DD222026A1 - PROCESS FOR THE PREPARATION OF THEOBROMINE - Google Patents

Abstract

Pure theobromine can be prepared by methylation of 3-methylxanthine with dimethyl sulfate by reacting the 3-methylxanthine in water or a mixture of water and a lower aliphatic alcohol having 1 to 3 carbon atoms in the presence of at least 1.5 molar Mange of alkali metal carbonate or mixtures of alkali metal carbonate and alkali metal hydroxide with dimethyl sulfate in 30-70% excess methylated with warming.

Description

Field of application of the invention

The invention relates to a process for the preparation of theobromine.

Djeses is used both as a pharmaceutical active substance and as an intermediate for the production of a range of perfusion-promoting agents.

Characteristic of the known technical solutions

It is known to methylate 3-methylxanthine with dimethyl sulfate in the presence of alkali metal hydroxide, optionally with the addition of alkali metal acetate and optionally with the addition of alcohols, in particular methanol, to theobromine (H. Bredereck, Ber.schsch. Chem. Ges., 83, 201 -211 (1950), especially pages 208 and 210, further DE-PS 864869).

A disadvantage of this process is that although yields of 91-92% of the theory are achieved in reactions of ί and 2 g, these decrease with increasing batch size (Bredereck, loc cit., P.208).

Thus, the yields according to this method are only 65-70% of theory for 1-moles, as our own experiments showed. '

A further disadvantage of this process is that the ¹ theobromine thus obtained still contains about 3-5% of unreacted 3-methylxanthine, which adversely affects the subsequent reactions and also reduces the quality of the secondary products.

Also at V. M.Likhacheva, N.G. Zaloznagy and G.T.Maevshaya, Khirri. Farm. Zh. 1975, 9 (7), 48 specified procedure to methylate 3-methylxanthine in the presence of aqueous potassium hydroxide at elevated temperatures with dimethyl sulfate, to obtain a crude hebromine, which still contains 5-7% 3-methylxanthine. The reported by the authors' yield of crude hebromine of 73-76% would decrease by the proportion of 3-methylxanthine, so that only about 70%, would receive Rohtheobromine. However, since 100% of the used Rphtheobromins are never recovered in the alkaline reprecipitation for the purpose of purification, the yield is still below 70%.

Object of the invention

By means of the invention it is possible to prepare theobromine in good yields and in high purity in a methylation process which is easy and straightforward for large-scale production from 3-methylxanthine without chloroform extraction, wherein in particular no starting product is contained in the crude hebrominine.

The following table shows the advantage of the method according to the invention over the current state of the art in a very special degree in the purity of the theobromine. The purity was determined by thin-layer chromatography.

Methylation process, input products ti Yield in%, based on 3-methylxanthine plus-mole batch Purity% 3-methylxanthine comment nfach DE-PS 864869 KbH / KAc / MeOH 65-70 3-5 Chloroform extraction to Khim. Farm. ZH 1975.9 (7), 48 73-76 5-7 no chloroform extraction ^ ₂ C (VMeOH 70-73 0 no chloroform extraction

Explanation of the essence of the invention.

The invention has for its object to develop a method for large-scale production, which allows to produce theobromine in good yields and high purity in a simple manner.

According to the present invention, this is achieved by reacting 3-methylxanthine in water or a mixture of water and a lower aliphatic alcohol having 1 to 3 carbon atoms in the presence of at least 1.5 molar amount of alkali metal carbonate or mixtures of alkali metal carbonate and Alkali lye with a 30-70% excess of dimethyl sulfate with heating methylated.

Qabei the alcohol can be used in an amount of 10 to 100% based on the amount of water used.

D, The reaction is advantageously carried out at temperatures of 40-100 ° C, but preferably at 65-80 ⁰ C performed.

A particular embodiment of the invention is that in the case of using a mixture of alkali metal carbonate and alkali, this contains up to 50 mol% alkali hydroxide.

The process according to the invention can be carried out, for example, by slurrying 3-methylxanthine in water

-2- 260 401 1

is added to this, at least the 1.5 molar amount of alkali carbonate and the mixture is brought into solution with stirring and heating. Now, the lower aliphatic alcohol in amounts of 10-100%, based on the volume of water to it and the amount of dimethyl sulfate is added dropwise in the heat quickly, with a temperature increase is observed. The theobromine precipitates during the dropwise addition of the reaction mixture and after cooling is filtered off with suction and washed well with water. Formed caffeine and theophylline remain under these conditions in the weakly alkaline mother liquor and only the crude theobromine remains.

Exemplary embodiments

example 1

166 g of 3-methylxanthine are suspended in 1000 ml of water and mixed with 210 g of potash. The mixture is heated to 90-95 ° C, the 3-methylxanthine goes into solution. It is allowed to cool to 65-70 ⁰ C and 100 ml of methanol added. Now added dropwise 198g dimethyl sulfate in about 20-30 minutes so that the temperature rises to 85 ° C, stirring for 1 hour and allowed to cool. The pH has been adjusted to 8-8.5. Now you sucked off and washed well with water. After drying, 129g & 73% of the theory of crude hebromine free of 3-methylxanthine, caffeine and theophylline is obtained. .

Example 2

166g of 3-methylxanthine are suspended in 750 ml of water and mixed with 159 g of soda. The mixture is heated to 90-95 ⁰ C, wherein the 3-methylxanthine goes into solution. The mixture is allowed to cool to 80 ⁰ C. and 100 ml of isopropanol to do so. Now added dropwise in about 20-30 minutes 198 g of dimethyl sulfate so that the temperature rises to 90 ^c C, stirring for 1 hour and allowed to stir. The pH has been adjusted to 8-8.5. It sucks and washed well with water. After drying, 126 g = 70% of the theory of crude hebromine, which is free from 3-methylxanthine, caffeine and theophylline.

Example 3

30 g (0.75 mol) of sodium hydroxide and 105 g (0.75 mol) of potassium carbonate are dissolved in 1000 ml of water. Subsequently, 166 g (1 mol) of 3-methylxanthine are added and the mixture is heated to 70-75 ⁰ C, whereby the 3-methylxanthine dissolves as alkali metal salt. To the solution is added dropwise in about 30 Minuteri 198g (1.5MoI) 96% strength dimethyl sulfate at 70-75 ⁰ C and stirred for 1 hour

according to this temperature. , , ,

The mixture is cooled, the precipitate is filtered off with suction and washed with water. After drying, 126 g = 70% of the theory of crude hebromine, which contains no caffeine and theophylline and less than 1% of 3-methylxanthine.

Claims (4)

} '-1 - 260 401 Invention claims: 1.,; Process for the preparation of theobromine by methylation of 3-methylxanthine with dimethyl sulfate in aqueous alcoholic solution in the presence of a base, characterized in that 3-methylxanthine in water or a '^ mixture of water and a lower aliphatic alcohol having 1 to 3 carbon atoms in the presence of at least 1.5 , molar amount of alkali carbonate or mixtures of alkali metal carbonate and caustic with dimethyl sulfate in 30-70% i. Excess methylated with warming. 2. The method according to item 1, characterized in that the alcohol in an amount of 10 to 100%, based on the * amount of water used. 3. The method according to points 1 and 2, characterized in that the methylation at temperatures of 40 to 100 ⁰ C, i preferably 65 to 80 ° C, is performed. 4. The method according to items 1 to 3, characterized in that the mixture of alkali metal carbonate and alkali metal hydroxide contains up to ^ 50 mol% alkali hydroxide.