阅读说明：本技术 一种醚菌胺的制备方法 (Preparation method of dimoxystrobin ) 是由 戚聿新 吕强三 王海涛 于 2019-08-22 设计创作，主要内容包括：本发明提供一种醚菌胺的制备方法。该方法利用2-卤代甲基卤代苯和2,5-二甲基苯酚经醚化反应制备2-(2,5-二甲基苯氧甲基)卤代苯,然后和金属镁经格氏反应制备相应的格氏试剂,所得含格氏试剂的反应液滴加至N-甲基草酸单酯单酰胺中制备N-甲基-2-(2,5-二甲基苯氧甲基)苯基草酰胺,最后和甲氧胺盐经缩合反应制备醚菌胺。本发明方法原料价廉易得,成本低；工艺流程简短,仅需三步反应即可制备醚菌胺；反应条件易于实现,操作安全简便,工艺废水产生量少,绿色环保；原料及中间产物稳定性高,反应活性和选择性高,副反应少；所得醚菌胺杂质少、纯度和产率高,利于醚菌胺的工业化生产。(The invention provides a preparation method of dimoxystrobin. The method comprises the steps of preparing 2- (2,5-dimethylphenoxymethyl) halogenated benzene by etherification of 2-halogenated methyl halogenated benzene and 2, 5-dimethylphenol, preparing a corresponding Grignard reagent by Grignard reaction of the halogenated benzene and metal magnesium, dropwise adding the reaction liquid containing the Grignard reagent into N-methyl oxalic acid monoester monoamide to prepare N-methyl-2- (2,5-dimethylphenoxymethyl) phenyl oxamide, and finally preparing dimoxystrobin by condensation reaction of the N-methyl oxalic acid monoester monoamide and methoxylamine. The method has the advantages of cheap and easily obtained raw materials and low cost; the process flow is short, and the dimoxystrobin can be prepared only by three steps of reactions; the reaction condition is easy to realize, the operation is safe and simple, the production amount of process wastewater is small, and the method is green and environment-friendly; the stability of raw materials and intermediate products is high, the reactivity and the selectivity are high, and the side reaction is less; the obtained dimoxystrobin has less impurities and high purity and yield, and is beneficial to the industrial production of the dimoxystrobin.)

1. A preparation method of dimoxystrobin comprises the following steps:

(1) preparing a compound of formula III by subjecting a compound of formula II and 2, 5-dimethylphenol to an etherification reaction;

wherein, in the structural formula of the compound shown in the formula II, X, Y is independently selected from Br, Cl or I; x in the structural formula of the compound of the formula III has the same meaning as that of X in the structural formula of the compound of the formula II;

(2) obtaining a reaction solution containing a Grignard reagent by carrying out Grignard reaction on a compound shown in a formula III and magnesium metal; dropwise adding the reaction liquid containing the Grignard reagent into a system containing the compound of the formula IV, and reacting with the compound of the formula IV to prepare a compound of the formula V;

wherein in the structural formula of the compound shown in the formula IV, R is C₁To C₄Alkyl groups of (a);

(3) etheramines (I) are prepared by subjecting a compound of formula V and methoxyamine salt to a condensation reaction.

2. The process for producing dimoxystrobin according to claim 1, wherein in step (1), the etherification reaction of the compound of formula ii with 2, 5-dimethylphenol is carried out in a solvent a in the presence of an acid-binding agent B.

3. The method of claim 2, comprising one or more of the following conditions:

a. the solvent A is one or the combination of more than two of acetonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether or toluene; the mass ratio of the solvent A to the compound shown in the formula II is (1-20) to 1;

b. the acid-binding agent B is inorganic base or organic base; the inorganic base is selected from potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium carbonate or lithium hydroxide; the organic base is selected from triethylamine, tri-N-propylamine, diisopropylethylamine, N-ethyl-N-propylamine or pyridine; preferably, the acid-binding agent B is potassium carbonate or sodium carbonate;

c. the molar ratio of the acid-binding agent B, the compound shown in the formula II and the 2, 5-dimethylphenol is (0.5-1.2): 1.0-1.1): 1; preferably, the molar ratio of the acid-binding agent B, the compound shown in the formula II and the 2, 5-dimethylphenol is (0.5-0.8): 1.0-1.1): 1;

d. the compound of formula II is added into the system in a dropwise manner for reaction.

4. The method for preparing dimoxystrobin according to claim 1, wherein in the step (1), the etherification reaction temperature of the compound of formula II and 2, 5-dimethylphenol is 0-90 ℃; preferably, the etherification reaction temperature is 30-55 ℃.

5. The process for preparing dimoxystrobin according to claim 1, wherein the step (2) for preparing the compound of formula v from the compound of formula iii comprises the steps of: mixing the solvent C, 6-12 wt% of the total mass of the compound in the formula III and magnesium powder, adding a Grignard reaction activator, and initiating a Grignard reaction under the protection of protective gas; then dropwise adding the rest of the mixed solution of the compound shown in the formula III and the solvent D, and continuing performing Grignard reaction under the protection of protective gas after 1-3 hours of dropwise adding to obtain reaction solution containing a Grignard reagent; dropwise adding the obtained reaction solution containing the Grignard reagent into a mixed solution of the compound shown in the formula IV and a solvent E, and reacting under the protection of protective gas; then the compound of the formula V is prepared by acidification treatment.

6. The method of claim 5, comprising one or more of the following conditions:

a. the solvent C is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, methoxycyclopentane or toluene; the types of the solvent D, the solvent E and the solvent C are the same; the mass ratio of the solvent C to the solvent D to the solvent E is 1-3:1-2: 1; the ratio of the total mass of the solvent C, the solvent D and the solvent E to the total mass of the compound shown in the formula III is (10-17) to 1;

b. the Grignard reaction activator is one or a combination of bromoethane, 1, 2-dibromoethane, 1-bromopropane or iodine; the mass of the Grignard reaction activator is (0.5-5.0)% of the total mass of the compound shown in the formula III; preferably, the mass of the Grignard activator is (1.0-3.0)% of the total mass of the compound of formula III;

c. the molar ratio of the magnesium powder to the compound shown in the formula IV to the compound shown in the formula III is (1.0-1.5) to (1.1-3.0) to 1; preferably, the molar ratio of the magnesium powder, the compound shown in the formula IV and the compound shown in the formula III is (1.05-1.25): 1.2-1.6): 1;

d. the temperature for initiating the Grignard reaction is 25-75 ℃; preferably, the temperature for initiating the Grignard reaction is 35 to 50 ℃;

e. the Grignard reaction temperature is 20-80 ℃; preferably, the Grignard reaction temperature is 40-55 ℃.

7. The method of claim 5, comprising one or more of the following conditions:

a. the dropping temperature of the reaction solution containing the Grignard reagent is-20 to 35 ℃; preferably, the dropping temperature is 10-30 ℃;

b. the reaction temperature of the reaction solution containing the Grignard reagent and the compound of the formula IV is-20 to 35 ℃; preferably, the reaction temperature is 10-30 ℃.

8. The method of claim 5, comprising one or more of the following conditions:

a. the acid used for the acidification treatment is a sulfuric acid aqueous solution with the mass concentration of 10-50 wt%, a hydrobromic acid aqueous solution with the mass concentration of 10-40 wt% or a saturated ammonium chloride aqueous solution; acidifying until the pH value of the system is 2.0-6.0; preferably, acidifying until the pH value of the system is 3.0-4.0;

b. the protective gas is nitrogen, argon or helium;

c. after the reaction of the reaction liquid containing the Grignard reagent and the compound of the formula IV is finished, recovering a solvent C, a solvent D and a solvent E by reduced pressure distillation, and adding water and dichloromethane into the remainder; then carrying out acidification treatment; separating layers, extracting water phase with dichloromethane, and combining dichloromethane phases; and distilling the dichloromethane phase to recover dichloromethane, and then carrying out reduced pressure distillation to obtain the compound of the formula V.

9. The method for preparing dimoxystrobin according to claim 1, wherein in step (3), the condensation reaction of the compound of formula V and methoxylamine salt is carried out in a solvent F under the action of an acid-binding agent G.

10. The method of claim 9, comprising one or more of the following conditions:

a. the solvent F is one or a combination of water, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the mass ratio of the solvent F to the compound of the formula V is (3-15) to 1;

b. the acid-binding agent G is inorganic base or organic base; the inorganic base is selected from potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide, lithium carbonate or lithium hydroxide; the organic base is selected from triethylamine, tri-n-propylamine, diisopropylethylamine or pyridine; preferably, the acid-binding agent G is potassium carbonate or sodium carbonate;

c. the methoxylamine is methoxylamine hydrochloride, methoxylamine nitrate, methoxylamine sulfate or methoxylamine acetate; preferably, the methoxyamine salt is methoxyamine hydrochloride;

d. the molar ratio of the acid-binding agent G, the methoxylamine salt and the compound of the formula V is (0.5-1.1): 1.0-1.4): 1; preferably, the molar ratio of the acid-binding agent G, the methoxyamine salt and the compound of the formula V is (0.8-1.1): 1.1-1.3): 1;

e. the condensation reaction temperature is 0-80 ℃; preferably, the condensation reaction temperature is 20-40 ℃.

Technical Field

The invention relates to a preparation method of dimoxystrobin, belonging to the technical field of pesticide chemistry.

Background

Dimoxystrobin (I), named Dimoxystrobin, CAS number 149961-52-4, named (E) -2- (2, 5-diphenoxymethyl) -alpha-methoxyimino-N-methylphenylacetamide, and having the following structural formula:

the dimoxystrobin is a novel methoxyacrylate systemic fungicide discovered by Japan salt wild-meaning company and developed by combining with Basff company, is mainly compounded with the triazole fungicide epoxiconazole, has protection, treatment and eradication activities, and can effectively prevent and treat main diseases of cereal crops and winter wheat; the global sales amount reaches 0.7 hundred million dollars in 2014, and the method has wide development and application prospects.

At present, the preparation method of dimoxystrobin in the prior art is as follows:

the patent documents US8575366 and US6008381 use 2-methylphenylacetic acid as a starting material, and the 2-chloromethylphenylacetic acid is obtained by chlorination with thionyl chloride, condensed into a ring under the action of sodium bicarbonate, and then oximated with isobutyl nitrite, and then subjected to O-methylation, chlorination, etherification and aminolysis to obtain dimoxystrobin, and the above process is described as the following synthetic route 1.

The synthetic route 1 has long steps and is complicated to operate; isobutyl nitrite is used, and the yield is low; dimethyl sulfate used for methylation has high toxicity, easily produces trans-products and has lower yield; the etherification reaction period is long; the use of thionyl chloride results in large amount of waste water, is not environment-friendly and is not suitable for industrial production.

U.S. Pat. Nos. 5,569359 and 6037495 describe the following synthetic route 2 by using 2-chloromethylbenzoyl chloride as a raw material, reacting with sodium cyanide to obtain 2-chloromethylbenzoyl cyanide, hydrolyzing, condensing with potassium acetate to obtain ester, oximating with methoxyamine, aminomethylating, chlorinating, and etherifying.

The synthetic route 2 has long steps; the virulent sodium cyanide is used, and the acyl cyanide hydrolysis yield is low; under the condition of potassium acetate, benzyl chloride reacts with amide groups, so that the yield is low, the product content is low, and the cost is high; the use of thionyl chloride results in large amount of waste water and is not environment-friendly.

U.S. Pat. Nos. 5,547,639 and 5,639 use O-dichloromethylbenzene as raw material, etherify with 2, 5-dimethylphenol, substitute with sodium cyanide, oximation, O-methylation, hydrolysis, and methylation to obtain dimoxystrobin, and the reaction process is described in the following scheme 3.

The synthetic route 3 has long steps; the o-dichloromethylbenzene and 2, 5-dimethylphenol can undergo secondary etherification, the reaction selectivity is low, and the yield is low; and the reaction uses virulent sodium cyanide and highly toxic dimethyl sulfate, which is unsafe; the use of butyl nitrite for oximation has low yield, low product content and high cost, and is not beneficial to industrial production.

Reference "pesticide, 2016, 55 (5): 324-327' uses O-methyl phenylacetonitrile as raw material, and obtains dimoxystrobin through oximation, O-methylation, hydrolysis, esterification, chlorination, etherification and aminolysis, and the reaction process is described as the following synthetic route 4.

In the synthetic route 4, butyl nitrite is used for oximation, so that the yield is low, and the product content is low; the etherification reaction period is long; the N-chlorosuccinimide is expensive and high in cost; and the amount of waste water generated is large, the waste water is difficult to treat and not environment-friendly, and the industrial amplification is not facilitated.

In conclusion, the existing preparation technology of dimoxystrobin has the defects of multiple steps, complex operation, large three-waste generation amount, environmental pollution, multiple side reactions, low product purity and yield and the like, so that the design of a synthetic route of dimoxystrobin with simple steps, environmental protection, low cost, easy realization, less side reactions, high selectivity, high yield and high purity has important significance.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a preparation method of dimoxystrobin. The method has the advantages of cheap and easily obtained raw materials and low cost; the process flow is short, and the dimoxystrobin can be prepared only by three steps of reactions; the reaction condition is easy to realize, the operation is safe and simple, the production amount of process wastewater is small, and the method is green and environment-friendly; the stability of raw materials and intermediate products is high, the reactivity and the selectivity are high, and the side reaction is less; the obtained dimoxystrobin has less impurities and high purity and yield, and is beneficial to the industrial production of the dimoxystrobin.

Description of terms:

a compound of formula II: 2-halomethyl halobenzenes;

a compound of formula III: 2- (2,5-dimethylphenoxymethyl) halobenzene;

a compound of formula IV: n-methyl oxalic acid monoester monoamide;

a compound of formula V: n-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide;

a compound of formula I: dimoxystrobin.

The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.

The technical scheme of the invention is as follows:

a preparation method of dimoxystrobin comprises the following steps:

(1) preparing a compound of formula III by subjecting a compound of formula II and 2, 5-dimethylphenol to an etherification reaction;

wherein, in the structural formula of the compound shown in the formula II, X, Y is independently selected from Br, Cl or I; x in the structural formula of the compound of the formula III has the same meaning as that of X in the structural formula of the compound of the formula II;

(2) obtaining a reaction solution containing a Grignard reagent by carrying out Grignard reaction on a compound shown in a formula III and magnesium metal; dropwise adding the reaction liquid containing the Grignard reagent into a system containing the compound of the formula IV, and reacting with the compound of the formula IV to prepare a compound of the formula V;

wherein in the structural formula of the compound shown in the formula IV, R is C₁To C₄Alkyl groups of (a);

(3) etheramines (I) are prepared by subjecting a compound of formula V and methoxyamine salt to a condensation reaction.

According to the invention, in step (1), the etherification reaction of the compound of formula II and 2, 5-dimethylphenol is carried out in a solvent A in the presence of an acid-binding agent B.

Preferably, the solvent A is one or the combination of more than two of acetonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, methyl tertiary butyl ether or toluene; the mass ratio of the solvent A to the compound shown in the formula II is (1-20) to 1; further preferably, the mass ratio of the solvent A to the compound of the formula II is (1-5): 1.

Preferably, the acid-binding agent B is an inorganic base or an organic base; the inorganic base is selected from potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium carbonate or lithium hydroxide; the organic base is selected from triethylamine, tri-N-propylamine, diisopropylethylamine, N-ethyl-N-propylamine or pyridine; further preferably, the acid-binding agent B is potassium carbonate or sodium carbonate.

Preferably, the molar ratio of the acid-binding agent B, the compound shown in the formula II and the 2, 5-dimethylphenol is (0.5-1.2): 1.0-1.1): 1; preferably, the molar ratio of the acid-binding agent B, the compound shown in the formula II and the 2, 5-dimethylphenol is (0.5-0.8): 1.0-1.1): 1.

Preferably, the compound of formula II is added dropwise into the system for reaction.

According to the invention, in the step (1), the etherification reaction temperature of the compound shown in the formula II and the 2, 5-dimethylphenol is 0-90 ℃; preferably, the etherification reaction temperature is 30-55 ℃. The etherification reaction time is 1 to 8 hours; preferably, the etherification reaction time is 1 to 3 hours. The above reaction temperature is too high, and high boiling point impurities are generated, so that the yield is reduced, and the product purity is reduced.

Preferably, according to the present invention, in step (2), the preparation of the compound of formula V from the compound of formula III comprises the steps of: mixing the solvent C, 6-12 wt% of the total mass of the compound in the formula III and magnesium powder, adding a Grignard reaction activator, and initiating a Grignard reaction under the protection of protective gas; then dropwise adding the rest of the mixed solution of the compound shown in the formula III and the solvent D, and continuing performing Grignard reaction under the protection of protective gas after 1-3 hours of dropwise adding to obtain reaction solution containing a Grignard reagent; dropwise adding the obtained reaction solution containing the Grignard reagent into a mixed solution of the compound shown in the formula IV and a solvent E, and reacting under the protection of protective gas; then the compound of the formula V is prepared by acidification treatment.

Preferably, the solvent C is one or a combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, methoxycyclopentane or toluene; the types of the solvent D, the solvent E and the solvent C are the same; the mass ratio of the solvent C to the solvent D to the solvent E is 1-3:1-2: 1; the ratio of the total mass of the solvent C, the solvent D and the solvent E to the total mass of the compound shown in the formula III is (10-17): 1.

Preferably, the Grignard reaction activator is one or a combination of bromoethane, 1, 2-dibromoethane, 1-bromopropane or iodine; the mass of the Grignard reaction activator is (0.5-5.0)% of the total mass of the compound shown in the formula III; further preferably, the mass of the Grignard activator is (1.0 to 3.0)% of the total mass of the compound of formula III.

Preferably, the molar ratio of the magnesium powder, the compound shown in the formula IV and the compound shown in the formula III is (1.0-1.5): 1.1-3.0): 1; further preferably, the molar ratio of the magnesium powder, the compound of the formula IV and the compound of the formula III is (1.05-1.25): 1.2-1.6): 1. The excessive magnesium powder is utilized, so that the Grignard reaction can be thorough; the excessive N-methyl oxalic acid monoester monoamide is utilized, so that the excessive N-methyl oxalic acid monoester monoamide in the system is high, and the side reaction of two molecules of Grignard reagent and one molecule of N-methyl oxalic acid monoester monoamide can be controlled.

Preferably, the temperature for initiating the Grignard reaction is 25 to 75 ℃; further preferably, the temperature at which the Grignard reaction is initiated is 35 to 50 ℃. The time for initiating the Grignard reaction is 0.1-1.0 hour; further preferably, the time for initiating the grignard reaction is 0.2 to 0.5 hour.

Preferably, the Grignard reaction temperature is 20-80 ℃; further preferably, the grignard reaction temperature is 40 to 55 ℃. The Grignard reaction time is 0.5-5 hours; further preferably, the grignard reaction time is 1 to 3 hours.

Preferably, the dropping temperature of the reaction solution containing the Grignard reagent is-20 to 35 ℃; further preferably, the dropping temperature is 10 to 30 ℃.

Preferably, the reaction temperature of the reaction solution containing the Grignard reagent and the compound of the formula IV is-20 to 35 ℃; further preferably, the reaction temperature is 10 to 30 ℃. The reaction time is 1-6 hours; further preferably, the reaction time is 2 to 4 hours. When the reaction temperature is too high, the stability of the addition product of the grignard reagent and the N-methyl oxalic acid monomethyl ester monoamide is not favorable, the reaction product is decomposed too early to generate the target compound containing a carbonyl group, the reaction product reacts with the grignard reagent further, and a double grignard addition by-product is finally generated, so that the yield of the target compound is reduced.

Preferably, the acid used for the acidification treatment is a sulfuric acid aqueous solution with the mass concentration of 10-50 wt%, a hydrobromic acid aqueous solution with the mass concentration of 10-40 wt% or a saturated ammonium chloride aqueous solution; acidifying until the pH value of the system is 2.0-6.0; further preferably, the acidification treatment is carried out until the pH value of the system is 3.0-4.0.

Preferably, the protective gas is nitrogen, argon or helium.

Preferably, after the reaction of the reaction solution containing the grignard reagent and the compound of the formula IV is finished, the solvent C, the solvent D and the solvent E are recovered by reduced pressure distillation, and water and dichloromethane are added into the residue; then carrying out acidification treatment; separating layers, extracting water phase with dichloromethane, and combining dichloromethane phases; and distilling the dichloromethane phase to recover dichloromethane, and then carrying out reduced pressure distillation to obtain the compound of the formula V.

Preferably, in step (3), the condensation reaction of the compound of formula V and the methoxyamine salt is carried out in a solvent F under the action of an acid-binding agent G.

Preferably, the solvent F is one or a combination of water, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the mass ratio of the solvent F to the compound of the formula V is (3-15) to 1; further preferably, the mass ratio of the solvent F to the compound of the formula V is (5-8): 1.

Preferably, the acid-binding agent G is an inorganic base or an organic base; the inorganic base is selected from potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide, lithium carbonate or lithium hydroxide; the organic base is selected from triethylamine, tri-n-propylamine, diisopropylethylamine or pyridine; further preferably, the acid-binding agent G is potassium carbonate or sodium carbonate.

Preferably, the methoxyamine salt is methoxyamine hydrochloride, methoxyamine nitrate, methoxyamine sulfate or methoxyamine acetate; further preferably, the methoxylamine salt is methoxylamine hydrochloride.

Preferably, the molar ratio of the acid-binding agent G, the methoxyamine salt and the compound of the formula V is (0.5-1.1): 1.0-1.4): 1; further preferably, the molar ratio of the acid-binding agent G, the methoxyamine salt and the compound of the formula V is (0.8-1.1): 1.1-1.3): 1.

Preferably, the condensation reaction temperature is 0-80 ℃; further preferably, the condensation reaction temperature is 20 to 40 ℃. The condensation reaction time is 2-15 hours; further preferably, the condensation reaction time is 3 to 6 hours.

The reaction process of the present invention is depicted as the following synthetic scheme 5:

wherein, in the structural formula of the compound shown in the formula II, X, Y is independently selected from Br, Cl or I; x in the structural formula of the compound of the formula III has the same meaning as that of X in the structural formula of the compound of the formula II; in the structural formula of the compound shown in the formula IV, R is C₁To C₄Alkyl group of (1).

The invention has the technical characteristics and beneficial effects that:

1. the invention provides a novel dimoxystrobin preparation method, which comprises the steps of preparing 2- (2,5-dimethylphenoxymethyl) halogenated benzene by etherification of 2-halogenated methyl halogenated benzene and 2, 5-dimethylphenol, preparing a corresponding Grignard reagent by Grignard reaction of the halogenated benzene and metal magnesium, dropwise adding the reaction liquid containing the Grignard reagent into N-methyl oxalic acid monoester monoamide to prepare N-methyl-2- (2,5-dimethylphenoxymethyl) phenyl oxamide, and finally preparing dimoxystrobin by condensation reaction of the N-methyl-2- (2,5-dimethylphenoxymethyl) phenyl oxamide and methoxylamine.

2. The invention designs a reaction route by fully utilizing the structural characteristics of raw materials, avoids the hydrolysis of the 2-halogenated methyl halogenated benzene by utilizing the characteristic that the 2, 5-dimethylphenol is easy to have substitution reaction with the 2-halogenated methyl halogenated benzene and the non-aqueous phase reaction, thereby fundamentally avoiding the side reaction of the 2-halogenated methyl halogenated benzene hydrolysate, namely the 2-hydroxymethyl halogenated benzene and the 2-halogenated methyl halogenated benzene, and the etherification reaction is easy to operate and has specific reaction. The etherification product 2- (2,5-dimethyl phenoxymethyl) halogenated benzene has high stability, the contained ether bond is stable under the conditions of Grignard reaction and post treatment, and the Grignard reaction selectivity is high; and the reaction liquid containing the Grignard reagent is dripped into the N-methyl oxalic acid monoester monoamide, so that the double Grignard side reaction is effectively reduced. Finally, the carbonyl of the N-methyl-2- (2,5-dimethyl phenoxymethyl) phenyl oxamide is condensed with free methoxyamine, the reaction is easy to carry out, and the selection is specific. The reaction route of the invention provides guarantee for preparing dimoxystrobin with high yield and high purity.

3. The method has the advantages of cheap and easily obtained raw materials and low cost; the preparation steps are simple and short, the operation is simple and convenient, the target product dimoxystrobin can be prepared by only 3 steps, and compared with the existing 6-step or 7-step process method, the process flow is greatly shortened; the reaction condition is easy to realize, toxic reagents with high toxicity are not used, the generation amount of waste water is small, the operation is safe, simple and convenient, and the environment is protected; the method has the advantages of high atom economy, high reaction selectivity, less side reaction, high yield and purity of the target product, and the yield can reach 85.5 percent, thereby being beneficial to industrialization.

Detailed Description

The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.

The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified.

The yields in the examples are all molar yields.

Example 1: 2- (2,5-Dimethylphenoxymethyl) bromobenzene (III)₁) Preparation of

Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 400 g of 1, 2-dichloroethane, 82.8 g (0.6 mol) of potassium carbonate and 122.2 g (1.0 mol) of 2, 5-dimethylphenol were charged, heated while maintaining the temperature between 40 and 45 ℃, and 215.8 g (1.05 mol) of 2-chloromethylbromobenzene (II) was added dropwise₁) After about 3 hours of dropwise addition, stirring the mixture at 45 to 50 ℃ for 2 hours, cooling the mixture to 20 to 25 ℃, filtering the mixture, washing the filter cake with 1, 2-dichloroethane (100 g each time), combining the organic phases, recovering the solvent by distillation, and distilling the mixture under reduced pressure (150 ℃ C./1 to 2mmHg) to obtain 275.7 g of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III)₁) The yield is 94.6 percent, and the gas phase purity is 99.9 percent.

The nuclear magnetic data of the product obtained are as follows:

¹H NMR(400MHz,DMSO-d₆):δ：2.16(s,3H),2.27(s,3H),4.78(s,2H),6.67-7.58(m,7H)。

example 2: 2- (2,5-Dimethylphenoxymethyl) bromobenzene (III)₁) Preparation of

To a constant pressure dripping funnel connected with a stirring thermometerA1000 ml four-necked flask equipped with a funnel and a reflux condenser was charged with 500 g of methylene chloride, 82.8 g (0.6 mol) of potassium carbonate, and 122.2 g (1.0 mol) of 2, 5-dimethylphenol, heated, maintained at 30 to 35 ℃ and charged with 262.5 g (1.05 mol) of 2-bromomethylbromobenzene (II)₂) After about 3 hours of dropwise addition, the reaction was stirred at 35 to 40 ℃ for 2 hours, cooled to 20 to 25 ℃, filtered, the filter cake was washed with dichloromethane (100 g each time), the organic phases were combined, the solvent was recovered by distillation, and distillation under reduced pressure (150 ℃ C./1-2 mmHg) gave 273.8 g of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III)₁) The yield is 94.0 percent, and the gas phase purity is 99.8 percent.

Example 3: preparation of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (V)

To a 500 ml four-necked flask equipped with a stirrer and a thermometer under nitrogen atmosphere were added 150 g of tetrahydrofuran, 2.7 g (0.11 mol) of powdered magnesium, 0.5 g of 1, 2-dibromoethane, and 1.5 g of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III) prepared in example 2₁) 0.05 g of iodine and initiating the Grignard reaction at 40-45 ℃ for 0.2 hour; 27.6 g (total 0.1 mol) of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III) prepared in example 1 was added dropwise at 40-45 deg.C₁) And 100 g of tetrahydrofuran, stirring and reacting for 3 hours at 45-50 ℃ under nitrogen after 2 hours of dripping, and cooling to 20-25 ℃ to obtain a reaction solution containing the Grignard reagent; the reaction solution containing the Grignard reagent was transferred to a constant pressure dropping funnel, maintained at 20 to 25 ℃, added dropwise to a mixed solution of 17.6 g (0.15 mol) of N-methyl oxalic acid monomethyl ester monoamide and 100 g of tetrahydrofuran, added dropwise over 2 hours, and then stirred under nitrogen at 20 to 25 ℃ for reaction for 3 hours. The solvent was recovered by distillation under reduced pressure, 50 g of water and 200 g of methylene chloride were added to the residue, the pH of the system was acidified to 3.0 to 4.0 with a saturated aqueous ammonium chloride solution, the layers were separated, the aqueous phase was extracted twice with 50 g of methylene chloride each time, the methylene chloride phases were combined, methylene chloride was recovered by distillation, and 27.3 g of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (V) was obtained by distillation under reduced pressure (160 ℃ C./1-2 mmHg), the yield was 91.8%, and the purity of the gas phase was 99.8%.

The nuclear magnetic data of the product obtained are as follows:

¹H NMR(400MHz,DMSO-d₆):δ：2.12(s,3H),2.26(s,3H),2.71(d,3H),4.23(b,1H),4.86(s,2H),6.61-7.55(m,7H)。

example 4: preparation of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (V)

To a 500 ml four-necked flask equipped with a stirrer and a thermometer under nitrogen atmosphere were added 200 g of tetrahydrofuran, 2.7 g (0.11 mol) of powdered magnesium, 0.5 g of 1, 2-dibromoethane, and 1.5 g of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III) prepared in example 1₁) 0.05 g of iodine and initiating the Grignard reaction at 40-45 ℃ for 0.2 hour; 27.6 g (0.1 mol total) of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III) prepared in example 2 was added dropwise at 40-45 deg.C₁) And 150 g of tetrahydrofuran, stirring and reacting for 3 hours at 45-50 ℃ under nitrogen after 2 hours of dripping, and cooling to 20-25 ℃ to obtain a reaction solution containing the Grignard reagent; the resulting reaction solution containing the Grignard reagent was transferred to a constant pressure dropping funnel, maintained at 10 to 15 ℃ and added dropwise to a mixed solution of 17.3 g (0.13 mol) of N-methyl oxalic acid monoethyl ester monoamide and 100 g of tetrahydrofuran, dropwise addition was completed within 2 hours, and then the reaction was stirred at 10 to 15 ℃ under nitrogen for 3 hours. The solvent was recovered by distillation under reduced pressure, 50 g of water and 200 g of methylene chloride were added to the residue, the pH of the system was acidified to 3.0 to 4.0 with a saturated aqueous ammonium chloride solution, the layers were separated, the aqueous phase was extracted twice with 50 g of methylene chloride each time, the methylene chloride phases were combined, methylene chloride was recovered by distillation, and 27.6 g of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (IV) was obtained by distillation under reduced pressure (160 ℃ C./180 ℃ C./1-2 mmHg), with a yield of 92.8% and a gas phase purity of 99.6%.

Example 5: preparation of dimoxystrobin (I)

To a 500 ml four-necked flask equipped with a stirrer and a thermometer, 50 g of methanol, 50 g of water, 6.9 g (0.05 mol) of potassium carbonate, 5.0 g (0.06 mol) of methoxyamine hydrochloride, and 14.9 g (0.05 mol) of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (IV) obtained in example 3 were added, and the mixture was stirred at 25 to 30 ℃ for 5 hours, filtered, and the filter cake was washed with 30 g of water and dried to obtain 15.8 g of dimoxystrobin (I), a yield was 96.8% and a liquid phase purity was 99.2%.

The nuclear magnetic data of the product obtained are as follows:

¹H NMR(400MHz,DMSO-d₆):δ：2.16(s,3H),2.28(s,3H),2.85(d,3H),3.93(s,3H),4.36(b,1H),4.91(s,2H),6.61-7.55(m,7H)。

example 6: preparation of dimoxystrobin (I)

To a 500 ml four-necked flask equipped with a stirrer and a thermometer, 100 g of methanol, 6.9 g (0.05 mol) of potassium carbonate, 5.0 g (0.06 mol) of methoxyamine hydrochloride, 14.9 g (0.05 mol) of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (IV) obtained in example 4 were charged, and the mixture was stirred at 30 to 35 ℃ for 4 hours, then inorganic salts were removed by filtration, 60 g of methanol was recovered by distillation from the filtrate, the residue was cooled to 20 to 25 ℃, then filtered, and the cake was washed with 30 g of water and dried to obtain 15.9 g of dimoxystrobin (I), with a yield of 97.4% and a liquid phase purity of 99.3%.

Comparative example 1: 2- (2,5-Dimethylphenoxymethyl) bromobenzene (III)₁) Preparation of

Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 400 g of toluene, 82.8 g (0.6 mol) of potassium carbonate and 122.2 g (1.0 mol) of 2, 5-dimethylphenol were charged, heated, maintained at 95 to 100 ℃ and 215.8 g (1.05 mol) of 2-chloromethylbromobenzene (II) was added dropwise₁) After about 3 hours of dropwise addition, stirring the mixture at 95 to 100 ℃ for 2 hours, cooling the mixture to 20 to 25 ℃, filtering the mixture, washing a filter cake with toluene 100 g each time, combining organic phases, recovering the solvent by distillation, and distilling the mixture under reduced pressure (150 ℃ C./1-2 mmHg) to obtain 251.2 g of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III)₁) The yield was 86.2% and the gas phase purity was 95.7%.

Comparative example 1 shows that: the dropping and reaction temperature is high, the yield is reduced, the purity is reduced, the contained high boiling point impurities are analyzed to be bis (2-bromophenyl methyl) ether through GC-MS, 2-chloromethyl bromobenzene is hydrolyzed to generate 2-hydroxymethyl bromobenzene under the high temperature condition and a small amount of water in the system (acid-binding agent potassium carbonate is converted into potassium bicarbonate after acid-binding, and potassium bicarbonate is decomposed at high temperature to generate a small amount of water), and the 2-hydroxymethyl bromobenzene further reacts with 2-chloromethyl bromobenzene to generate bis (2-bromophenyl methyl) ether.

Comparative example 2: preparation of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (V)

To a 500 ml four-necked flask equipped with a stirrer and a thermometer under nitrogen atmosphere were added 150 g of tetrahydrofuran, 2.7 g (0.11 mol) of powdered magnesium, 0.5 g of 1, 2-dibromoethane, and 1.5 g of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III) prepared in example 1₁) 0.05 g of iodine and initiating the Grignard reaction at 40-45 ℃ for 0.2 hour; 27.6 g (total 0.1 mol) of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III) prepared in example 1 was added dropwise at 40-45 deg.C₁) And 100 g of tetrahydrofuran, stirring and reacting for 3 hours at 45-50 ℃ under nitrogen after 2 hours of dripping, and cooling to 20-25 ℃ to obtain a reaction solution containing the Grignard reagent; a mixed solution of 17.6 g (0.15 mol) of N-methyl oxalic acid monomethyl ester monoamide and 100 g of tetrahydrofuran was added dropwise while maintaining the temperature between 20 and 25 ℃ for 2 hours, and then the reaction was stirred at 20 to 25 ℃ under nitrogen for 3 hours. The solvent was recovered by distillation under reduced pressure, 50 g of water and 200 g of methylene chloride were added to the residue, the pH of the system was acidified to 3.0 to 4.0 with a saturated aqueous ammonium chloride solution, the layers were separated, the aqueous phase was extracted twice with 50 g of methylene chloride each time, the methylene chloride phases were combined, methylene chloride was recovered by distillation, and 18.6 g of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (V) was obtained by distillation under reduced pressure (160 ℃ C./180 ℃ C./1-2 mmHg), yield 62.5% and gas phase purity 98.1%.

Comparative example 2 shows that when N-methyl oxalic acid monomethyl ester monoamide is added dropwise to the resulting reaction solution containing the grignard reagent, the concentration of the grignard reagent is high, and the excess grignard reagent reacts further with the carbonyl group of the target product to finally generate a double grignard addition by-product, resulting in a decrease in the yield of the target compound.

Comparative example 3: preparation of N-methyl-2- (2,5-dimethylphenoxymethyl) phenyloxamide (V)

To a 500 ml four-necked flask equipped with a stirrer and a thermometer under nitrogen atmosphere were added 150 g of tetrahydrofuran, 2.7 g (0.11 mol) of powdered magnesium, 0.5 g of 1, 2-dibromoethane, and 1.5 g of 2- (2,5-dimethylphenoxymethyl) bromobenzene (III) prepared in example 1₁) 0.05 g of iodine and initiating the Grignard reaction at 40-45 ℃ for 0.2 hour; 27.6 g (total 0.1 mol) of the product of example 1 are added dropwise between 40 and 45 DEG2- (2,5-Dimethylphenoxymethyl) bromobenzene (III)₁) And 100 g of tetrahydrofuran, and stirring and reacting for 3 hours at 45-50 ℃ under nitrogen after 2 hours of dripping to obtain a reaction solution containing the Grignard reagent; the reaction solution containing the Grignard reagent was transferred to a constant pressure dropping funnel, maintained at 40 to 45 ℃ and added dropwise to a mixed solution of 17.6 g (0.15 mol) of N-methyl oxalic acid monomethyl ester monoamide and 100 g of tetrahydrofuran, dropwise addition was completed for 2 hours, and then the reaction was stirred at 40 to 45 ℃ under nitrogen for 3 hours. Cooling to 20-25 deg.C, distilling under reduced pressure to recover solvent, adding 50 g water and 200 g dichloromethane into the residue, acidifying with saturated ammonium chloride aqueous solution to pH 3.0-4.0, layering, extracting the water phase with dichloromethane twice, 50 g each time, combining dichloromethane phases, distilling to recover dichloromethane, distilling under reduced pressure (160-.

Comparative example 3 shows that when the reaction temperature of the resulting reaction solution containing the grignard reagent and N-methyl oxalic acid monomethyl ester monoamide is high, the stability of the addition product of the grignard reagent and N-methyl oxalic acid monomethyl ester monoamide is not favorable, methoxy magnesium bromide in the addition product is removed, the premature decomposition generates a target compound containing a carbonyl group, the further reaction with the grignard reagent occurs, and a double grignard addition by-product is finally generated, so that the yield of the target compound is reduced.