CS252432B1 - Method for producing methenamine hippurate - Google Patents

Abstract

The method of producing methenamine hippurate consists in mixing a mixture of hippuric acid, hexamethylenetetramine, 2-propanol and water in a molar ratio of 1 to 1.1 mol of hippuric acid, 7 to 13 mol of 2-propanol and 0.3 to 5% by weight of water contained in the total reaction mixture at a temperature of 10 to 30 °C, thereby producing pure methenamine hippurate in high purity and yield, directly usable for pharmaceutical purposes.

Description

Method for producing methenamine hippurate

A method for producing methenamine hippurate consists in mixing a mixture of hippuric acid, hexamethylenetetramine, 2-propanol and water in a molar ratio per mole of hexamethylenetetramine of 1 to 1.1 mol of hippuric acid, 7 to 13 moles of 2-propanol and 0.3 to 5 % by weight of the water contained in the total mixture at 10 DEG to 30 DEG C. yields pure methenamine hippurate in high purity and yield, directly usable for pharmaceutical purposes.

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The invention relates to a process for producing methenamine hippurate, i.e. hexamethylenetetramine hippurate. which has use as a urinary tract deainfection.

Methenamine hippurate was prepared for the first time by A. Galat (U.S. Pat. No. 3,004,026) by dissolving equivalent amounts of hippuric acid and hexamethylenetetramine in methanol while boiling and adding water to clarify the solution. The yield and quality of the product is not stated by the author. In the reproduction, after evaporation, we obtained 87% of the 94% product. Another process protected by Dutch Patent No. 6,414,653 is; based on dissolution of both components in a ratio of 1 mole of hexamethylenetetramine to 1.12 mole of hippuric acid at boiling in 2-propanol. Yield is given to 75% of theory based on ha. starting from hexamethylenetetramine, product quality not defined.

The yield can be confirmed after repeated reproduction, but the content varied from 97 to 98% and therefore did not meet purity. S.E.Herlet protects the preparation of the methenamine hippurate dosage form by obtaining the active substance by moistening a mixture of the two components and processing it without isolation and separate qualitative evaluation by compression into tablets.

The above preparation procedures' do not guarantee the desired optimal pure methenamine hippurate (min. 99% content) at high yield for the drug. Since the substance is a salt of a weak acid and a weak base, this implies the difficulty of both its preparation in the pure state and its possible further purification by crystallization; Easy can. in solution decompose to the ammonium salt of hippuric acid, formalin and other degradation products of the starting components.

The methanamine hippurate of the desired quality in high yield is obtained according to the invention, which consists in the mixture of hexamethylenetetramine, hippuric acid, 2-propanol and water in a molar ratio of 1: 1 to 1.1: 7 to 13: 1. wherein the total water content of the mixture is 0.3 to 5%, stirred at 10 to 30 ° C, and the product obtained is isolated.

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The process according to the invention is characterized in that the reaction mixture is reacted. Stir at 20-25 ° C. after which the reaction is completed at 15 ° C.

The inventors have found that during mixing the nature of the stirred suspension of the reaction components changes; both components dissolve to form hippurate, which crystallizes. A reaction temperature of 20-25 ° C does not promote the formation of decomposition products of the starting components and, together with a limited amount of water present, ensures the formation of hippurate in high yield and quality directly usable for pharmaceutical purposes. The higher water content of the reaction mixture leads to a decrease in the yield, but in the anhydrous medium the reaction does not take place.

Following examples? The method of preparation of methenamine hippurate is merely illustrative of the invention but is not limited thereto.

Example 1

Mixture: 18.26 g (0.102 mol) of hippuric acid, 14.05 g (0.1 mol) of hexamethylenetetramine with 80 ml of 2-propanol and a water content of 0.3% (w / w) is stirred at 20-25 ° C for three hours, then for one hour at 15 ° C. After aspirating and washing the product with 5 ml of 2-propanol, 28/9 g (90.5% yield) of completely pure methenamine hippurate is obtained.

The purity of the product was verified by alkalimetric and acidimetric determination of content, TLC chromatography and IR spectrum as a chromatographically uniform substance with a content of 99.0%.

Example 2 ·

A mixture of 18.26 g of hippuric acid, 14.05 g of hexamethylenetetramine and 80 ml. 2-propanol with a water content of 0.5% (w / w) was treated in the same manner as in Example 1 to give 28.7 g (89.4% yield) of methenamine hippurate.

Example 3

A mixture of 18.26 g of hippuric acid, 14.05 g of hexamethylenetetramine and: 80 ml of 2-propanol with a water content of 5% (w / w) was treated in the same manner as in Example 1 to obtain.

25.5 g (79-, 8% yield) of methenamine hippurate.

Example 4

Mixture; 18.26 g of hippuric acid, 14.05 g of hexamethylenetetramine and 80 ml of 2-propanol with a water content of 0.3% (w / w) are stirred for 4 hours at 10 ° C and further processed in the same manner as described above. Example 1 gave 28.1 g (88.0% yield) of methenamine hippurate.

Example 5

A mixture of 18.26 g of hippuric acid, 14.05 g of hexamethylenethylamine and 80 ml of 2-propanol with a water content of 0.3% by weight is stirred at 30 ° C for 3 hours and 1 hour at 10 ° C. 28.7 g (89.9% yield) of methenamine hippurate are obtained.

Example 6

Mixture. 18.26 g of hippuric acid, 14.05 g of hexamethylenetetremine and 100 ml of 2-propanol with a water content of 0.3% (w / w) are added. stirred at 30 ° C for 3 hours and treated at 15 ° C for one hour; with the same procedure as in Example 1 to give 27.9 g (87.4% yield) of methenamine hippurate.

Example 7

A mixture of 18.26 g of hippuric acid; 14.05 g of hexamethylene tramin and 50 ml of 2-propanol; with a water content of 0.3% (w / w) was stirred at 30 ° C for 3 hours and held for 15 hours at 15 ° C and treated in the same manner as in Example 1. 29.5 g (92%) were obtained. , 4% yield) methenamine hippurate.

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of methenamine hippurate by reaction of hexamethylenetetramine, hippuric acid and 2-propanol, characterized in that said mixture is reacted in a molar ratio of 1 to 1 to 7 to 13 with water, the total water content of the mixture is 0.3 to 5% by weight, at a temperature of 10 to 30 ° C. , 2. The process of claim 1 wherein the reaction mixture; The mixture was stirred at 20-25 ° C, after which the reaction was completed at 15 ° C.