HK1136826A - Process for the preparation of substituted cynophenoxy-pyrimidinyloxy-phenyl acrylate derivatives - Google Patents

Description

Process for preparing substituted cyanophenoxy-pyrimidinyloxy-phenyl acrylate derivatives

Technical Field

The present invention relates to the field of chemical synthesis, and in particular to an improved method for the synthesis of substituted cyanophenoxy-pyrimidinyloxy-phenyl acrylate derivatives.

Background

In the field of industrial chemical synthesis, improvements in the yield and selectivity of chemical processes have a considerable impact on the industry. In particular, improvements are focused on reducing costs, simplifying the operation of the device and environmental considerations. These three factors are particularly important in the field of agrochemicals, where the amount of chemicals is large but the marginal profit is relatively small.

Among the many agrochemical compounds synthesized by multistage synthesis, methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (chemical common name: azoxystrobin) is particularly attracting the attention of the present inventors. Azoxystrobin, disclosed in U.S. patent No.5,395,837, is a plant protection fungicide with protective, therapeutic, spading, lamellar transfer (transminar) and systemic functions. The preparation of azoxystrobin as described in US 5,395,837 comprises an aromatic substitution reaction between 2-cyanophenol and (E) -methyl 2- [2- (6-chloropyrimidin-4-yloxy) phenyl ] -3-methoxyacrylate [ also known as (E) -methyl 2- [2- (6-chloropyrimidin-4-yloxy) -phenyl ] -3-methoxyacrylate ] in DMF at a temperature between 95 ℃ and 100 ℃ in the presence of a stoichiometric amount of potassium carbonate and a catalytic amount of copper (I) chloride. The reported yield of azoxystrobin was 65%, wherein the product was found to have a melting point of 110 ℃ to 111 ℃, indicating that the final product had a lower purity, which subsequently required further purification. It has been suggested that 2-cyanophenol or other isomers of phenol generally react in the presence of an alkaline reagent (which promotes phenolate formation) at temperatures of about 90 ℃ and above 90 ℃ to cause polymerization and tar formation. This is clearly a highly undesirable side effect.

There is therefore a long felt need for a process for aromatic substitution reactions in the presence of phenols with improved yield and selectivity.

It is therefore an object of the present invention to provide a process for reacting phenols under basic conditions, in which the yield and selectivity are improved.

Other objects of the present invention will become apparent after the description thereof.

Summary of the invention

The present invention provides a process for reacting a phenol (phenolate) derivative with an aromatic substrate (substrate) under phenolate (phenolate) forming conditions, the process comprising the steps of:

a) phenol derivatives are reacted with bases in polar organic solvents to give phenolates, with water being removed from the reaction mixture during the reaction.

b) Adding an aromatic substrate to the reaction mixture obtained in step (a),

c) heating the reaction mixture of step (b) to a temperature of 80 ℃ to 130 ℃, preferably 90 to 100 ℃, for 2 to 7 hours to obtain a phenoxy substituted aromatic substrate,

d) removing the solvent from the mixture of step (c) and then further isolating and purifying the phenoxy substituted aromatic substrate.

Optionally, the removal of water in step (a) is carried out in conjunction with the partial removal of organic solvent (inconjunction with).

Detailed description of the invention

The following description is illustrative of embodiments of the invention. The following description is not to be taken in a limiting sense, and it should be understood that numerous obvious variations of the present invention may be embodied by one skilled in the art. Throughout the specification the terms "phenols" and "phenol derivatives" include phenols and mono-and poly-substituted phenols, including 2-cyanophenol and other cyanophenol isomers.

The present invention provides a process for reacting a phenol derivative with an aromatic substrate under phenolate forming conditions wherein the formation of polymeric by-products and tars is minimized. The process of the present invention provides improved yields while minimizing byproduct and tar formation, with improved product isolation and purification. The process according to the invention gives yields of 90% and more, based on the aromatic substrate. It has surprisingly been found that the separate production of a phenate salt and the subsequent reaction of the phenate salt with an aromatic substrate prevents the formation of undesired by-products and tars.

The method of the invention comprises the following steps:

a) phenol derivatives are reacted with bases in polar organic solvents to give phenolates, with water being removed from the reaction mixture during the reaction.

Step (a) is carried out in which the molar ratio of phenol derivative to base is preferably between 1: 1 and 1: 1.5, preferably between 1: 1.125 and 1: 1.15. The time required to achieve step (a) of conversion to phenolate is 30-120 minutes at a temperature between 60 ℃ and 80 ℃ while partially removing solvent and water from the reaction mixture by vacuum distillation.

According to a preferred embodiment of the present invention, the phenol derivative may be phenol (phenol), mono-substituted phenol or poly-substituted phenol, and more preferably, cyanophenol derivatives (cyanophenol derivatives) including 2-cyanophenol (2-cyanophenol) and 4-cyanophenol (4-cyanophenol).

The base may be selected from hydroxide and carbonate bases including, but not limited to, metal hydroxides, alkali metal hydroxides, metal carbonates and alkali metal carbonates, preferably, sodium hydroxide or potassium hydroxide.

Non-limiting examples of preferred polar organic solvents are Dimethylformamide (DMF), Dimethylacetamide (DMAA) and Dimethylsulfoxide (DMSO), wherein the reagent/solvent ratio preferably ranges from 0.1 mole/150 ml to 0.1 mole/350 ml.

According to a particular embodiment of the invention, the phenolate is formed by partial removal of the solvent and water under reduced pressure.

b) Adding an aromatic substrate to the reaction mixture obtained in step (a).

According to a particular embodiment of the invention, the aromatic substrate is added together with a polar organic solvent selected from the aforementioned group of solvents. The aromatic substrate is added in an amount such that the molar ratio of the phenol derivative to the aromatic substrate is from 1: 0.8 to 1: 1.

In still further preferred embodiments of the present invention, the aromatic substrate is selected from the group consisting of mono-and poly-substituted pyridines, pyrimidines and phenyl groups. Preferably, at least monohalogen substituted and more preferably chloropyrimidine derivatives.

c) Heating the reaction mixture of step (b) to a temperature of 80 ℃ to 130 ℃, preferably about 100 ℃, for a period of 2 to 7 hours, preferably about 5 hours, to obtain a phenoxy substituted aromatic substrate,

d) removing the solvent from the mixture of step (c) and then further isolating and purifying the phenoxy substituted aromatic substrate.

The operation of step (d) can be carried out according to methods known to the person skilled in the art. The method comprises the following steps; the solvent is removed by distillation, wherein the distillation can be carried out under reduced pressure, by separation and purification of washing, extraction and crystallization.

According to a particularly preferred embodiment of the present invention, there is provided a process for the preparation of methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (azoxystrobin) comprising the steps of:

a) 2-cyanophenol is reacted with an alkali metal hydroxide or carbonate, preferably sodium hydroxide, in a polar organic solvent, preferably selected from DMF, DMAA and DMSO, more preferably DMAA, at a temperature between 60 ℃ and 80 ℃, preferably between 60 ℃ and 70 ℃, for about 1 hour, while water formed in the reaction is removed with the solvent by distillation under reduced pressure, preferably about 20-30 mbar. The molar ratio of 2-cyanophenol to alkali metal hydroxide is between 1: 1 and 1: 1.5.

b) An aromatic substrate, which is (E) -2- [2- (6-chloropyrimidin-4-yloxy) phenyl ] -3-methoxypropenoic acid (propenoate) methyl ester (a compound of formula (I)), is added to the reaction mixture obtained in step (a). Optionally, compound (I) is added to the reaction mixture as a solution in DMAA.

c) Heating the reaction mixture of step (b) to a temperature of 80-130 ℃, preferably 90-100 ℃, for 2-7 hours, preferably 4-6 hours, to obtain azoxystrobin,

d) removing the solvent from the mixture of step (c) by distillation under reduced pressure; the reaction mixture is then further washed and extracted with a non-polar organic solvent, non-limiting examples of which are toluene, xylene, at least C4 acetate (preferably, butyl acetate), then water is added to obtain an organic phase and an aqueous phase, after which the aqueous phase is discarded and azoxystrobin is crystallized from the organic phase by cooling the organic solvent, the precipitated solid is filtered and then washed with an alcohol (preferably methanol) to obtain azoxystrobin having a purity of 98% to 99%.

In yet another specific embodiment of the present invention, azoxystrobin is prepared according to the following method:

a) reacting 2-cyanophenol with sodium hydroxide in DMAA and DMSO, more preferably DMAA, at a temperature between 60 ℃ and 80 ℃ for about 1 hour, while removing the water formed in the reaction together with the solvent by distillation at a reduced pressure of about 20-30 mbar, wherein the molar ratio between 2-cyanophenol and sodium hydroxide is between 1: 1 and 1: 1.5;

b) an aromatic substrate, which is (E) -methyl 2- [2- (6-chloropyrimidin-4-yloxy) phenyl ] -3-methoxyacrylate (compound of general formula (I)), is added to the reaction mixture obtained in step (a), wherein compound (I) is added to the reaction mixture as a solution in DMAA.

c) Heating the reaction mixture of step (b) to a temperature in the range of 90 ℃ to 100 ℃ for 4-6 hours to obtain azoxystrobin,

d) removing the solvent from the mixture of step (c) by distillation under reduced pressure; the reaction mixture was then further washed and extracted with butyl acetate, then water was added to obtain an organic phase and an aqueous phase, after which the aqueous phase was discarded and azoxystrobin was crystallized from the organic phase by cooling the organic solvent, the precipitated solid was filtered and then washed with methanol to obtain azoxystrobin having a purity of 98% -99%.

The method for obtaining azoxystrobin according to the invention can obtain azoxystrobin with purity of 98-99% and yield higher than 90%. This is a significant improvement over the prior art methods which describe a process with a yield of 64%. Furthermore, unlike prior art processes, no tar is detected in the reaction mixture of the present invention, which produces tar, affecting the purity of the final product. The process of the invention is therefore more economical, produces lower by-products and impurities and, moreover, produces significantly lower waste streams due to improved yields. The work-up according to the method of the invention is therefore also improved in terms of environmental and work-safety.

Examples

Example I: preparation of azoxystrobin

Dimethylacetamide (DMAA, 400ml), 2-cyanophenol (0.2M, 28g) and NaOH (0.225M, 9g) were added at ambient temperature to a three-necked 1L flask equipped with a stirrer, condenser and thermometer. Half of the amount of DMAA containing traces of water was distilled off under vacuum 20 mbar/60-65 ℃ and the mixture was kept under vacuum 20 mbar/room temperature for 1 hour. The same amount of primer (prime) DMAA was added and compound (I) (0.2M, 64g) was added to the flask.

The reaction mixture was heated to 100 ℃ and maintained under these conditions for 5 hours (monitored by HPLC-conversion of compound (I) to azoxystrobin 98-99%).

DMAA was distilled off under vacuum 20 mbar/65-70 ℃. At the end of the distillation, the temperature can be raised to 90-100 ℃.

400g of butyl acetate (BuAc) and 200g of water were added to the reaction mixture at 50-60 deg.C, the temperature was raised to 80 deg.C and stirred for 10-15 minutes. The aqueous phase was separated at 80 ℃ to remove traces of DMAA and to remove inorganic salts.

For crystallization, the BuAc phase was slowly cooled from 80 ℃ to-5 ℃. Filtration was performed using filter # 2. The filter cake is washed with 60ml of cooled butyl acetate or methanol and then further dried in an oven at 80 ℃ in the course of 15 hours. Azoxystrobin is obtained with a purity of 98-99% and a yield of 90-92%.

Although embodiments of the present invention have been described by way of example, it is evident that many modifications, variations and adaptations may be made thereto without departing from the spirit or exceeding the scope of the invention.

Claims (18)

1. A process for reacting between a phenol derivative and an aromatic substrate under phenolate forming conditions, the process comprising the steps of:

a) reacting a phenol derivative with a base in a polar organic solvent to obtain a phenolate salt, wherein water is removed from the reaction mixture during the reaction,

b) adding an aromatic substrate to the reaction mixture obtained in step (a),

c) heating the reaction mixture of step (b) to a temperature of 80 ℃ to 130 ℃, preferably 90 to 100 ℃, for 2 to 7 hours to obtain a phenoxy substituted aromatic substrate,

d) removing the solvent from the mixture of step (c) and then further isolating and purifying the phenoxy substituted aromatic substrate.

2. The process according to claim 1, wherein in step (a) the removal of water is carried out in combination with the partial removal of organic solvent.

3. The process according to claim 1, wherein the molar ratio of phenol derivative to base is between 1: 1 and 1: 1.5, preferably 1: 1.125 to 1: 1.15.

4. A process according to claims 1-3 wherein the time required to effect step (a) conversion to phenate is 30-120 minutes at a temperature between 60 ℃ and 80 ℃ while partially removing solvent and water from the reaction mixture by vacuum distillation.

5. A process according to claims 1-4, wherein the phenol derivative is phenol, a mono-substituted phenol or a poly-substituted phenol, more preferably, a cyanophenol derivative comprising 2-cyanophenol and 4-cyanophenol.

6. Process according to claims 1 to 5, wherein the base is selected from the group consisting of hydroxide and carbonate bases, including metal hydroxides, alkali metal hydroxides, metal carbonates and alkali metal carbonates, preferably sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

7. The process according to claim 1, wherein preferred polar organic solvents are Dimethylformamide (DMF), Dimethylacetamide (DMAA) and Dimethylsulfoxide (DMSO), wherein the preferred range of reagent/solvent ratio is 0.1 mole/150 ml-0.1 mole/350 ml.

8. The process according to claim 1, wherein the aromatic substrate may be added in step (b) together with the polar organic solvent.

9. The process according to claim 1, wherein the aromatic substrate is added in an amount such that the molar ratio of phenol derivative to aromatic substrate is between 1: 0.8 and 1: 1, preferably 1: 1.

10. A process according to claim 1, wherein the aromatic substrate is selected from the group consisting of mono-and poly-substituted pyridines, pyrimidines and phenyl groups, preferably, at least mono-halogen substituted and more preferably chloro-pyrimidine derivatives.

11. The process according to claim 1, wherein the reaction mixture of step (b) is heated to a temperature of 80 ℃ to 130 ℃, preferably about 100 ℃, for 2 to 7 hours, preferably about 5 hours, to obtain the phenoxy substituted aromatic substrate.

12. A process according to any one of claims 1 to 11 for the preparation of methyl (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy ] phenyl } -3-methoxyacrylate (azoxystrobin) comprising the steps of:

a) 2-cyanophenol is reacted with an alkali metal hydroxide or carbonate in a polar organic solvent at a temperature of 60 to 80 c, preferably between 60 to 70 c, for about 1 hour, while water formed in the reaction is removed with the solvent by distillation under reduced pressure.

b) Adding an aromatic substrate, which is (E) -methyl 2- [2- (6-chloropyrimidin-4-yloxy) phenyl ] -3-methoxyacrylate (a compound of general formula (I)), to the reaction mixture obtained in step (a), optionally adding compound (I) to the reaction mixture as a solution in DMAA;

c) heating the reaction mixture of step (b) to a temperature of 80-130 ℃, preferably 90-100 ℃, for 2-7 hours, preferably 4-6 hours, to obtain azoxystrobin,

d) removing the solvent from the mixture of step (c) by distillation under reduced pressure; the reaction mixture is then further washed and extracted with a non-polar organic solvent, then water is added to obtain an organic phase and an aqueous phase, after which the aqueous phase is discarded and azoxystrobin is crystallized from the organic phase by cooling the organic solvent, the precipitated solid is filtered and then washed with an alcohol (preferably methanol) to obtain azoxystrobin having a purity of 98% -99%.

13. A process according to claim 12, wherein the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

14. The method according to claim 12 or 13, wherein the polar organic solvent is selected from DMF, DMAA and DMSO, more preferably DMAA.

15. The process according to any one of claims 12-14, wherein the water and solvent formed in the reaction of step (a) is removed by distillation under reduced pressure, preferably about 20-30 mbar, wherein the molar ratio of 2-cyanophenol to base is between 1: 1 and 1: 1.5.

16. The process according to claims 12 to 15, wherein the non-polar organic solvent of step (d) is selected from toluene, xylene, at least C4 acetate, preferably butyl acetate.

17. The method according to claim 12, which comprises:

a) reacting 2-cyanophenol with sodium hydroxide in DMAA and DMSO, more preferably DMAA, at a temperature between 60 ℃ and 80 ℃ for about 1 hour, while removing water and solvent formed in the reaction by distillation at a reduced pressure of about 20-30 mbar, wherein the molar ratio between 2-cyanophenol and sodium hydroxide is between 1: 1 and 1: 1.5;

b) adding an aromatic substrate, which is (E) -methyl 2- [2- (6-chloropyrimidin-4-yloxy) phenyl ] -3-methoxyacrylate (a compound of general formula (I)), to the reaction mixture obtained in step (a), wherein compound (I) is added to the reaction mixture as a solution in DMAA;

c) heating the reaction mixture of step (b) to a temperature in the range of 90 ℃ to 100 ℃ for 4-6 hours to obtain azoxystrobin,

d) removing the solvent from the mixture of step (c) by distillation under reduced pressure; the reaction mixture was then further washed and extracted with butyl acetate, then water was added to obtain an organic phase and an aqueous phase, after which the aqueous phase was discarded and azoxystrobin was crystallized from the organic phase by cooling the organic solvent, the precipitated solid was filtered and then washed with methanol to obtain azoxystrobin having a purity of 98% -99%.

18. The method as illustrated and described herein.