CS267313B1 - A method for producing 7- (2-hydroxyethyl) -teophyllin - Google Patents

Abstract

A method for preparing 7-(2-hydroxyethyl)-theophylline, which is used as a final substance in the pharmaceutical industry, from theophylline and 2-halogenoethanol with optional catalysis by iodide ions in the environment of anti-polar solvents in the presence of alkali metal hydroxides or carbonates is described.

Description

The invention relates to a process for the preparation of 7- (2-hydroxyethyl) -theophylline of the formula I.

A /, which finds wide application in therapeutic practice.

The compound of the formula I has hitherto been prepared in various ways, for example from theophylline and 2-chloroethanol in water in the presence of sodium hydroxide or potassium hydroxide / Cs. U.S. Patent 95,344, Fr. patent M 828, patents D.R.P. 191 106 and D.R.P. 281 008, Samejima, M., Yakugaku Zasshi I960, 80, .1706-12, Di Paco, G., Tauro, C.S., Ann. Chem. 1957, 47, 698-704./, of theophylline and ethylene oxide in the presence of a base (patent Ger. 1,235,927 and Ger./East/31,894., Both, H.J., Arch. Pham. 1959, 292, 234-8], or by pressure in an autoclave (patent D.B.P. 193 799./. An alternative method of preparing a compound of formula I is the reaction of theophylline with ethylene carbonate at high temperature [Pabbrini, L., Cencioni, R., Bamako Id. Sci. 1962, 17, 660-7./ resp. sodium salt of theophylline and chloroethanol boiled for 30 hours in Ν, Ν-dimethylfomamide (Ride, S.M., Farghaly, A.M., Ashour, B.A., Pharmazie 1977, 32/11 /, 672-6./.

The present invention relates to a process for the preparation of a compound of formula I, based on the reaction of theophylline with 2-haloethanol, wherein halogen represents chlorine, bromine, iodine, in aprotic dipolar solvents (e.g. Ν, Ν-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide / in the presence of alkali metal hydroxides or carbonates at temperatures of 50 ° C to 140 ° C, in a suitable molar arrangement of reactants. Said reaction and can be accelerated by the catalytic action of alkali metal iodides.

The main advantage of the process according to the invention over the previously described is the formation of only 7- (2-hydroxyethyl) theophylline without the concomitant addition of its isoneric derivative 9- (2-hydroxyethyl) theophylline of formula II.

AI /, which can be completely removed! by a conventional purification operation, e.g. crystallization, resulting in a reduction in the quality of the substance for pharmaceutical use. Other advantages of this procedure are the in situ generation of sodium resp. potassium salt of theophylline, achieving high yields, significantly shorter reaction times at lower reaction temperatures.

CS 267 313 Bl

In the following, the subject matter of the invention is described in the exemplary embodiments without being limited thereto.

Example 1

To 18 g (0.1 mol) of theophylline suspended in 60 ml of β, β-dimethylformamide are added 8.9 g (0.11 mol) of 2-chloroethanol and 11.7 g (0.11 mol) of sodium carbonate. The reactant mixture is heated at 120 DEG C. for four hours with stirring. The inorganic salts are filtered off! and the filtrate is evaporated to dryness under reduced pressure. 21.7 g of 7- (2-hydroxyethyl) theophylline are obtained in a yield of 97%. This can be crystallized from a suitable solvent, for example water, ethanol or a mixture thereof.

Example 2

The procedure is as in Example 1, but a further 2.5 g (0.015 mol) of potassium iodide are added to the reaction components and the mixture is heated at the indicated temperature for 2.5 hours. After work-up, 21.9 g of 7- (2-hydroxyethyl) -theophylline are obtained in a yield of 98%.

Claims (5)

A process for the preparation of 7- (2-hydroxyethyl) -theophylline of the formula I A /, characterized in that theophylline is reacted with 2-haloethanol in an aprotic dipole solvent in the presence of a base at a temperature of 50 ° C to 140 ° C, the reaction and knives being accelerated by suitable catalysts. 2. The process of claim 1, wherein the 2-haloethanol is 2-chloroethanol, 2-bromoethanol and / or 2-iodoethanol. 3. The process of claim 1, wherein the dipolar aprotic solvent is dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidone, sulfolane and / or hexamethylphosphoric triamide. 4. The process according to item 1, characterized in that sodium hydroxide, potassium hydroxide, sodium carbonate and / or potassium carbonate is used as the base. 5. The process of claim 1, wherein the reaction is catalyzed by the addition of 5 to 25 mole percent sodium iodide or potassium iodide.