SK278897B6 - Method for producing 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro- -1h-purine - Google Patents

Abstract

This invention solves the procedure closed to the production of 3,7-dimethyl-2,6 -dioxo-1,2,3,6-tetrahydro-1H-purine based on the reaction of 3-methyl-2,6-dioxo-1,2,3-tetrahydro-1,7H-purine or its salts with dimethylcarbonate in the reaction environment created based on solvent and this solvent can be represented by excess of dimethylcarbonate or by another suitable organic solvent, while dimethylformamide is suitable and this reaction is provided at the temperature of 50 Celsius degrees up to the boiling temperature of this solvent. This reaction is taking place when the suitable is or is not present and in the case of free compound application (see also formula II), and this agent is selected of the group with organic, inorganic basis, or inorganic oxides, while the catalyst is or is not present, while this catalyst is a phase transmission catalyst, while triethylbenzylammonium chloride is suitable. This invention can be applied in a chemical and pharmaceutical industry.

Description

Technical field

The invention relates to a process for the preparation of 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1H-purine, which is widely used in pharmaceutical production.

BACKGROUND OF THE INVENTION

The preparation of 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1H-purine is described by the alkylation of 3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-1. 7H-purine in an alkaline medium with methyl iodide in E. Fischer and F. Ach published in Bericht 31, p. 1980 (1898), and also in the work of W. Traube published in Bericht 33, p. 3035 (year 1900).

Other alkylation of 3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-1,7H-purine with dimethyl sulfate to prepare 3,7-dimethyl-2,6-dioxo-1,2,3,6 -tetrahydro-1H-purine is described in H. Bredereck, published in Bericht 83, p. 201 (1950) and in German patent no. 864,869 (H. Bredereck and H. G. von Shuh).

A disadvantage of these methods of preparation is the use of toxic agents, namely methyl iodide and dimethyl sulfate, which are classified as suspected chemical carcinogens.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1H-purine of formula (I),

which is widely used in pharmaceutical production.

The process for the preparation of the compound of formula (I) according to the invention is based on the reaction of 3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-1,7H-purine of formula (II),

(H) respectively. a salt thereof, with dimethyl carbonate in a reaction medium formed by a solvent, which may be an excess of dimethyl carbonate or other suitable organic solvent at a temperature of 50 ° C to the boiling point of the solvent used in the presence or absence of the solvent. in the absence of a suitable reagent, in the presence of a catalyst or in the absence of a catalyst.

The process according to the invention is preferably carried out by mixing the compound of the formula (II) and the compound of the formula (II), respectively. its dimethyl carbonate salt, a suitable reagent and a catalyst are heated under stirring in a suitable solvent at a temperature of 50 ° C to the boiling point of the solvent used.

The compound of formula (II) may also be used in the form of a preformed alkali or alkaline earth metal salt.

Organic and inorganic bases or inorganic oxides in an amount of 1 to 3 moles can be used as reagent using the free compound of formula (II).

An excess (1.1-10 moles) of dimethyl carbonate or an organic polar or non-polar solvent is used as the solvent, operating in a temperature range of 50 ° C to the boiling point of the solvent used.

Phase transfer catalysts, preferably triethylbenzylammonium chloride, in an amount of 0.01 to 1 mol can be used as the catalyst in the process of the invention.

The main advantage of the preparation of the compound of the formula (I) according to the invention is that the use of dimethyl carbonate in the alkylation of the compound of the formula (II) replaces the previously used dimethyl sulphate and the sulphate used in this reaction. methyl iodide. Both of these substances are suspected chemical carcinogens and their use in large quantities in production is associated with the need for very strict hygiene and safety measures. The literature data suggests that while for dimethyl sulfate the MPK values are 0.01 ppm and the LD ₅₀ values are 440 mg / kg, the same values for dimethyl carbonate are 100 ppm and 12,800 mg / kg. The significantly lower dimethyl carbonate toxicity is not accompanied by a reduced reactivity.

The invention is illustrated by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1H-purine

Example 1

8.3 g of 3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-1,7H-purine, 13.5 g of dimethyl carbonate, 8.3 g of anhydrous potassium carbonate powder, 1.2 g of triethylbenzylammonium chloride and 100 ml of Ν, Ν-dimethylformamide was stirred at 120 ° C for 3 hours. After cooling, the reaction mixture is concentrated, then extracted twice with 30 ml of chloroform. After extraction, the solid is stirred in 100 ml of water and the pH of the mixture is adjusted to 6-7 with acetic acid. The product is filtered off and washed twice with water and dried. 6.3 g of 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1H-purine of a white powdery consistency are obtained, having a min. 98% (HPLC), mp 345-350 ° C, representing 68.6% yield.

Example 2

The procedure of Example 1 was followed except that 5 g of sodium bicarbonate was used instead of anhydrous potassium carbonate and 1.5 g of aliguate 336 was used instead of triethylbenzylammonium chloride. The reaction mixture was stirred at 120 ° C for 12 hours. After working up according to Example 1, 6.7 g of 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1H-purine of a white powder consistency are obtained, with a min. 98% (HPLC), mp 345-350 ° C, representing 72.8% yield.

Industrial usability

The process for preparing 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1H-purine of the invention is useful in the chemical and pharmaceutical industries for the preparation of pharmaceutical substances.

Claims (6)

PATENT CLAIMS Process for the preparation of 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1H-purine of formula (I), characterized in that 3-methyl-2,6-dioxo-1 The 2,3,6-tetrahydro-1,7H-purine of formula (II) (H) or a salt thereof in an amount of 1 mol is reacted with 1 to 10 moles of dimethyl carbonate at temperatures of 50 ° C to the boiling point of the solvent. Process according to claim 1, characterized in that a pre-prepared alkali metal or alkaline earth metal salt of the compound of formula (II), preferably a sodium or potassium salt, is used. The process according to claim 1, wherein the free compound of formula (II) is additionally used in an amount of from 1 to 3 moles of an organic base, inorganic base or inorganic oxide. Method according to claims 1 to 3, characterized in that an excess of dimethyl carbonate in an amount of 1 to 10 moles or an organic polar or non-polar solvent, preferably dimethylformamide, is used as solvent. The process according to claims 1 to 4, wherein the reaction is carried out in the presence of a catalyst. The process according to claim 5, characterized in that the catalyst is a phase transfer catalyst, preferably triethylbenzylammonium chloride.