A process for the preparation of 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-YL]benzoic acid

Abstract

The present invention relates to a process for the preparation of 3-[5-(2- Fluorophenyl)-1,2,4-oxadiazol-3-yl] benzoic acid represented by the following structural Formula (1). The present invention also relates to a process for the purification of 3-[5-(2- Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (1) having purity greater than 99.9% by High performance liquid chromatography (HPLC).

Description

[0001] “A PROCESS FOR THE PREPARATION OF 3-[5-(2-FLUOROPHENYL)- l,2,4-OXADIAZOL-3-YL]BENZOIC ACID”

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a process for the preparation of 3-[5-(2- Fluorophenyl)-l,2,4-oxadiazol-3-yl] benzoic acid represented by the following structural Formula (1).

[0004] The present invention also relates to a process for the purification of 3-[5-(2- Fluorophenyl)-l,2,4-oxadiazol-3-yl]benzoic acid (1) having purity greater than 99.9% by High performance liquid chromatography (HPLC).

[0005] BACKGROUND OF THE INVENTION

[0006] 3-[5-(2- fluorophenyl)-l,2,4-oxadiazol-3-yl]benzoic acid is commonly known as Ataluren is an orally administered small-molecule compound for the treatment of patients with genetic disorders (e.g., Duchenne muscular dystrophy (DMD) and cystic fibrosis) caused due to a nonsense mutation. Ataluren is discovered and designed by PTC Therapeutics, Inc. and is sold under the trade name Translarna™ in the European Union. Translarna™ is the first treatment approved for the underlying cause of DMD. The European Medicines Agency (EMA) has designated ataluren as an orphan medicinal product.

[0007] W02006 / 110483 Al of PTC therapeutics reported a process for the preparation of Ataluren (1), which comprises 3 -cyanobenzoic acid methyl ester compound 1 was reacted with hydroxylamine to form oxime compound 2 as white powder. The oxime compound 2 was contacted with 2-fluorobenzoyl chloride to form compound 3 under basic condition. Then put compound 3 into toluene at high temperature to complete condensation and form oxadiazole compound 4. The compound 4 was subjected to hydrolysis conditions (aqueous NaOH) and then ataluren formed as white powder.

[0008] The overall yield from compound 1 to ataluren was about 73%.

[0009] The above process is schematically shown as below: Scheme-I

[0010] U.S. Patent Nos. 7,678,922 B2 and 8,367,841 B2 reported one-pot process for the preparation of Ataluren (1), which comprises 3 -cyanobenzoic acid methyl ester compound 1 without the isolation of compounds 2, 3 and 4 to afford ataluren. Jert-

[0011] Butanol was used as the main solvent system through this route, even in the final hydrolysis step. The overall yield from compound 1 to ataluren was about 67-69%.

[0012] Scheme-II U.S. Patent Nos. 7,678,922 B2 and 8,367,841 B2 reported another one-pot process for the preparation of Ataluren (1), which comprises 3 -cyanobenzoic acid, compound 5, without the isolation of compounds 6 and 7. tert-Butanol was also used as the main solvent system for this approach. The overall isolation yield of ataluren was about 76%.

[0013] (

[0014] Ataluren

[0015] Scheme-Ill

[0016] Although numerous approaches for preparing ataluren have been disclosed as discussed above, there is still an unmet need for a mild, cleaner, and easier process for industrial preparation of ataluren. The present processes disclosed herein address this need and other needs.

[0017] OBJECTIVE OF THE INVENTION

[0018] The present invention relates to a process for the preparation of Ataluren (1).

[0019] The present invention further relates to Ataluren (1) with purity greater than 99% by HPLC.

[0020] SUMMARY OF THE INVENTION

[0021] In one aspect, the present invention relates to a process for the preparation of Ataluren (1), which comprises: a) methylating 3 -cyanobenzoic acid of formula (6) with methanol and sulfuric acid (or) methyl iodide to provide methyl 3 -cyanobenzoate of formula (5), b) reacting the compound of formula (5) with aqueous hydroxylamine to provide methyl 3-(N-hydroxy carbamimidoyl) benzoate of formula (4), c) reacting the compound of formula (4) with 2-fluorobenzoyl chloride of formula (3) to provide methyl 3-(N-(2-fluorobenzoyl) carbamimidoyl)benzoate of formula (2), d) cyclizing and hydrolyzing the compound of formula (2) to provide Ataluren of formula (1).

[0022] In another aspect, the present invention relates to a process for the preparation of Ataluren (1), which comprises: a) reacting 3 -cyanobenzoic acid of formula (6) with aqueous hydroxylamine to provide 3-(N-hydroxycarbamimidoyl)benzoic acid of formula (7), b) reacting the compound of formula (7) with 2-fluorobenzoyl chloride of formula (3) to provide 3-(N-(2-fluorobenzoyloxy)carbamimidoyl)benzoic acid of formula (8), c) cyclizing the compound of formula (8) to provide Ataluren of formula (1).

[0023] In another aspect, the present invention provides a process for the purification of Ataluren of formula (1), which comprises: i) dissolving crude Ataluren of formula (1) in one or more solvents, and ii) isolating Ataluren of formula (1).

[0024] In another aspect, the present invention is to provide Ataluren (1) obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.9% by HPLC.

[0025] BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1: Illustrates X-Ray Diffraction (XRD) pattern of crystalline form of Ataluren (1) DETAILED DESCRIPTION OF THE INVENTION

[0027] As used herein the term “solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; “polar-aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, acetyl acetone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol mono ethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water and or mixtures thereof.

[0028] The “base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert- butoxide and the like; triethyl amine, methyl amine, ethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4-diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof.

[0029] The “acid” as used in the present invention is selected from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids;

[0030] In one embodiment, the present invention is to provide a process for the preparation of Ataluren (1), comprising one or more following steps:

[0031] Scheme-IV

[0032] In step a) of the forgoing process, the methylation reaction of 3 -cyanobenzoic acid of formula (6) with methanol and sulfuric acid (or) methyl iodide in the presence of a solvent under appropriate reaction conditions to provide methyl 3 -cyanobenzoate of formula (5). The solvent selected from alcohol solvents methanol, ethanol, isopropanol. The step a) reaction is carried out at a suitable temperature of about 65 °C to about 75 °C for a sufficient period till completion of the reaction.

[0033] In step b) of the forgoing process, the reaction of compound of formula (5) with aqueous hydroxylamine and a solvent under appropriate reaction conditions to provide methyl 3-(N-hydroxycarbamimidoyl)benzoate of formula (4). The solvent is selected from tert-butanol. The step b) reaction is carried out at a suitable temperature of about 50 to about 55°C for a sufficient period till completion of the reaction.

[0034] In step c) of the forgoing process, the reaction of compound of formula (4) with 2- fluorobenzoyl chloride of formula (3) in the presence of a solvent under appropriate reaction conditions to provide methyl 3-(N-(2- fluorobenzoyl)carbamimidoyl)benzoate of formula (2) followed by recrystallization in ethyl acetate. The solvent is selected from water. The step c) reaction is carried out at a suitable temperature of about 25 °C to about 35 °C for a sufficient period till completion of the reaction.

[0035] In step d) of the forgoing process, the cyclizing reaction of formula (2) in presence of base in a solvent. To this reaction mass hydrolyzing in presence of acid under appropriate reaction conditions to provide Ataluren of formula (1). The solvent is selected from as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t- butanol, 2-nitroethanol, 2-fluoroethanol; and dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2- dimethoxy ethane, anisole and the like. The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. The acid is selected from hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2- sulfonic, and other acids. The step e) reaction is carried out at a suitable temperature of about 55°C to about 65°C for a sufficient period till completion of the reaction.

[0036] In another embodiment, the present invention is to provide a process for the preparation of Ataluren (1), comprising one or more following steps:

[0037] In step a) of the forgoing process, the reaction of 3 -cyanobenzoic acid compound of formula (6) with aqueous hydroxylamine and a solvent under appropriate reaction conditions to provide 3-(N-hydroxycarbamimidoyl)benzoic acid of formula (7). The solvent is selected from ethanol. The step a) reaction is carried out at a suitable temperature of about 65 °C to about 75 °C for a sufficient period till completion of the reaction.

[0038] In step b) of the forgoing process, the reaction of compound of formula (7) with 2- fluorobenzoyl chloride (3) in the presence of a base and optionally a solvent under appropriate reaction conditions to provide 3-(N-(2- fluorobenzoyloxy)carbamimidoyl)benzoic acid of formula (8). The base is selected triethyl amine, and the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol; and dimethoxy methane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole and the like. The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. The step b) reaction is carried out at a suitable temperature of about 60°C to about 80°C for a sufficient period till completion of the reaction.

[0039] In step c) of the forgoing process, the cyclizing reaction of compound of formula (8) in a solvent under appropriate reaction conditions to provide Ataluren of formula (1). The solvent is selected from toluene. The step c) reaction is carried out at a suitable temperature of about 0°C to about 10°C for a sufficient period till completion of the reaction.

[0040] In another aspect, the present invention provides a process for the purification of Ataluren of formula (1), which comprises: i. dissolving crude Ataluren of formula (1) in one or more solvents, and ii. isolating Ataluren of formula (1).

[0041] In another embodiment, Ataluren (1) obtained in the present invention is crystalline form.

[0042] In another embodiment, crystalline form of Ataluren (1) obtained according to the present invention is characterised by X-ray powder diffractions (XRD) pattern as shown in figure 1 and 2 theta values as provided in Table 1 :

[0043] Table 1:

[0044] The Ataluren (1) obtained is having total impurities less than 1.0% (w / w), preferably less than 0.5% (w / w) which forms another embodiment of the invention. In another embodiment Ataluren (1) obtained according to the present invention is having purity greater than 99.5% as measured by High performance liquid chromatography (HPLC).

[0045] In another embodiment, Ataluren (1) obtained in the present invention is having water content not more than 2.0% (w / w), preferably not more than 1.0% (w / w).

[0046] The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:

[0047] Example 1: Preparation of methyl 3-cyanobenzoate of formula (5).

[0048] To a solution of 3 -Cyanobenzoic acid (44.14g) in DMF (0.6 L) was added K2CO3 (62.19g) and then stirred for 30 min at room temperature. To the suspension methyl iodide (28 mL) was added over 20 min, and the reaction mixture was stirred further 4h at room temperature. The reaction mixture was poured to 1.2L of ice water and stirred for 30 min, and the precipitate was filtered off. The white cake was dissolved in methanol (70 mL), and then re-precipitated in cold water. The desired product was obtained as a white powder. Yield: 78%. Purity: 99%

[0049] Example 2: Preparation of methyl 3-cyanobenzoate of formula (5).

[0050] To a solution of 3 -Cyanobenzoic acid (100 g) in methanol (1000 ml) was added H2SO4 (25 mL) and then stirred 70°C. The reaction mass was concentrated under vacuum to give a residue. The residue was diluted with water and extracted with sodium bicarbonate. The filtrate was concentrated under vacuum to afford the title compound as a white solid.

[0051] Yield: 95% Purity: 98%

[0052] Example 3: Preparation of methyl 3-(N-hydroxycarbamimidoyl)benzoate of formula (4)

[0053] To a solution of methyl 3-Cyanobenzoate (100 g) in tert-butanol (500 mL) was added 35% aqueous hydroxylamine (76.8 mL) at room temperature. The reaction mixture was stirred and the solvents were removed under reduced pressure, to get the title compound as a white powder. Yield: 90%. Purity: 98%

[0054] Example 4: Preparation of methyl 3-(N-(2- fluorobenzoyl)carbamimidoyl)benzoate of formula (2)

[0055] To a solution of 3-(N-Hydroxycarbamimidoyl)-benzoic acid methyl ester (60g) in water (1000 mL), and then to the mixture was added 2-fluorobenzoyl chloride (147.5 g). To this added to ethyl acetate (250 mL). The reaction mixture was stirred for at room temperature. The precipitate was filtered off and the filtrate was concentrated under reduced pressure, and then washed with water The solvent was removed under reduced pressure and the desired product was crystallized in 60% ethylacetate to get the title compound. Yield: 85%. Purity: 99% Example 5: Preparation of Ataluren (1)

[0056] To a solution of methyl 3 -(N- (2 -fluoro benzoyloxy) carbamimidoyl) benzoate (100 g) of formula (2) in isopropyl alcohol (200 mL) was added and water (600 mL). To this added to sodium hydroxide (18.9 g) to the reaction mixture and stirred. The reaction mixture was stirred and filtered. The white precipitate was filtered off and the white cake was washed with cold water and then dried under vacuum. To this added with hydrochloric acid in tetrahydrofuran and water. Stitted and filterd washed with water. Dried and to get the title the compound. Yield: 96%. Purity: 99%

[0057] Example 6: Preparation of 3-(N-hydroxycarbamimidoyl)benzoic acid of formula (7).

[0058] 3 -Cyanobenzoic acid (6) (10 g) was dissolved in ethanol (100 mL) at 25-35 °C . The reaction mass was heated reflux temperature and stirred. 50% aqueous hydroxylamine (5 g) was added. The reaction mass was completed after stirring to get the title compound. Yield: 95%. Purity: 98%

[0059] Example 7: Preparation of 3-(N-(2-fluorobenzoyloxy) carbamimidoyl)benzoic acid of formula (8).

[0060] 3-(N-hydroxycarbamimidoyl)benzoic acid of formula (8) was dissolved in tetrahydrofuran (10 vol) and triethylamine (10 g) was added, then 2-Fluorobenzoyl chloride (9 g) was added. The temperature was maintained at 24-27°C during the addition and stirred to get the title compound. Yield: 90%. Purity:98%

[0061] Example 8: Preparation of Ataluren (1)

[0062] To a solution of 3-(N-(2-fluorobenzoyloxy) carbamimidoyl)benzoic acid of formula (9) (3.3g) in toluene (100 mL). The reaction mixture was refluxed for 3-5h at 120 °C. The organic solvent was removed to get the solid. The obtained solid was filtered and dried to get the title compound. Yield: 95%. Purity:99.85%

Claims

We claim:

1. A process for the preparation of Ataluren (1),which comprises: a) methylation of 3 -cyanobenzoic acid of formula (6)with sulfuric acid (or) methyl iodide in presence of solvent to produce methyl3 -cyanobenzoate of formula (5)b) reacting formula (5) with aqueous hydroxylamine in presence of solvent to provide methyl 3-(N-hydroxy carbamimidoyl) benzoate of formula (4),c) reacting formula (4) with 2-fluorobenzoyl chloride of formula (3)in presence of solvent to provide methyl 3-(N-(2-fluorobenzoyl) carbamimidoyl)benzoate of formula (2),followed by recrystallization in ethyl acetate. d) cyclizing the compound of formula (2) in presence of base in a solvent and hydrolyzing to provide Ataluren of formula (1).

2. The process as claimed in claim 1, whereinIn step-a) of the present invention, the solvent is selected from solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t- butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2- ethoxyethanol, diethylene glycol, 1, 2, or 3 -pentanol, neo pentyl alcohol, t- pentyl alcohol, diethylene glycol mono ethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water and or mixtures thereof.In step-b) of the present invention, the suitable solvent is selected from alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, tertbutanol or mixture of thereof.In step-c) of the present invention, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, tert-butanol, water or mixture of thereof.In step-d) of the present invention, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2- nitroethanol, 2-fluoroethanol; and dimethoxy methane, tetrahydrofuran, 1,3- dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole, water or mixture thereof. The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. The acid is selected from hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic,tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids.

3. A process for the preparation of Ataluren (1),which comprises: a) reacting 3 -cyanobenzoic acid of formula (6) with aqueous hydroxylamine and a solvent to provide 3-(N- hydroxycarbamimidoyl)benzoic acid of formula (7),b) reacting the compound of formula (7) with 2-fluorobenzoyl chloride of formula (3) to provide 3-(N-(2- fluorobenzoyloxy)carbamimidoyl)benzoic acid of formula (8),c) cyclizing the compound of formula (8) in presence of solvent to provide Ataluren of formula (1).

4. The process as claimed in claim 3, wherein, In step-a) of the present invention, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, tert-butanol or mixture of thereof.In step b) base selected from triethyl amine, methyl amine, ethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1- methylimidazole, 1,2,4-triazole, 1,4-diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof. And the solvent is selected from dimethoxy methane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole.In step c) solvent is selected from n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p- xylene, nitromethane and ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole and the like.

5. A process for purification of Ataluren of formula (1) with purity greater than 99%, which comprises the steps of: i) dissolving crude Ataluren of formula (1) in one or more solvents, and ii) isolating Ataluren of formula (1).

6. The process as claimed in claim 5, wherein the solvent used in step (i) is selected from solvents such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane; ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole and the like; alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3 -pentanol, neo pentyl alcohol, t- pentyl alcohol, diethylene glycol mono ethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water and or mixtures thereof.

7. The process as claimed in claim 1, wherein Ataluren (1) obtained is crystalline in nature.

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