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
  • C07C249/08—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
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
  • C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
  • C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
  • C07C49/233—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings

Definitions

• the present invention relates to a novel improved process of preparing certain intermediates for highly active fungicides from the class of the strobilurins. Another aspect of the invention are the novel intermediates per se which have been prepared for the process of this invention.
• the fungicidal strobilurins have previously been described in e.g. WO-A-95/18789 or the later WO-A-95/21153 and WO-A-95/21154.
• the processes disclosed therein are typical laboratory routes which for large scale production are not in all steps suitable.
• the present invention now provides a new improved process designed for large scale industrial production which allows the production of strobilurins and its key intermediates in an industrial production process.
• the fungicidal strobilurins have the general formula I
• R 1 is hydrogen, fluoro or chloro
• R 2 is methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro or bromo, and
• X is NH or oxygen.
• the fungicidal strobilurins of formula I are synthesized by a conventional etherification step from the oxime compound of formula II
• X is as defined for formula I and Hal is halogen, preferably chlorine or bromine.
• the oximes of formula II are obtained by the process comprising reacting a propiophenone of formula IV
• Ri and R 2 are as defined for the compounds of formula I in the presence of hydrogen chloride with an organic nitrite, e.g. alkyl nitrite such as iso- or n-pentyl nitrite, and converting the resulting ketooxime of formula V
• Ri and R 2 are as defined for the compounds of formula I into the compound of formula II by reacting it with an aqueous solution of O-methyl-hydroxylamine-hydrochloride, and subsequent isomerisation of the (E,E/E,Z)-mixture of compound II into predominantly the (E/E)-form thereof.
• the two-step process of the invention ( IV ⁇ V ⁇ II ) may be carried out in large industrial scale vessels.
• the first step ( IV ⁇ V ) is advantageously conducted in an inert organic solvent, e.g. tetrahydrofurane, dioxane, toluene, xylenes or a cyclic hydrocarbon like cyclohexane, methylcyclohexane, or iso or n-pentanol, etc. at temperatures between -20°C and +60°C, with -5°C to +40°C, and especially +25°C to +40°C, and even more +10°C to +40°C being preferred.
• an inert organic solvent e.g. tetrahydrofurane, dioxane, toluene, xylenes or a cyclic hydrocarbon like cyclohexane, methylcyclohexane, or iso or n-pentanol
• the keto group is replaced by the methoximino function in a single step reaction.
• the resulting intermediate may be isomerised in situ in the work-up solution and it may be isolated therefrom, if desired.
• the product of formula II is preferably used in the from of the (E,E)-isomer for further coupling with the compound of formula III for producing the fungicidal stobilurins.
• the compounds of formula II may be obtained by diazotizing an aniline of formula VI
• the compounds of formula VIII may be obtained by diazotizing an aniline of the formula VI and reacting the resulting diazonium salt with isopropenylacetate of formula X
• the diazotization reaction is carried out in an organic solvent with an organic nitrite, e.g. an alkyl nitrite as isoamyl nitrite, or an aryl nitrite, as phenyl nitrite; or, more preferably, in aqueous solution with nitrous acid or a salt thereof, in presence of an acid.
• organic nitrites are sodium nitrite, potassium nitrite, magnesium nitrite, particularly preferred is sodium nitrite.
• Preferred acids are hydrochloric acid, sulfuric acid and nitrosulfuric acid.
• Advantageous is a temperature of -10°C to +30°C and a pH 0-3.
• the diazonium compound is preferably reacted in the presence of CuCI 2 or CuSO 4 at -10°C to +40°C, more preferably -10°C to +15°C, and at pH 2-7, more preferably at pH 3-5.
• the amount of the copper salt is 1 to 20 mol%, more preferably 3 to 6 mol%, in relation to the aniline of formula VI.
• Methylation of the ketooxime of formula VIII is carried out with a methylating agent such as methyl iodide, dimethylsulfate or diazomethane in presence of a base, e. g . potassium carbonate or sodium hydride in a suitable solvent at suitable reaction temperatures as described by H.S. Anker and H.T. Clarke in Organic Synthesis, Coll. Vol. 3,172.
• a methylating agent such as methyl iodide, dimethylsulfate or diazomethane
• a base e. g . potassium carbonate or sodium hydride
• suitable solvent e.g a suitable solvent at suitable reaction temperatures as described by H.S. Anker and H.T. Clarke in Organic Synthesis, Coll. Vol. 3,172.
• the introduction of the oxime function into the intermediate of formula XI is preferably carried out in an inert organic solvent, e.g.
• an organic nitrite e.g. an alkyl nitrite as iso- or n-pentyl nitrite, or an aryl nitrite, as phenyl nitrite
• the diazonium salt solution is added within 10 minutes to the anti-methylglyoxal-oxime solution at 0°C
• the viscous suspension is stirred for 5 hours at 0°C and then with continued stirring for 16 hours allowed to warm up to room temperature. After this period the yellow suspension can be stirred easily.
• reaction mixture is stirred for a further 10 hours at the reaction temperature of +85°C
• pH of the reaction mixture is then adjusted at +30°C to +35°C to less than pH 0.7 by the addition of approximately 30 g (0.26 mol) of 32 % hydrochloric acid.
• phase separation removes with the aqueous stream the waste containing triethylamine-hydrochloride.
• the (E,E E,Z)-1 -(2,4- dif luoro-phenyl)-propane-1 ,2-dione-1 -(O-methyl-oxime)-2-oxime product is separated from its side products by the addition of 200 g of water and 171 g (1.29 mol) of a 30 % sodium hydroxide solution at +20°C to +25°C. A second extraction with 50 g of water and 41 g (0.31 mol) of a 30 % sodium hydroxide solution is performed. The toluene stream containing the by-product waste is removed by phase separation.
• the (E,E/E,Z)-1 -(2,4-dif luoro- phenyl)-propane-1 ,2-dione- 1 -(O-methyl-oxime)-2-oxime product is set free from its sodium salt form by the addition of approximately 200 g (1.75 mol) of 32 % hydrochloric acid at +20°C to +25°C and 338g of fresh toluene is added in order to extract the organic product.
• the pH of the mixture is adjusted to less than pH 0.7 by the addition of a further small quantity of 32 % hydrochloric acid. Phase separation removes the aqueous phase containing the salt waste.
• the organic product phase is washed with 2 x 200 ml water and then dried over magnesium sulfate and filtered.
• hexane is added whereafter the pure ⁇ 2-[2-(2,4-dif luoro-phenyl)-2- methoxyimino-1-methyl-ethylideneaminooxymethyl]-phenyl ⁇ -methoxyimino-acetic acid methyl ester crystallizes from hexane: 24.9 g, 76.6 % of theory.
• the product is a mixture of two isomers, E.E.E and E,E,Z, at a ratio of 87:13, m.p. 110-119°C
• a mixture is prepared from 6.0 g copper sulfate pentahydrate, 180 ml of water, 0.9 g of concentrated sulfuric acid and 91.2 g (0.90 mol) of isopropenyl acetate.
• diazonium salt solution and 50.4 g of an aqueous 20% sodium sulfite solution is concurrently added over a period of 2 hours at 10-15°C
• the mixture is stirred for another hour before it is extracted with two portions of toluene.
• the combined organic layers are washed with a diluted bicarbonate solution and brine.

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• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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• 1999
  • 1999-12-09 EP EP99963458A patent/EP1137627A1/de not_active Withdrawn
  • 1999-12-09 WO PCT/EP1999/009705 patent/WO2000034229A1/en not_active Application Discontinuation
  • 1999-12-09 AU AU19748/00A patent/AU1974800A/en not_active Abandoned
  • 1999-12-09 JP JP2000586678A patent/JP2002531540A/ja active Pending

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