PROCESS FOR THE PREPARATION OF 2,4-DIHALOBENZOIC ACID

Field of the invention

The present invention provides a process for the preparation of 2,4-dihalobenzoic acid of Formula I.

Background of the invention

The 2,4-dihalobenzoic acids of Formula I are valuable intermediates used in organic synthesis and in the field of pharmaceuticals and agrochemicals. Particularly, 2,4-difluorobenzoic acid has been used as an intermediate in the preparation of potential anti-cancer agents. In addition, it has been used in the synthesis of antidepressant drugs.

where X is selected from fluorine, chlorine, bromine, iodine
Formula I

Zhou S. et al., Chinese Journal of Pharmaceuticals., 2001, 32(9), 420 provides a process for producing 2,4-difluorobenzoic acid by adding KMnO4 in batches to a solution of 2,4-dinitrotoluene, water and pyridine at 78° to 83°C for 6 to 7 hours followed by oxidation. The mixture was acidified with HCl to pH 2 to 3 to obtain 2,4-dinitrobenzoic acid and substituting with sodium fluoride in DMSO at 80° to 90°C for 10 hours.

The present inventors observed that though the prior art has a merit of being cost effective, the yields so obtained are low. Additionally, the effluent generation via prior art process is not preferred industrially on large scale. The present invention provides a process for the preparation of a compound of Formula I which is simple, easy to perform and industrially doable.

Summary of the invention
The present invention provides a process for the preparation of 2,4-dihalobenzoic acid of Formula I comprising;
a) reacting 2,4-dihalobenzaldehyde of Formula II with nitric acid to obtain 2,4-dihalobenzoic acid of Formula I, and

Formula I

Formula II
where X is selected from fluorine, chlorine, bromine, iodine
b) isolating a compound of Formula I from step a).

Detailed description of the invention

The present invention provides a process for the preparation of 2,4-dihalobenzoic acid of Formula I comprising;
a) reacting 2,4-dihalobenzaldehyde of Formula II with nitric acid to obtain 2,4-dihalobenzoic acid of Formula I, and

Formula I

Formula II
where X is selected from fluorine, chlorine, bromine, iodine
b) isolating a compound of Formula I from step a).

The compounds of Formula II may be obtained commercially or prepared by the process as known in the prior art, for example, 2,4-difluorobenzaldehyde may be prepared by fluorinating 2,4-dichlorobenzaldehyde with anhydrous potassium fluoride in the presence of sulfone as solvent at 200oC for 12 to 14 hours.

The step a) may be carried out at a temperature of about 40oC to 150oC, for example, about 70oC to 90oC for about 1 hours to 24 hours.

The compound of Formula I is isolated by any of the methods in the art, for example, crystallization, re-crystallization, distillation, evaporation and layer separation or mixture thereof.

The 2,4-difluorobenzoic acid, as obtained by the present invention, has purity of about greater than 98%, preferably greater than 99%.

The term ‘about’ refers to a variation of 10% on the higher and lower side of specified parameter.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.

Examples
Example 1: Preparation of 2,4-difluorobenzoic acid
The 2,4-difluorobenzaldehyde (400g) was mixed with 69% nitric acid (2827g) at room temperature. The reaction mixture was heated to 80oC for 10 hours to 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The solid was filtered, washed with water and toluene subsequently and dried at 70oC under vacuum to obtain the title compound.

Yield (%): 94.38
Purity (% by Gas Chromatography): 99.68%

CLAIMS:
We claim:
1. A process for the preparation of 2,4-dihalobenzoic acid of Formula I comprising;
a) reacting 2,4-dihalobenzaldehyde of Formula II with nitric acid to obtain 2,4-dihalobenzoic acid of Formula I, and

Formula I

Formula II
where X is selected from fluorine, chlorine, bromine, iodine
b) isolating a compound of Formula I from step a).
2. The process as claimed in claim 1, wherein the step a) is carried out at a temperature of about 40oC to 150oC.
3. The process as claimed in claim 2, wherein the step a) is carried out at a temperature 70oC to 90oC.
4. The process as claimed in claim 1, wherein the compound of Formula I is isolated by crystallization, re-crystallization, distillation, evaporation and layer separation or mixture thereof.
5. The 2,4-difluorobenzoic acid, as obtained by the process as claimed in claim 1, has purity of about greater than 98%.