KR20010073582A - Method of preparing an aromatic propionic acid derivative - Google Patents

Abstract

PURPOSE: A method for manufacturing 2-(2-fluoro-4-biphenylyl) propionic acid is provided which minimizes formation of side reacted substances, easily applied to commercial purposes, and has high purity and yield by using a metallic catalyst so as to alleviate reaction conditions. CONSTITUTION: The method comprises the process of manufacturing 2-(2-fluoro-4-biphenylrile) propionic acid of the following formula (I) by reacting a product with sodium 2-bromopropionate under the existence of a metallic catalyst after reacting 4-bromo-2-fluorobiphenyl of the following formula (II) with magnesium, wherein zinc, tin, copper, iron, mercury, palladium, antimony or bismuth salts (MXn) is used as the metallic catalyst.

Description

Method of preparing an aromatic propionic acid derivative {Method of preparing an aromatic propionic acid derivative}

The present invention relates to a method for producing 2- (2-fluoro-4-biphenylyl) propionic acid which is a propionic acid anti-inflammatory analgesic agent.

2- (2-fluoro-4-biphenylyl) propionic acid is a propionic acid-based anti-inflammatory analgesic, and various methods for preparing it have been reported. According to the method described in US Pat. No. 3,959,364, 2- (2-fluoro-4-biphenylyl) propionic acid synthesized from 4-bromo-2-fluoro biphenyl via metal reaction in tetrahydrofuran solvent Hydrochloric acid or sulfuric acid solution may be added to the sodium salt to prepare 2- (2-fluoro-4-biphenylyl) propionic acid.

However, there are various difficulties in preparing 2- (2-fluoro-4-biphenylyl) propionic acid according to the above method, for example, various side reactions are generated as the reaction proceeds at a high temperature. The reaction yield is low, and there is a problem that a purification process is required to increase the purity.

The present invention is to solve the problems of the prior art as described above, by using a metal catalyst to relax the reaction conditions to minimize the production of side reactions, easy to commercial application, high purity and high yield 2- (2- It is an object to provide a method for producing fluoro-4-biphenylyl) propionic acid.

The present invention reacts 4-bromo-2-fluorobiphenyl of formula (II) with magnesium, and then reacts with sodium 2-bromopropionate of formula (III) in the presence of a metal catalyst to formula (I To 2- (2-fluoro-4-biphenylyl) propionic acid.

Examples of the metal catalyst used in the reaction include zinc, tin, copper, iron, mercury, palladium, antimony or bismuth salt (MXn) and the like, and the amount thereof is used in terms of weight ratio based on the compound of formula (II) as a starting material. 0.5% to 10% is preferred. The solvent used includes organic solvents such as tetrahydrofuran, ether and isopropyl ether. The reaction temperature is in the range of -30 ° C to 100 ° C, and preferably in the range of -10 ° C to 30 ° C. When the reaction is completed, an acid is added to the reaction solution, extracted with an organic solvent, or extracted with an aqueous solvent, extracted with an aqueous layer, and then recrystallized with an acid to obtain a target compound.

At this time, the acid used includes sulfuric acid, hydrochloric acid, acetic acid, etc., the amount of use is 2 equivalents to 10 equivalents. As the solvent to be extracted, ethyl acetate, ether, benzene, toluene, nitrobenzene, methylene chloride, chloroform and the like are preferable. The extracted solution is concentrated and crystallized by adding an organic solvent. Examples of the solvent used for crystallization include organic solvents such as ethyl acetate, ether, acetone, benzene, toluene, 1,4-dioxane and tetrahydrofuran. Examples of the alkali used include caustic soda, potassium hydroxide, sodium bicarbonate and the like, and the amount of use thereof is 2 to 10 equivalents.

Example

Hereinafter, preferred examples and comparative examples are presented to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the present invention is not limited to the following examples.

Example 1: Preparation of 2- (2-fluoro-4-biphenylyl) propionic acid

2.64 g of magnesium and 250 g of ether are added and kept in a nitrogen atmosphere. 25 g of 4-bromo-2-fluoro biphenyl is added dropwise and reacted at 30 ° C. for 1 hour after completion of the dropwise addition. After the reaction, the reaction solution is cooled to 0 ° C or lower, and 0.25 g of zinc chloride is added to the reaction solution. 17 g sodium 2-bromopropionate is dispensed in portions. After completion of the addition, the reaction was carried out again at 30 ° C. for 1 hour. After completion of the reaction, 100 g of water was added and 1 N hydrochloric acid was added to separate the organic solvent. The organic layer is washed with 100 g of water and the solvent is removed under reduced pressure. Ether was added to the concentrate to crystallize, and the resulting crystals were filtered to give 19.6 g of the title compound. The yield was 80%, the purity was 99.2% and the melting point was 114 ° C.

Example 2: Preparation of 2- (2-fluoro-4-biphenylyl) propionic acid

2.64 g of magnesium, 130 g of tetrahydrofuran, and 0.25 g of bromotin are added thereto and kept in a nitrogen atmosphere. 25 g of 4-bromo-2-fluoro biphenyl is added dropwise, followed by reaction at room temperature for 1 hour after completion of the dropwise addition. After the reaction, the reaction solution is cooled to −10 ° C. or lower, and 17 g of sodium 2-bromopropionate is suspended in 130 g of tetrahydrofuran, and then injected into portions. After completion of the addition, the reaction was carried out again at 30 ° C. for 1 hour. After completion of the reaction, 100 g of water was added and 1 N hydrochloric acid was added to separate the organic solvent. The organic layer is washed with 100 g of water and the solvent is removed under reduced pressure. Ether was added to the concentrate to crystallize, and the resulting crystals were filtered to give 21.4 g of the title compound. The yield was 88%, purity 98.9%, melting point 113 degreeC.

Example 3: Preparation of 2- (2-fluoro-4-biphenylyl) propionic acid

2.64 g of magnesium, 250 g of ether, and 0.50 g of bromo iron are added and kept in a nitrogen atmosphere. 25 g of 4-bromo-2-fluoro biphenyl is added dropwise, followed by reaction at room temperature for 1 hour. After the reaction, the reaction solution is cooled to 0 ° C. or lower, and 17 g of sodium 2-bromopropionate is added in portions. After completion of the reaction, 100 g of water was added and 1 N hydrochloric acid was added to separate the organic solvent. The organic layer is washed with 100 g of water and the solvent is removed under reduced pressure. Ether was added to the concentrate to crystallize, and the resulting crystals were filtered to give 20.4 g of the title compound. The yield was 84%, purity 99.1%, melting point 114 degreeC.

Comparative Example: Preparation of 2- (2-fluoro-4-biphenylyl) propionic acid

A solution of 2.51 g of 4-bromo-2-fluoro biphenyl in 15 ml of dried tetrahydrofuran is added dropwise to a flask containing 0.25 g of magnesium under a stream of nitrogen. After completion of the dropwise addition, the mixture is heated to reflux and cooled for 30 minutes. A solution of 1.75 g of sodium 2-bromopropionate dissolved in 20 ml of dried tetrahydrofuran is added to the reaction solution. After the addition, the mixture was heated to reflux and cooled for another hour. After cooling, 10 ml of water and 5 ml of 20% sulfuric acid are added, followed by stirring for 15 to 20 minutes, followed by extraction with ether. The extracted solution is washed with water and then extracted with 1N potassium carbonate. The extract is washed with ether, and then 10 ml of concentrated hydrochloric acid and 20 ml of water are added. After stirring overnight the crystals are filtered off. The crystals are washed with water and then dried in vacuo. Yield 60%.

The present invention has the advantage that the selectivity of the main reaction is increased by using a metal catalyst to minimize the generation of side reactions, thereby producing an aromatic propionic acid derivative of formula (I), which is the target compound, in higher yield and purity than conventional methods.

Claims (2)

4-bromo-2-fluorobiphenyl of formula (II) is reacted with magnesium, followed by reaction with sodium 2-bromopropionate of formula (III) in the presence of a metal catalyst to Process for preparing 2- (2-fluoro-4-biphenylyl) propionic acid. The process of claim 1, wherein salts of zinc, tin, copper, iron, mercury, palladium, antimony or bismuth (MXn) are used as metal catalysts.