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

which comprises;
(a) reacting methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate (MMP) with 2-cyano phenol (2-CP) in presence of a phase transfer catalyst in a solvent, and a base.
(b) removing solvent completely
(c) adding aqueous alcohol solution
(d) isolating azoxystrobin (I).
2. The process as claimed in claim 1, wherein step a) is carried out at a temperature of 75-80 oC for 8-10 hrs.
3. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium iodide, sodium iodide, potassium iodide, and 1,4-diazabicyclo [2.2.2] octane.
4. The process as claimed in claim 1, wherein the solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, toluene, 1,2-dichloroethane and mono chlorobenzene.
5. The process as claimed in claim 1, wherein the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and magnesium carbonate.
6. The process as claimed in claim 1, wherein the product is isolated by filtration.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Azoxystrobin of Formula (I) using a phase transfer catalyst.

Formula (I)

BACKGROUND OF THE INVENTION
Strobilurins are a group of natural products and their synthetic analogs. Several strobilurins are used in agriculture as fungicides. They are part of the larger group of QoI inhibitors, which act to inhibit the respiratory chain at the level of Complex III.

Azoxystrobin is a strobilurin fungicide, and is chemically, methyl (2E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate with protective and curative action, which are effective against a number of diseases caused by Oomycetes sp. Ascomycetes sp., Basidiomycetes sp. and Deuteromycetes sp.

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.

IN5500/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 phase transfer catalyst under basic conditions in which the yield and purity is improved.

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of Azoxystrobin (I) using a phase transfer catalyst.

which comprises;
(a) reacting methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate (MMP) with 2-cyano phenol (2-CP) in presence of a phase transfer catalyst in a solvent, and a base.
(b) removing solvent completely
(c) adding aqueous alcohol solution
(d) isolating azoxystrobin (I).

In another aspect of the present invention is to provide a simple, economical, and commercially feasible process for the synthesis of azoxystrobin using a phase transfer catalyst with a high yield without any purification.

DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

For the purpose of clarity and as an aid in the understanding of the invention, as disclosed and claimed herein, the following terms and abbreviations are defined below:

MMP Methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate.
2-CP 2-cyano phenol.
DMF N, N-dimethylformamide
ACN Acetonitrile
PTC Phase transfer catalyst.
TBAB Tetrabutylammonium bromide
TBAI Tetrabutylammonium iodide
NaI Sodium iodide
KI Potassium iodide
DABCO 1,4-diazabicyclo [2.2.2] octane

The main embodiment of the present invention is to provide an improved process for the preparation of azoxystrobin (I)

which comprises;
(a) reacting methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate (MMP) with 2-cyano phenol (2-CP) in presence of a phase transfer catalyst in a solvent, and a base.
(b) removing solvent completely
(c) adding aqueous alcohol solution
(d) isolating azoxystrobin (I).

According to the present embodiment, process for preparing azoxystrobin involves, reaction of methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate (MMP) with 2-cyano phenol (2-CP) in a solvent, in the presence of phase transfer catalyst and a base at a temperature of 70oC to 80oC for 10 to 12 hrs to get the reaction mixture. The resulting reaction mixture is dissolved in a mixture of water and methanol at 60 to 65oC for 1-2 hrs. Cooled the reaction mixture to 0oC to 5oC, the obtained solid is filtered and dried to get azoxystrobin (I).

According to the present embodiment, the solvent used in the reaction is selected from polar-aprotic solvents such as N, N-dimethylformamide (DMF), dimethylacetamide (DMAc) and dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile, propionitrile and butyronitrile; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; ether solvents such as tetrahydrofuran and 1,4-dioxane; hydrocarbon solvents such as toluene and mono chlorobenzene; chlorinated solvents such as 1,2- dichloroethane.

According to the present embodiment, the base used in the reaction is selected from alkali metal carbonates, such as potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate and lithium carbonate.

According to the present embodiment, the phase transfer catalyst (PTC) used in the reaction is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), sodium iodide (NaI), potassium iodide (KI), and 1,4-diazabicyclo [2.2.2] octane (DABCO).
According to the present embodiment, the product is isolated by filtration, agitated thin film drier (ATFD) or lyophilization.

According to the present embodiment, process for the preparation of azoxystrobin using phase transfer catalyst provides commercially feasible with high yield without further purification.

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.

EXAMPLES

Preparation of Azoxystrobin with Phase transfer catalyst:
Example 1
DMF (300 mL, 3 vol), MMP (100 g, 1 eq), 2-CP (37 g, 1.0 eq), potassium carbonate (51.5g, 1.2 eq) and TBAB (5 g, 0.05 eq) were taken into a 4 neck RBF equipped with mechanical stirrer. The reaction mass was stirred to 75-80°C and maintained for 8-10 hrs. The reaction was monitored by HPLC till the MMPC content is less than 0.5 % (Area normalization). After the completion of reaction, the reaction mass was cooled to room temperature (25-30oC) and filtered under vacuum. The filtrate was collected and DMF was under vacuum at temp-80-90oC, the obtained crude material was treated with solution of 10% water in methanol and stirred and heated to 64-65oC and maintained for 1 hr. After completion of heating, the reaction mass was cooled to 0-5oC and maintained for 1 hr. filter the obtained precipitated solid under vacuum to afford 98% pure Azoxystrobin technical with 85-90% yield.

Preparation of Azoxystrobin without catalyst:
Example-2:
DMF (300 mL, 3 vol), MMP (100 g, 1 eq), 2-CP (37 g, 1.0 eq) and potassium carbonate (51.5g, 1.2 eq) were taken into a 4 neck RBF equipped with mechanical stirrer. The reaction mass was stirred to 75- 80 °C and maintained for 18-20 hrs. The reaction was monitored by HPLC till the MMPC content is less than 0.5 % (Area normalization). After the completion of reaction, the reaction mass was cooled to room temperature (25-30°C) and filtered under vacuum. The filtrate was collected and DMF was distilled under vacuum at temp-80-90°C, the obtained crude material was treated with solution of 10% water in methanol and stirred and heated to 64-65°C and maintained for 1 hr. After completion of heating, the reaction mass was cooled to 0-5°C and maintained for 1 hr., filter the obtained precipitated solid under vacuum to afford 98% pure Azoxystrobin technical with 73-75% yield.

Advantages of the present invention with phase transfer catalyst:
1. Reaction time reduces from 18-20 hrs to 8-10 hrs.
2. Yield improves from 73-75% to 85-90%.
3. Involves simple crystallization and filtration method.
4. Further purification is not required.
5. Industrially and economically robust process with safe operations.
6. Less reaction timings at moderate temperature