CS271988B1 - Method of 3-methyl-7-n-propyl-3,7-dihydro-1h-purine-2,6-dione preparation - Google Patents

Abstract

The process for the preparation of 3-methyl-7- -n-propyl-3,7-dihydro-1H-purine-2,6-dione ‘ of formula I by the fact that 6-amino-5-formyl-amino- - 1-methyl- (1H, 3H) -pyrimidine-2,6-dione of the formula II is reacted with n-propyl halide and alkaline carbonate in water and / or v an aliphatic alcohol having a carbon number of 1 to 3 and the compound of formula I is isolated. Compound Formula I is used in pharmaceutical chemistry as an intermediate in peripheral production propentophyllin vasodilators.

Description

(57) A method for the preparation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione of formula I is prepared by substituting 6-amino-5-formyl-amino-1 The methyl- (1H, 3H) -pyrimidine-2,6-dione of formula II is reacted with n-propyl halidoip and an alkali carbonate in water and / or an aliphatic alcohol having a carbon number of 1-3 and the compound of formula I is isolated. The compound of formula (I) is used in pharmaceutical chemistry as an intermediate in the production of peripheral propentophylline vasodilator.

271988 Bl tn

CS 27198B Bl

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

which is used in pharmaceutical chemistry as an intermediate in the preparation of peripheral propentophylline vasodilator. To date, the compound of formula 1 has been prepared by alkylating 3-methyl-3,7-dihydro-1H-purine-2,6-dione with n-propyl halide in the presence of an alkali metal carbonate in an aprotic solvent | A.Rybář et al .: CS AO 263595 | (by alkaline alkylation), 3-methyl-3,7-dihydro-1H-purine-2,6-dione salt with n-propyl halide in aprotic solvent | A.Rybář et al .: CS AO 263200 |, formylation of 5-n-propylamino-6-amino-1-methyl-1H-pyrimidine-2,6-dione to 5- | N- (n-propyl) formylamino | - 6-amino-1-methyl-1H-pyrimidine-2,4-dione, which by heating with alkali hydroxides or carbonates gives the alkali salt of a compound of formula I, which is liberated by acidification with an inorganic or organic acid | : CS AO 266291J, or by formylation of 5-n-propylamino-6-amino-1-methyl-1H-pyrimidine-2,6-dione by formamide treatment and on in-situ thermal cyclization

5- | Nao-propylformylamino | -6-amino-1-methyl-1H-pyrimidine-2,4-dione | A.Rybar et al .: CS

AO 267379 | .

A 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 purify 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). 1 H-pyrimidin-5-yl) -n-propylamine, which has a negative effect on the overall yield of propentophyllin synthesis. In the latter known method for the preparation of the compounds of formula I, a high reaction temperature of about 180 ° C is disadvantageous.

These disadvantages are overcome by the process of the invention, which is based on the reaction of 6-amino-5-formylamino-1-methyl- (1H, 3H) -pyrimidine-2,6-dione of Formula II

with n-propyl halide and alkali carbonate in water and / or in an aliphatic alcohol having a carbon number of 1 to 3.

The process according to the invention is carried out in such a way that 100 mol. parts of the compound of formula II are dissolved in an aqueous solution of 50 to 150 mol. parts of alkali carbonate and 100 to 150 mol. parts with 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 at 40 to 100 ° C for at least 5 h. Sodium carbonate or potassium carbonate may be used as the alkali carbonate. Halogen in n-propyl halide represents chlorine, bromine, iodine. As the aliphatic alcohol, methanol, 1-propanol, 2-propanol, preferably ethanol, may be used.

CS 271988 Bl

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 by weight of sodium iodide, potassium iodide or iodine per 100 mol. parts of n-propyl halide. Similarly, at least reactive n-propyl chloride in the presence of 0.5 to 20 moles may be used instead of n-propyl bromide. parts of sodium bromide or potassium bromide per 100 mol. parts of n-propyl chloride.

The contact of the reaction components can be improved by stirring or better by the addition of small amounts of interphase transfer catalysts of the inorganic tetraalkylammonium salt type e.g. tetrabutylammonium, triethylbenzylammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium in which the alkyl has a carbon number of 8 to 18, or is a mixture of these alkyls or by the addition of small amounts of anionic and nonionic surfactants, e.g. industrially produced sodium alkanesulfonates, sodium alkylbenzene sulfonates, polyethoxylated alcohols, polyethoxylated alkylphenols.

The compound of formula I is isolated from the reaction mixture in such a way that it is precipitated from the alkaline reacting cooled reaction mixture by addition of an inorganic or organic carboxylic acid, e.g. with dilute hydrochloric acid, sulfuric acid, formic acid, preferably acetic acid. The precipitated compound of formula (I) is filtered off, suctioned or centrifuged and dried at 100 DEG C., preferably under reduced pressure. A further crop of the compound of formula I can be obtained by vacuum concentration of the filtrate after separation of the first crop of the compound of formula I. Isolation and drying are carried out in an analogous manner. The yields of the compound of formula I (first + second fraction) range from 75 to 90%.

The main advantage of the process according to the invention is that it is not necessary to first cyclize the pyrimidine intermediate of formula II to a purine derivative and propylate it subsequently, but that both reactions can be carried out in one step. Another advantage is that the reaction medium does not need to use an aprotic solvent, but substantially cheaper water or lower alcohols while maintaining high yields and purity.

In the following, the invention is described in the examples without being limited thereto.

EXAMPLE

A mixture of 9.2 g (50 mmol) of the compound of formula II 7.8 g (57.5 mmol) of anhydrous potassium carbonate and 50 ml of water is heated to reflux until the compound of formula II is dissolved. The resulting beige solution was cooled to about 30 ° C and 7.07 g (5.23 mL; 57.5 mmol) of n-propyl bromide in 50 mL of 96% ethanol was added via a reflux condenser. While stirring, it is refluxed for 12 h, the reaction mixture is cooled, acetic acid is added to pH 7, after about 2 h the precipitated crystals are sucked off and dried at 100 ° C to constant weight. The filtrate is concentrated under vacuum on a water pump to about 1/4 of its original volume to give a second crop. A total of 9.9 g (95.1% of theory) of the compound of formula I is obtained, m.p. Mp 249-251 ° C.

Example 2

A mixture of 9.2 g (50 mmol) of the compound of formula II, 7.8 g (57.5 mmol) of anhydrous potassium carbonate and 50 ml of water is heated to reflux until the compound of formula II is dissolved. The heating of the solution is removed and stirring is continued using an efficient condenser. To the bottom of the reaction vessel was added 7.07 g (5.23 mL; 57.5 mmol) of n-propyl bromide, 75 mg (0.5 mmol) of sodium iodide in 50 mL of 1-propanol for 20 min. With stirring, reflux for 9 h. The reaction mixture was worked up analogously to Example 1. 8.5 g (81.6% of theory) of the compound of formula I were obtained, m.p. 249,5 CS 271988 Bl

- 251 ° C.

Example 3

A mixture of 9.2 g (50 mmol) of the compound of formula II, 6.09 g (57.5 mmol) of anhydrous sodium carbonate and 50 ml of water was heated to reflux until the compound of formula II dissolved. The resulting solution was cooled to room temperature and 7.07 g (5.23 mL, 57.5 mmol) of n-propyl bromide and 0.20 g (0.5 mmol) of dimethylbenzyl-Cg- ₁ g-alkylammonium bromide in 50 ml were poured through a reflux condenser. ml of 96% ethanol. With stirring, reflux for 10 h. The reaction mixture was worked up analogously to Example 1. 8.0 g (76.9% of theory) of the compound of formula I were obtained, mp 249.5-251.5 ° C.

Example 4 i

Analogously to Example 1, except that the reaction is carried out in the presence of 0.15 g (0.5 mmol) of sodium C 8-18 alkane sulfonate and the reaction mixture refluxes for 6 hours.

A total of 8.9 g (85.5% of theory) of the compound of formula I is obtained, m.p. 249.5-251 ° C.

SUBJECT

INVENTION

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

and

CD characterized in that 100 mol. parts of 6-amino-5-formyl-amino-1-methyl - (1H, 3H) -pyrimidine-2,6-dione of formula II

with 100 to 150 mol. dlelml of n-propyl halide and 50 to 150 mel. parts of an alkali carbonate in water and / or an aliphatic alcohol having a carbon number of 1 to 3 at a temperature of 40 to 100 ° C for at least 5 hours, and then the product is isolated.

2. The process of claim 1 wherein the n-propyl halide is n-propyl chloride, n-propyl bromide or n-propyl iodide.

81

1. The process according to claim 1, wherein the alkylating agent is propyl chloride or n-propyl bromide in the presence of 0.5 to 20 mol. parts by weight of potassium iodide or iodine per 100 mol. parts of n-propyl halide.

use sodium iodide-

Claims (8)

4. A process according to claim 1 or 2, wherein the propyl chloride is in the presence of 0.5 to 20% by weight per 100 mol. parts of n-propyl chloride by using as alkylating agent. parts of sodium bromide or draidide bromide. 5. The process of claim 1 wherein the reaction is carried out in the presence of an anionic or nonionic type interfacial transfer catalyst or surfactant. 6. A process according to claim 1, wherein the interfacial transfer catalyst is an inorganic tetraalkylammonium salt, such as tetrabutylammonium, triethylbenzylammonium, tri-n-octylmethylammonium, dimethylbenzylalkylammonium having an alkyl carbon number of 8 to 18. or a mixture of these alkyls. r 7. A process according to claim 1 or 5, wherein the nonionic surfactant is a polyethoxylated alkylphenol or a polyethoxylated aliphatic alcohol. 8. A process according to claim 1 or 5, wherein the anionic surfactant is an alkali salt of an alkanesulfonic acid having a carbon number of 10 to 16 or an alkali salt of an alkylarenesulfonic acid having a carbon number of 12 to 22.