CS242043B1 - Process for the purification of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine - Google Patents

Abstract

A method for purifying 2,4-diamino-5-(3,4-dimethoxybenzyl)pyrimidine (diaveridine) by direct action of an aqueous solution of hydrochloric, sulfuric or acetic acid. The resulting salt, after dissolution in boiling water, is quantitatively converted with ammonia or sodium hydroxide solution into completely pure 2,4-diamino-5-(3,4-dimethoxybenzyl)pyrimidine, which is obtained completely pure and in quantitative yield by the method according to the invention.

Description

The present invention relates to a process for the purification of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine which is used predominantly as a veterinary drug mainly against coccidiosis, either alone or in combination with other components, for example sulfonamides.

2,4-Dino-5- (3,4-dimethoxybenzyl) -pyrimidine base was first prepared by P. Stenbuck and M. Hood (U.S. Pat. No. 3,049,544; British Pat. No. 957) Other methods of preparation are known, for example, from RM Cresswell and JW Menthy (German Pat. Nos. 2,010,166 and 2,063,367 J and others).

The above process provides a base of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine of varying purity and often pharmaceutically unsatisfactory.The final purity of the base is of key importance.For subsequent use, the prepared base had to be purified by multiple crystallization in organic solvents. However, the use of a sorbent was ineffective for the purification operations, and these salts were first isolated according to AO No. 242 042. Both the method of purification by crystallization and precipitation from aqueous solutions of non-isolated salts of 2,4- The diamino-5- (3,4-dimethoxybenzyl) pyrimidine had to be carried out many times to reduce the resulting preparation efficiency, result in large yield losses and increase production costs.

The above-mentioned disadvantages are overcome by the process for the purification of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine according to the invention, which consists in the fact that the crude 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine is boiled is converted into a corresponding salt of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine with aqueous hydrochloric, sulfuric or acetic acid at a concentration of 1 to 2.8 M per liter, which is dissolved in crude form after removal of the mother liquor The resulting solution was purified by a sorbent and the pure 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine was precipitated completely quantitatively, which was isolated directly.

The inventors have found that the crude 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine is converted to the corresponding salt by boiling, in particular by treatment with 1.0 M hydrochloric acid per liter (1.7 wt. / /obj.J.

The purification process according to the invention has shown that the hydrochloride, sulfate mixture or 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine acetate have very advantageous properties useful for the purification of the base, a 1: 1 mixture of sulfates and hydrogen sulfates. Salts are well soluble in boiling water, while easily crystallized from cold water and easy to isolate.With dissolving these salts in water, the pH of the solution is so advantageous that it can also be used for decolourisation and purification. In the method according to the invention, other impurities which are chromatographically detectable adhere to the sorbent, so that the 2,4-diamino-5- (3,4- dimethoxybenzyl] pyrimidine is completely pure, practically in quantitative yield and can be easily The highly desired 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine base according to the invention yields a pure product in a high yield compared to the processes of the prior art.

The following examples illustrate the method of purification according to the invention, but do not limit it in any way.

Example 1

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

The still wet 2,4-dlamino-5- (3,4-dimethoxybenzyl) -pyrimidine hydrochloride was dissolved in boiling water (920 ml) and precipitated with 81 ml of concentrated ammonia (ca. 1000 mmol) at boiling. of the mixture, 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, 91.8 percent of pure 2,4-diamino-5- (3) theory. 4-dimethoxybenzyl] pyrimidine, mp 232-236 ° C.

Example 2

Dissolve 100 g of crude 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine (384 mmol) in 374 ml of dilute sulfuric acid (13.7% w / w, 561 mmol) while boiling and leave the solution without filtration. Crystallized 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine (mp 240-247 ° C) was filtered off with suction and the product obtained was found to be a 1: 1 mixture of sulphate: hydrogen sulphate. said base.

The still wet mixture of sulphates was dissolved at boiling in 2140 ml of demineralized water and 10 g of activated carbon (Norit type) were added to the solution. After a short boiling, it is filtered. The filtrate was again heated to boiling and 129 ml of a 10.7% aqueous sodium hydroxide solution (3 M per liter, 387 mmol) was added. After the addition of sodium hydroxide, the solution was boiled for 10 minutes to completely convert 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 until the sulphate ions in the filtrate disappear. After drying at 60 DEG C., 90.6 g (90.6% of theory) of pure 2,4-diamino base are obtained. -5- (3,4-dimethoxybenzyl) pyrimidine mp 233-235 ° C.

Example 3

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 [deg.] C. for 24 hours, and the precipitated crystalline 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine acetate (mp 233-234 degrees C, acetone) was filtered off with suction.

The still wet acetate is dissolved at boiling point

3

500 ml of demineralized water and after addition of 10 g of activated carbon (Noritit type, the solution is filtered while hot. The filtrate is reheated to near boiling point and precipitated with 81 ml of concentrated ammonia (about 1000 millimoles).

The resulting solution has a pH of about 10. After cooling the mixture to room temperature, the precipitate is filtered off with suction and washed with demineralized water until the reaction of the ammonium ions 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, and always a chromatographically uniform product was obtained. The purity of the salts obtained was also confirmed by thin layer chromatography.

Claims (3)

SUBJECT Process for the purification of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine, characterized in that the crude 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine is boiled with aqueous hydrochloric or sulfuric acid at boiling point or acetic acid at a concentration of 1 to 2.8 M per liter per corresponding salt of 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine, which is dissolved in the crude state by boiling in water, the resulting solution is purified by means of a sorbent and from the filtrate pure 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine is precipitated by alkaline quantitation, which is isolated directly. OF THE INVENTION 2. The process of claim 1 wherein the crude 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine is converted to boiling with 1.0 M aqueous hydrochloric acid (1.7 wt. to the hydrochloride. 3. The process of claim 1, wherein the pure 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine is precipitated from the filtrate by treatment with an aqueous solution of concentrated ammonia or 3M sodium hydroxide solution (10.7). % w / v).