DE2719365A1 - Di:alkyl-amino-alkyl chloride hydrochloride prepn. - comprises reaction of bromo-chloroalkane with di:alkylamine using ammonium- or phosphonium halide catalyst - Google Patents

Abstract

Dialkylamino-alkyl chloride hydrochlorides having formula (R1R2N-(CH2)x-Cl).HCl(I) (where R1 and R2 are alkyl and x is 2-4) are prepd. by (a) reacting the corresp. bromo-chloro-alkane with only slight (5-10%) stoichiometric excess of dialkylamine, in a 2-phase system contg. inert organic solvent and aq. NaOH soln. with the addn. as catalyst, of a water-soluble quat.ammonium or phosphonium salt having formula (R1R2R3R4X)+Hal- (where R1,R2,T3 and R4 are alkyl, aralkyl or aryl, X is N or P and Hal is Cl,Br or I) and (b) converting the dialkyl-amino-alkyl chloride (II) obtd to the hydrochloride. (II) are organic intermediates, e.g. for introducing the dialkylaminoalkyl gp. into organic mols. to form pharmaceutically active cpds. e.g. for use as local anethetics, anti-histamines and neuroleptics. The new prepn. process is economical and gives stable, pure (I) in 86-90% yields.

Description

Process for the production of dialkyl

amino-alkyl chloride-hydrochlorides The dialkylamino-alkyl halides, especially the lower representatives with an alkyl chain length of 2 - 4 carbon atoms, are important intermediates for preparative organic chemistry. For example they serve to introduce the dialkylaminoalkyl group into organic molecules, whereby pharmacologically valuable substances arise that can be used as local anesthetics, Find antihistamines and psychotropic drugs (neuroleptics).

Since dialkylamino-alkyl halides in the form of the free bases are not very stable and difficult to purify, the salts of these bases with strong acids are usually used for preparative purposes. The hydrochlorides are preferred for reasons of economy. The preparation usually takes place in the form that the corresponding bromochloroalkane is reacted in an inert, water-immiscible solvent with the dialkylamine used in excess. The excess (usually 100-140%) is required to bind the hydrogen bromide released. After the dialkylamine hydrobromide has been separated off, for example by filtration or removal of the saturated salt solution after the addition of water, hydrogen chloride gas is passed into the organic phase. The desired dialkylaminoalkyl chloride hydrochloride is precipitated R1, R2 = alkyl groups x = 2-4 in solid form. It can be separated off by filtration and dried.

However, this way of working is technical in several respects Implementation not very suitable.

First of all, it is disadvantageous that a large excess of the corresponding Dialkylamine must be applied in the form of worthless dialkylamine hydrobromide is lost and is also an unpleasant waste. But it will be the surplus reduced in dialkylamine of at least 2 moles per mole of bromo-chloroalkane, so fall the yields to an intolerable level.

In addition, the dialkylamino-alkyl chloride hydrochloride due to their poorly developed crystal structure and strong hygroscopicity Isolate poorly by filtration or centrifugation. The drying also provides special requirements for moisture exclusion and the avoidance of lump formation. The eni products have only limited storage stability in dry form, and the number of Impurities are constantly increasing due to the formation of by-products.

A production process for dialkylamino-alkyl chloride hydrochlorides has now been found which completely avoids the disadvantages described and thus becomes a very economical, technically easy process. The main features of the new process are: 1. The corresponding bromochloroalkane is mixed with only a slight excess (5-10% of theory) of dialkylamine in a two-phase system consisting of an inert organic solvent, preferably toluene or xylene, as well aqueous sodium hydroxide solution with the addition of small amounts of a water-soluble quaternary ammonium or phosphonium salt of the following structure: R1, R2, R3, R4 = alkyl, aralkyl or aryl groups X = nitrogen or phosphorus Hal = Cl, Br, J The required amount of sodium hydroxide solution is 0 - 5% excess of the amount required to bind the resulting hydrogen bromide. The amount of quaternary ammonium or phosphonium salt is on average 0.01 mol per mol of bromo-chloroalkane used.

2. The production is carried out in such a way that instead of gaseous Hydrogen chloride aqueous hydrochloric acid for salt formation of the dialkylamino-alkyl chloride base is used and thus the end product in the form of an approx. 60 dough aqueous solution is won.

This is characterized by high initial purity and excellent Storage stability. Since it doesn't matter for most uses, whether the dialkyl aminoalkyl chloride hydrochloride before the release of the base and the Further reaction is present in solid or dissolved form, the production can be perform this product class very quickly and economically in this way. All insulation, drying and waste problems are eliminated.

The yields of the process are 86-90 t of theory and thus completely correspond to the previous ones.

The following examples are intended to explain the method of operation in more detail: Example 1: Dimethyl aminopropyl chloride hydrochloride For a mixture of 250 parts by volume Toluene and 157.4 parts by weight of 1-bromo-3-chloro-propane are left at 35-400 ° C. 49.6 Parts of dimethylamine (liquid) flow in. Then 2.3 parts of trimethyl benzyl ammonium hromide are added and 84 parts of 50% or sodium hydroxide solution were added within 1 hour at 35-400 ° C. Vigorous stirring must be used throughout the process. After 1 hour of heating at 45 - 500 ° C, enough water is added that the crystal pulp formed is just goes into solution. The aqueous, lower phase is separated off and the reaction mixture washed again with 100 parts of water.

Then 50 parts of demineralized water are added to the organic phase 90 parts of concentrated hydrochloric acid (36 dough) flow in until a pH value of 4.5. - 5.0 is reached. After it has settled, the lower, aqueous phase is separated off. It 237.0 parts of a water-white, clear, oily liquid are obtained.

The content of dimethylaminopropyl chloride. HCl is 60.4% accordingly a yield of 90.5% of theory, based on 1-bromo-3-chloro-propane. The means Impurities detectable by GC and TLC are below 0.2. Storage trials up to 1 year at 400 C resulted in an increase in impurities of only 0.15%.

Example 2: Diethylaminopropyl chloride hydrochloride From 157.4 parts 1-Bromo-3-chloro-propane, 80.4 parts of diethylamine, 84 parts of sodium hydroxide solution (50%) are toluene in 250 parts by volume with the addition of 3.7 parts of triphenyl-ethyl-phosphonium bromide, as in Example 1) 267 parts of a colorless, Zaren aqueous solution with eene olt of 59.9% diethylaminopropyl chloride hydrochloride obtained. this corresponds to a yield of 85.9% of theory, based on 1-bromo-3-chloropropane.

The purity of the product (based on anhydrous substance) lies at 99.7 t. The storage stability test shows only a decrease in purity after 1 year to 99.5%.

Claims (2)

Claims: Process for the production of dialkylamino-alkylchloride hydrochlorides of the following formula: R1 and R2 = alkyl groups x = 2-4 by reacting the corresponding Rrom-chloroalkanes with dialkylamines and subsequent salt formation, characterized in that the reaction of the bromo-chloroalkane with the stoichiometrically essentially equivalent amounts of dialkylamine and aqueous sodium hydroxide solution under Addition of catalytically active amounts of a quaternary ammonium or phosphonium salt of the following structure R1, R2, R3, R4 = alkyl, aralkyl or aryl groups X = nitrogen or phosphorus Hal = C1, Br, J to give the corresponding dialkylaminoalkyl chloride and this is then converted into the hydrochloride. 2. The method according to claim 1, characterized in that the transfer of the dialkylamino-alkylchlorides into the hydrochloride in an inert organic Solvent, preferably toluene or xylene, with the addition of aqueous hydrochloric acid carried out and the reaction product in the form of a concentrated aqueous salt solution is isolated.