Claims:1. A process for preparing 5-bromo-2,4-difluorobenzoic acid from 2,4-difluorobenzonitrile, the process comprising:
(a) brominating 2,4-difluorobenzonitrile with at least one brominating agent in the presence of aqueous sulfuric acid having concentration in the range of 70% to 99% at a temperature in the range of 0 °C to 30 °C for a time period in the range of 6 to 18 hours to obtain an initial resultant mixture comprising 5-bromo-2,4-difluorobenzonitrile and aqueous sulfuric acid having concentration in the range of 70% to 99%;
(b) heating the initial resultant mixture at a temperature in the range of 100 °C to 130 °C for a time period in the range of 3 to 9 hours to obtain a final resultant mixture comprising 5-bromo-2,4-difluorobenzoic acid and aqueous sulfuric acid; and
(c) cooling the final resultant mixture to obtain a suspension comprising 5-bromo-2,4-difluorobenzoic acid and a liquid phase comprising aqueous sulfuric acid, followed by filtering out the suspension to obtain a filtrate comprising aqueous sulfuric acid and a residue comprising 5-bromo-2,4-difluorobenzoic acid.
2. The process as claimed in claim 1, wherein optionally the initial resultant mixture obtained in step (a) is diluted with water before the step of heating the initial resultant mixture.
3. A process for preparing 5-bromo-2,4-difluorobenzoic acid from 2,4-difluorobenzonitrile, the process comprising:
(1) brominating 2,4-difluorobenzonitrile with at least one brominating agent in the presence of aqueous sulfuric acid having a concentration in the range of 98% to 99% at a temperature in the range of 0 °C to 30 °C for a time period in the range of 6 to 18 hours to obtain an initial resultant mixture comprising 5-bromo-2,4-difluorobenzonitrile and aqueous sulfuric acid having concentration in the range of 98% to 99%;
(2) heating the initial resultant mixture at a temperature in the range of 10 °C to 60 °C for a time period in the range of 3 to 30 hours to obtain an intermediate resultant mixture comprising 5-bromo-2,4-difluorobenzamide and aqueous sulfuric acid having concentration in the range of 98% to 99%;
(3) heating the intermediate resultant mixture at a temperature in the range of 100 °C to 130 °C for a time period in the range of 3 to 9 hours to obtain a final resultant mixture comprising 5-bromo-2,4-difluorobenzoic acid and aqueous sulfuric acid; and
(4) cooling the final resultant mixture to obtain a suspension comprising 5-bromo-2,4-difluorobenzoic acid and a liquid phase comprising aqueous sulfuric acid, followed by filtering out the suspension to obtain a filtrate comprising aqueous sulfuric acid and a residue comprising 5-bromo-2,4-difluorobenzoic acid.
4. The process as claimed in claim 3, wherein optionally the intermediate resultant mixture obtained in step (2) is diluted with water before the step of heating the intermediate resultant mixture.
5. The process as claimed in any one of claim 1, and claim 3, wherein the brominating agent is at least one selected from the group consisting of N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin, sodium bromate (NaBrO3), and potassium bromate (KBrO3).
6. The process as claimed in claim 5, wherein the molar ratio of 2,4-difluorobenzonitrile and N-bromosuccinimide (NBS) is in the range of 1:0.95 to 1:1.05.
7. The process as claimed in claim 5, wherein the molar ratio of 2,4-difluorobenzonitrile and 1,3-dibromo-5,5-dimethylhydantoin is in the range of 1:0.48 to 1:0.52.
8. The process as claimed in claim 5, wherein the molar ratio of 2,4-difluorobenzonitrile and sodium bromate (NaBrO3) is in the range of 1:0.95 to 1:1.1.
9. The process as claimed in any one of claims 1 and 3, wherein sulfuric acid is recovered from the filtrate, which is optionally reused in the step of bromination.
, Description:FIELD
The present disclosure relates to an agrochemical, and pharmaceutical compound, particularly to 5-bromo-2,4-difluorobenzoic acid and the process for its preparation.
BACKGROUND
5-Bromo-2,4-difluorobenzoic acid is an important intermediate in the agrochemical and pharmaceutical industry.
Typically, preparation of 5-bromo-2,4-difluorobenzoic acid involves reacting 1,3-difluorobenzene with chlorotriethylsilane at -75°C in the presence of butyllithium to obtain (2,6-difluorophenyl) triethylsilane which on brominating with bromine in the presence of sec-butyllithium provides (3-bromo-2,6-difluorophenyl) triethylsilane which on carboxylation in the presence of butyllithium at -75°C, followed by hydrolysis provides 5-bromo-2,4-difluorobenzoic acid.
The above-mentioned method of preparation of 5-bromo-2,4-difluorobenzoic acid has significant drawbacks such as using expensive starting materials, subjecting starting materials, and intermediates to harsh reaction conditions such as -75 °C, treating intermediates with expensive reagents, highly flammable and environmentally hazardous chemicals such as butyllithium and sec-butyllithium in organic solvents which require specific handling and safety equipment.
Alternatively, 5-bromo-2,4-difluorobenzoic acid is also prepared by brominating 2,4-difluorobenzoic acid, an expensive starting material.
All these drawbacks make these processes uneconomical, hazardous and put severe burden on the environment.
There is, therefore, felt a need to provide simple, efficient and environmentally friendly process for preparing 5-bromo-2,4-difluorobenzoic acid with high purity, and high yield.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows.
An object of the present disclosure is to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
Another object of the present disclosure is to provide a simple and efficient process for the preparation of 5-bromo-2,4-difluorobenzoic acid.
Still another object of the present disclosure is to provide an economical process for the preparation of 5-bromo-2,4-difluorobenzoic acid with high yield, and high purity.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure relates to a process for the preparation of 5-bromo-2,4-difluorobenzoic acid from 2,4-difluorobenzonitrile.
In accordance with first aspect of the present disclosure, the process for preparing 5-bromo-2,4-difluorobenzoic acid from 2,4-difluorobenzonitrile comprises the step of brominating 2,4-difluorobenzonitrile with at least one brominating agent in the presence of aqueous sulfuric acid having a concentration in the range of 70% to 99% at a temperature in the range of 0 °C to 30 °C for a time period in the range of 6 to 18 hours to obtain an initial resultant mixture comprising 5-bromo-2,4-difluorobenzonitrile and aqueous sulfuric acid having concentration in the range of 70% to 99%. The initial resultant mixture is heated at a temperature in the range of 100 °C to 130 °C for a time period in the range of 3 to 9 hours to obtain a final resultant mixture comprising 5-bromo-2,4-difluorobenzoic acid and aqueous sulfuric acid. The final resultant mixture is cooled to obtain a suspension comprising 5-bromo-2,4-difluorobenzoic acid and a liquid phase comprising aqueous sulfuric acid. This is followed by filtering out the suspension to obtain a filtrate comprising aqueous sulfuric acid and a residue comprising 5-bromo-2,4-difluorobenzoic acid.
In accordance with the embodiments of the present disclosure, optionally the initial resultant mixture obtained in step (a) is diluted with water before the step of heating the initial resultant mixture.
In accordance with second aspect of the present disclosure, the process for preparing 5-bromo-2,4-difluorobenzoic acid from 2,4-difluorobenzonitrile comprises the step of brominating 2,4-difluorobenzonitrile with at least one brominating agent in the presence of aqueous sulfuric acid having a concentration in the range of 98% to 99% at a temperature in the range of 0 °C to 30 °C for a time period in the range of 6 to 18 hours to obtain an initial resultant mixture comprising 5-bromo-2,4-difluorobenzonitrile and aqueous sulfuric acid having concentration in the range of 98% to 99%. The initial resultant mixture is heated at a temperature in the range of 10 °C to 60 °C for a time period in the range of 3 to 30 hours to obtain an intermediate resultant mixture comprising 5-bromo-2,4-difluorobenzamide and aqueous sulfuric acid having concentration in the range of 98% to 99%. The intermediate resultant mixture is heated at a temperature in the range of 100 °C to 130 °C for a time period in the range of 3 to 9 hours to obtain a final resultant mixture comprising 5-bromo-2,4-difluorobenzoic acid and aqueous sulfuric acid. The final resultant mixture is cooled to obtain a suspension comprising 5-bromo-2,4-difluorobenzoic acid and a liquid phase comprising aqueous sulfuric acid, followed by filtering out the suspension to obtain a filtrate comprising aqueous sulfuric acid and a residue comprising 5-bromo-2,4-difluorobenzoic acid.
In accordance with the embodiments of the present disclosure, optionally the intermediate resultant mixture obtained in step (2) is diluted with water before the step of heating the intermediate resultant mixture.
In accordance with the embodiments of the present disclosure, the brominating agent is at least one selected from the group consisting of N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin, sodium bromate (NaBrO3) and potassium bromate (KBrO3).
In accordance with the embodiments of the present disclosure, the molar ratio of 2,4-difluorobenzonitrile and N-bromosuccinimide (NBS) is in the range of 1:0.95 to 1:1.05; or the molar ratio of 2,4-difluorobenzonitrile and 1,3-dibromo-5,5-dimethylhydantoin is in the range of 1:0.48 to 1:0.52; or the molar ratio of 2,4-difluorobenzonitrile and sodium bromate (NaBrO3) is in the range of 1:0.95 to 1:1.1.
In accordance with the embodiments of the present disclosure, sulfuric acid is recovered from the filtrate, which is optionally reused in the step of bromination.
The process of the present disclosure is environmentally friendly, has short reaction cycle and reduces production costs. Further, the process of the present disclosure is simple, efficient, and economical.
DETAILED DESCRIPTION
5-Bromo-2,4-difluorobenzoic acid (I) is an important intermediate in the agrochemical and pharmaceutical industry. The present disclosure envisages a simple, efficient and environmentally friendly process for the preparation of 5-bromo-2,4-difluorobenzoic acid (I) with high yield, and high purity.
The present disclosure provides a process for the preparation of 5-bromo-2,4-difluorobenzoic acid (I).

In accordance with the first aspect of the present disclosure, there is provided a process for the preparation of 5-bromo-2,4-difluorobenzoic acid (I) from 2,4-difluorobenzonitrile (II). The process involves the following steps.
2,4-difluorobenzonitrile (II) is brominated with at least one brominating agent in the presence of aqueous sulfuric acid having a concentration in the range of 70% to 99% at a temperature in the range of 0 °C to 30 °C for a time period in the range of 6 to 18 hours to obtain an initial resultant mixture comprising 5-bromo-2,4-difluorobenzonitrile (III) and aqueous sulfuric acid having concentration in the range of 70% to 99%.

The initial resultant mixture is heated at a temperature in the range of 100 °C to 130 °C for a time period in the range of 3 to 9 hours to obtain a final resultant mixture containing 5-bromo-2,4-difluorobenzoic acid (I) acid and aqueous sulfuric acid.

The final resultant mixture is cooled to obtain a suspension comprising 5-bromo-2,4-difluorobenzoic acid (I) and a liquid phase comprising aqueous sulfuric acid, followed by filtering out the suspension to obtain a filtrate comprising aqueous sulfuric acid and a residue comprising 5-bromo-2,4-difluorobenzoic acid (I).
In accordance with the embodiments of the present disclosure, the brominating agent is at least one selected from the group consisting of N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin, and sodium bromate (NaBrO3).
In accordance with one embodiment of the present disclosure, the brominating agent is NBS. The molar ratio of 2,4-difluorobenzonitrile (II) and NBS is in the range of 1:0.95 to 1:1.05.
In accordance with another embodiment of the present disclosure, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin. The molar ratio of 2,4-difluorobenzonitrile (II) and 1,3-dibromo-5,5-dimethylhydantoin is in the range of 1:0.48 to 1:0.52.
In accordance with yet another embodiment of the present disclosure, the brominating agent is sodium bromate. The molar ratio of 2,4-difluorobenzonitrile (II) and sodium bromate is in the range of 1:0.95 to 1:1.1.
In accordance with one embodiment of the present disclosure, the concentration of aqueous sulfuric acid used in the bromination step is 70% w/w.
In accordance with another embodiment of the present disclosure, the concentration of aqueous sulfuric acid used in the bromination step is 80% w/w.
In accordance with yet another embodiment of the present disclosure, the concentration of aqueous sulfuric acid used in the bromination step is 90% w/w.
In accordance with still another embodiment of the present disclosure, the concentration of aqueous sulfuric acid used in the bromination step is 95% w/w.
In accordance with still another embodiment of the present disclosure, the concentration of aqueous sulfuric acid used in the bromination step is 98.76% w/w.
In accordance with one embodiment of the present disclosure, the step of bromination is carried out at 25 °C.
In accordance with one embodiment of the present disclosure, the step of bromination is carried out for 12 hours.
In accordance with the preferred embodiment of the present disclosure, 5-bromo-2,4-difluorobenzonitrile (III) obtained in the step of bromination is not separated from the initial resultant mixture. The initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile (III) is directly taken to the next step.
In accordance with the embodiments of the present disclosure, the concentration of aqueous sulfuric acid used for heating the initial resultant mixture is in the range of 55% to 99% w/w.
In accordance with one embodiment of the present disclosure, the concentration of aqueous sulfuric acid used for heating the initial resultant mixture is 70 % w/w.
In accordance with one embodiment of the present disclosure, the concentration of aqueous sulfuric acid used in the bromination step and that in the step of heating the initial resultant mixture is the same.
In accordance with another embodiment of the present disclosure, the concentration of aqueous sulfuric acid used in the bromination step and that in the step of heating the initial resultant mixture is different. When the concentration of the aqueous sulfuric acid used in the bromination step is different from the concentration of aqueous sulfuric acid used in the heating step, the change in the concentration is brought about by adding calculated amount of water to the initial resultant mixture.
In accordance with the preferred embodiment of the present disclosure, the initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile (III) is heated at a temperature in the range of 115 °C to 120 °C.
In accordance with one embodiment of the present disclosure, the initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile (III) is heated at 118 °C.
In accordance with one embodiment of the present disclosure, the initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile (III) is heated for 6 hours.
In accordance with one embodiment of the present disclosure, the yield of 5-bromo-2,4-difluorobenzoic acid (I) is 83.4% with a purity of 93.4%.
In accordance with one embodiment of the present disclosure, the process of the present disclosure is carried out in one pot i.e. without isolation of 5-bromo-2,4-difluorobenzonitrile (III) as an intermediate. Consequently, the process of the present disclosure does not require intermediate separation, and purification. Therefore, the present process has short reaction cycle and reduces production costs.
The amount of by-products formed during the process of the present disclosure depends upon the concentration of aqueous H2SO4. It is observed that the use of 98.76% w/w aqueous H2SO4 results in formation of 4.57% of dibromo by-product i.e. 3,5-dibromo-2,4-difluorobenzoic acid, as an impurity. The use of lower concentration of aqueous H2SO4 led to formation of lesser amounts of 3,5-dibromo-2,4-difluorobenzoic acid. The use of aqueous H2SO4 having concentration in the range of 70% w/w to 80% w/w lead to formation of less than 1% of the di-brominated by-product. The use of 70 % w/w aqueous H2SO4 led to the formation of 0.13% of the di-brominated by-product.
It is observed that the amount of by-products formed during the process of the present disclosure also depends upon the brominating agent. The process of the present disclosure is carried out using different brominating agents in the presence of 80% w/w aqueous H2SO4. It is observed that the use of 1,3-dibromo-5,5-dimethylhydantoin as a brominating agent resulted in product containing 97.52% of desired mono-brominated product I, with 0.3% of di-brominated by-product and 1.26% of non-brominated product i.e. 2,4-difluorobenzoic acid. Whereas, using N-bromosuccinimide as a brominating agent resulted in product containing 97.34% of desired mono-brominated product with 0.58% of di-brominated by-product and leaving 0.83% of non-brominated product. On the other hand, sodium bromate as a brominating agent resulted in product containing 91.86% desired mono-brominated product with 2.61% of di-brominated by-product and 4.66% of non-brominated product. Thus, N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin provide higher amounts of desired product I as compared to sodium bromate. Also, N-bromosuccinimide is an easily available and inexpensive reagent for bromination.
Upon cooling the initial resultant mixture, it is found that 5-bromo-2,4-difluorobenzonitrile (III) is formed with high purity. Therefore, the process of the present disclosure is useful for preparing 5-bromo-2,4-difluorobenzonitrile (III).
In accordance with the second aspect of the present disclosure, there is provided a process for the preparation of 5-bromo-2,4-difluorobenzoic acid (I) from 2,4-difluorobenzonitrile (II). The process involves the following steps.
2,4-Difluorobenzonitrile (II) is brominated with at least one brominating agent in the presence of aqueous sulfuric acid having a concentration in the range of 98% to 99% at a temperature in the range of 0 °C to 30 °C for a time period in the range of 6 to 18 hours to obtain an initial resultant mixture comprising 5-bromo-2,4-difluorobenzonitrile (III) and aqueous sulfuric acid having concentration in the range of 98% to 99%.
The initial resultant mixture is heated at a temperature in the range of 10 °C to 60 °C for a time period in the range of 3 to 30 hours to obtain an intermediate resultant mixture comprising 5-bromo-2,4-difluorobenzamide (IV) and aqueous sulfuric acid having concentration in the range of 98% to 99%.

In accordance with one embodiment of the present disclosure, the concentration of aqueous sulfuric acid used in the step of heating the initial resultant mixture and that in the step of heating the intermediate resultant mixture is different. When the concentration of the aqueous sulfuric acid used in the step of heating the initial resultant mixture is different from the concentration of aqueous sulfuric acid used in the step of heating the intermediate resultant mixture, the change in the concentration is brought about by adding calculated amount of water to the intermediate resultant mixture.
The intermediate resultant mixture is heated at a temperature in the range of 100 °C to 130 °C for a time period in the range of 3 to 9 hours to obtain a final resultant mixture comprising 5-bromo-2,4-difluorobenzoic acid (I) and aqueous sulfuric acid.
The final resultant mixture is cooled to obtain a suspension comprising 5-bromo-2,4-difluorobenzoic acid (I) and a liquid phase comprising aqueous sulfuric acid, followed by filtering out the suspension to obtain a filtrate comprising aqueous sulfuric acid and a residue comprising 5-bromo-2,4-difluorobenzoic acid (I).
In accordance with the embodiments of the present disclosure, the brominating agent is at least one selected from the group consisting of N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin, and sodium bromate (NaBrO3).
In accordance with one embodiment of the present disclosure, the brominating agent is NBS. The molar ratio of 2,4-difluorobenzonitrile (II) and NBS is in the range of 1:0.95 to 1:1.05.
In accordance with another embodiment of the present disclosure, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin. The molar ratio of 2,4-difluorobenzonitrile (II) and 1,3-dibromo-5,5-dimethylhydantoin is in the range of 1:0.48 to 1:0.52.
In accordance with yet another embodiment of the present disclosure, the brominating agent is sodium bromate. The molar ratio of 2,4-difluorobenzonitrile (II) and sodium bromate is in the range of 1:0.95 to 1:1.1.
In accordance with one embodiment of the present disclosure, the step of bromination is carried out at 25 °C.
In accordance with one embodiment of the present disclosure, the step of bromination is carried out for 12 hours.
In accordance with the preferred embodiment of the present disclosure, 5-bromo-2,4-difluorobenzonitrile (III) obtained in the step of bromination is not separated from the initial resultant mixture. The initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile (III) is directly taken to the next step.
In accordance with one embodiment of the present disclosure, the concentration of aqueous sulfuric acid used for heating the initial resultant mixture is 98.76 % w/w.
In accordance with one embodiment of the present disclosure, the initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile (III) is heated at 35 °C.
In accordance with one embodiment of the present disclosure, the initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile (III) is heated for 15 hours.
In accordance with preferred embodiment of the present disclosure, 5-bromo-2,4-difluorobenzamide (IV) obtained is not separated from the intermediate resultant mixture. The intermediate resultant mixture containing 5-bromo-2,4-difluorobenzamide (IV) is directly taken to the next step.
In accordance with the embodiments of the present disclosure, the concentration of aqueous sulfuric acid used for heating the intermediate resultant mixture is in the range of 55% to 99% w/w.
In accordance with one embodiment of the present disclosure, the concentration of aqueous sulfuric acid used for heating the intermediate resultant mixture is 70 % w/w.
In accordance with the preferred embodiment of the present disclosure, the intermediate resultant mixture containing 5-bromo-2,4-difluorobenzamide (IV) is heated at a temperature in the range of 115 °C to 120 °C.
In accordance with one embodiment of the present disclosure, the intermediate resultant mixture containing 5-bromo-2,4-difluorobenzamide (IV) is heated at 118 °C.
In accordance with one embodiment of the present disclosure, the intermediate resultant mixture containing 5-bromo-2,4-difluorobenzamide (IV) is heated for 6 hours.
In accordance with one embodiment of the present disclosure, the yield of 5-bromo-2,4-difluorobenzoic acid (I) is 83.1% with a purity of 93.3%.
In accordance with the process of the present disclosure, the process step of cooling is carried out using crushed ice. The cooling is followed by isolation of the resultant mass by filtration or centrifugation.
The process of the present disclosure uses commonly available and inexpensive raw materials, reagents and fluid media, and recycles the fluid media. Hence, the process of the present disclosure is simple, efficient, and economical.
The disclosure will now be described with reference to the accompanying experiments which do not limit the scope and ambit of the disclosure. The description provided is purely by way of example and illustration.
The laboratory scale experiments provided herein can be scaled up to industrial or commercial scale.
EXPERIMENTS
Experiments 1-5: Preparation of 5-bromo-2,4-difluorobenzoic acid (I) from 2,4-difluorobenzonitrile (II) using varying concentrations of aqueous sulfuric acid (aqueous H2SO4).

N-bromosuccinimide (17.44 g, 0.098 mole) was added to a mixture of 2,4-difluorobenzonitrile (13.90 g, 0.1 moles) and 98.76% w/w aqueous H2SO4 (120 ml) in a flask to obtain a reaction mass. The reaction mass was stirred at 25 °C for 12 hours to obtain an initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile.
The initial resultant mixture was diluted with water (88.66 g) and the resultant initial mixture was heated at 118 °C for 6 hours to obtain a final resultant mixture containing 5-bromo-2,4-difluorobenzoic acid. The final resultant mixture was cooled to 25 °C to obtain a suspension containing 5-bromo-2,4-difluorobenzoic acid and liquid phase containing aqueous sulfuric acid. The suspension was filtered to obtain a residue containing 5-bromo-2,4-difluorobenzoic acid (20.38 g, yield 83.45%, purity 93.39%) and a filtrate containing aqueous H2SO4. The amounts of impurities 2,4-difluorobenzoic acid and 3,5-dibromo-2,4-difluorobenzoic acid in the product were 1.73% and 4.57% respectively.
5-Bromo-2,4-difluorobenzoic acid was characterized by 1H NMR spectroscopy and melting point. The 1H NMR resonances of 5-bromo-2,4-difluorobenzoic acid were observed at: 1H NMR (DMSO-d6, 400 MHz): d 7.60 (1H, t, J = 9.12 Hz, Ar-H), 8.12 (1H, t, J = 7.88 Hz, Ar-H), 13.59 (1H, broad s, -COOH). The melting point of 5-bromo-2,4-difluorobenzoic acid was found to be 147 °C - 149 °C.
In order to obtain product with high purity, the preparation of 5-bromo-2,4-difluorobenzoic acid was carried out in the presence of aqueous H2SO4 of various concentrations such as 70%, 80%, 90%, 95%, and 98.76% using the procedure mentioned herein above for 98.76% w/w aqueous H2SO4. The results are presented in Table 1.
Table 1: Preparation of 5-bromo-2,4-difluorobenzoic acid (I) using aqueous H2SO4 of various concentrations
Expt. No. Aqueous H2SO4
Product composition

Concentration of Aqueous H2SO4 (w/w) used for bromination Amount of Aqueous H2SO4 used in bromination step Amount of Water added before hydrolysis step Concentration of Aqueous H2SO4 used for hydrolysis step 5-Bromo-2,4-Difluoro
benzoic acid (%) 2,4-Difluoro
benzoic acid (%) 3,5-Dibromo
-2,4-Difluoro
benzoic acid (%)
1 98.76% 120 ml (88.66 ml) 70% 93.39 1.73 4.57
2 95% 120 ml (77 ml) 70 % 96.83 0.45 2.41
3 90% 120 ml (62 ml) 70% 97.79 0.25 1.79
4 80% 120 ml (29ml) 70% 97.34 0.83 0.58
5 70% 120 ml (0 ml) 70% 96.35 1.75 0.13

It is evident from Table 1 that use of aqueous H2SO4 having concentration in the range of 70% w/w to 95 % w/w results in 5-bromo-2,4-difluorobenzoic acid with more than 95% purity. The amount of impurity of 3,5-dibromo-2,4-difluorobenzoic acid formed in the brominating step decreases with decrease in the concentration of aqueous H2SO4.
Experiments 6-7: Preparation of 5-bromo-2,4-difluorobenzoic acid (I) from 2,4-difluorobenzonitrile (II) using different brominating agents.
The preparation of 5-bromo-2,4-difluorobenzoic acid was carried out using other brominating agents such as 1,3-dibromo-5,5-dimethylhydantoin, and sodium bromate in the presence of 80% w/w aqueous H2SO4 using the procedure mentioned above for the Table 1 (Experiment 4). The results are presented in Table 2.
Table 2: Preparation of 5-bromo-2,4-difluorobenzoic acid (I) using different brominating agents
Expt. No. Brominating agent Product composition
Brominating agent Amount of brominating agent used in bromination step 5-Bromo-2,4-difluorobenzoic acid (%) 2,4-Difluorobenzoic acid (%) 3,5-Dibromo-2,4-difluorobenzoic acid (%)
6 1,3-Dibromo-5,5-dimethylhydantoin 14.01 g (0.049 moles) 97.52 1.26 0.3
7 Sodium bromate 14.79 g (0.098mole) 91.86 4.66 2.61
Upon comparing results of experiments 4 (Table 1), 6, and 7 from Table 2, it is evident that the use of N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin as a brominating agent results in 5-bromo-2,4-difluorobenzoic acid with 97% or greater purity, whereas, the use of sodium bromate as a brominating agent results in 5-bromo-2,4-difluorobenzoic acid with 91.86% purity.
Experiment 8: Preparation of 5-bromo-2,4-difluorobenzoic acid (I) using recovered aqueous H2SO4 from experiment 5.
In order to achieve an environmentally friendly and economically feasible process, aqueous H2SO4 was recycled and/or re-used for the preparation of 5-bromo-2,4-difluorobenzoic acid. The results are presented in Table 3.
Table 3: Preparation of 5-bromo-2,4-difluorobenzoic acid (I) using N-bromosuccinimide in the presence of recovered 70 % w/w aqueous H2SO4 from experiment 5
Expt. No. Recovered 70 % w/w aqueous H2SO4 from previous batch used 5-Bromo-2,4-difluorobenzoic acid
Concentration of aqueous H2SO4 (w/w) used for bromination Amount of aqueous H2SO4 used in bromination step Purity (%) Yield (%)
8 70 % aqueous H2SO4 120 ml 91.95 85
From the results of experiment 8 (Table 3) it is evident that the use of recycled 70 % w/w aqueous H2SO4 from previous batch provided 5-bromo-2,4-difluorobenzoic acid with more than 91% purity, thereby affording an environmentally friendly process for the preparation of 5-bromo-2,4-difluorobenzoic acid.

Experiment 9-10: Preparation of 5-bromo-2,4-difluorobenzonitrile (III) using different brominating agents in the presence of 80 % w/w aqueous H2SO4.

A brominating agent was added to a mixture of 2,4-difluorobenzonitrile (13.90 g, 0.1 moles) and 80% w/w aqueous H2SO4 (120 ml) in a flask. The reaction mass was stirred at 25 °C for 12 hours to obtain an initial resultant mixture containing 5-bromo-2,4-difluorobenzonitrile. The initial resultant mixture was poured over crushed ice followed by filtration of the resultant mass to obtain 5-bromo-2,4-difluorobenzonitrile (17 g, yield = 75%, purity 94.14%).
5-Bromo-2,4-difluorobenzonitrile was characterized by 1H NMR spectroscopy, IR spectroscopy and melting point. The 1H NMR resonances of 5-bromo-2,4-difluorobenzonitrile were observed at: 1H NMR (DMSO-d6, 400 MHz): d 7.09 (1H, t, J = 8 Hz, Ar-H), 7.86 (1H, t, J = 8 Hz, Ar-H). The IR was recorded on KBr pallet. IR spectrum of 5-bromo-2,4-difluorobenzonitrile showed the presence of characteristic nitrile absorption band at: IR (KBr pallet) ? (cm-1): 2237 (C-N nitrile stretch). The melting point of 5-bromo-2,4-difluorobenzonitrile was found to be 52 °C - 55 °C.
Using a similar procedure, bromination of 2,4-difluorobenzonitrile was carried out using NBS and 1,3-dibromo-5,5-dimethylhydantoin and the results are presented in Table 4.

Table 4: Preparation and isolation of 5-bromo-2,4-difluorobenzonitrile (III) using different brominating agents in the presence of 80 % w/w aqueous H2SO4
Expt. No. Brominating agent 5-Bromo-2,4-difluorobenzonitrile (%)
Brominating agent Amount of brominating agent used in bromination step Purity (%) Yield (%)
9 N-bromosuccinimide 17.44 g (0.098 moles) 94.14 75
10 1,3-Dibromo-5,5-dimethylhydantoin 14.01 g (0.049 moles) 82 64.8
From the results of experiments 9-10 (Table 4) it is evident that bromination of 2,4-difluorobenzonitrile by NBS and 1,3-dibromo-5,5-dimethylhydantoin in the presence of 80 % w/w aqueous H2SO4 results in 5-bromo-2,4-difluorobenzonitrile with more than 80% purity.
Experiment 11: Preparation of 5-bromo-2,4-difluorobenzamide (IV) by hydrolysis of 5-bromo-2,4-difluorobenzonitrile (III).

5-Bromo-2,4-difluorobenzonitrile (0.1 moles), obtained in the experiment 9 and 98.76 % aqueous H2SO4 (1 mole) were heated at 10 °C to 60 °C for 15 hrs. The resultant mixture was poured over crushed ice and filtered to obtain 5-bromo-2,4-difluorobenzamide (20.3 g, 86%).
5-Bromo-2,4-difluorobenzamide was characterized by 1H NMR spectroscopy, IR spectroscopy and melting point. The 1H NMR resonances of 5-bromo-2,4-difluorobenzonitrile were observed at: 1H NMR (DMSO-d6, 400 MHz): d 7.57 (1H, t, J = 7.68 Hz, Ar-H), 7.73 (1H, broad s, -CONH2), 7.80 (1H, broad s, -CONH2), 7.94 (1H, t, J = 9.66 Hz, Ar-H). The IR was recorded on KBr pallet. IR spectrum of 5-bromo-2,4-difluorobenzamide showed the presence of characteristic amide band at: IR (KBr pallet) ? (cm-1): 3405 (NH stretch), 3208 (NH stretch) for primary amide, and 1655 (C=O Stretch).
The melting point of 5-bromo-2,4-difluorobenzamide was found to be 120 °C - 124 °C.
Hydrolysis of 5-bromo-2,4-difluorobenzamide in the presence of 70% w/w aqueous H2SO4 at a temperature of 118°C resulted in 5-bromo-2,4-difluorobenzoic acid.

TECHNICAL ADVANCES AND ECONOMICAL SIGNIFICANCE
The process of the present disclosure described herein above has several technical advantages including, but not limited to, the realization of;
• a simple, efficient, and environmentally friendly process for the preparation of 5-bromo-2,4-difluorobenzoic acid, and
• a process for the preparation of 5-bromo-2,4-difluorobenzoic acid with high yield and high purity.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.