DE2330741A1 - Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity - Google Patents

Abstract

Title cpds. of formula (I) (where >=1 of R1-R3 = 3-8C oxoalkyl with the CO gp(s) one or more C's removed from the xanthine nucleus, and the others are 1-6C alkyl). may be prepd. from the corresp. hydroxy alkyl cpds. by (a) dehydrogenation with O2 and a Gp VIII metal catalyst. (b) oxidation with Cr(VI), or (c) microbiological dehydrogenation.

Description

CHEMICAL CURRENCIES ALBERf AKTIENGESELLSCHAFT

Process for the preparation of oxoalkylxanthines

The invention relates to a process for the preparation of oxoalkylxanthines, in which the corresponding hydroxyalkyl compounds be subjected to catalytic dehydrogenation in the presence of oxygen.

It is known that oxoalkylxanthines can be obtained by reacting xanthines with vinyl ketones or bromine ketones. Also by reacting N-haloalkylxanthines with Sodium acetoacetic acid esters, subsequent saponification and Decarboxylation gave oxoalkylxanthines.

It has now been found that the hydroxyalkylxanthines advantageously with the aid of suitable catalysts in the presence of oxygen to give the desired oxoalkylxanthines let it dehydrate.

The invention relates to a process for the preparation of compounds of the general formula

OH 'N'

ή ²

12 3

in which R, R and R are in at least one case with oxoalkyl up to 8 carbon atoms and in the remaining cases alkyl with 1 to 6 carbon atoms, but this denotes the oxo oxygen carrying carbon atom is separated from the xanthine structure by at least one carbon atom. The procedure is characterized in that the corresponding hydroxyalkyl compound in the presence of one of the reaction conditions Inert solvents with the help of suitable catalysts in the presence of oxygen to the desired Oxoalkylxanthines are dehydrated.

ⁿ 409882/1108

The advantage of the new process is that you can go through environmentally friendly reactions can avoid the generation of waste products.

The xanthine derivatives used as suitable starting compounds have alkyl substituents with a secondary one Alcohol group in positions 1 and / or 3 and / or 7, such as 1- (2-hydroxy-propyl) -, 1- (3-hydroxy-butyl) -, 1- (4-hydroxy-pentyl) -, 1 - (5-Hydroxy-hexyl) -, 1- (6-Hydroxy-hexyl) -, 1- (6-Hydroxy-heptyl) - and 1- (7-Hydroxy-octyl) -3,7-dimethylxanthine, 1- (6-Hydroxy-hexyl) -3-methyl-7-ethyl- or -propylxanthine, the 3- (2-hydroxy-propyl) -1,7-dimethylxanthine, the 7- (2-Hydroxy-propyl) -, 7- (3-Hydroxy-butyl) -, 7- (3-Hydroxy-2-methyl-butyl) -, 7- (3-Hydroxy-2-ethyl-butyl) -, 7- (3-Hydroxypentyl) -, 7- (4-II-hydroxy-pentyl) -, 7- (5-Hydroxy-hexyl) -, 7- (6-Hydroxy-hexyl) -, 7- (6-Hydroxy -heptyl) - and 7- (7-hydroxy-octyl) -1,3-dimethylxanthine, 7- (6-hydroxy-hexyl) -3-methyl-i-ethyl- or propylxanthine, 7- (5-hydroxy-hexyl) -i-pentyl-3-methylxanthine and 1,3,7-tri- (2-hydroxypropyl) -xanthine. Such Connections can be made according to the method of German patent application P 22 07 860 and P of the same day. The use of compounds in where the hydroxyalkyl radical is in the 1- or 7-position, or of compounds which are in the 3-position and possibly also in the 1- or 7-position have a methyl radical or of compounds in

ι.

where the hydroxyl group is in ω-, (ω-1) or (ω-φ-position.

Suitable catalysts are dehydrogenation catalysts such as noble metal catalysts, in particular those from Group VIII of the periodic table, made of platinum, palladium, ruthenium, rhodium and / or silver in the usual form with or without Carriers.

/ 3

409T882 / 1 108

Activated carbon, minerals such as asbestos, Pumice stone, kieselguhr, silica gel or silica as well as oxides, carbonates and sulfates of magnesium, calcium or barium in question. Platinum in the form of platinum black or Raney platinum has proven to be particularly effective. Are usable but also cobalt, copper, zinc and nickel catalysts, as well as metal alloys.

The dehydrogenation is carried out at temperatures between 20 ⁰ C and 120 ° C in an inert solvent under the reaction conditions, preferably in water, in the presence of oxygen, if appropriate in mixtures with nitrogen and / or noble gases. Other solvents that may be mentioned are, for example, cyclohexanone and methyl butyl ketone.

In individual cases, the use of overpressure is advantageous. The point in time at which the reaction has ended can be determined, for example, with the aid of chromatographic methods. The process products can be isolated in a simple manner from the reaction solution by separating off the catalysts and solvents. If appropriate, the compounds obtained are subsequently recrystallized. The oxoalkylxanthines obtained according to the invention are largely known and have a circulation-promoting, broncholytic or fibrinolytic effect. In drug research £ 1 (1971) pages 117 ¹ I - 77 about this - improvement of the blood circulation in the area of the brain, muscle, liver, kidney and skin when using l- (5-oxo-hexyl) -3,7-dimethylxanthine reported.

The percentages in the examples relate to weight.

The process products obtained were identical to the respective compounds obtained by known processes.

409882/1108

Examples:

1) By a solution of 2.8 g of 1- (5-hydroxyhexyl) -3,7-dimethylxanthine in 70 ml of water, in the presence of 280 mg of platinum black, the mixture is finely divided at 70 ° C. using a glass frit Oxygen flow. With the help of thin-layer chromatography The test determines the end point of the dehydrogenation to l- (5-oxo-hexyl) -3,7-dimethylxanthine.

Thin layer chromatography:

Sorbent: silica gel prefabricated plates from Merck (F ₂ ci |) i superplasticizer: chloroform-xthanol (volume ratio 80:20); Running distance: 10 cm; Detection: UV 25 ¹ »nm; R _f : 0.70.

The catalyst is filtered off and the 1- (5-0xo-hexyl) -3,7-dimethylxanthine is isolated. It crystallizes from methanol in the form of colorless needles with a melting point of 105 C. Yield: 2> 7 g (97 % of theory). A smaller amount of catalyst and a lower temperature lead to the same result with a correspondingly longer reaction time.

2-9 ■ Following the procedure of Example 1, the following were also obtained: melting point

2) 1- (2-Qxo-propyl) -3,7-dimethylxanthine l67 ° C

3) l-C4-oxo-pentyl) -3,7-dimethylxanthine 111 ⁰ C.

1) l- (6-oxo-heptyl) -3,7-dimethylxanthine II9 - 120 ⁰ C.

5) 7- (2-Oxo-propyl) -1,3-dimethylxanthine 162 ° C

6) 7- (l-methyl-2-oxo-propyl) -l, 3-dimethylxanthinll8 - 120 ⁰ C.

2) 7- (3-Oxo-butyl) -l, 3-dimethylxanthine 1 ^ 0 - Uli ⁰ C

8) 7- (2-Methyl-3-oxo-butyl) -1,3-dimethylxanthine 133-135 ° C

9) 1.3 "7-tris-2-oxopropyl xanthine I79 - 180 ⁰ C!

/ 5

409882/1108

10) 1 g of Raney platinum is suspended in a solution of 10 g 1- (3-Hydroxy-butyl) -3,7-dimethylxanthine in 50 ml of water. A finely divided stream of air is then passed through the solution at 80 ° C. until the thin-layer chromatogram indicates the end of the reaction.

For chromatography see Example 1. Benzene-acetone (volume ratio 60:40) is used as the mobile phase. R _f O, 23.

The 1- (3-oxo-butyl) -3,7-dimethylxanthine isolated after the catalyst and water had been separated off had a melting point of 146 ° C. Yield 9.5 g (96 % of theory).

11-17) Following the procedure of Example ¹⁰ , the following oxoalkylxanthines were also prepared:

Melting point

11) 7- (2-Ethyl-3-oxo-butyl) -1,3-dimethylxanthine 107-108 ° C

12) 7- (3-oxo-pentyl) -1,3-dimethylxanthine 126-127 ° C

13) 7- (4-oxo-pentyl) -1,3-dimethylxanthine 86-88 ° C

14) 7- (5-0xo-hexyl) -1,3-dimethylxanthine 75-76 ° C

15) 7- (6-0xo-heptyl) -1,3-dimethylxanthine 69 ° C

16) 7- (7-Oxo-octyl) 1,3-dimethylxanthine 85 ° C

17) 7- (5-Oxo-hexyl) -1-pentyl-3-methylxanthine 78 ° C

409882/1108

Claims (2)

Claims Qj) Process for the preparation of compounds of the general formula j ₁ 5 h - ^ CK N N ι?
R. 12 3 in which R, R and R are in at least one case with oxoalkyl 3 to 8 carbon atoms and in the remaining cases alkyl having 1 to 6 carbon atoms, but where the carbon atom carrying the oxo oxygen is separated from the xanthine structure by at least 1 carbon atom, characterized in that that the corresponding Hydroxyalky! compounds with the aid of dehydrogenation catalysts in the presence of Oxygen and a solvent which is inert under the reaction conditions is dehydrated. 2) Process according to claim 1, characterized in that the catalysts used are noble metals from VIII. Qruppe des periodic system or alloys of these precious metals with or without a carrier. 409882/1108