WO2013144924A1 - Procédé amélioré de synthèse de fongicides de strobilurine c'est-à-dire de trifloxystrobine et de krésoxim-méthyl - Google Patents

Procédé amélioré de synthèse de fongicides de strobilurine c'est-à-dire de trifloxystrobine et de krésoxim-méthyl Download PDF

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WO2013144924A1
WO2013144924A1 PCT/IB2013/052565 IB2013052565W WO2013144924A1 WO 2013144924 A1 WO2013144924 A1 WO 2013144924A1 IB 2013052565 W IB2013052565 W IB 2013052565W WO 2013144924 A1 WO2013144924 A1 WO 2013144924A1
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formula
compound
preparation
ether
isomer
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PCT/IB2013/052565
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Pasumpon KAMARAJ
Vijay Shrikant SATAM
Mahalingappa Sridhara AJJANNA
Tapaskumar NANDI
Anna BOBADE
Ravindra SHINDE
Parag Naik
Dhanaji MOHITE
Subhash KADAM
Rama Mohan Hindupur
Hari Narayan PATI
Avinash Mane
Suphala Gopinath VADIRAJ
Prabhu Moodbidri VENKATESH
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Rallis India Ltd.
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    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to an improved process for the synthesis of strobilurin fungicides viz Trifloxystrobin and Kresoxim-methyl.
  • Trifloxystrobin which is (i?)-methoxyimino- ⁇ (i?)-2-[l-(3-trifluoromethylphenyl)- ethylideneaminooxymethyl]phenyl ⁇ acetic acid methyl ester belongs to the strobilurin class of fungicides. Trifloxystrobin and its process for preparation were first disclosed in US5238956. It has the following structural formula:
  • Kresoxim-methyl which is methyl (a£)-a-(methoxyimino)-2-[(2-methylphenoxy) methyl] phenylacetate also belongs to the strobilurin class of fungicides. Kresoxim-methyl was first disclosed in US4829085. It has the following structural formula:
  • US5334577 teaches conversion of compound of formula (IV) to compound of formula (VI) at Column 3, line 43 to line 65. It further teaches at Column 3, line 55 to line 68 and column 4, line 1 to line 6, conversion of compound of formula (VI) to formula (III).
  • US6407100 teaches at column 5; line 32-43, preparation of formula (II). It further discloses at column 4; line 45 to line 67 the process for condensation of formula (II) and formula (III).
  • the present inventors have surprisingly developed an improved process for the synthesis of compound of formula (5) and its conversion to Intermediate (I), when R is H, which ameliorates the drawbacks of the prior art.
  • keto compound of formula (4) contains alpha-substituted-o-toluic acid methyl ester, which is obtained as a by-product during the conversion of compound of formula (3) to compound of formula (4), to the extent of -20%.
  • the process of the present invention proceeds through selective hydrolysis of compound of formula (4) which remains in the aqueous layer as a sodium salt.
  • the by-product i.e. alpha-substituted-o-toluic acid methyl ester
  • alpha-substituted-o-toluic acid methyl ester is not hydrolyzed under the above reaction conditions and thus remains in the organic layer which is separated before carrying out next step and hydrolyzed separately using sodium hydroxide in presence of water to recover alpha-substituted-o-toluic acid i.e. compound of formula (1) having purity of -98 % by HPLC which is the starting material of the process of the present invention.
  • the present inventors have found that selective hydrolysis of compound of formula (4) in the presence of alpha-substituted-o-toluic acid methyl ester leads to recovery of compound of formula (1) i.e. alpha-substituted-o-toluic acid which is the starting material for the process of the present invention, thereby reducing the cost of the process and load on effluent treatment.
  • the recovered compound of formula (1) is used to make compound of formula (5) having same quality as compared to that obtained from compound of formula (1) available commercially.
  • compound of formula (4b) is obtained as a -50:50 mixture of Z and E isomers which on esterification using thionyl chloride and methanol gives compound of formula (5) having E-geometry, exclusively.
  • bromination reaction of compound of formula (5 a) using sodium bromate in combination with sodium bisulfite (NaBrCb / NaHSCb) in presence of light (UV or ordinary) in biphasic medium of water immiscible "ester class of organic solvents" such as ethyl acetate, n-butyl acetate, isopropyl acetate etc and water results in higher conversion of compound of formula (5a) into Intermediate (I) giving higher yield and purity than any other process reported in the literature.
  • the present inventors found that bromination reaction of compound of formula (5 a) using N-bromosuccinimide in combination with ⁇ or benzoyl peroxide in an organic solvent such as acetonitrile, ethyl acetate, dichloromethane, chloroform, chlorobenzene etc, results in higher conversion of compound of formula (5a) to Intermediate (I) giving higher yield as compared to the yield obtained by the use of other solvents such as DCM, EDC, CTC, ethyl acetate, chlorobenzene etc.
  • organic solvent such as acetonitrile, ethyl acetate, dichloromethane, chloroform, chlorobenzene etc
  • bromination reaction of compound of formula (5a) using bromine in presence of light (UV or ordinary) in biphasic reaction medium of dichloromethane and water results in higher conversion of compound of formula (5a) into Intermediate (I) giving higher yield and purity than any other process reported in the literature.
  • alkali metal bromide such as lithium bromide, sodium bromide, potassium bromide, etc in combination with sulphuric acid and hydrogen peroxide (LiBr, NaBr or KBr / H 2 SO 4 / H 2 O 2 )
  • halogenated solvent such as dichloromethane, chloroform, dichloroethane, etc results in higher conversion of compound of formula (5a) into Intermediate (I) giving higher
  • the crude Intermediate (I) is purified by recrystallization using diisopropyl ether, which, as per the procedures disclosed in the literature, is purified by column chromatography.
  • the purification of Intermediate (I) by recrystallization in diisopropyl ether is a simple, convenient and cost effective method to obtain highly pure Intermediate (I) compared to purification of Intermediate (I) by column chromatography.
  • the present inventors have developed an improved process in which compounds of formula (2), (3), (4), (4a) and (4b) are not isolated.
  • the compound of formula (4) is subjected to hydrolysis, methoxyimination and esterification, in situ, to obtain compound of formula (5) i.e. one pot synthesis of compound of formula (5).
  • the one pot reaction to obtain compound (5) from compound (1) reduces cycle time as the time spent on isolation and purification of each intermediate and solvent recovery is saved. Additionally, the cost of the process is reduced as solvent consumption is minimum and loss in isolation and purification of each intermediate is avoided.
  • an improved process for the preparation of compound of formula (5) which comprises the steps of: i. Reacting a compound of formula (1):
  • Formula (2) ii Converting compound of formula (2) to compound of formula (3) by using e in presence of water in an organic solvent;
  • an improved process for the preparation of Intermediate (I) from E-isomer of compound of formula (5), wherein R is Hydrogen i.e. compound of formula (5a) which comprises the steps of: i. Bromination of compound of formula (5a) to obtain Intermediate (I) using sodium bromate in combination with sodium bisulfite, (NaBrCb / NaHSCb) in biphasic medium of water immiscible "ester class of organic solvents" such as ethyl acetate, n-butyl acetate, isopropyl acetate etc and water in presence of
  • an improved process for the preparation of Intermediate (I) from E-isomer of compound of formula 5, wherein R is Hydrogen i.e. compound of formula (5a) which comprises the steps of: i. Bromination of compound of formula (5 a) to obtain Intermediate (I) using N- bromosuccinimide in combination with ⁇ or benzoyl peroxide in an organic solvent such as acetonitrile, ethyl acetate, dichloromethane, chloroform, chlorobenzene etc;
  • an improved process for the preparation of Intermediate (I) from E-isomer of compound of formula (5), wherein R is Hydrogen i.e. compound of formula (5a) which comprises the steps of: i. Bromination of compound of formula (5a) to obtain Intermediate (I) using bromine in biphasic medium comprising water and one of the halogenated solvent such as dichloromethane, chloroform, dichloroethane, etc in presence of UV or ordinary light.
  • step (i) Purification of crude Intermediate (I) obtained in step (i) by recrystallization using any of the "ether class of organic solvents” such as diethyl ether, di-n- propyl ether, di-isopropyl ether, methyl tert-b tyl ether, etc.
  • ether class of organic solvents such as diethyl ether, di-n- propyl ether, di-isopropyl ether, methyl tert-b tyl ether, etc.
  • an improved process for the preparation of Intermediate (I) from E-isomer of compound of formula (5), wherein R is Hydrogen i.e. compound of formula (5a) which comprises the steps of: i. Bromination of compound of formula (5a) to obtain Intermediate (I) using alkali metal bromide such as lithium bromide, sodium bromide, potassium bromide, etc in combination with sulphuric acid and hydrogen peroxide (LiBr,
  • the present invention provides a robust, efficient and economical synthesis of compound of formula (5) in good yield and high purity. It further relates to the use of compound of formula (5) (wherein R is Hydrogen) i.e. compound of formula (5a) for the synthesis of Intermediate (I) and its conversion to substantially pure Trifloxystrobin, compound of formula (I) in good yield.
  • substantially pure Trifloxystrobin means that purity is more than 98%.
  • metal cyanide used in step (ii) is selected from sodium cyanide, potassium cyanide, cuprous cyanide, etc.
  • alkali metal hydroxide used in step (iv) is sodium hydroxide.
  • organic solvent used in step (i) to step (iv) is selected from toluene, xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, etc.
  • compound of formula (4) is converted to compound of formula (5) comprising the steps of (i) selective hydrolysis, (ii) methoxyimination and (iii) esterification which are critical to yield the compound of formula (5) in E-isomer form with good yield and high purity.
  • Keto compound which is designated as compound of formula (4) contains alpha- substituted-o-toluic acid methyl ester which is obtained as a by-product during the conversion of compound of formula (3) to compound of formula (4) to the extent of -20%.
  • the process of the present invention proceeds through selective hydrolysis of compound of formula (4) which remains in the aqueous layer as a sodium salt.
  • the by-product i.e. alpha-substituted-o-toluic acid methyl ester, is not hydrolyzed under the above reaction condition and thus remain in organic layer which is separated before carrying out methoxyimination of compound of formula (4a) and hydrolyzed separately using sodium hydroxide in presence of water to recover alpha-substituted-o-toluic acid, compound of formula (1) having purity of -98 % by HPLC which is the starting material of the process of the present invention.
  • compound of formula (4a) is carried forward to methoxyimination using methoxyamine hydrochloride to obtain compound of formula (4b) which is obtained as a -50:50 mixture of Z and E isomers which on esterification using thionyl chloride and methanol gets converted to compound of formula (5) having E-geometry exclusively.
  • (Z, E)-Isomers of compound of formula (4b) first react with thionyl chloride to form acid chloride. During this reaction, Z-isomer of compound of formula (4b) gets converted into E-isomer of acid chloride of compound of formula (4b), which then reacts with methanol to furnish E-isomer of compound of formula (5), exclusively.
  • compound of formula (2), (3), (4), (4a) and (4b) are not isolated.
  • the compound of formula (4) is subjected to hydrolysis, methoxyimination and esterification, in situ, to obtain compound of formula (5).
  • bromination reaction carried out using sodium bromate in combination with sodium bisulfite (NaBrCb / NaHSCb) in biphasic medium of water immiscible "ester class of organic solvents" such as ethyl acetate, n- butyl acetate, isopropyl acetate etc and water in presence of UV or ordinary light, results in higher conversion of compound of formula (5 a) into Intermediate (I) giving higher yield and purity than any other process reported in the literature.
  • sodium bisulfite NaBrCb / NaHSCb
  • biphasic medium of water immiscible "ester class of organic solvents” such as ethyl acetate, n- butyl acetate, isopropyl acetate etc and water in presence of UV or ordinary light
  • an improved process for the preparation of Intermediate (I) from E-isomer of compound of formula (5) (wherein R is Hydrogen) i.e. compound of formula (5a) which comprises the steps of: i. Bromination of compound of formula (5 a), to obtain Intermediate (I) using N- bromosuccinimide in combination with ⁇ or benzoyl peroxide in an organic solvent such as acetonitrile, ethyl acetate, dichloromethane, chloroform, chlorobenzene etc.
  • acetonitrile, ethyl acetate, dichloromethane, chloroform, chlorobenzene etc is used as a solvent during bromination of compound of formula (5), wherein R is Hydrogen i.e. compound of formula (5a) using N-bromosuccinimide in combination with ⁇ or benzoyl peroxide to obtain Intermediate (I) giving higher yield as compared to the yield obtained by the use of other solvent such as DCM, EDC, CTC, ethyl acetate, chlorobenzene etc.
  • an improved process for the preparation of Intermediate (I) from E-isomer of compound of formula (5) (wherein R is Hydrogen) i.e. compound of formula (5a) which comprises the steps of: i. Bromination of compound of formula (5a) to obtain Intermediate (I) using alkali metal bromide such as lithium bromide, sodium bromide, potassium bromide, etc in combination with sulphuric acid and hydrogen peroxide (LiBr,
  • bromination reaction carried out using alkali metal bromide such as lithium bromide, sodium bromide, potassium bromide, etc in combination with sulphuric acid and hydrogen peroxide (NaBr (KBr) / H 2 SO 4 / H 2 O 2 ) in halogenated solvent such as dichloromethane, chloroform, dichloroethane, etc in presence of UV or ordinary light, results in higher conversion of compound of formula (5a) into Intermediate (I) giving higher yield and purity than any other process reported in the literature.
  • alkali metal bromide such as lithium bromide, sodium bromide, potassium bromide, etc in combination with sulphuric acid and hydrogen peroxide (NaBr (KBr) / H 2 SO 4 / H 2 O 2 )
  • halogenated solvent such as dichloromethane, chloroform, dichloroethane, etc in presence of UV or ordinary light
  • compound of formula (5a) which comprises the steps of: i. Bromination of compound of formula (5a) to obtain Intermediate (I) using bromine in biphasic medium comprising water and one of the halogenated solvent such as dichloromethane, chloroform, dichloroethane, etc in presence of UV or ordinary light.
  • halogenated solvent such as dichloromethane, chloroform, dichloroethane, etc in presence of UV or ordinary light.
  • bromination reaction carried out using bromine in biphasic medium comprising water and one of the halogenated solvent such as dichloromethane, chloroform, dichloroethane, etc in presence of UV or ordinary light, results in higher conversion of compound of formula (5a) into Intermediate (I) giving higher yield and purity than any other process reported in the literature.
  • halogenated solvent such as dichloromethane, chloroform, dichloroethane, etc
  • the crude Intermediate (I) is purified by recrystallization in diisopropyl ether.
  • an improved process for the preparation of Trifloxystrobin, compound of formula (I) having purity more than 98% which comprises the steps of: i. Reacting intermediate (II) with intermediate (I) as obtained by the process of the resent invention in the presence of base in an organic solvent;
  • base used in the step of condensation of Intermediate (I) and Intermediate (II) is selected from the group consisting of inorganic base or organic base.
  • Inorganic base includes alkali metal carbonate, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide or alkali metal hydride, such as sodium hydride, potassium hydride or potassium ieri-butoxide or sodium amide.
  • alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate or alkali metal hydroxide
  • lithium hydroxide sodium hydroxide, potassium hydroxide, cesium hydroxide or alkali metal hydride, such as sodium hydride, potassium hydride or potassium ieri-butoxide or sodium amide.
  • Organic base includes triethylamine, di-isopropylethyl amine, N-methylmorpholine, piperidine, pyridine etc.
  • an organic solvent used in the step of condensation of Intermediate (I) and Intermediate (II) is selected from the group consisting of "ketone class of organic solvents" such as acetone, methyl isobutyl ketone, etc or polar aprotic solvents such as dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, N-methylpyrrolidine, etc or cyclic and acyclic ethers such as tetrahydrofuran, dioxane, dimethoxyethane, etc or "ester class of organic solvents” such as ethyl acetate, ft-butyl acetate, isopropyl acetate, isobutyl acetate, etc or acetonitrile.
  • ketone class of organic solvents such as acetone, methyl isobuty
  • organic solvent used in the step of purifying the product i.e. Trifloxystrobin compound of formula (I) is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, w-butanol, acetonitrile, ethyl acetate, diethyl ether, diisopropyl ether, methyl isobutyl ether etc.
  • compound of formula (I) wherein Intermediate (I) is condensed with Intermediate (II) using alkali metal carbonate in MIBK at 115 °C. The excess alkali metal carbonate is recovered and reused in the subsequent batch.
  • alkali metal bromide is formed as a byproduct which is recovered and reused for the bromination of compound of formula (5a) to obtain Intermediate (I).
  • Trifloxystrobin compound of formula (I) is obtained with purity more than 98% Batch wise data of o-toluic acid methyl ester formed during synthesis of compound of formula (4); wherein R is hydrogen,
  • Example 1 Preparation of compound of formula (2); wherein R is H o-Toluic acid (100.0 g) was added in xylene (450.0 ml) at ambient temperature. To the slurry was added DMF (9.1 g). To the reaction mass was added thionyl chloride (100 g). The reaction mass was heated at 50 °C for 1.0 hr. The reaction mass was cooled to room temperature after removing excess thionyl chloride. This reaction mass contains o-toluoyl chloride, compound of formula (2).
  • Example 2 Preparation of compound of formula (3); wherein R is H
  • Reaction mass obtained in example 1 was added drop wise into the biphasic mixture of xylene (-550.0 ml) and water (100.0 ml) containing sodium cyanide (16.0 g) and TBAB (1.0 g), under stirring below 20 °C. While the addition was continued, solution of sodium cyanide (30.0 g) in water (200.0 ml) was added simultaneously into the reaction mass. The reaction mass was stirred for 2.0 hrs at room temperature. The organic layer was separated, washed with water (3 x 200 ml), dried over sodium sulphate and cooled to -5 to 0 °C. This organic layer contains 2-oxo-o-tolylacetonitrile, compound of formula (3).
  • Example 4 Preparation of compound of formula (5); wherein R is H i.e. compound of formula (5a).
  • Aqueous layer was extracted with DCM (100.0 ml). The organic layers were combined and dried. This combined organic layer contains a -50:50 mixture of E- and Z-isomers of methoxyimino-o-tolylacetic acid, compound of formula (4b). To it was added DMF (5.0 g) followed by thionyl chloride (120.0 g) at room temperature. The reaction mass was heated at 40-45 °C for 8.0 hrs and then concentrated to obtain gummy mass. To this gummy mass was added methanol (150.0 ml). The reaction mixture was heated at 60-65 °C for 1.0 hr, cooled to 5-10 °C and filtered.
  • Method-A Methoxyimino-o-tolylacetic acid methyl ester, compound of formula (5a), (10.0 g) was dissolved in acetonitrile (100.0 ml). To the clear solution was added NBS (11.17 g) and AIBN (0.48 g) at room temperature. The reaction mass was heated to 60 °C for 6.0 hrs and then concentrated to remove acetonitrile. To the crude product obtained was added diisopropyl ether (50.0 ml) and stirred to get clear solution. The solution was washed with 10% aqueous sodium bisulfite solution (2 x 25 ml) followed by water (25.0 ml).
  • Method-B Sodium bromate (3.3 g) was dissolved in water (16.0 ml). To the clear solution was added solution of methoxyimino-o-tolylacetic acid methyl ester, compound of formula (5a), (3.0 g) in ethyl acetate (10.0 ml) and stirred at room temperature. To the biphasic clear solution was added solution of sodium bisulfite (2.3 g) in water (10.0 ml) maintaining temperature between 30-40 °C over a period of 15 min. The reaction mass was stirred for 8.0 hrs at room temperature while it was exposed to UV light. Organic layer was separated and washed with 10% aqueous sodium bisulfite solution (2 x 3 ml) followed by water (5 ml).
  • 3-Trifluoromethylacetophenone (100.0 g) was dissolved in methanol (500.0 ml). To the solution was added hydroxylamine hydrochloride (37.0 g) at room temperature. To the reaction mass was added solution of sodium hydroxide (32.0 g) in water (150.0 ml) slowly over a period of 1.0 hr at room temperature and stirred for 10.0 hrs. Methanol was distilled off to obtain gummy product which was dissolved in ethyl acetate (500.0 ml). The solution was washed with water (150.0 ml).
  • Example 9 Preparation of Trifloxystrobin i.e. compound of formula (I) using potassium carbonate recovered from Example 8.
  • Example 10 Preparation of (2-bromomethylphenyl)methoxyiminoacetic acid methyl ester (Intermediate-I) using potassium bromide by-product recovered from Example 8 or Example 9.
  • Example 8 or Example 9 The solid isolated after filtration in Example 8 or Example 9 (3.76 g) was dissolved in water (4.0 ml). The solution was added into the solution of methoxyimino-o-tolylacetic acid methyl ester, compound of formula (5a), (1.0 g) in dichloromethane (8.0 ml). To the reaction mixture was added hydrogen peroxide (30%, 0.76 ml) at room temperature. To the reaction mixture was added concentrated sulfuric acid (0.43 ml) over a period of 5 minutes at room temperature. The reaction mass was stirred for 6.0 hrs at room temperature while it was exposed to UV light. Organic layer was separated and washed with 10% aqueous sodium bisulfite solution (2 x 3 ml) followed by water (5 ml).
  • Reaction mass obtained in example 9 was added drop wise into the biphasic mixture of xylene (200.0 ml) and water (35.0 ml) containing sodium cyanide (5.0 g) and TBAB (0.15 g), under stirring below 10 °C over a period of 4.0 hrs. While the addition was continued, solution of sodium cyanide (10.0 g) in water (70.0 ml) was added simultaneously into the reaction mass. The reaction mass was stirred for 2.0 hrs at room temperature. The organic layer was separated, washed with water (3 x 75 ml), dried over sodium sulphate and cooled to -5 to 0 °C. This organic layer contains, compound of formula (3).
  • Example 13 Preparation of compound of formula (4); wherein R is 2- methylphenoxy-
  • reaction mass obtained in example 10 was purged dry hydrogen chloride gas at -5 to 0 °C. After 2.0 hr, while continuing dry hydrogen chloride gas purging, methanol (21.2 ml) was added into the reaction mass under stirring over a period of 10 hrs. Dry hydrogen chloride gas was purged into the reaction mass for another 10 hrs. Methanol (30.0 ml) was added into the reaction mass at 15-20 °C. The reaction mass then heated to 40-45 °C and to it was added sulfuric acid (45.0 g) maintaining the temperature between 40-45 °C. The reaction mass was stirred for 3.0 hr.
  • Example 14 Preparation of compound of formula (5b); wherein R is 2- methylphenoxy-.
  • the reaction mixture was heated to 95-100 °C for 2-3 hrs and cooled to 25-30 °C.
  • the aqueous layer was separated and cooled to 10-15 °C.
  • the pH of the aqueous layer was adjusted to 4 using sulphuric acid.
  • the solid obtained was filtered and washed with water (100.0 ml).
  • 2-o-Tolyloxymethylbenzoic acid (1) so obtained was dried at 45-50 °C (18.0 g). Purity- 98% by HPLC.
  • Table 2 Comparison of percentage of Z-isomer of compound of formula 5(b) i.e. Kresoxim-methyl obtained by the process of the present invention vis-a-vis acknowledge prior art US5221762).
  • Table 4 Comparison of percentage yiek of compound of formula (I) i.e Trifloxystrobin obtained by the process of the present invention vis-a-vis US6407100. Table: 4

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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne un procédé amélioré de synthèse d'isomère E du composé de formule (5). Elle concerne en outre la conversion de la formule (5), où R est H, en intermédiaire (I) et, par la suite, en Trifloxystrobine sensiblement pure, composé de formule (I), avec un bon rendement.
PCT/IB2013/052565 2012-03-29 2013-03-30 Procédé amélioré de synthèse de fongicides de strobilurine c'est-à-dire de trifloxystrobine et de krésoxim-méthyl WO2013144924A1 (fr)

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CN107043336A (zh) * 2017-03-22 2017-08-15 京博农化科技股份有限公司 一种2‑（2‑甲基苯氧基）‑亚甲基苯甲酰氰的制备方法
CN108863845A (zh) * 2018-08-21 2018-11-23 湖南大学 一种肟菌酯及其中间体的制备方法
WO2019049167A1 (fr) 2017-09-11 2019-03-14 Hikal Limited Procédé amélioré pour la préparation de trifloxystrobine
CN109485572A (zh) * 2018-11-02 2019-03-19 永农生物科学有限公司 含取代基的溴化苄的制备方法
CN111333535A (zh) * 2020-04-20 2020-06-26 江苏食品药品职业技术学院 一种肟菌酯的制备方法
CN113402416A (zh) * 2021-05-29 2021-09-17 浙江锦华新材料股份有限公司 一种甲氧胺盐酸盐的制备方法
CN113683527A (zh) * 2021-10-26 2021-11-23 江苏七洲绿色科技研究院有限公司 一种肟菌酯的制备方法
CN114773193A (zh) * 2022-05-17 2022-07-22 荆州瑞东医药科技有限公司 2-氧代-2-{2-[(2-甲基苯氧基)甲基]苯基}乙酸甲酯的制备方法

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WO2019049167A1 (fr) 2017-09-11 2019-03-14 Hikal Limited Procédé amélioré pour la préparation de trifloxystrobine
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JP2020533349A (ja) * 2017-09-11 2020-11-19 ヒカル リミテッド トリフロキシストロビンの改善された調製方法
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