WO2017085747A2 - A novel process for the preparation of trifloxystrobin - Google Patents

A novel process for the preparation of trifloxystrobin Download PDF

Info

Publication number
WO2017085747A2
WO2017085747A2 PCT/IN2016/050411 IN2016050411W WO2017085747A2 WO 2017085747 A2 WO2017085747 A2 WO 2017085747A2 IN 2016050411 W IN2016050411 W IN 2016050411W WO 2017085747 A2 WO2017085747 A2 WO 2017085747A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
novel process
methyl
acid
Prior art date
Application number
PCT/IN2016/050411
Other languages
French (fr)
Other versions
WO2017085747A3 (en
WO2017085747A4 (en
Inventor
Ajit Singh Gujral
Kenal V. Shah
Bhavesh V. Shah
Subhash KADAM
Nilesh N. JANI
Ravindra Y SHINDE
Original Assignee
Gsp Crop Science Pvt. Ltd,
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gsp Crop Science Pvt. Ltd, filed Critical Gsp Crop Science Pvt. Ltd,
Priority to CN201680071842.3A priority Critical patent/CN108368033B/en
Publication of WO2017085747A2 publication Critical patent/WO2017085747A2/en
Publication of WO2017085747A3 publication Critical patent/WO2017085747A3/en
Publication of WO2017085747A4 publication Critical patent/WO2017085747A4/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/08—Preparation of carboxylic acid nitriles by addition of hydrogen cyanide or salts thereof to unsaturated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/29—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with halogen-containing compounds which may be formed in situ
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
    • C07C67/20—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from amides or lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
    • C07C67/22—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups

Definitions

  • the present invention relates to a novel process for preparation of methyl ( ⁇ )-( ⁇ - (methoxyimino)-2-[[[(E)-[l-[3- (trifluoromethyl) phenyl] ethylidene] amino] oxy]methyl] benzeneaceate (Trifloxystrobin) of formula (I) in free form or in agro chemically acceptable salt form useful as a pest control agent.
  • Trifloxystrobin and its process for preparation were first disclosed in US5238956.It is most commonly used on bananas, cereals, citrus, coffee, corn, cotton, field beans, grapes, hops, nuts, ornamentals, peanuts, pome fruits, potatoes, rice, small fruits, soybeans, stone fruits, sugar beets, sunflowers, tea, tropical fruits, turf, vegetables and various other crops.
  • a reaction process of the synthesis method includes water diversion treatment. By virtue of a water carrying process, the influence of water formed in the reaction on the reaction is effectively avoided, thereby reducing side reaction, and improving product yield and product quality.
  • a reaction liquid solvent is directly used for crystallization after the reaction so as to avoid change of crystallization solvent and to avoid cross infection of the solvents, thus further enhancing product quality.
  • WO2013144924 teaches process for the synthesis of methyl (2E)-[2-(bro mo methyl) phenyl] (methoxyimino) ethanoate. It further relates to the conversion of methyl (2E)-[2-(bro mo methyl) phenyl] (methoxyimino) ethanoate, subsequently to substantially pure Trifloxystrobin, compound of formula (I). Synthesis for preparation of methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoateas shown in scheme as follows:
  • WO2013144924 also teaches preparation of methyl (2E)-[2-(bromo methyl) phenyl] (methoxyimino) ethanoate wherein R is H can be re resented as shown in scheme as follows:
  • WO2013144924 process incorporates hydrolysis of acyl cyanide that results a formation of 2- methyl benzoic acid formed due to decarboxylation & resulting formation of about 40 to 50% of acyl cyanide byproduct,2-Methyl Benzoic Acid .
  • One of the objectives of the present invention is to provide a novel process for the preparation of methyl(aE)-(a-(methoxyimino)-2-[[[(E)-[l-[3(trifluoromethyl) phenyl] ethylidene] amino] oxy] methyl] benzeneacetateof formula (I) in free form or in agro chemically acceptable salt form starting from readily accessible and cheap intermediates which are easy to handle, which process makes it possible to prepare Trifloxystrobin of formula (I) in simple manner and in good yield.
  • Still another objective of the present invention is to provide novel process for the preparation of an intermediate, (2-Bromomethyl-phenyl)-methoxyimino-acetic acid methyl esterof formula ( X), which is further used in the synthesis of final methyl(aE)-(a-(methoxyimino)-2-[[[(E)-[l- [3(trifluoromethyl) phenyl] ethylidene] amino] oxy] methyl] benzeneaceate (Trifloxystrobin) of formula (I) in free form or in agro chemically acceptable salt.
  • Still another objective of the present invention is to provide novel process for the preparation of an intermediate, oxy-o-tolyl-acetic acid of formula (VI)
  • the present invention provides a novel process for the preparation of methyl(aE)-(a- (methoxyimino)-2-[[[(E)-[l-[3(trifluoromethyl) phenyl] ethylidene] amino] oxy]methyl] benzeneaceate (Trifloxystrob
  • the invention provides a simple, economically viable and efficient process for preparing methyl (aE)-(a-(methoxyimino)-2-[[[(E)-[l-[3(trifluoromethyl) phenyl] ethylidene] amino] oxy] methyl] benzeneaceate(Trifloxystrobin) of formula (I)
  • the present invention provides a novel process for the preparation of hydro xy- (2-methylphenyl)-acetonitrileof formula (III) by reacting 2-methylbenzaldehyde of formula (II) with a cyanation agent that is selected from but not limited to Sodium Cyanide or Potassium Cyanide in presence of acid or Sodium metabisulfite and solvent.
  • a cyanation agent that is selected from but not limited to Sodium Cyanide or Potassium Cyanide in presence of acid or Sodium metabisulfite and solvent.
  • Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol;chloro solvents like methylene chloride,ethylene chloride, chloroform, monochlorobenzene, ; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane
  • alcohols such as methanol, ethanol, propanol, butanol
  • chloro solvents like methylene chloride,ethylene chloride, chloroform, monochlorobenzene, ; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane
  • the present invention provides a novel process for the preparation of 2- hydroxy-2-(2-methylphenyl) acetamide of formula (IV) by hydro lyzing hydroxy (2-methylphenyl) acetonitrile of formula (III) in presence of acids.
  • the aqueous solution of sulphuric acid was added drop wise and with stirring at the temperature of about 50°-25°C for hydrolyzing hydroxy (2- methylphenyl) acetonitrile of formula (III).
  • the resultant crude amide of formula (II) was neutralized by the addition of sodium carbonate with stirring.
  • the sodium carbonate is reacted with sulfuric acid in the filtrate to obtain sodium sulphate.
  • the present invention provides a novel process for the preparation of Hydro xy-o-tolyl- acetic acid methyl ester of formula (VI) by reacting 2-Hydroxy-2-o-tolyl- acetamide formula (IV) with methanol in resence of acids and sol ent.
  • the present invention provides a novel process for the preparation of Hydro xy-o-tolyl- acetic acid methyl ester of formula (VI) by reacting hydroxy (2-methylphenyl) acetonitrile of formula (III) with methanol in presence of acid and solvent, wherein the acid is selected form hydrochloride acid and inor anic or or anic acids or mixture thereof.
  • Inorganic or organic acids are added into solution of Hydrochloric acid to generate hydrochloric acid gas.
  • the hydrochloric acid gas passes through sulphuric acid trap into cyanohydrins reaction mass.
  • the purging of hydrochloric gas into reaction mass was carried out at about -15°C to 0° C.Hydrochloric gas and methanol are continually purged in reaction mass at -15 to 10°c for 2 to 10 hours.
  • Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof.
  • Hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane;
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; Alcohols such as methanol, ethanol, propanol, butanol; Chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride.
  • Suitable inorganic or organic acids is selected from but not limited.
  • Inorganic acids are mineral acids such as hydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuric acids, phosphoric acids and nitric acids.
  • Organic acids are aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha. -hydroxy acids, such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylic acid.
  • dicarboxylic acids include oxalic acid, malic acid, succinic acid, tataric acid and maleic acid.
  • An example of a tricarboxylic acid is citric acid.
  • the present invention provides a novel process for the preparation of Hydro xy-o-tolyl- acetic acid methyl ester of formula (VII) by oxidation of Oxo-o-tolyl-acetic acid methyl ester of formula (VI) in presence of oxidizing agent and a catalytic amount of a weak base such as 2,2,6, 6-t O.
  • the reaction of Oxo-o-tolyl-acetic acid methyl ester of formula (VI) expressed by the above reaction with oxidizing agent to obtain Hydroxy-o-tolyl-acetic acid methyl ester of formula (VII) is performed in the range of -10°C to 10°C, preferably in the range of -5°C to 5°C.
  • Oxidizing agent is used in the range of 1.0 to 2.0 molar equivalents to Oxo-o-tolyl-acetic acid methyl ester of formula (VI). It is preferred to use halogenated hydrocarbon as a solvent such as dichlorome thane, chloroform, carbon tetrachloride and 1, 2-dichloroethane.
  • Oxidizing agent is selected from Sodium hypobromite (NaOBr), Potasium Hypobromite (KOBr), N-bromosuccinimide, bromine isocyanuric acid, peracids, 2KHSOs, KHSO4, K2SO4, H2O2, and mixtures thereof.
  • NaOBr Sodium hypobromite
  • KOBr Potasium Hypobromite
  • N-bromosuccinimide N-bromosuccinimide
  • bromine isocyanuric acid peracids
  • 2KHSOs KHSO4, K2SO4, H2O2
  • Sodium hypobromite and potassium hypobromite can be generated easily by reacting 2 equivalents of sodium hydroxide or potassium hydroxide with 1 equivalent of bromine in aqueous solution in the range of -5 ⁇ 0°C [Org. Syn. Coll., 5, 8 (1973)].
  • unreacted oxidizing agent such as sodium hypobromite
  • salts of thiosulfate sodium thiosulfate 100ml of water and 124g of Na2S203- 5H20. If necessary, high purity of the desired product can be obtained by conventional methods.
  • the present invention provides a novel process for the preparation of Methoxyimino-o-tolyl-acetic acid of formula (VIII) by reacting Oxo-o-tolyl-acetic acid methyl ester of formula (VII) with Methoxyamine hydrochloride in presence of a base in an solvent optionally in the presence of phase transfer catalyst such as, TBAB, TEBAC, and base used is selected from but not limited to sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diethylamine or mixtures thereof.
  • phase transfer catalyst such as, TBAB, TEBAC
  • Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, , and and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane
  • alcohols such as methanol, ethanol, propanol, butanol
  • chloro solvents like methylene chloride, chloroform, monochlorobenzene, , and and ethylene chloride
  • hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and
  • the present invention provides a novel process for the preparation of Hydroxy-O-tolyl-acetic acid sodium salt of formula (Va) by reacting hydroxy (2-methylphenyl) acetonitrile of formula (III) in presence of inorganic or organic acids.
  • the cone .Hydrochloric acid was added drop wise and with stirring at the temperature of about 25°C-50°C followed by carried out hydrolysis in presence of base.
  • Suitable solvent is selected from but not limited to water and chloro solvents like Dichloro methane, Dichloroethane, chloroform, monochlorobenzene, hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.
  • the present invention provides a novel process for the preparation of Hydroxy-o-tolyl-acetic acid of formula (V)by oxidation of Hydroxy-O-tolyl-acetic acid sodium salt of the formula (Va) using sodium hypochlorite or Sodium Hypobromite in presence of metal oxide catalysts such as Platinum, Ruthenium, Rhodium, Molybdenum yeralytic amount and/or a weak base such as 2,2,6,6-tetramethylpiperidine 1- oxyl, hereinafter abbreviated as TEMPO or its derivatives such as 4-acetoxy-2,2,6,6-tetramethylpiperidinyl-l-oxyetcin presence of phase transfer catalysts selected from the group consisting of quaternary ammonium cations, quaternary phosphoniumcations, and cyclic polyethers such as tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, te
  • Obtained resultant sodium salt of oxo-toyl-acetic acid followed by treated with the acids such as Hydrochloric Acid or Sulphuric Acid in presence of solvents such as water and chloro solvents like Methylenedichloride, Ethylenedichloride, chloroform, monochlorobenzene, hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene to give the oxo-o-toyl-acetic acid.
  • solvents such as water and chloro solvents like Methylenedichloride, Ethylenedichloride, chloroform, monochlorobenzene, hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene to give the oxo-o-toyl-acetic acid.
  • Formula(Va) Formula(V)
  • the reaction of Oxo-o-tolyl-acetic acid of formula (V)expressed by the above reaction prepared by with oxidizing agent is performed in the range of -10°Cto50°C, preferably in the range of - 5°Cto5°C.
  • Oxidizing agent is used in the range of 2 mole %tol0 mole % toHydroxy-o-tolyl-acetic acid sodium salt of formula (Va).
  • halogenated hydrocarbon as a solvent such as dichloro methane, chloroform, carbon tetrachloride and 1, 2-dichloroethane and more preferably dichloroethane.
  • Oxidizing agent is selected from Sodium hypobromite (NaOBr), Potasium Hypobromite (KOBr), N-bromosuccinimide (NBS), bromineisocyanuric acid, peracids, Benzoyl peroxide, free radical initiator AIBN, 2KHS0 5 , KHS0 4 , K2SO4, H2O2, and mixtures thereof.
  • Sodium hypobromite and potassium hypobromite can be generated easily by reacting 2 equivalents of sodium hydroxide or potassium hydroxide with 1 equivalent of bromine in aqueous solution in the range of -5 ⁇ 0°C [Org. Syn. Coll., 5, 8 (1973)].
  • unreacted oxidizing agent such as sodium hypobromite
  • salts of thiosulfate sodium thiosulfate 100ml of water and 124g of Na2S203- 5H20. If necessary, high purity of the desired product can be obtained by conventional methods.
  • the present invention provides a novel process for the preparation of Methoxyimino-o-tolyl-acetic acid of formula (VIII) by reactingOxo-o-tolyl- acetic acid of formula (V) with Methoxyamine hydrochloride in presence of a base in an solvent optionally in the presence of phase transfer catalyst selected from the group consisting of quaternary ammonium cations, quaternary phosphoniumcations, and cyclic polyethers such as tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutylphosnhonium chloride, t
  • Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol;chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane
  • alcohols such as methanol, ethanol, propanol, butanol
  • chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride
  • hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexan
  • the present invention provides a novel process for the preparation of methyl (2E)-(methoxyimino) (2-methylphenyl) ethanoate of formula(IX) by methylation of (2E/Z)-(methoxyimino) (2-methylphenyl) Ethanoicacid of formula (VIII) in presence of thionyl chloride or triphosgene using methanol solvent.
  • the solvents used in step of the methylation are chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane; polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; or mixtures thereof.
  • chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride
  • hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane
  • polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane
  • alcohols such as methanol, ethanol,
  • In another embodiment of the present invention provides a novel process for the preparation of methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoate of formula (X) by brominatingmethyl (2E)-(methoxyimino) (2-methylphenyl)Ethanoate of formula (IX) in presence of brominating agent and an organic solvent optionally in the presence of a phase transfer catalyst.
  • the solvents used in step of the bromination are polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane or mixtures thereof.
  • These solvents are liquid at room temperature and preferably have a boiling point of 35°C to 130°C, more preferably 50°C to 100°C and in particular of 75 °C to 85 °C.
  • Brominating agents are selected from but not limited to phenyltrimethyl ammoniumtribromide; dibromodimethylhydantoin (DBDMH); potassium bromide; Sodium bromide; Br 2 ; hydrobromic acid; N-bromophthalimide; N-bromoacetamide, N-bromosuccinimide (NBS) or mixtures thereof.
  • the bromination agent is added to a solution of a compound of Formula (IX) in a solvent.
  • the mixture is preferably kept at a temperature within the range of from room temperature to reflux temperature.
  • the reaction mixture is preferably stirred for an additional time period of few minutes to 5 to 50 hours maintaining temperature between 20°C to 60°C.
  • the crude product methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoate of formula (X) is purified by recrystallizationin presences of ether class of organic solvent such as diethylether, di-isopropylether, methyl tert -butyl ether or mixture thereof.
  • ether class of organic solvent such as diethylether, di-isopropylether, methyl tert -butyl ether or mixture thereof.
  • the invention provides a novel process for the synthesis of Methoxyimino-[2-[l-(3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-phenyl]-acetic acid methyl ester of formula (I), which comprises reacting (2E)-[2-(bromo methyl) phenyl] (methoxyimino) ethanoate of formula (X) with l-(3-Trifluoromethyl-phenyl)-ethanoneoxime of formula (XI) in presence solvent and optionally in presence of a base or phase transfer catalyst.
  • base is selected from the group comprising like alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate, organolithium, organomagnesium compounds, organic base and the like or mixtures thereof.
  • Alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate used herein above are selected from NaOH, KOH, LiOH, NaHC03, KHC03, LiHC03, Na2C03, K2C03, Li2C03, Mg(OH)2, Ca(OH)2, CaC03, MgC03, Ba(OH)2, Be(OH)2, BaC03, SrC03, (CH3)3COK and the like or mixtures thereof.
  • Organolithium used herein above are selected fromn-BuLi, sec-BuLi, t-BuLi, MeLi, PhLi.
  • Organomagnesium used herein above are selected from phenylmagnesiumbromide, ethylmagnesium bromide.
  • Organic base used herein above are selected from nitrogen containing base such as pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
  • Suitable solvent is selected from but not limited to water, methyl isobutyl ketone, acetone, DMF, acetonitrile, DMSO, sulfolane; methanol, ethanol, propanol, butanol;methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; toluene, xylene, heptane, cyclohexane and hexane.
  • phase transfer catalyst is selected selected from the group consisting of quaternary ammonium cations, quaternary phosphoniumcations, and cyclic polyethers such as tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutylphosnhonium chloride, tetraoctylphosphonium bromide, and mixtures thereof.
  • the above process- 1 can be represented stepwise as shown below:
  • process-2 can also be represented stepwise as shown below:
  • 2-Methyl benzaldehyde 120.15gm 1.0 mole was slowly added with starring and within 0.50 hours at temperature 8°C to 10°C in four necked flask contain solution of water (125ml) and sodium cyanide 49.00gm (l.Omole). The solution was prepared by added sodium cyanide 49.00 gm (1.0 mole) drop wise to water (125ml) the mixture was stirred over 30 minutes, during which the temperature was maintained at -5°C to 5°C and then temperature was raised to 8°C to 10°C.
  • the aqueous layer with product was further hydrolysed in presence of 47% caustic lye (sodium hydroxide 100 gm in 112 gm water, 2.5 moles) at 30°C and the reaction was maintained for 30°C to40°C for 3 to 4 hours in presence of 1.0 gm Tetrabutylammonium bromide. After completion of reaction, reaction mass was washed with solvents such as Toluene, Xylene, EDC, MDC ETC, etc. The product obtained Hydroxy-o-tolyl-acetic acid sodium salt (182 to 183gm) having purity > 97% and the yield is 97 to98 % of the theoretical amount.
  • caustic lye sodium hydroxide 100 gm in 112 gm water, 2.5 moles
  • NaOBr sodium hypobromite
  • sodium hydroxide solution 700ml of water and 96g (2.4mol) of sodium hydroxide Cooled the reaction mixture to -5°C
  • Bromine 62ml 1.2mol was added into a dropping funnel and dropped slowly to the sodium hydroxide solution for 2 hours, keeping the internal temperature at -5°C to generate sodium hypobromite (NaOBr).
  • Oxo-o-tolyl-acetic acid (164.16 gm 1.0 mole) was dissolved in 300 ml Dichloromethane in four necked flask equipped with stirrer, thermometer, addition funnel arrangement, and in four necked flask.
  • the raeaction mass was charged with Tetrabutyl Ammonium Bromide (2.0 gm) and sodium hydroxide solution slowly at 40°C to 45°C within 2 hour.After completion of addition of sodium hydroxide solution reaction mass was maintained at 45°C for 2 to 3 hours. After 0.5 hour settling time organic layer and aqueous layer was separated.
  • N, N-Dimethylformamide (5gm) and 380 ml EDC was charged in four necked flask equipped with an overhead stirrer, thermometer and dropping funnel.
  • Methoxyimino-o-tolyl-acetic acid (193.20 gm 1.0 mole) in EDC andthionyl chloride(178.5gm 1.50 mole) was charged in reaction mass at 40 to 45 °c & completed it within 2 to 3 hours.
  • the reaction mass was maintain for 10 to 12 hours at 60°C till the z-isomer conversion is less than 1%.
  • After completion of reaction degassing the reaction mass by purging nitrogen gas for 1 hour to remove HCl and SO2 gas.Solvent was recovered by atmospheric distillation and finally under reduced pressure.
  • Methyl (2E)-(methoxyimino)(2-methylphenyl)ethanoate (207.23 gm, 1.0 mole) and N- bromosuccinamide (232 gm 1.30 mole) was charged in 1000 ml Acetonitrile.Reaction mixture was maintained at 58°C to62°C for 2 to 4 hours.After completion of reaction recovered acetonitrile under reduced pressure.The reaction mixture was turned to reddish in color and the process of the reaction monitored byTLC. After completion of reaction recovered acetonitrile under reduced pressure. The reaction mixture was charged with 100 ml water and 300 ml diisopropyl ether.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention relates to a novel process for preparation of methyl (αE)-(α- (methoxyimino)-2-[[[(E)-[1-[3- (trifluoromethyl) phenyl] ethylidene] amino] oxy] methyl] benzeneaceate (Trifloxystrobin) compound of formula (I) in free form or in agro chemically acceptable salt form useful as a pest control agent.The present invention also relates to a novel process for preparation of methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoate of formula (X) intermediate of Trifloxystrobin. [Formula should be inserted here].

Description

Title of the invention - A NOVEL PROCESS FOR THE PREPARATION OF
TRIFLOXYSTROBIN
FIELD OF THE INVENTION
The present invention relates to a novel process for preparation of methyl (αΕ)-(α- (methoxyimino)-2-[[[(E)-[l-[3- (trifluoromethyl) phenyl] ethylidene] amino] oxy]methyl] benzeneaceate (Trifloxystrobin) of formula (I) in free form or in agro chemically acceptable salt form useful as a pest control agent.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION Methyl (aE)-(a-(methoxyimino)-2-[[[(E)-[l-[3- (trifluoromethyl) phenyl] ethylidene] amino ]oxy] methyl] benzeneaceatebelongs to the strobilurin class of fungicides. Trifloxystrobin and its process for preparation were first disclosed in US5238956.It is most commonly used on bananas, cereals, citrus, coffee, corn, cotton, field beans, grapes, hops, nuts, ornamentals, peanuts, pome fruits, potatoes, rice, small fruits, soybeans, stone fruits, sugar beets, sunflowers, tea, tropical fruits, turf, vegetables and various other crops.
CN103787916Ateaches process for the preparation of Trifloxystrobin. A reaction process of the synthesis method includes water diversion treatment. By virtue of a water carrying process, the influence of water formed in the reaction on the reaction is effectively avoided, thereby reducing side reaction, and improving product yield and product quality. According to the synthesis method, a reaction liquid solvent is directly used for crystallization after the reaction so as to avoid change of crystallization solvent and to avoid cross infection of the solvents, thus further enhancing product quality.
Figure imgf000003_0001
WO2013144924teaches process for the synthesis of methyl (2E)-[2-(bro mo methyl) phenyl] (methoxyimino) ethanoate. It further relates to the conversion of methyl (2E)-[2-(bro mo methyl) phenyl] (methoxyimino) ethanoate, subsequently to substantially pure Trifloxystrobin, compound of formula (I). Synthesis for preparation of methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoateas shown in scheme as follows:
Figure imgf000003_0002
Figure imgf000003_0003
WO2013144924 also teaches preparation of methyl (2E)-[2-(bromo methyl) phenyl] (methoxyimino) ethanoate wherein R is H can be re resented as shown in scheme as follows:
Figure imgf000003_0004
i = NBS / AIBN or benzoyl peroxide
ii = NaBrOs / NaHSOs, UV or ordinary light
iii= Br / H2O2, UV or ordinary light
iv = alkali metal bromide / H2SO4 / H2O2, UV or ordinary light Rambaud, M. et al., Synthesis, 564(1988); and Korean Patent No. 88,673 PCT/KR 95/00020), teaches process for the synthesis ofmethyl (2E)-[2-(bromo methyl) phenyl] (methoxyimino) ethanoateas shown in reaction scheme:
Figure imgf000004_0001
The prior art processes for the preparation of methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoate suffer from one or other drawback like low yield, high cycle time, byproduct formation and formation of a mixture of Z and E isomers. Additionally, recovery of compound of formula (I) is not possible. This leads to an increase in the effluent treatment load, feasibility and high overall cost.
The processes for the preparation of methyl (2E)-[2-(bromo methyl) phenyl] (methoxyimino) ethanoate disclosed in the prior art do not yield E-isomer in good yield and high purity.In a subsequent step, methyl (2E)-[2-(bro mo methyl) phenyl] (methoxyimino) ethanoate is converted to Trifloxystrobin.
The prior art processes have some difficulties that may affect overall process economics. Thus WO2013144924 process incorporates hydrolysis of acyl cyanide that results a formation of 2- methyl benzoic acid formed due to decarboxylation & resulting formation of about 40 to 50% of acyl cyanide byproduct,2-Methyl Benzoic Acid .
In the light of above disadvantages there is a need to develop an improved process for the preparation of methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoate in good yield and high purity. Methyl (2E)-[2-(bromo methyl) phenyl] (methoxyimino) ethanoateis further used in the preparation of substantially pure Trifloxystrobin in good yield. There is a need to develop a commercially viable process which has the capacity to produce products in good yield, high purity, and which also has the provision to recover useful starting material and reagents from the byproduct formed during the course of the reaction. The present invention is directed to the above drawbacks, the purpose is to provide novel process for the preparation of Trifloxystrobin of formula (I) which is a mild reaction conditions, simple operation, less expensive cost effective process. OBJECTIVES OF THE INVENTION
One of the objectives of the present invention is to provide a novel process for the preparation of methyl(aE)-(a-(methoxyimino)-2-[[[(E)-[l-[3(trifluoromethyl) phenyl] ethylidene] amino] oxy] methyl] benzeneacetateof formula (I) in free form or in agro chemically acceptable salt form starting from readily accessible and cheap intermediates which are easy to handle, which process makes it possible to prepare Trifloxystrobin of formula (I) in simple manner and in good yield.
Still another objective of the present invention is to provide novel process for the preparation of an intermediate, (2-Bromomethyl-phenyl)-methoxyimino-acetic acid methyl esterof formula ( X), which is further used in the synthesis of final methyl(aE)-(a-(methoxyimino)-2-[[[(E)-[l- [3(trifluoromethyl) phenyl] ethylidene] amino] oxy] methyl] benzeneaceate (Trifloxystrobin) of formula (I) in free form or in agro chemically acceptable salt.
Still another objective of the present invention is to provide novel process for the preparation of an intermediate, oxy-o-tolyl-acetic acid of formula (VI)
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for the preparation of methyl(aE)-(a- (methoxyimino)-2-[[[(E)-[l-[3(trifluoromethyl) phenyl] ethylidene] amino] oxy]methyl] benzeneaceate (Trifloxystrob
Figure imgf000005_0001
Thus, the invention provides a simple, economically viable and efficient process for preparing methyl (aE)-(a-(methoxyimino)-2-[[[(E)-[l-[3(trifluoromethyl) phenyl] ethylidene] amino] oxy] methyl] benzeneaceate(Trifloxystrobin) of formula (I) The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated and briefly described as follows.
In one embodiment the present invention provides a novel process for the preparation of hydro xy- (2-methylphenyl)-acetonitrileof formula (III) by reacting 2-methylbenzaldehyde of formula (II) with a cyanation agent that is selected from but not limited to Sodium Cyanide or Potassium Cyanide in presence of acid or Sodium metabisulfite and solvent.
Figure imgf000006_0001
hydroxy(2-methylphenyl)acetonitrile
2-methylbenzaldehyde
Formula (III)
Formula (II)
The process for the preparation of hydroxy (2-methylphenyl) acetonitrileof formula (III) by cyanation was carried with Hydrochloride salt of 2-methylbenzaldehyde of formula (II) orbisulfite adduct of 2-methylbenzaldehyde of formula (II) with Sodium metabisulfite Or bisulfite adduct of 2-methylbenzaldehyde of formula (II) with sulphuric acid.
Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol;chloro solvents like methylene chloride,ethylene chloride, chloroform, monochlorobenzene, ; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.
In another embodiment the present invention provides a novel process for the preparation of 2- hydroxy-2-(2-methylphenyl) acetamide of formula (IV) by hydro lyzing hydroxy (2-methylphenyl) acetonitrile of formula (III) in presence of acids. The aqueous solution of sulphuric acid was added drop wise and with stirring at the temperature of about 50°-25°C for hydrolyzing hydroxy (2- methylphenyl) acetonitrile of formula (III). The resultant crude amide of formula (II) was neutralized by the addition of sodium carbonate with stirring. The sodium carbonate is reacted with sulfuric acid in the filtrate to obtain sodium sulphate.
Figure imgf000007_0001
hydroxy(2-methylphenyl)acetonitrile 2-hydroxy-2-(2-methylphenyl)acetamide Formula (III) Formula (IV)
In another embodiment the present invention provides a novel process for the preparation of Hydro xy-o-tolyl- acetic acid methyl ester of formula (VI) by reacting 2-Hydroxy-2-o-tolyl- acetamide formula (IV) with methanol in resence of acids and sol ent.
Figure imgf000007_0002
2-Hydroxy-2-0-tolyl-acetamide Hydroxy-O-tolyl-acetic acid methyl ester
Formula (IV) Formula (VI)
In another embodiment the present invention provides a novel process for the preparation of Hydro xy-o-tolyl- acetic acid methyl ester of formula (VI) by reacting hydroxy (2-methylphenyl) acetonitrile of formula (III) with methanol in presence of acid and solvent, wherein the acid is selected form hydrochloride acid and inor anic or or anic acids or mixture thereof.
Figure imgf000007_0003
Inorganic or organic acids are added into solution of Hydrochloric acid to generate hydrochloric acid gas. The hydrochloric acid gas passes through sulphuric acid trap into cyanohydrins reaction mass. The purging of hydrochloric gas into reaction mass was carried out at about -15°C to 0° C.Hydrochloric gas and methanol are continually purged in reaction mass at -15 to 10°c for 2 to 10 hours.
Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane; Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; Alcohols such as methanol, ethanol, propanol, butanol; Chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride.
Suitable inorganic or organic acids is selected from but not limited. Inorganic acids are mineral acids such as hydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuric acids, phosphoric acids and nitric acids. Organic acids are aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha. -hydroxy acids, such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tataric acid and maleic acid. An example of a tricarboxylic acid is citric acid.
In another embodiment the present invention provides a novel process for the preparation of Hydro xy-o-tolyl- acetic acid methyl ester of formula (VII) by oxidation of Oxo-o-tolyl-acetic acid methyl ester of formula (VI) in presence of oxidizing agent and a catalytic amount of a weak base such as 2,2,6, 6-t O.
Figure imgf000008_0001
Hydroxy-O-tolyl-acetic acid methyl ester Oxo-O-tolyl-acetic acid methyl ester
Formula (VI) Formula (VII)
The reaction of Oxo-o-tolyl-acetic acid methyl ester of formula (VI) expressed by the above reaction with oxidizing agent to obtain Hydroxy-o-tolyl-acetic acid methyl ester of formula (VII) is performed in the range of -10°C to 10°C, preferably in the range of -5°C to 5°C. Oxidizing agent is used in the range of 1.0 to 2.0 molar equivalents to Oxo-o-tolyl-acetic acid methyl ester of formula (VI). It is preferred to use halogenated hydrocarbon as a solvent such as dichlorome thane, chloroform, carbon tetrachloride and 1, 2-dichloroethane.
Oxidizing agent is selected from Sodium hypobromite (NaOBr), Potasium Hypobromite (KOBr), N-bromosuccinimide, bromine isocyanuric acid, peracids, 2KHSOs, KHSO4, K2SO4, H2O2, and mixtures thereof. Sodium hypobromite and potassium hypobromite can be generated easily by reacting 2 equivalents of sodium hydroxide or potassium hydroxide with 1 equivalent of bromine in aqueous solution in the range of -5 ~ 0°C [Org. Syn. Coll., 5, 8 (1973)].
After oxidation, unreacted oxidizing agent such as sodium hypobromite can be decomposed easily by treatment with salts of thiosulfate (sodium thiosulfate 100ml of water and 124g of Na2S203- 5H20). If necessary, high purity of the desired product can be obtained by conventional methods.
In another embodiment the present invention provides a novel process for the preparation of Methoxyimino-o-tolyl-acetic acid of formula (VIII) by reacting Oxo-o-tolyl-acetic acid methyl ester of formula (VII) with Methoxyamine hydrochloride in presence of a base in an solvent optionally in the presence of phase transfer catalyst such as, TBAB, TEBAC, and base used is selected from but not limited to sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diethylamine or mixtures thereof.
Figure imgf000009_0001
Oxo-O-tolyl-acetic acid methyl ester Methoxyimino-O-tolyl-acetic acid
Formula (VII) Formula(VIII)
Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, , and and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.
In another embodiment the present invention provides a novel process for the preparation of Hydroxy-O-tolyl-acetic acid sodium salt of formula (Va) by reacting hydroxy (2-methylphenyl) acetonitrile of formula (III) in presence of inorganic or organic acids.The cone .Hydrochloric acid was added drop wise and with stirring at the temperature of about 25°C-50°C followed by carried out hydrolysis in presence of base.
Figure imgf000010_0001
Hydroxy-o-tolyl-acetic acid sodium salt
Hydroxy-o-tolyl-acetonitrile
Formula-( III) Formula(Va)
Suitable solvent is selected from but not limited to water and chloro solvents like Dichloro methane, Dichloroethane, chloroform, monochlorobenzene, hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.
In another embodiment the present invention provides a novel process for the preparation of Hydroxy-o-tolyl-acetic acid of formula (V)by oxidation of Hydroxy-O-tolyl-acetic acid sodium salt of the formula (Va) using sodium hypochlorite or Sodium Hypobromite in presence of metal oxide catalysts such as Platinum, Ruthenium, Rhodium, Molybdenum incatalytic amount and/or a weak base such as 2,2,6,6-tetramethylpiperidine 1- oxyl, hereinafter abbreviated as TEMPO or its derivatives such as 4-acetoxy-2,2,6,6-tetramethylpiperidinyl-l-oxyetcin presence of phase transfer catalysts selected from the group consisting of quaternary ammonium cations, quaternary phosphoniumcations, and cyclic polyethers such as tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutylphosnhonium chloride, tetraoctylphosphonium bromide, and mixtures thereof.
Obtained resultant sodium salt of oxo-toyl-acetic acid followed by treated with the acids such as Hydrochloric Acid or Sulphuric Acid in presence of solvents such as water and chloro solvents like Methylenedichloride, Ethylenedichloride, chloroform, monochlorobenzene, hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene to give the oxo-o-toyl-acetic acid.
Figure imgf000010_0002
Hydroxy-o-tolyl-acetic acid sodium salt Oxo-o-tolyl-acetic acid
Formula(Va) Formula(V) The reaction of Oxo-o-tolyl-acetic acid of formula (V)expressed by the above reaction prepared by with oxidizing agentis performed in the range of -10°Cto50°C, preferably in the range of - 5°Cto5°C. Oxidizing agent is used in the range of 2 mole %tol0 mole % toHydroxy-o-tolyl-acetic acid sodium salt of formula (Va). It is preferred to use halogenated hydrocarbon as a solvent such as dichloro methane, chloroform, carbon tetrachloride and 1, 2-dichloroethane and more preferably dichloroethane.
Oxidizing agent is selected from Sodium hypobromite (NaOBr), Potasium Hypobromite (KOBr), N-bromosuccinimide (NBS), bromineisocyanuric acid, peracids, Benzoyl peroxide, free radical initiator AIBN, 2KHS05, KHS04, K2SO4, H2O2, and mixtures thereof.
Sodium hypobromite and potassium hypobromite can be generated easily by reacting 2 equivalents of sodium hydroxide or potassium hydroxide with 1 equivalent of bromine in aqueous solution in the range of -5 ~ 0°C [Org. Syn. Coll., 5, 8 (1973)].
After oxidation, unreacted oxidizing agent such as sodium hypobromite can be decomposed easily by treatment with salts of thiosulfate (sodium thiosulfate 100ml of water and 124g of Na2S203- 5H20). If necessary, high purity of the desired product can be obtained by conventional methods.
In another embodiment the present invention provides a novel process for the preparation of Methoxyimino-o-tolyl-acetic acid of formula (VIII) by reactingOxo-o-tolyl- acetic acid of formula (V) with Methoxyamine hydrochloride in presence of a base in an solvent optionally in the presence of phase transfer catalyst selected from the group consisting of quaternary ammonium cations, quaternary phosphoniumcations, and cyclic polyethers such as tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutylphosnhonium chloride, tetraoctylphosphonium bromide, and mixtures thereof. Base used is selected from but not limited to sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diethylamine or mixtures thereof.
Figure imgf000012_0001
Οχο-σ-tolyl-acetic acid Methoxyimino-o-tolyl-acetic acid
Formula (V) Formula(VIII)
Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol;chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.
In another embodiment the present invention provides a novel process for the preparation of methyl (2E)-(methoxyimino) (2-methylphenyl) ethanoate of formula(IX) by methylation of (2E/Z)-(methoxyimino) (2-methylphenyl) Ethanoicacid of formula (VIII) in presence of thionyl chloride or triphosgene using methanol solvent.
Figure imgf000012_0002
(2EZ)-(methoxyimino)(2 -msthylphenyl)ethanoic acid methyl(2E)-(methoxyimino)(2 -methylphenyl)ethanoate
Formula (VIII) Formula (IX)
The solvents used in step of the methylation are chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane; polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; or mixtures thereof.
In another embodiment of the present invention provides a novel process for the preparation of methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoate of formula (X) by brominatingmethyl (2E)-(methoxyimino) (2-methylphenyl)Ethanoate of formula (IX) in presence of brominating agent and an organic solvent optionally in the presence of a phase transfer catalyst.
Figure imgf000013_0001
Methoxyimino-o-tolyl-acetic acid methyl ester (2-Bromomethyl-phenyl)-methoxyimino-acetic acid methyl ester
Formula (IX) Formula(X)
The solvents used in step of the bromination are polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane or mixtures thereof. These solvents are liquid at room temperature and preferably have a boiling point of 35°C to 130°C, more preferably 50°C to 100°C and in particular of 75 °C to 85 °C.
Brominating agents are selected from but not limited to phenyltrimethyl ammoniumtribromide; dibromodimethylhydantoin (DBDMH); potassium bromide; Sodium bromide; Br2; hydrobromic acid; N-bromophthalimide; N-bromoacetamide, N-bromosuccinimide (NBS) or mixtures thereof.
In the process of the present invention the bromination agent is added to a solution of a compound of Formula (IX) in a solvent. During the addition of the bromination agent the mixture is preferably kept at a temperature within the range of from room temperature to reflux temperature. After the addition of the bromination agent is completed the reaction mixture is preferably stirred for an additional time period of few minutes to 5 to 50 hours maintaining temperature between 20°C to 60°C. The crude product methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoate of formula (X) is purified by recrystallizationin presences of ether class of organic solvent such as diethylether, di-isopropylether, methyl tert -butyl ether or mixture thereof.
In a preferred embodiment, the invention provides a novel process for the synthesis of Methoxyimino-[2-[l-(3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-phenyl]-acetic acid methyl ester of formula (I), which comprises reacting (2E)-[2-(bromo methyl) phenyl] (methoxyimino) ethanoate of formula (X) with l-(3-Trifluoromethyl-phenyl)-ethanoneoxime of formula (XI) in presence solvent and optionally in presence of a base or phase transfer catalyst.
Figure imgf000014_0001
Methoxyimino-{2-[l-(3-trifluoromethyl-phenyl)-
Figure imgf000014_0002
ethylideneaminooxymethyl]-phenyl)-acetic acid methyl ester
Formula (X) Formula (XI) Formula (I)
In a preferred embodiment, base is selected from the group comprising like alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate, organolithium, organomagnesium compounds, organic base and the like or mixtures thereof. Alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate used herein above are selected from NaOH, KOH, LiOH, NaHC03, KHC03, LiHC03, Na2C03, K2C03, Li2C03, Mg(OH)2, Ca(OH)2, CaC03, MgC03, Ba(OH)2, Be(OH)2, BaC03, SrC03, (CH3)3COK and the like or mixtures thereof. Organolithium used herein above are selected fromn-BuLi, sec-BuLi, t-BuLi, MeLi, PhLi. Organomagnesium used herein above are selected from phenylmagnesiumbromide, ethylmagnesium bromide. Organic base used herein above are selected from nitrogen containing base such as pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
Suitable solvent is selected from but not limited to water, methyl isobutyl ketone, acetone, DMF, acetonitrile, DMSO, sulfolane; methanol, ethanol, propanol, butanol;methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; toluene, xylene, heptane, cyclohexane and hexane.
In a preferred embodiment, phase transfer catalyst is selected selected from the group consisting of quaternary ammonium cations, quaternary phosphoniumcations, and cyclic polyethers such as tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutylphosnhonium chloride, tetraoctylphosphonium bromide, and mixtures thereof. The above process- 1 can be represented stepwise as shown below:
Figure imgf000015_0001
Formula (VI)
NaOBr
Figure imgf000015_0002
Formula (VIII) Formula (VII)
Formula (X)
Figure imgf000015_0003
he above process-2 can also be represented stepwise as shown below:
Figure imgf000016_0001
Formula (II) Formula (III) Formula (Va)
Figure imgf000016_0002
The process of the invention is illustrated with reference to the following Examples and is not intended to limit the scope of the invention. Any permutations and modifications in the process are possible without limiting the scope of the invention.
Example 1; Preparation of Hydroxy-o-tolyl-acetonitrile (Process: A)
Figure imgf000016_0003
2-Methyl-benzaldehyde Hydroxy-o-tolyl-acetonitrile
Formula(II) Formula (ΠΙ)
2-Methyl benzaldehyde (120.15gm 1.0 mole) was slowly added with starring and within 0.50 hours at temperature 8°C to 10°C in four necked flask contain solution of water (125ml) and sodium cyanide 49.00gm (l.Omole).The solution was prepared by added sodium cyanide 49.00 gm (1.0 mole) drop wise to water (125ml) the mixture was stirred over 30 minutes, during which the temperature was maintained at -5°C to 5°C and then temperature was raised to 8°C to 10°C. After completion of addition reaction mass was stirred for 15 minutes and then 40 % sulfuric acid [83.0 gm sulphuric acid (0.84 mole) in 125 ml water] was added over a period of three hours, the temperature was maintained between 10°C and 20°Candreaction mixture was stirredfor fifteen minutes. After completion of reaction the product was extracted in dichloroethane and dried over anhydrous sodium sulfate. The dichloroethane layer taken as such for next reaction .In dichloroethane layer contains Hydroxy-o-tolyl-acetonitrile having purity >98.5% and the yield is 98-99 % of the theoretical amount. Example 2:Preparation of Hydroxy-o-tolyl-acetonitrile (Process: B)
2-Methylbenzaldehyde (24.03gm, 0.2 moles) was charged to solution of Con. Hydrochloric acid (18 ml, 21.6 g, and 0.2 mole) and water (17ml) in a 200 ml three neck flask at 0°C.The resulting mixture was cooled to -5°C to give slurry of 2-Methylbenzaldehyde hydrochloride. The reaction mixture was charged with solution of sodium cyanide (11.00 g, 0.22 moles) in 40 grams of water, drop wise and stirred mixture over 30 minutes, during which the temperature was maintained at - 5°C to -l°C.During the addition a yellow solution was obtained after approximately half the cyanide solution has been added but slurry is again formed towards the end of the addition. Stirring was continued for one hour after the addition was complete. Hydrochloric acid (1 ml) was added to bring the mixture to pH=7. After completion of reaction the product was extracted in ethyl acetate was added and the mixture warmed to 10°C whereupon two clear layers were obtained. Ethyl acetate layer was removed and evaporated to give a 28 gm Hydroxy-o-tolyl-acetonitrile having purity >96% and the yield is 95 % of the theoretical amount
Example 3:Preparation of Hydroxy-o-tolyl-acetonitrile (Process-C)
2-Methylbenzaldehyde (120.15 gm 1.0 mole) was charged to solution of Sodium bisulfite (105 gm 1.0 mole) in water (475 gm) at room temperature and temperature was maintained below 35 °C. To the reaction mixture sodium cyanide (49 gm 1.0 mole) was addedin portions to the solution and the temperature was maintained between 25°Cto 35°C. An oil phase separated out as an upper layer and this was separated from the lower aqueous layer. The aqueous layer was then extracted with dichloroethane and the resulting dichloroethane extracts were combined with the separated oil layer. Organic layer was dried over anhydrous sodium sulfate, and subjected to vacuum distillation at a heating bath temperature of 40°C to remove the dichloroethane. The residue obtained of Hydroxy (2-methylphenyl) acetonitrile was 132 grams. The yield of Hydroxy (2- methylphenyl) acetonitrile was 90%. Example 4: Pre aration of H drox -o-tol l-acetic acid sodium salt Process- A)
Figure imgf000018_0001
Hydroxy-o-tolyl-acetic acid sodium salt
Hydroxy-o-tolyl-acetonitnle J J J
Formula-( III) Formula(IVa)
Hydroxy-O-tolyl-acetonitrile (147.17gm 1.0 mole)was added to 300 ml dichloroethane in four necked flask equipped with an overhead stirrer, thermometer and dropping funnel and further added Tetrabutyl ammonium bromide (1.0 mole%). The reaction mass was treated with Hydrochloric acid (125 gm, 1.03 mole, 30% HCl ) at 30°C. The reaction mass was maintained for 20 to 22 hours at 30°C. After completion of reaction product was separated in aqueous layer and organic layer. The aqueous layer with product was further hydrolysed in presence of 47% caustic lye (sodium hydroxide 100 gm in 112 gm water, 2.5 moles) at 30°C and the reaction was maintained for 30°C to40°C for 3 to 4 hours in presence of 1.0 gm Tetrabutylammonium bromide. After completion of reaction, reaction mass was washed with solvents such as Toluene, Xylene, EDC, MDC ETC, etc. The product obtained Hydroxy-o-tolyl-acetic acid sodium salt (182 to 183gm) having purity > 97% and the yield is 97 to98 % of the theoretical amount.
Example 5: Preparation of Oxo-o-tolyl-acetic acid (Process-A)
Figure imgf000018_0002
sodium hydroxy(2-methylphenyl)acetate (2-methylphenyl)(oxo)acetic acid
Formula (Va) Formula (V)
Sodium hypobromite (NaOBr) was generated by bromine with sodium hydroxide solution (700ml of water and 96g (2.4mol) of sodium hydroxide Cooled the reaction mixture to -5°C), Bromine (62ml 1.2mol) was added into a dropping funnel and dropped slowly to the sodium hydroxide solution for 2 hours, keeping the internal temperature at -5°C to generate sodium hypobromite (NaOBr).
Hydroxy-o-tolyl-acetic acid sodium salt (188.16 gm lmol) in 700ml of dichloromethane was charged to the solution of sodium hypobromite (NaOBr) and 4-acetoxy-2, 2, 6, 6- tetramethylpiperidinyl-l-oxy (5 mole%) and 10 ml of IN sulfuric acidso that the temperature was not exceeding 0°C.The reaction mixtures was stirred for 24 hours at room temperature. After completion of reaction pH was adjusted to 3.0 to 4.0 with hydrochloric acid.The organic layer and aqueous layer was separated. The aqueous layer was extracted twice with dichlorome thane. Removed solvent on a rotary evaporator under reduced pressure to get a target compound. 154.31gm oxo-o-tolyl acetic acid having purity <97% and Yield = 94%.
Example 6: Preparation of Oxo-o-tolyl-acetic acid (Process: B)
Hydro xy-o-tolyl- acetic acid sodium salt (37.63g 200 mmol) dissolved in methylene chloride (100 ml) and charged sodium hypochlorite (148.8 g 240 mmol), and cool at 5°C. To the reaction mixture 4-acetoxy-2, 2, 6, 6-tetramethylpiperidinyl-l-oxy (86mg 0.4 mmol) and sodium hydrogen carbonate (3.02 g 0.18 mmol) was added. The reaction mass was maintained for 24 hours at same temperature.After disappearing the starting material reaction terminated by adding 100 ml of 5% sodium thiosulfate aqueous solution. Organic and aqueous layer where separated andthe organic phase washed with 50 ml of 5% sodium thiosulfate aqueous solution and then with 100 ml of 1% sodium carbonate aqueous solution. Solvent was removed on a rotary evaporator under reduced pressure to obtain Oxy-o-tolyl -acetic acid (30.06gm (92% Yield).
Example 7: Preparation of Oxo-o-tolyl-acetic acid (Process: C)
Hydro xy-o-tolyl- acetic acid sodium salt ( 18.81g 100 mmol) was dissolved in methylene chloride (50 ml) in 200 ml flask and was charged with of sodium hypochlorite (72.6 g (purity 12.3%, 120 mmol)), and cool at 6°C. To the reaction mixture was added 43 mg (0.2 mmol) of 4-acetoxy-2, 2, 6, 6-tetramethylpiperidinyl-l-oxy and further added 10 ml of IN hydrochloric acid. The reaction mass was maintained for 1 hour. After the completion of reaction, reaction was stopped by adding 10 ml of 5% sodium thiosulfate aqueous solution and separated by organic and aqueous layer. The organic phase was washed with 25 ml of 5% sodium thiosulfate aqueous solution and then 50ml of 1% sodium carbonate aqueous solution. Solvent was removed on a rotary evaporator under reduced pressure to obtain compoundoxy-o-tolyl -acetic acid. Wt. =16.41gm. The yield =90%
Example 8: Preparation of Oxo-o-tolyl-acetic acid (Process: E)
According to the same procedure as described in Example 7, Hydroxy-o-tolyl-acetic acid sodium salt (18.81 g 100 mmol) was dissolved in methylene chloride (50 ml), and tehn treated with 72.6 g (purity 12.3%, 120 mmol) of sodium hypochlorite, 5 mole% (2,2,6,6-Tetramethyl-piperidin-l- yl-)oxyl (TEMPO), 5mole% TBAB and 10 ml of IN sulfuric acid, to obtain compound oxy-o-tolyl -acetic acid (15.03 g). The yield was 92%. Example 9: Preparation of Methoxyimino-o-tolyl-acetic acid
Figure imgf000020_0001
Oxo-o-tolyl-acetic acid Methoxyimino-o-tolyl-acetic acid Formula (V) Formula(VIII)
Oxo-o-tolyl-acetic acid (164.16 gm 1.0 mole) was dissolved in 300 ml Dichloromethane in four necked flask equipped with stirrer, thermometer, addition funnel arrangement, and in four necked flask. The raeaction mass was charged with Tetrabutyl Ammonium Bromide (2.0 gm) and sodium hydroxide solution slowly at 40°C to 45°C within 2 hour.After completion of addition of sodium hydroxide solution reaction mass was maintained at 45°C for 2 to 3 hours. After 0.5 hour settling time organic layer and aqueous layer was separated. In the aqueous layer 300 ml Dichloromethane and 30% solution of Methoxyamine Hydrochloride (125gm, 1.5 mole) was charged at 30°C to 40 °C. the reaction mass was maintained for 1 hour at 45 °C. The reaction mass was separated by layer separation after 0.5 hour settling time separated the organic layer and aqueous layer. Organic layer contains Methoxyimino-o-tolyl-acetic acid (197gm) and the product was taken as such for water removal azeotropically. The final product obtained wasmethoxyimino-o-tolyl acetic acid (181.60 gm). % Yield = 94% %Purity = 97% (E & Z isomer).
ExamplelO: Preparation of Methyl(2E)-(methoxyimino)(2-methylphenyl)ethanoate
(Process-A)
Figure imgf000020_0002
Formula (VIII) Formula (IX)
N, N-Dimethylformamide (5gm) and 380 ml EDCwas charged in four necked flask equipped with an overhead stirrer, thermometer and dropping funnel.Methoxyimino-o-tolyl-acetic acid (193.20 gm 1.0 mole) in EDC andthionyl chloride(178.5gm 1.50 mole) was charged in reaction mass at 40 to 45 °c & completed it within 2 to 3 hours. The reaction mass was maintain for 10 to 12 hours at 60°C till the z-isomer conversion is less than 1%. After completion of reaction degassing the reaction mass by purging nitrogen gas for 1 hour to remove HCl and SO2 gas.Solvent was recovered by atmospheric distillation and finally under reduced pressure. Then charge 200 ml methanol in reaction mass and reflux for 2 hours till to get clear solution.Then gradually the reaction mass was cooled upto 10°C.Filter the reaction mass and treated with chilled methanol wash to cake. Wt. of Methyl (2E)-(methoxyimino) (2-methylphenyl) ethanoate= 186.50 gm % yield = 90% ; % Purity>97%
Example!!: Preparation of Methyl (2E)-(methoxyimino) (2-methylphenyl) ethanoate Process: B
N, N-Dimethylformamide (5 gm) in EDC 300 ml was charged in four necked flask equipped with thermometer, stirrer, and additional funnel arrangement. Methoxyimino-o-tolyl-acetic acid (193.20 gm 1.0 mole) in EDCand Triphosgene (119 gm 0.40 mole) was added in reaction mass at 40°C to 45°Cand completed it in within 2 to 3 hours and further reaction was maintained for 10 to 12 hours at 60°C till the z-isomer conversion is less than l%.If z-isomer is greater than 1% then add triphosgene again maintain for another two hours.Degassing the reaction mass by purging nitrogen gas by 1 hour to remove HC1 and SO2 gas. Solvent was recovered by atmospheric distillation and finally under reduced pressure. Then charge 190 ml methanol in reaction mass and reflux for 2 hours till to get clear solution. Then gradually the reaction mass was cooled upto 10°C. Filter the reaction mass and treated with chilled methanol wash to cake. Wt. of Methyl (2E)- (methoxyimino) (2-methylphenyl) ethanoate =195 gm to 196 gm. % yield = 94to 95% ;
% Purity>97%
Example 12: Preparation of methyl(2E)-r2-(bromomethyl)phenyll(methoxyimino) ethanoate
Figure imgf000021_0001
Methoxyimino-o-tolyl-acetic acid methyl ester (2-Bromomethyl-phenyl)-methoxyimino-acetic acid methyl ester
Formula (IX) Formula(X)
Methyl (2E)-(methoxyimino)(2-methylphenyl)ethanoate (207.23 gm, 1.0 mole) and N- bromosuccinamide (232 gm 1.30 mole) was charged in 1000 ml Acetonitrile.Reaction mixture was maintained at 58°C to62°C for 2 to 4 hours.After completion of reaction recovered acetonitrile under reduced pressure.The reaction mixture was turned to reddish in color and the process of the reaction monitored byTLC. After completion of reaction recovered acetonitrile under reduced pressure. The reaction mixture was charged with 100 ml water and 300 ml diisopropyl ether. The solutions was washed with 10%aqueous sodium bisulfate solution2*300 ml.Finally washed with water 2*300 ml.Organic layer dried over sodium sulphate and chill to -5°C and filtered. The solid washed with chill Diisopropyl ether to obtain methyl (2E)-[2-(bromoMethyl) phenyl] (methoxyimino) ethanoate. Wt. of the product= 241 gm % Purity of the product= 98% ; %Yield =84%
Example 13: Preparation of Trifloxystrobin
Figure imgf000022_0001
(2-Bromomethyl-phenyl)-methoxyimino 1 -(3-Trifluoromethyl-phenyl) Methoxyimino-{2-[l-(3-trifruoromethyl-phenyl)- -acetic acid methyl ester -ethanone oxime ethylideneaminooxymethyl]-phenyl}-acetic acid methyl ester
Formula (X) Formula (XI) (E-isomer)
Formula (I)
(2-bromomethyl-phenyl)-methoxyiminoacetic acid methyl ester (315 gm, 1.10 mole)was dissolved in 1500 ml methyl isobutyl ketone.To this solution was added Intermediate-II (203.16gm 1.0 mole ) at room temperature followed by potassium carbonate ( 145gm 1.05 mole).The reaction mixture was heated to 115°c for 12 to hours. After completion of reaction mixture was cooled to room temperature and filtered to remove potassium bromide by-product and excess potassium carbonate. The solid obtained after filtration was washed with methyl isobutyl ketone and recycled in next batch for the preparation of Trifloxystrobin. The filtrate was washed with water and dried over anhydrous sodium sulphate and concentrated under vacuum to obtain crude product. The crude product was recrystallised in methanol to give off white colored product of Trifloxystrobin =348 gm. % Yield= 85% ; %Purity>98%

Claims

CLAIMS: We Claims
[Claim 1], An novel process for the preparation of the compound of formula (X) which comprises the steps of :
a) methylation of (2E/Z)-(methoxyimino) (2-methylphenyl) Ethanoic acid compound of formula (VIII) in presence of thionyl chloride or triphosgene and solvent to obtain methyl (2E)-(methoxyimino) (2- methylphenyl) ethanoate compound of formula (IX);
Figure imgf000023_0001
Formula (VIII) Formula (IX)
b) brominating methyl (2E)-(methoxyimino) (2-methylphenyl) Ethanoate compound of formula (IX) in presence of brominating agent and an organic solvent optionally in the presence of a phase transfer catalyst to obtain methyl (2E)-[2-(bromomethyl) phenyl] (methoxyimino) ethanoate of formula (X)
Figure imgf000023_0002
[Claim 2]. A novel process as claimed in claim 1 wherein, suitable solvent is selected from the group consistingmethylene chloride, chloroform, monochlorobenzene, ethylene chloride, toluene, xylene, heptane, cyclohexane, hexane, acetone, DMF, acetonitrile, DMSO, sulfolane, methanol, ethanol, propanol, butanol, or mixtures thereof.
[Claim 3], A novel process as claimed in claim 1 wherein, brominating agent are selected from the group consisting phenyltrimethyl ammoniumtribromide; dibromodimethylhydantoin (DBDMH); potassium bromide; Sodium bromide ; Br2; hydrobromic acid; N-bromophthalimide; N-bromoacetamide, N- bromosuccinimide (NBS), in Combination with the AIBN or Benzoyl peroxide or mixtures thereof.
[Claim 4]. A novel process as claimed in claim 1 wherein phase transfer catalyst selected from the group consisting Tetrabuylammonium bromide, Tetrabutyammonium chloride, of quaternary ammonium cations, quaternary phosphoniumcations, and cyclic polyethers such as tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutylphosnhonium chloride, tetraoctylphosphonium bromide, and mixtures thereof.
[Claim 5], A novel process for the preparation of the compound of the formula (VIII) comprises the steps of :
Figure imgf000024_0001
Formula (VIII)
a) Reacting the compound of the formula (II) with Metal Cyanide in presence of acid and water to obtain compound of the formula (III)
Figure imgf000025_0001
Formula (II)
Formula (III) b) Hydrolysed the compound of the formula (III) by using acid and sodium hydroxide in presence of solvent to obtain compound of the formula (Va).
Figure imgf000025_0002
Formula-( III) Formula(Va)
c) Oxidation of the compound of the formula (Va) with oxidizing agent to obtain com ound of the formula (V)
Figure imgf000025_0003
Formula(Va) Formula(V)
d) Compound of the formula (V) reacted with Methoxyamine hydrochloride in presence of base and chlorinated solventselected from the group consisting Dichloroethane, Dichloromethane, Toluene,xylene monochlorob (VIII)
Figure imgf000025_0004
Formula (V) Formula(VIII)
[Claim 6], A novel process for the preparation of the compound of the formula (VIII) comprises the steps of :
Figure imgf000026_0001
Formula (VIII)
a) Reacting the compound of the formula (II) with Metal Cyanide in presence of acid and water to obtain compound of the formula (III)
Figure imgf000026_0002
Formula (II) Formula (III) b) hydrolyzing hydroxy (2-methylphenyl) acetonitrile of formula (III) in presence of acids to obtain compound of compound of formula (IV);
Figure imgf000026_0003
Formula (III) Formula (IV) c) reacting2-Hydroxy-2-o-tolyl-acetamide compound of formula (IV) with methanol in presence of acids to obtain compound of compound of formula (VI)
Figure imgf000026_0004
Formula (IV) Formula (VI)
OR
reacting hydroxy (2-methylphenyl) acetonitrile of formula (III) with methanol in presence of acid to obtain compound of compound of formula (VI)
Figure imgf000027_0001
Formula (III) Formula (VI)
d) oxidation of Oxo-o-tolyl-acetic acid methyl ester of formula (VI) in presence of oxidizing agent and a catalytic amount of a weak base 2,2,6,6- tetramethylpiperidine 1- oxyl (TEMPO) to obtain the compound of the formula (VII)
Figure imgf000027_0002
Formula (VI) Formula (VII)
e) Reacting Oxo-o-tolyl-acetic acid methyl ester of formula (VII) with Methoxyamine hydrochloride in presence of a base and optionally in the presence of phase transfer catalyst to obtain the compound of the formula (VIII)
Figure imgf000027_0003
Formula (VII) Formula(Vffl)
[Claim 7], A novel process as claimed in claim 6 & 7 wherein the metal cyanide are Sodium
Cyanide, Potassium Cyanide, Cuprous Cyanide.
[Claim 8]. A novel process as claimed in claim 6 & 7wherein the acid are Con. hydrochloric acid or Hydrochloride gas.
[Claim 9]. A novel process as claimed in claim 6 & 7wherein oxidizing reagents are Sodium
Hypochlorite (NaOCl), Sodium Hypobromite (NaOBr).
[Claim 10]. A novel process as claimed in claim 6 & 7wherein oxidizing catalysts selected from the group consisting Ruthenium Dioxide,Tempo (2,2,6,6-Tetramethyl- piperidin-l-yl)oxyl), 4-acetoxy-2,2,6,6-tetramethylpiperidinyl-l-oxy,Tetrabutyl ammonium bromide or mixture thereof.
[Claim 11], A novel process as claimed in claim 6 & 7wherein methoxyimination carried out in presence of base selected from the group consisting sodium hydroxide potassium hydroxide, sodium carbonate, potassium carbonate.
[Claim 12]. An improved process for the preparation of the compound of the formula ( I ) by reacting compound of the formula ( X ) with the compound of the formula (XI) in presence of solventselected from Toluene Xylene, Methylisobutyl ketone, acetonitrile, N, N-Dimethylformamideand optionally in presence of a base or phase transfer catalyst.
Figure imgf000028_0001
[Claim 13]. A novel process as claimed in claim 12 wherein baseis selected from Sodium
Hydroxide, Potassium Hydroxide, Sodium Carbonate, Potassium Carbonate, triethylamine.
[Claim 14]. A novel process as claimed in claim 12 wherein phase transfer catalyst selected from the group consisting of quaternary ammonium cations, quaternary phosphoniumcations, and cyclic polyethers such as tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutylphosnhonium chloride, tetraoctylphosphonium bromide, and mixtures thereof.
[Claim 15]. A novel process as claimed in claim 12 wherein the compound of the formula (I) obtained having purity >97%.
PCT/IN2016/050411 2015-11-19 2016-11-18 A novel process for the preparation of trifloxystrobin WO2017085747A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680071842.3A CN108368033B (en) 2015-11-19 2016-11-18 Method for preparing trifloxystrobin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3957/MUM/2015 2015-11-19
IN3957MU2015 2015-11-19

Publications (3)

Publication Number Publication Date
WO2017085747A2 true WO2017085747A2 (en) 2017-05-26
WO2017085747A3 WO2017085747A3 (en) 2017-08-03
WO2017085747A4 WO2017085747A4 (en) 2017-10-26

Family

ID=57963396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2016/050411 WO2017085747A2 (en) 2015-11-19 2016-11-18 A novel process for the preparation of trifloxystrobin

Country Status (2)

Country Link
CN (1) CN108368033B (en)
WO (1) WO2017085747A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019049167A1 (en) 2017-09-11 2019-03-14 Hikal Limited "an improved process for the preparation of trifloxystrobin"

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113480517B (en) * 2021-07-30 2022-09-09 海南海神同洲制药有限公司 Synthetic method of 3-bromomethyl-7-chlorobenzo [ b ] thiophene
CN114436833A (en) * 2021-12-27 2022-05-06 南京红太阳医药研究院有限公司 Preparation method of telmisartan key intermediate 4' -methylbiphenyl-2-carboxylic ester

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3917352A1 (en) * 1989-05-27 1990-11-29 Basf Ag NEW OXIMETERS AND FUNGICIDES CONTAINING THEM
WO2003000840A2 (en) * 2001-06-21 2003-01-03 Diversa Corporation Nitrilases
WO2013144924A1 (en) * 2012-03-29 2013-10-03 Rallis India Ltd. An improved process for the synthesis of strobilurin fungicides viz trifloxystrobin and kresoxim-methyl

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019049167A1 (en) 2017-09-11 2019-03-14 Hikal Limited "an improved process for the preparation of trifloxystrobin"
JP2020533349A (en) * 2017-09-11 2020-11-19 ヒカル リミテッド Improved method of preparing trifloxystrobin
JP7160906B2 (en) 2017-09-11 2022-10-25 ヒカル リミテッド Improved method for preparing trifloxystrobin
US11649204B2 (en) 2017-09-11 2023-05-16 Hikal Limited Process for the preparation of trifloxystrobin

Also Published As

Publication number Publication date
WO2017085747A3 (en) 2017-08-03
WO2017085747A4 (en) 2017-10-26
CN108368033B (en) 2021-05-04
CN108368033A (en) 2018-08-03

Similar Documents

Publication Publication Date Title
AU612621B2 (en) Benzoylpiperidines and benzoylpiperidine oxides and oximes and their preparation
WO2017085747A2 (en) A novel process for the preparation of trifloxystrobin
WO2013144924A1 (en) An improved process for the synthesis of strobilurin fungicides viz trifloxystrobin and kresoxim-methyl
JP2020158517A (en) Recovery of carboxylic acid from their magnesium salts by precipitation using hydrochloric acid, useful for fermentation broth work-up
EA027341B1 (en) Recovery of carboxylic acid from its magnesium salts by precipitation using hydrochloric acid, useful for fermentation broth work-up
CN110437138B (en) Improved synthesis process of fluopyram
JP7399850B2 (en) Method for producing aromatic nitrile compounds
US20160060248A1 (en) Synthesis of dabigatran
US10723693B2 (en) Method for preparing benzoic acid amide compound
EP3592724A2 (en) Process for preparation of halo substituted benzoic acid compound and intermediates thereof
JP5009306B2 (en) Process for producing 2-isopropenyl-5-methyl-4-hexen-1-yl 3-methyl-2-butenoate
NO341142B1 (en) Process for the preparation of entacapone
JP2002255954A (en) METHOD FOR PRODUCING 2-n-BUTYL-5-NITROBENZOFURAN
JP3481623B2 (en) Method for producing hydroxylamine ether and salts thereof and intermediate product therefor
CN112341362B (en) Cis-para-substituted cyclohexyl amino nitrile malate, and preparation and application thereof
CN104030942B (en) A kind of preparation method of L-alpha-amido butanamide hydrochloride
JP4838465B2 (en) Process for producing 4-hydroxyphenylpyruvic acid
JP4300739B2 (en) Preparation of 2-amino-5-halogenoindole
JP2009242243A (en) alpha-HYDROXYIMINO CARBOXYLIC ACID ESTER DERIVATIVE AND METHOD FOR PRODUCING alpha-AMINO-alpha-HALOALKYL CARBOXYLIC ACID ESTER DERIVATIVE BY USING THE SAME
JPH10273475A (en) Production of 3-hydroxy-2-methylbenzoic acid and 3-acetoxy-2-methylbenzoic acid
JP4000278B2 (en) Process for producing ω-bromoalkylmalonic acid and ω-bromoalkylcarboxylic acid
JP4273648B2 (en) Method for producing ω-cyanoaldehyde compound
RU2722316C2 (en) New method of producing teriflunomide
CN116354846A (en) Synthesis process method of pesticide kresoxim-methyl
JP2010222302A (en) Method for producing 7,8-difluoro-2-naphthol

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16834126

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16834126

Country of ref document: EP

Kind code of ref document: A2