NO118809B - - Google Patents
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- NO118809B NO118809B NO522368A NO522368A NO118809B NO 118809 B NO118809 B NO 118809B NO 522368 A NO522368 A NO 522368A NO 522368 A NO522368 A NO 522368A NO 118809 B NO118809 B NO 118809B
- Authority
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- Norway
- Prior art keywords
- phenthiazine
- group
- bis
- propyl
- dimethylamino
- Prior art date
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- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical class C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 37
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- -1 phenthiazine compound Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 108010021119 Trichosanthin Proteins 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- YVWGMAFXEJHFRO-UHFFFAOYSA-N halopropane Chemical compound FC(F)C(F)(F)CBr YVWGMAFXEJHFRO-UHFFFAOYSA-N 0.000 claims description 3
- 229950000188 halopropane Drugs 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 150000003459 sulfonic acid esters Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 239000002585 base Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012259 ether extract Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- YIUIVFFUEVPRIU-UHFFFAOYSA-N 8-chlorotheophylline Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21 YIUIVFFUEVPRIU-UHFFFAOYSA-N 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical group CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000288049 Perdix perdix Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 230000006203 ethylation Effects 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002005 ganglioplegic effect Effects 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical group [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 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
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F24—HEATING; RANGES; VENTILATING
- F24F—AIR-CONDITIONING; AIR-HUMIDIFICATION; VENTILATION; USE OF AIR CURRENTS FOR SCREENING
- F24F13/00—Details common to, or for air-conditioning, air-humidification, ventilation or use of air currents for screening
- F24F13/02—Ducting arrangements
- F24F13/06—Outlets for directing or distributing air into rooms or spaces, e.g. ceiling air diffuser
Landscapes
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Combustion & Propulsion (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Air-Flow Control Members (AREA)
- Duct Arrangements (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte for fremstilling av fentiazinderivater. Process for the preparation of phenthiazine derivatives.
Nærværende oppfinnelse angår en fremgangsmåte for fremstilling av nye fentiazinderivater. The present invention relates to a method for the production of new phenthiazine derivatives.
Det er kjent at forskjellige 10-amino-alkyl-fentiaziner er i besiddelse av interes-sante terapeutiske egenskaper. Utstrakte . forsøk og eksperimentering har imidlertid vist at både størrelsen av den terapeutiske indeks og naturen av den terapeutiske ef-fekt som oppvises av visse forbindelser av denne type kan radikalt forandres (og og-så elimineres) selv ved små forandringer i den kjemiske struktur. Særlig er dette tilfelle ved variasjoner i naturen og leng-den av sidekjeden bundet til natrogenato-met i.lO-stilling. It is known that various 10-amino-alkyl-phenthiazines possess interesting therapeutic properties. Extended . however, trials and experimentation have shown that both the magnitude of the therapeutic index and the nature of the therapeutic effect exhibited by certain compounds of this type can be radically changed (and even eliminated) even by small changes in the chemical structure. This is particularly the case with variations in the nature and length of the side chain bound to the nitrogen atom in the 10 position.
Det er nå uventet erkjent at hittil ukjente fantiazinderivater med, den generelle formel: It is now unexpectedly recognized that hitherto unknown fanthiazine derivatives with, the general formula:
og deres salter, inkludert deres kvaternære ammoniumderivater, innehar fremra-gende terapeutisk verdi i medisinen og ve-terinærmedisinen. and their salts, including their quaternary ammonium derivatives, have outstanding therapeutic value in medicine and veterinary medicine.
I foranstående formel betyr X et hydrogen- eller halogenatom, eller en lavere alkyl-, lavere, alkoksy-, eller lavere acyl-gruppe, fortrinsvis i 3-stillingen i fentia-zinkjernen (nummerering etter Beilstein), A betyr en treverdig alifatisk kjede inneholdende tre kullstoff atomer, hvert av hvilke er bundet til et forskjellig nitrogenatom, og gruppene R betyr metyl- eller etylgrupper. Uttrykket «lavere», som brukt i denne beskrivelse og de tilknyttede påstan-der, betyr at omhandlede gruppe ikke in-neholder mere enn fire kullstoffatomer. In the above formula, X means a hydrogen or halogen atom, or a lower alkyl, lower, alkoxy or lower acyl group, preferably in the 3-position of the phenthiazine nucleus (numbering according to Beilstein), A means a trivalent aliphatic chain containing three carbon atoms, each of which is attached to a different nitrogen atom, and the groups R mean methyl or ethyl groups. The term "lower", as used in this description and the associated claims, means that the group in question does not contain more than four carbon atoms.
Ifølge nærværende oppfinnelse fremstilles forannevnte nye forbindelser ved innvirkning av "en fentiazinforbindelse inneholdende en struktur som angitt ved formelen: med en forbindelse Q,. og gruppen P og forbindelsen Q er valgt' slik at Q vil rea-gere med forbindelsen av formelen II for å innføre eller danne i ringens 10-stilling en substituentgruppe med strukturen: According to the present invention, the above-mentioned new compounds are prepared by the action of "a phenthiazine compound containing a structure as indicated by the formula: with a compound Q, and the group P and the compound Q are selected" so that Q will react with the compound of the formula II to introducing or forming in the 10-position of the ring a substituent group with the structure:
hvor X og R er som foran definert og -Ai enten betyr gruppen A som foran definert eller en gruppe som ved reduksjon kan omdannes til gruppen A) og hvor Ai betyr en gruppe forskjellig fra A, reduksjon av gruppen Ai til den alifatiske kjede A. ' where X and R are as defined above and -Ai either means the group A as defined above or a group which by reduction can be converted into the group A) and where Ai means a group different from A, reduction of the group Ai to the aliphatic chain A. '
Spesielle utførelsesformer for den generelle prosess definert i sist foranstående avsnitt er følgende: (1) Innvirkning av et fentiazin med den generelle';;formel: med et bis(dialkylamino)halogenpropan, spesielt et l:3-bis(dialkylamino)-2-klorpro-pan, hvor alkylgruppene er metyl- eller etylgrupper, eller et., surt addisjonssalt av disse. (2) Kondensasjon av dimetylamin eller dietylamin med et fentiazinderivat av arten: (hvor Z betyr et residum av en reaksjons-dyktig ester, som et halogenatom eller et svovel-sulfonsyreester-residuum og Zi er enten den samme som Z eller betyr en -N(R)2gruppe og de andre variable er som foran definert). Det er fordelaktig å utføre reaksjonen i en autoklav, spesielt når del-aktig å utføre reaksjonen i en autoklav, spesielt når det anvéndte amin er dimetylamin. (3) Metylering eller etylering etter kjente metoder (særlig metylering med formaldehyd og hydrogen i nærvær av en katalysator) av et amin overensstemmen-de med formel I i hvilken i det minste en av symbolene R betyr et hydrogenatom. (4) Reduksjon av de tilsvarende ami- der som f. eks.: idet R' er slik at R'CH2 = R, fortrinsvis ved bruk av litiumaluminiumhydrid i et oppløs-ningsmiddel som tetrahydrofuran. (5) Reduksjon i nærvær av dimetylamin eller dietylamin av et derivat av arten: hvor T betyr gruppen CN eller gruppen CHQ, f. eks. ved katalytisk iiydrering under bruk av katalysatorer. Ifølge et ytterligere trekk ved oppfin-nelsen består en alternativ fremgangsmåte for fremstilling av fentiazinderivatene med . en generell formel I i cyklisering fortrinns- vis i et organisk oppløsningsmiddel av et substituert amid av en lavere alifatisk sy-re (som formamid eller acetamid) i nærvær av et kondensasjonsmiddel (f. eks. al-kalimetallhydroksyd eller -karbonat) og, hvis ønsket, i nærvær av en katalysator som kobberpulver, av et difenylsulfid av typen: (hvor Hal betyr et halogenatom og R, X og Ai er som foran definert) og, hvor Ai er en gruppe forskjellig fra Åi reduserer gruppen Ai til den alifatiske kjede A. Av foranstående metoder er den «første •(kondensasjon av et bis(dialkylamino)ha-logenpropan med et egnet fentiazin) den . mest fordelaktige. Denne reaksjon utføres med eller uten et oppløsningsmiddel og i nærvær eller fravær av et kondensasjonsmiddel. Det er fordelaktig å arbeide i et aromatisk kullvannstof f oppløsningsmiddel (f. eks. toluol eller xylol) i nærvær av et kondensasjonsmiddel, fortrihsvis i form av et alkalimetall eller derivat av dette (som Special embodiments of the general process defined in the last preceding paragraph are the following: (1) Impact of a phenthiazine with the general formula: with a bis(dialkylamino)halopropane, especially a 1:3-bis(dialkylamino)-2-chloropropane, where the alkyl groups are methyl or ethyl groups, or et., acid addition salts thereof. (2) Condensation of dimethylamine or diethylamine with a phenthiazine derivative of the species: (where Z means a residue of a reactive ester, such as a halogen atom or a sulfur sulphonic acid ester residue and Zi is either the same as Z or means a -N(R) 2 group and the other variables are as defined above). It is advantageous to carry out the reaction in an autoclave, especially when partially carrying out the reaction in an autoclave, especially when the amine used is dimethylamine. (3) Methylation or ethylation by known methods (in particular methylation with formaldehyde and hydrogen in the presence of a catalyst) of an amine corresponding to formula I in which at least one of the symbols R represents a hydrogen atom. (4) Reduction of the corresponding ami- where, for example: where R' is such that R'CH2 = R, preferably using lithium aluminum hydride in a solvent such as tetrahydrofuran. (5) Reduction in the presence of dimethylamine or diethylamine of a derivative of the species: where T means the group CN or the group CHQ, e.g. by catalytic conversion using catalysts. According to a further feature of the invention, an alternative method for producing the phenthiazine derivatives consists of a general formula I in cyclization preferably show in an organic solvent of a substituted amide of a lower aliphatic acid (such as formamide or acetamide) in the presence of a condensing agent (e.g. alkali metal hydroxide or carbonate) and, if desired, in the presence of a catalyst such as copper powder, of a diphenyl sulfide of the type : (where Hal means a halogen atom and R, X and Ai are as defined above) and, where Ai is a group different from Åi, the group Ai is reduced to the aliphatic chain A. Of the above methods, the "first •(condensation of a bis( dialkylamino) halopropane with a suitable phenthiazine) the . most beneficial. This reaction is carried out with or without a solvent and in the presence or absence of a condensing agent. It is advantageous to work in an aromatic hydrocarbon f solvent (e.g. toluene or xylol) in the presence of a condensing agent, preferably in the form of an alkali metal or derivative thereof (eg
f. eks. hydrid, amid, hydroksyd, alkoholat e.g. hydride, amide, hydroxide, alcoholate
eller metallalkyl eller -aryl) og spesielt me-tallisk natrium, natriumamid, pulverisert natrium eller kalium, litium, natrium ter-tiært butylat, butyllitium eller fenyllitium. Reaksjonen utføres fortrinsvis ved koke-temperaturen for oppløsningsmidlet. or metal alkyl or -aryl) and especially metallic sodium, sodium amide, powdered sodium or potassium, lithium, sodium tertiary butylate, butyllithium or phenyllithium. The reaction is preferably carried out at the boiling temperature of the solvent.
Det er fordelaktig å bruke halogendiaminet i form av den frie base i oppløs-ning, f. eks. med toenzol, toluol eller xylol; og tilsette denne til blandingen av de andre reaksjonsdeltagerne, i hvilke fentia-zinet allerede kan være nærværende, i det minste delvis, i formen av et alkalimetall-salt. Reaksjonen kan også utføres under bruk av et salt av halogendiaminet, men i dette tilfelle må klart en større mengde av kondensasjbnsmidlet brukes for å nøy-tralisere syren fra det anvendte salt. It is advantageous to use the halogendiamine in the form of the free base in solution, e.g. with toenzol, toluene or xylol; and adding this to the mixture of the other reactants, in which the phenthiazine may already be present, at least partially, in the form of an alkali metal salt. The reaction can also be carried out using a salt of the halogendiamine, but in this case clearly a larger amount of the condensing agent must be used to neutralize the acid from the salt used.
I løpet av den i foranstående avsnitt beskrevne kondensasjon finner en isomeri-sasjon sted, og der oppnås en blanding av de to isomerer: During the condensation described in the preceding section, an isomerization takes place, and a mixture of the two isomers is obtained:
Hvor R = CH3 overveier isomeren (a). Where R = CH3, the isomer (a) predominates.
Separering av isomeren kan utføres ved f. eks. fraksjonert krystallisering av' saltene som dihydrokloridene fra et egnet oppløs-ningsmiddel som alkohol. Det er imidlertid ikke vesentlig å utføre separeringen da de to isomerene har meget lignende farmako-dynamiske egenskaper. Separation of the isomer can be carried out by e.g. fractional crystallization of the salts as the dihydrochlorides from a suitable solvent such as alcohol. However, it is not essential to carry out the separation as the two isomers have very similar pharmacodynamic properties.
Produktene oppnådd ifølge oppfinnel-sen har særdeles verdifulle farmakodyna-miske egenskaper (ganglioplegiske, lokal anestetiske og spesielt spasmolytiske), og som følge herav kan de anvendes i medisinen. Av fremtredende betydning er for-bindelsene 10-[2:3-bis(dimetylamino)-l-propyl]fentiazin, 3-metyl-10- [2:3-bis (dime-tylamino)-l-propyl]fentiazin og l-klor-10-[2:3-bis(dimetylamino)-l-propyl]fentiazin og deres salter og kvaternære ammoniumderivater, og isomere blandinger inneholdende disse forbindelser, ' av hvilke den mest betydningsfulle forbindelse er 10-[2:3-bis(dimetylamino)-l-prbpyI]fentiazin som er ytterst kraftig spasmolytisk virksom. The products obtained according to the invention have particularly valuable pharmacodynamic properties (ganglioplegic, local anesthetic and especially spasmolytic), and as a result they can be used in medicine. Of prominent importance are the compounds 10-[2:3-bis(dimethylamino)-1-propyl]phenthiazine, 3-methyl-10-[2:3-bis(dimethylamino)-1-propyl]phenthiazine and 1 -chloro-10-[2:3-bis(dimethylamino)-1-propyl]phenthiazine and their salts and quaternary ammonium derivatives, and isomeric mixtures containing these compounds, of which the most important compound is 10-[2:3-bis (dimethylamino)-l-prbpyI]phenthiazine, which is extremely powerful spasmolytically active.
For terapeutiske formål anvendes fen-tiazinbasene av den, gener elle-formel I fortrinsvis i form av sure addisjonssalter inneholdende farmasøytisk akseptable anjo-ner (som hydroklorider og andre hydroha-logenider og 8-klorteofyllinater) eller av kvaternære ammoniumsalter oppnådd ved reaksjon med organiske halogenider (f. eks. metyljodid) eller andre reaksjonsdyktige estere. For therapeutic purposes, the phenthiazine bases of the formula I are preferably used in the form of acid addition salts containing pharmaceutically acceptable anions (such as hydrochlorides and other hydrohalides and 8-chlorotheophylline) or of quaternary ammonium salts obtained by reaction with organic halides (e.g. methyl iodide) or other reactive esters.
De følgende viser hvordan oppfinnel-sen kan utføres i praksis (de angitte smel-tepunkter er bestemt med Kofler-apparat). The following shows how the invention can be carried out in practice (the stated melting points are determined with a Kofler apparatus).
Eksempel 1.. Example 1..
Fentiazin (30 g) oppvarmes under til-bakeløp i 1/2 time med natriumamid (7.5 g) 1 xylol (100 cm<3>). Eh oppløsning av 1:3-bis(dimetylamino)-2-klorpropan (32 g) fremstilt etter en metode analog til den beskrevet i INGOLD and ROTHSTEIN J. Phenthiazine (30 g) is heated under reflux for 1/2 hour with sodium amide (7.5 g) 1 xylol (100 cm<3>). Eh solution of 1:3-bis(dimethylamino)-2-chloropropane (32 g) prepared by a method analogous to that described in INGOLD and ROTHSTEIN J.
C. S. 1931, 1676) i xylol (30 cm<3>) tilsettes i løpet av 2 timer. Oppvarming fortsettes i C. S. 1931, 1676) in xylol (30 cm<3>) is added during 2 hours. Heating is continued in
ytterligere 1/2 time, og derpå tås blandingen opp i vann (400 cm<3>) og saltsyre another 1/2 hour, and then the mixture is dissolved in water (400 cm<3>) and hydrochloric acid
(d = 1.19; 23 cm<3>). Det dekanterte sure lag behandles med kaustisk soda (d = 1.33; (d = 1.19; 23 cm<3>). The decanted acidic layer is treated with caustic soda (d = 1.33;
30 cm3), og basen ekstraheres med eter 30 cm3), and the base is extracted with ether
(2 x 50 cm3), som derpå tørres over kaliumkarbonat. Ved destillasjon oppnås ved 214-215° C/0.5 mm Hg en blanding innehol- (2 x 50 cm3), which is then dried over potassium carbonate. By distillation at 214-215° C/0.5 mm Hg, a mixture containing
dende en større mengde 10-[2:3-bis(dime-tylamino)-l-propyl] fentiazin og en mindre mengde 10-[l:3-bis(dimetylamino)-2-pro-pyl] fentiazin. containing a larger amount of 10-[2:3-bis(dimethylamino)-1-propyl] phenthiazine and a smaller amount of 10-[1:3-bis(dimethylamino)-2-propyl] phenthiazine.
Eksempel 2. Example 2.
Fentiazin (20 g) oppvarmes under til-bakeløp i 1 time med natriumamid (5 g) 'i xyjol (80 cm<3>). En oppløsning av 1:3-bis(dietylamino)-2-klorpropan (27 g) (INGOLD and ROTHSTEIN, J. C. S., 1931, 1676) i xylol (30 cm<:i>) tilsettes derpå i løpet av 2 timer. Blandingen oppvarmes en ytterligere time og tas derpå opp i vann («270 cm<3>) og saltsyre (d = 1.19; 20 cm<3>). Det dekantérte sure lag behandles med kaustisk soda (d = 1.33; 25 cm<3>), og basen ekstraheres med eter som derpå tørres over kaliumkarbonat. Ved destillasjon oppnås ved 218—220° C/0.6 mm Hg en blanding (20 g) av 10 [2:3-bis(dietylamino)-l-pro-pyl]-tfentiazin og 10 [l:3-:bis(dietylamino)-2-propyl]-fentiazin. Phenthiazine (20 g) is heated under reflux for 1 hour with sodium amide (5 g) in xyjol (80 cm<3>). A solution of 1:3-bis(diethylamino)-2-chloropropane (27 g) (INGOLD and ROTHSTEIN, J. C. S., 1931, 1676) in xylol (30 cm<:i>) is then added over 2 hours. The mixture is heated for a further hour and then taken up in water («270 cm<3>) and hydrochloric acid (d = 1.19; 20 cm<3>). The decanted acid layer is treated with caustic soda (d = 1.33; 25 cm<3>), and the base is extracted with ether, which is then dried over potassium carbonate. By distillation, at 218-220° C/0.6 mm Hg, a mixture (20 g) of 10 [2:3-bis(diethylamino)-1-propyl]-phenthiazin and 10 [1:3-:bis(diethylamino )-2-propyl]-phenthiazine.
Eksempel 3. Example 3.
En blanding av baser (11 g) oppnådd som beskrevet i eksempel 2 oppløses i iso-propanol (25. cm3). Eter (25 cm<3>) inneholdende tørt klorvannstoff (2 g) tilsettes, biandingen overlates til krystallisering over natten i kjøleskap, og produktet filtreres fra, vaskes og tørres. Der oppnås således et salt (2.5 g), sm. p. 245° C (Maquenne-blokk plutselig), som er 10-[l:3-bis(dietyl-amino)-2-propyl]fentiazin-hydroklorid. Ved nedstigende kromatagrafi på Arches papir nr. 302 med Partridge's blanding under bruk av Bromofenol blått som fremkaller gir dette produkt en rf på 0.75. A mixture of bases (11 g) obtained as described in example 2 is dissolved in iso-propanol (25 cm3). Ether (25 cm<3>) containing dry hydrogen chloride (2 g) is added, the mixture is left to crystallize overnight in a refrigerator, and the product is filtered off, washed and dried. A salt (2.5 g), sm. m. 245° C. (Maquenne block sudden), which is 10-[1:3-bis(diethylamino)-2-propyl]phenthiazine hydrochloride. By descending chromatography on Arches paper No. 302 with Partridge's mixture using Bromophenol blue as developer, this product gives an rf of 0.75.
Ved fordampning av moderlutene fra forannevnte hydroklorid oppnås et residuum fra hvilket isoleres dets isomer, 10-[2:3-bis(dietylamino)-l-propyl]fentiazin, og basen krystalliserer fra etanol og smelter ved 58° C (kapillar)'. Rf for dette produkt under foran angitte betingelser er 0.85. On evaporation of the mother liquors from the aforementioned hydrochloride, a residue is obtained from which its isomer, 10-[2:3-bis(diethylamino)-1-propyl]phenthiazine, is isolated, and the base crystallizes from ethanol and melts at 58° C (capillary)'. The Rf for this product under the above conditions is 0.85.
Strukturen av disse to Isomerer er blitt bekreftet ved sammenligning av deres infra-røde absorbsjonsspektra med dem fira beslektede produkter av kjent struktur, nemlig i2-^( 10-!f en1?iazinyl):-l-dietylamino-propan og l-( 10-f entiazinyl)-2-dietylamino-propan. The structure of these two isomers has been confirmed by comparison of their infrared absorption spectra with those of four related products of known structure, namely i2-^( 10-!f en1?iazinyl):-1-diethylamino-propane and l-( 10 -pentiazinyl)-2-diethylamino-propane.
Eksempel 4. Example 4.
En blanding av basene (1.14 kg) oppnådd som beskrevet i eksempel 1 oppløses A mixture of the bases (1.14 kg) obtained as described in example 1 is dissolved
i absolutt etanol (4.5 1) og en 8.8 N opp-løsning (0.96 1) av tørt klorvannstoff i absolutt etanol tilsettes. Etter smitting overlates blandingen til krystallisasjon i 24 timer i kjøleskap. Det krystallinske produkt filtreres fra, vaskes med absolutt etanol og tørres i vakuum ved 40° C. Der oppnås slik 10-[2:2-bis(dimetylamino)-l-pro-pyl]fentiazin-dihydroklorid (1.2 kg), som renses, ved å omdanne basen ved behand-ling med alkali i vandig oppløsning og ennå en gang krystallisere dihydrokloridet under samme betingelser som foran. Dihydrokloridet har følgende karakteristikka; sm. p-. in absolute ethanol (4.5 1) and an 8.8 N solution (0.96 1) of dry hydrogen chloride in absolute ethanol are added. After infection, the mixture is left to crystallize for 24 hours in a refrigerator. The crystalline product is filtered off, washed with absolute ethanol and dried in vacuum at 40° C. 10-[2:2-bis(dimethylamino)-1-propyl]phenthiazine dihydrochloride (1.2 kg) is thus obtained, which is purified , by converting the base by treatment with alkali in aqueous solution and once again crystallizing the dihydrochloride under the same conditions as before. The dihydrochloride has the following characteristics; sm. p-.
(Kofler mikroapparat) 200—222° C (ikke skarpt), sm. p. (Maquenne-blokk momen-, tant) 232° C. Ved papirkromatografi under betingelser angitt i eksempel 3 gir dette produkt en rf varierende fra 0.79 til 0.83. (Kofler microapparatus) 200—222° C (not sharp), sm. p. (Maquenne block moment) 232° C. By paper chromatography under the conditions indicated in example 3, this product gives an rf varying from 0.79 to 0.83.
Ved fordampning av moderlutene fra krystallisasjonen oppnås et residuum fra hvilket isoleres isomeren, 10-[l:3-bis(dime-tylamino)-2-propyl]f entiazin. Ved kromato-grafi under samme betingelser som foran gir dette produkt en rf varierende fra 0.59 til 0.63. When the mother liquors from the crystallization are evaporated, a residue is obtained from which the isomer, 10-[1:3-bis(dimethylamino)-2-propyl]phenthiazine, is isolated. By chromatography under the same conditions as above, this product gives an rf varying from 0.59 to 0.63.
Strukturen av disse to isomerer er bekreftet ved sammenligning av deres infra-røde spektra med dem for beslektede produkter av kjent struktur, nemlig l-(10-fen-tiazinyl)-2-dimetylaminopropan og 2-(10-f entiazinyl)-1-dimetylaminopropan. The structure of these two isomers has been confirmed by comparison of their infrared spectra with those of related products of known structure, namely 1-(10-phenthiazinyl)-2-dimethylaminopropane and 2-(10-phentiazinyl)-1- dimethylaminopropane.
Eksempel 5. Example 5.
1- (10;-f entiazinyi) H2-klor-3-dimetylami-nopropanhydroklorid (4.4 g) oppløses i en 1-(10;-fentiazinyi) H2-chloro-3-dimethylaminopropane hydrochloride (4.4 g) is dissolved in a
6.3 n oppløsning (30 cm<3>) av dimetylamin 6.3 n solution (30 cm<3>) of dimethylamine
i etanol og oppvarmes i et forseglet rør i 5 timer ved 120° C. Etter kjøling åpnes in ethanol and heated in a sealed tube for 5 hours at 120° C. After cooling, open
røret, oppløsningsmidlet fjernes ved fordampning under redusert trykk, residuet behandles med fortynnet saltsyre, og den tube, the solvent is removed by evaporation under reduced pressure, the residue is treated with dilute hydrochloric acid, and the
sure oppløsning ekstraheres med eter. Ved å gjøre denne oppløsning alkalisk, bunnfeller en base som ekstraheres med eter. acid solution is extracted with ether. By making this solution alkaline, a base is precipitated which is extracted with ether.
Ved destillasjon av oppløsningsmidlet og fordampning i vakuum oppnås 10-[2:3-bis-(dimetylamino)-l-propyl]fentiazin (2.3 g), k.p 1.70—175° C/2 mm Hg. Dette produkt gir et infra-rødt absorbsjonsspektrum som overlagrer det for produktet beskrevet i form av dets hydroklorid i eksempel 4. 1- (10-f entiazinyl) -2-klor-3-dimetyl-aminopropanhydroklorid (sm. p. av rått produkt 189—190° C, Kofler momentan) oppnås ved innvirkning av tionylklorid i benzol på l-( 10-f entiazinyl)-2-hydroksy-3-dimetylaminopropan (k. p. 175—177° C/2 mm Hg, sm. p. hydroklorid 117—118° C kapilart). Distillation of the solvent and evaporation in vacuo yield 10-[2:3-bis-(dimethylamino)-1-propyl]phenthiazine (2.3 g), b.p. 1.70-175° C/2 mm Hg. This product gives an infrared absorption spectrum which superimposes that of the product described in the form of its hydrochloride in Example 4. 1-(10-phentiazinyl)-2-chloro-3-dimethyl-aminopropane hydrochloride (cf. p. of crude product 189 —190° C, Kofler momentary) is obtained by the action of thionyl chloride in benzene on 1-(10-pentiazinyl)-2-hydroxy-3-dimethylaminopropane (b.p. 175—177°C/2 mm Hg, m.p. hydrochloride 117 -118° C capillary).
Ved å gå frem som beskrevet foran men gå ut fra 1-(3-acetyl-10-f entiazinyl)-2-klor-3-dimetyl-aminopropan oppnås der 3-acetyl-10-[2:3-his (dimetylamino)-l'-pro-pyl]fentiazin, hvis nøytrale fumerat smelter ved 315° C. By proceeding as described above but starting from 1-(3-acetyl-10-phentiazinyl)-2-chloro-3-dimethyl-aminopropane is obtained where 3-acetyl-10-[2:3-his (dimethylamino) -1'-propyl]phenthiazine, whose neutral fumarate melts at 315° C.
Eksempel 6. Example 6.
3-metoksyfentiazin (11.5 g) oppvarmes i 11/2 time under tilbakeløp med xylol (100 cm3) og natriumamid (2.3 g). En xyloloppløsning (40 cm<3>) inneholdende 1:3-bis (dimetylamino)-2-klorpropan (9 g) tilsettes i løpet av 1 time, og blandingen opp-, varmes i ytterligere 3 timer under tilbake-løp. Vann (50 cm<3>) tilsettes derpå, og xylol-laget dekanteres og ekstraheres med 10 pst. saltsyre (50 cm<3>). Det vandige, sure lag dekanteres, natriunmhydroksyd (25 cm3, d = 1.33) tilsettes og basen ekstraheres med eter (2 x 25 cm<3>). En base (12 g) oppnås, k.p. 205—210° C/0.9 mm Hg, som om-fatter en blanding av en større mengde 3-metoksy-10- [2:3-bis (dimetylamino) -1-pro-pyl] fentiazin, rf = 0.82, og en mindre mengde 3-metoksy-10-[l: 3-bis (dimetylami-no )-2-propyl] fentiazin, rf = 0.71. Struktu-rene bekreftes ved infra-røde spektra. 3-Methoxyphentazine (11.5 g) is heated for 11/2 hours under reflux with xylol (100 cm 3 ) and sodium amide (2.3 g). A xylene solution (40 cm<3>) containing 1:3-bis(dimethylamino)-2-chloropropane (9 g) is added over 1 hour, and the mixture is heated for a further 3 hours under reflux. Water (50 cm<3>) is then added, and the xylol layer is decanted and extracted with 10% hydrochloric acid (50 cm<3>). The aqueous, acidic layer is decanted, sodium hydroxide (25 cm3, d = 1.33) is added and the base is extracted with ether (2 x 25 cm<3>). A base (12 g) is obtained, b.p. 205-210° C/0.9 mm Hg, comprising a mixture of a large amount of 3-methoxy-10-[2:3-bis(dimethylamino)-1-propyl] phenthiazine, rf = 0.82, and a small amount of 3-methoxy-10-[1:3-bis(dimethylamino)-2-propyl] phenthiazine, rf = 0.71. The structures are confirmed by infrared spectra.
Eksempel 7. Example 7.
Ved å gå frem som beskrevet i foregående eksempel, men gå ut fra 3-metyl-fentiazin (10.7 g) oppnås en base (14.2 g), k. p. 195—200° C/0.8 mm Hg, omfattende en blanding av en større mengde 3-metyl-10-[2:3-bis-dimetylamino)-l-propyl]fentiazin, rf = 0.84, og en mindre mengde 3-metyl 10- [ 1:3-bis (dimetylamino) -2-propyl] fentiazin, rf = 0.74. Proceeding as described in the preceding example, but starting from 3-methyl-phenthiazine (10.7 g), a base (14.2 g) is obtained, b.p. 195-200° C/0.8 mm Hg, comprising a mixture of a large amount of 3 -methyl-10-[2:3-bis-dimethylamino)-1-propyl]phenthiazine, rf = 0.84, and a smaller amount of 3-methyl 10-[1:3-bis(dimethylamino)-2-propyl]phenthiazine, rf = 0.74.
Eksempel 8. Example 8.
Ved å gå frem som i foregående eksempel, men begynne med 3-klorfentiazin (11.7 g) oppnås en base (13 g), k. p. 200— 205° C/l, mm Hg, omfattende en blanding av en større mengde 3-klor-10-[2:3-bis(di-m/etylamino)-l-propyl];fentiazin, rf = 0,82, og en mindre mengde 3-klor-10-[l:3-bis(di-metylamino)-2-propyl]fentiazin, rf = 0.75. By proceeding as in the preceding example, but starting with 3-chlorophenthiazine (11.7 g), a base (13 g) is obtained, b.p. 200—205° C/l, mm Hg, comprising a mixture of a larger amount of 3-chloro- 10-[2:3-bis(di-m/ethylamino)-1-propyl];phenthiazine, rf = 0.82, and a minor amount of 3-chloro-10-[1:3-bis(dimethylamino) -2-propyl]phenthiazine, rf = 0.75.
Eksempel 9. Example 9.
Ved å gå frem som i foregående eksempel, men begynne med 1-klorfentiazin (11.7 g) oppnås en base (16 g), k. p. 205— 210° C/l mm Hg, omfattende en blanding av en større mengde l-klor-10-[2:3-bis(di-metylamino)-l-propyl]fentiazin, rf = 0,84, og en liten mengde l-klor-10-[l:3-ibis-(di-metylamino)-2-propyl]fentiazin, rf = 0.75. Proceeding as in the previous example, but starting with 1-chlorophenthiazine (11.7 g), a base (16 g) is obtained, b.p. 205—210° C/l mm Hg, comprising a mixture of a larger amount of 1-chloro-10 -[2:3-bis(dimethylamino)-1-propyl]phenthiazine, rf = 0.84, and a small amount of 1-chloro-10-[1:3-ibis-(dimethylamino)-2- propyl]phenthiazine, rf = 0.75.
■ Eksempel 10. ■ Example 10.
i0-[2:3-bis(dimetylamino)-l-propyl] - fentiazin base (5 g) oppløses i aceton (20 cm3), etyljodid (5 cm<3>) tilsettes litt etter litt, og blandingen settes tilside over natten. Der oppnås fine, hvite nåler av 10-[2:3-bis(dimetylaminio)-l-propyl]fentiazin mo-noetjodid (6.9 g), som etter omkrystalli-sasjon fra vann (100 cm3) hår sm. p. 178— 180° C. i0-[2:3-bis(dimethylamino)-1-propyl]-phenthiazine base (5 g) is dissolved in acetone (20 cm3), ethyl iodide (5 cm<3>) is added little by little, and the mixture is set aside overnight . Fine, white needles of 10-[2:3-bis(dimethylamino)-1-propyl]phenthiazine monoethiodide (6.9 g) are obtained, which after recrystallization from water (100 cm 3 ) hair sm. p. 178— 180° C.
Eksempel 11. Example 11.
10-[2:3-bis(dimetylamino)-l-propyl]--fentiazin (3.3 g) oppvarmes i 5 timer under tilbakeløp med metyljodid (14 g) og dimetyl-formamid (14 g). 10-[2:3-bis(dimethylamino)-1-propyl]-phenthiazine (3.3 g) is heated for 5 hours under reflux with methyl iodide (14 g) and dimethylformamide (14 g).
Blandingen kjøles og det faste produkt filtreres fra og omkrystalliseres fra vann The mixture is cooled and the solid product is filtered off and recrystallized from water
(50 cm<3>. Der oppnås således 10-[2:3-bis-(dimetylamino)-l-propyl]fentiazin-dimet-jodid (4.1 g), sm. p. (Maquenne-blokk) 274° C med spaltning. (50 cm<3>). There is thus obtained 10-[2:3-bis-(dimethylamino)-1-propyl]phenthiazine dimeth iodide (4.1 g), m.p. (Maquenne block) 274° C with cleavage.
Eksempel 12. Example 12.
En blanding av 2'-[2:3-bis(dimetyl-amino)propyl]amino-2-bromodifenyl-suIfid (8.8 g), dimetyl-formamid (75 cm<3>), kaliumkarbonat (4.3 g) og kopperpulver (0.4 g) oppvarmes under tilbakeløp i 72 timer under omrøring under en svak kvelstoff-strøm. Etter avkjøling filtreres uoppløseli-ge mineraliske bestanddeler fra, og filtra-tet helles i vann. Den oljeaktige base som bunnfeller, ekstraheres med eter (2 x 100 cm<3> fulgt av 2 x 50 cm<3>) og de kombinerte eterekstrakter med n saltsyre (45 cm3 fulgt av 2 x 20 cm<3>). De kombinerte saltsyreek-strakter vaskes med eter og gjøres alkalisk med vandig natriumhydroksyd (d = 1.33; 10 cm<3>), eterekstraktene tørkes over natriumsulfat, og eteren destilleres fra ved vannbad. A mixture of 2'-[2:3-bis(dimethylamino)propyl]amino-2-bromodiphenyl sulfide (8.8 g), dimethylformamide (75 cm<3>), potassium carbonate (4.3 g) and copper powder ( 0.4 g) is heated under reflux for 72 hours with stirring under a weak nitrogen flow. After cooling, insoluble mineral components are filtered off, and the filtrate is poured into water. The oily base which precipitates is extracted with ether (2 x 100 cm<3> followed by 2 x 50 cm<3>) and the combined ether extracts with n hydrochloric acid (45 cm3 followed by 2 x 20 cm<3>). The combined hydrochloric acid extracts are washed with ether and made alkaline with aqueous sodium hydroxide (d = 1.33; 10 cm<3>), the ether extracts are dried over sodium sulfate, and the ether is distilled off on a water bath.
Der oppnås rått 10-2:3-bis (dimetylami-no)-l-propyl fentiazin (7.6 g) som renses ved omdannelse i alkohol til dihydrokloridet ved tilsetning av alkoholisk klorvannstoff. Dihydrokloridet smelter ved 236— 238° C (Maquenne-blokk) momentant. Crude 10-2:3-bis(dimethylamino)-1-propyl phenthiazine (7.6 g) is obtained, which is purified by conversion in alcohol to the dihydrochloride by addition of alcoholic hydrogen chloride. The dihydrochloride melts at 236— 238° C (Maquenne block) instantaneously.
2'-[2:3-bis (dimetylamino)propyl]ami-no-2-bromodifenyl sulfidet brukt som ut-gangsmateriale fremstilles som følger: En blanding av 2-brom-2'-aminodife-nyl sulfid (20 g) vannfri xylen (125 cm<3>) The 2'-[2:3-bis(dimethylamino)propyl]amino-2-bromodiphenyl sulfide used as starting material is prepared as follows: A mixture of 2-bromo-2'-aminodiphenyl sulfide (20 g) anhydrous xylene (125 cm<3>)
og natriumamid (96 pst.) (3,16 g) oppvarmes i 1'1/2 time under tilbakeløp under and sodium amide (96 per cent) (3.16 g) are heated for 1'1/2 hours under reflux under
omrøring. En 26 pst. oppløsning (54 cm<3>) stirring. A 26 percent resolution (54 cm<3>)
av 1:3-bis (dimetylamino)-2-kloropropan i of 1:3-bis(dimethylamino)-2-chloropropane i
xylen innføres i løpet ay 30 minutter i xylene is introduced during ay 30 minutes i
den oppnådde kokende suspensjon, og blandingen beholdes under tilbakeløpet i ytterligere 16 timer med svak sirkulasjon av the obtained boiling suspension, and the mixture is kept under reflux for a further 16 hours with gentle circulation of
kvelstoff i apparatet. nitrogen in the device.
Etter avkjøling vaskes blandingen med After cooling, the mixture is washed with
vann (50 cm3 fulgt av 30 cm<3>), og xylen-oppløsningen ekstraheres med n saltsyre water (50 cm3 followed by 30 cm<3>), and the xylene solution is extracted with n hydrochloric acid
(140 cm<3> fulgt av 2 x 30 cm<3>). Saltsyre-ekstraktene forenes, vaskes med eter og (140 cm<3> followed by 2 x 30 cm<3>). The hydrochloric acid extracts are combined, washed with ether and
gjøres alkalisk med vandig natriumhydroksyd (d = 1.33; 22 cm<3>). Den oljeaktige made alkaline with aqueous sodium hydroxide (d = 1.33; 22 cm<3>). The oily one
base bunnfelles, ekstraheres med eter (100 base is collected at the bottom, extracted with ether (100
cm<3> fulgt av 2 x 50 cm<3>), og etter vasking cm<3> followed by 2 x 50 cm<3>), and after washing
med vann (50 cm<3>) tørkes eterekstraktene with water (50 cm<3>) the ether extracts are dried
over natriumsulfat, og eteren destilleres fra over sodium sulphate, and the ether is distilled from
med vannbad. Residuuet destilleres i vakuum, og der oppnåes således 2'-[2:3-his-(dimetylamino)propyl]amino-2-bromodife-nylsulfid (9.25 g), k. p. 203—213° C/0.5 with water bath. The residue is distilled in vacuo, and 2'-[2:3-his-(dimethylamino)propyl]amino-2-bromodiphenyl sulfide (9.25 g), b.p. 203-213° C/0.5
mm Hg. mm Hg.
Claims (3)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE18070/67A SE326012B (en) | 1967-12-29 | 1967-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO118809B true NO118809B (en) | 1970-02-16 |
Family
ID=20304224
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO522368A NO118809B (en) | 1967-12-29 | 1968-12-28 |
Country Status (6)
Country | Link |
---|---|
DE (1) | DE1816732B2 (en) |
FI (1) | FI47607C (en) |
FR (1) | FR1601287A (en) |
GB (1) | GB1225874A (en) |
NO (1) | NO118809B (en) |
SE (1) | SE326012B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2528473B1 (en) * | 1982-06-14 | 1985-07-05 | Oth Nord | METHOD AND DEVICE FOR INSULATING ROOM WALLS CONTAINING AIR AT DIFFERENT TEMPERATURES |
DE102016220527A1 (en) | 2016-10-19 | 2018-04-19 | Wilhelm Bruckbauer | Arch element for a ventilation system |
-
1967
- 1967-12-29 SE SE18070/67A patent/SE326012B/xx unknown
-
1968
- 1968-12-23 DE DE19681816732 patent/DE1816732B2/en active Pending
- 1968-12-24 GB GB1225874D patent/GB1225874A/en not_active Expired
- 1968-12-27 FI FI373368A patent/FI47607C/en active
- 1968-12-27 FR FR1601287D patent/FR1601287A/fr not_active Expired
- 1968-12-28 NO NO522368A patent/NO118809B/no unknown
Also Published As
Publication number | Publication date |
---|---|
FR1601287A (en) | 1970-08-10 |
FI47607B (en) | 1973-10-01 |
DE1816732B2 (en) | 1971-12-02 |
GB1225874A (en) | 1971-03-24 |
SE326012B (en) | 1970-07-13 |
FI47607C (en) | 1974-01-10 |
DE1816732A1 (en) | 1969-09-18 |
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