CN116606206A - Preparation process of picoxystrobin intermediate methyl o-chloromethyl phenylacetate - Google Patents

Abstract

The invention relates to the technical field of chemical production, and specifically discloses a preparation process of a picoxystrobin intermediate, methyl o-chloromethylphenylacetate. The preparation process of the picoxystrobin intermediate methyl o-chloromethylphenylacetic acid provided by the invention uses o-tolylacetic acid as a raw material and arylphosphine as a catalyst to suppress the generation of dichloromethylphenylacetic acid impurities, The purity of o-chloromethylphenylacetic acid is improved, and subsequently, under the action of an arylphosphine catalyst, o-chloromethylphenylacetic acid directly reacts with thionyl chloride and the methanol added in the previous step to generate methyl o-chloromethylphenylacetic acid , to achieve the purpose of directly preparing methyl o-chloromethylphenylacetate in one pot, the content of the prepared methyl o-chloromethylphenylacetate> 99.5%, which is conducive to effectively improving the purity of picoxystrobin products, and simplifying The post-treatment process of picoxystrobin crude product improves the production efficiency of picoxystrobin.

Description

A kind of preparation technology of picoxystrobin intermediate o-chloromethylphenylacetic acid methyl ester

technical field

The invention relates to the technical field of chemical production, in particular to a process for preparing a picoxystrobin intermediate, methyl o-chloromethylphenylacetate.

Background technique

Picoxystrobin is currently one of the most effective methoxyacrylate fungicides, first launched by Syngenta in Europe in 2001. Picoxystrobin is mainly used to prevent and control foliar diseases of wheat, such as leaf blight, leaf rust, glume blight, brown spot, powdery mildew, etc. Compared with other existing methoxyacrylate fungicides, Picoxystrobin has a stronger control effect on wheat leaf blight, net spot and moire.

At present, the main synthetic route of picoxystrobin in industry is as follows. Using o-methylphenylacetic acid as a raw material, first undergo the steps of free radical chlorination, alkali dissolution, acidic ring closure and methanol recrystallization to obtain 3-isochromone with high purity; then use 3-isochromone as raw material, The chlorination ring-opening reaction is carried out to obtain methyl o-chloromethylphenylacetate, which is then condensed and docked with pyridone, and the subsequent reaction is carried out to synthesize picoxystrobin. As can be seen from the process route, methyl o-chloromethylphenylacetate is a key intermediate in the synthesis of picoxystrobin.

3-Isochromone is an important intermediate of methoxyacrylate fungicides, and the market supply is relatively large. In order to reduce the process links of 3-isochromone, many picoxystrobin manufacturers also avoid 3-isochromone In the production process, a large amount of waste salt (mainly sodium chloride, sodium o-dichloromethylphenylacetate, sodium o-trichloromethylphenylacetate and other mixed salts) is produced, and 3-isochromone is directly purchased as raw material during the treatment process. However, the cost of 3-isochromone is high (about 120,000/ton), and 3-isochromone is easy to absorb moisture and agglomerate during storage and feeding, is not easy to store, and will also affect the reaction and mass transfer effect. O-chloromethylphenylacetic acid will be produced in the ring-opening process, and more thionyl chloride will be consumed, resulting in waste of raw materials and increased production costs. Therefore, at present, more manufacturers still choose to synthesize picoxystrobin with the above-mentioned mainstream process. However, the yield and purity of picoxystrobin products prepared from o-tolylacetic acid through multi-step reactions are low and need to be further improved. .

Contents of the invention

Aiming at the problems that the existing method for synthesizing picoxystrobin has long process route, low product yield and purity, and a large amount of waste salt will be produced in the reaction process, the invention provides a kind of picoxystrobin intermediate o-chloroform The preparation technology of methyl phenylacetate.

In order to solve the problems of the technologies described above, the technical solution provided by the invention is:

A preparation process of picoxystrobin intermediate o-chloromethylphenylacetic acid methyl ester, comprising the following steps:

Step a, add o-tolueneacetic acid, free radical initiator and triaryl phosphine catalyst in the mixed solvent of chlorobenzenes and methanol, mix uniformly, heat up, pass into chlorine gas, react to dichloromethylphenylacetic acid impurity HPLC content ≤ 3%, stop flowing chlorine gas, cool down, obtain o-chloromethylphenylacetic acid reaction liquid;

In step b, add thionyl chloride dropwise to the o-chloromethylphenylacetic acid reaction liquid to carry out esterification reaction until the HPLC contents of o-chloromethylphenylacetic acid and o-toluylacetic acid are all ≤1%, stop dripping Add thionyl chloride, remove methanol and chlorobenzene solvents, and distill to obtain methyl o-chloromethylphenylacetate.

The purity of the intermediate methyl o-chloromethylphenylacetate directly affects the purity of the picoxystrobin product. Therefore, if the purity of the intermediate methyl o-chloromethylphenylacetate can be improved, the quality of the picoxystrobin product can be effectively improved , and reducing the post-treatment and refining process of crude picoxystrobin is of great significance for improving the production efficiency of picoxystrobin.

The inventor found in the test process that the purity of the intermediate methyl o-chloromethylphenylacetate prepared by the existing traditional process is difficult to reach more than 99%. After analyzing the reasons in many ways, the inventor believes that 3-isochromone During the ring process, the following methoxy-substituted impurity is produced, and the structural characterization of the impurity is shown in Figure 1. Therefore, the inventor has carried out following test:

Add 3-isochromone and excess methanol to toluene, add thionyl chloride dropwise, react at 60-62°C until the HPLC content of isochromone < 0.5% for 3 hours, distill and remove toluene, and the kettle material is o-chloromethyl Methyl phenylacetate, take 1 drop of feed solution and add in 20mL diluent (25% acetonitrile aqueous solution), filter, HPLC detects, the result finds that the content of the methoxyl substitution impurity is about 2%-3%. After analyzing the reason, the inventor believes that there is a large amount of methanol in the ring-opening process of 3-isochromone, resulting in the generation of methoxyl-substituted impurities with a content of 2%-3% as shown below, and this impurity cannot be removed along with toluene In addition, the content and yield of the subsequent condensation reaction product and the final product picoxystrobin are affected.

Compared with the prior art, the preparation process of the picoxystrobin intermediate methyl o-chloromethylphenylacetate provided by the invention uses o-tolylacetic acid as a raw material, adds methanol as a reaction solvent in the chlorination stage, and uses aromatic Phosphine is used as a catalyst to suppress the generation of dichloromethylphenylacetic acid impurities and improve the purity of o-chloromethylphenylacetic acid; and subsequently, under the action of arylphosphine catalyst, And the direct reaction of the methanol added in the previous step generates methyl o-chloromethylphenylacetate, which avoids the generation process of 3-isochromone, therefore, avoids the ring-opening process of 3-isochromone, and then also avoids the methoxy Substituting the production of impurities, the content of the prepared methyl o-chloromethylphenylacetate is >99.5%, which significantly improves the purity of the intermediate methyl o-chloromethylphenylacetate, which in turn helps to effectively improve the purity of the picoxystrobin product , and simplify the post-treatment process of picoxystrobin crude product, improve the production efficiency of picoxystrobin.

The preparation technology of picoxystrobin intermediate methyl o-chloromethylphenylacetate provided by the invention realizes the purpose of directly preparing methyl o-chloromethylphenylacetate in a one-pot method, which not only effectively improves production efficiency, but also avoids The separation steps of 3-isochromone and the production of a large amount of waste salt in the 3-isochromone process reduce the cost of hazardous waste treatment for enterprises, are suitable for industrial production, have high economic and environmental benefits, and are of high value for promotion and application.

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

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

Further preferably, in step a, the free radical initiator is azobisisobutyronitrile.

The preferred free radical initiator can promote the free radical chlorination reaction of o-toluic acid and chlorine, and improve the reaction efficiency.

Preferably, in step a, the triarylphosphine catalyst is triphenylphosphine.

Triphenylphosphine reacts with chlorine to produce intermediate triphenylphosphine dichloride, as shown below. The presence of triphenylphosphine dichloride can maintain the chlorine free radicals in the system at a stable level, prevent the excessive content of chlorine free radicals in the solvent, thereby inhibiting the formation of dichlorinated impurities and improving the selectivity of monochlorinated compounds ; In addition, triphenylphosphine can also catalyze o-chloromethylphenylacetic acid and sulfur oxychloride, methyl alcohol to directly carry out acyl chloride and esterification, directly obtain methyl o-chloromethylphenylacetic acid, avoid 3-iso The generation of chromone intermediate, thereby also avoided the process that 3-isochromone ring-opening prepares the methyl o-chloromethyl phenylacetate, and then avoided the generation of methoxy substitution impurity, effectively improved o-chloromethyl phenylacetic acid The purity of the methyl ester product.

Preferably, in step a, the chlorobenzenes are at least one of chlorobenzene, o-dichlorobenzene or m-dichlorobenzene.

Further preferably, in step a, the chlorobenzenes are chlorobenzenes.

The preferred reaction solvent is inert to the reactants, which is beneficial to reduce the generation of dichlorinated impurities.

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

Further preferably, in step a, the added amount of the free radical initiator is 0.2%-0.6% of the mass of o-toluic acid.

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

Further preferably, in step a, the added amount of the triarylphosphine catalyst is 0.015% of the mass of o-toluylacetic acid.

The preferred addition amount of the free radical initiator and the catalyst can reduce the production cost under the premise of ensuring that the reaction is fully promoted.

It should be noted that, in order to minimize the generation of dichlorinated impurities, chlorine gas is introduced at a lower rate within the first 0.5h of chlorine gas injection, and the chlorine gas rate is controlled to be 10-15mL/min/50g o-toluylacetic acid. After the reaction feed liquid changed from yellowish to color and receded, feed chlorine gas at a faster rate, and the rate of chlorine gas was controlled to be 20-30mL/min/50g o-methylphenylacetic acid.

Preferably, in step a, the mass ratio of chlorobenzenes to methanol in the mixed solvent is 1-9:1.

Further preferably, in step a, the mass ratio of chlorobenzenes to methanol in the mixed solvent is 3-5:1.

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

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

In the traditional process, the quality of general methanol is 5-6 times of the quality of raw material o-methylphenylacetic acid, and the amount of methanol in the methyl o-chloromethylphenylacetic acid provided by the invention is greatly reduced, only 1% of the quality of o-methylphenylacetic acid. times, effectively reducing the amount of methanol.

Preferably, in step a, the temperature is raised to 40°C-65°C.

Preferably, in step a, the molar ratio of chlorine to o-toluic acid is 0.6-1.2:1.

It should be noted that in step a and step b, ultra-high performance liquid phase detection is used to monitor the progress of the reaction. The specific detection conditions for dichloromethylphenylacetic acid impurities, o-chloromethylphenylacetic acid and o-methylphenylacetic acid are as follows:

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

Mobile phase: 25% acetonitrile aqueous solution, phosphoric acid to adjust the pH value to 2.5;

Flow rate: 1.3mL/min;

Column temperature: 30°C;

Injection volume: 5μL

Detection wavelength: 215nm;

Isocratic elution.

Among them, the peak eluting time of dichloromethylphenylacetic acid impurity, o-chloromethylphenylacetic acid and o-toluic acid is about 11.2min, 7.2min, 6.3min.

The methoxy-substituted impurity generated during the ring-opening process of 3-isochromone was also detected by the above method, and the peak eluting time was about 3 minutes.

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

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

The traditional process of preparing methyl o-chloromethylphenylacetate with 3-isochromone as raw material has the following problems: the selectivity of the chlorination reaction of 3-isochromone is low, and the dichlorinated and trichlorinated products account for about 40%; and need to add a large amount of thionyl chloride, the addition of thionyl chloride is 2-3 times of 3-isochromone molar weight, consumption is bigger, causes the waste of thionyl chloride raw material, simultaneously, 3 -The ring-opening reaction of isochromone can also generate methoxyl to replace impurities, thereby causing the purity and yield of methyl o-chloromethylphenylacetate product to be lower.

The present invention is by using o-chloromethylphenylacetic acid as raw material, under the condition that aryl phosphine catalyst exists, direct one-step reaction prepares methyl o-chloromethylphenylacetic acid, effectively improves the selectivity of chlorination reaction, and avoids The extraction of 3-isochromone and the ring-opening process of 3-isochromone avoid the generation of dichloride, trichloride and methoxy substitution impurities; in addition, the first step of free radical chlorination The produced by-product hydrogen chloride can replace thionyl chloride, which greatly reduces the usage of thionyl chloride, thereby effectively reducing production costs and avoiding waste of raw materials.

Preferably, in step b, the temperature of the esterification reaction is 0°C-30°C

Further preferably, in step b, the temperature of the esterification reaction is 10°C-20°C.

Preferably, in step b, the specific steps of the distillation are: distillation at a vacuum degree of 30Pa-50Pa, and when the HPLC content of methyl o-chloromethylphenylacetate in the detected fraction is >98%, the front fraction is cut out to obtain o-formaldehyde Methyl phenylacetate, continue to distill until the kettle temperature is 130°C-132°C, then stop the distillation to obtain methyl o-chloromethylphenylacetate.

Utilizing the difference in boiling point between methyl o-chloromethylphenylacetate and methyl o-chloromethylphenylacetate, the two are separated by distillation, which effectively improves the quality of the methyl o-chloromethylphenylacetate product.

Compared with the prior art, the present invention has the advantages of:

(1) The present invention uses o-methylphenylacetic acid as a raw material and arylphosphine as a catalyst to realize the one-pot preparation of the intermediate methyl o-chloromethylphenylacetic acid, which greatly simplifies the production process and improves production efficiency ;

(2) Avoid the extraction and ring-opening process of 3-isochromone, improve the selectivity of the chlorination reaction, reduce the generation of polychlorinated impurities and methoxyl-substituted impurities, and effectively increase the concentration of o-chloromethylphenylacetic acid Purity and yield of methyl ester products;

(3) Utilize the distillation separation to obtain the methyl o-chloromethyl phenylacetate product, which simplifies the process and improves the quality of the methyl o-chloromethyl phenylacetate product;

(4) The raw material price of o-methylphenylacetic acid (about 40,000/ton) is significantly lower than that of 3-isochromone (about 120,000/ton), and other raw materials such as chlorine, thionyl chloride and methanol are cheap raw materials , so that the cost of the present invention is about 2 times lower than the direct use of 3-isochromone as raw material to prepare methyl o-chloromethylphenylacetate;

(5) It avoids a large amount of waste salt produced in the production process of 3-isochromone, reduces the cost of hazardous waste treatment of enterprises, and is more green and environmentally friendly. It is a green production route suitable for industrialization.

Description of drawings

Fig. 1 is the mass spectrogram of methoxy substitution impurity.

Detailed ways

In order to make the object, technical solution and advantages of the present invention more clear, the present invention will be further described in detail below in conjunction with the examples. It should be understood that the specific embodiments described here are only used to explain the present invention, not to limit the present invention.

In the following examples and comparative examples, the UPLC specific detection of o-methylphenylacetic acid, dichloromethylphenylacetic acid impurity, o-chloromethylphenylacetic acid, o-chloromethylphenylacetic acid methyl ester, o-methylphenylacetic acid methyl ester The conditions are as follows:

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

Mobile phase: 25% acetonitrile aqueous solution, phosphoric acid to adjust the pH value to 2.5;

Flow rate: 1.3mL/min;

Column temperature: 30°C;

Injection volume: 5μL

Detection wavelength: 215nm;

Isocratic elution.

Among them, the peak eluting time of o-methylphenylacetic acid, o-chloromethylphenylacetic acid, methyl o-chloromethylphenylacetic acid, methyl o-chloromethylphenylacetic acid and dichloromethylphenylacetic acid is 6.3min and 7.2min respectively , 9min, 10.2min, 11.2min.

Example 1

This embodiment provides a process for preparing the picoxystrobin intermediate, methyl o-chloromethylphenylacetate, comprising the following steps:

Step a, add 50g (0.3330mol) o-methylphenylacetic acid, 0.2g azobisisobutyronitrile, 0.0075g triphenylphosphine, 100g chlorobenzene and 25g methanol to a four-neck flask, start heating and stirring, and heat up to At 60°C, start to feed chlorine gas. Slowly feed chlorine gas within 0.5 hours before ventilation at a rate of 13mL/min. After the feed liquid turns slightly yellow until the yellow color of the feed liquid fades, speed up the ventilation and feed chlorine gas at a rate of 25mL/min. Sampling detection in the reaction process, when the HPLC content of dichloromethylphenylacetic acid impurity≤3%, stop flowing chlorine gas, cool down, get o-chloromethylphenylacetic acid reaction solution; now o-chloromethylphenylacetic acid liquid phase full area content At 10%-14%, the ventilation is completed in about 5 hours;

In step b, the temperature of the o-chloromethylphenylacetic acid reaction solution is controlled at 15°C, and thionyl chloride is added dropwise for esterification reaction. During the reaction process, samples are taken for detection. When the HPLC content of o-chloromethylphenylacetic acid and o-methylphenylacetic acid is All ≤ 1%, stop the dropwise addition of thionyl chloride, the total amount of thionyl chloride added is 6g, and the acidic tail gas adopts two-stage water absorption and two-stage alkali absorption;

Step c, after removing methanol under normal pressure, control the vacuum degree to 0.085MPa, the kettle temperature is 68°C, and desolventize for 1-2h until no fraction is evaporated, and the chlorobenzene is completely removed, and then continue vacuum distillation with a vacuum degree of 50Pa. The temperature of the kettle material rises to 93°C, and when the content of methyl o-toluene acetate in the fraction detected by sampling is less than 2%, the front fraction is cut out, and the front fraction is methyl o-toluene acetate; continue distillation until the temperature of the kettle is 130°C , Stop the distillation to get the methyl o-chloromethylphenylacetate product, the HPLC content is 99.70%, and the single-pass total yield is 68.30%.

Mix the previous fraction of methyl o-tolylacetic acid with the next batch of o-tolylacetic acid raw materials and apply them mechanically to step a to step c. After the system stabilizes, the total yield is 95.30%.

Example 2

This embodiment provides a process for preparing the picoxystrobin intermediate, methyl o-chloromethylphenylacetate, comprising the following steps:

Step a, add 50g (0.3330mol) of o-toluic acid, 1g of benzoyl peroxide, 0.005g of triphenylphosphine, 75g of chlorobenzene and 75g of methanol into a four-neck flask, start heating and stirring, and raise the temperature to 65°C , start to feed chlorine gas, and slowly feed chlorine gas within 0.5h before ventilation, at a rate of 10mL/min. Sampling detection, when the HPLC content of dichloromethylphenylacetic acid impurity≤3%, stop logical chlorine gas, cool down, obtain o-chloromethylphenylacetic acid reaction liquid; Now o-chloromethylphenylacetic acid liquid phase total area content is in 10 %-14%, the ventilation is completed in about 4.5 hours;

Step b, control the reaction solution of o-chloromethylphenylacetic acid to 30°C, add thionyl chloride dropwise to carry out esterification reaction, and take samples for detection during the reaction process, when the HPLC content of o-chloromethylphenylacetic acid and o-methylphenylacetic acid All ≤ 1%, stop the dropwise addition of thionyl chloride, the total amount of thionyl chloride added is 7.9g, and the acidic tail gas adopts two-stage water absorption and two-stage alkali absorption;

Step c, after removing methanol under normal pressure, control the vacuum degree to 0.095MPa, the kettle temperature is 65°C, and desolventize for 1-2h until no distillate is evaporated, and the chlorobenzene is completely removed, and then continue vacuum distillation with a vacuum degree of 30Pa. The temperature of the kettle material rises to 92°C, and when the content of methyl o-toluene acetate in the fraction detected by sampling is less than 2%, the front fraction is cut out, and the front fraction is methyl o-toluene acetate; continue distillation until the temperature of the kettle is 130°C , Stop the distillation to get the methyl o-chloromethylphenylacetate product, the HPLC content is 99.60%, and the single-pass total yield is 63.30%.

Mix the former fraction of methyl o-toluene acetate with the next batch of o-toluene acetic acid raw materials and apply them mechanically to step a to step c. After the system stabilizes, the total yield is 95.70%.

Example 3

This embodiment provides a process for preparing the picoxystrobin intermediate, methyl o-chloromethylphenylacetate, comprising the following steps:

Step a, add 50g (0.3330mol) o-methylphenylacetic acid, 0.1g azobisisobutyronitrile, 0.01g triphenylphosphine, 225g chlorobenzene and 25g methanol to a four-necked flask, start heating and stirring, and heat up to 50°C, start to feed chlorine gas, and slowly feed chlorine gas within 0.5h before ventilation, at a rate of 15mL/min. After the feed liquid turns slightly yellow until the yellow color of the feed liquid fades, speed up the ventilation, and feed chlorine gas at a rate of 30mL/min. Sampling detection in the reaction process, when the HPLC content of dichloromethylphenylacetic acid impurity≤3%, stop flowing chlorine gas, cool down, get o-chloromethylphenylacetic acid reaction solution; now o-chloromethylphenylacetic acid liquid phase full area content At 10%-14%, the ventilation is completed in about 7 hours;

Step b, control the reaction solution of o-chloromethylphenylacetic acid to 0°C, add thionyl chloride dropwise to carry out esterification reaction, and take samples for detection during the reaction process, when the HPLC content of o-chloromethylphenylacetic acid and o-methylphenylacetic acid All ≤ 1%, stop adding thionyl chloride dropwise, the total amount of thionyl chloride added is 7.0g, acid tail gas adopts two-stage water absorption and two-stage alkali absorption;

Step c, after removing methanol under normal pressure, control the vacuum degree to 0.09MPa, the kettle temperature is 60°C, and desolventize for 1-2h until no fraction is evaporated, and the chlorobenzene is completely removed, and then continue vacuum distillation with a vacuum degree of 40Pa. The temperature of the kettle material rises to 91°C, and when the content of methyl o-toluene acetate in the fraction detected by sampling is <2%, the front fraction is cut out, and the front fraction is methyl o-toluene acetate; continue distillation until the temperature of the kettle is 130°C , Stop the distillation to get the methyl o-chloromethylphenylacetate product, the HPLC content is 99.77%, and the single-pass total yield is 62.60%.

Mix the previous fraction of methyl o-tolylacetic acid with the next batch of o-tolylacetic acid raw materials and apply them mechanically to step a to step c. After the system stabilizes, the total yield is 95.90%.

Example 4

This embodiment provides a process for preparing the picoxystrobin intermediate, methyl o-chloromethylphenylacetate, comprising the following steps:

Step a, add 50g (0.3330mol) o-methylphenylacetic acid, 0.05g benzoyl peroxide, 0.006g triphenylphosphine, 75g chlorobenzene and 25g methanol to a four-necked flask, start heating and stirring, and heat up to 40 ℃, start to feed chlorine gas, and slowly feed chlorine gas within 0.5h before ventilation, at a rate of 12mL/min. Process sampling detection, when the HPLC content of dichloromethylphenylacetic acid impurity≤3%, stop logical chlorine gas, cool down, obtain o-chloromethylphenylacetic acid reaction liquid; Now o-chloromethylphenylacetic acid liquid phase total area content is in 10%-14%, about 9 hours to complete the ventilation;

Step b, control the reaction liquid of o-chloromethylphenylacetic acid to 20°C, add thionyl chloride dropwise to carry out esterification reaction, take samples for detection during the reaction, when the HPLC content of o-chloromethylphenylacetic acid and o-methylphenylacetic acid All ≤ 1%, stop the dropwise addition of thionyl chloride, the total amount of thionyl chloride added is 11.8g, and the acidic tail gas adopts two-stage water absorption and two-stage alkali absorption;

Step c, after removing methanol under normal pressure, control the vacuum degree to 0.088MPa, the kettle temperature is 70°C, and desolventize for 1-2h until no distillate is evaporated, the chlorobenzene is completely removed, and then continue vacuum distillation with a vacuum degree of 35Pa. The temperature of the kettle material rises to 93°C, and when the content of methyl o-toluene acetate in the fraction detected by sampling is less than 2%, the front fraction is cut out, and the front fraction is methyl o-toluene acetate; continue distillation until the temperature of the kettle is 130°C , Stop the distillation to get the methyl o-chloromethylphenylacetate product, the HPLC content is 99.70%, and the single-pass total yield is 62.30%.

Mix the former fraction of methyl o-toluene acetate with the next batch of o-toluacetic acid raw materials and apply them mechanically to step a to step c. After the system stabilizes, the total yield is 96.11%.

Example 5

This embodiment provides a process for preparing the picoxystrobin intermediate, methyl o-chloromethylphenylacetate, comprising the following steps:

Step a, add 50g (0.3330mol) o-methylphenylacetic acid, 0.3g azobisisobutyronitrile, 0.007g triphenylphosphine, 200g chlorobenzene and 50g methanol to a four-neck flask, start heating and stirring, and heat up to 60°C, start to feed chlorine gas, and slowly feed chlorine gas within 0.5h before ventilation at a rate of 14mL/min. After the feed liquid turns slightly yellow until the yellow color of the feed liquid fades, speed up the ventilation and feed chlorine gas at a rate of 25mL/min. Sampling detection in the reaction process, when the HPLC content of dichloromethylphenylacetic acid impurity≤3%, stop flowing chlorine gas, cool down, get o-chloromethylphenylacetic acid reaction solution; now o-chloromethylphenylacetic acid liquid phase full area content At 10%-14%, the ventilation is completed in about 4.5 hours;

In step b, the temperature of the o-chloromethylphenylacetic acid reaction solution is controlled at 10°C, and sulfur oxychloride is added dropwise for esterification reaction. During the reaction process, samples are taken for detection. When the HPLC content of o-chloromethylphenylacetic acid and o-methylphenylacetic acid is All ≤ 1%, stop the dropwise addition of thionyl chloride, the total amount of thionyl chloride added is 4.0g, and the acidic tail gas adopts two-stage water absorption and two-stage alkali absorption;

Step c, after removing methanol under normal pressure, control the vacuum degree to 0.092MPa, the kettle temperature is 68°C, and desolventize for 1-2h until no distillate is evaporated, and the chlorobenzene is completely removed, and then continue vacuum distillation with a vacuum degree of 45Pa. The temperature of the kettle material rises to 90°C, and when the content of methyl o-toluene acetate in the fraction detected by sampling is less than 2%, the front fraction is cut out, and the front fraction is methyl o-toluene acetate; continue distillation until the temperature of the kettle is 130°C , Stop the distillation to obtain the methyl o-chloromethylphenylacetate product, the HPLC content is 99.80%, and the total yield per pass is 63.33%.

Mix the former fraction of methyl o-toluene acetate with the next batch of o-toluene acetic acid raw materials and apply them mechanically to step a to step c. After the system stabilizes, the total yield is 95.81%.

Comparative example 1

This comparative example provides a kind of preparation technology of picoxystrobin intermediate o-chloromethylphenylacetic acid methyl ester, comprises the following steps:

Step a, add 50g (0.3330mol) of o-tolueneacetic acid, 10.0g of azobisisobutyronitrile, and 250g of chlorobenzene into a four-neck flask, start heating and stirring, raise the temperature to 60°C, and start to introduce chlorine gas. Slowly feed chlorine gas within 0.5h at a rate of 13mL/min. After the feed liquid turns slightly yellow until the yellow color of the feed liquid fades, speed up ventilation and feed chlorine gas at a rate of 25mL/min. Sampling and detection during the reaction process. The HPLC content of phenylacetic acid impurity≤3%, stop flowing chlorine, cool down, obtain o-chloromethylphenylacetic acid reaction solution; At this time, the total area content of o-chloromethylphenylacetic acid liquid phase is 20%-30%, and ventilate for about 5h complete;

Step b, reduce the temperature of the feed liquid to 20°C, keep it warm for 1h and filter, rinse the filter cake with ice chlorobenzene (0-5°C) to obtain o-chloromethylphenylacetic acid; the filtrate is o-methylphenylacetic acid, evaporate to dryness Return the benzene back to the sleeve; add 200g of water to another four-neck bottle, add o-chloromethylphenylacetic acid into the water, control the temperature at 40-50°C, and slowly add 40g of aqueous sodium hydroxide solution with a concentration of 30-32% for cyclization Reaction, the dropwise addition time is about 1 hour, control the pH to 8-9, detect the HPLC content of o-chloromethylphenylacetic acid <1%, stop the reaction, filter at 20°C, and dry to obtain the crude product of 3-isochromone;

Step c, rinse the crude 3-isochromone with ice methanol (0-5°C), dry it, add it to 300g of methanol, control the temperature at 20°C, slowly add 18g of thionyl chloride dropwise, and detect the content of 3-isochromone <1%, after the methanol is removed under negative pressure, the distillation is continued to obtain methyl o-chloromethylphenylacetate product, the HPLC content is 99.00%, and the total yield per pass is 47.20%.

The o-methylphenylacetic acid was returned to the jacket, and after the system was stabilized, the total yield was 60.5%.

Comparative example 2

This comparative example provides a preparation process of picoxystrobin intermediate o-chloromethylphenylacetic acid methyl ester, the specific steps are the same as in Example 1, except that the triphenylphosphine in Example 1 is replaced by o-phenyl Dicarboximide, the rest is exactly the same.

The prepared methyl o-chloromethylphenylacetate product has an HPLC content of 98.08% and a single-pass total yield of 58.20%.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention. Any modification, equivalent replacement or improvement made within the spirit and principles of the present invention shall be included in the protection of the present invention. within range.

Claims (10)

1. The preparation process of picoxystrobin intermediate methyl o-chloromethyl phenylacetate is characterized by comprising the following steps of:

step a, adding o-methyl phenylacetic acid, a free radical initiator and a triarylphosphine catalyst into a mixed solvent of chlorobenzene and methanol, uniformly mixing, heating, introducing chlorine, reacting until the HPLC content of the dichloro methyl phenylacetic acid impurity is less than or equal to 3%, stopping introducing the chlorine, and cooling to obtain o-chloromethyl phenylacetic acid reaction solution;

and b, dropwise adding thionyl chloride into the o-chloromethyl phenylacetic acid reaction solution to perform esterification reaction until the HPLC contents of the o-chloromethyl phenylacetic acid and the o-methyl phenylacetic acid are less than or equal to 1%, stopping dropwise adding thionyl chloride, removing methanol and chlorobenzene solvents, and distilling to obtain the o-chloromethyl phenylacetic acid methyl ester.

2. The process for preparing picoxystrobin intermediate methyl o-chloromethyl phenylacetate according to claim 1, wherein in step a, the free radical initiator is at least one of azobisisobutyronitrile or benzoyl peroxide; and/or

In the step a, the triarylphosphine catalyst is triphenylphosphine;

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

3. The process for preparing picoxystrobin intermediate methyl o-chloromethylphenylacetate according to claim 1 or 2, wherein in step a, the free radical initiator is added in an amount of 0.1% -2% of the mass of the o-methyl phenylacetic acid; and/or

In the step a, the addition amount of the triarylphosphine catalyst is 0.01-0.02% of the mass of the o-methyl phenylacetic acid.

4. The process for preparing picoxystrobin intermediate o-chloromethyl phenylacetate according to claim 3, wherein in step a, the free radical initiator is added in an amount of 0.2% -0.6% of the mass of o-methyl phenylacetate; and/or

In the step a, the addition amount of the triarylphosphine catalyst is 0.015% of the mass of the o-methyl phenylacetic acid.

5. The process for preparing picoxystrobin intermediate methyl o-chloromethylphenylacetate according to claim 1 or 2, wherein in step a, the mass ratio of chlorobenzene to methanol in the mixed solvent is 1-9:1; and/or

In the step a, the mass ratio of the mixed solvent to the o-methyl phenylacetic acid is 2-5:1.

6. The process for preparing picoxystrobin intermediate o-chloromethyl phenylacetate according to claim 5, wherein in step a, the mass ratio of chlorobenzene to methanol in the mixed solvent is 3-5:1; and/or

In the step a, the mass ratio of the mixed solvent to the o-methyl phenylacetic acid is 2-3:1.

7. The process for preparing picoxystrobin intermediate methyl o-chloromethyl phenylacetate according to claim 1, wherein in step a, the temperature is raised to 40-65 ℃; and/or

In the step a, the molar ratio of the chlorine to the o-methyl phenylacetic acid is 0.6-1.2:1.

8. The process for preparing picoxystrobin intermediate o-chloromethyl phenylacetate according to claim 1, wherein in step b, the molar ratio of thionyl chloride to o-methyl phenylacetic acid is 0.1-0.3:1; and/or

In the step b, the temperature of the esterification reaction is 0-30 ℃.

9. The process for preparing picoxystrobin intermediate o-chloromethyl phenylacetate according to claim 8, wherein in step b, the molar ratio of thionyl chloride to o-methyl phenylacetic acid is 0.15-0.2:1; and/or

In the step b, the temperature of the esterification reaction is 10-20 ℃.

10. The process for preparing picoxystrobin intermediate methyl o-chloromethylphenylacetate according to claim 1, wherein in step b, the specific steps of distillation are as follows: distilling at vacuum degree of 30Pa-50Pa, cutting off the front cut when detecting that the HPLC content of the methyl o-chloromethylphenylacetate in the cut is more than 98%, obtaining the methyl o-chloromethylphenylacetate, continuing distilling until the kettle temperature is 130-132 ℃, stopping distilling, and obtaining the methyl o-chloromethylphenylacetate product.