EP4396164A1

EP4396164A1 - A process for preparation of bixafen

Info

Publication number: EP4396164A1
Application number: EP22863821.9A
Authority: EP
Inventors: Prashant Vasant KINI; Atul Balasaheb BHOSALE
Original assignee: UPL Ltd
Current assignee: UPL Ltd
Priority date: 2021-08-31
Filing date: 2022-08-30
Publication date: 2024-07-10
Also published as: WO2023031959A1; EP4396164A4; CN117836277A; AU2022336652A1

Abstract

The present invention relates to a process for preparation of a substantially colour-free Bixafen which comprises treating the crude bixafen with an organic solvent.

Description

TITLE: A PROCESS FOR PREPARATION OF BIXAFEN Field of Invention The present invention relates to a process for preparation of a substantially colour- free Bixafen. Background of the Invention Bixafen is a pyrazole-carboxamide fungicide used to control diseases on rape plants and cereals. Bixafen inhibits fungal respiration by binding to mitochondrial respiratory complex II. The chemical name of Bixafen is N-(3',4'-dichloro-5- fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4- carboxamide and it is represented by the compound of formula (I). Bixafen was first disclosed in U.S Patent No.7,329,633. A method commonly used for preparation of Bixafen involves Suzuki coupling reaction of fluoroanilines with substituted boronic acids in presence palladium catalyst to obtain a 2‐ aminobiphenyl intermediate, which is then reacted with 1- methyl -3- difluoromethyl -4- pyrazole formyl chloride to yield Bixafen. Another process known in art involves Gomberg–Bachmann reaction of aryl diazotate and para fluoro-aniline to obtain 2‐ aminobiphenyl intermediate which is reacted with 1-methyl-3-difluoromethyl-4- pyrazole formyl chloride to get Bixafen. The processes described above provide purified Bixafen by using tedious column purification. However, use of column chromatography on large scale is not feasible. Further, like any synthetic compound, Bixafen also contains extraneous compounds or impurities. These impurities may be, for example, are starting materials, by- products of the reaction, products of side reactions, or degradation products. Impurities in Bixafen, or any active ingredient are undesirable, and may lead to genotoxicity or mutagenicity in extreme cases. It has been observed that preparation of Bixafen by known processes leads to formation of Impurity A, having following structure Presence of impurity A may lead to the final product of poor quality. Due to the structural similarity of Bixafen and impurity A, a cumbersome process like column chromatography is required for separation of said impurity from final product. Furthermore, pure Bixafen is known to appear as white powder with no noticeable odour. However, it is observed that Bixafen obtained using the processes in prior art have undesirable unknown impurities which even if present at ppm level imparts colour to Bixafen. Aside from the undesirability of contamination of the product with the impurities which does not possess the properties of the original compound intended, the unnatural colour in many instances make the product unsaleable in the market, as colour and odour suggests an undesirable contamination of the material with which it is associated. The purity of an active ingredient produced in a manufacturing process is critical and it is always desirable that the technical grade active ingredient be relatively free of impurities. Hence, a need therefore exists for an industrially-practical method which provides a simple and industrially viable process for removal of impurities from technical grade Bixafen. Object of the invention It is an object of the present invention to provide a process for preparation of Bixafen. It is an object of the present invention to provide a substantially colour-free Bixafen. It is another object of the present invention to provide a process for obtaining a substantially colour-free Bixafen. It is an object of the present invention to provide a process for obtaining a substantially colour-free Bixafen which is simple, economical and acceptable at industrial scale. It is yet another object of present invention to provide a novel crystalline form of Bixafen. It is yet another object of present invention to provide Bixafen substantially free of impurity A. Summary of the Invention: According to an aspect of the present invention, there is provided a process for preparation of Bixafen. According to an aspect of the present invention, there is provided a process for obtaining a substantially colour-free Bixafen. According to an aspect of the present invention, there is provided a process for obtaining a substantially colour-free Bixafen which comprises treating crude Bixafen with an organic solvent selected from an alcohol or an ester. According to an aspect of the present invention, there is provided a process for obtaining a substantially colour-free Bixafen which comprises treating the crude Bixafen with an alcohol. According to an aspect of the present invention, there is provided a process for obtaining a substantially colour-free Bixafen which comprises treating the crude Bixafen with an ester. According to another aspect of present invention, there is provided a process for obtaining a substantially colour-free Bixafen, comprising: a) reacting compound of formula (II) with compound of formula (III) b) isolating resulting bixafen of formula (I) by adding water; and c) treating the isolated bixafen of formula (I) with an organic solvent selected from an alcohol or an ester, to obtain substantially colour-free Bixafen. According to another aspect of present invention, there is provided Bixafen having HPLC purity of more than 98%. According to another aspect of present invention, there is provided Bixafen substantially free of impurity A.

According to yet another aspect of the present invention, there is provided Bixafen, further characterized by having D₅₀ particle size value of less than 50μm, preferably less than 25μm. According to yet another aspect of the present invention, there is provided Bixafen, having bulk density of about 0.3 mg/ml to 0.9 mg/ml. According to another aspect of present invention, there is provided a crystalline form of Bixafen. Brief Description of Drawing Fig.1 illustrates powder X-ray diffraction (PXRD) pattern of substantially colour- free Bixafen prepared according to present invention. Detailed Description of the Invention Those skilled in art will be aware that 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, compositions and methods referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more said steps or features. Definitions: For convenience, before further description of the present invention, certain terms employed in the specification, examples are described here. These definitions should be read in light of the remainder of the disclosure and understood as 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. The term “room temperature” unless stated otherwise, essentially means temperature in range of 20 to 35 °C. The term "purity" means purity as determined by HPLC ("High Pressure Liquid Chromatography"). The term “crude Bixafen” used herein means Bixafen obtained by methods known to person skilled in art, having low HPLC purity or having colouring impurity with high HPLC purity. The term “about” or “approximately” as used herein is inclusive of the stated value and means within an acceptable range of deviation for particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity (i.e., the limitations of the measurement system). For example, “about” can mean within one or more standard deviations, or within ± 10 or ± 5 of the stated value. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided. For example, “0.1-80%” includes 0.1%, 0.2%, 0.3%, etc. up to 80%. 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 term “substantially colour-free Bixafen” means Bixafen that visually appears white to off-white in colour. The term “Bixafen substantially free of impurity A ” means Bixafen containing less than 2% of impurity A, preferably less than 1%. The inventors of present invention found that most of the prior art process provides Bixafen which appears to be coloured. Efforts were taken to obtain Bixafen which is pure and white in appearance as per internationally acceptable specifications. However, even by using purification methods known in art, the desired colour-free Bixafen was not obtained. It was observed by inventors of present invention that the undesired colour in Bixafen was due to presence of impurities. Another concern was on long term storage these impurities imparting colour to Bixafen may further enhance this undesired colour, which might make the product unsaleable to the intended use. These colour imparting impurities may also have adverse impact on the quality of formulation. Therefore, it is of utmost importance to remove these colour imparting impurities even if they are present at ppm level. The inventors of the present invention surprisingly found a simple and cost- effective process for obtaining a substantially colour-free Bixafen and overcome all the above-mentioned uncertainties. According to an aspect of the present invention, there is provided a process for obtaining a substantially colour-free Bixafen. According to an aspect of the present invention, there is provided a process for obtaining a substantially colour-free Bixafen which comprises treating crude bixafen with an organic solvent selected from an alcohol or an ester. In an embodiment, the crude Bixafen used as starting material can be prepared by methods known in the art. For instance, one of the methods for preparation of Bixafen involves the reaction of compound of formula (III) with compound of formula (II) to obtain Bixafen. In an embodiment, the organic solvent used is an alcohol. The alcohol used is selected from, but not limited to, C₁ to C₈ alcohol like methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol and the likes. In an embodiment, the alcohol used is methanol. In an embodiment, the organic solvent used is an ester. The ester used is selected from, but not limited to, ethyl acetate, isopropyl acetate, butyl acetate and the likes. In an embodiment, the ester used is ethyl acetate. In an embodiment, the ester used is isopropyl acetate. In an embodiment, the ester used is butyl acetate. In another embodiment, the treatment of obtained Bixafen with an organic solvent is carried out at temperature ranging from 0°C to 100°C. According to an aspect of the present invention, there is provided a process for obtaining a substantially colour-free Bixafen which comprises treating the crude Bixafen with an alcohol. According to an aspect of the present invention, there is provided a process for obtaining a substantially colour-free Bixafen which comprises treating the crude Bixafen with an ester. According to another aspect of present invention, there is provided a process for obtaining a substantially colour-free Bixafen, comprising: a) reacting compound of formula (II) with compound of formula (III) to obtain Bixafen of formula (I): b) isolating resulting bixafen of formula (I) by adding water; and c) treating the isolated bixafen of formula (I) with an organic solvent selected from an alcohol or an ester, to obtain substantially colour-free Bixafen. In an embodiment, the compound of formula (II) used in step a) is prepared from 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid, having structural formula

In an embodiment, the compound of formula (II) is prepared from 3- Difluoromethyl-1-methylpyrazole-4-carboxylic acid and is reacted with compound of formula (III) without requiring further purification. In an embodiment, the compound of formula (II) is prepared by reacting 3- Difluoromethyl-1-methylpyrazole-4-carboxylic acid with a chlorinating agent in presence of a suitable solvent at temperature ranging from 40 to 80°C. In an embodiment, the amount of 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid used for preparation of compound of formula (II), with respect to compound of formula (III) is in the range of 0.75 to 2 moles. The chlorinating agent used is selected from phosphorus trichloride (PCl3), phosphorus pentachloride ⁽PCl5), phosphorus oxychloride (POCl3), thionyl chloride, sulfuryl chloride, oxalyl chloride, sulfonyl chloride, acetyl chloride, phosgene and the likes. The amount of chlorinating agent used with respect to 3-Difluoromethyl-1- methylpyrazole-4-carboxylic acid is in the range of 0.5 to 2 moles. The suitable solvent used is selected from aliphatic, alicyclic or aromatic hydrocarbons such as, for example, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as, for example, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1.2-dimethoxyethane, 1,2-diethoxyethane or anisole; or amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methyl pyrrolidone or hexamethylphosphoric triamide or mixture thereof. In an embodiment, the compound of formula (II) is prepared in presence of toluene as solvent. In an embodiment, the compound of formula (II) is prepared in presence of catalytic amount of N,N-dimethylformamide. The amount of suitable solvent used with respect to pyrazole carboxylic acid is about 1 to 10 times. In an embodiment, the compound of formula (III) used in the step a) is prepared by conventionally known processes. In an embodiment, the step a) reaction is carried out in presence of a base and an organic solvent. The base used is selected from, but not limited to, base selected from alkaline earth metal or alkali metal hydrides, hydroxides, amides, alkoxides, acetates, carbonates, bicarbonates or tertiary amines. The base used is selected from, but not limited to, alkaline earth metal or alkali metal hydrides, hydroxides, amides, alkoxides, acetates, carbonates or bicarbonates, such as, for example, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate or caesium carbonate, and also tertiary amines, such as trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane(DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU). Preferably, tertiary amines are used. In an embodiment, the step a) reaction is carried out in presence of triethylamine. The amount of base used with respect to compound of formula (III) is in the range of 1 to 2.5 moles. In an embodiment, in the step a) the organic solvent is selected from aliphatic, alicyclic or aromatic hydrocarbons; halogenated hydrocarbons; ethers; or amides. The organic solvent used is selected from, but not limited to, aliphatic, alicyclic or aromatic hydrocarbons such as, for example, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as, for example, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1.2-dimethoxyethane, 1,2- diethoxyethane or anisole; or amides, such as N,N-dimethylformamide, N,N- dimethylacetamide, N-methylformanilide, N-methyl pyrrolidone or hexamethylphosphoric triamide. In an embodiment, the step a) is carried out in presence of an organic solvent preferably selected from aromatic hydrocarbons such as toluene and halogenated hydrocarbons such as dichloromethane. In an embodiment, the step a) is carried out at temperatures of from 0° C to 150° C. In an embodiment, in the step b) the crude Bixafen is isolated by addition of water. In an embodiment, crude Bixafen can be isolated by adding water and separating the layers obtained. The organic layer obtained can be optionally washed with water and the crude can be yielded by conventionally known methods such as addition of anti-solvent, evaporation of organic solvent and so on. In an embodiment, the crude Bixafen is precipitated by addition of water into reaction mixture. In another embodiment, the crude Bixafen precipitated after addition of water is isolated by filtration, centrifugation, etc. or other techniques known in prior art. In an embodiment, the step c) treatment comprises purification of crude Bixafen with an organic solvent selected from an alcohol or an ester. In an embodiment, in the step c) organic solvent used is an alcohol. In an embodiment, the step c) treatment comprises of washing the crude Bixafen with the alcohol. In another embodiment, the step c) treatment comprises of making slurry of the crude Bixafen with the alcohol and isolating substantially colour-free Bixafen. In another embodiment, the step c) treatment comprises of dissolving the crude Bixafen in the alcohol and recrystallizing the substantially colour-free Bixafen from the solution obtained. In another embodiment, the alcohol used in step c) is selected from linear or branched C₁ to C₆ alcohols such as methanol, ethanol, n-propanol, isopropanol and the likes. In another embodiment, the alcohol used in step c) is methanol. In an embodiment, in the step c) organic solvent used is an ester. In an embodiment, the step c) treatment comprises of washing the crude Bixafen with the ester. In another embodiment, the step c) treatment comprises of making slurry of the crude Bixafen with the ester and isolating substantially colour-free Bixafen. In another embodiment, the step c) treatment comprises of dissolving the crude Bixafen in the ester and recrystallizing the substantially colour-free Bixafen from the solution obtained. In another embodiment of the present invention, the ester used in step c) is selected from, but not limited to, ethyl acetate, isopropyl acetate, butyl acetate and the likes. In another embodiment of the present invention, the amount of organic solvent used in step c) with respect to crude Bixafen is about 1 to 10 times. In yet another embodiment, the step c) treatment is carried out at temperature ranging from 0°C to 100°C. It was found by the inventors that during the course of the reaction for preparing Bixafen, an undesired impurity referred to as “impurity A” is formed which contaminates final product. The impurity A have structure similar to that of Bixafen and requires tedious and cumbersome purification processes like column chromatography to ensure removal of said impurity A from final product. However, inventors of present invention found that simple treatment of Bixafen with organic solvent selected from alcohol and/or ester according to present invention, ensures removal of said impurity to great extent. Impurity A was found to be much more soluble in organic solvents like alcohol and/or ester as compared to Bixafen. Hence, on treatment of crude Bixafen with said organic solvents, using solubility difference, impurity A can be removed. In yet another embodiment, the step c) treatment provides substantially colour-free Bixafen. In yet another embodiment, the step c) treatment provides Bixafen substantially free of impurity A. According to another aspect of present invention, there is provided substantially colour-free Bixafen. In another aspect of present invention, there is provided Bixafen having HPLC purity of more than 98%. According to another aspect of present invention, there is provided Bixafen substantially free of impurity A According to another aspect of present invention, there is provided a process for preparation of Bixafen substantially free of impurity A. In an embodiment, there is provided a process for preparation of Bixafen substantially free of impurity A comprising treating the crude Bixafen with an organic solvent selected from an alcohol or an ester. According to another aspect of present invention, there is provided Bixafen substantially free of impurity A. In an embodiment, there is provided Bixafen containing less than 2% of impurity A. In another embodiment, there is provided Bixafen containing less than 1% of impurity A. According to yet another aspect of the present invention, there is provided Bixafen, further characterized by having D50 particle size value of less than 50μm, preferably less than 25μm. According to yet another aspect of the present invention, there is provided Bixafen, having bulk density of about 0.3 mg/ml to 0.9 mg/ml. According to another aspect of present invention, there is provided a crystalline form of Bixafen. According to yet another aspect of the present invention, there is provided Bixafen characterized by an X-ray powder diffraction pattern exhibiting at least three peaks selected from 9.25, 12.50, 14.65, 16.54, 18.25, 18.56, 19.47, 20.42, 21.36, 21.84, 22.35, 22.65, 24.35, 24.45, 25.11, 25.15, 25.75, 26.35, 26.78, 27.91, 29.42, 30.46, 31.23, 33.49, 38.73, 39.552Ɵ ± 0.2° 2Ɵ. According to another aspect of present invention, there is provided a substantially colour-free Bixafen characterized by powder X-ray diffraction (PXRD) pattern represented in FIG.1. According to another embodiment, the present invention provides a fungicidal composition comprising Bixafen prepared according to the present invention optionally with agriculturally acceptable excipients/carriers or additives. In an embodiment, the fungicidal composition comprising Bixafen prepared according to the present invention and at least one agriculturally acceptable excipient or additive. In an embodiment, the fungicidal composition comprises Bixafen in an amount ranging from 0.01% to 90% by weight of the total composition. In an embodiment, agriculturally acceptable excipient/ carriers or additives can be selected from one or more diluents, emulsifiers, fillers, anti-foaming agents, thickening agents, anti-freezing agents, freezing agents, a surfactant, a preservative, a coloring agent, a pH adjusting agent, dispersing agent, wetting agent, anti-caking agent and solvent. However, it should be appreciated that any other agriculturally acceptable excipients, as known to a person skilled in the art, may be used to serve its intended purpose. In an embodiment, the agriculturally acceptable excipients are present in an amount ranging from 0.01% to 90% by weight of the total composition. The examples of the fungicidal composition comprising Bixafen prepared according to process as described herein; are water-soluble concentrate (SL) , an emulstifiable concentrate (EC) , an emulsion (EW) , a micro-emulsion (ME) , a suspension concentrates (SC) , an oil-based suspension concentrates (OD) , a flowable suspension (FS) , a water-dispersible granule (WG) , water-soluble granule (SG) , a water-dispersible powder (WP) , a water soluble powder (SP) , a granule (GR) , an encapsulated granule (CG) , a fine granule (FG) , a macrogranule (GG) , an aqueous suspo-emulsion (SE) , capsule suspension (CS) and a microgranule (MG). In an embodiment, the fungicidal composition comprising Bixafen prepared according to process as described herein; is a water-dispersible powder (WP). In an embodiment, the composition prepared is a water-dispersible powder (WP) comprising Bixafen, at least one dispersing agent and at least one wetting agent. In an embodiment, the dispersing agent/ wetting agent used is selected from, but not limited to, group comprising of anionic, cationic or zwitterionic and/or non- ionic surface-active compounds (surfactants) or combinations thereof, preferably anionic surfactant is used. Examples of anionic surfactants include: anionic derivatives of fatty alcohols having 10-24 carbon atoms in the form of ether carboxylates, sulfonates, sulfates, and phosphates, and their inorganic salts (e.g., alkali metal and alkaline earth metal salts) and organic salts (e.g., salts based on amine or alkanolamine); anionic derivatives of copolymers consisting of EO(ethylene oxide), PO (propylene oxide) and/or BO (butylene oxide) units, in the form of ether carboxylates, sulfonates, sulfates, and phosphates, and their inorganic salts (e.g., alkali metal and alkaline earth metal salts) and organic salts (e.g., salts based on amine or alkanolamine) or acrylic/styrene copolymers, methacrylic copolymers; linear (C8-C15) alcohol derivative and their salts; alkyl aryl sulfonates including but not limited to alkyl benzenesulfonates; alkyl naphthalene sulfonates and salts thereof and salts of ligninsulfonic acid; derivatives of alkylene oxide adducts of alcohols, in the form of ether carboxylates, sulfonates, sulfates and phosphates, and their inorganic salts (e.g., alkali metal and alkaline earth metal salts) and organic salts (e.g., salts based on amine or alkanolamine); anionic derivatives of fatty acid alkoxylates, in the form of ether carboxylates, sulfonates, sulfates and phosphates, and their inorganic salts (e.g., alkali metal and alkaline earth metal salts) and organic salts (e.g., salts based on amine or alkanolamine); alkyl ether phosphate, alkyl sulfosuccinate mono ester and diester salts. In an embodiment, the composition may further comprise an anti-caking agent. The anti-caking agent used is selected from, but not limited to, group comprising of sodium and ammonium phosphates; sodium acetate; sodium metasilicate; magnesium, zinc and calcium sulfate; magnesium hydroxide; anhydrous calcium chloride; sodium alkyl sulfosuccinates; calcium and barium oxides; and precipitated silica. In an embodiment, the composition may further comprise a filler, fillers may be selected from insoluble fillers and soluble fillers. In an embodiment, the fungicidal composition comprises Bixafen prepared according to process as described herein; and a second fungicide. In an embodiment, the second fungicide used may be selected from multisite contact fungicide or systemic fungicide. In an embodiment, the second fungicide used may be selected from, but not limited to, the group consisting of azole fungicide such as imidazole fungicide, triazole fungicide; a dithiocarbamates fungicide, a phthalimides fungicide, a chloronitriles fungicide, an inorganic fungicides, a sulfamides fungicide, a bis-guanidines fungicide, a triazines fungicide, a quinones fungicide, a quinoxalines fungicide, a dicoarboxamides fungicide, a strobilurin fungicide, a conazole fungicide, a quinone outside inhibitor, a quinone inside inhibitor, a demthylation inhibitor, a succinate dehydrogenase inhibitor and the likes. According to an embodiment, Bixafen having bulk density of about 0.3 mg/ml to 0.9 mg/ml is used for preparation of an agrochemical compositions. According to an embodiment, crystalline form of Bixafen according to present invention is used for preparation of agrochemical compositions. According to yet another embodiment, there is provided an agrochemical composition comprising Bixafen characterized by an X-ray powder diffraction pattern exhibiting at least three peaks selected from 9.25, 12.50, 14.65, 16.54, 18.25, 18.56, 19.47, 20.42, 21.36, 21.84, 22.35, 22.65, 24.35, 24.45, 25.11, 25.15, 25.75, 26.35, 26.78, 27.91, 29.42, 30.46, 31.23, 33.49, 38.73, 39.552Ɵ ± 0.2° 2Ɵ. Bixafen prepared according to present invention can be processed into an agricultural composition of various dosage forms by conventionally known methods. Advantages of the present invention 1. The present invention provides a highly pure and substantially colour-free Bixafen, without requiring use of tedious process like column chromatography. 2. Said process for obtaining highly pure and substantially colour-free Bixafen is simple, economical and acceptable at industrial scale. 3. Said process provides Bixafen substantially free of impurity A. 4. Said process also provides a novel crystalline form of Bixafen. EXAMPLES The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The examples provided below are merely illustrative of the invention and are not intended to limit the same to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention. Analytical Method Details: 1. X‐ ray powder diffraction method (XPRD) pattern was carried out on Bruker make 2^nd generation D2 Phaser Powder X-Ray diffractometer; 2. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was carried out on Sciex make Qtrap 6500+ LC-MS/MS. 3. High-performance liquid chromatography (HPLC):HPLC Column: SB C8 (250 mm x 4.6 mm, 5 μm) UV-Wavelength : 220 nm Column temperature : 40°C Run time : 30 min. Example 1: Preparation of colour-free Bixafen Step I: Preparation of compound of formula (II) 91.5 gm of pyrazole carboxylic acid, 300 ml of toluene and 2.5 gm of dimethylformamide was added in a reaction vessel at 25-30°C. The reaction mixture formed was heated to 55-60°C and 71.2 gm of thionyl chloride was added dropwise. The reaction mass was then maintained under stirring at 55-60°C for 5 hours (till unreacted pyrazole carboxylic acid is <2%). Toluene and excess thionyl chloride were distilled out under reduced pressure to obtain 112 gm of compound of formula (II). Step II: Preparation of crude Bixafen 127 gm of compound formula (III), 500 ml of toluene and 76.2 gm of triethylamine was taken in reaction vessel and the mixture was heated to 55-60°C. To this mixture was then added 112 gm of compound of formula (II) obtained in step I. Then the reaction mixture was stirred at 50-55°C for 2-4 hrs. After completion of reaction, the reaction mixture was cooled to 25-30°C and 300ml of water was added to it. The reaction mass was stirred for 1 hr at 25-30°C and the resultant precipitate was filtered, to obtain crude Bixafen. Step III: Purification of crude Bixafen The crude Bixafen obtained in step II, was added to 300 ml of methanol and stirred at 25-30°C. The slurry thus formed was filtered and the solid product was isolated and dried to yield 142 gm of colour-free Bixafen with HPLC purity greater than 99%. Particle Size Distribution: D10 = 4.489μm; D50 = 15.68μm and D90 = 33.573μm Bulk density: 0.62mg/ml Example 2: Preparation of colour-free Bixafen Step I: Preparation of compound of formula (II) 36 gm of pyrazole carboxylic acid, 150 ml of toluene and 1.5 gm of dimethylformamide was added to a reaction vessel at 25-30°C. The reaction mixture thus formed, was heated to 55-60°C and 28 gm of thionyl chloride was added dropwise. The reaction mixture was stirred and maintained at 55-60°C for 5 hours (till pyrazole carboxylic acid is <2%). Toluene and excess thionyl chloride were distilled out under reduced pressure to obtain 45 gm of compound of formula (II). Step II: Preparation of crude Bixafen 50 gm of compound formula (III), 250ml of dichloromethane and 30 gm of triethylamine was added to reaction vessel. The reaction mixture was heated to 30- 35°C and 45 gm of compound of formula (II) obtained in step I was added dropwise. Then the reaction mixture was stirred at 30-35°C for 2-4 hrs. After completion of the reaction, the reaction mixture was cooled to 25-30°C and 100ml of water was added to it. The mixture was stirred for 1hour at 25-30°C and the layers were separated. The organic phase was washed with 100 ml of water and the dichloromethane was distilled out under reduced pressure to get crude Bixafen (impurity A content: 2.54% A/A). Impurity A was analysed by Liquid chromatography–Mass spectrometry having LC-MS (m/z): 572 (M+H)⁺ Step III: Purification of crude Bixafen The crude Bixafen was added to 250 ml of methanol and the mixture was heated to 60-65°C under stirring for 1 hour. The mixture was then cooled to 0-5°C and the solid product obtained was filtered, washed with 50ml of pre-cooled methanol and dried to yield 52 gm of colour-free Bixafen with HPLC purity 98.8%(impurity A content: 0.78%). Particle Size Distribution: D10 = 3.409μm; D50 = 9.714μm and D90 = 27.772μm Bulk density: 0.61mg/ml Example 3: Preparation of colour-free Bixafen (EA) Step I: Preparation of crude Bixafen 325 gm of compound formula (III), 1000 ml of dichloromethane and 192 gm of triethylamine was added to reaction vessel. The reaction mixture was warmed to 30-35°C and 281 gm of compound of formula (II) was added. Then the reaction mixture was stirred at 30-35°C for 2-4 hrs. After completion of reaction, 975 ml of water was added to reaction mixture and layers were separated. Organic layer was distilled out to get 490 gm of crude Bixafen(impurity A content: 2.2% A/A) Step II: Purification of crude Bixafen To 490 gm of crude Bixafen obtained in step I, was added to 600 ml of ethyl acetate and the mixture was heated to 65-70°C to get clear solution. The clear solution was cooled slowly to 0-5°C and maintained for 2-3 hours, crystals formed were filtered and dried to get 390 gm of pure colour-fee Bixafen having HPLC purity of 99.6%. (impurity A content: not detectable) Example 4: Preparation of colour-free Bixafen Crude Bixafen was prepared as provided in any of above examples and then was divided in to equal four parts for purification. 4A. Purification of crude Bixafen using Ethyl acetate 75g of crude Bixafen obtained in step II, was added to 200ml ethyl acetate and the mixture was heated to 70-75°C for an hour to get clear solution. The clear solution was cooled slowly to 0-5°C and maintained for 2-3 hours, crystals formed were filtered and dried to get 62g of pure colour-fee Bixafen having HPLC purity greater than 98%. 4B. Purification of crude Bixafen using Butyl acetate 75g of crude Bixafen obtained in step II, was added to 200ml butyl acetate and mixture was heated to 70-75°C for an hour to get clear solution. The clear solution was cooled slowly to 0-5°C and maintained for 2-3 hours, crystals formed were filtered and dried to get 58g of pure colour-fee Bixafen having HPLC purity greater than 98%. 4C. Purification of crude Bixafen using Isopropyl acetate 75g of crude Bixafen obtained in step II, was added to 200ml isopropyl acetate and mixture was heated to 70-75°C for an hour to get clear solution. The clear solution was cooled slowly to 0-5°C and maintained for 2-3 hours, crystals formed were filtered and dried to get 60g of pure colour-fee Bixafen having HPLC purity greater than 98%. 4D. Purification of crude Bixafen using Methanol 75g of crude Bixafen obtained was added to 200ml methanol and mixture was heated to 60-65°C for an hour to get clear solution. The clear solution was cooled slowly to 0-5°C and maintained for 2-3 hours, crystals formed were filtered and dried to get 64g of pure colour-fee Bixafen having HPLC purity greater than 98%. Example 5 Using the standard method, a wettable powder formulation of Bixafen was prepared. Composition of formulation is as given below:

Claims

We claim: 1. A process for obtaining a substantially colour-free Bixafen which comprises treating crude Bixafen with an organic solvent selected from an alcohol or an ester. 2. The process as claimed in claim 1, wherein said alcohol is selected from C1 to C8 alcohol. 3. The process as claimed in claim 1, wherein the alcohol is methanol. 4. The process as claimed in claim 1, wherein said ester is selected from ethyl acetate, isopropyl acetate or butyl acetate. 5. A process for obtaining a substantially colour-free Bixafen, the process comprising: a) reacting compound of formula (II) with compound of formula (III) to obtain Bixafen of formula (I); b) isolating resulting Bixafen of formula (I) by adding water; and c) treating isolated Bixafen of formula (I) with an organic solvent selected from an alcohol or an ester, to obtain substantially colour-free Bixafen. 6. The process as claimed in claim 5, wherein said compound of formula (II) is prepared from 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid and is reacted with compound of formula (III) without purification. 7. The process as claimed in claim 5, wherein the step a) reaction is carried out in presence of a base and an organic solvent.

8. The process as claimed in claim 7, wherein said base is selected from alkaline earth metal or alkali metal hydrides, hydroxides, amides, alkoxides, acetates, carbonates, bicarbonates or tertiary amines. 9. The process as claimed in claim 7, wherein said organic solvent is selected from aliphatic, alicyclic or aromatic hydrocarbons; halogenated hydrocarbons; ethers; or amides. 10. The process as claimed in claim 5, wherein in the step b) crude Bixafen is isolated by addition of water. 11. Bixafen substantially free of impurity A 12. Bixafen as claimed in claim 11, containing less than 2% of impurity A 13. Bixafen as claimed in claim 11, containing less than 1% of impurity A 14. Bixafen having D50 particle size value of less than 50μm. 15. Bixafen having bulk density of about 0.3 mg/ml to 0.9 mg/ml 16. A crystalline form of Bixafen. 18. The crystalline form of Bixafen as claimed in claim 16, characterized by an X-ray powder diffraction pattern exhibiting at least three peaks selected from 9.25, 12.50, 14.65, 16.54, 18.25, 18.56, 19.47, 20.42, 21.36, 21.84, 22.35, 22.65, 24.35, 24.45, 25.11, 25.15, 25.75, 26.35, 26.78, 27.91, 29.42, 30.46, 31.23, 33.49, 38.73, 39.552Ɵ ± 0.2° 2Ɵ.

19. An agrochemical composition comprising Bixafen prepared by the process as claimed in claim 1 or 5 and at least one agriculturally acceptable excipient or additive.