CS195193B1 - Method of producing 1-substituted derivatives of 6-azauracil - Google Patents

Description

The invention relates to a process for the preparation of 1-substituted 6-azauracil derivatives of the general formula I

wherein R ¹ is allyl, benzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2,4-chlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl and 2,5-dimethy 1-4-chlorobenzyl.

Some 6-azauracyl derivatives of the general formula I, especially those in which the radical R @ 1 is ribofuranose or optionally acetylated ribofuranosyl, already have 6-azauridine and 6-azauridine triacetate as medicinal products.

Recently / J. Copper. Chem. 20, 475 (1977) that, in cases where R is a benzyl group and especially a substituted benzyl group in the aromatic ring, the substances in question have a considerable action against poultry coccidiosis. Particularly good activity has been found in such 1-benzyl derivatives of 6-azauracil, wherein the aromatic nucleus of the benzyl group is substituted with one or more electronegative groups such as chlorine or bromine atoms or cyano or tertiary groups.

1-benzy1-6 azauraci-1 was' ^Vl "first ready straight-benzylation of 6-azauracil / A. Novacek, D. Hesoun, Coll. Czechoslov. Chem. Commun. 30, 3890 (1965)]. However, this method yielded a product that was contaminated with 3-benzyl- and 1,3-dibenzyl-6-azauration.

Pure 1-benzyl derivatives were further prepared by reaction of 3,5-bis (trimethylsilyloxy) -as-triazine (J). Heterocycle. Chem. 4, 291, 1967 / s benzyl halide in acetonitrile. This method, which provides yields ranging from 3 to 40%, is limited to small amounts of reactants and cannot be used for industrial purposes.

Another possible preparation of pure 1-substitution derivatives of 6-azauracil is based on the reversible 3-position blocking of 6-azauracil. The methods of position 3 protection used to substitute 6-azauracil to position 1 so far are of laboratory importance only.

There is also a known process starting from 3-benzoyl-6-azauracyl which is reacted with an equimolecular amount of reactive halide in the presence of an alkali metal carbonate, in an inert inert solvent such as dimethylformamide. It is practically the first process that can be implemented industrially.

In search of other economically advantageous processes for the industrial manufacture of pure 1-substitution derivatives of 6-azauracil, the present inventors have found that the semicarbazone 2-benzyl derivative of glyoxylic acid / A previously prepared by them was previously prepared. Newbie,, D. The slogan mentioned above can be advantageously used for this purpose.

According to the invention, the 1-substituted derivatives of 6-azauracil of the formula I are prepared by reacting the 2-substituted derivatives of the semicarbazone glyoxylic acid of the formula II

195193 '

COOR ¹ 'C / ^NH 2

N '/ ^X N ^ O. z · ¹¹ /

TO

Wherein R is the same as in formula I and R ^{x is} only hydrogen, methyl or ethyl, cyclized by treatment with alkaline reacting agents, preferably alkali metal hydroxides, in an inert inert solvent environment boiling above 100 ° C, preferably in ethylene glycol at 115-130 ° C.

The starting 2-substituted semicarbazone glyoxylic acid derivatives of formula (II) are accessible by reacting semicarbazone glyoxylic acid with reactive halogeno derivatives, for example benzyl halides, which may be substituted in the aromatic ring or with suitable diesters of sulfuric acid in the presence of alkali metal hydroxides or alcoholates. water, in dilute or anhydrous alcohol.

Further, the 2-substituted derivatives of the formula II can be prepared from 1-benzylidensemicarbazide under analogous conditions to the previous case and by transforming the 2-substituted 1-benzylidensemicarbazides thus formed by treatment with glyoxylic acid in an aqueous medium in the presence of a mineral acid.

The 2-substituent derivatives of formula (II) have also been successfully prepared by reacting 1-substituted semicarbazide derivatives with β benzylaldehyde and subsequently converting the resulting 2-substituted 1-benzylidenesemicarbazides with glyoxylic acid.

An advantage of the process according to the invention is that only the 1-substituted 6-azauracil derivatives alone are obtained without by-products and that it is not necessary to use protecting groups in this case. Another advantage of this method is that it is simple, provides the best yields and very good product quality from the known methods and is feasible on an industrial scale. It is therefore particularly suitable for the manufacture of veterinary medicaments, the cost of which is a limiting factor for implementation.

The details of the process according to the invention are apparent from the following examples.

Example 1

2.4 g (0.060 mol) of sodium hydroxide are dissolved in 20 ml of ethylene glycol under stirring at 120 DEG-125 DEG C. and 5.1 g (0.02 mq-1) of 2- (3-chlorobenzyl) are added at this temperature. semicarbazone glyoxylic acid. The reaction mixture is kept at this temperature for 2 h. After cooling to 80 ° C, 100 ml of water are added and the solution is acidified with dilute hydrochloric acid (1: 1) to pH 2, with the precipitated 1- (3-chlorobenzyl) -6-azauracil. at 20 ° C, the product is filtered off with suction, washed with water and dried. 3.36 g (71% of theory) of m.p. 179 DEG-181 DEG C. (ethanol), Example 2

Sodium hydroxide (3.68 g, 0.092 mol) was dissolved in 25 ml of ethylene glycol with stirring at 115-120 ° C. 5.13 g (0.03 mol) of 2-allyl semicarbazone glyoxylic acid is added over 15 minutes and the reaction mixture is maintained at this temperature for 2 hours. It is then diluted with 100 ml of water, hot filtered with activated carbon and acidified. to pH 2 with dilute hydrochloric acid. The precipitated substance is filtered off with suction at 20 DEG C., washed with water and dried. Yield 3.16 g (69% of theory) of 1-allyl-6-azauracil, m.p. 278 DEG-280 DEG.

Example 3 '

2.4 g (0.060 mol) of sodium hydroxide is dissolved with stirring in 20 ml of ethylene glycol at 120 to 125 ° C and after addition of 5.1 g (0.02 mol) of 2 - (4-chlorobenzylated) The reaction mixture is maintained at this temperature for 2 h. The reaction mixture is then diluted with 100 ml of water and acidified to pH 2 with dilute hydrochloric acid. dried. Yield 3.41 g (72% of theory) of a material having a melting point of 234 DEG-236 DEG C. after crystallization from ethanol.

Similarly prepare:

1-benzyl-6-azauracil, b, mp 185-187 ° C,

1- (3,4-dichlorobenzyl) -6-azauration, m.p.

174-176 ° C,

Ί- (2,4-dichlorobenzyl) -6-azauracil, m.p.

213 DEG -214 DEG C. and

1- (2,5-dimethyl-4-chlorobenzyl) -6-azauracil, mp 178-186 ° C.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 1-substituted 6-azauracil derivatives of formula (I) R ¹ (1) wherein R 1 is allyl, benzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl and 2,5-dimethyl-4-chlorobenzyl, characterized in that the 2-substituted glyoxylic acid semicarbazone derivatives of formula II. if, ^NH 2 N / 11 /, V.-if 'in which the same as in formula I and' R 'is hydrogen, methyl or ethyl, cyclize by treatment with alkali reacting agents, preferably by treatment with alkali metal hydroxides in an inert inert solvent with a boiling point above 100 ° C , preferably in ethylene glycol, at a temperature of 115 to 130 ° C.