CS270546B1

CS270546B1 - Preparation of 3-methyl-1- (5-oxohexyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione

Info

Publication number: CS270546B1
Application number: CS889073A
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: CS907388A1

Abstract

Riešenia sa týká pripravy 3-uetyl-l5-oxohexyl)-7-n-propyl-3,7-dihydro-lH- ' -2,6-dionO vzorca I, ktorý sa použiva v medicine ako periférne vazodílatans a hemorsologlkum propeeitofylin. Postup spo-i čiva v to», že sa 3-«etyl-3,7-dihydro- í -lH-purin-2,6-dion vzorca II nechá rea-r š govaf s n-propylhalogenidois za prltoanos-: ti alkalického uhličitanu v prostředí vody alebo jej zeesi s alifatickým alko-j holom s počtoa uhlikov 1 až 3, pri teplo-' te 50 až 100 °C a po skončeni reakcie sa i přidá alkalický uhličitan alsbo hydroxid ' a 5-oxohexylhalogenií v aromatickom aleboi chlórovanom uhlovodicu a nechá sa rsago- : vat za přítomnosti katalyzátora aedzifázového přenosu pri taplote 30 až 120 OC.The solution relates to the preparation of 3-methyl-15-oxohexyl)-7-n-propyl-3,7-dihydro-1H-'-2,6-dione of formula I, which is used in medicine as a peripheral vasodilator and hemostatic agent propeitophyllin. The procedure consists in reacting 3-ethyl-3,7-dihydro-1H-purine-2,6-dione of formula II with n-propyl halides under the influence of alkali carbonate in water or its solution with an aliphatic alcohol with 1 to 3 carbon numbers, at a temperature of 50 to 100 °C and after the reaction is complete, alkali carbonate or hydroxide and 5-oxohexyl halide in an aromatic or chlorinated hydrocarbon are added and the reaction is allowed to proceed in the presence of a phase transfer catalyst at a temperature of 30 to 120 °C.

Description

Vynález sa týká sposobu přípravy 3-metyl-l-(5-oxohexyl)-7-n-propyl-3-,7-dihydrolH-purín-2,6-dionu vzorce IThe invention relates to a process for the preparation of 3-methyl-1- (5-oxohexyl) -7-n-propyl-3-, 7-dihydrol-1H-purine-2,6-dione of formula I

ch₃ (i) ktorý sa používá v medicine ako periférne vazodilatane a hemoreologlkum propentofylin.ch ₃ (i) which is used in medicine as peripheral vasodilates and hemorheology of propentofylline.

□oposial sa zlúčenina vzerca I připravovala reakciou 3-metyl-7-n-propyl-3,7-dihydro-lH-purin-2,6-dionu a 5-oxohexylbromidom vo vodno-akoholickom prostředí za přítomnosti hydroxidu alkalického kovu /W. Moehlsr, M- Qayme, 3. Komárek: OE OS 2 330 742/, v vepřed pripravenej alkalické] soli 3-metyl-7-n-propyl-3,7-dihydro-lH-purín-2,6-dionu a 5-oxohexylhalogenidu v aprotickom rozpúétadle alebo in sítu pripravene] draselné] soli z 3-«etyl-7-n-propyl-3,7-dihydro-lH-purín-2,6-dionu a bezvodého uhličitanu draselného v aprotickom rozpúStadle /W. Moehler, M. Oayme, □ . Komárek: CA 1 075 690/. dalšou známou metodou přípravy zlúčeniny vzroca I je alkylácia alkalické] soli 3,-metyl-7-n-propyl-3,7-dihydro-lH-purin-2,6-dionu a alkán- reap, arén-aulfonátmi 5-oxohexanolu v dimetylformaaide /Shiratori Seiyaku Co. Ltd.: Ορη. Kokai Tokkyo Koho 80 76 877/, připadne alkylácia 3-metyl-7-n-propyl-3,7-dihydro-lH-purin-2,6-dionu a alkán·*, rasp, arénaulfonátmi 5-oxohexánilu v dimetylformaaid/H. Furrer: DE OS 2 929 566/. Saláiu známu metodu přípravy zlúčeniny vzorca I představuje adicia vody na trojitú vazbu 3-inetyl-l-(5~hexinyl)~7-n-propyl-3.7 dihydro-lH-purin-2,6-dionu za katalýzy airanu ortutnatého a kyseliny sirové] /Shiratori Seiyaku Co. Ltd.: Ορη. Kokai Tokkyo Koho 81 45 474/. Poslednými známými metodami přípravy zlúčeniny vzorca I sú alkylácia 3-metyl-7-n-propyl-3,7-dihydro-lH-purin-2,6-di·* onu s oxohexylvromodom za podmienok medzifázove] katalýzy v zmesi díchlórmetán - vodný roztok hydroxidu sodného za přítomnosti tetrabutylamonium hydrogénsulfátu /F. Calvo Mon;delo: pát. ES 549 162/, reap, alkylácia 3-metyl-7-propyl-3,7-dihydro-lH-purin-2,6-dionu s oxohexylbromidom za přítomnosti neutrálneho oxida hlinitého posobenim ultrazvuku vo vodno-toleuénovom prostředí /P. Mora Ruedas: pat. ES 549 102/ a alkylácia tetraalkylamóniovej soli 3-metyl-7-n-propyl-3,7-dihydro-lH-purín-2,6-dionu s 5-oxohexylhalogenidom v prostředí organického rozpúátadla /A. Rybář a spo.: ČS AO 266 291/Opposite the compound of formula I was prepared by reacting 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and 5-oxohexyl bromide in an aqueous-alcoholic medium in the presence of an alkali metal hydroxide / W. Moehlsr, M-Qayme, 3. Mosquito: OE OS 2 330 742 /, in a pre-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 in situ prepared] potassium salts of 3-ethyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and anhydrous potassium carbonate in an aprotic solvent (W. Moehler, M. Oayme, □. Mosquitoes: CA 1,075,690 /. Another known method for the preparation of the compound of formula I is the alkylation of the alkaline] salt of 3, -methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione and alkane reap, arene sulfonates of 5-oxohexanol 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 alkane, * rasp, with 5-oxohexanil arenulfonates in dimethylformamide / H . Furrer: DE OS 2 929 566 /. A well-known method for preparing 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 catalyzed by mercuric airane and sulfuric acid. ] / Shiratori Seiyaku Co. Ltd .: Cr. Kokai Tokkyo Koho 81 45 474 /. The last 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-diionone with oxohexyl bromide under interfacial catalysis conditions in a mixture of dichloromethane and aqueous solution. sodium hydroxide in the presence of tetrabutylammonium hydrogen sulphate / F. Calvo Mon, cannon: Fri. ES 549 162 /, reap, 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 Ruedas: pat. ES 549 102) and alkylation of the tetraalkylammonium salt of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione with 5-oxohexyl halide in an organic solvent medium (A). Rybář a spo .: ČS AO 266 291 /

Nevýhodou doposiaX známých eposobov přípravy zlúčeniny vzorca I je ziskanie farebne tmavého propentofylínu, ktorý sa musí náročné čistit, aby sa získala substancia vhodná pre farmaceutické použitie. .A disadvantage of the hitherto known epochs of preparation of the compound of the formula I is the obtaining of a color-dark propentofylline which must be difficult to purify in order to obtain a substance suitable for pharmaceutical use. .

Tieto nevýhody odstraňuje postup podZa vynálezu, založený na tom, že sa 3-metyl-3,7-dihydro-lH-purín-2,6-dion vzorca IIThese disadvantages are eliminated by the process according to the invention, based on the fact that 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II

CH3 (II)CH3 (II)

CS 270 546 Bl nechá reagovat s n-propylhalogenidom za přítomnosti alkalického uhličitanu v prostředí vody alebo jej zmesi s alifatickým alkoholem s počtom uhlíkov 1 až 3 a vzniká reakčná zmes, ktorá sa za přítomnosti alkalického hydroxidu alebo uhličitanu za podmienok medzifázovej katalýzy nechá následné reagovat s 5-oxohexylhalogenidom.CS 270 546 B1 is reacted with n-propyl halide in the presence of an alkali carbonate in a medium of water or a mixture thereof with an aliphatic alcohol having 1 to 3 carbons and a reaction mixture is formed which is subsequently reacted with 5-oxohexyl halide.

Postup padla vynálezu sa uskutečňuje tak, že sa 100 mol. dielov zlúčeniny vzorca II rozpustí zahrievanim vo vodnom roztoku 50 až 150 mol. dielov alkalického uhličitanu, k vzniklému roztoku sa přidá 100 až 150 mol. dielov n-propylhalogenidu bud samotného alebo v alifatickém alkohole s počtom uhlíkov 1 až 3, a zmes sa zohrieva na teplotu 50 až 100 °C výhodou na 65 až 80 °C po dobu min. 4 h. Po skončení reakcie sa přidá k reakčnej zmesi 100 až 120 mol. dielov alkalického Uhličitanu alebo alkalického hydroxidu a 100 až 120 mol. dielov 5-oxohexylhalogenidu v aromatickém alebo v chlórovaném uhlovodíku a za přítomnosti 1 až 10 mol. dielov katalyzátora medzifázového přenosu sa zahrieva na teplotu 30 až 120 °C min. 6 h.The process of 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 an aliphatic alcohol having 1 to 3 carbons, and the mixture is heated to 50 to 100 ° C, preferably to 65 to 80 ° C for min. After completion of the reaction, 100 to 120 mol of water are added to the reaction mixture. parts of alkali carbonate or alkali hydroxide and 100 to 120 mol. parts of 5-oxohexyl halide in an aromatic or chlorinated hydrocarbon and in the presence of 1 to 10 mol. parts of the interfacial transfer catalyst are heated to a temperature of 30 to 120 ° C for min. 6 h.

Ako alkalický uhličitan alebo hydroxid možno použit uhličitan sodný, alebo draselný, hydroxid sodný, alebo draselný. Ako n-propylhalogenid a 5-oxohexylhalogenid možno použit příslušné chloridy, bromidy alebo jodidy. Namiesto .najreaktivnějších jodidov možno použit menej reaktivně chloridy alebo bromidy za přítomnosti 0,5 až 10 mol. dielov alkalického jodidu alebo bromidu, připadne jódu na 100 ml. dielov zlúčeniny vzorca II. Ako katalyzátory medzifázového přenosu sa použijú anorganické soli tetraalkylamónia, napr. tetrabutylamónia.trietýlběnzylamóniá , tri-n-oktylmethylamónia, dimetylbenzylaikylamónia, v ktorom má alkyl 8 až 18 uhlíkov, připadne sa jedná o zmes týchto alkylov s počtom uhlíkov 8 až 18. Postup možno upravit takým spósobom, že katalyzátor medzifázového přenosu sa přidá už před prldavkom n-propylhalogenidu, tj. v prvej etapa postupu. Ako aromatický alebo chlórovaný uhlovodík možno použit benzén, toluén, xylén, chloroform, dichlórmetán. Reakčnú zmes po reakcii s n-propylhalogenidom možno čistit pomocou sorbentov, napr. aktívneho uhlia.Sodium or potassium carbonate, sodium hydroxide or potassium carbonate can be used as the alkali carbonate or hydroxide. Appropriate chlorides, bromides or iodides can be used as n-propyl halide and 5-oxohexyl halide. Instead of the most reactive iodides, chlorides or bromides can be used less reactively in the presence of 0.5 to 10 mol. parts of alkaline iodide or bromide, or iodine per 100 ml. parts of a compound of formula II. Inorganic salts of tetraalkylammonium are used as interfacial transfer catalysts, for example tetrabutylammonium, triethylbenzylammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium, in which the alkyl has 8 to 18 carbons, or it is a mixture of these alkyls having a carbon number of 8 to 18. in such a way that the interfacial transfer catalyst is added before the addition of n-propyl halide, i.e. in the first stage of the process. Benzene, toluene, xylene, chloroform, dichloromethane can be used as the aromatic or chlorinated hydrocarbon. After reaction with n-propyl halide, the reaction mixture can be purified using sorbents, e.g. activated carbon.

Zlúčenina vzorce I sa z reakčnej zmesi vyizoluja tak, že sa vrstva aromatického alebo chlórovaného uhlovodíka oddali, premyje vodou, vysuší e rozpúšladlo se oddeatiluje na závěr ze zníženého tleku. Surová zlúčenine vzorce I se prekryštelizuje z vhodného rozpúštadla. Roztok zlúčeniny vzorce I v aromatickou alebo chlórovenom uhlovodíku možno po vysušení čistit pomocou sorbentov.The compound of formula I is isolated from the reaction mixture by separating the aromatic or chlorinated hydrocarbon layer, washing with water, drying and finally distilling off the solvent from 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 with sorbents after drying.

Hlavnou výhodou postupu podfa vynálezu je zjednodušenie postupu přípravy zlúčeniny vzorca I zo. zlúčeniny vzorce II bez potřeby izolácie a čistenie in situ vznikájúceho 3-metyl-7-n-propyl-3,7-dihydro-lH-purin-2,6-dionu, čo se přejev! v skráteni doby přípravy, eliminácii strát a tým vo zvýšeni výte^kov na 70 - 85 % pri zachovaní čistoty zlúčeniny okolo 99 %.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. compounds of formula II without the need for isolation and in situ purification of the resulting 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione, as shown in! in shortening the preparation time, eliminating losses and thus increasing the yield to 70-85% while maintaining the purity of the compound around 99%.

V ňalšom je predmet vynálezu popisaný v příkladech prevedenia bez toho, že by sa na tieto obmedzoval.In the following, the subject matter of the invention is described in the exemplary embodiments without being limited thereto.

Přiklad 1 Suspenzia 16,60 g (0,10 mól) zlúčeniny vzorca II v roztoku 12,18 g (0,115 mól) bezvodého uhličitanu sodného a 100 ml vody za zahřeje na 80 °C a mieša sa do rozpustenia zlúčeniny vzorca II. Vzniklý roztok sa vychladí na cca 30 °C, prileje sa 14,14 g (10,46 ml; 0,115 mól) n-propylbromidu v 60 ml metanolu a za miešania sa zahrieva na teplotu 75 až 80 ⁰ počas 12 h. Po tomto čase sa zmes vychladí na laboratórnu teplotu, za miešania sa po častiach přidá 4,0 g (0,10 mól) hydroxidu sodného, po jeho rozpuštění sa přidá 13,45 g (0,10 mól) 5-oxohexylchloridu v 100 ml toluénu a 3,22 g (0,01 mól) tetrabutylamóniumbromidu. Získaná zmes sa zahrieva za silného miešania a teplote 110 °C počas 7 h. Po ukončení reakcie sa vodná vrstva oddělí, organická fáza sa premyje vodou, vysuší a rozpúštadlo sa odpaří. Získaný sirupovitý zvyšok sa prekryštalizuje z metyl-terc. butyleteru. Získá saExample 1 A suspension of 16.60 g (0.10 mol) of a compound of formula II in a solution of 12.18 g (0.115 mol) of anhydrous sodium carbonate and 100 ml of water is heated to 80 DEG C. and stirred until the compound of formula II is dissolved. The resulting solution was cooled to about 30 ° C, quenched with 14.14 g (10.46 ml, 0.115 mol) n-propyl bromide in 60 ml of methanol under stirring and heated at 75-80 ⁰ for 12 h. After this time, the mixture is cooled to room temperature, 4.0 g (0.10 mol) of sodium hydroxide are added portionwise with stirring, after its dissolution 13.45 g (0.10 mol) of 5-oxohexyl chloride in 100 ml of toluene are added and 3 , 22 g (0.01 mol) of tetrabutylammonium bromide. The resulting mixture was heated with vigorous stirring at 110 ° C for 7 h. After completion of the reaction, the aqueous layer was separated, the organic phase was washed with water, dried, and the solvent was evaporated. The syrupy residue obtained is recrystallized from methyl tert. butyl ether. It is obtained

CS 27C 546 31 3CS 27C 546 31 3

26,0 g (85 % teorie) zlúčeniny vzorca I, s t.t. 65-70,5 °C.26.0 g (85% of theory) of the compound of formula I, m.p. 65-70.5 ° C.

Příklad 2Example 2

Suspenzia 16,60 g (0,10 mol) zlúčeniny vzcrca II v roztoku 15,89 g (0,115 mol) bezvodého uhličitanu draeelného a 100 ml vody sa zahřeje na 80 °C a mieša sa do rozpustenia zlúčeniny vzorca II. Roztok sa vychladí na labor, teplotu, prileje sa 14,14 g (10,46 ml; 0,115 mol) n-propylbromidu v 65 ml n-propylalkoholu a za miešania sa zahrieva na teplotu 75 až 80 °C počas 10 h. Vychladí sa na labor, teplotu, za miešania sa po častiach přidá 5,61 g (0,10 mol) hydroxidu draselného, po rozpuštění sa přidá aktivně uhlie, nechá sa miešat 15 min, aktivně uhlie sa odfiltruje, k filtrátu sa přidá 13,45 g (0,10 mol) 5-oxohexylchloridu v 100 ml toluénu a 4,00 g (0,01 mol) benzyldimetylalkylamónlumbromidu. Získaná zmes sa zahrieva za silného miešania pri 110 °C počas 7 h. Po ukončeni reakcie sa vodná vrstva oddělí a organická vrstva sa spracuje ako v příklade 1. Získaný sirupovitý zvyšok sa prekryštalizuje z benzinu. Získá sa 24,2 g (79 % teorie) zlúčeniny vzorca I, t.t. 68,5-70 °C. .A suspension of 16.60 g (0.10 mol) of the compound of formula II in a solution of 15.89 g (0.115 mol) of anhydrous potassium carbonate and 100 ml of water is heated to 80 DEG C. and stirred until the compound of formula II is dissolved. The solution is cooled to room temperature, 14.14 g (10.46 ml; 0.115 mol) of n-propyl bromide in 65 ml of n-propyl alcohol are added and the mixture is heated to 75-80 [deg.] C. with stirring for 10 h. It is cooled. to room temperature, 5.61 g (0.10 mol) of potassium hydroxide are added portionwise with stirring, after dissolution, activated carbon is added, it is allowed to stir for 15 minutes, the activated carbon is filtered off, 13.45 g is added to the filtrate. (0.10 mol) of 5-oxohexyl chloride in 100 ml of toluene and 4.00 g (0.01 mol) of benzyldimethylalkylammonium bromide. The resulting mixture was heated with vigorous stirring at 110 ° C for 7 h. After completion of the reaction, the aqueous layer was separated and the organic layer was worked up as in Example 1. The obtained syrupy residue was recrystallized from gasoline. 24.2 g (79% of theory) of the compound of the formula I are obtained, m.p. 68.5-70 ° C. .

Příklad 3 'Example 3 '

Suspenzia 16,60 g (0,10 mól) zlúčeniny vzorca II v roztoku 12,18 g (0,115 mol) bezvodého uhličitanu sodného a 100 ml vody sa zahřeje na 80 °C a mieša sa do rozpustenia zlúčenlny vzorca II. Roztok sa vychladí na cca 30 °C, prileje sa 9,03 g (10.13 ml; 0,115 mól) n-propylchloridu v 20 ml etanolu, přidá sa ešte 1,50 g (0,01 mól) jodidu sodného a za miešania sa zahrieva na teplotu 75 až 80 °C počas 10 h. Vychladí sa na labor, teplotu, po častiach sa pridé 10,6 g (0,10 mól) bezvodého uhličitanu sodného, po rozpuštění sa přidá aktivně uhlie, mieša sa 15 min, aktivně uhlie sa odfiltruje a k filtrátu sa přidá 17,90 g (0,10 mól) 5-oxohexylbromidu v 100 ml chloroformu a 4,04 g (0,01 mól) metyl-tri-n-oktylamóniumchloridu. Zmes sa zahrieva za silného niešanla pri 110 °C počas 7 h. Po vychladnuti sa vodné vrstva oddali a organické vrstva sa spracuje ako v příklade 1. Získaný sirupovitý zvyšok sa prekryštalizuje z octanu etylového-cyklohexánu. Získá sa 22,4 g (73 % teorie) zlúčeniny vzorca I, t.t. 68-69,5 °C.A suspension of 16.60 g (0.10 mol) of the compound of formula II in a solution of 12.18 g (0.115 mol) of anhydrous sodium carbonate and 100 ml of water is heated to 80 DEG C. and stirred until the compound of formula II has dissolved. The solution is cooled to about 30 DEG C., 9.03 g (10.13 ml; 0.115 mol) of n-propyl chloride in 20 ml of ethanol are added, a further 1.50 g (0.01 mol) of sodium iodide are added and the mixture is heated with stirring. to 75-80 ° C for 10 h. Cool to room temperature, add 10.6 g (0.10 mol) of anhydrous sodium carbonate in portions, after dissolution add charcoal, stir for 15 min, charcoal is filtered off and 17.90 g (0.10 mol) of 5-oxohexyl bromide in 100 ml of chloroform and 4.04 g (0.01 mol) of methyl tri-n-octylammonium chloride are added to the filtrate. The mixture is heated under strong stirring at 110 DEG C. for 7 hours. After cooling, the aqueous layer is separated and the organic layer is worked up as in Example 1. The syrupy residue obtained is recrystallized from ethyl cyclohexane acetate. 22.4 g (73% of theory) of the compound of the formula I are obtained, m.p. 68-69.5 ° C.

Přiklad 4Example 4

Suspenzia 16,60 g (0,10 mól) zlúčeniny vzorca II v roztoku 15,89 g (0,115 mol) bezvodého uhličitanu draselného a 100 ml vody sa zahřeje na 80 °C a mieša sa do rozpustenia zlúčeniny vzorca II. Roztok sa vychladí na labor, teplotu, prileje sa 14,14 g (0,115 mól) n-propylbromidu v 50 ml etanolu, přidá sa 1,66 g (0,01 aól) jodidu draselného a za miešania sa zahrieva na teplotu 75 až 80 °C počas 9 h. Vychladí sa na labor, teplotu, po častiach sa přidá 13,82 g (0,10 mól) bezvodého uhličitanu draselného, po rozpuštění sa přidá aktivně uhlie, po 15 min miešani sa uhlie odfiltruje a k filtrátu sa přidá 13,45 g (0,10 mól) 5-oxohexylchloridu v 100 ml xylénu a 3,40 g (0,01 mol) tetrabutylamoniumhydrogénduslfátu. Zmes sa zahrieva za silného niešanla pri 110 °C počas 7 h. Po vychladnuti sa vodná vrstva oddělí a organická vrstva sa spracuje ako' v příklade 1 Získaný sirupovitý zvyšok sa prekryštalizuje v toluénu-cyklohexanu. Získá sa 23,0 g (75 % teorie) zlú•čeniny vzorca I, t.t. 68-69,5 °C»·A suspension of 16.60 g (0.10 mol) of the compound of formula II in a solution of 15.89 g (0.115 mol) of anhydrous potassium carbonate and 100 ml of water is heated to 80 DEG C. and stirred until the compound of formula II is dissolved. The solution is cooled to room temperature, 14.14 g (0.115 mol) of n-propyl bromide in 50 ml of ethanol are added, 1.66 g (0.01 mol) of potassium iodide are added and the mixture is heated to 75-80 with stirring. The mixture is cooled to room temperature, 13.82 g (0.10 mol) of anhydrous potassium carbonate are added portionwise, after dissolution the activated carbon is added, after stirring for 15 minutes the carbon is filtered off and the filtrate is added 13 , 45 g (0.10 mol) of 5-oxohexyl chloride in 100 ml of xylene and 3.40 g (0.01 mol) of tetrabutylammonium hydrogen sulphate. The mixture is heated under strong stirring at 110 DEG C. for 7 hours. After cooling, the aqueous layer is separated and the organic layer is worked up as in Example 1. The syrupy residue obtained is recrystallized from toluene-cyclohexane. 23.0 g (75% of theory) of the compound of the formula I are obtained, m.p. 68-69.5 ° C »·

Claims

OBJECT OF THE INVENTION

Process for the preparation of 3-methyl-1- (5-osohexyl) -7-n-propyl-3,7-dihydro-1H-purine-2,6-dione of the formula I

CS 270 546 Bl

CH ₃ - CO- (CH ₂ ) ₄

(I) characterized in that 100 ml. parts of 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II

(II) is reacted with 100 to 150 mol. parts of n-propyl halide in the presence of 50 to 150 mol. 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 50 to 100 ° C, and after completion of the reaction, 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 and reacted 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 preparation method according to item 1, characterized in that the reaction with n-propyl halide is allowed to proceed 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 albbo 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. The process according to item 1, characterized in that an inorganic tetraalkylammonium salt such as tetrabutylammonium salt, triethylbenzylammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium having a carbon number of 8 to 18 in the alkyl is used as the interfacial transfer catalyst, but it is a mixture of these alkyls having a carbon number of 8 to 18.

8. The preparation method according to item 1, characterized in that benzene, toluene, xylene, chloroform, dichloromethane is used as the aromatic or chlorinated hydrocarbon.

9. The process of claim 1, wherein the compound of formula I is isolated by separating a layer of aromatic or chlorinated hydrocarbon containing the compound of formula I, washing with water, drying and distilling off the volatile components.