Synthesis method of methyl (E)-2-methyl-α-methoxyiminophenylacetate

Abstract

The present invention relates to the technical field of organic synthesis, and discloses a method for synthesizing methyl (E)-2-methyl-α-methoxyiminophenylacetate. In the present invention, o-methylphenylacetonitrile is used as a raw material, and through a series of steps such as oximation, first methylation, alkali hydrolysis, second methylation, and acidic rearrangement, methyl (E)-2-methyl-α-methoxyiminophenylacetate is obtained. The method provided by the present invention greatly reduces the by-product salt amount and significantly improves the atom utilization rate; the amount of organic solvent used is reduced, and the equipment utilization rate is greatly improved; by optimizing the conditions of the methylation reaction, the present invention obtains high reaction activity while reducing the amount of methylation reagent used, and at the same time, the amount of methyl chloride used is reduced, so that the excessive methyl chloride to be recovered and treated is greatly reduced, the tail gas treatment amount is small, the equipment is relatively simple, and the operation cost is low; except for the crystallization operation, the whole reaction process is a gas-liquid or liquid-liquid reaction, the mass transfer and heat transfer effects are improved, which is more conducive to subsequent continuous transformation.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing methyl (E)-2-methyl-α-methoxyiminophenylacetate. Background Art

[0002] Methyl (E)-2-methyl-α-methoxyiminophenylacetate (oxime ether) is a key intermediate for methoxyacrylate fungicides such as trifloxystrobin, kresoxim-methyl, orysastrobin, dimoxystrobin, and enestroburin. The existing main synthesis processes are as follows:

[0003] Route 1: o-Tolunitrile Process

[0004] US5332752 provides a method for obtaining methyl o-methylphenylglyoxylate by acidolysis and esterification using o-tolunitrile as the starting material. Methyl o-methylphenylglyoxylate continues to react with methoxyamine hydrochloride to obtain (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate, which can be further acid-rearranged to obtain the target product methyl (E)-2-methyl-α-methoxyiminophenylacetate. The process is as follows:

[0005] 。

[0006] Route 2: o-Toluidine Process

[0007] Li Yan et al. (Stereoselective Synthesis and Biological Activity of Methyl (αE,E)-α-(Methoxyimino)-2-[1-(Aromatic Aldehyde Ketoxime Oxy)Methyl]Phenylacetate, Chinese Journal of Organic Chemistry, 2006, 26(1), 110-115) and Chai Bing et al. (New Process for the Synthesis of Trifloxystrobin, Agrochemicals, 2013, 52(4), 258-259) respectively used o-toluidine as the starting material, and obtained the target product methyl (E)-2-methyl-α-methoxyiminophenylacetate through diazotization, coupling, and methylation. The yields were 37.3% and 62.6% respectively based on o-toluidine diazonium hydrochloride. The process is as follows: 。

[0008] Route 3: o-Bromotoluene Process

[0009] CN108250102B provides a process which uses o-bromotoluene as a raw material. First, it reacts with zinc to form 2-methylphenylzinc bromide. Then, in the presence of a palladium-based catalyst, or a palladium-based catalyst and a palladium-based catalyst ligand, or a nickel-based catalyst and a nickel-based catalyst ligand, it reacts with methyl 2-chloro-2-(methoxyimino)acetate to obtain methyl (E)-2-methyl-α-methoxyiminophenylacetate. Among them, methyl 2-chloro-2-(methoxyimino)acetate is obtained by oximation and halogenation of methoxyamine hydrochloride and monomethyl oxalyl chloride oxime, or by esterification of methyl methoxyamino glyoxylate, and the highest yield is 91%. This process has the following problems: the raw material methoxyamine hydrochloride is expensive, the synthesis process requires noble metals or ligand-containing catalysts, and it involves the dangerous Grignard reaction which needs to be quenched. The process is as follows:

[0010] 。

[0011] Route 4: o-Methylphenylacetonitrile process

[0012] Zhu Xiaomeng (Master's thesis of Shandong Normal University, 2013) reported a method for preparing methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate from o-methylphenylacetonitrile as a raw material through oximation, acidification, etherification, alkali hydrolysis, and esterification. The total yield of the reaction is 60.75%. Although the yield is relatively low, since the raw materials are easily available and cheap, it is more suitable for industrial production. This process has the following problems: theoretically, when producing 1 mol of methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate, more than 3 mol of salts will be by-produced (in actual reaction, an excessive amount of alkali is needed to promote the reaction, and the amount of by-produced salts is even higher). In addition, when using dimethyl sulfate as the methylation reagent, monomethyl sulfate salt is by-produced, and alkali is needed for hydrolysis during post-treatment, resulting in a large amount of wastewater that is difficult to treat. The process is as follows:

[0013] 。

[0014] Li Renhong (Master's thesis of Hebei University of Science and Technology, 2015) also used o-methylphenylacetonitrile as the starting material. After oximation and methyl etherification, it was alkaline hydrolyzed to obtain (E / Z)-2-methyl-α-methoxyiminophenylacetic acid, and then the target product methyl (E)-2-methyl-α-methoxyiminophenylacetate was obtained by sulfuric acid-catalyzed methanol esterification. Based on o-methylphenylacetonitrile, the total yield of synthesizing methyl (E)-2-methyl-α-methoxyiminophenylacetate is 54.7%. This process theoretically produces 3 mol of salts (acidification, methylation, alkali hydrolysis) when producing 1 mol of methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate; although the amount of dimethyl sulfate used is reduced by 50%, due to the poor thermal stability of (E)-2-methyl-α-methoxyiminophenylacetic acid, it decomposes during the sulfuric acid-catalyzed esterification process, resulting in a relatively low final yield. The process is as follows:

[0015] .

[0016] CN112851546B uses 2-methyl-α-hydroxyiminophenylacetonitrile as a raw material, which is subjected to alkaline hydrolysis and acidification to obtain 2-methyl-α-hydroxyiminophenylacetic acid. After separation, a polar organic solvent such as DMF, acetonitrile, DMSO, etc. is added, and salt formation occurs in the presence of a basic substance, and then it reacts with a methylation reagent such as dimethyl sulfate or haloalkane to obtain methyl (E)-2-methyl-α-methoxyiminophenylacetate. Based on 2-methyl-α-hydroxyiminophenylacetonitrile, the total reaction yield reaches 82.5 - 86.5%, and the cost is reduced. The reaction process is as follows:

[0017] .

[0018] However, in theory, when producing 1 mol of methyl (E)-2-methyl-α-methoxyiminophenylacetate by this process, more than 4 mol of NaCl is by-produced, the atom utilization rate is low, and the large amount of wastewater causes an increase in post-treatment energy consumption. In addition, a large amount of hydrophilic polar solvents are required in the methylation process to disperse the insoluble salt-forming intermediate. For example, in the examples, when the solvent is DMF, the dosage (by mass) is 6.4 times that of 2-methyl-α-hydroxyiminophenylacetic acid; when the solvent is acetonitrile, the dosage (by mass) is 8.7 times that of 2-methyl-α-hydroxyiminophenylacetic acid. Therefore, it not only reduces the equipment production capacity, but also generates a large amount of waste mixed solvent containing water. In addition, since methyl bromide and methyl iodide are too expensive, methyl chloride is usually used as the methylation reagent in industrial production. However, methyl chloride has lower reactivity than methyl bromide and methyl iodide. Usually, a large excess of methyl chloride is required during the reaction process to promote the complete conversion of 2-methyl-α-hydroxyiminophenylacetic acid. For example, in Examples 8 and 10, the feeding amount of methyl chloride (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, a device for recovering a large amount of methyl chloride needs to be added, increasing the equipment investment cost, and there is also an additional cost to ensure the safe operation of the methyl chloride recovery device.

[0019] CN110396054B also uses o-methylphenylacetonitrile as the starting material, and obtains methyl (E)-2-methyl-α-methoxyiminophenylacetate through oximation, methylation, hydrolysis, and esterification. The reaction process is as follows:

[0020] .

[0021] Compared with CN112851546B, the by-product salt amount of CN110396054B is reduced. The theoretical by-product salt for synthesizing 1 mol of methyl (E)-2-methyl-α-methoxyiminophenylacetate is 2 mol. However, during the preparation of 2-methyl-α-methoxyiminobenzyl cyanide from 2-methyl-α-cyanobenzaldoxime or 2-methyl-α-cyanobenzaldoxime salt, 4 to 6 times the amount of organic solvent of 2-methyl-α-cyanobenzaldoxime or 2-methyl-α-cyanobenzaldoxime salt still needs to be added to disperse the insoluble salt-forming intermediate (data from the examples), resulting in a significant reduction in equipment utilization rate. In addition, when preparing methyl (E)-2-methyl-α-methoxyiminophenylacetate by methylating 2-methyl-α-methoxyiminobenzyl cyanide, although the reaction is carried out in an aqueous solvent, the methylation reagent B used is dimethyl sulfate with high activity, and an equimolar amount of methyl sulfate salt is produced as a by-product and enters the aqueous phase, which needs to be hydrolyzed into sulfate and methanol, making the wastewater treatment difficult and costly; or methyl bromide or methyl iodide with extremely high prices, which is not conducive to large-scale industrial production.

[0022] Therefore, there is an urgent need to develop a method for synthesizing methyl (E)-2-methyl-α-methoxyiminophenylacetate with less by-product salt, less usage of methylation reagent and organic solvent, simple post-treatment, and suitable for industrial production. Summary of the Invention

[0023] The purpose of the present invention is to overcome the problems existing in the prior art and provide a method for synthesizing methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0024] To achieve the above purpose, the present invention provides a method for synthesizing methyl (E)-2-methyl-α-methoxyiminophenylacetate, wherein the method comprises the following steps:

[0025] (1) Using o-methylphenylacetonitrile as a raw material, obtaining a solution of 2-methyl-α-cyanobenzaldoxime salt through an oximation reaction;

[0026] (2) Adding a first catalyst to the solution of 2-methyl-α-cyanobenzaldoxime salt obtained in step (1), continuously introducing chloromethane under a closed system condition to carry out a first methylation reaction, obtaining an oily substance; subjecting the oily substance to alkaline hydrolysis to obtain a solution of 2-methyl-α-methoxyiminophenylacetate salt;

[0027] (3) Adding a first organic solvent and a second catalyst to the solution of 2-methyl-α-methoxyiminophenylacetate salt obtained in step (2), introducing chloromethane under a closed system condition to carry out a second methylation reaction, obtaining a solution of (E / Z)-2-methyl-α-methoxyiminophenylacetate;

[0028] (4) Acidic rearrangement of the solution of methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate gives methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0029] By the above technical solutions, the beneficial technical effects achieved by the present invention are as follows:

[0030] (1) The method provided by the present invention greatly improves the atomic utilization rate, significantly reduces the by-product salt amount, and has low energy consumption; the amount of organic solvent used is reduced, and the equipment utilization rate is greatly improved;

[0031] (2) By optimizing the conditions of the methylation reaction, the present invention obtains high reaction activity while reducing the amount of methylation reagent used. At the same time, the reduction in the amount of methyl chloride used greatly reduces the excess methyl chloride that needs to be recycled and treated, with less tail gas treatment, relatively simple equipment, and reduced raw material and operation costs;

[0032] (3) In the prior art, a gas-liquid-solid three-phase reaction system is used in the methylation process. Except for the crystallization operation, the whole reaction process of the present invention is a gas-liquid or liquid-liquid reaction, which improves the mass transfer and heat transfer efficiency and provides technical support for continuous production. Description of the Drawings

[0033] Figure 1 It is a comparison diagram of the material states of Example 1, Comparative Example 2-2, Comparative Example 3, and Comparative Example 4 of the present invention. Among them, A is the liquid separation state in 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; D is the material state before methylation of Comparative Example 4. Detailed Embodiments

[0034] The endpoints and any values within the ranges disclosed herein are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0035] The present invention provides a method for synthesizing methyl (E)-2-methyl-α-methoxyiminophenylacetate, wherein the method comprises the following steps:

[0036] (1) Using o-methylphenylacetonitrile as a raw material, 2-methyl-α-cyanobenzaldoxime salt solution is obtained through an oximation reaction;

[0037] (2) Add a first catalyst to the 2-methyl-α-cyanobenzaldoxime salt solution obtained in step (1), and continuously introduce chloromethane under a closed system condition to carry out the first methylation reaction to obtain an oily substance; after alkali hydrolysis of the oily substance, a 2-methyl-α-methoxyiminophenylacetic acid salt solution is obtained;

[0038] (3) Add a first organic solvent and a second catalyst to the 2-methyl-α-methoxyiminophenylacetic acid salt solution obtained in step (2), and introduce chloromethane under a closed system condition to carry out the second methylation reaction to obtain a solution of methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate;

[0039] (4) Carry out acid rearrangement on the solution of methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate to obtain methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0040] In the present invention, after the oximation reaction is completed, the reaction solution is directly subjected to methylation without adding any additional organic solvents; after the methylation reaction, phase separation treatment is carried out, and the catalyst can be directly recycled after desalting (concentration or nanofiltration) of the aqueous phase. Therefore, compared with the prior art, the amount of organic solvent used in the present invention is reduced (by more than 50%), and the equipment utilization rate is significantly improved.

[0041] The present invention avoids using highly toxic chemicals such as dimethyl sulfate with low atom utilization rate and relatively expensive methyl bromide and methyl iodide as methylation reagents, uses low-cost chloromethane as the methylation reagent, and improves its reaction activity by adding a catalyst. At the same time, by introducing chloromethane into the closed reaction system for reaction to increase the concentration of chloromethane in the system (far lower than the amount of chloromethane required to dissolve DMF and acetonitrile to saturation), while improving the atom utilization rate and equipment utilization rate, the cost of treating excessive chloromethane is reduced.

[0042] In the present invention, after the reaction solution obtained after the second methylation reaction is phase-separated, the oily phase (still in solution form) can be subjected to acid rearrangement to obtain the target product. The present invention can obtain a relatively high conversion rate of the raw material (o-methylphenylacetonitrile).

[0043] The reaction route is as follows:

[0044] .

[0045] Among them, " " represents that the compound includes cis and trans isomers.

[0046] In some embodiments of the present invention, in step (1), the 2-methyl-α-cyanobenzaldoxime salt is 2-methyl-α-cyanobenzaldoxime sodium and / or 2-methyl-α-cyanobenzaldoxime potassium.

[0047] In some embodiments of the present invention, in the 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).

[0048] 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.

[0049] 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.

[0050] 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.

[0051] In some embodiments of the present invention, the time of the first methylation reaction is 6 - 12 h, or 7 - 10 h.

[0052] In some embodiments of the present invention, in the step (2), sodium hydroxide solution and / or potassium hydroxide solution is used for alkali hydrolysis.

[0053] In some embodiments of the present invention, the temperature of the alkali hydrolysis is 90 - 105°C, or 100 - 105°C.

[0054] In some embodiments of the present invention, in the step (3), the first organic solvent is a water-insoluble organic solvent, preferably selected from at least one of 1,2-dichloroethane, toluene, dichloromethane, and xylene.

[0055] The present invention selects a water-insoluble organic solvent and water (from the solution of sodium 2-methyl-α-methoxyiminophenylacetate) as the methylation mixed solvent. After the reaction is completed, phase separation is directly carried out, and after vacuum distillation, it can be recycled, avoiding the problem of high treatment cost caused by the complex post-treatment of water-soluble solvents such as DMF, acetonitrile, and DMSO commonly used in the current oximation-methylation process route, which requires water treatment before reuse.

[0056] In some embodiments of the present invention, the second catalyst is a complex of a phase transfer catalyst and an iodide. The iodide is, for example, a metal iodide.

[0057] 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.

[0058] In some embodiments of the present invention, the iodide is sodium iodide and / or potassium iodide.

[0059] In some embodiments of the present invention, the second catalyst is selected from at least one of the complex of tetrabutylammonium bromide and sodium iodide, the complex of benzyltriethylammonium chloride and potassium iodide, the complex of benzyltriethylammonium bromide and potassium iodide, or dodecyltrimethylammonium bromide and sodium iodide.

[0060] 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.

[0061] 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.

[0062] In some embodiments of the present invention, the pressure of the second methylation reaction is 0.25~1.1 MPa, or 0.25~0.45 MPa, or 0.3~0.4 MPa, or 0.34~0.35 MPa, or 0.35~0.36 MPa, or 0.38~0.40 MPa, or 0.39~0.41 MPa, or 0.42~0.44 MPa.

[0063] In some embodiments of the present invention, the time of the second methylation reaction is 5~10 h, or 6~9 h, or 7 h.

[0064] In some embodiments of the present invention, in step (3), after the solution of methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate is desolvated, a second organic solvent and an acidic catalyst are added for acidic rearrangement.

[0065] In some embodiments of the present invention, the acidic catalyst is sulfuric acid and / or HCl.

[0066] In some embodiments of the present invention, the second organic solvent is methanol and / or ethanol.

[0067] In some embodiments of the present invention, the temperature of the acidic rearrangement is 10~70°C, or 20~60°C.

[0068] In some embodiments of the present invention, the time of the acidic rearrangement is 1 to 10 h, or 2 to 8 h.

[0069] In some embodiments of the present invention, after the acidic rearrangement, the temperature is lowered for crystallization to obtain methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0070] In some embodiments of the present invention, after the crystallization by cooling, filtration is carried out, and washing is carried out with a second organic solvent to obtain methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0071] In some embodiments of the present invention, the mother liquor and / or the washing liquor after the crystallization by cooling are recycled for the acidic rearrangement.

[0072] The present invention will be described in detail below by way of examples.

[0073] In the following examples and comparative examples, those without specific conditions noted are carried out under conventional conditions. For the reagents or instruments without the manufacturer noted, they are all conventional products that can be obtained through commercial channels.

[0074] Example 1

[0075] This example is used to illustrate the preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0076] (1) Preparation of sodium 2-methyl-α-cyanobenzaldoxime

[0077] 66.2 g (0.5 mol) of o-methylphenylacetonitrile, 33 g of methanol and 75.0 g (content 32%, 0.6 mol) of liquid sodium hydroxide were added to a four-necked flask, the temperature of the feed liquid was controlled at 34 to 37 °C, and 40.1 g (content 99%, 0.65 mol) of methyl nitrite was continuously and slowly introduced. The gas introduction time was 8 h, and after the gas introduction was completed, the temperature was kept for 2 h to obtain 211.3 g of a sodium 2-methyl-α-cyanobenzaldoxime solution. The external standard content of the remaining o-methylphenylacetonitrile was 0.41%, and the conversion rate of o-methylphenylacetonitrile was 98.68%.

[0078] (2) Preparation of sodium 2-methyl-α-methoxyiminophenylacetate

[0079] To the 2-methyl-α-cyanobenzaldoxime sodium solution obtained in step (1), add 8.2 g of TBAB (99% content, 0.025 mol), transfer it to an autoclave, control the temperature of the feed liquid at 28 - 30 °C, close the system, continuously introduce chloromethane and control the system pressure at 0.38 - 0.40 MPa, keep warm for 6 h until the reaction ends, relieve the pressure (the tail gas is absorbed by excessive DMF, the weight gain is 9.0 g, corresponding to 0.18 mol of excessive chloromethane), discharge the material, separate the phases to obtain 89.7 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 160 g.

[0080] Transfer 89.7 g of the oily substance obtained by phase separation above to a four-necked flask, add 87.5 g of liquid alkali (32% content, 0.7 mol) and 52.5 g of water, heat up to 100 °C for alkali hydrolysis, control the content of (E / Z)-2-methyl-α-methoxyiminophenylacetamide in the middle control to be less than 1%, and after the reaction ends, obtain 218 g of 2-methyl-α-methoxyiminophenylacetic acid sodium solution (E:Z = 1:22).

[0081] (3)Preparation of (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate

[0082] Add 218 g of the 2-methyl-α-methoxyiminophenylacetic acid sodium solution obtained in step (2) to an autoclave, add 155 g of 1,2-dichloroethane, 11.4 g of TBAB (99% content, 0.035 mol), and 2.65 g of NaI (99% content, 0.018 mol), heat up to 60 °C, close the air release valve, continuously introduce chloromethane to maintain the system pressure at 0.4 MPa, keep warm and react for 10 h, then stop introducing gas, cool down and relieve the pressure (the tail gas is absorbed by excessive DMF, the weight gain is 23.7 g, corresponding to 0.470 mol). The feed liquid is clear (see A in Figure 1 . Take a sample to detect that the content of 2-methyl-α-methoxyiminophenylacetic acid sodium is less than 0.5%, separate the phases, the weight of the aqueous phase is 157.6 g, and the oil phase is a dichloroethane solution containing (E)-methyl 2-methyl-α-methoxyiminophenylacetate and (Z)-methyl 2-methyl-α-methoxyiminophenylacetate, with a weight of 259.73 g (E / Z = 1:8). Externally standardize (E)-methyl 2-methyl-α-methoxyiminophenylacetate and (Z)-methyl 2-methyl-α-methoxyiminophenylacetate in the oil phase respectively, and the total conversion rate is 91.9% (calculated based on o-methylphenylacetonitrile).

[0083] (4)Preparation of (E)-methyl 2-methyl-α-methoxyiminophenylacetate

[0084] The oil phase obtained in step (3) was subjected to vacuum distillation until no solvent was distilled out. Then, 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, and the mixture was stirred and kept warm for 8 h. Then, the temperature was lowered to 0 °C and kept warm for 1 h for crystallization. After filtration, it was washed with 10 g of methanol at 0 °C to obtain white methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0085] Example 2

[0086] This example is used to illustrate the preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0087] (1) Preparation of sodium 2-methyl-α-cyanobenzaldoxime

[0088] 66.2 g (0.5 mol) of o-methylphenylacetonitrile, 17 g of methanol, and 68.8 g of liquid sodium hydroxide (content 32%, 0.55 mol) were added to a four-necked flask. The temperature of the feed liquid was controlled at 28 - 30 °C, and 49.3 g (content 99%, 0.80 mol) of methyl nitrite was continuously and slowly introduced. The gas introduction time was 10 h. After the gas introduction was completed, it was kept warm for 2 h to obtain 184.3 g of a sodium 2-methyl-α-cyanobenzaldoxime solution. The external standard content of the remaining o-methylphenylacetonitrile was 0.56%, and the conversion rate of o-methylphenylacetonitrile was 98.46%.

[0089] (2) Preparation of sodium 2-methyl-α-methoxyiminophenylacetate

[0090] 11.0 g (content 99%, 0.04 mol) of TEBAB was added to the sodium 2-methyl-α-cyanobenzaldoxime solution obtained in step (1), and then it was transferred to an autoclave. The temperature of the feed liquid was controlled at 33 - 35 °C, and methyl chloride was continuously introduced while controlling the system pressure at 0.33 - 0.35 MPa. After keeping warm for 7 h, the reaction ended. The pressure was released, and the product was discharged. After phase separation, 90.12 g of an oily substance (containing (E / Z)-2-methyl-α-methoxyiminoacetonitrile and (E / Z)-2-methyl-α-methoxyiminoacetamide) was obtained, and the weight of the aqueous phase was 131.5 g.

[0091] The 90.12 g of the oily substance obtained by the above phase separation was transferred to a four-necked flask, 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 alkali hydrolysis. During the process, the content of (E / Z)-2-methyl-α-methoxyiminoacetamide was controlled to be less than 1%. After the reaction ended, 231.6 g of a sodium 2-methyl-α-methoxyiminophenylacetate solution (E:Z = 1:21) was obtained.

[0092] (3) Preparation of (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate

[0093] Add 231.6 g of the sodium 2-methyl-α-methoxyiminophenylacetate solution obtained in step (2) to an autoclave, then add 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). Heat up to 65 °C, close the air release valve, continuously introduce chloromethane to maintain the system pressure at 0.35 - 0.36 MPa, keep the temperature for reaction for 9 h, then stop introducing gas, cool down and release the pressure. Take a sample for detection, and the content of sodium 2-methyl-α-methoxyiminophenylacetate is less than 0.7%. Separate the phases. The weight of the aqueous phase is 178.4 g, and the oil phase is a dichloroethane solution containing methyl (E)-2-methyl-α-methoxyiminophenylacetate and methyl (Z)-2-methyl-α-methoxyiminophenylacetate, with a weight of 261.2 g (E / Z = 1:9). Externally standardize methyl (E)-2-methyl-α-methoxyiminophenylacetate and methyl (Z)-2-methyl-α-methoxyiminophenylacetate in the oil phase respectively, and the total conversion rate is 90.2% (calculated based on o-methylphenylacetonitrile).

[0094] (4)Preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate

[0095] Distill the oil phase obtained in step (3) under reduced pressure until no solvent is distilled out. Add 60 g of ethanol and 18.38 g of sulfuric acid (content 80%, 0.15 mol). Heat up to 50 °C, stir and keep the temperature for 10 h, then cool down to 0 °C and keep the temperature for 2 h for crystallization. Filter, and wash with 10 g of ethanol at 0 °C to obtain white methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0096] Example 3

[0097] This example is used to illustrate the preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0098] (1)Preparation of sodium 2-methyl-α-cyanobenzaldoxime

[0099] Add 66.2 g (0.5 mol) of o-methylphenylacetonitrile, 66 g of methanol, and 75.0 g of liquid sodium hydroxide (content 32%, 0.6 mol) to a four-necked flask. Control the temperature of the feed liquid at 26 - 28 °C, continuously and slowly introduce 55.5 g (content 99%, 0.90 mol) of methyl nitrite. The gas introduction time is 9 h. After the gas introduction is completed, keep the temperature for 2 h to obtain 238.4 g of a sodium 2-methyl-α-cyanobenzaldoxime solution. The externally standard content of the remaining o-methylphenylacetonitrile is 0.67%, and the conversion rate of o-methylphenylacetonitrile is 97.56%.

[0100] (2)Preparation of sodium 2-methyl-α-methoxyiminophenylacetate

[0101] To the 2-methyl-α-cyanobenzaldoxime sodium solution obtained in step (1), add 9.77 g of TBAB (content 99%, 0.03 mol), transfer it to an autoclave, control the temperature of the feed liquid at 25-27 °C, continuously introduce chloromethane and control the system pressure at 0.30-0.32 MPa, keep the temperature for 10 h until the reaction ends, relieve the pressure, discharge the material, distill at atmospheric pressure until 70 °C, cool down and separate the phases to obtain 92.1 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 103 g.

[0102] Transfer 92.1 g of the oily substance obtained by phase separation above to a four-necked flask, add 87.5 g of liquid alkali (content 32%, 0.7 mol) and 99.0 g of water, heat up to 90 °C for alkali hydrolysis, control the content of (E / Z)-2-methyl-α-methoxyiminophenylacetamide in the middle control to be less than 1%, and after the reaction ends, obtain 268.2 g of 2-methyl-α-methoxyiminophenylacetic acid sodium solution (E:Z = 1:22).

[0103] Preparation of (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate

[0104] Add 268.2 g of the 2-methyl-α-methoxyiminophenylacetic acid sodium solution obtained in step (2) to an autoclave, add 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), heat up to 75 °C, close the air release valve, continuously introduce chloromethane to maintain the system pressure at 0.39-0.41 MPa, keep the temperature for 5 h to stop gas introduction, cool down and relieve the pressure, sample and detect that the content of 2-methyl-α-methoxyiminophenylacetic acid sodium is less than 0.5%, separate the phases, the weight of the aqueous phase is 191.0 g, and the oil phase is a dichloroethane solution containing (E)-methyl 2-methyl-α-methoxyiminophenylacetate and (Z)-methyl 2-methyl-α-methoxyiminophenylacetate, with a weight of 259.7 g (E / Z = 1:9). Perform external standard for (E)-methyl 2-methyl-α-methoxyiminophenylacetate and (Z)-methyl 2-methyl-α-methoxyiminophenylacetate in the oil phase respectively, and the total conversion rate is 93.1% (calculated based on o-methylphenylacetonitrile).

[0105] Preparation of (E)-methyl 2-methyl-α-methoxyiminophenylacetate

[0106] Distill the oil phase obtained in step (3) under reduced pressure until no solvent is extracted, add 50 g of methanol, introduce 18.41 g of HCl (content 99%, 0.50 mol), heat up to 30 °C, stir and keep the temperature for 10 h, cool down to 0 °C and keep the temperature for 2 h to crystallize, filter, and wash with 10 g of methanol at 0 °C to obtain white (E)-methyl 2-methyl-α-methoxyiminophenylacetate.

[0107] Example 4

[0108] This example is used to illustrate the preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0109] (1) Preparation of potassium 2-methyl-α-cyanobenzaldoxime

[0110] 66.2 g (0.5 mol) of o-methylphenylacetonitrile, 20 g of methanol and 70.0 g (content 48%, 0.6 mol) of liquid potassium hydroxide were added to a four-necked flask. The temperature of the feed liquid was controlled at 33-35 °C, and 43.1 g (content 99%, 0.7 mol) of methyl nitrite was continuously and slowly introduced. The gas introduction time was 8 h, and after the gas introduction was completed, it was kept warm for 2 h to obtain 193.1 g of a potassium 2-methyl-α-cyanobenzaldoxime solution. The external standard content of the remaining o-methylphenylacetonitrile was 0.53%, and the conversion rate of o-methylphenylacetonitrile was 98.38%.

[0111] (2) Preparation of potassium 2-methyl-α-methoxyiminophenylacetate

[0112] 8.14 g (content 99%, 0.025 mol) of TBAB was added to the potassium 2-methyl-α-cyanobenzaldoxime solution obtained in step (1), and it was transferred to an autoclave. The temperature of the feed liquid was controlled at 25-27 °C, and methyl chloride was continuously introduced while controlling the system pressure at 0.30-0.32 MPa. After keeping warm for 12 h, the reaction was completed, the pressure was released, and the material was discharged. Phase separation gave 93.8 g of an oily substance (containing (E / Z)-2-methyl-α-methoxyiminoacetonitrile and (E / Z)-2-methyl-α-methoxyiminoacetamide), and the weight of the aqueous phase was 137.7 g.

[0113] The 93.8 g of the oily substance obtained by the above phase separation was transferred to a four-necked flask, 87.5 g (content 48%, 0.75 mol) of potassium hydroxide solution and 122.5 g of water were added, and the temperature was raised to 105 °C for alkali hydrolysis. The content of (E / Z)-2-methyl-α-methoxyiminoacetamide in the middle control was lower than 1%. After the reaction was completed, 293.7 g of a potassium 2-methyl-α-methoxyiminophenylacetate solution (E:Z = 1:22) was obtained.

[0114] (3) Preparation of (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate

[0115] Add 293.7 g of the potassium 2-methyl-α-methoxyiminophenylacetate solution obtained in step (2) to an autoclave, then 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 bleed valve, and introduce chloromethane at 20 °C until the pressure stabilizes at 0.34 - 0.35 MPa for 0.5 h. Then close the inlet valve, heat up to 60 °C, and the maximum autoclave pressure reaches 1.1 MPa. As the reaction proceeds, the pressure gradually decreases to 0.7 MPa, keep the temperature for reaction for 2 h, cool down and then release the pressure. Take a sample for detection, and the content of potassium 2-methyl-α-methoxyiminophenylacetate is less than 0.5%. Separate the phases. The weight of the aqueous phase is 247.0 g, and the oil phase is a 1,2-dichloroethane solution containing methyl (E)-2-methyl-α-methoxyiminophenylacetate and methyl (Z)-2-methyl-α-methoxyiminophenylacetate, with a weight of 260.7 g (E / Z = 1:9). Perform external standard calibration on methyl (E)-2-methyl-α-methoxyiminophenylacetate and methyl (Z)-2-methyl-α-methoxyiminophenylacetate in the oil phase respectively, and the total conversion rate is 91.7% (calculated based on o-methylphenylacetonitrile).

[0116] (4)Preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate

[0117] Distill the oil phase obtained in step (3) under reduced pressure until no solvent is distilled out. Add 50 g of methanol and 24.5 g of sulfuric acid (content 80%, 0.20 mol), heat up to 30 °C, stir and keep the temperature for 6 h, then cool down to 0 °C and keep the temperature for 2 h for crystallization. Filter, and wash with 15 g of methanol at 0 °C to obtain white methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0118] Example 5

[0119] This example is used to illustrate the preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0120] (1)Preparation of sodium 2-methyl-α-cyanobenzaldoxime

[0121] Add 66.2 g (0.5 mol) of o-methylphenylacetonitrile, 33 g of methanol, and 75.0 g of liquid sodium hydroxide (content 32%, 0.6 mol) to a four-necked flask. Control the temperature of the feed liquid at 38 - 40 °C, and continuously and slowly introduce 40.3 g (content 99%, 0.65 mol) of methyl nitrite. The gas introduction time is 8 h. After the gas introduction is completed, keep the temperature for 2 h to obtain 211.5 g of a sodium 2-methyl-α-cyanobenzaldoxime solution. The external standard content of the remaining o-methylphenylacetonitrile is 0.40%, and the conversion rate of o-methylphenylacetonitrile is 98.71%.

[0122] (2)Preparation of sodium 2-methyl-α-methoxyiminophenylacetate

[0123] 8.14 g of TBAB (99% content, 0.025 mol) was added to the 2-methyl-α-cyanobenzaldoxime sodium solution obtained in step (1), and the mixture was transferred to an autoclave. The temperature of the feed liquid was controlled at 28 - 30 °C, and methyl chloride was continuously introduced while controlling the system pressure at 0.38 - 0.40 MPa. After holding the temperature for 6 h, the reaction ended. The pressure was released, and the product was discharged. After phase separation, 89.5 g of an oily substance (containing (E / Z)-2-(2'-methylphenyl)-α-methoxyiminophenylacetonitrile and (E / Z)-2-(2'-methylphenyl)-α-methoxyiminophenylacetamide) was obtained, and the weight of the aqueous phase was 160 g.

[0124] The aqueous phase obtained in step (3) of Example 1 was concentrated under reduced pressure and filtered to remove salts, obtaining 80 g of a salt-containing mother liquor.

[0125] The 89.5 g of the oily substance obtained from the above phase separation was transferred to a four-necked flask, 87.5 g of liquid alkali (32% content, 0.7 mol) and the above 80 g of the salt-containing mother liquor were added, and the temperature was raised to 100 °C for alkali hydrolysis. The content of (E / Z)-2-methyl-α-methoxyiminophenylacetamide in the middle control was less than 1%. After the reaction ended, 246.3 g of a 2-methyl-α-methoxyiminophenylacetic acid sodium solution (E:Z = 1:22) was obtained.

[0126] (3) Preparation of (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate

[0127] 246.3 g of the 2-methyl-α-methoxyiminophenylacetic acid sodium solution obtained in step (2) was added to an autoclave, 155 g of 1,2-dichloroethane, 5.86 g of TBAB (99% content, 0.018 mol), and 1.51 g of NaI (99% content, 0.01 mol) were added. The temperature was raised to 73 - 75 °C, the air release valve was closed, and methyl chloride was continuously introduced to maintain the system pressure at 0.42 - 0.44 MPa. After holding the temperature for 10 h, the gas introduction was stopped, the temperature was lowered, and the pressure was released. The content of 2-methyl-α-methoxyiminophenylacetic acid sodium was detected to be less than 0.5%. After phase separation, the weight of the aqueous phase was 180.2 g, and the oil phase was a 1,2-dichloroethane solution containing (E)-methyl 2-methyl-α-methoxyiminophenylacetate and (Z)-methyl 2-methyl-α-methoxyiminophenylacetate, with a weight of 256.2 g (E / Z = 1:8). External standards were carried out for (E)-methyl 2-methyl-α-methoxyiminophenylacetate and (Z)-methyl 2-methyl-α-methoxyiminophenylacetate respectively, and the total conversion rate was 92.3% (calculated based on o-methylphenylacetonitrile).

[0128] (4) Preparation of (E)-methyl 2-methyl-α-methoxyiminophenylacetate

[0129] The oil phase obtained in step (3) was distilled under reduced pressure until no solvent was distilled out, 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, then cooled to 0 °C and kept warm for 2 h for crystallization. After filtration, it was washed with 15 g of methanol at 0 °C to obtain white methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0130] Example 6

[0131] This example is used to illustrate that the mother liquor and washing liquor obtained after acid rearrangement can be reused multiple times.

[0132] Steps (1)-(3) of Example 1 were repeated, and 8 batches of feeding and reaction were carried out to obtain a total of 2075 g of 1,2-dichloroethane solution containing methyl (E)-2-methyl-α-methoxyiminophenylacetate and methyl (Z)-2-methyl-α-methoxyiminophenylacetate after phase separation (calculated based on the fed o-methylphenylacetonitrile, theoretically containing 4 mol of (E / Z)-2-methyl-α-methoxyiminophenylacetate).

[0133] (1) Take 259 g of the above solution, distill it under reduced pressure until no solvent is distilled out, add 50 g of methanol and 12.3 g of sulfuric acid (content 80%, 0.1 mol), heat up to 60 °C, stir and keep warm for 8 h, then cool to 0 °C and keep warm for 1 h for crystallization. After filtration, it was washed with 10 g of methanol at 0 °C to obtain white methyl (E)-2-methyl-α-methoxyiminophenylacetate, and the mother liquor and washing liquor were combined.

[0134] (2) Weigh 259 g of the above solution again, distill it under reduced pressure until no solvent is distilled out, add the combined mother liquor and washing liquor above, heat up to 60 °C, stir and keep warm for 8 h, then cool to 0 °C and keep warm for 1 h for crystallization. After filtration, it was washed with 10 g of methanol at 0 °C to obtain white methyl (E)-2-methyl-α-methoxyiminophenylacetate, and the mother liquor and washing liquor were combined.

[0135] (3) Repeat step (2), and the mother liquor and washing liquor were reused for 7 batches in total. The filter cake obtained was dried to obtain a total of 753.4 g of methyl (E)-2-methyl-α-methoxyiminophenylacetate (E / Z = 99.5:0.5), the external standard content was 98.7%, and the total yield was 89.8%; the remaining mother liquor was 91.6 g, the external standard E-ester content was 8.2%, accounting for 0.9% of the total conversion rate, the external standard Z-ester content was 11.6%, accounting for 1.3% of the total conversion rate.

[0136] Example 7

[0137] This example is used to illustrate the preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0138] (1) Preparation of sodium 2-methyl-α-cyanobenzaldoxime

[0139] 66.2 g (0.5 mol) of o-methylphenylacetonitrile, 17 g of methanol and 68.8 g (content 32%, 0.55 mol) of liquid sodium hydroxide were added to a four-necked flask. The temperature of the feed liquid was controlled at 33-35 °C, and 46.3 g (content 99%, 0.75 mol) of methyl nitrite was continuously and slowly introduced. The gas introduction time was 9 h. After the gas introduction was completed, the mixture was kept warm for 2 h to obtain 183.3 g of a sodium 2-methyl-α-cyanobenzaldoxime solution. The external standard content of the remaining o-methylphenylacetonitrile was 0.66%, and the conversion rate of o-methylphenylacetonitrile was 98.17%.

[0140] (2) Preparation of sodium 2-methyl-α-methoxyiminophenylacetate

[0141] 12.46 g (content 99%, 0.04 mol) of DTAB was added to the sodium 2-methyl-α-cyanobenzaldoxime solution obtained in step (1), and the mixture was transferred to an autoclave. The temperature of the feed liquid was controlled at 33-35 °C, and chloromethane was continuously introduced while controlling the system pressure at 0.36-0.38 MPa. After keeping warm for 6 h, the reaction was completed, the pressure was released, and the product was discharged. Phase separation gave 90.32 g of an oil (containing (E / Z)-2-methyl-α-methoxyiminophenylacetonitrile and (E / Z)-2-methyl-α-methoxyiminoacetanilide), and the weight of the aqueous phase was 132.1 g.

[0142] The 90.32 g of the oil obtained by phase separation above was transferred to a four-necked flask, 93.75 g (content 32%, 0.75 mol) of liquid alkali and 56.30 g of water were added, and the temperature was raised to 105 °C for alkaline hydrolysis. The content of (E / Z)-2-methyl-α-methoxyiminoacetanilide in the middle control was less than 1%. After the reaction was completed, 231.4 g of a sodium 2-methyl-α-methoxyiminophenylacetate solution (E:Z = 1:21) was obtained.

[0143] (3) Preparation of methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate

[0144] Add 231.4 g of the sodium 2-methyl-α-methoxyiminophenylacetate solution obtained in step (2) to an autoclave, then add 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). Heat up to 65 °C, close the air release valve, continuously introduce chloromethane to maintain the system pressure at 0.38 - 0.40 MPa, keep the temperature for reaction for 7 h, then stop the gas supply, cool down and release the pressure. Take a sample for detection and the content of sodium 2-methyl-α-methoxyiminophenylacetate is less than 0.8%. Separate the phases. The weight of the aqueous phase is 179.6 g, and the oil phase is a toluene solution containing methyl (E)-2-methyl-α-methoxyiminophenylacetate and methyl (Z)-2-methyl-α-methoxyiminophenylacetate, with a weight of 282.15 g (E / Z = 1:9). Perform external standard for methyl (E)-2-methyl-α-methoxyiminophenylacetate and methyl (Z)-2-methyl-α-methoxyiminophenylacetate in the oil phase respectively, and the total conversion rate is 90.7% (calculated based on o-methylphenylacetonitrile).

[0145] (4)Preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate

[0146] Distill the oil phase obtained in step (3) under reduced pressure until no solvent is distilled out. Add 80 g of ethanol and introduce 11.05 g of HCl (content 99%, 0.30 mol). Heat up to 50 °C, stir and keep the temperature for 10 h, then cool down to 0 °C and keep the temperature for 2 h for crystallization. Filter and wash with 10 g of ethanol at 0 °C to obtain white methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0147] Example 8

[0148] This example is used to illustrate the preparation of methyl (E)-2-methyl-α-methoxyiminophenylacetate.

[0149] (1)Preparation of potassium 2-methyl-α-cyanobenzaldoxime

[0150] Add 66.2 g (0.5 mol) of o-methylphenylacetonitrile, 33.0 g of methanol, and 61.83 g of liquid potassium hydroxide (content 48%, 0.53 mol) to a four-necked flask. Control the temperature of the feed liquid at 35 - 37 °C, continuously and slowly introduce 43.15 g of methyl nitrite (content 99%, 0.70 mol), with the gas introduction time of 9 h. After the gas introduction is completed, keep the temperature for 2 h to obtain 193.53 g of potassium 2-methyl-α-cyanobenzaldoxime solution. The external standard content of the remaining o-methylphenylacetonitrile is 0.56%, and the conversion rate of o-methylphenylacetonitrile is 98.36%.

[0151] (2)Preparation of potassium 2-methyl-α-methoxyiminophenylacetate

[0152] To the 2-methyl-α-cyanobenzaldoxime potassium solution obtained in step (1), add 11.0 g of TEBAB (content 99%, 0.04 mol), transfer it to an autoclave, control the temperature of the feed liquid at 33 - 35 °C, continuously introduce methyl chloride and control the system pressure at 0.36 - 0.38 MPa, keep the temperature for 10 h until the reaction ends, relieve the pressure, discharge the material, and separate the phases to obtain 90.11 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 141.15 g.

[0153] Transfer 90.11 g of the oily substance obtained from the above phase separation into a four-necked flask, add 81.67 g of potassium hydroxide solution (content 48%, 0.70 mol) and 102.4 g of water, heat up to 95 °C for alkaline hydrolysis, control the content of (E / Z)-2-methyl-α-methoxyiminophenylacetamide in the middle control to be less than 1%, and after the reaction ends, obtain 265.5 g of 2-methyl-α-methoxyiminophenylacetic acid potassium solution (E:Z = 1:21).

[0154] (3) Preparation of (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate

[0155] Add 265.5 g of the 2-methyl-α-methoxyiminophenylacetic acid potassium solution obtained in step (2) to an autoclave, add 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), heat up to 60 °C, close the air release valve, continuously introduce methyl chloride to maintain the system pressure at 0.35 - 0.36 MPa, keep the temperature for 10 h to stop ventilation, cool down and relieve the pressure, sample and detect that the content of sodium 2-methyl-α-methoxyiminophenylacetate is less than 0.8%, separate the phases, the weight of the aqueous phase is 216.01 g, and the oil phase is a dichloromethane solution containing (E)-methyl 2-methyl-α-methoxyiminophenylacetate and (Z)-methyl 2-methyl-α-methoxyiminophenylacetate, with a weight of 262.6 g (E / Z = 1:10). Separate and externally standardize (E)-methyl 2-methyl-α-methoxyiminophenylacetate and (Z)-methyl 2-methyl-α-methoxyiminophenylacetate in the oil phase, and the total conversion rate is 89.3% (calculated based on o-methylphenylacetonitrile).

[0156] (4) Preparation of (E)-methyl 2-methyl-α-methoxyiminophenylacetate

[0157] Distill the oil phase obtained in step (3) under reduced pressure until no solvent is distilled out, add 60 g of methanol, introduce 14.73 g of HCl (content 99%, 0.4 mol), heat up to 50 °C, stir and keep the temperature for 10 h, cool down to 0 °C and keep the temperature for 2 h for crystallization, filter, and wash with 10 g of methanol at 0 °C to obtain white (E)-methyl 2-methyl-α-methoxyiminophenylacetate.

[0158] Comparative Example 1-1

[0159] (1) Repeat step (1) of Example 1 to obtain 210.9 g of a 2-methyl-α-cyanobenzaldoxime sodium solution;

[0160] (2) Control the temperature of the feed liquid at 28-30 °C, and introduce methyl chloride under normal pressure for 10 h. Monitor the feed liquid in the middle. When the content of 2-methyl-α-cyanobenzaldoxime sodium is greater than 85%, the reaction terminates.

[0161] It can be seen that under normal pressure and without a catalyst, the first methylation reaction is difficult to proceed.

[0162] Comparative Example 1-2

[0163] (1) Repeat steps (1) and (2) of Example 1 to obtain 218 g of a sodium 2-methyl-α-methoxyiminophenylacetate solution;

[0164] (2) Control the temperature of the feed liquid at 60-70 °C, and introduce methyl chloride under normal pressure for 10 h. The feed liquid is clear. Take a sample for in-process control. The content of (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate is less than 1%.

[0165] It can be seen that under normal pressure and without a catalyst, the second methylation reaction is difficult to proceed.

[0166] Comparative Example 2-1

[0167] (1) Repeat step (1) of Example 1 to obtain 211 g of a 2-methyl-α-cyanobenzaldoxime sodium solution;

[0168] (2) Control the temperature of the feed liquid at 28-30 °C, and introduce methyl chloride with the system pressure of 0.38-0.4 MPa for 6 h. Monitor the feed liquid in the middle. The content of (E / Z)-2-methyl-α-methoxyiminoacetonitrile is less than 7%.

[0169] It can be seen that without a catalyst, the first methylation reaction is difficult to proceed.

[0170] Comparative Example 2-2

[0171] (1) Repeat steps (1) and (2) of Example 1 to obtain 218 g of a sodium 2-methyl-α-methoxyiminophenylacetate solution;

[0172] (2) Add 11.4 g of TBAB (content 99%, 0.035 mol) and 2.65 g of NaI (content 99%, 0.018 mol) to the obtained sodium 2-methyl-α-methoxyiminophenylacetate solution. Control the temperature of the feed liquid at 60 °C, and introduce methyl chloride under normal pressure for 10 h. The feed liquid is slightly turbid (see Figure 1In B), during sampling and control, the content of methyl (E / Z)-2-methyl-α-methoxyiminophenylacetate is less than 4%.

[0173] It can be seen that only adding the catalyst and carrying out the second methylation reaction under normal pressure and without a second organic solvent cannot achieve the desired effect.

[0174] Comparative Example 3

[0175] (1) Repeat steps (1) and (2) of Example 1 to obtain 217.6 g of sodium 2-methyl-α-methoxyiminophenylacetate solution;

[0176] (2) Add 11.4 g of TBAB (content 99%, 0.035 mol) and 2.65 g of NaI (content 99%, 0.018 mol) to the sodium 2-methyl-α-methoxyiminophenylacetate solution, heat up to 60 °C, close the air release valve, continuously introduce chloromethane to maintain the system pressure at 0.4 MPa, keep the temperature for reaction for 10 h, stop ventilation, cool down and relieve the pressure. The material is turbid and a large amount of oily substances precipitate (see C in Figure 1 ), separate the phases, extract the aqueous phase with 150 g of dichloroethane, and combine to obtain 248.2 g of oily phase (E / Z = 1:9). Perform external standard calibration on methyl (E)-2-methyl-α-methoxyiminophenylacetate and methyl (Z)-2-methyl-α-methoxyiminophenylacetate respectively, and the total conversion rate is 75.8% (calculated based on o-methylphenylacetonitrile).

[0177] It can be seen that under the condition of not adding a second organic solvent, the conversion rate is relatively low.

[0178] Comparative Example 4 (refer to CN108863845B and CN112851546B)

[0179] Add 66.2 g (0.5 mol) of o-methylphenylacetonitrile and 92 g of methanol to a four-necked flask, control the temperature at 20 - 25 °C, and add 25.0 g (content 96%, 0.6 mol) of sodium hydroxide in batches; cool down to about 10 °C, slowly introduce 43.1 g (content 99%, 0.7 mol) of methyl nitrite, and after introducing, heat up to 30 °C and stir for 2 h;

[0180] Add 176 g of water and 25.0 g (content 96%, 0.6 mol) of sodium hydroxide, heat up to distill off methanol until the temperature of the material liquid reaches 105 °C, react for 3 h and then cool down to 15 °C; dropwise add 149 g of hydrochloric acid (content 32%, 1.31 mol), stir and keep warm for 1 h. Filter and 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 91.5 g of solid, perform external standard quantification, the content is 95.6% (0.4885 mol), the yield is 97.7%, and the NaCl content is 2.8%.

[0181] 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%.

[0182] Comparative Example 5

[0183] Take steps 1-3 of Example 1 of CN110396054B as Comparative Example 5.

[0184] Step 1: Preparation of 2-methyl-α-cyanobenzyl oxime

[0185] 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%.

[0186] Theoretical by-product calculation:

[0187] 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).

[0188] Step 2: Preparation of 2-(2-methylphenyl)-2-methyliminoacetonitrile

[0189] 2-Methyl-α-cyanobenzaldoxime (0.1 mol, 16 g), acetone (50 g), water (40 g), and sodium hydroxide (0.12 mol, 4.9 g) were added to a four-necked flask. The temperature was lowered to 11 °C, and dimethyl sulfate (0.13 mol, 16.7 g) was added dropwise to the system. After the addition was complete, the mixture was kept at 11 - 15 °C for 0.5 h. After the insulation, the solvent was recovered by atmospheric distillation. After the distillation was complete, 50 g of water was added to the system, and the mixture was stirred and then filtered to obtain 2-(2-methylphenyl)-2-methyliminoacetonitrile (yield 94%, content 96%).

[0190] Theoretical by-product calculation:

[0191] Based on the excess dimethyl sulfate, the sodium sulfate obtained after the hydrolysis of the by-product monomethyl sulfate sodium salt was 0.13 mol, which was converted to oxime ether as 0.13 mol / (0.1 mol × 94% × 91%) = 1.520 mol / mol of the product, and the by-product methanol was 4.48 g.

[0192] Step 3: Preparation of methyl E-2-methyl-α-methoxyiminophenylacetate

[0193] 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 added to a four-necked flask. The temperature was raised to 70 °C, and after keeping at 70 - 75 °C for 3 hours, the temperature was lowered to 5 - 10 °C. Dimethyl sulfate (0.12 mol, 15.4 g, 98% content) was added dropwise to the system. After the addition was complete, methyl E-2-methyl-α-methoxyiminophenylacetate was filtered (yield 91%, content 94%).

[0194] Theoretical by-product calculation:

[0195] The sodium sulfate by-produced after the hydrolysis of dimethyl sulfate in the reaction was converted to oxime ether as 0.12 mol / (0.1 × 91%) = 1.319 mol / mol of the product, ammonia 1.7 g, NaOH 2.4 g, and methanol 4.48 g.

[0196] Table 1 shows the comparison results of Example 6 of the present invention and Comparative Examples 4 - 5.

[0197] In the present invention, the calculation of the by-product salt amount (mol / mol of the product) is as follows:

[0198] Based on 0.5 mol of the charged o-methylphenylacetonitrile, 0.6 mol of sodium hydroxide is charged in the oximation stage and converted to sodium chloride in the first methylation stage, which is 0.6 mol; the base hydrolysis of 2-methyl-α-methoxyiminophenylacetonitrile consumes 0.7 mol of base (NaOH), and is converted to NaCl in the second methylation stage, with a production amount of 0.7 mol. The total by-product salt produced from 0.5 mol of the charged o-methylphenylacetonitrile is 1.3 mol.

[0199] The yield from o-methylphenylacetonitrile to the product is 89.8%. 0.449 mol of methyl (E)-2-methyl-α-methoxyiminophenylacetate is obtained from 0.5 mol of the charged o-methylphenylacetonitrile, which is 0.5 × 89.8% = 0.449 mol.

[0200] Therefore, the by-product salt produced for the production of 1 mol of methyl (E)-2-methyl-α-methoxyiminophenylacetate is 2.90 mol.

[0201] The calculation of the amount of organic solvent used (t / t product) is as follows:

[0202] In step (3), the solvent 1,2-dichloroethane is used, with a dosage of 155 g, and 0.449 mol of the product is obtained. After purification, it is 93.05 g. That is, the amount of solvent that needs to be distilled and recovered for the production of 1 t of the product is 155 / 93.05 = 1.67 t / t product.

[0203] The maximum volume (m 3 ) for the production of 1 t of the product is calculated as follows:

[0204] The stage with the largest material weight and material liquid volume in the reaction appears in the process of (E / Z)-methyl 2-methyl-α-methoxyiminophenylacetate. The total material weight is 417.33 g, and the volume is approximately 370 mL. That is, the maximum material liquid volume in the reaction stage for the production of 1 t of the pure product is 4.08 m 3 .

[0205] The calculation of the amount of methyl chloride that needs to be recovered for the production of 1 t of the product is as follows:

[0206] According to Example 1, 0.5 mol of o-methylphenylacetonitrile is charged, and the amount of methyl chloride absorbed is 9.0 g + 23.7 g = 32.7 g. 93.05 g of the product is obtained. That is, the weight of methyl chloride that needs to be recovered for the production of 1 t of the product is 32.7 / 93.05 = 0.35 t / t.

[0207] Table 1

[0208] .

[0209] As can be seen from the results in Table 1, the by-product salt of the present invention is reduced by about 45% compared with the existing comparative technology, the amount of organic solvent that needs to be distilled is reduced by more than 72%, and it can be directly recycled without dehydration. The production efficiency of the same methylation equipment is increased by more than 1 time, and the amount of methyl chloride to be recovered is reduced by 69.08% (0.81t of methyl chloride is reduced per 1t of product), greatly reducing the tail gas recovery pressure.

[0210] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within 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, obtaining a 2-methyl-α-cyanobenzyloxime salt solution through an oximation reaction; wherein the 2-methyl-α-cyanobenzyloxime salt is 2-methyl-α-cyanobenzyloxime sodium and / or 2-methyl-α-cyanobenzyloxime potassium; (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; The first catalyst is selected from at least one of tetrabutylammonium bromide, benzyltriethylammonium bromide, benzyltriethylammonium chloride and dodecyltrimethylammonium bromide; (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; The first organic solvent is selected from at least one of 1,2-dichloroethane, toluene, dichloromethane and xylene; The second catalyst is a phase transfer catalyst and an iodide; the iodide is sodium iodide and / or potassium iodide; (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: The molar ratio of the first catalyst to o-methylbenzeneacetonitrile is 0.03-0.08:

1.

3. The method according to claim 1, wherein: The molar ratio of the first catalyst to o-methylbenzeneacetonitrile is 0.05-0.06:

1.

4. The method according to claim 1, wherein: The temperature of the first methylation reaction is 20-40°C; and / or, the pressure of the first methylation reaction is 0.25-0.45 MPa; And / or, the time of the first methylation reaction is 6 to 12 hours.

5. The method according to claim 1, wherein: The temperature of the first methylation reaction is 25-35°C; and / or, the pressure of the first methylation reaction is 0.30-0.40 MPa; And / or, the time of the first methylation reaction is 7 to 10 hours.

6. The method according to claim 1, wherein: The temperature of the first methylation reaction is 25-27°C; And / or, the pressure of the first methylation reaction is 0.30-0.32 MPa.

7. The method according to claim 1, wherein: The temperature of the first methylation reaction is 28-30°C; And / or, the pressure of the first methylation reaction is 0.33-0.35 MPa.

8. The method according to claim 1, wherein: The temperature of the first methylation reaction is 33-35°C; And / or, the pressure of the first methylation reaction is 0.36-0.38 MPa.

9. The method according to claim 1, wherein: The pressure of the first methylation reaction is 0.38~0.40MPa.

10. 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 temperature of the alkaline hydrolysis is 90-105°C.

11. The method according to claim 1, wherein: The temperature of the alkaline hydrolysis is 100-105°C.

12. The method according to claim 1, wherein: The second catalyst is selected from at least one of tetrabutylammonium bromide and sodium iodide, benzyltriethylammonium chloride and potassium iodide, benzyltriethylammonium bromide and potassium iodide, and dodecyltrimethylammonium bromide and sodium iodide.

13. The method according to claim 1, 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.

14. The method according to claim 1, wherein: The molar ratio of the phase transfer catalyst, the iodide and the o-methylbenzene acetonitrile is 0.07:0.036:

1.

15. The method according to claim 1, wherein: The molar ratio of the phase transfer catalyst, the iodide and the o-methylbenzene acetonitrile is 0.1:0.05:

1.

16. The method according to claim 1, wherein: The molar ratio of the phase transfer catalyst, the iodide and the o-methylbenzene acetonitrile is 0.15:0.06:

1.

17. The method according to claim 1, wherein: The molar ratio of the phase transfer catalyst, the iodide and the o-methylbenzene acetonitrile is 0.1:0.1:

1.

18. The method according to claim 1, wherein: The molar ratio of the phase transfer catalyst, the iodide and the o-methylbenzene acetonitrile is 0.036:0.02:

1.

19. The method according to claim 1, wherein: The molar ratio of the phase transfer catalyst, the iodide and the o-methylbenzene acetonitrile is 0.1:0.06:

1.

20. The method according to claim 1, wherein: The molar ratio of the phase transfer catalyst, the iodide and the o-methylbenzene acetonitrile is 0.1:0.05:

1.

21. The method according to claim 1, wherein: The temperature of the second methylation reaction is 50~75℃; and / or, the pressure of the second methylation reaction is 0.25-1.1 MPa; And / or, the second methylation reaction time is 5 to 10 hours.

22. The method according to claim 1, wherein: The temperature of the second methylation reaction is 60~75℃; and / or, the pressure of the second methylation reaction is 0.25-0.45 MPa; And / or, the time of the second methylation reaction is 6 to 9 hours.

23. The method according to claim 1, wherein: The temperature of the second methylation reaction was 65°C; and / or, the pressure of the second methylation reaction is 0.3-0.4 MPa; And / or, the time of the second methylation reaction is 7 hours.

24. The method according to claim 1, wherein: The pressure of the second methylation reaction is 0.34~0.35MPa.

25. The method of claim 1, wherein: The pressure of the second methylation reaction is 0.35~0.36MPa.

26. The method of claim 1, wherein: The pressure of the second methylation reaction is 0.38~0.40MPa.

27. The method of claim 1, wherein: The pressure of the second methylation reaction is 0.39~0.41MPa.

28. The method of claim 1, wherein: The pressure of the second methylation reaction is 0.42~0.44MPa.

29. The method of claim 1, wherein: In the step (4), 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 rearrangement; And / or, the temperature of the acidic rearrangement is 10-70°C; And / or, the acidic rearrangement time is 1 to 10 hours.

30. The method of claim 29, wherein: The acidic catalyst is sulfuric acid and / or HCl; And / or, the second organic solvent is methanol and / or ethanol.

31. The method of claim 1, wherein: The temperature of the acidic rearrangement is 20-60°C; And / or, the time of the acidic rearrangement is 2 to 8 hours.

32. The method according to any one of claims 1 to 31, wherein: After the acidic rearrangement is completed, the temperature is lowered and crystallization is carried out to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester.

33. The method of claim 32, wherein: After cooling and crystallization, the mixture is filtered and eluted with a second organic solvent to obtain (E)-2-methyl-α-methoxyiminophenylacetic acid methyl ester; And / or, the second organic solvent is methanol and / or ethanol; And / or, the mother liquor and / or the eluent after cooling and crystallization are recycled for acid rearrangement.

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