FI59986C - PROCEDURE FOR FRAMSTATION OF AV P-ACETAMIDOPHENYL-2-ACETOXYBENZOATE - Google Patents

Description

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Patent · och registerstyrelaen Anadkan utlagd och utl. Ginevra U, Lugano, Switzerland-Switzerland (CK) (72) Mario Portelli, Vicenza, Giorgio Renzi, Vicenza, Italy-Italy (1T) (7 ^) 0y Kolster Ab (5l) Process for the preparation of p-acetamidophenyl-2-acetoxybenzoate - Preparation of p-acetamidophenyl-2-acetoxybenzoate

The present invention relates to a new process for the preparation of p-acetamidophenyl-2-acetoxyacid, internationally known as benorilate, which is a well-known anti-inflammatory analgesic and antipyretic drug.

U.S. Patent 3,131,293 discloses a process for preparing benorilate by reacting p-acetyl-p-aminophenol with acetylsalicyloyl chloride. and U.S. Patent No. 1,168,289 discloses a process for preparing this product by reacting cetylacetylsalicylic anhydride with p-aminofencil.

The above methods have the disadvantage of the formation of certain numerous by-products which may make pharmaceutical use impossible (Manufacturing Chemist, August 1972, p. 35) ·

The invention is characterized in that one molar equivalent of acetylsalicylic acid is reacted with one molar equivalent of N-acetyl-p-amino-1'-enol in the presence of a condensing agent which is dicyclohexylcartodiimide, benzenesulphochloride or ethyl chlorocarbonate; a tertiary amine and a solvent which is tetrahydrofuran or dimethylformamide at a temperature not exceeding 0 ° C.

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In addition, the process of the invention has the advantage over known processes that it does not require the preparation and separation of intermediates such as acetylsalicylic acid chloride or anhydride. The method can therefore be performed in one step.

Suitable tertiary amines include pyridine and triethylamine. Isolation of para-acetamidophenyl-2-acetoxyhentoate from the reaction mixture can be accomplished by evaporating the solvent or cooling the reaction mixture with water.

If dicyclohexylcarbodiimide is used as condensing agent, it is first necessary to remove the dicyclohexylurea from the reaction mixture and then proceed by evaporation or water cooling.

The following examples illustrate the invention.

Example 1

A solution of 6.8 g (0.033 M) of dicyclohexylcarbodiimide in 10 ml of tetrahydrofuran was added with stirring to a solution of 5 → ** g (0.03 M) of acetylsalicylic acid, 1.5 g (0.03 M) of acetylsalicylic acid. 3 M) N-acetyl-p-aminophenol, 2. h ml (0.03 M) pyridine and 30 ml tetrahydrofuran, which had been pre-cooled to 0 ° C and the temperature was kept below 0 ° C. Stirring was continued overnight at 0 ° C. The precipitate formed by dicyclohexylurea was then filtered off and the solvent and pyridine were evaporated off in vacuo.

A crystalline residue was obtained. This was filtered and dried after washing with ethyl ether.

There was thus obtained 6 kg (68% of theory) of p-acetamidophenyl 2- • · / "O / '/ - O... · Acetoxybenzoate, m.p. 162-166 ° C. After crystallization after purification with ethyl alcohol, the product melts 176- 17T ° C.

Analysis: Calculated for C 18 H 18 NO%: C 65.17, H U, 82, N b, hl Found%: 65.30 H, 79 U, k 7

Example 2 5.82 g (0.033 M) of benzenesulphochloride was slowly added with stirring to a solution of 5.0 g (0.03 M) of acetylsalicylic acid, H, 5 g (0.03 M) of N-acetyl-p-aminophenol, 30 ml dimethylformamide and 1U, 2 ml of pyridine and which. ,, o. .....

was cooled to 15 ° C or lower.

After maintaining said conditions for four hours, the solution was poured into 200 ml of ice water. This precipitated p-acetamidophenyl-2-acetoxybenzoate. This was filtered, washed with water and dried.

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5.1 g (5% of theoretical yield) of product with a melting point of 15-161 ° C were obtained.

After purification of the product by crystallization from ethyl alcohol, it had a melting point of 176-177 ° C.

Analysis: Calculated for C

Example 3 3.27 g (0.03 M) of ethyl chlorocarbonate was added slowly with stirring to a solution of 5.1+ g (0.03 M) of acetylsalicylic acid, 8.1+ ml (0.06 M) of triethylamine and 30 ml of tetrahydrofuran cooled to -15 ° C or lower and stirring was continued while maintaining the reaction temperature below -15 ° C.

After 30 minutes, 1.5 g (0.03 M) of N-acetyl-p-aminophenol were added. After maintaining the conditions for 1 hour, the solution was poured into 200 ml of ice water. p-Acetamidophenyl-2-acetoxybenzoate precipitated and was filtered, washed with water and dried.

6.5 g (68% of theory) of product with a melting point of 11 + 8-163 ° C were obtained.

After purification by crystallization from ethyl alcohol, the product had a melting point of 176-177 ° C.

Analysis:% calculated for C

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