WO2021024135A1

WO2021024135A1 - An improved process for preparation of methyl (2e)-2-(2-{[6-(2-cyanophenoxy)pyrimidin-4-yl]oxy}phenyl)-3-methoxyacrylate

Info

Publication number: WO2021024135A1
Application number: PCT/IB2020/057273
Authority: WO
Inventors: Venkata Krishna Kishore NARKEDIMILLI; Ramesh Kumar DURGA; Balram BHAVANI; Aminul Islam
Original assignee: Coromandel International Limited
Priority date: 2019-08-03
Filing date: 2020-07-31
Publication date: 2021-02-11
Also published as: MX2022001424A; BR112022001999A2

Abstract

The present invention relates to an improved processses for synthesizing preparing substituted cyanophenoxy-pyrimidinyloxy-phenyl acrylate derivatives. The present invention specifically relates to an improved process for the preparation of methyl (2E)-2-(2-{[6-(2-cyanophenoxy)pyrimidin-4-yl]oxy}phenyl)-3-methoxyacrylate having the following Formula I.

Description

AN IMPROVED PROCESS FOR PREPARATION OF METHYL (2E)-2-(2- {[6-(2-CYANOPHENOXY)PYRIMIDIN-4-YL]OXY}PHENYL)-3-

METHOXYACRYLATE

FIELD OF THE INVENTION

The present invention relates to an improved process for preparing substituted cyanophenoxy-pyrimidinyloxy-phenyl acrylate derivatives.

The present invention specifically relates to an improved process for the preparation of methyl (2E)-2-(2-{[6-(2-cyanophenoxy)pyrimidin-4-yl]oxy}phenyl)-3- methoxyacrylate having the following Formula I.

BACKGROUND OF THE INVENTION

Azoxystrobin is disclosed in US 5,395,837 and is a plant protection fungicide with protectant, curative, eradicant, translaminar and systemic properties. Azoxystrobin is a systemic fungicide commonly used in agriculture.

US 5,395,837 discloses a process for the preparation of Azoxystrobin which involves reaction between 2-cyanophenol and (E)-methyl 2-[2-(6-chlorpyridimin-4- yloxy)phenyl]-3-methoxypropenoate at temperatures ranging between 95 °C to 100 °C in dimethyl formamide in the presence of stoichiometric amounts of potassium carbonate and a catalytic amount of copper(I) chloride which is shown below :

US 8,124,761 B2 claims a process for the preparation of Azoxystrobin reacting a compound of formula II with 2-cyanophenol, or a salt thereof, in the presence of between 0.1 and 2 moles of 1, 4-diazabicyclo [2.2.2] octane, or reacting a compound of the formula III with a compound of the formula IV in the presence of between 0.1 and 2 moles of 1,4-diazabicyclo [2.2.2]octane which is shown below :

wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO₂CH₃)=CHOCH₃ or the methyl 2-(3,3-dimethoxy) propanoate group C(CO₂CH₃)CH(OCH₃)₂, or a mixture of the two groups.

US 8,471,013 B2 A1 discloses a process for the preparation of Azoxystrobin by reacting a cyanophenol derivative with a base in a polar organic solvent to obtain a phenolate salt followed by condensation of the aromatic substrate as shown in the scheme given below:

WO 2017/060917 A1 discloses a process for the preparation of Azoxystrobin as shown in the scheme given below:

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

CN 102690237 discloses a process for the preparation of Azoxystrobin as shown in the scheme given below:

CN 102952085 discloses a process for the preparation of Azoxystrobin as shown in the scheme given below:

The bases used in the above method are selected from potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide and solvents employed are methanol, ethanol or toluene.

IN 5500/CHE/2015 discloses a process for the preparation of Azoxystrobin as shown in the scheme given below:

The solvents used are N-methyl pyrrolidone, N, N-dimethyl formamide, N,N-dimethyl acetamide, acetonitrile, acetone, methanol, ethanol, C to C₈ alcohols, N,N-dibutyl formamide and more preferably acetonitrile, N,N dimethyl acetamide, N, N-dimethyl formamide and the bases employed are alkali hydroxides, alkali carbonates, organic carbonates, and preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, DBU.

The above published methods for synthesizing Azoxystrobin, however, are often complicated, such as by using a multiple step and/or time consuming synthesis process. Further, many of the above published methods do not produce high yields of the active ingredient.

Accordingly there is an ongoing and long felt need for a process for aromatic substitution reactions in the presence phenols with improved yield and selectivity.

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. OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of methyl (2E)-2-(2-{[6-(2-cyanophenoxy)pyrimidin-4- yl]oxy}phenyl)-3-methoxyacrylate having the following Formula I.

It is therefore an object of the present invention to provide a simple, economical and commercially feasible process for the synthesis methyl (2E)-2-(2-{[6-(2- cyanophenoxy)pyrimidin-4-yl]oxy}phenyl)-3-methoxyacrylate with a high yield and high purity.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of compound of Formula (I)

wherein the process comprises the steps of: condensing compound of Formula II

with compound of Formula (III) or a salt thereof,

using tetramethyl ammonium hydroxide (TMAH) in an aromatic hydrocarbon solvent optionally in the presence of an additional base to obtain compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of compound of Formula (I) i.e. methyl (2E)-2-(2-{[6-(2-cyanophenoxy) pyrimidin-4- yl]oxy}phenyl)-3-methoxyacrylate by reacting compound of Formula (II) with compound of Formula (III) using tetramethyl ammonium hydroxide (TMAH) in an aromatic hydrocarbon solvent optionally in the presence of an additional base.

The reaction of compound of Formula (II) with compound of Formula (III) is effectively carried out in the presence of a tetramethylammonium hydroxide solution (TMAH) (25%) optionally in the presence of an additional base. The tetra methyl ammonium hydroxide (TMAH) acts as base as well catalyst.

The tetramethyl ammonium hydroxide (TMAH) employed in the present invention is used in the range of 0.01-2 moles. Preferably, the reaction is carried out in the presence of 0.01 to 0.12 moles of tetramethyl ammonium hydroxide (TMAH).

The aromatic hydrocarbon solvents employed are toluene, xylene, phenol, benzene, chlorobenzene, dichlorobenzene, cyclohexane, methylcyclohexane. When carrying out the process of the invention, the reaction temperature can be varied within a relatively wide range. The temperature chosen will depend on the nature of the solvent or diluent, for example on its boiling point and/or its effectiveness for promoting the desired reaction, and on the speed at which the reaction is to be carried out. In any given solvent or diluent, the reaction will tend to progress more slowly at lower temperatures. In general, the reaction may be carried out at a temperature of from 0 to 120 °C.

Optionally, process of the invention is conveniently carried out in the presence or absence of base. Suitable bases are all customary inorganic and organic bases. These include, for example, alkaline earth metal and alkali metal hydroxides, acetates, carbonates, bicarbonates and hydrides such as sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydride, sodium hydride and potassium hydride, and tertiary amines. Particularly suitable bases are the alkaline earth metal and alkali metal carbonates, especially potassium carbonate and sodium carbonate and. More suitably, the base employed is potassium carbonate

The process for the preparation of compound of Formula (I) involves dissolving compound of Formula (II) and compound of Formula (III) in toluene followed by addition of tetramethyl ammonium hydroxide solution (25%)(TMAH) at 25 °C and optionally another base. The reaction mixture is heated to 105-110 °C and water is collected azeotropically. After, water was collected, the reaction was maintained at 108- 110 °C for about 8-9 hrs. After completion of the reaction, the reaction mixture is cooled and water is added to the reaction mixture. The organic layer is separated, washed with water and toluene removed under reduced pressure to get the crude compound of Formula (I). The compound of Formula (I) was purified in methanol.

The process for obtaining azoxystrobin according to the present invention gave azoxystrobin with purity of 98%-99% and a yield of above 85 %. This is a significant improvement in comparison to the prior art methods which describe a process with a yield of 64%. Hence the process of the present invention is more economical, produces less by-products and impurities and further generates considerably less effluents as a result of the improved yield. The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example- 1:

Preparation methyl (2E)-2-(2-{[6-(2-cyanophenoxy) pyrimidin-4-yl]oxy} phenyl)-3- methoxy aery late (Azoxystrobin):

(E)-methyl 2-[2-(6-chlorpyridimin-4-yloxy) phenyl]-3-methoxy propenoate (25g, 0.078moles, l.Oeq) was dissolved in 50 ml toluene and 2-cyanophenol (10.2g, 0.086moles, l.leq) was added and the reaction mixture was stirred for 5-10 minutes. Potassium carbonate (8.6g, 0.062moles, 0.8 eq) was added and tetramethyl ammonium hydroxide solution (TMAH) (25%) (14.2g, 0.038moles, 0.5 eq) was charged into the reaction mixture at 25°C. The reaction mixture was heated to 105-110°C and water was removed azeotropically. After removal of water, the reaction was maintained at 108- 110 °C for about 8-9 hrs. After completion of the reaction, the reaction mass was cooled to 30-35 °C followed by addition of water. The organic and aqueous layer was separated and toluene was distilled off completely at reduced pressure below 60 °C. The obtained crude compound was recrystallized in methanol.

Example-2:

(E)-methyl 2-[2-(6-chlorpyridimin-4-yloxy) phenyl]- 3 -methoxypropenoate (25g, 0.078moles, l.Oeq) was dissolved in 50 ml toluene and 2-cyanophenol (10.2g, 0.085moles, l.leq) was added and the reaction mixture was stirred for 5-10 minutes. Tetramethyl ammonium hydroxide solution (25%) (TMAH) (28.4g, 0.078moles, 1.0 eq) was charged into the reaction mixture at 25 °C. The reaction mixture was heated to 105- 110 °C and water was removed azeotropically. After removal of water, the reaction was maintained at 108-110 °C for about 12-14 hrs. After completion of the reaction, the reaction mass was cooled to 30-35 °C followed by addition of water. The organic and aqueous layer was separated and toluene was distilled off completely at reduced pressure below 60 °C. The obtained crude compound was recrystallized in methanol.

Example-3:

(E)-methyl 2-[2-(6-chlorpyridimin-4-yloxy)phenyl]-3-methoxypropenoate (25g, 0.078moles, l.Oeq) was dissolved in 50 ml toluene and 2-cyanophenol (10.2g, 0.085moles, l.leq) was added and the reaction mixture was stirred for 5-10 minutes. Tetramethyl ammonium hydroxide solution (25%) (TMAH) (14.2g, 0.039moles, 0.5eq) was charged into the reaction mixture at 25 °C. The reaction mixture was heated to 105- 110 °C and water was removed azeotropically. After removal of water, the reaction was maintained at 108-110 °C for about 24-28 hrs. After completion of the reaction, the reaction mass was cooled to 30-35 °C followed by addition of water. The organic and aqueous layer was separated and toluene was distilled off completely at reduced pressure below 60 °C. The obtained crude compound was recrystallized in methanol.

Example-4 :

(E)-methyl 2-[2-(6-chlorpyridimin-4-yloxy) phenyl]- 3 -methoxypropenoate (25g, 0.078moles, l.Oeq) was dissolved in 50 ml toluene and 2-cyanophenol (10.2g, 0.085moles, l.leq) was added and the reaction mixture was stirred for 5-10 minutes. Tetramethyl ammonium hydroxide solution (25%) (TMAH) (42.5g, 0.116moles, 1.5 eq) was charged into the reaction mixture at 25 °C. The reaction mixture was heated to 105- 110 °C and water was removed azeotropically. After removal of water, the reaction was maintained at 108-110 °C for about 12-14 hrs. After completion of the reaction, the reaction mass was cooled to 30-35 °C followed by addition of water. The organic and aqueous layer was separated and toluene was distilled off completely at reduced pressure below 60 °C. The obtained crude compound was recrystallized in methanol.

Claims

We Claim:

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

wherein the process comprises the steps of condensing the compound of Formula II,

with compound of Formula (III) or a salt thereof,

2. The process of claim 1, wherein tetramethyl ammonium hydroxide (TMAH) is in the range of 0.01 to 2 moles.

3. The process of claim 1, wherein aromatic hydrocarbon solvents is selected from toluene, xylene, phenol, benzene, chlorobenzene, dichlorobenzene, cyclohexane, methylcyclohexane, more preferably toluene.

4. The process of claim 1, wherein the additional base employed is selected from the group consisting of including alkali metal hydroxides, metal carbonates, alkali metal carbonates, and mixtures thereof.

5. The process of claim 4, wherein the alkali metal hydroxides or carbonates is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

6. The process according to claim 1, wherein the reaction is carried out at a temperature from 0 to 120 °C.