DESC:
FORM 2

THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1.Title of the invention– AN IMPROVED PROCESS FOR THE PREPARATION OF AZOXYSTROBIN

2. Applicant(s)

(a) NAME: GSP CROP SCIENCE PVT. LTD

(b) NATIONALITY: an Indian Company

(c) ADDRESS: 404, Lalita Complex, 352/3
Rasala Road, Navrangpura,
Ahmedabad-380009, Gujarat, India

3. PREAMBLE TO THE DESCRIPTION

The following specification describes the invention and the manner in which it has to be performed:

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 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 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.

WO 01/72719 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.

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 uses number of raw materials like 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.

Thus, it is the objective of the present invention to provide a process for reacting phenols under basic conditions in which the yield and selectivity is improved.

The present invention is directed to the above drawbacks, the purpose is to provide novel process for the preparation of Azoxystrobin of formula I which is a mild reaction conditions, simple operation, less expensive & cost effective process.

OBJECTIVES OF THE INVENTION

One of the objectives of the present invention is to provide novel process for the preparation of Azoxystrobin in the presence of a catalyst.

Further objective of the present invention is to provide novel process wherein catalysts are selected form a group of Crown ethers or Polyethylene glycol (PEG). wherein Crown ethers are selected form a group 18-Crown-6, Dicyclohexano-18-Crown-6, Dibenzo-18-Crown-6, 4,13-Diaza-18-Crown-6, 15-crown-5, 12-crown-4, bis (4-t-butylbenzo)-21-Crown-7, Tetrabenzo-24-crown-8, monocyclohexano-27-crown-9, 30-crown-10 or Polyethylene glycol (PEG) are selected form a group PEG (PEG-200, PEG-300, PEG 400, PEG 600, PEG 1000, PEG-1500, PEG-4000, and PEG-6000).

In a further objective of the present invention is to provide novel process method involves in 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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of compound of formula (I).

Wherein W is the methyl (E)-2-(3-methoxy) acrylate group C(CO2CH3)=CHOCH3.

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.

The present invention provides an improved process for the preparation of compound of formula (I) using Crown ethers or Polyethylene glycol (PEG) as a catalyst, the order of addition of the reaction components has an effect on the yield and reaction rate.

In one embodiment the present invention provides an improved process for the preparation of compound of formula (I). This process involves reacting o-cyanophenol compound of formula (III) with compound of formula (II) in the presence of base or acid acceptor like alkali salt of a carbonate and an alkali salt of hydrogen carbonate with the action of catalyst. The catalyst can be added before the base or acid acceptor or along with the base or acid acceptor.

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 and an alkali salt of hydrogen carbonate with the action of catalyst in suitable solvent. 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.

Typically, the base or acid acceptor is selected from a mixture of an alkali salt of a carbonate and an alkali salt of hydrogen carbonate. Alkali salts refer to salts containing preferably sodium and/or potassium as cations. The carbonate and the phosphate 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, and mixtures thereof. The base contains especially preferred mixtures of potassium carbonate and potassium hydrogen carbonate; or sodium carbonate and sodium hydrogen carbonate.

The base or acid acceptor chosen in this process involves generally alkali hydroxides, alkali carbonates, organic carbonates, and preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, DBU, and most preferably sodium carbonate and potassium carbonate.

The ratio of base or acid acceptor to raw material is 1.0: 1.0 to 2.0 generally and most preferably between 1.0:1.0 to 1.5. The two raw materials are in the ratio of 1.0: 1.0 to 1.3, and most preferably 1.0: 1.0 to 1.1.

The catalysts chosen in this process is Crown ethers or Polyethylene glycol (PEG) wherein Crown ethers are selected form group ethers 18-crown-6 (1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane), dibenzo-18-crown-6 (2, 3, 11, 12-dibenzo-1, 4, 7, 10, 13, 16-hexaoacyclootadeca-2, 11-diene), and dicyclohexano-18-crown-6 (2, 3, 11, 12-dicyclohexano-1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane) also names as 2, 5, 8, 15, 18, 21-hexaoxatricyclo [20.4.0.09,14 ] hexacosane, 12-crown-4, monobenzo-15-crown-5, bis(4-t-butylbenzo)-21-crown-7, tetrabenzo-24-crown-8, monocyclohexano-27-crown-9, 30-crown-10 or a mixture thereof; wherein Polyethylene glycol (PEG) are selected form group PEG-200, PEG-300, PEG -400, PEG- 600, PEG- 1000, PEG-1500, PEG-4000, PEG-6000 or a mixture thereof.

Crown ethers or Polyethylene glycol (PEG) facilitate in catalyzing the reaction for greater purity and higher conversion of (E) 2-Methyl-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate to Azoxystrobin using o-cyanophenol. The catalysts soluble in water and can be easily removed by washing with water from the organic layer.

The catalyst of choice 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 0.01:1.0 to 0.1:1.0. The catalyst mole ratio with raw material generally is 0.01mole % to 100 mole %. The most preferred catalyst ratio is between 0.05 to 2.0 mole %.

The solvents involved in this process are selected form group alcohols, methanol, ethanol, C3 to C8 alcohols, nonpolar solvents like xylene, toluene, hexane, heptane, benzene, chlorinated solvents like ethylene dichloride, methylene dichloride, chloroform, chloro benzene, dichloro benzene, tetrachloroethylene, N,N-dimethyl formamide, acetonitrile, N-methylpyrrolidone, N,N-dimethylacetamide, dibutylformamide, acetone, Dimethyl sulfoxide or mixture thereof.

The solvents involved in reaction process are selected form group N, N-dimethyl formamide, acetonitrile, N-methylpyrrolidone, N, N-dimethylacetamide, dibutylformamide, acetone, Dimethyl sulfoxide or mixture thereof.

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

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 solvent , then adding base and other raw material o-cyanophenol compound of formula (III), heating to desired temperature and then adding catalyst in lots 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 to art, then adding water insoluble solvent and separating phases, and removal of solvents under vacuum to isolate Azoxystrobin.

The above process can be represented stepwise as shown below:

The process of the invention is illustrated with reference to the following working Examples and is not intended to limit or enlarge the scope of the invention.

Example 1:-

(E)-methyl-2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-methoxypropenoate (320 gm at 96.1% strength) was added to 1500 ml N, N-Dimethyformamide followed by 2-Cyanophenol (130 gm), PEG-6000 (3.00 gm ) and potassium carbonate (208 gm) and was heated to 80°C and monitored for the end of the reaction (complete after 10 hours).Solvent was removed under vacuum. Toluene was added to the resulting concentrate and washed with water .Analysis of the Toluene layer revealed a 97.8% yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin (Azoxystrobin)

Example 2:-

(E)-methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (320gm at 96.1% strength) was added to N, N-Dimethyformamide followed by 2-Cyanophenol (130gm) , PEG-4000 (3.10gm) and potassium carbonate (208gm ) and was heated to 80°c and monitored for the end of the reaction ( complete after 10 hours).Solvent was removed under vacuum. Toluene was added to the resulting concentrate and washed with water .Analysis of the Toluene layer revealed a 97.5% yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy]phenyl}-3-methoxystrobin(Azoxystrobin)

Example 3:-

(E)-methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (320gm at 96.1% strength) was added to N,N-Dimethylacetamide followed by 2-Cyanophenol (130gm), PEG -1000 (4.1gm) and potassium carbonate (208gm) and was heated to 80°C and monitored for the end of the reaction (complete after 8 hours). Solvent was removed under vacuum. Toluene was added to the resulting concentrate and washed with water .Analysis of the Toluene layer revealed a 96.1 % yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin (Azoxystrobin)

Example 4:-

(E)-methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (320gm at 96.1% strength) was added to Acetonitrile followed by 2-Cyanophenol (130gm), PEG -2000 (3.0gm) and potassium carbonate (208gm) and was heated to 80°C and monitored for the end of the reaction (complete after 8 hours). Solvent was removed under vacuum. Toluene was added to the resulting concentrate and washed with water. Analysis of the Toluene layer revealed a 93.2 % yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin (Azoxystrobin).

Example 5:-

(E)-methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (320 gm at 96.1% strength) was added to, N-Mehyl pyrrolidone followed by 2-Cyanophenol (130 gm), PEG-4000 (4.1gm) and potassium carbonate (208gm) and was heated to 80°C and monitored for the end of the reaction (complete after 08 hours). Solvent was removed under vacuum. Toluene was added to the resulting concentrate and washed with water. Analysis of the Toluene layer revealed a 92.8% yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin (Azoxystrobin).

Example 6:-

(E)-methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (320gm at 96.1% strength) was added to Acetonitrile followed by 2-Cyanophenol (130gm) ,PEG -4000 (4.0gm) and potassium carbonate (207gm) and was heated to 80°c and monitored for the end of the reaction ( complete after 11 hours).Solvent was removed under vacuum. Toluene was added to the resulting concentrate and washed with water. Analysis of the Toluene layer revealed a 93.4 % yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy] phenyl}-3-methoxystrobin (Azoxystrobin).

Example 7:-

(E)-methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (320gm at 96.1% strength) was added to N, N-Dimethyformamide followed by 2-Cyanophenol (130gm), 18-CROWN-6 (3.20gm) and potassium carbonate (207gm) and was heated to 80°C and monitored for the end of the reaction (complete after 12 hours).Solvent was removed under vacuum. Dichloroethane was added to the resulting concentrate and washed with water. Analysis of the Toluene layer revealed a 93.5% yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy]phenyl}-3-methoxystrobin (Azoxystrobin)

Example 8:-

(E)-methyl-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (320gm at 96.1% strength) was added to N,N-Dimethyformamide followed by 2-Cyanophenol(130gm), 15-crown-5 (3.10gm ) and potassium carbonate (207gm) and was heated to 80°c and monitored for the end of the reaction (complete after 12 hours). Solvent was removed under vacuum. Dichloroethane was added to the resulting concentrate and washed with water. Analysis of the Toluene layer revealed a 93.0 % yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy]phenyl}-3-methoxystrobin (Azoxystrobin)
,CLAIMS:CLAIMS:-

1) An improved process for the preparation of compound of the formula (I)

comprising the reaction of compound of the formula (II) with the 2-Cyanophenol compound of the formula (III) or a salt thereof in the presence of base like alkali salt of a carbonate and an alkali salt of hydrogen carbonate with the action of catalyst in suitable solvent; the said catalyst is selected from Crown ethers or Polyethylene glycol (PEG) or a mixture thereof.

2) An improved process as claimed in claim 1 product of the formula (I) wherein W is the methyl (E)-2-(3-methoxy) acrylate group C(CO2CH3)=CHOCH3.

3) An improved process as claimed in claim 1 wherein compound of formula II is 2-Methyl-3-Methoxy(2-(2-(6-Chloropyrimidine)-4-yloxy phenyl) Acrylate.

4) An improved process as claimed in claim 1 wherein compound of formula I is 2-{2-[6-(2-Cyano-phenoxy)-pyrimidin-4-yloxy]-phenyl}-3-methoxy-acrylic acid methyl ester.

5) An improved process as claimed in claim 1 wherein reaction is carried out at a temperature from 0 °c to 150°C.

6) An improved process as claimed in claim 1 wherein polyethylene glycol or Crown Ethers or a mixture thereof is in ratio of 0.05 to 2.0 mole %.

7) An improved process as claimed in claim 1 wherein catalysts crown ethers are selected from 18-crown-6 (1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane), dibenzo-18-crown-6 (2, 3, 11, 12-dibenzo-1, 4, 7, 10, 13, 16-hexaoacyclootadeca-2, 11-diene), and dicyclohexano-18-crown-6 (2, 3, 11, 12-dicyclohexano-1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane) also names as 2, 5, 8, 15, 18, 21-hexaoxatricyclo [20.4.0.09,14 ] hexacosane, 12-crown-4, monobenzo-15-crown-5, bis(4-t-butylbenzo)-21-crown-7, tetrabenzo-24-crown-8, monocyclohexano-27-crown-9, 30-crown-10 or a mixture thereof.

8) An improved process as claimed in claim 7 wherein preferred crown ethers are selected from 18-crown-6 or 15-crown-5 mixture thereof.

9) An improved process as claimed in claim 1 wherein catalyst Polyethylene glycol (PEG) are selected form group PEG-200, PEG-300, PEG 400, PEG 600, PEG 1000, PEG-1500, PEG-4000, PEG-6000 or a mixture thereof.

10) An improved process as claimed in claim 9 wherein preferred polyethylene glycol is PEG-200, PEG 400, PEG 600, PEG-4000 or PEG-6000 or mixture thereof.

11) An improved process as claimed in claim 1 wherein reaction is carried out in presence of base or acid acceptor.

12) An improved process as claimed in claim 11 wherein base or acid acceptor are selected from a mixture of an alkali salt of a carbonate.

13) An improved process as claimed in claim 12 wherein carbonates are selected from sodium carbonate, potassium carbonate, and mixtures thereof.

14) An improved process as claimed in claim 1 wherein using dipolar aprotic solvents such as N,N-dimethyl formamide, acetonitrile, N-methylpyrrolidone, N,N-dimethylacetamide, or mixtures thereof.