Description:IMPROVED BATCH PROCESS FOR THE PREPARATION OF (2R)-2-[4-[(6-CHLORO-1, 3-BENZOXAZOL-2-YL) OXY] PHENOXY]-N-(2-FLUOROPHENYL)-N-METHYLPROPANAMIDE

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of (2R)-2-[4-[(6-chloro-2-benzoxazolyl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

BACKGROUND OF THE INVENTION

2-[4-[(6-chloro-2-benzoxazolyl) oxy] phenoxy]-N—(2-fluorophenyl)-N-methyl propanamide is an aryloxy phenoxy propionate (APP) herbicide that inhibits the activity of acetyl-CoA carboxylase (ACCase) of sensitive weeds and a post-emergence herbicide which exhibits high control efficacy against sensitive weeds. The aryloxyphenoxypropionate (AOPP) post-emergence herbicide shows an exclusive whole plant safety to rice with a high control efficacy to annual grass weeds, especially barnyard grass.

The conventional process for preparing 2-[4-[(6-chloro-2-benzoxazolyl) oxy] phenoxy]-N—(2-fluorophenyl)-N-methyl propanamide have inherent complexities and changes. The process are usually four, two or one-step reactions. One-step reactions often employ hazardous chemicals such as tetrahydrofuran (THF), phosphorous-based hydrocarbons, and carbon tetrachloride (CCl4), which pose risks due to their toxicity. Further, owing to the similar boiling points of CCl4 and THF solvent recovery, it is complex, expensive, and difficult to scale. Two-step processes typically utilize solvents which contribute to higher effluent loads and increased solvent recovery and complicate the waste management processes. Four-step reactions often begin with the formation of R-HPPI and proceed to generate sodium salt of R-HPPA, further complicating the synthesis.

Additionally, some processes utilize sodium hydride (NaH) as an acid-binding agent. NaH is a notably unstable and highly exothermic agent, posing significant hazards at a commercial scale, necessitating stringent temperature control measures, such as the application of chilled brine at -35°C. Other methods require sodium hydroxide combined with methyl iodide to facilitate nucleophilic substitution reactions, which are costly and challenging to handle, especially at a commercial scale, due to its serious environmental and health hazards. The synthesis often involves the formation of intermediate compounds like chloro-2-sulfhydryl-benzoxazoles and bis-(trichloromethyl) carbonic esters, using catalysts like N, N-dimethylformamide. These processes, which may also involve four steps and ammonium-based catalysts, typically result in wastewater high in ammoniacal nitrogen, presenting significant treatment challenges.

Moreover, other known processes disclose crystallization techniques for 2-[4-[(6-chloro-2-benzoxazolyl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methyl propanamide in various solvents or require large volumes of a solvent such as chlorobenzene. These pose a challenge for large-scale production, leading to increased costs and a substantial adverse environmental impact. Additionally, the conventional process often overlooks the critical step of separating organic and aqueous layers using methylene dichloride, essential for efficient solvent recovery and waste minimisation.

CN113717123B discloses a one-step process involving the addition of (R)-2-(4-hydroxyphenoxy)propionic acid-N-(2-fluorophenyl)-N-methylamide to an alkaline solution, followed by the introduction of 2,6-dichlorobenzoxazole and a phase transfer catalyst to obtain 2-[4-[(6-chloro-2-benzoxazolyl) oxy]phenoxy]-N—(2-fluorophenyl)-N-methyl propanamide.

Accordingly, to overcome the drawbacks of the existing processes, there is a need for a novel process that achieves high yields and high quality in the preparation of 2-[4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenoxy]-N—(2-fluorophenyl)-N-methylpropanamide that is both environmentally friendly and economically viable is required. Thus, the present invention relates to a cost-effective and green process for synthesizing 2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methyl propanamide, which also provides high purity and good commercial yield.
OBJECTIVES OF THE INVENTION
The primary objective of the present invention is to provide a novel process for the preparation of (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N—(2-fluorophenyl)-N-methyl propanamide.

Another objective of the present invention is to provide a process that reduces the effluent load and environmental impact.
Another objective of the present invention is to provide a process with a mild base, mitigate side reactions and simplify temperature control.

Another objective of the present invention is to provide a process with improved purity and yield.

Yet another objective of the present invention is to provide a cost-effective and environmentally friendly process.

SUMMAY OF THE INVENTION
Accordingly, the present invention provides a novel process for the preparation of metamifop i.e., (2R)-2-[4-[(6-chloro-2-benzoxazolyl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methyl propanamide comprising the steps of:
a. reacting a compound of formula I or formula I’
formula I

or

formula I’
with a compound of formula II

in the presence of base in a solvent to provide a compound of formula III

b. acylating the compound of formula III with an agent in chlorinated hydrocarbons to form a compound of formula IV
c. reacting compound of formula IV with a compound of formula V
in presence of solvent, base, and chlorinated hydrocarbons to provide (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

In another aspect of the present invention, wherein the base used in step a) and step c) is selected from a group consisting of sodium carbonate, sodium methoxide, triethylamine, potassium carbonate and sodium bicarbonate.

In another aspect of the present invention, the solvent used in step a) is selected from acetonitrile, water, C1-C7 alcohol, C5-C7 hydrocarbon or any combination thereof, and the temperature of step c) is in the range of 5 to 20?.

In another aspect of the present invention, the agent of step b) is selected from group comprising of thionyl chloride, oxalyl chloride, phosphorous oxy chloride, phosphorous oxybromide, phosphorous pentachloride, and phosphorus trichloride.

In another aspect of the present invention, the chlorinated hydrocarbon of step b) and step c) is selected from the group comprising ethylene dichloride, methylene dichloride, methanol, C1-C7 alcohol, C5-C7 hydrocarbon or any combination thereof, and the solvent is dimethyl formamide.

In further aspect of the present invention, the temperature used in step c) is in a range of 5 to 20?.

In another aspect of the present invention, the purity of (2R)-2-[4-[(6-chloro-2-benzoxazolyl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide is at least 95%.

In another aspect, the process of preparation comprises of:
a. reacting a compound of formula I’

with a compound of formula II

in the presence of sodium carbonate in acetonitrile/water at a temperature in the range of 60 to 70 ? to provide a compound of formula III

b. acylating the compound of formula III with thionyl chloride
in presence of ethylene dichloride, dimethylformamide at temperature in the range of 55 to 60? to form a compound of formula IV

c. reacting compound of formula IV with a compound of formula V

in presence of solvent, base, and chlorinated hydrocarbons to provide (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

In yet another aspect, the process of preparation comprises the steps of:
a. reacting a compound of formula I

with a compound of formula II

in the presence of sodium carbonate in acetonitrile/water at a temperature in the range of 60 to 70? to provide a compound of formula III

b. acylating the compound of formula III with thionyl chloride
in presence of ethylene dichloride, dimethylformamide at a temperature in the range of 55 to 60? to form a compound of formula IV

c. reacting compound of formula IV with a compound of formula V

in the presence of solvent, base, and chlorinated hydrocarbons to provide (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

BRIEF DESCRIPTION OF DRAWINGS

Figure. 1 illustrates the HPLC Chromatogram of one batch for preparation of (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methyl propanamide with high purity.

DETAILED DESCRIPTION OF THE INVENTION
Those skilled in the art will be aware that the invention described herein is subject to variations and modifications other than those specifically described. It is to be understood that the invention described herein includes all such variations and modifications. The invention also includes all such steps, features, and methods referred to or indicated in this specification, individually or collectively, as well as any and all combinations of any two or more said steps or features.

Definitions:
For convenience, before further description of the present invention, examples of certain terms employed in the specification are described here. These definitions should be read in light of the remainder of the disclosure and understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. The terms used throughout this specification are defined as follows unless otherwise limited in specific instances.

The terms used herein are defined as follows.

As used in the specification and the claims, the singular forms “a”, “an”, and “the” include plural referents unless the context dictates otherwise.

The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only.

The term “purity” means purity as determined by HPLC (“High Pressure Liquid Chromatography”).

The term “about” shall be interpreted to mean “approximately” or “reasonably close to” and any statistically insignificant variations therefrom.

As used herein, the terms “comprising”, “including”, “having”, “containing”, “involving”, and the like are to be understood to be open-ended, i.e., to mean including but not limited to.

The terms “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits under certain circumstances. In an embodiment, the aspects and embodiments described herein shall also be interpreted to replace the clause “comprising” with either “consisting of” or with “consisting essentially of” or with “consisting substantially of”.

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.

The present invention aims to provide a batch process for the preparation of (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methyl propanamide.
The process for preparation of (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methyl propanamide comprises the step of:
a. reacting a compound of formula I or formula I’
formula I
or

formula I’
with a compound of formula II

in the presence of base in a solvent to provide a compound of formula III

b. acylating the compound of formula III with an agent in chlorinated hydrocarbons to form a compound of formula IV

c. reacting compound of IV with a compound of formula V
in the presence of solvent, base, and chlorinated hydrocarbons to provide (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

In an embodiment of the present invention, the base or mild base is selected from a group comprising of sodium carbonate, sodium methoxide, triethylamine, potassium carbonate, sodium bicarbonate or any combination thereof. The base/mild base helps to control other side reactions and leads to high yield.

In another embodiment, the solvent and chlorinated hydrocarbon are selected from a group comprising of acetonitrile, ethylene dichloride, methylene dichloride, dimethyl formamide, methanol, water, C1-C7 alcohol, C5-C7 hydrocarbon or any combination thereof.

In another embodiment, the agent/acylating agent is selected from a group comprising thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous oxybromide, phosphorous pentachloride, Phosphorous trichloride or any combination thereof.

In another embodiment, the temperature of steps a) and c) ranges from 25 to 70? and 5 to 20?.

The process of the present disclosure is simple and efficient and provides (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy]phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide in a high yield, and with a high purity. The process may be carried out by using a continuous flow reactor to reduce the residence time of the product exposure to a higher temperature to prevent the quality deterioration of (R)-2-[4-(6-chloro-2-benzoxazolyl oxy phenoxy] propanoyl chloride and improve the quality. Therefore, the process of the present disclosure is environment friendly.

The exemplary processes are described in the following schemes:

SCHEME-1
Step-1

+

=

6-chloro-2-benzoxazolinone 2-(4-Hydroxyphenoxy) propionic acid 2-{4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenoxy}propanoic acid)

+

2-[4-[(6-chloro-2-benzoxazolyl)oxy]phenoxy]propionic acid oxalyl chloride (R)-2-[4-(6-chloro-2-benzoxazoyloxy)-phenoxy]propionicacid chloride

+

=

(2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide 2-fluoro-N-methylaniline

SCHEME-2

Step-1

+
sodium carbonate

acetonitrile/water
2,6-dichloro-1,3-benzoxazole 2-(4-hydroxyphenoxy)propanoic acid ((R)-2-{4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenoxy}propanoic acid)

Step-2
or

Acylation

((R)-2-{4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenoxy}propanoic acid) thionyl chloride
or oxalyl chloride (R)-2[(4-(6-Chloro-2-benzoxazolyl)oxy phenoxy] propanoyl chloride

Step-3

+

Condensation

(R)-2[(4-(6-Chloro-2-benzoxazolyl)oxy phenoxy] propanoyl chloride 2-fluoro-N-methylaniline (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide

In an embodiment, the present invention provides a process for the preparation of (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide, comprising the steps of:

a. reacting a compound of formula I

with a compound of formula II

in the presence of a sodium carbonate, acetonitrile/water at a temperature in the range of 25 to 70? to provide a compound of formula III

b. acylating the compound of formula III

with oxalyl chloride
in the presence of methylene dichloride, N, N-dimethylformamide at a temperature in a range of 25-60? to form a compound of formula IV.

c. reacting the compound of formula IV with a compound of formula V
in presence of ethylene dichloride, sodium bicarbonate, methanol at 8-10°C to obtain (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

In another embodiment of the present invention, the process for the preparation of (2R)2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methyl propanamide, comprising the steps of:
a. reacting a compound of formula I

with a compound of formula II

in the presence of a sodium carbonate, acetonitrile/water at a temperature in the range of 25 to 70? to provide a compound of formula III

b. acylating the compound of formula III

with thionyl chloride
in the presence of methylene dichloride, N, N-dimethylformamide at temperature in a range of 25-70? to form a compound of formula IV
c. reacting the compound of formula IV with a compound of formula V

in the presence of ethylene dichloride, sodium bicarbonate, methanol at 8-10°C to obtain a (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

In an embodiment of the present invention, the purity of (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide obtained is in the range of 95 to 99%.

In another preferred embodiment of the present invention, the agent is selected from thionyl chloride, oxalyl chloride, and phosphorous oxychloride. More preferably from thionyl chloride and oxalyl chloride.

In a preferred embodiment of the present invention, steps b) and c) are continuous reactions.

In another embodiment, the present invention provides an alternative process for the preparation of (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide, comprising the steps of:

Step 1: (R)-2[(4-(6-Chloro-2-benzoxazolyl) oxy phenoxy] propanoyl chloride
Ethylene dichloride (EDC), (R)-2-{4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy} propanoic acid and DMF are charged in a reactor. Thionyl chloride is slowly added, the reaction mass is heated to 60? and maintained at 60-62? for about 6 – 7 hours. EDC and excess thionyl chloride are distilled to obtain (R)-2[(4-(6-Chloro-2-benzoxazolyl) oxy phenoxy] propanoyl chloride.

Step 2: (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide

To a solution of (R)-2[(4-(6-Chloro-2-benzoxazolyl) oxy phenoxy] propanoyl chloride in EDC, 2-Fluoro-N-Methyl aniline is added, followed by the addition of sodium bicarbonate. The reaction is carried out at 8-10? and maintained for about 8 hours. After the reaction, water is added, and the aqueous layer is separated. The organic layer is collected, and EDC is recovered to give an oily mass, which on crystallization with C1-C7 alcohol or C5-C7 hydrocarbon or mixture of both gives (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

EXAMPLES
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be constructed to limit the scope of the invention.

Exemplary amount of materials used in Step a)
S. No. Raw material Unit Quantity
1. (R)-(+)-2-(4-Hydroxyphenoxy) propionic acid gm/g 100.0
2. 2,6-Dichlorobenzoxazole gm/g 113.6
3. Sodium Carbonate gm/g 96
4. Acetonitrile ml 100
5. Water ml 600
6. Benzyl triethyl ammonium chloride gm/g 5
7. Methylene Dichloride (MDC) ml 200+100
8. 30% Hydrochloric acid gm/g 125

Exemplary amount of materials used in steps b) and c):
S. No. Raw material Unit Quantity M.W. Mole Mole ratio
1. (R)-2-[4-(6-Chloro-2-benzoxazolyl oxy phenoxy] propanoyl chloride gm/g 100 333.7 0.2996 1.000
2. Thionyl chloride gm/g 39.2 119 0.3294 1.0995
3. N, N-Dimethyl formamide gm/g 2 - - -
4. Methylene Dichloride (MDC)/ Ethylene dichloride (EDC) ml 500 - - -
5. 2-Fluoro-N-methyl aniline gm/g 34.8 125 0.8784 0.9292
6. Sodium bicarbonate gm/g 30 84 0.3571 1.1919

Example-I
Step a:
Preparation of (R)-2-[4-(6-Chloro-2-benzoxazolyl) oxy phenoxy] propionic acid (CBP)

Add 100g of (R)-(+)-2-(4-Hydroxyphenoxy) propionic acid, 600 ml of water, and stir at 25-30°C. Slowly add 32g of Sodium Carbonate while stirring at 25-30°C, then add 113.6 g of 2,6-dichloro-1,3-benzoxazole, 64g of Sodium Carbonate, and 100 ml of Acetonitrile with constant stirring at 25-30°C. Raise the mass temperature to 60-70°C and maintain it at 60-70°C for 6–10 hours until the reaction completion. Distil out acetonitrile and water under a vacuum at 45-60°C. Recover 150-200 ml of ACN and water under vacuum at 45-60°C. Cool the mass to 25-30°C, then add 200 ml of Dichloromethane (MDC) and stir for 30 minutes at 25-30°C. Allow the mixture to settle for layer separation, to separate the lower organic layer (MDC layer) at 25-30°C. Further, extract the aqueous layer 1 with 200 ml of MDC at 25-30°C. Distil out MDC under atmospheric distillation at 38 to 60°C. Cool the reaction mass to 50-55°C, adjust the pH to 4.0 - 4.45, and maintain the mass at 50-55°C for 30 minutes. Filter and dry, then add 500 ml of water to form a wet cake. Stir at 25-30°C for 1-2 hours, filter the slurry to form a wet cake, and dry the product at 60-70°C to obtain dried (R)-2-[4-(6-Chloro-2-benzoxazolyl) oxy phenoxy] propionic acid. Stir and maintain the reaction mass for 30 minutes at 25-30°C, settle for 1-2 hours, and separate the layers at 25-30°C. Separate the lower organic layer at 25-30°C. Take aqueous layer 2 in RBF and start the recovery of MDC at 40 to 65°C mass temperature. Adjust the aqueous layer pH to 4 - 4.5 with a 30% Hydrochloric acid solution (120g at 25-30°C in 1.5-2 hours). (Initial pH of the aqueous layer = 8.35; after 30% Hydrochloric acid solution pH = 4.27). Stir and maintain the reaction mass for 30 minutes at 25-30°C. Filter the slurry mass at 25-30°C under reduced pressure. The slurry wash of wet CBP in RBF: Take wet CBP in RBF and charge DI water 500.0ml at 50°C. Stir and maintain the reaction mass for 1-2 hours at 50°C. Filter the material at 50°C. Running wash of wet cake with DI water 100.0ml at 30 to 35°C, dry under vacuum for maximum ml pooling. Unload the wet cake CBP at RT/30°C. Wet weight CBP equals gram, dry the material at 70°C in a hot air oven for 12-15 hours until m/c <0.50%. Dry weight is equal to yield, yield is equal to w/w, and molar yield is equal to wrt R-HPPA to obtain Off-white to peach-colored powder (CBP) with a yield of 88-98%.

Step-b: Preparation of (R)-2[(4-(6-Chloro-2-benzoxazolyl) oxy) phenoxy] propanoyl chloride

Check the 2.0 L 4-neck RBF for cleanliness and dryness. Charge 500 ml of methylene dichloride into the RBF at room temperature (RT). Add 100g of CBP into the RBF at RT. Stir and maintain the reaction mass for 5 minutes at RT. Charge 2.0 g of N, N-Dimethyl formamide into the reaction mass at RT. Stir and maintain the reaction mass for 5 minutes at RT. Slowly add 47g of thionyl chloride into the reaction mass within 30 to 60 minutes at RT. Stir and slowly raise the reaction mass temperature to 39°C. Maintain the reaction mass at 39°C for 7 hours. Check HPLC for CBP, ensuring it's not more than 0.5%. Distil out the mixture of ethylene dichloride and thionyl chloride under vacuum at below 60°C. Degas the ethylene dichloride and thionyl chloride mixture under vacuum at below 60°C. Stir and cool the oily reaction mass to 45-50°C. Charge 200 ml of methylene dichloride into the reaction mass at 45-50°C. Stir and cool the reaction mass to RT in RBF-1.

Step-c:
Preparation of (2R)-2-[4-[(6-Chloro-2-benzoxazolyl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide

Charge 100 ml of methylene dichloride into the (Round Bottle Flask) RBF at RT. Add 35.14 g of 2-Fluoro-N-methylaniline into the RBF at RT. Slowly add 30.20 g of anhydrous sodium bicarbonate into the reaction mass within 5 minutes at RT. Stir and cool the reaction mass to 2 to 5°C. Slowly add the acid chloride mass (from RBF-1) into the mixed reaction mass (RBF-2) within 1 hour at 2 to 5°C. After complete addition, stir and raise the temperature of the reaction mass to 8 to 10°C. Maintain the reaction mass at 8 to 10°C until the reaction is complete (completes after 6.5 hours). Add 100 ml of 8% sodium bicarbonate solution and stir, maintaining the reaction mass for 30 minutes at RT. Charge 200 ml of DI water into the reaction mass at 34 to 36°C. Settle and separate layers. Collect the organic layers (methylene dichloride layer) at RT and discard the aqueous layer. Repeat the process by adding 100 ml of 8% sodium bicarbonate solution to the organic layer, stirring, and maintaining the reaction mass for 30 minutes at RT. Settle and separate layers, collect the organic layers at RT, and discard the aqueous layer. Add 100 ml of water to the organic layer, stir, and maintain the reaction mass for 30 minutes at RT. Settle and separate layers, discarding the aqueous layer at RT. Repeat the process by adding 100 ml of water to the organic layer, stirring, and maintaining the reaction mass for 30 minutes at RT. Settle and separate layers, collect the organic layers at RT, and discard the aqueous layer. Take the organic layers and distil out methylene dichloride under vacuum at below 50°C. Degas and remove traces of methylene dichloride under vacuum at below 50°C. The resulting viscous, sticky, oily mass should be reddish-brown below 50°C. Charge 300 ml of methyl alcohol into the oily reaction mass at below 50°C. Stir and check the clarity of the reaction mass at 40 to 50°C. Slowly cool the reaction mass to 20°C and slowly add 50 to 75 ml of water for crystallization. Charge 0.2 g of (R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide (seeding) into the reaction mass when solids begin to form. Stir and cool the reaction mass at 15 to 20°C. Maintain the reaction mass for 2 to 3 hours for complete crystallization at 15 to 20°C. Filter the material at 15 to 20°C, dry it, wash it with chilled methyl alcohol (50 ml at 15 to 20°C), dry it again, and unload the material at room temperature (RT). Dry the material at RT in the atmosphere to obtain the dried product (R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy] phenoxy] -n- (2-fluorophenyl) -n- methyl propanamide with a yield of 88-98%.

Example 2
Preparation of (2R)-2-[4-[(6-chloro-1, 3-benzoxazol-2-yl) oxy]phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide with the batch process using oxalyl chloride

Step I:
Preparation of (R)-2-[4-(6-Chloro-2-benzoxazolyl) oxy phenoxy] propionic acid (CBP)

1. Dissolving sodium hydroxide in water and cool the solution to 0°C.
2. Adding propionic acid in batches while stirring to form a salt solution.
3. Adding the salt solution of the above step to 2, 6-dichlorobenzoxazole dissolved in toluene.
4. Raise the temperature to 50°C, react for 3 hours, and then reflux for 1 hour.
5. Cool the reaction mixture to room temperature, separate the toluene layer, and acidify the water layer to pH 3-4 to precipitate the product.
6. Filter, wash, and dry the precipitate to obtain (R)-2-[4-(6-Chloro-2-benzoxazolyl) oxy phenoxy] propionic acid (CBP).
Step II
1. Dissolve CBP in dry 1, 2-dichloroethane.
2. Add N, N-Dimethyl formamide into the solution cooled to 5°C with an ice bath, followed by dropwise addition of oxalyl chloride.
3. Remove the ice bath and reflux the mixture for 2 hours, then distil under reduced pressure to remove excess oxalyl chloride and solvent.
4. Dissolve the obtained brown solid in dry 1, 2-dichloroethane.
5. Add 2-Fluoro-N-methylaniline and triethylamine into the reactor, cool to below 5°C, and add propionyl chloride solution dropwise.
6. React at room temperature for 2 hours, then raise the temperature and continue for 3 hours.
7. Wash the reaction mixture sequentially with dilute hydrochloric acid, saturated sodium carbonate solution, and brine.
8. Dry with anhydrous sodium sulfate and evaporate under reduced pressure to obtain the crude product.
9. Recrystallizing the crude product from methanol to obtain (2R)-2-[4-[(6-Chloro-2-benzoxazolyl) oxy] phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide as a light brown solid.

It is evident from the above process that the process of the present invention enhances layer separation and prevents/minimizes the formation of unwanted by-products. Thus, it eliminates the need for filtration units, thereby simplifying the process and making it scalable. The enhanced layer separation ensures that the organic and aqueous phases/layers are separated easily and leading to a simpler and faster process. Further, the process utilises solvents such as acetonitrile to remove impurities effectively and prevent the degradation of sensitive molecules such as benzoxazole, which may occur under the acidic and high-temperature conditions of the process.

Advantages of the present process:
• enhanced layer separation,
• effective impurity removal,
• minimization of molecule degradation,
• solvent optimization, and improved operational efficiency,
• sustainable, scalable, and cost-effective process, and
• high purity and high yield of the final product.

While considerable emphasis has been placed herein on the compounds and compounds 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.
, Claims:We Claim:
1. A process for the preparation of (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide, comprising the steps of:

a. reacting a compound of formula I or formula I’
formula I

or

formula I’
with a compound of formula II

in the presence of base in a solvent to provide a compound of formula III

b. acylating the compound of formula III with an agent in chlorinated hydrocarbons, and solvent to form a compound of formula IV
c. reacting compound of formula IV with a compound of formula V
in presence of solvent, base, and chlorinated hydrocarbons to provide (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

2. The process as claimed in claim 1, wherein the base used in step a) and step c) is selected from a group consisting of sodium carbonate, sodium methoxide, triethylamine, potassium carbonate and sodium bicarbonate.

3. The process as claimed in claim 1, wherein the solvent used in step a) is selected from acetonitrile, water, C1-C7 alcohol, C5-C7 hydrocarbon or any combination thereof.

4. The process as claimed in claim 1, wherein the temperature used in step a) is in the range of 25 to 70?.

5. The process as claimed in claim 1, wherein the agent of step b) is selected from group comprising of thionyl chloride, oxalyl chloride, phosphorous oxy chloride, phosphorous oxybromide, phosphorous pentachloride, and phosphorus trichloride.

6. The process as claimed in claim 1, wherein the chlorinated hydrocarbon of step b) and step c) is selected from the group comprising ethylene dichloride, methylene dichloride, methanol, C1-C7 alcohol, C5-C7 hydrocarbon or any combination thereof, and the solvent is dimethyl formamide.

7. The process as claimed in claim 1, wherein the temperature used in step c) is in a range of 5 to 20?.

8. The process as claimed in claim 1, wherein the purity of (2R)-2-[4-[(6-chloro-2-benzoxazolyl) oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide is at least 95%.

9. The process as claimed in claim 1, comprises the steps of:
a. reacting a compound of formula I’

with a compound of formula II

in the presence of sodium carbonate in acetonitrile/water at a temperature in the range of 60 to 70 ? to provide a compound of formula III

b. acylating the compound of formula III with thionyl chloride
in presence of ethylene dichloride, dimethylformamide at temperature in the range of 55 to 60? to form a compound of formula IV

c. reacting compound of formula IV with a compound of formula V

in presence of solvent, base, and chlorinated hydrocarbons to provide (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.

10. The process as claimed in claim 1, comprises the steps of:

a. reacting a compound of formula I

with a compound of formula II

in the presence of sodium carbonate in acetonitrile/water at a temperature in the range of 60 to 70? to provide a compound of formula III

b. acylating the compound of formula III with thionyl chloride
in presence of ethylene
dichloride, dimethylformamide at a temperature in the range of 55 to 60? to form a compound of formula IV

c. reacting compound of formula IV with a compound of formula V

in the presence of solvent, base, and chlorinated hydrocarbons to provide (2R)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]-phenoxy]-N-(2-fluorophenyl)-N-methylpropanamide.