CS267796B1 - Process for preparing 3-methyl-7-u-propyl-3,7-dihydro-1H-purine-2,6-dione - Google Patents

Process for preparing 3-methyl-7-u-propyl-3,7-dihydro-1H-purine-2,6-dione Download PDF

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CS267796B1
CS267796B1 CS886561A CS656188A CS267796B1 CS 267796 B1 CS267796 B1 CS 267796B1 CS 886561 A CS886561 A CS 886561A CS 656188 A CS656188 A CS 656188A CS 267796 B1 CS267796 B1 CS 267796B1
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methyl
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CS656188A1 (en
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Alfonz Ing Csc Rybar
Marian Ing Tegza
Milan Clen Korespondent Repas
Dusan Ing Csc Hesek
Richard Doc Ing Csc Frimm
Fridrich Rndr Csc Szemes
Michal Judr Ing Guttmann
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Rybar Alfonz
Tegza Marian
Milan Clen Korespondent Repas
Hesek Dusan
Frimm Richard
Szemes Fridrich
Guttmann Nichal
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Abstract

Spósob přípravy 7-n-propyl-3-metyl- -3,7-dihydro-1H-purln-2,6—dionu, RieSenie spočívá v tom, že sa 100 moí. dielov 3-metyl-3,7-dihydro-IH-purín-2,6-dionu vzorca II neohé reagovat so 100 až 150 mol, dielmi n-propylhalogenidu a 50 až 150 mol. dielmi alkalického uhličitanu vo vodě a/alebo v alifatiokom alkohole s počtom uhlíkov 1 až 3 pri teplote 40 až 100 °C a zlúčenina vzoroa I sa izoluje, Zlúčenina vzoroa I sa používá ako medziprodukt pri výrobě periférneho vazodilatans propentofylín.The method for the preparation of 7-n-propyl-3-methyl-3,7-dihydro-1H-purln-2,6-dione, Riesenie consists in washing 100 of 3-methyl-3,7-dihydro-1H-purine-2,6-dione of the formula II cannot be reacted with 100 to 150 mol, of n-propyl halide and 50 to 150 mol. parts of an alkali carbonate in water and/or in an aliphatic alcohol having 1 to 3 carbon numbers at a temperature of 40 to 100 °C and the compound of formula I is isolated. Compound of formula I is used as an intermediate in the production of the peripheral vasodilator propentophylline.

Description

Vynález sa týká spósobu přípravy 3-metyl-7-n-propyl-3,7-dlhydro-1H-purín-2,6-dionu vzorca IThe invention relates to a process for the preparation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione of formula I

ktorý sa používá ako medziprodukt při príprave periférneho vazodilatans propentofylín.which is used as an intermediate in the preparation of the peripheral vasodilator propentofylline.

Doposiaí sa zláčenina vzorca I připravovala alkyláoiou 3-metyl-3,7-dihydro-purin-2,6—dionu b n-propylhalogenidom za přítomnosti uhličitanu alkalického kovu v aprotiokom mzpášladle /A. Rybář, a spol.: CS AO 2ó3595/( alkyláciou alkalické J soli 3-metyl-3,7-dihydro-1H-purín-2,6-dionu s n.propylhalogenidom v aprotiokom rozpúšladle /A. Rybář a spol.: CS AO 2632ΟΟ/, fornyláoiou 5-n-propylamino-6-amino-1-metyl-1H-pyrimidin-2,6-dionu na 5- N-(n-propyl)formylamino-6-amine-1-metyl-1H-pyrimidin-2,4-dionu, ktorý zahrievaním 3 alkalickými hydroxidmi alebo uhličitanmi poskytne alkalická sol zlúčeniny vzorca I, z ktorej sa táto uvolní okyselením s anorganickou alebo organickou kyselinou alebo forrayláoiou 5-n~propylamino-6~amino~1-metyl-1H~pyriraidin-2,6-dionu posobením formamidu a na temniokej oyklizáoii in situ vznikajáoeho 5— N-(n-propyl)fornzy lamino -6- amino-1-metyl~1H—pyrimidín-2,4—dionu.To date, the compound of formula I has been prepared by alkylation of 3-methyl-3,7-dihydro-purine-2,6-dione with n-propyl halide in the presence of an alkali metal carbonate in an aprotic moiety [A]. Rybář, et al .: CS AO 2-3595 / ( alkylation of the alkaline J salt of 3-methyl-3,7-dihydro-1H-purine-2,6-dione with n-propyl halide in an aprotic solvent) AO 2632α-5-n-propylamino-6-amino-1-methyl-1H-pyrimidine-2,6-dione to 5-N- (n-propyl) formylamino-6-amine-1-methyl-1H- pyrimidine-2,4-dione which, by heating with 3 alkali hydroxides or carbonates, gives an alkaline salt of a compound of formula I, which is liberated by acidification with an inorganic or organic acid or a 5- n -propylamino-6-amino-1-methyl-1H salt pyrimidine-2,6-dione by treatment with formamide and the in situ 5-N- (n-propyl) phenylamino-6-amino-1-methyl-1H-pyrimidine-2,4-dione formed on the dark cyclic in situ.

Nevýhodou prvých dvoch známých metod přípravy Je potřeba aprotického rozpúšladla. Nevýhodou ňalšíoh dvoch známých metod jo potřeba vyžietonia východzieho 5-n-propylamino-6—amino-1—metyl-1H-pyrimidín-2,4-dionu od sprevádzajúceho bis-(6-amino-1-metyl-2,4-dioxo-1H-pyrimidín-5~yl)-n-propylaminu, čo má negativny vplyv na celkový výlažok syntézy propentofylínu. U poslednej z uvedených známých metod přípravy zláčeniny vzorca I je nevýhodná vysoká reakčná teplota okolo 180 °C.The disadvantage of the first two known methods of preparation is the need for an aprotic solvent. A disadvantage of the other two known methods is the need to use the starting 5-n-propylamino-6-amino-1-methyl-1H-pyrimidine-2,4-dione from the accompanying bis- (6-amino-1-methyl-2,4-dioxo -1H-pyrimidin-5-yl) -n-propylamine, which has a negative effect on the overall yield of propentofylline synthesis. In the latter known method of preparing the compound of formula I, a high reaction temperature of about 180 ° C is disadvantageous.

Teraz bolo zistenó, že alkyláoiu 3~mety1-3»7—dlhydro-1H-purín-2,6-dionu vzorca IIIt has now been found that the alkylation of 3- methyl- 3,7-dihydro-1H-purine-2,6-dione of formula II

ch3 s n-propylhalogenidom za přítomnosti uhličitanu alkalického kovu možno výhodné uskutečnil aj vo vodnom prostředí, resp. v zmesi vody s nižšími alifatickými alkoholmi, připadne v samotném alkohole.ch 3 with n-propyl halide in the presence of alkali metal carbonate can advantageously also be carried out in an aqueous medium or in an aqueous medium. in a mixture of water with lower aliphatic alcohols, optionally in the alcohol itself.

Postup podlá vynálezu sa uskutečňuje tak, že sa 100 mol. dielov zláčeniny vzorca II znbrt«νηη-fm rozpustí vo vodném roztoku 5θ až 150 mol. dielov uhličitanu alkalického kovu a k vzniklém.» roztoku sa přidá 100 až 150 mol. dielov n.propylhalogenidu bu3 samotného alebo v roztoku alifatických alkoholov s počtem uhlíkov 1 až 3 a vzniklá zmes sa zahrieva na 40 až 100 °C, s výhodou na 65 až 80 °C. Ako alkalický uhličitan možno použil uhličitan sodný alebo uhličitan draselný, Halogén v n—propylhalogenide představuje chlór, bróm alebo Jod. Ako alifatický alkohol možno použil metanol, 1-proThe process according to the invention is carried out in such a way that 100 mol. parts of the compound of formula II znbrt «νηη-fm are dissolved in an aqueous solution of 5θ to 150 mol. parts of alkali metal carbonate and to the resulting. » 100 to 150 mol. parts of n-propyl halide either alone or in a solution of aliphatic alcohols having a carbon number of 1 to 3 and the resulting mixture is heated to 40 to 100 ° C, preferably to 65 to 80 ° C. Sodium carbonate or potassium carbonate can be used as the alkali carbonate. The halogen in n-propyl halide represents chlorine, bromine or iodine. Methanol, 1-pro can be used as the aliphatic alcohol

CS 26? 796 Bl ραηοΐ, 2-propanol, a výhodou etanol,CS 26? 796 B1 ραηοΐ, 2-propanol, and preferably ethanol,

Namiesto najreoktívnejšieho n-propyljodidu je možné použil aj menej reoktívny n—propylohlorid alebo n—propylbromid za přítomnosti 0,5 až 20 mol. dielov.jodidu sodného, jodidu draselného alebo jódu na 100 mol. dielov n-propylhalogenidu. Podobno namiesto n-propyIbromidu možno použil najmenej reaktívny n-propylohlorid za přítomnosti 0,5 až 20 mol. dielov bromidu sodného alebo bromidu draselného na 100 mol, dielov n-propylchloridu.Instead of the most reactive n-propyl iodide, it is also possible to use less reactive n-propyl chloride or n-propyl bromide in the presence of 0.5 to 20 mol. parts of sodium iodide, potassium iodide or iodine per 100 mol. parts of n-propyl halide. Similarly, instead of n-propyl bromide, the least reactive n-propyl chloride can be used in the presence of 0.5 to 20 mol. parts of sodium bromide or potassium bromide per 100 mol, parts of n-propyl chloride.

Styk reakčných komponent možno zlepšil miešaním alebo lepšíc prídavkom malých tnnožstiev katalyzátorov medzifázového přenosu typu anorganických solí tetraalkylamánia, dime ty lbenzy laiky lamónia, v ktorom mé alkyl 8 až 18 uhlíkov, připadne sa jedná o zmes týohto alkylov, alebo prídavkom malých množstiev ionogenných, resp, neionogenných detergentov, napr, priemyselno vyráběných alkánsulfonátov sodných, polyetoxylovaných alkoholov, polyetoxylovanýoh alkylfenolov.The contact of the reactants can be improved by stirring or better by adding small amounts of interphase transfer catalysts of the inorganic salt of tetraalkylammonium, dimethylbenzylammonium in which the alkyl is 8 to 18 carbons, or a mixture of these alkyls, or by adding small amounts of ionic or. nonionic detergents, e.g. industrially produced sodium alkanesulfonates, polyethoxylated alcohols, polyethoxylated alkylphenols.

Zlúčenina vzoroa I sa z reakčnej zmesi vyizoluje tak, že sa z alkalickéj reagujúcej vyohladenej reakčnej zmesi vyzráža prídavkom anorganickéj alebo organickej karboxylovej kyseliny, Ako kyselinu možno použil zriedenú kyselinu chlorovodíkové, kyselinu sirovu, kyselinu mravčiu alebo s výhodou kyselinu octové. Vylúčená zlúčenina vzorca I sa oddělí filtráciou odstředěním alebo odsátím. Ďalši podiel zlúčeniny vzorca I možno získal vákuovým zahuštěním filtrátu po oddělení prvého podielu zlúčeniny vzorca I. Obidva podlely zlúčeniny vzoroa I sa sušia pri oca 100 °C, s výhodou za zniženého tlaku. Čistota obidvoch podielov zlúčeniny vzoroa I je okolo 99 % (plošné £, kvapalinová chromatografia),The compound of the formula I is isolated from the reaction mixture by precipitating it from an alkaline-reacted cooled reaction mixture by adding an inorganic or organic carboxylic acid. Dilute hydrochloric acid, sulfuric acid, formic acid or, preferably, acetic acid can be used as the acid. The precipitated compound of the formula I is separated by filtration by centrifugation or suction filtration. A further portion of the compound of formula I can be obtained by concentrating the filtrate in vacuo after separating the first portion of the compound of formula I. Both portions of the compound of formula I are dried at about 100 ° C, preferably under reduced pressure. The purity of both portions of the compound of formula I is about 99% (area E, liquid chromatography).

Hlavnou výhodou postupu podlá vynálezu je náhrada aprotiokého rozpúšladla podstatné lecnajžími rozpúšladlami vodou a nižšími alkoholu! pri zachovaní vysokých výlažkov zlúčeniny vzoroa I v rozsahu 80 až 90 í a čistoto okolo 99 í. Ďalšou výhodou Je skutočnosl, že nie je potřebné vopred připravoval alkalická sol výohodzej zlóčeniny vzorca II a že nežiadúoi produkt dvojnásobnej propyláoie, tj. 3-tnetyl-1,7-di-n-propyl-3,7-dihydro-1H-purín-2,6—dion vzniká iba v stopových množstváoh.The main advantage of the process according to the invention is the replacement of the aprotic solvent by essentially better solvents with water and lower alcohols. while maintaining high yields of the compound of formula I in the range of 80 to 90% and a purity of about 99%. Another advantage is the fact that it is not necessary to prepare the alkaline salt of the preferred compound of formula II in advance and that the undesired product of double propylation, i. 3-Methyl-1,7-di-n-propyl-3,7-dihydro-1H-purine-2,6-dione is formed only in trace amounts.

V ňalšom je předmět vynálezu popásaný v príkladooh prevedenia bez toho, že by sa na tieto obmedzoval.In the following, the subject matter of the invention is described in an exemplary embodiment without being limited thereto.

Příklad 1Example 1

Zmes 8,3 g (50 mmol) zlúčeniny vzoroa II, 7,8 g (57,5 mmol) bezvodého uhličitanu draselného a 100 ml vody sa zahřeje na 80 °C a mieša sa až sa zlúčenina vzorca II rozpustí, Vzniklý roztok sa vychladí na oca 3θ °C, prileje sa 7,07 B (5,23 mlj 57,5 mmol) n-propyIbromidu v 50 ml 96 %-ného etanolu a za miešania sa ohrieva na teplotu 75 až 80 °C pod účinným spatným ohladičom počas 8 h, Reakčná zmes sa vychladí na 00a 20 °C a jej pH sa upraví prídavkom kys. ootovej na hodnotu 7. Po cca 2 h sa vylúčené kryštaly odsajú a sušia při 100 °C do konštantnej hmotnosti. Filtrát sa zahustí za vákua na oca t/k povodného objemu, čím sa získá druhý podiel produktu. Spolu sa získá 8,75 B (84 jó teorie) zlúčeniny vzoroa I, t.t. 249-251 °C.A mixture of 8.3 g (50 mmol) of the compound of formula II, 7.8 g (57.5 mmol) 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 resulting solution is cooled. to 3θ ° C, 7.07 B (5.23 ml, 57.5 mmol) of n-propyl bromide in 50 ml of 96% ethanol are added and the mixture is heated to 75-80 ° C with stirring under an effective reflux condenser for 8 h. The reaction mixture is cooled to 00 and 20 ° C and its pH is adjusted by adding acid. After about 2 hours, the precipitated crystals are filtered off with suction and dried at 100 [deg.] C. to constant weight. The filtrate is concentrated in vacuo to about t / k flood volume to give a second crop of product. A total of 8.75 B (84% of theory) of the compound of formula I is obtained, m.p. 249-251 ° C.

Příklad 2Example 2

Zmes 8,3 g (50 mmól) zlúčeniny vzoroa II, 6,09 g (57,5 mmól) bezvodného uhličitanu sodného a 100 ml vody sa zahřeje na 80 °C a mleta sa do rozpustenia zlúčeniny vzorca II, K roztoku sa přidává počas 20 min. ku dnu re akčněj nádoby za miešania a použitia účinného spatného ohladiča 7,07 g (5,23 ml, 57,5 mmól) n-propyIbromidu, 75 mg (0,5 nanól) jodidu sodného v 50 ml 2-propanolu a clalej ca zahrieva 10 h pri 75-80 °C. Reakčná zmes sa spraoujo analogicky ako v příklade 1, Získá sa 8,96 g (86 teorie) zlúčeniny vzorA mixture of 8.3 g (50 mmol) of the compound of formula II, 6.09 g (57.5 mmol) of anhydrous sodium carbonate and 100 ml of water is heated to 80 DEG C. and ground until the compound of formula II dissolves. 20 min. to the bottom of the reaction vessel with stirring and the use of an efficient reflux condenser 7.07 g (5.23 ml, 57.5 mmol) of n-propyl bromide, 75 mg (0.5 nanol) of sodium iodide in 50 ml of 2-propanol and heat at 75-80 ° C for 10 h. The reaction mixture is worked up analogously to Example 1 to give 8.96 g (86 theory) of the compound of formula

CS 267 796 B1 ca I, t.t. 249,5-251 °C.CS 267 796 B1 ca I, m.p. 249.5-251 ° C.

Příklad 3Example 3

Analogicky ako v příklade 1 len s tým rozdielom, že reakcia sa uskutečňuje za přítomnosti 100 mg diraetylbenzylalkylaminoumbromidu počas 6 h pri 75-8Ο °C. Získá sa 8,44 g (81 já teorie) zlúčeniny vzorca I 3 t.t. 249-251,5 °C.In analogy to Example 1, except that the reaction is carried out in the presence of 100 mg of diethylbenzylalkylamine bromide for 6 hours at 75-8 ° C. 8.44 g (81% of theory) of the compound of formula I 3 are obtained, m.p. 249-251.5 ° C.

Claims (7)

CS 267 796 B, 3 ca I, t.t. 249,5-251 °C. Příklad 3 Analogicky ako v přiklade 1 len s tým rozdielom, že reakcia sa uskutočňuje za přítom-nosti 100 mg diraetylbenzylalkylaminoumbromidu počas 6 h pri 75-8Ο °C. Získá sa8,44 g (81 jí teorie) zlúčeniny vzorca I 3 t.t. 249-251,5 °C. PŘED MET VYNÁLEZU I. Sposob přípravy 3-metyl-7-n-propyl-3,7-dihydro-1H-purín-2,6-dionu vzorná ICS 267 796 B, 3 and I, m.p. 249.5-251 ° C. EXAMPLE 3 Analogously to Example 1, except that the reaction was carried out in the presence of 100 mg of di-ethylbenzylalkylamine bromide for 6 h at 75-8 ° C. 8.44 g (81% of theory) of the compound of formula I 3 is obtained. 249-251.5 ° C. BEFORE METHOD OF INVENTION I. Preparation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione exemplary I I ch3 spočívájúci v reakcii 100 mol. dielov 3-metyl-3,7-dihydro-1H-purin-2,6-dionu vzorca IIThe reaction consisting of 100 moles in the reaction. parts of 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II I ch3 so 100 až 15Ο mol. dielmi n-propylhalogonidu a 50 až 150 mol. dielmi alkalického uhli-čitanu, vyznačujúoi sa tým, že reakoia prebieha vo vodě a/alebo v alifatickom alkoholes počtom uhlikov 1 až 3 pri teploto 40 až 100 °C a potom sa produkt izoluje.I ch3 with 100 to 15Ο mol. n-propyl halide and 50 to 150 mol. characterized in that the reaction takes place in water and / or in an aliphatic alcohol with a number of carbons 1 to 3 at a temperature of 40 to 100 ° C and then the product is isolated. 2. Sposob podlá bodu 1, vyznačujúci sa tým, že reakcia prebieha za přítomnosti katalyzá-tora medzifázového přenosu alebo emulgátora ionogenného připadne neionogennáho typu,2. Process according to claim 1, characterized in that the reaction is carried out in the presence of an interphase transfer catalyst or an ionic or non-ionic type emulsifier, 3. Sposob podlá bodu 1, vyznačujúci sa tým, že reakoia prebieha pri teploto 65 až 80 °C.3. Process according to claim 1, characterized in that the reaction takes place at a temperature of 65 to 80 ° C. 4. Sposob podlá bodu 2, vyznačujúci sa tým, že sa ako katalyzátor medzifázového přenosupoužije anorganická sol tetraalkylamónia, ako je sol tetrabutylamónia, trietylbenzyl-amónia, tri-n-oktylmetylamónia, dimetylbenzylalkylamónia 3 počtom uhlikov 8 až 18 v alkyle alebo sa jedná o zmes týohto alkylov,4. Process according to claim 2, characterized in that an inorganic salt of tetraalkylammonium such as tetrabutylammonium salt, triethylbenzyl ammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium 3 in the alkyl number of 8 to 18 is used as the interphase transfer catalyst. these alkyls, 5. Sposob podlá bodu 2, vyznačujúci sa tým, že sa ako neionogenný emulgátor použije po-lyetoxylovaný alkylťenol alebo polyetoxylovaný alifatický alkohol,5. A process according to claim 2, wherein the nonionic emulsifier is a polyethoxylated alkylthenol or a polyethoxylated aliphatic alcohol. 6. Sposob podlá bodu 2, vyznačujúoi sa tým, že sa ako ionogénny emulgátor použije alka-lická sol alkánsulfónovej kyseliny.6. A process according to claim 2 wherein the ionic emulsifier is an alkanesulfonic acid alkali salt. 7. Sposob podlá bodu 1, vyznačujúoi sa tým, že sa zlúčenina vzorca I izoluje z alkalickyreagujúoej vychladenej reakčnej zmesi vyzrážaním zriedenou minerálnou kyselinou, akoje kyselina chlorovodíková, kyselina sírová alebo organickou karboxylovou kyselinou,ako je kyselina mravčia alebo kyselina octová.7. Process according to claim 1, characterized in that the compound of formula I is isolated from an alkaline-reacted cooled reaction mixture by precipitation with dilute mineral acid such as hydrochloric acid, sulfuric acid or an organic carboxylic acid such as formic acid or acetic acid.
CS886561A 1988-10-03 1988-10-03 Process for preparing 3-methyl-7-u-propyl-3,7-dihydro-1H-purine-2,6-dione CS267796B1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2114847C1 (en) * 1992-11-10 1998-07-10 Хехст АГ Method of synthesis of 3,7-dialkylxanthines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2114847C1 (en) * 1992-11-10 1998-07-10 Хехст АГ Method of synthesis of 3,7-dialkylxanthines

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