HK1119435B

HK1119435B - Processes for the preparation of azoxystrobin using dabco as a catalyst and novel intermediates used in the processes

Info

Publication number: HK1119435B
Application number: HK08111203.2A
Authority: HK
Inventors: Alan John Whitton; Ewan Campbell Boyd; Jack Vass
Original assignee: Syngenta Limited
Priority date: 2005-04-26
Filing date: 2006-04-13
Publication date: 2013-04-26

Description

Process for preparing azoxystrobin using DABCO as catalyst and novel intermediates used in the process

The invention relates to a method for preparing strobilurin fungicide (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxy methyl acrylate (azoxystrobin) and a novel precursor thereof.

A process for the preparation of azoxystrobin is described in WO 92/08703. In one method, azoxystrobin is prepared by reacting 2-cyanophenol with (E) -methyl 2- [2- (6-chloro-pyrimidin-4-yloxy) phenyl ] -3-methoxyacrylate.

A process for the preparation of asymmetric 4, 6-bis (aryloxy) pyrimidine derivatives in high yield is disclosed in WO01/72719, wherein 6-chloro-4-aryloxy pyrimidine is reacted with phenol, optionally in the presence of a solvent and/or a base, and 2-40 mol% of 1, 4-diazabicyclo [2.2.2] octane (DABCO) is added.

The present invention is based on the discovery that when using DABCO as a catalyst to prepare azoxystrobin or a novel azoxystrobin acetal precursor, the relatively expensive catalyst is used in significantly less amount than expected in WO01/72719 without a reduction in yield. In addition to reducing production costs, this increases environmental benefits and reduces catalyst emissions in water treatment effluents.

Thus, according to the present invention, there is provided a process for the preparation of a compound of formula (I):

wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂Or a mixture of these two groups, which process comprises

(a) Reacting a compound of formula (II):

wherein W has the meaning given above, with 2-cyanophenol or a salt thereof (suitably potassium 2-cyanophenol) in the presence of 0.1 to 2 mol% of 1, 4-diazabicyclo [2.2.2] octane, or

(b) Reacting a compound of formula (III):

with a compound of formula (IV);

wherein W has the meaning given above, in the presence of 0.1 to 2 mol% of 1, 4-diazabicyclo [2.2.2] octane.

In a particular embodiment, the method of the invention comprises reacting a compound of formula (II):

wherein W has the meaning given above, with 2-cyanophenol or a salt thereof (suitably 2-cyanophenol) in the presence of 0.1-2 mol% of 1, 4-diazabicyclo [2.2.2] octane.

Wherein W is a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂[ that is, the compound 2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy)]Phenyl } -3, 3-dimethoxypropionic acid methyl ester (hereinafter referred to as 'azoxystrobin acetal')]Is a novel compound and forms part of the present invention. In particular, the invention includes azoxystrobin acetal isolated in substantially pure form [ i.e. an isolated form comprising 85 to 100 wt% azoxystrobin acetal, preferably 90 to 100 wt% azoxystrobin acetal]。

When the process of the invention is carried out using a compound of formula (II) wherein W is methyl 2- (3, 3-dimethoxy) propionate group or using a compound of formula (IV) wherein W is methyl 2- (3, 3-dimethoxy) propionate group, the product obtained may comprise a moiety of a compound of formula (I) wherein W is methyl (E) -2- (3-methoxy) acrylate group. This occurs because methanol may be removed from the methyl 2- (3, 3-dimethoxy) propionate group under the process conditions. For the same reason, if the process is carried out using a compound of formula (II) or a compound of formula (IV) wherein W is a mixture of methyl 2- (3, 3-dimethoxy) propionate and methyl (E) -2- (3-methoxy) acrylate (and the invention includes such a process), the product obtained will be a compound of formula (I) wherein W is a mixture of methyl 2- (3, 3-dimethoxy) propionate and methyl (E) -2- (3-methoxy) acrylate; however, due to this potential methanol scavenging, the proportion of compounds of formula (I) in which W is the methyl (E) -2- (3-methoxy) acrylate group is higher than would be expected for the (E) -2- (3-methoxy) acrylate group in the mixed starting materials. This is not a true result, since it is normally necessary to convert the product of formula (I) wherein W is methyl 2- (3, 3-dimethoxy) propionate group to a compound of formula (I) wherein W is methyl (E) -2- (3-methoxy) acrylate group by scavenging methanol as discussed below.

Conveniently, the process of the present invention is carried out in a suitable inert solvent or diluent. Such inert solvents or diluents include, for example, aliphatic, alicyclic, and aromatic hydrocarbons such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, and decalin; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane and trichloroethane; heteroaromatic solvents such as pyridine or substituted pyridines, for example 2, 6-lutidine; ethers, e.g. diethyl ether, diisopropyl ether, methyl tert-butyl ether, diAlkane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane and anisole; ketones such as acetone, butanone, methyl isobutyl ketone and cyclohexanone; nitriles; such as acetonitrile, propionitrile, n-and iso-butyronitrile and benzonitrile; amides such as N, N-dimethylformamide, N-dimethylacetamide, N-methyl-pyrrolidone and hexamethylphosphoric triamide; tertiary amines, especially of the formula R¹R²R³Amines of N, wherein R¹、R²And R³Each independently is C_1-10(especially C)_1-8) Alkyl radical, C_3-6Cycloalkyl, aryl (especially phenyl) or aryl (C)_1-4) Phenyl (especially benzyl); or R¹、R²And R³2 or 3 together with the nitrogen atom to which they are attached form a 1, 2 or 3 5-, 6-or 7-membered aliphatic ring which is optionally fused and optionally contains a second ring nitrogen atom, examples of suitable tertiary amines are N, N-diisopropylethylamine (Hunig's base), N-bisMethylaniline, triethylamine, tert-butyldimethylamine, N-diisopropylmethylamine, N-diisopropylisobutylamine, N-diisopropyl-2-ethylbutylamine, tri-N-butylamine, N-dicyclohexylmethylamine, N-dicyclohexylethylamine, N-tert-butylcyclohexylamine, N-dimethylcyclohexylamine, 1, 5-diazabicyclo [4.3.0]]-non-5-ene, 1, 8-diazabicyclo [5.4.0]Undec-7-ene or 2-dimethylaminopyridine; esters such as methyl acetate, ethyl acetate and isopropyl acetate; sulfoxides, such as dimethyl sulfoxide; sulfones, such as sulfolane; and mixtures of these solvents and diluents and mixtures of one or more of them with water. Particularly suitable diluents are ketones [ e.g.methyl isobutyl ketone and cyclohexanone]Esters [ e.g. isopropyl acetate ]]Tertiary amines [ e.g. [ N, N-diisopropylethylamine (Hunig's base) ]]And amides [ e.g. N, N-dimethylformamide]. In a particular aspect of the invention, methyl isobutyl ketone is used as diluent. In another aspect of the invention, cyclohexanone is used as the diluent. In another aspect of the invention, isopropyl acetate is used as the diluent. In another aspect of the invention, N-dimethylformamide is used as the diluent. In another aspect of the invention, N, N-diisopropylethylamine (Hunig's base) is used as the diluent. Most suitably, the diluent according to the present invention is N, N-dimethylformamide.

In another embodiment of the invention, the process is carried out in an aqueous two-phase solvent system. Suitably, in this embodiment, when said compound of formula (II) is reacted with a 2-cyanophenol, the 2-cyanophenol is present as a salt. Most preferably, the salt is potassium 2-cyanophenol. Advantageously, water is excluded throughout the reaction. Suitable co-solvents for the aqueous process are solvents of which at least part is water-immiscible, such as cyclohexanone, methyl isobutyl ketone and isopropyl acetate. Most suitably, when the aqueous system is used, the salt of 2-cyanophenol is potassium 2-cyanophenol and the diluent is cyclohexanone, methyl isobutyl ketone and isopropyl acetate. It should be noted that when 2-cyanophenol is added to the process as an aqueous solution of potassium 2-cyanophenol, it is possible to reduce the amount of acid acceptor (see below) used.

Furthermore, the process of the present invention is conveniently carried out in the presence of an acid acceptor. Suitable acid acceptors are all customary inorganic and organic bases.

They include, for example, hydroxides, acetates, carbonates, hydrogen carbonates and hydrides of alkaline earth metals and alkali metals [ e.g.sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydride, sodium hydride and potassium hydride ], guanidines, phosphazenes (see, for example, Liebigs Ann.1996, 1055-1081), propaphotranes (see, for example, JACS1990, 9421-9422) and tertiary amines [ e.g.the possible solvents or diluents mentioned above ]. Particularly suitable acid acceptors are alkaline earth and alkali metal carbonates, especially potassium carbonate and sodium carbonate, and the tertiary amines 1, 5-diazabicyclo [4.3.0] non-5-ene and 1, 8-diazabicyclo [5.4.0] undec-7-ene. More suitably, the acid acceptor is potassium carbonate. Most suitably, the invention is carried out in the presence of methyl isobutyl ketone, cyclohexanone, isopropyl acetate, N-diisopropylethylamine (Hunig's base) or N, N-dimethylformamide and potassium carbonate as acid acceptor.

The process of the invention is carried out in the presence of 0.1-2 mol% 1, 4-diazabicyclo [2.2.2] octane (DABCO), i.e. above 0.1 but below 2 mol% DABCO. Preferably, the method is carried out in the presence of 0.2-2 mol% of DABCO. Any amount of DABCO between 0.1 or 0.2 and 2 mol%, 0.1 or 0.2 and 1.9 mol%, 0.1 or 0.2 and 1.8 mol%, 0.1 or 0.2 and 1.7 mol%, 0.1 or 0.2 and 1.6 mol%, and 0.1 or 0.2 and 1.5 mol% is suitable, but the amount of DABCO used is particularly advantageously 0.2 to 1.4 mol%. Typically, DABCO is used in an amount of 0.5 to 1.4 mol%, particularly 0.8 to 1.2 mol%, for example about 1 mol%.

In a particular embodiment of the invention, the process is carried out in the presence of about 1 mol% DABCO and, as diluent, methyl isobutyl ketone, cyclohexanone, isopropyl acetate, N-diisopropylethylamine (Hunig's base) or N, N-dimethylformamide. Suitably, the acid acceptor is potassium carbonate.

When carrying out the process of the invention, the reaction temperature can be varied within a relatively wide range. The choice of temperature depends on the nature of the solvent and diluent, for example on its boiling point and/or its effect on promoting the desired reaction, and on the speed at which the reaction is carried out. In any given solvent or diluent, the reaction will tend to proceed more slowly at lower temperatures. Generally, the reaction may be carried out at a temperature of from 0 to 120 ℃, suitably 40 to 100 ℃ and especially 45 to 90 ℃, for example 60 to 85 ℃.

For carrying out the process according to the invention, from 0.8 to 4mol of 2-cyanophenol, generally from 0.95 to 1.2mol of 2-cyanophenol, are used per mol of compound of the formula (II); and a similar amount (0.8 to 4mol, usually 0.95 to 1.2mol) of a compound of formula (IV) is used per mol of a compound of formula (III).

Conveniently, the process of the invention is carried out by mixing one of the components of the reaction, preferably in the presence of a solvent or diluent, with a base. The other components are then added, if appropriate in the presence of a solvent or diluent, and the mixture is stirred, usually at elevated temperature. The DABCO catalyst may be added at any stage, but is preferably added as the last component, which helps to increase the yield of the product. After the reaction is judged to be complete, the reaction mixture is worked up and the product isolated using conventional techniques well known to the skilled chemist.

2-cyanophenol is a commercially available material.

Wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Wherein W is a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂The compound of formula (II) can be prepared from 3- (. alpha. -methoxy) methylenebenzofuran-2 (3H) -one (represented by benzofuran) as described in WO92/08703Pyran-2 (3H) -one) and 4, 6-dichloropyrimidine. The compounds of formula (II) wherein W is a methyl (E) -2- (3-methoxy) acrylate group may also be prepared by elimination of methanol (i.e.by demethanization) from compounds of formula (II) wherein W is a methyl 2- (3, 3-dimethoxy) propionate group, as described in WO92/08703 or WO 98/07707. Compounds of formula (II) wherein W is methyl 2- (3, 3-dimethoxy) propionate may be prepared as described in GB-A-2291874 by reacting a compound of formula (IV) wherein W is methyl 2- (3, 3-dimethoxy) propionate and 4, 6-dichloropyrimidine. May be purified by known techniques prior to use or used in an unpurified state from a previous reaction, for example in a 'one-pot' reaction.

Compounds of formula (IV) wherein W is the methyl 2- (3, 3-dimethoxy) propionate group may be prepared from 3- (. alpha. -methoxy) methylene-benzofuran-2 (3H) -one as described in GB-A-2291874. The compound of formula (IV) wherein W is a methyl (E) -2- (3-methoxy) acrylate group can be prepared by the demethanolysis of a compound of formula (IV) wherein W is a methyl 2- (3, 3-dimethoxy) propionate group. In this case, the phenol group needs to be protected, for example benzylation prior to demethanolysis and subsequent deprotection.

In another aspect, the invention includes a process for preparing a compound of formula (IV) wherein W is a methyl (E) -2- (3-methoxy) acrylate group, comprising the steps of:

(i) a compound of formula (IV) wherein W is the methyl 2- (3, 3-dimethoxy) -propionate group and a reagent which protects the hydroxyl group of this compound from reaction during subsequent demethanolysis;

(ii) (ii) elimination of methanol from the hydroxy-protected compound formed in step (i); and

(iii) (ii) removing the hydroxy-protecting group formed in step (i) to form a compound of formula (IV) wherein W is methyl (E) -2- (3-methoxy) acrylate.

In step (i) of the process, a compound of formula (IV) wherein W is the methyl 2- (3, 3-dimethoxy) propionate group is reacted with a standard protecting reagent, for example a benzyl halide or substituted benzyl halide [ e.g. 2-nitrobenzyl halide ], such as benzyl bromide or 2-nitrobenzyl bromide, conveniently in a suitable solvent, such as N, N-dimethylformamide, and a suitable base, such as potassium carbonate, to form a compound of formula (V):

wherein Q is a protecting group, such as benzyl or 2-nitrobenzyl.

In step (ii) of the process, methanol is eliminated by any suitable physical or chemical means, for example as described in WO92/08703 or WO 98/07707. Conveniently, the elimination is carried out by treating the compound of formula (V) with methanesulfonic acid in the presence of acetic anhydride, at a temperature ranging, for example, from 20 ℃ to 110 ℃, generally from 20 ℃ to 80 ℃, and preferably from 30 ℃ to 60 ℃, for example about 40 ℃.

In step (iii) of the process, the protecting group may be removed by any standard technique for removing protecting groups, for example by reduction in ethyl acetate at room temperature using hydrogen and a 10% palladium on carbon catalyst.

The invention also includes novel intermediates of formula (V) wherein Q is a protecting group, in particular intermediates of formula (V) wherein Q is benzyl [ i.e. the compound methyl 2- (2-benzyloxyl) phenyl-3, 3-dimethoxypropionate ]. More specifically, the invention comprises isolating methyl 2- (2-benzyloxy) phenyl-3, 3-dimethoxypropionate in substantially pure form [ i.e. an isolated form comprising 85 to 100 wt.%, preferably 90 to 100 wt.% of methyl 2- (2-benzyloxy) phenyl-3, 3-dimethoxy-propionate ].

The following examples illustrate the invention. The following abbreviations have been used for all examples:

DMF ═ dimethylformamide DABCO ═ 1, 4-diazabicyclo [2.2.2] octane

MIBK ═ methyl isobutyl ketone NMR ═ nuclear magnetic resonance

MHz-Ar-aryl-Py-pyrimidinyl

Examples

Example 1

This example describes the sequence of experiments designed to show the effect of decreasing DABCO concentration.

a) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene Coupling of methyl acid ester with 2-cyanophenol in DMF with 2 mol% DABCO

A slurry containing (E) -methyl 2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol), potassium carbonate (52.8g, 98%, 0.375mol) and 2-cyanophenol (33.6g, 97.5%, 0.275mol) in DMF (130mL) was heated to about 60 ℃. A solution of DABCO (0.56g, 0.005mol) in DMF (10mL) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 60 minutes. DMF was removed by vacuum distillation. Toluene (160mL) and water (265mL) were added to the distillation residue and the mixture of the two phases was heated to 70-80 ℃. The mixture was stirred for 40 minutes and then settled, and the lower aqueous phase was separated. The toluene solution (237.8g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (41.3% w/w), 97.5% of theory.

b) (E) -2- (2- [ 6-chloropyrimidin-4-yloxy)]Phenyl } -3-methoxypropan Methyl enoate was coupled with 2-cyanophenol in DMF with 1 mol% DABCO.

A slurry containing (E) -methyl 2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol), potassium carbonate (52.8g, 98%, 0.375mol) and 2-cyanophenol (33.6g, 97.5%, 0.275mol) in DMF (130mL) was heated to about 60 ℃. A solution of DABCO (0.28g, 0.0025mol) in DMF (10mL) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 60 minutes. DMF was removed by vacuum distillation. Toluene (160mL) and water (265mL) were added to the distillation residue and the mixture of the two phases was heated to 70-80 ℃. The mixture was stirred for 40 minutes and then settled, and the lower aqueous phase was separated. The toluene solution (227.9g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (43.6% w/w), 98.7% of theory.

c) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene The acid methyl ester was coupled with 2-cyanophenol in DMF with 0.2 mol% DABCO.

A slurry containing (E) -methyl 2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol), potassium carbonate (52.8g, 98%, 0.375mol) and 2-cyanophenol (33.6g, 97.5%, 0.275mol) in DMF (130mL) was heated to about 60 ℃. A solution of DABCO (0.056g, 0.0005mol) in DMF (10mL) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 300 minutes. DMF was removed by vacuum distillation. Toluene (160mL) and water (265mL) were added to the distillation residue at 60 ℃ and the mixture of the two phases was heated to 70-80 ℃. The mixture was stirred for 40 minutes and then settled, and the lower aqueous phase was separated. The toluene solution (243.1g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (38.6% w/w), 93.1% of theory.

d) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene The acid methyl ester was coupled with 2-cyanophenol in DMF with 0.1 mol% DABCO.

A slurry containing (E) -methyl 2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol), potassium carbonate (52.8g, 98%, 0.375mol) and 2-cyanophenol (33.6g, 97.5%, 0.275mol) in DMF (130mL) was heated to about 60 ℃. A solution of DABCO (0.028g, 0.00025mol) in DMF (10mL) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 300 minutes. DMF was removed by vacuum distillation. Toluene (160mL) was added to the distillation residue, maintaining the temperature between 70-80 deg.C, followed by addition of water (265mL) heated to 60 deg.C. The mixture was stirred at 80 ℃ for 40 minutes, then settled, and the lower aqueous phase was separated. The toluene solution (226.7g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (41.5% w/w), 93.4% of theory.

e) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene Methyl ester was coupled with 2-cyanophenol in DMF without DABCO.

A slurry containing methyl (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol), potassium carbonate (52.8g, 98%, 0.375mol) and 2-cyanophenol (33.6g, 97.5%, 0.275mol) in DMF (130mL) was heated to about 80 ℃ and maintained at that temperature for 8 hours. DMF was removed by vacuum distillation to a temperature of up to 100 ℃. Toluene (160mL) was added to the distillation residue, maintaining the temperature between 60-70 deg.C, followed by addition of water (265mL) heated to 60 deg.C, again maintaining the temperature between 60-70 deg.C. The mixture was heated at 80 ℃ for 40 minutes, then settled, and the lower aqueous phase was separated. The toluene solution (223.3g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (38.8% w/w), 86.6% of theory.

A summary of these test results is shown in the following table:

TABLE 1

Concentration of DABCO	Recovered azoxystrobin% of theoretical value)
		2.0mol％	97.5
1.0mol％	98.7
		0.2mol％	93.1
0.1mol％	93.4
		0	86.6

It can thus be seen that, surprisingly, the yield of azoxystrobin formed in this process does not decrease substantially when the concentration of DABCO is reduced below 2 mol%: even a concentration of DABCO as low as 0.1 mol% is sufficient to obtain a yield of 93.4% of theory. In addition, it should be noted that not only the experiment without DABCO gave very low yields, but also it took 8 hours to reach this point, while it took 5 hours for 0.1 mol% and 0.2 mol% DABCO and 60 minutes for 1.0 mol% and 2.0 mol% DABCO (in this respect, it should also be noted that the experiment with 1.0 mol% DABCO surprisingly gave similar yields in the same time as the experiment with 2.0 mol% DABCO).

Example 2

Another single experiment was performed to investigate the yields obtained with low concentrations of DABCO when using various solvents. In addition, characteristic data for methyl 2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3, 3-dimethoxypropionate are given in example 2 c).

a) By reacting 2-cyanophenol with (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Benzene and its derivatives Coupling of methyl-3-methoxyacrylate with 1 mol% DABCO in DMF to prepare the Mycilomycetes And (3) an ester.

To a solution of methyl (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (96.2 g; prepared as described in WO 92/08703) in DMF (ca. 100g) was added a solution of 2-cyanophenol (78.5g, 50% w/w 2-cyanophenol) in DMF followed by potassium carbonate (63.5g) and DABCO (0.34 g). The mixture was heated to 80 ℃ and maintained for 75 minutes. DMF was removed by vacuum distillation to a final temperature of 100 ℃.

Toluene (165.8g) was added to the distillation residue before hot water (318.6g) was added and stirring at 80 ℃ for 30 minutes, and the temperature was returned to 75 ℃. The aqueous phase was removed and the toluene layer was sampled for analysis. (E) The solution yield of methyl (azoxystrobin) 2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate was 90.0%. The toluene was distilled off under vacuum. Methanol (88g) was added to the distillation residue at 70 ℃ and the mixture was cooled to < 5 ℃, filtered and the cake was washed with methanol (2 × 30mL) to give (E) -methyl 2- {2- [6- (2-cyano-phenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (83.2% yield) after drying.

b) By reacting 2-cyanophenol with (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Benzene and its derivatives Preparation of pyrimidine coupling of methyl Yl } -3-Methoxyacrylate in Cyclohexanone with 0.9 mol% DABCO And (4) bacterial ester.

To a solution of methyl (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (64.4 g; prepared as described in WO 92/08703) in cyclohexanone (about 80g) were added 2-cyanophenol (26.6g) and cyclohexanone (26.6 g). The mixture was heated to 50 ℃ and DABCO (0.2g) in cyclohexanone (2g) and potassium carbonate (42.4g) were added. The reaction was heated to 90 ℃ and maintained for 3 hours. The temperature was adjusted to 50-60 ℃, hot water (88g) was added, stirred for 15 minutes, and the aqueous phase was separated. Analysis of the cyclohexanone layer gave 91.3% yield of methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (azoxystrobin).

Cyclohexanone was removed by vacuum distillation and methanol (59g) was added to the distillation residue at 80 ℃. The methanol solution was slowly cooled to 0-5 ℃, filtered, and the cake was washed with methanol (2 × 15.8g) to give methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (yield 87.0%).

c) By reacting 2-cyanophenol with 2- (2- [ 6-chloropyrimidin-4-yloxy)]Phenyl } - Preparation of azoxystrobin by coupling of 3, 3-dimethoxypropionic acid methyl ester in cyclohexanone with 1.0 mol% DABCO And azoxystrobin acetal.

A crude mixture (53g) containing methyl 2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3, 3-dimethoxypropionate (43g) and methyl (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (6.1g), prepared as described in WO92/08703, was dissolved in cyclohexanone (156 g). Potassium carbonate (21.9g), 2-cyanophenol (15.6g) and DABCO (0.14g) were added, and the mixture was heated to 90 ℃ and maintained at that temperature for 4 hours. Water (100mL) was added at 90 ℃ and the mixture was stirred for 10 minutes, settled and the aqueous phase separated. Aqueous hydrochloric acid (1%) and sodium chloride (10g) were added, the mixture was stirred, settled and the aqueous layer was removed. Analysis of the cyclohexanone solution showed methyl 2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3, 3-dimethoxypropionate (73%) and methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (27%).

2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] having the formula]Phenyl radical } -methyl 3, 3-dimethoxypropionate (wherein W is methyl 2- (3, 3-dimethoxypropionate) Data characterizing the compounds of formula (I) of the radicals):

table 2:¹HNMR, 200MHz in CDCl₃In

Chemical shift (ppm)	Multiple and severe degree	Cumulative number	Coupling constant (Hz)	Attribution
					8.32	s	1H	--	PyH2
7.66-7.55	m	3H	--	ArH
					7.31-7.09	m	5H	--	ArH
6.44	s	1H	--	PyH5
					4.95	d	1H	9	(CH₃O)₂CHCH
4.18	d	1H	9	(CH₃O)₂CHCH
					3.50	s	3H	--	OCH₃
3.35	s	3H	--	OCH₃
					3.11	s	3H	--	OCH₃

In the above table:

ArH is hydrogen bonded to a benzene ring;

the hydrogens shown in bold in the ascribed columns are those associated with a particular signal;

'm' represents a multiplet signal; the signals for individual hydrogens are not completely separated;

'd' represents a double peak;

's' represents a single peak;

the cumulative number represents the number of hydrogens associated with the signal;

pyrimidine hydrogen is represented by PyHx, where x refers to the position at which hydrogen is attached to the pyrimidine ring.

Differential scanning calorimetry of some samples of methyl 2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3, 3-dimethoxypropionate showed a melting endotherm at about 129 ℃ followed by an exothermic transition and another melting endotherm at about 139 ℃. This behavior strongly predicts the presence of one (or more) polymorphic forms of the substance, the main polymorphism depending on the crystallization solvent and conditions. Powder X-ray diffraction before and after the transition at 129 ℃ indicated the presence of different crystalline forms.

d) By reacting 2-cyanophenol with (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Benzene and its derivatives Preparation of pyrimidine coupling of methyl 3-methoxy-3-yl-acrylate in MIBK/Water with 1 mol% DABCO And (4) bacterial ester.

Methyl (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (20g, concentration 97.1%; prepared as described in WO 92/08703) was added to MIBK (77mL) and water (11mL), followed by 2-cyanophenol (8.0g), DABCO (0.07g), and potassium carbonate (14.1 g). The reaction was heated to 80 ℃ and monitored to the end of the reaction (complete after 8 hours). The reaction mixture was washed with water at 80 ℃. Analysis of the MIBK layer showed a yield of 95.7% of methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (azoxystrobin).

e) By reacting 2-cyanophenol with (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Benzene and its derivatives Preparation of pyrimidine coupling of methyl 3-methoxy-3-yl-acrylate in MIBK with 1.5 mol% DABCO And (4) bacterial ester.

Methyl (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (98.4g, 97.7% strength; prepared as described in WO 92/08703) was added to MIBK (214g) and heated to 45-50 ℃. 2-cyanophenol (40.1g), potassium carbonate (63.4g) and DABCO (0.51g) were added, and the temperature was raised to 80 ℃ and maintained at that temperature for 4.5 hours. Water (316g) was added, stirring was continued for 30 minutes, then the aqueous layer was settled and separated. Analysis of the MIBK solution showed 97.2% yield of methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (azoxystrobin).

f) By reacting 2-cyanophenol with (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Benzene and its derivatives Preparation of methyl ester of yl } -3-methoxyacrylate by coupling in MIBK/water with 1.5 mol% DABCO Azoxystrobin.

Methyl (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (98.4g, 97.7% strength; prepared as described in WO 92/08703) was added to MIBK (210g) and water (38.3g) and heated to 45-50 ℃. 2-cyanophenol (40.1g), potassium carbonate (63.4g) and DABCO (0.51g) were added and the temperature was raised to 80 ℃ and maintained for 5.5 hours. Water (316g) was added and stirring was continued for 30 minutes, then the aqueous layer was settled and separated. Analysis of the MIBK solution showed a yield of 91.8% of methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (azoxystrobin). .

g)2- [2- (6-Chloropyrimidin-4-yloxy) phenyl]-3, 3-Dimethoxypropionic acid Methyl ester and 2-cyanophenol coupled in isopropyl acetate with 1.3 mol% DABCO

To isopropyl acetate (80g) was added 2-cyanophenol (15.02g, 99%, 0.125mol), potassium carbonate (23.39g, 0.169mol), 2- [2- (6-chloropyrimidin-4-yloxy) phenyl]-methyl 3, 3-dimethoxypropionate (40.61g, 98.3%, 0.113mol) comprising (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (0.69g, 0.0022mol), and finally DABCO (0.172g, 0.0015mol) was added. Additional isopropyl acetate (80.3g) was added and the mixture heated to reflux for 6.5 hours. The reaction was cooled to room temperature and after standing overnight was cooled to 5 ℃ again for 1 hour, then filtered. The filter cake was a slurry, washed with water (2 × 100g) and then dried under vacuum (45 ℃, 400 mbar). The dried solid contains 2- [2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy ] oxy]Phenyl radical]-methyl 3, 3-dimethoxypropionate (90.8% w/w), 74.1% of theory and (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (2.41% w/w), 2.1% of theory. The isopropyl acetate filtrate contains 2- [2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy ] phenyl]Phenyl radical]-methyl 3, 3-dimethoxypropionate (3.44% w/w), 8.75% of theory and (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (1.8% w/w), 4.95% of theory. Wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂The overall yield of compound (I) under (2) was 89.8% of theory.

h)2- [2- (6-Chloropyrimidin-4-yloxy) phenyl]-3, 3-Dimethoxypropionic acid Methyl ester and 2-cyanophenol coupled with 1.3 mol% DABCO in Cyclohexanone

To cyclohexanone (75.6g) was added 2-cyanophenol (15.02g, 99%, 0.125mol), potassium carbonate (23.39g, 0.169mol) containing (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (0.69g, 0.0022mol) 2- [2- (6-chloropyrimidin-4-yloxy) phenyl]Methyl 3, 3-dimethoxypropionate (40.61g, 98.3%, 0.113mol), and finally DABCO (0.1 mol) was added72g, 0.0015 mol). Cyclohexanone (76.3g) was additionally added and the mixture was heated to 90 ℃ for 140 minutes. Cyclohexanone was removed by vacuum distillation. Water (100g) and methylene chloride (200g) were added to the distillation residue, and the resulting mixture was heated to 60 ℃ and maintained for 30 minutes. The mixture was filtered and the phases were separated. Methylene chloride was distilled off from the organic phase to give a brown oily solid which was triturated with methanol (20mL) to give a pale beige solid. Part of the methanol was removed in vacuo and water (125g) was added. The resulting slurry was filtered, sucked dry on the filter and then dried under vacuum (45 ℃, 400 mbar). The dried solid contains 2- [2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy ] oxy]Phenyl radical]-methyl 3, 3-dimethoxypropionate (81.19% w/w), 74.0% of theory and (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (18.55% w/w), 18.3% of theory. Wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂The overall yield of compound (I) under (2) was 92.3% of theory.

i) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene Methyl ester of acid and 2-cyanophenol in N, N-diisopropylethylamine (Hunigs base) at 1.0 mol% DABCO coupling and use of 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU) as Is a base.

A slurry containing (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate methyl ester (65.4g, 98%, 0.2mol), 2-cyanophenol (26.8g, 97.5%, 0.22mol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) (36.9g, 99%, 0.24mol) in N, N-diisopropylethylamine (105mL) was heated to 50-60 ℃. A solution of DABCO (0.224g, 0.002mol) in N, N-diisopropylethylamine (10mL) was added. The mixture was stirred at this temperature until the reaction was complete (3 hours). The solvent was removed by vacuum distillation to 90 ℃. Toluene (130mL) was added to the distillation residue, maintaining the temperature between 70-80 deg.C, followed by addition of water (210mL), maintaining the temperature as before. The mixture was stirred at 80 ℃ for 10 minutes, then settled and the lower aqueous phase separated. The toluene solution (180.2g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (39.1% w/w), 87.4% of theory.

j) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl radical]-3-methoxypropene Methyl ester and 2-cyanophenol were coupled in isopropyl acetate with 1.0 mol% DABCO.

A slurry containing (E) -methyl 2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol), potassium carbonate (52.8g, 98%, 0.375mol) and 2-cyanophenol (33.6g, 97.5%, 0.275mol) in isopropyl acetate (130mL) was heated to about 60 ℃. A solution of DABCO (0.28g, 0.0025mol) in isopropyl acetate (10mL) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 360 minutes. The isopropyl acetate was removed by vacuum distillation up to a temperature of 80 ℃. Toluene (160mL) was added to the distillation residue, maintaining the temperature between 60-70 deg.C, followed by addition of water (265mL) heated to 60 deg.C, again maintaining the temperature between 60-70 deg.C. Stirred at 80 ℃ for 40 minutes, settled and the lower aqueous phase separated. The toluene solution (229.8g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (41.2% w/w), 94.2% of theory.

k)2- [2- (6-Chloropyrimidin-4-yloxy) phenyl]-3, 3-Dimethoxypropionic acid Methyl ester and 2-cyanophenol coupled in isopropyl acetate with 1.3 mol% DABCO

To isopropyl acetate (160.3g) was added 2-cyanophenol (15.02g, 99%, 0.125mol), potassium carbonate (18.3g, 98%, 0.13mol) and a mixture containing (E) -2- {2- [ 6-chloropyrimidin-4-yloxy group in this order at room temperature]Phenyl } -3-methoxy-acrylic acid methyl ester (0.29g, 9.1X 10)^-4mol) of 2- [2- (6-chloropyrimidin-4-yloxy) phenyl]Methyl 3, 3-dimethoxypropionate (40.39g, 98.84%, 0.113 mol). The mixture was heated to 60 ℃ and maintained for 10 minutes. Adding DABCO (0.172g, 0.0015mol) and the mixture was heated to reflux (. about.90 ℃). The reaction was completed within 6 hours. The mixture was cooled to 85 ℃ and water (100g) was slowly added so that the temperature was not lower than 75 ℃. After stirring for 15 minutes, the reaction was allowed to settle and the aqueous phase was separated. Water (100g) was added thereto and washed in the same manner. The washed organic phase (201.6g) contained 2- [2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy ] group]Phenyl radical]-methyl 3, 3-dimethoxypropionate (22.5% w/w), 91.45% of theory and (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (1.00% w/w), 4.4% of theory. Wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂The overall yield of compound (I) under (2) was 95.85% of theory.

It can be seen that the conditions used in the process of examples 2a) -k) give azoxystrobin in good yields.

Example 3

This example relates to an experiment conducted to investigate whether the order of addition of the components led to a different yield of azoxystrobin. In particular, this example investigates whether the yield is higher if DABCO is added as the last component.

a) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene Methyl ester of acid with 2-cyanophenol in MIBK 1 mol% of 2-cyanophenol added later DABCO (i.e. last added) coupling.

A slurry of (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate methyl ester (80.9g, 99%, 0.25mol), potassium carbonate (52.8g, 98%, 0.375mol) and 2-cyanophenol (33.6g, 97.5%, 0.275mol) in MIBK (160mL) was heated to about 60 ℃. A solution of DABCO (0.28g, 0.0025mol) in MIBK (10mL) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 360 minutes. Water (300mL) was added to the reaction maintaining the temperature in the range of 70-80 ℃. The mixture was stirred for 70 minutes, then settled and the aqueous phase separated. The MIBK solution (235.3g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (41.0% w/w), 95.8% of theory.

b) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene Methyl ester of acid with 2-cyanophenol in MIBK 1 mol% of that added before 2-cyanophenol DABCO coupling.

To a slurry of (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol) and potassium carbonate (52.8g, 98%, 0.375mol) in MIBK (160mL) was added a solution of DABCO (0.28g, 0.0025mol) in MIBK (10 mL). The mixture was heated to about 60 ℃ and then 2-cyanophenol (33.6g, 97.5%, 0.275mol) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 350 minutes. The reaction mixture was cooled to room temperature overnight and then reheated to 80 ℃. Water (300mL) was added to the reaction maintaining the temperature in the range of 70-80 ℃. The mixture was stirred for 40 minutes and then settled, and the lower aqueous phase was separated. The MIBK solution (237.5g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (39.0% w/w), 91.9% of theory.

c) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene Methyl ester of acid with 2-cyanophenol in MIBK 1 mol% of 2-cyanophenol added later DABCO (i.e. last added) coupling.

A slurry of (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate methyl ester (80.9g, 99%, 0.25mol), potassium carbonate (52.8g, 98%, 0.375mol) and 2-cyanophenol (33.6g, 97.5%, 0.275mol) in MIBK (160mL) was heated to about 60 ℃. A solution of DABCO (0.28g, 0.0025mol) in MIBK (10mL) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 240 minutes (4.4% of residual (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate at the end of the reaction, calculated as GC peak area). Water (300mL) was added to the reaction at 60 ℃ maintaining the temperature in the range of 70-80 ℃. The mixture was stirred for 40 minutes and then settled, and the lower aqueous phase was separated. The MIBK solution (237.1g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (38.7% w/w), 89.1% of theory.

d) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene Methyl ester of acid with 2-cyanophenol in MIBK 1 mol% of that added before 2-cyanophenol DABCO coupling.

To a slurry of (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol) and potassium carbonate (52.8g, 98%, 0.375mol) in MIBK (160mL) was added a solution of DABCO (0.28g, 0.0025mol) in MIBK (10 mL). The mixture was heated to about 60 ℃ and then 2-cyanophenol (33.6g, 97.5%, 0.275mol) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 360 minutes (5.8% of residual (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate at the end of the reaction, calculated as GC peak area). Water (300mL) was added to the reaction at 60 ℃ maintaining the temperature in the range of 70-80 ℃. The mixture was stirred for 40 minutes and then settled, and the lower aqueous phase was separated. The MIBK solution (232.6g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (35.3% w/w), 81.6% of theory.

In addition, to provide a control, example 3e) below gives an indication of the expected yield when using a higher concentration of DABCO (2 mol%):

e) (E) -2- {2- [ 6-Chloropyrimidin-4-yloxy]Phenyl } -3-methoxypropene The acid methyl ester was coupled with 2 mol% DABCO in MIBK.

To a slurry of (E) -2- {2- [ 6-chloropyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (80.9g, 99%, 0.25mol) and potassium carbonate (52.8g, 98%, 0.375mol) in MIBK (160mL) was added a solution of DABCO (0.56g, 0.005mol) in MIBK (10 mL). The mixture was heated to about 60 ℃ and then 2-cyanophenol (33.6g, 97.5%, 0.275mol) was added. The mixture was heated to 80 ℃ and maintained at this temperature for 280 minutes. Water (300mL) was added to the reaction maintaining the temperature in the range of 70-80 ℃. The mixture was stirred for 40 minutes and then settled, and the lower aqueous phase was separated. The MIBK solution (237.0g) contained methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (40.2% w/w), 94.5% of theory.

A summary of the results of these experiments is shown in the following table:

TABLE 3

Examples	Concentration of DABCO	Solvent(s)	Adding DABCO	Recovered azoxystrobin (% of theory)
					3a	1.0mol％	MIBK	Finally, the	95.8
3b	1.0mol％	MIBK	Before the 2-cyanophenol	91.9
					3c	1.0mol％	MIBK	Finally, the	89.1¹
3d	1.0mol％	MIBK	Before the 2-cyanophenol	81.6¹
					3e	2.0mol％	MIBK	Before the 2-cyanophenol	94.5

¹The overall yield in these experiments is not predictive of the yield obtainable with 1.0 mol% DABCO in MIBK, since the reaction was not complete.

It can thus be seen that, surprisingly, the yield of azoxystrobin recovered from the process is increased when DABCO is added after 2-cyanophenol.

It should be noted that example 3e (2.0 mol% DABCO) compared with examples 3a and 3b (1.0 mol% DABCO) demonstrates the results obtained in different solvents (DMF) in example 1: surprisingly, the yield of the experiment that has been completed with 1.0 mol% DABCO is similar to that obtained with 2.0 mol% DABCO.

Example 4

This example relates to experiments performed in water systems.

a)2- [2- (6-Chloropyrimidin-4-yloxy) phenyl]-3, 3-Dimethoxypropionic acid Methyl ester with 2-cyanophenol in isopropyl acetate added after potassium 2-cyanophenol solution 1.0 mol% DABCO (i.e., last added) coupling.

Stirring 2- [2- (6-chloropyrimidin-4-yloxy) phenyl]A solution of methyl (40.6g, 99%, 0.113mol) 3, 3-dimethoxypropionate in isopropyl acetate (161.3g) was heated to 50 ℃ and then an aqueous solution of potassium 2-cyanophenol (32.44g, 46.0%, 0.126mol) was added followed by an aqueous solution of potassium carbonate (5.95g, 40%, 0.017mol) and an aqueous solution of DABCO (0.644g, 20%, 0.00115 mol). The mixture was stirred at reflux for 5.5 hours, during which the reflux temperature was increased from 82 ℃ to 88 ℃. The water was removed in a Dean and Stark trap. The reaction mixture was washed with water (100mL) at 70 ℃ followed by 1% aqueous HCl (100mL) at 70 ℃. Isopropyl acetate solution (164.3g) contained 2- [2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy ] oxy]Phenyl radical]-methyl 3, 3-dimethoxypropionate (22.05% w/w), 75.4% of theory and (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (3.04% w/w), 11% of theory. Wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂The overall yield of compound (I) under (2) was 86.4% of theory.

b)2- [2- (6-Chloropyrimidin-4-yloxy) phenyl]-3, 3-Dimethoxypropionic acid Methyl ester and 2-cyanophenol in isopropyl acetate are added after the potassium 2-cyanophenol solutionIs/are as follows 1.4 mol% DABCO (i.e., last added) coupling.

Will contain (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (8.52g, 0.0266mol) 2- [2- (6-chloropyrimidin-4-yloxy) phenyl]A mixture of methyl (96.0g, 83.72%, 0.228mol) 3, 3-dimethoxypropionate and isopropyl acetate (305.4g) was heated to 50 ℃. Potassium carbonate (27g, 98%, 0.19mol) and aqueous potassium 2-cyanophenol (90.0g, 50%, 0.286mol) were added followed by aqueous DABCO (8.17g, 5%, 0.0036 mol). The reaction mixture was heated at reflux for 225 minutes. During the reaction water was removed in a Dean and Stark trap. The mixture was cooled to 75 ℃ and water (241.4g) was slowly added. The mixture was stirred at 75 ℃ for 20 minutes, settled and the aqueous phase removed. Water (99.2g) was added to the isopropyl acetate solution. The mixture was stirred at 75 ℃ for 30 minutes, settled and the aqueous phase removed. The organic phase (353.1g) contained 2- [2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy ] phenyl]Phenyl radical]-methyl 3, 3-dimethoxypropionate (22.8% w/w), 72.6% of theory and (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (4.47% w/w), 15.4% of theory. Wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂The overall yield of compound (I) under (2) is 88% of theory.

c)2- [2- (6-Chloropyrimidin-4-yloxy) phenyl]-3, 3-Dimethoxypropionic acid Methyl ester with 2-cyanophenol in isopropyl acetate added after potassium 2-cyanophenol solution 1.4 mol% DABCO (i.e., last added) coupling.

Will contain (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (6.16g, 0.019mol) 2- [2- (6-chloropyrimidin-4-yloxy) phenyl]A mixture of methyl (69.4g, 83.72%, 0.165mol) 3, 3-dimethoxypropionate and isopropyl acetate (220.8g) was heated to 50 ℃ and stirred at this temperature for 10 minutes. Adding carbonAqueous potassium solution (19.5g, 40%, 0.0565mol) was added followed by aqueous potassium 2-cyanophenol solution (65.0g, 50%, 0.207 mol). Finally, aqueous DABCO (5.91g, 5.0%, 0.0026mol) was added. The reaction mixture was heated at reflux for 300 minutes. During the reaction water was removed in a Dean and Stark trap. The reaction mixture was cooled to 70-75 ℃ and water (174.5g) was slowly added to maintain this temperature. The mixture was stirred at 75 ℃ for 20 minutes, settled and the aqueous phase removed. Water (71.7g) was added to the isopropyl acetate solution. The mixture was stirred at 75 ℃ for 20 minutes, settled and the aqueous phase removed. The organic phase (233.1g) contained 2- [2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy ] oxy]Phenyl radical]-methyl 3, 3-dimethoxypropionate (25.09% w/w), 73% of theory and (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (4.96% w/w), 15.6% of theory. Wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂The overall yield of compound (I) under (2) was 88.6% of theory.

d)2- [2- (6-Chloropyrimidin-4-yloxy) phenyl]-3, 3-Dimethoxypropionic acid Methyl ester with 2-cyanophenol in isopropyl acetate added before the potassium 2-cyanophenol solution 1.4 mol% DABCO coupling.

Will contain (E) -2- {2- [ 6-chloropyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (8.78g, 0.0274mol) 2- [2- (6-chloropyrimidin-4-yloxy) phenyl]A mixture of methyl (99.0g, 83.72%, 0.235mol) 3, 3-dimethoxypropionate and isopropyl acetate (314.9g) was heated to 50 ℃ and at this temperature for 10 minutes. Aqueous potassium carbonate (27.8g, 40%, 0.081mol) was added followed by aqueous DABCO (8.42g, 5%, 0.0038 mol). Finally, an aqueous solution of potassium 2-cyanophenol (92.8g, 50%, 0.295mol) was added. The reaction mixture was heated at reflux for 260 minutes. During the reaction water was removed in a Dean and Stark trap. The mixture was cooled to 70 ℃ and water (249g) was slowly added. The mixture was stirred at 75 ℃ for 20 minutes, settled andthe aqueous phase was removed. Water (102.3g) was added to the isopropyl acetate solution. The mixture was stirred at 75 ℃ for 20 minutes, settled and the aqueous phase removed. The organic phase (373.2g) contained 2- [2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy ] phenyl]Phenyl radical]-methyl 3, 3-dimethoxypropionate (20.8% w/w), 68% of theory and (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]Methyl phenyl } -3-methoxyacrylate (3.52% w/w), 12.4% of theory. Wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or a methyl 2- (3, 3-dimethoxy) propionate group C (CO)₂CH₃)CH(OCH₃)₂The overall yield of compound (I) under (2) was 80.4% of theory.

A summary of the results of these experiments is shown in the following table:

TABLE 4

Examples	Concentration of DABCO	Solvent(s)	Adding DABCO	Recovered azoxystrobin (% of theory)
					4a	1.0mol％	Acetic acid isopropyl ester	Finally, the	86.4
4b	1.4mol％	Acetic acid isopropyl ester	Finally, the	88.0
					4c	1.4mol％	Acetic acid isopropyl ester	Finally, the	88.6
4d	1.4mol％	Acetic acid isopropyl ester	Before the 2-cyanophenol	80.4

From these results it can be seen that the process of the invention can also be carried out in aqueous systems. In addition, the surprising result seen in example 3 for the order of DABCO addition is also seen in the aqueous system-the addition of DABCO after 2-cyanophenol (in the form of potassium 2-cyanophenol), i.e. last addition, gives a higher yield than the yield obtained with the previous addition.

Example 5

Preparation of methyl (E) -2- (2-hydroxyphenyl) -3- (methyloxy) acrylate.

Step 1: preparation of methyl 2- [ (2-benzyloxyl) phenyl ] - (3, 3-dimethoxy) propanoate.

Crude methyl 2- (2-hydroxyphenyl) -3, 3- (dimethoxy) propionate (15g), DMF (82g) and potassium carbonate (8.7 g) were stirred at room temperature and benzyl bromide (9.8g) was added over 15 minutes. After 6 hours, additional benzyl bromide (1.0g) was added. After stirring overnight, water (200mL) was added. The solid formed was isolated by suction filtration, washed with water and dried on the filter to give methyl 2- [ (2-benzyloxyphenyl ] - (3, 3-dimethoxy) propionate (57%).

Step 2: preparation of methyl (E) -2- (2-benzyloxyl) phenyl-3-methoxyacrylate.

A solution of methyl 2- [ (2-benzyloxy) phenyl ] - (3, 3-dimethoxy) propanoate (5 g; from step 1) in acetic anhydride (7.0g) was heated to 40 ℃ and methanesulfonic acid (0.33g) was added. After 90 minutes, the mixture was cooled to room temperature and toluene (25mL) was added. The resulting solution was washed with water (3X 75mL) and the toluene was evaporated in vacuo to give a liquid. Crystals formed after standing overnight. The separation is carried out by filtration. After further concentration, the second product was isolated from the filtrate and triturated with ethanol.

(E) The total yield of methyl (2-benzyloxyl) phenyl-3-methoxyacrylate) was 44%.

And step 3: preparation of methyl (E) -2- (2-hydroxy) phenyl-3-methoxyacrylate.

Ethyl acetate (25mL) was degassed by application of vacuum and purged with nitrogen. Methyl (E) -2- (2-benzyloxyl) phenyl-3-methoxyacrylate (0.8g) and palladium on carbon (0.02g) were added to ethyl acetate (10 mL). The nitrogen atmosphere was replaced with hydrogen and the reaction was stirred at room temperature. After about 40 hours, the catalyst was filtered off and the reaction was restarted with fresh catalyst (0.02 g). After 2 hours, the reaction was complete. The reaction flask was purged with nitrogen. The catalyst was filtered, washed with ethyl acetate and the combined filtrate and washings evaporated in vacuo to give methyl (E) -2- (2-hydroxy) phenyl-3-methoxyacrylate as an oil which crystallised on standing.

2- (2-Phenylmethyloxy) phenyl-3, 3-Dimethoxypropionic acid methyl ester of the formula (Compound (V) wherein Q is benzyl) (see Table 5):

table 5:¹HNMR, 200MHz in CDCl₃In

Chemical shift (ppm)	Multiple and severe degree	Cumulative number	Coupling constant (Hz)	Attribution
					7.44-7.13	m	7H	--	ArH
6.93-6.85	m	2H	--	ArH
					5.04	s	2H	--	ArCH₂O
5.0	d	1H	9	(CH₃O)₂CHCH
					4.56	d	1H	9	(CH₃O)₂CHCH
3.58	s	3H	--	OCH₃
					3.38	s	3H	--	OCH₃
3.10	s	3H	--	OCH₃

(E) -2- (2-Phenylmethyloxy) phenyl-3-methoxyacrylic acid having the formula Data characteristic of methyl esters (see table 6):

table 6:¹HNMR, 200MHz in CDCl₃In

Chemical shift (ppm)	Multiple and severe degree	Cumulative number	Coupling constant (Hz)	Attribution
					7.43	s	1H	--	CH3OCH＝
7.3-6.85	m	～9H	--	ArH
					4.99	s	2H	--	ArCH₂O
3.71	s	3H	--	OCH₃
					3.57	s	3H	--	OCH₃

Characteristic data of methyl (E) -2- (2-hydroxy) phenyl-3-methoxyacrylate (compound (IV) wherein W is the methyl (E) -2- (3-methoxy) acrylate group) having the following formula (see Table 7):

table 7:¹HNMR, 200MHz in CDCl₃In

Chemical shift (ppm)	Multiple and severe degree	Cumulative number	Coupling constant (Hz)	Attribution
					7.56	s	1H	--	CH3OCH＝
7.2-7.06	m	～2H	--	ArH
					6.9-6.8	m	2H	--	ArH
3.80	s	3H	--	OCH₃
					3.69	s	3H	--	OCH₃

In the above table:

ArH is hydrogen bonded to a benzene ring;

'd' represents a double peak;

's' represents a single peak;

the cumulative number represents the number of hydrogens associated with the signal.

Claims

1. A process for preparing a compound of formula (I):

it includes:

(a) reacting a compound of formula (II)

With 2-cyanophenol or salts thereof in the presence of more than 0.1 and less than 2 mol% of 1, 4-diazabicyclo [2.2.2] octane; or

(b) Reacting a compound of formula (III)

With compounds of the formula (IV)

In the presence of more than 0.1 and less than 2 mol% of 1, 4-diazabicyclo [2.2.2] octane;

wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or the methyl 2- (3, 3-dimethoxy) propionate group CH (CO)₂CH₃)CH(OCH₃)₂Or a mixture of said two groups, wherein said 1, 4-diazabicyclo [2.2.2]Octane is the last component added.

2. The process according to claim 1, which is carried out in the presence of 0.2 to 1.4 mol% of 1, 4-diazabicyclo [2.2.2] octane.

3. The process of claim 1, which is carried out in an inert solvent or diluent.

4. The process of claim 3 wherein the inert solvent or diluent is methyl isobutyl ketone, cyclohexanone, N-diisopropylethylamine, isopropyl acetate or N, N-dimethylformamide.

5. The process of claim 4 wherein the inert solvent or diluent is N, N-dimethylformamide.

6. A process according to any one of claims 1 to 5, which is carried out in the presence of 1.0 mol% 1, 4-diazabicyclo [2.2.2] octane.

7. The method of any one of claims 1-5, which is carried out in an aqueous system.

8. The process according to claim 7, wherein potassium 2-cyanophenol is used as the salt of 2-cyanophenol.

9. The process according to any one of claims 1 to 5, which is carried out in the presence of an acid acceptor.

10. The process of claim 9 wherein the acid acceptor is potassium carbonate or sodium carbonate.

11. The process according to any one of claims 1 to 5, which is carried out at a temperature of from 0 to 100 ℃.

12. A process for preparing a compound of formula (I):

it includes:

(a) reacting a compound of formula (II)

(b) Reacting a compound of formula (III)

With compounds of the formula (IV)

wherein W is a methyl (E) -2- (3-methoxy) acrylate group C (CO)₂CH₃)＝CHOCH₃Or the methyl 2- (3, 3-dimethoxy) propionate group CH (CO)₂CH₃)CH(OCH₃)₂Or a mixture of said two groups,

wherein the process is carried out in N, N-dimethylformamide.

13. The process according to claim 12, which is carried out in the presence of 0.2 to 1.4 mol% of 1, 4-diazabicyclo [2.2.2] octane.

14. The process according to claim 12, which is carried out in the presence of 1.0 mol% of 1, 4-diazabicyclo [2.2.2] octane.

15. The method of any one of claims 12-14, which is carried out in an aqueous system.

16. The process according to claim 15, wherein potassium 2-cyanophenol is used as the salt of 2-cyanophenol.

17. The process according to any one of claims 12 to 15, which is carried out in the presence of an acid acceptor.

18. The method of claim 17 wherein the acid acceptor is potassium carbonate or sodium carbonate.

19. The process according to any one of claims 12 to 15, which is carried out at a temperature of from 0 to 100 ℃.

20. A process according to any one of claims 12 to 15 wherein the 1, 4-diazabicyclo [2.2.2] octane is the last component added.