CS263595B1 - Process for preparing 7-n-propyl-3-methyl-3,7-dihydro-1h-purin-2,6-dione - Google Patents

Abstract

The solution is to have 100 moles. 3-methyl-3,7-dihydro-1H-purine-2,6-dione Formula II is reacted with 100 to 150 mole parts of n-propyl halide and 50 to 150 mole. alkali carbonate in aprotic solvent and the resulting 7-n-propyl- -3-methyl-3,7-dihydro-1H-purine-2, 6-dione of formula I is isolated. The compound of formula I is used in pharmaceutical chemistry as an intermediate in the production of peripheral vasodilators and xanthine hemorrhage.

Description

The present invention relates to a process for the preparation of 7-n-propyl-3-m, ethyl-3,7-dihydro-1H-purine-2,6-dlone of formula I

The compound of formula (I) is used in pharmaceutical chemistry as an intermediate in the production of peripheral vasodilators and xanthine-type haemorheologies.

The preparation of a physico-analytical characteristic of the compound of formula I is not yet described. The patent literature describes the exclusive use of a compound of formula I in alkylation reactions. Only methods for the preparation of related derivatives, e.g. 7- (3-butenyl) -, 7-benzyl derivative (U. Gebert, I. Okyayuz-Baklonti, W. Thorwart, DE OS 3,525,801).

The process for the preparation of the compound of formula I according to the invention is based on the reaction of 3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula II

with n-propyl halide and alkali carbonate in an aprotic solvent environment.

The process according to the invention is carried out by suspending the compound of formula II in an aprotic solvent, to which 50 to 150 molar parts of alkali carbonate and 100 to 150 moles are added. parts of n-propyl halide per 100 mol. parts of the compound of formula II and the resulting mixture is heated to 50 to 150 ° C, preferably to 90 to 110 ° C with stirring. The alkylation reaction takes 1 to 7 hours, depending on the alkyl halide used and the intensity of stirring. As the aprotic solvent, acetone, dimethylsulfoxide, sulfolane, hexamethylphosphotriamide, dimethylacetamide, preferably dimethylformamide can be used. Halogen in n-propyl halide is chlorine, bromine or iodine. Instead of n-propyl iodide, n-propyl chloride or n-propyl bromide can be used in the presence of 0.5 to 20 moles. parts of sodium or potassium iodide or iodine per 100 mol. parts of said n-propyl halides. Similarly, n-propyl chloride can be used in the presence of 0.5 to 20 moles instead of n-propyl bromide. parts of sodium or potassium bromide per 100 mol. parts of n-propyl chloride. As the alkali carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate can be used.

The compound of formula I is isolated from the reaction mixture by distilling off the excess n-propyl halide and the aprotic solvent, preferably under reduced pressure, and the increased mixture of the compound of formula I and inorganic salts is separated by dissolving the compound of formula I in a suitable organic solvent in which they are inorganic. salts very little, respectively. not insoluble at all. Suitable organic solvents are e.g. anhydrous ethanol, 2-propanol, 1-propanol, chloroform, dichloromethane. Concentration or complete evaporation of the thus obtained solution of the compound of formula I in a suitable organic solvent gives a compound of formula I contaminated with 1,7-di-n-propyl-3-methyl-3,7-dihydro-1H-purine-2,6-dione, t. j. the product of double alkylation. This impurity can be removed by crystallization from the abovementioned alcohols or from chlorinated hydrocarbons. extraction with carbon tetrachloride at elevated temperature, respectively. column chromatography on silica gel, eluting with chloroform or mixtures thereof with lower aliphatic alcohols having a carbon number of 1 to 3. Removal of inorganic salts of 1, 7-di-n-propyl-3-methyl-3,7-dihydro-1H-purine-2,6 Preferably, the dione can be carried out in a single operation by dissolving the residue after distilling off the excess n propyl halide and aprotic solvent in at least an equivalent amount of a dilute aqueous alkali hydroxide solution to form the alkali salt of the compound of formula I. The predominantly insoluble 1,7-di-n-propyl-3-methyl 3,7-dihydro-1H-purine-2,6-dione is extracted more conveniently with a chlorinated solvent, e.g. dichloromethane, chloroform or carbon tetrachloride. The aqueous solution devoid of 1,7-di-n-propyl-3-methyl-3,7-dihydro-1H-purine-2,6-dione and any other organic impurities is acidified with a dilute mineral or organic carboxylic acid, preferably carboxylic acid acid, preferably acetic acid. A compound of formula I is precipitated as a fine curd precipitate. Acidification of the aqueous alkaline solution devoid of 1,7-di-n-propyl-3-methyl-3,7-dlhydro-1H-purine-2,6-dione can also be carried out in such a way that the excess alkali carbonate introduced is not decomposed.

The main advantage of the process according to the invention

2S3595 are high yields of a compound of formula I, in a solution of 88 to 94%. Further advantages are: obtaining a practically chromatographically pure compound of formula I and the fact that it is not necessary to pre-prepare the alkali salt of the starting compound of formula II.

The invention is further described in the examples without being limited thereto.

Example 1

A mixture of 8.31 g (50 mmol) of the compound of formula (II), 8.60 g (62.3 mmol) of colorless. potassium carbonate, 100 ml of dry dimethylformamide and 7.66 g (5.66 ml; 62.3 mmol) of n-propyl bromide are heated to 100 ° C with stirring for 5 h. The reaction mixture is gently cooled and excess n-propyl bromide and dimethylforraamide are distilled off under vacuum. 50 ml of ΙΜ-NaOH and 50 ml of water are added to the cooled distillation residue and dissolved by stirring. Organic impurities are extracted from the resulting aqueous solution of the alkali salt of the compound of formula I with 3 X 20 ml of dichloromethane. The pH of the aqueous alkaline solution is adjusted to 7 with acetic acid with stirring. The suspension of the precipitated compound of formula I is allowed to stand at room temperature for several hours, preferably cold, and the compound of formula I is sucked off and dried to constant weight at 100 ° C. preferably under reduced pressure. 9.8 g (i.e. 94% of theory) of 7-n-propyl-3-methyl-3,7-dihydro-1H-purine-2,6-dione are obtained in the form of a pale beige powder of m.p. t. Mp 249-252 ° C.

Crystallization from ethanol gave tiny white needles of mp 250-252 ° C. TLC on Silufole (UV 254, chloroform-methanol 9: 1) _Rf 0.45, -0.50. Elem. Analysis: For C 9 H 12 N 4 O 2 (208.2) calculated: C 51.91, H 5.81, N 26.91; Found:% C, 51.80;% H, 6.00;% N, 26.95.

Example 2

A mixture of 8.31 g (50 mmol) of the compound of formula (II), 8.60 g (62.3 mmol) of colorless. potassium carbonate, 0.41 g (2.7 mmol) of sodium iodide, 100 ml of dry dimethylformamide and 7.66 g (5.66 ml; 62.3 mmol) of n-propyl bromide are heated to 100 [deg.] C. with stirring. , 5 h. The reaction mixture was worked up analogously to Example 1. 9.3 g (i.e. 89% of theory) of the product with m.p. t. Mp 248-251 ° C.

Example 3

A mixture of 8.31 g (50 mmol) of the compound of formula

II, 6.60 g (62.3 mmol) bezv. sodium carbonate, 100 mL of dry dimethylformamide and 7.66 g (5.66 mL; 62.3 mmol) of n-propyl bromide were heated to 100 ° C with stirring for 5 h. The reaction mixture was worked up analogously to Example 1 except that the extraction of the organic impurities was carried out with 3 X 20 ml of chloroform instead of dichloromethane. 9.6 g (i.e. 92% of theory) of the product with m.p. t. 249 to 251

Example 4

A mixture of 8.31 g (50 mmol) of the compound of formula II, 6.60 g (62.3 mmol) of anhydrous sodium carbonate, 100 ml of dry dimethylsulfoxide and 4.89 g (3.52 ml; 62.3 mmol) of n- The reaction mixture is worked up analogously to Example 1. 9.2 g (ie 88% of theory of the product of m.p. 248 DEG-251 DEG C.) are obtained.

A mixture of 8.31 g (50 mmol) of the compound of formula II, 8.60 g (62.3 mmol) anhydrous, potassium carbonate, 100 ml dry dimethylacetamide and 10.58 g (6.07 ml; 62.3 mmol) n- of propyl iodide is heated to 100 ° C with stirring for 1 h. The reaction mixture is worked up analogously to Example 1. 9.5 g (i.e.

% of theory) of the product with m.p. t. Mp 249-251 ° C. Example 6

A mixture of 332.4 g (2.00 moles) of the compound of formula JI, 344.0 g (2.49 moles) was used. potassium carbonate, 4 L of dry dimethylformamide and 306.4 g (226.4 mL; 2.94 mol) of n-propyl bromide are heated to 100 ° C with stirring for 5 h. The reaction mixture was worked up analogously to Example 1 except that dichloromethane was used in an amount of 4 X 400 mL to extract organic impurities from the alkaline aqueous solution. 370 g (i.e. 89% of theory) of the product with m.p. t. Mp 249-251 ° C.

Example 7

A mixture of 8.31 g (50 mmol) of the compound of formula II, 10.46 g (125 mmol) of sodium bicarbonate, 100 ml of dry dimethylformamide and 7.66 g (5.66 ml; 62.3 mmol) of n-propyl bromide are stirred with stirring Heat at 100 ° C for 6 h. The reaction mixture was worked up analogously to Example 1. 9.6 g (i.e.

% of theory) of the product with m.p. t. Mp 248-250 ° C.

Claims (7)

1. Process for the preparation of 7-n-propyl-3-methyl-3,7-dihydro-1H-purine-2,6-dione of formula I <1 li (I) characterized in that 100 molar parts of 3-methyl-3,7-dihydro-1H-purine-2,6-dione of the formula II H N Tj ------ Thunderstorm. It is reacted with 100 to 150 moles. parts of n-propyl halide and 50 to 150 mol. parts of alkali carbonate in an aprotic solvent and the product isolated. 2. A process according to claim 1, wherein n-propyl halide is n-propyl bromide in the presence of 0.5 to 20 moles. propyl iodide. 3. A process according to claim 1, wherein n-propyl chloride or 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. 4. The process of claims 1 and 2, wherein n-propyl chloride is used in the presence of 0.5 to 20 moles. parts of sodium or potassium bromide per 100 mol. parts of n-propyl chloride. 5. The method of claim 1, wherein the alkali carbonate is sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate. 6. The sposoib of claim 1, wherein the aprotic solvent is acetone, dimethylsulfoxide, sulfolane, hexamethylphosphotriamide, dimethylacetamide or preferably dimethylformamide. 7. The process of claim 1, wherein the compound of formula I is isolated from the reaction mixture by distilling off excess, n-propyl halide and an aprotic solvent, preferably under reduced pressure, dissolving the distillation residue in at least an equivalent amount of aqueous alkaline hydroxide solution. the organic impurities are extracted with chlorinated solvents and the compound of formula I is precipitated from the aqueous alkaline solution by dilute mineral acid or an organic carboxylic acid, preferably acetic acid.