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WO2023031959A1 - Procédé de préparation de bixafène - Google Patents

Procédé de préparation de bixafène Download PDF

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Publication number
WO2023031959A1
WO2023031959A1 PCT/IN2022/050770 IN2022050770W WO2023031959A1 WO 2023031959 A1 WO2023031959 A1 WO 2023031959A1 IN 2022050770 W IN2022050770 W IN 2022050770W WO 2023031959 A1 WO2023031959 A1 WO 2023031959A1
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Prior art keywords
bixafen
formula
free
crude
alcohol
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Ceased
Application number
PCT/IN2022/050770
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English (en)
Inventor
Prashant Vasant KINI
Atul Balasaheb BHOSALE
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UPL Ltd
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UPL Ltd
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Filing date
Publication date
Application filed by UPL Ltd filed Critical UPL Ltd
Priority to CN202280053965.XA priority Critical patent/CN117836277A/zh
Priority to EP22863821.9A priority patent/EP4396164A4/fr
Priority to AU2022336652A priority patent/AU2022336652A1/en
Publication of WO2023031959A1 publication Critical patent/WO2023031959A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides

Definitions

  • 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.
  • 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.
  • 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.
  • Bixafen and impurity A 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.
  • a process for obtaining a substantially colour-free Bixafen which comprises treating the crude Bixafen with an alcohol.
  • a process for obtaining a substantially colour-free Bixafen which comprises treating the crude Bixafen with an ester.
  • 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.
  • Bixafen having HPLC purity of more than 98%.
  • Bixafen substantially free of impurity A there is provided.
  • Bixafen further characterized by having D 50 particle size value of less than 50 ⁇ m, preferably less than 25 ⁇ m.
  • Bixafen having bulk density of about 0.3 mg/ml to 0.9 mg/ml.
  • a crystalline form of Bixafen 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.
  • room temperature unless stated otherwise, essentially means temperature in range of 20 to 35 °C.
  • purity means purity as determined by HPLC ("High Pressure Liquid Chromatography").
  • 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).
  • 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.
  • 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”.
  • substantially colour-free Bixafen means Bixafen that visually appears white to off-white in colour.
  • 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.
  • 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.
  • 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.
  • the organic solvent used is an alcohol.
  • the alcohol used is selected from, but not limited to, C 1 to C 8 alcohol like methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol and the likes.
  • the alcohol used is methanol.
  • 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.
  • the ester used is ethyl acetate.
  • the ester used is isopropyl acetate.
  • the ester used is butyl acetate.
  • the treatment of obtained Bixafen with an organic solvent is carried out at temperature ranging from 0°C to 100°C.
  • a process for obtaining a substantially colour-free Bixafen which comprises treating the crude Bixafen with an alcohol.
  • a process for obtaining a substantially colour-free Bixafen which comprises treating the crude Bixafen with an ester.
  • 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.
  • the compound of formula (II) used in step a) is prepared from 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid, having structural formula
  • 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.
  • 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.
  • 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-methyl
  • 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), diaza
  • tertiary amines are used.
  • 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.
  • 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- dimethylacet
  • 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.
  • the crude Bixafen is isolated by addition of water.
  • 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.
  • the crude Bixafen is precipitated by addition of water into reaction mixture.
  • the crude Bixafen precipitated after addition of water is isolated by filtration, centrifugation, etc. or other techniques known in prior art.
  • the step c) treatment comprises purification of crude Bixafen with an organic solvent selected from an alcohol or an ester.
  • organic solvent used is an alcohol.
  • the step c) treatment comprises of washing the crude Bixafen with the alcohol.
  • the step c) treatment comprises of making slurry of the crude Bixafen with the alcohol and isolating substantially colour-free Bixafen.
  • the step c) treatment comprises of dissolving the crude Bixafen in the alcohol and recrystallizing the substantially colour-free Bixafen from the solution obtained.
  • the alcohol used in step c) is selected from linear or branched C 1 to C 6 alcohols such as methanol, ethanol, n-propanol, isopropanol and the likes.
  • the alcohol used in step c) is methanol.
  • organic solvent used is an ester.
  • the step c) treatment comprises of washing the crude Bixafen with the ester.
  • 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.
  • the ester used in step c) is selected from, but not limited to, ethyl acetate, isopropyl acetate, butyl acetate and the likes.
  • the amount of organic solvent used in step c) with respect to crude Bixafen is about 1 to 10 times.
  • 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.
  • 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.
  • the step c) treatment provides substantially colour-free Bixafen.
  • the step c) treatment provides Bixafen substantially free of impurity A.
  • substantially colour-free Bixafen there is provided Bixafen having HPLC purity of more than 98%.
  • Bixafen substantially free of impurity A 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.
  • Bixafen further characterized by having D50 particle size value of less than 50 ⁇ m, preferably less than 25 ⁇ m. 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.
  • 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, 39.552 ⁇ ⁇ 0.2° 2 ⁇ .
  • PXRD powder X-ray diffraction
  • the present invention provides a fungicidal composition comprising Bixafen prepared according to the present invention optionally with agriculturally acceptable excipients/carriers or additives.
  • the fungicidal composition comprising Bixafen prepared according to the present invention and at least one agriculturally acceptable excipient or additive.
  • the fungicidal composition comprises Bixafen in an amount ranging from 0.01% to 90% by weight of the total composition.
  • 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.
  • diluents emulsifiers
  • fillers emulsifiers
  • anti-foaming agents thickening agents
  • anti-freezing agents freezing agents
  • a surfactant e.g., a preservative, a coloring agent, a pH adjusting agent, dispersing agent, wetting agent, anti-caking agent and solvent.
  • any other agriculturally acceptable excipients as known to a person skilled in the art, may be used to serve its intended purpose.
  • 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).
  • SL water-soluble concentrate
  • EW emulsion
  • the fungicidal composition comprising Bixafen prepared according to process as described herein; is a water-dispersible powder (WP).
  • the composition prepared is a water-dispersible powder (WP) comprising Bixafen, at least one dispersing agent and at least one wetting agent.
  • 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.
  • 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
  • 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.
  • the composition may further comprise a filler, fillers may be selected from insoluble fillers and soluble fillers.
  • the fungicidal composition comprises Bixafen prepared according to process as described herein; and a second fungicide.
  • the second fungicide used may be selected from multisite contact fungicide or systemic fungicide.
  • 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.
  • azole fungicide such as imidazole fungicide,
  • Bixafen having bulk density of about 0.3 mg/ml to 0.9 mg/ml is used for preparation of an agrochemical compositions.
  • crystalline form of Bixafen according to present invention is used for preparation of agrochemical compositions.
  • 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, 39.552 ⁇ ⁇ 0.2° 2 ⁇ .
  • 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.
  • Said process for obtaining highly pure and substantially colour-free Bixafen is simple, economical and acceptable at industrial scale.
  • Said process provides Bixafen substantially free of impurity A.
  • Said process also provides a novel crystalline form of Bixafen.
  • 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 ⁇ m) 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%.
  • 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.
  • 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.
  • 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.
  • Example 5 Using the standard method, a wettable powder formulation of Bixafen was prepared. Composition of formulation is as given below:

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Abstract

La présente invention concerne un procédé de préparation d'un bixafène sensiblement non coloré qui comprend le traitement du bixafène brut avec un solvant organique.
PCT/IN2022/050770 2021-08-31 2022-08-30 Procédé de préparation de bixafène Ceased WO2023031959A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN202280053965.XA CN117836277A (zh) 2021-08-31 2022-08-30 用于制备联苯吡菌胺的方法
EP22863821.9A EP4396164A4 (fr) 2021-08-31 2022-08-30 Procédé de préparation de bixafène
AU2022336652A AU2022336652A1 (en) 2021-08-31 2022-08-30 A process for preparation of bixafen

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IN202121039454 2021-08-31
IN202121039454 2021-08-31

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