CS274592B1 - Method of 2-/(4-aminobenzoamido) ethyl/-diethylammonium chloride preparation - Google Patents

Abstract

The solution concerns a method of preparation of 2-[(4-aminobenzoamido)ethyl]-diethyl ammonium chloride in methanol at the temperatures up to 40 degrees C and pressures ranging from 1.4 to 1.8 kPa. The product is obtained by crystallization from ethanol or 2-propanol and serves for human medicine.

Description

The present invention relates to a process for the preparation of 2 - [(4-aminobenzaraido) ethyl] diethylammonium chloride in methanol at temperatures up to 40 ° C and pressures in the range of 1.4 to 1, 8 kPa. The product is obtained by crystallization from ethanol or 2-propanol and is used for human medicine.

CS 274 592 B1

The present invention relates to a process for the preparation of 2 - [(4-aminobenzamido) ethyl] diethylammonium formula I chloride, an active drug used in cardiac disorders.

2 - [(4-aminobenzamido) ethyl] diethylammonium chloride of the formula I Is a dibasic salt

2 - [(4-aminobenzamido) ethyl] diethylanine and hydrogen chloride formed by the hydrogen chloride bond in the diethylammonium group.

This necessary condition has determined the technology for preparing the compound of formula I by reducing the nitro group of 2 - [(4-nitrobenzamido) ethyl] diethylammonium chloride. Ammonium sulfide, electrolytic reduction or catalytic hydrogenation were used for the reduction, most often on Adamson platinum catalyst.

The disadvantages of these processes for the preparation of the compound of formula I are the simultaneous course of hydrogenolytic reactions, which are accompanied by the hydrogenation or electrolytic reduction of 2 - [(4-nitrobenzamido) ethyl] diethylammonium chloride. The products of these hydrogenolytic reactions are colored. Its formation reduces the yield of reduction or hydrogenation and increases the technical difficulty of isolating 2 - [(4-arainobenzamido) ethyl] diethylammonium chloride I.

Later, methods for preparing 2- (4-aminobenzaraido) ethyl] diethylammonium chloride by aminolysis of ethyl 4-arainobenzoate with diethylaminoethylamine have emerged. The resulting 2 - [(4-aminobenzamido) ethyl] diethylamine following reaction with hydrogen chloride affords 2 - [(4-aminobenzamido) ethyl] diethylammonium chloride of formula X.

These methods of preparing 2 - [(4-arainobenzamido) ethyl] diethylammonium chloride sample I, however, have eliminated the adverse effects of the hydrogenolytic reactions associated with catalytic hydrogenation or the electrolytic reduction of 2 - [(4-nitrobenzamido) ethyl] diethylammonium chloride. , which is manifested in the preparation of the final product, i.e. in the reaction of 2 - [(4-aminobenzamido) ethyl] diethylamine with hydrogen chloride. This reaction is accompanied by a change in the color of the reaction medium in direct dependence on the temperature and relative proportions of the reactants.

Experimental study of the color changes of the reaction medium in the reaction of 2 - [(4-aminobenzamido) ethyl] diethylamine with anhydrous hydrogen chloride in ethanol revealed that significant color changes in the reaction medium occurred when the hydrogen chloride concentration exceeded 0.7 mol vs. 1 mol 2 - [(4-aminobenzaraido) ethyl] diethylamine. The compound of formula (I) isolated from this colored reaction medium by crystallization is also colored.

Experimental study of the color changes of the reaction medium during the reaction of 2 - [(4-aminobenzaraido) ethyl] dlethylamine with hydrochloric acid in ethanol revealed that this reaction proceeds without significant color changes even in the reaction of equivalent amounts of reactants. However, significant color changes in the reaction medium occur at elevated temperatures necessary to remove water from the reaction medium by azeotropic distillation with added toluene.

Experimental study of color changes of the reaction medium of chloride preparation

2- (4-aminobenzamido) ethyl diethylammonium formula X by reaction of 2 - [(4-aralnobenzamido) ethyl] diethylaine with ammonium chloride or alkylammonium chloride in methanol gave

It was found that this reaction was carried out without significant color changes until the product was isolated when the concentration of the alkylammonium or ammonium chloride used did not exceed 0.7 moles relative to 1 mol of 2 - [(4-aminobenzamido) ethyl] diethylamine and the reaction temperature. the mixture did not exceed 40 ° C. Methylammonium chloride, ethylammonium chloride and diethylammonium chloride were used as alkylammonium chloride for this study.

By this experimental study, the optimum conditions for the formation of 2- (4-aminobenzamido) ethyl-3-diethylaraonic acid of formula (I) by reacting 2- (4-arainobenzamido) ethyl] diethylamine with ammonium or alkylammonium chloride of formula II are avoided. of this reaction. A process for the preparation of 2-f (4-aminobenzamido) ethyl] diethylammonium chloride of the formula I under these reaction conditions is an object of the present invention.

Process for preparing 2- (4-arainobenzamido) ethyl diethylammonium chloride by reacting 2 - [(4-aminobenzamido) ethyl] diethylamine and ammonium chloride or an alkylammonium halide of formula II

II in which R ₁ is hydrogen, a group of atoms CHj- or group of atoms CGH ^ - ^{and R} ^ i 2 ^considerably the same as p in the alkanol having a carbon number from 1 to 3 according to the invention consists in that the reaction takes place at temperatures up to 40 ° C and 1.3 to 1.8 kPa in methanol, reacting 1.3 to 1.5 moles of 2 - [(4-aminobenzamido) ethyl] diethylamine against 1 mol of ammonium chloride or alkylammonium chloride present II and the resulting 2 - [(4-aminobenzamido) ethyl] diethylammonium chloride of formula I is obtained from the reaction mixture by crystallization from ethanol or 2-propanol.

The reaction equilibrium of the reaction of ammonium chloride or alkylammonium chloride of the formula II with 2- [(4-aminobenzamido) ethyl] diethylamine is in the reaction conditions according to the invention, i.e. at reaction temperatures up to 40 ° C and pressures of 1.3 to 1.5 kPa. , is disturbed in favor of the formation of the compound of formula I by separating the resulting ammonia or alkylamine by distilling it with methanol.

The increased feed of 2- (4-aminobenzamido) ethyl diethylamine over the feed of ammonium chloride or alkylammonium chloride of formula (II) is not detrimental to the yield of the reaction, since 2- (4-aminobenzamido) ethyl] diethylamine stored in mother liquors can be repeated convert to 2- [(4-aminobenzamido) ethyl] diethylammonium chloride of formula I.

Advantages of the process for the preparation of 2- [ _i (4-aminobenzamido) ethyl] diethylammonium chloride according to the invention are that the 2-i (4-aminobenzamido) ethyl] diethylamine used can be converted to 2 - [(4-aminobenzamido) chloride in almost quantitative yield. diethyl laraonic acid, which, by virtue of its qualitative properties, significantly exceeds the properties of this compound of formula I obtained by other known methods of preparation.

The process of the invention is readily practicable in the chemical production equipment used. The process according to the invention makes it possible to return the solvents used to production and thus is waste-free.

CS 274 592 B1

The process for preparing 2- (4-aminobenzamido) ethyl] diethylammonium chloride according to the invention is illustrated in the following Examples.

Example 1

235 g (1 mol) of 2 - [(4-aminobenzamidoyl) diethylamine are dissolved in 400 ml of methanol in a suitably selected vessel, and the solution is left stirring for 12 hours with 12 g of finely divided kieselguhr, after which time the diatomaceous earth is collected by filtration and washed. 40 ml of methanol was transferred to a 2.5 L flask equipped with a stirrer, descending condenser and a thermometer containing 37 g (0.7 mol) of ammonium chloride. After stirring at a pressure reduced to 1.4 to 1.8 kPa, methanol and the ammonia formed were distilled off as the temperature of the reaction mixture increased, 400 ml of 2-propanol were added to the reaction mixture under atmospheric pressure and cooling. crystallization of the product, which was collected by filtration from the mother liquors and washed three times with 50 ml of 2-propanol to give, after drying, 163 g (0.6 mol) of 2- (4-aminobenzamido) eth chloride The mother liquors were concentrated by distilling off the 2-propanol under reduced pressure. The densifier contains 70 g (0.29 mol) of 2- (4-aminobenzamido) ethyl-3-diethylamine and 27 g (0.1 mol) of 2- (4-aminobenzamido) ethyl] diethylammonium chloride.

This mixture was dissolved in 400 mL of methanol together with 142 g (0.6 mol) of 2 - [(4-aminobenzamido) ethyl] diethylamine. After addition of 12 g of diatomaceous earth, the solution is filtered after stirring for one hour. The diatomaceous earth was washed with 40 ml of methanol. The filtered solution was placed in a 2.5 L flask along with 32 g of ammonium chloride (0.6 mol). After stirring for 2 hours at a pressure of 1.4 to 1.8 kPa, methanol and the ammonia formed are distilled off. 400 ml of 2-propanol are added to the crystallizing reaction mixture with stirring and cooling. After cooling for 5 hours, the crystalline product is separated from the mother liquors by filtration, washed three times with 50 ml of 2-propanol and dried. 162 g (0.6 mol) of 2- [4- (4-aminobenzamido) ethyl] diethylaraonic acid chloride of formula I are obtained.

Example 2

235 g (1 mol) of 2- (4-aminobenzamido) ethyl [diethylamine] are dissolved in a suitably selected vessel in 400 ml of methanol. The solution was stirred for 2 h together with 12 g of added diatomaceous earth. After separating the diatomaceous earth by filtration and washing it with 40 ml of methanol, the filtered solution is placed in a 2.5 L flask together with 47.25 g (0.7 mol) of methylammonium chloride. After stirring at 1.4-1.8 kPa for 2 hours, methanol and the resulting methylamine are distilled off by gradually increasing the temperature of the reaction mixture. Ethanol (400 ml) was added to the reaction mixture under stirring and cooling at atmospheric pressure. After cooling for 5 hours, the crystalline product is separated from the mother liquors by filtration and washed three times with 50 ml of ethanol. After drying, 152 g (0.56 mol) of 2- (4-aminobenzamido) ethyl] diethylammonium chloride are obtained. The mother liquors are concentrated by distilling off the ethanol under reduced pressure. The condenser contains 37 g (0.13 mol) of 2- [(4-aminobenzamido) ethyl] diethylammonium chloride and 70 g (0.29 mol) of 2 - [(4-aminobenzarido) ethyl] diethylamine. This is dissolved in 400 ml of methanol together with 133 g (0.56 mol) of 2- (4-arainobenzamido) ethyl] diethylamine. The solution is filtered after stirring for one hour with 12 g of diatomaceous earth. The diatomaceous earth was washed with 40 ml of methanol. The filtered solution was placed in a 2.5 L flask along with 38 g (0.56 g) of methylammonium chloride. After stirring at 1.4-1.8 kPa for 2 hours, methanol together with the methylamine formed are distilled off at a gradually elevated temperature of the reaction mixture. Ethanol (400 ml) was added to the reaction mixture at atmospheric pressure and cooling. After cooling for 5 hours, the crystalline product is collected by filtration, washed three times with 50 ml of ethanol and dried. 149 g (0.55 mol) of 2- [(4-aminobenzamido) ethyl] diethylammonium chloride I are obtained.

CS 274 592 B1

Claims (1)

OBJECT OF THE INVENTION t Process for preparing 2- [1,4-arainobenzamido) ethyl] diethylammonium chloride by reaction of ammonium chloride or alkylammonium chloride of the general formula II R ₂ -N -H H II in which R ₁ denotes hydrogen, or a group -CH = -CgH ^ ^{and R} ^ 2 ^brands - * ^tot · EZ as R ₁ and £ 2- (4-aminobenzamide) ethylJdiethylaminu alkanol having a carbon number of 1-3, characterized in that the reaction is carried out at temperatures of the reaction mixture of up to 40 ° C and pressures of 1.3 to 1.5 ° C 1.8 kPa in methanol, reacting 1.3-1.5 moles of 2- (4-aminobenzamido) ethyl] diethylamine versus 1 mol of ammonium chloride or alkylammonium chloride of formula (II) and the resulting 2- (4-aminobenzamido) chloride ethyl diethylammonium is obtained from the reaction mixture by crystallization from ethanol or 2-propanol.