Synthesis method of (E)-2-methyl-alpha-methoxyimino methyl phenylacetate

Abstract

The invention relates to the technical field of organic synthesis, and discloses a synthesis method of (E)-2-methyl-alpha-methoxyimino methyl phenylacetate. According to the invention, o-methyl phenylacetonitrile is used as a raw material, and a series of steps such as oximation, first methylation, alkaline hydrolysis, second methylation and acidic rearrangement are carried out to obtain (E)-2-methyl-alpha-methoxyimino methyl phenylacetate. According to the method provided by the invention, the byproduct salt amount is greatly reduced, and the atom utilization rate is greatly improved; the organic solvent dosage is reduced, and the equipment utilization rate is greatly improved; according to the method, methylation reaction conditions are optimized, high reaction activity is obtained while the use amount of a methylation reagent is reduced, meanwhile, excessive methane chloride needing to be recycled is greatly reduced due to the fact that the use amount of methane chloride is reduced, the tail gas treatment amount is small, equipment is relatively simple, and the operation cost is low; besides crystallization operation, the whole reaction process is gas-liquid or liquid-liquid reaction, so that the mass and heat transfer effect is improved, and subsequent continuous transformation is facilitated.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester. Background Art

[0002] (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester (oxime ether) is a key intermediate of the methoxyacrylate fungicides trifloxystrobin, kresoxim-methyl, orysastrobin, kresoxim-methyl, and enoxamyl. The main synthesis process is as follows: Route 1: o-Toluoyl nitrile process US5332752 provides a method for obtaining methyl o-methyl benzoyl nitrile by acidolysis and esterification using o-methyl benzoyl nitrile as a starting material. Methyl o-methyl benzoyl nitrile is further reacted with methoxyamine hydrochloride to obtain (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, which can be further subjected to acid rearrangement to obtain the target product (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester. The process is as follows: .

[0003] Route 2: o-Toluidine process Li Yan et al. (Stereoselective Synthesis and Biological Activity Study of (αE,E)-α(Methoxyimino)-2-[1-(Aromatic Aldehyde Ketoximo)methyl]phenylacetic Acid Methyl Ester, Organic Chemistry, 2006, 26 (1), 110-115) and Chai Bing et al. (New Process for Synthesis of Trifloxystrobin, Pesticides, 2013, 52 (4), 258-259) used o-methylaniline as the starting material and obtained the target product (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester through diazotization, coupling and methylation. The yields were 37.3% and 62.6% respectively based on o-methylaniline diazonium hydrochloride. The process is as follows: .

[0004] Route 3: o-bromotoluene process CN108250102B provides a process using o-bromotoluene as a raw material, first reacting with zinc to generate 2-methylphenylzinc bromide, and then reacting with 2-chloro-2-(methoxyimino)acetic acid methyl ester in the presence of a palladium catalyst, or a palladium catalyst and a palladium catalyst ligand, or a nickel catalyst and a nickel catalyst ligand to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, wherein 2-chloro-2-(methoxyimino)acetic acid methyl ester is obtained by oximation of methoxyamine hydrochloride with oxalyl chloride monomethyl ester and then halogenation or esterification of methoxyamine glyoxylate methyl ester, with a maximum yield of 91%. The process has the following problems: the raw material methoxyamine hydrochloride is expensive, the synthesis process requires the use of precious metals or ligand-containing catalysts, and it involves a dangerous process Grignard reaction, which requires quenching. The process is as follows: .

[0005] Route 4: o-Methylphenylacetonitrile process Zhu Xiaomeng (Master's thesis of Shandong Normal University, 2013) reported a method for preparing (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester from o-methylbenzene acetonitrile through oximation, acidification, etherification, alkaline hydrolysis and esterification, with a total reaction yield of 60.75%. Although the yield is low, it is more suitable for industrial production because the raw materials are readily available and cheap. The process has the following problems: theoretically, the production of 1 mol of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester will produce more than 3 mol of salt as a by-product (in actual reaction, excess base is required to promote the reaction, and the amount of by-product salt is higher). In addition, when dimethyl sulfate is used as the methylation reagent, monomethyl sulfate salt is produced as a by-product, and the post-treatment requires the consumption of base for hydrolysis, resulting in a large amount of wastewater and difficulty in treatment. The process is as follows: .

[0006] Li Renhong (Master's thesis of Hebei University of Science and Technology, 2015) also used o-methylbenzene acetonitrile as the starting material, and after oximation and methyl etherification, alkaline hydrolysis was performed to obtain (E / Z)-2-methyl-α-methoxyiminophenylacetic acid, and then sulfuric acid-catalyzed methanol esterification was used to obtain the target product (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester. The total yield of synthesizing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester was 54.7% based on o-methylbenzene acetonitrile. The process theoretically produces 1 mol of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and produces 3 mol of salt (acidification, methylation, alkaline hydrolysis); although the amount of dimethyl sulfate was reduced by 50%, due to the poor thermal stability of (E)-2-methyl-α-methoxyiminophenylacetic acid, it decomposed during the sulfuric acid-catalyzed esterification process, resulting in a low final yield. The process is as follows: .

[0007] CN112851546B uses 2-methyl-α-hydroxyiminophenylacetonitrile as raw material, obtains 2-methyl-α-hydroxyiminophenylacetic acid through alkaline hydrolysis and acidification, separates and adds polar organic solvents such as DMF, acetonitrile, DMSO, etc., forms salt in the presence of alkaline substances, and then reacts with methylating agents such as dimethyl sulfate and methyl halide to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester. Based on 2-methyl-α-hydroxyiminophenylacetonitrile, the total yield of the reaction reaches 82.5~86.5%, and the cost is reduced. The reaction process is as follows: .

[0008] However, the process theoretically produces 1 mol of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and produces more than 4 mol of NaCl as a by-product, resulting in low atomic utilization and large wastewater volume, which increases the energy consumption of post-processing. In addition, the methylation process requires a large amount of hydrophilic polar solvents to disperse insoluble salt-forming intermediates. For example, in the embodiment, when the solvent is DMF, the amount (by mass) is 6.4 times that of 2-methyl-α-hydroxyiminophenylacetic acid; when the solvent is acetonitrile, the amount (by mass) is 8.7 times that of 2-methyl-α-hydroxyiminophenylacetic acid. Therefore, it not only reduces the equipment capacity, but also produces a large amount of aqueous waste mixed solvent. In addition, since methyl bromide and methyl iodide are too expensive, methyl chloride is usually used as a methylating agent in industrial production. However, methyl chloride has lower reactivity than methyl bromide and methyl iodide. Generally, a large excess of methyl chloride is required in the reaction process to promote the complete conversion of 2-methyl-α-hydroxyiminophenylacetic acid. For example, in Examples 8 and 10, the amount of methyl chloride added (in molar amount) is 5 times that of 2-methyl-α-hydroxyiminophenylacetic acid, and the theoretical excess is 3 times (data from the examples). After the reaction is completed, a device for recovering a large amount of methyl chloride needs to be added, which increases the equipment investment cost, and also incurs additional costs for ensuring the safe operation of the methyl chloride recovery device.

[0009] CN110396054B also uses o-methylbenzene acetonitrile as the starting material, and obtains (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester through oximation, methylation, hydrolysis and esterification. The reaction process is as follows: .

[0010] Compared with CN112851546B, the amount of by-product salt in CN110396054B is reduced, and the theoretical by-product salt of synthesizing 1 mol of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester is 2 mol. However, in the process of preparing 2-methyl-α-methoxyiminophenylacetonitrile from 2-methyl-α-cyanobenzyloxime or 2-methyl-α-cyanobenzyloxime salt, it is still necessary to add 4 to 6 times the amount of organic solvent of 2-methyl-α-cyanobenzyloxime or 2-methyl-α-cyanobenzyloxime salt to disperse the insoluble salt-forming intermediate (data from the examples), resulting in a significant reduction in equipment utilization. In addition, when preparing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester by methylation of 2-methyl-α-methoxyiminophenylacetonitrile, although the reaction is carried out in an aqueous solvent, the methylation reagent B used is dimethyl sulfate, which has a relatively high activity. An equal amount of monomethyl sulfate salt is produced as a byproduct and enters the aqueous phase, and needs to be hydrolyzed into sulfate and methanol, which makes wastewater treatment difficult and costly. Alternatively, methyl bromide or methyl iodide, which are extremely expensive, are not conducive to large-scale industrial production.

[0011] Therefore, it is urgent to develop a method for synthesizing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester with less by-product salt, less methylation reagent and organic solvent, simple post-treatment, and suitable for industrial production. Summary of the invention

[0012] The purpose of the present invention is to overcome the problems existing in the prior art and to provide a method for synthesizing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0013] In order to achieve the above object, the present invention provides a method for synthesizing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, wherein the method comprises the following steps: (1) Using o-methylbenzeneacetonitrile as a raw material, 2-methyl-α-cyanobenzyloxime salt solution is obtained through oximation reaction; (2) adding a first catalyst to the 2-methyl-α-cyanobenzyl oxime salt solution obtained in step (1), and continuously passing chloroform under closed system conditions to carry out a first methylation reaction to obtain an oily substance; and subjecting the oily substance to alkaline hydrolysis to obtain a 2-methyl-α-methoxyiminophenyl acetate solution; (3) adding a first organic solvent and a second catalyst to the 2-methyl-α-methoxyiminophenylacetic acid salt solution obtained in step (2), and passing chloroform in a closed system to carry out a second methylation reaction to obtain a (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester solution; (4) A solution of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester is subjected to acidic rearrangement to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0014] Through the above technical solution, the beneficial technical effects achieved by the present invention are as follows: (1) The method provided by the present invention has greatly improved atomic utilization, greatly reduced by-product salt amount, low energy consumption, reduced organic solvent usage, and greatly improved equipment utilization; (2) The present invention optimizes the conditions of the methylation reaction, thereby reducing the amount of methylation reagent used and obtaining high reaction activity. At the same time, the amount of methyl chloride used is reduced, so that the excess methyl chloride that needs to be recovered and treated is greatly reduced, the tail gas treatment amount is small, the equipment is relatively simple, and the raw material and operating costs are reduced; (3) In the prior art, the methylation process adopts a gas-liquid-solid three-phase reaction system. In the present invention, except for the crystallization operation, the entire reaction process is a gas-liquid or liquid-liquid reaction, which improves the mass transfer and heat transfer efficiency and provides technical support for continuous production. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 13 is a material state comparison diagram of Example 1, Comparative Example 2-2, Comparative Example 3 and Comparative Example 4 of the present invention, wherein A is the liquid separation state of step 3) of Example 1; B is the esterification material state of Comparative Example 2-2; C is the esterification material state of Comparative Example 3; and D is the material state of Comparative Example 4 before methylation. DETAILED DESCRIPTION

[0016] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0017] The present invention provides a method for synthesizing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, wherein the method comprises the following steps: (1) Using o-methylbenzeneacetonitrile as a raw material, 2-methyl-α-cyanobenzyloxime salt solution is obtained through oximation reaction; (2) adding a first catalyst to the 2-methyl-α-cyanobenzyl oxime salt solution obtained in step (1), and continuously passing chloroform under closed system conditions to carry out a first methylation reaction to obtain an oily substance; and subjecting the oily substance to alkaline hydrolysis to obtain a 2-methyl-α-methoxyiminophenyl acetate solution; (3) adding a first organic solvent and a second catalyst to the 2-methyl-α-methoxyiminophenylacetic acid salt solution obtained in step (2), and passing chloroform in a closed system to carry out a second methylation reaction to obtain a (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester solution; (4) A solution of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester is subjected to acidic rearrangement to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0018] In the present invention, after the oximation reaction is completed, the reaction solution is directly methylated without adding any additional organic solvent; after the methylation reaction, phase separation treatment is performed, and the catalyst in the aqueous phase can be directly reused after desalting (concentration or nanofiltration). Therefore, compared with the prior art, the amount of organic solvent used in the present invention is reduced (more than 50%), and the equipment utilization rate is significantly improved.

[0019] The present invention avoids using dimethyl sulfate, a highly toxic chemical with low atomic utilization rate, and monobromomethane and monoiodomethane with high cost as methylating agents, and uses monochloromethane with low cost as methylating agents, and improves its reaction activity by adding a catalyst. Meanwhile, by passing monochloromethane into a closed reaction system for reaction to increase the concentration of monochloromethane in the system (much lower than the amount of monochloromethane required for dissolving DMF and acetonitrile to saturation), the atomic utilization rate and equipment utilization rate are improved, and the cost of treating excessive monochloromethane is reduced.

[0020] In the present invention, the reaction solution obtained after the second methylation reaction can be phase-separated, and the oil phase (still in the form of solution) can be acid rearranged to obtain the target product. The present invention can obtain a higher conversion rate of the raw material (o-methylbenzene acetonitrile).

[0021] The reaction route is as follows: .

[0022] in," " means that the compound includes cis isomers and trans isomers.

[0023] In some embodiments of the present invention, in step (1), the 2-methyl-α-cyanobenzaldehyde salt is 2-methyl-α-cyanobenzaldehyde sodium and / or 2-methyl-α-cyanobenzaldehyde potassium.

[0024] In some embodiments of the present invention, in step (2), the first catalyst is selected from at least one of tetrabutylammonium bromide (TBAB), benzyltriethylammonium bromide (TEBAB), benzyltriethylammonium chloride (TEBAC) and dodecyltrimethylammonium bromide (DTAB).

[0025] In some embodiments of the present invention, the molar ratio of the first catalyst to o-methylphenylacetonitrile is 0.03-0.08:1, or 0.05-0.06:1.

[0026] In some embodiments of the present invention, the temperature of the first methylation reaction is 20-40°C, or 25-35°C, or 25-27°C, or 28-30°C, or 33-35°C.

[0027] In some embodiments of the present invention, the pressure of the first methylation reaction is 0.25-0.45 MPa, or 0.30-0.40 MPa, or 0.30-0.32 MPa, or 0.33-0.35 MPa, or 0.36-0.38 MPa, or 0.38-0.40 MPa.

[0028] In some embodiments of the present invention, the first methylation reaction time is 6 to 12 hours, or 7 to 10 hours.

[0029] In some embodiments of the present invention, in step (2), alkaline hydrolysis is performed using sodium hydroxide solution and / or potassium hydroxide solution.

[0030] In some embodiments of the present invention, the temperature of the alkaline hydrolysis is 90-105°C, or 100-105°C.

[0031] In some embodiments of the present invention, in step (3), the first organic solvent is a water-insoluble organic solvent, preferably at least one selected from 1,2-dichloroethane, toluene, dichloromethane and xylene.

[0032] The present invention selects a non-water-soluble organic solvent and water (from a sodium 2-methyl-α-methoxyiminophenylacetic acid solution) as a methylation mixed solvent, directly separates the phases after the reaction is completed, and can be recycled after reduced pressure distillation, thereby avoiding the problem of complicated post-treatment of water-soluble solvents such as DMF, acetonitrile, DMSO, etc. conventionally used in the current oximation-methylation process route, and the problem of excessively high treatment costs caused by the need for water removal treatment before recycling.

[0033] In some embodiments of the present invention, the second catalyst is a complex of a phase transfer catalyst and an iodide, such as a metal iodide.

[0034] In some embodiments of the present invention, the phase transfer catalyst is selected from at least one of tetrabutylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide or dodecyltrimethylammonium bromide.

[0035] In some embodiments of the present invention, the iodide is sodium iodide and / or potassium iodide.

[0036] In some embodiments of the present invention, the second catalyst is selected from at least one of a complex of tetrabutylammonium bromide and sodium iodide, a complex of benzyltriethylammonium chloride and potassium iodide, a complex of benzyltriethylammonium bromide and potassium iodide, and dodecyltrimethylammonium bromide and sodium iodide.

[0037] In some embodiments of the present invention, the molar ratio of the phase transfer catalyst, iodide and o-methylphenylacetonitrile is (0.036~0.15):(0.02~0.1):1, or 0.07:0.036:1, or 0.1:0.05:1, or 0.15:0.06:1, or 0.1:0.1:1, or 0.036:0.02:1, or 0.1:0.06:1, or 0.1:0.05:1.

[0038] In some embodiments of the present invention, the temperature of the second methylation reaction is 50-75°C, or 60-75°C, or 65°C.

[0039] In some embodiments of the present invention, the pressure of the second methylation reaction is 0.25~1.1MPa, or 0.25~0.45MPa, or 0.3~0.4MPa, or 0.34~0.35MPa, or 0.35~0.36MPa, or 0.38~0.40MPa, or 0.39~0.41MPa, or 0.42~0.44MPa.

[0040] In some embodiments of the present invention, the second methylation reaction time is 5 to 10 hours, or 6 to 9 hours, or 7 hours.

[0041] In some embodiments of the present invention, in step (3), after the (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester solution is desolventized, a second organic solvent and an acidic catalyst are added to carry out acidic rearrangement.

[0042] In some embodiments of the present invention, the acidic catalyst is sulfuric acid and / or HCl.

[0043] In some embodiments of the present invention, the second organic solvent is methanol and / or ethanol.

[0044] In some embodiments of the present invention, the temperature of the acidic rearrangement is 10-70°C, or 20-60°C.

[0045] In some embodiments of the present invention, the acidic rearrangement time is 1 to 10 hours, or 2 to 8 hours.

[0046] In some embodiments of the present invention, after the acidic rearrangement is completed, the temperature is lowered and crystallization is performed to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0047] In some embodiments of the present invention, the crystallization is carried out by cooling and filtering, and the second organic solvent is used for elution to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0048] In some embodiments of the present invention, the mother liquor and / or the eluent after the cooling and crystallization are recycled for the acidic rearrangement.

[0049] The present invention will be described in detail below through examples.

[0050] In the following examples and comparative examples, if no specific conditions are specified, the experiments were carried out under conventional conditions. The reagents or instruments used, if no manufacturer is specified, are conventional products that can be obtained through commercial channels.

[0051] Example 1 This example is used to illustrate the preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0052] (1) Preparation of 2-methyl-α-cyanobenzyloxime sodium Add 66.2g (0.5mol) of o-methylbenzeneacetonitrile, 33g of methanol and 75.0g of liquid sodium hydroxide (content 32%, 0.6mol) into a four-necked bottle, control the temperature of the feed liquid at 34-37°C, and continue to slowly introduce 40.1g of methyl nitrite (content 99%, 0.65mol) for 8h. After the ventilation is completed, keep warm for 2h to obtain 211.3g of 2-methyl-α-cyanobenzaldehyde sodium solution. The remaining o-methylbenzeneacetonitrile external standard content is 0.41%, and the conversion rate of o-methylbenzeneacetonitrile is 98.68%.

[0053] (2) Preparation of sodium 2-methyl-α-methoxyiminophenylacetate 8.2 g of TBAB (content 99%, 0.025 mol) was added to the sodium 2-methyl-α-cyanobenzyloxime solution obtained in step (1), and the mixture was transferred into an autoclave. The temperature of the feed liquid was controlled at 28-30 ° C. The system was sealed, and methyl chloride was continuously introduced and the system pressure was controlled at 0.38-0.40 MPa. The reaction was completed after 6 h of heat preservation. The pressure was released (the tail gas was absorbed by excess DMF, and the weight was increased by 9.0 g, which was equivalent to 0.18 mol of excess methyl chloride). The material was discharged and phase separated to obtain 89.7 g of an oily substance (containing (E / Z)-2-methyl-α-methoxyiminophenylacetonitrile and (E / Z)-2-methyl-α-methoxyiminophenylacetamide). The weight of the aqueous phase was 160 g.

[0054] 89.7 g of the oily substance obtained by the above phase separation was transferred into a four-necked bottle, and 87.5 g of liquid alkali (content 32%, 0.7 mol) and 52.5 g of water were added. The temperature was raised to 100°C for alkaline hydrolysis. The (E / Z)-2-methyl-α-methoxyiminophenylacetamide content was controlled to be less than 1%. After the reaction, 218 g of 2-methyl-α-methoxyiminophenylacetic acid sodium solution was obtained (E:Z=1:22).

[0055] (3) Preparation of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester 218 g of the sodium 2-methyl-α-methoxyiminophenylacetic acid solution obtained in step (2) was added to an autoclave, and 155 g of 1,2-dichloroethane, 11.4 g of TBAB (content 99%, 0.035 mol), and 2.65 g of NaI (content 99%, 0.018 mol) were added. The temperature was raised to 60°C, the vent valve was closed, and monochloromethane was continuously passed to maintain the system pressure at 0.4 MPa. The reaction was kept warm for 10 h, and then the ventilation was stopped. The temperature was lowered and the pressure was released (the tail gas was absorbed by excess DMF, and the weight was increased by 23.7 g, equivalent to 0.470 mol). The feed liquid was clear (see Figure 1A in the sample. The content of sodium 2-methyl-α-methoxyiminophenylacetic acid was less than 0.5%. The phases were separated. The weight of the aqueous phase was 157.6 g. The oil phase was a dichloroethane solution containing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, weighing 259.73 g (E / Z=1:8). The (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester in the oil phase were externally calibrated, and the total conversion rate was 91.9% (based on o-methylphenylacetonitrile).

[0056] (4) Preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester The oil phase obtained in step (3) was distilled under reduced pressure until no solvent was extracted, 50 g of methanol and 12.3 g of sulfuric acid (content 80%, 0.1 mol) were added, the temperature was raised to 60°C, stirred and kept warm for 8 h, the temperature was lowered to 0°C and kept warm for 1 h to crystallize, filtered, and rinsed with 10 g of methanol at 0°C to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0057] Example 2 This example is used to illustrate the preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0058] (1) Preparation of 2-methyl-α-cyanobenzyloxime sodium Add 66.2g (0.5mol) of o-methylbenzeneacetonitrile, 17g of methanol and 68.8g of liquid sodium hydroxide (content 32%, 0.55mol) into a four-necked bottle, control the liquid temperature at 28-30°C, and continue to slowly introduce 49.3g of methyl nitrite (content 99%, 0.80mol) for 10h. After the ventilation is completed, keep warm for 2h to obtain 184.3g of 2-methyl-α-cyanobenzeneformoxime sodium solution. The remaining o-methylbenzeneacetonitrile external standard content is 0.56%, and the conversion rate of o-methylbenzeneacetonitrile is 98.46%.

[0059] (2) Preparation of sodium 2-methyl-α-methoxyiminophenylacetate To the sodium 2-methyl-α-cyanobenzyloxime solution obtained in step (1), 11.0 g of TEBAB (content 99%, 0.04 mol) was added, and the mixture was transferred into an autoclave. The temperature of the feed liquid was controlled at 33-35° C., chloroform was continuously introduced, and the system pressure was controlled at 0.33-0.35 MPa. The reaction was kept warm for 7 h until the reaction was completed. The pressure was released, the material was discharged, and the phases were separated to obtain 90.12 g of an oily substance (containing (E / Z)-2-methyl-α-methoxyiminophenylacetonitrile and (E / Z)-2-methyl-α-methoxyiminophenylacetamide). The weight of the aqueous phase was 131.5 g.

[0060] 90.12 g of the oily substance obtained by the above phase separation was transferred into a four-necked bottle, and 93.75 g of liquid alkali (content 32%, 0.75 mol) and 56.25 g of water were added. The temperature was raised to 105°C for alkaline hydrolysis. The (E / Z)-2-methyl-α-methoxyiminophenylacetamide content was controlled to be less than 1%. After the reaction, 231.6 g of 2-methyl-α-methoxyiminophenylacetic acid sodium solution was obtained (E:Z=1:21).

[0061] (3) Preparation of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester 231.6 g of the sodium 2-methyl-α-methoxyiminophenylacetic acid solution obtained in step (2) was added to an autoclave, and 160 g of 1,2-dichloroethane, 13.75 g of TEBAB (content 99%, 0.05 mol), and 4.19 g of KI (content 99%, 0.025 mol) were added. The temperature was raised to 65° C., the vent valve was closed, and methyl chloride was continuously passed to maintain the system pressure at 0.35-0.36 MPa. The reaction was kept warm for 9 h, and then ventilation was stopped. The temperature was lowered and the pressure was released. Samples were taken to detect that the content of sodium 2-methyl-α-methoxyiminophenylacetic acid was less than 0.7%. The phases were separated, and the weight of the aqueous phase was 178.4 g. The oil phase was a dichloroethane solution containing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, and the weight was 261.2 g (E / Z=1:9). The (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester in the oil phase were externally standardized, and the total conversion rate was 90.2% (calculated as o-methylphenylacetonitrile).

[0062] (4) Preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester The oil phase obtained in step (3) was distilled under reduced pressure until there was no solvent, and 60 g of ethanol and 18.38 g of sulfuric acid (content 80%, 0.15 mol) were added, the temperature was raised to 50°C, stirred and kept warm for 10 h, the temperature was lowered to 0°C and kept warm for 2 h to crystallize, filtered, and rinsed with 10 g of 0°C ethanol to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0063] Example 3 This example is used to illustrate the preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0064] (1) Preparation of 2-methyl-α-cyanobenzyloxime sodium Add 66.2g (0.5mol) of o-methylbenzeneacetonitrile, 66g of methanol and 75.0g of liquid sodium hydroxide (content 32%, 0.6mol) into a four-necked bottle, control the temperature of the feed liquid at 26-28°C, and continue to slowly introduce 55.5g (content 99%, 0.90mol) of methyl nitrite. The aeration time is 9h. After the aeration is completed, keep warm for 2h to obtain 238.4g of 2-methyl-α-cyanobenzaldehyde sodium solution. The remaining o-methylbenzeneacetonitrile external standard content is 0.67%, and the conversion rate of o-methylbenzeneacetonitrile is 97.56%.

[0065] (2) Preparation of sodium 2-methyl-α-methoxyiminophenylacetate 9.77 g of TBAB (content 99%, 0.03 mol) was added to the sodium 2-methyl-α-cyanobenzyloxime solution obtained in step (1), and the mixture was transferred into an autoclave. The temperature of the feed liquid was controlled at 25-27 ° C. Methyl chloride was continuously introduced and the system pressure was controlled at 0.30-0.32 MPa. The reaction was heated for 10 h until the reaction was completed. The pressure was released, the mixture was discharged, and the mixture was distilled to 70 ° C at normal pressure. The temperature was lowered and the phases were separated to obtain 92.1 g of an oily substance (containing (E / Z)-2-methyl-α-methoxyiminophenylacetonitrile and (E / Z)-2-methyl-α-methoxyiminophenylacetamide). The weight of the aqueous phase was 103 g.

[0066] 92.1 g of the oily substance obtained by the above phase separation was transferred into a four-necked bottle, and 87.5 g of liquid alkali (content 32%, 0.7 mol) and 99.0 g of water were added. The temperature was raised to 90°C for alkaline hydrolysis. The (E / Z)-2-methyl-α-methoxyiminophenylacetamide content was controlled to be less than 1%. After the reaction, 268.2 g of 2-methyl-α-methoxyiminophenylacetic acid sodium solution was obtained (E:Z=1:22).

[0067] (3) Preparation of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester 268.2 g of the sodium 2-methyl-α-methoxyiminophenylacetic acid solution obtained in step (2) was added to an autoclave, and 160 g of 1,2-dichloroethane, 24.4 g of TBAB (content 99%, 0.075 mol), and 4.54 g of NaI (content 99%, 0.03 mol) were added. The temperature was raised to 75° C., the vent valve was closed, and methyl chloride was continuously passed to maintain the system pressure at 0.39-0.41 MPa. The reaction was kept warm for 5 h, and then ventilation was stopped. The temperature was lowered and the pressure was released. Samples were taken to detect that the content of sodium 2-methyl-α-methoxyiminophenylacetic acid was less than 0.5%. The phases were separated, and the weight of the aqueous phase was 191.0 g. The oil phase was a dichloroethane solution containing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, and the weight was 259.7 g (E / Z=1:9). The (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester in the oil phase were externally standardized, and the total conversion rate was 93.1% (calculated as o-methylphenylacetonitrile).

[0068] (4) Preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester The oil phase obtained in step (3) was distilled under reduced pressure until no solvent was extracted, 50 g of methanol was added, 18.41 g of HCl (content 99%, 0.50 mol) was introduced, the temperature was raised to 30°C, stirred and kept warm for 10 h, the temperature was lowered to 0°C and kept warm for 2 h to crystallize, filtered, and eluted with 10 g of methanol at 0°C to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0069] Example 4 This example is used to illustrate the preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0070] (1) Preparation of potassium 2-methyl-α-cyanobenzyl oxime Add 66.2g (0.5mol) of o-methylbenzeneacetonitrile, 20g of methanol and 70.0g of liquid potassium hydroxide (content 48%, 0.6mol) into a four-necked bottle, control the temperature of the feed liquid at 33-35°C, and continue to slowly introduce 43.1g of methyl nitrite (content 99%, 0.7mol) for 8h. After the ventilation is completed, keep warm for 2h to obtain 193.1g of 2-methyl-α-cyanobenzaldehyde potassium solution. The remaining o-methylbenzeneacetonitrile external standard content is 0.53%, and the conversion rate of o-methylbenzeneacetonitrile is 98.38%.

[0071] (2) Preparation of potassium 2-methyl-α-methoxyiminophenyl acetate To the potassium 2-methyl-α-cyanobenzyloxime solution obtained in step (1), add 8.14 g of TBAB (content 99%, 0.025 mol), transfer to an autoclave, control the feed liquid temperature at 25-27 ° C, continue to pass chloroform and control the system pressure at 0.30-0.32 MPa, keep warm for 12 h until the reaction is completed, release the pressure, discharge the material, and separate the phases to obtain 93.8 g of an oily substance (containing (E / Z)-2-methyl-α-methoxyiminophenylacetonitrile and (E / Z)-2-methyl-α-methoxyiminophenylacetamide), and the weight of the aqueous phase is 137.7 g.

[0072] 93.8 g of the oily substance obtained by the above phase separation was transferred into a four-necked bottle, and 87.5 g of potassium hydroxide solution (content 48%, 0.75 mol) and 122.5 g of water were added. The temperature was raised to 105°C for alkaline hydrolysis. The (E / Z)-2-methyl-α-methoxyiminophenylacetamide content was controlled to be less than 1%. After the reaction, 293.7 g of 2-methyl-α-methoxyiminophenylacetic acid potassium solution (E:Z=1:22) was obtained.

[0073] (3) Preparation of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester Add 293.7 g of the potassium 2-methyl-α-methoxyiminophenylacetic acid solution obtained in step (2) into an autoclave, add 160 g of 1,2-dichloroethane, 16.28 g of TBAB (content 99%, 0.05 mol), and 7.57 g of NaI (content 99%, 0.05 mol), close the air release valve, introduce chloroform at 20°C until the pressure reaches 0.34-0.35 MPa and stabilize for 0.5 h, close the air inlet valve, raise the temperature to 60°C, and the autoclave pressure reaches a maximum of 1.1MPa, as the reaction proceeds, the pressure gradually decreases to 0.7MPa, keep the temperature for 2h, cool down and release the pressure, take samples to detect the content of potassium 2-methyl-α-methoxyiminophenylacetate is less than 0.5%, separate the phases, the weight of the water phase is 247.0g, the oil phase is a dichloroethane solution containing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, the weight is 260.7g (E / Z=1:9). The (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester in the oil phase were externally calibrated, and the total conversion rate was 91.7% (calculated as o-methylphenylacetonitrile).

[0074] (4) Preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester The oil phase obtained in step (3) was distilled under reduced pressure until no solvent was extracted, 50 g of methanol and 24.5 g of sulfuric acid (content 80%, 0.20 mol) were added, the temperature was raised to 30°C, stirred and kept warm for 6 h, the temperature was lowered to 0°C and kept warm for 2 h to crystallize, filtered, and rinsed with 15 g of methanol at 0°C to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0075] Example 5 This example is used to illustrate the preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0076] (1) Preparation of 2-methyl-α-cyanobenzyloxime sodium Add 66.2g (0.5mol) of o-methylbenzeneacetonitrile, 33g of methanol and 75.0g of liquid sodium hydroxide (content 32%, 0.6mol) into a four-necked bottle, control the temperature of the feed liquid at 38-40°C, and continue to slowly introduce 40.3g of methyl nitrite (content 99%, 0.65mol) for 8h. After the ventilation is completed, keep warm for 2h to obtain 211.5g of 2-methyl-α-cyanobenzeneformoxime sodium solution. The remaining o-methylbenzeneacetonitrile external standard content is 0.40%, and the conversion rate of o-methylbenzeneacetonitrile is 98.71%.

[0077] (2) Preparation of sodium 2-methyl-α-methoxyiminophenylacetate 8.14 g of TBAB (content 99%, 0.025 mol) was added to the sodium 2-methyl-α-cyanobenzyloxime solution obtained in step (1), and the mixture was transferred into an autoclave. The temperature of the feed liquid was controlled at 28-30° C., chloroform was continuously introduced, and the system pressure was controlled at 0.38-0.40 MPa. The reaction was kept warm for 6 h until the reaction was completed. The pressure was released, the material was discharged, and the phases were separated to obtain 89.5 g of an oily substance (containing (E / Z)-2-(2'-methylphenyl)-α-methoxyiminophenylacetonitrile and (E / Z)-2-(2'-methylphenyl)-α-methoxyiminophenylacetamide). The weight of the aqueous phase was 160 g.

[0078] The aqueous phase obtained in step (3) of Example 1 was concentrated under reduced pressure and filtered to remove salt, thereby obtaining 80 g of a salt-containing mother liquor.

[0079] 89.5 g of the oily substance obtained by the above phase separation was transferred into a four-necked bottle, and 87.5 g of liquid alkali (content 32%, 0.7 mol) and 80 g of the above salt-containing mother liquor were added. The temperature was raised to 100°C for alkaline hydrolysis. The (E / Z)-2-methyl-α-methoxyiminophenylacetamide content was controlled to be less than 1%. After the reaction, 246.3 g of 2-methyl-α-methoxyiminophenylacetic acid sodium solution was obtained (E:Z=1:22).

[0080] (3) Preparation of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester 246.3 g of the sodium 2-methyl-α-methoxyiminophenylacetic acid solution obtained in step (2) was added to an autoclave, and 155 g of 1,2-dichloroethane, 5.86 g of TBAB (content 99%, 0.018 mol), and 1.51 g of NaI (content 99%, 0.01 mol) were added. The temperature was raised to 73-75° C., the vent valve was closed, and methyl chloride was continuously passed to maintain the system pressure at 0.42-0.44 MPa. The reaction was kept warm for 10 h and then ventilation was stopped. The temperature was lowered and the pressure was released. Samples were taken to detect that the content of sodium 2-methyl-α-methoxyiminophenylacetic acid was less than 0.5%. The phases were separated, and the weight of the aqueous phase was 180.2 g. The oil phase was a dichloroethane solution containing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, and the weight was 256.2 g (E / Z=1:8). (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester were used as external standards, and the total conversion rate was 92.3% (calculated based on o-methylphenylacetonitrile).

[0081] (4) Preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester The oil phase obtained in step (3) was distilled under reduced pressure until no solvent was extracted, and 50 g of methanol and 65.3 g of sulfuric acid (content 75%, 0.50 mol) were added, and the mixture was stirred and kept warm at 60°C for 2 h. The mixture was cooled to 0°C and kept warm for 2 h for crystallization, filtered, and rinsed with 15 g of methanol at 0°C to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0082] Example 6 This example is used to illustrate that the mother liquor and eluent obtained after acidic rearrangement can be used multiple times.

[0083] Steps (1) to (3) of Example 1 were repeated, and 8 batches of materials were added for reaction to obtain 2075 g of 1,2-dichloroethane solution containing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester after phase separation (theoretically containing 4 mol of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester based on the added o-methylphenylacetonitrile).

[0084] (1) Take 259 g of the above solution, distill under reduced pressure until no solvent is extracted, add 50 g of methanol and 12.3 g of sulfuric acid (content 80%, 0.1 mol), raise the temperature to 60°C, stir and keep warm for 8 h, cool to 0°C and keep warm for 1 h to crystallize, filter, elute with 10 g of methanol at 0°C to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, and combine the mother liquor with the eluent.

[0085] (2) Weigh 259 g of the above solution again, distill under reduced pressure until no solvent is extracted, add the combined mother liquor and eluent, raise the temperature to 60°C, stir and keep warm for 8 h, cool to 0°C and keep warm for 1 h to crystallize, filter, elute with 10 g of 0°C methanol to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, and combine the mother liquor and the eluent.

[0086] (3) Repeat step (2) and use 7 batches of mother liquor and eluent in total to obtain a filter cake for drying. A total of 753.4 g (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester (E / Z=99.5:0.5) was obtained, with an external standard content of 98.7% and a total yield of 89.8%. The remaining mother liquor was 91.6 g, with an external standard E ester content of 8.2%, accounting for 0.9% of the total conversion rate, and an external standard Z ester content of 11.6%, accounting for 1.3% of the total conversion rate.

[0087] Example 7 This example is used to illustrate the preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0088] (1) Preparation of 2-methyl-α-cyanobenzyloxime sodium Add 66.2g (0.5mol) of o-methylbenzeneacetonitrile, 17g of methanol and 68.8g (content 32%, 0.55mol) of liquid sodium hydroxide into a four-necked bottle, control the temperature of the feed liquid at 33-35°C, and continue to slowly introduce 46.3g of methyl nitrite (content 99%, 0.75mol) for 9h. After the ventilation is completed, keep warm for 2h to obtain 183.3g of 2-methyl-α-cyanobenzoxime sodium solution. The remaining o-methylbenzeneacetonitrile external standard content is 0.66%, and the conversion rate of o-methylbenzeneacetonitrile is 98.17%.

[0089] (2) Preparation of sodium 2-methyl-α-methoxyiminophenylacetate To the sodium 2-methyl-α-cyanobenzyloxime solution obtained in step (1), 12.46 g of DTAB (content 99%, 0.04 mol) was added, and the mixture was transferred into an autoclave. The temperature of the feed liquid was controlled at 33-35 °C, chloroform was continuously introduced, and the system pressure was controlled at 0.36-0.38 MPa. The reaction was carried out by heat preservation for 6 h until the reaction was completed. The pressure was released, the material was discharged, and the phases were separated to obtain 90.32 g of an oily substance (containing (E / Z)-2-methyl-α-methoxyiminophenylacetonitrile and (E / Z)-2-methyl-α-methoxyiminophenylacetamide). The weight of the aqueous phase was 132.1 g.

[0090] 90.32 g of the oily substance obtained by the above phase separation was transferred into a four-necked bottle, and 93.75 g of liquid alkali (content 32%, 0.75 mol) and 56.30 g of water were added. The temperature was raised to 105°C for alkaline hydrolysis. The (E / Z)-2-methyl-α-methoxyiminophenylacetamide content was controlled to be less than 1%. After the reaction, 231.4 g of 2-methyl-α-methoxyiminophenylacetic acid sodium solution was obtained (E:Z=1:21).

[0091] (3) Preparation of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester 231.4 g of the sodium 2-methyl-α-methoxyiminophenylacetic acid solution obtained in step (2) was added to an autoclave, and 180 g of toluene, 15.57 g of DTAB (content 99%, 0.05 mol), and 4.54 g of NaI (content 99%, 0.03 mol) were added. The temperature was raised to 65° C., the vent valve was closed, and methyl chloride was continuously passed to maintain the system pressure at 0.38-0.40 MPa. The reaction was kept warm for 7 h, and then ventilation was stopped. The temperature was lowered and the pressure was released. Samples were taken to detect that the sodium 2-methyl-α-methoxyiminophenylacetic acid content was less than 0.8%. The phases were separated, and the weight of the aqueous phase was 179.6 g. The oil phase was a toluene solution containing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, and the weight was 282.15 g (E / Z=1:9). The (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester in the oil phase were externally standardized, and the total conversion rate was 90.7% (calculated as o-methylphenylacetonitrile).

[0092] (4) Preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester The oil phase obtained in step (3) was distilled under reduced pressure until no solvent was extracted, 80 g of ethanol was added, 11.05 g of HCl (content 99%, 0.30 mol) was introduced, the temperature was raised to 50°C, stirred and kept warm for 10 h, the temperature was lowered to 0°C and kept warm for 2 h to crystallize, filtered, and rinsed with 10 g of 0°C ethanol to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0093] Example 8 This example is used to illustrate the preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0094] (1) Preparation of potassium 2-methyl-α-cyanobenzyl oxime Add 66.2g (0.5mol) of o-methylbenzeneacetonitrile, 33.0g of methanol and 61.83g of liquid potassium hydroxide (content 48%, 0.53mol) into a four-necked bottle, control the temperature of the feed liquid at 35-37°C, and continue to slowly introduce 43.15g of methyl nitrite (content 99%, 0.70mol) for 9h. After the ventilation is completed, keep warm for 2h to obtain 193.53g of 2-methyl-α-cyanobenzaldehyde potassium solution. The remaining o-methylbenzeneacetonitrile external standard content is 0.56%, and the conversion rate of o-methylbenzeneacetonitrile is 98.36%.

[0095] (2) Preparation of potassium 2-methyl-α-methoxyiminophenyl acetate To the 2-methyl-α-cyanobenzyloxime potassium solution obtained in step (1), 11.0 g of TEBAB (content 99%, 0.04 mol) was added, and the mixture was transferred into an autoclave. The temperature of the feed liquid was controlled at 33-35 ° C. Monochloromethane was continuously introduced and the system pressure was controlled at 0.36-0.38 MPa. The reaction was heated for 10 h until the reaction was completed. The pressure was released, the material was discharged, and the phases were separated to obtain 90.11 g of an oily substance (containing (E / Z)-2-methyl-α-methoxyiminophenylacetonitrile and (E / Z)-2-methyl-α-methoxyiminophenylacetamide). The weight of the aqueous phase was 141.15 g.

[0096] 90.11 g of the oily substance obtained by the above phase separation was transferred into a four-necked bottle, and 81.67 g of potassium hydroxide solution (content 48%, 0.70 mol) and 102.4 g of water were added. The temperature was raised to 95°C for alkaline hydrolysis. The (E / Z)-2-methyl-α-methoxyiminophenylacetamide content was controlled to be less than 1%. After the reaction, 265.5 g of 2-methyl-α-methoxyiminophenylacetic acid potassium solution (E:Z=1:21) was obtained.

[0097] (3) Preparation of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester 265.5 g of the potassium 2-methyl-α-methoxyiminophenylacetic acid solution obtained in step (2) was added to an autoclave, and 160 g of 1,2-dichloromethane, 13.75 g of TEBAB (content 99%, 0.05 mol), and 4.19 g of KI (content 99%, 0.025 mol) were added. The temperature was raised to 60° C., the vent valve was closed, and methyl chloride was continuously passed to maintain the system pressure at 0.35-0.36 MPa. The reaction was kept warm for 10 h and then the ventilation was stopped. The temperature was lowered and the pressure was released. Samples were taken to detect the content of sodium 2-methyl-α-methoxyiminophenylacetic acid, which was less than 0.8%. The phases were separated, and the weight of the aqueous phase was 216.01 g. The oil phase was a dichloromethane solution containing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, and the weight was 262.6 g (E / Z=1:10). The (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester in the oil phase were externally standardized, and the total conversion rate was 89.3% (calculated as o-methylphenylacetonitrile).

[0098] (4) Preparation of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester The oil phase obtained in step (3) was distilled under reduced pressure until no solvent was extracted, 60 g of methanol was added, 14.73 g of HCl (content 99%, 0.4 mol) was introduced, the temperature was raised to 50°C, stirred and kept warm for 10 h, the temperature was lowered to 0°C and kept warm for 2 h to crystallize, filtered, and rinsed with 10 g of methanol at 0°C to obtain white (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

[0099] Comparative Example 1-1 (1) Repeat step (1) of Example 1 to obtain 210.9 g of 2-methyl-α-cyanobenzaldehyde sodium solution; (2) The feed liquid temperature is controlled at 28-30°C, and chloroform is passed through the feed liquid at normal pressure for 10 hours. When the feed liquid content is greater than 85%, the reaction is terminated.

[0100] It can be seen that under normal pressure and without a catalyst, the first methylation reaction is difficult to proceed.

[0101] Comparative Example 1-2 (1) Repeat steps (1) and (2) of Example 1 to obtain 218 g of sodium 2-methyl-α-methoxyiminophenylacetate solution; (2) The feed liquid temperature was controlled at 60-70°C, and methyl chloride was passed through the feed liquid at normal pressure for 10 h. The feed liquid was clarified and sampled for central control. The content of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester was less than 1%.

[0102] It can be seen that the second methylation reaction is difficult to proceed under normal pressure and without a catalyst.

[0103] Comparative Example 2-1 (1) Repeat step (1) of Example 1 to obtain 211 g of 2-methyl-α-cyanobenzyloxime sodium solution; (2) The feed liquid temperature was controlled at 28-30°C and the system pressure was controlled at 0.38-0.4 MPa. Methyl chloride was passed through the feed liquid for 6 hours. The (E / Z)-2-methyl-α-methoxyiminophenylacetonitrile content was less than 7%.

[0104] It can be seen that the first methylation reaction is difficult to proceed without the addition of a catalyst.

[0105] Comparative Example 2-2 (1) Repeat steps (1) and (2) of Example 1 to obtain 218 g of sodium 2-methyl-α-methoxyiminophenylacetic acid solution; (2) Add 11.4 g TBAB (content 99%, 0.035 mol) and 2.65 g NaI (content 99%, 0.018 mol) to the obtained sodium 2-methyl-α-methoxyiminophenylacetic acid solution, control the temperature of the feed solution to 60°C, and pass chloroform at normal pressure for 10 hours. The feed solution is slightly turbid (see Figure 1 B in the sample), the content of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester is less than 4%.

[0106] It can be seen that the expected effect cannot be achieved by only adding a catalyst and carrying out the second methylation reaction at normal pressure without a second organic solvent.

[0107] Comparative Example 3 (1) Repeat steps (1) and (2) of Example 1 to obtain 217.6 g of sodium 2-methyl-α-methoxyiminophenylacetic acid solution; (2) Add 11.4 g TBAB (content 99%, 0.035 mol) and 2.65 g NaI (content 99%, 0.018 mol) to the sodium 2-methyl-α-methoxyiminophenylacetic acid solution, raise the temperature to 60°C, close the vent valve, continue to pass chloroform to maintain the system pressure at 0.4 MPa, keep the reaction at this temperature for 10 h, stop passing gas, cool down and release the pressure. The material is turbid and a large amount of oily matter is precipitated (see Figure 1 C in the reaction mixture), phase separation, extraction of the aqueous phase with 150 g of ethylene dichloride, and combination to obtain 248.2 g of the oil phase (E / Z = 1:9). External standardization was performed on (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester and (Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, respectively, and the total conversion rate was 75.8% (based on o-methylphenylacetonitrile).

[0108] It can be seen that without adding the second organic solvent, the conversion rate is low.

[0109] Comparative Example 4 (Refer to CN108863845B and CN112851546B) Add 66.2g (0.5mol) of o-methylbenzene acetonitrile and 92g of methanol into a four-necked bottle, control the temperature at 20-25°C, add 25.0g (96% content, 0.6mol) of sodium hydroxide in batches; cool to about 10°C, slowly pass 43.1g (99% content, 0.7mol) of methyl nitrite, raise the temperature to 30°C and stir for 2h after passing; Add 176g of water and 25.0g of sodium hydroxide (content 96%, 0.6mol), heat up to evaporate methanol until the feed liquid temperature is 105℃, react for 3h and then cool to 15℃; add 149g of hydrochloric acid (content 32%, 1.31mol) dropwise, stir and keep warm for 1h. After filtering, wash the filter cake with cold water to obtain a white powdery solid (E)-2-methyl-α-hydroxyiminophenylacetic acid with a bitter almond smell, dry it to obtain 91.5g of solid, and the content is 95.6% (0.4885mol) according to external standard quantification, the yield is 97.7%, and the NaCl content is 2.8%.

[0110] Disperse 91.5 g of (E)-2-methyl-α-hydroxyiminophenylacetic acid in 640 g of DMF (water content <1%), add 44.8 g of granular sodium hydroxide (content 96%, 1.075 mol) in batches after dissolution, stir at room temperature for 0.5 h to obtain a thick slurry (see Figure 1 D in the reaction vessel), control the temperature of the reaction vessel at 15-20°C, introduce 154g of chloromethane (content 99%, 3.02mol, theoretical excess 2.043mol), complete ventilation, close the reaction vessel, heat to 45°C for 6h, cool to about 20°C, use a diaphragm pump to vacuum until the system weight remains unchanged, the material weight is 828.6g, and the weight before and after vacuum is reduced by 101.7g. Filter, wash the filter cake with 100gDMF, combine the filtrate and washing liquid, and distill under reduced pressure to 85°C without fraction extraction, recover 724gDMF, and contain 3.18% water. After the solvent is recovered, add methanol to the material and heat it up to dissolve, cool it down and crystallize to obtain 88.9g of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, with an external standard content of 98.3% and a yield of 86.4%.

[0111] Comparative Example 5 Take steps 1-3 of Example 1 of CN110396054B as Comparative Example 5.

[0112] Step 1: Preparation of 2-methyl-α-cyanobenzyl oxime Add 50g of n-butanol and 8g of sodium hydroxide (0.2mol) into a four-necked bottle, stir and cool to 10°C, add 13.1g of o-methylbenzeneacetonitrile (0.1mol) at one time, slowly add 16.3g of n-butyl nitrite (0.15mol), keep warm for 1h after the addition, add hydrochloric acid to the system to adjust the pH to 4, and separate 2-methyl-α-cyanobenzyl oxime with a yield of 92% and a content of 95.5%.

[0113] Theoretical by-product calculation: The by-product NaCl converted to oxime ether is: 0.2 mol / (0.1 mol×92%×94%×91%)=2.541 mol / mol product; 97.7 g of aqueous n-butanol (azeotropic water content is 37.5%, which needs to be dehydrated before use).

[0114] Step 2: Preparation of 2-(2-methylphenyl)-2-methyliminoacetonitrile 2-Methyl-α-cyanobenzyl oxime (0.1 mol, 16 g), acetone (50 g), water (40 g), and sodium hydroxide (0.12 mol, 4.9 g) were placed in a four-necked flask, cooled to 11°C, and dimethyl sulfate (0.13 mol, 16.7 g) was added dropwise to the system. After the addition was completed, the system was kept warm at 11-15°C for 0.5 h. After the insulation was completed, the solvent was recovered by atmospheric distillation. After the distillation was completed, 50 g of water was added to the system, and the system was stirred and filtered to obtain 2-(2-methylphenyl)-2-methyliminoacetonitrile (yield 94%, content 96%).

[0115] Theoretical by-product calculation: The excess dimethyl sulfate was calculated by hydrolysis of sodium monomethyl sulfate, which was 0.13 mol. The converted oxime ether was 0.13 mol / (0.1 mol×94%×91%)=1.520 mol / mol product. The by-product methanol was 4.48 g.

[0116] Step 3: Preparation of E-2-methyl-α-methoxyiminophenylacetic acid methyl ester Water (50 g), sodium hydroxide (0.3 mol, 12.3 g), and 2-(2-methylphenyl)-2-methyliminoacetonitrile (0.1 mol, 18.3 g, content 95%) were put into a four-necked bottle, and the temperature was raised to 70°C. After keeping at 70-75°C for 3 hours, the temperature was lowered to 5-10°C, and dimethyl sulfate (0.12 mol, 15.4 g, content 98%) was added dropwise to the system. After the addition was completed, E-2-methyl-α-methoxyiminophenylacetic acid methyl ester (yield 91%, content 94%) was filtered off by suction.

[0117] Theoretical by-product calculation: After the reaction of dimethyl sulfate, hydrolysis produces sodium sulfate as a by-product, which is converted into oxime ether at 0.12 mol / (0.1×91%)=1.319 mol / mol product, 1.7 g ammonia, 2.4 g NaOH, and 4.48 g methanol.

[0118] Table 1 shows the comparison results of Example 6 of the present invention and Comparative Examples 4-5.

[0119] In the present invention, the amount of by-product salt (mol / mol product) is calculated as follows: Based on 0.5 mol of o-methylbenzene acetonitrile, 0.6 mol of sodium hydroxide is added in the oximation stage, which is converted into 0.6 mol of sodium chloride in the first methylation stage; 0.7 mol of alkali (NaOH) is consumed in the alkaline hydrolysis of 2-methyl-α-methoxyiminobenzene acetonitrile, which is converted into NaCl in the second methylation stage, with a production amount of 0.7 mol. A total of 1.3 mol of by-product salt is produced when 0.5 mol of o-methylbenzene acetonitrile is added.

[0120] The yield of o-methylbenzeneacetonitrile to product was 89.8%. When 0.5 mol of o-methylbenzeneacetonitrile was added, the yield of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester was 0.5×89.8%=0.449 mol.

[0121] Therefore, the amount of by-produced salt per 1 mol of (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester is 2.90 mol.

[0122] The amount of organic solvent (t / t product) is calculated as follows: In step (3), 1,2-dichloroethane is used as solvent in an amount of 155 g to obtain 0.449 mol of product, which is 93.05 g pure. That is, the amount of solvent that needs to be distilled and recovered to produce 1 t of product is 155 / 93.05=1.67 t / t of product.

[0123] Maximum volume per step for producing 1 ton of product (m 3 ) is calculated as follows: The largest stage of feed weight and feed liquid volume in the reaction occurs in the (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester process, with a total feed weight of 417.33 g and a volume of about 370 mL. That is, the maximum feed liquid volume in the reaction stage for producing 1 t of pure product is 4.08 m 3 .

[0124] The amount of methyl chloride that needs to be recovered to produce 1 t of product is calculated as follows: According to Example 1, 0.5 mol of o-methylbenzene acetonitrile is added, the amount of methyl chloride absorbed is 9.0 g + 23.7 g = 32.7 g, and 93.05 g of product is obtained, that is, the weight of methyl chloride required to be recovered to produce 1 t of product is 32.7 / 93.05 = 0.35 t / t.

[0125] Table 1 .

[0126] It can be seen from the results in Table 1 that the present invention reduces by-product salt by about 45% compared with the existing comparative technology, reduces the amount of organic solvent that needs to be distilled by more than 72%, and can be directly reused without dehydration. The production efficiency of the same methylation equipment is improved by more than 1 times, and the amount of monochloromethane that needs to be recovered is reduced by 69.08% (0.81t of monochloromethane is reduced for 1t of product), which greatly reduces the pressure of tail gas recovery.

[0127] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for synthesizing (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester, characterized in that: The method comprises the following steps: (1) Using o-methylbenzeneacetonitrile as a raw material, 2-methyl-α-cyanobenzyloxime salt solution is obtained through oximation reaction; (2) adding a first catalyst to the 2-methyl-α-cyanobenzyl oxime salt solution obtained in step (1), and continuously passing chloroform under closed system conditions to carry out a first methylation reaction to obtain an oily substance; and subjecting the oily substance to alkaline hydrolysis to obtain a 2-methyl-α-methoxyiminophenyl acetate solution; (3) adding a first organic solvent and a second catalyst to the 2-methyl-α-methoxyiminophenylacetic acid salt solution obtained in step (2), and passing chloroform in a closed system to carry out a second methylation reaction to obtain a (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester solution; (4) A solution of (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester is subjected to acidic rearrangement to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

2. The method according to claim 1, wherein: In the step (1), the 2-methyl-α-cyanobenzaldehyde salt is 2-methyl-α-cyanobenzaldehyde sodium and / or 2-methyl-α-cyanobenzaldehyde potassium.

3. The method according to claim 1, wherein: In the step (2), the first catalyst is selected from at least one of tetrabutylammonium bromide, benzyltriethylammonium bromide, benzyltriethylammonium chloride and dodecyltrimethylammonium bromide; And / or, the molar ratio of the first catalyst to o-methylphenylacetonitrile is 0.03-0.08:1, or 0.05-0.06:

1.

4. The method according to claim 1, wherein: The temperature of the first methylation reaction is 20-40°C, or 25-35°C, or 25-27°C, or 28-30°C, or 33-35°C; and / or, the pressure of the first methylation reaction is 0.25-0.45 MPa, or 0.30-0.40 MPa, or 0.30-0.32 MPa, or 0.33-0.35 MPa, or 0.36-0.38 MPa, or 0.38-0.40 MPa; And / or, the first methylation reaction time is 6 to 12 hours, or 7 to 10 hours.

5. The method according to claim 1, wherein: In the step (2), alkaline hydrolysis is carried out using sodium hydroxide solution and / or potassium hydroxide solution; And / or, the alkaline hydrolysis temperature is 90-105°C, or 100-105°C.

6. The method according to claim 1, wherein: In the step (3), the first organic solvent is a water-insoluble organic solvent; and / or, the first organic solvent is selected from at least one of 1,2-dichloroethane, toluene, dichloromethane and xylene; And / or, the second catalyst is a complex of a phase transfer catalyst and an iodide; And / or, the phase transfer catalyst is selected from at least one of tetrabutylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide or dodecyltrimethylammonium bromide; And / or, the iodide is sodium iodide and / or potassium iodide; And / or, the second catalyst is selected from at least one of a complex of tetrabutylammonium bromide and sodium iodide, a complex of benzyltriethylammonium chloride and potassium iodide, a complex of benzyltriethylammonium bromide and potassium iodide, and a complex of dodecyltrimethylammonium bromide and sodium iodide.

7. The method according to claim 6, wherein: The molar ratio of the phase transfer catalyst, the iodide and the o-methylbenzene acetonitrile is (0.036-0.15):(0.02-0.1):1, or 0.07:0.036:1, or 0.1:0.05:1, or 0.15:0.06:1, or 0.1:0.1:1, or 0.036:0.02:1, or 0.1:0.06:1, or 0.1:0.05:

1.

8. The method according to claim 1, wherein: The temperature of the second methylation reaction is 50-75°C, or 60-75°C, or 65°C; and / or, the pressure of the second methylation reaction is 0.25 to 1.1 MPa, or 0.25 to 0.45 MPa, or 0.3 to 0.4 MPa, or 0.34 to 0.35 MPa, or 0.35 to 0.36 MPa, or 0.38 to 0.40 MPa, or 0.39 to 0.41 MPa, or 0.42 to 0.44 MPa; And / or, the second methylation reaction time is 5 to 10 hours, or 6 to 9 hours, or 7 hours.

9. The method according to claim 1, wherein: In the step (3), after the (E / Z)-2-methyl-α-methoxyiminophenylacetic acid methyl ester solution is desolvated, a second organic solvent and an acidic catalyst are added to carry out rearrangement; And / or, the acidic catalyst is sulfuric acid and / or HCl; And / or, the second organic solvent is methanol and / or ethanol; and / or, the temperature of the acidic rearrangement is 10-70° C., or 20-60° C.; And / or, the time of the acidic rearrangement is 1 to 10 hours, or 2 to 8 hours.

10. The method according to any one of claims 1 to 9, wherein: After the acidic rearrangement is completed, the temperature is lowered and crystallization is performed to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester; and / or, cooling and crystallizing, filtering, and eluting with a second organic solvent to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester; And / or, the mother liquor and / or the eluent after cooling and crystallization are recycled for acid rearrangement.

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