JP2002531540A - Method for producing a strobilurin intermediate - Google Patents

Abstract

(57) Summary The present invention relates to new and improved methods and intermediates for preparing oxime intermediates of formula (II). Wherein R ₁ is hydrogen, fluoro or chloro, and R ₂ is methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro or bromo. This novel method comprises diazotizing an aniline of formula (VI), reacting the resulting diazonium salt with isopropenyl acetate of formula (X), and converting the resulting ketone of formula (XI) with an organic nitrite. Reacting in the presence of hydrogen chloride and methylating the resulting ketoxime of formula (VIII) with a methylating agent and reacting the resulting O-methylketoxime of formula (IX) with hydroxylamine. The compounds of the formula (II) are intermediates of highly active fungicides from the class of strobilurins.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a fungicid, a highly active fungicide from the class of strobilurins.
e) a new and improved process for preparing certain intermediates. Another aspect of the present invention is the novel intermediate itself prepared for the process of the present invention.

The fungicide strobilurin has previously been described, for example, in WO-A-95 / 1
8789, or later WO-A-95 / 2153 and WO-A-
95/2154. The method disclosed therein is a typical laboratory route that is not suitable for large-scale manufacturing at all steps. The present invention now provides a new and improved process designed for large-scale industrial production that allows the production of strobilurulin and its basic intermediates in industrial production processes.

The fungicidal and fungicidal strobilurins have the general formula I

[0004]

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Wherein 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).

[0006] The known individual strobilurins of formula I are listed in the following table.

[0007]

[Table 1]

[0008] The fungicidal strobilurin of the formula I has the formula Il

[0009]

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Wherein R ₁ and R ₂ are as defined for formula I, in the presence of a base, from the oxime compound

[0011]

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Wherein X is as defined for formula I, and Hal is halogen, preferably chlorine or bromine, is synthesized by a conventional etherification step.

Most of the members of the coupling component III and the oxime of the formula II are known.

According to the process of the present invention, the oxime of formula II is

[0015]

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Wherein R ₁ and R ₂ are as defined for the compounds of formula I, and an organic nitrite, such as an alkyl nitrite such as iso- or n-pentyl nitrite And in the presence of hydrogen chloride,
And equation V

[0017]

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The resulting ketoxime, wherein R ₁ and R ₂ are as defined for the compound of formula I, is reacted with an aqueous solution of O-methyl-hydroxylamine hydrochloride, followed by reaction of compound II Most of the (E, E / E, Z) mixture is (E / E
)) To give a compound of formula II by isomerization into the form.

The two-step process (IV → V → II) of the present invention may be performed in a large industrial scale vessel. The first step (IV → V) is carried out in an inert organic solvent, for example tetrahydrofuran, dioxane, toluene, xylene or a cyclic hydrocarbon such as cyclohexane, methylcyclohexane, or iso- or n-pentanol in −20. Preference is given to temperatures between 0 ° C and + 60 ° C, from -5 ° C to + 40 ° C
Particularly, the temperature is preferably from + 25 ° C to + 40 ° C, more preferably from + 10 ° C to + 40 ° C. In the second step, the keto group is replaced with a methoxyimino function in a single step reaction. The resulting intermediate is isomerized in-system in the finishing solution and may be isolated from the solution if desired. However, for large-scale manufacturing processes, it is more advantageous to use the finishing solution directly for coupling intermediate II with intermediate III.

The product of the formula II is preferably used in the form of the (E, E) isomer for further coupling with a compound of the formula III for the production of fungicidal strobilurins.

Alternatively, the compound of formula II is of the formula VI

[0022]

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Aniline of formula VII and the resulting diazonium salt of formula VII

[0024]

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With methylglyoxal-1-oxime of the formula VIII

[0026]

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The resulting ketoxime is methylated with a methylating agent and the compound of formula IX

[0028]

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Can be obtained by reacting the obtained O-methylketoxime with hydroxylamine.

Alternatively, in a variation, the compound of formula VIII is obtained by diazotizing an aniline of formula VI and obtaining the resulting diazonium salt with a compound of formula X

[0031]

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With isopropenyl acetate of formula XI

[0033]

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The ketone obtained in the above can be reacted with an organic nitrite in the presence of hydrogen chloride.

The diazotization reaction is carried out in an organic solvent with an organic nitrite, for example, an alkyl nitrite such as isoamyl nitrite, or an aryl nitrite such as phenyl nitrite, or more preferably, an aqueous solution. In the presence of an acid using nitrous acid or a salt thereof. Preferred nitrites are sodium nitrite,
Potassium nitrite and magnesium nitrite are used, and particularly preferred is sodium nitrite. Preferred acids are hydrochloric, sulfuric and nitrosulfuric acids. Advantageously, -1
The temperature is from 0 ° C to + 30 ° C and the pH is 0-3. This diazonium compound, preferably in the presence of CuCl ₂ or CuSO _4, from -10 ° C. + 40 ° C., further preferably at + 15 ° C. from -10 ° C., also PH2-7, more preferably reacted in pH 3-5. The amount of copper salt is from 1 to 20 mol%, more preferably from 3 to 6 mol%, based on the aniline of formula VI. Methylation of the ketoxime of formula VIII is described in S
. Anker and H.S. T. Organic Syntheses by Clarke
is, Coll. Vol. The reaction is carried out with a methylating agent such as methyl iodide, dimethyl sulfate or diazomethane as described in 3,172 in the presence of a base, for example potassium carbonate, sodium hydride, in a suitable solvent at a suitable reaction temperature. . The introduction of the oxime function into the intermediate of the formula XI is preferably carried out with an inert organic solvent, for example tetrahydrofuran, dioxane, toluene, xylene or a cyclic hydrocarbon such as cyclohexane, methylcyclohexane, or iso- or n-pentanol. In such, at a temperature between -20 ℃ and +60 ℃, -5 ℃ to +40 ℃,
Particularly at + 25 ° C to + 40 ° C and even at + 10 ° C to + 40 ° C, for example, in the presence of hydrogen chloride, organic nitrites, for example alkyl nitrites such as iso- or n-pentyl nitrite, or nitrites such as phenyl nitrite. Performed by treatment with aryl.

According to the method of the present invention, the following intermediate of formula II can be obtained in high yield.
The novel intermediates of the formula II constitute another feature of the present invention.

[0037]

[Table 2]

The following examples serve to illustrate the invention and do not impose any restrictions.

Example 1 (E, E / E, Z) -1- (4-chloro-phenyl) -propane- 1,2-dione-1- (O-methyl-oxime) -2-oxime

[0040]

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A) (E) -1- (4-chlorophenyl) -propane-1,2-dione-2-
Oxime

[0042]

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440 g (2.437 mol) of 4-chloropropiophenone and 335 g (2.
925 mol) of t-butyl nitrite in 700 g of tetrahydrofuran
97.8 g (2.681 mol) of gaseous hydrochloric acid are added from + 25 ° C. to +4 over 2 hours.
Blow at 0 ° C. Following the end of the addition, the batch is stirred at + 15 ° C. to + 30 ° C. for 2 hours. The reaction mixture is neutralized by adding 630.5 g of a 20% sodium carbonate solution at + 25 ° C. Add some brine and methylcyclohexane and separate the phases. Upon concentration, the product crystallizes from the organic phase. The product is isolated by filtration and the filter cake is washed at 75C with 75 g of methylcyclohexane. 438.9 g of (E) -1- (4-chlorophenyl) -propane-1
, 2-dione-2-oxime (mp 115-115 ° C.) in a yield of 91.1%.

B) 99.8 g (0.50 mol) of (E) -1 in 200 g of chlorobenzene
192 .- (4-Chlorophenyl) propane-l, 2-dione-2-oxime.
7 g (0.60 mol) of a 26% aqueous solution of O-methylhydroxylamine hydrochloride are added. The pH of the resulting solution is adjusted to 3.3 by adding 100 g (1.26 mol) of pyridine. Following the addition, the reaction mixture is brought to a reaction temperature of + 75 ° C. for 7 hours.
Stir for hours. The reaction mixture is concentrated by evaporation of the chlorobenzene and the residue is stirred with water and ethyl acetate. The organic phase is washed neutral with 32% HCl and water, and the combined aqueous phases are extracted again with ethyl acetate. Upon evaporation of the solvent, the product crystallizes from methylcyclohexane and is dried. Yield: 95.7 g (E, E / E, Z
) -1- (4-Chloro-phenyl) -propane-1,2-dione-1- (O-methyl-oxime) -2-oxime (84.0% yield of 1: 1 isomer mixture), m.p.
p. 162 ° C.

[0045] Example 2: (E, E / E , Z) -1- (2,4- difluoro - phenyl) - flop propane-1,2-dione 1-(O-methyl - oxime) 2-oxime

[0046]

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A) 1- (2,4-difluoro-phenyl) -propane-1,2-dione-1
-Oxime

[0048]

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While stirring, 45 ml of 10.0 g (0.1 mol) sulfuric acid (95-97%)
Diluted with water. At + 20 ° C., 12.9 g (0.1 mol) of 2,4-difluoroaniline are added in one portion. The solution warms to + 38 ° C. and a 2,4-difluoroaniline sulfate precipitate precipitates as a white crystalline powder. Cool the suspension to 0 ° C. 7.0 g (0.101 mol) of sodium nitrite continuously within 20 minutes
0 ml of the aqueous solution is added at 0 ° C to 5 ° C. When the addition is nearing completion, the diazonium salt suspension is diluted with 150 ml of water to allow for further stirring. The viscous suspension is stirred for a further 15 minutes, after which 0.6 g of amidosulphuric acid in 4 ml of water is added to inactivate the excess nitrite.

In a separate beaker, 8.7 g of anti-methylglyoxal-1-oxime is added to a mixture of 8.3 g of sulfuric acid (95-97%) and 60 ml of water. To this mixture is added 5.0 g of copper sulfate pentahydrate and 5 g of sodium sulfite. Cool the dark greenish solution to 0 ° C. and store.

With vigorous stirring and cooling, the diazonium salt solution is added to this anti-methylglyoxal-oxime solution at 0 ° C. within 10 minutes. Remove this viscous suspension to 0
Stir at C for 5 h and warm to room temperature with continued stirring for 16 h. After this period, the yellow suspension can be easily stirred.

[0052] The mixture is saturated with solid NaCl and filtered. 50 brownish residues
Wash with ml of water. The crude product is made up to 100 ml of 1N sodium hydroxide solution and filtered again. Discard the residue. The orange filtrate is added to 40 g of ice and 2N
Adjust to pH 1 by adding HCl. Separate the solid residue and wash with water. For further purification, the residue was washed with 300 ml of ethyl acetate / hexane (1: 1).
) And filter through 20 g of silica gel. The solvent was evaporated and dried, yielding 7.52 g of 1- (2,4-difluoro-phenyl) -propane-1,2-
Dione-1-oxime is obtained. m. p. 126-129 ° C. After recrystallization from methylcyclohexanone, the melting point is 133-135 ° C.

B) (E) -1- (2,4-difluoro-phenyl) -propane-1,2-dione-1- (O-methyl-oxime)

[0054]

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258 g of potassium carbonate was converted to 310 g of 1- (2,4-difluoro-phenyl)
Add to a solution of 2 l of propane-1,2-dione-1-oxime in acetonitrile. After stirring for 30 minutes, 265 g of methyl iodide was added from + 35 ° C to + 40 ° C.
Add with drops. The reaction mixture is stirred for 5 hours and then diluted with 2 l of water. After extraction with 5 l of ethyl acetate, the organic layer was extracted with 2 l of sodium chloride solution (25%).
Wash and dry over sodium sulfate. After evaporation of the volatiles, 323 g of a brown oil remain, which is composed of 100 g of Hyflo and 13 g of activated carbon containing 1 g of activated carbon.
. Purify by heating in 2 l of toluene at + 70 ° C. for 10 minutes, followed by filtering the cold solution over silica gel. 80% by evaporating the solvent and drying
This gives 317 g of an orange oil containing (E) -1- (2,4-difluoro-phenyl) -propane-1,2-dione-1- (0-methyl-oxime).

C) (E, E) -1- (2,4-difluoro-phenyl) -propane-1,2
-Dione-1- (O-methyl-oxime) -2-oxime 4.26 g of (E) -1- (2,4-difluoro-phenyl) -propane-1
A solution of 2,2-dione-1- (O-methyl-oxime) and 1.5 g of hydroxylamine hydrochloride in 20 ml of pyridine is heated at + 90 ° C. for 2 hours. After the addition of 50 ml of ice-cold water, a yellow oil precipitates and crystallizes within a few hours. Filtration, washing with water and drying gives 4.4 g of a yellow solid.
Purification by recrystallization in ethyl acetate / hexane gave 4.0 g of (E, E)
-1- (2,4-difluoro-phenyl) -propane-1,2-dione-1- (
O-methyl-oxime) 2-oxime is obtained as white crystals. m. p115-1
17 ° C.

[0057] Example 3: (E, E / E , Z) -1- (2,4- difluoro - phenyl - propane-1,2-dione-1-(O-methyl - oxime) 2-oxime

[0058]

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A) (E) -1- (2,4-Difluoro-phenyl) -propane-1,2-dione-2-oxime

[0060]

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200 g of 170 g (1.00 mol) of 2,4-difluoropropiophenone
37 g (1.01 mol) of gaseous hydrochloric acid in a solution of
Blow at 3 ° C. for 3 hours. Thereafter, 120 g (1.04 mol) of pentyl nitrite are added to the reaction mixture at + 10 ° C. to + 15 ° C. over 3 to 4 hours. Following the end of the addition, the batch is stirred at + 10 ° C. to + 15 ° C. for 1 hour, during which a suspension forms. Then the reaction mixture is cooled to 0 ° C. and stirred for another hour.
The product is isolated by filtration and the filter cake is washed at 0 ° C. with 75 g of methylcyclohexane. 176 g of (E) -1- (2,4-difluoro-phenyl) -propane-1,2-dione-2-oxime (mp 99-101 ° C.) are obtained in a yield of 88.6%.

B) In 400 g of toluene, 200 g (1.00 mol) of (E) -1- (2,2)
4-difluoro-phenyl) propane-1,2-dione-2-oxime and 338
g (1.21 mol) of a 30% aqueous solution of O-methylhydroxylamine hydrochloride are added. The resulting mixture is heated to + 65 ° C. and 178 g (1.76 mol) of triethylamine are added over 1.5 to 2 hours. During the addition, the internal temperature is increased by + 85 ° C. Following the addition, the reaction mixture is stirred at a reaction temperature of + 85 ° C. for a further 10 hours. The pH of the reaction mixture is then adjusted from + 30 ° C. to + 35 ° C. below pH 0.7 by addition to approximately 30 g (0.26 mol) of 32% hydrochloric acid. Subsequent phase separation removes waste containing triethylamine hydrochloride along with the water stream. By adding 200 g of water and 171 g (1.29 mol) of a 30% sodium hydroxide solution at + 20 ° C. to + 25 ° C., the (E, E / E, Z) -1-
The (2,4-difluoro-phenyl) -propane-1,2-dione-1- (O-methyl-oxime) -2-oxime product is separated from by-products. 50g of water and 4
A second extraction is carried out with 1 g (0.31 mol) of a 30% sodium hydroxide solution. The toluene stream containing by-product waste is removed by phase separation. Almost 200g (
(1.75 mol) of 32% hydrochloric acid at + 20 ° C. to + 25 ° C.
E, E / E, Z) -1- (2,4-difluoro-phenyl) -propane-1,2
The dione-1- (O-methyl-oxime) -2-oxime product is released from the sodium salt form and 338 g of fresh toluene are added in order to extract the organic product. The pH of the mixture was reduced to 0.7 by the addition of a small amount of 32% hydrochloric acid.
Adjust to less than. The aqueous phase containing the salt waste is removed by phase separation. 7g (0.0
6 mol) of 32% hydrochloric acid at + 63 ° C. to + 65 ° C., followed by stirring for 2 hours, to allow the isomerization of the product to an isomer ratio (E, E / E, Z: 92: 8). (If desired). Addition of 78 g of water at + 63 ° C. to + 65 ° C. and subsequent phase separation removes the final traces of acid. Any remaining traces of water are removed by azeotropic vacuum distillation. Finally, 82 g of 1-methyl 2-pyrrolidone is added to the product solution to prevent precipitation of the product upon storage at room temperature. The yield of the reaction (all isomers) is 64%, with a 146% content of 146% relative to the product solution.
g (0.64 mol) are obtained.

Example 4: {2- [2- (4-Chloro-phenyl) -2-methoxyimino-1 -methylethylidene-aminooxymethyl] phenyl} -methoxyimino-acetic acid methyl ester

[0064]

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In 150 ml of acetonitrile, 17.0 g (75.0 mmol) of 1- (4
-Chloro-phenyl) -propane-1,2 dione 1- (O-methyl-oxime)
2-oxime, 21.5 g (75.0 mmol) of (2-bromomethyl-phenyl) -methoxyimino-acetic acid methyl ester and 16.6 g (120 mmol)
Of potassium carbonate is added. The resulting suspension is heated at + 80 ° C. for 3 hours. At room temperature, 400 ml of water are added to the suspension, followed by extraction with 3 × 200 ml of ethyl acetate. The organic product phase is washed with 2 × 200 ml of water, dried over magnesium sulfate and filtered. Hexane is added to the crude oil obtained by evaporation of the solvent, followed by pure {2- [2- (4-chloro-phenyl) -2-methoxyimino-1-methylethylideneaminooxymethyl] -phenyl ｝ -Methoxyiminoacetic acid methyl ester crystallizes from hexane. 25.5 g, 78. of theory.
7%, m. p. 115-117 ° C.

[0066] Example 5: {2- [2- (2,4-difluoro - phenyl) -2-Metokishii amino-1-methyl - ethylideneamino oxymethyl] - phenyl} - Metokishii amino - acid methyl ester

[0067]

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In 150 ml of acetonitrile 17.1 g (75.0 mmol) of (E, E
/ E, Z) -1- (2,4-difluorophenyl) -propane-1,2-dione-1- (0-methyl-oxime) 2-oxime, 21.5 g (75.0 mmol) of (2 -Bromomethyl-phenyl) -methoxyimino-acetic acid methyl ester and 16.6 g (120 mmol) of potassium carbonate are added. The resulting suspension is heated at + 80 ° C. for 3 hours. At room temperature, 400 ml of water are added to the suspension, followed by 3
Extract with 200 ml of ethyl acetate. 2x200 ml of this organic product phase
And then dried over magnesium sulfate and filtered. Hexane was added to the crude oil obtained by evaporation of the solvent, followed by pure {2- [2-
(2,4-Difluoro-phenyl) -2methoxyimino-1-methyl-ethylideneaminooxy] -phenyl} -methoxyimino-acetic acid methyl ester crystallizes from hexane. 24.9 g, 76.6% of theory. The product is a mixture of the two isomers, E, E, E and E, E, Z in a ratio of 87:13. m. p. 110
-119 [deg.] C.

Example 6: 1- (2,4-difluoro-phenyl) propan-2-one

[0070]

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With vigorous stirring and cooling, 132.0 g (1.32 mol) of concentrated sulfuric acid
Dilute with 1 liter of water. At 10-15 ° C., 78.7 g (0.60 mol) of 2,4-difluoroaniline are added and the resulting suspension is treated with 104.6 g (0.606 mol) of a 40% solution of sodium nitrite in water. At 0-3 ° C for 45 minutes.

In a separate reactor, the mixture was charged with 6.0 g of copper sulfate pentahydrate, 180 ml of water, 0.1 g of water.
Made from 9 g concentrated sulfuric acid and 91.2 g (0.90 mol) isopropenyl acetate. To this mixture, a diazonium salt solution and 50.4 g of a 20% aqueous sodium sulfite solution are added simultaneously at 10-15 ° C. over a period of 2 hours. The mixture is stirred for another hour and then extracted with two portions of toluene. Wash the combined organic layers with dilute bicarbonate solution and brine. The solvent is removed under reduced pressure and the remaining crude oil is distilled at 75-80 ° C./5 mbar. 85.8 g of pale yellow 1-
(2,4-Difluoro-phenyl) -propan-2-one is obtained in a yield of 82.9%.

Example 7: (E) -1- (2,4-difluoro-phenyl) -propane-1,2 -dione-1-oxime

[0074]

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A solution of 140.2 g (0.80 mol) of 1- (2,4-difluoro-phenyl) -propan-2-one in 550 g of methylcyclohexane is warmed to 30-35 ° C. While supplying a gentle stream of dry hydrogen chloride into the reactor below the liquid level, 2
Over the course of time, 96.6 g (0.80 mol) of isoamyl nitrite are added. Following the end of the addition, the batch is stirred at 30-35 ° C for 15 minutes, after which the suspension is cooled to 0 ° C. The product is isolated by filtration and 150 g of filter cake
And washed with methylcyclohexane at 0 ° C. 146.9 g of (E) -1- (
2,4-difluoro-phenyl) -propane-1,2-dione 1-oxime (m
p. 133-135 ° C) with a yield of 89.5%.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // C07B 61/00 300 C07B 61/00 300 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (71) Applicant D-51368 Leverkusen, Germany (72) Inventor Tweakler, Hyugo Switzerland C.H. 4108 Bittelsville・ Imborne Atsuka 15 (72) Inventor Wang, Linghua 70817 Baton, Louisiana, United States of America Luton Carrington Place 13062 F term (reference) 4H006 AA01 AA02 AA03 AB84 AC27 AC44 AC59 AC82 BD70 BE01 4H039 CA72 CD20

Claims (6)

[Claims] 1. A compound of the formula II Wherein R ₁ is hydrogen, fluoro or chloro, and R ₂ is methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro or bromo. Having the formula VI Is obtained by diazotizing an aniline of the formula With isopropenyl acetate of formula XI Of the resulting ketone with organic nitrous acid in the presence of hydrogen chloride;
I The resulting ketoxime is methylated with a methylating agent and of formula IX Reacting the obtained O-methylketoxime with hydroxylamine. 2. Compound 2, 4-difluorophenylacetone 3. A compound of formula II Wherein R ₁ is hydrogen, fluoro or chloro, and R ₂ is methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro or bromo. Having the formula VI Of the aniline of formula I and the resulting diazonium salt is represented by the formula VII With methylglyoxal-1-oxime of formula VIII The resulting ketoxime is methylated with a methylating agent and of formula IX Reacting the obtained O-methylketoxime with hydroxylamine. 4. A compound of formula II Wherein R ₁ is hydrogen, fluoro or chloro, and R ₂ is methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro or bromo. Having the formula IV Wherein R ₁ and R ₂ are as defined for Formula II. Propiophenone is reacted with an organic nitrite, such as pentyl nitrite, in the presence of hydrochloric acid to form Formula V (Wherein R ₁ and R ₂ are as defined for Formula II), and the resulting ketoxime is reacted with an aqueous solution of O-methyl-hydroxylamine hydrochloride, and then the racemate of Compound II is substantially eluted with E- Converting to a compound of formula II by isomerizing to a form. 5. A compound of formula II obtainable by the method according to claim 1, 3 or 4. 6. A compound of formula I according to claim 5, of formula I Wherein R ₁ and R ₂ are as defined for formula II in claim 1, wherein X is NH or oxygen, for the manufacture of a fungicidal strobilurin, The compound of formula II in the etherification step of formula III in the presence of a base Wherein X is as defined for formula I and Hal is halogen, preferably chlorine or bromine.