CN111807990B - Intermediate for preparing trifloxystrobin and synthetic method thereof - Google Patents

Intermediate for preparing trifloxystrobin and synthetic method thereof Download PDF

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CN111807990B
CN111807990B CN202010720937.1A CN202010720937A CN111807990B CN 111807990 B CN111807990 B CN 111807990B CN 202010720937 A CN202010720937 A CN 202010720937A CN 111807990 B CN111807990 B CN 111807990B
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sodium
oxime
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蔡凡平
李新明
张彦斌
杨显文
符雨
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Fuxin Fulongbao Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/70—Metal complexes of oximes

Abstract

The invention relates to an intermediate for preparing trifloxystrobin and a synthesis method thereof, which takes 2-oxime-o-tolylacetonitrile as a raw material, and the raw material is heated and hydrolyzed in an alkaline aqueous solution to obtain 2-oxime-o-tolylacetic acid or monosodium salt/monopotassium salt or disodium salt/dipotassium salt thereof; reacting with a methylating agent under an alkaline condition to obtain (E) -2- (methoxyimino) -o-methyl phenylacetic acid methyl ester. The method has the characteristics of easily obtained raw materials, single trans-configuration of the product and simple and convenient operation, and is suitable for industrial production.

Description

Intermediate for preparing trifloxystrobin and synthetic method thereof
Technical Field
The invention relates to the technical field of organic synthesis, relates to preparation of pesticide intermediates, and particularly relates to an intermediate for preparing trifloxystrobin and a synthesis method thereof.
Background
Trifloxystrobin (trifloxystrobin, trade name Flint) chemical name: (2Z) -2-methoxyimino-2- [2- [ [1- [3- (trifluoromethyl) phenyl ] ethylamino ] oxymethyl ] phenyl ] acetic acid methyl ester:
Figure BDA0002599868840000011
the trifloxystrobin is a bactericide which is created by Zhangda and developed by Germany Bayer company, and has the characteristics of high efficiency, broad spectrum, protection, treatment, eradication, permeation, systemic activity, rain wash resistance, long lasting period and the like. . Has good activity on almost all fungal diseases. Is safe to crops, and is safe to the environment because the fertilizer can be quickly degraded in soil and water.
The prior art discloses a synthesis process route of a plurality of trifloxystrobin, and the routes suitable for industrial production are basically consistent: the following two fragments II and III were docked under alkaline conditions. Although the preparation of intermediate II is more complex, the most competitive route is the bromination of intermediate I.
Figure BDA0002599868840000012
The prior art reports preparation processes of various intermediates I and II, but all have different problems: either the raw materials are expensive, or virulent cyanides are used, or the reaction conditions are harsh (such as the use of metal reagents) or the three wastes are serious (diazotization or heavy metal oxidation), etc.
Plum red [ the master paper of the university of Hebei science and technology, 2015] reports a process for preparing the trifloxystrobin intermediate I, wherein the process has easily available raw materials. The trifloxystrobin intermediate I is obtained by taking o-methyl phenylacetonitrile as a raw material and carrying out six-step reaction of oximation, acidification, etherification, hydrolysis, acidification and esterification. Although the raw material o-methyl phenylacetonitrile is easy to obtain, the preparation route is long, and the equipment and labor investment required by the application in production are large; and assuming that each step of reaction is carried out quantitatively, the preparation of 1 molar equivalent of the trifloxystrobin intermediate I from 1 molar equivalent of o-tolylacetonitrile requires at least more than 6 equivalents of sodium hydroxide or potassium hydroxide strong base, and the neutralization of the obtained salt intermediate requires at least equal equivalents of acid, which not only results in the production of the trifloxystrobin intermediate I by adopting the process and generates a large amount of three wastes, but also has large raw material consumption and high production cost. Further, even if the crude trifloxystrobin intermediate I prepared by the process is subjected to two purification operations of reduced pressure distillation and petroleum ether recrystallization to obtain the required (E) -2- (methoxyimino) -o-tolylacetic acid methyl ester, the purity of the obtained crude trifloxystrobin intermediate I is only 93.77%, when the intermediate with the content is used for preparing trifloxystrobin, the obtained crude trifloxystrobin product needs to be further purified by adopting purification operations such as recrystallization and the like in order to obtain a trifloxystrobin product meeting the market demand purity, and the important factor that the yield of the finally prepared trifloxystrobin is not high is caused. Wherein the yield of each step is 93%, 85%, 89% and 77% respectively. The reaction process is as follows:
Figure BDA0002599868840000021
CN108863845A discloses the following reaction process, which requires four steps, and the total yield of example 4 is 75%; in the patent, methylation is carried out twice, a process of repeatedly adjusting alkali and then adjusting acid exists, 5.4 equivalent of alkali and 4.4 equivalent of acid are consumed in four steps, and the amount of three wastes is large; the product is extracted from the reaction system by organic solvent in each step, and the cost is high.
Figure BDA0002599868840000022
By combining the existing literature reports, a process route for preparing the key intermediate I (namely (E) -2- (methoxyimino) -o-methylphenylacetic acid methyl ester) of trifloxystrobin at the same time has the advantages of simple operation, safety, reliability, less three wastes, low cost, high yield and high purity.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a key intermediate of (E) -2- (methoxyimino) -o-methyl phenylacetic acid methyl ester and a method for synthesizing (E) -2- (methoxyimino) -o-methyl phenylacetic acid methyl ester by using the key intermediate. The process is simple, safe in production, less in three wastes, low in cost, high in yield, high in purity and suitable for industrial preparation.
The technical scheme of the invention is as follows:
an intermediate for preparing trifloxystrobin, shown as formula I:
Figure BDA0002599868840000031
wherein M1 is selected from Na, K or H;
m2 is selected from Na, K or H.
Further preferred is an intermediate for the preparation of trifloxystrobin, wherein the compound of formula I is selected from the following table:
compound numbering M1 M2
1 Na Na
2 K K
3 H H
4 Na H
5 H Na
6 K H
7 H K
The invention provides a synthetic method of an intermediate formula I for preparing trifloxystrobin, which comprises the following steps:
(1) when M1 and M2 are K or Na at the same time, adding water and a sodium or potassium-containing base into 2-oxime-o-tolylacetonitrile to carry out reaction;
(2) when one or two of M1 or M2 is H, the method further comprises the step of adding acid treatment to the product obtained in the step (1).
In the step (1), the alkali is selected from one or more of the following: sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide or sodium tert-butoxide; and may be selected from sodium hydroxide or potassium hydroxide.
The invention provides a synthesis method of an intermediate (E) -2- (methoxyimino) -o-methyl phenylacetic acid methyl ester for preparing trifloxystrobin, which comprises the following steps:
Figure BDA0002599868840000041
dissolving the intermediate for preparing the trifloxystrobin in an organic solvent, and adding alkali and a methylation reagent for reaction.
The methylation reagent is selected from one or more of the following: methyl chloride, methyl bromide, methyl iodide, dimethyl carbonate, methyl p-toluenesulfonate or dimethyl sulfate; alternatively methyl chloride, dimethyl carbonate or dimethyl sulfate.
The methylation reaction organic solvent is selected from DMF, DMA, DMSO or acetonitrile, preferably DMF and DMSO.
The methylation reaction conditions are as follows: the temperature is-25 to 45 ℃, preferably-10 to 45 ℃.
Further, a synthesis method of an intermediate (E) -2- (methoxyimino) -methyl o-tolylacetate for preparing trifloxystrobin adopts a one-pot reaction to carry out the following reactions:
Figure BDA0002599868840000042
the invention adopts a one-pot method to carry out alkaline hydrolysis reaction to obtain free acid, monosodium salt/monopotassium salt or disodium salt/dipotassium salt of trans-2-oxime-o-tolylacetic acid, and then carries out double methylation reaction to obtain (E) -2- (methoxyimino) -o-tolylacetic acid methyl ester.
The one-pot method is a general expression mode in the chemical industry. The intermediate is not separated, and the next reaction is directly carried out in the same reaction kettle.
The invention relates to a synthesis method of an intermediate (E) -2- (methoxyimino) -methyl o-phenylacetate for preparing trifloxystrobin, which comprises the following steps:
the first step, the preparation of 2-oxime-o-tolylacetic acid or mono sodium salt/mono potassium salt or disodium salt/dipotassium salt:
(1) when M1 and M2 are K or Na at the same time, adding water and a sodium or potassium-containing base into 2-oxime-o-tolylacetonitrile to carry out reaction;
(2) when one or two of M1 or M2 is H, the method further comprises the step of adding acid treatment to the product obtained in the step (1);
second step, preparation of (E) -2- (methoxyimino) -o-methylphenylacetic acid methyl ester: dissolving free acid of 2-oxime-o-tolylacetic acid or monosodium salt/monopotassium salt or disodium salt/dipotassium salt thereof in an organic solvent, adding alkali and a methylating reagent for reaction, and obtaining (E) -2- (methoxyimino) -o-tolylacetic acid methyl ester.
Further, in the above technical solution, in the first hydrolysis reaction, the alkali is selected from sodium hydroxide or potassium hydroxide.
Further, in the above technical solution, the acid of the first step is concentrated hydrochloric acid.
Further, in the above technical solution, the molar ratio of the acid to the base in the first step (1.28-2.30): 2.29.
in the first step, when one of M1 or M2 is H, the molar ratio of acid to base is 1.28: 2.29; when two of M1 or M2 are H, the ratio of acid to base is 2.30: 2.29.
further, the reaction product of the first step of the present invention can be directly used in the second step without purification.
Further, in the above technical scheme, in the second step of reaction, the alkali is selected from potassium carbonate, sodium hydroxide or potassium hydroxide. Sodium hydroxide or potassium hydroxide is preferred.
Further, in the above technical scheme, in the second step of reaction, the solvent is selected from DMF, DMA, DMSO or acetonitrile. DMF and DMSO are preferable.
Further, in the above technical scheme, in the second step of reaction, the methylating agent is selected from methyl chloride, methyl bromide, methyl iodide, dimethyl carbonate, methyl p-toluenesulfonate or dimethyl sulfate. Methyl chloride, dimethyl carbonate or dimethyl sulfate are preferred.
Further, in the above technical scheme, in the second step of the reaction, the molar ratio of the (E) -2-oxime-o-tolylacetic acid or mono-sodium salt/mono-potassium salt or di-sodium salt/di-potassium salt, the base and the methylating agent is 1: (0-2.42): (2.31-2.42).
Preferably, in the second reaction step, the molar ratio of the (E) -2-oxime-o-methylphenylacetic acid, the base and the methylating agent is 1: 2.42: 2.42.
or preferably, in the second reaction step, the molar ratio of the monosodium/monopotassium salt of (E) -2-oxime-o-tolylacetic acid, the base and the methylating agent is 1: 1.21: 2.31.
or preferably, in the second step reaction, the molar ratio of the disodium salt/dipotassium salt of the (E) -2-oxime-o-methylphenylacetic acid to the methylating agent is 1: 2.31.
further, the synthesis method of the intermediate (E) -2- (methoxyimino) -methyl o-phenylacetate for preparing trifloxystrobin comprises the following steps:
first step, (E) -2-oxime-o-tolylacetic acid or mono-sodium/mono-potassium or di-sodium/di-potassium salt preparation:
adding 2-oxime-o-tolylacetonitrile, sodium hydroxide or potassium hydroxide and water into a reaction bottle, heating to reflux, and intermittently decompressing and steaming to remove methanol; the temperature in the system is continuously raised and finally reaches 106 ℃, and the total time is 6 hours; cooling to room temperature, adding acid to adjust the pH value to 1-2, extracting for 3 times by using ethyl acetate, combining, washing with water, drying and concentrating to obtain g (E) -2-oxime-o-methylphenylacetic acid;
or adding 2-oxime-o-tolylacetonitrile, sodium hydroxide and water into a reaction bottle, heating to reflux, and intermittently decompressing and steaming to remove methanol; the temperature in the system is continuously increased to finally reach 106 ℃, and the total time is 6 hours; cooling to 0 ℃, dropwise adding concentrated hydrochloric acid while stirring until the pH value is 10, directly concentrating the reaction solution, distilling to remove water, and drying to obtain (E) -2-oxime-o-tolylacetic acid monosodium salt/potassium salt;
or adding 2-oxime-o-tolylacetonitrile, sodium/potassium hydroxide and water into a reaction bottle, heating to reflux, and intermittently decompressing to remove methanol. The temperature in the system was raised continuously and finally reached about 106 ℃ for 6 hours. Cooling to 0 ℃, directly concentrating the reaction solution, evaporating to remove water, and drying to obtain (E) -2-oxime-o-tolylacetic acid disodium salt/potassium salt;
second step, preparation of (E) -2- (methoxyimino) -o-methylphenylacetic acid methyl ester:
(E) dissolving 2-oxime-o-tolylacetic acid or its monosodium/monopotassium salt in DMF, adding sodium hydroxide, and stirring at room temperature for 1 hour until the sodium hydroxide particles substantially disappear; then cooling the reaction system to-10-45 ℃, and dropwise adding 1mol of dimethyl sulfate or methyl chloride gas; after dropwise adding or ventilating, maintaining the temperature of-10-25 ℃ for reacting for 2 hours, and intermittently replenishing sodium hydroxide particles; after the liquid phase monitoring shows that the content of the raw materials is less than 1%, the reaction temperature is increased to 0-45 ℃, the stirring is continued for 2 hours, and dimethyl sulfate is intermittently added; then, pouring the reaction solution into ice hydrochloric acid under stirring, separating out a large amount of solids, filtering, washing with water, and drying to obtain (E) -2- (methoxyimino) -o-methylphenylacetic acid methyl ester; the molar ratio of the (E) -2-oxime-o-methylphenylacetic acid to the sodium hydroxide to the methylating agent is 1: 2.42: 2.42; or the molar ratio of the monosodium/monopotassium salt of (E) -2-oxime-o-tolylacetic acid, sodium hydroxide and methylating agent is 1: 1.21: 2.31 of;
or dissolving the disodium salt/dipotassium salt of the (E) -2-oxime-o-tolylacetic acid in DMF, cooling the reaction system to-10 ℃, dropwise adding dimethyl sulfate for 45 minutes, and after dropwise adding, maintaining the temperature at-10 ℃ for reaction for 2 hours. And after the liquid phase monitoring shows that the content of the raw materials is less than 1%, the reaction temperature is increased to 0 ℃, the stirring is continued for 2 hours, and dimethyl sulfate is intermittently supplemented. Then, the reaction solution was poured into ice hydrochloric acid with stirring at a pH of 7, filtered, washed with water, and dried to obtain (E) -methyl 2- (methoxyimino) -o-tolylacetate.
Has the advantages that:
the invention has the following advantages: the method has the advantages of simple route, easily obtained raw materials, mild reaction conditions and suitability for industrial production, a product with a single trans-configuration is obtained, a liquid phase is a single peak, and a hydrogen spectrum is consistent with that reported in literatures. The method comprises the following specific steps:
1. the compound of the formula I obtained by the invention is a necessary intermediate of trifloxystrobin intermediate (E) -2- (methoxyimino) -methyl o-tolylacetate, and has a single trans-configuration. The intermediate has simple synthesis process. The intermediate can be used for realizing the synthesis of the (E) -2- (methoxyimino) -o-methyl phenylacetic acid methyl ester with high yield and high purity by one-step methylation.
2. Patent CN108863845 and document plum red [ the Master thesis of Hebei science and technology university, 2015] are etherified and esterified in two steps, with a yield of 75%. The invention successfully completes two steps and one pot with high yield by using proper alkali and adjusting proper reaction temperature in the synthesis step of (E) -2- (methoxyimino) -o-methyl phenylacetic acid methyl ester, and the yield reaches more than 80%. Can be more obvious than the fractional method: the preparation yield is improved, the resource consumption is reduced, the generation and treatment cost of wastewater and solid waste is reduced, and the preparation production cost is reduced.
3. Similar routes are available as CN108863845 and plum red [ the Master thesis of Hebei science and technology university, 2015], and the raw materials for the two methylation reactions are all from alkaline reaction solution, and need to be adjusted to neutral by adding acid and extracted. The invention can use free acid as methylation raw material, or use mono or bi-sodium salt/sylvite as raw material without acid regulation or partial acid regulation. CN108863845 divides the methylation into two times, and there is a process of repeatedly adjusting alkali and adjusting acid, and the three steps consume 5.4 equivalent of alkali and 4.4 equivalent of acid. According to the second-step methylation reaction, even if free acid is used as a raw material, compared with CN108863845, the use of a part of sub-base is reduced; when the monosodium salt or the monopotassium salt is used as the raw material, the use of one molecule of acid is further reduced, so that the use of one molecule of alkali is reduced in the second step; in the second step, a disodium salt or dipotassium salt raw material is used, so that the use amount of acid in the first step and the use amount of alkali in the second step are further reduced; is beneficial to environmental protection. Further, in the present invention, when the disodium salt/dipotassium salt is used, only 2.29 equivalents of the base are used, and only 0.35 equivalent of the acid is consumed. When the monosodium/monopotassium salt is used, a total of 3.5 equivalents of base and 1.6 equivalents of acid are used. The invention has two steps, which obviously reduces the usage of acid and alkali. From the perspective of controlling three wastes, the waste water and solid waste amount is obviously less. Each of the three steps of patent CN108863845 requires organic solvent extraction. When the monosodium salt/potassium salt or the disodium salt/potassium salt is used as a methylation substrate, an extraction solvent is not needed, and the cost is greatly reduced. When using the free acid as a methylation substrate, the extraction solvent is also used only in the first step; compared with the patent CN108863845, the extraction solvent is used in three steps, so that the cost is still saved. By comprehensive comparison, the technical scheme for preparing the compound shown in the formula I and the (E) -2- (methoxyimino) -methyl o-phenylacetate not only greatly reduces the resource consumption, but also greatly reduces the production and treatment costs of waste water and solid waste, thereby greatly reducing the production cost.
Detailed Description
The invention is further illustrated by the following specific examples, which do not limit the scope of the invention.
Example 1 (free acid for the double methylation reaction)
Preparation of 2-oxime-o-tolylacetonitrile: for example, CN108863845A example 1 is prior art.
Figure BDA0002599868840000071
(E) Preparation of-2-oxime-o-tolylacetic acid:
to a reaction flask, 2-oxime-o-tolylacetonitrile (64.1 g, 0.4mol), 36.6g of sodium hydroxide (0.916mol), 120ml of methanol and 100ml of water were added, heated to reflux, and methanol was distilled off under intermittent reduced pressure. The temperature in the system was raised continuously and finally reached about 106 ℃ for about 6 hours. Cooling to room temperature, adding 230 ml (0.92mol) of 4N hydrochloric acid to adjust the pH value to 1-2, extracting with ethyl acetate for 3 times, combining, washing with water, drying, and concentrating to obtain 68.3 g of (E) -2-oxime-o-methylphenylacetic acid, wherein the content of the trans-configuration is more than 99% and the yield is 95% as shown by a liquid phase.
1H NMR(DMSO-d6，400MHz)δ2..10(s,3H),7.05(d,,J＝7.6Hz,,1H),7.15-7.35(m,3H),12.23(s,1H),12.75-13.24(brs,1H)。
(E) Preparation of methyl (E) -2- (methoxyimino) -o-tolylacetate: 35.8 g of (E) -2-oxime-o-tolylacetic acid (0..2mol) were dissolved in 180ml of DMF, and 17.6 g of sodium hydroxide (0.44mol) were added and stirred at room temperature for about 1 hour until the sodium hydroxide particles substantially disappeared. Then the reaction system was cooled to-10 ℃ and 55.44 g (0.44mol) of dimethyl sulfate was added dropwise over 30 minutes. After the dropwise addition, the reaction is maintained at 25 ℃ for 2 hours, about 1.76 g of sodium hydroxide particles are intermittently supplemented, the reaction temperature is increased to 45 ℃ after the liquid phase monitoring shows that the content of the raw materials is less than 1%, the stirring is continued for 2 hours, and 5.5 g of dimethyl sulfate is intermittently supplemented. Then, the reaction solution was poured into 700 ml of 0.1N (mol/l) glacial hydrochloric acid with stirring, and a large amount of solid was precipitated, filtered, washed with water, and dried to obtain 33.5 g of methyl (E) -2- (methoxyimino) -o-tolylacetate, which was 99% in purity by HPLC and 81% in yield.
1H NMR(CDCl3，400MHz)δ2.19(s,3H),3.87(s,3H),4.05(s,3H),7.11(d,1H,J＝7.9Hz),7.20-7.36(m,3H)。
Example 2 (monosodium salt for double methylation reaction)
Preparation of 2-oxime-o-tolylacetonitrile: for example, CN108863845A example 1 is prior art.
Figure BDA0002599868840000081
(E) Preparation of-2-oxime-o-tolylacetic acid monosodium salt:
Figure BDA0002599868840000082
adding 2-oxime-o-methylbenzonitrile (64.1 g, 0.4mol), 36.6g of sodium hydroxide (0.916mol, 120ml of methanol and 100ml of water) into a reaction bottle, heating to reflux, intermittently reducing pressure to evaporate the methanol, continuously increasing the temperature in the system, finally reaching about 106 ℃, sharing about 6 hours, cooling to 0 ℃, dropwise adding 43 ml of concentrated hydrochloric acid (0.51mol) under stirring, directly concentrating the reaction solution, distilling to remove water, and drying to obtain (E) -2-oxime-o-methylbenzeneacetic acid monosodium salt which is not purified and is directly used for the next methylation reaction, wherein the purity is 99% by HPLC (high performance liquid chromatography).
1H NMR(D2O，400MHz)δ2.19(s,3H)，7.16(d,J＝7.1Hz,1H),,7.24-7.48(m,3H).m/E:202(M+1),224(M+23)
(E) Preparation of methyl (E) -2- (methoxyimino) -o-tolylacetate:
the above monosodium salt of (E) -2-oxime-o-tolylacetic acid (0.4mol) was dissolved in 360ml of DMF, and 17.6 g of sodium hydroxide (0.44mol) was added thereto, followed by stirring at room temperature for about 1 hour until the sodium hydroxide particles were substantially disappeared. Then the reaction system was cooled to-10 ℃ and 111 g (0.88mol) of dimethyl sulfate was added dropwise over 45 minutes. After the dropwise addition, the temperature is maintained at minus 10 ℃, the reaction is carried out for 2 hours, and when the pH value of the reaction solution is lower than 8, about 1.76 g of sodium hydroxide particles are intermittently supplemented to maintain the pH value of the reaction solution at 8-9. Liquid phase monitoring shows that the reaction temperature is increased to 0 ℃ after the content of the raw materials is less than 1 percent, the stirring is continued for 2 hours, and 5.5 grams of dimethyl sulfate is intermittently supplemented. The reaction mixture was then poured into 1.4 l of 0.1N glacial hydrochloric acid with stirring to a pH of 7. Filtration, washing with water and drying gave 71.2 g of methyl (E) -2- (methoxyimino) -o-tolylacetate with a purity of > 99% by HPLC and a yield of 86%.
1H NMR(CDCl3，400MHz)δ2.19(s,3H),3.87(s,3H),4.05(s,3H),7.11(d,1H,J＝7.9Hz),7.20-7.36(m,3H)。
Example 3 (replacement of NaOH by KOH, Mono-Potassium salt/methyl chloride for methylation reaction)
Preparation of 2-oxime-o-tolylacetonitrile: for example, CN108863845A example 1 is prior art.
(E) Preparation of-2-oxime-o-tolylacetic acid monopotassium salt:
Figure BDA0002599868840000091
2-oxime-o-tolylacetonitrile (64.1 g, 0.4mol), 51.3g of potassium hydroxide (0.916mol), 120ml of methanol and 300ml of water were added to a reaction flask, and heated to reflux, and methanol was distilled off under intermittent reduced pressure for about 6 hours, the temperature in the system was continuously increased, and finally reached about 106 ℃ for about 6 hours. Cooling to 0 ℃, dropwise adding 43 ml of concentrated hydrochloric acid (0.51mol) while stirring, directly concentrating the reaction solution, distilling to remove water, and drying to obtain (E) -2-oxime-o-methylphenylacetic acid monopotassium salt which is directly used for the next methylation reaction without purification, wherein the purity detected by HPLC is higher than 99%.
1H NMR(D2O，400MHz)δ2.22(s,3H)，7.19(d,J＝7.1Hz,1H),7.24-7.48(m,3H)。m/E:218(M+1),256(M+39)。
(E) Preparation of methyl (E) -2- (methoxyimino) -o-tolylacetate:
the above monopotassium salt of (E) -2-oxime-o-tolylacetic acid (0.4mol) was dissolved in 500ml of DMF, and 24.6 g of potassium hydroxide (0.44mol) was added thereto, followed by stirring at room temperature for about 1 hour until the potassium hydroxide particles were substantially disappeared. Then, the reaction system was cooled to 0 ℃ and 46.7 g (0.92mol) of methyl chloride gas was introduced thereinto. After the end of the aeration, the reaction was carried out at 0 ℃ for 2 hours. At a pH below 8, additional potassium hydroxide particles of about 2.4 grams were intermittently added and stirring continued at room temperature for 2 hours. Then, the reaction solution was poured into 1.4 liters of 0.1N glacial hydrochloric acid with stirring. Filtration, washing with water and drying gave 68.4 g of methyl (E) -2- (methoxyimino) -o-tolylacetate in 99% purity by HPLC and 83% yield.
Example 4 (Ethyl nitrite for oximation reaction, disodium salt/dimethyl sulfate for bismethylation reaction)
Preparation of 2-oxime-o-tolylacetonitrile: for example, CN108863845A example 1 is prior art.
(E) Preparation of-2-oxime-o-tolylacetic acid disodium salt:
to a reaction flask, 2-oxime-o-tolylacetonitrile (64.1 g, 0.4mol), 36.6g of sodium hydroxide (0.916mol), 120ml of methanol and 100ml of water were added, heated to reflux, and methanol was distilled off under intermittent reduced pressure. The temperature in the system was raised continuously and finally reached about 106 ℃ for about 6 hours. Cooling to 0 ℃, directly concentrating the reaction solution, evaporating to remove water, drying to obtain disodium salt, detecting the content by HPLC to be 99%, and then using the disodium salt for the next reaction.
1H NMR(DMSO-d6，400MHz)δ2.07(s,3H),6.85-7.15(m,4H)。
(E) Preparation of methyl (E) -2- (methoxyimino) -o-tolylacetate:
the disodium salt of (E) -2-oxime-o-tolylacetic acid (0.4mol) was dissolved in 360ml of DMF, and the reaction system was cooled to-10 ℃ and 111 g of dimethyl sulfate (0.88mol) was added dropwise over 45 minutes. After the completion of the dropwise addition, the reaction was carried out for 2 hours while maintaining-10 ℃. Liquid phase monitoring shows that the reaction temperature is increased to 0 ℃ after the content of the raw materials is less than 1 percent, the stirring is continued for 2 hours, and 5.5 grams of dimethyl sulfate is intermittently supplemented. The reaction mixture was then poured into 1.4 l of 0.1N glacial hydrochloric acid with stirring to a pH of 7. Filtration, washing with water and drying gave 70.0 g of (E) -methyl 2- (methoxyimino) -o-tolylacetate with a purity of > 99% by HPLC and a yield of 84%.
Example 5 the first step was the same as example 4, with only the second step being different
The disodium salt (0.4mol) of the (E) -2-oxime-o-tolylacetic acid was dissolved in 360ml of DMSO, the reaction system was cooled to-10 ℃ and 111 g (0.88mol) of dimethyl sulfate was added dropwise, which took 45 minutes. After the completion of the dropwise addition, the reaction was carried out for 2 hours while maintaining-10 ℃. Liquid phase monitoring shows that the reaction temperature is increased to 0 ℃ after the content of the raw materials is less than 1 percent, the stirring is continued for 2 hours, and 5.5 grams of dimethyl sulfate is intermittently supplemented. The reaction mixture was then poured into 1.4 l of 0.1N glacial hydrochloric acid with stirring to a pH of 7. Filtration, washing with water and drying gave 68.4 g of methyl (E) -2- (methoxyimino) -o-tolylacetate with a purity of > 99% by HPLC and a yield of 83%.
Methyl (E) -2- (methoxyimino) -o-tolylacetate in examples 2 to 5 was the same as in example 1 NMR.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (17)

1. An intermediate for preparing trifloxystrobin, which is shown in formula I:
Figure FDA0002887248160000011
wherein M1 is selected from Na, K or H;
m2 is selected from Na, K or H;
and MI and M2 are not H at the same time.
2. The intermediate for the preparation of trifloxystrobin in claim 1, wherein the compound of formula I is selected from the following table:
compound numbering M1 M2 1 Na Na 2 K K 3 Na H 4 H Na 5 K H 6 H K
。
3. A synthetic method of an intermediate for preparing trifloxystrobin in claim 1, comprising the following steps;
(1) when M1 and M2 are K or Na at the same time, adding water and a sodium or potassium-containing base into 2-oxime-o-tolylacetonitrile to carry out reaction;
(2) when one of M1 or M2 is H, the method further comprises the step of adding acid treatment to the product obtained in the step (1).
4. A synthesis process according to claim 3, characterised in that the base is selected from one or more of the following: sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide or sodium tert-butoxide.
5. A synthetic method of an intermediate (E) -2- (methoxyimino) -o-methyl phenylacetic acid methyl ester for preparing trifloxystrobin comprises the following steps:
Figure FDA0002887248160000021
dissolving the intermediate for preparing trifloxystrobin in claim 1 in an organic solvent, and adding a base and a methylating agent for reaction.
6. The method of claim 5, wherein the methylating agent is selected from one or more of the following: methyl chloride, methyl bromide, methyl iodide, dimethyl carbonate, methyl p-toluenesulfonate or dimethyl sulfate.
7. The synthesis method according to claim 5, characterized in that the reaction conditions are: the temperature is-25 to 45 ℃.
8. The synthesis method according to claim 5, which adopts a one-pot method to carry out the following reaction, and comprises the following steps:
Figure FDA0002887248160000022
the first step, preparation of mono-sodium salt/mono-potassium salt or di-sodium salt/di-potassium salt of 2-oxime-o-tolylacetic acid:
(1) when M1 and M2 are K or Na at the same time, adding water and a sodium or potassium-containing base into 2-oxime-o-tolylacetonitrile to carry out reaction;
(2) when one of M1 or M2 is H, the method further comprises the step of adding acid treatment to the product obtained in the step (1); the base is selected from: sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide or sodium tert-butoxide;
second step, preparation of (E) -methyl 2- (methoxyimino) -o-tolylacetate: dissolving the mono-sodium salt/mono-potassium salt or the disodium salt/dipotassium salt of the 2-oxime-o-tolylacetic acid in an organic solvent, adding alkali or not adding alkali and a methylating reagent for reaction to obtain (E) -2- (methoxyimino) -o-tolylacetic acid methyl ester, wherein the alkali is selected from potassium carbonate, sodium hydroxide or potassium hydroxide.
9. The synthesis method according to claim 8, wherein the solvent in the second step reaction is selected from DMF, DMA, DMSO or acetonitrile.
10. The synthesis method according to claim 8, wherein in the first hydrolysis reaction, the alkali is selected from sodium hydroxide or potassium hydroxide, the acid is concentrated hydrochloric acid, and the molar ratio of the acid to the alkali is (1.28-2.30): 2.29;
in the second reaction step, the molar ratio of the mono-sodium salt/mono-potassium salt or the disodium salt/dipotassium salt of the (E) -2-oxime-o-tolylacetic acid, the alkali and the methylating agent is 1: (0-2.42): (2.31-2.42).
11. The method of claim 4, wherein the base is sodium hydroxide or potassium hydroxide.
12. The method of synthesis of claim 6, wherein the methylating agent is methyl chloride, dimethyl carbonate or dimethyl sulfate.
13. The synthesis method according to claim 7, characterized in that the reaction conditions are: the temperature is-10 to 45 ℃.
14. The method of synthesis according to claim 10, characterized in that: the alkali in the first step and the second step is sodium hydroxide or potassium hydroxide.
15. The method of claim 10, wherein the solvent in the second step is DMF or DMSO.
16. The synthesis method according to claim 10, wherein when one of M1 or M2 is H, the molar ratio of acid to base in the first hydrolysis reaction is 1.28: 2.2.
17. the synthesis process according to claim 10, wherein in the second reaction step, the molar ratio of the monosodium/monopotassium salt of (E) -2-oxime-o-tolylacetic acid, base and methylating agent is 1: 1.21: 2.31 of;
or in the second step, the molar ratio of the disodium salt/dipotassium salt of the (E) -2-oxime-o-methylphenylacetic acid to the methylating agent is 1: 2.31.
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