DESC:FIELD
The present disclosure relates to a process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Chlorantraniliprole is a broad-spectrum anthranilic diamide insecticide. Chlorantraniliprole, when consumed by insects, it interrupts normal muscle contraction, resulting in the death of the insects. The structural formula for Chlorantraniliprole is given below.

2-amino-5-chloro-3-methylbenzoic acid is an important intermediate used in the production of Chlorantraniliprole.
Conventional methods for the preparation of 2-amino-5-chloro-3-methylbenzoic acid involve multiple steps, high amount of fluid medium, and require high temperatures. The known methods employ chlorinating agents and solvents that are water-miscible and, as a result, cannot be recovered, resulting in the loss of chlorinating agents and solvents. Moreover, known processes are associated with the drawbacks such as impurities and low yield of the product. Such methods require further purification and are not economical. The impurities in the final product may affect the efficacy, safety, and stability of the final formulation. The yield/productivity of 2-amino-5-chloro-3-methylbenzoic acid obtained from the known processes is considerably low.
Therefore, there is felt a need to provide a process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid that mitigates the aforestated drawbacks or at least provide an alternative solution.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the background or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid.
Yet another object of the present disclosure is to provide a process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid with comparatively better purity and yield.
Still another object of the present disclosure is to provide a simple and cost-effective process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid.
Another object of the present disclosure is to provide an environment-friendly and commercially scalable process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid.
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 preparing 2-amino-5-chloro-3-methylbenzoic acid. The process comprises chlorinating 2-amino-3-methylbenzoic acid (AMBA) by using a chlorinating agent in at least one fluid medium at a predetermined temperature to obtain 2-amino-5-chloro-3-methylbenzoic acid (ACMBA).
In an embodiment of the present disclosure, the fluid medium is at least one selected from the group consisting of ethylene dichloride (EDC), methylene dichloride (MDC), acetic acid, dimethylformamide (DMF), and monochlorobenzene (MCB).
In an embodiment of the present disclosure, the first predetermined temperature is in the range of 10°C to 80°C.
In an embodiment of the present disclosure, the chlorinating agent is at least one selected from the group consisting of chlorine, N-chlorosuccinimide, sulfuryl chloride, cyanuric chloride, and 1,3-dichloro-5,5-dimethylhydantoin.
In an embodiment of the present disclosure, a mole ratio of 2-amino-3-methylbenzoic acid to the chlorinating agent is in the range of 1:1 to 1:4.
In another embodiment of the present disclosure, a mole ratio of 2-amino-3-methylbenzoic acid to the chlorinating agent is in the range of 1:1 to 1:3.
In yet another embodiment of the present disclosure, a mole ratio of 2-amino-3-methylbenzoic acid to the chlorinating agent is in the range of 1:1 to 1:2.
In an embodiment of the present disclosure, the process of chlorination is carried out by using at least one additive.
In an embodiment of the present disclosure, the additive is at least one selected from the group consisting of a catalyst and an acid scavenger.
In an embodiment of the present disclosure, the catalyst is at least one selected from the group consisting of iron powder, ferric chloride, iodine, and ferrocene.
In an embodiment of the present disclosure, the acid scavenger is at least one selected from the group consisting of caustic soda (lye), calcium carbonate, and sodium acetate.
DETAILED DESCRIPTION
The present disclosure relates to a process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid.
Embodiments, of the present disclosure, will now be described herein. Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
Chlorantraniliprole is a broad-spectrum anthranilic diamide insecticide. Chlorantraniliprole, when consumed by insects, it interrupts normal muscle contraction, resulting in the death of the insects. The structural formula for Chlorantraniliprole is given below.

(I)
2-amino-5-chloro-3-methylbenzoic acid is an important intermediate used in the production of Chlorantraniliprole.
Conventional methods for the preparation of 2-amino-5-chloro-3-methylbenzoic acid involve multiple steps, a high amount of fluid medium, and require high temperatures. The known methods employ chlorinating agents and solvents that are water-miscible and, as a result, cannot be recovered, resulting in the loss of chlorinating agents and solvents. Moreover, known processes are associated with drawbacks such as impurities and low yield of the product. Such methods require further purification and are not economical. The impurities in the final product may affect the efficacy, safety, and stability of the final formulation. The yield/productivity of 2-amino-5-chloro-3-methylbenzoic acid obtained from the known processes is considerably low.
The present disclosure provides an improved process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid.
The process of the present disclosure is simple, environment friendly, economical, results in improved yield and higher purity of 2-amino-5-chloro-3-methylbenzoic acid, and is commercially scalable.
In an aspect of the present disclosure, there is provided a process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid.
In an embodiment of the present disclosure, the process for preparing 2-amino-5-chloro-3-methylbenzoic acid comprises chlorinating 2-amino-3-methylbenzoic acid (AMBA) by using a chlorinating agent in at least one fluid medium at a predetermined temperature to obtain 2-amino-5-chloro-3-methylbenzoic acid (ACMBA).
In an embodiment of the present disclosure, the fluid medium is at least one selected from the group consisting of ethylene dichloride (EDC), methylene dichloride (MDC), acetic acid, dimethylformamide (DMF), and monochlorobenzene (MCB). In an exemplary embodiment of the present disclosure, the fluid medium is ethylene dichloride (EDC). In another exemplary embodiment of the present disclosure, the fluid medium is methylene dichloride (MDC). In yet another exemplary embodiment of the present disclosure, the fluid medium is acetic acid.
In an embodiment of the present disclosure, the first predetermined temperature is in the range of 10°C to 80°C.
In an embodiment of the present disclosure, the chlorinating agent is at least one selected from the group consisting of chlorine, N-chlorosuccinimide, sulfuryl chloride, cyanuric chloride, and 1,3-dichloro-5,5-dimethylhydantoin. In an exemplary embodiment, the chlorinating agent is chlorine.
In an embodiment of the present disclosure, the chlorinating agent is chlorine gas.
In an embodiment of the present disclosure, the process of chlorination is carried out by using at least one additive.
In an embodiment of the present disclosure, the additive is at least one selected from the group consisting of a catalyst and an acid scavenger.
In an embodiment of the present disclosure, the catalyst is at least one selected from the group consisting of iron powder, ferric chloride, iodine, and ferrocene. In an exemplary embodiment of the present disclosure, the catalyst is ferric chloride. In another exemplary embodiment of the present disclosure, the catalyst is ferrocene. In yet another exemplary embodiment of the present disclosure, the catalyst is iodine. In still another exemplary embodiment of the present disclosure, the catalyst is iron powder.
In an embodiment of the present disclosure, the acid scavenger is at least one selected from the group consisting of caustic soda (lye), calcium carbonate, and sodium acetate. In an exemplary embodiment of the present disclosure, the acid scavenger is caustic soda (lye). In another exemplary embodiment of the present disclosure, the acid scavenger is calcium carbonate.
The acid scavengers such as caustic soda react with acetic acid to form sodium acetate which reacts with HCl generated during chlorination resulting in the formation of sodium chloride and acetic acid. Sodium acetate and calcium carbonate also work similarly.
In an embodiment of the present disclosure, the mole ratio of 2-amino-3-methylbenzoic acid to said chlorinating agent is in the range of 1:1 to 1:4.
In another embodiment of the present disclosure, the mole ratio of 2-amino-3-methylbenzoic acid to the chlorinating agent is in the range of 1:1 to 1:3.
In yet another embodiment of the present disclosure, the mole ratio of 2-amino-3-methylbenzoic acid to the chlorinating agent is in the range of 1:1 to 1:2.
A schematic representation for the preparation of ACMBA is given as scheme A.

Scheme A
In an embodiment of the present disclosure, 2-amino-5-chloro-3-methylbenzoic acid can have a purity of >93%.
In another embodiment of the present disclosure, 2-amino-5-chloro-3-methylbenzoic acid can have a purity of >95%.
In yet another embodiment of the present disclosure, 2-amino-5-chloro-3-methylbenzoic acid can have a purity of >99%.
Further, the chlorine gas and fluid medium are immiscible in water, hence the fluid medium is recovered and reused.
In an embodiment of the present disclosure, the yield and the purity of the 2-amino-5-chloro-3-methylbenzoic acid are critically dependent on the choice of fluid medium, temperature, and additives.
The present disclosure provides a simple and economical process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA) with a comparatively higher yield and better purity.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments are scalable to industrial/commercial process.
EXPERIMENTAL DETAILS
EXPERIMENT 1: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
500 ml of ethylene dichloride (EDC) was charged into a reactor followed by adding 152 gm (~ 1 mole) of 2-amino-3-methylbenzoic acid (AMBA) and heated to 60°C under stirring for 60 min to obtain a first mixture. To the first mixture, 1.89 mole/mole of chlorine gas was passed below the surface to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
To the second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid, 100 ml of fresh EDC was added followed by distillation at 58°C to 60°C to remove 95 ml of distillate under vacuum to obtain a third mixture. The distillation process helps to remove traces of HCl and chlorine from the second mixture. The third mixture was cooled to 28°C under stirring to obtain a fourth mixture. The fourth mixture was filtered to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 50 ml (each) of ethylene dichloride to obtain a second wet cake (459 gm). The second wet cake was slurried in 500 ml of water under stirring at 32°C for 30 min to obtain a slurry. The slurry was filtered to obtain a third wet cake. The third wet cake was washed twice with 70 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (Crop-I) was 152 gm and the HPLC purity was 97.2%.
EXPERIMENT 2: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA) - Recycle of EDC filtrate
130 ml of ethylene dichloride (EDC) and 370 ml of a mixture of the filtrate and the wash from Experiment 1 were charged into a reactor followed by adding 152 gm (~ 1 mole) of 2-amino-3-methylbenzoic acid (AMBA) and heated to 60°C under stirring for 60 min to obtain a first mixture. To the first mixture, 1.78 mole/mole of chlorine gas was passed below the surface to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was cooled to 28°C under stirring to obtain a third mixture. The third mixture was filtered to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 50 ml (each) of ethylene dichloride to obtain a second wet cake (432 gm). The second wet cake was slurried in 500 ml of water under stirring at 30°C for 30 min to obtain a slurry. The slurry was filtered to obtain a third wet cake. The third wet cake was washed twice with 70 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 162 gm and the HPLC purity was 96.4%.
EXPERIMENT 3: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
750 ml of ethylene dichloride (EDC) was charged into a reactor followed by adding 151 gm (~ 1 mole) of 2-amino-3-methylbenzoic acid (AMBA) and heated to 30°C under stirring for 5 minutes to obtain a first mixture. To the first mixture, 1.41 mole/mole of chlorine gas was passed below the surface at 30°C under stirring to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The so obtained second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was heated at 78°C for 1 hour to obtain a third mixture. The third mixture was cooled to 30°C under stirring to obtain a fourth mixture. The fourth mixture was filtered to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 100 ml (each) of ethylene dichloride to obtain a second wet cake. The second wet cake was slurried in 500 ml of water under stirring at 29°C to obtain a slurry. The slurry was filtered to obtain a third wet cake. The third wet cake was washed twice with 200 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 141 gm and the purity was 96.8%.
EXPERIMENT 4: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
750 ml of ethylene dichloride (EDC) was charged into a reactor followed by adding 151 gm (~ 1 mole) of 2-amino-3-methylbenzoic acid (AMBA) and heated to 73°C under stirring for 60 minutes to obtain a first mixture. To the first mixture, 1.86 mole/mole of chlorine gas was passed below the surface at 73°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The so obtained second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was cooled to 60°C followed by adding 100 ml of water and maintained at 68°C for 15 minutes to obtain a third mixture. The third mixture was filtered to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 50 ml (each) of ethylene dichloride to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 183 gm and the HPLC purity was 94%.
EXPERIMENT 5: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
375 ml of ethylene dichloride (EDC) was charged into a reactor followed by adding 75.6 gm (~ 0.5 mole) of 2-amino-3-methylbenzoic acid (AMBA), 1 gm of ferric chloride, 0.125 gm of iodine and heated to 43°C under stirring for 30 minutes to obtain a first mixture. To the first mixture, 1.35 mole/mole of chlorine gas was passed below the surface at 43°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
Maintaining the temperature at 43°C, 200 ml of water was added to the second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid under stirring to obtain a third mixture. The third mixture was filtered to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 50 ml (each) of ethylene dichloride and washed twice with 50 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 72 gm and the HPLC purity was 96.7%.
EXPERIMENT 6: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
750 ml of ethylene dichloride (EDC) was charged into a reactor followed by adding 227 gm (~ 1.5 mole) of 2-amino-3-methylbenzoic acid (AMBA), 3 gm of ferric chloride, 0.37 gm of iodine and heated to 43°C under stirring for 50 min to 60 min to obtain a first mixture. To the first mixture, 1.6 mole/mole of chlorine gas was passed below the surface at 43°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. While passing the chlorine gas the reaction mass became unstirrable, hence added 150 ml of ethylene dichloride (EDC). The reaction was monitored by HPLC.
Workup:
The so obtained second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was drowned in 600 ml of water and heated to 73°C and equilibrated for 1 hour to obtain a third mixture. The third mixture was filtered at 70°C to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 100 ml (each) of ethylene dichloride and washed twice with 100 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 214 gm and the HPLC purity was 97.3%.
EXPERIMENT 7: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
500 ml of ethylene dichloride (EDC) was charged into a reactor followed by adding 155 gm (~ 1 mole) of 2-amino-3-methylbenzoic acid (AMBA), 0.1 gm of ferrocene and heated to 43°C under stirring for 60 min to obtain a first mixture. To the first mixture, 1.57 mole/mole of chlorine gas was passed below the surface at 43°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The so obtained second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was mixed with 400 ml of water and heated to 43°C followed by heating at 73°C for 1 hour to obtain a third mixture. The third mixture was filtered to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 50 ml (each) of ethylene dichloride and washed twice with 50 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 136 gm and the HPLC purity was 98.88%.
EXPERIMENT 8: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
300 ml of methylene dichloride (MDC) was charged into a reactor followed by adding 76 gm (~ 0.5 mole) of 2-amino-3-methylbenzoic acid (AMBA) to obtain a first mixture. To the first mixture, 1.96 mole/mole of chlorine gas was passed below the surface at 53°C, to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was filtered to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 100 ml (each) of methylene dichloride to obtain a second wet cake (91 gm). The second wet cake was slurried in 350 ml of water under stirring at 30°C for 1 hr to obtain a slurry. The slurry was filtered to obtain a third wet cake. The third wet cake was washed twice with 100 ml (each) of water to obtain 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 71 gm and the HPLC purity was 98%.
EXPERIMENT 9: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
500 ml of acetic acid was charged into a reactor followed by adding 151 gm (~ 1 mole) of 2-amino-3-methylbenzoic acid (AMBA) and stirred at 30°C for 5 minutes to obtain a first mixture. To the first mixture, 1.9 mole/mole of chlorine gas was passed below the surface at 30°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was filtered to obtain a first wet cake and a filtrate. The so obtained first wet cake was washed twice with 50 ml (each) of acetic acid to obtain a second wet cake. The second wet cake was slurried in 500 ml of water under stirring at 30°C for 30 minutes to obtain a slurry. The slurry was filtered to obtain a third wet cake. The third wet cake was washed twice with 50 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 116 gm and the HPLC purity was 98%.
EXPERIMENT 10: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
375 ml of acetic acid was charged into a reactor followed by adding 35 ml of 18N Caustic lye and heated to 29°C under stirring for 30 minutes to obtain a first mixture. The first mixture was further stirred for 15 minutes and 76.5 gm (~ 0.5 mole) of 2-amino-3-methylbenzoic acid (AMBA) was added to obtain a second mixture. To the second mixture, 1.3 mole/mole of chlorine gas was passed below the surface at 33°C to obtain a third mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The so obtained third mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was distilled at 78°C under vacuum to remove 320 ml of distillate to obtain a fourth mixture. The fourth mixture was slurried in 1000 ml of water under stirring at 28°C for 1 hour to obtain a slurry. The slurry was filtered to obtain a third wet cake. The third wet cake was washed twice with 100 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid (crop-I).
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 79 gm and purity was 97%.
EXPERIMENT 11: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
500 ml of dimethylformamide was charged into a reactor followed by adding 151 gm (~ 1 mole) of 2-amino-3-methylbenzoic acid (AMBA) to obtain a first mixture. To the first mixture, 1.69 mole/mole of chlorine gas was passed below the surface at 33°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was cooled to 28°C for 30 minutes under stirring to obtain a third mixture. The third mixture was filtered to obtain a first wet cake and a first filtrate. The so obtained first wet cake was washed twice with 20 ml (each) of dimethylformamide to obtain 2-amino-5-chloro-3-methylbenzoic acid (122 gm) (crop-I; HPLC purity = 92.85%) and a second filtrate.
The first filtrate and the second filtrate were mixed and concentrated followed by slurrying in 1000 ml of water under stirring to obtain a slurry. The slurry was filtered to obtain a third wet cake. The third wet cake was filtered to obtain the 2-amino-5-chloro-3-methylbenzoic acid (111 gm) (crop-II; HPLC purity = 77.65%).
The so obtained 2-amino-5-chloro-3-methylbenzoic acid (crop-I and crop-II) was mixed with 480 ml 2.5N NaOH solution to obtain a mixture. The mixture was heated at 60°C for 30 minutes to obtain a heated mixture. The so obtained heated mixture was filtered through hyflo bed to obtain a filtrate. The hyflo bed was washed twice with 50 ml (each) of water to obtain a wash. The filtrate and wash were mixed with 1.05 m/m 5N HCl solutions to obtain a reaction mass. The reaction mass was heated at 60°C under stirring for 1 hour to obtain a slurry. The so obtained slurry was filtered to obtain a wet cake. The wet cake was washed twice with 70 ml (each) of water to obtain the purified 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid was 148 gm and the HPLC purity was 95%.
EXPERIMENT 12: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
500 ml of monochlorobenzene (MCB) was charged into a reactor followed by adding 75.6 gm (~ 0.5 mole) of 2-amino-3-methylbenzoic acid (AMBA) and heated to 43°C under stirring for 30 minutes to obtain a first mixture. To the first mixture, 1.68 mole/mole of chlorine gas was passed below the surface at 43°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was heated at 75°C for 1 hour to obtain a third mixture. The third mixture was cooled to 30°C to obtain a fourth mixture. The fourth mixture was filtered to obtain a wet cake. The wet cake was washed twice with 50 ml (each) of monochlorobenzene to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 80 gm and the HPLC purity was 94%.
EXPERIMENT 13: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
500 ml of monochlorobenzene (MCB) was charged into a reactor followed by adding 75.6 gm (~ 0.5 mole) of 2-amino-3-methylbenzoic acid (AMBA) and 50 gm of calcium carbonate and heated to 43°C under stirring for 40 minutes to obtain a first mixture. To the first mixture, 1.8 mole/mole of chlorine gas was passed below the surface at 43°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was mixed with 300 ml of water and heated at 78°C to obtain a slurry. The so obtained wet slurry was filtered to obtain a wet cake. The wet cake was washed twice with 100 ml (each) of monochlorobenzene and twice with 100 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid (crop-I).
The so obtained 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was mixed with 240 ml of 2.5N NaOH solution at 60°C to obtain a mixture. The mixture was maintained at 60°C for 30 minutes to obtain a heated mixture. The so obtained heated mixture was filtered to obtain a wet cake and a filtrate. The wet cake was washed twice with 50 ml (each) of water to obtain a washed wet cake and a second filtrate. The second filtrate was mixed with 2.5N HCl at 60°C till the pH of the filtrate reaches 2 to obtain a slurry. The slurry was filtered to obtain a resultant wet cake. The resultant wet cake was washed twice with 50 ml (each) of water to obtain the purified 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid was 44 gm and the HPLC purity was 96.5%.
EXPERIMENT 14: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
500 ml of monochlorobenzene (MCB) was charged into a reactor followed by adding 75.6 gm (~ 0.5 mole) of 2-amino-3-methylbenzoic acid (AMBA) and heated to 73°C under stirring for 30 min to 40 min to obtain a first mixture. To the first mixture, 1.575 mole/mole of chlorine gas was passed below the surface at 43°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.

Workup:
The second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was cooled to 43°C and mixed with 250 ml of water under stirring to obtain a third mixture. The third mixture was heated at 73°C for 1 hour under stirring to obtain a slurry. The slurry was filtered to obtain a wet cake. The wet cake was washed twice with 50 ml (each) of monochlorobenzene and washed twice with 50 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (Crop-I) was 71 gm and the HPLC purity was 98%.
EXPERIMENT 15: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
750 ml of ethylene dichloride (EDC) was charged into a reactor followed by adding 151 gm (~ 1 mole) of 2-amino-3-methylbenzoic acid (AMBA), 2 gm of iron powder, 0.2 gm of iodine, and heated to 43°C under stirring for 15 min to 20 min to obtain a first mixture. To the first mixture, 1.52 mole/mole of chlorine gas was passed below the surface at 43°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The so obtained second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was drowned in 400 ml of water and heated to 75°C and equilibrated for 1 hour at 73°C to obtain a third mixture. The third mixture was filtered at 70°C to obtain a wet cake and a filtrate. The so obtained wet cake was washed twice with 100 ml (each) of ethylene dichloride and washed twice with 100 ml (each) of water to obtain the 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 137 gm and the HPLC purity was 97.47%.
EXPERIMENT 16: Preparation of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
3000 ml of monochlorobenzene (MCB) was charged into a reactor followed by adding 302 gm (~ 2 moles) of 2-amino-3-methylbenzoic acid (AMBA) to obtain a first mixture. The first mixture was cooled to 18°C to obtain a cooled first mixture. To the cooled first mixture, 1.945 mole/mole of chlorine gas was passed below the surface at 43°C to obtain a second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid. The reaction was monitored by HPLC.
Workup:
The so obtained second mixture comprising 2-amino-5-chloro-3-methylbenzoic acid was mixed with 2000 ml of NaOH solution (10%) under stirring to obtain a third mixture with alkaline pH. The third mixture was heated to 50°C, followed by equilibrated for 1 hr at 53°C to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer. The first organic layer was mixed with 400 ml of water to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The so obtained second organic layer was concentrated to obtain a concentrated mass (60gm).
The first aqueous layer and the second aqueous layer were mixed, followed by acidification by adding 630 ml of H2SO4 (5N) at 60°C for 1 hr to obtain a fourth mixture. The fourth mixture was equilibrated for 1 hr at 60°C to obtain a slurry. The so obtained slurry was filtered to obtain a first wet cake. The first wet cake was washed twice with 250 ml (each) of water and suck dried to obtain a second wet cake. The second wet cake was re-slurried in 1000 ml of water, heated to 68°C for 1 hour followed by filtration to obtain a third wet cake. The so obtained third wet cake was washed with hot water and dried to obtain 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (crop-I) was 301 gm, the HPLC purity was 99.3% and the yield on purity was 80.5%.
Experiments 1 through 16 demonstrate that optimizing the quantity of the fluid medium, in combination with temperature and additives, results in achieving a purity of more than 94%. The majority of the fluid media used in the present disclosure are immiscible with water and hence can be recovered appropriately and reused thereby making the process economic and environment friendly.
Moreover, HCL gas is generated during the formation of ACMBA, therefore additives such as CS lye or calcium carbonate were used to form a salt effluent thereby making the process environment friendly.
EXPERIMENT 17: Purification of 2-amino-5-chloro-3-methylbenzoic acid (ACMBA)
636 gm of 2-amino-5-chloro-3-methylbenzoic acid (94.8% purity) was mixed with 1908 ml (3 ml/gram) of acetic acid to obtain a mixture. The mixture was heated at 78°C and maintained for 1 hour to obtain a heated mixture. The heated mixture was cooled to 35°C to obtain a cooled mixture. The cooled mixture was filtered to obtain a wet cake. The cake was washed twice with 100 ml (each) of acetic acid to obtain a washed wet cake. The washed wet cake was mixed with 100 ml of water and stirred for 30 min to obtain a slurry. The slurry was filtered to obtain a third wet cake. The third wet cake was washed twice with 200 ml (each) of water to obtain the purified 2-amino-5-chloro-3-methylbenzoic acid.
The yield of 2-amino-5-chloro-3-methylbenzoic acid (Crop-I) was 470 gm and the HPLC purity was 98.24%.
TECHNICAL ADVANCEMENT
The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of 2-amino-5-chloro-3-methylbenzoic acid that
• uses less amount of a solvent, hence economical;
• proceeds under mild reaction conditions;
• is simple and environment friendly; and
• provides 2-amino-5-chloro-3-methylbenzoic acid having comparatively high purity and high yield.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
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 invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.
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 given for various physical parameters, dimensions, and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions, and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment 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.
,CLAIMS:WE CLAIM:
1. A process for preparing 2-amino-5-chloro-3-methylbenzoic acid, said process comprising chlorinating 2-amino-3-methylbenzoic acid (AMBA) by using a chlorinating agent in at least one fluid medium at a predetermined temperature to obtain 2-amino-5-chloro-3-methylbenzoic acid (ACMBA).
2. The process as claimed in claim 1, wherein said chlorination is carried out by using at least one additive.
3. The process as claimed in claim 1, wherein said fluid medium is at least one selected from the group consisting of ethylene dichloride (EDC), methylene dichloride (MDC), acetic acid, dimethylformamide (DMF), and monochlorobenzene (MCB).
4. The process as claimed in claim 1, wherein said predetermined temperature is in the range of 10°C to 80°C.
5. The process as claimed in claim 1, wherein said chlorinating agent is at least one selected from the group consisting of chlorine, N-chlorosuccinimide, sulfuryl chloride, cyanuric chloride, and 1,3-dichloro-5,5-dimethylhydantoin.
6. The process as claimed in claim 1, wherein said chlorinating agent is chlorine gas.
7. The process as claimed in claim 1, wherein a mole ratio of 2-amino-3-methylbenzoic acid to said chlorinating agent is in the range of 1:1 to 1:4.
8. The process as claimed in claim 1, wherein a mole ratio of 2-amino-3-methylbenzoic acid to said chlorinating agent is in the range of 1:1 to 1:3.
9. The process as claimed in claim 1, wherein a mole ratio of 2-amino-3-methylbenzoic acid to said chlorinating agent is in the range of 1:1 to 1:2.
10. The process as claimed in claim 2, wherein said additive is at least one selected from the group consisting of a catalyst, and an acid scavenging agent.
11. The process as claimed in claim 10, wherein said catalyst is at least one selected from the group consisting of iron powder, ferric chloride, iodine, and ferrocene.
12. The process as claimed in claim 10, wherein said acid scavenging agent is at least one selected from the group consisting of caustic soda (lye), calcium carbonate, and sodium acetate.

Dated this 15th Day of November, 2023

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
of R.K. DEWAN & CO.
Authorized Agent of Applicant

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, AT MUMBAI