NO115658B - - Google Patents
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- NO115658B NO115658B NO15363064A NO15363064A NO115658B NO 115658 B NO115658 B NO 115658B NO 15363064 A NO15363064 A NO 15363064A NO 15363064 A NO15363064 A NO 15363064A NO 115658 B NO115658 B NO 115658B
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- ether
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- -1 ethylene, trimethylene Chemical group 0.000 claims description 9
- 150000001768 cations Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 150000003556 thioamides Chemical class 0.000 claims description 4
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 150000003672 ureas Chemical class 0.000 claims description 2
- 235000013312 flour Nutrition 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 5
- 239000004927 clay Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012259 ether extract Substances 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 150000003951 lactams Chemical class 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- 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
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- DWOBGCPUQNFAFB-UHFFFAOYSA-N 2-benzylaniline Chemical compound NC1=CC=CC=C1CC1=CC=CC=C1 DWOBGCPUQNFAFB-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
- 238000006237 Beckmann rearrangement reaction Methods 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
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 238000006434 Ritter amidation reaction Methods 0.000 description 1
- 238000006085 Schmidt reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- UEDBHEFYEKZZBA-UHFFFAOYSA-N ac1np5zy Chemical compound C1=CC=[C+]=C[CH]1 UEDBHEFYEKZZBA-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- RJGDLRCDCYRQOQ-UHFFFAOYSA-N anthrone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 RJGDLRCDCYRQOQ-UHFFFAOYSA-N 0.000 description 1
- 150000008425 anthrones Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005518 carboxamido group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000002903 catalepsic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- NYIODHFKZFKMSU-UHFFFAOYSA-N n,n-bis(methylamino)ethanamine Chemical compound CCN(NC)NC NYIODHFKZFKMSU-UHFFFAOYSA-N 0.000 description 1
- DHSLOIFKVQGCQU-UHFFFAOYSA-N n-(10h-anthracen-9-ylidene)hydroxylamine Chemical class C1=CC=C2C(=NO)C3=CC=CC=C3CC2=C1 DHSLOIFKVQGCQU-UHFFFAOYSA-N 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- KSMWLICLECSXMI-UHFFFAOYSA-N sodium;benzene Chemical compound [Na+].C1=CC=[C-]C=C1 KSMWLICLECSXMI-UHFFFAOYSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 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
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003571 thiolactams Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/238—Cyclohexane rings substituted by two guanidine radicals, e.g. streptomycins
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Fremgangsmåte for fremstilling av terapeutisk virksomme 6-basisk substituerte morfantridiner. Process for the production of therapeutically effective 6-basically substituted morphanthridines.
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av 6-basisk substituerte morfantridiner av formelen: The present invention relates to a method for the production of 6-basically substituted morphanthridines of the formula:
samt av syre-addisjonssalter av disse. I formel I betyr R en rett eller forgrenet alkylengruppe med høyst 5 C-atomer. R, er hydrogen, lavere alkyl, lavere hydroksyalkyl, acylert lavere hydroksyalkyl eller alkoksyalkyl med høyst 5 C-atomer. R2og R3er like eller forskjellige og er hydrogen, lavere alkyl eller sammen en etylen-gruppe, og i dette tilfelle er R en etylen-, trime-.tylen- eller propylengruppe, og i dette tilfelle er R en etylen-, trimetylen- eller propylengruppe. R4og R- er like eller forskjellige og betyr hydrogen eller halogen. Med uttrykket «lavere» alkyl osv. forståes slike med 1 til 3 C-atomer. Fortrinnsvis er den basiske substituent i 6-stilling en 4-metyl-l-piperazinylgruppe. Eventuelle sub-sti tu enter i benzenkjernene befinner seg fortrinnsvis i 3- eller 8-stilling. as well as of acid addition salts thereof. In formula I, R means a straight or branched alkylene group with no more than 5 C atoms. R, is hydrogen, lower alkyl, lower hydroxyalkyl, acylated lower hydroxyalkyl or alkoxyalkyl with at most 5 C atoms. R 2 and R 3 are the same or different and are hydrogen, lower alkyl or together an ethylene group, and in this case R is an ethylene, trimethylene or propylene group, and in this case R is an ethylene, trimethylene or propylene group . R4 and R- are the same or different and mean hydrogen or halogen. The term "lower" alkyl etc. means those with 1 to 3 C atoms. Preferably, the basic substituent in the 6-position is a 4-methyl-1-piperazinyl group. Any substituents in the benzene nuclei are preferably in the 3- or 8-position.
De nevnte forbindelser I fåes når en reak-sjonsblanding som inneholder nitrilium-, resp. imoniumkationer av formelen: hvor R4og Rr, har den ovenfor angitte betydning, omsettes med et amin av formelen: The aforementioned compounds I are obtained when a reaction mixture containing nitrilium, resp. imonium cations of the formula: where R4 and Rr, having the above meaning, are reacted with an amine of the formula:
hvor R, R,, R2og R3 har den ovenfor angitte betydning. where R, R1, R2 and R3 have the above meaning.
Nitrilium-, resp. imoniumkationene av formelen II kan oppfattes som dissosiasjonsproduk-ter av forbindelser av formelen: Nitrilium-, resp. The imonium cations of the formula II can be understood as dissociation products of compounds of the formula:
hvor R, og R5har den ovenfor angitt betydning, og X er et halogenatom, sulfhydrylgruppen eller en eventuelt aktivert alkoksy- eller alkyltiogrup-pe, f. eks. en p-nitrobenzyltiogruppe. Slike forbindelser IV får man f. eks. ved overføring av laktamer av formelen: hvor R4og R3har den ovenfor angitte betydning, til tiolaktamene, om ønskes under etter-følgende alkylering av sistnevnte, eller ved om-setning av laktamene V med et halogenerings-middel, som fosforoksyklorid eller fosforpentaklorid, fortrinnsvis i nærvær av katalytiske mengder av dimetylanilin eller dimetylformamid. Laktamene V kan på sin side f. eks. fåes ved rmgslutning av tilsvarende o-isocyanatdifenyl-metaner med aluminiumklorid. Alt etter den kjemiske natur av resten X og også eventuelle substituehter R4og R5 er forbindelsene IV i de oppnådde reaksjonsblandinger mer eller mindre sterkt dissosiert i nitrilium-, resp. imoniumkationene, slik at reaksjonsblandingene kan anvendes direkte for omsetningen med aminet av formel III. Til dels kan de på denne eller annen måte fremstilte forbindelser av formel IV iso-leres i udissosiert form og gir da ved oppløs-ning i et passende, fortrinnsvis polart oppløs-ningsmiddel, eventuelt under oppvarmning og i nærvær av aminet av formel III, som også kan tjene som oppløsningsmiddel, de ønskede nitrilium-, resp. imoniumkationer II. Reaksjonsblandingene som inneholder kationer av formel II, kan videre f. eks. fremstilles ved intramolekylær Ritter-reaksjon (angrep av en nitrilgrup-pe på en fenylkation) ved o-cyandifenylmetaner, ved Beckmann'sk omleiring av eventuelt passende substituert antronoksim eller ved Schmidt-reaksjon av eventuelt passende substituert antron med nitrogenhydrogensyre. De to sistnevnte reaksjoner fører visstnok, i tilfelle man går ut fra usymmetrisk substituerte antronoksimer, resp. antron, til isomerblandinger, som om nød-vendig etterpå må skilles fra hverandre. Som anioniske komponenter kan i de nevnte reaksjonsblandinger foruten de som utledes fra sub-stituenten X i formelen IV, alt etter dannelse-måten for kationene II f. eks. opptre anioner av svovelsyre, toluensulfonsyre, fosforsyre, fluss-syre, borfluorhydrogensyre osv. Forbindelser av formel I fåes videre når urinstoffderivater av formelen where R, and R5 have the above meaning, and X is a halogen atom, the sulfhydryl group or an optionally activated alkoxy or alkylthio group, e.g. a p-nitrobenzylthio group. Such compounds IV are obtained, e.g. by transferring lactams of the formula: where R 4 and R 3 have the above meaning, to the thiolactams, if desired during subsequent alkylation of the latter, or by reacting the lactams V with a halogenating agent, such as phosphorus oxychloride or phosphorus pentachloride, preferably in the presence of catalytic amounts of dimethylaniline or dimethylformamide. The lactams V, on the other hand, can e.g. obtained by reaction of corresponding o-isocyanate diphenyl methanes with aluminum chloride. Depending on the chemical nature of the residue X and also any substituents R4 and R5, the compounds IV in the obtained reaction mixtures are more or less strongly dissociated in nitrilium-, resp. the imonium cations, so that the reaction mixtures can be used directly for the reaction with the amine of formula III. In part, the compounds of formula IV prepared in this or another way can be isolated in undissociated form and then give when dissolved in a suitable, preferably polar solvent, possibly under heating and in the presence of the amine of formula III, which can also serve as a solvent, the desired nitrilium-, resp. imonium cations II. The reaction mixtures containing cations of formula II can further e.g. is produced by intramolecular Ritter reaction (attack of a nitrile group on a phenyl cation) with o-cyandiphenylmethanes, by Beckmann rearrangement of any suitably substituted anthrone oxime or by Schmidt reaction of any suitably substituted anthrone with nitric acid. The two latter reactions apparently lead, in the case of starting from unsymmetrically substituted anthrone oximes, resp. anthrone, to isomeric mixtures, which must be separated from each other if necessary afterwards. As anionic components in the aforementioned reaction mixtures, in addition to those derived from the substituent X in formula IV, depending on the method of formation of the cations II, e.g. appear anions of sulfuric acid, toluenesulfonic acid, phosphoric acid, hydrofluoric acid, borofluorohydrogen acid, etc. Compounds of formula I are further obtained when urea derivatives of the formula
hvor R, R,, R2, R3, R4og R5har den ovenfor angitte betydning, dehydratiseres, eksempelvis ved flere timers innvirkning av dehydratiseringsmid-ler som sinkdiklorid, aluminiumklorid, tinn-te-traklorid, fosforsyre og lignende, fortrinnsvis imidlertid av fosforoksyklorid, eventuelt i nærvær av et inert oppløsningsmiddel med passende kokepunkt, som benzen, toluen osv. where R, R1, R2, R3, R4 and R5 have the above meaning, are dehydrated, for example by exposure for several hours to dehydrating agents such as zinc dichloride, aluminum chloride, stannous tetrachloride, phosphoric acid and the like, preferably, however, by phosphorus oxychloride, possibly in the presence of an inert solvent of suitable boiling point, such as benzene, toluene, etc.
Videre får man forbindelser i henhold til formel I, når syreamider eller tioamider av formelen: Furthermore, compounds according to formula I are obtained when acid amides or thioamides of the formula:
hvor R, R1;<R>2, Ra, R4samt R5har den ovenfor angitte betydning, og Y er et oksygen- eller svo-velatom, ved intramolekylær kondensering bringes til ringslutning. En rent termisk kondensering lykkes som regel ikke ved syreamider som på sin side f. eks. er tilgjengelige ved reduksjon av tilsvarende nitroforbindelser, snarere derimot ved tioamidene, som man f. eks. får ved behandling av syreamidene med fosforspentasulfid, og som før den etterfølgende kondensering ikke be-høver å bli isolert. Særlig ved syreamidene er det hensiktsmessig å arbeide i nærvær av konden-seringsmidler, som f. eks. fosforpentaklorid, fosforoksyklorid, fosgen, polyfosforsyre og lignende. Det må antas at ringslutningen herunder tildels forløper over mellom-trinn, som imidklorid, amidklorid, imidofosfat, amidofosfat eller salt-aktige derivater av disse, hvilke som regel ikke kan pågripes. Kondenseringen av tioamidene kan begunstiges ved nærvær av kvikksølvsalter eller ved intermediær dannelse av eventuelt aktiverte imidotioetere. Oppvarmning og eventuell anvendelse av et inert fortynningsmiddel er fordelak-tig og når det arbeides med fosforoksyklorid og fosforpentaklorid også tilsetningen av katalytiske mengder av dimetylformamid eller dimetylanilin. Endelig får man forbindelser av formel I idet aminer av formelen hvor R4og R, har den ovenfor angitte betydning, eller i aminogruppen lav-monoalkylerte derivater av disse, behandles med reaksjonsdyktige estere av alkoholer av formelen: where R, R1; <R>2, Ra, R4 and R5 have the meaning given above, and Y is an oxygen or sulfur atom, by intramolecular condensation ring closure is achieved. A purely thermal condensation is usually not successful with acid amides which, in turn, e.g. are available by reduction of corresponding nitro compounds, rather by the thioamides, which e.g. obtained by treating the acid amides with phosphorus pentasulphide, and which before the subsequent condensation does not need to be isolated. Especially with the acid amides, it is appropriate to work in the presence of condensing agents, such as e.g. phosphorus pentachloride, phosphorus oxychloride, phosgene, polyphosphoric acid and the like. It must be assumed that the ring closure below partly proceeds via intermediate steps, such as imide chloride, amide chloride, imidophosphate, amidophosphate or salt-like derivatives of these, which as a rule cannot be detected. The condensation of the thioamides can be favored by the presence of mercury salts or by intermediate formation of possibly activated imidothioethers. Heating and possible use of an inert diluent is advantageous and when working with phosphorus oxychloride and phosphorus pentachloride also the addition of catalytic amounts of dimethylformamide or dimethylaniline. Finally, compounds of formula I are obtained when amines of the formula where R4 and R, have the above meaning, or in the amino group low-monoalkylated derivatives thereof, are treated with reactive esters of alcohols of the formula:
hvor R, Rj og R2har den ovenfor anførte betydning, om nødvendig etter forutgående eller sam-tidig innvirkning av en basisk katalysator eller et metalliseringsmiddel som natriumamid, liti-umamid, natriumhydrid, butyl-litium, fenylna-trium, natrium-etylat eller kalium-t-butylat. Som estere kommer særlig slike av halogenhy-drogensyrer i betraktning, samt av sulfonsyrer eller karbonsyrer. De nødvendige aminer VIII og deres lav-monoalkylerte derivater får man ved innvirkning av ammoniakk, resp. lavere al-kylamin på reaksjonsblandinger som inneholder nitrilium-, resp. imoniumkationer av formel II. where R, Rj and R2 have the meaning stated above, if necessary after prior or simultaneous action of a basic catalyst or a metallizing agent such as sodium amide, lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylate or potassium t-butylate. As esters, those of halogenated acids come into consideration, as well as of sulphonic acids or carboxylic acids. The necessary amines VIII and their low-monoalkylated derivatives are obtained by the action of ammonia, resp. lower alkylamine on reaction mixtures containing nitrilium-, resp. imonium cations of formula II.
Såfremt det etter en av disse fremgangs-måter oppnåes forbindelser i henhold til formel I, i hvilke en eller flere av restene R^ R2og R3er hydrogen, kan restene Rx og/eller R2og/eller R3i de ovenfor angitte andre betydninger etterpå innføres hver for seg, f. eks. ved at de sekundære eller primære aminer fremstilt på den ovenfor beskrevne måte omsettes med reaksjonsdyktige estere av alkoholer av formelen R^OH resp. R2-OH resp. R3-OH. If, according to one of these procedures, compounds according to formula I are obtained in which one or more of the residues R^, R2, and R3 are hydrogen, the residues Rx and/or R2 and/or R3 in the above-mentioned other meanings can subsequently be introduced separately , e.g. in that the secondary or primary amines produced in the manner described above are reacted with reactive esters of alcohols of the formula R^OH resp. R2-OH or R 3 -OH.
De på den beskrevne måte oppnådde baser er i de fleste tilfeller krystalliserbare og kan de-stilleres uspaltet i høyvakuum. De danner med anorganiske og organiske syrer, eksempelvis saltsyre, bromhydrogensyre, svovelsyre, salpetersyre, fosforsyre, eddiksyre, oksalsyre, vinsyre, toluensulfonsyre og lignende, i vann-bestandige addisjonssalter, i hvilken form produktene likeledes kan anvendes. The bases obtained in the manner described are in most cases crystallizable and can be distilled without splitting in high vacuum. They form with inorganic and organic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, toluenesulfonic acid and the like, in water-resistant addition salts, in which form the products can also be used.
De på den beskrevne måte erholdte baser og deres syreaddisjonssalter er nye forbindelser, som kan finne anvendelse som virksomme stoffer i legemidler. Særlig kommer produktene i betraktning som neuroplegika, neuroleptika og analge-tika. Enkelte av dem er egnet til behandling av psykotiske tilstander. Virkningen ytrer seg far-makologisk ved en sterk motilitetsdempning hos mus, som kan innnebære en kataleptisk virk-ning. Motilltetsdempningen påvises ved måling av løpeaktiviteten etter Caviezel og Baillod (Pharm. Acta Heiv., 33, 469 (1958)). Løpeaktivi-tetsverdiene av noen produkter fremstilt i henhold til oppfinnelsen samt deres toksisitet er i følgen tabell I oppført sammenlignet med de tilsvarende tall for klorpromazin. The bases obtained in the manner described and their acid addition salts are new compounds, which may find use as active substances in pharmaceuticals. In particular, products such as neuroplegics, neuroleptics and analgesics come into consideration. Some of them are suitable for the treatment of psychotic conditions. The effect manifests itself pharmacologically by a strong suppression of motility in mice, which may involve a cataleptic effect. Antibody suppression is demonstrated by measuring the running activity according to Caviezel and Baillod (Pharm. Acta Heiv., 33, 469 (1958)). The running activity values of some products manufactured according to the invention as well as their toxicity are listed in the accompanying table I compared with the corresponding figures for chlorpromazine.
Eksempel 1 : Example 1 :
En blanding av 4,9 g 5,6-dihydro-6-okso-morfantridin, 37 ml fosforoksyklorid og 1,5 ml dimetylanilin oppvarmes i 3 timer under til-bakeløp. Den ved inndampning av reaksj onsblandingen i vakuum ved 60° C oppnådde seigt-f ly tende olje fortynnes med 20 ml absolutt dioksan og oppvarmes etter tilsetning av 30 ml N-metylpiperazin i 4 timer under tilbakeløp. Den oppnådde klare oppløsning inndampes i vakuum ved 60° C til tørrhet. Residuet fordeles mellom eter og ammoniakkvann. Eteroppløsningen fraskilles, vaskes med vann og ekstraheres derpå med ln eddiksyre. Det eddiksure uttrekk tilsettes ammoniakkvann og ekstraheres derpå med eter. Eter-oppløsningen vaskes med vann, tør-kes over natriumsulfat, filtreres gjennom leirjord og inndampes. Residuet bringes til krystal-lisering fra eter/petroleter og omkrystalliseres fra aceton/petroleter. Man får 6,0 g (88 % av teorien) 6-(4-metyl-l-piperazinyl)-morfantridin med smeltepunkt 138—138,5° C. A mixture of 4.9 g of 5,6-dihydro-6-oxomorphantridine, 37 ml of phosphorus oxychloride and 1.5 ml of dimethylaniline is heated for 3 hours under reflux. The viscous liquid oil obtained by evaporating the reaction mixture in vacuum at 60° C. is diluted with 20 ml of absolute dioxane and heated after the addition of 30 ml of N-methylpiperazine for 4 hours under reflux. The clear solution obtained is evaporated in vacuo at 60° C. to dryness. The residue is distributed between ether and ammonia water. The ether solution is separated, washed with water and then extracted with 1N acetic acid. The acetic acid extract is added to ammonia water and then extracted with ether. The ether solution is washed with water, dried over sodium sulphate, filtered through clay and evaporated. The residue is crystallized from ether/petroleum ether and recrystallized from acetone/petroleum ether. 6.0 g (88% of theory) of 6-(4-methyl-1-piperazinyl)-morphantridine with a melting point of 138-138.5° C are obtained.
Det som utgangsmateriale anvendte 5,6-di-hydro-6-okso-morfantridin fåes hensiktsmessig på følgende måte. The 5,6-dihydro-6-oxo-morphantridine used as starting material is conveniently obtained in the following manner.
Man oppløser 30,2 g o-aminodifenylmetan i 65 ml absolutt toluen og lar ved 0 til — 10° C under omrøring tildryppe 140 ml av en 20%'s fosgenoppløsning i toluen. Den melkeaktige blanding oppvarmes under langsom gjennomledning av fosgen i løpet av 30 minutter til tilbakeløps-temperatur og denne opprettholdes i ca. 20 minutter. I den kokende reaksj onsblanding inn-ledes i løpet av 10 minutter under kraftig om-røring tørr nitrogen. Etter avdampning av opp-løsningsmidlet får man ved vakuumdestillasjon 29,7 g (86% av teorien) o-isocyanatodifenyl-metan med kokepunkt 169° C/12 Torr. 30.2 g of o-aminodiphenylmethane is dissolved in 65 ml of absolute toluene and allowed to add 140 ml of a 20% phosgene solution in toluene at 0 to - 10° C with stirring. The milky mixture is heated under slow passage of phosgene over 30 minutes to reflux temperature and this is maintained for approx. 20 minutes. Dry nitrogen is introduced into the boiling reaction mixture during 10 minutes with vigorous stirring. After evaporation of the solvent, 29.7 g (86% of theory) of o-isocyanatodiphenylmethane with a boiling point of 169° C/12 Torr are obtained by vacuum distillation.
Man oppvarmer 21,1 g aluminiumklorid i 110 ml o-diklorbenzen til 80° C og lar under om-røring tildryppe en oppløsning av 29,7 g o-isocya-natodifenylmetan i 60 ml o-diklorbenzen, hvorunder blandingen oppvarmes til 120° C. Denne temperatur opprettholdes i 1 time under omrør-ing. Etter avkjøling heller man reaksj onsblandingen i 200 ml 2n saltsyre, hvorunder det dannes en bunnfelling. Etter vanndampdestillasjon isolerer man residuet ved filtrering og krystalli-serer fra aceton/vann. Man får 28,6 g (97 % av teorien) 5,6-dihydro-6-oksomorfantridin med smeltepunkt 201—203° C. 21.1 g of aluminum chloride in 110 ml of o-dichlorobenzene is heated to 80°C and, with stirring, a solution of 29.7 g of o-isocyanatodiphenylmethane in 60 ml of o-dichlorobenzene is added dropwise, during which the mixture is heated to 120°C This temperature is maintained for 1 hour with stirring. After cooling, the reaction mixture is poured into 200 ml of 2N hydrochloric acid, during which a precipitate forms. After steam distillation, the residue is isolated by filtration and crystallized from acetone/water. 28.6 g (97% of theory) of 5,6-dihydro-6-oxomorphanthridine with melting point 201-203° C are obtained.
Eksempel 2: Example 2:
33,5 g 5,6-dihydro-6-okso-morfantridin over-helles med 10 ml N,N-dimetylanilin, og etter tilsetning av 300 ml fosforoksyklorid oppvarmes i 4 timer under tilbakeløp. Reaksj onsblandingen inndampes i vakuum. Residuet suspenderes i absolutt xylen. Det ved inndampning av denne suspensjon i vakuum oppnådde residuum opptas i eter og heller på is/vann. Eter-fasen fraskilles og vaskes tre ganger med fortynnet saltsyre, hvorunder de saltsure vaskevann tilbakevaskes med eter. De forente eter-faser vaskes etter hverandre med vann, natriumbikarbonatoppløs-ning, vann og mettet natriumkloridoppløsning, tørkes over natriumsulfat, behandles med aktivt kull, filtreres gjennom leirjord og konsentreres i vidtgående grad. Ved tilsetning av petroleter får man 30,2 g (83 % av teorien) 6-klor-formantridin i form av svakt gulaktig fargede prismer med smeltepunkt 49—51° C. 33.5 g of 5,6-dihydro-6-oxo-morphantridine is poured over with 10 ml of N,N-dimethylaniline, and after the addition of 300 ml of phosphorus oxychloride is heated for 4 hours under reflux. The reaction mixture is evaporated in vacuo. The residue is suspended in absolute xylene. The residue obtained by evaporating this suspension in vacuum is taken up in ether and rather on ice/water. The ether phase is separated and washed three times with dilute hydrochloric acid, during which the hydrochloric acid washings are backwashed with ether. The combined ether phases are washed successively with water, sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate, treated with activated carbon, filtered through clay and concentrated to a large extent. By adding petroleum ether, 30.2 g (83% of theory) of 6-chloro-formantridine is obtained in the form of slightly yellowish colored prisms with a melting point of 49-51° C.
7,5 g av på denne måte oppnådd 6-klormor-fantridin blir i 100 ml absolutt xylen oppvarmet i 4 timer under tilbakeløp med 15 ml N,N-dime-tylaminoetylamin. Reaksj onsblandingen tilsettes vann og konsentrert natronlut. Den vandige fase fraskilles og vaskes med eter og den til vaskin-gen anvendte eter forenes med xylenfasen. Den organiske fase ekstraheres fullstendig med fortynnet saltsyre. De forente sure uttrekk vaskes med eter, gjøres alkalisk med konsentrert natronlut og ekstraheres derpå med eter. Eter-uttrekket vaskes med vann og mettet natrium-kloridoppløsning, tørkes over natriumsulfat, behandles med aktivt kull og inndampes. Residuet opptas i petroleter. Oppløsningen filtreres gjennom leirjord og inndampes i vidtgående grad. Ved avkjøling av den konsentrerte oppløsning dannes hvite prismatisk-tavleaktige krystaller. Man får 7,2 g 6-(|3-dimetylaminoetylamino)-morfantridin med smeltepunkt 92—94° C. 7.5 g of 6-chloromorphantridine obtained in this way are heated in 100 ml of absolute xylene for 4 hours under reflux with 15 ml of N,N-dimethylaminoethylamine. Water and concentrated caustic soda are added to the reaction mixture. The aqueous phase is separated and washed with ether and the ether used for washing is combined with the xylene phase. The organic phase is extracted completely with dilute hydrochloric acid. The combined acid extracts are washed with ether, made alkaline with concentrated caustic soda and then extracted with ether. The ether extract is washed with water and saturated sodium chloride solution, dried over sodium sulphate, treated with activated charcoal and evaporated. The residue is taken up in petroleum ether. The solution is filtered through clay soil and evaporated to a large extent. On cooling the concentrated solution, white prismatic-tablet-like crystals are formed. 7.2 g of 6-(|3-dimethylaminoethylamino)-morphantridine with melting point 92-94° C is obtained.
Eksempel 3: Example 3:
6,7 g o-[(4-metyl-l-piperazinyl)karboksami-do]difenylmetan oppvarmes med 75 ml fosfor-syreklorid i 30 timer under tilbakeløp. Reaksj onsblandingen inndampes til tørrhet i vakuum. Residuet tilsettes under kjøling med vann og gjø-res alkalisk med konsentrert natronlut. Det ved to gangers utrystning med eter oppnådde uttrekk vaskes to ganger med vann, og ekstra heres derpå fullstendig med fortynnet saltsyre. De forente saltsure uttrekk vaskes med vann, gjøres alkalisk med konsentrert natronlut og ut-rystes to ganger med eter. Eter-uttrekket vaskes med vann og mettet natriumkloridoppløs-ning, tørkes over natriumsulfat, filtreres gjennom leirjord og inndampes. Residuet krystalliseres fra petroleter. Man får 3,0 g 6-(4-metyl-l-piperazinyl)-morfantridin med smeltepunkt 138 6.7 g of o-[(4-methyl-1-piperazinyl)carboxamido]diphenylmethane are heated with 75 ml of phosphoric acid chloride for 30 hours under reflux. The reaction mixture is evaporated to dryness in vacuo. The residue is added while cooling with water and made alkaline with concentrated caustic soda. The extract obtained by shaking out twice with ether is washed twice with water, and the excess is then completely diluted with dilute hydrochloric acid. The combined hydrochloric acid extracts are washed with water, made alkaline with concentrated caustic soda and shaken twice with ether. The ether extract is washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered through clay and evaporated. The residue is crystallized from petroleum ether. 3.0 g of 6-(4-methyl-1-piperazinyl)-morphantridine with a melting point of 138
—138,5° C, som er identisk med produktet ifølge eksempel 1, -138.5° C, which is identical to the product according to example 1,
Eksempel 4: Example 4:
16,6 g 2-amino-difenylmetan-2'-tiokarbon-syre-(4-metyl)-piperazid kokes i 24 timer under tilbakeløp med 17,0 g finpulverisert kvikksølv-II-acetat i 200 ml xylen. Etter filtrering av reaksj onsblandingen ekstraheres den sterke base som inneholdes i filtratet ved utrystning med fortynnet eddiksyre. Den fra de eddiksure ekstrak-ter med ammoniakk frigjorte base opptas i eter. Det tre ganger med vann vaskede og over natriumsulfat tørkede eter-uttrekk inndampes og filtreres over aluminiumoksyd. Det til tørrhet overførte filtrat kan krystallisere fra petroleter. Man får 8,7 g 6-(4-metyl-l-piperazinyl)-morfantridin med smeltepunkt 138—138,5° C, som er identisk med produktet ifølge eksempel 1. 16.6 g of 2-amino-diphenylmethane-2'-thiocarbonic acid-(4-methyl)-piperazide are boiled for 24 hours under reflux with 17.0 g of finely powdered mercuric II-acetate in 200 ml of xylene. After filtering the reaction mixture, the strong base contained in the filtrate is extracted by shaking with dilute acetic acid. The base liberated from the acetic acid extracts with ammonia is taken up in ether. The ether extract, washed three times with water and dried over sodium sulfate, is evaporated and filtered over aluminum oxide. The filtrate transferred to dryness can crystallize from petroleum ether. 8.7 g of 6-(4-methyl-1-piperazinyl)-morphantridine with melting point 138-138.5° C is obtained, which is identical to the product according to example 1.
På analog måte som ved de foran anførte In an analogous way as with those listed above
eksempler får man fra tilsvarende utgangsstof-fer de i følgende tabell II anførte produkter. Her har R, Rx, R2, R3, R4og Rri den tidligere angitte betydning. I høyre kolonne betyr Ac aceton, E eter, K kloroform, Me metanol og Pe petroleter. examples are obtained from corresponding starting materials the products listed in the following table II. Here, R, Rx, R2, R3, R4 and Rri have the previously stated meaning. In the right column, Ac means acetone, E ether, K chloroform, Me methanol and Pe petroleum ether.
Eksempel 5: Example 5:
10,3 g 6-amino-morfantridin kokes med 4,0 g pulverisert natriumamid i 100 ml absolutt dioksan 1 time under tilbakeløp. Under fortsatt til-bakeløp tildryppes i løpet av 30 minutter en løs-ning av 8,0 g metyl-bis-|3-kloretylamin i 25 ml absolutt dioksan. Etter ytterligere 15 timer til-bakeløp inndampes til tørrhet i vakuum, og inn-dampningsresten fordeles mellom eter og vann. Etter to gangers utvaskning av eter-fasen med vann adskilles de basiske andeler ved uttømmen-de ekstraksjon med fortynnet eddiksyre. Det eddiksure uttrekk tilsettes ammoniakkvann og ekstraheres deretter med eter. Eterløsningen vaskes med vann, tørkes over natriumsulfat, filtreres gjennom leirjord og inndampes. Inn-dampningsresten krystalliseres fra eter/petroleter og omkrystalliseres fra aceton/petroleter. Man får 7,1 g (49 % av teorien) 6-(4-metyl-l-piperazinyl)-morfantridin med smeltepunkt 137,5—138,5° C, som er identisk med det ifølge eksemplene 1 og 3 oppnådde produkt. 10.3 g of 6-aminomorphantridine is boiled with 4.0 g of powdered sodium amide in 100 ml of absolute dioxane for 1 hour under reflux. During continued reflux, a solution of 8.0 g of methyl-bis-1-chloroethylamine in 25 ml of absolute dioxane is added dropwise over the course of 30 minutes. After a further 15 hours of reflux, the mixture is evaporated to dryness in vacuo, and the evaporation residue is distributed between ether and water. After washing out the ether phase twice with water, the basic portions are separated by exhaustive extraction with dilute acetic acid. The acetic acid extract is added to ammonia water and then extracted with ether. The ether solution is washed with water, dried over sodium sulphate, filtered through clay and evaporated. The evaporation residue is crystallized from ether/petroleum ether and recrystallized from acetone/petroleum ether. 7.1 g (49% of theory) of 6-(4-methyl-1-piperazinyl)-morphantridine with melting point 137.5-138.5° C are obtained, which is identical to the product obtained according to examples 1 and 3.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH741363A CH436302A (en) | 1963-06-14 | 1963-06-14 | Process for the preparation of 6-basic substituted morphanthridines |
US37415864A | 1964-06-10 | 1964-06-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO115658B true NO115658B (en) | 1968-11-11 |
Family
ID=25701285
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO15363064A NO115658B (en) | 1963-06-14 | 1964-06-11 |
Country Status (10)
Country | Link |
---|---|
BE (1) | BE649284A (en) |
BR (1) | BR6459986D0 (en) |
DE (1) | DE1470427C3 (en) |
DK (1) | DK115402B (en) |
FI (1) | FI42561B (en) |
FR (1) | FR3490M (en) |
GB (1) | GB1006156A (en) |
NL (1) | NL140239B (en) |
NO (1) | NO115658B (en) |
SE (4) | SE318279B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH624682A5 (en) * | 1976-11-10 | 1981-08-14 | Sandoz Ag | |
WO2005063254A2 (en) | 2003-12-22 | 2005-07-14 | Acadia Pharmaceuticals Inc. | Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders |
-
1964
- 1964-05-29 GB GB22367/64A patent/GB1006156A/en not_active Expired
- 1964-06-02 DE DE19641470427 patent/DE1470427C3/en not_active Expired
- 1964-06-11 NO NO15363064A patent/NO115658B/no unknown
- 1964-06-12 NL NL646406700A patent/NL140239B/en unknown
- 1964-06-12 FI FI128164A patent/FI42561B/fi active
- 1964-06-12 FR FR978010A patent/FR3490M/en active Active
- 1964-06-12 SE SE718864A patent/SE318279B/xx unknown
- 1964-06-12 SE SE1631765A patent/SE331684B/xx unknown
- 1964-06-12 SE SE1631665A patent/SE331683B/xx unknown
- 1964-06-12 BR BR15998664A patent/BR6459986D0/en unknown
- 1964-06-15 BE BE649284A patent/BE649284A/xx unknown
-
1965
- 1965-02-19 DK DK86965A patent/DK115402B/en unknown
- 1965-06-12 SE SE1631865A patent/SE331685B/xx unknown
Also Published As
Publication number | Publication date |
---|---|
SE318279B (en) | 1969-12-08 |
BR6459986D0 (en) | 1973-07-19 |
NL6406700A (en) | 1964-12-15 |
SE331685B (en) | 1971-01-11 |
FI42561B (en) | 1970-06-01 |
DE1470427C3 (en) | 1975-07-03 |
DE1470427A1 (en) | 1969-12-18 |
SE331683B (en) | 1971-01-11 |
NL140239B (en) | 1973-11-15 |
SE331684B (en) | 1971-01-11 |
FR3490M (en) | 1965-08-16 |
DE1470427B2 (en) | 1974-11-14 |
GB1006156A (en) | 1965-09-29 |
BE649284A (en) | 1964-12-15 |
DK115402B (en) | 1969-10-06 |
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