DD297404A5 - PROCESS FOR PREPARING A SALT OF THE COMPOUND 4- [3- [ETHYL- (3- (PROPYLSULFINYL) -PROPYL] -AMINO) -2-HYDROXY-PROPOXY] -BENZONITRILE - Google Patents
PROCESS FOR PREPARING A SALT OF THE COMPOUND 4- [3- [ETHYL- (3- (PROPYLSULFINYL) -PROPYL] -AMINO) -2-HYDROXY-PROPOXY] -BENZONITRILE Download PDFInfo
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Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung eines Salzes der Verbindung * das fuer die Verwendung in der Human- und Veterinaermedizin zu antiarrhythmischen Praeparaten verarbeitet werden kann. Die Aufgabe besteht darin, eine Verbindung in Form eines Feststoffes herzustellen. Die Aufgabe wird erfindungsgemaesz dadurch geloest, dasz man die Verbindung * mit Polystyrolsulfonsaeure umsetzt und gegebenenfalls das erhaltene Salz mit wenigstens einem pharmazeutisch vertraeglichen Hilfsstoff zu pharmazeutischen Anwendungsformen verarbeitet.{Polystyrolsulfonat; Humanmedizin; Veterinaermedizin; Salz; Praeparat, antiarrhythmisch; Feststoff; Polystyrolsulfonsaeure; Anwendungsform, pharmazeutisch; Hilfsstoff, vertraeglich; Hilfsstoff, pharmazeutisch}The invention relates to a process for the preparation of a salt of the compound which can be processed for use in human and veterinary medicine for antiarrhythmic preparations. The object is to produce a compound in the form of a solid. The object is achieved according to the invention by reacting the compound with polystyrenesulfonic acid and, if appropriate, processing the salt obtained with at least one pharmaceutically acceptable excipient into pharmaceutical forms of application {polystyrenesulfonate; Human medicine; Veterinary medicine; Salt; Prepart, antiarrhythmic; Solid; polystyrene; Application form, pharmaceutical; Excipient, trusted; Excipient, pharmaceutical}
Description
Anwendungsgebiet der ErfindungField of application of the invention
Das durch das erfindungsgemäße Verfahren hergestellte neue Polystyrolsulfonat kann für die Verwendung in der Humanmedizin und Veterinärmedizin zu antiarrhythmischen Präparaten verarbeitet werden.The novel polystyrenesulfonate prepared by the process of the present invention can be processed into antiarrhythmic preparations for use in human and veterinary medicine.
Charakteristik des bekannten Standes der TechnikCharacteristic of the known state of the art
Die nicht vorveröffentlichte PCT-Anmeldung PCT/SE88/00691 mit Anmeldedatum vom 20. Dezember 1988 betrifft eine Gruppe neuer Verbindungen, die bei der akuten Behandlung oder Langzeitbehandlung von Herzarrhythmien unterschiedlichen Ursprungs brauchbar sind. Unter diesen Verbindungen ist die Verbindung 4-[3-[Ethyl-[3-(propylsulfinyl)-propyl)-amino]-2-hydroxypropoxyj-benzonitril der Formel INon-prepublished PCT application PCT / SE88 / 00691, filed on December 20, 1988, relates to a group of novel compounds useful in the acute treatment or long-term treatment of cardiac arrhythmias of various origins. Among these compounds, the compound is 4- [3- [ethyl- [3- (propylsulfinyl) -propyl) -amino] -2-hydroxypropoxy-benzonitrile of the formula I.
(I)(I)
CNCN
beschrieben, die als ein Stereoisomerengemisch sowie in der Fo«,η der unterschiedlichen Stereoisomeren erhalten werden kann, wie beispielsweise alsdescribed which can be obtained as a stereoisomer mixture and in the Fo «, η the different stereoisomers, such as as
•t-I3-[Ethyl-|3-(propylsulfinyl)-propyll-amin]-2(R)-hydroxypropoxy]-benzonitriloder 4-(3-[Ethyl-[3-(propyisulfinyl)-propyll-amino]-2(S)-hydroxypropoxy]-benzonitril.• t-I3- [ethyl- [3- (propylsulfinyl) -propyl-amine] -2 (R) -hydroxypropoxy] -benzonitrile or 4- (3- [ethyl- [3- (propylsulfinyl) -propyl-amino] -2 (S) -hydroxypropoxy] -benzonitrile.
Das Stereoisomerengeinisch sowie die oben erwähnten reinen Stereoisomeren können durch Oxidieren des 4-[3-[Ethyl-[3-(propylthio)-propyll-amino]-2-hydroxyl-benzoniirils mit m-Chlorperbenzoesäure oder analog den in der oben erwähnten PCT-Anmeldung beschriebenen Methoden erhalten werden.The stereoisomeric ginses and the above-mentioned pure stereoisomers can be prepared by oxidizing the 4- [3- [ethyl- [3- (propylthio) -propyl-amino] -2-hydroxylbenzonitrile with m-chloroperbenzoic acid or analogously to those described in the above-mentioned PCT Registration methods described.
Die Verbindung der Formel I in der Basenform ist ein Öl.The compound of formula I in the base form is an oil.
2IeI der Erfindung2Ie of the invention
Ziel der Erfindung ist die Herstellung einer berser verabreichbaren Verbindung mit antiarrhythmischer Wirkung.The aim of the invention is the preparation of a berser administered compound with antiarrhythmic activity.
Darlegung des Wesens der ErfindungExplanation of the essence of the invention
Die Aufgabe der Erfindung ist ein Verfahren zur Herstellung einer Verbindung mit der gleichen Wirkung gegen Herzarrhythmien v·^ die Verbindung I, jedocn in der Form eines Feststoffes. Diese Verbindung ist ein Salz der Verbindung der Formel I mit Polystyrolsulfonsäure.The object of the invention is a process for the preparation of a compound having the same activity against cardiac arrhythmias, compound I, but in the form of a solid. This compound is a salt of the compound of formula I with polystyrenesulfonic acid.
Gemäß einer Ausführungsform der Erfindung liegt dieses Salz in der Form eines Stereoisomerengemisches vor. Nach einer anderer Ausführungsform liegt es in der Form eines der reinen Stereoisomeren vor. Beispiele hierfür sind folgende:According to one embodiment of the invention, this salt is in the form of a stereoisomeric mixture. In another embodiment, it is in the form of one of the pure stereoisomers. Examples are the following:
4-(3-[Ethyl-[3-((R*)-propylsulfinyl)-propyl]-amino]-2(R)-hydroxypropoxyl-benzonitril, 4-13-[Ethyl-(3-{(S»)-propylsulfinyl)-propyl]-aminol-2(R)-hydroxypropoxyl-benzonitril, 4-[3-[Eihyl-(3-((R*)-propylsulfinyl)-propyll-amino)-2(S)-hydroxypropcxy)-benzonitriloder 4-[3-|Ethyl-(3-((S*)-propylsulfinyl)-prop,yl]-amino]-2(S)-hydroxypropoxy]-ben;onitril.4- (3- [Ethyl- [3 - ((R *) -propylsulfinyl) -propyl] -amino] -2 (R) -hydroxypropoxyl-benzonitrile, 4-13- [ethyl- (3 - {(S)} -propylsulfinyl) -propyl] -aminol-2 (R) -hydroxypropoxyl-benzonitrile, 4- [3- [ethyl] (3 - ((R *) -propylsulfinyl) -propyl-amino) -2 (S) -hydroxypropoxy) benzonitrile or 4- [3- | ethyl- (3 - ((S) -propylsulfinyl) -prop, yl] -amino] -2 (S) -hydroxypropoxy] -benzonitrile.
Die Polystyrolsulfonsäure wird vorzugsweise in der Form kleiner Teilchen verwendet. Gewöhnlich ist die Polystyrolsulfonsäure mit Divinylbenzol vernetzt, wobei der Vernetzungsgrad vorzugsweise 2 bis 10% beträgt.The polystyrene sulfonic acid is preferably used in the form of small particles. Usually, the polystyrenesulfonic acid is crosslinked with divinylbenzene, the degree of crosslinking preferably being from 2 to 10%.
Nach einer Ausführungsform des Verfahrens gemäß der Erfindung werden kleine Teilchen von Polystyrolsulfonsäure, entweder in der Säureform (H+) oder in der Form eines Salzes mit einem Metallion, das für lonenaustauschreaktionen geeignet ist, z.B.According to one embodiment of the method according to the invention, small particles of polystyrenesulphonic acid, either in the acid form (H + ) or in the form of a salt with a metal ion, which is suitable for ion exchange reactions, for example
Ma+, K+ oder Ca2+, zu einer Lösung der Verbindung der Formel I bzw. eines geeigneten Salzes dieser Verbindung in einem geeigneten Reaktionsmedium zugesetzt.Ma + , K + or Ca 2+ , added to a solution of the compound of formula I or of a suitable salt of this compound in a suitable reaction medium.
Nach einer anderen Ausführungsform des Verfahrens der Erfindung werden kleine Teilchen von Polystyrolsulfonsäure in der Form eines Salzes mit einem Metallion, das für lonenaustauschreaktionen geeignet ist, in eine Säule für lonenaustauschbetrieb gepackt, und eine Lösung der Verbindung der Formel I in der Form einges geeigneten Salzes wird auf die Säule aufgegeben.According to another embodiment of the process of the invention, small particles of polystyrenesulphonic acid in the form of a salt with a metal ion suitable for ion exchange reactions are packed in a column for ion exchange operation and a solution of the compound of formula I in the form of a suitable salt abandoned to the pillar.
Das erfindungsgemäß hergestellte Salz eignet sich zur Verhinderung oder Reduzierung von Herzarrhythmien bei Säugetieren einschließlich Menschen, indem man dem Patienten eine wirksame Menge des Salzes der Verbindung der Formel I mit Polystyrolsulfonsäure verabreicht.The salt prepared according to the invention is useful in preventing or reducing cardiac arrhythmias in mammals, including humans, by administering to the patient an effective amount of the salt of the compound of formula I with polystyrene sulfonic acid.
Ausführungsbeispiele Beispiel 1Exemplary embodiments Example 1
Zu einer gerührten Lösung von 4-[3-[Ethyl-[3-(propylsulfinyl)-propyl]-arnino]-2-hydroxypropoxy)-benzonitril (92,28g) in Methanol (900ml) wurde Polystyrolsulfonsäure (63,15g) bei O0C unter einer Stickstoffa'mosphäre zugegeben. Rühren wurde 18h fortgesetzt. Das Harz wurde filtriert, mit Methanol (500ml) ge·/ aschen, in einem Soxhlet-Extraktor bei Raumtemperatur über Nacht mit Ethanol extrahiert und schließlich unter Hochvakuum Κ·3 zu konstantem Gewicht getrocknet. Die Analyse zeigte 59,3% Bindung von aktiver Substanz.To a stirred solution of 4- [3- [ethyl- [3- (propylsulfinyl) -propyl] -arnino] -2-hydroxypropoxy) -benzonitrile (92.28g) in methanol (900ml) was added polystyrene sulfonic acid (63.15g) O 0 C added under a Stickstoffa'mosphäre. Stirring was continued for 18 hours. The resin was filtered, washed with methanol (500 ml), extracted with ethanol in a Soxhlet extractor at room temperature overnight, and finally dried to constant weight under high vacuum. The analysis showed 59.3% binding of active substance.
Polystyrolsulfonat von 4-[3-[Ethyl-[3-(propylsulfinyl)-propyl]-amino]-2-hydroxvpropoxy]-benzonitril Zu einer gerührten Lösung von 4-(3-[Ethyl-[3-(propylsulfinyl)-propyl]-amino]-2-r ydroxypropoxyl-benzonitril · HCI (5,5g) in EthanohWasser (1:1) (30ml) wurde Natriumpolystyrolsulfonat (5g) bei Raumter iperatur zugegeben. Nach 30 min wurde das Harz abfiltriert und mit EthanohWasser (1:1) dreimal gewaschen und unter Hoch\ akuum bis zu konstantem Gewicht getrocknet.Polystyrenesulfonate of 4- [3- [ethyl- [3- (propylsulfinyl) -propyl] -amino] -2-hydroxvpropoxy] -benzonitrile To a stirred solution of 4- (3- [ethyl- [3- (propylsulfinyl) -propyl Sodium polystyrenesulfonate (5g) was added at room temperature, and after 30 min, the resin was filtered off and washed with ethanol (1: 1) (30 g) in ethanolic water (1: 1) : 1) washed three times and dried under high vacuum to constant weight.
Die Analyse zeigte 32% Bindung aktiver Substanz.The analysis showed 32% binding of active substance.
4-[3-[Ethyl-[3-(propylsulfinyl)-prop l]-amino]-2-hydroxypropoxy]-benzonitril 2,45g 4-[3-[Ethyl-[3-(propylthio)-propyl]-amino]-2-hydroxypropoxy]-benzonitril und 1,4g p-Toluolsulfonsäure wurden in 50ml Ethanol miteinander vermischt. Das Gemisch wurde auf -10°C gekühlt, und 1,7 g m-Chlorperbenzoesäure wurden in kleinen Anteilen zugegeben. Das Gemisch wurde 0,5 h bei -10°C und 1 h bei Raumtemperatur gerührt und dann eingedampft. Der4- [3- [Ethyl- [3- (propylsulfinyl) -prop1-amino] -2-hydroxypropoxy] -benzonitrile 2.45 g of 4- [3- [ethyl- [3- (propylthio) -propyl] -amino ] -2-hydroxypropoxy] -benzonitrile and 1.4 g of p-toluenesulfonic acid were mixed together in 50 ml of ethanol. The mixture was cooled to -10 ° C and 1.7 g of m-chloroperbenzoic acid were added in small portions. The mixture was stirred for 0.5 h at -10 ° C and for 1 h at room temperature and then evaporated. The
Rückstand wurde in Dichlormethan gelöst und mit drei Anteilen Natriumcarbonatlösung und zweimal mit Wasser gewaschen und danach über Natriumsulfat getrocknet, filtriert und eingedampft. Der Rückstand, 2,3g eines gelben Öls, wurde durch SäulenchromatograpKo gereinigt. Ausbeute: 1,4g der in der Überschrift angegebenen Verbindung. NMR: 13C in CDCI3:11,21,11,33,13,11,16,02,20,30,20,43,47,41,47,45,49,69,49,95,52,18,52,41,54,29,54,41,56,06,56,09, 66,08, 76, 41, 03, 70, 649,115, 09,118,83, 133,62, 161,88 ppm.The residue was dissolved in dichloromethane and washed with three portions of sodium carbonate solution and twice with water and then dried over sodium sulfate, filtered and evaporated. The residue, 2.3 g of a yellow oil, was purified by column chromatography. Yield: 1.4 g of the title compound. NMR: 13 C in CDCl 3 : 11,21,11,33,13,11,16,02,20,30,20,43,47,41,47,45,49,69,49,95,52, 18, 52, 41, 54, 29, 54, 41, 56, 106, 56, 69, 66, 68, 41, 03, 70, 649, 115, 09, 118, 83, 133, 62, 161, 88, ppm.
4-[3-[Ethyl-[3-(propylsulfinyl)-propyl]-amlno]-2(R)-hydroxypropoxy]-benzonltrll Oxiation'von 4-(3-[Ethyl-[3-(propylthio)-propyll-amino]-2(R)-hydroxypropoxy]-benzonitril mit m-Chlorperbenzoesäure erfolgte wie für das Stereoisomerengemisch im Beispiel 3 beschrieben.4- [3- [Ethyl- [3- (propylsulfinyl) -propyl] -amino] -2 (R) -hydroxypropoxy] -benzonitrile Oxidation of 4- (3- [ethyl- [3- (propylthio) -propyl] amino] -2 (R) -hydroxypropoxy] -benzonitrile with m-chloroperbenzoic acid was carried out as described for the stereoisomer mixture in Example 3.
[a]h°- 18,6°(c= 1,0,CH3OH). [a] h ° - 18.6 ° (c = 1.0, CH 3 OH).
NMR: 13C InCDCI3:11,35,11,47,13,30,16,24,20,47,20,62,47,59,47,63,49,83,50,12,52,30,52,57,54,53,54,66,56,28,56,31,66,13, 70,52,70,60,104,08,115,24,119,02,133,85,162,0ppm.NMR: 13 C InCDCI 3 : 11,35,11,47,13,30,16,24,20,47,20,62,47,59,47,63,49,83,50,12,52,30 , 52.57, 54, 53, 54, 66, 56, 28, 36, 31, 66, 133, 70, 52, 70, 60, 104, 15, 162, 19, 12, 133, 15, 162, ppm ppm.
4-[3-[Ethyl-[3-(propylsulflnyl)-propyl]-amlno]-2(S) hydroxypropoxyl-benzonltril Die in der Überschrift angegebene Verbindung wurde analog zu der im Beispiel 4 und im Beispiel 3 beschriebenen Methode hergestellt. [a)l° + 18,0° (c = 1,0, CH3OH).4- [3- [Ethyl- [3- (propylsulfinyl) -propyl] -amino] -2 (S) -hydroxypropoxyl-benzonitrile The title compound was prepared analogously to the method described in Example 4 and Example 3. [a) l ° + 18.0 ° (c = 1.0, CH 3 OH).
NMR: 13C in CDCI3:11,31,11,43,13,26,16,18,20,41,20,57,47,53,47,58,49,8,50,08,52,26,52,53,54,48,54,61,56,22,56,24,66,09, 70,48,70,57,104,0,115,20,118,97,133,79,161,96ppm.NMR: 13 C in CDCl 3 : 11,31,11,43,13,26,16,18,20,41,20,57,47,53,47,58,49,8,50,08,52, 26,52,53,54,48,54,61,56,22,56,24,66,09, 70,48,70,57,104,0,115,20,118,97,133,79,161.96ppm.
Jedes der gemäß den Beispielen 4 und 5 hergestellten Isomeren kann das Stereoisomerengemisch, das in den Beispielen 1 und verwendet wurde, ersetzen.Each of the isomers prepared according to Examples 4 and 5 can replace the stereoisomeric mixture used in Examples 1 and 5.
Beispiele 4-[3-tEthyl-[3-((S»)-propylsulfinyl)-propyl]-amino]-2(R)-hydroxypropoxy]-benzonitrllExamples 4- [3-ethyl-3 - ((S) -propylsulfinyl) -propyl] amino] -2 (R) -hydroxypropoxy] -benzonitrile
a) Ethyl-(3-(S*)-propylsulfinyl)-propylamina) Ethyl (3- (S *) propylsulfinyl) propylamine
Eine heiße Lösung von 27,2g (0,1 Mol) (-)-1,3,2-Dioxaphosphorinan-5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-2-oxid und 17,73g (0,1 Mol) racemisches Ethyl-(3-propylsulfinyl)-propylamin in 750ml Aceton und 32,5ml Methanol ließ man auf Raumtemperatur abkühlen, was 23,9g kristallines Material ergab. Das Experiment wurde im Maßstab von 0,25 Mol wiederholt, was diesmal 53,0g Kristalle ergab. Die vereinigten Ausbeuten wurden fünfmal aus Aceton-Methanol umkristallisiert, was schließlich 8,95g Salz ergab.A hot solution of 27.2 g (0.1 mol) of (-) - 1,3,2-dioxaphosphorinane-5,5-dimethyl-2-hydroxy-4- (2-methoxyphenyl) -2-oxide and 17.73 g (0.1 mol) of racemic ethyl (3-propylsulfinyl) -propylamine in 750 mL of acetone and 32.5 mL of methanol was allowed to cool to room temperature, yielding 23.9 g of crystalline material. The experiment was repeated on a scale of 0.25 mol, yielding 53.0 g of crystals this time. The combined yields were recrystallized five times from acetone-methanol, which finally gave 8.95 g of salt.
Eine Lösung von 15,06g (0.0392 Mol) Trioctylamin in Dichlormethan wurde mit 19,6 ml 2 M Salzsäure geschüttelt. Die Phasen wurden getrennt, und die organische Schicht wurde mit Wasser gewaschen. Die organische Phase, die nun Trioctylammoniumchlorid enthielt, wurde 90min mit einer Lösung von 8,8g (0,0196 Mol) des oben erwähnten aufgetrennten Salzes in Wasser gerührt. Die Phasen wurden getrennt, und die organische Schicht wurde mit Wasser gewaschen. Die vereinigten wäßrigen Phasen wurden mit Dichlormethan gewaschen und dann mit 10 M Natriumhydroxid auf pH 11,5 gebracht. Viermalige Extraktion mit Dichlormethan ergab 2,3g linksdrehende Aminbase, die willkürlich als S* bezeichnetA solution of 15.06 g (0.0392 mol) trioctylamine in dichloromethane was shaken with 19.6 ml 2 M hydrochloric acid. The phases were separated and the organic layer was washed with water. The organic phase, now containing trioctylammonium chloride, was stirred for 90 minutes with a solution of 8.8 g (0.0196 mol) of the above-mentioned separated salt in water. The phases were separated and the organic layer was washed with water. The combined aqueous layers were washed with dichloromethane and then brought to pH 11.5 with 10 M sodium hydroxide. Extraction four times with dichloromethane gave 2.3 g of levorotatory amine base, which is arbitrarily designated S *
(alä°-8,0° (C = 1,CH3OH).(ala ° -8.0 ° (C = 1, CH 3 OH).
13C NMR (als Salz mit (-)-1,3,2,-Dioxaphosphorinan-5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-2-oxid) in CDCI3:10,80, 12.95,15,81,17,55,19,49,19,58,20,41,36,59,36,61,42,37,45,50,48,73,53,67,54,71,76,79,76,83,77,34,109,63,119,69,126,42, 126,50,128,33,128,93,155,83. 13 C NMR (as a salt with (-) - 1,3,2-dioxaphosphorinane-5,5-dimethyl-2-hydroxy-4- (2-methoxyphenyl) -2-oxide) in CDCl 3 : 10.80, 12.95,15,81,17,55,19,49,19,58,20,41,36,59,36,61,42,37,45,50,48,73,53,67,54,71, 76, 79, 76, 83, 67, 134, 109, 63, 119, 196, 42, 42, 126, 123, 128, 123, 155, 533
b) (R)-4-(Oxiranylmethoxy)-benzonitrilb) (R) -4- (oxiranylmethoxy) benzonitrile
Eine Lösung von 2,71 g (2S)-1-(4-Cyanophenoxy)-3-methansulfonyloxypropan-2-ol in 40ml 1,2-Dimethoxyethan wurde mit 1,0g pulverisiertem Natriumhydroxid bei Raumtemperatur während 22h gerührt. 10ml gesättigte Natriumchloridlösung wurden zugegeben, und das Gemisch wurde zweimal mit Ether extrahiert. Waschen mit 5%iger Natriumhydrogencarbonatlösung, Trocknen über Magnesiumsulfat, Filtration und Eindampfen ergaben 1,76g kristallines Material, F. = 67,5°C, laß0 - 14,7° (c = 1, Aceton)A solution of 2.71 g of (2S) -1- (4-cyanophenoxy) -3-methanesulfonyloxypropan-2-ol in 40 ml of 1,2-dimethoxyethane was stirred with 1.0 g of powdered sodium hydroxide at room temperature for 22 hours. 10 ml of saturated sodium chloride solution was added and the mixture was extracted twice with ether. Washing with 5% sodium bicarbonate, drying over magnesium sulfate, filtration and evaporation gave 1.76 g crystalline material, mp = 67.5 ° C, let 0 to 14.7 ° (c = 1, acetone)
NMR:'3C in CDCI3:44,40,49,71,69,02,104,59,115,34,118,95,133,98,161,66ppm.NMR: ' 3 C in CDCl 3 : 44, 40, 49, 71, 69, 102, 104, 59, 15, 34, 18, 95, 133, 98, 161, 66 ppm.
c) 4-|3-[Ethyl-[3-((S*)-propylsulfinyl)-propyl]-amino]-2(R)-hydroxypropoxy]-benzonitrilc) 4- | 3- [Ethyl- [3 - ((S *) -propylsulfinyl) -propyl] -amino] -2 (R) -hydroxypropoxy] -benzonitrile
Ein Gemisch von 3g Ethyl-(3-(S**-propylsulfinyl)-propylamin und 3,18g (R)-4-(Oxiranylmethoxy)-benzonitril wurden 16h in 25ml Isopropylalkohol unter Rückfluß erhitzt. Nach Verdampfen des Lösungsmittels wurde das Rohprodukt in 2 M Salzsäure gelöst, mit Ether gewaschen, die Lösung wurde mit 2 M Natronlauge auf pH 11,5 gebracht und mit Dichlormethan extrahiert.A mixture of 3 g of ethyl (3- (S-propylsulfinyl) -propylamine and 3.18 g of (R) -4- (oxiranylmethoxy) -benzonitrile was refluxed in 25 mL of isopropyl alcohol for 16 h After evaporating the solvent, the crude product was dissolved in Dissolved 2 M hydrochloric acid, washed with ether, the solution was brought to pH 11.5 with 2 M sodium hydroxide solution and extracted with dichloromethane.
Eindampfen der organischen Phase ergab 6,11 g eines Öls.Evaporation of the organic phase gave 6.11 g of an oil.
13C NMR in CDCI3: 11,23,13,17,16,08,20,46,47,41,49,98,52,41,54,46,56,11,66,05,70,50,103,80,115,13,118,92,133,69, 161,92ppm. 13 C NMR in CDCl 3 : 11,23,13,17,16,08,20,46,47,41,49,98,52,41,54,46,56,11,66,05,70,50,103 , 80,115,13,118.92, 133.69, 161.92 ppm.
4-[3-[Ethyl-[3-((R*)-propylsulfinyl)-propyl]-arnino]-2(S)-hydroxypropoxy]-benzonitril a) Ethyl-(3-(R*)-propylsulfinyl)-propylamin4- [3- [Ethyl- [3 - ((R *) - propylsulfinyl) -propyl] -arnino] -2 (S) -hydroxypropoxy] -benzonitrile a) Ethyl- (3- (R *) -propylsulfinyl) - propylamine
Auftrennung von racemischem Ethyl-(3-propylsulfinyl)-propylamin mit (+)-1,3,2-Dioxaphosphorinan-5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-2-oxid analog dem Beispiel 1 a ergab rechtsdrehende Aminbase. Diese Verbindung, die willkürlich als R* bezeichnet wird, hat die folgenden physikalischen Kennwerte:Separation of racemic ethyl (3-propylsulfinyl) propylamine with (+) - 1,3,2-dioxaphosphorinane-5,5-dimethyl-2-hydroxy-4- (2-methoxyphenyl) -2-oxide analogously to Example 1 a gave dextrorotatory amine base. This compound, which is arbitrarily designated as R *, has the following physical characteristics:
[aß0 + 7,6° (c= 1,CH3OH).[ate 0 + 7.6 ° (c = 1, CH 3 OH).
'3C NMR (als Salz mit (+J-1,3,2,-Dioxaphosphorinan-5,5-dimethyl-2-hydroxy-4-(2-Tiethoxyphenyl)-2-oxid) in CDCI3:10,92, 13,07,15,93,17,66,1956,19,70,20,52,36,72,36,73,42,48,45,61,48,85,53,79,54,82,76,92,76,96,77,45,77,49,109,73,119,81, 126,54,126,62,128,44,129,06,155,95.' 3 C NMR (as a salt with (+ J-1,3,2-dioxaphosphorinane-5,5-dimethyl-2-hydroxy-4- (2-tiethoxyphenyl) -2-oxide) in CDCl 3 : 10.92 , 13,07,15,93,17,66,1956,19,70,20,52,36,72,36,73,42,48,45,61,48,85,53,79,54,82 , 76,92,76,96,77,45,77,49,109,73,119,81, 126,54,126,62,128,44,129,06,155,95.
b) (S)-4-(Oxiranylmethoxy)-benzonitrilb) (S) -4- (oxiranylmethoxy) benzonitrile
Aus 2,7g(2R)-1-(4-Cyanophenoxy)-3-methansulfonyloxypropan-2-ol analog zu Beispiel 1b wurden 1,75g kristallines Material erhalten, F. = 68,O0C, Ia)I0 + 14,5° (c = 1, Aceton).From 2.7 g of (2R) -1- (4-cyanophenoxy) -3-methanesulfonyloxypropan-2-ol analogously to Example 1b, 1.75 g of crystalline material were obtained, mp = 68, O 0 C, Ia) I 0 +14 , 5 ° (c = 1, acetone).
'3C NMR in CDCI3: 44,21,49,58, 68,90,104,25,115,20,118,86,133,80,161,53.' 3 C NMR in CDCl 3 : 44,21,49,58, 68,90,104,25,115,20,118,86,133,80,161,53.
c) 4-I3-lEthyl-[3-((R*)-propylsulfinyl)-propyll-amino]-2 (S)-hydroxypropoxy]-benzonitrilc) 4-I3-Ethyl [3 - ((R *) -propylsulfinyl) -propyl-amino] -2 (S) -hydroxypropoxy] -benzonitrile
Ein Gemisch von 2,3g Ethy!-(3-(R*)-propylsulfinyl)-propylam!n und 3,18g (S)-4-(Oxiranylmethoxy)-benzonitril in 19ml Isopropylalkohol wurde 16h unter Rückfluß erhitzt und danach analog dem Beispiel 1 c aufgearbeitet, was 4,1 g eines Öls ergab. [a]§° + 26,5° (c = 1, CH3OH).A mixture of 2.3 g of ethyl- (3- (R *) -propylsulfinyl) -propylam- nium and 3.18 g of (S) -4- (oxiranylmethoxy) -benzonitrile in 19 ml of isopropyl alcohol was refluxed for 16 hours and then heated analogously to Example 1c worked up, giving 4.1 g of an oil. [a] § ° + 26.5 ° (c = 1, CH 3 OH).
13C NMR in CDCI3:11,16,13,05,15,96, 20,37,47,38,49,87, 52,37, 54,31, 56,05, 66,10,70,47,103,65,115,06,118,78,133,55, 13 C NMR in CDCl 3 : 11,16,13,05,15,96, 20,37,47,38,49,87, 52,37, 54,31, 56,05, 66,10,70,47,103 , 65,115,06,118,78,133,55,
4-[3-[Ethyl-[3-((R*)-propylsulf)nyl)-propyl]-amino]-2(R)-hydroxypropoxy]-benzonitril Ein Gemisch von 2,3g Ethyl-[(R*)-3-propylsulfinyl]-propylamin und 2,5g (R)-4-(Oxyranylmethoxy)-benzonitri! wurde 16h in4- [3- [Ethyl- [3 - ((R *) -propylsulfonyl) -propyl] -amino] -2 (R) -hydroxypropoxy] -benzonitrile A mixture of 2.3 g of ethyl - [(R *) 3-propylsulfinyl] -propylamine and 2,5g (R) -4- (oxyranylmethoxy) -benzonitrile! was in 16h
19ml Isopropylalkohol analog Beispiel 1 c unter Rückfluß erhitzt. Übliche Aufarbeitung ergab 4,27g eines Öls, [a]jj0 - 13,4° (C = 1,CH3OH).19 ml of isopropyl alcohol as in Example 1 c heated under reflux. Usual work-up gave 4,27g of an oil, [a] jj 0 to 13.4 ° (C = 1, CH 3 OH).
13C NMR in CDCI3:11,58,13,36,16,29, 20,57,47,70,49,96, 52,41,54,64, 56,36,66,24,70,63,104,18,115,33,119,07,133,91,162,09. 13 C NMR in CDCl 3 : 11.58, 13.36, 16.29, 20.57, 47, 70, 49, 96, 52, 41, 54, 64, 56, 36, 66, 24, 70, 63, 104 , 18,115,33,119,07,133,91,162,09.
Ein Gemisch von 2,3g Ethyl-[3-(S*)-propylsulfinyl)-propylamin und 2,5 (S)-4-(Oxiranylmethoxy)-benzonitril in 19mlA mixture of 2.3 g of ethyl [3- (S *) -propylsulfinyl) -propylamine and 2,5 (S) -4- (oxiranylmethoxy) -benzonitrile in 19 ml
Isopropylalkohol wurde 24 h analog zu Beispiel 1 c unter Rückfluß erhitzt. Übliches Aufarbeiten ergab 3,65g eines Öls, [a]g0 +11,1° Ic= 1,CH3OH).Isopropyl alcohol was refluxed for 24 h analogously to Example 1c. Typical work up gave 3.65 g of an oil, [a] g 0 + 11.1 ° Ic = 1, CH 3 OH).
13C NMR in CDCI3: 11 ,BP 13,33,16,25, 20,54,47,71,49,92, 52,42,54,53,56,31,66,33,70,64,104,03,115,33,119,06,133,86,162,11. 13 C NMR in CDCI 3: 11, BP 13,33,16,25, 20,54,47,71,49,92, 52,42,54,53,56,31,66,33,70,64,104, 03,115,33,119,06,133,86,162,11.
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8902235A SE8902235D0 (en) | 1989-06-20 | 1989-06-20 | NOVEL CYCLODEXTRIN INCLUSION COMPLEXES |
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| DD297404A5 true DD297404A5 (en) | 1992-01-09 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD90341729A DD297404A5 (en) | 1989-06-20 | 1990-06-16 | PROCESS FOR PREPARING A SALT OF THE COMPOUND 4- [3- [ETHYL- (3- (PROPYLSULFINYL) -PROPYL] -AMINO) -2-HYDROXY-PROPOXY] -BENZONITRILE |
Country Status (15)
| Country | Link |
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| EP (1) | EP0478677A1 (en) |
| JP (1) | JPH04506212A (en) |
| KR (1) | KR920702674A (en) |
| AU (1) | AU641670B2 (en) |
| CA (1) | CA2058996A1 (en) |
| DD (1) | DD297404A5 (en) |
| FI (1) | FI915935A7 (en) |
| GR (1) | GR1000747B (en) |
| HU (1) | HUT59085A (en) |
| IE (1) | IE902162A1 (en) |
| LT (1) | LTIP1725A (en) |
| LV (1) | LV10249A (en) |
| PT (1) | PT94415A (en) |
| SE (1) | SE8902235D0 (en) |
| WO (1) | WO1990015792A1 (en) |
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| SE8902236D0 (en) * | 1989-06-20 | 1989-06-20 | Haessle Ab | NOVEL POLYSTYRENESULPHONATE |
| DE4207922A1 (en) * | 1992-03-13 | 1993-09-23 | Pharmatech Gmbh | New water-soluble inclusion complexes contg randomly substd. methyl-beta-cyclodextrin - for admin. of substances which are only sparingly soluble in water |
| DE4227569C1 (en) * | 1992-08-20 | 1994-06-09 | Inst Chemo Biosensorik | Enzymatic determn. of inorganic phosphate - using combination of di:saccharide phosphorylase, phosphatase or maltose synthase, and glucose oxido-reductase |
| US7141555B2 (en) * | 2000-12-19 | 2006-11-28 | Cephalon, Inc. | Modafinil compound and cyclodextrin mixtures |
| TWI373473B (en) * | 2005-09-02 | 2012-10-01 | Otsuka Pharma Co Ltd | Anticancer agent |
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| GB1457876A (en) * | 1972-12-15 | 1976-12-08 | Ici Ltd | Alkanolamine derivatives device for use in |
| GB1433920A (en) * | 1973-10-01 | 1976-04-28 | Ici Ltd | Alkanolamine derivatives |
| HU177081B (en) * | 1978-12-12 | 1981-07-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing the occlusion complex of allicin with cyclodextrin |
| HU181703B (en) * | 1980-05-09 | 1983-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing aqueus solutuins of water insoluble or hardly soluble vitamines, steroides, localanesthetics, prostanoides and non-steroid and antiphlogistic agents |
| JPS5718602A (en) * | 1980-05-28 | 1982-01-30 | Hokko Chem Ind Co Ltd | Herbicide |
| EP0094157B1 (en) * | 1982-04-30 | 1987-07-29 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its use |
| GB8506792D0 (en) * | 1985-03-15 | 1985-04-17 | Janssen Pharmaceutica Nv | Derivatives of y-cyclodextrin |
| SE8705150D0 (en) * | 1987-12-23 | 1987-12-23 | Haessle Ab | NOVEL ANTIARRHYTHMIC AGENTS |
| SE8902236D0 (en) * | 1989-06-20 | 1989-06-20 | Haessle Ab | NOVEL POLYSTYRENESULPHONATE |
| SE8902237D0 (en) * | 1989-06-20 | 1989-06-20 | Haessle Ab | NOVEL STEREOISOMERS |
-
1989
- 1989-06-20 SE SE8902235A patent/SE8902235D0/en unknown
-
1990
- 1990-06-15 IE IE216290A patent/IE902162A1/en unknown
- 1990-06-16 DD DD90341729A patent/DD297404A5/en not_active IP Right Cessation
- 1990-06-18 GR GR900100458A patent/GR1000747B/en unknown
- 1990-06-19 EP EP90910159A patent/EP0478677A1/en not_active Ceased
- 1990-06-19 HU HU905542A patent/HUT59085A/en unknown
- 1990-06-19 CA CA002058996A patent/CA2058996A1/en not_active Abandoned
- 1990-06-19 JP JP2509477A patent/JPH04506212A/en active Pending
- 1990-06-19 KR KR1019910701912A patent/KR920702674A/en not_active Withdrawn
- 1990-06-19 FI FI915935A patent/FI915935A7/en not_active Application Discontinuation
- 1990-06-19 WO PCT/SE1990/000436 patent/WO1990015792A1/en not_active Ceased
- 1990-06-19 PT PT94415A patent/PT94415A/en not_active Application Discontinuation
- 1990-06-19 AU AU59374/90A patent/AU641670B2/en not_active Ceased
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1993
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Also Published As
| Publication number | Publication date |
|---|---|
| AU641670B2 (en) | 1993-09-30 |
| GR1000747B (en) | 1992-12-30 |
| WO1990015792A1 (en) | 1990-12-27 |
| LTIP1725A (en) | 1995-07-25 |
| JPH04506212A (en) | 1992-10-29 |
| HU905542D0 (en) | 1992-03-30 |
| FI915935A0 (en) | 1991-12-17 |
| HUT59085A (en) | 1992-04-28 |
| PT94415A (en) | 1991-02-08 |
| CA2058996A1 (en) | 1990-12-21 |
| FI915935A7 (en) | 1991-12-17 |
| LV10249A (en) | 1994-10-20 |
| EP0478677A1 (en) | 1992-04-08 |
| AU5937490A (en) | 1991-01-08 |
| GR900100458A (en) | 1991-11-15 |
| IE902162L (en) | 1990-12-20 |
| SE8902235D0 (en) | 1989-06-20 |
| IE902162A1 (en) | 1991-01-02 |
| KR920702674A (en) | 1992-10-06 |
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