CS270547B1

CS270547B1 - Preparation of 3-methyl-1- (5-oxohexyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione

Info

Publication number: CS270547B1
Application number: CS889074A
Authority: CS
Inventors: Alfonz Ing Csc Rybar
Original assignee: Rybar Alfonz
Priority date: 1988-12-30
Filing date: 1988-12-30
Publication date: 1990-07-12
Also published as: CS907488A1

Abstract

Riešenia sa týká sposobu přípravy 3-mety1-1-(5-oxohexyl)-7-n-propy1-3,7- . -dihyďro-lH-purln-2,6-dionu vzorca I, ktorá sa používá v medicína ako parifárna vazodilatans a hemoreologikum propantofylin. Postup spočívá v tom, že ea 6-amino-5-foraylamino-l-metyl-(lH,3H)-pyrimidin-2,6-dion vzorca II nechá reagovat a n-propylhalogenidom za přítomnosti alkalického uhličitanu v prostředí vody alebo jej zaesi s alifatickým alkoholom a počtom uhlíkov 1 až 3, pri teplota O až 100 oe a po skončeni reakcia aa k zmesi přidá alkalický uhličitan alebo hydroxid a nechá sa reagovat s 5-oxohexylhalogenidom v aromatickou alebo v chlórováno· uhlovodíku za přítomnosti katalyzátora medzifázového přenosu pri teplote 30 až 120 OC.The solution relates to a method of preparing 3-methyl-1-(5-oxohexyl)-7-n-propyl-3,7-. -dihydro-1H-purine-2,6-dione of formula I, which is used in medicine as a peripheral vasodilator and hemorrheologic agent propantophylline. The procedure consists in reacting 6-amino-5-formylamino-1-methyl-(1H,3H)-pyrimidine-2,6-dione of formula II with n-propyl halide in the presence of alkali carbonate in water or by esterifying it with an aliphatic alcohol having 1 to 3 carbons, at a temperature of 0 to 100°C, and after the reaction is complete, alkali carbonate or hydroxide is added to the mixture and reacted with 5-oxohexyl halide in an aromatic or chlorinated hydrocarbon in the presence of an interphase transfer catalyst at a temperature of 30 to 120°C.

Description

EN 270 547 B1 1

The invention relates to a process for the preparation of 3-methyl-1- (5-bxohexyl) -7-n-propyl-3,7-dihydro-1H-

which is used in medicine as peripheral vasodletlet and the hemorrhage propentophyllin.

To date, the compound of formula I has been prepared by reacting 3-methyl-7-n-propyl-3,7-dibromo-1H-purine-2,6-dione and 5-oxohexylbromide in an aqueous-alcoholic medium in the presence of an alkali metal hydroxide. / W. Moehler, M. 3ayme, 3. Komárek: DE OS 2 330 742 /, a previously prepared alkaline salt of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and 5-oxohexyl halide in an aprotic solvent or an in situ sieve of the prepared potassium salt of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and anhydrous potassium carbonate and an aprotic solvent (W). Moehler, M. 3ayme, 3rd Komarek: CA 1075 690 /. Another known method for the preparation of a compound of formula I is the alkylation of the alkali salt of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione with alkene and the like. of 5-oxohexanol aramidosulfonates in dimethylformamide / Shlratori Seiyaku Co. Utd .: 3pn. Coca! Tokkyo Koho 80 76 877 /, where appropriate, the alkylation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione s-alkene, respectively. 5-oxohexanol arene sulfonates in dimethylformamide / H. Furrer: OE OS 2 929 566 /. A further known method for the preparation of a compound of formula I is 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 under the catalysis of mercuric sulphate and sulfuric acid / Sgiratori Seiyaku Co. Ltd.: 3pn. Kokal Tokkyo Koho 81 45,474 /. The latest known methods for the preparation of the compound of formula I are the alkylation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and oxohexylbromide to provide interfacial catalysis in a mixture of dichloromethane - aqueous hydroxide solution sodium in the presence of tetrbutylammonium hydrogen sulphate / F. Calvo MOndelo: pat. EC 549 162 /, resp. alkylation of 3-methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione with oxohexylbromide in the presence of neutral aluminum oxide under ultrasound in aqueous / toluene medium. Mora Ruedas: Pat. ES 549 102 / and alkylating the tetralkylammonium salt of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione with 5-oxohexyl halide in an organic solvent (A). Rybář et al .: CS AO266 291 /.

A disadvantage of doposic methods of preparing the compound of formula (I) is to obtain a pharmacologically dark propentophyllin which has to be difficult to purify in order to obtain a substitute for pharmaceutical use.

These disadvantages are eliminated by the process of the invention, which is based on reacting 6-amino-5-formylamino-1-methyl- (1H, 3H) -pyrimidine-2,6-dione of formula II

O

CH3 (II) with n-propyl halide in the presence of alkali carbonate in an environment of water or a mixture thereof with an aliphatic alcohol having a carbon number of 1 to 5, adding an alkali carbonate or hydroxide to the resulting reaction mixture and reacting with 5-oxohexyl halide in aro - a matric or chlorinated hydrocarbon under the condition of interfacial catalysis. 2 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 formula II is soluble! heating in an aqueous solution of 50 to 150 mol. parts of alkali carbonate, 100 to 150 moles are added. parts of n-propyl halide either alone or in a solution of an aliphatic alcohol having a carbon number of 1 to 3 and heating the mixture to a temperature of 40 to 100 Cmin. for 5 h, after which 100 to 120 moles are added to the reaction mixture. parts of an alkali carbonate or alkali hydroxide and 100 to 120 moles. parts of 5-oxohexyl halide in an aromatic or chlorinated hydrocarbon and in the presence of 1 to 10 mol. parts of the phase transfer catalyst are heated to 30 to 120 ° C for min. 6 h.

Sodium or potassium carbonate, sodium or potassium hydroxide may be used as the alkali carbonate or hydroxide. The halide in the n-propyl halide and the 5-oxohexyl halide is chlorine, bromine or iodine. Instead of the most reactive iodides, less reactive chlorides or bromides can be used in the presence of 0.5 to 20 moles. parts of alkaline iodine or bromide are iodine per 100 mol. of the respective n-propyl halide. Inorganic salts of tetraalkylammonium, e.g. hydro-chlorides, hydrobramides, tetrabutylammonium hydrogen sulfates, triethylbenzylammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium having a carbon number of 8 to 18 in the alkyl, are used as catalysts for interfacial transfer; As the aromatic or chlorinated hydrocarbon, benzene, toluene, chloroform, xylene, dichloromethane may be used. Reaction mixture after reaction! n-propyl halide can be purified using 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 the compound of Formula 1! in an aromatic or chlorinated hydrocarbon can be dried by sorbents *

The main advantage of the process according to the invention is the simplified process for the preparation of the compound of formula I from the compound of formula IX without the need to isolate and purify successive "in situ" formed 3-methyl-3,7-dihydro-1H-purine-2,6-dione, respectively. 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione, which was taken into account in the shortened preparation time, the elimination of losses and thus the elevation of the extracts to 65-80 χ while maintaining Example 1 '36.8 g (0.2 mol) of the compound of the formula II and 31.8 g (0.23%) of the compound are about 99% pure. mole) of potassium carbonate in 150 ml of water is heated to 80 DEG C. and stirred until a solution is formed, cooled to room temperature and 28.3 g of 20.9 ml (0.23 mol) of n-propyl bromide are added. 50 ml of ethanol together with 3.32 g (0.02 mole) of potassium iodide The mixture is heated with stirring at 80 ° C for 10 h.

After this time, the reaction mixture was cooled to room temperature, sodium hydroxide (8.0 g, 0.2 mole) was added and 5-oxohexyl bromide (35.8 g, 0.2 mole) in toluene (150 ml) and dissolved in toluene. 08 g (0.02 mol) of methyl tri-n-octylammonium chloride. The mixture was heated to 110 ° C with stirring for 6 h. After cooling, the aqueous layer was separated, the organic layer was washed with water, dried over anhydrous sodium sulfate. Silica gel is added to the dried toluene layer and stirred at room temperature. heat 15 min. After filtering off the silica gel, the volatile components are distilled off, preferably under reduced pressure, and the remaining syrup product is recrystallized from methyl tert-butyl ether. There are 52.1 g (85% of theory) of the compound of formula I, mp 68.5-70 ° C. Example 2 36.8 g (0.2 mol) of the compound of formula II and 24.4 g (0.23 mol) of sodium carbonate in 150 ml of water are heated to 80 ° C and stirred until a solution is obtained. Add to the cooled solution

Claims

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 and are stirred at 80 ° C. The reaction was cooled, added charcoal and stirred at room temperature. temperature 15 min. After filtering off the charcoal, 21.2 g (0.2 mol) of sodium carbonate are added and, after dissolution, 35.8 g (0.2 mol) of 5-oxohexyl bromide in 150 ml of toluene are added. The mixture is stirred at 110 ° C with stirring. 7 h. The aqueous layer was separated and the toluene layer treated as in Example 1. The syrup was covered with toluene-hexone. 50.2 g (82% of theory) of the compound of formula X are obtained, m.p. 68.5-70.5 ° C. Example 3 36.8 g (0.2 mol) of the compound of formula II and 31.8 g (0.23 mol) of potassium carbonate in 150 ml are heated to 80 ° C and stirred until a solution is obtained. The solution was cooled to room temperature and 18.06 20.26 ml (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 is heated to 80 ° C for 10 h with stirring. After this time, the reaction mixture is cooled, charcoal and stirring are added at room temperature. heat-to 15 min. Activated charcoal is filtered off with suction, 11.22 g (0.2 mol) of potassium hydroxide are added. After dissolving, 26.9 (0.2 sol) of 5-oxohexyl chloride in 150 ml of xylene and 8.0 g (0.02 mM) of benzyldimethylalkylammonium bromide are added. The mixture was stirred with stirring at 110 ° C for 8 h. After cooling, the aqueous layer was separated and the xylan layer was worked up as in Example 1. The sulfur residue was crystallized from ethanol-hexane. 39.8 g (65% of theory) of the compound of formula I, m.p. 69-70.5 Example 4 36.8 g (0.2 mol) of the compound of formula I and 31.8 g (0.23 mol) of potassium carbonate in 150 ml are heated to 80 ° C and stirred until a solution is obtained. After cooling to room temperature, 28.3 g> 20.9 n-prspyl bromide in 50 ml of ethanol is added and the mixture is heated at 80 ° C for 10 h with stirring. After cooling, 27.64 g (0%) is added. 2 mol of potassium carbonate, after dissolution of 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-butyl-ammonium bromide. The mixture was heated with stirring at 110 ° C for 7 h. After cooling, the aqueous layer was separated, the chloroform layer was washed with water and worked up as in Example 1. The syrupy product was crystallized from gasoline. 42.9 (70% of theory) of the compound of formula I, m.p. 68.5-70.5 ° C. BACKGROUND OF THE INVENTION

1. Preparation of 3-methyl-1- (5-oxohexyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione of formula X Λ CH2CM2CH3 IXN CH3-CO- (CH2 > 4 - N CH 3 (X) characterized in that 100 parts of 6-amino-5-formylamino-1-methyl- (1H, 3H) -pyrimidine-2,2-dione of formula II 4 CS 270 547 B1

being reacted with 100 to 150 mol. parts of n-propyl halide in the presence of 50-150 moles of alkali carbonate in a water environment or a mixture thereof with an aliphatic alcohol, counting carbon 1-3 to 40-100 ° C and adding 100-120 moles to the mixture. alkaline carbonate or hydroxide and is reacted with 100 to 120 mol. parts of the 5-oxohexyl halide in the aromatic or chlorinated hydrocarbon presence of an intermediate phase catalyst at 30-120 ° C and compound I is isolated.

2. Process according to claim 1, characterized in that the reaction with n-propyl halide is carried out at a temperature of 65 to 80 ° C.

3. A process according to claim 1, wherein n-propyl chloride, n-propyl bromide or n-propyl iodide is used as the n-propyl halide.

4. A process according to claim 1, wherein n-propyl chloride or n-propyl bromide is used in the presence of 0.5 to 20 mol. sodium iodide or potassium iodide, iodine per 100 mol. parts of said n-propyl halides.

5. A process according to claim 1, wherein n-propylchloride is used in the presence of 0.5 to 20 mol. parts of sodium or potassium bromide to 100 moles of n-propyl chloride.

6. A process according to claim 1, wherein 5-oxohexyl chloride, 5-oxohexyl bromide or 5-oxohexyl iodide is used as the 5-oxohexyl halide.

7. A process as claimed in claim 1, wherein an inorganic salt of tetraalkylammonium, such as tetrabutylammonium salt, triethylbenzylammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium having a carbon number of 8 to 18 in the alkyl, is used as the inter-phase transfer catalyst. o a mixture of these alkyls having a carbon number of 8 to 18.

8. A process according to claim 1 wherein the aromatic or chlorinated hydrocarbon is benzene, toluene, xylene, chloroform, dichloromethane.

9. A process according to claim 1, wherein the compound of formula (I) is isolated by separating an aromatic or chlorinated hydrocarbon-containing layer of the compound of formula (I), washing with water, drying and volatile components distilling off.