CS243583B1 - Process for the purification of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine - Google Patents

Abstract

A method for purifying 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine (trimethoprim) 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 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine, which is obtained completely pure and in quantitative yield by the method according to the invention.

Description

(54) A method for purifying 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine

2

Method for purifying 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (trimethoprim) by direct treatment with an aqueous solution of hydrochloric, sulfuric or acetic acid.

After dissolution in water with boiling, the resulting salt is quantitatively converted with ammonia or sodium hydroxide solution to 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine, which is obtained in a pure and quantitative yield by the process according to the invention.

The present invention relates to a process for the purification of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine, which is used predominantly as a human drug, mainly as a chemotherapeutic, either alone or with components such as sulfonamides.

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). Other methods of preparation are known, for example, from RM Cresswell and JW Menthy (German Pat. Nos. 2,010,166 and 2,065,367) and others.

According to these processes, a 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine base of varying purity and often pharmaceutically unsatisfactory is obtained, and the final purity of the base is of key importance. in organic solvents or by repeated precipitation from aqueous solutions of their acid salts.

However, the use of a sorbent was ineffective for cleaning operations. These salts were first isolated according to the description of the invention to U.S. Pat. No. 243,582. Both the method of purification of crystallization of crystals and precipitation from aqueous solutions of non-isolated 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine salts had to be carried out many times, thus reducing the resulting preparation efficiency, large yield losses and production costs increased.

The above-mentioned disadvantages are overcome by the process for the purification of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine according to the invention, which comprises the formation of crude 2,4-diamino-5- (3,4,5- trimethoxybenzyl) pyrimidine is converted by boiling with an aqueous sulfuric, hydrochloric or acetic acid of 1 to 1,5 M per liter into the corresponding acid salt

2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine, which, after removal of the mother liquor in crude form, is dissolved in boiling water with boiling and the solution is purified by sorbent and the pure 2,4- diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine, which is directly isolated.

The inventors have found that the crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine is boiled to the corresponding salt by boiling, in particular, with sulfuric acid at a concentration of 1.5 M per liter (17.3%). % by weight).

The purification process according to the invention has shown that 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine hydrochloride, a mixture of sulphates or acetate has very advantageous properties useful for the purification of the base. The salts are well soluble in boiling water, while they easily crystallize from cold water and can be well isolated.

When dissolving these salts in water, the pH of the solution is so advantageous that, for decolourisation and purification, it is also possible to use activated carbon free of heavy metals, which according to the prior art is ineffective and practically without effect. In the purification process according to the invention, other chromatographically detectable impurities also adhere to the sorbent, so that the 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine acid salt obtained is completely pure, practically in quantitative yield, and can be readily purified therefrom The process of the present invention yields a pure product in high yield over the yields 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

Dissolve 100 g of crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (345 mmol) in a hot solution of hydrochloric acid prepared from 320 ml of demineralised water and 35 ml of concentrated hydrochloric acid (385 mmol). has a pH of about 5 and is allowed to crystallize with cooling at 5 ° C for 12 h.

2,4-Diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (m.p. 280-285 ° C) was aspirated and washed with 3 X 20 mL ice-cold demineralized water.

The still wet product, ie 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine hydrochloride, is dissolved under boiling in 590 ml of demineralized water and after addition of 6 g of heavy metal ion-free activated carbon (e.g. Norit) is filtered while hot. The filtrate is again heated to boiling and precipitated with 80 ml of concentrated ammonia (1000 mmol). After cooling to room temperature (overnight), the precipitate was filtered off with suction and washed with demineralized water until the positive reaction of chloride ions in the filtrate disappeared. After drying at 60 ° C, 90.2 g, 90.2% of pure 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine base, melting point 201-202 ° C, is obtained.

Example 2

100 g of crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (345 mmol) is dissolved in boiling in 345 ml of dilute sulfuric acid (13.7% w / w, i.e. 1.5 M acid). sulfuric acid, 518 mmol) and the solution was allowed to crystallize at 5 ° C for 24 h without filtration Crystalline 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine sulfate (mp 230-242 ° C) was suctioned off. The product was found to be a 6: 4 mixture of sulphate and hydrogen sulphate of said base.

The still wet mixture of sulphates is dissolved in boiling water in 590 ml of demineralized water and 6 g of Noritic charcoal are 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 (3M, 387 mmol) was added and the solution was boiled for 10 minutes after complete addition of the sodium hydroxide solution to completely convert the salt to the free base.

After cooling the mixture to room temperature (overnight), the precipitate was filtered off with suction and washed with demineralized water until the sulphate ions in the filtrate disappeared. After drying at 60 ° C, 91.8 g (91.8 percent of theory) of pure 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine base is obtained, 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 are dissolved in 226 ml of demineralised water, 400 mmol) and the solution was left to crystallize without filtration at 5 [deg.] C. for 24 h, and the precipitated crystalline 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine acetate (mp 187-202 degrees Cj) was filtered off with suction.

The still wet acetate was dissolved in 590 ml of demineralized water and after the addition of 6 g of activated carbon (Noritit type, the solution was filtered while hot. The filtrate was reheated to near boiling point and precipitated with 80 ml of concentrated ammonia (1000 mmol). pH = 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 ion in the filtrate disappears, and dried at 60 DEG C. to give 85.1 g (85.1% of theory) of pure base.

2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine, mp 201-202 ° C.

Note:

In all cases, the purity of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine was checked by thin-layer chromatography and a uniform product was always 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- (3,4,5-trimethoxybenzyl) pyrimidine, characterized in that the crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine is boiled with aqueous hydrochloric, sulfuric or acetic acid at a concentration of 1 to 1,5 M per liter per corresponding salt of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine acid, which is dissolved in the crude state on boiling water, The resulting solution is purified by means of a sorbent and pure 2,4-diamino- (3,4,5-trimethoxybenzyl) pyrimidine is precipitated from the filtrate in an alkaline manner, which is isolated directly. 2. The process of claim 1 wherein the crude 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine is converted to boiling with 1.5M aqueous sulfuric acid while boiling. per liter, i.e. 13.7% w / v, to the corresponding 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine sulphate mixture. 3. The process of claim 1, wherein the pure 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine is precipitated from the filtrate by treatment with an aqueous solution of concentrated ammonia or 3M sodium hydroxide solution, ie 10.7 wt.