CS267380B1 - Method of 6-amino-5-bromo-1-methyl-1 h-pyrimidine-2,4-dione preparation - Google Patents

Abstract

The solution relates to a method of preparing 6-amine 5-bromo-1-methyl-1H-pyrimidine-2,4-dione of formula I which is used in pharmaceutical formulations chemistry as an intermediate in drug synthesis prepentophyllin. Prepared from 6-amino-1-methyl-1H-pyrimidine-2,6-dione of formula II and bromine in acetic acid in the presence of acetate sodium or potassium binding releasing hydrogen bromide at 15 to 80 ° C.

Description

The invention relates to a process for the preparation of 6-amino-5-bromo-1-methyl-1H-pyrimidine-2,4-dione of formula I

ABOUT

which is used in pharmaceutical chemistry as an intermediate in the synthesis of the vasodilator propentophylline.

Hitherto, this compound was prepared from 6-amino-1-methyl-1H-pyrimidine-2,6-dione of formula II

ABOUT

h by bromination in an aqueous medium at room temperature in a yield of 23% [G. R. Barker, N. G. Luthy: J. Chem. Soc. 1956. 920] or in acetic acid in a yield of more than 90% (crude product) [J. Wojciechowski: Acta Polon. Pharm. 18, 409 (1961): PL 42, 976]. The disadvantage of the first process is the work in an aqueous medium in which the amino group in position 6 of the compound of the formula II is hydrolyzed in part. In the second process, the hydrobromic acid formed by the reaction also causes undesired reactions. The formation of impurities in the reaction results in a substantial reduction in the yields of purification of the compound of formula 1 and also in a reduction in the quality of the product after recrystallization, which results from a comparison of the melting point of the product according to the procedure described in the second liter. reference (265 ° C) and the procedure of the 1st lit. reference (278-280 ° C). This process is overcome by a process for the preparation of a compound of formula I according to the invention, which consists in brominating a compound of formula II in an acetic acid medium in the presence of sodium or potassium acetate, which bind hydrogen bromide liberating in the reaction at a temperature of 15 to 80 ° C.

The process according to the invention is carried out in such a way that

CS 267 380 B1 2 that 1.0 mol. part of the compound of formula II and 1.0 to 1.1 mol. part of the sodium or potassium acetate is suspended in acetic acid and 1.0 to 1.1 mol are added with stirring. part of bromine at room temperature. After the reaction, which is indicated by decolorization of the reaction mixture, the compound of the formula I is filtered off with suction, washed with water and recrystallized from water. Finally, it is dried at elevated temperature, preferably in vacuo.

The compound of formula II can first be dissolved by boiling with acetic acid, then sodium or potassium acetate is added and, after cooling to about 60-70 ° C, the addition of bromine is started in small portions over about 15 minutes. After cooling, the reaction mixture is worked up analogously to the preceding procedure. The molar ratios of the reactants are also analogous to the previous procedure.

The main advantage of the process according to the invention is that a purer compound of formula I is obtained by eliminating the hydrogen bromide liberated in the reaction, which results in e.g. from a comparison of melting points and in obtaining higher yields of recrystallized product.

In the following, the subject matter of the invention is described in the exemplary embodiments without being limited thereto.

Example 1

To a mixture of 14.1 g (0.10 mol) of the compound of formula II, 15.0 g (0.11 mol) of crystalline sodium acetate and 100 ml of acetic acid are added in small portions over about 15 minutes with stirring. 17.58 g (0.11 mol) of bromine. The thick suspension is stirred at room temperature for a further 1 h to react, the product is filtered off with suction, washed with cold water and recrystallized from water. 18.0 g (81.8% of theory) of the compound of the formula I with 1.1 are obtained. 280-283 ° C. The first lit. the reference indicates 1.1. 278-280 ° C (H ₂ O) and second lit. reference indicates 265 ° C (H ₂ O). For C ₅ H ₆ BrN ₃ O ₂ (220.0) calculated: 27.29% C, 2.75% H, 19.10% N, 36.32% Br; Found: 26.97% C, 2.64% H, 19.14% N, 36.10% Br.

Example 2

14.1 g (0.10 mol) of the compound of formula II are dissolved by heating to boiling in 750 ml of acetic acid, 10.8 g (0.11 mol) of potassium acetate are added, the resulting solution is cooled to 70 ° C and to it after small doses of I7.58 g (0.11 mol) of bromine for about 0.5 h. The reaction mixture is stirred to cool to room temperature, the product is filtered off with suction, washed with water and recrystallized from water. 17.6 g (80.0% of theory) of the compound of the formula I with 1.1 are obtained. 279-282 ° C.

Claims (1)

Process for the preparation of 6-amino-5-bromo-1-methyl-1H-pyrimidine-2,4-dione of formula 1 ABOUT from 6-amino-1-methyl-1H-pyrimidine-2,6-dione of formula II ABOUT and bromine, in an acetic acid medium, characterized in that the reaction is carried out in the presence of sodium or potassium acetate at a temperature of 15 to 80 ° C.