NO143224B - PROCEDURE FOR THE PREPARATION OF HYDROXYALKYLXANTHINES - Google Patents

Description

Medicines have previously been known which as active ingredient contain dimethylxanthine derivatives which have a (co-1)-hydroxyalkyl residue in the 1- or 7-position. These are available by reduction of the corresponding keto compounds, the production of which, among other things, takes place via halogen ketones and which are reduced, e.g. with the help of metal hydrides. Halogen ketones and hydrides are partly not stable, which is particularly unfortunate

when manufacturing on a larger scale. Furthermore, from DT-BP 1,067,025 a method is known for the production of 1-((3-hydroxypropyl)-3,7-dimethylxanthine (= 1-((3-hydroxypropyl)-theobromine)) by which, using water addition catalysts, such as concentrated sulfuric acid, water is added to 1-ally1-3,7-dimethylxanthine. According to this patent, the known reaction is only specific for 1-ally1-theobromine, since all 7-allyl -theophylline is not possible with this reaction.

It has now been shown that this difficulty can be overcome when the corresponding (u-1)-alkenylxanthine is converted independently of the alkenyl group by addition of water in the presence of certain dilute acids to the desired (two-1)-hydroxyalkylxanthine. This turnover is possible in almost quantitative yield.

The present invention therefore relates to a process for the production of hydroxyalkylxanthines of the general formula (I) where one of the residues R 1 , R 2 and R is a (CJ -1)-hydroxyalkyl residue with 4-8 carbon atoms, as in (CJ -1) -position does not bear any branching, and where the other residues are alkyl residues with 1-12 carbon atoms, since R<1> and/or R<3> can also be hydrogen, and the method is characterized by the fact that to the corresponding (CJ-1 )-alkenyxanthines precipitate water according to Markownikoff's rule in the presence of a dilute mineral acid or sulphonic acid or an ion exchanger containing a sulphonic acid group present in hydrogen form as a catalyst.

Preferably, the hydroxyalkyl residue is in the 1- or 7-position and is unbranched. It has now been found that the hydroxyl group in the new method is always assigned according to Markownikoff's rule to the hydrogen-poor carbon atom, i.e. in the (CO -1) position. This is of course surprising, as Markownikoff's rule only applies conditionally in the case of compounds with double bonds at the end.

Suitable starting materials for use in the new process for the production of (u-1)-hydroxyalkylxanthine are e.g. 1-(3-butenyl)-, 1-(4-pentenyl)-, 1-(5-hexenyl)- and 1-(2-methyl-3-butenyl)-3,7-dimethylxanthine, 1-(5- hexenyl)-3-methyl-7-alkylxanthine, such as -7-ethyl-, -7-propyl-, -7-but-yl-, -7-isobutyl- and -7-decylxanthine, further 1,3-dimethyl -7-(2-methyl-3-butenyl)-, -7-(3-butenyl)-, -7-(4-pentenyl)-, -7-(5-hexenyl)- and -7-(6- heptenyl)-xanthine, as well as 3-methyl-7-(5-hexenyl)-xanthine and its derivative with propyl, isobutyl, pentyl or hexyl groups present in the 1-position.

According to the present invention, both hydroxyl-alkylmethylxanthines and their homologues can be prepared, in which at least one methyl residue is replaced by an alkyl residue with 2-12 C atoms. For example, the latter compounds can

/ 12

be of such a nature that at least one of the residues R , R and

3

R has at least 5 carbon atoms.

The water deposition according to the invention is carried out in aqueous solutions or suspensions in the presence of dilute mineral acids, such as sulfuric acid, hydrohalogenic acids, nitric acid or phosphoric acid, or sulphonic acids, such as trifluoromethyl sulphonic acid, or an ion exchanger containing sulphonic acid groups present in hydrogen form, whereby the amount of acid must not exceed step the corresponding concentration of a 2-normal acid, preferably more than 0.5-normal, and preferably 1.-2-normal. Optionally, the use of a solvent inert to diluted acid, such as 1,4-dioxane, benzene or toluene, is advantageous, whereby the volume fraction of solvent is preferably equal to or less than the amount of water.

The water deposition usually takes place at temperatures from 40 to 150°C, preferably from 60 to 120°C. The progress of the reaction as well as the time of complete reaction can be very easily followed by thin-layer chromatographic methods. The reaction product present in the aqueous phase can be isolated fweks. by extraction with chlorohydrocarbons, such as methylene chloride or chloroform. If a second, organic phase is present, possibly further parts of the process product can be isolated by evaporation of the solvent, e.g. under reduced pressure.

The hydroxylalkyl-xanthines produced according to the method are known and can be used therapeutically. Thus, for example, 1-(5-hydroxyhexyl)-3,7-dimethylxanthine is characterized by the fact that it promotes blood circulation.

Example 1

1) 1-(5- hydroxyhexyl)- 3, 7- dimethnyl~xanthine

a) 1-(5-hexenyl)-3,7-dimethylxanthine 10.3 g of 1-bromo-hexene-(5) was reacted with 20.2 g of theobromine sodium in 200 ml of dimethylformamide at 120°C under stirring until the reaction by thin-layer chromatography was complete after approx. 6 - 8 hours, after which the solvent was removed under reduced pressure. The residue was dissolved in 100 ml of methylene chloride at 20°C, separated from soluble sodium bromide and purified over a bath of neutral aluminum oxide to remove small amounts of maroon-colored accompanying substances. From n-hexane, fine needles crystallized there, united to druses with a melting point of 76-77°C. Yield: 24.1 g (92% of theoretical). After thin-layer chromatography on Merck DC-Fertigplatten Kieselgel 60 F~ 254 with benzene/acetone (volume ratio 6:4) as eluent, the product had an Rf value of 0.47, and with nitromethane/benzene/pyridine (volume ratio 20:10: 3) as a fluid, an Rf value pi 0.60. UV light was used as an indicator, whereby the pyridine in the fluid, due to its fluorescence-dissolving properties, must however be removed at 50°C using reduced pressure. b) 1-(5-hydroxyhexyl)-3,7-dimethyl-xanthine 2.6 g of the 1-(5-hexenyl)-3,7-dimethyl-xanthine described under point a) was heated to boiling with 25 ml 1-normal sulfuric acid approx. 24 hours. A sample of the clear solution was then examined by thin-layer chromatography, as described above, with regard to the degree of water deposition, whereby the desired process product showed fluorescence extinction in the range from Rf 0.30 to 0.37 (nitromethane/benzene/pyridine) . After completion of the reaction, the product was neutralized and extracted with methylene chloride. From the extract solution, the process product was obtained in the form of colorless crystals which, after recrystallization from methanol, had a melting point of 126°C. Yield: 2.6 g (93% of theoretical).

Examples 2-18

By following the method described in example 1, the following hydroxylalkyl-xanthines were produced and identified in a similar way as described in example 1:

Example 19

Addition of water to 1-allyl theobromine

2.2 g of 1-allyl theobromine was boiled with 25 ml of 1-normal sulfuric acid for 24 hours. The mixture was then neutralized, and the reaction product was extracted with methylene chloride. After evaporation of the methylene chloride, 1-(2-hydroxypropyl)-theobromine remained in the form of colorless crystals. After recrystallization from isopropanol, the compound gave a melting point of 138°C. The yield was 0.47 g (= 20% of the theoretical).

Example 20 Addition of water to 7-allyltheophylline

2.2 g of 7-allyl theophylline was boiled with 25 ml of 1-normal sulfuric acid for 24 hours. By proceeding in a similar manner as in example 19, 0.48 g of 7-(2-hydroxypropyl)-theophylline (= 20% of the theoretical) was obtained with a melting point of 135 - 136°C.

Example 21 (Comparison example)

Conversion of 1-(5-hexenyl)-theobromine according to West German patent document 1 067 025.

2.2 g of 1-(5-hexenyl)-theobromine were dissolved in 3 ml of concentrated sulfuric acid with stirring, the temperature not being allowed to rise above 30°C. The mixture was then, with constant stirring, gradually heated to 70-80°C over the course of 1 hour. The reaction mixture was then added to 30 ml of water while stirring, and the resulting solution was boiled for 2 hours with reflux cooling. After cooling, the mixture was neutralized with caustic soda, filtered and evaporated to dryness in vacuo. The residue was boiled with isopropanol and the solution evaporated to dryness. Resinous polymerization products and a small amount of a sulphonic acid ester were obtained which, after boiling in water for several hours, did not allow itself to be hydrolysed, which was demonstrated by thin layer chromatography.

Example 22

2.3 g of 1,3-dimethyl-7-(3-butenyl)-xanthine are heated

in 25 ml IN hydrochloric acid for approx. 24 hours. The solution is then neutralized and extracted with methylene chloride. From the extract solution, 1,3-dimethyl-7-(3-hydroxybutyl)-xanthine with a melting point of 124°C is obtained in a yield of 93% of the theoretical.

Example 2 3

2.3 g of 1,3-dimethyl-7-(3-butenyl)-xanthine is heated in 25 ml of a mixture of dioxane and water in a 1:1 ratio with a suspension of a sulfonic acid group-containing cation exchanger. After 24 hours, the changer is filtered off, and 1, 3-dirnethyl-7-r(3-hydroxybutyl)-xanthine is isolated from the solution with a yield of 91%. Melting point 124°C.

Claims (1)

Process for the preparation of hydroxyalkylxanthines of the general formula (I) where one of the residues R , R and R is a (ul -1)-hydroxyalkyl residue with 4-8 carbon atoms, which in the (iO-1) position does not bear any branching, and where the other residues are alkyl residues with 1-12 carbon atoms , where R 1 and/or R 3 can also be hydrogen, characterized in that water is added to the corresponding (u)-1)-alkenylxanthines according to Markownikoff's rule in the presence of a dilute mineral acid or sulphonic acid or an ion exchanger containing a sulphonic acid group present in hydrogen form as a catalyst .