CH489465A - Process for the preparation of a new amine - Google Patents
Process for the preparation of a new amineInfo
- Publication number
- CH489465A CH489465A CH1432369A CH1432369A CH489465A CH 489465 A CH489465 A CH 489465A CH 1432369 A CH1432369 A CH 1432369A CH 1432369 A CH1432369 A CH 1432369A CH 489465 A CH489465 A CH 489465A
- Authority
- CH
- Switzerland
- Prior art keywords
- isopropylamino
- propane
- hydroxy
- salts
- hydrolysis
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000001412 amines Chemical class 0.000 title description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 239000001294 propane Substances 0.000 claims description 9
- 239000012458 free base Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 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 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000000155 melt Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- -1 oxycarbonyl radical Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 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 2
- FNEJKCGACRPXBT-UHFFFAOYSA-N 2-prop-2-enoxyphenol Chemical compound OC1=CC=CC=C1OCC=C FNEJKCGACRPXBT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- 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
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-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
- FHIATTMLFDJJKY-UHFFFAOYSA-N 2-hydroxy-1-(4-hydroxyphenyl)-2-phenylethanone Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=C(O)C=C1 FHIATTMLFDJJKY-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
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 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
- 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
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-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
- 240000001879 Digitalis lutea Species 0.000 description 1
- 206010015856 Extrasystoles Diseases 0.000 description 1
- 241000282326 Felis catus Species 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
- 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
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 241000252496 Siluriformes Species 0.000 description 1
- 244000028419 Styrax benzoin Species 0.000 description 1
- 235000000126 Styrax benzoin Nutrition 0.000 description 1
- 235000008411 Sumatra benzointree Nutrition 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
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960002130 benzoin Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 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
- 235000019382 gum benzoic Nutrition 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940039009 isoproterenol Drugs 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
- 229910052751 metal Chemical class 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 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
- 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229950000244 sulfanilic acid Drugs 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
Landscapes
- 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-(o-allyl oxy-phenoxy)-propans der Formel
EMI1.1
und seiner Salze.
Die neue Verbindung besitzt wertvolle pharmakologische Eigenschaften. Insbesondere bewirkt sie eine Hemmung adrenergischer #-Rezeptoren. So hemmt sie z. B. an der mit Dial narkotisierten Katze oder am wachen Hund durch Isoproterenol hervorgerufene Blut- drucksenkungen in Dosen von 0,01-1 ma'kg i. v. oder 2-3 mg li p. o. Sie ist in der Lage Digitalis-induzierte Extrasystolen zu unterdrücken, wie z. B. aus Experimenten mit einer Dosis von 0,3-1 mg/kg i. v. am narkotisierten Hund hervorgeht. Die Verbindung kann dementsprechend bei Herz-und Kreistauferkrankungen als Medikament angewendet werden.
Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindung ist dadurch gekennzeichnet, dass man in einem 1-Isopropylamino-2-hydroxy-3- (o-allyl- oxy-phenoxy)-propan oder einem Salz davon, das am Stickstoffatom und an der 2-Hydroxylgruppe je einen einwertigen oder zusammen einen zweiwertiren durch Hydrolyse abspaltbaren Rest aufweist. diesen abspähet.
Durch Hydrolyse abspaltbare einwertie Reste sind z. B. Acylreste von Carbonsuuren. wie niedere A) kano- ylreste, z. B. der Acetvlrest oder Oxycarbonylreste, wie der Benzytoxycarbonytrest oder der tert.-Butoxycar- bonylrest. Verbindungen mit durch Hydrolyse abspatt- baren zweiwertigen Resten sind z. B. die der Formel a)
EMI1.2
worin X'für die Carbonylyruppe oder f r eine Alkyli- dengruppe steht.
Die Hydrolyse kann in üblicher Weise vorgenommen werden. Die Hydrolyse einer Verbindung der Formet a), worin X' f r eine Alkylidengruppe steht, wird vorzugsweise in saurer Lösung durchgeführt.
Die Ausgangsstoffe sind bekannt oder können nach an sich bekannten Methoden gewonnen werden.
Die Salze des Endstoffes können in an sich bekannter Weise, z. B. mit Alkalien oder Ionenaustauschern in die freie Base übergeführt werden. Von der letzteren lassen sich durch Umsetzung mit organischen oder anorganischen Sauren, insbesondere solchen, die zur Bildung von therapeutisch verwendbaren Saizcn geeignet sind, Salze gewinnen. Als solche S : iuren scien beispiels- weise genannt : Halogenwasserstoffsäuren, Schwefelsau- ren, PhosphorsÏuren, SalpetersÏure. Perchlorsäure. ali- phatische, alicyclische, aromatische o ter heterocyclischc Carbon-oder Sulfonsäurcn, wie Ameisen-, Essig-. Propion-, Bernstein-, Glykol-, Milch-. ¯pfel-. Wein-.
Zitronen-, Ascorbin-, Malein-, Hydroxymalein- oder Brenztraubensäure ; Phenylessig-, Benzoe-, p-Amino- benzoe-, Anthranil-, p-Hydroxy-benzoe-. Salicyl- oder p-AminosalicylsÏure, Embonsäure, Methansulfon-, Athansulfon-, HydroxyÏthansulfon-. ¯thylensulfonsÏure: Halogenbenzolsulfon-, Toluolsulfon-, Naphthalinsult'on silure oder Sulfanilsaiurc : Mlrtliiunin. Tryptophan, Lysin oder Ar,, inin.
Diese oder andere Salze der neuen Verbindung, wie z. B. die Pikrate, können auch zur Reinigung der erhaltenen freien Base dienen, indem man die freie Base in Salze überführt, diese abtrennt 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 Erfindung betrifft auch diejenigen Ausführungs- formen des Verfahrens, bei denen man die Ausgangs- stoffe unter den Reaktionsbedingungen bildet.
Die neue Verbindung kann als Racemat oder in Form der Antipoden vorliegen. Das Racemat lässt sich in üblicher Weise in die Antipoden zerlegen.
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 Trägermate- rial enthalten.
Verbindungen, die am Stickstoffatom und an der 2-Hydroxylgruppe einen durch Hydrolyse abspaltbaren Rest aufweisen, erhilt man z. B. durch Kondensation einer Verbindung der Formel
EMI2.1
mit einer Verbindung der Formel
EMI2.2
wobei X. fUr einen durch Hydrolyse abspaltbaren Rest und einer der Reste Xi und Y1 für eine reaktionsfähig veresterte Hydroxylgruppe steht, und der andere eine Aminogruppe bedeutet, die durch einen abspaltbaren Rest substituiert ist.
Ferner sind diese am Stickstoff und an der 2-Hydr oxylgruppe substituierten Verbindungen auch dadurch erhait) ich. dass man ein o-Allyloxyphenol oder ein Salz davon mit einer Verbindung der Formel
EMI2.3
umsetzt, worin X eine reaktionsfähig veresterte Hydr oxylgruppe und die Reste X, und X,'durch Hydrolyse abspaltbare Reste sind.
Die Verbindungen der Formel a) kann man z. B. durch Umsetzuna von o-Allyloxy-phenol oder eines Metallsalzes davon mit einer Verbindung der Formel
EMI2.4
worin X'die Carbonylgruppe oder eine Alkylidengruppe und X eine reaktionsfähig veresterte Hydroxylgruppe bedeutet, erhalten.
In den folgenden Beispielen sind die Temperaturen in Celsiusgraden angegeben.
Beispiel I
10,0 g 3-Isopropyl-5- (o-allyloxy-phenoxymethyl)- oxazolidinon- (2) werden mit 50 ml 10-n Natronlauge während 15 Minuten unter gutem Rühren auf 120 erhitzt. Hierauf gibt man 200 ml Wasser zu und extrahiert mit Ather. Die Ather-Schicht wird abgetrennt, getrocknet und im Wasserstrahlvakuum eingedampft. Es verbleibt das
I-Isopropylamino-2-hydroxy-3- (o-allyloxy- phenoxy)-propan der Formel
EMI2.5
das nach Uml ; ristallisation aus Hexan bei 78-81 schmilzt. Das Hydrochlorid schmilzt bei 107-109".
Beispiel 2
26 g racemisches I-Isopropylamino-2-hydroxy-3- (o-allyloxy-phenoxy)-propan und 14,8 g L- (+)-Glut- aminsäure werden in 50 ml Wasser bei 60-70D gelöst.
Nachdem die Lösung filtriert und auf Zimmertemperatur abgekühlt worden ist, gibt man 200 ml absolutes Athanol zu. Es scheidet sich ein kristalliner Niederschlag aus, den man aus Methanol umkristallisiert. Das so erhaltene Glutaminat des (+)-I-Isopropylamino-2-hydroxy-3-(o-allyloxy- phenoxy)-propans wird in Wasser gelöst und die Lösung durch Zugabe von 10-n Natronlauge alkalisch gestellt. Es scheidet sich das (+)-1-Isopropylamino-2-hydroxy-3-(o-allyloxy phenoxy)-propan aus, das nach Umkristallisation aus Petrolather bei 60-62 schmilzt und eine spezifische Drehun von M 2 # 0,5 (Athanol, 0,2%) zeigt.
Das Hydrochlorid schmilzt bei 80-82 und hat eine spezifische Drehung von [a20D = -13# = 0,5# (Wasser. c = 2%).
In analoger Weise kann aus racemischem -1-Isopropylamino-2-hydroxy-3-(o-allyloxy phenoxy)-propan mit D-(-)-Glutaminsäure der linksdrehende Antipode abgetrennt werden. Das
1-1-Isopropylamino-2-hydroxy-3-(o-allyloxy- phenoxy)-propan-hydrochlorid schmilzt bei 80-82 und hat eine spezifische Drehung von [a]20D -. -13 # 0,5 (Äthanol, c = 2 %).
Beispiel 3
1 g
1-(N-Acetyl-isopropylamino)-2-acetoxy-3 (o-allyloxy-phenoxy)-propan wird in 7 ml absolutem Alkohol und 3,5 ml 5-n Na- tronlauge während 7 Stunden am Rückfluss gekocht.
Die Reaktionslösung wird im Vakuum eingeengt. Den Eindampfrückstand versetzt man mit Wasser und schüt- telt mit Äther aus. Nach Eindampfen der getrockneten Ätherlösung erhält man als Rückstand das I-Isopropylamino-2-hydroxy-3- (o-allyloxy- phenoxy)-propan der Formel
EMI3.1
dessen Hydrochlorid bei 107-109 schmilzt.
Beispiel 4
Zu einer Lösung von 5, 0 g 3-Isopropyl-5- (o-allyl- oxy-phenoxymethyl)-oxazolidin in 50 ml ¯thanol gibt man 25 ml 2-n. Salzsäure und erwärmt eine Stunde auf 70¯. Anschlief3end wird der Alkohol abdestilliert und den Rückstand versetzt man mit 75 ml 2-n. Natronlauge. Es scheidet sich ein O1 ab, das mit Ather extrahiert wird. Nach dem Trocknen und Eindampfen des Äthers bleibt das I-Isopropylamino-2-hydroxy-3-(o-allyloxy- phenoxy)-propan der Formel
EMI3.2
dessen Hydrochlorid bei 107-109 schmilzt, zurück.
Process for the preparation of a new amine
The invention relates to a process for the preparation of 1-isopropylamino-2-hydroxy-3- (o-allyl oxy-phenoxy) propane of the formula
EMI1.1
and its salts.
The new compound has valuable pharmacological properties. In particular, it has the effect of inhibiting adrenergic # receptors. So it inhibits z. B. in the cat anesthetized with Dial or in the conscious dog caused by isoproterenol lowering blood pressure in doses of 0.01-1 ma'kg i. v. or 2-3 mg li p. o. It is able to suppress digitalis-induced extrasystoles, such as B. from experiments with a dose of 0.3-1 mg / kg i. v. on the anesthetized dog. The compound can accordingly be used as a medicament for heart and circulatory diseases.
The inventive method for the preparation of the new compound is characterized in that in a 1-isopropylamino-2-hydroxy-3- (o-allyl oxy-phenoxy) propane or a salt thereof, which is on the nitrogen atom and on the 2- Hydroxyl group each has a monovalent or together a bivalent radical which can be split off by hydrolysis. spying on them.
Valuable residues which can be split off by hydrolysis are e.g. B. acyl residues of carboxylic acids. like lower A) kanoyl residues, z. B. the acetyl radical or oxycarbonyl radical, such as the benzytoxycarbony radical or the tert-butoxycarbonyl radical. Compounds with divalent radicals that can be removed by hydrolysis are e.g. B. those of the formula a)
EMI1.2
where X 'stands for the carbonyl group or for an alkylidene group.
The hydrolysis can be carried out in the usual way. The hydrolysis of a compound of the formula a) in which X 'is an alkylidene group is preferably carried out in acidic solution.
The starting materials are known or can be obtained by methods known per se.
The salts of the end product can in a manner known per se, for. B. be converted into the free base with alkalis or ion exchangers. Salts can be obtained from the latter by reaction with organic or inorganic acids, especially those which are suitable for the formation of therapeutically useful acids. 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 acid. Propionic, amber, glycol, milk. Apple. Wine-.
Citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; Phenylacetic, benzoin, p-amino-benzoin, anthranil, p-hydroxy-benzoin. Salicylic or p-aminosalicylic acid, emboxylic acid, methanesulfonic, ethanesulfonic, hydroxythanesulfonic. Ethylenesulphonic acid: halobenzenesulphonic, toluenesulphonic, naphthalenesult'on silure or sulphanilic acid: Mlrtliiunin. Tryptophan, lysine or ar ,, inine.
These or other salts of the new compound, such as. B. the picrates, can also be used to purify the free base obtained by converting the free base into salts, separating them 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 meaningfully and expediently also means the corresponding salts.
The invention also relates to those embodiments of the process in which the starting materials are formed under the reaction conditions.
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. can be used in the form of pharmaceutical preparations 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.
Compounds which have a residue on the nitrogen atom and on the 2-hydroxyl group which can be split off by hydrolysis are obtained, for. B. by condensation of a compound of the formula
EMI2.1
with a compound of the formula
EMI2.2
where X. stands for a radical which can be split off by hydrolysis and one of the radicals Xi and Y1 stands for a reactive esterified hydroxyl group, and the other stands for an amino group which is substituted by a split-off radical.
Furthermore, these compounds substituted on the nitrogen and on the 2-hydroxyl group are also obtained in this way. that one o-allyloxyphenol or a salt thereof with a compound of the formula
EMI2.3
converts, in which X is a reactive esterified hydroxyl group and the radicals X, and X, 'are radicals which can be split off by hydrolysis.
The compounds of formula a) can be, for. B. by Umsetzuna of o-allyloxyphenol or a metal salt thereof with a compound of the formula
EMI2.4
where X 'denotes the carbonyl group or an alkylidene group and X denotes a reactive esterified hydroxyl group.
In the following examples the temperatures are given in degrees Celsius.
Example I.
10.0 g of 3-isopropyl-5- (o-allyloxyphenoxymethyl) -oxazolidinone- (2) are heated to 120 for 15 minutes with 50 ml of 10N sodium hydroxide solution while stirring well. 200 ml of water are then added and the mixture is extracted with ether. The ether layer is separated off, dried and evaporated in a water jet vacuum. It remains that
I-isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane of the formula
EMI2.5
that after Uml; crystallization from hexane at 78-81 melts. The hydrochloride melts at 107-109 ".
Example 2
26 g of racemic I-isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane and 14.8 g of L- (+) - glutamic acid are dissolved in 50 ml of water at 60-70D.
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 (+) - I-isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane obtained in this way is dissolved in water and the solution is made alkaline by adding 10N sodium hydroxide solution. The (+) - 1-isopropylamino-2-hydroxy-3- (o-allyloxy phenoxy) propane separates out, which, after recrystallization from petroleum ether, melts at 60-62 and has a specific rotation of M 2 # 0.5 ( Ethanol, 0.2%).
The hydrochloride melts at 80-82 and has a specific rotation of [a20D = -13 # = 0.5 # (water. C = 2%).
In an analogous manner, the levorotatory antipode can be separated from racemic -1-isopropylamino-2-hydroxy-3- (o-allyloxy phenoxy) propane with D - (-) - glutamic acid. The
1-1-Isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane hydrochloride melts at 80-82 and has a specific rotation of [a] 20D -. -13 # 0.5 (ethanol, c = 2%).
Example 3
1 g
1- (N-Acetyl-isopropylamino) -2-acetoxy-3 (o-allyloxyphenoxy) -propane is refluxed in 7 ml of absolute alcohol and 3.5 ml of 5N sodium hydroxide solution for 7 hours.
The reaction solution is concentrated in vacuo. The evaporation residue is mixed with water and extracted with ether. After evaporating the dried ether solution, the residue obtained is I-isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane of the formula
EMI3.1
its hydrochloride melts at 107-109.
Example 4
25 ml of 2-n are added to a solution of 5.0 g of 3-isopropyl-5- (o-allyl-oxy-phenoxymethyl) -oxazolidine in 50 ml of ethanol. Hydrochloric acid and heated to 70¯ for one hour. The alcohol is then distilled off and 75 ml of 2N are added to the residue. Caustic soda. An O1 separates out and is extracted with ether. After drying and evaporation of the ether, the I-isopropylamino-2-hydroxy-3- (o-allyloxyphenoxy) propane of the formula remains
EMI3.2
its hydrochloride melts at 107-109.
Claims (1)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH403370A CH489466A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of a new amine |
| CH403270A CH490324A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of a new amine |
| CH1432369A CH489465A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of a new amine |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH962965A CH484172A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of a new oxazolidinone |
| CH1432369A CH489465A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of a new amine |
| CH1432269A CH490405A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of new oxazolidine derivatives |
| CH1585465A CH500216A (en) | 1965-07-09 | 1965-11-17 | 3-Isopropyl 5-phenoxymethyloxazolidines |
| CH1585565A CH512504A (en) | 1965-07-09 | 1965-11-17 | Process for the preparation of new oxazolidin-2-one compounds |
| CH505966A CH507271A (en) | 1965-07-09 | 1966-04-06 | Oxazolidinones inhibiting adrenergic beta-receptors |
| CH667066 | 1966-05-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH489465A true CH489465A (en) | 1970-04-30 |
Family
ID=27561101
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1432369A CH489465A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of a new amine |
| CH403370A CH489466A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of a new amine |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH403370A CH489466A (en) | 1965-07-09 | 1965-07-09 | Process for the preparation of a new amine |
Country Status (1)
| Country | Link |
|---|---|
| CH (2) | CH489465A (en) |
-
1965
- 1965-07-09 CH CH1432369A patent/CH489465A/en not_active IP Right Cessation
- 1965-07-09 CH CH403370A patent/CH489466A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH489466A (en) | 1970-04-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |