DE931828C - Process for the preparation of ethylene diamine derivatives - Google Patents

Description

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.

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.

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.

In the following, the spasmolytic effect against histamine on the surviving guinea pig intestine, the toxicity and the therapeutic range calculated from this of a compound according to the present invention is compared with the corresponding data of the analogous chlorine-free compound: Antihistamine toxicity activity, -D. 1.50, iv mouse therapeutic same effect m width at the following dose g / kg en C H3 / CH, - CH, -N \ HCl 1'27 32 26 # T # N CH3 C H2 - @ CH, CH, -CH2-N \ HCl 0.577 4 $ 84 # NJ- N / \ CH, CH, - (D- Cl The ethylenediamine derivatives defined at the outset are prepared by methods known per se. For example, one can start from the amine of the formula R - N H2 (I) in which R has the meaning defined at the beginning, and in this, according to the methods customary for the alkylation of amines, in any order one ß-dimethylamino-ethyl and one Introduce p-halobenzyl radical. Compounds which are suitable for introducing the radicals mentioned are above all the reactive esters of the corresponding alcohols. Examples of reactive esters which may be mentioned are the esters with hydrohalic acids, in particular the chlorides, bromides and iodides, the esters with sulfuric acid, with aliphatic and with aromatic sulfonic acids. The esters with hydrogen chloride are mostly preferred because of their easy accessibility.

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.

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.

Some of the possibilities resulting from this general process are listed below: a) Reaction of a diamine of the formula with a reactive ester of a p-halobenzyl alcohol Y = Cl, Br, I, aryl-SO2-O-, alkyl-SO2-O- or. Like. b) Reaction of a diamine of the formula (II) with a p-halobenzaldehyde in the presence of a reducing agent II -f - O = CH 7 j- halogen + 2 H -> - III -f- H2 O c) Implementation of an amine of the formula with a reactive ester of ß-dimethylamino-ethanol IV -E- Y-CH2-CH2-N (CH3) 2 - + - III + HY (Y has the same meaning as above.) You can also use 2-halopyridine go out and this compound with a secondary amine of the formula realize. The reaction takes place by heating the two components in the presence of acid-binding agents such as pyridine, quinoline, potash and the like, or else a second mole of the amine of the formula (V). Catalysts facilitating the elimination of hydrogen halide, such as. B. copper bronze can be added.

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.

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 °.

Warming the base with excess methyl iodide gives the iodine methylate as almost colorless crystals that are easily soluble in water.

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.

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.

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 °.

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.

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.

Claims (2)

PATENT CLAIMS: i. Process for the preparation of ethylenediamine derivatives of the formula wherein R denotes the 2-pyridyl radical, characterized in that a β-dimethylaminoethyl and a p-halobenzyl radical are introduced into 2-aminopyridine by the methods customary for the alkylation of amines in any order, with fluorine under halogen , Chlorine and bromine are to be understood. 2. The method according to claim : [, characterized in that one in the compound of the formula introduces the p-halobenzyl radical by the methods customary for the alkylation of amines. 3. The method according to claim 1, characterized in that one is in a compound of the formula introduces the ß-dimethylamino-ethyl radical according to the methods customary for the alkylation of amines. 4. Modification of the method according to claim 1, characterized in that a compound of the formula R - halogen in which halogen is Cl, Br or J and R is a 2-pyridyl radical, with a compound of the formula implements. 5. Process for the preparation of salts of ethylenediamine derivatives according to Claims 1 to 4, characterized in that the bases are reacted with inorganic or organic acids. Referred to: Swiss Medicine. Weekly Vol. 79, pp. 476 to 48o (1949) Journ. At the. Chem. Soc., Vol. 69, p. 1549 (1947); Vol. 67, p. 1643 (1945); Vol. 69, pp. 98o-981 (1947); Bull. John Hopkins Hospital, Vol. 81, pp. 55-64 (1947); French Patent No. 913931; French Patent Amendment No. 53854; Produits pharmaceutiques, Vol. 2, No. 2, p. 53 to 64 (1947); Journ. of org. chemistry, Vol. 14, p. 228 (1949).