CS237719B1 - Preparation method of dimethyl-(5-oxohexyl)-xanthine - Google Patents

Abstract

substances that are used on the preparation of circulatory drugs. The method of preparation is based on the reaction theobromine or theophylline with 6-halo-2- -hexanones in the presence of alkaline carbonate in the be, aprotic environment solvents.

Description

(54) A process for the preparation of dimethyl- (5-oxohexyl) -xanthenes

The invention relates to the preparation of pharmaceutical substances which are used for the preparation of medicaments of the circulatory system.

The preparation process is based on the reaction of theobromine or theophylline with 6-halo-2-hexanones in the presence of an alkali carbonate in be, an aqueous aprotic solvent.

The invention relates to a process for the preparation of dimethyl- (5-oxohexyl) -xanthines of the general formula X

CH ₃

2 wherein one of the substituents R or R represents methyl and the other 5-oxohexyl. Said compounds of formula I are used in medicine as a curative circulatory system.

To date, the subject compounds of formula I have been prepared from the alkali salts of theobromine or theophylline and 6-bromo-2-hexanone (itohler W., Reer M., Popendiker K., NSR Pat.

235,320 (Sep 5, 1964); Uohler W., Reiser II., Popendiker K., von Schuh H. 0, US Pat.

422,107 (Jan. 14, 1969); štibrányi L., Rybář A., Jendrichovský J., Ss. AO 164 643 (Sep. 15, 1976)], or from alkali salts of theobromine and 2-hexanone-6-yl esters of organic sulfoacids in various reaction media (kobayashi Y., Wakabayashi 11, Kodaira R., Jpn. Kokal Tokkyo Koho 79 36 291 (Mar 16, 1979); 79 61 192 (May 17, 1979); 79 6, 193 (May 17, 1979); 79 61 196 (May 17, 1979); Miyagaki M., Hoři M Kokal Tokkyo Koho 80 13 215 (Jan. 30, 1980)], optionally from alkaline earth salts of theobromine and 2-hexanone-6-yl esters of organic sulfoacids ^ quinomiya H., Kobayashi Y., Wakabayashi 11,

Kodaira R. Jpn. Kokai Tokkyo Koho 79 55,597 (May 2, 1979).]

Another known process for the preparation of compounds of formula I is based on the reaction of alkali salts of theobromine with acetals or ketals of 2-hexanone-6-yl esters of organic sulfoacids and subsequent hydrolysis of the acetal and ketal intermediates (Shone T.

Kobayashi V., Wakabayashi M., Kodaira R., Jpn. Kokai Tokkyo Koho 79 44 698 (Apr 9, 1979) ·] Ammonium salts (eg, tetrastylammonium salt of theobromine, (Ueno S., Kawashima T., Kanai T., Yokoyama M, Jpn. Kokai) may also be used instead of alkali salts). Tokkyo Koho 79 112 893 (Sep 4, 1979).]

The known methods for preparing the compounds of formula I are reaction-based. halopropylteobromine and theobromine-1-propyl esters of organic sulfoacids with a suitable beta-diketocompound [Kobayashi Y., Ichinomiya H., Sone T., Wakabayashi M., Jpn. Kokai Tokkyo Koho 79 92,990 (Jul 23, 1979); Okada T., Naitoh K., Kikuchi T., Jpn. Kokai Tokkyo Koho

151,999 (Nov. 29, 1979); Miyagaki M., Hori M., Jpn Kokai Tokkyo Koho 80 13 216 (Jan. 30, 1980); Kigaeawa K., Hiiragl M., Wagatsuma N, Uryu T., Jpn Kokal Tokkyo Koho

28,902 (Feb. 29, 980); 80 76 876 (Jun 10, 1980); Shimlzu Sh., Takano H., Jpn, Kokai Tokkyo Koho 80 49 380 (April 9, 1980)], possibly due to dehydration condensation of theobromine with 6-hydroxy-2-hexanone or its ketal in the presence of N, N-dicyclohexylcarbodilmide [Kobayashi Y., Sonna T., Wakabayashi M., Jpn. Kokai Tokkyo Koho 79, 60,394 (Dec 19, 1979);

163,594 (Dec 26, 1979)]

Further described methods for the preparation of compounds of formula I are based on the reaction of triethylsilylioxy theobromine with 6-halo-2-hexanone (kobayashi Y., Sonna T., Sako K., Wakabayashi M., Kodaira R., Jpn. Kokai Tokkyo Koho 79 27 596 (1.3.1979)] and cyclization, respectively

4,5-diamino-3-methyl-1- (5-oxohexyl) uracil with formic acid, or its salts and esterml [Hayashi H., Saito T., Jpn. Kokai Tokkyo Koho 78, 47,091 (Feb. 21, 1978).]

The last group of described processes for the preparation of compounds of formula I is based on amldation

4-amino-5-carbalkoxy-1-methylimidazole with 6-amino-2-hexanone followed by cyclization

5- (N-oxohexyl) emido-4-amino-1-methylimidazole with phosgene, or esters or semi-esters removed therefrom (koyashi H., Saito T., Jpn. Takano Y., Murata H., Tanaka N., Jpn. Kokal Tokkyo Koho 79 12 397 (January 30, 1979).]

23771

The principle of the present invention is that theobromine of formula IX

O

(II) or theophylline formula III (III) CH ₃ is reacted with 6-halo-2-hexanone of the formula IV CH ₃ -C-CH ₂ CH ₂ CH ₂ CH ₂ -X (IV) in which X represents chlorine, or bromine in a polar aprotic solvent medium in the presence of an alkali carbonate and at an elevated temperature.

The process of the invention is carried out by alkylating theobromine or theophylline with a compound of formula IV in a polar aprotic solvent such as dimethylsulfoxide, hexamethylphosphoramide, sulfolane, preferably dimethylformamide in the presence of an alkali carbonate, preferably potassium carbonate at 50 to 130 Deň: 32 ° C.

The amount of 6-halo-2-hexanone used in the reaction is between 0.7 and 1.3 moles and the amount of alkali carbonate is between 1.0 and 1.3 moles per 1 mol of theobromine or theophylline. Higher reaction temperatures are required using 6-chloro-2-hexanone.

In the case where 6-bromo-2-hexanol is used, the reaction temperature is in the lower half of the temperature range. The reaction temperature can also be lowered when an alkali iodide, preferably sodium iodide, per mole of theobromine or theophylline is used together with 6-chloro-2-hexanone.

The compound of formula I formed by the alkylation reaction is isolated by vacuum distilling off an aprotic solvent after removal of the inorganic salts from the reaction mixture by pressure filtration, centrifugation or suction and crystallization of the crude compound of formula I from a suitable solvent.

The main advantage of the preparation of the compounds of the formula I according to the invention is the high conversion of the alkylation reaction also achieved in working volumes. Another advantage of the process according to the invention is that in the alkylation reaction virtually no elimination reactions of 6-hexene-2-hexanones are practically competitive, as is the case with the theobromin or theophylline alkaline salts of the methods described so far. Halo hexanones form hexenone and theobromine or theophylline alkali salts theobromine or theophylline, which both reduce the yield of the final compounds of formula I and contaminate the product.

In the following, the procedure is illustrated in the examples without being limited to these.

Example 1

A mixture of 180 ml of dimethylformamide, 34.6 g (0.25 mol) of anhydrous potassium carbonate,

35.4 g (0.26 mol) of 6-chloro-2-hexanone and 45.0 g (0.25 mol) of theobromine are heated to 120 ° C with stirring. The reaction mixture is held at this temperature for 1 hour, then the temperature is raised to 125-130 ° C and stirred at this temperature for 3 hours. The reaction mixture is filtered hot, the inorganic salts on the filter are washed with 20 ml of warm (80 ml). ° C) dimethylformamide and the solution is cooled to 20 ° C. To the solution was added 7 g of anhydrous strong basic anion exchange resin in an OH-cycle and stirred for 1 h.

The solution was filtered and evaporated to dryness in vacuo. 200 ml of ethanol, g of activated carbon, 4 g of anhydrous strong acid ketex in an H ⁺ cycle are added to the residue and filtered while hot. The product precipitates from the solution after cooling to 10-15 ° C, which is filtered off and dried at 80 ° C. There was obtained 59.0 g of 1- (5-oxohexyl) theobromine, mp 104-105 ° C, yield.

Example 2

A mixture of 180 ml of dimethylformamide, 34.6 g (0.25 mol) of anhydrous potassium carbonate,

47.0 g (0.26 mol) of 6-bromo-2-hexanone and 45.0 g (0.25 mol) of theobromine are stirred at 80-90 ° C for 5 h. The reaction mixture is worked up as in Example 1. 48.0 g of 1- (5-oxohexyl) theobromine are obtained with mp 102-104 ° C, 70% yield.

Example 3

A mixture of 180 ml of dimethylformamide, 34.6 g (0.25 mol) of anhydrous potassium carbonate,

35.4 g (0.26 mol) of 6-chloro-2-hexanone and 45.0 g (0.25 mol) of theophylline are stirred at 80 to 00 ° C for 3 h. The reaction mixture is filtered while hot and evaporate in vacuo to dryness.

150 ml of 2-propanol are added to the residue, heated to boiling and diethyl ether is added to the solution until turbid. After cooling to 15-20 ° C, the product precipitates, which is filtered off with suction and dried.

There was obtained 51.0 g of 7- (5-oxohexyl) theophylline, m.p. 73-75 [deg.] C., 75% yield.

Example 4

A mixture of 180 ml of dimethylformamide, 34.6 g (0.25 mol) of anhydrous potassium carbonate,

30.0 g (0.22 mol) of 6-chloro-2-hexanone, 45.0 g (0.25 mol) of theobromine and 3.0 g (0.02 mol) of sodium iodide are stirred at 80-90 ° C. The inorganic salts are aspirated and the filtrate is evaporated to dryness. Toluene (200 ml) was added to the residue and heated to boiling to give a solution, charcoal was added and suction filtered. From the solution after glaze, 51.0 g of 1- (5-oxohexyl) theobromine are obtained, m.p. 102-104 ° C, 73% solution.

Claims (5)

BEFORE THE INVENTION 1. A process for the preparation of dimethyl (5-oxohexyl) xanthines of the general formula I-lySr O' N I ch ₃ (I) 1 2 wherein one of R or R is methyl and the other 5-oxohexyl, characterized in that theobromine of the formula II CH ₃ or ^CH theophylline of the formula III and Γι CH, (III) is reacted with 6-halo-2-hexanone of formula IV CK -CO-CH ₂ CH ₂ CH ₂ CH ₂ -X (IV) wherein X represents chlorine or bromine in the presence of alkali carbonates, preferably potassium carbonate. 2. The method of claim 1, wherein the reaction is a pre-pyrosis in a polar aprotic solvent such as dimethylsulfoxide, sulfolane, hexamethylphosphoramide, preferably dimethylformamide. 3. The method of claim 1, wherein the reaction is carried out at a temperature of 50 to 130 ° C. 4. A method according to claim 1, characterized in that from 0.7 mol to 1.3 mol of 6-halo-2-hexanone of formula IV and from 1.0 mol to 1.3 mol of alkali are used per mol of theobromine or theophylline. carbonate. 5. The process of claim 1 wherein the reaction is carried out in the presence of 0.01 to 0.1 moles of alkali iodide.