Synthesis method of picoxystrobin intermediate

Abstract

The invention discloses a synthesis method of a picoxystrobin intermediate, which comprises the following steps: (1) dispersing 3-isochromone, alcohol metal salt and formate in a non-polar organic solvent, and carrying out condensation reaction to obtain a reaction solution containing a hydroxyl sodium intermediate shown as a formula I. The water content of the non-polar organic solvent is less than 50ppm, and the water content of the non-polar organic solvent is less than 50ppm; the molar ratio of the 3-isochromone to the alcohol metal salt to the alkenylation reagent is 1: (1.05 to 1.4): (1.05 to 1.4); and (2) continuing to add quaternary ammonium salt as a catalyst and halomethane as a methylation reagent into the reaction liquid, and carrying out etherification reaction to obtain the picoxystrobin intermediate with a structure as shown in a formula II. According to the method, no water is introduced in the reaction process, only alkali is added in the first-step condensation reaction, no alkali is supplemented in the etherification process, residual alkali in the synthesis process of the hydroxyl sodium intermediate shown in the formula I is used for manufacturing an alkaline environment, the alkali consumption is greatly reduced, halogenated methane can be adopted as a methylation reagent in subsequent etherification, the raw material cost is lower, and the method is suitable for industrial production. The post-treatment is simpler, and the method is more environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to a compound synthesis method, in particular to a synthesis method of picoxystrobin intermediate. BACKGROUND

[0002] Picoxystrobin belongs to the methoxy acrylate class of systemic fungicides, which has low toxicity and broad fungicidal spectrum, and has a significant control effect on wheat leaf diseases (including leaf blight, leaf rust, leaf blight, brown spot and powdery mildew). Compared with similar fungicides, picoxystrobin shows more excellent curative activity on wheat leaf blight, net blotch and septoria disease.

[0003] In the synthesis process of picoxystrobin, the methoxy intermediate (4-methoxy methylene-3-isochromone) is a key intermediate for constructing its core structure. The intermediate is mainly prepared from 3-isochromone as a raw material, and sequentially undergoes ketone alpha-site condensation alkenylation and etherification reaction. For example, CN 104230794 A discloses a synthesis method of a high-efficiency green agricultural fungicide, CN 107266316 A discloses a synthesis process of (E)-2-(2-chloromethylphenyl)-3-methoxy methyl acrylate, and CN 108558818 A discloses a preparation method of a methoxy methylene compound. The common point of these schemes is that an excess of base is introduced to create an alkaline environment during the condensation alkenylation reaction to remove the active hydrogen at the alpha position of the carbonyl group; the introduction of base increases the reactivity of the hydroxyl group during the etherification reaction, and an excess of highly active dimethyl sulfate is used as a methylation reagent. These reactions have the following technical defects: 1) Two-step synthesis reactions require an excess of base, resulting in high raw material costs; 2) Environmental risk: After the etherification reaction is completed, the unreacted dimethyl sulfate and sodium monomethyl sulfate waste water / solid waste are difficult to dispose of; 2) Cost problem: Whether in the feeding process or in the post-processing, special protection and waste disposal processes are required for highly toxic reagents, resulting in increased production costs; 3) Process safety: Dimethyl sulfate is a highly toxic substance, which poses a risk to occupational health.

[0004] Therefore, developing a green process that avoids the use of dimethyl sulfate and can efficiently synthesize the methoxy intermediate (4-methoxy methylene-3-isochromone) has become a key direction to break through the technical bottleneck in this field. SUMMARY

[0005] The purpose of the present application is to provide an environmentally friendly synthesis method of picoxystrobin intermediate.

[0006] Technical scheme: The synthesis method of the picoxystrobin intermediate provided by the present application comprises the following steps:

[0007] (1) dispersing 3-isochromone, alcohol metal salt, formate in non-polar organic solvent, carrying out condensation reaction, obtaining reaction solution containing hydroxyl sodium intermediate shown in formula I, the non-polar organic solvent contains less than 50 ppm of water, and the molar ratio of 3-isochromone, alcohol metal salt, alkenylating agent is 1:1.05-1.4:1.05-1.4;

[0008] ;

[0009] (2) continuing to add quaternary ammonium salt as catalyst to the reaction solution, adding methylating agent, carrying out etherification reaction, obtaining pyricandofen intermediate shown in formula II.

[0010] Preferably, in step (1), in order to improve the solubility of 3-isochromone, the non-polar organic solvent is toluene.

[0011] Preferably, in step (1), the alcohol metal salt is sodium methoxide, sodium ethoxide or sodium tert-butoxide.

[0012] Preferably, in step (1), the molar ratio of 3-isochromone, alcohol metal salt, methyl formate is 1:1.05-1.3:1.05-1.3. More preferably, the molar ratio is 1:1.08-1.2:1.1-1.25.

[0013] Preferably, in step (1), the reaction temperature is 0-30°C. In order to further improve the reaction progress and the total yield of multi-step reaction, more preferably, the reaction temperature is 10-20°C.

[0014] Preferably, in step (1), the methylating agent is at least one of dimethyl sulfate, dimethyl carbonate, chloromethane, bromomethane and iodomethane.

[0015] Preferably, the formate is methyl formate or ethyl formate.

[0016] On the basis of the foregoing, in order to improve the reactivity of hydroxyl sodium intermediate shown in formula I and reduce the toxicity of methylating agent used in etherification reaction, in step (1), the reaction is carried out in a continuous reactor, including but not limited to dynamic tubular reactor, multi-layer stirring reactor, continuous stirred tank reactor (CSTR) and the like, 3-isochromone is fed in non-polar organic solvent, and the mass fraction of 3-isochromone is 5-30%; the formate, alcohol metal salt and non-polar organic solvent form a slurry, and the mass fraction of alcohol metal salt is 2-10%.

[0017] Preferably, the mass fraction of 3-isochromone is 6-15%, and the mass fraction of alcohol metal salt is 2-8%.

[0018] Preferably, in step (1), the reaction duration is 1-3 hours.

[0019] Preferably, in step (2), in order to reduce the toxicity of the methylating agent, the methylating agent is chloromethane, bromomethane or iodomethane.

[0020] Preferably, in step (2), the molar ratio of the sodium hydroxyl intermediate shown in Formula I to the methylating agent is 1:1.01~3, more preferably, the ratio is 1:1.01~1.5, and most preferably 1:1.01~1.1.

[0021] Preferably, in step (2), the reaction temperature is 20~80℃. More preferably, to improve the overall yield of the multi-step reaction, the reaction temperature is 40~70℃, and most preferably 40~60℃.

[0022] Preferably, in step (2), the quaternary ammonium salt is tetrabutylammonium bromide, tetrabutylammonium iodide, or benzyltriethylammonium chloride.

[0023] Preferably, in step (2), the molar ratio of the sodium hydroxyl intermediate shown in Formula I to the quaternary ammonium salt is 1:0.003~0.008.

[0024] Preferably, in order to reduce the reaction pressure and improve safety, in step (2), the reaction is carried out in a continuous reactor, including but not limited to dynamic tubular reactor, multi-layer stirred reactor, continuous batch reactor (CSTR), etc. The product obtained in step (1) is mixed with the quaternary ammonium salt and fed into the reactor, and the reaction pressure is 0.01~0.5 MPa.

[0025] Beneficial Effects: Compared with the prior art, the present invention has the following significant advantages: 1. The synthesis method of the azoxystrobin intermediate of the present invention involves the introduction of no water in the reaction process. Alkali is added only in the first step of the condensation reaction. During the etherification process, no alkali is added. The residual alkali from the synthesis of the sodium hydroxyl intermediate shown in Formula I is directly used to create an alkaline environment, significantly reducing the amount of alkali used, resulting in lower raw material costs, simpler post-processing, and greater environmental friendliness; 2. By changing the reactor type, the duration of the alkenylation reaction is greatly shortened while reducing the raw material concentration, thus improving reaction efficiency. Simultaneously, the particle size of the sodium hydroxyl intermediate obtained in the first step of the reaction is reduced, and its reactivity is enhanced. The first step of the reaction can reuse the residual base to carry out the methylation reaction with the haloalkane, and the second step of the etherification reaction can use the haloalkane to replace dimethyl sulfate, which greatly reduces the toxicity of the reaction raw materials and post-processing, and improves safety; 3. Cost advantage: Haloalkane, especially chloromethane, is inexpensive and readily available, which can effectively reduce production costs; 4. Mild process conditions, avoiding high pressure conditions, and achieving safe production; 5. Simple post-processing: After the etherification reaction, only the byproduct sodium chloride needs to be removed by filtration, and the filtrate can be concentrated to obtain the high-purity target product without complicated purification steps; 6. Reduction of three wastes: No wastewater is generated in the reaction process, and unreacted chloromethane can be recycled and reused. Detailed Implementation

[0026] The technical solution of the present invention will be further described below with reference to the embodiments.

[0027] Examples 1-3: Synthesis of sodium hydroxyl intermediate (Formula I) via condensation reaction

[0028] The chemical equation is as follows:

[0029]

[0030] The general procedure is as follows: In a 1L dynamic tubular reactor, a toluene slurry containing 10% sodium methoxide (180 g / h), methyl formate (21 g / h), and a pre-prepared 10% 3-isochromone toluene solution (444 g / h) are simultaneously pumped in. The reactor is kept at a certain temperature for the reaction. The reaction progress is monitored by gas chromatography at the reactor outlet. The residence time of the reaction solution in the dynamic tubular reactor is approximately 1.5 h.

[0031] Examples 1 to 3, the variables and reaction results of each example are shown in Table 1.

[0032] Table 1:

[0033]

[0034] Examples 4-9: Synthesis of azoxystrobin intermediates via etherification reaction

[0035] The chemical equation is as follows:

[0036]

[0037] The general procedure is as follows: The toluene slurry solution of the sodium hydroxyl intermediate (645 g / h, sodium hydroxyl intermediate content 58 g / h) after the reaction in Example 2 is premixed with tetrabutylammonium bromide toluene solution (10 g / h, containing 0.5 g / h tetrabutylammonium bromide) in a static mixer, and then pumped into a 2L dynamic tubular reactor. At the same time, chloromethane gas (17.8 g / h) is pumped in, and the pressure is controlled to not exceed 0.5 MPa. The reactor is kept at a certain reaction temperature for the reaction. The reaction progress is monitored by gas chromatography at the reactor outlet. The residence time of the reactants in the dynamic tubular reactor is about 2 hours.

[0038] After the reaction is complete, the material from the outlet of the dynamic tubular reactor enters the gas-liquid separator, where a slight negative pressure is applied to evacuate the gas and recover unreacted chloromethane gas for reuse. The reaction solution is filtered, and the filtrate is concentrated to obtain the azoxystrobin intermediate (Formula II).

[0039] Examples 4 to 9, the variables and reaction results of each example are shown in Table 2.

[0040] Table 2:

[0041]

[0042] Example 10: The material from the reaction in Example 2, a toluene slurry solution of the sodium hydroxyl intermediate (645 g / h, sodium hydroxyl intermediate content 58 g / h), was premixed with tetrabutylammonium bromide toluene solution (10 g / h, containing 0.5 g / h tetrabutylammonium bromide) in a static mixer, and then pumped into a 2L dynamic tubular reactor. Dimethyl sulfate (44.4 g / h) was pumped in simultaneously. The temperature of the dynamic tubular reactor was controlled at 40~50℃ for the reaction. The reaction was monitored by gas chromatography at the reactor outlet. The conversion rate of the pyridoxine intermediate was greater than 99%.

[0043] After the reaction is complete, the material from the outlet of the dynamic tubular reactor is pumped together with water (200 g / h) into another dynamic tubular reactor (2 L, 60 °C) for continuous water washing. The resulting liquid enters a continuous phase separator for phase separation. The organic phase solution is pumped together with water (200 g / h) into another dynamic tubular reactor (2 L, 60 °C) for continuous water washing. The resulting liquid enters a continuous phase separator for phase separation. The organic phase is filtered, and the filtrate is concentrated to obtain azoxystrobin intermediate (Formula II) with a purity of 96% and a yield of 95%. The aqueous phase separated by the two water washings enters a collection vessel and is kept at 60 °C to further hydrolyze monomethyl sulfate into sulfuric acid and methanol.

[0044] Comparative Example 1: This comparative example uses the same materials as in Example 2. The procedure is as follows: a toluene slurry solution of the sodium hydroxyl intermediate (645 g / h, sodium hydroxyl intermediate content 58 g / h) is premixed with a tetrabutylammonium bromide toluene solution (10 g / h, containing 0.05 g / h tetrabutylammonium bromide) in a static mixer, and then pumped into a 2L dynamic tubular reactor. Simultaneously, chloromethane gas (17.8 g / h) is pumped in. The temperature of the dynamic tubular reactor is controlled at 40-50°C for the reaction. The reaction is monitored by gas chromatography at the reactor outlet. At the end of the reaction, the conversion rate of the pyridoxine intermediate (Formula I) is only 82%, and a high-purity product cannot be obtained.

[0045] Comparative Example 2: In this comparative example, the solvent toluene in Example 2 was replaced with methanol. The methanol solution of the sodium hydroxyl intermediate (640 g / h, sodium hydroxyl intermediate content approximately 56 g / h) was premixed with tetrabutylammonium bromide methanol solution (10 g / h, containing 0.5 g / h tetrabutylammonium bromide) in a static mixer, and then pumped into a 2L dynamic tubular reactor. Simultaneously, chloromethane gas (16.6 g / h) was pumped in as a methylation reagent, controlling the pressure to not exceed 0.5 MPa. The reactor was maintained at 40-50°C for the reaction, and the reaction progress was monitored by gas chromatography at the reactor outlet. After the reaction, the post-processing was the same as in Example 4, yielding azoxystrobin intermediate (Formula II) with a purity of 78% and a yield of 76%.

[0046] The sodium hydroxyl intermediate obtained by the condensation step in Comparative Example 2 had a purity of approximately 94%. Compared to Example 2, the yields of both the condensation and methylation steps decreased. This may be because the use of methanol as a solvent introduced active hydrogen into the reaction system, resulting in a competing reaction.

[0047] Comparative Example 3: In this comparative example, the solvent toluene in Example 2 was replaced with methanol. The methanol solution of the sodium hydroxyl intermediate (640 g / h, sodium hydroxyl intermediate content approximately 56 g / h) was premixed in a static mixer with tetrabutylammonium bromide methanol solution (10 g / h, containing 0.5 g / h tetrabutylammonium bromide) and sodium methoxide methanol solution (15 g / h, containing 9.1 g / h sodium methoxide). This mixture was then pumped into a 2L dynamic tubular reactor, simultaneously pumping in chloromethane gas (16.6 g / h) as a methylation reagent. The pressure was controlled to not exceed 0.5 MPa, and the reactor was maintained at 40-50°C for the reaction. The reaction progress was monitored by gas chromatography at the reactor outlet. After the reaction, the post-treatment was the same as in Example 4, yielding azoxystrobin intermediate (Formula II) with a purity of 81% and a yield of 78%. Compared to Comparative Example 2, the methylation yield in this comparative example showed no significant change, indicating that the addition of alkali did not significantly promote the reaction when methanol was used as the solvent.

[0048] Comparative Examples 4-5: The reaction vessel was changed to synthesize the azoxystrobin intermediate.

[0049] (1) Condensation reaction to synthesize sodium hydroxyl intermediate: In a stirred reactor, add 200 mL of toluene, start stirring, add 19 g of solid sodium methoxide, cool the reactor by passing water through the jacket, and control the reactor temperature to 10-20℃. Add methyl formate dropwise to the reactor, and finish the addition in about 0.5 h. After the addition is finished, keep the temperature and stir for 30 min. Control the reaction temperature to 10-20℃ and add 450 g of 3-isochromone toluene solution (containing 45 g of 3-isochromone) dropwise to the reactor. Keep the temperature at 10-20℃ and continue stirring for 6-7 hours. Take a sample for analysis. If the chromone content is <1%, the reaction is qualified.

[0050] (2) Etherification reaction to synthesize azoxystrobin intermediate: Continue to add dimethyl sulfate dropwise to the reactor or introduce chloromethane, control the temperature at 40-50℃, monitor the reaction progress by liquid chromatography, and stop the reaction when the sodium hydroxyl intermediate is less than 1%. The post-processing is the same as in the previous related examples. The variables and reaction results of comparative examples 5-6 are shown in Table 4.

[0051] Table 4:

[0052]

[0053] Using dimethyl sulfate as the methylating agent, the yield of Comparative Example 5 did not change significantly compared to Example 10, but the yield of Comparative Example 6 decreased significantly compared to Example 6. The reason is that the reaction time in step (1) was significantly increased by using a slurry reactor, and the generated sodium hydroxyl intermediate underwent a kind of "aging", with an increased particle size and decreased reactivity. Moreover, the reactivity of chloromethane is lower than that of dimethyl sulfate. Even if the amount of chloromethane was increased and the reaction time was extended, the purity and yield were difficult to further improve and could not exceed that of dimethyl sulfate. Furthermore, as the amount of chloromethane increased, the reaction pressure also increased, which increased the risk and reduced the safety.

Claims

1. A method for synthesizing a pyridoxine intermediate, characterized in that, Includes the following steps: (1) Disperse 3-isochromone, metal alcohol salt, and methyl formate in a non-polar organic solvent and carry out a condensation reaction to obtain a reaction solution containing the structure shown in Formula I. The non-polar organic solvent contains less than 50 ppm of water, and the molar ratio of 3-isochromone, metal alcohol salt, and alkenylating agent is 1:1.05~1.4:1.05~1.

4. ； (2) Continue to add quaternary ammonium salt as a catalyst and halomethane as a methylating agent to the reaction solution to carry out the etherification reaction and obtain the pyrimethanil intermediate with the structure shown in Formula II.

2. The method for synthesizing the pyridoxine intermediate according to claim 1, characterized in that, In step (1), the nonpolar organic solvent is toluene.

3. The method for synthesizing the pyridoxine intermediate according to claim 1, characterized in that, In step (1), the methylating agent is at least one of dimethyl sulfate, dimethyl carbonate, chloromethane, bromomethane, and iodomethane, the metal alcohol salt is sodium methoxide, sodium ethoxide, or sodium tert-butoxide, and the formate ester is methyl formate or ethyl formate.

4. The method for synthesizing the pyridoxine intermediate according to claim 1, characterized in that, In step (1), the molar ratio of 3-isochromone, sodium alkoxide and methyl formate is 1:1.05~1.3:1.05~1.3, and the reaction temperature is 0~30℃.

5. The method for synthesizing the pyridoxine intermediate according to any one of claims 1 to 4, characterized in that, In step (1), the reaction is carried out in a continuous reactor, which is a dynamic tubular reactor, a multi-layer stirred reactor, or a continuous batch reactor. The 3-isochromone is fed in a non-polar organic solvent, and the mass fraction of the 3-isochromone is 5-30%. The formate ester, the metal alcohol salt, and the non-polar organic solvent are fed in a slurry, and the mass fraction of the metal alcohol salt is 2-10%.

6. The method for synthesizing the pyridoxine intermediate according to claim 5, characterized in that, In step (1), the mass fraction of 3-isochromone is 6-15%, the mass fraction of metal alkoxide is 2-8%, and the reaction duration is 1-3 hours.

7. The method for synthesizing the pyridoxine intermediate according to claim 5, characterized in that, In step (2), the molar ratio of the compound with the structure shown in Formula I to the methylating agent is 1:1.01~3, and the reaction temperature is 20~80℃.

8. The method for synthesizing the pyridoxine intermediate according to claim 7, characterized in that, The reaction temperature is 40~70℃.

9. The method for synthesizing the pyridoxine intermediate according to claim 5, characterized in that, In step (2), the quaternary ammonium salt is tetrabutylammonium bromide, tetrabutylammonium iodide or benzyltriethylammonium chloride, and the molar ratio of the sodium hydroxyl intermediate shown in Formula I to the quaternary ammonium salt is 1:0.003~0.

008.

10. The method for synthesizing the pyridoxine intermediate according to claim 5, characterized in that, In step (2), the reaction is carried out in a continuous reactor, which is a dynamic tubular reactor, a multi-layer stirred reactor or a continuous batch reactor, and the reaction pressure is 0.01~0.5 MPa.

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