CN113912513B - Preparation method of oximido acetate compound and intermediate thereof - Google Patents

Preparation method of oximido acetate compound and intermediate thereof Download PDF

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CN113912513B
CN113912513B CN202111376217.9A CN202111376217A CN113912513B CN 113912513 B CN113912513 B CN 113912513B CN 202111376217 A CN202111376217 A CN 202111376217A CN 113912513 B CN113912513 B CN 113912513B
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oximido
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CN113912513A (en
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葛尧伦
刘克峰
叶慎争
孔令乐
焦庆全
李碧青
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Qingdao Hengning Biotechnology 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
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
    • C07C17/14—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the side-chain of aromatic compounds
    • 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
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/60—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

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Abstract

The invention discloses a preparation method of an oximido acetate compound intermediate, which uses o-xylene as a starting material, obtains the oximido acetate compound intermediate with high yield and high content through chlorination, cyanidation, oximation, methylation, hydrolysis and esterification reaction, can be directly used in the process of preparing the oximido acetate compound without purification and separation, and can simplify the operation and reduce the production cost; the invention also provides a preparation method of the oximido acetate compound, which has the advantages of simple operation, mild reaction conditions and environmental friendliness; compared with the prior art, the method has the advantages of greatly improved yield, obviously reduced impurity content, mild reaction condition and reduced production cost, and is suitable for industrial production.

Description

Preparation method of oximido acetate compound and intermediate thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an oxime acetate compound and an intermediate thereof.
Background
The Strobilurin bactericide belongs to an agricultural efficient bactericide, has the characteristics of high efficiency, broad spectrum, protection, treatment, permeation, systemic activity, rain wash resistance, long lasting period and the like, is a novel agricultural bactericide with high development potential and high market activity, and the currently commercialized bactericide such as methoxy acrylic acid mainly comprises kresoxim-methyl, azoxystrobin, pyraclostrobin, trifloxystrobin, phenoxymycetan, picoxystrobin and the like, wherein the kresoxim-methyl is the earliest marketed variety, and is developed by BASF (basic group of industrial control system) and marketed in 1996. Trifloxystrobin is a methoxy acrylic acid ester bactericide marketed in 2001, is developed by Syngenta corporation, is mainly used for stem and leaf treatment, has excellent protective activity, has certain therapeutic activity and is not influenced by environment, so that the trifloxystrobin is considered as a second-generation methoxy acrylic acid ester bactericide, and is still active in the front edge of the world agrochemicals field.
The oximido acetate bactericide represented by kresoxim-methyl and trifloxystrobin is characterized in that the pharmacophore part of the bactericide has C=N bond, and (E) alpha-methylimino- (2-o-methylphenyl) methyl acetate is a key intermediate for synthesizing kresoxim-methyl, trifloxystrobin and other compounds. The synthesis research of the intermediate (E) alpha-methylimino- (2-o-methylphenyl) methyl acetate at home and abroad has a plurality of routes, but has the defects. For example, o-methylacetophenone is used as a raw material to prepare the intermediate by oxidation, esterification, oximation and bromination, the route has higher total yield, but a large amount of KMnO is used in the oxidation step 4 And the produced waste water and waste residue are more, so that industrialization is not ideal.
The existing literature reports only pay attention to research yield and purity, do not improve the defects of high boiling point solvent, easy product loss, easy generation of solid waste residues and the like in the prior art, do not meet the requirements of green environmental protection, and have higher industrial production cost. Thus, improvements to existing methods of preparation are highly desirable.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a method for preparing an intermediate of an oxime-based acetate compound, which uses o-xylene as a starting material, and obtains the intermediate of the oxime-based acetate compound in high yield and high content through chlorination, cyanidation, oximation, methylation, hydrolysis and esterification reactions, and can be directly used in the process of preparing the oxime-based acetate compound without purification and separation, thereby simplifying the operation and reducing the production cost; the invention also provides a preparation method of the oximido acetate compound, which is suitable for industrial production.
In order to achieve the above and other related objects, the preparation method of the intermediate of the oximido acetate compound provided by the invention specifically comprises the following steps:
reacting a compound of formula (E) with an alkali metal salt of bromine in an aqueous sulfuric acid solution having a mass fraction of at least 70% to obtain a reaction solution containing a compound of formula (F), and adding C to the reaction solution containing a compound of formula (F) 1-4 Heating alcohols to reflux, and obtaining an oxime acetate compound intermediate shown in a formula (G) through post-treatment after the reaction is finished; r in formula (G) 1 Is C 1-4 An alkyl group.
Still further, R 1 Is methyl.
Further, the molar ratio of the compound of formula E to sulfuric acid to alkali metal salt of bromine is 1:4.0-4.5:0.13-0.15.
Further, the temperature of the sulfuric acid aqueous solution with the mass fraction of more than or equal to 70% is less than or equal to 35 ℃, sodium bromide or potassium bromide is added, then the temperature is raised, the compound of the formula (E) is dropwise added, and the reaction liquid containing the compound of the formula (F) is obtained.
Further, after the temperature is raised to 40-45 ℃, the compound of the formula (E) is dropwise added for 2-2.5 hours, and after dropwise adding, the reaction is carried out for 0.5-1 hour at a constant temperature.
Further, the C 1-4 The alcohols are methanol, ethanol, n-propanol or isopropanol, and the corresponding R 1 Is methyl, ethyl, n-propyl or isopropyl.
Further, C is added to the reaction liquid containing the compound of formula (F) 1-4 Heating the alcohols to reflux, and then preserving the heat for 3-5h.
Further, the post-treatment comprises the steps of removing alcohols from crude product liquid of the compound of the formula (G) obtained after the reaction is finished, adding the crude product liquid into water, stirring and crystallizing, adding a nonpolar solvent for washing, cooling, carrying out suction filtration, and washing a filter cake with water.
Further, the preparation method of the compound of formula (E) is as follows:
at the time of adding R 2 R of ONa 2 Adding a compound of formula (C) into OH, dropwise adding n-butyl nitrite at the temperature of-5-0 ℃, then carrying out heat preservation reaction for 1 hour, then carrying out aftertreatment to obtain a compound of formula (D), reacting the compound of formula (D) with a methylation reagent in toluene added with an inorganic alkaline aqueous solution, and then carrying out aftertreatment to obtain a compound of formula (E); the R is 2 Is C 1-4 An alkyl group.
Still further, the methylating agent is any one of methyl iodide, methyl bromide, dimethyl sulfate and dimethyl carbonate.
Still further, the inorganic base is any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
Still further, the molar ratio of the amount of the material is the compound of formula (D) to the methylating agent to the inorganic base=1:1.1-1.3:1.1-1.5.
Further, the preparation method of the compound of formula (C) is as follows:
adding the compound of the formula (A) into o-xylene, heating and refluxing, introducing chlorine to obtain the compound of the formula (B), adding cyanide into toluene containing tetrabutylammonium bromide, dropwise adding dilute hydrochloric acid, heating to 30-35 ℃, and then adding the compound of the formula (B) to react under the condition of heat preservation to obtain the compound of the formula (C).
Still further, the reflux reaction temperature is 140-145 ℃.
Still further, the chlorine gas is introduced by using ultraviolet light to perform a photocatalytic reaction.
Still further, the molar ratio of o-xylene to chlorine flux is 1:2-2.5.
Still further, the step of preparing the compound of formula (C) from the compound of formula (B) is specifically: toluene is taken as a solvent, sodium cyanide and tetrabutyl sodium bromide are added, hydrochloric acid is added dropwise, then the compound of the formula (B) is added dropwise at a certain temperature, the reaction is carried out for 2 hours at a certain temperature, water is washed, the solvent is removed by reduced pressure distillation, and the compound of the formula (C) is obtained by distillation;
still further, the temperature of the dropwise addition of hydrochloric acid is 25-30 ℃, and the temperature of the dropwise addition of the compound of formula (C) is 30-35 ℃;
the invention also provides a method for preparing the oximido acetate compound, which comprises the following specific steps:
the compound of formula (G) is prepared according to the preparation method, and the compound of formula (H) and R are obtained after bromination 3 OH reacts to obtain the oximido acetate compound shown in the formula (I).
Further, the bromination is performed in the presence of hydrogen peroxide and hydrobromic acid.
By adopting the technology, compared with the prior art, the invention has the remarkable advantages that:
1) The present invention relates to the use of sulfuric acid systems for hydrolysis in the preparation of compounds of formula (F) and in particular to the addition of alkali metal salts of bromine by studying the reaction mechanism and discussing the factors influencing the reaction and the cause of the generation of impurities; the alkali metal salt of bromine is easy to dissolve in water, can react with a sulfuric acid system to generate hydrogen bromide, can be combined with a compound of a formula (E) to provide an acyl bromide intermediate, and the alpha-halogen atom of the intermediate can enhance the hydrolysis process of cyano through induction, so that the hydrolysis of cyano is promoted, the product yield is improved, and the problems of low hydrolysis yield and incomplete reaction are greatly improved;
2) According to the technical scheme, sulfuric acid is used for hydrolyzing cyano into acid, esterification is continuously carried out, and meanwhile, the conversion of the compound configuration is carried out, so that the product with the E-type target is obtained, the content is high, and the conversion rate is good;
3) The technical scheme of the invention has the advantages of simple operation, mild reaction conditions and environmental friendliness; meanwhile, compared with the prior art, the method has the advantages of greatly improved yield, obviously reduced impurity content, mild reaction condition and reduced production cost, and is suitable for industrial production.
Detailed Description
For a better understanding of the present invention, the present invention will be described in further detail with reference to the following specific examples. These examples are given to illustrate the main reaction and essential features of the present invention, and are not limited to the following examples, which may be further modified according to specific requirements, but are not specified in general.
The invention will be further illustrated by the following description of examples in conjunction with the accompanying examples.
Example 1
Synthesis of Compound B:
200ml of o-xylene (1.655 mol) was added to a 500ml reaction flask, heated to reflux, then chlorine gas (about 80g/h,3.31 mol) was introduced under ultraviolet light, the reaction progress was monitored by GC method, ventilation was continued for more than 2 hours, and the chlorination reaction was stopped. 198.5g of the product obtained under the conditions of 100-102 ℃/10mmHg is distilled and collected, the yield is 83.6%, and the purity is 98%.
Example 2
Synthesis of Compound C:
a500 ml reaction flask was charged with 172.5g (1.856 mol) of toluene, 0.36g (1.092 mmol, hereinafter referred to as TBAB) of tetrabutylammonium bromide, 45.9g (281.2 mmol) of 30% aqueous sodium cyanide solution, and 5.2g (27.3 mmol) of diluted hydrochloric acid was added dropwise at a temperature of 25 to 30℃for 20 minutes. 39.2g (purity 98%,273 mmol) of o-methylbenzyl chloride is added at the temperature of 30-35 ℃ and the dripping is completed within 1.0-1.5 h. Preserving heat for 1h, sampling and analyzing, wherein the o-methylbenzyl chloride is less than or equal to 1.0%, the o-methylbenzonitrile is more than or equal to 96.0%, and preserving heat can be continued after the unreacted reaction is finished. After the heat preservation is completed, water is added for washing, after the water layer is removed, the toluene is removed from the organic phase by a water pump under negative pressure, the solvent residue is reduced to below 1%, and the crude product is cooled. The temperature is reduced to below 30 ℃, oil pump negative pressure distillation is used, the bottom temperature is 140 ℃, heating is stopped, and the bottom residue is treated, thus obtaining 31.3g of product with the yield of 85.6 percent and the content of 98 percent.
Example 3
Synthesis of Compound C:
into a 500ml reaction flask were charged 183.7g (1.856 mmol) of dichloroethane, 0.36g (1.092 mmol) of TBAB, 45.9g (281.2 mmol) of 30% aqueous sodium cyanide solution, and 5.2g (27.3 mmol) of dilute hydrochloric acid was added dropwise at 25-30℃for 20 min. 39.2g (273 mmol) of o-methylbenzyl chloride is added dropwise at the temperature of 30-35 ℃ within 1.0-1.5 h. Preserving heat for 1h, sampling and analyzing, wherein the o-methylbenzyl chloride is less than or equal to 1.0%, the o-methylbenzonitrile is more than or equal to 96.0%, and preserving heat can be continued after the unreacted reaction is finished. After the heat preservation is completed, water is added for washing, after the water layer is removed, the toluene is removed from the organic phase by a water pump under negative pressure, the solvent residue is reduced to below 1%, and the crude product is cooled. The temperature is reduced to below 30 ℃, oil pump negative pressure distillation is used to reach the bottom temperature of 140 ℃, heating is stopped, and bottom residue is treated. 29.4g of a product was obtained, the yield was 80.4% and the content was 98%.
Example 4
Synthesis of Compound D:
to the reaction flask were added ethanol (30 ml), naOEt (8.5 g,125.5 mmol), and after stirring, the temperature was lowered to 0℃and 14g of o-methylbenzonitrile (purity 98%, 104.6 mmol) solution was added dropwise to the solution. N-butyl nitrite (14.1 g,136 mmol) is added dropwise at the temperature of-5-0 ℃, after the dropwise addition is finished and the temperature is kept for 1 hour, ethyl acetate is added into the system, hydrochloric acid, sodium bicarbonate aqueous solution and water are used for washing, and the reaction solution is desolventized; ethyl acetate/cyclohexane was added for recrystallization to give 16.1g of compound D crystals, which were dried, yield 93.2%, content 97%.
Example 5
Synthesis of compound E:
compound D (purity 97%,16.1 g), toluene (50 g) and 10% aqueous sodium hydroxide solution (0.12 mol,5 g) were put into a four-necked flask, cooled to 7-10 ℃, dimethyl sulfate (0.12 mol,15.5 g) was added dropwise into the system, the temperature was kept at 15-20 ℃ for 1h, after the temperature was kept at 15-20 ℃, the solvent was recovered by desolventizing, 50g of water was continuously added into the system, and after stirring, the mixture was suction-filtered to obtain compound e16.2g, yield 93.5%, content 98%.
Example 6
Synthesis of compound F:
into a 250ml four-necked flask, water (14 g,0.778 mol) and 98% by mass of concentrated sulfuric acid (90 g,0.900 mol) were added, respectively, and the mixture was cooled to 30℃or lower under stirring. Sodium bromide (3.1 g,0.03 mol) was added to the system and the temperature was raised to 40-45 ℃ (note bromine formation). And (3) dropwise adding the compound E (with the purity of 98 percent and 16.2 g) at the temperature of 40-45 ℃ for 2-2.5h, carrying out heat preservation reaction at the temperature of 45 ℃ for 0.5h after the dropwise adding, sampling, controlling the concentration, controlling the raw material to be less than 1 percent, and obtaining the reaction solution of the compound F after the reaction.
Example 7
Synthesis of Compound G:
adding the obtained reaction solution of the compound F into a 250ml four-neck flask, continuously adding methanol (200 g) into the system, heating to reflux, carrying out heat preservation reaction for 3-5h, and carrying out HPLC (high performance liquid chromatography) central control, wherein the compound F is less than 1%; cooling to 20-25deg.C, keeping the temperature for 6-8h, and controlling Z type in HPLC to be less than 3%; and after the reaction is finished, removing methanol to obtain crude product liquid of the compound G. 100G of water is added into the other four-mouth bottle, the temperature is reduced to 5-10 ℃, the crude product liquid of the compound G is poured into the bottle, stirring crystallization is carried out, 40G of petroleum ether is added, beating washing is carried out, the temperature is reduced to below 0 ℃, suction filtration is carried out, the filter cake is added with water and washed to be neutral, 17.6G of the compound G is obtained, and the yield is 91.3% (based on the compound E) and the content is 98%.
Example 8
Synthesis of Compound G:
the obtained reaction solution of the compound F is respectively added into a 250ml four-neck flask; continuously adding methanol (200G) into the system, heating to 75 ℃ for reflux, preserving heat for reaction for 4 hours, and removing the methanol after the reaction is finished to obtain crude product liquid of the compound G. 100G of water is added into the other four-mouth bottle, the temperature is reduced to 5 ℃, the crude product liquid of the compound G is poured into the bottle, the mixture is stirred and crystallized, 40G of cyclohexane is added, the mixture is pulped and washed, the temperature is reduced to below 0 ℃, suction filtration is carried out, the filter cake is added with water and washed to be neutral, and the compound G17.9G is obtained, and the yield is 92.8% (based on the compound E), and the content is 98 percent.
Example 9
Synthesis of Compound G:
the obtained reaction solution of the compound F is respectively added into a 250ml four-neck flask; continuously adding methanol (200G) into the system, heating to 80 ℃ for reflux, preserving heat for reaction for 4 hours, and removing the methanol after the reaction is finished to obtain crude product liquid of the compound G. 100G of water is added into the other four-mouth bottle, the temperature is reduced to 5 ℃, the crude product liquid of the compound G is poured into the bottle, the mixture is stirred and crystallized, 40G of normal hexane is added, the mixture is pulped and washed, the temperature is reduced to below 0 ℃, suction filtration is carried out, the filter cake is added with water and washed to be neutral, 17.8G of the compound G is obtained, and the yield is 90.4% (based on the compound E), and the content is 96%.
Example 10
Synthesis of compound H:
50G (purity 98%,0.236 mol) of the compound G prepared by the method is added into a 500ml four-neck flask, hydrogen peroxide (30%, 41.5G) and hydrobromic acid (48%, 44.4G) are added dropwise for bromination reaction, and the organic phase is desolventized to prepare a brominated product, namely 66.8G of compound H, with a yield of 95.8% and a content of 97%.
Example 11
Synthesis of Compound I (trifloxystrobin):
continuously adding 125g of DMF, 52.7g of m-trifluoromethyl acetophenone oxime and 14g of sodium methoxide into a reaction bottle with the compound H; the stirring temperature is controlled to be 25-30 ℃, the temperature is kept for 2 hours, the ketoxime in the liquid phase is less than 0.5%, the reaction is qualified, the reaction liquid is transferred into a crystallization reaction bottle which is added with 150g of ice-water mixture in advance, the temperature is controlled to be-5-0 ℃, the temperature is reduced to-5 ℃, the filtration is carried out, and the crude trifloxystrobin is obtained after leaching. Adding crude product, methanol and water into a recrystallization bottle, heating and refluxing until the crude product of trifloxystrobin is fully dissolved, then starting cooling crystallization, slowly cooling to-5 ℃, preserving heat for 1 hour, filtering, leaching for 1 time by using a small amount of cold methanol, and drying a filter cake to obtain 85.7G of trifloxystrobin product, wherein the yield is 90% (calculated by the compound G), and the content is 98%.
Example 12
Synthesis of Compound I (kresoxim-methyl):
adding 125G of DMF, 28G of o-methylphenol, 65.2G of potassium carbonate and a small amount of cuprous chloride into a four-mouth bottle with the compound H, heating to 70 ℃, refluxing for 2 hours, filtering, distilling the filtrate to recover the solvent, adding methanol for recrystallization, cooling, suction filtering, and drying the filter cake to obtain 69.3G of kresoxim-methyl product with the yield of 91.7% (calculated by the compound G) and the content of 98%.
The above embodiments are only preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the protection scope of the present invention should be defined by the claims, including the technical equivalents of the technical features in the claims, as the protection scope, that is, the equivalent replacement and improvement within the protection scope of the present invention.

Claims (7)

1. A preparation method of an oxime acetate compound intermediate is characterized by comprising the following steps:
adding sodium bromide or potassium bromide into a sulfuric acid aqueous solution with the mass fraction of more than or equal to 70% at the temperature of less than or equal to 35 ℃, heating and dropwise adding the compound of the formula (E) to react to obtain a reaction solution containing the compound of the formula (F), heating to 40-45 ℃, dropwise adding the compound of the formula (E) for 2-2.5h, reacting for 0.5-1h at the temperature of the dropwise adding, and adding C into the reaction solution containing the compound of the formula (F) 1-4 Heating alcohols to reflux, and obtaining an oxime acetate compound intermediate shown in a formula (G) through post-treatment after the reaction is finished; r in formula (G) 1 Methyl, ethyl, n-propyl or isopropyl; the C is 1-4 The alcohol is methanol, ethanol, n-propanol or isopropanol.
2. The process according to claim 1, wherein C is added to the reaction mixture containing the compound of the formula (F) 1-4 Heating the alcohols to reflux, and then preserving the heat for 3-5h.
3. The preparation method according to claim 2, wherein the post-treatment comprises removing alcohols from the crude solution of the compound of formula (G) obtained after the reaction, adding the crude solution into water, stirring for crystallization, adding a nonpolar solvent for washing, cooling, filtering, and washing a filter cake with water.
4. The process according to claim 1, wherein the process for the preparation of the compound of formula (E) is as follows:
at the time of adding R 2 R of ONa 2 Adding a compound of formula (C) into OH, dropwise adding n-butyl nitrite at the temperature of-5-0 ℃, then carrying out heat preservation reaction for 1 hour, then carrying out aftertreatment to obtain a compound of formula (D), reacting the compound of formula (D) with a methylation reagent in toluene added with an inorganic alkaline aqueous solution, and then carrying out aftertreatment to obtain a compound of formula (E); the R is 2 Is C 1-4 An alkyl group.
5. The process according to claim 4, wherein the process for preparing the compound of formula (C) is as follows:
adding the compound of the formula (A) into o-xylene, heating and refluxing, introducing chlorine to obtain the compound of the formula (B), adding cyanide salt into toluene containing tetrabutylammonium bromide, dropwise adding dilute hydrochloric acid, heating to 30-35 ℃, and then adding the compound of the formula (B) to react under the condition of heat preservation to obtain the compound of the formula (C).
6. A method for preparing an oximido acetate compound is characterized by comprising the following specific steps:
wherein R is 3 Representation->Or (b)The method comprises the steps of carrying out a first treatment on the surface of the The process according to any one of claims 1 to 5, wherein the compound of formula (G) is obtained by bromination of a compound of formula (H), wherein the compound of formula (H) is obtained by reacting R 3 OH reacts to obtain the oximido acetate compound shown in the formula (I).
7. The process of claim 6, wherein the bromination is carried out in the presence of hydrogen peroxide and hydrobromic acid.
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