WO2023203574A1

WO2023203574A1 - A process for preparation of azoxystrobin

Info

Publication number: WO2023203574A1
Application number: PCT/IN2023/050378
Authority: WO
Inventors: Meka BHOOPAL; S. Venkatreddy; Tirupathi SATYANARAYANA GOUD; Ande CHANDRA SEKHAR; Malisetti RAJA; Akubathini SHASHIDHAR KUMAR; Sunil Kumar Singh
Original assignee: Nacl Industries Limited
Priority date: 2022-04-22
Filing date: 2023-04-19
Publication date: 2023-10-26

Abstract

A process for preparation of azoxystrobin is provided. The process includes two different routes for preparing the azoxystrobin using catalyst selected from a group consisting of 4-methylmorpholine, 1,4-dimethylpiperazine, 2,2,6,6-tetramethylpiperidine, 1-methylpiperidine, and 2,2'-oxybis (N, N- dimethylethan-1-amine). The catalysts used in the process are cost-effective and have low boiling point, thus are easily recyclable. The process provided by the present invention provides higher yields and purity of the azoxystrobin than the conventional methods.

Description

A PROCESS FOR PREPARATION OF AZOXYSTROBIN

FIELD OF THE INVENTION

Embodiments of the present invention relate to process of synthesis of compounds and more particularly, it relates to a process for preparation of azoxystrobin.

BACKGROUND OF THE INVENTION

Azoxystrobin is a broad- spectrum and high-efficient fungicide product used in agriculture, which has the world's largest sales at present and is widely produced and used. The newly published report titled as, Global “Azoxystrobin Market” Research Report 2022, that studies the scope of the market along with primary growth factors and offers major market insights. This report discloses that the Azoxystrobin Market was valued at US $ 0.91 Bn. in 2021, and it is expected to reach US $ 1.93 Bn. by 2029 with a CAGR of 9.88% during the forecast period.

The azoxystrobin intermediate (E) -2- [2- (6-chloropyrimidine-4-methoxy) phenyl] -3-methoxy methyl acrylate is an indispensable critical substance for producing azoxystrobin and is a bottleneck with lower yield and more rigorous conditions in the whole production step.

Recent research is directed to increasing a reaction rate and reducing side reactions by adding a catalyst such as Azabicyclo, Diazabicyclo (Dabco), Tetraazatricyclo compounds or salts, Trimethylamine, Hexamine, Triphenyl phosphine, and Adamantane etc.

However, these catalysts are expensive, and have a high boiling point and thus is difficult to recycle. Moreover, these catalysts may cause environmental hazards. Hence, there is a need for a low-cost and high-efficient method for preparing azoxystrobin and azoxystrobin key intermediates to address the aforementioned issue/s.

SUMMARY

In accordance with an embodiment of the present invention, a process for preparation of azoxystrobin is provided. The process includes carrying out route I reactions for obtaining the azoxystrobin. The route I reactions include a stage one reaction, a stage two reaction, and a stage three reaction. The stage one reaction includes reacting of (E’)-3-(mcthoxy methylene) benzofuran-2(3H)-one with sodium methoxide and 4,6-dichloropyrimidine in presence of a catalyst to obtain azoxystrobin intermediates. The stage two reaction includes reacting azoxystrobin intermediates with methane sulfonic acid to obtain methyl (E)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate. The stage three reaction includes coupling of 2-cy anophenol with methyl (E)-2-{2-[6-chloropyrimidin-4- yloxy]phenyl}-3-methoxyacrylate to obtain the azoxystrobin.

In accordance with alternate embodiment of the present invention, a process for preparation of azoxystrobin including route II reactions is provided. The route II reactions include a stage one reaction, a stage two reaction, and a stage three reaction. The stage one reaction includes reacting of (E’)-3-(mcthoxy methylene) benzofuran-2(3H)-one with sodium methoxide and 4,6- dichloropyrimidine in presence of a catalyst to obtain azoxystrobin intermediates. The stage two reaction includes coupling of 2-cyanophenol with azoxystrobin intermediates to obtain variants of azoxystrobin. The stage 3 reaction includes reacting the variants of azoxystrobin with P-Toluene sulfonic acid to isolate the azoxystrobin.

To further clarify the advantages and features of the present invention, a more particular description of the invention will follow by reference to specific embodiments thereof, which are illustrated in the appended figures. It is to be appreciated that these figures depict only typical embodiments of the invention and are therefore not to be considered limiting in scope. The invention will be described and explained with additional specificity and detail with the appended figures.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure will be described and explained with additional specificity and detail with the accompanying figures in which:

FIG. 1 represents a flowchart including steps of a process for preparation of azoxystrobin via route I, in accordance with an embodiment of the present invention;

FIG. 2 represents structural representation of route I reactions of a process for preparing azoxystrobin, in accordance with an embodiment of the present invention;

FIG. 3 represents a flowchart including steps of the process for preparation of azoxystrobin via route II, in accordance with an embodiment of the present invention;

FIG. 4 represents structural representation of route II reactions of the process for preparing the azoxystrobin, in accordance with an embodiment of the present invention;

FIG. 5 represents structural representation of stage one reaction of the route I reactions, in accordance with an embodiment of the present invention; FIG. 6 represents structural representation of stage two reaction of the route I reactions, in accordance with an embodiment of the present invention;

FIG. 7 represents structural representation of alternate stage two reaction of the route I reactions, in accordance with an embodiment of the present invention;

FIG. 8 represents structural representation of stage three reaction of the route I reactions, in accordance with an embodiment of the present invention;

FIG. 9 represents structural representation of stage two reaction of the route II reactions, in accordance with an embodiment of the present invention;

FIG. 10 represents structural representation of stage three reaction of the route II reactions, in accordance with an embodiment of the present invention; and

FIG. 11 represents structural representation of alternate stage three reaction of the route II reactions, in accordance with an embodiment of the present invention.

Further, those skilled in the art will appreciate that elements in the figures are illustrated for simplicity and may not have necessarily been drawn to scale. Furthermore, in terms of the method steps, chemical compounds, and parameters used herein may have been represented in the figures by conventional symbols, and the figures may show only those specific details that are pertinent to understanding the embodiments of the present disclosure so as not to obscure the figures with details that will be readily apparent to those skilled in the art having the benefit of the description herein.

DETAILED DESCRIPTION

For the purpose of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe them. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Such alterations and further modifications in the illustrated system, and such further applications of the principles of the disclosure as would normally occur to those skilled in the art are to be construed as being within the scope of the present disclosure.

The terms "comprise", "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such a process or method. Similarly, one or more components, compounds, and ingredients preceded by "comprises... a" does not, without more constraints, preclude the existence of other components or compounds or ingredients or additional components. Appearances of the phrase "in an embodiment", "in another embodiment" and similar language throughout this specification may, but not necessarily do, all refer to the same embodiment.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The system, methods, and examples provided herein are only illustrative and not intended to be limiting.

In the following specification and the claims, reference will be made to a number of terms, which shall be defined to have the following meanings. The singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.

Embodiments of the present invention relate to a process for preparation of azoxystrobin. The mainly includes cost-effective catalysts for preparation of the azoxystrobin.

In an embodiment, the process for preparation of the azoxystrobin is provided.

FIG. 1 represents a flowchart including steps of a process for preparation of azoxystrobin via route I, in accordance with an embodiment of the present invention.

FIG. 2 represents structural representation of route I reactions of a process for preparing azoxystrobin, in accordance with an embodiment of the present invention.

The process for preparation of the azoxystrobin begins with carrying out route I reactions for obtaining the azoxystrobin at step 102. The route I reactions include a stage one reaction, a stage two reaction, and a stage three reaction.

The stage one reaction includes reacting of (E)-3 -(methoxy methylene) benzofuran-2(3H)-one with sodium methoxide and 4,6-dichloropyrimidine in presence of a catalyst to obtain azoxystrobin intermediates. The catalyst is selected from a group consisting of 4-methylmorpholine, 1,4- dimethylpiperazine, 2,2,6,6-tetramethylpiperidine, 1 -methylpiperidine, and 2,2'-oxybis (N, N- dimethylethan- 1 -amine). The Azoxystrobin intermediates comprises Methyl 2-[2-(6- chloropyrimidin-4-yloxy) phenyl]-3,3-dimethoxypropionate and Methyl (E)-2-{2-[6- chloropyrimidin-4-yloxy] phenyl}-3-methoxyacrylate. The reaction medium used herein includes alkali-Potassium carbonate and solvent-toluene. The reaction is carried out for a duration of 6-8 hours at room temperature. The stage two reaction includes reacting azoxystrobin intermediates with methane sulfonic acid to obtain methyl (E)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate. The reaction medium used herein includes toluene and acetic anhydride as solvent. In one embodiment, propionic anhydride and toluene are used as solvent. The stage two reaction is carried out at 80-85 °C for a duration of 4 hours.

The stage three reaction includes coupling of 2-cyanophenol with methyl (E)-2-{2-[6- chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate to obtain the azoxystrobin. The reaction medium used herein includes one of potassium carbonate and dimethyl formamide. The stage three reaction is carried out in presence of the catalyst Bis[2-(N,N-dimethylamino)ethyl] ether.

In an alternate embodiment of the present invention, a process for preparation of azoxystrobin including route II reactions is provided at step 302.

FIG. 3 represents a flowchart including steps of the process for preparation of azoxystrobin via route II, in accordance with an embodiment of the present invention.

FIG. 4 represents structural representation of the route II reactions of the process for preparing the azoxystrobin, in accordance with an embodiment of the present invention.

The route II reactions include a stage one reaction, a stage two reaction, and a stage three reaction.

The stage one reaction includes reacting of (E)-3 -(methoxy methylene) benzofuran-2(3H)-one with sodium methoxide and 4,6-dichloropyrimidine in presence of a catalyst to obtain azoxystrobin intermediates. The catalyst is selected from a group consisting of 4-methylmorpholine, 1,4- dimethylpiperazine, 2,2,6,6-tetramethylpiperidine, 1 -methylpiperidine, and 2,2'-oxybis (N, N- dimethylethan- 1 -amine). The Azoxystrobin intermediates comprises Methyl 2-[2-(6- chloropyrimidin-4-yloxy) phenyl]-3,3-dimethoxypropionate and Methyl (E)-2-{2-[6- chloropyrimidin-4-yloxy] phenyl}-3-methoxyacrylate. The reaction medium used herein includes alkali-Potassium carbonate and solvent-toluene. The reaction is carried out for a duration of 6-8 hours at room temperature.

The stage two reaction includes coupling of 2-cyanophenol with azoxystrobin intermediates to obtain variants of azoxystrobin. The reaction medium used herein includes one of potassium carbonate and dimethyl formamide. The stage two reaction is carried out in presence of the catalyst Bis[2-(N,N- dimethyl amino)ethyl] ether. The stage 3 reaction includes reacting the variants of azoxystrobin with P-Toluene sulfonic acid to isolate the azoxystrobin. The reaction medium used herein includes a mixture of AC2O and one of toluene and P-Toluene sulfonic acid as solvent. In one embodiment, methane sulfonic acid and propionic anhydride are used as solvent. The stage two reaction is carried out at 80-85°C for a duration of 2 to 6 hours.

The present invention is explained further in the following specific examples, which are only by way of illustration and are not to be construed as limiting the scope of the invention.

Example 1: Process for the synthesis of Azoxystrobin via route I

Stage-1:

Table 1 enlists raw material used for reaction of stage 1.

Table 1

Experimental Process:

Arranged 500 mL four neck RB flask along with thermo packet, condenser and cooling tub. Charged 250 mL of toluene into the RBF and charged 50 g of (E)-3-(methoxy methylene) benzofuran-2(3H)- one into the RBF at 20-25°C (Observation: No clear solution). To the reaction mass charged potassium carbonate (l.Oeq), 4,6-Dichloropyrimidine (l.leq) at 20-25°C. Reaction mixture stirred for 5 min at 20-25°C (Observation: No clear solution, brown red colour mass). To the reaction mass charged 0.04eq of Bis[2-(N,N-dimethyl amino)ethyl] ether (catalyst, Lot- 1) and cool to 0-5°C. To the reaction mass slowly added 0.8 eq of NaOMe (Lot-I) at 0-5°C for Ih (Observation: fast addition leads to methoxy formation). After completion of addition reaction mass allowed to 20-25°C and maintained for 3h at 20-25°C. Reaction mass sample check GC after 3h (pick the sample for GC). Charged catalyst Lot-II 0.02 eq of Bis[2-(N,N-dimethyl amino)ethyl] ether at 20-25°C followed by Lot-II NaOMe (0.2eq) addition at 20-25°C for 20-30min. Reaction mass maintained for 2h at 20- 25°C. Reaction mass pick the sample for GC after 4h (Total 7h) and charged Lot-Ill Bis[2-(N,N- dimethyl amino)ethyl] ether (O.Oleq) followed by Lot-Ill of (O.leq) NaOMe addition for 15 min at 20-25 °C. Reaction mass maintained for 2h and pick the sample for GC (after 9h total). After completion of reaction mass filtered under vacuo and washed with 2vol of toluene suck dried for lOmin under vacuo. Filtered MLs distilled at lower temperature 40°C under vacuo up to 3vol of recovered toluene (To remove low boiler MeOH). To the reaction mass crude charged 4vol of water. Stirred for 15min at 20-25°C. Separated organic and aqueous layers, organic layer washed with 3Vol of water, separated organic layer and distilled completely under vacuo at 50°C (Repeatedly three times total). Dried crude product at 60°C for Ih.

Crude weight: 98 g, Purity: 98.04%, Purity corrected: 86.28g, Theoretical yield: 99g, Purity basis yield: 87.15%

Note: Final aqueous layer PH should be neutral, if not one more washing required.

Solvents used: Ethylene dichloride (EDC), toluene, chlorobenzene, C-IX solvent and mixture of solvent (EDC+Methanol, EDC+DMF, EDC+DMAc)

Bases used: Potassium carbonate, Sodium bicarbonate, Sodiumbi bicarbonate, NaOH, KOH, Organic bases (TEA, DIPA ETC)

Temperature ranges: 0-5°C, 0-25°C, 0-50°C

Catalysts: Bis[2-(N,N-dimethylamino)ethyl] ether, 1,4-Dimethylpiperazine, N-Methylmorpholine, and 2,2, 6 ,6-Tetramethy Ipiperdidine .

FIG. 5 represents structural representation of stage one reaction of the route I reactions, in accordance with an embodiment of the present invention.

Stage-2:

Table 2 enlists raw material used for reaction of stage 2.

Table 2 Experimental Process:

Arranged 500 mL of four neck RBF along with thermo packet, condenser and oil bath. Charged stage- I crude into the RBF and charged leq of AC2O, 0.2eq of methane sulfonic acid into the reaction mass and heated to 80-85°C. Reaction mass maintained for 2hour at 80-85°C checked TLC and GC. After completion of reaction, Reaction mass allowed to 20-25 °C and added 5 Vol of water at 0-5 °C followed by 3Vol of toluene. Allowed to 20-25°C at organic layer separated and washed the aqueous layer with 2Vol of toluene, combined organic layers and washed with of 3Vol water. Separated organic layer and distilled completely under vacuo.

Output: 27.09g, Purity corrected: 20.52g, Theoretical yield: 27.66g, Purity corrected yield: 74.10%.

FIG. 6 represents structural representation of stage two reaction of the route I reactions, in accordance with an embodiment of the present invention.

Stage-2: alternative process

Table 3 enlists raw material used for reaction of stage 3.

Table 3

Experimental Process:

Arranged 500 mL of four neck RBF along with thermo packet, condenser and oil bath. Charged stage- I crude into the RBF and charged leq of Propionic anhydride, 0.2eq of methane sulfonic acid into the reaction mass and heated to 80-85°C. Reaction mass maintained for 2hour at 80-85°C checked TLC and GC. After completion of reaction, Reaction mass allowed to 20-25°C and added 5Vol of water at 0-5°C followed by 3 Vol of EDC. Allowed to 20-25°C at organic layer separated and washed the aqueous layer 2Vol of EDC, combined organic layers and washed with 3 Vol water. Separated organic layer and distilled completely under vacuo. Output: 36g, Purity corrected: 30.8g, Theoretical yield: 31.82g, Purity corrected yield: 96.7%

FIG. 7 represents structural representation of alternate stage two reaction of the route I reactions, in accordance with an embodiment of the present invention.

Stage-3:

Table 4 enlists raw material used for reaction of stage 4.

Table 4

Experimental Process:

Arranged 500 mL four neck RB flask along with Thermo packet and condenser. Charge stage-II compound into the RBF and charged DMF 1.8 Vol in to the RBF and charged 2-cyanophenol(l.leq) into the RBF, 1.5eq of K2CO3 into the RBF at 20-25°C followed by 0.08 eq of Bis[2-(N,N- dimethylamino)ethyl] ether (catalyst) charged in to the reaction mass at 20-25°C. Reaction mass heated to 80-85°C and maintained for 6 h and reaction mass checked GC, 2-Cyanophenol observed (below 0.5%) and stopped heating and allowed the Reaction mass at 20-25°C. Reaction mass filtered w/v and washed with IVol of DMF, suck dried for 15 min, filtered MLs (Alternate) distilled completely at 50-55°C under vacuo and co-distilled with 2 Vol of EDC, crude obtained. To the crude 3Vol of EDC, 3Vol of water into the reaction mixture stirred for 15min at separated organic layer, aqueous layer washed with 2Vol of EDC separated organic layer, combined both organic layers and distilled completely under vacuo crude solid obtained. To the crude solid charged 1.2vol of (80% aq) Methanol into the RBF and heated to reflux temperature and maintained for 30min at under reflux. Reaction mass cooled to 20-25°C gradually (solid formation observed). Reaction mass cooled to 0- 5°C. Reaction mass filtered under vacuo and washed with 0.5vol of chilled (80% aq) methanol suck dry for 30min. Compound unload and dried at 50°C till get constant weight.

Output: 36g, Purity corrected: 35g, theoretical yield: 57.3g, Purity corrected yield: 65.95% Solvents used: DMF, DMAc, DMF + Toluene, C9 solvent, DMF + MCB, NMP, and MCB

Bases used: Potassium carbonate, Sodium carbonate, Sodium bicarbonate, NaOH, KOH, and Organic bases (TEA, DIPA ETC)

Temperature ranges: 0-5°C, 0-25°C, 0-50°C, 0-150°C

FIG. 8 represents structural representation of stage three reaction of the route I reactions, in accordance with an embodiment of the present invention.

Example 2: Process for the synthesis of Azoxy strobin via route II

Stage-1:

For stage-1 (route-2), process is same as stage-1 (Route-1).

Stage-2:

Table 5 enlists raw material used for reaction of stage 5.

Table 5

Experimental Process:

Arranged a 1.0 Lit 4neck RBF along with thermo packet, condenser, oil bath. Charged I.8V0I of DMF (142 mL) into the RBF and charged 79.0g of stage-I crude into the RBF at 20-25°C. To the reaction mass charged l.Oeq (26.30g) of Potassium carbonate into the reaction mass at 20-25°C under stirring. To the reaction charged 2-Cyanophenol (25.21g) l.leq into the reaction mass at 20-25°C stirred for 5 min. To the reaction charged 0.08 eq of (2.46g) Bis[2-(N,N-dimethyl amino)ethyl] ether (catalyst) into the reaction mass at 20-25°C. Reaction mass heated to 80-85°C. Reaction maintained for 8h, checked GC, S.M is present 1-2%. Reaction stopped heating and allowed to cool at 20-25°C. Reaction mass filtered under vacuo and washed with 0.5 Vol of DMF, suck dried for lOmin. Filtered MLs distilled completely under vacuo at 55-60°C. To the crude charged 3 Vol of EDC (237mL) and 3 Vol of Water (237mL) (based on batch size). Stirred for 15min at 50°C (hot separation done), (separation is clearly observed). Organic layer separated and aq layer washed with IVol of EDC at 50°C. Separated organic layer and combined all organic layers and washed with 1 Vol (79mL) of 2.5% of NaOH solution at 50°C, stirred for 15min. Separated Organic layer and distilled completely under vacuo at 50°C. Dried the crude at 55-60°C for 30min under vacuum.

Note: base wash to remove polymeric material; Crude weight: 79.0g; G.C purity: 79.24%; Purity corrected crude weight: 62.60g; 100% Theory weight: 81.21g; 76.84% purity corrected yield; and Overall yield from M-177: 63.27%.

Solvents used: DMF, DMAc, DMF + Toluene, C9 solvent, DMF + MCB, NMP, and MCB.

Bases used: Potassium carbonate, Sodium bicarbonate, Sodiumbi carbonate, NaOH, KOH, Organic bases (TEA, DIPA ETC)

Temperature ranges: 0-5°C, 0-25°C, 0-50°C, 0-150°C

Catalysts: Bisr2-(N.N-dimethvlamino)ethyl1 ether, 1,4-Dimethylpiperazine, N-Methylmorpholine, and 2,2, 6 ,6-Tetramethy Ipiperdidine .

FIG. 9 represents structural representation of stage two reaction of the route II reactions, in accordance with an embodiment of the present invention.

Stage-3:

Table 6 enlists raw material used for reaction of stage 6.

Table 6 Experimental Process:

Arranged 500mL four neck RBF along with thermo packet condenser and oil bath. Charged 1.5Vol of Toluene (118.5mL) into the RBF and Charged 0.06 eq of (1.67mg)p-toluene sulfonic acid, 14.79g of Acetic anhydride (l.Oeq) into the RBF at 20-25°C. Reaction mass heated to 80-85°C, Reaction mass attained to 80-85°C. To the reaction mass slowly added a solution of Stage-II (79g) dissolved in 3Vol of Toluene (237mL) into the reaction mass at 80-85°C for 30min. After addition completion reaction mass maintained for 2h at 80-85°C. Reaction mass checked TLC reaction very slowly observed (low boilers removed by using dean martin apparatus collection observed 10-15min at 110°C. Reaction heated to 110°C. Reaction mass maintained for 4h, reaction mass checked TLC for every 2h, starting material completed by TLC (GC monitoring there is no separation observed). Stopped reaction heating and allowed to 20-25°C, to the reaction mass charged 3Vol of water and stirred for 15 min at 50-55°C hot separation done. Organic layer washed with IVol of water stirred for 15min at 50-55°C. Separated organic layer and distilled completely under vacuum. Crude weight: 62.0g. To the crude charged 80% aqueous Methanol (80.0mL) (1.25Vol) (based on input batch size). Heated to 60-65°C reflux observed. To the reaction mass charged 2.5% of activated charcoal (1.975g) into the reaction mass and maintained for 30min under reflux and filtered by through hyflow and washed with 0.5 Vol of 80% aq. MeOH hot (40 mL of 80% aq. MeOH hot) suck well. Filtered MLs taken into 250mL of four neck RBF and slowly allowed to RT and maintained for 2h at 20-25°C, no solid formation observed. Seeded lOOmg of pure Stage-IV material into reaction mass. Stirred for 2hour at 20-25°C. Reaction mass slightly solid formation observed. Reaction mass slowly cooled to 10-15°C maintained for Ih at 10-15°C (more solid formation observed).. Reaction mass further cooled to 0-5°C.. Reaction mass attained to 0-5°C and maintained for 2h at 0-5°C. Reaction mass filtered under vacuum and washed 0.25 Vol of chilled Methanol (80% aq. MeOH), suck dry for 15min under vacuo.

Wet solid weight: 46.0g, Compound dried in hot air oven at 50-55°C, till constant weight is achieved. Dry weight: 38.0g (GC purity: 91.39%) (MLs distilled under vacuo at 50-55°C, Crude weight: 18.0g, GC purity: 69%).

Purity basis: 34.72g

Crude yield: 59.8% (based on purity)

(From 435.43

403.39) 91.59g (From M-176) Theory weight: 34.72g, Practical weight: (from M-176) (37.90% overall yield from stage-I).

FIG. 10 represents structural representation of stage three reaction of the route II reactions, in accordance with an embodiment of the present invention.

Stage-3: Alternative Process

Table 7 enlists raw material used for reaction of stage 7.

Table 7

Experimental Process:

Arranged 500mL four neck RBF along with thermo packet condenser and oil bath, take the crude compound (stage-II) into the RBF. Charged 0.06 eq of (1.67mg) methane sulfonic acid, propionic anhydride into the RBF at 20-25°C. Reaction mass heated to 80-85°C, Reaction mass attained to 80- 85°C. Mass maintained for 2h at 80-85°C. Reaction mass checked TLC complies. Separate the layer at hot condition at 50°C. Organic layer wash with water 3X2 Vol at 50°C. Separated organic layer and distilled completely under vacuum (Crude weight: 44.5g). To the reaction mass charged 2.5% of activated charcoal (1.0g) into the reaction mass and maintained for 30min under reflux and filtered by through hyflow and washed with 0.5 Vol of 80% aq. MeOH hot (39.5mL of 80% aq. MeOH hot) suck well. Filtered MLs taken into 250mL of four neck RBF and slowly allowed to RT and maintained for 2h at 20-25°C, No solid formation observed. Seeded lOOmg of pure Stage-IV material into reaction mass. Stirred for 2h at 20-25°C. Reaction mass slightly solid formation observed. Reaction mass slowly cooled to 10-15°C maintained for Ihour at 10-15°C (more solid formation observed). Reaction mass further cooled to 0-5°C (thick mass observed) hot condition then cooled RT. Reaction mass attained to 0-5°C and maintained for 2h at 0-5°C. Reaction mass filtered under vacuum and washed 0.25 Vol of chilled Methanol (80% aq.MeOH), suck dry for 15min under vacuum.

Wet solid weight: 29.0g, dry solid weight: 25.0g.

FIG. 11 represents structural representation of alternate stage three reaction of the route II reactions, in accordance with an embodiment of the present invention. The present invention provides the process for preparation of the azoxystrobin. The process includes cost-effective method of preparing azoxystrobin using cost-effective catalyst. The process enables reduction of environmental hazardous caused by catalysts used in conventional methods for the preparation of the azoxystrobin. The catalysts used in the process have low boiling point, thus are easily recyclable. The process provided by the present invention provides higher yields and purity of the azoxystrobin than the conventional methods.

While specific language has been used to describe the invention, any limitations arising on account of the same are not intended. As would be apparent to a person skilled in the art, various working modifications may be made to the method in order to implement the inventive concept as taught herein.

The figures and the foregoing description give examples of embodiments. Those skilled in the art will appreciate that one or more of the described elements may well be combined into a single functional element. Alternatively, certain elements may be split into multiple functional elements. Elements from one embodiment may be added to another embodiment. For example, order of processes described herein may be changed and are not limited to the manner described herein. Moreover, the actions of any flow diagram need not be implemented in the order shown; nor do all of the acts need to be necessarily performed. Also, those acts that are not dependent on other acts may be performed in parallel with the other acts. The scope of embodiments is by no means limited by these specific examples.

Claims

CLAIMS We Claim:

1. A process for the preparation of Azoxystrobin of formula- 1, comprising:

(a) reacting (E)-3-(methoxy methylene) benzofuran-2(3H)-one of formula-2 with sodium methoxide and 4,6-dichloropyrimidine in presence of a catalyst to obtain the mixture of azoxystrobin intermediates of formula-4, and formula-5;

(b) reacting the mixture of azoxystrobin intermediates of formula-4, and formula-5 with methanesulfonic acid or p-toluenesulfonic acid to obtain methyl (E)-2-{2-[6- chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate of formula-5; and

(c) coupling of 2-cyanophenol with methyl (E)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3- methoxyacrylate of formula-5 to obtain the azoxystrobin of formula- 1.

2. The process as claimed in claim 1, the catalyst used in stage (a) is selected from a group consisting of 4-methylmorpholine, 1,4-dimethylpiperazine, 2,2,6,6-tetramethylpiperidine, 1- methylpiperidine, and 2,2'-oxybis (N, N-dimethylethan-l-amine).

3. The process as claimed in claim 1, the reaction medium used in stage (a) includes an inorganic base selected from potassium carbonate or sodium carbonate.

4. The process as claimed in claim 1, the solvent used in stage (a) selected from toluene or ethylene dichloride.

5. The process as claimed in claim 1, the mixture of the azoxystrobin intermediates comprise methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3,3-dimethoxypropionate of formula-4 and methyl (E)-2-{2-[6-chloropyrimidin-4-yloxy] phenyl }-3-methoxyacrylate of formula-5. The process as claimed in claim 1, reaction medium used in stage (b) includes acetic anhydride or propionic anhydride. The process as claimed in claim 1, solvent used in stage (b) selected from toluene or ethylene dichloride. The process as claimed in claim 1, stage (c) is carried out in presence of the catalyst bis[2-(N,N- dimethylamino)ethyl] ether. The process as claimed in claim 1, the reaction medium used in stage (c) includes potassium carbonate and dimethyl formamide. A process for the preparation of Azoxystrobin of formula- 1, comprising:

(b) coupling of 2-cyanophenol with the mixture of azoxystrobin intermediates of formula-4, and formula-5 to obtain the mixture of variants of azoxystrobin of formula-7, and formula- 1; and

(c) reacting the mixture of variants of azoxystrobin of formula-7, and formula- 1 with methanesulfonic acid or p-toluenesulfonic acid to isolate the pure azoxystrobin of formula- 1.

The process as claimed in claim 10, the catalyst used in stage (a) is selected from a group consisting of 4-methylmorpholine, 1,4-dimethylpiperazine, 2,2,6,6-tetramethylpiperidine, 1- methylpiperidine, and 2,2'-oxybis (N, N-dimethylethan-l-amine). The process as claimed in claim 10, the reaction medium used in stage (a) includes an inorganic base selected from potassium carbonate or sodium carbonate. The process as claimed in claim 10, the solvent used in stage (a) selected from toluene or ethylene dichloride. The process as claimed in claim 10, the mixture of azoxystrobin intermediates comprise methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl] -3, 3 -dimethoxypropionate of formula-4 and methyl (E)-2- { 2- [6-chloropyrimidin-4-yloxy] phenyl } -3-methoxyacrylate formula-5. The process as claimed in claim 10, the catalyst used in stage (b) is bis[2-(N,N- dimethylamino)ethyl] ether. The process as claimed in claim 10, the reaction medium used in stage (b) includes potassium carbonate and dimethyl formamide. The process as claimed in claim 10, the reaction medium used in stage (c) includes acetic anhydride or propionic anhydride. The process as claimed in claim 10, the solvent used in stage (c) selected from toluene or ethylene dichloride.