DE931828C - Process for the preparation of ethylene diamine derivatives - Google Patents
Process for the preparation of ethylene diamine derivativesInfo
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- DE931828C DE931828C DEP20695D DEP0020695D DE931828C DE 931828 C DE931828 C DE 931828C DE P20695 D DEP20695 D DE P20695D DE P0020695 D DEP0020695 D DE P0020695D DE 931828 C DE931828 C DE 931828C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
Verfahren zur Herstellung von Äthylendiaminderivaten N-(2-Pyridyl)-N-benzyl-N', N'-dimethyl-äthylendiamine, welche in der p-Stellung des Benzylrestes durch Halogen substituiert sind, sind bisher nicht bekanntgeworden. Vorliegende Erfindung betrifft nun die Herstellung dieser Verbindungen sowie ihrer Salze und quaternären Ammoniumverbindungen. Die erfindungsgemäß herstellbaren neuen Verbindungen entsprechen der allgemeinen Formel worin R den 2-Pyridylrest und Halogen ein Fluor-, Chlor- oder Bromatom bedeutet. Äthylendiaminderivate sind bereits in großer Zahl bekannt. Derivate des N-Benzyl-N', N'-dimethyläthylendiamins, welche denjenigen der vorliegenden Erfindung konstitutionell nahestehen, sind ebenfalls bekannt. Von ihnen wurden als synthetische Antihistamine in die Therapie eingeführt und sind im Handel: N-(2-Pyridyl)-N-(p-methoxybenzyl)-N',N'-dimethyl-äthylendiamin und N-(2-Pyridyl)-N-benzyl-N', N'-dimethyl-äthylendiamin. Es ist außerdem für N-Benzyl-N', N'-dialkyl-äthylendiaminverbindungen bekannt, daß die Substitution des Benzylrests durch Alkyl- oder Alkoxygruppen im allgemeinen die Antihistaminaktivität solcher Verbindungen herabsetzt, zum Teil sogar aufhebt. Eine Ausnahme von dieser Regel bilden nur einige p-Methoxysubstitutionsprodukte.Process for the preparation of ethylenediamine derivatives N- (2-pyridyl) -N-benzyl-N ', N'-dimethyl-ethylenediamines, which are substituted by halogen in the p-position of the benzyl radical, have not yet become known. The present invention now relates to the preparation of these compounds and their salts and quaternary ammonium compounds. The new compounds which can be prepared according to the invention correspond to the general formula wherein R is the 2-pyridyl radical and halogen is a fluorine, chlorine or bromine atom. Ethylenediamine derivatives are already known in large numbers. Derivatives of N-benzyl-N ', N'-dimethylethylenediamine which are constitutionally similar to those of the present invention are also known. They were introduced into therapy as synthetic antihistamines and are commercially available: N- (2-pyridyl) -N- (p-methoxybenzyl) -N ', N'-dimethyl-ethylenediamine and N- (2-pyridyl) -N -benzyl-N ', N'-dimethyl-ethylenediamine. It is also known for N-benzyl-N ', N'-dialkyl-ethylenediamine compounds that the substitution of the benzyl radical by alkyl or alkoxy groups generally reduces the antihistamine activity of such compounds, in some cases even abolishes it. Only some p-methoxy substitution products are an exception to this rule.
Wie nun gefunden wurde, setzt auch Substitution des Benzylrests durch Chlor in o- oder in m-Stellung die Wirksamkeit herab und erhöht teilweise die Toxizität der Verbindungen, selbst dann, wenn gleichzeitig die p-Stellung des Benzylrests durch Chlor substituiert ist.As has now been found, the benzyl radical is also substituted Chlorine in the o or m position the effectiveness decreases and increases partly the toxicity of the compounds, even if the p-position is at the same time of the benzyl radical is substituted by chlorine.
Es konnte deshalb nicht vorausgesehen werden und ist überraschend, daß im Benzylrest in 4-Stellung durch Halogen substituierte Äthylendiaminderivate gemäß obiger Formel, insbesondere die p-Chlorverbindung, im Gegensatz zu anderen Substitutionsprodukten eine größere therapeutische Breite (errechnet aus dem Verhältnis Toxizität zu Antihistaminaktivität) aufweisen als die entsprechenden nichtsubstituierten Grundkörper. Dieser Effekt kann durch Steigerung der Antihistaminaktivität, durch Verminderung der Toxizität oder durch ein Zusammenwirken beider Faktoren zustande kommen. Es ist klar, daß die Vergrößerung der therapeutischen Breite einen wesentlichen Vorteil für die therapeutische Verwendung bedeutet.It could therefore not be foreseen and is surprising that in the benzyl radical in the 4-position by halogen substituted ethylene diamine derivatives according to the above formula, in particular the p-chloro compound, in contrast to others Substitution products have a greater therapeutic range (calculated from the ratio Toxicity to antihistamine activity) than the corresponding unsubstituted Base body. This effect can be achieved by increasing antihistamine activity Reduced toxicity or a combination of both factors come. It is clear that the broadening of the therapeutic index is an essential factor Means advantage for therapeutic use.
Im folgenden sei die spasmolytische Wirkung gegen Histamin am überlebenden
Meerschweinchendarm, die Toxizität und die daraus errechnete therapeutische Breite
einer Verbindung nach vorliegender Erfindung mit den entsprechenden Daten der analogen
chlorfreien Verbindung verglichen:
Die Umsetzung des Amins der Formel (I), -seines ß-Dimethylamino-äthyl-substitutionsprodukts oder seines p-Halogen-benzylderivats mit einem reaktionsfähigen Ester des ß-Dimethylamino-äthanols bzw. eines p-Halogen-benzylalkohols erfolgt unter Austritt einer Säure. Obwohl das Produkt selbst mindestens eine basische Gruppe aufweist, kann es zur Beschleunigung der Reaktion oder zur Ermöglichung einer niedrigeren Reaktionstemperatur erwünscht sein, säurebindende Mittel zuzusetzen. Ein Überschuß eines der basischen Reaktionspartner kann dazu benutzt werden, doch können auch andere organische oder anorganische Basen verwendet werden, wie Pyridin, Chinolin, Dimethyl und Diäthylanilin, Trimethylamin, Triäthanolamin, Pottasche, Sodä u. dgl. Es ist jedoch vorzuziehen, das zu ersetzende Wasserstoffatom vor oder während der Reaktion gegen ein Metallatom zu vertauschen, was durch Einwirkung von Natriumamid, Lithiumamid, Natrium oder Kalium u. dgl. bewirkt werden kann. Im Falle der Amine der Formel kann das stickstoffständige Wasserstoffatom auch durch die Gruppe -MB-Halogen ersetzt werden, indem die Amine mit einer Grignardverbindung umgesetzt werden. Als Grignardverbindung läßt sich in den meisten Fällen mit gutem Erfolg das leicht zugängliche Äthyl-Magnesium-bromid verwenden, doch können beliebige andere Grignardverbindungen ebenfalls benutzt werden.The reaction of the amine of formula (I), its ß-dimethylamino-ethyl substitution product or its p-halo-benzyl derivative with a reactive ester of ß-dimethylamino-ethanol or a p-halo-benzyl alcohol takes place with the escape of an acid. Although the product itself has at least one basic group, it may be desirable to add acid-binding agents to accelerate the reaction or to enable a lower reaction temperature. An excess of one of the basic reactants can be used, but other organic or inorganic bases can also be used, such as pyridine, quinoline, dimethyl and diethylaniline, trimethylamine, triethanolamine, potash, soda, and the like. However, it is preferable to replace that To exchange hydrogen atom for a metal atom before or during the reaction, which can be effected by the action of sodium amide, lithium amide, sodium or potassium and the like. In the case of the amines of the formula the nitrogen atom can also be replaced by the group -MB-halogen by reacting the amines with a Grignard compound. The readily available ethyl magnesium bromide can in most cases be used as the Grignard compound with good success, but any other desired Grignard compounds can also be used.
Falls @ die Einführung des p-Halogenbenzylrestes in das Amin der Formel (I) zuerst vorgenommen wird, kann sie auch durch reduktive Kondensation des Amins R - N H2 mit einem p-Halogen-benzaldehyd oder einer diesen Aldehyd leicht abgebenden Verbindung, wie der Natriumbisulfitverbindung, erfolgen. Als Reduktionsmittel eignet sich z. B. katalytisch erregter Wasserstoff oder amalgamiertes Aluminium. Vorteilhaft ist auch die Verwendung von Ameisensäure als Reduktionsmittel, weil sich damit der Gebrauch von Kondensations- oder Lösungsmitteln erübrigt.If @ the introduction of the p-halobenzyl radical into the amine of the formula (I) is done first, it can also be done by reductive condensation of the amine R - N H2 with a p-halobenzaldehyde or an aldehyde that readily releases this aldehyde Compound, such as the sodium bisulfite compound. As a reducing agent is suitable e.g. B. catalytically excited hydrogen or amalgamated aluminum. The use of formic acid as a reducing agent is also advantageous because This eliminates the need to use condensation agents or solvents.
Einige der Möglichkeiten, welche sich aus diesem allgemeinen Verfahren
ergeben, seien nachstehend aufgezählt: a) Umsetzung eines Diamins der Formel
mit einem reaktionsfähigen Ester eines p-Halogenbenzylalkohols
Y =Cl, Br, J, Aryl-S02-O-, Alkyl-S02-O-od. dgl. b) Umsetzung eines Diamins der Formel
(II) mit einem p-Halogen-benzaldehyd bei Gegenwart eines Reduktionsmittels
Die erhaltenen neuen Äthylendiaminderivate sind stark basische Flüssigkeiten, die in Wasser praktisch unlöslich sind. Sie bilden mit anorganischen und mit organischen Säuren, welche für die Herstellung von Salzen für die therapeutische Verwendung üblicherweise benutzt werden, wie z. B. . mit Salzsäure, Schwefelsäure, Bromwasserstoffsäure, Phosphorsäure, Essigsäure, Citronensäure, Milchsäure, Apfelsäure, Schleimsäure, Bernsteinsäure, Maleinsäure, Methansulfonsäure, Äthandisulfonsäure, in Wasser lösliche Salze, die zum Teil gutes Kristallisationsvermögen besitzen. Außerdem bilden sie durch Anlagerung von reaktionsfähigen Estern von aliphatischen und araliphatischen Alkoholen, wie Alkylchloriden, -bromiden und -jodiden, Dialkylsulfaten oder Aralkylchloriden, -bromiden und -jodiden, z. B. Äthylbromid, Allylbromid, Dimethylsulfat oder Benzylchlorid, quaternäre Ammoniumsalze, die leicht wasserlöslich sind.The new ethylenediamine derivatives obtained are strongly basic liquids, which are practically insoluble in water. They form with inorganic and with organic Acids used in the manufacture of salts for therapeutic use commonly used, such as. B. with hydrochloric acid, sulfuric acid, hydrobromic acid, Phosphoric acid, acetic acid, citric acid, lactic acid, malic acid, mucic acid, Succinic acid, maleic acid, methanesulphonic acid, ethane disulphonic acid, soluble in water Salts, some of which have a good ability to crystallize. They also educate through addition of reactive esters of aliphatic and araliphatic Alcohols, such as alkyl chlorides, bromides and iodides, dialkyl sulfates or aralkyl chlorides, bromides and iodides, e.g. B. ethyl bromide, allyl bromide, dimethyl sulfate or benzyl chloride, quaternary ammonium salts that are easily soluble in water.
Einige der genannten Verfahren seien in den nachstehenden Beispielen ausführlich beschrieben. Teile bedeuten immer Gewichtsteile, Temperaturangaben Celsiusgrade. Unter verdünnten Säuren und Laugen sind etwa i- bis 2-normale Lösungen zu verstehen. Beispiel = Zu einer Lösung von z6,5 Teilen 2-(ß-Dimethylamino-äthylamino)-pyridin in 75 Teilen Toluol wird eine Suspension von q. Teilen gepulvertem Natriumamid in io Teilen Toluol zufließen gelassen. Das Gemisch wird unter gutem Rühren bis zum Aufhören der Ammoniakentwicklung (2 bis 3 Stunden) unter Rückfluß zum Sieden erhitzt und dann auf ungefähr q.0° abgekühlt. Unter weiterem Rühren werden x6,5 Teile p-Chlor-benzylchlorid zutropfen gelassen, worauf wieder erwärmt und 15 Stunden bei iio bis i2o° Badtemperatur gerührt wird. Nach dem Abkühlen wird das Reaktionsgemisch zuerst mit Wasser gewaschen, hernach die abgetrennte Toluolschicht mit verdünnter Salzsäure ausgeschüttelt, der salzsaure wäßrige Auszug mit gesättigter Sodalösung oder 30%iger Natronlauge stark alkalisch gestellt und die ausgeschiedene Base in Äther aufgenommen. Nach Trocknen der ätherischen Lösung mit wasserfreiem Natriumsulfat und Abdampfen des Lösungsmittels wird das erhaltene braune basische Öl im Vakuum bei o,2 mm Druck fraktioniert; aus der Fraktion von 15o bis 16o° erhält man durch nochmalige Destillation 2o bis 25 Teile N, N-Dimethyl-N'- (p-chlor-benzyl)-N'-(2-pyridyl)-äthylendiamin vom Siedepunkt 154 bis i55° bei o,2 mm Druck als blaßgelbliches, viskoses Öl. Das Pikrat schmilzt bei i88 bis igo° und das Hydrochlorid, ein weißes Kristallpulver, das in Wasser gut löslich ist, bei i72 bis i74°.Some of the processes mentioned are described in detail in the examples below. Parts always mean parts by weight, temperatures are degrees Celsius. Dilute acids and alkalis are roughly 1 to 2 normal solutions. Example = A suspension of q. Parts of powdered sodium amide in 10 parts of toluene are allowed to flow in. The mixture is refluxed with vigorous stirring until the evolution of ammonia ceases (2 to 3 hours) and then cooled to approximately 0 °. With further stirring, x6.5 parts of p-chloro-benzyl chloride are added dropwise, whereupon the mixture is heated again and stirred for 15 hours at a bath temperature of 110 ° to 120 °. After cooling, the reaction mixture is first washed with water, then the separated toluene layer is shaken out with dilute hydrochloric acid, the hydrochloric acid aqueous extract is made strongly alkaline with saturated sodium carbonate solution or 30% sodium hydroxide solution and the base which has precipitated is taken up in ether. After drying the essential solution with anhydrous sodium sulfate and evaporation of the solvent, the brown basic oil obtained is fractionated in vacuo at 0.2 mm pressure; From the fraction from 150 to 16o °, 20 to 25 parts of N, N-dimethyl-N'- (p-chloro-benzyl) -N '- (2-pyridyl) -ethylenediamine with a boiling point of 154 to 155 ° are obtained by repeated distillation at 0.2 mm pressure as a pale yellowish, viscous oil. The picrate melts at 188 to igo ° and the hydrochloride, a white crystal powder which is readily soluble in water, at 172 to 174 °.
Durch Erwärmen der Base mit überschüssigem Methyljodid erhält man das jodmethylat als fast farblose Kristalle, die leicht wasserlöslich sind.Warming the base with excess methyl iodide gives the iodine methylate as almost colorless crystals that are easily soluble in water.
Beispiel e 15,8 Teile 2-Brompyridin, 21,3 Teile N, N-Dimethyl-N'-(p-chlor-benzyl)-äthylendiamin (dargestellt durch Kochen einer alkoholischen Lösung von 2 Mol p-Chlorbenzylamin mit i Mol Dimethylarnino-äthylchlorid) und 8 Teile wasserfreies Pyridin werden in geschlossenem Gefäß io Stunden auf 16o° erwärmt. Nach dem Abkühlen wird das Reaktionsgemisch in überschüssiger verdünnter Salzsäure kalt gelöst, Neutralteile werden mit Äther ausgeschüttelt, die salzsaure wäßrige Lösung wird mit verdünnter Natronlauge stark alkalisch gestellt, das ausgeschiedene basische Öl abgetrennt, über gepulvertem Kaliumhydroxyd getrocknet und im Vakuum fraktioniert destilliert; nach 2 bis 3 Destillationen erhält man io bis 15 Teile eines blaßgelben Öls, das mit dem im Beispiel i erhaltenen N, N-Dimethyl-N'- (p-chlor-benzyl) - N'-(2-pyridyl)-äthylendiamin identisch ist. Beispiel 3 Man ersetzt im Beispiel i das p-Chlorbenzylchlorid durch 25 Teile p-Brombenzylbromid, läßt dieses bei ungefähr 4o° unter Kühlen zutropfen und erwärmt nach Abklingen der stark exothermen Reaktion noch i Stunde am Dämpfbad. Nach analoger Aufarbeitung erhält man das N, N-Dimethyl-N'-(p-brombenzyl)-N'-(2-pyridyl)-äthylendiamin als hellgelbes, leicht viskoses Öl vom Siedepunkt i62° bei o,i mm Druck. Das Hydrochlörid, ein weißes Kristallpulver, schmilzt bei 187 bis i88°.Example e 15.8 parts of 2-bromopyridine, 21.3 parts of N, N-dimethyl-N '- (p-chloro-benzyl) -ethylenediamine (prepared by boiling an alcoholic solution of 2 moles of p-chlorobenzylamine with 1 mole of dimethylamino-ethyl chloride) and 8 parts of anhydrous pyridine are heated to 160 ° for 10 hours in a closed vessel. After cooling, the reaction mixture is dissolved cold in excess dilute hydrochloric acid, neutral parts are extracted with ether, the hydrochloric acid aqueous solution is made strongly alkaline with dilute sodium hydroxide solution, the precipitated basic oil is separated off, dried over powdered potassium hydroxide and fractionally distilled in vacuo; After 2 to 3 distillations, 10 to 15 parts of a pale yellow oil are obtained which are identical to the N, N-dimethyl-N'- (p-chloro-benzyl) -N '- (2-pyridyl) -ethylenediamine obtained in Example i is. Example 3 In Example i, the p-chlorobenzyl chloride is replaced by 25 parts of p-bromobenzyl bromide, this is allowed to drop in at about 40 ° with cooling and, after the strongly exothermic reaction has subsided, the mixture is heated for an hour in the steam bath. After a similar work-up, the N, N-dimethyl-N '- (p-bromobenzyl) -N' - (2-pyridyl) ethylenediamine is obtained as a pale yellow, slightly viscous oil with a boiling point of 162 ° at 0.1 mm pressure. The hydrochloride, a white crystal powder, melts at 187 to 188 degrees.
Nach den in den vorausgegangenen Beispielen beschriebenen und den in der Beschreibung genannten Verfahren kann außerdem folgende Verbindung hergestellt werden: N, N-Dimethyl-N'- (p-fluor-benzyl)-N'-(2-pyridyl)-äthylendiamin Beispiel 4 22 Teile 2-(p-Chlor-benzyl-amino)-pyridin, dargestellt durch reduktive Kondensation von 2-Aminopyridin mit p-Chlorbenzaldehyd mittels g5 °/oiger Ameisensäure, 4 Teile Natriumamid und 8o Teile absolutes Benzol werden 3 Stunden am Rückfluß gekocht, dann wird unter Rühren eine Lösung von 12 Teilen ß-Dimethylamino-äthylchlorid in 25 Teilen Benzol zugetropft und i2 Stunden unter Rühren am Rückfluß weitergekocht.The following compound can also be prepared according to the processes described in the preceding examples and those mentioned in the description: N, N-dimethyl-N'- (p-fluoro-benzyl) -N '- (2-pyridyl) ethylenediamine Example 4 22 parts of 2- (p-chloro-benzyl-amino) -pyridine, prepared by reductive condensation of 2-aminopyridine with p-chlorobenzaldehyde using g5% formic acid, 4 parts of sodium amide and 80 parts of absolute benzene are refluxed for 3 hours boiled, then a solution of 12 parts of β-dimethylaminoethyl chloride in 25 parts of benzene is added dropwise with stirring and the mixture is refluxed for a further 12 hours with stirring.
Nach dem Abkühlen wird das Reaktionsgemisch zuerst mit Wasser gewaschen, hernach die abgetrennte Benzolschicht mit verdünnter Salzsäure ausgeschüttelt, der salzsaure wäßrige Auszug mit gesättigter Sodalösung oder 3o °/oiger Natronlauge stark alkalisch gestellt und die ausgeschiedene Base in Äther aufgenommen. Nach Trocknen der ätherischen Lösung mit wasserfreiem Natriumsulfat und Abdampfen des Lösungsmittels wird das erhaltene braune basische Öl im Vakuum bei o,2 mm Druck fraktioniert; aus der Fraktion von 15o bis 16o° erhält man durch nochmalige Destillation das N, N-Dimethyl-N'-(p-chlorbenzyl)-N'-(2-pyridyl)-äthylendiamin vom Siedepunkt 154 bis i55° bei o,2 mm Druck als blaßgelbliches, viskoses Öl. Das Pikrat schmilzt bei 188 bis igo° und das Hydrochlorid bei 172 bis i74°.After cooling, the reaction mixture is first washed with water, then shaken the separated benzene layer with dilute hydrochloric acid, the Hydrochloric acid aqueous extract with saturated soda solution or 30% sodium hydroxide solution made strongly alkaline and taken up the precipitated base in ether. To Dry the essential solution with anhydrous sodium sulfate and evaporate the The brown basic oil obtained is solvent in vacuo at 0.2 mm pressure fractional; from the fraction from 15o to 16o ° is obtained by repeated distillation the N, N-dimethyl-N '- (p-chlorobenzyl) -N' - (2-pyridyl) -ethylenediamine from the boiling point 154 to 155 ° with 0.2 mm pressure as a pale yellowish, viscous oil. The picrat melts at 188 to igo ° and the hydrochloride at 172 to i74 °.
Die Beispiele lassen sich in mancher Hinsicht modifizieren. So können z. B. andere neutrale, inerte Lösungsmittel verwendet werden, wie Benzol, Xylol, Petroleumdestillate von geeignetem Siedeintervall (zwischen etwa 50 und 2oo°), sowie andere Kohlenwasserstoffe, außerdem Äther, wie Di-isoamyläther oder Dioxan.The examples can be modified in some ways. So z. B. other neutral, inert solvents can be used, such as benzene, xylene, petroleum distillates with a suitable boiling range (between about 50 and 200 °), and other hydrocarbons, as well as ethers, such as di-isoamyl ether or dioxane.
Als Ausgangsmaterialien können an Stelle der freien Basen auch die Salze derselben, vor allem die leicht zugänglichen, wie die Hydrochloride, verwendet werden, besonders. wenn durch Zusatz einer Base die Bindung der zusätzlich frei werdenden Säure bewirkt wird.Instead of the free bases, the starting materials can also be used Salts of the same, especially the easily available ones, such as the hydrochloride, are used be, especially. if the addition of a base releases the binding of the additional resulting acid is effected.
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FR913931A (en) * | 1943-06-22 | 1946-09-24 | Rhone Poulenc Sa | Process for the preparation of substituted diamines |
FR53854E (en) * | 1943-06-22 | 1947-01-10 |
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FR913931A (en) * | 1943-06-22 | 1946-09-24 | Rhone Poulenc Sa | Process for the preparation of substituted diamines |
FR53854E (en) * | 1943-06-22 | 1947-01-10 |
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