NO122246B - - Google Patents
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- NO122246B NO122246B NO168071A NO16807167A NO122246B NO 122246 B NO122246 B NO 122246B NO 168071 A NO168071 A NO 168071A NO 16807167 A NO16807167 A NO 16807167A NO 122246 B NO122246 B NO 122246B
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- Prior art keywords
- formula
- carbon atoms
- dibenzo
- given above
- alkyl
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 150000003141 primary amines Chemical class 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- QPJORFLSOJAUNL-UHFFFAOYSA-N dibenzo[a,d][7]annulene Chemical class C1=CC2=CC=CC=C2CC2=CC=CC=C21 QPJORFLSOJAUNL-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- PJQCANLCUDUPRF-UHFFFAOYSA-N dibenzocycloheptene Chemical class C1CC2=CC=CC=C2CC2=CC=CC=C12 PJQCANLCUDUPRF-UHFFFAOYSA-N 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- -1 hydrohalic acids Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- RZJLDZMIOKCPJA-UHFFFAOYSA-N cycloheptene;hydrochloride Chemical compound Cl.C1CCC=CCC1 RZJLDZMIOKCPJA-UHFFFAOYSA-N 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-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
- 238000010992 reflux Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- CJDMGGVKOZCNJH-UHFFFAOYSA-N 1-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yl)-n,n-dimethylmethanamine Chemical compound C1CC2=CC=CC=C2C(CN(C)C)C2=CC=CC=C21 CJDMGGVKOZCNJH-UHFFFAOYSA-N 0.000 description 1
- KRGZWDPNVIINFY-UHFFFAOYSA-N 1-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yl)-n-methylmethanamine Chemical compound C1CC2=CC=CC=C2C(CNC)C2=CC=CC=C21 KRGZWDPNVIINFY-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
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- WEFIZNULHWPABZ-UHFFFAOYSA-N N-methyltetracyclo[7.6.1.02,7.010,15]hexadeca-2,4,6,10,12,14-hexaen-8-imine Chemical compound CN=C1C2C3=C(C(C4=C1C=CC=C4)C2)C=CC=C3 WEFIZNULHWPABZ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-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
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005905 alkynylation reaction Methods 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WWBGONGKRSWMGE-UHFFFAOYSA-N cycloheptene Chemical compound [CH]1CCCC=CC1 WWBGONGKRSWMGE-UHFFFAOYSA-N 0.000 description 1
- 150000001933 cycloheptenes Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960002601 protriptyline Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 229910001023 sodium amalgam Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- GSCKMHFCKGEORH-UHFFFAOYSA-N tetracyclo[7.6.1.02,7.010,15]hexadeca-2,4,6,10,12,14-hexaen-8-imine Chemical class C1C2C3=C(C(C1C1=C2C=CC=C1)=N)C=CC=C3 GSCKMHFCKGEORH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
- C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
Description
Analogifremgnagsmåte for fremstilling av Analogy method for the production of
terapeutisk virksomme 10,ll-dihydro-5H-dibenzo-|a,dj cyklohepten-derivater. therapeutically active 10,11-dihydro-5H-dibenzo-|a,dj cycloheptene derivatives.
Oppfinnelsens gjenstand er analogifremgangsmåter for fremstilling av nye 5-aminometylerte 10,ll-dihydro-5H-dibenzo-[a,d]cykloheptener av formelen: The object of the invention is analogous methods for the production of new 5-aminomethylated 10,11-dihydro-5H-dibenzo-[a,d]cycloheptenes of the formula:
i hvilken betyr et hydrogenatom eller en alkylgruppe med 1-3 in which means a hydrogen atom or an alkyl group of 1-3
karbonatomer, R2betyr en alkyl-, alkenyl- eller alkynylgruppe med 1-3 karbonatomer, R3betyr en alkylgruppe med 1-3 karbonatomer, og én av restene R^og R,- betyr et hydrogenatom og den andre et hydrogen- eller halogenatom, eller en alkylgruppe med 1-3 karbonatomer, samt syre-addisjonssalter herav, og fremgangsmåten erkarakterisert vedat enten carbon atoms, R2 means an alkyl, alkenyl or alkynyl group with 1-3 carbon atoms, R3 means an alkyl group with 1-3 carbon atoms, and one of the radicals R^ and R,- means a hydrogen atom and the other a hydrogen or halogen atom, or a alkyl group with 1-3 carbon atoms, as well as acid addition salts thereof, and the method is characterized by either
a) omsettes reaksjonsdyktige estere av alkoholer av formelen: a) reactive esters of alcohols of the formula are reacted:
har de foran anførte betydninger, med et amin av formelen HNR2R3, has the above meanings, with an amine of the formula HNR2R3,
hvor R2og R^har de foran anførte betydninger, eller where R 2 and R 2 have the previously stated meanings, or
b) primære eller sekundære aminer av formelen: b) primary or secondary amines of the formula:
i hvilken R1, R4og R,- har de foran anførte betydninger, og R' in which R 1 , R 4 and R 1 - have the meanings given above, and R'
betyr et hydrogenatom eller en alkyl-, alkenyl- eller alkynylgrup- means a hydrogen atom or an alkyl, alkenyl or alkynyl group
pe med 1-3 karbonatomer, alkyleres, alkenyleres eller alkynyleres til det ønskede tertiære amin, eller at man pe with 1-3 carbon atoms, is alkylated, alkenylated or alkynylated to the desired tertiary amine, or that one
c) for fremstilling av produkter i hvilke R2og R3betyr alkylgruppe r , spalter reduktivt kvartære ammoniumsalter av formelen: c) for the production of products in which R2 and R3 are alkyl groups, reductively split quaternary ammonium salts of the formula:
hvor R^, R2, R3, R4og R,- har de ovenfor anførte betydninger, og betyr en syrerest, eller at man d) for fremstilling av produkter i hvilke R2ogR3betyr alkyl grupper, hydrogenerer 5-aminometylerte 5H-dibenzo[a,d]cyklohepte-ner av formelen: where R^, R2, R3, R4 and R,- have the meanings given above, and means an acid residue, or that d) for the production of products in which R2 and R3 are alkyl groups, hydrogenate 5-aminomethylated 5H-dibenzo[a,d] cycloheptenes of the formula:
i hvilken , , R3, R4og R^har de foran anførte betydninger, in which , , R 3 , R 4 and R 4 have the above meanings,
hvorpå det erholdte reaksjonsprodukt isoleres som fri base, eller i form av et syreaddisjonssalt. whereupon the reaction product obtained is isolated as a free base, or in the form of an acid addition salt.
De nevnte forbindelser oppviser, slik som dette kan på-vises ved elektrosjokkforsøket [metode avGoodmann et al: "J.Pharmacol.", 108, 168(1953)], en sterk antikonvulsiv virksomhet, og kommer derfor særlig i betraktning som anti-epileptika. The mentioned compounds show, as can be demonstrated by the electroshock test [method of Goodmann et al: "J.Pharmacol.", 108, 168(1953)], a strong anticonvulsant activity, and therefore come particularly into consideration as anti-epileptics .
Det skal bemerkes at en analog av fremgangsmåteforbindel-sene , 5-(N-metylaminopropyl)-5H-dibenzo[a,d]cyklohepten, kjent som "Protriptyline" ikke har noen anti-konvulsiv virkning. It should be noted that an analogue of the process compounds, 5-(N-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene, known as "Protriptyline" has no anticonvulsant effect.
Omsetningen av nevnte estere med et amin av formelen HNR2R.J kan finne sted ved moderat inntil sterk oppvarmning av de reaksjonsdeltagende stoffer i et passende inert oppløsningsmiddel, som benzen, toluen eller xylen og i nærvær av et overskudd av det anvendte amin eller esi annen syrebindende base som trietyl-amin. Som reaksjonsdyktige estere av alkoholer er særlig egnet halogenhydrogen- eller p-toluensulfonsyreestere. The reaction of said esters with an amine of the formula HNR2R.J can take place by moderate to strong heating of the substances participating in the reaction in a suitable inert solvent, such as benzene, toluene or xylene and in the presence of an excess of the amine used or some other acid-binding agent base such as triethylamine. As reactive esters of alcohols, halogen hydrogen or p-toluenesulphonic acid esters are particularly suitable.
De som utgangsstoffer nødvendige estere kan fåes ved forestring av tilsvarende alkoholer, f.eks. tionylklorid.Alko-holene kan på sin side fåes ved reduksjon av tilsvarende syrer, som på sin side igjen kan fåes fra de tilsvarende nitriler. The esters required as starting materials can be obtained by esterification of corresponding alcohols, e.g. thionyl chloride. The alcohols can in turn be obtained by reduction of corresponding acids, which in turn can be obtained from the corresponding nitriles.
Alkyleringen av de nevnte primære eller sekundære aminer kan finne sted ved omsetning med tilsvarende aldehyder under an-vendelse av et reduksjonsmiddel, som maursyre, eller, som også en alkenylering eller alkynylering, ved omsetning med reaksjonsdyktige estere av tilsvarende alkoholer, særlig halogenidene. The alkylation of the mentioned primary or secondary amines can take place by reaction with corresponding aldehydes using a reducing agent, such as formic acid, or, as also an alkenylation or alkynylation, by reaction with reactive esters of corresponding alcohols, especially the halides.
De som utgangsstoffer nødvendige primære aminer fåes fortrinnsvis ved reduksjon av tilsvarende nitriler. De sekundære aminer dannes f.eks. ved omsetning av reaksjonsdyktige estere av The primary amines required as starting materials are preferably obtained by reduction of corresponding nitriles. The secondary amines are formed e.g. by conversion of reactive esters of
alkoholer med aminer av formelen I^N-I^- alcohols with amines of the formula I^N-I^-
Den reduktive spaltning av de kvartære ammoniumsalter kan f.eks. gjennomføres med natriumamalgam i alkoholisk eller med Raney-nikkel-legering i alkalisk oppløsning. The reductive cleavage of the quaternary ammonium salts can e.g. carried out with sodium amalgam in alcoholic or with Raney-nickel alloy in alkaline solution.
De som utgangsstoffer anvendbare kvartære ammoniumsalter kan på sin side f.eks. fåes når 5,ll-metylenimino-10,11-dihydro-5H-dibenzo[a,d]cykloheptener av formelen: The quaternary ammonium salts that can be used as starting materials can, for their part, e.g. is obtained when 5,11-methyleneimino-10,11-dihydro-5H-dibenzo[a,d]cycloheptenes of the formula:
i hvilken , R4, R^og R<1>har de foran anførte betydninger, kvartæriseres med et alkylerings-, alkenylerings- eller alkynyle-ringsmiddel. in which , R 4 , R 1 and R< 1> have the meanings given above, is quaternized with an alkylating, alkenylating or alkynylating agent.
De ønskede forbindelser hvor R2 og r^ betyr alkylgrupper fåes sluttelig også når 5-amino-metylerte 5H-dibenzo[a,d]cyklo-heptener av formelen: The desired compounds where R 2 and r 2 mean alkyl groups are also finally obtained when 5-amino-methylated 5H-dibenzo[a,d]cycloheptenes of the formula:
i hvilken R^, R2, R^, R^og R5har de foran anførte betydninger, hydrogeneres. in which R 1 , R 2 , R 2 , R 2 and R 5 have the above meanings, is hydrogenated.
Hydrogeneringen finner fortrinnsvis sted i et organisk oppløsningsmiddel, f.eks. en alkohol eller ester, ved behandling med hydrogen i nærvær av en katalysator, som palladiumkull, Raney-nikkel, platina eller lignende. The hydrogenation preferably takes place in an organic solvent, e.g. an alcohol or ester, by treatment with hydrogen in the presence of a catalyst, such as palladium charcoal, Raney nickel, platinum or the like.
De etter denne fremgangsmåte erholdte forbindelser sva- The compounds obtained according to this procedure are
rende til formelen kan utvinnes og anvendes såvel som frie baser som også i form av deres addisjonssalter med passende syrer, som halogenhydrogensyrer, toluensulfonsyrer, svovelsyre, salpetersyre, fosforsyre , eddiksyre, oksalsyre, malonsyre, ravsyre, eplesyre, maleinsyre eller vinsyre. leading to the formula can be extracted and used as well as free bases and also in the form of their addition salts with suitable acids, such as hydrohalic acids, toluenesulfonic acids, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid or tartaric acid.
Eksempel 1 Example 1
2,57 g 5-klormetyl-10,ll-dihydro-ll-metyl-5H-dibenzo- 2.57 g of 5-chloromethyl-10,11-dihydro-11-methyl-5H-dibenzo-
[a,d]cyklohepten (kokepunkt 129-132°c/0,3Torr) og 1,5 g dimetyl-amin opphetes i 40 ml benzen i bomberør i 7 timer til 110°C. Reaksjonsblandingen avkjøles derpå, vaskes seks ganger med vann og utrystes derpå fire ganger med 2n saltsyre. De vandig-sure uttrekk innstilles alkalisk med 2n natronlut og utrystes fem ganger med kloroform. Kloroformuttrekkene vaskes én gang med vann, tørkes med natriumsulfat og inndampes. Den erholdte olje overføres til hydrokloridet, hvorunder man' etter omkrystallisering fra metanol/eter får 2,5 g (83% av teorien) 5-dimetylaminometyl-10, 11-dihydro-ll-me-tyl-5H-dibenzo[,a,d]cyklohepten-hydroklorid i form av farveløse nåler av smeltepunkt 245-246°C. [a,d]cycloheptene (boiling point 129-132°c/0.3Torr) and 1.5 g of dimethylamine are heated in 40 ml of benzene in a bomb tube for 7 hours to 110°C. The reaction mixture is then cooled, washed six times with water and then shaken four times with 2N hydrochloric acid. The aqueous-acidic extracts are made alkaline with 2N caustic soda and shaken five times with chloroform. The chloroform extracts are washed once with water, dried with sodium sulfate and evaporated. The oil obtained is transferred to the hydrochloride, during which, after recrystallization from methanol/ether, 2.5 g (83% of theory) of 5-dimethylaminomethyl-10, 11-dihydro-11-methyl-5H-dibenzo[,a, d]cycloheptene hydrochloride in the form of colorless needles of melting point 245-246°C.
Eksempel 2 Example 2
6 g 5-aminometyl-10,ll-dihydro-ll-metyl-5H-dibenzo[ a,d] - cyklohepten (hydroklorid: smp. 244-248°C) opphetes med 5,4 g 6 g of 5-aminomethyl-10,11-dihydro-11-methyl-5H-dibenzo[a,d]-cycloheptene (hydrochloride: m.p. 244-248°C) is heated with 5.4 g
35%'s formaldehydoppløsning og 4,65 g maursyre i.3 timer under tilbakeløp. Reaksjonsblandingen inndampes derpå i vakuum, tilsettes vann, innstilles alkalisk med 2n natronlut og utrystes fem ganger med kloroform. Kloroformuttrekkene vaskes med vann, tør-kes med natriumsulfat og inndampes. Det oljeaktige residuum over-føres til hydrokloridet, hvorunder man etter omkrystallisering fra metanol/eter får 5,5 g (72% av teorien) 5-dimetylaminometyl-10,ll-dihydro-ll-metyl-5H-dibenzo[a,d]cyklohepten-hydroklorid i form av farveløse nåler av smeltepunkt 245-246°C, hvilket produkt er identisk med den i henhold til eksempel 1 erholdte forbindelse. Eksempel 3 35% formaldehyde solution and 4.65 g of formic acid for 3 hours under reflux. The reaction mixture is then evaporated in vacuo, water is added, made alkaline with 2N caustic soda and shaken five times with chloroform. The chloroform extracts are washed with water, dried with sodium sulphate and evaporated. The oily residue is transferred to the hydrochloride, during which, after recrystallization from methanol/ether, 5.5 g (72% of theory) of 5-dimethylaminomethyl-10,11-dihydro-11-methyl-5H-dibenzo[a,d] are obtained cycloheptene hydrochloride in the form of colorless needles of melting point 245-246°C, which product is identical to the compound obtained according to example 1. Example 3
3,0 g 5-metylaminometyl-10,ll-dihydro-5H-dibenzo[a,d]-cyklohepten (hydroklorid: smp. 256-257°C) opphetes med 1,3 g tri-etylamin og 1,55 g allylbromid i 35 ml toluen i 12 timer under til-bakeløp. Reaksjonsblandingen filtreres derpå, vaskes med vann, tørkes med natriumsulfat og inndampes. Det oljeaktige residuum overføres til hydrokloridet, hvorunder man etter omkrystallisering fra metanol/eter får 3,5 g (88% av teorien) 5-(metylallyl)amino-metyl-10,ll-dihydro-5H-dibenzo[a,d]cyklohepten-hydroklorid i form av farveløse nåler av smeltepunkt 205- 206°C. 3.0 g of 5-methylaminomethyl-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene (hydrochloride: m.p. 256-257°C) is heated with 1.3 g of tri-ethylamine and 1.55 g of allyl bromide in 35 ml of toluene for 12 hours under reflux. The reaction mixture is then filtered, washed with water, dried with sodium sulfate and evaporated. The oily residue is transferred to the hydrochloride, during which, after recrystallization from methanol/ether, 3.5 g (88% of theory) of 5-(methylallyl)amino-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene are obtained -hydrochloride in the form of colorless needles of melting point 205-206°C.
Eksempel 4 Example 4
10 g 5-dimetylaminometyl-5H-dibenzo[a,d]cyklohepten (hydroklorid: smp. 207-209°C) hydreres i 250 ml absolutt etanol i nærvær av Raney-nikkel ved 45°C under normaltrykk med hydrogen. Derpå filtreres reaksjonsblandingen for å fraskille katalysatoren og i tilslutning hertil inndampes. Man får 9,7 g (97% av teorien) av et oljeaktig residuum bestående av 5-dimetylaminometyl-lO,11-dihydro-5H-dibenzo[a,d]cyklohepten. Ved behandling av dette residuum med etanolisk saltsyre får man det tilsvarende hydroklorid, som etter omkrystallisering fra metanol/eter viser smeltepunktet 290-291°C. 10 g of 5-dimethylaminomethyl-5H-dibenzo[a,d]cycloheptene (hydrochloride: m.p. 207-209°C) is hydrated in 250 ml of absolute ethanol in the presence of Raney nickel at 45°C under normal pressure with hydrogen. The reaction mixture is then filtered to separate the catalyst and subsequently evaporated. 9.7 g (97% of theory) of an oily residue consisting of 5-dimethylaminomethyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene are obtained. When this residue is treated with ethanolic hydrochloric acid, the corresponding hydrochloride is obtained, which after recrystallization from methanol/ether shows a melting point of 290-291°C.
Eksempel 5 Example 5
Til en suspensjon av 1,35 g N-metyl-5,11-metylenimino-10,ll-dihydro-5H-dibenzo[a,d]cyklohepten-metojodid (smp. 236-237°C) i 15 ml 20%'s natronlut tilsettes i små porsjoner under kjøling og omrøring 1,4 g Raney-nikkellegering. Derpå videreomrøres reaksjonsblandingen i 4 timer og oppvarmes langsomt i 4 timer til 40°C. Etter avkjøling utrystes reaksjonsblandingen fem ganger med eter. Eteruttrekkene ekstraheres fire ganger med 2n saltsyre, og de saltsure ekstrakter innstilles alkalisk med 30%'s natronlut og utrystes fem ganger med eter. Eteruttrekkene vaskes med vann, tørkes med natriumsulfat og inndampes. Det erholdte oljeaktige residuum overføres til hydrokloridet, hvorunder man etter omkrystallisering fra metanol/eter får 0,64 g (62% av teorien) 5-dimetylaminometyl-10,ll-dihydro-5H-dibenzo[a,d]cyklohepten-hydroklorid i form av farveløse nåler av smeltepunkt 290-291°C, hvilket produkt er identisk med den i henhold til eksempel 4 erholdte forbindelse . To a suspension of 1.35 g of N-methyl-5,11-methyleneimino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene methoiodide (m.p. 236-237°C) in 15 ml of 20%' s caustic soda is added in small portions while cooling and stirring 1.4 g Raney nickel alloy. The reaction mixture is then further stirred for 4 hours and slowly heated for 4 hours to 40°C. After cooling, the reaction mixture is shaken five times with ether. The ether extracts are extracted four times with 2N hydrochloric acid, and the hydrochloric acid extracts are made alkaline with 30% caustic soda and shaken five times with ether. The ether extracts are washed with water, dried with sodium sulphate and evaporated. The oily residue obtained is transferred to the hydrochloride, during which, after recrystallization from methanol/ether, 0.64 g (62% of theory) of 5-dimethylaminomethyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene hydrochloride is obtained in the form of colorless needles of melting point 290-291°C, which product is identical to the compound obtained according to example 4.
Ved å gå frem på analog måte som angitt i de foran nevnte eksempler, får man av de tilsvarende utgangsstoffer ennvidere f.eks. de i den følgende tabell angitte produkter. I tabellen har R1, R2, R^, R4og R,, den tidligere nevnte betydning. By proceeding in an analogous way as indicated in the above-mentioned examples, one further obtains from the corresponding starting substances e.g. the products listed in the following table. In the table, R1, R2, R^, R4 and R1 have the previously mentioned meaning.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH678166A CH473759A (en) | 1966-05-10 | 1966-05-10 | Process for the preparation of 10,11-dihydro-5H-dibenzo (a, d) -cycloheptene derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO122246B true NO122246B (en) | 1971-06-07 |
Family
ID=4314928
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO168071A NO122246B (en) | 1966-05-10 | 1967-05-09 |
Country Status (12)
| Country | Link |
|---|---|
| AT (3) | AT283311B (en) |
| BE (1) | BE698198A (en) |
| CH (3) | CH481055A (en) |
| CS (4) | CS154229B2 (en) |
| DE (1) | DE1643212A1 (en) |
| ES (1) | ES340257A1 (en) |
| FI (1) | FI47348C (en) |
| FR (1) | FR6502M (en) |
| GB (1) | GB1170798A (en) |
| GR (1) | GR36291B (en) |
| NL (1) | NL6706480A (en) |
| NO (1) | NO122246B (en) |
-
1966
- 1966-05-10 CH CH1716868A patent/CH481055A/en not_active IP Right Cessation
- 1966-05-10 CH CH678166A patent/CH473759A/en not_active IP Right Cessation
- 1966-05-10 CH CH1716968A patent/CH481869A/en not_active IP Right Cessation
-
1967
- 1967-05-03 FI FI671285A patent/FI47348C/en active
- 1967-05-03 DE DE19671643212 patent/DE1643212A1/en active Pending
- 1967-05-05 GB GB20979/67A patent/GB1170798A/en not_active Expired
- 1967-05-08 GR GR670136291A patent/GR36291B/en unknown
- 1967-05-08 ES ES340257A patent/ES340257A1/en not_active Expired
- 1967-05-09 AT AT870569A patent/AT283311B/en not_active IP Right Cessation
- 1967-05-09 BE BE698198D patent/BE698198A/xx unknown
- 1967-05-09 NL NL6706480A patent/NL6706480A/xx unknown
- 1967-05-09 NO NO168071A patent/NO122246B/no unknown
- 1967-05-09 AT AT870769A patent/AT283312B/en not_active IP Right Cessation
- 1967-05-09 AT AT434967A patent/AT283303B/en not_active IP Right Cessation
- 1967-05-10 CS CS281170*1A patent/CS154229B2/cs unknown
- 1967-05-10 CS CS337867A patent/CS154228B2/cs unknown
- 1967-05-10 CS CS281370*1A patent/CS154231B2/cs unknown
- 1967-05-10 FR FR105888A patent/FR6502M/fr not_active Expired
- 1967-05-10 CS CS281270*1A patent/CS154230B2/cs unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AT283303B (en) | 1970-08-10 |
| CH473759A (en) | 1969-06-15 |
| FI47348C (en) | 1973-11-12 |
| CS154230B2 (en) | 1974-03-29 |
| AT283312B (en) | 1970-08-10 |
| CH481055A (en) | 1969-11-15 |
| GR36291B (en) | 1969-01-20 |
| CS154228B2 (en) | 1974-03-29 |
| DE1643212A1 (en) | 1971-03-11 |
| CS154231B2 (en) | 1974-03-29 |
| FI47348B (en) | 1973-07-31 |
| AT283311B (en) | 1970-08-10 |
| FR6502M (en) | 1968-12-02 |
| BE698198A (en) | 1967-11-09 |
| CS154229B2 (en) | 1974-03-29 |
| CH481869A (en) | 1969-11-30 |
| GB1170798A (en) | 1969-11-19 |
| ES340257A1 (en) | 1968-09-01 |
| NL6706480A (en) | 1967-11-13 |
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