CH622519A5 - Process for the preparation of hydroxyalkylxanthines - Google Patents

Abstract

Process for the preparation of xanthine derivatives, in which one of the radicals in the 1-, 3- and 7-position is an ( omega -1)-hydroxyalkyl radical having 4 to 8 carbon atoms which does not bear a branch in the ( omega -1)-position and in which the other radicals can be alkyl radicals having 1 to 12 carbon atoms, but the radical in the 1- and/or 7-position can also be hydrogen, addition of water to corresponding ( omega -1)-alkenylxanthines being carried out according to Markownikov's rule in the presence of a dilute acid as the water addition catalyst. The compounds can also be prepared by addition of hydrogen halide to appropriate ( omega -1)-alkenylxanthines and subsequent hydrolysis of the resulting ( omega -1)-haloalkylxanthines. The hydroxyalkylxanthines promote circulation and can be used as medicaments.

Description

The invention relates to a process for the preparation of compounds of the general formula I (see claim 1), in which one of the radicals R1, R2 and R3 is a (co-l) -hydroxyalkyl radical having 4 to 8 carbon atoms, which in ( cü-l) position has no branching and the other two residues are straight-chain or branched alkyl residues with 1 to 12 carbon atoms, but R1 and / or R3 can also be hydrogen. The process is characterized in that water is added to the corresponding (co-l) alkenylxanthines in the presence of a dilute acid as a water addition catalyst.

The hydroxyalkyl radical is preferably in the 1- or 7-position and is unbranched. It has now been found that the hydroxyl group in the procedure according to the invention always attaches to the lower hydrogen carbon atom, ie in the (oo-l) position, according to the Markovnikoff rule. This is surprising insofar as Markovnikoff's rule applies only to a limited extent, especially in the case of compounds with terminal double bonds.

Suitable starting compounds for the production of the (tü-l) -hydroxyalkylxanthines according to the invention are e.g. l- (3-butenyl) -, l- (4-pentenyl) -, l- (5-hexenyl) -, and l- (2-methyl-3-butenyl) -3,7-dimethylxanthine, the l- ( 5-hexenyl) -3-methyl-7-alkylxanthines, such as -7-ethyl-, -7-propyl-, -7-butyl-, -7-isobutyl- and -7-decyl-xanthine, furthermore l, 3- Dimethyl-7- (2-methyl-3-butenyl) -, -7- (3-butenyl) -, -7- (4-pentenyl) -, -7- (5-hexenyl) - and -7- (6 -heptenyl) -xanthine and 3-methyl-7- (5-hexenyl) xanthine and its derivatives with propyl, isobutyl, pentyl or hexyl groups in the 1-position.

According to the present invention, both hydroxy-alkylmethylxanthines and their homologs can be prepared in which at least one methyl radical has been replaced by an alkyl radical having 2 to 12 carbon atoms. For example, these latter compounds can be such that at least one of the radicals R1, R2 or R3 has at least 5 carbon atoms.

The water addition according to the invention is carried out in aqueous solutions or suspensions in the presence of acids, e.g. Mineral acids, such as sulfuric acid, hydrohalic acids, nitric acid, phosphoric acid or sulfonic acids, such as trifluoromethylsulfonic acid or ion exchangers present in the hydrogen form and containing sulfonic acid groups, the amount of acid not exceeding the concentration corresponding to a 2-normal acid, expediently more than 0.5-normal and preferably 1 to be 2-normaI. If appropriate, the use of an organic solvent which is inert to dilute acids, such as 1,4-dioxane, benzene or toluene, is advantageous, the volume fraction of solvent advantageously being equal to or below the amount of water.

The water addition is generally carried out at temperatures from 40 to 150 ° C, preferably from 60 to 120 ° C. The course of the reaction and the point in time of the complete implementation can be followed very easily using thin-layer chromatography methods. The reaction products in the aqueous phase let them e.g. isolate by extraction with chlorinated hydrocarbons such as methylene chloride or chloroform. If a second - organic - phase is present, additional portions of the

s

10th

xs

20th

25th

30th

35

40

45

50

55

60

65

3rd

622 519

Fahrensprodukîes by evaporating the solvent e.g. be isolated under reduced pressure.

The hydroxyalkylxanthines obtained according to the invention are known and can be used therapeutically in many ways. For example, the l- (5-hydroxyhexyl) -3,7-dimethyl-xan-thin by promoting blood circulation.

Rf value of 0.47 and with nitromethane / benzene / pyridine (volume ratio 20: 10: 3) as flow agent an Rf value of 0.60. UV light served as an indicator, although the pyridine of the superplasticizer had to be removed at 50 ° C under reduced pressure because of its fluorescence quenching properties.

Examples

1) 1 - (5-Hydroxyhexyl) -3,7-dimethyl-xanthine a) l- (5-hexenyl) -3,7-dimethyl-xanthine io

10.3 g of l-bromo-hexene (5) are reacted with 20.2 g of theobromine sodium in 200 ml of dimethylformamide at 120 ° C. with stirring until the completion of the reaction can be seen in the thin-layer chromatogram after about 6 to 8 hours, whereupon the Solvent is removed under reduced pressure. The residue is dissolved in 100 ml of methylene chloride at 20 ° C., separated from the insoluble sodium bromide and purified on a column with neutral aluminum oxide to remove small amounts of dark-colored accompanying substances. It crystallizes from n-hexane in colorless 20 needles from the melting point 76 to 77 ° C, which are combined into druses. Yield: 24.1 g (92% of theory). After thin layer chromatography on Merck TLC ready-made silica gel 60 F: m plates with benzene / acetone (volume ratio 6: 4) as flow agent, the product has a b) l- (5-hydroxyhexyl) -3,7-dimethyl-xanthine

2.6 g of the l- (5-hexenyl) -3,7-dimethyl-xanthine described under a) are heated to the boil for about 24 hours with 25 ml of 1-normal sulfuric acid. A sample of the clear solution is then checked for the degree of water attachment by thin layer chromatography as described above, the desired process product showing the fluorescence quenching in the range from Rf 0.30 to 0.37 (nitromethane / benzene / pyridine). After the reaction has ended, the product is neutralized and extracted with methylene chloride. The process product is obtained from the extract solutions in the form of colorless crystals which, when recrystallized from methanol, have a melting point of 126 ° C. Yield: 2.6 g (93% of theory).

2 to 18) According to the procedure of Example 1, the following hydroxyalkyl xanthines are prepared and identified in the same way as in Example 1:

Table 1

Melting point C

2)

1- (5-hydroxyhexyl) -3-methyl-7-propyl-xanthine

76-77

3)

l-propyl-3-methyl-7- (5-hydroxyhexyl) xanthine

53

4)

1-Pentyl-3-methyl 1- 7- (5-hydroxyhexyl) xanthine

65-67

5)

1- (3-hydroxybutyl) -3,7-dimethyl-xanthine

130

6)

1- (4-Hydroxypentyl) -3,7-dimethyl-xanthine

100

7)

1- (5-hydroxyhexyl) -3-methyl-7-ethyl-xanthine

87

8th)

1- (5-hydroxyhexyl) -3-methyl-7-butyl-xanthine

56-57

9)

1- (5-Hydroxyhexyl) -3-methyl-7-isobutyl-xanthine

54-55

10)

1- (5-Hydroxyhexyl) -3-methyl-7-decyl-xanthine

37-38

11)

l-isobutyl-3-methyl-7- (5-hydroxyhexyl) xanthine

62-63

12)

l-hexyl-3-methyl-7- (5-hydroxyhexyl) xanthine

68-69

13)

1- (2-Methyl-3-hydroxybutyl) -3,7-dimethyl-xanthine syrupy

14)

1,3-Dimethyl-7- (2-methyl-3-hydroxybutyl) xanthine syrupy

15)

1,3-Dimethyl-7- (3-hydroxybutyl) xanthine

124

16)

1,3-dimethyl-7- (4-hvdroxypentyl) xanthine

84

17)

1,3-dimethyl-7- (5-hydroxyhexyl) xanthine

93-94

18)

1,3-dimethyl-7- (6-hydroxyheptyl) xanthine

109

B

Claims (7)

622519 1 year R "r-_N _ r3 i, i: 7! (I) in which one of the residues R1, R2 and R3 is a (co-l) -hydroxyalkyl residue with 4 to 8 carbon atoms, which has no branching in the ((ul) position and in which the other residues are alkyl residues with 1 to 12 carbon atoms, R1 and / or R3 can also be hydrogen, characterized in that water is added to corresponding (lo-l) alkenyl xanthines in the presence of a dilute acid as a water addition catalyst. 2. The method according to claim 1, characterized in that mineral acids, sulfonic acids or in the hydrogen form, sulfonic acid groups containing ion exchangers, preferably sulfuric acid, are used as the water attachment catalyst. 2nd PATENT CLAIMS 1. Process for the preparation of compounds of the general formula 0 3. The method according to claim 1 or 2, characterized in that the amount of acid used does not exceed the concentration corresponding to a 2-normal acid, expediently more than 0.5-normal and preferably 1- to 2-normal. 4. The method according to claims 1 to 3, characterized in that the water addition takes place at temperatures of 40 to 150 ° C, preferably from 60 to 120 ° C. 5. The method according to claims 1 to 4, characterized in that l- (5-hydroxyhexyl) -3,7- or 7- (5-hydroxyhexyl) -l, 3-dimethylxanthine by water addition to l- (5-hexenyl ) -3,7- or 7- (5-hexenyl) -l, 3-dimethylxane-thin. 6. A process for the preparation of compounds of the general formula I in which R1, R2 and R3 have the meaning given in claim 1, characterized in that hydrogen halide is initially added to corresponding (wl) -alkenylxanthines and the resulting (lO-l) -Halogen-alkylxanthine saponified to (co-l) -hydroxyalkyl compounds. Medicaments are known which contain dimethyl-xanthine derivatives as active ingredients, which are in 1- or 7-position have a (co-l) -hydroxyalkyl radical. These are accessible by reducing the corresponding keto compounds, their production u. a. takes place via halogen ketones and which e.g. be reduced with the help of metal hydrides. Halogen ketones and hydrides are sometimes not very stable, which has a disadvantageous effect, especially with larger batches. Furthermore, from DT-BP 1 067 025 a process for the preparation of l- (ß-hydroxypropyl) -3,7-dimethylxanthine (= l- (ß-hydroxypropyl) theobromine) is known, in which using concentrated catalysts such as water Sulfuric acid water is added to l-allyl-3,7-dimethyl-xanthine. According to this patent specification, however, the known reaction is specific for 1-allyl-theobromine, since even 7-allyl-theophylline is not amenable to this reaction. It has now been shown that these difficulties can be overcome if the corresponding (co-1) alkenylxanthines are added to the desired (o) -l) regardless of the position of the alkenyl group by addition of water in the presence of dilute sulfuric acid -Hydroxyal-kylxanthinen implemented. This implementation is possible in almost quantitative yield.