CS267100B1 - Method of 3,7-dimethyl-3,7-dihydro-1 h-purine-2,6-dione preparation - Google Patents

Abstract

The present invention relates to a process for the preparation of a compound of formula I, which is used in pharmaceutical industry as a raw material for production drugs for cardiac diseases. Approach is that it reacts 3- -methyl-3,7-dihydro-1H-purine-2,6-dione of formula With methyl chloride in the presence of alkali hydroxide and / or alkali carbonate in aliphatic alcohols having a of carbon 3 to 3 and / or water in the presence of a catalytic amount of bromide or an alkali metal iodide. reaction is carried out at a temperature of 35 to 110 ° C, preferably at 60 to 80 ° C.

Description

The invention relates to a process for the preparation of 3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione of formula I

which is used in the pharmaceutical industry as a raw material for the manufacture of drugs for cardiovascular diseases.

To date, the compound of formula I has been prepared as follows: by methylation of the Pb salt of 3,7-dihydro-1H-purine-2,6-dione with iodomethane at 100 ° C (E. Fischer, Ann. 215, 311), by heating the 3-methyl- Of 3,7-dihydro-1H-purine-2,6-dione, iodomethane and 1M-potassium hydroxide at 80 ° C (E. Fischer, E. Ach, Ber. 31, 1987), by the action of nitric acid on 3,7- dimethyl-3,7-dihydro-1H-purin-6-imino-2-one (E. Fischer, Ber. 30, 1845), from 3,7-dimethyl-8-chloro-3,7-dihydro-1H -purine-2,6-dione by boiling with fuming hydroiodic acid and phosphonium iodide (E. Fischer, E. Ach, Ber. 31, 1985), by boiling 3,7-dimethyl-8-trichloromethyl-3,7-dihydro-1H- of purine-2,6-dione with water (Boehringer u. Sbhne, DRP 151 133), from 3,7-dihydro-1H-purine-2,6-dione or from 3-methyl-3,7-dihydro-1H- purine-2,6-dione by treatment with dimethyl sulfate in an aqueous or aqueous-methanolic medium in the presence of sodium or potassium hydroxide (H. Bredereck et al., Chem. Ber. 83, 210; 86, 349), from 3-methyl-3. 7-dihydro-1H-purine-2,6-dione with dimethyl sulphate in aqueous hydroxide solution with at pH 9.0 to 7.6 (V. M. Lichačeva et al., Farm. OF. 9/7 /, 48), from 3-methyl-3,7-dihydro-1H-purine-2,6-dione by the action of dimethyl sulphate in the presence of an alkali carbonate or a mixture thereof with an alkali hydroxide in an aqueous or aqueous-alkaline medium (H. Niegel et al., GDR pat. 222 026), by reacting 3-methyl-3,7-dihydro-1H-purine-2,6-dione potassium salt with potassium monomethyl sulfate in toluene (H. Wittek, DRP 534 907), alkylation of the potassium salt of 3-methyl-3,7-dihydrop-1H-purine-2,6-dione with dimethyl sulfate in an aqueous-methanolic medium (AB Solovjeva et al., Med. Prom. SSR 20/1 /, 31), heating 3-methyl-8-trichloroethyl-3,7-dihydro-1H-purine-2,6-dione with dilute hydrochloric acid (E. Golovchinskaya et al., Ž. Ex. Chim. 31, 1241, 1244), heating 6-amino-5-methylamino-1-methyl- (1H, 3H) -pyrrolidine-2,4-dione with formamide or 6-amino-5-formamido-1-methyl- (1H, 3H) -pyrimidine-2 Of 6-dione with N-methyl-formamide at 180 ° C (J. Wojciechowski, Acta Polon. Pharm. 18, 409), by heating 6-amino-5-formamido-1-methyl- (1H, 3H) -pyrimidine- 2,4-dione u with aqueous sodium hydroxide and finally with dimethyl sulphate (B. Gepner, L. Kreps, Ž. obšč. chim. 16, 185).

A disadvantage of the hitherto known and in practice used processes for the preparation of the compounds of the formula I is that they use methyl iodide and dimethyl sulphate as methylating agents, which are suspected as carcinogens.

This disadvantage is eliminated by the process for the preparation of the compound of formula I according to the invention, which is based on the reaction of 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II

(II)

CS 267 100 B1 3 with methyl chloride in the presence of an alkali hydroxide and / or an alkali carbonate in the presence of an aliphatic alcohol having 1 to 3 carbons, in a mixture with water or in water alone ♦

The process according to the invention is carried out in such a way that 100 mol. parts of the compound of formula II are suspended in water, 95 to 130 mol are added. parts of alkali hydroxide or alkali carbonate, or mixtures thereof, and 95 to 160 mol. parts of chloromethane dissolved in an aliphatic alcohol having 1 to 3 carbons, e.g. ethanol, 2-propanol, preferably methanol, and heated with stirring in a closed vessel to 35 to 110 ° C, preferably at 60 to 80 ° C . Chloromethane can be added to the reaction mixture in a pressure vessel. also gaseous or liquid itself, or it can be metered from the pressure bottle continuously at the reaction temperature. In this case, too, the aliphatic alcohol specified above can be used as the reaction medium, a mixture thereof with water or water alone. 1 to 10 mol can be added to the reaction mixture to accelerate the methylation reaction. parts of alkali metal bromide or iodide. When using an alkali carbonate, the compound of the formula II can first be dissolved by heating the two components in water and the dichloromethane is metered in to the resulting solution subsequently or only after it has cooled down.

The reaction time depends on the reaction temperature and the possible presence of alkali metal bromide or iodide as catalyst. It ranges from 1 to 10 h.

The compound of formula I is easily isolated from the reaction mixture after degassing the pressure vessel by filtering its contents. The easy isolation of the compound of formula I is due to its low solubility in said reaction medium. After drying, a technically pure compound of the formula I is obtained, which can be purified, for example, by precipitation through its alkali salt, by treatment with hydrogen peroxide, recrystallization from water and the like.

The main advantage of the process according to the invention is the high yields of the technically pure compound of the formula I in the range from 80 to 95% of theory. Another advantage is to obtain a compound of formula I with a low content of colored impurities, which is not common in the hitherto known processes for the preparation of this compound.

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

Example 1

To a solution of 8.3 g (50 mmol) of the compound of formula II in 50 ml of 1M-NaOH in a pressure vessel is cooled to about -10 ° C and cooled to the same temperature with a solution of dichloromethane in methanol (3.28 g in 21.9 ml). solution (65 mmol), the autoclave is closed and heated to 80 DEG C. for 4 h with stirring. After cooling the autoclave with cold water, it is deaerated and the resulting suspension of the compound of the formula I is filtered off with suction. After washing with water or ethanol, the product is dried at 100 to 110 ° C to constant weight. Yield 8.23 g (91.4% of theory) of a white powdery product, m.p. 244.5-246 ° C. The melting point is in accordance with the data in the introduction of the cited literature.

Example 2. ,

A mixture of 8.3 g (50 mmol) of the compound of formula II, 7.05 g (51 mmol) of anhydrous potassium carbonate and 50 ml of water is refluxed with stirring until the compound of formula I is in solution. The solution obtained is poured into a pressure vessel, cooled to about -10 DEG C. and a solution of dichloromethane in methanol (2.90 g in 19.4 ml of solution; 57.4 mmol) cooled to the same temperature is added, the autoclave is closed and stirred. is heated to 80 [deg.] C. for 10 h. The reaction mixture is worked up as in Example 1. Yield 8.10 g (90.0% of theory) of a white powdery product, m.p. 245-247 ° C.

CS 267 100 Bl

Example 3

To a solution obtained by refluxing 8.3 g (50 mmol) of the compound of formula II, 7.30 g (53 mmol) of anhydrous potassium carbonate and 50 ml of water are added 0.165 g (1.1 mmol) of sodium iodide, cooled to -10 ° C. C in an autoclave, a cooled solution of dichloromethane in methanol (2.90 g in 19.4 ml of solution; 57.4 mmol) is also added, the autoclave is closed and heated to 75 [deg.] C. with stirring for 1 h. The reaction mixture is worked up as in Example 1. Yield 7.94 g (88.1% of theory), mp 245-246.5 ° C.

Example4.

To a solution obtained at reflux 8.3 g (50 mmol) of the compound of formula II 6.36 g (60 mmol) of anhydrous sodium carbonate and 50 ml of water are added 0.165 g (1.1 mmol) of sodium iodide, cooled to -10 ° C in autoclave, a cooled solution of dichloromethane in methanol (3.53 g in 30 ml of solution; 70 mmol) was added, the autoclave was sealed and heated with stirring at 80 ° C for 2 h. The reaction mixture was worked up as in Example 1. Yield 7 , 50 g (83.3% of theory) of a white fine powder with a mp of 245.5-247 ° C.

Example 5

To a solution obtained by refluxing 83 g (0.5 mol) of the compound of formula II, 63.6 g (0.6 mol) of anhydrous sodium carbonate and 500 ml of water are added 1.65 g (11 mmol) of sodium iodide, the autoclave is sealed and while stirring and heating to 80 ° C, dichloromethane gas is added from a low volume pressure vessel. After consumption of about 30 g (0.6 mol) of dichloromethane, the reaction is stopped and the reaction mixture is worked up as in Example 1. Yield 74.1 g (82.3% of theory) of a white product, m.p. 245.5-247 ° C.

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of 3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione of formula I (I) ch ₃ characterized in that 100 mol. parts of 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II (II) is reacted with 95 to 160 mol, parts of dichloromethane, in the presence of 95 to 130 mol. parts of alkali hydroxide and / or alkali carbonate in an aliphatic alcohol medium having 1 to 3 carbons and / or water, at a temperature of 35 to 110 ° C. CS 267 100 Bl 5 2. The process according to item 1, characterized in that the reaction is carried out in the presence of 1 to 10 mol. parts of alkali metal bromide or iodide. 3. The process according to item 1, characterized in that the reaction takes place at a temperature of 60 to 80 ° C.