CH464178A - Process for the preparation of a new amine - Google Patents
Process for the preparation of a new amineInfo
- Publication number
- CH464178A CH464178A CH1213567A CH1213567A CH464178A CH 464178 A CH464178 A CH 464178A CH 1213567 A CH1213567 A CH 1213567A CH 1213567 A CH1213567 A CH 1213567A CH 464178 A CH464178 A CH 464178A
- Authority
- CH
- Switzerland
- Prior art keywords
- propane
- hydroxy
- salts
- amino
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001412 amines Chemical class 0.000 title description 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000001294 propane Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 6
- -1 isopropyl halide Chemical class 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- HNUALPPJLMYHDK-UHFFFAOYSA-N C[CH]C Chemical compound C[CH]C HNUALPPJLMYHDK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- 239000002253 acid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BZVHVRVBYPQBCI-UHFFFAOYSA-N 2-(3-amino-2-hydroxypropoxy)phenol Chemical compound NCC(O)COC1=CC=CC=C1O BZVHVRVBYPQBCI-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229940072033 potash Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- FTJSDHRLVNMSLN-UHFFFAOYSA-N 1-(propan-2-ylamino)-3-(4-prop-2-enoxyphenoxy)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC=C(OCC=C)C=C1 FTJSDHRLVNMSLN-UHFFFAOYSA-N 0.000 description 1
- FZKCAHQKNJXICB-UHFFFAOYSA-N 2,1-benzoxazole Chemical compound C1=CC=CC2=CON=C21 FZKCAHQKNJXICB-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- CCZCXFHJMKINPE-UHFFFAOYSA-N 2-phenylmethoxyphenol Chemical compound OC1=CC=CC=C1OCC1=CC=CC=C1 CCZCXFHJMKINPE-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung eines neuen Amins
Gegenstand der Erfindung ist ein Verfahren zur Herstellung des 1 -Isopropylamino-2-hydroxy-3 -(0-allyl oxy-phenoxy)-propans der Formel
EMI1.1
und seiner Salze.
Die neue Vebindung besitzt wertvolle pharmakologsiche Eigenschaften. Insbesondere bewirkt sie eine Hemmung adrenergischer 8 Rezeptoren. Sie kann dem- entsprechend bei Herz- und Kreislauferkrankungen als Medikament angewendet werden.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man in die Aminogruppe des 1-Amino2-hydroxy-3-(o-allyloxy-phenoxy)- propans oder einem Salz davon den Isopropylrest einführt.
Dies kann in üblicher Weise geschehen, zweckmässig durch Umsetzung mit einem reaktionsfähigen Ester des Isopnopanols.
Ein reaktionsfähiger Ester ist dabei z. B. derjenige einer starken organischen oder anorganischen Säure, wie vor allem einer Halogenwasserstoffsäure, z. B. der Chlor-, Brom oder Jodwasserstoffsäure, oder einer Sulfonsäure, wie einer Arylsulfonsäure, z. B. der p-Toluolsulfonsäure. Bei dieser Reaktion verwendet man vorteilhaft ein basisches Kondensationsmittel oder einen Überschuss an Amin.
Die Ausgangsstoffe sind bekannt oder können nach an sich bekannten Methoden gewonnen werden. Sie können auch in Form ihrer Salze eingesetzt werden.
Je nach den Verfahrensbedingungen und Ausgangsstoffen kann der Endstoff in freier Form oder in der eben- falls in der Erfindung inbegriffenen Form seiner Salze erhalten werden. Die Salze des Endstoffs können in an sich bekannter Weise, z. B. mit Alkalien oder Ionen austauschern in die freie Base übergeführt werden.
Von der letzteren lassen sich durch Umsetzung mit organischen oder anorganischen Säuren, insbesondere solchen, die zur Bildung von therapeutisch verwendbaren Salzen geeignet sind, Salze gewinnen. Als solche Säuren seien beispielsweise genannt: Halogenwasserstoffsäuren, Schwefelsäuren, Phosphorsäuren, Salpetersäure, Perchlorsäure, aliphatische, alicyclische, aromatische oder heterocyclische Carbon oder Sulfonsäuren, wie Ameisen-, Essig-, Propion-, Bernstein ;, Glykol-, Milch¯, Sipfel-, Wein-, Zitronen-, Ascorbin-, Malein-, Hydroxymalein- oder Brenztraubensäure;
Phenylessig-, Benzoe-, p-Aminobenzoe-, Anthranil p-Hydroxybenzoe, Sali- cyl- oder p-Aminosalicylsäune, Embonsäure, Methans sulfon-, Athansulfon-, Hydroxyäthansulfon-, Athylen- sulfonsäure; Halogenbenzolsulfon-, Toluolsulfon-, Naph thalinsulfonsäure oder Sulfanilsäure; Methionin, Tryptophan, Lysin oder Arginin.
Diese oder andere Salze den neuen Verbindung, wie z. B. die Pikrate, können auch zur Reinigung der erhaltenen freien Basen dienen, indem man die freie Base in Salze überführt, diese abbrennt und aus den Salzen wiederum die Base freimacht. Infolge der engen Beziehungen zwischen der neuen Verbindung in freier Form und in Form ihrer Salze sind im vorausgegangenen und nachfolgend unter der freien Base sinn- und zweckmässig, gegebenenfalls auch die entsprechenden Salze zu verstehen.
Die neue Verbindung kann als Racemat oder in Form der Antipoden vorliegen. Das Racemat kann in üblicher Weise in die Antipoden zerlegt werden.
Die neue Verbindung kann z. B. in Form pharmazeutischer Präparate Verwendung finden, welche sie in freier Form oder gegebenenfalls in Form ihrer Salze in Mischung mit einem für die enterale oder parenterale Applikation geeigneten pharmazeutischen, organischen oder anorganischen, festen oder flüssigen Trägermaterial enthalten.
Im folgenden Beispiel werden die Temperaturen in Celsiusgraden angegeben.
Beispiel
Eine Lösung von 15,0 g 1-Amino-2-hydroxy-3 (o-allyloxy-phenoxy)-propan und 8,0 g Isopropylbromid in 150 ml Alkohol wird nach Zugabe von 5,0 g Pottasche während 4 Stunden zum Sieden erhitzt. Hierauf wird der ungelöste Anteil filtriert. Das Filtrat dampft man ein. Der Rückstand wird mit 100 mi 2n Salzsäune verseift und mit Äther extrahiert. Die wässrige Schicht stellt man mit lOn Natronlauge alkalisch und extrahiert die ausgeschiedene Base mit Äther. Der nach dem Trocknen und Eindampfen des Lösungsmittels verbleibende Rückstand wird mehrmals aus Hexan urnkristallisiert.
Man erhält das 1-Isopropylamino-2-hydroxy-3-(o- allyloxy-phenoxy) -prop an der Formel
EMI2.1
in Kristallen vom F. 76 bis 800. F. des Hydrochlorids -107 bis 1090.
Das als Ausgangsmaterial verwendete l-Amino-2 hydroxy-3-(o-allyloxy-phenoxy)-prop an lässt sich aute folgendem Wege herstellen:
Ein Gemisch von 200 g o-Benzyloxyphenol, 200 g Epichlorhydrin, 200 g Pottasche und 800 ml Aceton wird während 12 Stunden unter Rühren zum Sieden erhitzt. Die ungelösten Anteile filtriert man ab und gibt zum Filtrat 1000 ml Äther. Zur Entfernung phenolischer Anteile wird mit Natronlauge ausgeschüttelt. Die Äther- lösung wird über Natriumsulfat getrocknet und dann im Wasserstrahlvakuum eingedampft. Den Rückstand destilliert man im Hochvakuum.
Man erhält das 3-(o Benzyloxy-phenoxy)-1, ,2-epoxy-propan als öl, das bei
142 bis 1530/0,1 mm siedet.
30 g 3-(o-Benzyloxy-phenoxy)-1 2-epoxy-propan werden mit 30 g Benzylamin in 30 ml Äthanol während 4 Stunden zum Sieden erhitzt. Anschliessend dampft man im Wasserstrahlvakuum ein, löst den Rückstand in 200 ml 2n Salzsäure und extrahiert mit Äther. Die saure Lösung wird mit lOn Natronlauge alkalisch gestellt.
Man extrahiert die ausgeschiedene Base mit Äther, trocknet den Extrakt über Natriumsulfat und destilliert das Lösungsmittel ab. Es verbleibt das l-Benzylamino-2- hydroxy-3-(o-benzyloxy-phenoxy)-propan, das nach Umkristallisation aus Isopropanol bei 82 bis 830 schmilzt.
25 g 1 -B enzylamino-2-hydroxy-3 -(o-b enzyloxy- phenoxy)-propan werden in 250 ml Äthanol gelöst und nach Zugabe von 3,0 g Palladiumkohle bei Zimmertemperatur und Normaldruck hydriert. Nach Beendigung der Wasserstoff-Aufnahme filtriert man den Katalysator ab und dampft im Vakuum ein. Man erhält das 1 -Amino-2-hydroxy-3 -(o-hydroxy-phenoxy)- propan, dessen Hydrochlorid bei 175 bis 1770 schmilzt.
Zu einer Lösung von 5,4 g Natriummethylat in 200 ml Äthanol gibt man 22 g 1-Amino-2-hydroxy-3 (o-hydroxy-phenoxy)-propan und lässt langsam 12,0 g Allylbromid zutropfen. Man rührt 4 Stunden bei Zimmertemperatur und filtriert dann ab. Das Filtrat dampft man in Vakuum ein. Man erhält das l-Amino 2-hydroxy-3-(o-allyloxy-phenoxy)-propan als Ö1, das direkt weiterverarbeitet wird.
26 g racemisches l-lsopropylamino-2-hydroxy-3- (o-allyloxy-phenoxy)-propan und 14,8 g L-(+)-Glutaminsäure werden in 50 ml Wasser bei 60 bis 700 gelöst.
Nachdem die Lösung filtriert und auf Zimmertemperatur abgekühlt worden ist gibt man 200 ml absolutes Äthanol zu. Es scheidet sich ein kristalliner Niederschlag aus, den man aus Methanol umkristallisiert. Das so erhaltene Glutaminat des (+)-l-Isopropylamino-2-hydroxy-3-(o- allyloxy-phenoxy)-propans wird in Wasser gelöst und die Lösung durch Zugabe von 1 von Natronlauge alkalisch gestellt. Es scheidet sich das (+)-1-Isopropylamino-2- hydroxy-3-(o-allyloxy-phenoxy)-propan aus, das nach Umkristallisation aus Petroläther r bei 60 bis 620 schmilzt und eine spezifische Drehung von [a] D = +6,2 + 050 (Äthanol, c = 2 S) zeigt.
In analoger Weise kann aus racemischem 1-Isopropylamino-2-hydroxy-3-(o-allyloxy- phenoxy)-propan mit D-(-)-Glutaminsäure der linksdrehende Antipode abgetrennt werden.
Process for the preparation of a new amine
The invention relates to a process for the preparation of 1-isopropylamino-2-hydroxy-3 - (0-allyl oxy-phenoxy) propane of the formula
EMI1.1
and its salts.
The new compound has valuable pharmacological properties. In particular, it inhibits adrenergic receptors. Accordingly, it can be used as a medication for heart and circulatory diseases.
The process according to the invention is characterized in that the isopropyl radical is introduced into the amino group of 1-amino2-hydroxy-3- (o-allyloxyphenoxy) propane or a salt thereof.
This can be done in the usual way, expediently by reaction with a reactive ester of isopnopanol.
A reactive ester is z. B. that of a strong organic or inorganic acid, such as especially a hydrohalic acid, e.g. B. chlorine, bromine or hydroiodic acid, or a sulfonic acid such as an aryl sulfonic acid, e.g. B. p-toluenesulfonic acid. A basic condensing agent or an excess of amine is advantageously used in this reaction.
The starting materials are known or can be obtained by methods known per se. They can also be used in the form of their salts.
Depending on the process conditions and starting materials, the end product can be obtained in free form or in the form of its salts, which is also included in the invention. The salts of the end product can in a conventional manner, for. B. exchanging with alkalis or ions are converted into the free base.
Salts can be obtained from the latter by reaction with organic or inorganic acids, in particular those which are suitable for the formation of therapeutically useful salts. Examples of such acids are: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, amber, glycolic, lactic, sipfelic, Tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid;
Phenylacetic, benzoic, p-aminobenzoic, anthranil, p-hydroxybenzoic, salicyl or p-aminosalicylic acid, emboxylic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid; Methionine, tryptophan, lysine or arginine.
These or other salts of the new compound, such as. B. the picrates can also be used to purify the free bases obtained by converting the free base into salts, burning them off and in turn frees the base from the salts. As a result of the close relationships between the new compound in free form and in the form of its salts, in the preceding and in the following the free base is meaningfully and expediently to be understood as meaning the corresponding salts, if appropriate.
The new compound can be present as a racemate or in the form of the antipodes. The racemate can be broken down into the antipodes in the usual way.
The new connection can e.g. B. in the form of pharmaceutical preparations are used which they contain in free form or optionally in the form of their salts mixed with a pharmaceutical, organic or inorganic, solid or liquid carrier material suitable for enteral or parenteral administration.
In the following example the temperatures are given in degrees Celsius.
example
A solution of 15.0 g of 1-amino-2-hydroxy-3 (o-allyloxyphenoxy) propane and 8.0 g of isopropyl bromide in 150 ml of alcohol is heated to boiling for 4 hours after adding 5.0 g of potash . The undissolved portion is then filtered. The filtrate is evaporated. The residue is saponified with 100 ml of 2N salt acid and extracted with ether. The aqueous layer is made alkaline with 10N sodium hydroxide solution and the precipitated base is extracted with ether. The residue remaining after drying and evaporation of the solvent is recrystallized several times from hexane.
The 1-isopropylamino-2-hydroxy-3- (o-allyloxy-phenoxy) -prop of the formula is obtained
EMI2.1
in crystals of m. 76 to 800. m. of the hydrochloride -107 to 1090.
The l-amino-2-hydroxy-3- (o-allyloxy-phenoxy) -propane used as starting material can be produced in the following way:
A mixture of 200 g of o-benzyloxyphenol, 200 g of epichlorohydrin, 200 g of potash and 800 ml of acetone is heated to the boil for 12 hours while stirring. The undissolved components are filtered off and 1000 ml of ether are added to the filtrate. To remove phenolic fractions, it is extracted with sodium hydroxide solution. The ether solution is dried over sodium sulfate and then evaporated in a water-jet vacuum. The residue is distilled in a high vacuum.
The 3- (o benzyloxyphenoxy) -1,, 2-epoxy-propane is obtained as an oil, the
142 to 1530 / 0.1 mm boils.
30 g of 3- (o-benzyloxyphenoxy) -1 2-epoxy-propane are heated to boiling with 30 g of benzylamine in 30 ml of ethanol for 4 hours. It is then evaporated in a water jet vacuum, the residue is dissolved in 200 ml of 2N hydrochloric acid and extracted with ether. The acidic solution is made alkaline with 10N sodium hydroxide solution.
The precipitated base is extracted with ether, the extract is dried over sodium sulfate and the solvent is distilled off. The l-benzylamino-2-hydroxy-3- (o-benzyloxyphenoxy) propane remains, which melts at 82 to 830 after recrystallization from isopropanol.
25 g of 1-b-enzylamino-2-hydroxy-3 - (o-b enzyloxyphenoxy) propane are dissolved in 250 ml of ethanol and, after addition of 3.0 g of palladium carbon, hydrogenated at room temperature and normal pressure. After the uptake of hydrogen has ended, the catalyst is filtered off and evaporated in vacuo. 1-Amino-2-hydroxy-3 - (o-hydroxyphenoxy) propane, the hydrochloride of which melts at 175 to 1770, is obtained.
22 g of 1-amino-2-hydroxy-3 (o-hydroxyphenoxy) propane are added to a solution of 5.4 g of sodium methylate in 200 ml of ethanol, and 12.0 g of allyl bromide are slowly added dropwise. The mixture is stirred for 4 hours at room temperature and then filtered off. The filtrate is evaporated in vacuo. The l-amino 2-hydroxy-3- (o-allyloxyphenoxy) propane is obtained as an oil, which is further processed directly.
26 g of racemic l-isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane and 14.8 g of L - (+) - glutamic acid are dissolved in 50 ml of water at 60-700.
After the solution has been filtered and cooled to room temperature, 200 ml of absolute ethanol are added. A crystalline precipitate separates out and is recrystallized from methanol. The glutaminate of (+) - 1-isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane obtained in this way is dissolved in water and the solution is made alkaline by adding 1 of sodium hydroxide solution. The (+) - 1-isopropylamino-2-hydroxy-3- (o-allyloxy-phenoxy) -propane separates out, which after recrystallization from petroleum ether melts r at 60 to 620 and a specific rotation of [a] D = +6.2 + 050 (ethanol, c = 2 S) shows.
In an analogous manner, the levorotatory antipode can be separated from racemic 1-isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane with D - (-) - glutamic acid.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1213564 | 1964-09-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH464178A true CH464178A (en) | 1968-10-31 |
Family
ID=4380209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1213567A CH464178A (en) | 1964-09-10 | 1964-09-10 | Process for the preparation of a new amine |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH464178A (en) |
-
1964
- 1964-09-10 CH CH1213567A patent/CH464178A/en unknown
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