CS242042B1 - Salts of 2,4-diainino-5- (3,4-dimethoxybenzylpyrimidine) - Google Patents

Abstract

The solution relates to acid salts of 2,4-diamino-5-(3,4-dimethoxybenzyl)pyrimidine of the general formula I NHa in which X denotes hydrochloric, sulfuric or acetic acid. These salts serve to purify crude 2,4-diamino-5-(3,4-dimethoxybenzyl)pyrimidine, which is used in veterinary medicine, alone or in combination with sulfonamides, especially against coccidiosis.

Description

The present invention relates to 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine acid salts of the formula I

in which

X represents hydrochloric, sulfuric or acetic acid.

The 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine (diaveridine) base of formula I is a pharmaceutically important substance which is used to potentiate the action of certain sulfonamides and in admixture with various components as a veterinary drug, for example against coccidiosis.

The 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine base was first prepared by P. Stenbuck et al. M. Hood (U.S. Pat. No. 3,049,544; British Pat. No. 957,797). Other methods of preparation are described by R. M. Cresswell and J. W. Mentha (DE 2 010 166; DE No. 2 065 367).

Said processes yield a base of formula I of varying purity and often pharmaceutically unsatisfactory. For subsequent use it is necessary to purify the prepared base of formula I by repeated crystallization in organic solvents or by repeated precipitation from aqueous solutions of its salts with acids which have not been isolated as such. Both the method of purification by crystallization and precipitation from aqueous solutions of non-isolated salts of the base of the formula I must be carried out many times, therefore it is poorly effective and high losses occur and, above all, production costs are increased.

These disadvantages are overcome by the isolated salts of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine acids of the general formula I in which:

X represents hydrochloric, sulfuric or acetic acid.

Surprisingly, these hitherto unwritten salts of the invention have been found to have advantageous properties useful for purifying the base of Formula I. They are well soluble in hot water while crystallizing in cold water and easy to isolate. In addition, when the salts of the invention are dissolved in hot water, the pH of the solution is so advantageous that activated carbon can be used to decolourize and purify it, which is ineffective according to the original methods. In addition, other chromatographically detectable impurities adhere to activated carbon, so that the 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine acid salt obtained is completely pure, in practically quantitative yield, and can be used to prepare a pharmaceutically highly desired base by a simple method. 4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine.

The salts of the 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine of the invention are prepared by hot solution of the crude base of formula I in an aqueous solution of a dilute acid, especially hydrochloric, sulfuric or acetic acid. After the salt has been isolated, all the impurities and a substantial part of the coloring undesirable substances remain in the mother liquor. For practical use in pharmacy, it is not necessary to dry the isolated crystalline acid salt of the invention, but can be used directly in the wet state to prepare the 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine base.

By way of illustration, the solubility values of the salts in water at various temperatures are given in Table 1 below.

N (I)

Table 1 2,4-Diamino-5- (3,4-dimethoxybenzyl) pyrimidine salt Concentration of salt solution (mg / 100 ml water) when boiling water at 4 ° C at 20 ° C hydrochloride 2555 2655 29 000 sulphate mixture (1: 1) sulphate: hydrogen sulphate 237 277 6500 acetate 1285 1585 1800

In particular, 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine hydrochloride has proven to be useful, and the 1: 1 mixture of sulphates and dibasulphates is not separable and has also been successfully used as such in the purification of the crude base 2 4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine.

The following examples illustrate, but do not limit, the substance of the present invention.

Example 1

100 g of crude 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine (384 mmol) was dissolved in hot in a solution of hydrochloric acid prepared from 800 ml of demineralized water and 38.5 ml of concentrated hydrochloric acid (385 mmol). the solution has a pH of about 6 and, after addition of 5 g of heavy metal ion-free activated carbon (for example, Norit is filtered while hot. The filtrate is cooled at 5 ° C for 12 hours and crystallized 2,4-diamino-5- (3, 4-Dimethoxybenzyl] pyrimidine (mp 269-272 ° C) was aspirated and washed 3 times with 100 ml ice-cold demineralized water.

The still wet 2,4-diamino-5- (3,4-dimethoxybenzyl) -pyrimidine hydrochloride was dissolved in boiling water in 920 ml of demineralized water and precipitated with 81 ml of concentrated ammonia (ca. 1000 mmol). The solution obtained had a pH of ca. 10. After cooling The precipitate is filtered off with suction and washed with demineralized water until the positive reaction of chloride ions in the filtrate disappears, and dried at 60 DEG C. to give 91.8 g, which is 91.8 percent of the pure 2,4-diamino-5- (3, 4-dimethoxybenzylpyrimidine, mp 232-236 ° C.

Example 2

100 g of crude 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine (384 mmol) was dissolved in 374 ml of dilute sulfuric acid (13.7% by weight, i.e. 3N sulfuric acid) at boiling point and the solution was left The mixture was filtered to crystallize at 5 [deg.] C. for 24 hours, and crystallized 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine (mp 240-247 [deg.] C.) was filtered off with suction. % of the hydrogen sulphate of said base.

The still wet mixture of sulphates is dissolved at boiling with 2140 ml of demineralized water and 10 g of Norituj activated carbon are added to the solution. After a short boil, it is filtered. After addition of sodium hydroxide, the solution is boiled for 10 minutes to complete the conversion of the salt to the free base. After cooling the mixture to room temperature (overnight), the precipitate is filtered off with suction and washed with demineralized water. After drying at 60 ° C, 90.6 g (90.6% of theory) of pure 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine mp 233-235 ° C are obtained.

Dissolve 100 g of crude 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine (384 mmol) in 175 ml of dilute acetic acid (26.0 g of glacial acetic acid are mixed with 150 ml of demineralised water, 430 millimoles). ) and the solution was allowed to crystallize without filtration at 5 ° C for 24 hours, and the precipitated crystalline 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine acetate (mp 233-234 ° C, acetone) was filtered off with suction.

The still wet acetate was dissolved by boiling in 500 ml of demineralized water and after addition of 10 g of activated carbon (Norit type) the solution was filtered hot. The filtrate is reheated to near boiling point and precipitated with 81 ml of concentrated ammonia (about 1000 millimoles). The solution obtained has a pH of ca.

10. After cooling the mixture to room temperature, the precipitate is filtered off with suction and washed with demineralized water until the ammonium ion reaction in the filtrate disappears. After drying at 60 DEG C., 84.7 g (84.7% of theory) of pure 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine base, m.p. 234 DEG-236 DEG C., is obtained.

Note:

In all cases, the purity of the 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine obtained was checked by thin-layer chromatography to obtain a uniform chromatographic product, and the purity of the salts obtained was confirmed by thin-layer chromatography.

Claims (1)

SUBJECT VYNALEZU The salts of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine acids of formula (I) wherein: X represents hydrochloric, sulfuric or acetic acid.