A preparation process of picoxystrobin intermediate o-chloromethyl methyl phenylacetate

Abstract

This invention relates to the field of chemical production technology, specifically disclosing a preparation process for methyl o-chloromethylphenylacetate, an intermediate of azoxystrobin. The preparation process of methyl o-chloromethylphenylacetate provided by this invention uses o-methylphenylacetic acid as a raw material and arylphosphine as a catalyst to suppress the formation of dichloromethylphenylacetic acid impurities, thereby improving the purity of o-chloromethylphenylacetic acid. Subsequently, under the action of the arylphosphine catalyst, o-chloromethylphenylacetic acid reacts directly with thionyl chloride and methanol added in the previous step to produce methyl o-chloromethylphenylacetate, achieving the goal of one-pot direct preparation of methyl o-chloromethylphenylacetate. The content of the prepared methyl o-chloromethylphenylacetate is >99.5%, which is beneficial for effectively improving the purity of azoxystrobin products, simplifying the post-processing of crude azoxystrobin, and improving the production efficiency of azoxystrobin.

Description

Technical Field

[0001] This invention relates to the field of chemical production technology, and in particular to a preparation process of methyl o-chloromethylphenylacetate, an intermediate of pyridoxine. Background Technology

[0002] Azoxystrobin is one of the most effective methoxyacrylate fungicides currently available, first introduced in Europe by Syngenta in 2001. Azoxystrobin is mainly used to control foliar diseases in wheat, such as leaf blight, leaf rust, glume blight, brown spot, and powdery mildew. Compared to other existing methoxyacrylate fungicides, azoxystrobin has a stronger control effect on wheat leaf blight, net blight, and clouding disease.

[0003] Currently, the main industrial synthetic route for azoxystrobin is as follows: Using o-methylphenylacetic acid as a raw material, it undergoes free radical chlorination, alkali dissolution, acidic cyclization, and methanol recrystallization to obtain 3-isochromone with high purity. Then, using 3-isochromone as a raw material, a chlorination ring-opening reaction is carried out to obtain methyl o-chloromethylphenylacetate, which is then condensed and docked with pyridone for subsequent reactions to synthesize azoxystrobin. As can be seen from the process route, methyl o-chloromethylphenylacetate is a key intermediate in the synthesis of azoxystrobin.

[0004]

[0005] 3-Isochromone is an important intermediate in methoxyacrylate fungicides, with a large market supply. Many azoxystrobin manufacturers directly purchase 3-isochromone as a raw material to reduce the number of processing steps involved and to avoid the disposal of large amounts of waste salts (mainly sodium chloride, sodium o-dichloromethylphenylacetate, sodium o-trichloromethylphenylacetate, etc.) generated during its production. However, 3-isochromone is expensive (approximately 120,000 RMB / ton), and it is prone to moisture absorption and clumping during storage and feeding, making it difficult to store and affecting mass transfer in the reaction. The presence of moisture can lead to the formation of o-chloromethylphenylacetic acid during ring-opening, consuming a significant amount of thionyl chloride, resulting in raw material waste and increased production costs. Therefore, most manufacturers currently choose to synthesize azoxystrobin using the aforementioned mainstream process. However, the yield and purity of azoxystrobin products prepared from o-methylphenylacetic acid through multiple steps are relatively low and require further improvement. Summary of the Invention

[0006] To address the problems of long process routes, low product yield and purity, and the generation of large amounts of waste salt in existing methods for synthesizing azoxystrobin, this invention provides a process for preparing methyl o-chloromethylphenylacetate, an intermediate of azoxystrobin.

[0007] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0008] A process for preparing methyl o-chloromethylphenylacetate, an intermediate of azoxystrobin, includes the following steps:

[0009] Step a: Add o-methylphenylacetic acid, free radical initiator and triarylphosphine catalyst to a mixed solvent of chlorobenzene and methanol, mix well, heat, and introduce chlorine gas. React until the HPLC content of dichloromethylphenylacetic acid impurity is ≤3%, stop the chlorine gas, cool down, and obtain o-chloromethylphenylacetic acid reaction solution.

[0010] Step b: Add thionyl chloride dropwise to the o-chloromethylphenylacetic acid reaction solution to carry out the esterification reaction until the HPLC contents of o-chloromethylphenylacetic acid and o-methylphenylacetic acid are both ≤1%. Stop adding thionyl chloride, remove methanol and chlorobenzene solvents, and distill to obtain methyl o-chloromethylphenylacetic acid.

[0011] The purity of the intermediate methyl o-chloromethylphenylacetate directly affects the purity of azoxystrobin products. Therefore, improving the purity of methyl o-chloromethylphenylacetate can effectively improve the quality of azoxystrobin products and reduce the post-processing and refining of crude azoxystrobin, which is of great significance for improving the production efficiency of azoxystrobin.

[0012] During the experiment, the inventors discovered that the purity of the intermediate methyl o-chloromethylphenylacetate prepared by existing traditional processes is difficult to reach above 99%. After analyzing the reasons from various aspects, the inventors believe that the methoxy-substituted impurity is generated during the ring-opening process of 3-isochromone. The structural characterization of this impurity is described in [link to relevant documentation]. Figure 1 As shown. Therefore, the inventor conducted the following experiment:

[0013] 3-Isochromone and excess methanol were added to toluene, followed by dropwise addition of thionyl chloride. The reaction was carried out at 60-62℃ for 3 hours. After the isochromone content was <0.5% by HPLC, the toluene was removed by distillation. The reactor feed was methyl o-chloromethylphenylacetate. One drop of the feed solution was added to 20 mL of diluent (25% acetonitrile aqueous solution), filtered, and analyzed by HPLC. The results showed that the content of methoxy-substituted impurities was approximately 2%-3%. The inventors analyzed the cause and concluded that the presence of a large amount of methanol during the ring-opening process of 3-isochromone led to the formation of methoxy-substituted impurities at a content of 2%-3%, as shown below. This impurity could not be removed with the toluene, thus affecting the content and yield of the subsequent condensation reaction product and the final product, azoxystrobin.

[0014]

[0015] Compared with existing technologies, the preparation process of methyl o-chloromethylphenylacetate, an intermediate of azoxystrobin, provided by this invention uses o-methylphenylacetic acid as raw material, adds methanol as a reaction solvent during the chlorination stage, and uses arylphosphine as a catalyst to suppress the formation of dichloromethylphenylacetic acid impurities, thereby improving the purity of o-chloromethylphenylacetic acid. Furthermore, under the action of the arylphosphine catalyst, o-chloromethylphenylacetic acid reacts directly with thionyl chloride and the methanol added in the previous step to generate methyl o-chloromethylphenylacetate, avoiding the formation process of 3-isochromone. Therefore, the ring-opening process of 3-isochromone is avoided, and consequently, the generation of methoxy-substituted impurities is also avoided. The content of the prepared methyl o-chloromethylphenylacetate is >99.5%, significantly improving the purity of the intermediate methyl o-chloromethylphenylacetate. This is beneficial for effectively improving the purity of azoxystrobin products, simplifying the post-processing of crude azoxystrobin, and improving the production efficiency of azoxystrobin.

[0016] The preparation process of methyl o-chloromethylphenylacetate, an intermediate of pyridoxine, provided by this invention, achieves the goal of directly preparing methyl o-chloromethylphenylacetate in a one-pot process. This not only effectively improves production efficiency but also avoids the separation step of 3-isochromone and the generation of a large amount of waste salt in the 3-isochromone process, reducing the hazardous waste treatment cost for enterprises. It is suitable for industrial production, has high economic and environmental benefits, and has extremely high value for promotion and application.

[0017] It should be noted that the structure of the dichloromethylphenylacetic acid impurity is as follows:

[0018]

[0019] Preferably, in step a, the free radical initiator is at least one of azobisisobutyronitrile or benzoyl peroxide.

[0020] More preferably, in step a, the free radical initiator is azobisisobutyronitrile.

[0021] The preferred free radical initiator can promote the free radical chlorination reaction between o-tolueneacetic acid and chlorine, thereby improving the reaction efficiency.

[0022] Preferably, in step a, the triarylphosphine catalyst is triphenylphosphine.

[0023] Triphenylphosphine reacts with chlorine to form the intermediate triphenyldichloride, as shown below. The presence of triphenyldichloride maintains a stable level of chlorine free radicals in the system, preventing excessive chlorine free radical content in the solvent, thereby inhibiting the formation of dichloro impurities and improving the selectivity of monochloro derivatives. In addition, triphenylphosphine can catalyze the direct acylation and esterification reactions of o-chloromethylphenylacetic acid with thionyl chloride and methanol to directly obtain methyl o-chloromethylphenylacetic acid, avoiding the formation of the 3-isochromone intermediate. This also avoids the ring-opening process of 3-isochromone to prepare methyl o-chloromethylphenylacetic acid, thus preventing the formation of methoxy-substituted impurities and effectively improving the purity of the methyl o-chloromethylphenylacetic acid product.

[0024]

[0025] Preferably, in step a, the chlorobenzene is at least one of chlorobenzene, o-dichlorobenzene, or m-dichlorobenzene.

[0026] More preferably, in step a, the chlorobenzene is chlorobenzene.

[0027] The preferred reaction solvent is inert to the reactants, which helps to reduce the formation of dichloro impurities.

[0028] Preferably, in step a, the amount of the free radical initiator added is 0.1%-2% of the mass of o-methylphenylacetic acid.

[0029] More preferably, in step a, the amount of the free radical initiator added is 0.2%-0.6% of the mass of o-methylphenylacetic acid.

[0030] Preferably, in step a, the amount of the triarylphosphine catalyst added is 0.01%-0.02% of the mass of o-methylphenylacetic acid.

[0031] More preferably, in step a, the amount of the triarylphosphine catalyst added is 0.015% of the mass of o-methylphenylacetic acid.

[0032] The optimal amount of free radical initiator and catalyst added can reduce production costs while ensuring sufficient promotion of the reaction.

[0033] It should be noted that, in order to minimize the formation of dichloro impurities, chlorine gas should be introduced at a low rate for the first 0.5 hours, with the chlorine gas rate controlled at 10-15 mL / min / 50g o-methylphenylacetic acid. After the reaction solution changes from slightly yellow to the color fading, chlorine gas should be introduced at a faster rate, with the chlorine gas rate controlled at 20-30 mL / min / 50g o-methylphenylacetic acid.

[0034] Preferably, in step a, the mass ratio of chlorobenzene to methanol in the mixed solvent is 1-9:1.

[0035] More preferably, in step a, the mass ratio of chlorobenzene to methanol in the mixed solvent is 3-5:1.

[0036] Preferably, in step a, the mass ratio of the mixed solvent to o-methylphenylacetic acid is 2-5:1.

[0037] More preferably, in step a, the mass ratio of the mixed solvent to o-methylphenylacetic acid is 2-3:1.

[0038] In traditional processes, the mass of methanol is generally 5-6 times the mass of the raw material o-methylphenylacetic acid. The amount of methanol used in the o-chloromethylphenylacetic acid methyl ester provided by this invention is significantly reduced, to only about 1 times the mass of o-methylphenylacetic acid, effectively reducing the amount of methanol used.

[0039] Preferably, in step a, the temperature is raised to 40℃-65℃.

[0040] Preferably, in step a, the molar ratio of chlorine gas to o-methylphenylacetic acid is 0.6-1.2:1.

[0041] It should be noted that ultra-high performance liquid chromatography (UHPLC) was used to monitor the reaction in steps a and b. The specific detection conditions for dichloromethylphenylacetic acid impurities, o-chloromethylphenylacetic acid, and o-methylphenylacetic acid are as follows:

[0042] Chromatographic column: Xtimate UHPLC C18, 1.8μm, 4.6mm×100mm;

[0043] Mobile phase: 25% acetonitrile aqueous solution, pH adjusted to 2.5 with phosphoric acid;

[0044] Flow rate: 1.3 mL / min;

[0045] Column temperature: 30℃;

[0046] Injection volume: 5 μL

[0047] Detection wavelength: 215nm;

[0048] Isocratic elution.

[0049] The peak elution times of dichloromethylphenylacetic acid impurity, o-chloromethylphenylacetic acid, and o-methylphenylacetic acid were approximately 11.2 min, 7.2 min, and 6.3 min, respectively.

[0050] The methoxy-substituted impurities generated during the ring-opening process of 3-isochromone were also detected using the above method, with a specific peak elution time of approximately 3 minutes.

[0051] Preferably, in step b, the molar ratio of thionyl chloride to o-methylphenylacetic acid is 0.1-0.3:1.

[0052] More preferably, in step b, the molar ratio of thionyl chloride to o-methylphenylacetic acid is 0.15-0.2:1.

[0053] The traditional process for preparing methyl o-chloromethylphenylacetate from 3-isochromone has the following problems: the chlorination reaction of 3-isochromone has low selectivity, with dichloro and trichloro products accounting for about 40%; and a large amount of thionyl chloride needs to be added, which is 2-3 times the molar amount of 3-isochromone, resulting in a waste of thionyl chloride raw material. At the same time, the ring-opening reaction of 3-isochromone can also generate methoxy-substituted impurities, resulting in low purity and yield of methyl o-chloromethylphenylacetate.

[0054] This invention directly prepares methyl o-chloromethylphenylacetate from o-chloromethylphenylacetic acid in a one-step reaction under the presence of an arylphosphine catalyst. This effectively improves the selectivity of the chlorination reaction and avoids the extraction and ring-opening process of 3-isochromone, thereby preventing the formation of dichloro, trichloro, and methoxy-substituted impurities. In addition, the byproduct hydrogen chloride produced by the first-step free radical chlorination reaction can replace thionyl chloride, greatly reducing the amount of thionyl chloride used, thus effectively reducing production costs and avoiding raw material waste.

[0055] Preferably, in step b, the esterification reaction is carried out at a temperature of 0°C-30°C.

[0056] More preferably, in step b, the temperature of the esterification reaction is 10℃-20℃.

[0057] Preferably, in step b, the specific steps of distillation are as follows: distillation is carried out under a vacuum of 30Pa-50Pa. When the HPLC content of methyl o-chloromethylphenylacetate in the fraction is >98%, the fore fraction is cut off to obtain methyl o-methylphenylacetate. Distillation is continued until the kettle temperature is 130℃-132℃, at which point distillation is stopped to obtain the methyl o-chloromethylphenylacetate product.

[0058] By utilizing the boiling point difference between methyl o-chloromethylphenylacetate and methyl o-methylphenylacetate, the two can be separated by distillation, which effectively improves the quality of methyl o-chloromethylphenylacetate products.

[0059] Compared with the prior art, the advantages of the present invention are:

[0060] (1) This invention uses o-methylphenylacetic acid as raw material and arylphosphine as catalyst to realize the one-pot preparation of the intermediate o-chloromethylphenylacetic acid methyl ester, which greatly simplifies the production process and improves production efficiency.

[0061] (2) It avoids the extraction and ring-opening process of 3-isochromone, improves the selectivity of chlorination reaction, reduces the generation of polychlorinated impurities and methoxy-substituted impurities, and effectively improves the purity and yield of o-chloromethylphenylacetic acid methyl ester product.

[0062] (3) Methyl chloromethylphenylacetate was obtained by distillation, which simplified the process and improved the quality of the methyl chloromethylphenylacetate product.

[0063] (4) The price of o-methylphenylacetic acid (about 40,000 RMB / ton) is significantly lower than that of 3-isochromone (about 120,000 RMB / ton), and other raw materials such as chlorine, thionyl chloride and methanol are inexpensive, which makes the cost of this invention about twice as low as that of the process of preparing o-chloromethylphenylacetic acid methyl ester directly using 3-isochromone as raw material.

[0064] (5) It avoids the large amount of waste salt generated in the production of 3-isochromone, reduces the enterprise's hazardous waste treatment costs, is more green and environmentally friendly, and is a green production route suitable for industrialization. Attached Figure Description

[0065] Figure 1 This is the mass spectrum of a methoxy-substituted impurity. Detailed Implementation

[0066] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0067] In the following examples and comparative examples, the specific UPLC detection conditions for o-methylphenylacetic acid, dichloromethylphenylacetic acid impurities, o-chloromethylphenylacetic acid, methyl o-chloromethylphenylacetic acid, and methyl o-methylphenylacetic acid are as follows:

[0068] Chromatographic column: Xtimate UHPLC C18, 1.8μm, 4.6mm×100mm;

[0069] Mobile phase: 25% acetonitrile aqueous solution, pH adjusted to 2.5 with phosphoric acid;

[0070] Flow rate: 1.3 mL / min;

[0071] Column temperature: 30℃;

[0072] Injection volume: 5 μL

[0073] Detection wavelength: 215nm;

[0074] Isocratic elution.

[0075] The peak elution times of o-methylphenylacetic acid, o-chloromethylphenylacetic acid, methyl o-methylphenylacetic acid, methyl o-chloromethylphenylacetic acid, and dichloromethylphenylacetic acid were 6.3 min, 7.2 min, 9 min, 10.2 min, and 11.2 min, respectively.

[0076] Example 1

[0077] This embodiment provides a process for preparing methyl o-chloromethylphenylacetate, an intermediate of pyridoxine, including the following steps:

[0078] Step a: Add 50g (0.3330mol) of o-methylphenylacetic acid, 0.2g of azobisisobutyronitrile, 0.0075g of triphenylphosphine, 100g of chlorobenzene, and 25g of methanol to a four-necked flask. Turn on heating and stirring, and raise the temperature to 60℃. Start purging with chlorine gas. In the first 0.5h, slowly purge the chlorine gas at a rate of 13mL / min. After the solution turns slightly yellow and the yellow color fades, increase the purging rate to 25mL / min. Take samples for analysis during the reaction. When the HPLC content of dichloromethylphenylacetic acid impurities is ≤3%, stop purging with chlorine gas, cool down, and obtain the o-chloromethylphenylacetic acid reaction solution. At this time, the total surface area content of o-chloromethylphenylacetic acid in the liquid phase is 10%-14%. The purging process is completed in about 5h.

[0079] Step b: Control the o-chloromethylphenylacetic acid reaction solution at 15°C, add thionyl chloride dropwise to carry out the esterification reaction, and take samples for detection during the reaction process. When the HPLC contents of o-chloromethylphenylacetic acid and o-methylphenylacetic acid are both ≤1%, stop adding thionyl chloride. The total amount of thionyl chloride added is 6g. The acidic tail gas is absorbed by two-stage water absorption and two-stage alkali absorption.

[0080] Step c: After removing methanol under normal pressure, control the vacuum degree to 0.085 MPa and the kettle temperature to 68℃ for 1-2 hours until no more distillate is distilled off, indicating complete removal of chlorobenzene. Then continue vacuum distillation at a vacuum degree of 50 Pa and raise the kettle temperature to 93℃. When the content of methyl o-methylphenylacetate in the distillate is <2%, the fore-fraction is discarded as methyl o-methylphenylacetate. Continue distillation until the kettle temperature reaches 130℃, then stop distillation to obtain methyl o-chloromethylphenylacetate product with an HPLC content of 99.70% and a single-pass overall yield of 68.30%.

[0081] The fore-fraction of methyl o-methylphenylacetate was mixed with the next batch of o-methylphenylacetic acid feedstock and reused in steps a to c. After the system stabilized, the overall yield was 95.30%.

[0082] Example 2

[0083] This embodiment provides a process for preparing methyl o-chloromethylphenylacetate, an intermediate of pyridoxine, including the following steps:

[0084] Step a: Add 50g (0.3330mol) o-methylphenylacetic acid, 1g benzoyl peroxide, 0.005g triphenylphosphine, 75g chlorobenzene, and 75g methanol to a four-necked flask. Turn on heating and stirring, and raise the temperature to 65℃. Start purging with chlorine gas. In the first 0.5h, slowly purge the chlorine gas at a rate of 10mL / min. After the solution turns slightly yellow and the yellow color fades, increase the purging rate to 20mL / min. Take samples for analysis during the reaction. When the HPLC content of dichloromethylphenylacetic acid impurities is ≤3%, stop purging with chlorine gas, cool down, and obtain the o-chloromethylphenylacetic acid reaction solution. At this time, the total surface area content of o-chloromethylphenylacetic acid in the liquid phase is 10%-14%, and the purging is completed in about 4.5h.

[0085] Step b: Control the o-chloromethylphenylacetic acid reaction solution at 30°C, add thionyl chloride dropwise to carry out the esterification reaction, and take samples for detection during the reaction process. When the HPLC contents of o-chloromethylphenylacetic acid and o-methylphenylacetic acid are both ≤1%, stop adding thionyl chloride. The total amount of thionyl chloride added is 7.9g. The acidic tail gas is absorbed by two-stage water absorption and two-stage alkali absorption.

[0086] Step c: After removing methanol under normal pressure, control the vacuum degree to 0.095 MPa and the kettle temperature to 65℃ for 1-2 hours until no more distillate is distilled off, indicating complete removal of chlorobenzene. Then continue vacuum distillation at a vacuum degree of 30 Pa and raise the kettle temperature to 92℃. When the content of methyl o-methylphenylacetate in the distillate is <2%, the fore-fraction is discarded as methyl o-methylphenylacetate. Continue distillation until the kettle temperature reaches 130℃, then stop distillation to obtain methyl o-chloromethylphenylacetate product with an HPLC content of 99.60% and a single-pass overall yield of 63.30%.

[0087] The fore-fraction of methyl o-methylphenylacetate was mixed with the next batch of o-methylphenylacetic acid feedstock and reused in steps a to c. After the system stabilized, the overall yield was 95.70%.

[0088] Example 3

[0089] This embodiment provides a process for preparing methyl o-chloromethylphenylacetate, an intermediate of pyridoxine, including the following steps:

[0090] Step a: Add 50g (0.3330mol) of o-methylphenylacetic acid, 0.1g of azobisisobutyronitrile, 0.01g of triphenylphosphine, 225g of chlorobenzene, and 25g of methanol to a four-necked flask. Turn on heating and stirring, and raise the temperature to 50℃. Start purging with chlorine gas. In the first 0.5h, slowly purge the chlorine gas at a rate of 15mL / min. After the solution turns slightly yellow and the yellow color fades, increase the purging rate to 30mL / min. Take samples for analysis during the reaction. When the HPLC content of dichloromethylphenylacetic acid impurities is ≤3%, stop purging with chlorine gas, cool down, and obtain the o-chloromethylphenylacetic acid reaction solution. At this time, the total surface area content of o-chloromethylphenylacetic acid in the liquid phase is 10%-14%. The purging process is completed in about 7h.

[0091] Step b: Control the o-chloromethylphenylacetic acid reaction solution at 0°C, add thionyl chloride dropwise to carry out the esterification reaction, and take samples for detection during the reaction process. When the HPLC contents of o-chloromethylphenylacetic acid and o-methylphenylacetic acid are both ≤1%, stop adding thionyl chloride. The total amount of thionyl chloride added is 7.0g. The acidic tail gas is absorbed by two-stage water absorption and two-stage alkali absorption.

[0092] Step c: After removing methanol under normal pressure, control the vacuum degree to 0.09 MPa and the kettle temperature to 60℃ for 1-2 hours until no more distillate is distilled off, indicating complete removal of chlorobenzene. Then continue vacuum distillation at a vacuum degree of 40 Pa and raise the kettle temperature to 91℃. When the content of methyl o-methylphenylacetate in the distillate is <2%, the fore-run fraction is discarded as methyl o-methylphenylacetate. Continue distillation until the kettle temperature reaches 130℃, then stop distillation to obtain methyl o-chloromethylphenylacetate product with an HPLC content of 99.77% and a single-pass overall yield of 62.60%.

[0093] The fore-fraction of methyl o-methylphenylacetate was mixed with the next batch of o-methylphenylacetic acid feedstock and reused in steps a to c. After the system stabilized, the overall yield was 95.90%.

[0094] Example 4

[0095] This embodiment provides a process for preparing methyl o-chloromethylphenylacetate, an intermediate of pyridoxine, including the following steps:

[0096] Step a: Add 50g (0.3330mol) of o-methylphenylacetic acid, 0.05g of benzoyl peroxide, 0.006g of triphenylphosphine, 75g of chlorobenzene, and 25g of methanol to a four-necked flask. Turn on heating and stirring, and raise the temperature to 40℃. Start purging with chlorine gas. In the first 0.5h, slowly purge the chlorine gas at a rate of 12mL / min. After the solution turns slightly yellow and the yellow color fades, increase the purging rate to 26mL / min. Take samples for analysis during the reaction. When the HPLC content of dichloromethylphenylacetic acid impurities is ≤3%, stop purging with chlorine gas, cool down, and obtain the o-chloromethylphenylacetic acid reaction solution. At this time, the total surface area content of o-chloromethylphenylacetic acid in the liquid phase is 10%-14%. The purging process is completed in about 9h.

[0097] Step b: Control the o-chloromethylphenylacetic acid reaction solution at 20°C, add thionyl chloride dropwise to carry out the esterification reaction, and take samples for detection during the reaction process. When the HPLC contents of o-chloromethylphenylacetic acid and o-methylphenylacetic acid are both ≤1%, stop adding thionyl chloride. The total amount of thionyl chloride added is 11.8g. The acidic tail gas is absorbed by two-stage water absorption and two-stage alkali absorption.

[0098] Step c: After removing methanol under normal pressure, control the vacuum degree to 0.088 MPa and the kettle temperature to 70℃ for 1-2 hours until no more distillate is distilled off, indicating complete removal of chlorobenzene. Then continue vacuum distillation at a vacuum degree of 35 Pa and raise the kettle temperature to 93℃. When the content of methyl o-methylphenylacetate in the distillate is <2%, the fore-run fraction is discarded as methyl o-methylphenylacetate. Continue distillation until the kettle temperature reaches 130℃, then stop distillation to obtain methyl o-chloromethylphenylacetate product with an HPLC content of 99.70% and a single-pass overall yield of 62.30%.

[0099] The fore-fraction of methyl o-methylphenylacetate was mixed with the next batch of o-methylphenylacetic acid feedstock and reused in steps a to c. After the system stabilized, the overall yield was 96.11%.

[0100] Example 5

[0101] This embodiment provides a process for preparing methyl o-chloromethylphenylacetate, an intermediate of pyridoxine, including the following steps:

[0102] Step a: Add 50g (0.3330mol) of o-methylphenylacetic acid, 0.3g of azobisisobutyronitrile, 0.007g of triphenylphosphine, 200g of chlorobenzene, and 50g of methanol to a four-necked flask. Turn on heating and stirring, and raise the temperature to 60℃. Start purging with chlorine gas. In the first 0.5h, slowly purge the chlorine gas at a rate of 14mL / min. After the solution turns slightly yellow and the yellow color fades, increase the purging rate to 25mL / min. Take samples for analysis during the reaction. When the HPLC content of dichloromethylphenylacetic acid impurities is ≤3%, stop purging with chlorine gas, cool down, and obtain the o-chloromethylphenylacetic acid reaction solution. At this time, the total surface area content of o-chloromethylphenylacetic acid in the liquid phase is 10%-14%, and the purging is completed in about 4.5h.

[0103] Step b: Control the o-chloromethylphenylacetic acid reaction solution at 10°C, add thionyl chloride dropwise to carry out the esterification reaction, and take samples for detection during the reaction process. When the HPLC contents of o-chloromethylphenylacetic acid and o-methylphenylacetic acid are both ≤1%, stop adding thionyl chloride. The total amount of thionyl chloride added is 4.0g. The acidic tail gas is absorbed by two-stage water absorption and two-stage alkali absorption.

[0104] Step c: After removing methanol under normal pressure, control the vacuum degree to 0.092 MPa and the kettle temperature to 68℃ for 1-2 hours until no more distillate is distilled off, indicating complete removal of chlorobenzene. Then continue vacuum distillation at a vacuum degree of 45 Pa and raise the kettle temperature to 90℃. When the content of methyl o-methylphenylacetate in the distillate is <2%, the fore-run fraction is discarded as methyl o-methylphenylacetate. Continue distillation until the kettle temperature reaches 130℃, then stop distillation to obtain methyl o-chloromethylphenylacetate product with an HPLC content of 99.80% and a single-pass overall yield of 63.33%.

[0105] The fore-fraction of methyl o-methylphenylacetate was mixed with the next batch of o-methylphenylacetic acid feedstock and reused in steps a to c. After the system stabilized, the overall yield was 95.81%.

[0106] Comparative Example 1

[0107] This comparative example provides a process for preparing methyl o-chloromethylphenylacetate, an intermediate of azoxystrobin, including the following steps:

[0108] Step a: Add 50g (0.3330mol) o-methylphenylacetic acid, 10.0g azobisisobutyronitrile, and 250g chlorobenzene to a four-necked flask. Turn on heating and stirring, and raise the temperature to 60℃. Start purging with chlorine gas. In the first 0.5 hours, slowly purge the chlorine gas at a rate of 13mL / min. After the solution turns slightly yellow and the yellow color fades, increase the purging rate to 25mL / min. Take samples during the reaction process. When the HPLC content of dichloromethylphenylacetic acid impurities is ≤3%, stop purging with chlorine gas, cool down, and obtain the o-chloromethylphenylacetic acid reaction solution. At this time, the total surface area content of o-chloromethylphenylacetic acid in the liquid phase is 20%-30%. The purging process is completed in about 5 hours.

[0109] Step b: Lower the temperature of the feed solution to 20℃, keep it at this temperature for 1 hour, filter, and wash the filter cake with glacial chlorobenzene (0-5℃) to obtain o-chloromethylphenylacetic acid; the filtrate is o-methylphenylacetic acid, evaporate the chlorobenzene and return it to the flask; add 200g of water to another four-necked flask, add o-chloromethylphenylacetic acid to the water, control the temperature at 40-50℃, slowly add 40g of 30-32% sodium hydroxide aqueous solution to carry out the cyclization reaction, the addition time is about 1 hour, control the pH at 8-9, detect the HPLC content of o-chloromethylphenylacetic acid <1%, stop the reaction, filter at 20℃, dry, and obtain crude 3-isochromone;

[0110] Step c: The crude 3-isochromone was washed with ice-cold methanol (0-5℃), dried, added to 300g of methanol, and 18g of thionyl chloride was slowly added dropwise while maintaining the temperature at 20℃. The content of 3-isochromone was found to be <1%. After removing methanol under negative pressure, distillation was continued to obtain methyl o-chloromethylphenylacetate product with an HPLC content of 99.00% and a single-pass total yield of 47.20%.

[0111] After re-inserting o-methylphenylacetic acid and stabilizing the system, the overall yield was 60.5%.

[0112] Comparative Example 2

[0113] This comparative example provides a preparation process for methyl o-chloromethylphenylacetate, an intermediate of pyridoxine. The specific steps are the same as in Example 1, except that triphenylphosphine in Example 1 is replaced with phthalimide. All other steps are exactly the same.

[0114] The prepared methyl o-chloromethylphenylacetate product had an HPLC purity of 98.08% and a single-pass total yield of 58.20%.

[0115] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of picoxystrobin intermediate o-chloromethyl methyl phenyl acetate, characterized in that, Includes the following steps: Step a: o-Tolueneacetic acid, a free radical initiator, and a triarylphosphine catalyst are added to a mixed solvent of chlorobenzene and methanol, mixed thoroughly, heated, and chlorine gas is introduced. The reaction proceeds until the HPLC content of dichloromethylphenylacetic acid impurities is ≤3%. The chlorine gas is then stopped, and the mixture is cooled to obtain an o-chloromethylphenylacetic acid reaction solution. The triarylphosphine catalyst is triphenylphosphine. In step a, the mass ratio of chlorobenzene to methanol in the mixed solvent is 1-9:1; the mass ratio of the mixed solvent to o-methylphenylacetic acid is 2-5:

1. Step b: Add thionyl chloride dropwise to the o-chloromethylphenylacetic acid reaction solution to carry out the esterification reaction until the HPLC contents of o-chloromethylphenylacetic acid and o-methylphenylacetic acid are both ≤1%. Stop adding thionyl chloride, remove methanol and chlorobenzene solvents, and distill to obtain methyl o-chloromethylphenylacetic acid; the molar ratio of thionyl chloride to o-methylphenylacetic acid is 0.1-0.3:

1.

2. A process for the preparation of picoxystrobin intermediate o-chloromethyl phenylacetic acid methyl ester as claimed in claim 1, wherein, In step a, the free radical initiator is at least one of azobisisobutyronitrile or benzoyl peroxide; and / or ​ In step a, the chlorobenzene is at least one of chlorobenzene, o-dichlorobenzene, or m-dichlorobenzene.

3. Process for the preparation of picoxystrobin intermediate o-chloromethyl phenylacetic acid methyl ester according to claim 1 or 2, characterized in that, In step a, the amount of the free radical initiator added is 0.1%-2% of the mass of o-methylphenylacetic acid; and / or In step a, the amount of the triarylphosphine catalyst added is 0.01%-0.02% of the mass of o-methylphenylacetic acid.

4. The preparation process of methyl o-chloromethylphenylacetate, the intermediate of azoxystrobin as described in claim 1 or 2, is characterized in that, In step a, the mass ratio of chlorobenzene to methanol in the mixed solvent is 1-9:1; and / or In step a, the mass ratio of the mixed solvent to o-methylphenylacetic acid is 2-5:

1.

5. The preparation process of methyl o-chloromethylphenylacetate, the intermediate of azoxystrobin as described in claim 4, is characterized in that, In step a, the mass ratio of chlorobenzene to methanol in the mixed solvent is 3-5:1; and / or In step a, the mass ratio of the mixed solvent to o-methylphenylacetic acid is 2-3:

1.

6. The preparation process of methyl o-chloromethylphenylacetate, the intermediate of azoxystrobin as described in claim 1, is characterized in that, In step a, the temperature is raised to 40℃-65℃; and / or In step a, the molar ratio of chlorine gas to o-methylphenylacetic acid is 0.6-1.2:

1.

7. The preparation process of methyl o-chloromethylphenylacetate, the intermediate of azoxystrobin as described in claim 1, is characterized in that, In step b, the esterification reaction is carried out at a temperature of 0°C-30°C.

8. The preparation process of methyl o-chloromethylphenylacetate, the intermediate of azoxystrobin as described in claim 7, is characterized in that, In step b, the molar ratio of thionyl chloride to o-tolueneacetic acid is 0.15-0.2:1; and / or In step b, the esterification reaction is carried out at a temperature of 10°C-20°C.

9. The preparation process of methyl o-chloromethylphenylacetate, the intermediate of azoxystrobin as described in claim 1, is characterized in that, In step b, the specific steps of distillation are as follows: distillation is carried out under a vacuum of 30Pa-50Pa. When the HPLC content of methyl o-chloromethylphenylacetate in the fraction is >98%, the fore fraction is cut off to obtain methyl o-methylphenylacetate. Distillation is continued until the kettle temperature is 130℃-132℃, at which point distillation is stopped to obtain the methyl o-chloromethylphenylacetate product.

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