Claims:1. A process for the preparation of Azoxystrobin compound of Formula (I), consisting of:

a) heating the reaction mixture of 2-cyanophenol compound of Formula (III) in a solvent and in presence of a base at a temperature of 85-120 oC,
b) adding compound of Formula (II) and a catalyst to the above reaction mixture at a temperature of 85-120 oC,
c) cool the reaction mixture to room temperature,
d) isolating, followed by recrystallization to get pure Azoxystrobin.
2. The process as claimed in claim 1, wherein the catalyst is selected from 4-(2-hydroxyethyl)morpholine, triethanolamine, or benzyl trimethyl ammonium hydroxide.
3. The process as claimed in claim 1, wherein the solvent is selected from acetonitrile, propionitrile, butyronitrile, N, N-dimethyl formamide, N, N-dimethylacetamide, diethylene glycol dimethyl ether, diglyme, dioxane, toluene, and mono chlorobenzene.
4. The process as claimed in claim 1, wherein the base is selected from the group consisting of including alkali metal carbonates and bicarbonates, and mixtures thereof.
5. The process as claimed in claim 4, wherein the alkali metal carbonate is sodium carbonate or potassium carbonate.
6. The process as claimed in claim 1, wherein the reaction is carried out at a temperature from 85 °C to 120 °C.
, Description:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Azoxystrobin having the following Formula (I), in presence of a catalyst.

Formula (I)

BACKGROUND OF THE INVENTION

Azoxystrobin is disclosed in US 5,395,837 and is a plant protection fungicide with protectant, curative, eradicant, translaminar and systemic properties. Azoxystrobin is a systemic fungicide commonly used in agriculture.
US 5,395,837 discloses a process for the preparation of Azoxystrobin which involves reaction between 2-cyanophenol and (E)-methyl 2-[2-(6-chlorpyridimin-4-yloxy)phenyl]-3-methoxypropenoate at temperatures at 95 °C to 100 °C in dimethyl formamide in the presence of stoichiometric amounts of potassium carbonate and a catalytic amount of copper(I) chloride which is shown below :

US 8,124,761 B2 claims a process for the preparation of Azoxystrobin reacting a compound of formula II with 2-cyanophenol, or a salt thereof, in the presence of between 0.1 and 2 moles of 1, 4-diazabicyclo [2.2.2] octane, or reacting a compound of the formula III with a compound of the formula IV in the presence of between 0.1 and 2 moles of 1,4-diazabicyclo [2.2.2]octane which is shown below :

wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)-CHOCH3 or the methyl 2-(3,3-dimethoxy) propanoate group C(CO2CH3)CH(OCH3)2, or a mixture of the two groups.
US 8,471,013 B2 A1 discloses a process for the preparation of Azoxystrobin by reacting a cyanophenol derivative with a base in a polar organic solvent to obtain a phenolate salt followed by condensation of the aromatic substrate as shown in the scheme given below:

WO 2017/060917 A1 discloses a process for the preparation of Azoxystrobin as shown in the scheme given below:
wherein W is the methyl (E)-2-(3-methoxy) acrylate group C(CO2CH3)=CHOCH3.

CN 102690237 discloses a process for the preparation of Azoxystrobin as shown in the scheme given below:

CN 102952085 discloses a process for the preparation of Azoxystrobin as shown in the scheme given below:

The bases used in the above method are selected from potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide and solvents employed are methanol, ethanol or toluene.
IN 5500/CHE/2015 discloses a process for the preparation of Azoxystrobin as shown in the scheme given below:

The solvents used are N-methyl pyrrolidone, N, N-dimethyl formamide, N,N-dimethyl acetamide, acetonitrile, acetone, methanol, ethanol, C3 to C8 alcohols, N,N-dibutyl formamide and more preferably acetonitrile, N,N dimethyl acetamide, N, N-dimethyl formamide and the bases employed are alkali hydroxides, alkali carbonates, organic carbonates, and preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, DBU.
The above published methods for synthesizing Azoxystrobin, however, are often complicated, such as by using a multiple step and/or time-consuming synthesis process. Further, many of the above published methods do not produce high yields of the active ingredient.
Accordingly, there is an ongoing and long felt need for a process for aromatic substitution reactions in the presence phenols with improved yield and selectivity.
The present invention is directed to the above drawbacks, the purpose is to provide novel process for the preparation of Azoxystrobin of formula (I) which is a mild reaction conditions, simple operation, less expensive & cost-effective process.
Thus, it is the objective of the present invention to provide a process for reacting phenols in presence of catalyst under basic conditions in which the yield and purity is improved.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a process for the preparation of Azoxystrobin compound of Formula (I) in presence of a catalyst.

Formula (I)

Further objective of the present invention, wherein the catalyst is selected form 4-(2-hydroxyethyl)morpholine, triethanolamine, or benzyl trimethyl ammonium hydroxide.
In a further objective of the present invention is to provide a simple, economical and commercially feasible process for the synthesis of Azoxystrobin with a high yield and high purity.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a process for the preparation of Azoxystrobin, compound of Formula (I) in presence of a catalyst.

The further aspect of the present invention provides the process for the preparation of Azoxystrobin compound of Formula (I), consisting the steps of:
a) heating the reaction mixture of 2-cyanophenol compound of Formula (III) in a solvent and in present of a base at a temperature of 85-120 oC,
b) adding compound of Formula (II) and a catalyst to the above reaction mixture at a temperature of 85-120 oC,
c) cool the reaction mixture to room temperature,
d) isolating, followed by recrystallization to get pure Azoxystrobin.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the present invention is to provide a process for the preparation of Azoxystrobin compound of Formula (I), by reacting compound of Formula (II) with a reaction mixture of 2-cyanophenol compound Formula (III) in a solvent and base in presence of a catalyst.

According to the present embodiment, the process for the preparation of Azoxystrobin consisting the steps of:
a) heating the reaction mixture of 2-cyanophenol compound of Formula (III) in a solvent and in presence of a base at a temperature of 85-120 oC,
b) adding monomethoxy propionate (MMP) compound of Formula (II) and a catalyst to the above reaction mixture at a temperature of 85-120 oC,
c) cool the reaction mixture to room temperature,
d) isolating, followed by recrystallization to get pure Azoxystrobin.

According to the present embodiment, the catalyst is selected from 4-(2-hydroxyethyl)morpholine, triethanolamine, or benzyl trimethyl ammonium hydroxide.

According to the present embodiment, the solvent is selected from acetonitrile, propionitrile, butyronitrile, N, N-dimethyl formamide, N, N-dimethylacetamide, diethylene glycol dimethyl ether, diglyme, dioxane, toluene and mono chlorobenzene.

According to the present embodiment, the base is selected from inorganic bases. These includes, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, and alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate. Preferably, the base employed is potassium carbonate.

According to the present embodiment, the reaction temperature can be varied within a relatively wide range. The temperature chosen will depend on the nature of the solvent or diluent, for example on its boiling point and/or its effectiveness for promoting the desired reaction, and on the speed at which the reaction is to be carried out. In any given solvent or diluent, the reaction will tend to progress more slowly at lower temperatures. In general, the reaction may be carried out at a temperature of from 85 °C to 120 °C.

According to the present embodiment, the process for the preparation of Azoxystrobin compound of Formula (I), involves reacting compound of Formula (II) with a reaction mixture of compound of Formula (III) in a solvent and base in presence of a catalyst at a temperature of 85°C to 120°C. After completion of the reaction, the reaction mixture was cooled to room temperature, and isolation followed by recrystallization to get the desired product.

According to the present embodiment, the process for obtaining Azoxystrobin is having a purity of 98%-99% and a yield of above 85 %. This is a significant improvement in comparison to the prior art methods which describe a process with a yield of 64%. Hence, the process of the present invention is more economical, produces less by-products and impurities and further generates considerably less effluents as a result of the improved yield.

The further embodiment of the present invention is illustrated by the following examples, which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-1: Preparation of Azoxystrobin

Acetonitrile (250 mL), K2CO3 (23.664 g, 1.1 eq) and 2-cyanophenol (21.482 g, 1.1 eq) compound of Formula (III) charged at room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 82-84oC and maintain for 1 hr. 4-(2-hydroxyethyl)morpholine (4.089 g, 0.2 eq) and mono methoxy propionate (MMP) compound of Formula (II) (50.0 g, 1.0 eq) was added to the reaction mixture at 82-84oC and maintained for 22-24 h. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with Acetonitrile (25 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Add methanol (75 mL) to residue, heat to reflux under stirring to obtain clear solution and continued for 1 h. Reaction mass allowed to obtain RT and further cooled to 0 to 5oC and maintained this up to 2 h. Filter the product at 0oC through Buckner funnel and wash it with precooled methanol (25 mL). Collect the compound and dry it at 70-75°C till the constant weight. Finally, the required Azoxystrobin obtained as solid with HPLC purity of 96-97% (w/w) and yield is 82-86% (51.56 – 54.06 g).

Example-2: Preparation of Azoxystrobin

Butyronitrile (250 mL), K2CO3 (23.664 g, 1.1 eq) and 2-cyanophenol (21.482 g, 1.1 eq) compound of Formula (III) charged room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 110oC and maintain for 1 hr. 4-(2-hydroxyethyl)morpholine (4.089 g, 0.2 eq) and mono methoxy propionate (MMP) compound of Formula (II) (50.0 g, 1.0 eq) was added to the reaction mixture at 120oC and maintained for 10-12 hrs. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with Butyronitrile (25 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Add methanol (75 mL) to residue, heat to reflux under stirring to obtain clear solution and continued for 1 h. Reaction mass allowed to obtain RT and further cooled to 0 to 5oC and maintained this up to 2 h. Filter the product at 0oC through Buckner funnel and wash it with precooled methanol (25 mL). Collect the compound and dry it at 70-75°C till the constant weight. Finally, the required Azoxystrobin obtained as solid with HPLC purity of 96-97% (w/w) and yield is 82-86% (51.56 – 54.06 g).

Example-3: Preparation of Azoxystrobin

N, N-Dimethylformamide (100 mL), K2CO3 (9.466 g, 1.1 eq) and 2-cyanophenol (8.162 g, 1.1 eq) compound of Formula (III) charged at room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 100 oC and maintain for 1 h. 4-(2-hydroxyethyl)morpholine (1.636 g, 0.2 eq) and mono methoxy propionate (MMP) compound of Formula (II) (20.0 g, 1.0 eq) was added to the reaction mixture at 100oC and maintained for 7-8 h. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with DMF (10 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Add methanol (30 mL) to residue, heat to reflux under stirring to obtain clear solution and continued for 1 h. Reaction mass allowed to obtain RT and further cooled to 0 to 5oC and maintained this up to 2 h. Filter the product at 0oC through Buckner funnel and wash it with precooled methanol (10 mL). Collect the compound and dry it at 70-75°C till the constant weight. Finally, the required Azoxystrobin obtained as solid with HPLC purity of 96-97% (w/w) and yield is 82-86% (20.62 – 21.63 g).

Example-4: Preparation of Azoxystrobin

Diethylene glycol dimethyl ether (250 mL), K2CO3 (23.664 g, 1.1 eq) and 2-cyanophenol (21.482 g, 1.1 eq) compound of Formula (III) charged at room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 120oC and maintain for 1 hr. 4-(2-hydroxyethyl)morpholine (4.089 g, 0.2 eq) and mono methoxy propionate (MMP) compound of Formula (II) (50.0 g, 1.0 eq) was added to the reaction mixture at 120oC and maintained for 4-5 hrs. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with diglyme (25 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Add methanol (75 mL) to residue, heat to reflux under stirring to obtain clear solution and continued for 1 h. Reaction mass allowed to obtain RT and further cooled to 0 to 5oC and maintained this up to 2 h. Filter the product at 0oC through Buckner funnel and wash it with precooled methanol (25 mL). Collect the compound and dried at 70-75°C
To get Azoxystrobin with HPLC purity of 96-97% (w/w) and yield is 82-86% (51.56 – 54.06 g).

Example-5: Preparation of Azoxystrobin

Diethylene glycol dimethyl ether (25 mL), K2CO3 (2.689 g, 1.25 eq) and 2-cyanophenol (2.041 g, 1.1 eq) compound of Formula (III) charged room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 120oC and maintain for 1 hr. 4-(2-hydroxyethyl)morpholine (0.204 g, 0.1 eq) and mono methoxy propionate (MMP) compound of Formula (II) (5.0 g, 1.0 eq) was added to the reaction mixture at 120oC and maintained for 4-5 hrs. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with diglyme (2.5 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Add methanol (7.5 mL) to residue, heat to reflux under stirring to obtain clear solution and continued for 1 h. Reaction mass allowed to obtain RT and further cooled to 0 to 5oC and maintained this up to 2 h. Filter the product at 0oC through Buckner funnel and wash it with precooled methanol (2.5 mL). Collect the compound and dry it at 70-75 °C till the constant weight. Finally, the required Azoxystrobin obtained as solid with HPLC purity of 96-97% (w/w) and yield is 82-86% (5.156 – 5.406 g).

Example-6: Preparation of Azoxystrobin

Diethylene glycol dimethyl ether (25 mL), K2CO3 (2.689 g,1.25 eq) and 2-cyanophenol (2.041 g, 1.1 eq) compound of Formula (III) charged room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 120oC and maintain for 1 hr. 4-(2-hydroxyethyl)morpholine (0.102 g, 0.05 eq) and mono methoxy propionate (MMP) compound of Formula (II) (5.0 g, 1.0 eq) was added to the reaction mixture at 120oC and maintained for 4-5 hrs. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with diglyme (2.5 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Add methanol (7.5 mL) to residue, heat to reflux under stirring to obtain clear solution and continued for 1 h. Reaction mass allowed to obtain RT and further cooled to 0 to 5oC and maintained this up to 2 h. Filter the product at 0oC through Buckner funnel and wash it with precooled methanol (2.5 mL). Collect the compound and dry it at 70-75 °C till the constant weight. Finally, the required Azoxystrobin obtained as solid with HPLC purity of 96-97% (w/w) and yield is 82-86% (5.156 – 5.406 g).

Example-7: Preparation of Azoxystrobin

Dioxane (50 mL), K2CO3 (6.454 g, 1.5 eq) and 2-cyanophenol (4.081 g, 1.1 eq) compound of Formula (III) charged at room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 100oC and maintain for 1 hr. 4-(2-hydroxyethyl)morpholine (0.818 g, 0.2 eq) and mono methoxy propionate (MMP) compound of Formula (II) (10.0 g, 1.0 eq) was added to the reaction mixture at 100oC and maintained for 22-24 h. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with dioxane (5 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Crude product recrystallized in methanol.

Example-8: Preparation of Azoxystrobin

Propionitrile (10 mL), K2CO3 (0.946 g, 1.1 eq) and 2-Cyanophenol (0.816 g, 1.1 eq) compound of Formula (III) charged at room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 100oC and maintain for 1 h. 4-(2-hydroxyethyl)morpholine (0.163 g, 0.2 eq) and mono methoxy propionate (MMP) compound of Formula (II) (2.0 g, 1.0 eq) was added to the reaction mixture at 100oC and maintained for 16-18 h. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with Propionitrile (2 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Crude product recrystallized in methanol.

Example-9: Preparation of Azoxystrobin

N, N-Dimethylformamide (25 mL), K2CO3 (2.689 g, 1.25 eq) and 2-cyanophenol compound of Formula (III) (2.041 g, 1.1 eq) charged at room temperature (RT) into 4-neck round bottom flask equipped with temperature socket and condenser under stirring. The reaction mass was heated to 100oC and maintain for 1 hr. Triethanolamine (0.465 g, 0.2 eq) and mono methoxy propionate (MMP) compound of Formula (II) (5.0 g, 1.0 eq) was added to the reaction mixture at 100oC and maintained for 9-10 h. Monitor the reaction by HPLC till the MMP content is less than 2.0% (Area normalization). After completion of reaction, reaction mass was cooled to room temperature and filter it, followed by wash the inorganic cake with DMF (2.5 mL) and concentrate all the filtrate under reduced pressure till no more distillate found. Add methanol (7.5 mL) to residue, heat to reflux under stirring to obtain clear solution and continued for 1 h. Reaction mass allowed to obtain RT and further cooled to 0 to 5oC and maintained this up to 2 h. Filter the product at 0oC through Buckner funnel and wash it with precooled methanol (2.5 mL). Collect the compound and dry it at 70-75°C till the constant weight. Finally, the required Azoxystrobin obtained as solid with HPLC purity of 94-96% (w/w) and yield is 78-82% (4.905 g-5.156 g).

Example-10: Preparation of Azoxystrobin

Charge mono chlorobenzene (125 mL, K2CO3 (10.747 g, 1.0 eq.) and 2-cyanophenol compound of Formula (III) (10.194 g, 1.1 eq.) and benzyl trimethyl ammonium hydroxide (25%) in methanol (10.420 g, 0.2 eq.) at room temperature (RT) in clean & dry 4-neck round bottom flask equipped with temperature socket and downward distillation condenser fitted with single neck round bottom flask under stirring. Heat the reaction mixture up to 80-85oC and distill out methanol. Monomethoxy propionate compound (MMP) of Formula (II) (25.0 g, 1.0 eq.) was added to the reaction mixture at 80-85oC and stirred at 95-100oC for 9-11 h. Monitor the reaction by HPLC, MMP limit not more than 2.0%.
Cool the reaction mass to RT and filter it, followed by wash the inorganic cake with mono chlorobenzene (12.5 mL) and concentrate all the solvent from reaction mass under reduced pressure till no more distillates found. Crude product recrystallized from methanol and dry at 70-75 °C to get 26 gm azoxystrobin (82%) with 99% purity by HPLC.