NO121948B - - Google Patents
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- NO121948B NO121948B NO148572A NO14857263A NO121948B NO 121948 B NO121948 B NO 121948B NO 148572 A NO148572 A NO 148572A NO 14857263 A NO14857263 A NO 14857263A NO 121948 B NO121948 B NO 121948B
- Authority
- NO
- Norway
- Prior art keywords
- compound
- dibenzo
- general formula
- cycloheptene
- propyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 150000008508 dibenzocycloheptenes Chemical class 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 230000001430 anti-depressive effect Effects 0.000 claims description 3
- 239000000935 antidepressant agent Substances 0.000 claims description 3
- 229940005513 antidepressants Drugs 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- -1 alkaryl radical Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- QPJORFLSOJAUNL-UHFFFAOYSA-N dibenzo[a,d][7]annulene Chemical compound C1=CC2=CC=CC=C2CC2=CC=CC=C21 QPJORFLSOJAUNL-UHFFFAOYSA-N 0.000 description 2
- NGPAITITALWALP-UHFFFAOYSA-M magnesium;n,n-dimethylpropan-1-amine;chloride Chemical compound [Mg+2].[Cl-].CN(C)CC[CH2-] NGPAITITALWALP-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940050176 methyl chloride Drugs 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 2
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- XUDMFUCJNFYMRZ-UHFFFAOYSA-N 11-chloro-11h-dibenzo[1,2-a:1',2'-e][7]annulene Chemical compound C1=CC2=CC=CC=C2C(Cl)C2=CC=CC=C21 XUDMFUCJNFYMRZ-UHFFFAOYSA-N 0.000 description 1
- YVBGGZGCBWNVDX-UHFFFAOYSA-N 3-(11h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yl)-n,n-dimethylpropan-1-amine Chemical compound C1=CC2=CC=CC=C2C(CCCN(C)C)C2=CC=CC=C21 YVBGGZGCBWNVDX-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000037396 body weight Effects 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
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- UTVGIBFBKOPUGN-UHFFFAOYSA-N ethyl N-methyl-N-[3-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaenyl)propyl]carbamate Chemical compound CN(C(=O)OCC)CCCC1C2=C(C=CC3=C1C=CC=C3)C=CC=C2 UTVGIBFBKOPUGN-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000002035 hexane extract Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003236 psychic effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- YPSUCTSXOROPBS-UHFFFAOYSA-N s-methyl chloromethanethioate Chemical compound CSC(Cl)=O YPSUCTSXOROPBS-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Fremgangsmåte til fremstilling av nye dibenzo-cyclohepten-derivater med antidepressiv aktivitet. Process for the preparation of new dibenzo-cycloheptene derivatives with antidepressant activity.
Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av nye dibenzocycloheptenderivater med den generelle formel: The present invention relates to a process for the production of new dibenzocycloheptene derivatives with the general formula:
I denne generelle formel betyr den strekede linje i IO - 11-stillingen at forbindelsen her kan være mettet eller umettet, mens X og X<1>hver betegner hydrogen eller halogen. In this general formula, the dashed line at the IO - 11 position means that the compound here can be saturated or unsaturated, while X and X<1> each represent hydrogen or halogen.
Oppfinnelsen omfatter ogsa fremstilling av syreaddisjonssalter av sådanne forbindelser. The invention also includes the production of acid addition salts of such compounds.
Forbindelsene er fordelaktige til anvendelse i mentalhygi-enen, da de er antidepresjonsmidler og tjener til å forhbye sinns-stemningen, eller psykiske energiseringsmidler. For slike formål anvendes forbindelsene fortrinnsvis i form av deres syreaddisjbnssalter. The compounds are advantageous for use in mental hygiene, as they are antidepressants and serve to improve the mood, or psychic energisers. For such purposes, the compounds are preferably used in the form of their acid addition salts.
De karakteristiske hovedtrekk ved oppfinnelsen er at man på kjent måte omsetter en forbindelse med den generelle formel: The characteristic main features of the invention are that a compound with the general formula is reacted in a known manner:
i hvilken X og X' har de ovenfor angitte betydninger, med et substituert halogenformiat med en av de generelle formler ROCOX" og RSCOX" (i in which X and X' have the meanings given above, with a substituted haloformate of one of the general formulas ROCOX" and RSCOX" (in
i in
hvilke R betegner en alkyl-, aryl-, aralkyl- eller alkarylgruppe og X" betegner halogen), hvorved man får en forbindelse med den generelle formel: where R denotes an alkyl, aryl, aralkyl or alkaryl group and X" denotes halogen), whereby a compound with the general formula is obtained:
i hvilken X, X<1>og R har de ovenfor angitte betydninger, mens Z betegner oxygen eller svovel, hvorpå man underkaster denne forbindelse hydrolyse, in which X, X<1>and R have the meanings given above, while Z denotes oxygen or sulphur, whereupon this compound is subjected to hydrolysis,
i i in i
Når der onskes å fremstille syreaddisjonssalter av en således erholdt forbindelse, overfores den til sådanne salter på i og for sig kjent måte. When it is desired to produce acid addition salts of a compound thus obtained, it is converted to such salts in a manner known per se.
Fremgangsmåten ifolge foreliggende oppfinnelse kan vises ved folgende reaksjonsskjema i hvilket de strekede linjer i 10 - 11-stillingen betyr at forbindelsene kan være mettet eller umettet, X og X' har de ovenfor angitte betydninger, mens X" betegner halogen, Z betegner oxygen eller svovel og R, som fjernes under prosessen, hen-siktsmessig er et alkyl- eller arylradikal eller en kombinasjon av slike radikaler som et aralkyl- eller alkaryl-radikal. The method according to the present invention can be shown by the following reaction scheme in which the dashed lines in the 10 - 11 position mean that the compounds can be saturated or unsaturated, X and X' have the meanings given above, while X" denotes halogen, Z denotes oxygen or sulfur and R, which is removed during the process, is suitably an alkyl or aryl radical or a combination of such radicals such as an aralkyl or alkaryl radical.
Som vist i ovenstående reaksjonsskjema omfatter forste trinn i fremgangsmåten ifolge oppfinnelsen kondensasjon av et tertiært aminopropylderivat av et 5H-dibenzo[a,djcyclohepten med et substituert halogenformiat eller halogen-thioformiat, hvorved man får et urethan eller thiourethan som mellomprodukt. I en typisk utforelsesform omsettes 5-[3-N-dimethylaminopropyl]-5H-dibenzo[a,d]cyclohepten med methylklorformiat, hvorved der dannes urethan-prbduktet, 5[3-(N-methyl-N-carbomethoxyamino)-propyl]-5H-dibenzo-[a,d]-cyclohepten og methylklorid. På lignende måte omsettes 5 (3-(N-dimethylamino) - propyl)-5H-diben-zo-[a,d]-cyclohepten med methylklorthioformiat, hvorved der dannes thiourethan-produktet, 5(3-(N-methy1-N-methylmercaptoformylamino)-pro-pyl )-5H-dibenzo[a,d]-cyclohepten og methylklorid. As shown in the above reaction scheme, the first step in the method according to the invention comprises the condensation of a tertiary aminopropyl derivative of a 5H-dibenzo[a,djcycloheptene with a substituted halogenformate or halogen-thioformate, whereby a urethane or thiourethane is obtained as an intermediate product. In a typical embodiment, 5-[3-N-dimethylaminopropyl]-5H-dibenzo[a,d]cycloheptene is reacted with methyl chloroformate, thereby forming the urethane product, 5[3-(N-methyl-N-carbomethoxyamino)-propyl] -5H-dibenzo-[a,d]-cycloheptene and methyl chloride. In a similar manner, 5-(3-(N-dimethylamino)-propyl)-5H-dibenzo-[a,d]-cycloheptene is reacted with methylchlorothioformate, whereby the thiourethan product is formed, 5(3-(N-methyl-N -methylmercaptoformylamino)-propyl)-5H-dibenzo[a,d]-cycloheptene and methyl chloride.
Denne reaksjon kan utfores i fravær av opplosningsmidler, men det foretrekkes å anvende et opplosningsmiddel. Egnet er opplosningsmidler som er inerte under reaksjonen, som aromatiske hydrocarboner, f.eks. benzen og toluen, alifatiske hydrocarboner„ f.eks. hep-ten, hexan og lignende, halogenerte hydrocarboner, som kloroform og carbontetraklorid, samt ethere, som tetrahydrofuran. Reaksjonen kan utfores ved romtemperatur, men der foretrekkes å utfore den ved kokning under tilbakelopskjoling i et passende tidsrom, fortrinnsvis opp til flere timer. This reaction can be carried out in the absence of solvents, but it is preferred to use a solvent. Suitable solvents are inert during the reaction, such as aromatic hydrocarbons, e.g. benzene and toluene, aliphatic hydrocarbons„ e.g. heptene, hexane and the like, halogenated hydrocarbons, such as chloroform and carbon tetrachloride, and ethers, such as tetrahydrofuran. The reaction can be carried out at room temperature, but it is preferred to carry it out by boiling under reflux for a suitable period of time, preferably up to several hours.
Ved avslutning av reaksjonen ekstraheres opplbsningen med fortynnet syre og inndampes til tbrrhet, hvorved man får det onskede urethan. I en foretrukken utforelsesform fremstilles 5-[3-N-methyl-amino]propyl-5H-dibenzo[a,d]-cyclohepten fra den tilsvarende N-dimeth-ylforbindelse. At the end of the reaction, the solution is extracted with dilute acid and evaporated to dryness, whereby the desired urethane is obtained. In a preferred embodiment, 5-[3-N-methyl-amino]propyl-5H-dibenzo[a,d]-cycloheptene is prepared from the corresponding N-dimethyl-yl compound.
Det således fremstillede mellomprodukt bestående av et urethan underkastes derpå hydrolyse, hvorved den substituerte carbamyl-gruppe i urethanet eller thiocarbamylgruppen i thiourethanet overfores til et hydrogenatom. Denne hydrolyse utfores fortrinnsvis under basi-ske eller sure betingelser. Hydrolyse i en alkalisk opplbsning i al-kohol under kokning med tilbakelopskjoling er egnet. Fortrinnsvis utfores imidlertid den hydrolytiske omdannelse av thiourethan-mellomproduktet ved forst å oxydere thiourethanet med et oxydasjonsmiddel, for-delaktig med hydrogenperoxyd i eddiksyre. Imidlertid kan der også anvendes andre oxydasjonsmidler som perbenzoesyre, pereddiksyre, krom-syre eller kaliumpermanganat. Det oxyderte mellomprodukt bringes derpå i kontakt med en alkalisk opplbsning som en natriumhydroxydopplos-ning. Urethan-mellomproduktet oppvarmes fortrinnsvis i riitrogenatmo-sfære i en opplbsning av kaliumhydroxyd i n-butanol. Når hydrolysen er fullfort, fordampes opplbsningsmidlet i vakuum, hvorpå residuet ekstraheres med passende opplosningsmidler for å isolere det hydroly-serte produkt. Produktet fra hydrolysen er det onskede sekundære aminopropylderivat av et 5H-dibenzo[a,d]-cyclohepten eller 5H-dibenzo-[a,d]-10,11-dihydrocyclohepten.(The thus produced intermediate consisting of a urethane is then subjected to hydrolysis, whereby the substituted carbamyl group in the urethane or the thiocarbamyl group in the thiourethane is transferred to a hydrogen atom. This hydrolysis is preferably carried out under basic or acidic conditions. Hydrolysis in an alkaline solution in alcohol under reflux is suitable. Preferably, however, the hydrolytic conversion of the thiourethane intermediate is carried out by first oxidizing the thiourethane with an oxidizing agent, advantageously with hydrogen peroxide in acetic acid. However, other oxidizing agents such as perbenzoic acid, peracetic acid, chromic acid or potassium permanganate can also be used. The oxidized intermediate is then brought into contact with an alkaline solution such as a sodium hydroxide solution. The urethane intermediate is preferably heated in a nitrogen atmosphere in a solution of potassium hydroxide in n-butanol. When the hydrolysis is complete, the solvent is evaporated in vacuo, after which the residue is extracted with suitable solvents to isolate the hydrolysed product. The product of the hydrolysis is the desired secondary aminopropyl derivative of a 5H-dibenzo[a,d]-cycloheptene or 5H-dibenzo-[a,d]-10,11-dihydrocycloheptene.
I det fblgende beskrives som eksempler noen utforelsesfor-mer for oppfinnelsen. In the following, some embodiments of the invention are described as examples.
Eksempel I Fremstilling av 5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]- cyclohepten Example I Preparation of 5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]-cycloheptene
Magnesium-spon (1,08 g, 0,0442 gramatom) anbringes i en 200 ni trehalset kolbe forsynt med rdreverk, dryppetrakt og tilbake-lbpskjbler forsynt med et torreror. Under hele reaksjonen opprett-holdes der en atmosfære av torr nitrogen i apparatet. Der tilsettes en krystall jod og derpå IO ml torr tetrahydrofuran. Derafter tilsettes 3 ml 3-dimethylaminopropyl-magnesiumklorid fra et foregående for-sok, og blandingen oppvarmes til kokning på dampbad. Der tilsettes så dråpevis en opplbsning av 3-dimethylaminopropylklorid (5,37 g, 0,0442 mol) i 35 ml torr tetrahydrofuran, idet man opprettholder kok-ningen under tilbakelopskjoling ved å tilfore varme når dette er nbd-vendig. Når alt er tilsatt, oppvarmes blandingen under tilbakelopskjoling i 2 timer, hvorved nesten hele mengden magnesium opplbses. Magnesium shavings (1.08 g, 0.0442 gram atom) are placed in a 200 nine three-necked flask fitted with a stirrer, dropping funnel and reflux shaker fitted with a drying tube. During the entire reaction, an atmosphere of dry nitrogen is maintained in the apparatus. A crystal of iodine is added and then 10 ml of dry tetrahydrofuran. Afterwards, 3 ml of 3-dimethylaminopropyl magnesium chloride from a previous experiment is added, and the mixture is heated to boiling on a steam bath. A solution of 3-dimethylaminopropyl chloride (5.37 g, 0.0442 mol) in 35 ml of dry tetrahydrofuran is then added dropwise, maintaining the boil under reflux by adding heat when necessary. When everything has been added, the mixture is heated under reflux for 2 hours, whereby almost the entire amount of magnesium is heated.
I stedet for å anvende 3-diméthylaminopropylmagnesiumklorid til å innlede reaksjonen kan der anvendes ethylbromid i en mengde på 0,05 mol pr. mol magnesium. Instead of using 3-dimethylaminopropylmagnesium chloride to initiate the reaction, ethyl bromide can be used in an amount of 0.05 mol per moles of magnesium.
Den ffemstillede Grignard-opplbsning avkjbles til romtemperatur og omrbres mens den dråpevis tilsettes en opplbsning av 5,05 g (0,0221 mol) 5-klor-5H-dibenzo-[a,d]-cyclohepten (fremstillet efter en fremgangsmåte som er beskrevet i litteraturen) i 25 ml tort tetrahyd-rof uran, idet man efter behov anvender utvendig kjbling for å holde temperaturen i nærheten av romtemperatur. Når alt er tilsatt, oppvarmes blandingen under tilbakelopskjoling i 15 minutter. Hovedmengden av tetrahydrofuranet avdestilleres derpå under forminsket trykk, idet man holder vannbadets temperatur på 50 - 60°C. Det herved erholdte sirupsaktige residuum opplbses i 75 ml benzen og vann, 15 ml tilsettes dråpevis under omrbring. Benzenskiktet dekanteres fra det gelatinbse bunnfall som derpå ekstraheres påny med tre 20 ml porsjoner kokende benzen. Benzenekstraktene blandes, vaskes med vann og ekstraheres med tre 15 ml porsjpner 3 N saltsyre. Det sure ekstrakt gjbres alkalisk med natriumhydroxyd, og den gule oljeaktige base som herved utskilles, ekstraheres med hexan. Efter vaskning av de blandede ekstrakter med vann avdestilleres hexanet, og man får produktet som et gult oljeaktig stoff med et utbytte på 4,61 g. The five-stage Grignard solution is cooled to room temperature and stirred while adding dropwise a solution of 5.05 g (0.0221 mol) 5-chloro-5H-dibenzo-[a,d]-cycloheptene (prepared according to a procedure described in the literature) in 25 ml of dry tetrahydrofuran, using external cooling as necessary to keep the temperature close to room temperature. When everything has been added, the mixture is heated under reflux for 15 minutes. The main amount of the tetrahydrofuran is then distilled off under reduced pressure, keeping the temperature of the water bath at 50 - 60°C. The syrupy residue thus obtained is dissolved in 75 ml of benzene and water, 15 ml is added dropwise while stirring. The benzene layer is decanted from the gelatinous precipitate, which is then extracted again with three 20 ml portions of boiling benzene. The benzene extracts are mixed, washed with water and extracted with three 15 ml portions of 3 N hydrochloric acid. The acidic extract is made alkaline with sodium hydroxide, and the yellow oily base which is thereby separated is extracted with hexane. After washing the mixed extracts with water, the hexane is distilled off, and the product is obtained as a yellow oily substance with a yield of 4.61 g.
Eksempel II Fremstilling av 5[3-(N-methyl-N-carbethoxyamino)-propyl]- 5H- dibenzo[ a, d]- cyclohepten , Example II Preparation of 5[3-(N-methyl-N-carbethoxyamino)-propyl]-5H-dibenzo[a,d]-cycloheptene,
27,7 g 5-[3-(N-dimethylamino)propyl]-5H-dibenzo[a,d]-cyclohepten (0,1 mol) opplost i 100 ml benzen tilsettes i lopet av 1 time til en opplbsning av 32,4 g ethylklorformiat (0,3 mol) i lOO ml benzen ved romtemperatur. Den erholdte opplosning oppvarmes under tilbakelopskjoling og omroring i 20 timer, hvorpå den avkjoles til romtemperatur og ekstraheres med tre 100 ml porsjoner 2,5 N saltsyre. Der vaskes derpå med vann (to ganger 50 ml), opplbsningen befries for vann med magnesiumsulfat og inndampes til torrhet. Man får et tyktflytende oljeaktig stoff som består av det rene urethan. Utbyttet er 29,5 g tilsvarende 88 % av det teoretiske utbytte.<1>27.7 g of 5-[3-(N-dimethylamino)propyl]-5H-dibenzo[a,d]-cycloheptene (0.1 mol) dissolved in 100 ml of benzene is added over the course of 1 hour to a solution of 32, 4 g of ethyl chloroformate (0.3 mol) in 100 ml of benzene at room temperature. The obtained solution is heated under reflux and stirring for 20 hours, after which it is cooled to room temperature and extracted with three 100 ml portions of 2.5 N hydrochloric acid. It is then washed with water (twice 50 ml), the solution is freed from water with magnesium sulphate and evaporated to dryness. You get a viscous, oily substance that consists of pure urethane. The yield is 29.5 g corresponding to 88% of the theoretical yield.<1>
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Eksempel III Fremstilling av 5[3-(N-methyl-N-carbomethoxyamino)-propyl]- 5H- dibenzo[ a, d]- IO, 11- dihydrocyclohepten Example III Preparation of 5[3-(N-methyl-N-carbomethoxyamino)-propyl]-5H-dibenzo[a,d]-10,11-dihydrocycloheptene
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52.4 g 5[3-^-dimethylamino)propyl]-5H-dibenzo-[a, d]-dibenzo[a,d]-10,11-dihydrocyclohepten (0,188 mol) opplbses i 216 ml benzen, og den erholdte opplosning tilsettes en opplosning av 65 g methylklorformiat i 580 ml benzen i lopet av ca. 15 minutter, hvorun-der blandingen omarores ved, romtemperatur. Opplbsningen oppvarmes under tilbakelopskjoling og omroring i 2 timer, hvorpå den avkjoles til romtemperatur og filtreres,. Filtratet ekstraheres med 'tre 200 ml porsjoner 2,5 N saltsyre, vaskes med vann, befries for vann med magnesiumsulfat og inndampes i vakuum. Man får et tyktflytende farvelbst, oljeaktig stoff bestående av 56 g av urethanet. 52.4 g of 5[3-^-dimethylamino)propyl]-5H-dibenzo-[a,d]-dibenzo[a,d]-10,11-dihydrocycloheptene (0.188 mol) are dissolved in 216 ml of benzene, and the resulting solution is added a solution of 65 g of methyl chloroformate in 580 ml of benzene over the course of approx. 15 minutes, during which the mixture is stirred at room temperature. The mixture is heated under reflux and stirring for 2 hours, after which it is cooled to room temperature and filtered. The filtrate is extracted with three 200 ml portions of 2.5 N hydrochloric acid, washed with water, freed from water with magnesium sulphate and evaporated in vacuo. A viscous, oily substance consisting of 56 g of the urethane is obtained.
Når man går frem således som beskrevet i eksempel I under anvendelse av ekvivalente mengder av 5-[3-(N-dimethylamino)propyliden] 5H-dibenzo[a,d]-10,11-dihydrocyclohepten får man det tilsvarende 5-[3-(N-methyl-N-carbethoxyamino)propyliden]-5H-dibenzo[a,d]-10,11-dihydro-cyclohepten. When proceeding as described in example I using equivalent amounts of 5-[3-(N-dimethylamino)propylidene] 5H-dibenzo[a,d]-10,11-dihydrocycloheptene, the corresponding 5-[3 -(N-methyl-N-carbethoxyamino)propylidene]-5H-dibenzo[a,d]-10,11-dihydro-cycloheptene.
Eksempel IV Fremstilling av 5-[3-(N-methylamino-pfopyl]5H-dibenzo-[ a, d] - cyclohepten Example IV Preparation of 5-[3-(N-methylamino-phenyl]5H-dibenzo-[a,d]-cycloheptene
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29.5 g 5-[3-(N-methyl-N-carbethoxyamino)-propyl]-5H-diben-zo[a,d]-cyclohepten oppvarmes under tilbakelopskjoling i 24 timer i nitrogenatmosfære og i en opplbsning av 36,3 g kaliumhydroxyd i 378 ml n-butanol. Den erholdte opplbsning avkjoles derpå til romtemperatur, opplbsningsmidlet fordampes i vakuum, residuet omrbres med 200 ml vann og 300 ml n-hexan. Skiktene skilles fra hverandre, og det vandige skikt ekstraheres med lOO ml n-hexan. Hexanekstraktene blandes og vaskes med to lOO ml porsjoner vann og defefter med 0,5 N svovelsyre 29.5 g of 5-[3-(N-methyl-N-carbethoxyamino)-propyl]-5H-dibenzo[a,d]-cycloheptene are heated under reflux for 24 hours in a nitrogen atmosphere and in a solution of 36.3 g of potassium hydroxide in 378 ml of n-butanol. The solution obtained is then cooled to room temperature, the solvent is evaporated in vacuo, the residue is stirred with 200 ml of water and 300 ml of n-hexane. The layers are separated, and the aqueous layer is extracted with 100 ml of n-hexane. The hexane extracts are mixed and washed with two 100 ml portions of water and defatted with 0.5 N sulfuric acid
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(lOO x 80 x 80 ml). Derefter gjores den sure opplosning alkalisk og ekstraheres med ether. Ekstraktet befries for vann med magnesiumsulfat og inndampes til torrhet. Det erholdte produkt er en praktisk talt ren monomethyl-base som renses ytterligere ved å overfores til oxalatet (sm.p. 181°C), frigjoring av basen og overforing til hydro-kloridet (sm.p. 169 - 170°C). (100 x 80 x 80 ml). The acidic solution is then made alkaline and extracted with ether. The extract is freed from water with magnesium sulphate and evaporated to dryness. The product obtained is a practically pure monomethyl base which is further purified by transfer to the oxalate (m.p. 181°C), liberation of the base and transfer to the hydrochloride (m.p. 169 - 170°C).
Når man går frem således som ovenfor angitt under anvendelse av ekvivalente mengder 5-[3-(n-methyl-N-carbomethoxyamino)propyl]-5H-dibenzo[a,d]-10,11-dihydrocyclohepten, får man det tilsvarende 5-[3-(N-methylamino)propyl]-5H-dibenzo-[a,d]-10,11-dihydrocyclohepten. When proceeding as indicated above using equivalent amounts of 5-[3-(n-methyl-N-carbomethoxyamino)propyl]-5H-dibenzo[a,d]-10,11-dihydrocycloheptene, one obtains the corresponding 5 -[3-(N-methylamino)propyl]-5H-dibenzo-[a,d]-10,11-dihydrocycloheptene.
Eksempel V Example V
Når man går frem således som beskrevet i eksempel II under anvendelse av ekvivalente mengder av 5-[3-(N-methyl-N-methylmercapto-formylamino)propyl]-5H-dibenzo-[a,d]-10,11-dihydrocyclohepten, eller 5-[3-(N-methyl-N-methylmercaptoformylamino)propyl]-5H-dibenzo[a,d]-cyclohepten, får man de tilsvarende 5-[3-(N-methylamino)propyl]-5H-dibenzo[a,d]-10,11-dihydrocyclohepten, henholdsvis 5-[3-(N-methyl-amino) -propyl]-5H-dibenzo[a,d]-cyclohepten. When proceeding thus as described in Example II using equivalent amounts of 5-[3-(N-methyl-N-methylmercapto-formylamino)propyl]-5H-dibenzo-[a,d]-10,11-dihydrocycloheptene , or 5-[3-(N-methyl-N-methylmercaptoformylamino)propyl]-5H-dibenzo[a,d]-cycloheptene, the corresponding 5-[3-(N-methylamino)propyl]-5H-dibenzo [a,d]-10,11-dihydrocycloheptene, respectively 5-[3-(N-methyl-amino)-propyl]-5H-dibenzo[a,d]-cycloheptene.
Til bekreftelse av den effekt som oppnåes ved produkter fremstillet ved fremgangsmåten ifolge oppfinnelsen, henvises til neden-stående tabellariske fremstilling oppstillet på basis av data i artik-kelen i J. Med. Chem., 11, sider 325 - 32 (19.68). Disse data finnes på side 328 i dette litteratursted og angår den antidepressive effekt og ED5q for en forbindelse fremstillet ifolge oppfinnelsen, nemlig For confirmation of the effect achieved by products produced by the method according to the invention, reference is made to the tabular presentation below drawn up on the basis of data in the article in J. Med. Chem., 11, pages 325 - 32 (19.68). These data can be found on page 328 of this literature site and relate to the antidepressant effect and ED5q for a compound produced according to the invention, namely
5-(3-methylaminopropyl)-5H-dibenzo[a,d]cyclohepten og for noen kjente dibenzocycloheptenderivater som har en aminopropylidensubstituent i 5-stillingen. Den terapeutiske effekt er som det sees uttrykt relativt til effekten av førstnevnte forbindelse, satt lik 1, mens ED^q er uttrykt i mg pr. kg legemsvekt. 5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene and for some known dibenzocycloheptene derivatives which have an aminopropylidene substituent in the 5-position. As can be seen, the therapeutic effect is expressed relative to the effect of the first-mentioned compound, set equal to 1, while ED^q is expressed in mg per kg body weight.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19466062A | 1962-05-14 | 1962-05-14 | |
| US194659A US3324170A (en) | 1962-05-14 | 1962-05-14 | Derivatives of 5h-dibenzo[a, d]cycloheptene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO121948B true NO121948B (en) | 1971-05-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO148572A NO121948B (en) | 1962-05-14 | 1963-05-06 |
Country Status (9)
| Country | Link |
|---|---|
| BR (1) | BR6349044D0 (en) |
| CH (1) | CH446310A (en) |
| DE (1) | DE1287573B (en) |
| DK (2) | DK122073B (en) |
| ES (1) | ES288362A1 (en) |
| FI (1) | FI41020B (en) |
| GB (1) | GB1034931A (en) |
| NO (1) | NO121948B (en) |
| SE (1) | SE318867B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4136116A (en) * | 1968-05-03 | 1979-01-23 | Hoffmann-La Roche Inc. | Tricyclic compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH356759A (en) * | 1958-04-03 | 1961-09-15 | Hoffmann La Roche | Process for the preparation of dibenzo-cycloheptaenes |
| CH356760A (en) * | 1958-04-03 | 1961-09-15 | Hoffmann La Roche | Process for the preparation of dibenzo-cycloheptaenes |
| BE609095A (en) * | 1960-10-12 | 1962-04-12 | Kefalas As | Method for preparing dibenzo [a, d] cyclohepta [1,4] dienes, as well as their acid addition salts. |
| DE1792679A1 (en) * | 1961-02-08 | 1972-02-17 | Hoffmann La Roche | Pharmaceutical preparations |
-
1963
- 1963-05-06 DE DEM56710A patent/DE1287573B/en active Pending
- 1963-05-06 NO NO148572A patent/NO121948B/no unknown
- 1963-05-09 GB GB18414/63A patent/GB1034931A/en not_active Expired
- 1963-05-10 BR BR149044/63A patent/BR6349044D0/en unknown
- 1963-05-13 FI FI0990/63A patent/FI41020B/fi active
- 1963-05-13 ES ES288362A patent/ES288362A1/en not_active Expired
- 1963-05-13 SE SE5277/63A patent/SE318867B/xx unknown
- 1963-05-14 CH CH603263A patent/CH446310A/en unknown
- 1963-05-14 DK DK227363AA patent/DK122073B/en unknown
-
1964
- 1964-03-17 DK DK136064AA patent/DK119608B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES288362A1 (en) | 1963-12-16 |
| BR6349044D0 (en) | 1973-07-12 |
| CH446310A (en) | 1967-11-15 |
| FI41020B (en) | 1969-04-30 |
| DK122073B (en) | 1972-01-17 |
| SE318867B (en) | 1969-12-22 |
| DE1287573B (en) | 1969-01-23 |
| GB1034931A (en) | 1966-07-06 |
| DK119608B (en) | 1971-02-01 |
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