Claims:
1. An improved process for the preparation of methyl (E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (Azoxystrobin) compound of formula (I):

comprising the steps of:

i. reacting o-cyanophenol compound of formula (III) with Methyl 3-methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl) acrylate compound of formula (II) in a solvent in the presence of base and a catalyst at a temperature in the range of 60ºC to 100ºC to obtain compound of formula (I);
ii. adding water insoluble solvent to the reaction mixture obtained in step (i);
iii. separating the phases followed by distillation of water insoluble solvent to obtain crude product;
iv. crude product as obtained in step (iii) was crystallized with organic solvent to obtain compound of formula (I).

2. An improved process for the preparation of Azoxystrobin as claimed in claim 1, wherein the base is a selected from alkali hydroxides such as sodium hydroxide or potassium hydroxide or mixture thereof, alkali salt of carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or mixture thereof, alkali salt of hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate, or mixtures thereof, triethylamine, 1,8-Diazabicyclo[5.4.0] undec-7-ene (DBU) or mixture of an alkali salt of a carbonate and an alkali salt of hydrogen carbonate.

3. An improved process for the preparation of Azoxystrobin as claimed in claim 1, wherein the ratio of base to raw material (i.e. base to compound of formula III) is in the ratio of 1.0: 1.0 to 2.0.

4. An improved process for the preparation of Azoxystrobin as claimed in claim 1, wherein the ratio of ((E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy acrylate) to base are in the ratio of 1.0: 1.0 to 2.0.

5. An improved process for the preparation of Azoxystrobin as claimed in claim 1, wherein the ratio of compound of formula II and compound of formula III is in the ratio of 1.0: 1.0 to 1.3.

6. An improved process for the preparation of Azoxystrobin as claimed in claim 1, wherein the catalyst is selected from the group consisting of Piperidine, N,N-Dimethyl Piperidine or N-methyl piperidine, Trimethyl amine, Triethyl amine, Tri n-propyl amine, Diethyl n-methyl amine, Dimethyl n-ethyl amine, and it’s mineral acid salts such as HCl, H2SO4, HNO3, H3PO4 optionally in combination with Polyethylene glycol (PEG) selected form group PEG-200, PEG-300, PEG 400, PEG 600, PEG 1000, PEG- 1500, PEG-4000, PEG-6000.

7. An improved process for the preparation of Azoxystrobin as claimed in claim 6, wherein the ratio of Polyethylene glycol (PEG) to catalyst are in the ratio of 1.0: 0.1 to 1.0.

8. An improved process for the preparation of Azoxystrobin as claimed in claim 1, wherein the ratio of catalyst to raw material are in the ratio of 1: 0.01-1:5.0.

9. An improved process for the preparation of Azoxystrobin as claimed in claim 1, wherein the catalyst can be added in one lot or in lots at regular intervals.

10. An improved process for the preparation of Azoxystrobin as claimed in claim 1, wherein the water insoluble solvent used in step (ii) is ethylene dichloride and organic solvent used in step (iv) is methanol.

, Description:FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of methyl (E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy] phenyl}-3-methoxyacrylate (Azoxystrobin) of formula (I) in free form or in agro chemically acceptable salt form useful as a pest control agent.

BACKGROUND OF THE INVENTION

In the field of industrial chemical synthesis, the improvement of the yield and selectivity of chemical processes bears considerable impact on the industry. Particularly, the focus in said improvements is on lowering costs, simplifying unit operations and environmental considerations. These three factors are particularly important in the field of agrochemicals where the volume of chemicals is large and the marginal profit is relatively small.

Of the many agrochemical compounds which are synthesized by multi-stage synthesis, methyl (E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy] phenyl}-3-methoxyacrylate (chemical common name: azoxystrobin), particularly drew the attention of the present inventors. Azoxystrobin, disclosed in U.S. Pat. No. 5,395,837, is a plant protection fungicide with protectant, curative, eradicant, translaminar and systemic properties. The preparation of azoxystrobin as described in Example 3 of U.S. Pat. No. 5,395,837 involves an aromatic substitution reaction between 2-cyanophenol and (E)-Methyl 2-[2-(6-chlorpyridimin-4-yloxy)phenyl]-3-methoxypropenoate also known as (E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)-phenyl]-3-methoxyacrylate, at temperatures at 95° to 100° C. in DMF in the presence of stoichiometric amounts of potassium carbonate and a catalytic amount of copper(I) chloride. The reported yield of azoxystrobin is 65% wherein the product was found to have a melting point of 110° C.-111° C., indicating a final product of relatively low purity, which subsequently required further purification. It has been suggested that reactions of 2-cyanophenol or other isomers of cyanophenol or phenols in general under conditions of temperatures of about 90° C. and above, in the presence of basic reagents which can promote the formation of phenolate salts, may cause polymerization and the formation of tars. This clearly is a highly undesirable side effect.

WO01/72719 discloses A method for producing asymmetrical 4,6-bis(aryloxy)pyrimidine derivatives in which a 6-chloro-4-aryloxypyrimidine is reacted with a phenol, optionally in the presence of a solvent and/or a base, with the addition of from 2 to 40 mol % of 1,4-diazabicyclo[2.2.2]octane (DABCO). In addition, it has previously been found by the present inventors that even lower concentrations of DABCO (for example, between 0.1 and 2 mol %) are also able to catalyze this reaction.

Chinese patent CN101157657 discloses process for the preparation of Azoxystrobin using Lewis acid such as titanium tetrachloride with trimethylorthoformate or methyl formate for formylating 2-(2-[6-chloropyrimidloxy]phenyl)methylacetate. The above process involves usage of titanium tetrachloride in excess; which is unfavorable for the industry and major drawback of this reaction lies in the hydrolysis of the said formylated product. Without completion of hydrolysis the yields of the reaction are quite low. One of the other drawbacks is that this process number of raw materials likes titanium tetrachloride; triethylamine; hydrochloric acid; methyl formate or trimethylorthoformate; then dimethylsulfate for esterification and caustic soda lye. Other drawback is that dimethylsulfate is used in molar quantities and it requires lot of care as Dimethylsulfate is poisonous.
WO1998/07707 discloses process for the preparation of Azoxystrobin using with acetic anhydride and methane sulfonic acid. The above patent also mentions formation of Azoxystrobin in the presence of sodium methoxide employing Methyl formate as solvent. Methyl formate is very low boiling solvent and industrially distillation losses are unavoidable. The reaction process involves formation of major impurity 4-chloro-6-methoxy pyrimidine which affects the yield. According to the patent after completion of reaction methyl formate was distilled under atmospheric conditions; which cannot be made industrially as sodium methoxide is used in excess and its presence in the reaction mass will not allow to distill the solvent without neutralizing it.

Accordingly there is an ongoing and long felt need for an improved process for preparation of Azoxystrobin in which selectivity, rate of reaction and yield of the final product is improved.

The present inventors have surprisingly discover that, when preparing azoxystrobin using Piperidine, N,N-Dimethyl Piperidine or N-methyl piperidine, Trimethyl amine, Triethyl amine, Tri n-propyl amine, Diethyl n-methyl amine, Dimethyl n-ethyl amine, and it’s mineral acid salts optionally in combination with Polyethylene glycol (PEG) selected form the group consisting of PEG-200, PEG-300, PEG 400, PEG 600, PEG 1000, PEG- 1500, PEG-4000, PEG-6000 as a catalyst, the order of addition of the reaction components has an effect on the yield, selectivity and reaction rate.

The process of the present invention employs a selective catalyst that provides better selectivity to provide improved yield of Azoxystrobin. Moreover the present invention also utilizes a green chemistry process involving water as reaction media and this will eliminates the usage of solvents like N,N-dimethyl formamide, Methyl isobutyl ketone, Cyclohexanone, Isopropyl acetate and N,N-diisopropylethylamine.

The present invention is directed to overcome the above drawbacks of prior art and provide a novel process for the preparation of Azoxystrobin of formula I with mild reaction conditions, simple operation, less expensive and cost effective process.

The method of the present invention involves preparing the Azoxystrobin in greater yield. The product obtained in this method is of high purity with high yield. The method even though involves higher time for maximum conversion than the said above process, productivity is more. The product can be crystallized in solvents easily.

OBJECTS OF THE INVENTION

An object of the present invention is to provide a method of preparing Azoxystrobin in aqueous media and in the presence of a selective catalyst that provides better selectivity to provide improved yield of Azoxystrobin.

It is another object of the present invention is to provide a process for reacting phenols under basic conditions and aqueous media in which the yield and selectivity is improved.

It is another object of the present invention to provide a process for the preparation of Azoxystrobin of formula I with a mild reaction conditions, simple operation, less expensive and cost effective process.

It is yet another object of the present invention to provide a process for preparation of Azoxystrobin in greater yield with high purity.

SUMMARY OF THE INVENTION

According to an aspect of the present invention there is provided an improved process for the preparation of methyl (E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (Azoxystrobin) compound of formula (I):

comprising the steps of:

i. reacting o-cyanophenol compound of formula (III) with Methyl 3-methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl) acrylate compound of formula (II) in a solvent in the presence of base and a catalyst at a temperature in the range of 60ºC to 100ºC to obtain compound of formula (I);
ii. adding water insoluble solvent to the reaction mixture obtained in step (i);
iii. separating the phases followed by distillation of water insoluble solvent to obtain crude product;
iv. crude product as obtained in step (iii) was crystallized with organic solvent to obtain compound of formula (I).
DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention provides an improved process for the preparation of methyl (E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy] phenyl}-3-methoxyacrylate (Azoxystrobin) compound of formula (I).

The following description is illustrative of embodiments of the invention. The following description is not to be construed as limiting, it being understood that the skilled person may carry out many obvious variations to the invention.

In an embodiment there is provided an improved process for the preparation of methyl (E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (Azoxystrobin) compound of formula (I):

comprising the steps of:

i. reacting o-cyanophenol compound of formula (III) with Methyl 3-methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl) acrylate compound of formula (II) in a solvent in the presence of base and a catalyst at a temperature in the range of 60ºC to 100ºC,
ii. adding water insoluble solvent such as ethylene dichloride to the reaction mixture obtained in step (i) and organic was washed with water and then water insoluble solvent such as ethylene dichloride was distilled off. Crude product obtained was crystallized with organic solvent such as methanol to obtain compound of formula (I);
In one embodiment the present invention provides an improved process for the preparation of Azoxystrobin. This process involves reacting o-cyanophenol compound of formula (III) with Methyl 3-methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl) acrylate compound of formula (II) in the presence of base like alkali salt of a carbonate or an alkali salt of hydrogen carbonate with the action of catalyst. The catalyst can be added before the base or along with the base.

For higher productivity catalyst can be added in one lot or in lots as per convenience in regular intervals.

The bases employed in the process of the present invention generally are selected from alkali hydroxides, alkali carbonates, alkali hydrogen carbonates, preferably alkali hydroxides are such as sodium hydroxide, potassium hydroxide or mixture thereof, alkali carbonates are such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixture thereof, alkali hydrogen carbonates are such as sodium hydrogen carbonate, potassium hydrogen carbonate, or mixtures thereof, triethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), and most preferred base is sodium carbonate or potassium carbonate.

In one embodiment base is selected as a mixture of an alkali salt of a carbonate and an alkali salt of hydrogen carbonate. Alkali salts refer to salts containing preferably sodium or potassium as cations. The carbonate and the hydrogen carbonate may be present in any crystal modification, in pure form, as technical quality, or as hydrates.

Especially preferred carbonates are selected from sodium carbonate, potassium carbonate, and mixtures thereof. In another form, especially preferred hydrogen carbonates are selected from sodium hydrogen carbonate, potassium hydrogen carbonate, or mixtures thereof. The base contains especially preferred mixtures of potassium carbonate and potassium hydrogen carbonate; or sodium carbonate and sodium hydrogen carbonate.

The ratio of base to raw material (Methyl 3-methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl) acrylate, compound of formula II and o-cyanophenol, compound of formula III) is 1.0: 1.0 to 2.0 generally, and most preferably between 1.0:1.0 to 1.5. The two raw materials (Methyl 3-methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl) acrylate, compound of formula II and o-cyanophenol, compound of formula III) are in the ratio of 1.0: 1.0 to 1.3, and most preferably 1.0: 1.0 to 1.1.
The catalyst is selected from the group consisting of Piperidine, N,N-Dimethyl Piperidine or N-methyl piperidine, Trimethyl amine, Triethyl amine, Tri n-propyl amine, Diethyl n-methyl amine, Dimethyl n-ethyl amine, and it’s mineral acid salts optionally in combination with Polyethylene glycol (PEG) are selected form group PEG-200, PEG-300, PEG 400, PEG 600, PEG 1000, PEG- 1500, PEG-4000, PEG-6000, preferred catalyst is Trimethyl amine optionally in combination with PEG-6000.

The mineral acid salts may be selected from HCl, H2SO4, HNO3, or H3PO4.

The catalyst facilitates the condensation reaction of (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate with o-cyanophehnol at a higher rate. It facilitates the reaction for greater purity and higher conversion of (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate to Azoxystrobin using o-cyanophenol. The catalyst are highly water soluble catalyst, which helps in removal of the catalyst by water wash, without carrying forward till the end of product.

The ratio of Polyethylene glycol (PEG) selected form group PEG-200, PEG-300, PEG 400, PEG 600, PEG 1000, PEG- 1500, PEG-4000, PEG-6000 with respect to the catalyst selected from Piperidine, N,N-Dimethyl Piperidine or N-methyl piperidine, Trimethyl amine, Triethyl amine, Tri n-propyl amine, Diethyl n-methyl amine, Dimethyl n-ethyl amine, and it’s mineral acid salts is 1.0 : 0.1 to 5.0 generally, and most preferably between 1.0 : 0.1 to 1.0.

The catalyst employ in the present invention has high solubility and does not remain in product when washed. The catalyst promotes the reaction by acting on o-cyanophenol compound of formula (III) to convert it into its corresponding phenolate salt and thus reacting with Methyl 3-methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl) acrylate compound of formula (II) to form Azoxystrobin compound of formula (I).

The catalyst to raw material ratio generally lies between 1:0.01-1:5.0. The catalyst mole ratio with raw material generally is 0.01mole % to 100 mole%. The most preferred ratio is 1.0: 0.5mole %.

The solvents/reaction media involved in this process of the present invention is Water.

In another embodiment the present invention provides an improved process for the preparation of Azoxystrobin comprising the following steps:

In one embodiment the reaction can be conducted in simple ways like, taking Methyl 3-methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl) acrylate compound of formula (II) into a aqueous media, then adding base and o-cyanophenol compound of formula (III), heating to a temperature in the range from 60°C to 100°C, preferably to 80°C and then adding catalyst in lots optionally with PEG till the end of raw material. After reaction is completed, inorganics can be separated from the reaction mass through filtration or by any means known in the art, then adding water insoluble solvent such as Ethylene dichloride and separating phases, and removal of solvents under vacuum and then crystallizing the product for higher purity.

In another embodiment (E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy acrylate compound of formula II was added to Water, 2-cyanophenol, catalyst in one lot optionally with PEG and base were then added, heated to 60°C to 100°C, preferably to 80°C. After reaction is completed, inorganics can be separated from the reaction mass through filtration or by any means known in the art, then adding water insoluble solvent such as (Ethylene dichloride) and separating phases, and removal of solvents under vacuum and then crystallizing the product for higher purity.

The above process can be represented stepwise as shown below:

Example 1

(E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy acrylate (160 gm, at a concentration of 96.1%) was added to 350 ml of Water, 2-cyanophenol (65 gm), N-Methyl piperidine with PEG-6000 1.8gm and Sodium carbonate (65 gm) were then added, heated to 60° C to 100° C , and the termination of the reaction was monitored (completed after 10 hours). Ethylene dichloride was added to the obtained concentrate and washed with water. Final ethylene dichloride layer was taken for distillation and then crude product was recrystallized by using methanol and then filtered off the methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin and dried it. Final Yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin 92.6% with 99.1% Purity

Example 2

(E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy acrylate (160 gm, at a concentration of 96.1%) was added to 350 ml of Water, 2-cyanophenol (65 gm), Trimethyl Amine Solution 1.0gm with PEG-6000 and Sodium carbonate (65 gm) were then added, heated to 60° C to 100° C °, and the termination of the reaction was monitored (completed after 3 hours). Ethylene dichloride was added to the obtained concentrate and washed with water. Final ethylene dichloride layer was taken for distillation and then crude product was recrystallized by using methanol and then filtered off the methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin Final Yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin 92.4% with 99.2% Purity

Example 3

(E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy acrylate (160 gm, at a concentration of 96.1%) was added to 350 ml of Water, 2-cyanophenol (65 gm), Trimethyl Amine Hydrochloride salt 2.0gm with PEG-6000 and Sodium carbonate (65 gm) were then added, heated to 60° C to 100° C °, and the termination of the reaction was monitored (completed after 3 hours). Ethylene dichloride was added to the obtained concentrate and washed with water. Final ethylene dichloride layer was taken for distillation and then crude product was recrystallized by using methanol and then filtered off the methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin. Final Yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin 92.9% with 99.3% Purity

Example 4

(E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy acrylate (160 gm, at a concentration of 96.1%) was added to 350 ml of Water, 2-cyanophenol (65 gm), Trimethyl Amine hydrochloride 1.4gm PEG-6000 and Sodium carbonate (65 gm) were then added, heated to 60° C to 100° C °, and the termination of the reaction was monitored (completed after 3 hours). Ethylene dichloride was added to the obtained concentrate and washed with water. Final ethylene dichloride layer was taken for distillation and then crude product was recrystallized by using methanol and then filtered off the methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin Final Yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin 92.8% with 99.4% Purity

Example 5

(E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy acrylate (160 gm, at a concentration of 96.1%) was added to 350 ml of Water, 2-cyanophenol (65 gm), Trimethyl Amine hydrochloride 1.4gm PEG-400 and Sodium carbonate (65 gm) were then added, heated to 60°C to 100°C, and the termination of the reaction was monitored (completed after 3 hours). Ethylene dichloride was added to the obtained concentrate and washed with water. Final ethylene dichloride layer was taken for distillation and then crude product was recrystallized by using methanol and then filtered off the methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin Final Yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin 92.3% with 99.0% Purity

Example 6

(E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy acrylate (160 gm, at a concentration of 96.1%) was added to 350 ml of Water, 2-cyanophenol (65 gm), Trimethyl Amine hydrochloride 1.4gm PEG-400 and Potassium carbonate (63 gm) were then added, heated to 60° C to 100° C °, and the termination of the reaction was monitored (completed after 3 hours). Ethylene dichloride was added to the obtained concentrate and washed with water. Final ethylene dichloride layer was taken for distillation and then crude product was recrystallized by using methanol and then filtered off the methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin. Final Yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin 91.2% with 99.0% Purity

Data demonstrating that reaction of the present invention can be proceed and yield the product Azoxystrobin by using Base such as TMA 30% Solution only but Base such as TMA has very bad odor and therefore employing TMA.HCl salt is preferable as it does not have any odor.

Catalyst Base Base Yield (%)
TMA 30% SOLUTION Sodium Carbonate 91.36%
TMA .HCl 20% SOLUTION Sodium Carbonate 92.07%

The Data further demonstrate that by using of PEG and TMA.HCl solution as a combination will give little better yield and quality, which is reflect in following data:

Catalyst Base Combination Catalyst Base Yield (%) Purity (%)
TMA 30% Solution PEG-6000 Sodium Carbonate 92.4 99.2
TMA.HCl Salt PEG-6000 Sodium Carbonate 92.9 99.3
N-Methyl Piperidine PEG-6000 Sodium Carbonate 92.6 99.1
TMA.HCl Salt PEG-400 Potassium Carbonate 91.2 99.0
TMA.HCl Salt PEG-400 Sodium Carbonate 92.3 99.0