JPS5825676B2 - Method for producing oxoalkyl↓-dialkylxanthine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an oxoalkyl-dialkylxanthine represented by the following formula (I).

The compound represented by the above formula (I) is known as a drug having a vasodilatory effect. Conventionally, this compound has been produced by a method (i) of reacting an alkali metal salt of a dialkylxanthine with an oxoalkyl halide (particularly Kosho 45-213
2) A method of reacting a haloalkyl-dialkylxanthine with an alkali salt of acetoacetate, saponifying the reaction product, and then decarboxylating it (see Japanese Patent Publication No. 1982-21308), '3 ) A method of oxidizing hydroxyalkyldialkylxanthine (see Japanese Patent Application Laid-Open No. 51298/1983) is known.

However, all of these methods require complicated operations, including steps to obtain raw material intermediates, and (1)
The method has extremely low yield.

In addition, method (2) involves reacting haloalkyl-dimethylxanthine with an alkali salt of acetoacetate, saponifying the resulting intermediate by heating it in an alkaline aqueous solution, and then decarboxylating it by heating it in an acidic aqueous solution. This process requires three complicated steps starting from haloalkyl-dimethylxanthine.

Method (3) is a practically meaningless method in which hydroxyalkyl-dialkylxanthine is produced from the target product, oxoalkyl-dialkylxanthine, and then oxidized.

In view of this background, the inventors of the present invention have conducted extensive research and have completed the present invention.

The object of the present invention is to provide an industrially advantageous method for producing the compound of formula (I) above.

The present invention will be explained in detail below.

The present invention relates to the following formula (II) [In the formula, X represents a halogen atom.

This is a method for directly obtaining a compound represented by the above formula (I) by reacting a haloalkyl-dialkylxanthine represented by the above with acetylacetone in the presence of a base.

Bases used in this reaction include anhydrous alkali carbonate (e.g. potassium carbonate), alkali hydroxide (e.g. sodium hydroxide, potassium hydroxide), alkali metal (e.g. sodium, potassium), alkali metal alcoholade (e.g. sodium ethoxide, potassium t-butoxide)
, alkaline amides (eg, sodium amide), and the like.

This reaction is generally carried out in a solvent containing a large amount of water (preferably).

As the solvent, common organic solvents such as alcohols such as methanol, ethanol, and impropanol, aromatic hydrocarbons such as benzene, toluene, xylene, and ethers such as isopropyl ether, tetrahydrofuran, and dioxane are used.

As described above, the present invention provides oxoalkyl-
This is an extremely industrially advantageous method that allows dialkylxanthines to be obtained in one step.

Next, examples of the present invention will be shown, but the present invention is not limited by these examples unless it departs from the gist thereof.

Example 1 Acetylacetone 15f (0.15 mol), 99.5%
Anhydrous potassium carbonate 20.7f in 100ml ethanol
(0.15 mol) and stirred, 1-(3'
-bromopropyl)-3,7-dimethylxanthine 30
．． Add 1 f (0.1 mol) and heat to reflux for 3 hours.

After the reaction, insoluble materials are separated, and the solvent is distilled off from the lachrymal fluid under reduced pressure.

Add 70 ml of methanol to the residue, heat to dissolve, cool, and separate the precipitated crystals.

The lachrymal fluid is concentrated to dryness and the residue is recrystallized with isopropanol.

Further, recrystallization with isopropanol gave 1-(5'-oxohexyl)-3,7-dimethylxanthine 18.8
I got 1.

Yield 67.6%, melting point 102-104°C.

Example 2 In the same manner as in Example 1, using sodium ethoxide 10.2P (0.15 mol) instead of anhydrous potassium carbonate, 1-(5'-oxohexyl)-3,7-dimethyl Xanthine 20.1? I got it.

Yield 72.3%, melting point 102-104°C.

Example 3 Anhydrous potassium carbonate and 1-(
Instead of 3'-bromopropyl)-3,7-dimethylxanthine, sodium ethoxide 10.2P (0.15 mol), 1-(3'-chloropropyl)-3,7-dimethylxanthine 25.7P ( 0.1 mol) and otherwise operated in the same manner as in Example 1 to obtain 13.7P of l-(5'-oxohexyl)-3,7-dimethylxanthine.

Yield 49.3%, melting point 102-104°C.

Example 4 Acetylacetone 4oP (o, 4 mol), anhydrous potassium carbonate 55.2f (
0.4 mol) was added and stirred, and 60.2 mol of 1-(3'-bromopropyl)-3,7-dimethylxanthine was added thereto.
1 (0.2 mol) and heated under reflux for 3 hours.

After the reaction, the solvent is distilled off, and water 11 is added to the residue to dissolve it.

This aqueous solution is extracted twice with 1801 nl of chloroform.

After washing the obtained organic layer with water, chloroform was distilled off,
The residue was recrystallized with isopropanol to obtain 1(5/-oxynehexyl)-3,7-dimethylxanthe 738.2f.

Yield 68.7%, melting point 102-104°C.

Example 5 40 g (0.4 mol) of acetylacetone, 27.2 ml of sodium ethoxide in 180 ml of 99.5% ethanol
f (0.4 mol) was added and stirred, and 1-(
60.2 P (0.2 mol) of 3'-bromopropyl)-3,7-dimethylxanthine is added, and the mixture is heated under reflux for 3 hours.

Thereafter, the same treatment as in Example 4 was carried out to obtain 39.1' of 1-(5'-oxohexyile)-3,7-dimethylxanthine.

Yield 71.6%, melting point 102-104°C.

Claims (1)

[Claims] Formula 1 [wherein X represents a halogen atom]. ] A method for producing an oxoalkyl-dialkylxanthine, which comprises reacting a haloalkyl-dialkylxanthine represented by the following with acetylacetone in the presence of a base.