JPH0551348A - Production of 2-halogeno-4,5-difluorobenzoic acid - Google Patents

Abstract

PURPOSE:To industrially obtain in a single step in high yield the title compound useful as an intermediate for medicines by reaction of, as the starting material, an industrially readily available 3,4-difluorobenzoic acid alkali metal salt with a halogenating agent. CONSTITUTION:The objective compound (e.g. 2-chloro-4,5-difluorobenzoic acid) can be obtained by reaction between (A) a 3,4-difluorobenzoic acid alkali metal salt readily producible by mixing 3,4-difluorobenzoic acid with an alkali hydroxide and (B) a halogenating agent (e.g. gaseous chlorine). The 3,4-difluorobenzoic acid as the starting material can be easily obtained by hydrolysis of industrially readily available 4-difluorobenzonitrile with an acid. The present compound is useful as an intermediate for fluorine-contg. quinolonecarboxylic acid- or fluorine-contg. pyridonecarboxylic acid-based synthetic antibacterial agents. The present method will accomplish high selectivity and high yield.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is directed to US Pat.
The present invention relates to a process for producing 2-halogeno-4,5-difluorobenzoic acid, which is useful as an intermediate raw material for synthetic antibacterial agents such as fluorine-containing quinolone carboxylic acid or fluorine-containing pyridone carboxylic acid-based synthetic antibacterial agents described in EP-A-9615 or European Patent Publication No. 0215650.

[0002]

As a method for producing 2-chloro-4,5-difluorobenzoic acid, 4,5-difluoroanthranilic acid is converted to a diazonium salt with a strong acid and sodium nitrite,
Then, a method of decomposing with cuprous chloride is known (Sand Meyer method described in JP-A-2-215744 and JP-A-2-17147). In the above method, since the intermediate diazonium salt is very unstable and there is a risk of explosion,
It was difficult to manufacture on an industrial scale.

A method is also known in which 2-chloro-4,5-difluorobenzotrifluoride is hydrolyzed with trifluoromethyl group in concentrated sulfuric acid to obtain 2-chloro-4,5-difluorobenzoic acid. (Japanese Patent Laid-Open No. 62-10883
9). In the above method, hydrogen fluoride is by-produced during hydrolysis. Therefore, it requires a special reactor and material, is dangerous in operation, and is not suitable for production on an industrial scale.

[0004]

DISCLOSURE OF THE INVENTION The present invention does not require the use of a diazonium salt which is unstable and has a risk of explosion, which has been a conventional problem, and there is no by-product of hydrogen fluoride. It is intended to provide a method for industrially obtaining 5,5-difluorobenzoic acid in good yield.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the problems of the prior art, the present inventors have surprisingly found that an alkali metal salt of 3,4-difluorobenzoic acid (hereinafter 3,4- It was found that 2-halogeno-4,5-difluorobenzoic acid can be obtained with high selectivity and high yield by reacting a halogenating agent with DFBA salt). Came to.

That is, the present invention provides a method for producing 2-chloro-4,5-difluorobenzoic acid, which comprises reacting an alkali metal salt of 3,4-difluorobenzoic acid with a halogenating agent. Is.

The salt of 3,4-DFBA used as a raw material can be easily obtained by mixing 3,4-DFBA and alkali hydroxide. 3,4-DFBA is easily obtained by hydrolyzing an industrially available 3,4-difluorobenzonitrile with an acid. Examples of the alkali hydroxide used include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The amount of alkali hydroxide used is 3,4-DFB
It is used in the range of 0.1 to 100 mol, preferably 0.5 to 10 mol, per 1 mol of A.

As the halogenating agent, chlorine, alkali hypochlorite, alkali hypobromite, bromine, sulfuryl chloride and the like can be used, and as the alkali, sodium, potassium and lithium are used. The amount of halogenating agent used is 0.1 to 1 mol of 3,4-DFBA.
It is used in an amount of 50 mol, preferably 0.5 to 10 mol. In the above operation, since the pH changes due to the introduction of the halogenating agent, it is advisable to appropriately add alkali hydroxide during the process.

Any solvent may be used as long as it is inert to the reaction. For example, water or a lower alcohol such as methanol or ethanol may be used alone or in combination. The amount of the solvent used is 0.01 to 10 l, preferably 0.1 to 1 mol of 3,4-DFBA.
You may use it in the range of 1l.

The reaction temperature is 0 to 150 ° C., preferably 20.
The reaction solution after completion of the reaction is acid-deposited with hydrochloric acid or the like, and the precipitated crystals are filtered and dried to easily obtain 2-halogeno-4,5-difluorobenzoic acid.

[0011]

The present invention will be specifically described with reference to the following examples. Example 1 3.95 g (25 mmol) 3,4-difluorobenzoic acid,
Sodium hydroxide 1.00 g (25 mmol) and water 50
ml was charged into a reaction vessel and heated to 70 ° C. Chlorine gas was introduced into this solution at a rate of about 20 ml / min. When chlorine was introduced for about 30 minutes, the system became cloudy, so 0.50 g (12.5 mmol) of sodium hydroxide was added to make the system uniform and chlorine was introduced again. When the reaction liquid was analyzed by gas chromatography at the time point when the white turbidity and the addition of sodium hydroxide were repeated 5 times, the conversion of 3,4-DFBA was 94.3% and the selectivity of the monochlorinated product was 70. Three
%, And the selectivity of 2-chloro-4,5-difluorobenzoic acid in the monochloro compound was 95.7%. Hydrochloric acid was added to this reaction solution to make it acidic, the precipitated solid was collected by filtration, and recrystallized from n-hexane to obtain
2-Chloro-4,5-difluorobenzoic acid with a purity of 98% (40% of theoretical yield) was obtained.

[0012]

INDUSTRIAL APPLICABILITY According to the method of the present invention, 2-chloro-4,5-difluorobenzoic acid useful as a pharmaceutical intermediate in a one-step reaction from industrially easily available 3,4-difluorobenzoic acid. Can be industrially obtained in high yield.

Claims (1)

[Claims] 1. A method of reacting an alkali metal salt of 3,4-difluorobenzoic acid with a halogenating agent, 2.
-Method for producing halogeno-4,5-difluorobenzoic acid.