WO2013026391A1

WO2013026391A1 - Synthesis method of azoxystrobin and exclusive intermediate in the synthesis thereof

Info

Publication number: WO2013026391A1
Application number: PCT/CN2012/080434
Authority: WO
Inventors: 丁永良; 代小妮; 蔡宗杨; 邓术清; 韩丹; 杨莹; 曹超
Original assignee: 重庆紫光化工股份有限公司
Priority date: 2011-08-24
Filing date: 2012-08-21
Publication date: 2013-02-28
Also published as: CN102311392B; CN102311392A

Abstract

Disclosed are a synthesis method of Azoxystrobin and an intermediate in the synthesis thereof, comprising the steps of: mixing the starting materials 3-(α-methoxyl) methylene benzofuran-2-(3H)-ketone and potassium carbonate in methylbenzene solvent, cooling to 0-10℃, adding sodium methoxide, reacting for 0.4-0.6 hours; adding 4, 6-dichloropyrimide and a catalyst DABCO, reacting for 1-2 hours, filtrating and removing the inorganic salt, washing the filtrate, distilling and recovering the methylbenzene; adding a catalyst potassium hydrosulphate to the distilled residue of the previous step, under reduced pressure, heating to 132-145℃for reaction; afterward, directly adding 2-hydroxy-benzonitril to synthesize the Azoxystrobin, or, after dissolving with methylbenzene, washing, and recovering the solvent, then recrystallizing and filtrating to give the intermediate (E)-2-[2-(6-chloropyrimide-4-yl-oxy) phenyl]-3-methoxyl methyl acrylate.

Description

Synthesis method of azoxystrobin and special intermediates in its synthesis

The invention relates to a process for synthesizing chemical substances, in particular to synthesis

(E) -2- [2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate; and a method for finally synthesizing azoxystrobin using the same.

Background technique

(E)-2-[2-(6-Chloropyridin-4-yloxy)phenyl]-3-decyloxydecyl acrylate is an important intermediate for the synthesis of azoxystrobin. The existing synthesis process of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenyl acrylate is mainly as follows:

1. One-pot method: starting with 3_(α-decyloxy)-fluorenylenebenzofuran_2_(3H)-ketone, with sodium decoxide and 4,6-2 dichloropyrimidine (DCP) One-pot synthesis, this method takes a long time (about 50h). The chemical reaction formula is:

The main side effects are:

The disadvantages of this synthetic method are: 1) the reaction time is too long and the yield is low; 2) 3⁄4-product

2. Step-by-step method: The main reaction formula is:

N^N

The disadvantages are:

1. There are many steps and the operation is cumbersome;

2, a large excess of sodium sterol, raw materials: sodium decoxide = 1: 4, poor atomic economy; excessive sodium sterol needs to be neutralized with acetic acid, not only consume a large amount of organic acid, but also produce solid waste sodium acetate;

3. Neutralization of excess sodium sterol needs to be carried out at low temperature (_20 ° C), high energy consumption;

4. Neutralization of the obtained ring-opening product requires multiple steps of organic solvent extraction, washing, drying, and recovery of the solvent;

5. It is necessary to consume carbonic acid 4 and DMF to produce solid waste. The product needs multiple steps of organic solvent extraction, washing, drying and solvent recovery;

6. The ring-opening product is easily closed to the by-product under acidic conditions, and the corresponding side reaction is:

It not only reduces the yield of the product, but also increases the difficulty of purification of the product and reduces the production efficiency.

Summary of the invention

The main object of the present invention is to provide a method for synthesizing (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate. Single can significantly increase the yield of the product and shorten the synthesis time.

The technical solution adopted by the present invention is: a synthetic (E) -2- [2-(6-chloropyrimidine-4- The method for the base oxy)phenyl] _ 3-decyloxy decyl acrylate, the steps comprising: a: the raw material 3_(α-decyloxy) fluorenylenebenzofuran-2_(3H)-one with a carbonic acid clock The mixture is stirred in a solvent of 0. 4 - 0. 6 hours;

b: adding 4,6-dichloropyrimidine and catalyst DABC0 to the reaction solution, reacting for l-2h, filtering and removing inorganic salts, washing the filtrate with water, and distilling and recovering toluene;

c: adding a catalyst potassium hydrogen sulfate to the reaction residue of the upward step reaction, and heating to a pressure of 1 32 to 145 ° C under reduced pressure;

d: The reaction system is dissolved in toluene, washed with water to remove a water-soluble substance such as an inorganic salt, and then distilled to recover a solvent of toluene, and then the crude product is dissolved in butyl acetate to filter impurities, followed by liquid phase cooling and recrystallization to obtain a target product.

Production of synthetic (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenyl acrylate by the production process of the present invention has high yield and operation The raw materials and processes used are conventional reagents and methods.

The sodium algoxide may be added to the sodium alginate solution in step a, or a solid sodium sterol and a sterol may be added. And the weak base added in step a (such as 4A) ensures that the ring opening reaction is always in an alkaline atmosphere, avoiding the opening of the ring-opening product to produce by-products. The addition of the catalyst DABC0 allows the coupling reaction to be completed quickly, greatly reducing the reaction time. In this way, the production time can be controlled within 10 hours, and the production efficiency is greatly improved.

Further, in the step c, it is detected that the content of the coupling product in the reaction system is less than 1% as the reaction end point. At this time, the target product content can reach more than 80%, and the final product yield is above 70%. And it also saves production time to the greatest extent.

5小时。 The reaction time was 0. 5 hours. The cooling temperature is the cooling temperature of the commonly used industrial cooling equipment, which is convenient for the equipment; the preferred time is the time value that can guarantee the process index and the most economical. 5小时。 The reaction time was 1. 5 hours. In the step c described, the heating temperature was 140 °C. The rate of reaction and conversion at this temperature have outstanding effects. The main chemical reaction formula for production is:

Another object of the present invention is to provide a process for producing the above-mentioned synthetic (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate. The azoxystrobin method allows the synthesis process of azoxystrobin to be simple, which can significantly improve the yield of the product and shorten the synthesis time.

The technical solution adopted is: a method for synthesizing azoxystrobin, the steps comprising: a: mixing the raw material 3_(α-mercaptooxy)-fluorenylenebenzofuran-2-(3H)-one with a carbonic acid clock in the crucible In a benzene solvent, it is cooled to 0-10 ° C, sodium decoxide is added, and the reaction is carried out for 0.4-0.6 hours;

c: adding a catalyst potassium hydrogen hydride to the residue of the reaction distillation step, and heating to 132 ~ 145 ° C under reduced pressure;

d: Then add azoxystrobin to the system to synthesize azoxystrobin.

As can be seen from the above technical scheme, a large amount of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate intermediate has been obtained in the step c. Azoxystrobin can then be obtained by adding salicylonitrile. The azoxystrobin end product can be obtained by further separation and purification. This eliminates the recrystallization and separation of the intermediates, achieves an intensive effect, and saves production time, raw materials, and energy costs. As for the synthesis of the intermediate with salicylonitrile and the separation and purification of azoxystrobin, it can be determined with reference to the prior art, and the technical content itself is not the present invention. The invention is not described here.

Further, in the step C, it is detected that the content of the coupling product in the reaction system is less than 1% as the reaction end point, and then the operation of the step d is performed. At this time, the amount of (E) -2- [2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy decyl acrylate can be more than 80%, and the synthesis of azoxystrobin The product yield is also the largest, while at the same time maximizing production time.

5小时。 The same as the reaction time was 0. 5 hours. The cooling temperature is the cooling temperature of the commonly used industrial cooling equipment, which is convenient for the equipment; the preferred time is the time value that can guarantee both the process index and the most economical. Similarly, in the step b, the reaction time is 1.5 hours. In the step c, the heating temperature was 140 °C. The rate of reaction and conversion at this temperature have outstanding effects.

The improvement of the invention lies in the improvement of the process and the control index. As for the ratio of the raw materials, the amount of the catalyst, etc., it can be determined according to the theoretical calculation or referring to the prior art, and is not the technical improvement of the present invention, and the space is no longer saved. A detailed description.

detailed description

In order to enable those skilled in the art to understand the production process and technical effects of the present invention in detail, the application and technical effects of the present invention will be further described below with specific production examples.

Embodiment 1

The steps are:

a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-ketone 0. lmol and carbonic acid clock 0. 05mol mixed in 80mL of toluene solvent, cooling temperature (TC, added 28% 4小时; The reaction of 0. 4 hours;

b: 4,6-dichloropyrimidine 0. l lmol and catalyst DABC0 1. 7g are added to the reaction solution, and the reaction is carried out for 1 hour. The inorganic salt is removed by filtration, the filtrate is washed with water, and the benzene is distilled by distillation;

5小时,冷冷却冷却。 After the step of distillation to the residue was added to the catalyst potassium hydrogen sulfate 1. 5g, heated to 132 ° C under -0.55MPa reaction 1. 5 hours, cooling and cooling. d: The reaction mixture of the above step is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) 2) g of phenyl] phenyl methoxy acrylate, the product yield was 71.1%. By HPLC, purity 98.6% ₀

Embodiment 2

The steps are:

a: The raw material 3_(α-decyloxy) fluorenylene benzofuran-2_(3H)-ketone 0. Imol and carbonic acid clock 0. Imol mixed in 80mL of benzene solvent, cooling temperature 5 ° C, added 28 21.2 g of sodium sterol sodium sterol solution (containing 0.11 mol of sodium decyl alcohol), and reacted for 0.5 hour;

b: 4,6-dichloropyrimidine 0. llmol and catalyst DABC0 1.7g were added to the reaction solution, and the reaction was carried out for 1.2 hours. The inorganic salt was removed by filtration, the filtrate was washed with water, and toluene was recovered by distillation;

c: a catalyst of 1.5 g of potassium hydrogen hydride was added to the reaction residue of the upward reaction, and the reaction was heated to 138 ° C at -0.04 MPa until the content of the coupling product in the reaction system was 0.85% as the reaction end point by HPLC;

d: The reaction mixture of the above step is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) The base is phenyl]_3-indenyl decyl acrylate 23.6 g, and the product yield is 73.6 %. By HPLC, purity 99.5% ₀

Embodiment 3

The steps are:

a: The raw material 3_(α-decyloxy) fluorenylene benzofuran-2_(3H)-ketone 0. Imol and carbonic acid clock 0. Imol mixed in lOOmL benzene solvent, cooling temperature 8 ° C, successively added Sodium sterol 0. llmoK sterol 10mL, reaction for 0.5 hours;

b: 4,6-dichloropyrimidine 0. llmol and catalyst DABC02.0g were added to the reaction solution, and the reaction was carried out for 1.5 hours. The inorganic salt was removed by filtration, the filtrate was washed with water, and toluene was recovered by distillation; c: the reaction residue was distilled up to the reaction step. 1.5 g of potassium hydrogen hydride catalyst was added, and the reaction was heated to 140 ° C at -0.03 MPa until the coupling in the reaction system was detected by HPLC. The product content is 0.9% as the reaction end point;

d: The reaction system is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) Phenyl]-3-indolyl acrylate acrylate 25. Og, product yield 78.0%. The purity of the product was 99. Ί by HPLC.

Embodiment 4

The steps are:

a: The raw material 3_(α-decyloxy) fluorenylene benzofuran-2_(3H)-ketone 0. Imol and carbonic acid clock 0. Imol mixed in lOOmL benzene solvent, cooling temperature 5 ° C, successively added Sodium sterol 0. llmoK sterol 10mL, reaction for 0.5 hours;

b: 4,6-dichloropyrimidine 0. llmol and catalyst DABC02.0g were added to the reaction solution, and the reaction was carried out for 1.5 hours. The inorganic salt was removed by filtration, the filtrate was washed with water, and toluene was recovered by distillation; c: the reaction residue was distilled up to the reaction step. 1.5 g of catalyst potassium hydrogen hydride was added, and the reaction was heated to 140 ° C at -0.03 MPa until the content of the coupling product in the reaction system was 0.86% as the reaction end point by HPLC;

d: The reaction system is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) Phenyl]-3-decyloxy decyl acrylate 25.42 g, product yield 79.3%. The purity of the product was 99. Ί by HPLC.

It can be seen from Examples 3 and 4 that in step a, sodium decoxide and decyl alcohol are successively added, and other preferred process conditions are combined, and the yield and product purity are unexpectedly significantly improved.

Embodiment 5

The steps are:

a: The raw material 3_(α-decyloxy) fluorenylene benzofuran 2 - (3H)-ketone 0. Imol and carbonic acid 0. Imol mixed in 80mL of benzene solvent, cooling temperature 8 ° C, added 28 % of sodium sterol sodium sterol solution 21.2g (containing sodium decoxide 0. llmol), the reaction is 0.6 hours;

b: 4,6-dichloropyrimidine 0. llmol and catalyst DABC0 were added to the reaction solution. 1.7g, reaction for 2h, the inorganic salt is removed by filtration, the filtrate is washed with water, and the benzene is distilled by distillation; c: 1.7 g of potassium hydrogen hydride catalyst is added to the reaction residue of the upward reaction, and heated to 140 ° C under -0. IMPa until the reaction is completed. The content of the coupling product in the reaction system was determined by HPLC to be 0.83 ° /. The end of the reaction;

d: The reaction system is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) Phenyl]-3-decyloxy decyl acrylate was 23.2 g, and the product yield was 72.4%. The purity of the product was 98. Ί% by HPLC.

Embodiment 6

The steps are:

a: Mixing raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one 0.2mol with 0.22 mol of carbonic acid clock in 150 mL of toluene solvent, cooling temperature 10 ° C, adding 28% 42.4 g of sodium sterol sterol solution (containing 0.22 mol of sodium decoxide), and reacting for 0.5 hour;

b: 4,6-dichloropyrimidine and catalyst DABC03.4g were added to the reaction solution, and the reaction was carried out for 1.5 hours. The inorganic salt was removed by filtration, the filtrate was washed with water, and toluene was recovered by distillation;

c: adding 3.0 g of potassium hydrogen hydride to the reaction residue of the upward reaction, and heating to 145 ° C at -0.02 MPa until the content of the coupling product in the reaction system was 0.92% by HPLC.

d: The reaction system is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) 47.5 g of phenyl]-3-decyloxy decyl acrylate, the product yield was 74.1%. By HPLC, purity 97.6% ₀

Example 7

The steps are:

a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one 0.2 mol and 0.22 mol of carbonic acid clock were mixed in 150 mL of toluene solvent, the cooling temperature was 8 ° C, and 28% was added. 42.4 g of sodium sterol sterol solution (containing 0.22 mol of sodium decyl alcohol), and reacting for 0.5 hour; b: adding 0.22 mol of 4,6-dichloropyrimidine and 03.4 g of catalyst DABC to the reaction solution, reacting for 1.5 h, removing inorganic salts by filtration, washing the filtrate with water, and recovering toluene by distillation; c: adding the distillation residue to the upper step reaction Catalyst potassium hydrogen sulfate 3. Og, heated to 140 ° C at - 0.03MPa, until the content of the coupling product in the reaction system was 0.9% as the reaction end point;

d: Then, azoxystrobin was directly added to the system, and the azoxystrobin product was isolated and purified to obtain 52.6 g of azoxystrobin product, and the yield of azoxystrobin was 65.2%. The purity of azoxystrobin was 96.9 °/ by HPLC. .

Example eight

The steps are:

a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one 0.2 mol and 0.22 mol of carbonic acid clock were mixed in 150 mL of toluene solvent, the cooling temperature was 8 ° C, and 28% was added. 42.4 g of sodium sterol sterol solution (containing 0.22 mol of sodium decoxide), and reacting for 0.5 hour;

b: adding 0.22 mol of 4,6-dichloropyrimidine and 03.4 g of catalyst DABC to the reaction solution, reacting for 1.5 h, removing inorganic salts by filtration, washing the filtrate with water, and recovering toluene by distillation; c: adding the distillation residue to the upper step reaction Catalyst potassium hydrogen sulfate 3. Og, heated to 140 ° C at - 0.03 MPa, until the content of the coupling product in the reaction system was 0.8% as the reaction end point;

d: Then, azoxystrobin was directly added to the system, and 59.4 g of azoxystrobin product was isolated and purified, and the yield of azoxystrobin was 67.5%. The purity of azoxystrobin was 97.9% by HPLC.

Claims

Rights request

A method for synthesizing (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]_3-decyloxy decanoate, the steps comprising:

a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one is mixed with a carbonic acid clock in a solvent of toluene, cooled to 0-10 ° C, and sodium decoxide is added, and the reaction is 0.4. -0.6 hours;

2. The method according to claim 1, wherein in the step c, the content of the coupling product in the reaction system is detected to be less than 1°/. For the end of the reaction.

The method according to claim 1 or 2, wherein in the step a, the cooling temperature is 8 ° C and the reaction time is 0.5 hour.

4. The method according to claim 1 or 2, wherein in the step b, the reaction time is 1.5 hours.

The method according to claim 1 or 2, wherein in the step c, the heating temperature is 140 °C.

6. A method for synthesizing azoxystrobin, the steps comprising:

b: adding 4,6-dichloropyrimidine and catalyst DABC0 to the reaction solution, reacting L-2h, the inorganic salt is removed by filtration, the filtrate is washed with water, and the benzene is distilled by distillation; c: the catalyst hydrogen chloride is added to the reaction residue of the upward step, and heated to a pressure of 1 32 to 145 ° C under reduced pressure;

d: Then add azoxystrobin to the system to synthesize azoxystrobin.

7. The method according to claim 6, wherein in the step c, the content of the coupling product in the reaction system is detected to be less than 1 ° /. For the end of the reaction.

5小时。 The method of the method of the present invention, wherein the cooling time is 0 ° C, the reaction time is 0.5 hours.

9. The method according to claim 6 or 7, wherein in the step b, the reaction time is 1.5 hours.

The method according to claim 6 or 7, wherein in the step c, the heating temperature is 140 °C.