CS270545B1

CS270545B1 - Method of 3-methyl-1/5-oxohexyl/-7-n-propyl-3,7-dihydro-1h-purine 2,6-dione preparation

Info

Publication number: CS270545B1
Application number: CS889072A
Authority: CS
Inventors: Alfonz Ing Csc Rybar; Marian Ing Tegza; Milan Clen Korespondent Repas; Fridrich Rndr Csc Szemes; Richard Doc Ing Csc Frimm; Dusan Ing Csc Hesek; Michal Judr Ing Guttmann; Peter Mudr Cscsc Turcani; Juraj Ing Csc Tuleja; Vaclav Rndr Csc Konecny; Lubor Ing Bystricky; Miroslav Ing Csc Kriz
Original assignee: Rybar Alfonz; Tegza Marian; Milan Clen Korespondent Repas; Szemes Fridrich; Frimm Richard; Hesek Dusan; Guttmann Nichal; Peter Mudr Cscsc Turcani; Juraj Ing Csc Tuleja; Konecny Vaclav; Bystricky Lubor; Miroslav Ing Csc Kriz
Priority date: 1988-12-30
Filing date: 1988-12-30
Publication date: 1990-07-12
Also published as: CS907288A1

Abstract

Riešenie sa týká sposobu pripravy 3-mety1-1-(S-oxohexy1)-7-n-propy1-3,7- -dihydro-lH-purin-2,6-dionu vzorca I, ktorá sa používá v medicine ako periférne vazodilátans a hemoreologikum propentofylln. Postup spočívá v tom, že sa 3-metyl-3,7-dihydro-lH-purin-2,6-dion vzorca II nechá reagovat s n-propylhalogenidom za přítomnosti uhličitanu al* kalickáho kovu v prostředí dimetylformamidu pri teplote 60 až 150 oc, dimetylformamid sa po ukončeni reakcie odstráni, zvyšok ea rozpustí vo vodnom roztoku uhličitanu alebo hydroxidu alkalického kovu a vzniklý roztok sa nechá reagovat s 5-oxohe^ylhalogenidom v aromatickom alebo chlorovanou) uhlovodíku za přítomnosti katalyzátora medzifázového přenosu pri teplote 30 až 120 oc.The solution relates to the method of preparation 3-mety1-1- (oxohexy1 S) -7-n-propy1-3,7- -dihydro-1H-purine-2,6-dione of formula I, which is used in medicine as peripheral vasodilator and propentophyllin hemorrhage. The procedure consists in being 3-methyl-3,7-dihydro-purine-2,6-dione of formula II is reacted with n-propyl halide in the presence of al * carbonate calcium metal in dimethylformamide at 60 to 150 DEG C., dimethylformamide is removed after the reaction is complete, the remainder e dissolved in an aqueous solution alkaline carbonate or hydroxide metal and the resulting solution is reacted with a 5-oxoalkyl halide in the aromatic or chlorinated) hydrocarbon the presence of an interfacial catalyst transfer at 30 to 120 ° C.

Description

CS 270 545 B1

The present invention relates to a process for the preparation of 3-methyl-1- (5-oxohexyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione of the formula Iq C HZC H3 CH which is used in medicine as a peripheral vasodilator and a heaoreologic propentophylline.

Ooposium X was prepared by reacting 3-methyl-7-n-propyl-3, 7-dihydro-1H-purine-2,6-dione and 5-oxohexylbroraide in an aqueous / alkaline environment with the presence of alkali metal hydroxide. / W. Moehler, M. 3ay * e, 3. Komárek: DE OS 2 330 742 /, from the previously prepared 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione 5 alkaline salt -oxohexyl halide in aprotic solvent or in situ prepared potassium salt from 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and anhydrous potassium carbonate in an aprotic solvent / W . Moehler, M. Oayme, 3. Keaarek: CA 1,075,690 /. Another method of preparing the compound of Formula 1 is the alkylation of the alkali salt of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione with alkene. 5-oxohexanol arenesulfonates in dimethylformamide / Shiratorl Saiyaku Co. Ltd.: Opn. Coca! Tokkyo Koho 80 76 877 /, where appropriate, the alkylation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and alkene, respectively. 5-oxohexanol arene sulfonates in dimethylformamide / H. Furrer: DE OS 2 929 566]. The BalSlu known method of preparing the compound of Formula I is the addition of water to the triple bond of 3-methyl-1- (5-haxinyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione from catalysis of mercuric sulfate and sulphate / Shiratorl Saiyaku Co. Ltd.: Opn. Kokei Tokkyo Koho 81 45.474 /. The last known methods for the preparation of the compound of formula I are the alkylations of 3-aethyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione with oxohexyl bromide from the conditions of inter-catalysis in dichloromethane - aqueous hydroxide solution sodium in the presence of tatrabutylaaonium hydrogen sulphate / F. Calvo Mondelo: Pat. EC 549 162 /, resp. alkylation of 3-ethyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione with oxohexylbromide in the presence of neutral aluminum oxide by sonication in water-toluene medium (P-Mora Ruedae: pat) . ES 549 102 / alkylation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purin-2,6-dione 3-tetraalkylammonium salt with 5-oxohexyl halide in an organic solvent / A. Fisherman and apo .: Cs.AO266 291).

A disadvantage of the above described processes for the preparation of the compound of formula I is to obtain a colorlessly 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, based on the fact that 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II is not reacted.

with n-propyl halide in the presence of an alkali metal carbonate in a dimethylformamide medium which is dissolved in a dilute aqueous solution of alkali metal hydroxide or alkali metal carbonate after the centrifugation reaction, preferably by vacuum distillation, and the resulting solution is reacted with a solution of 5-oxohexyl-2 CS 27C 545 B1 halide in an aromatic or chlorinated hydrocarbon under interfacial catalysis conditions

The process of the invention is carried out by mixing 100 ml. parts of compound (II), 100 to 150 mol. n-propyl halide and 50 to 150 mol. parts of the alkali metal carbonate are heated in dimethylformamide to 60 to 150 ° C, preferably 90 to 110 ° C, for min. After 1 h, the dimethylformamide was distilled off under reduced pressure, and the distillation residue was dissolved in an aqueous solution of 100-120 mol. parts of an alkali metal carbonate or alkali metal hydroxide, 100 to 120 moles are added to the resulting solution. parts of the 5-oxohexyl halide in solution in an aromatic or chlorinated hydrocarbon, 1 to 10 moles are added. parts of the interfacial transfer catalyst are heated to 30 to 120 ° C for min. 6 h.

Appropriate chlorides, bromides or iodides can be used as n-propyl halide and 5-oxohexyl halide. 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 an iodide or an alkaline bromide, iodine to 100 mol. of the respective n-propyl halide. Sodium or potassium carbonate, sodium or potassium hydroxide may be used as carbonate or alkali metal hydroxide. Inorganic solitetraalkylammoniums such as hydrochlorides, hydrobromides, tetrabutylammonium hydrogen sulfates, triethylbenzylammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium with carbon numbers of 8 to 18 in the alkyl, or a mixture of these alkyls having carbon numbers of 8 to 18 are used as interfacial transfer catalysts. or the chlorinated hydrocarbon may be benzene, toluene, xylene, chloroform, dichloromethane. After reaction of the n-propyl halide, the reaction mixture can be purified by 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 reduced pressure. The crude compound of formula I is recrystallized from a suitable solvent. A solution of the compound of formula I in an aromatic or chlorinated hydrocarbon can be purified by 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 for isolation and purification of the 3-methyl-7-n-propyl-3,7-dihydro-1H-purine. 2,6-dione, which results in a shortening of the preparation time, elimination of losses and thus an increase in yields of 70-85% while maintaining a pure compound of about 99%. In Salsh, the subject matter of the invention is described in exemplary embodiments without limiting the invention. Example 1

A mixture of 33.2 g (0.20 mol) of the compound of formula II, 24.4 g (0.23 mol) of anhydrous sodium carbonate, 28.3 g (0.23 mol) of n-propylbrooid, 3.0 g ( 0.02 moles of sodium iodide in 100 ml of dimethylformamide was heated to 100-110 ° C with stirring for 4.5 h. After this time, the dimethylformamide was distilled off under reduced pressure and the remaining solid residue was dissolved in 75 ml of 3M-NaOH and 20 ml of water. Charcoal is added to the solution and stirring is continued for 15 min. pri labor. the temperature is filtered. To the filtered solution was added 100 mL of toluene, 26.9 g (0.20 mol) of 5-oxohexyl chloride and 6.44 g (0.02 mol) of tetrabutylammonium bromide and heated to 110 ° C for 6 h. the organic layer was washed with water and dried over anhydrous sodium sulfate. The toluene was dried to dryness and stirred at room temperature. heat for 15 min. After filtration of the silica gel, the volatiles were distilled off under reduced pressure and the resulting syrup was recrystallized from toluene-hexane. 50.9 g (83% of theory) of the compound of formula I are obtained, mp 68.5-70 ° C.

Claims

Example 2 A mixture of 33.2 g (0.20 mol) of the compound of formula XI, 31.8 g (0.23 mol) of potassium carbonate base, 18.06 g (20.3 ml; 0, 23 mol of n-propyl chloride, 3.32 g (0.02 mol) of potassium iodide in 100 ml of dimethylformamide are heated with stirring at 100 to 110 ° C for 4 h. Dimatylformamide is distilled off under reduced pressure, the residue after distillation is distilled. dissolved in a mixture of 75 ml of 3M-KOH and 25 ml of water. 100 ml of toluene, 35.8 g (0.2 mol) of 5-oxohexyl bromide and 6.8 g (0.02 mol) of tatrabutylammonium hydrogen sulphate are added and the mixture is heated at 110 DEG C. for 6 h. 1. The syrup residue is coated with methanol. 44.7 g (73% of theory) of the compound of formula I, m.p. 69-70.5 ° C. EXAMPLE 3 A mixture of 33.2 g (0.20 mol) of the compound of formula ZI, 31.8 g (0.23 mol) of potassium carbonate base, 18.06 g (20.3 ml; 0.23 mol) of n- of propyl chloride, 2.06 g (0.02 mol) of sodium bromide in 100 ml of dimethylformamide * are heated with stirring at 100 to 110 ° C for 5 h. The dimethylformamide is distilled off under reduced pressure, the residue after distillation is dissolved in a solution of 31.1 g (0.225 mol) of potassium carbonate in 100 ml of water. 100 ml of xylene, 26.9 g (0.20 mol) of 5-oxohexyl chloride and 8.08 g (0.02 mol) of methyltri-n-octylammonium chloride are added and stirred at 110 ° C for 7 h. and the organic layer is worked up as in Example 1. The syrup residue is overcoated from the tert-butyl. butyl ether. 48.4 g (79% of theory) of the compound of formula I, m.p. 68.5-70 ° C. Example 4 A mixture of 33.2 g (0.2 mol) of the compound of formula IX, 24.4 g (0.23 mol) of sodium carbonate base, 28.3 g (20.9 ml; 0.23 mol) of n- propyl bromide in 100 ml of DMF was heated to 100-110 ° C for 5 h under stirring. Dimatylformamide was removed by distillation under reduced pressure, the residue after distillation was dissolved in 75 ml of 3M-NaOH and 30 ml of water, 100 ml of chloroform was added , 35.8 g (0.2 mole) of 5-oxohexyl bromide, 8.0 g (0.02 mole) of benzyldimethyl-alkylammonium bromide and heat to 110 ° C for 8 h while stirring. and as described in Example 1. The syrup residue is recrystallized from ethyl acetate-hexane. 47.2 g (77% of theory) of the compound of formula X, m.p. 68-69.5 ° C, SUBJECT OF THE INVENTION

A process for the preparation of 3-methyl-1- (6-oxohaxyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione of formula I CH 2 CH 2 CH 3

Characterized in that 100 mol. parts of 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II CS 270 545 B1 x.

C 1 H 5 is reacted with 100 to 150 mol. dialml n-propyl halide, in the presence of 50-150 mol. of the alkali metal carbonate in dimethylformamide at 60-150 ° C, the dimethylformamide is removed after the reaction is complete, and the residue is dissolved in a dilute aqueous solution of 100-120 mol. % of an alkali metal carbonate or hydroxyalcaline metal carbonate, and the resulting solution is reacted with a solution of 100-120 mol. 5-oxohexyl halide in an aromatic or chlorinated hydrocarbon in the presence of a phase transfer catalyst at 30-120 ° C and the compound of formula 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 SO to 110 ° C.

3. A process according to claim 1, wherein n-propyl chloride, n-propyl bromoride 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 raal. sodium iodide or potassium iodine per 100 mol. parts of said n-propyl halides.

5. A process according to claim 1, wherein n-propyl chloride is used in the presence of 0.5 to 20 mol. parts of sodium or potassium bromide to 100 mM. 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. Process according to claim 1, characterized in that an inorganic salt of tetraalkylammonium, such as tetrabutylammonium salt, triethylbenzylammonium, tri-n-octylmethylammonium salt, dimethylbenzylalkylammonium salt of S-18 in the alkyl, is used as the intermediate phase catalyst it is a mixture of these alkyls with carbon numbers of 8 to 18.

8. Process according to claim 1, characterized in that benzene, toluene, xylene, chloroform, dichloromethane are used as the aromatic or chlorinated hydrocarbon.

9. Process according to claim 1, characterized in that the compound of the formula I is isolated by separating the aromatic or chlorinated hydrocarbon-containing compound of the formula I, washing with water, drying and the volatile components being distilled off. »