Field of the invention

The present invention provides a process for the purification of a compound of Formula I.

Background of the invention

The compounds represented by Formula I are versatile building block in pharmaceutical and polymer industry. The compounds of Formula I, particularly, 2-chloro-3-nitrobenzoic acid, is used in the preparation of an anti-cancer drug dabrafenib.

Formula I
wherein X is selected from H, F, Cl, Br, I, OH, NO2, SO3H, aryl group, heterocycle group, C3-C10 cycloalkyl.

Formula II

wherein X is selected from H, F, Cl, Br, I, OH, NO2, SO3H, aryl group, heterocycle group,
C3-C10 cycloalkyl.

Generally, the oxidation of compound of Formula II to compound of Formula I is achieved by using oxidizing agents such as KMnO4, CrO3, Na2Cr2O7, TiO2, NaIO4 and HNO3. However, these metallic reagents are often required in stoichiometric amounts, thereby producing large effluents at the industrial scale causing environmental pollution. Moreover, purification of the reaction products is often very tedious because of the difficulty in separation of the metal residues from the desired product.

The Chinese patent no.1296940 discloses an environmentally friendly process for preparing benzoic acid from benzaldehyde or benzyl alcohol or benzyl halide using hydrogen peroxide in the presence of catalysts such as sodium tungstate dehydrate, trioctyl methyl ammonium bisulfate. The process disclosed in the patent is uneconomical and hence industrially unfavourable.

Synthetic communications, 2010,40:2922-2929, provides a process for the preparation of benzoic acid from methylarenes using bromide/bromate in water. The crude was subjected to repeated water washings to obtain the final product. However, yet again the product was industrially non-feasible due to high effluent and many process operations. Moreover, the literature does not disclose the purity of the benzoic acid.

The present invention provides a process of purification of a compound of Formula I. The compound of Formula I as obtained by the process of the present invention has a purity greater than 97%. The process of the present invention is environmental-friendly, simple, economically viable and industrially doable.

Summary of the invention

The present invention provides a process for the purification of a compound of Formula I, comprising;
a) contacting a compound of Formula II with sodium bromate, sodium bromide and an acid to obtain the compound of Formula I,
b) extracting the compound of Formula I with a solvent,
c) subjecting step b) solvent containing the compound of Formula I to acid-base treatment, and
d) isolating the compound of Formula I from step c), wherein the isolated compound of Formula I has purity greater than 97%.

Formula I
wherein X is selected from H, F, Cl, Br, I, OH, NO2, SO3H, aryl group, heterocycle group,
C3-C10 cycloalkyl.


Formula II
wherein X is selected from H, F, Cl, Br, I, OH, NO2, SO3H, aryl group, heterocycle group, C3-C10 cycloalkyl.

Detailed description of the invention

The present invention provides a process for the purification of a compound of Formula I, comprising;
a) contacting a compound of Formula II with sodium bromate, sodium bromide and an acid to obtain the compound of Formula I,
b) extracting the compound of Formula I with a solvent,
c) subjecting step b) solvent containing the compound of Formula I to acid-base treatment, and
d) isolating the compound of Formula I from step c), wherein the isolated compound of Formula I has purity greater than 97%.

Formula I
wherein X is selected from H, F, Cl, Br, I, OH, NO2, SO3H, aryl group, heterocycle group,
C3-C10 cycloalkyl.

Formula II
wherein X is selected from H, F, Cl, Br, I, OH, NO2, SO3H, aryl group, heterocycle group, C3-C10 cycloalkyl.

The step a) may be carried out at a temperature in the range of 50oC to 140oC.

The step a) is carried out in the presence of an acid selected from sulfuric acid, hydrochloric acid, hydrobromic acid and oleum.

The step a) may be carried out in the presence of solvent selected from water, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, isopropyl alcohol and acetic acid or a mixture thereof.

The solvent used in step b) is selected from ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, methyl tert-butyl ether and benzene or a mixture thereof.

The acid used in step c) is selected from hydrochloric acid, hydrobromic acid and dilute sulphuric acid or a mixture thereof.

The base used in step c) is selected from sodium bicarbonate, potassium carbonate, sodium carbonate and any weak base as known in the art or a mixture thereof.

The compound of Formula II may be obtained commercially or may be prepared by any of the methods known in the art, for example, as in the Zhongguo Yiyao Gongye Zazhi, 34(1),4-6:2003

The isolation of the compound of Formula I is carried out by filtration, crystallization or re-crystallization or mixture thereof.

The compound of Formula I, obtained by the process of the present invention has a purity greater than 97% by gas chromatography.

The compound of Formula I having more than 97% purity, as obtained by the present invention, as an intermediate to prepare methyl 2-fluoro-3-nitrobenzoate by any method known in the art.

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: Purification of 2-chloro-3-nitrobenzoic acid
Sodium bromate (325.4g) was dissolved in water (3.6 litres) and 2-chloro-1-methyl-3-nitrobenzene (369g), was added to it in a round bottom flask. The reaction mass was heated to reflux under visible light irradiation. The sodium bromide (443.6g) in water (200ml) and sulfuric acid (317.2g) mixture was added drop-wise to the reaction mass for minimum 4 hours. The reaction mass was stirred under visible light irradiation for 20 hours at reflux temperature and the reaction was monitored by thin layer chromatography. After reaction completion, the reaction mass was cooled to room temperature. The compound 2-chloro-3-nitrobenzoic acid, was extracted with 3× 1 litre ethyl acetate. To the ethyl acetate layer, sodium bicarbonate (300g) dissolved in 3 litre water was added and the compound was extracted from ethyl acetate layer. 10% hydrochloric acid was added to adjust the pH to 2 to get precipitated compound. The title compound was filtered and washed with 1 litre 2% hydrochloric acid and dried.
Yield (%): 70
Purity (%): 98

CLAIMS:
We claim:
1. A process for the purification of a compound of Formula I, comprising;
a) contacting a compound of Formula II with sodium bromate, sodium bromide and an acid to obtain the compound of Formula I,
b) extracting the compound of Formula I with a solvent,
c) subjecting step b) solvent containing the compound of Formula I to acid-base treatment, and
d) isolating the compound of Formula I from step c), wherein the isolated compound of Formula I has purity greater than 97%.

Formula I
wherein X is selected from H, F, Cl, Br, I, OH, NO2, SO3H, aryl group, heterocycle group,
C3-C10 cycloalkyl.


Formula II
wherein X is selected from H, F, Cl, Br, I, OH, NO2, SO3H, aryl group, heterocycle group, C3-C10 cycloalkyl.

2. The process as claimed in claim 1, wherein the step a) is carried out at a temperature in the range of 50oC to 140oC.

3. The process as claimed claim 1, wherein the step a) is carried out in the presence of an acid selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid and oleum.

4. The process as claimed in claim 1, wherein the step a) is carried out in the presence of solvent selected from the group consisting of water, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, isopropyl alcohol and acetic acid or a mixture thereof.

5. The process as claimed in claim 1, wherein the solvent of step b) is selected from the group consisting of ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, methyl tert-butyl ether and benzene or a mixture thereof.

6. The process as claimed in claim 1, wherein the acid used in step c) is selected from the group consisting of hydrochloric acid, hydrobromic acid and dilute sulphuric acid or a mixture thereof.

7. The process as claimed in claim 1, wherein the base used in step c) is selected from the group consisting of sodium bicarbonate, potassium carbonate and sodium carbonate or mixture thereof.