, som f ieks. absolutt eter, benzen eller tetrahydrofuran, til den i flytende ammoniakksuspenderte alkalimetallorganiske forbindelse med formel III. Spaltningen av den dannede organiske metall-forbindelse finner med fordel sted under praktisk talt noytrale betingelser f.eks. ved hydrolyse med fast ammoniumklorid eller i vandig ammoniumkloridopplosning. This conversion is advantageously carried out via a sodium, potassium or lithium compound. Appropriately, the tricyclic ketones are added either in solid, finely powdered form or in an indifferent solvent, such as absolute ether, benzene or tetrahydrofuran, to the alkali metal organic compound of formula III suspended in liquid ammonia. The cleavage of the metal-organic compound formed advantageously takes place under practically neutral conditions, e.g. by hydrolysis with solid ammonium chloride or in aqueous ammonium chloride solution.
På denne måte oppnås de dannede, tertiære aminogrupper inne-holdende dibenzo/~a,e7cyklohepta/~l,57dien- eller dibenzo/~a,e7 cyklohepta/~l,3,57trien-forbindelser direkte i fri form og kan ved behandling med egnede, med vann ikke blandbare organiske opplosningsmidler, som f.eks. eter, eddiksyreetylester, kloroform, metylenklorid, skilles og isoleres fra biproduktene ved reaksjonen. In this way, the formed tertiary amino groups containing dibenzo/~a,e7cyclohepta/~1,57diene or dibenzo/~a,e7cyclohepta/~1,3,57triene compounds are obtained directly in free form and can by treatment with suitable, water-immiscible organic solvents, such as e.g. ether, acetic acid ethyl ester, chloroform, methylene chloride, are separated and isolated from the by-products of the reaction.
De erholdte produkter modifiseres ved den etterfolgende hydrogenering på den ene side ved den tredobbelt umettede binding i sidekjeden og debenzyleres på den annen side. Hydrogeneringen gjennomfores hensiktsmessig under de under a) beskrevne betingelser. The products obtained are modified by the subsequent hydrogenation on the one hand at the triple unsaturated bond in the side chain and debenzylated on the other hand. The hydrogenation is appropriately carried out under the conditions described under a).
Dehydratiseringen av forbindelser med formel JI utfores spesielt fordelaktig under oppvarming ved hjelp av alkoholisk saltsyre. Den lykkes imidlertid også med de vanlige andre reagenser, The dehydration of compounds of formula JI is particularly advantageously carried out under heating with the aid of alcoholic hydrochloric acid. However, it also succeeds with the usual other reagents,
som f.eks. med fosforoksyklorid, p-toluensulfoklorid, svovelsyre, sinkklorid, kaliumbisulfat osv. i inerte organiske opplosningsmidler, som f.eks. kloroform og metylenklorid. like for example. with phosphorus oxychloride, p-toluene sulphochloride, sulfuric acid, zinc chloride, potassium bisulphate etc. in inert organic solvents, such as e.g. chloroform and methylene chloride.
De etter fremgangsmåten ifolge oppfinnelsen erholdte tricykliske forbindelser består, såfremt den ene aromatiske ringen er substituert med halogen og/eller sidekjeden i 5-stilling er forgrenet, av en isomerblanding. Denne kan skilles etter i og for seg kjente metoder, f.eks. på grunn av forskjellig opp-loselighet av basene eller addisjonssaltene ved fraksjonert krystallisasjon i cis-, trans- og/eller optisk aktive anti-poder . The tricyclic compounds obtained by the method according to the invention consist, provided that one aromatic ring is substituted with halogen and/or the side chain in the 5-position is branched, of a mixture of isomers. This can be separated according to methods known in and of themselves, e.g. due to different solubility of the bases or addition salts by fractional crystallization in cis-, trans- and/or optically active anti-pods.
Oppfinnelsen omfatter også fremstillingen av syreaddisjons-. salter av de foran nevnte tricykliske forbindelser. Slike salter er f.eks. de med uorganiske syrer, som klorhydrogen-syre, bromhydrogensyre, svovelsyre, og de med organiske syrer, som f.eks. eddiksyre, oksalsyre, sitronsyre, melkesyre, vinsyre. The invention also covers the production of acid addition-. salts of the aforementioned tricyclic compounds. Such salts are e.g. those with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and those with organic acids, such as e.g. acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid.
De ifolge oppfinnelsen erholdte forbindelser utmerker seg ved de mangfoldige virkninger på nervesystemet. Således er nar-kosepotenserende, adrenolytiske, sedative, antihistaminlig-nende, antiemetiske, antipyretiske, lokal-anestetiske og hypoterme virkninger fastslått. Spesielt påfallende er den raske virkningsinntreden ved administrasjon av disse substanser. The compounds obtained according to the invention are distinguished by their diverse effects on the nervous system. Thus, anesthetic potentiating, adrenolytic, sedative, antihistamine-like, antiemetic, antipyretic, local anesthetic and hypothermic effects have been established. Particularly striking is the rapid onset of action when these substances are administered.
Særlig foretrukket er 5-(31-metylamiho-propyliden)-dibenzo /~a, e7cyklohepta/~l,57dien og dets syreaddisjonssalter, da disse forbindelser oppviser en særlig gunstig kombinasjon av terapeutiske egenskaper. Particularly preferred are 5-(31-methylaminopropylidene)-dibenzo[alpha],[beta]cyclohepta[beta]1,57diene and its acid addition salts, as these compounds exhibit a particularly favorable combination of therapeutic properties.
Ved norsk patent nr. 112.olo, som ikke tilhorer teknikkens stand, er beskyttet en annen fremgangsmåte for fremstilling av bl.a. forbindelsene med formel I ovenfor. Norwegian patent no. 112.olo, which does not belong to the state of the art, protects another method for the production of i.a. the compounds of formula I above.
EKSEMPEL 1EXAMPLE 1
2 g 5-hydroksy-5-(31-metylamino-propyl)-dibenzo/<->a,e7cyklo-hepta/~l,J57dien, 2o ml absolutt alkohol og 2 ml av en 2o%'ig saltsyreopplosning i alkohol oppvarmes i 3 timer på dampbad under tilbakelopskjoling og opplosningen dampes inn til torrhet under forminsket trykk. Resten lar seg omkrystallisere fra etanol-eter og gir 5-(3<1->metylamino-propyliden)-dibenzo/~a,d7 cyklohepta/~l, _5_7dienhydroklorid med smeltepunkt 22o - 222°. 2 g of 5-hydroxy-5-(31-methylamino-propyl)-dibenzo[->a,e7cyclo-hepta]~1,J57diene, 20 ml of absolute alcohol and 2 ml of a 20% hydrochloric acid solution in alcohol are heated in 3 hours in a steam bath under reflux and the solution is evaporated to dryness under reduced pressure. The residue can be recrystallized from ethanol-ether and gives 5-(3<1->methylamino-propylidene)-dibenzo/~a,d7 cyclohepta/~1,_5_7diene hydrochloride with melting point 22o - 222°.
Det som utgangsforbindelse anvendte 5-hydroksy-5-(3<1->metyl-amino-propyl) -dibenzo/~a,e7cyklohepta/~l/57dien kan fremstilles som folger: I en 1-liters trehalskolbe som er forsynt med rorer, dråpe-trakt og kjoler, overdekkes lo g Gilman-legering med 2o ml torr eter og tilsettes o,5 ml metyljodid. The 5-hydroxy-5-(3<1->methyl-amino-propyl)-dibenzo/~a,e7cyclohepta/~1/57diene used as starting compound can be prepared as follows: In a 1-liter three-necked flask fitted with stirrups , dropping funnel and skirts, cover the Gilman alloy with 20 ml of dry ether and add 0.5 ml of methyl iodide.
Etter at den livlige reaksjon har tatt noe av, tilsettes dråpevis en opplosning av 6o g l-klor-3-(metyl-benzyl-amino)-propan i 18o ml torr eter slik at reaksjonsblandingen holdes i kok. Den kokes ytterligere i 4 timer ved 45° under tilbakelop. After the lively reaction has subsided, a solution of 60 g of 1-chloro-3-(methyl-benzyl-amino)-propane in 180 ml of dry ether is added dropwise so that the reaction mixture is kept at a boil. It is boiled for a further 4 hours at 45° under reflux.
Derpå avkjoles reaksjonsblandingen med isvann, en opplosning av 21,2 g dibenzo/~a,d7cyklohepta/~l,57dien-5-on i 25o ml torr eter tilsettes dråpevis i lopet av 1 time, og det hele rores ytterligere i 17 timer under tilbakelop ved 4o°. Den folgende dag avkjoles enda en gang med isvann og reaksjonsblandingen tilsettes en kold, mettet ammoniumkloridopplosning. Det organiske sjikt skilles fra, den vandige fase rystes ut The reaction mixture is then cooled with ice water, a solution of 21.2 g of dibenzo[a,d7cyclohepta[l,57dien-5-one in 250 ml of dry ether is added dropwise over the course of 1 hour, and the whole is stirred for a further 17 hours under reflux at 4o°. The following day, it is cooled once more with ice water and a cold, saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated, the aqueous phase is shaken out
to ganger, hver gang med 15o ml eter og de forenede eterporsjoner torkes over natriumsulfat og dampes inn. Resten gir etter omkrystallisasjon fra hbytkokende petroleter fargelbse krystaller av 5-hydroksy-5-/~3'-(metyl-benzyl-amino)-propyl7-dibenzo/~a,e7cyklohepta/~l,57dien. Utbytte 73%. twice, each time with 15o ml of ether and the combined ether portions are dried over sodium sulfate and evaporated. The residue gives, after recrystallization from high-boiling petroleum ether, colorless crystals of 5-hydroxy-5-[3'-(methyl-benzyl-amino)-propyl7-dibenzo[a,e7cyclohepta][1,57diene. Yield 73%.
11,5 g 5-hydroksy-5-/~3'-(metyl-benzyl-amino)-propyl27-dibenzo /~a,e7cyklohepta/~l,57dien opploses i 9o ml metanol og hydrogeneres i nærvær av 3 g palladiumkull i 8 timer ved loo° under loo atm. Når hydrogeneringen er ferdig, filtreres opplosningen 11.5 g of 5-hydroxy-5-[3'-(methyl-benzyl-amino)-propyl27-dibenzo/~a,e7cyclohepta/~1,57diene are dissolved in 90 ml of methanol and hydrogenated in the presence of 3 g of palladium charcoal in 8 hours at loo° below loo atm. When the hydrogenation is finished, the solution is filtered
for katalysator og dampes inn til torrhet. Resten omkrystalliseres fra hoytkokende petroleter og gir fargelose krystaller av 5-hydroksy-5-(3<1->metylamino-propyl)-dibenzo/~a,e7cyklohepta /~l,57dien som smelter ved 94 - 96°. for catalyst and evaporated to dryness. The residue is recrystallized from high-boiling petroleum ether and gives colorless crystals of 5-hydroxy-5-(3<1->methylamino-propyl)-dibenzo/~a,e7cyclohepta/~1,57diene which melt at 94 - 96°.
Den samme forbindelse kan også fremstilles på folgende måte:The same compound can also be prepared in the following way:
I en 2-liters trehalskolbe, som er forsynt med rorer, dråpe-trakt og ammoniakk-kjoler, innfores 5oo ml flytende ammoniakk, og man torker ved innforing av natriumspon inntil opptreden av en bestandig blå farge. Deretter innforer man i små por-sjoner 7,25 g natrium og rorer ytterligere i 15 minutter. Into a 2-liter wooden-necked flask, which is equipped with stirrups, dropping funnel and ammonia skirts, introduce 500 ml of liquid ammonia, and dry by introducing sodium shavings until a permanent blue color appears. 7.25 g of sodium are then introduced in small portions and stirred for a further 15 minutes.
Den erholdte opplosning tilsettes dråpevis 54,2 g 3-metyl-benzyl-amino-propin-(1), hvorved den blå farge forsvinner. Nå tilsetter man dråpevis 67,5 g dibenzo/~a,e7cyklohepta/~l,57dien-5-on, rorer i 5 timer, behandler porsjonsvis med 5o g ammoniumklorid, fortynner med 4oo ml eter og lar, etter at man har utbyttet ammoniakk-kjoleren med en vannkjoler, ammoniakken fordampes av over natten. Den folgende dag behandler man med vann, skiller eteren fra og torker. Etter avdestillasjonen av eteren omkrystalliseres resten fra hoytkokende petroleter, hvorved man får 5-hydroksy-5-/~31 -(metyl-benzyl-amino)-propin-(l<1>)-yl7-dibenzo/~a,e7cyklohepta/~l,57dien med smeltepunkt 98 - loo°. The resulting solution is added dropwise to 54.2 g of 3-methyl-benzyl-amino-propyne-(1), whereby the blue color disappears. Now 67.5 g of dibenzo/~a,e7cyclohepta/~1,57dien-5-one are added dropwise, stirred for 5 hours, treated in portions with 5o g of ammonium chloride, diluted with 4oo ml of ether and left, after the ammonia has been recovered - the coater with a water coater, the ammonia evaporates overnight. The following day, treat with water, separate the ether and dry. After the ether has been distilled off, the residue is recrystallized from high-boiling petroleum ether, whereby 5-hydroxy-5-[31-(methyl-benzyl-amino)-propyne-(l<1>)-yl7-dibenzo[a,e7cyclohepta] is obtained l.57dien with melting point 98 - loo°.
7,34 g 5-hydrbksy- 5-/~ 31 - (metyl- benzyl- amino) -propin- (1' ) -yl7-dibenzo/~a,e7cyklohepta/~l,57dien hydreres i nærvær av o,8 g platinaoksyd i 25o ml isopropanol under normalt trykk og ved romtemperatur. Etter opptagelse av den teoretiske beregnede mengde hydrogen filtreres opplosningen åv fra katalysatoren, dampes inn og resten omkrystalliseres fra petroleter. Det erholdte 5-hydroksy-5-/"31 -(mety1-benzyl-amino)-propyl7-dibenzo /~a, e7cyklohepta/~l, j>7dien smelter ved 122 - 124°. Denne forbindelse debenzyleres ved hydrogenering på den ovenfor angitte måte til 5-hydroksy-5-(3<1->metylamino-propyl)-dibenzo/~a,e7 cyklohepta(1,5)-dien. 7.34 g of 5-hydroxy-5-[31-(methyl-benzyl-amino)-propyne-(1')-yl7-dibenzo[a,e7cyclohepta][1,57diene] is hydrogenated in the presence of 0.8 g platinum oxide in 25o ml of isopropanol under normal pressure and at room temperature. After absorption of the theoretically calculated amount of hydrogen, the solution is filtered off from the catalyst, evaporated and the remainder recrystallized from petroleum ether. The resulting 5-hydroxy-5-[31-(methyl-benzyl-amino)-propyl-7-dibenzo[a]cyclohepta[1]diene melts at 122 - 124°. This compound is debenzylated by hydrogenation on the above stated manner to 5-hydroxy-5-(3<1->methylamino-propyl)-dibenzo[a,e7]cyclohepta(1,5)-diene.
EKSEMPEL 2EXAMPLE 2
3 g 5-hydroksy-5-(2 '-mety 1-3 1-metyalmino-propyl)-dibenzo/~a,e7 cyklohepta/~l,57dien, 3o ml absolutt alkohol og 3 ml av en 2o%'ig saltsyreopplbsning i alkohol oppvarmes 3 timer på dampbadet under tilbakelbpskjSling og opplosningen dampes inn til torrhet under forminsket trykk. Resten lar seg omkrystallisere fra etanol-eter og gir 5-(2<1->mety1-3<1->metyl-amino-propy1iden)-dibenzo/<->a,d7cyklohepta/~1,57dien-hydroklorid med smp. 195 - 196°, 3 g of 5-hydroxy-5-(2'-methyl 1-3 1-methylamino-propyl)-dibenzo[a,e7]cyclohepta[1,57diene, 30 ml of absolute alcohol and 3 ml of a 20% hydrochloric acid solution in alcohol is heated for 3 hours on the steam bath under reflux and the solution is evaporated to dryness under reduced pressure. The residue can be recrystallized from ethanol-ether and gives 5-(2<1->methyl-3<1->methyl-amino-propy1idene)-dibenzo/<->a,d7cyclohepta/~1,57diene-hydrochloride with m.p. 195 - 196°,
Det som utgangsforbindelse anvendte 5-hydroksy-5-(21-mety1-31-metyalmino-propyl)-dibenzo/~a,d7cyklohepta/~l,57dien kan fremstilles som folger: I en 1-liters trehalskolbe, som er forsynt med rorer, dråpe-trakt og kjoler overdekkes lo g Gilman-legering med 2o ml torr eter og tilsettes o,5 ml metyljodid. The 5-hydroxy-5-(21-methyl-31-methylamino-propyl)-dibenzo/~a,d7cyclohepta/~1,57diene used as starting compound can be prepared as follows: In a 1-liter three-necked flask, which is fitted with stirrups , dropping funnel and skirts are covered with Gilman alloy with 20 ml of dry ether and 0.5 ml of methyl iodide is added.
Etter at den livlige reaksjon har tatt noe av,tilsettes dråpevis en opplosning av 6o g l-klor-2-metyl-3-metyl-benzylamino-propan (fremstilt fra l-klor-2-metyl-3-brompropan og benzyl-metylamin) i 18o ml torr eter, k.p. 114 - 116°/o,5 mm således at reaksjonsblandingen holdes i kok. Den kokes ytterligere i 5 timer ved 45° under tilbakelop. After the lively reaction has subsided, a solution of 60 g of 1-chloro-2-methyl-3-methyl-benzylamino-propane (prepared from 1-chloro-2-methyl-3-bromopropane and benzyl-methylamine) is added dropwise ) in 18o ml of dry ether, b.p. 114 - 116°/o.5 mm so that the reaction mixture is kept at a boil. It is boiled for a further 5 hours at 45° under reflux.
Derpå avkjoles reaksjonsblandingen med isvann, en opplosning av 21,2 g dibenzo/~a,e7cyklohepta/~l,57dien-5-on i 25o ml torr eter tilsettes dråpevis i lopet av 1 time og det hele rores ytterligere i 2o timer ved 4o° under tilbakelop. Den folgende dag avkjoles enda en gang med isvann og reaksjonsblandingen tilsettes en kold mettet ammoniumkloridopplosning. Det organiske sjikt skilles fra, den vandige fase rystes ut to ganger, hver gang med 2oo ml eter og de forenede eterporsjoner tbrkes over natriumsulfat og dampes inn. Resten gir etter omkrystallisasjon fra hoytkokende petroleter fargelbse krystaller av 5-hydroksy-5-(2<1->mety1-3'-metyl-benzyl-amino-propyl)-dibenzo /~a,e7cyklohepta/~l,57-dien som smelter ved 99 - loo°. Utbytte 7o%. The reaction mixture is then cooled with ice water, a solution of 21.2 g of dibenzo[a,e7cyclohepta[l,57dien-5-one in 25o ml of dry ether is added dropwise over the course of 1 hour and the whole is stirred for a further 2o hours at 4o ° during backflow. The following day, it is cooled once more with ice water and a cold saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated, the aqueous phase is shaken out twice, each time with 200 ml of ether and the combined portions of ether are dried over sodium sulphate and evaporated. The residue gives, after recrystallization from high-boiling petroleum ether, colorless crystals of 5-hydroxy-5-(2<1->methyl-3'-methyl-benzyl-amino-propyl)-dibenzo /~a,e7cyclohepta/~1,57-diene which melts at 99 - loo°. Dividend 7o%.
7,71 g 5-hydroksy-5-(2<1->mety1-3<1->metyl-benzylamino-propyl)-dibenzo^/~a, e7cyklohepta/~l, 57dien opploses i 6o ml metanol og hydrogeneres i nærvær av 2 g palladiumkull i 8 timer ved loo° under loo atm. Når hydrogeneringen er ferdig, filtreres opplosningen for katalysator og dampes i:inn til torrhet. Resten omkrystalliseres fra hoytkokende petroleter og gir fargelose krystaller av 5-hydroksy-5-(2'-mety1-3<1->metyl-amino-propyl)-dibenzo/~a,e7cyklohepta/~l,57dien, som smelter ved lo3 - lo4°. 7.71 g of 5-hydroxy-5-(2<1->methyl-3<1->methyl-benzylamino-propyl)-dibenzo[/~a,e7cyclohepta/~l,57diene is dissolved in 60 ml of methanol and hydrogenated in presence of 2 g of palladium charcoal for 8 hours at loo° under loo atm. When the hydrogenation is complete, the solution is filtered for catalyst and evaporated to dryness. The residue is recrystallized from high-boiling petroleum ether and gives colorless crystals of 5-hydroxy-5-(2'-methyl-3<1->methyl-amino-propyl)-dibenzo/~a,e7cyclohepta/~1,57diene, melting at lo3 - lo4°.
Claims (2)
Priority Applications (1)
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NO17100867A NO134616C (en) | 1961-02-08 | 1967-12-15 |
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CH146761A CH419104A (en) | 1961-02-08 | 1961-02-08 | Process for the preparation of tricyclic compounds |
CH1106361 | 1961-09-22 | ||
CH1212561 | 1961-10-19 | ||
NO14316962 | 1962-02-08 | ||
NO17100867A NO134616C (en) | 1961-02-08 | 1967-12-15 |
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NO134616B true NO134616B (en) | 1976-08-09 |
NO134616C NO134616C (en) | 1976-11-17 |
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