CS243582B1 - Salts of 2,4-dianiino-5- (3,4,5-triethoxybenzyl) pyrimidine acids - Google Patents

Abstract

The invention relates to acid salts of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine of the general formula I in which X represents hydrochloric, sulfuric or acetic acid. These salts serve to purify crude 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, which is used in human medicine, alone or in combination with sulfonamides, especially against bacterial infections as a chemotherapeutic agent.

Description

(54) 2,4-Dianiino-5- (3,4,5-triinethoxybenzyl) pyrimidine acid salts

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

in which

X represents hydrochloric, sulfuric or acetic acid.

These salts serve to purify crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine, which is used in human medicine, alone or in combination with sulfonamides, especially against bacterial infections as a chemotherapeutic.

The invention relates to salts of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine acids of the formula I

X represents hydrochloric, sulfuric or acetic acid.

The 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (trimethoprim) 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, or as such, in human medicine.

2,4-Diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine base was first prepared by P. Stenbuck and M. Hood (U.S. Pat. No. 3,049,544; British Pat. No. 957). 797 (other methods of preparation are described, for example, by RM Cresswell and JW Menthou, German Pat. No. 2,010,166; 2,065,367).

Said processes yield a base of formula I of varying purity and often pharmaceutically unsatisfactory. For subsequent use, the prepared base of formula I must be purified by multiple crystallizations in organic solvents or by repeated precipitation from aqueous solutions of non-isolated salts of the base of formula I must be performed multiple times because it is poorly effective and high losses and above all increase production costs.

These disadvantages are overcome by the isolated salts of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine acids of the general formula I according to the invention 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 1. They are well soluble in hot water, whereas they crystallize in cold water and can be well isolated. 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, 1 other chromatographically detectable impurities adhere to the activated carbon so that the 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine acid salt obtained is completely pure, in practically quantitative yield, and can be used in a simple method to prepare the pharmaceutically desired 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine base.

The salts of the 2,4-diamino-5- (3,4,5-trimethoxybeznyl) pyrimidine acids of the present invention are prepared by dissolving the hot base of formula (I) hot in an aqueous solution of dilute acid, especially hydrochloric, sulfuric or acetic acid. Upon cooling of the solution, the corresponding acid salt of formula I precipitates in crystalline form. After isolation of the salt, impurities and a substantial part of the coloring undesirable substances remain in the mother liquor.

Upon dissolution of the crude salt thus obtained in hot water and filtration with activated carbon and subsequent alkalization of the filtrate with an alkali metal hydroxide, the completely pure colorless base of the invention precipitates in high yield. 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 base

2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine.

For illustrative purposes, Table I below shows the solubility values of the salts in water at various temperatures.

CI-LO NH.

(AND)

243382

WITH

Table 1

Salt 2,4-diamino-5- (3,4,5- Salt concentration (mg / 100 ml water)

(trimethoxybenzyl) pyrimidine at 20 ° C while boiling water

hydrochloride 7 720 95 000 9 mixture of sulphates 6: 4, sulphate: hydrogen sulphate 7 200 430 000 acetate 11860 - 190 000

In particular, the mixture of sulphates and hydrogen sulphates of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine in a molecular ratio of 6: 4 has proven to be practical, it cannot be separated and has been successfully used as such in the purification of the crude 2,4- diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine.

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

Example 1

Dissolve 100 g of crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (345 mmol) hot in a solution of hydrochloric acid prepared from 320 ml of demineralized water and 25 ml of concentrated hydrochloric acid (385 mmol) . The resulting solution has a pH of about 5 and is allowed to crystallize with cooling at 5 ° C for 12 h. The crystallized 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine hydrochloride (m.p. 280-285 ° C) is suctioned off and washed with 3 X 20 ml of ice-cold demineralized water.

The still wet 2,4-diamino-5-trimethoxybenzyl) pyrimidine hydrochloride is dissolved in boiling water in 590 ml of demineralized water and, after addition of 6 g of heavy ion-free activated carbon (e.g. Noritus), filtered hot. The filtrate is again heated to boiling and precipitated with 80 ml of concentrated ammonia (1000 mmol). The resulting solution has a pH of about 10. After cooling the mixture to room temperature (overnight), the precipitate is filtered off with suction and washed with demineralized water until the positive reaction of chloride ions in the filtrate disappears. After drying at 60 DEG C., 90.2 g (90.2% of theory of pure 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine base) are obtained, m.p. Mp 201-202 ° C.

Example 2

Dissolve 100 g of crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (345 mmol) in 345 ml of dilute sulfuric acid (13,7% w / w, ie 1,5 M sulfuric acid). (518 mmol) and the solution was left to crystallize at 5 ° C for 24 h without filtration. the crystalline 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine sulfate (m.p. 230-242 ° C) was filtered off with suction. The product obtained was found to be a 6: 4 mixture of sulphate and hydrogen sulphate of said base.

The still wet sulphate mixture was dissolved at boiling point in bSE) ml of demineralized water and 6 g of activated carbon (Norite type) were added to the solution. After a short boiling, it is filtered. The filtrate was again heated to boiling and 129 mL of 10.7% aqueous sodium hydroxide solution (3M, 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 to room temperature (overnight), the precipitate is filtered off with suction and washed with demineralized water until the sulphate ions in the filtrate disappear, and dried at 60 DEG C. to give 91.8 g (91.8% of theory) of pure base 2.4. -diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine, m.p. 202-203 ° C.

Example 3

Dissolve 100 g of crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (345 mmol) in 250 ml of dilute acetic acid (24.0 g of glacial acetic acid in 226 ml of demineralised water) (400 mmol) and the solution was left to crystallize at 5 ° C without filtration. The precipitated crystalline 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine acetate (m.p. 187-202 ° C) is filtered off with suction.

The still wet product is dissolved by boiling in 590 ml of demineralized water and, after addition of 6 g of activated carbon (Norit type), the solution is filtered while hot. The filtrate is reheated to near boiling point and precipitated with 80 ml of concentrated ammonia (ca. 1000 mmol). 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 ° C, 85.1 g (85.1 percent of theory) of pure 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine base, m.p. 201-202 ° C, is obtained.

Note:

In all cases, the purity of the 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine obtained was checked by thin-layer chromatography, and a chromatographically uniform product was always obtained. The purity of the salts obtained was also confirmed by thin layer chromatography.

Claims (1)

OBJECT OF INVENTION Salts of 2,4-diamino-5- (3,4,5-trimetho) acid in which xybenzyl] pyrimidine of formula I X represents hydrochloric, sulfuric or acetic acid.