WO2017060917A1 - Process for the preparation of azoxystrobin - Google Patents

Process for the preparation of azoxystrobin Download PDF

Info

Publication number
WO2017060917A1
WO2017060917A1 PCT/IN2016/050088 IN2016050088W WO2017060917A1 WO 2017060917 A1 WO2017060917 A1 WO 2017060917A1 IN 2016050088 W IN2016050088 W IN 2016050088W WO 2017060917 A1 WO2017060917 A1 WO 2017060917A1
Authority
WO
WIPO (PCT)
Prior art keywords
peg
crown
improved process
formula
mixture
Prior art date
Application number
PCT/IN2016/050088
Other languages
French (fr)
Inventor
Ajit Singh Gujral
Kenal V. Shah
Bhavesh V. Shah
Subhash KADAM
Nilesh N. JANI
Ravindra Y SHINDE
Original Assignee
Gsp Crop Science Pvt. Ltd,
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gsp Crop Science Pvt. Ltd, filed Critical Gsp Crop Science Pvt. Ltd,
Priority to CN201680017913.1A priority Critical patent/CN107428704A/en
Publication of WO2017060917A1 publication Critical patent/WO2017060917A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms

Definitions

  • 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.
  • Azoxystrobin methyl (E)-2- ⁇ 2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy] phenyl ⁇ -3 -methoxyacry late (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.
  • 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.
  • 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 l,4-diazabicyclo[2.2.2]octane (DABCO).
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • 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.
  • 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.
  • 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.
  • One of the objectives of the present invention is to provide novel process for the preparation of Azoxystrobin in the presence of a catalyst.
  • 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-lO 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).
  • PEG Polyethylene glycol
  • 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.
  • the present invention provides an improved process for the preparation of compound of formula (I).
  • the present invention provides an improved process for the preparation of methyl (E)-2- ⁇ 2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy] phenyl ⁇ -3 -methoxyacry late
  • 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.
  • 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.
  • 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.
  • 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-l, 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, monocyclohe
  • 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 0.01 mole % 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, C 3 to Cs alcohols, nonpolar solvents like xylene, toluene, hexane, heptane, benzene, chlorinated solvents like ethylene dichloride, methylene dichloride, chloroform, chloro benzene, dichloro benzene, tetrachloroethylene, ⁇ , ⁇ -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.
  • 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.
  • 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.

Abstract

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.

Description

PROCESS FOR THE PREPARATION OF AZOXYSTROBIN
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.
Figure imgf000003_0001
AZOXYSTROBIN
Formula (I)
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 -methoxyacry late (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.-l l l° 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 l,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.
Figure imgf000005_0001
AZOXYSTROBIN
Formula (I)
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-lO 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).
Figure imgf000006_0001
Formula (I)
Wherein W is the methyl (E)-2-(3-methoxy) acrylate group C(C02CH3)=CHOCH3. The present invention provides an improved process for the preparation of methyl (E)-2- { 2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy] phenyl} -3 -methoxyacry late
(Azoxystrobin) compound of formula (I).
Figure imgf000007_0001
AZOXYSTROBIN
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.
Figure imgf000007_0002
Formula (II) Formula (III)
Formula (I) 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-l, 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-lO 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).
Figure imgf000010_0001
AZOXYSTROBIN
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 0.01 mole % 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 Cs alcohols, nonpolar solvents like xylene, toluene, hexane, heptane, benzene, chlorinated solvents like ethylene dichloride, methylene dichloride, chloroform, chloro benzene, dichloro benzene, tetrachloroethylene, Ν,Ν-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:
Me
pyri
Figure imgf000011_0001
midine)-4-yl) oxyphenyl) acrlate
AZOXYSTROBIN
Formula (II) Formula (III)
Formula (I)
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. lOgm) 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

WE CLAIM
CLAIMS:-
An improved process for the preparation of compound of the formula (I)
Figure imgf000015_0001
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.
Figure imgf000015_0002
Formula (II) Formula (III)
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(C02CH3)=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. An improved process as claimed in claim 1 wherein reaction is carried out at a temperature from 0 °c to 150°C.
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 %.
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-l, 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-lO or a mixture thereof.
An improved process as claimed in claim 7 wherein preferred crown ethers are selected from 18-crown-6 or 15-crown-5 mixture thereof.
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.
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.
An improved process as claimed in claim 1 wherein reaction is carried out in presence of base or acid acceptor. 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.
An improved process as claimed in claim 12 wherein carbonates are selected from sodium carbonate, potassium carbonate, and mixtures thereof.
An improved process as claimed in claim 1 wherein using dipolar aprotic solvents such as Ν,Ν-dimethyl formamide, acetonitrile, N-methylpyrrolidone, N,N-dimethylacetamide, or mixtures thereof.
PCT/IN2016/050088 2015-10-06 2016-03-17 Process for the preparation of azoxystrobin WO2017060917A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680017913.1A CN107428704A (en) 2015-10-06 2016-03-17 The method for preparing Fluoxastrobin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3782/MUM/2015 2015-10-06
IN3782MU2015 2015-10-06

Publications (1)

Publication Number Publication Date
WO2017060917A1 true WO2017060917A1 (en) 2017-04-13

Family

ID=56178410

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2016/050088 WO2017060917A1 (en) 2015-10-06 2016-03-17 Process for the preparation of azoxystrobin

Country Status (2)

Country Link
CN (1) CN107428704A (en)
WO (1) WO2017060917A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3770147A4 (en) * 2018-03-23 2021-10-13 Purpana (Beijing) Technologies Co., Ltd Preparation method for azoxystrobin and intermediate thereof
WO2023203574A1 (en) * 2022-04-22 2023-10-26 Nacl Industries Limited A process for preparation of azoxystrobin
WO2023226456A1 (en) 2022-05-26 2023-11-30 安徽广信农化股份有限公司 Method for preparing azoxystrobin and intermediate thereof
US11952350B2 (en) 2019-04-18 2024-04-09 Upl Ltd. Process for the preparation of fungicidally active strobilurin compounds and intermediates thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108997209B (en) * 2018-06-11 2020-08-04 山东罗欣药业集团恒欣药业有限公司 Preparation method of regorafenib
CN113831279A (en) * 2021-09-27 2021-12-24 江苏禾裕泰化学有限公司 Synthesis method of diflufenican

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5395837A (en) 1989-02-10 1995-03-07 Zeneca Limited Fungicides
WO2001072719A1 (en) 2000-03-24 2001-10-04 Bayer Aktiengesellschaft Method for producing asymmetrical 4,6-bis(aryloxy)pyrimidine derivatives
CN101157657A (en) 2007-10-24 2008-04-09 北京颖新泰康科技有限公司 Method for preparing azoxystrobin and its analogue
WO2008043977A1 (en) * 2006-10-09 2008-04-17 Syngenta Limited Process for preparing 6-phen0xypyrimidin-4-ol derivatives in the presence of a quinuclidine or a n-methyl pyrrolidine derivative

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101239919B (en) * 2008-01-11 2011-01-12 南京工业大学 Method for synthesizing aromatic diamines monomer
CN101885670A (en) * 2010-07-19 2010-11-17 扬州大学 Synthesis method of m-phenoxytoluene

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5395837A (en) 1989-02-10 1995-03-07 Zeneca Limited Fungicides
WO2001072719A1 (en) 2000-03-24 2001-10-04 Bayer Aktiengesellschaft Method for producing asymmetrical 4,6-bis(aryloxy)pyrimidine derivatives
WO2008043977A1 (en) * 2006-10-09 2008-04-17 Syngenta Limited Process for preparing 6-phen0xypyrimidin-4-ol derivatives in the presence of a quinuclidine or a n-methyl pyrrolidine derivative
CN101157657A (en) 2007-10-24 2008-04-09 北京颖新泰康科技有限公司 Method for preparing azoxystrobin and its analogue

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PARRA J ET AL: "Concise and modular synthesis of regioisomeric haptens for the production of high-affinity and stereoselective antibodies to the strobilurin azoxystrobin", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 67, no. 3, 21 January 2011 (2011-01-21), pages 624 - 635, XP027564155, ISSN: 0040-4020, [retrieved on 20101217] *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3770147A4 (en) * 2018-03-23 2021-10-13 Purpana (Beijing) Technologies Co., Ltd Preparation method for azoxystrobin and intermediate thereof
US11214552B2 (en) 2018-03-23 2022-01-04 Purpana (Beijing) Technologies Co., Ltd Preparation method for azoxystrobin and intermediate thereof
US11952350B2 (en) 2019-04-18 2024-04-09 Upl Ltd. Process for the preparation of fungicidally active strobilurin compounds and intermediates thereof
WO2023203574A1 (en) * 2022-04-22 2023-10-26 Nacl Industries Limited A process for preparation of azoxystrobin
WO2023226456A1 (en) 2022-05-26 2023-11-30 安徽广信农化股份有限公司 Method for preparing azoxystrobin and intermediate thereof

Also Published As

Publication number Publication date
CN107428704A (en) 2017-12-01

Similar Documents

Publication Publication Date Title
WO2017060917A1 (en) Process for the preparation of azoxystrobin
EP3107884B1 (en) Process for producing 2,5-dihalophenolethers
DK2102174T3 (en) PROCEDURE FOR PREPARING SUBSTITUTED CYNOPHENOXY-PYRIMIDINYLOXY-PHENYLACRYLATE DERIVATIVES
EP3770147B1 (en) Preparation method for azoxystrobin and intermediate thereof
KR20140085204A (en) A method for preparing methyl (E)-2-[2-[6-(2-cyanophenoxy)pyrimidine-4-yloxy]phenyl]-3-methoxyacrylate
US10160770B2 (en) Method for preparing thienopyrimidine compound and intermediates used therein
JP5689321B2 (en) Process for producing 2-amino-4-trifluoromethylpyridines
CN104628653A (en) Method for synthesizing key intermediate of rosuvastatin calcium
TWI483934B (en) 4,6-dialkoxy-2-cyanomethylpyrimidine and a synthetic intermediate
TWI476183B (en) Pyrimidinyl acetonitrile derivatives and their synthesis intermediates
JP2023532362A (en) Method for producing phenylisoxazoline compound
JPH0550514B2 (en)
WO2015102016A1 (en) Process for the preparation of methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3,3- dimethoxypropionate
EP1431278A1 (en) Process for producing (2-nitrophenyl)acetonitrile derivative and intermediate therefor
Liu et al. A concise synthesis of azoxystrobin using a Suzuki cross-coupling reaction
JP4032861B2 (en) Process for producing β-oxonitrile derivative or alkali metal salt thereof
JP5516567B2 (en) Process for producing 4-amino-2-alkylthio-5-pyrimidinecarbaldehyde
JP5507147B2 (en) Process for producing pyrimidinyl alcohol derivatives and synthetic intermediates thereof
JP5205971B2 (en) Method for producing tetrahydropyran compound
JP4608888B2 (en) Method for producing 2-cyano-2- (4-tetrahydropyranyl) acetate
CN110655491B (en) Simple preparation method of 2-aminopyrimidine-5-formic ether
CN104447527A (en) Method for preparing pyridine-2,3-dicarboxylic ester compound
JP2007031331A (en) Method for producing 5-hydroxy-4-methoxy-2-nitrobenzoic acid compound
JP2006342081A (en) 1-alkoxy-4,4-dihydrocarbyloxy-1-buten-3-one and manufacturing method thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16731348

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16731348

Country of ref document: EP

Kind code of ref document: A1