CH622018A5 - Process for the preparation of novel monoalkenyldialkylxanthines - Google Patents

Description

The invention therefore relates to a process for the preparation of new monoalkenyl dialkylxanthines of the general formula

1 O R3

\ A I (i)

Ni F1

O I 2

in which one of the radicals R1, R2 and R3 is ((ol) -alken-l-yl with 4 to 8 carbon atoms, which has no branching in the (co-l) position, and the other two alkyl radicals with 1 to The process is characterized in that an l-halo-Ct-Cs-alkene with a terminal double bond which does not contain a tertiary C atom is reacted with a corresponding alkali metal salt of a dialkylxanthine. Haloalkenes with an unbranched carbon chain are preferably used .

According to the invention, mono-alkenyldialkylxanthines can advantageously be prepared according to formula I, in which one of the two alkyl radicals has 2 to 12 carbon atoms.

The reaction of the haloalkene with the alkali salt of diethylxanthine can be carried out in a conventional manner, e.g. using dimethylformamide as aprotic solvent at 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 can be evaporated e.g. be isolated under reduced pressure.

The alkenylxanthines prepared according to the invention are suitable as starting materials for the preparation of therapeutically usable hydroxyalkylxanthine compounds, of which e.g. the l- (5'-hydroxyhexyl) theobromine is characterized by a promotion of blood circulation.

example 1

l- (5'-Hexen-l / -yl) -theobromine: 10.3 g of l-bromohexene (5) are reacted with 20.2 g of theobromine sodium in 200 ml of dimethylformamide at 120 ° C with stirring until Thin-layer chromatogram shows the completion of the reaction after about 8 h, after which the solvent is removed under reduced pressure. The residue is dissolved in 100 ml of methylene chloride at 20 ° C., it is separated from the insoluble sodium bromide and purified on a column with neutral aluminum oxide to remove small amounts of dark-colored accompanying substances. The end product crystallizes from n-hexane in colorless needles of mp. 76 to 77 ° C. which are combined to form drusen.

Yield: 24.1 g (92% of theory)

After thin layer chromatography on Merck TLC ready-made silica gel 60 F254 plates with benzene / acetone (vol. Ratio 6: 4 as flow agent 1) (see table of further examples), the product has an Rf value of 0.47 and with Nitromethane / benzene / pyridine (vol. Ratio 20: 10: 3 as solvent 2) has an Rf value of 0.60. UV light served as an indicator, but the pyridine of the flow agent 2) must be removed at 50 ° C. under reduced pressure because of its fluorescence quenching properties.

The compound can be processed into l- (5'-hydroxy-hexyl) theobromine as follows: 2.6 g of the l- (5'-hexen-l'-yl) theobromine described above are mixed with 25 ml of 1N sulfuric acid 24 h heated to boiling. 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 an mp of 126 ° C.

Yield: 2.6 g (93% of theory).

The following mono- (alken-l-yl) dialkylxanthines are prepared analogously to Example 1:

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

3 622018

example

connection

Rf

Mp ° C

i)

2)

2nd

l- (3'-butene-l'-yl) theo-bromin - colorless sticks

acetone

0.52

0.50

115

3rd

l- (4'-pentene-l'-yl) theobromine - colorless

Witch needles -

0.54

0.46

94

4th

7- (3'-butene-l'-yl) theophylline - colorless needles

from acetone

0.54

0.65

110

5

7- (4'-pentene-l'-yl) theophylline - colorless

Hexane sticks -

0.66

0.52

92

6

7- (5 '-hexen-1' -yl) -theophylline - colorless rods

chen from hexane

0.61

0.67

42

7

1 - (n-Hexyl) -3-methyl-7 - (5 '-hexen-1' -yl) -xanthine

Kp. 193 (at 0.3 mm Hg)

Claims (3)

622018 1 I o in which one of the radicals R1, R2 and R3 is (co-l) -alken-l-yl with 4 to 8 carbon atoms, which has no branching in the (lo-l) position, and the other two alkyl radicals are with 1 to 12 carbon atoms, characterized in that a 1-halo-C4-Ca-alkene with terminal, but not containing a tertiary carbon atom double bond is reacted with a corresponding alkali metal salt of a dialkylxanthine. 2. The method according to claim 1, characterized in that haloalkenes are used with an unbranched carbon chain. 2nd PATENT CLAIMS 1. Process for the preparation of new monoalkenyl dialkylxanthines of the general formula 0 * R1 II R \ / \ I Ni m t1) 3. The method according to any one of claims 1 and 2 for the preparation of monoalkenyl dialkylxanthines of the general formula I, in which one of the two alkyl radicals has 2 to 12 carbon atoms. Medicaments are known which contain theobromines or theophyllines as active ingredients and which have a (co-1) hydroxyalkyl radical in the 1- or 7-position. These are accessible by reducing the corresponding keto compounds, the production of which includes 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 DE-PS 1 067 025 a process for the preparation of l- (β-hydroxypropyl) theobromine is known, in which water is added to 1-allyl-theo-bromine using water addition catalysts such as concentrated sulfuric acid. According to this DE-PS, however, the known reaction is specific for 1-allyl-theobromine, because even 7-allyl-theophylline is not accessible to this reaction. It has now been shown that these difficulties can be overcome by adding water to mono- (C4-Cs-alkene-l-yl) dialkylxanthines regardless of the position of the alkenyl group in the presence of dilute sulfuric acid. This conversion to the desired (co-l) -hydro-xyalkyl-dialkyl-xanthines is possible in almost quantitative yield. However, such mono- (C4-C8-alkene-1-yl) dialkyl xanthines are not yet known.