CS267796B1 - Method of 3-methyl-7-n-propyl-3,7-dihydro-1h-purine-2,6-dione preparation - Google Patents
Method of 3-methyl-7-n-propyl-3,7-dihydro-1h-purine-2,6-dione preparation Download PDFInfo
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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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- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- MHNVSFOURBQRPK-UHFFFAOYSA-N 3-methyl-7-propylpurine-2,6-dione Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2CCC MHNVSFOURBQRPK-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- -1 n-propyl halide Chemical class 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- GMSNIKWWOQHZGF-UHFFFAOYSA-N 3-methyl-9H-xanthine Chemical compound O=C1NC(=O)N(C)C2=C1N=CN2 GMSNIKWWOQHZGF-UHFFFAOYSA-N 0.000 claims abstract description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 159000000011 group IA salts Chemical class 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims 2
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- ZUZLIXGTXQBUDC-UHFFFAOYSA-N methyltrioctylammonium Chemical compound CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC ZUZLIXGTXQBUDC-UHFFFAOYSA-N 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 239000012875 nonionic emulsifier Substances 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 claims 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims 1
- 239000000810 peripheral vasodilating agent Substances 0.000 abstract description 2
- 229960002116 peripheral vasodilator Drugs 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- RBQOQRRFDPXAGN-UHFFFAOYSA-N Propentofylline Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCC RBQOQRRFDPXAGN-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229960002934 propentofylline Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- ZILMLSNWARFPQM-UHFFFAOYSA-N 3-methyl-1,7-dipropylpurine-2,6-dione Chemical compound CN1C(=O)N(CCC)C(=O)C2=C1N=CN2CCC ZILMLSNWARFPQM-UHFFFAOYSA-N 0.000 description 1
- PXXPWRGFQVGQAZ-UHFFFAOYSA-N 6-amino-1-methyl-5-(propylamino)pyrimidine-2,4-dione Chemical compound CCCNC1=C(N)N(C)C(=O)NC1=O PXXPWRGFQVGQAZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000006207 propylation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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.Process for the preparation of 7-n-propyl-3-methyl- -3,7-dihydro-1H-purine-2,6-dione, RieSeIe it consists in having 100 molars. parts 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II may not react with 100 to 150 mol, parts of n-propyl halide and 50 to 150 mol. alkaline carbonate in water and / or in an aliphatic alcohol with a carbon number of 1 to 3 at 40 ° C to 100 ° C and the compound of Formula I is isolated, The compound of Formula I is used as an intermediate in the production of peripheral vasodilators propentophyllin.
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)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS886561A CS267796B1 (en) | 1988-10-03 | 1988-10-03 | Method of 3-methyl-7-n-propyl-3,7-dihydro-1h-purine-2,6-dione preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS886561A CS267796B1 (en) | 1988-10-03 | 1988-10-03 | Method of 3-methyl-7-n-propyl-3,7-dihydro-1h-purine-2,6-dione preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS656188A1 CS656188A1 (en) | 1989-07-12 |
| CS267796B1 true CS267796B1 (en) | 1990-02-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| CS886561A CS267796B1 (en) | 1988-10-03 | 1988-10-03 | Method of 3-methyl-7-n-propyl-3,7-dihydro-1h-purine-2,6-dione preparation |
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| Country | Link |
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| CS (1) | CS267796B1 (en) |
Cited By (1)
| 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 |
-
1988
- 1988-10-03 CS CS886561A patent/CS267796B1/en unknown
Cited By (1)
| 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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| Publication number | Publication date |
|---|---|
| CS656188A1 (en) | 1989-07-12 |
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