DD274334A3 - PROCESS FOR PREPARING PURE 3,7-DIMETHYL-1- (5-OXOHEXYL) -XANTHINE - Google Patents

Abstract

3,7-Dimethyl-1- (5-oxohexyl) -xanthine can be prepared technically simple and economically in very good yields purely by reacting theobromine with 1-chlorohexanone-5 in the presence of a Saureeacceptors in a dipolar aprotic solvent with heating ,

Description

Field of application of the invention

The invention relates to a process for the preparation of pure 3,7-dimethyl-1- (5-oxohexyl) -xamhin of the formula

0GH,

Ko - GO - (GHp). -

which is a well-known drug for circulatory disorders.

Characteristics of the known technical solutions

Quite generally, 3,7-dimethyl-1 (5-oxohexyl) -xanthine can be prepared according to DE AS 1235320 and 1S45687 by reacting the alkali metal salt of theobromine with 1-halohexanone-5 By instability of the halocarbons, in particular 1-bromohexanone-5 However, which already discolored during or shortly after the distillation, however, occur numerous side reactions, whereby the technical preparation is difficult and only contaminated I is obtained, which can not be obtained even by repeated recrystallization in the purity required for pharmaceutical end products.

As extensive own experiments showed obtained by this method, when using i-Bromhoxanon-5, a contaminated product (TLC:> 1% impurity) of mp. 101-102 ° C in yields of only 50-55% of theory , Further purification operations further reduce this yield and thus make the entire process uneconomical.

Furthermore, 'was prepared by dehydrogenation of the corresponding Kydroxyalkylverbindung (DE-OS 2302772, 2234202, 2330741). However, these processes have the disadvantage that the preparation of the required as a precursor 1-bromohexene technically difficult and the purification of 1-! 5-hexenyl) -3,7-dimethylxanthins by column chromatography is very expensive (DE-OS 2432702, Example 1) ,

I was also obtained by reacting 1- (3-bromopropyl) -3,7-dimethylxanthine with sodium acetoacetic acid ester followed by saponification and decarboxylation. In this method, however, a complicated purification by column chromatography is also required (DE-AS 1235320, Example 6).

In DD-PS 129911 therefore the production of I from theobromine and the 2- (4-bromobutyl) -2-methyl-1,3-dioxolane in the presence of acid acceptors, such as alkali metal carbonate, followed by acid hydrolysis of the. To avoid byproducts I ketals described (yields: 65- 70%).

A similar reaction with the 1-bromohexanone-5-ethylene ketal and theobromine in the presence of NaH is listed in Japanese Patent Laid-Open No.56147787. In two other Japanese Patent Laid-Open Nos. 54112893 and 56059775, the reaction of the tetraethylammonium chloride of theobromine with 1-bromohexanone-5 in the presence of the phase transfer catalyst tetrabutylammonium bromide or with triethyl-benzylammonium bromide (JP-OS 56110683) is described. In JP-OS 56110687, the reaction of the reactants in hexamethylphosphoric triamide is carried out. These processes are very complicated by the separate preparation of the tetraalkylammonium salts or the potassium salt of theobromine, require special solvents and usually two times recrystallization of the crude I or, as described in DD-PS 129911 and animal JP-OS 56147787, the additional preparation of Ketals haloketone and after the reaction with theobromine the hydrolysis of the first formed I-ketal.

From CS-PS 201 558 and 201657 is known, the potassium salt dp · Theobromins, which must be prepared separately, with 1-bromohexanone-5, optionally in the presence of NaJ, in dimethylformamide to implement.

Disadvantages of this procedure are the separate, complicated production of the theobromine K salt and the insufficient purity of the final product, which is expressed in the low melting points.

Eigone extensive experiments with 1-bromohexanone-5 showed that end products with a melting point from 101 ° C in the DC each contain impurities of 1% and more and are therefore not suitable for pharmaceutical use. If, instead of the theobromine potassium salt, theobromine is used in the presence of acid acceptors, such as potassium carbonate, and using 1-bromohexanone-5 g, only contaminated I could be obtained in yields of 50-60% according to our own experiments.

From the large number of patents for the production of I goht forth that its pure production on an industrial scale difficult and / or economic b. 5r is not yet solved satisfactorily.

There is therefore a real social need for a process which makes it possible to produce I in a technically simple and economical manner in a very good yield.

Object of the invention

ü ^: -ä invention has the goal to produce I technically simple and economical in very good yields.

Presenting the essence of the invention

The present invention has for its object to produce 3,7-dimethyl-1- (5-oxohexyl) xanthine technically simple and economical in very good yields.

According to the invention, this is achieved by reacting theobromine with 1-chlorohexanone-5 in the presence of an acid acceptor in a dipolar aprotic solvent with heating.

As a dipolar aprotic solvent, according to the present invention, for example! Dimethylformamide, Dimcthylsulfoxid or Hexamethylphosphorsäuretriamid be used.

A particular embodiment of the invention is dariri that the reaction mixture is heated to 100 to 150 ⁰ C, wherein each optimum temperature may be different from solvent to solvent and in particular by its properties such as boiling point and stability can be influenced.

Suitable acid acceptors for the process according to the invention are, for example, alkali metal carbonates, such as sodium or potassium carbonate.

The resulting reaction mixture can be worked up in various ways according to the present invention.

Thus, for example, after the reaction has taken place, part of the solvent is distilled off from the reaction mixture obtained, water is added, the pH is adjusted to 12 to 13 and the 3,7-dimethyl-1- (5-oxohexyl) -xanthine is combined with water immiscible solvent, for example chloroform, extracted and the crude product obtained after concentration are recrystallized.

However, after successful reaction, the inorganic salts can first be suctioned off, the solvent subsequently distilled off, the residue taken up with water, the pH adjusted to 12 to 13 and the 3,7-dimethyl-1- (5-oxohexyl) -xenthin extract with a water-immiscible solvent, for example chloroform, and recrystallize the crude product obtained after concentration.

The process according to the invention has the following Vc parts in comparison to known processes:

1. In the implementation, theobromine in place of Tfc.rnalkylQ ¹ ? monium salts or the potassium salt of the theobromine, so that their separate, elaborate Lord ·· allur; 3ntfällt.

2. There is no need to use special phase transfer catalysts.

3. In place dos dioxolane, whose technical preparation is expensive, the free ketone can be used.

Since the free haloketones generally lead to side reactions as a result of their reactivity, such. For example, 1-bromohexanone-5, which was therefore ketalized (see DWP 129911), it was utterly; Surprisingly and unforeseeably, i-chlorohexanone-5 not only gives rise to no side reactions but, moreover, gives i in contrast to i-bromo-5-oxanone-5 in very high yields with high purity after only one recrystallization.

• Furthermore, the patent literature does not describe any examples of the preparation of I using 1-chlorohexanone-5, since it is to be expected that the chlorine derivative would have a lower reactivity with the bromine derivative and thus lead to lower yields.

embodiments

example 1

54 g of theobromine and 46 g of potassium carbonate are stirred in 300 ml of dimethylformamide for one hour at 120-130 ° C.

Then trop '. Rnan 45g i-chloro-hexanone-5 in 15 minutes and heated for a further 4 hours boi 120-130 ° C with stirring.

Then 150-20OmI dimethylformamide are distilled off, 200 ml of water was added, stirred for 15 minutes and adjusted with concentrated sodium hydroxide to a pH of 12 to 13.

The alkaline solution is extracted with 225 ml of chloroform and the chloroform solution is washed with 150 ml of water. The chloroform is distilled off and the residue recrystallized with the addition of activated carbon from methanol.

Yield: 70 = 84% of theory 3,7-dimethyl-1- (5-oxohexyl) -xanthine of melting point 104-105 ° C

DC result: 0.1% contamination

Example 2

54gTheobromin and 46g of potassium carbonate are stirred in 300 ml of dimethylformamide, 1 Stuiidebei 120-130 ⁰ C. Then added dropwise 45g 1-Chloriiexanon-5in 15 minutes and heated for a further 4 hours at 120-130 ⁰ C with stirring.

After cooling, the salts are filtered off with suction and washed with a little dimethylformamide.

The dimethylformamide is distilled off under reduced pressure, the residue is dissolved in 150 ml of water and the pH is divided into 12 to 13 with concentrated sodium hydroxide solution.

The alkaline solution is further worked up as in Example 1.

Yield: 68 g = 81.5% of theory 3,7-Dimelhyl-1- (5-oxohexyl) -xanthine of melting point 104-105 ° C

DC result: 0.1% contamination

Claims (7)

1. A process for the preparation of 3,7-dimethyl-1- (5-oxohexyl) -xanthine by reacting the alkali metal salts of theobromine with 1-halohexanone-5 in aqueous-organic solution, characterized in that theobromine with 1-chlorohexanone 5 in the presence of an acid acceptor in a dipolar aprotic solvent with heating. 2. The method according to item 1, characterized in that is used as the dipolar aprotic solvent dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide. 3. The method according to points 1 and 2, characterized in that the reaction mixture is heated to temperatures of 100 to 150 ⁰ C. 4. Process according to items 1 to 3, characterized in that alkali metal carbonates are used as acid acceptors. 5. The method according to points 1 to 4, characterized in that are used as Aikalikarbonate sodium carbonate or potassium carbonate. 6. The method according to items 1 to 5, characterized in that distilled off after successful reaction from the resulting reaction mixture, a portion of the solvent, water was added, the pH adjusted to 12-13 and das3,7-dimethyl-1- (5 -oxohexyl) -exanthin with a water-immiscible solvent, such as chloroform, extracted and the crude product recovered after concentration is recrystallized. 7. The method according to points 1 to 5, characterized in that after the reaction, the inorganic salts are filtered off with suction, the solvent is distilled off, the residue taken up with water, the pH adjusted to 12 to 13 and das3,7-dimethyl-1 - (5-oxuhoxyl) -xanthine with a water-immiscible solvent, such as for example chloroform, extracted and the crude product obtained after concentration is recrystallized.