CS270547B1 - Method of 3-methyl-1-/5-oxohexyl/-7-n-propyl-3,7-dihydro-1h-purine-2,6-dione preparation - Google Patents

Abstract

The solution relates to the method of preparation 3-methyl-1- (5-oxohexyl) -7-n-propyl-3,7-. -dihydro-1H-purine-2,6-dione of formula I, which is used as medicine in medicine vasodilators and haemorrhea propantophylline. The process is characterized in that a 6-amino-5-forylamino-1-methyl- (1H, 3H) -pyrimidine-2,6-dione Formula II is reacted with a n-propyl halide in the presence of alkali carbonate in water or. \ t containing it with an aliphatic alcohol and a number carbon atoms 1 to 3, at 0 to 100 oe and after the reaction aa to the mixture is completed adding an alkali carbonate or hydroxide and reacted with 5-oxohexyl halide in aromatic or chlorinated · hydrocarbon in the presence of a catalyst interphase transfer at 30 to 120 OC.

Description

The invention relates to a process for the preparation of 3-methyl-1- (5-bexhexyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione of formula I ⁰ CH ₂ CH _{2 CH 3}

CK3 _(I) which is used in medicine as a peripheral vasodilator and hemorelogist propentofylline.

DopoeiaX ea and a compound of formula I were prepared by reacting 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione with 5-oxohexyl bromide in an aqueous-alcoholic medium in the presence of an alkali metal hydroxide / W. Moehler, M. Qayme, 3. Komárek: DE OS 2 330 742 /, from a pre-prepared alkaline eole of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and 5 -oxohexyl halide in aprotic potassium or in situ prepared potassium eol from 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and anhydrous potassium carbonate in aprotic solvent (W. Moehler, M. 3ayme, 3. Komárek: CA 1075 690 /. Another known method for the preparation of a compound of formula I is the alkylation of the alkali metal salt of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and the alkane reap, 5-oxohexanol arenesulfonates in dimethylformamide. / Shiratori Seiyaku Co. Ltd .: Cr. Kokai Tokkyo Koho 80 76 877 /, optionally alkylation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and α-alkane, reap, with 5-oxohexanol arenesulfonates in dimethylformamide / H. Furrer: DE OS 2 929 566 /. The known method for preparing a compound of formula I predetermines the addition of water to the triple bond of 3-methyl-1- (5-hexynyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione catalyzed by mercuric sulfate. and kyeeliny eírová / Sgiratori Seiyaku Co. Ltd .: 3pn. Kokai Tokkyo Koho 81 45 474 /. The known methods for the preparation of a compound of formula I are the alkylation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and oxohexyl bromide under interfacial catalysis conditions in a mixture of dichloromethane and aqueous sodium hydroxide in the presence of tetrabutylammonium hydro-. gene sulfate / F. Calvo MOndelo: pat. ES 549 162 /, raep. alkylation of 3-methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione with oxohexyl bromide in the presence of neutral alumina by sonication in an aqueous-toluene medium / P. Mora Ruedae: pat. ES 549 102 / and alkylation of the tetralkylammonium] salt of 3-butyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione with 5-oxohaxyl halide in an organic solvent medium (A. Fisherman and epol .: CS AO 266 291 /.

A disadvantage of the preferred processes for the preparation of the compound of the formula I is the use of a color-dark propentofylline which is difficult to read in order to obtain a substance suitable for pharmaceutical use.

The process according to the invention eliminates these disadvantages by reacting 6-amino-5-formylamino-1-methyl- (1H, 3H) -pyrimidine-2,6-dione of the formula II *

with n-propyl halide in the presence of an alkali carbonate in an aqueous medium or a mixture thereof with an aliphatic alcohol having 1 to 5 carbons, an alkali carbonate or hydroxide is reacted to form a 5-oxohexyl halide in an aromatic or chlorinated hydrocarbon under the conditions interfacial catalysis.

CS 270 547 Bl

The process according to the invention is carried out in such a way that 100 mol. parts of the compound of the formula II are dissolved in aqueous solution by heating 50 to 150 mol. parts of alkali carbonate, 100 to 150 mol. parts of n-propyl halide either alone or in a solution of an aliphatic alcohol having a carbon number of 1 to 3 and the mixture is heated to a temperature of 40 to 100 ° C. for 5 h, after which time 100 to 120 mol. parts of alkali carbonate or alkali hydroxide and 100 to 120 mol. parts of 5-oxohexyl halide in an aromatic or chlorinated hydrocarbon.a in the presence of 1 to 10 mol. parts of the interfacial transfer catalyst is heated to a temperature of 30 to 120 ° C for min. 6 h.

Sodium or potassium carbonate, sodium or potassium hydroxide can be used as the alkali carbonate or hydroxide. The halide in n-propyl halide and in 5-oxohexyl halide represents chlorine, bromine or iodine. Instead of the most reactive iodides, chlorides or bromides can be used less reactively in the presence of 0.5 to 20 mol. parts of alkali iodide or bromide or iodine per 100 mol. parts of the corresponding n-propyl halide. Inorganic tetraalkylammonium salts, e.g. hydrochlorides, hydrobramides, hydrogen sulphates of tetrabutylammonium, triethylbenzylammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium with a carbon number of 8 to 18 in alkyl, or a mixture of these alkyls with a carbon number of 8 to 18. As the aromatic or chlorinated hydrocarbon, benzene, benzene can be used , xylene, dichloromethane. The reaction mixture after the reaction of n-propyl halide can be purified by means of sorbents e.g. activated carbon.

The compound of formula I is isolated from the reaction mixture by separating the aromatic or chlorinated hydrocarbon layer, washing with water, drying and distilling off the solvent, finally under vacuum. The crude compound of formula I obtained is recrystallized from a suitable solvent. A solution of a compound of formula ¹ ! in an aromatic or chlorinated hydrocarbon can be purified with sorbents after drying.

The main advantage of the process according to the invention is the simplification of the process for the preparation of the compound of formula I from the compound of formula II without the need to isolate and purify successively in situ the resulting 3-methyl-3,7-dihydro-1H-purine-2,6-dione or 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione, which results in a shortening of the preparation time, the elimination of losses and thus in an increase in yields to 65-80 χ while maintaining the purity of the compound about 99%.

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

Example 1 · ’

36.8 g (0.2 mol) of the compound of the formula II and 31.8 g (0.23 mol) of potassium carbonate in 150 ml of water are heated to 80 DEG C. and stirred until a solution is formed. It is cooled to room temperature and 28.3 g (20.9 ml) (0.23 mol) of n-propyl bromide in 50 ml of ethanol are added together with 3.32 g (0.02 mol) of potassium iodide. The mixture was heated at 80 ° C for 10 h with stirring. After this time, the reaction mixture is cooled to room temperature, 8.0 g (0.2 mol) of sodium hydroxide are added and, after dissolving it, 35.8 g (0.2 mol) of 5-oxohexyl bromide in 150 ml of toluene and 8.08 g are dissolved. g (0.02 mol) of methyl tri-n-octylammonium chloride. The mixture was heated at 110 ° C for 6 h with stirring. After cooling, the aqueous layer was separated, the organic layer was washed with water, dried over anhydrous sodium sulfate. Silica gel was added to the dried toluene layer and stirred at room temperature for 15 minutes. After filtering off the silica gel, the volatiles are distilled off, preferably under reduced pressure, and the remaining syrupy product is recrystallized from methyl tert; butyl ether. 52.1 g (85% of theory) of the compound of the formula I are obtained, m.p. 68.5 - 70 ° C. .

Example 2

36.8 g (0.2 mol) of the compound of the formula II and 24.4 g (0.23 mol) of sodium carbonate in 150 ml of water are heated to 80 DEG C. and stirred until a solution is formed. It is added to the cooled solution

CS 270 547 Bl 3

28.3 g of 20.9 ml (0.23 mol) of n-propyl bromide in 50 ml of methanol and 6.8 g (0.02 mol) of tetra-n-butylammonium hydrogen sulphate are heated with stirring at 80 DEG C. for 8 hours. The reaction mixture was cooled, activated carbon was added and stirred at room temperature for 15 minutes. After filtering off the activated carbon, 21.2 g (0.2 mol) of sodium carbonate are added and, after dissolving it, 35.8 g (0.2 mol) of 5-oxohexyl bromide in 150 ml of toluene. The mixture is heated at 110 DEG C. with stirring. for 7 h. The aqueous layer was separated and the toluene layer was worked up as in Example 1. The syrupy residue was recrystallized from toluene-hexane. 50.2 g (82% of theory) of the compound of the formula I are obtained, m.p. 68.5-70.5 ° C.

Example 3

36.8 g (0.2 mol) of the compound of the formula II and 31.8 g (0.23 mol) of potassium carbonate in 150 ml of water are heated to 80 DEG C. and concentrated to a solution. The solution was cooled to room temperature and 18.06 · 20.26 [mu] l (0.23 mol) of n-propyl chloride in 50 ml of n-propanol and 3.32 g (0.02 mol) of potassium iodide were added. The mixture was heated at 80 ° C for 10 h with stirring. After this time, the reaction mixture is cooled, activated carbon is added and stirred at room temperature for 15 minutes. Activated carbon is filtered off with suction, and 11.22 g (0.2 mol) of potassium hydroxide are added. After its dissolution, 26.9 (0.2 mol) of 5-oxohaxyl chloride in 150 ml of xylene and 8.0 g (0.02 mol) of benzyldimethylalkylasonium bromide are added. The mixture was heated at 110 ° C for 8 h with stirring. After cooling, the aqueous layer was separated and the xylan layer was worked up as in Example 1. The syrupy residue was recrystallized from ethanol-hexane. 39.8 g (65% of theory) of the compound of the formula I are obtained, m.p. 69-70.5 te.

Example 4

36.8 g (0.2 mol) of the compound of the formula I and 31.8 g (0.23 mol) of potassium carbonate in 150 ml of water are heated to 80 DEG C. and stirred until a solution is obtained. After cooling to room temperature, 28.3 g of 20.9 n-propyl bromide in 50 ml of ethanol are added and the mixture is heated at 80 DEG C. for 10 hours with stirring. After cooling, 27.64 g (0.2 mol) of potassium carbonate are added, after dissolving 26.9 g (0.2 mol) of 5-oxohexyl chloride in 100 ml of chloroform and 6.44 g (0.02 mol) of tetra- n-bbtylaosnium bromide. The mixture was heated with stirring at 110 ° C for 7 h. After cooling and separating the aqueous layer, the chloroform layer was washed with water and treated as in Example 1. The syrupy product was recrystallized from gasoline. 42.9 (70% of theory) of the compound of formula I are obtained, m.p. 68.5-70.5 ° C.

Claims (9)

BACKGROUND OF THE INVENTION Process for the preparation of 3-setyl-1- (5-oxohexyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione of formula I characterized in that 100 mol. parts of 6-amino-5-formylamino-1-methyl- (1H, 3H) -pyrimidine-2,6-dione of formula II reacted with 100 to 150 mol. parts of n-propyl halide in the presence of 50 to 150 mol. ₄ parts of alkali carbonate in a medium of water or a mixture thereof with an aliphatic alcohol having a carbon number of 1 to 3 at a temperature of 40 to 100 ° C, and after completion of the reaction, 100 to 120 mol are added to the mixture. parts of alkali carbonate or hydroxide and reacted with 100 to 120 mol. parts of 5-oxoxyl halide in an aromatic or chlorinated hydrocarbon in the presence of an interfacial transfer catalyst at a temperature of 30 to 120 ° C and the compound of formula I is isolated. 2. The process according to item 1, characterized in that the reaction with n-propyl halide is carried out at a temperature of 65 to 80 ° C. 3. The process according to item 1, characterized in that n-propyl chloride, n-propyl bromide or n-propyl iodide is used as the n-propyl halide. 4. The process according to items 1 and 3, characterized in that n-propyl chloride or n-propyl bromide is used in the presence of 0.5 to 20 mol. parts of sodium or potassium iodide, or iodine per 100 mol. parts of said n-propyl halides. 5. The process according to items 1 and 3, characterized in that n-propyl chloride is used in the presence of 0.5 to 20 mol. parts of sodium or potassium bromide per 100 mol. parts of n-propyl chloride. 6. The preparation method according to item 1, characterized in that 5-oxohexyl chloride, 5-oxohexyl bromide or 5-oxohexyl iodide is used as the 5-oxohexyl halide. 7. A process according to claim 1, characterized in that an inorganic salt of tetraalkylammonium, such as tetrabutylammonium salt, triethylbenzylammonium, tri-n-: octylmethylammonium, dimethylbenzylalkylammonium having a carbon number of 8 to 18 in alkyl, is used as the interfacial transfer catalyst. a mixture of these alkyls having 8 to 18 carbons. 8. The preparation process according to item 1, characterized in that benzene, toluene, xylene, chloroform, dichloromethane are used as the aromatic or chlorinated hydrocarbon. · 9. A process according to claim 1, wherein the compound of formula I is isolated by separating a layer of aromatic or chlorinated hydrocarbon containing a compound of formula I, washing with water, drying and distilling off the volatile components.