A process for the preparation of a fungicide

Abstract

The present disclosure relates to a process for the preparation of a fungicide, particularly azoxystrobin The process of the present disclosure is simple, efficient, environment friendly and provides azoxystrobin with comparatively high purity and high yield.

Description

[0001] A PROCESS FOR THE PREPARATION OF A FUNGICIDE

[0002] FIELD

[0003] The present disclosure relates to a process for the preparation of a fungicide.

[0004] BACKGROUND

[0005] The background information herein below relates to the present disclosure but is not necessarily prior art.

[0006] Azoxystrobin is a broad spectrum fungicide with systemic activity and both protectant and curative actions on a broad range of crops including fruits, vegetables, small grains, and turf grass. It inhibits mitochondrial respiration of fungi by blocking the electron transport.

[0007] Azoxystrobin is chemically known as methyl (2E)-2-(2-{[6-(2-cyanophenoxy) pyrimidin-4-yl] oxy} phenyl)-3-methoxyprop-2-enoate compound and represented as Formula (I) below:

[0008] Formula I

[0009] Conventional methods for the preparation of azoxystrobin are associated with drawbacks such as more number of process steps, use of expensive and corrosive reagents, tedious work-up steps, formation of impurities, low purity and low yield of the product. The impurities in azoxystrobin may affect the efficacy, safety, and stability of the final formulation.

[0010] Therefore, there is felt a need to provide a process for the preparation of azoxystrobin that mitigates the aforestated drawbacks or at least provides an alternative solution.

[0011] OBJECTS

[0012] Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:

[0013] It is an object of the present disclosure to ameliorate one or more problems of the background or to at least provide a useful alternative.

[0014] An object of the present disclosure is to provide a process for the preparation of azoxystrobin. Another object of the present disclosure is to provide a process for the preparation of azoxystrobin with a comparatively high purity and high yield.

[0015] Still another object of the present disclosure is to provide a simple and cost-effective process for the preparation of azoxystrobin.

[0016] Yet another object of the present disclosure is to provide a single step synthesis of a mixture comprising methyl 2-(2-((6-cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3,3- dimethoxypropionate and azoxystrobin.

[0017] Still another object of the present disclosure is to provide an environment-friendly and commercially scalable process for the preparation of azoxystrobin.

[0018] Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.

[0019] SUMMARY

[0020] The present disclosure relates to a process for the preparation of azoxystrobin. The process comprises the following steps: a. mixing (Z)-3 -(methoxymethylene) benzofuran-2(3H)-one (Formula-II) in a first fluid medium at a temperature in the range of 25 °C to 40 °C to obtain a solution; b. adding a first base to the solution at a first predetermined temperature and stirring by maintaining the first predetermined temperature for a first predetermined time period to obtain a resultant solution; c. adding 4-chloro-6-(2-cyanophenoxy)-pyrimidine (Formula-Ill), a second base and a first catalyst to the resultant solution under stirring at the first predetermined temperature and allowing to reach to a temperature in the range of 25 °C to 40 °C and further stirred for a second predetermined time period to obtain a mixture comprising methyl 2-(2-((6-cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3,3- dimethoxypropionate (Formula IV) and azoxystrobin (Formula I); d. adding a second fluid medium in the mixture followed by adding a second catalyst and optionally adding a dealcoholizing agent under stirring at a temperature in the range of 25 °C to 40 °C to obtain a reaction mixture; and e. heating the reaction mixture to a second predetermined temperature for a third predetermined time period to obtain a product mixture comprising azoxystrobin (Formula I). The first fluid medium is at least one selected from the group consisting of acetonitrile, dichloromethane, benzyl nitrile, dimethyl formamide, dimethyl acetamide, sulfolane, N-methyl pyrrolidine, 1,4-dioxane, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, toluene, benzene, xylene, ethylene dichloride, ethyl acetate, tert-butanol, methyl tert-butyl ether, acetone and dimethyl sulfoxide.

[0021] The first fluid medium is an equivalent mixture of acetonitrile and dichloromethane.

[0022] The first base is selected from sodium methoxide and potassium methoxide.

[0023] The first predetermined temperature is in the range of -20 °C to 10 °C.

[0024] The first predetermined time period is in the range of 30 minutes to 120 minutes.

[0025] The second base is selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, calcium hydroxide and potassium hydroxide.

[0026] The first catalyst is selected from 1,4-diazabicyclo [2.2.2] octane (DABCO) and 1, 8- Diazabicyclo [5.4.0] undec-7-ene (DBU).

[0027] The second predetermined time period is in the range of 1 hour to 4 hours.

[0028] The molar ratio of (Z)-3 -(methoxymethylene) benzofuran-2(3H)-one (Formula-II) to (4- chloro-6-(2-cyanophenoxy)-pyrimidine) (Formula-Ill) is in the range of 1:0.9 to 1: 1.2.

[0029] The second fluid medium is at least one selected from the group consisting of toluene, benzyl nitrile, dimethyl acetamide, sulfolane, N-methyl pyrrolidine, 1,4-dioxane, tetrahydrofuran, benzene, xylene, ethylene dichloride, ethyl acetate, tert-butanol and methyl tert-butyl ether.

[0030] The second catalyst is para-toluene sulfonic acid.

[0031] The dealcoholizing agent is selected from the group consisting of phosphorous tribromide, phosphorous trichloride, phosphorous pentoxide, thionyl chloride, sulfur trichloride, phosphorous pentachloride, p-toluyl sulfonyl chloride and sulfur dioxide.

[0032] The second predetermined temperature is in the range of 60 °C to 120 °C.

[0033] The third predetermined time period is in the range of 30 minutes to 360 minutes.

[0034] The yield of azoxystrobin (Formula I) is in the range of 75% to 95% and the purity of azoxystrobin (Formula I) is in the range of 95 % to 99.8%. In an embodiment of the present disclosure, the yield of azoxystrobin (Formula I) is in the range of 75 % to 85 % and the purity of azoxystrobin (Formula I) is in the range of 99 % to 99.8 %.

[0035] In a preferred embodiment of the present disclosure, the yield of azoxystrobin (Formula I) is in the range of 77 % to 84 % and the purity of azoxystrobin (Formula I) is in the range of 99.3 % to 99.5 %.

[0036] Azoxystrobin has a purity in the range of 95 % to 99.8 %.

[0037] In an embodiment of the present disclosure, azoxystrobin has a purity in the range of 99 % to 99.8 %.

[0038] In a preferred embodiment of the present disclosure, azoxystrobin has a purity in the range of 99.3 % to 99.5 %.

[0039] DETAILED DESCRIPTION

[0040] The present disclosure relates to a process for the preparation of a fungicide.

[0041] Embodiments, of the present disclosure, will now be described herein. Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.

[0042] The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and / or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.

[0043] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed elements.

[0044] The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.

[0045] The conventional methods for the preparation of azoxystrobin are associated with drawbacks such as impurities, low yield and low purity of the product. These conventional processes thus require further purification of the crude product to remove impurities. The impurities in azoxystrobin may affect the efficacy, safety, and stability of the final formulation. The conventional processes for the preparation of azoxystrobin involve tedious process steps and use of expensive reagents.

[0046] The present disclosure provides an improved process for the preparation of azoxystrobin.

[0047] The process of the present disclosure is simple, economical, environment friendly, and results in higher yield and higher purity of azoxystrobin.

[0048] In an embodiment of the present disclosure, the process for the preparation of azoxystrobin comprises the following steps: a. mixing (Z)-3 -(methoxymethylene) benzofiiran-2(3H)-one (Formula-II) in a first fluid medium at a temperature in the range of 25 °C to 40 °C to obtain a solution; b. adding a first base to the solution at a first predetermined temperature and stirring by maintaining the first predetermined temperature for a first predetermined time period to obtain a resultant solution; c. adding 4-chloro-6-(2-cyanophenoxy)-pyrimidine (Formula-Ill), a second base and a first catalyst to the resultant solution under stirring at the first predetermined temperature and allowing to reach to a temperature in the range of 25 °C to 40 °C and further stirred for a second predetermined time period to obtain a mixture comprising methyl 2-(2-((6-cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3,3- dimethoxypropionate (Formula IV) and azoxystrobin (Formula I); d. adding a second fluid medium in the mixture followed by adding a second catalyst and optionally adding a dealcoholizing agent under stirring at a temperature in the range of 25 °C to 40 °C to obtain a reaction mixture; and e. heating the reaction mixture to a second predetermined temperature for a third predetermined time period to obtain a product mixture comprising azoxystrobin (Formula I).

[0049] The process is described in detail below:

[0050] In a first step, (Z) -3 -(methoxymethylene) benzofuran-2(3H)-one (Formula-II) is mixed in a first fluid medium at a temperature in the range of 25 °C to 40 °C to obtain a solution.

[0051] In an embodiment of the present disclosure, the first fluid medium is at least one selected from the group consisting of acetonitrile, dichloromethane, benzyl nitrile, dimethyl formamide, dimethyl acetamide, sulfolane, N-Methyl pyrrolidine, 1,4-di oxane, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, toluene, benzene, xylene, ethylene dichloride, ethyl acetate, tert-butanol, methyl tert-butyl ether, acetone and dimethyl sulfoxide.

[0052] In an embodiment of the present disclosure, the first fluid medium is an equivalent mixture of acetonitrile and dichloromethane.

[0053] In accordance with the present disclosure, the process of the present disclosure is one-pot synthesis.

[0054] In a second step, a first base is added to the solution at a first predetermined temperature and stirred by maintaining the first predetermined temperature for a first predetermined time period to obtain a resultant solution.

[0055] In an embodiment of the present disclosure, the first base is selected from sodium methoxide and potassium methoxide. In an exemplary embodiment of the present disclosure, the first base is sodium methoxide.

[0056] In an exemplary embodiment, the first base is 30 % of sodium methoxide in methanol solution.

[0057] In an embodiment of the present disclosure, the molar ratio of (Z)-3-

[0058] (methoxymethylene) benzofuran-2(3H)-one (Formula-II) to the first base is in the range of 1 : 1 to 1.5. In an exemplary embodiment of the present disclosure, the molar ratio of (Z)-3- (methoxymethylene) benzofuran-2(3H)-one (Formula-II) to the first base is 1: 1.06.

[0059] In an embodiment of the present disclosure, the first predetermined temperature is in the range of -20 °C to 10 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is -10 °C.

[0060] In an embodiment of the present disclosure, the first predetermined time period is in the range of 30 minutes to 120 minutes. In an exemplary embodiment of the present disclosure, the first predetermined time period is 60 minutes.

[0061] In a third step, 4-chloro-6-(2-cyanophenoxy)-pyrimidine (Formula-Ill), a second base and a first catalyst is added to the resultant solution under stirring at the first predetermined temperature and allowing to reach to a temperature in the range of 25 °C to 40 °C and further stirred for a second predetermined time period to obtain a mixture comprising methyl 2-(2-((6- cyanophenoxy) pyrimidin-4-yl) oxy) phenyl) -3, 3 -dimethoxypropionate (Formula IV) and azoxystrobin (Formula I).

[0062] In an embodiment of the present disclosure, the second base is selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, calcium hydroxide and potassium hydroxide. In an exemplary embodiment of the present disclosure, the second base is potassium carbonate.

[0063] In an embodiment of the present disclosure, the first catalyst is selected from 1,4-diazabicyclo [2.2.2] octane (DABCO) and 1, 8 -Diazabicyclo [5.4.0] undec-7-ene (DBU). In an exemplary embodiment of the present disclosure, the first catalyst is 1,4-diazabicyclo [2.2.2] octane (DABCO).

[0064] In an embodiment of the present disclosure, the second predetermined time period is in the range of 1 hour to 4 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 2 hours.

[0065] In an embodiment of the present disclosure, the molar ratio of (Z)-3- (methoxymethylene)benzofuran-2(3H)-one (Formula-II) to (4-chloro-6-(2-cyanophenoxy)- pyrimidine) (Formula-Ill) is in the range of 1 :0.9 to 1 : 1.2. In an exemplary embodiment of the present disclosure, the molar ratio of (Z)-3-(methoxymethylene) benzofuran-2(3H)-one (Formula-II) to (4-chloro-6-(2-cyanophenoxy)-pyrimidine) (Formula-Ill) is 1: 1.02. In an embodiment of the present disclosure, the molar ratio of (Z)-3-(methoxymethylene) benzofuran-2(3H)-one (Formula-II) to the second base is in the range of 1:0.5 to 1: 1.5. In an exemplary embodiment of the present disclosure, the molar ratio of (Z) -3 -(methoxymethylene) benzofuran-2(3H)-one (Formula-II) to the second base is 1: 1.

[0066] In an embodiment of the present disclosure, the molar ratio of (Z)-3-(methoxymethylene) benzofuran-2(3H)-one (Formula-II) to the first catalyst is in the range of 1:0.1 to 1:0.4. In an exemplary embodiment of the present disclosure, the molar ratio of (Z)-3- (methoxymethylene)benzofuran-2(3H)-one (Formula-II) to the first catalyst is 1:0.19.

[0067] In an embodiment of the present disclosure, the first fluid medium is distilled from the mixture followed by adding water and a first solvent at a temperature in the range of 25 °C to 40 °C and stirring for a time period in the range of 5 minutes to 20 minutes to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer.

[0068] In an embodiment of the present disclosure, the first solvent is at least one selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, benzene, xylene, ethylene dichloride, ethyl acetate and methyl tert-butyl ether.

[0069] In an embodiment of the present disclosure, the first organic layer from the biphasic mixture is separated and concentrated to obtain a mixture comprising methyl 2-(2-((6-cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I).

[0070] In an embodiment of the present disclosure, the mass ratio of methyl 2-(2-((6- cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3,3-dimethoxypropionate (Formula IV) to azoxystrobin (Formula I) in the mixture is in the range of 70 to 85:5 to 20.

[0071] In an exemplary embodiment of the present disclosure, the mass ratio of methyl 2-(2-((6- cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3, 3 -dimethoxypropionate (Formula IV) to azoxystrobin (Formula I) in the mixture is 75: 10.

[0072] In a fourth step, a second fluid medium is added in the mixture followed by adding a second catalyst and optionally adding a dealcoholizing agent under stirring at a temperature in the range of 25 °C to 40 °C to obtain a reaction mixture.

[0073] In an embodiment of the present disclosure, the second fluid medium is at least one selected from the group consisting of toluene, benzyl nitrile, dimethyl acetamide, sulfolane, N-methyl pyrrolidine, 1,4-dioxane, tetrahydrofuran, benzene, xylene, ethylene dichloride, ethyl acetate, tert-butanol and methyl tert-butyl ether. In an exemplary embodiment of the present disclosure, the second fluid medium is toluene.

[0074] In an embodiment of the present disclosure, the second catalyst is para-toluene sulfonic acid.

[0075] In an embodiment of the present disclosure, the dealcoholizing agent is selected from the group consisting of phosphorous tribromide, phosphorous trichloride, phosphorous pentoxide, thionyl chloride, sulfur trichloride, phosphorous pentachloride, p-toluyl sulfonyl chloride and sulfur dioxide.

[0076] In an exemplary embodiment of the present disclosure, phosphorus trichloride is used as a dealcoholizing agent in the presence of para-toluene sulfonic acid (second catalyst). In another exemplary embodiment of the present disclosure, the dealcoholysis is carried out only in the presence of para-toluene sulfonic acid (second catalyst). In yet another exemplary embodiment of the present disclosure, thionyl chloride is used as a dealcoholizing agent in the presence of para-toluene sulfonic acid (second catalyst).

[0077] In an embodiment of the present disclosure, the molar ratio of the mixture comprising methyl 2-(2-((6-cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3, 3 -dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) to the second catalyst is in the range of 1:0.1 to 1:3. In an exemplary embodiment of the present disclosure, the molar ratio of the mixture comprising methyl 2-(2-((6-cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) to the second catalyst is 1: 1.75. In another exemplary embodiment of the present disclosure, the molar ratio of the mixture comprising methyl 2-(2-((6-cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) to the second catalyst is 1:2.67. In yet another exemplary embodiment of the present disclosure, the molar ratio of the mixture comprising methyl 2-(2-((6-cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) to the second catalyst is 1:0.12.

[0078] In an embodiment of the present disclosure, the molar ratio of the mixture comprising methyl 2-(2-((6-cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3, 3 -dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) to dealcoholizing agent is in the range of 1: 1 to 1:2. In an exemplary embodiment of the present disclosure, the molar ratio of the mixture comprising methyl 2-(2-((6-cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) to phosphorus trichloride is 1: 1.75. In another exemplary embodiment of the present disclosure, the molar ratio of the mixture comprising methyl 2-(2-((6-cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) to thionyl chloride is 1: 1.93.

[0079] In a final step, the reaction mixture is heated to a second predetermined temperature for a third predetermined time period to obtain a product mixture comprising azoxystrobin (Formula I).

[0080] In an embodiment of the present disclosure, the second predetermined temperature is in the range of 60 °C to 120 °C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is 80 °C.

[0081] In an embodiment of the present disclosure, the third predetermined time period is in the range of 30 minutes to 420 minutes. In an exemplary embodiment of the present disclosure, the third predetermined time period is 60 minutes. In another exemplary embodiment of the present disclosure, the third predetermined time period is 360 minutes. In yet another exemplary embodiment of the present disclosure, the third predetermined time period is 240 minutes.

[0082] In accordance with an embodiment of the present disclosure, the use of dealcoholizing agent i.e. phosphorus trichloride along with pTSA as a catalyst significantly reduces the time period for completion of reaction as well as provides enhanced purity and enhanced yield. Further, the process of the present disclosure avoids the use of acetic anhydride which is conventionally used for dealcoholization.

[0083] In an embodiment of the present disclosure, water is added to the product mixture at the second predetermined temperature and stirred for a time period in the range of 5 minutes to 20 minutes to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer.

[0084] In an embodiment of the present disclosure, the second organic layer is separated from the second biphasic mixture and concentrated to obtain solids comprising crude azoxystrobin.

[0085] In an embodiment of the present disclosure, the crystallization of crude azoxystrobin is carried out by using at least one second solvent selected from the group consisting of methanol, 2- methoxy-2-methylpropane, methyl tert-butyl ether (MTBE), isopropanol, ethanol, heptane, ethyl acetate, acetone and 10% aqueous methanol to obtain pure Azoxystrobin. In an exemplary embodiment, the second solvent is 1: 1 mixture of methanol and methyl tert-butyl ether (MTBE). In an embodiment of the present disclosure, the yield of azoxystrobin (Formula I) is in the range of 75 % to 95 % and the purity of azoxystrobin (Formula I) is in the range of 95 % to 99.8 %. In an embodiment of the present disclosure, the yield of azoxystrobin (Formula I) is in the range of 75 % to 85 % and the purity of azoxystrobin (Formula I) is in the range of 99 % to 99.8 %. In a preferred embodiment of the present disclosure, the yield of azoxystrobin (Formula I) is in the range of 77 % to 84 % and the purity of azoxystrobin (Formula I) is in the range of 99.3 % to 99.5 %. In an exemplary embodiment of the present disclosure, the yield of azoxystrobin (Formula I) is 84% and the purity of azoxystrobin (Formula I) is 99.5%. In another exemplary embodiment of the present disclosure, the yield of azoxystrobin (Formula I) is 77 % and the purity of azoxystrobin (Formula I) is 99.3%.

[0086] Azoxystrobin prepared by the process of the present disclosure has a purity in the range of 95 % to 99.8 %.

[0087] In an embodiment of the present disclosure, azoxystrobin prepared by the process of the present disclosure has a purity in the range of 99 % to 99.8 %.

[0088] In a preferred embodiment of the present disclosure, azoxystrobin prepared by the process of the present disclosure has a purity in the range of 99.3 % to 99.5 %.

[0089] In an exemplary embodiment of the present disclosure, the schematic representation for the preparation of azoxystrobin is illustrated as Scheme I below:

[0090] Scheme I

[0091] The foregoing description of the embodiments has been provided for purposes of illustration and is not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure. The present disclosure is further described in light of the following experiments which are set forth for illustration purposes only and not to be construed as limiting the scope of the disclosure. The following experiments are scalable to industrial / commercial process.

[0092] EXPERIMENTAL DETAILS

[0093] EXPERIMENT 1: Preparation of azoxystrobin using PCh and pTSA in accordance with the present disclosure (Using PCh as a dealcoholizing agent)

[0094] In a one liter four necked round bottomed flask equipped with a condenser, thermometer pocket, a dropping funnel, and an agitator 50 g of (Z)-3-(methoxymethylene) benzofuran- 2(3H)-one (Formula-II) was charged and mixed with 300 mL of a mixture of acetonitrile and DCM in the ratio of 1 : 1 at 30 °C (room temperature) to obtain a solution.

[0095] 54.02 g of 30% sodium methoxide in methanol (MeOH) was added to the solution at -10 °C and stirring by maintaining the temperature at -10 °C for 1 hour to obtain a resultant solution.

[0096] 68 g of 4-chloro-6-(2-cyanophenoxy)-pyrimidine (Formula-Ill), 40 g of potassium carbonate and 6 g of DABCO were added to the resultant solution under stirring at -10 °C and allowing to reach to 30 °C and further stirred for 2 hours to obtain a mixture comprising methyl 2-(2- ((6-cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula-IV) and azoxystrobin (Formula-I).

[0097] The solvents acetonitrile (ACN) and dichloromethane (DCM) were distilled out from the mixture followed by adding 200 ml water and 200 ml dichloromethane (DCM) at 30 °C and stirred for 10 minutes to obtain a biphasic mixture comprising a first organic layer and a first aqueous layer. The first organic layer and the first aqueous layers were separated. The first aqueous layer was extracted with 100 ml dichloromethane (DCM). The combined organic layers (DCM layers) were washed with 150 ml water. Dichloromethane (DCM) from the combined organic layer was distilled to obtain a mixture comprising 120 g of 2-(2-((6- cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) in the ratio of 75: 10.

[0098] 400 ml toluene was added to 120 g of the mixture comprising 2-(2-((6-cyanophenoxy) pyrimidin-4-yl) oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) (75: 10) under stirring at 30 °C and stirred for 5 minutes followed by addition of 11.8 g of p- toluene sulfonic acid and slow addition of 9.4 g of phosphorus trichloride under stirring at 30 °C over 20 minutes to obtain a reaction mixture. The reaction mixture was heated under stirring to 90 °C for 60 minutes to obtain a product mixture comprising azoxystrobin.

[0099] 200 ml water was slowly added to the product mixture at 80 °C and stirred for 10 minutes to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer and the second aqueous layers were separated. The second aqueous layer was extracted with 100 ml toluene. The combined organic layer (toluene layer) was concentrated to obtain solids comprising crude 100 g azoxystrobin (Purity 89%).

[0100] The crystallization of obtained crude azoxystrobin was carried out by using 1 : 1 mixture of methanol and methyl tert-butyl ether (MTBE) to obtain 70 g (Purity: 99.5 %) of pure azoxystrobin.

[0101] EXPERIMENT 2: Preparation of azoxystrobin using pTSA in accordance with the present disclosure

[0102] In a one liter four necked round bottomed flask equipped with a condenser, thermometer pocket, a dropping funnel, and an agitator 50 g of (Z)-3-(methoxymethylene) benzofuran- 2(3H)-one (Formula-II) was charged and mixed with 300 m of a mixture of acetonitrile and DCM in the ratio of 1: 1 at 30 °C (room temperature) to obtain a solution. 54.02 g of 30% sodium methoxide in MeOH was added to the solution at -10 °C and stirring by maintaining the temperature at -10 °C for 1 hour to obtain a resultant solution. 68 g of 4-chloro-6- (2-cyanophenoxy)-pyrimidine (Formula-Ill), 40 g of potassium carbonate and 6 g of DABCO were added to the resultant solution under stirring at -10 °C and allowing to reach to 30 °C and further stirred for 2 hours to obtain a mixture comprising methyl 2-(2-((6-cyanophenoxy) pyrimidin-4-yl) oxy) phenyl)-3, 3 -dimethoxypropionate and azoxystrobin.

[0103] The solvents acetonitrile (ACN) and dichloromethane (DCM) were distilled out from the mixture followed by adding 200 ml water and 200 ml dichloromethane (DCM) at 30 °C and stirred for 10 minutes to obtain a biphasic mixture comprising a first organic layer and a first aqueous layer. The first organic layer and the first aqueous layers were separated. The first aqueous layer was extracted with 100 ml dichloromethane (DCM). The combined organic layers (DCM layers) were washed with 150 ml water. Dichloromethane (DCM) from the combined organic layer was distilled to obtain a mixture comprising 120 g of 2-(2-((6- cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) in the ratio of 75: 10. 400 ml toluene was added to 120 g of the mixture comprising 2-(2-((6- cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) (75: 10) under stirring at 30 °C and stirred for 5 minutes followed by addition of 18.9 g of p- toluene sulfonic acid under stirring at 30 °C to obtain a reaction mixture. The reaction mixture was heated under stirring to 90 °C for 6 hours to obtain a product mixture comprising azoxystrobin.

[0104] 200 ml water was slowly added to the product mixture at 80 °C and stirred for 10 minutes to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer and the second aqueous layers were separated. The second aqueous layer was extracted with 100 ml toluene. The combined organic layer (toluene layer) was concentrated to obtain solids comprising crude 100 g azoxystrobin (Purity 89%).

[0105] The crystallization of obtained crude azoxystrobin was carried out by using 1 : 1 mixture of methanol and methyl tert-butyl ether (MTBE) to obtain 64 g (Purity: 99.3 %) of pure azoxystrobin.

[0106] EXPERIMENT 3: Preparation of azoxystrobin using pTSA and thionyl chloride in accordance with the present disclosure (Using thionyl chloride as a dealcoholizing agent) In a one liter four necked round bottomed flask equipped with a condenser, thermometer pocket, a dropping funnel, and an agitator 50 g of (Z)-3-(methoxymethylene) benzofuran- 2(3H)-one (Formula-II) was charged and mixed with 300 mb of a mixture of acetonitrile (ACN) and di chloromethane (DCM) in the ratio of 1: 1 at 30 °C (room temperature) to obtain a solution. 54.02 g of 30% sodium methoxide in MeOH was added to the solution at -10 °C and stirring by maintaining the temperature at -10 °C for 1 hour to obtain a resultant solution. 68 g of 4-chloro-6-(2-cyanophenoxy)-pyrimidine (Formula-Ill), 40 g of potassium carbonate and 6 g of DABCO were added to the resultant solution under stirring at - 10 °C and allowing to reach to 30 °C and further stirred for 2 hours to obtain a mixture comprising 120 g of methyl 2-(2-((6-cyanophenoxy) pyrimidin-4-yl)oxy)phenyl)-3, 3 -dimethoxypropionate and azoxystrobin.

[0107] The solvents acetonitrile (ACN) and dichloromethane (DCM) were distilled out from the mixture followed by adding 200 ml water and 200 ml dichloromethane (DCM) at 30 °C and stirred for 10 minutes to obtain a biphasic mixture comprising a first organic layer and a first aqueous layer. The first organic layer and the first aqueous layers were separated. The first aqueous layer was extracted with 100 ml dichloromethane (DCM). The combined organic layers (DCM layers) were washed with 150 ml water. Dichloromethane (DCM) from the combined organic layer was distilled to obtain a mixture comprising 120 g of 2-(2-((6- cyanophenoxy) pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxy strobin (Formula I) in the ratio of 75: 10.

[0108] 400 ml toluene was added to 120 g of the mixture comprising 2-(2-((6- cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I) (75: 10) under stirring at 30 °C and stirred for 5 minutes followed by addition of 3 g of p- toluene sulfonic acid under stirring at

[0109] 30 °C and slow addition of 32.8 g of thionyl chloride under stirring at 30 °C to obtain a reaction mixture. The reaction mixture was heated under stirring to 90 °C for 4 hours to obtain a product mixture comprising azoxystrobin.

[0110] After completion of the reaction, 200 ml water was added slowly to the product mixture at 40 °C and stirred for 10 minutes to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer and the second aqueous layers were separated. The second aqueous layer was extracted with 100 ml toluene The combined organic layer (toluene layer) was concentrated to obtain solids comprising crude azoxystrobin (Purity 93 %).

[0111] The crystallization of obtained crude azoxystrobin was carried out by using 1 : 1 mixture of methanol and methyl tert-butyl ether (MTBE) to obtain 85 g (Purity: 99.3 %) of pure azoxystrobin.

[0112] TECHNICAL ADVANCEMENT

[0113] The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of azoxystrobin that:

[0114] • provides comparatively high purity and high yield of azoxystrobin;

[0115] • has a shorter reaction time and easy purification steps, hence simple;

[0116] • is cost-effective and environment friendly; and

[0117] • is commercially scalable. The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0118] The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and / or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

[0119] The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.

[0120] Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.

[0121] The numerical values given for various physical parameters, dimensions, and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions, and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.

[0122] While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

Claims

CLAIMS:

1. A process for the preparation of azoxystrobin, said process comprising the following steps: a. mixing (Z)-3-(methoxymethylene)benzofuran-2(3H)-one (Formula-II) in a first fluid medium at a temperature in the range of 25 °C to 40 °C to obtain a solution; b. adding a first base to said solution at a first predetermined temperature and stirring by maintaining said first predetermined temperature for a first predetermined time period to obtain a resultant solution; c. adding 4-chloro-6-(2-cyanophenoxy)-pyrimidine (Formula-Ill), a second base and a first catalyst to said resultant solution under stirring at said first predetermined temperature and allowing to reach to a temperature in the range of 25 °C to 40 °C and further stirred for a second predetermined time period to obtain a mixture comprising methyl 2-(2-((6-cyanophenoxy)pyrimidin-4- yl)oxy)phenyl)-3,3-dimethoxypropionate (Formula IV) and azoxystrobin (Formula I); d. adding a second fluid medium in said mixture followed by adding a second catalyst and optionally adding a dealcoholizing agent under stirring at a temperature in the range of 25 °C to 40 °C to obtain a reaction mixture; and e. heating said reaction mixture to a second predetermined temperature for a third predetermined time period to obtain a product mixture comprising azoxystrobin (Formula I).

2. The process as claimed in claim 1, wherein said first fluid medium is at least one selected from the group consisting of acetonitrile, dichloromethane, benzyl nitrile, dimethyl formamide, dimethyl acetamide, sulfolane, N-methyl pyrrolidine, 1,4- dioxane, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, toluene, benzene, xylene, ethylene dichloride, ethyl acetate, tert-butanol, methyl tert-butyl ether, acetone and dimethyl sulfoxide.

3. The process as claimed in claim 2, wherein said first fluid medium is an equivalent mixture of acetonitrile and dichloromethane.

4. The process as claimed in claim 1, wherein said first base is selected from sodium methoxide and potassium methoxide.

5. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of -20 °C to 10 °C.

6. The process as claimed in claim 1 wherein said first predetermined time period is in the range of 30 minutes to 120 minutes.

7. The process as claimed in claim 1, wherein said second base is selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, calcium hydroxide and potassium hydroxide.

8. The process as claimed in claim 1, wherein said first catalyst is selected from DABCO (1,4-diazabicyclo [2.2.2] octane) and 1, 8 -Diazabicyclo [5.4.0] undec-7-ene (DBU).

9. The process as claimed in claim 1 wherein said second predetermined time period is in the range of 1 hour to 4 hours.

10. The process as claimed in claim 1, wherein the molar ratio of (Z)-3- (methoxymethylene) benzofuran-2(3H)-one (Formula-II) to (4-chloro-6-(2- cyanophenoxy) -pyrimidine) (Formula-Ill) is in the range of 1:0.9 to 1: 1.2.

11. The process as claimed in claim 1, wherein said second fluid medium is at least one selected from the group consisting of toluene, benzyl nitrile, dimethyl acetamide, sulfolane, N-methyl pyrrolidine, 1,4-dioxane, tetrahydrofuran, benzene, xylene, ethylene dichloride, ethyl acetate, tert-butanol and methyl tert-butyl ether.

12. The process as claimed in claim 1 wherein said second catalyst is para-toluene sulfonic acid.

13. The process as claimed in claim 1 wherein said dealcoholizing agent is selected from the group consisting of phosphorous tribromide, phosphorous trichloride, phosphorous pentoxide, thionyl chloride, sulfur trichloride, phosphorous pentachloride, p-toluyl sulfonyl chloride and sulfur dioxide.

14. The process as claimed in claim 1, wherein said second predetermined temperature is in the range of 60 °C to 120 °C.

15. The process as claimed in claim 1, wherein said third predetermined time period is in the range of 30 minutes to 420 minutes.

16. The process as claimed in claim 1, wherein the yield of azoxystrobin (Formula I) is in the range of 75 % to 95 % and the purity of azoxystrobin (Formula I) is in the range of 95 %to 99.8 %.

17. The process as claimed in claim 1, wherein the yield of azoxystrobin (Formula I) is in the range of 75 % to 85 % and the purity of azoxystrobin (Formula I) is in the range of 99 %to 99.8 %.

18. The process as claimed in claim 1, wherein the yield of azoxystrobin (Formula I) is in the range of 77 % to 84 % and the purity of azoxystrobin (Formula I) is in the range of 99.3 % to 99.5 %.

19. Azoxystrobin prepared by the process as claimed in claims 1 to 15 has a purity in the range of 95 % to 99.8 %.

20. Azoxystrobin prepared by the process as claimed in claims 1 to 15 has a purity in the range of 99 % to 99.8 %.

21. Azoxystrobin prepared by the process as claimed in claims 1 to 15 has a purity in the range of 99.3 % to 99.5 %.

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