Synthesis method of phenyl isoxazoline compound

Abstract

The invention relates to the technical field of organic synthesis, in particular to the field of IPC C07D239, and more particularly relates to a synthesis method of a phenyl isoxazoline compound. Comprising the following steps: step 1, using a benzaldehyde compound as an initial raw material, and reacting with hydroxylamine hydrochloride to generate a benzaldoxime compound; 2, carrying out a chlorination reaction on the benzaldoxime compound generated in the step 1 and liquid chlorine through a microchannel reactor to generate a chlorinated benzaldoxime compound; and 3, carrying out ring closing on the chlorobenzaldoxime compound generated in the step 2 and an alkene compound to obtain the phenyl isoxazoline compound. A metal catalyst is not used in the preparation method, so that the solid waste treatment cost is reduced; in the step 2, a continuous flow reaction technology of a microchannel reactor is adopted, the reaction time is shortened, compared with a kettle type intermittent process, the productivity is greatly improved, and the reaction safety is higher.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to the field of IPC C07D239, and more particularly to a synthesis method of phenyl isoxazoline compounds. BACKGROUND

[0002] Phenyl isoxazoline compounds and their derivatives are widely used in the development and application of pesticide active molecules. For example, WO2016095768 reports a class of phenyl isoxazoline compounds with good herbicidal activity, which can effectively control weeds such as dogtail grass, heterotypic sedge, water sedge, zinnia, portulaca, nightshade, and cassia, and can achieve good herbicidal effect at low dosage, and can be used as herbicides in agriculture.

[0003] Synthesizing phenyl isoxazoline compounds from benzaldehyde compounds is a relatively common method. For example, patent CN113149924 uses benzaldehyde, p-toluenesulfonyl hydrazide, olefin, and nitrous acid ester as reaction substrates in the presence of a base and a copper catalyst in an organic solvent to obtain isoxazoline. This method has the advantages of wide substrate universality, simple operation, and mild reaction conditions, but it uses a metal catalyst, increasing the cost of solid waste treatment, and the reaction scale only stays at the laboratory micro-reaction stage, with uncertain industrial application prospects.

[0004] Patent CN113880774 reports a preparation method from benzaldehyde compounds to phenyl isoxazoline compounds. The method prepares benzaldehyde oxime by reacting benzaldehyde with hydroxylamine hydrochloride, and then reacts benzaldehyde oxime with chlorinating reagent NCS, and then adds base and olefin to prepare phenyl isoxazoline. The raw materials used in this method are easy to obtain and the post-reaction treatment is simple, and the industrial application prospect is good, but the second step uses NCS (N-chlorosuccinimide) as a chlorinating reagent, which has low atomic utilization and does not conform to the concept of green chemistry.

[0005] Patent CN105481787 reports a one-pot method for preparing phenyl isoxazoline from benzaldehyde oxime. The method uses chlorine gas as a chlorinating reagent to react with benzaldehyde oxime, and then passes in ethylene under the condition of an acid binding agent for cyclization reaction. This method has the advantages of simple process flow, safe operation, mild reaction conditions, and low production cost. However, the use of chlorine gas for pot chlorination has long chlorine passing and reaction time, and low production capacity. SUMMARY

[0006] In view of the deficiencies in the prior art, the present application aims to provide a new method for preparing phenyl isoxazoline compounds from benzaldehyde compounds. This method does not use metal catalysts, and uses continuous flow reaction technology in the chlorination reaction step of benzaldehyde oxime, which greatly improves the production capacity without affecting the reaction yield.

[0007] The synthesis method of the phenyl isoxazoline compound provided by the application comprises the following steps:

[0008] Step 1: using benzaldehyde compounds as starting materials, reacting with hydroxylamine hydrochloride to generate benzaldehyde oxime compounds;

[0009] Step 2: chlorinating the benzaldehyde oxime compounds generated in step 1 with liquid chlorine through a micro-channel reactor to generate chlorobenzaldehyde oxime compounds;

[0010] Step 3: ring-closing the chlorobenzaldehyde oxime compounds generated in step 2 with olefin compounds to obtain phenyl isoxazoline compounds.

[0011] The synthesis reaction is shown in formula 1:

[0012]

[0013] In the formula, R1 is selected from one or more of hydrogen, alkyl, fluorine, chlorine, bromine, carboxylate, amide, ether, thioether, difluoromethyl, trifluoromethyl, nitro, cyano, sulfone group;

[0014] R2 is selected from one or more of hydrogen, alkyl, halogenated alkyl, halogen, cyano;

[0015] R3 is selected from one or more of hydrogen, alkyl, halogenated alkyl, ether, amide, carboxylate.

[0016] Specifically, the step 1 is: adding benzaldehyde compounds I into a solvent, mixing with hydroxylamine hydrochloride, heating to 60-130 DEG C, and reacting for 1-5 h to generate benzaldehyde oxime compounds II.

[0017] The molar ratio of the benzaldehyde compounds I to hydroxylamine hydrochloride is 1:(1-2).

[0018] Preferably, the molar ratio of the benzaldehyde compounds I to hydroxylamine hydrochloride is 1:(1-1.3).

[0019] The solvent comprises at least one of methanol, ethanol, ethyl acetate, isopropyl acetate, toluene, and N,N-dimethylformamide.

[0020] Preferably, the solvent of the step is ethyl acetate or isopropyl acetate.

[0021] Specifically, the step 2 is: chlorinating the benzaldehyde oxime compounds II obtained in step 1 with liquid chlorine in a micro-channel reactor to prepare chlorobenzaldehyde oxime compounds III.

[0022] The feeding speed of the benzaldehyde oxime compounds II is 20-100 g / min.

[0023] Preferably, the feed rate of the benzaldehyde oxime compound II is 60-80 g / min.

[0024] The feed molar ratio of benzaldehyde compound II to liquid chlorine is 1:(1 to 1.5).

[0025] Preferably, the feed molar ratio of benzaldehyde compound II to liquid chlorine is 1:(1.05~1.2).

[0026] The microchannel reactor has an oil bath temperature of -30 to 10°C, a reaction time of 20 to 10 minutes, and a reaction pressure of 0 to 10 bar.

[0027] Preferably, the oil bath temperature of the microchannel reactor is controlled at -15 to 5°C, the reaction time is 0.5 to 1 min, and the reaction pressure is 2 to 3 bar.

[0028] The channels of the microchannel reactor have a heart-shaped or straight structure, and the number of reaction modules used in the microchannel reactor is 2 to 6.

[0029] Preferably, the microchannel reactor uses 4 to 5 reaction modules.

[0030] Step 3 specifically involves: mixing the chlorobenzaldehyde oxime compound III obtained in step 2 with a base and an alkene compound to carry out a cyclization reaction, thereby preparing a phenylisoxazoline compound IV.

[0031] The cyclization reaction is carried out at a temperature of -10 to 15°C for 2 to 6 hours.

[0032] Preferably, the cyclization reaction is carried out at a temperature of -5 to 5°C for 2 to 4 hours.

[0033] The base includes at least one of sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, and pyridine.

[0034] The molar ratio of the chlorobenzaldehyde oxime compound III, the base, and the alkene compound is 1:(1-3):(1-2).

[0035] Preferably, the molar ratio of the chlorobenzaldehyde oxime compound III, the base, and the alkene compound is 1:(1-2):(1-1.5).

[0036] Beneficial effects:

[0037] 1. The preparation method in this application does not use a metal catalyst, thus reducing the cost of solid waste treatment.

[0038] 2. In step 2, liquid chlorine is used as the chlorination reagent, which has a higher atom utilization rate compared to NCS.

[0039] 3. The continuous flow reaction technology using microchannel reactors shortens the reaction time, significantly increases production capacity compared to batch reactor processes, and offers higher reaction safety.

[0040] 4. The overall yield of phenylisoxazoline compounds synthesized in this application is approximately 90%. Attached Figure Description

[0041] Figure 1 The diagram shows a heart-shaped microchannel reactor in Example 1, which has 5 reaction modules. Detailed Implementation

[0042] Example 1

[0043] A method for synthesizing a phenylisoxazoline compound (compound IV-1) is shown in Formula 2:

[0044]

[0045] (1) Add 1.5 kg of 2-chloro-4-fluoro-5-nitrobenzaldehyde (I-1, 98.5% purity) and 3 kg of isopropyl acetate to a 10 L reactor. Start stirring and add 0.54 kg of hydroxylamine hydrochloride solid after the solid has completely dissolved. Turn on the integrated heating and cooling system (set to 120℃) and heat for about 1.5 h until the temperature inside the reactor reaches 85℃. Start the reflux reaction and take samples to control the reaction until the content of 2-chloro-4-fluoro-5-nitrobenzaldehyde drops below 0.5 wt%. The reaction ends when the temperature inside the reactor drops to 30℃ after cooling for 1 h. Discharge the material and let it stand to precipitate. Separate the excess hydroxylamine hydrochloride solid to obtain 4.86 kg of isopropyl acetate solution of compound II-1. The isopropyl acetate solution of II-1 is directly used in the next reaction.

[0046] (2) The isopropyl acetate solution and liquid chlorine obtained in step (1) are mixed by introducing them into the first plate of the microchannel reactor through a plunger pump (e.g., Figure 1 As shown, material 1 is an isopropyl acetate solution of II-1, and material 2 is liquid chlorine. The reactor oil bath temperature is controlled at -10℃. The feed flow rate of the isopropyl acetate solution of II-1 is 70.0 g / min, and the feed flow rate of the liquid chlorine is 10.5 g / min. The reaction proceeds through the last four plates, with a residence time of 1 min and a reaction pressure of 2.0 bar. During the reaction, the reaction liquid flows out from the outlet of the fifth plate and is collected in a 10L reactor. Nitrogen gas is bubbled into the reactor for 4 hours to remove excess chlorine and hydrogen chloride generated in the reaction. After the removal is complete, 5.04 kg of isopropyl acetate solution of III-1 is obtained for use in the next reaction step.

[0047] (3) Turn on the integrated heating and cooling system of the 10L reactor to lower the temperature of the isopropyl acetate solution of III-1 obtained in step (2) to below 0℃. Add a mixture of 1.09kg ethyl methacrylate (1.2eq) and 1.04kg triethylamine (1.3eq) dropwise. Control the temperature of the reaction system within 0-10℃ during the dropwise addition process. After the dropwise addition is completed, keep the temperature and continue the reaction for 2 hours. The reaction is considered complete when the content of III-1 in the liquid chromatography is less than 0.5wt%. After the reaction is completed, add 1.2kg of water and stir to mix. Let it stand to separate the layers. Separate the lower aqueous phase and obtain 5.2kg of the upper organic phase, which is the isopropyl acetate solution of IV-1.

[0048] Example 2

[0049] A method for synthesizing a phenylisoxazoline compound (compound IV-2) is shown in Formula 3:

[0050]

[0051] (1) Add 1.5 kg of 2-chloro-4-fluoro-5-nitrobenzaldehyde (I-1, 98.5% purity) and 3 kg of isopropyl acetate to a 10 L reactor. Start stirring and add 0.54 kg of hydroxylamine hydrochloride solid after the solid has completely dissolved. Turn on the integrated heating and cooling system (set to 120℃). After heating for about 1.5 h, the temperature inside the reactor reaches 85℃, and the reflux reaction begins. Take samples and control the reaction until the content of 2-chloro-4-fluoro-5-nitrobenzaldehyde drops below 0.5 wt%, at which point the reaction ends. After cooling for 1 h, the temperature inside the reactor drops to 30℃. Discharge the material and allow it to settle. Separate the excess hydroxylamine hydrochloride solid to obtain 4.83 kg of isopropyl acetate solution of compound II-1. The isopropyl acetate solution of II-1 is directly used in the next reaction step.

[0052] (2) The isopropyl acetate solution and liquid chlorine obtained in step (1) are mixed by introducing them into the first plate of the microchannel reactor through a plunger pump (e.g., Figure 1 As shown, material 1 is an isopropyl acetate solution of II-1, and material 2 is liquid chlorine. The reactor oil bath temperature is controlled at -10℃. The feed flow rate of the isopropyl acetate solution of II-1 is 70.0 g / min, and the feed flow rate of the liquid chlorine is 10.0 g / min. The reaction proceeds through the last four plates, with a residence time of 1 min and a reaction pressure of 2.0 bar. During the reaction, the reaction liquid flows out from the outlet of the fifth plate and is collected in a 10 L reactor. Nitrogen gas is bubbled into the reactor for 4 h to remove excess chlorine and hydrogen chloride generated in the reaction. After the removal is complete, 5.01 kg of isopropyl acetate solution of III-1 is obtained for use in the next reaction step.

[0053] (3) Turn on the integrated heating and cooling system of the 10L reactor to lower the temperature of the isopropyl acetate solution of III-1 obtained in step (2) to below 0℃. Add dropwise a mixture of 0.96kg methyl methacrylate (1.2eq) and 1.04kg triethylamine (1.3eq). During the dropwise addition, control the temperature of the reaction system within 0-10℃. After the dropwise addition is complete, keep the temperature and continue the reaction for 2 hours. The reaction is considered complete when the content of III-1 in the liquid chromatography is less than 0.5wt%. After the reaction is complete, add 1.2kg of water and stir to mix. Let it stand to separate the layers. Separate the lower aqueous phase and obtain 5.1kg of the upper organic phase, which is the isopropyl acetate solution of IV-2.

[0054] Example 3

[0055] A method for synthesizing a phenylisoxazoline compound (compound IV-3) is shown in Formula 4:

[0056]

[0057] (1) Add 1.5 kg of 2-chloro-4-fluoro-5-nitrobenzaldehyde (I-1, 98.5% purity) and 3 kg of isopropyl acetate to a 10 L reactor. Start stirring and add 0.54 kg of hydroxylamine hydrochloride solid after the solid has completely dissolved. Turn on the integrated heating and cooling system (set to 120℃). After heating for about 1.5 h, the temperature inside the reactor reaches 85℃, and the reflux reaction begins. Take samples and control the reaction until the content of 2-chloro-4-fluoro-5-nitrobenzaldehyde drops below 0.5 wt%, at which point the reaction ends. After cooling for 1 h, the temperature inside the reactor drops to 30℃. Discharge the material and allow it to settle. Separate the excess hydroxylamine hydrochloride solid to obtain 4.85 kg of isopropyl acetate solution of compound II-1. The isopropyl acetate solution of II-1 is directly used in the next step of the reaction.

[0058] (2) The isopropyl acetate solution of II-1 obtained in step (1) and liquid chlorine were mixed by introducing them into the first plate of the microchannel reactor using a plunger pump. The oil bath temperature of the reactor was controlled at -10℃. The feed flow rate of the isopropyl acetate solution of II-1 was 60.0 g / min, and the feed flow rate of liquid chlorine was 9.0 g / min. The reaction proceeded through the next four plates, with a residence time of 70 s and a reaction pressure of 1.5 bar. During the reaction, the reaction liquid flowed out from the outlet of the fifth plate and was collected into a 10L reactor. Nitrogen gas was bubbled into the reactor for 4 hours to remove excess chlorine and hydrogen chloride generated in the reaction. After the removal was completed, 5.1 kg of isopropyl acetate solution of III-1 was obtained for use in the next reaction step.

[0059] (3) Turn on the integrated heating and cooling system of the 10L reactor to lower the temperature of the isopropyl acetate solution of III-1 obtained in step (2) to below 0℃. Add dropwise a mixture of 1.12kg isopropyl methacrylate (1.2eq) and 1.04kg triethylamine (1.3eq). During the dropwise addition, control the temperature of the reaction system within 0-10℃. After the dropwise addition is complete, keep the temperature and continue the reaction for 2 hours. The reaction is considered complete when the content of III-1 in the liquid chromatography is less than 0.5wt%. After the reaction is complete, add 1.2kg of water and stir to mix. Let it stand to separate the layers. Separate the lower aqueous phase and obtain 5.3kg of the upper organic phase, which is the isopropyl acetate solution of IV-3.

[0060] Comparative Example 1

[0061] A method for synthesizing a phenylisoxazoline compound (compound IV-1) is shown in Formula 5:

[0062]

[0063] (1) Add 1.5 kg of 2-chloro-4-fluoro-5-nitrobenzaldehyde (I-1, 98.5% purity) and 3 kg of isopropyl acetate to a 10 L reactor. Start stirring and add 0.54 kg of hydroxylamine hydrochloride solid after the solid has completely dissolved. Turn on the integrated heating and cooling system (set to 120℃) and heat for about 1.5 h until the temperature inside the reactor reaches 85℃. Start the reflux reaction and take samples to control the reaction until the content of 2-chloro-4-fluoro-5-nitrobenzaldehyde drops below 0.5 wt%. The reaction ends when the temperature inside the reactor drops to 30℃ after cooling for 1 h. Discharge the material and let it stand to precipitate. Separate the excess hydroxylamine hydrochloride solid to obtain 4.86 kg of isopropyl acetate solution of compound II-1. The isopropyl acetate solution of II-1 is directly used in the next reaction.

[0064] (2) Place the isopropyl acetate solution II-1 obtained in step (1) into a 10L reactor, turn on the integrated heating and cooling system, and set the temperature to -10℃. Start stirring and slowly introduce chlorine gas into the reactor, controlling the internal temperature of the reaction to always be below 0℃. The reaction tail gas is absorbed by a two-stage process of water and alkali. The reaction is considered complete when the content of II-1 in the liquid chromatography is less than 0.5wt%. After the reaction is complete, bubble nitrogen gas into the reactor for 4 hours to remove excess chlorine gas and hydrogen chloride generated in the reaction. After the removal is complete, 5.0kg of isopropyl acetate solution III-1 is obtained for use in the next reaction.

[0065] (3) Turn on the integrated heating and cooling system of the 10L reactor to lower the temperature of the isopropyl acetate solution of III-1 obtained in step (2) to below 0℃. Add dropwise a mixture of 1.08kg ethyl methacrylate (1.2eq) and 1.04kg triethylamine (1.3eq). During the dropwise addition, control the temperature of the reaction system within 0-10℃. After the dropwise addition is complete, keep the temperature and continue the reaction for 2 hours. The reaction is considered complete when the content of III-1 in the liquid chromatography is less than 0.5wt%. After the reaction is complete, add 1.2kg of water and stir to mix. Let it stand to separate the layers. Separate the lower aqueous phase and obtain 5.1kg of the upper organic phase, which is the isopropyl acetate solution of IV-1.

[0066] Performance testing methods and data

[0067] The contents and yield of each step in the examples and comparative examples were determined by liquid chromatography, and the test data are listed in Table 1.

[0068] Table 1

[0069] Example 1 Example 2 Example 3 Comparative Example 1 Step (1) product liquid chromatography qualitative content / % 97.02 97.18 97.23 96.98 Step (1) product yield / % 98.2 98.4 98.9 98.1 Step (2) product liquid chromatography qualitative content / % 96.85 96.96 97.01 96.75 Step (2) product single step yield / % 98.7 98.2 98.3 97.9 Step (3) product single step yield / % 93.5 93.1 93.0 92.8 Overall yield / % 90.6 89.9 90.4 89.1 Step (2) reaction time / min 70 70 70 180

[0070] As can be seen from the examples and comparative examples, the chlorination reaction in step (2) is carried out using a microchannel reactor, and the reaction time is significantly shortened compared to batch chlorination.

Claims

1. A method for synthesizing a phenylisoxazoline compound, characterized by, The method comprises the following steps: Step 1: using benzaldehyde compounds as starting materials, and reacting with hydroxylamine hydrochloride to generate benzaldehyde oxime compounds; Step 2: chlorinating the benzaldehyde oxime compounds generated in step 1 with liquid chlorine through a micro-channel reactor to generate chlorobenzaldehyde oxime compounds; Step 3: mixing the chlorobenzaldehyde oxime compounds generated in step 2 with olefin compounds to perform cyclization reaction to obtain phenyl isoxazoline compounds.

2. The method for synthesizing phenylisoxazoline compounds according to claim 1, characterized in that, The synthesis reaction is shown in formula 1: In the formula, R1 is selected from one or more of hydrogen, alkyl, fluorine, chlorine, bromine, carboxylate, amide, ether, sulfide, difluoromethyl, trifluoromethyl, nitro, cyano, sulfone group; R2 is selected from one or more of hydrogen, alkyl, halogenated alkyl, halogen, cyano; R3 is selected from one or more of hydrogen, alkyl, halogenated alkyl, ether, amide, carboxylate.

3. The method for synthesizing phenylisoxazoline compounds according to claim 2, characterized in that, The step 1 is specifically: adding benzaldehyde compounds I into a solvent, mixing with hydroxylamine hydrochloride, heating to 60-130 DEG C, and reacting for 1-5 h to generate benzaldehyde oxime compounds II; the molar ratio of the benzaldehyde compounds I to hydroxylamine hydrochloride is 1:(1-2).

4. The method for synthesizing phenylisoxazoline compounds according to claim 3, characterized in that, The solvent includes at least one of methanol, ethanol, ethyl acetate, isopropyl acetate, toluene, and N,N-dimethylformamide.

5. The method of synthesizing a phenylisoxazoline compound according to claim 3 or 4, wherein The step 2 is specifically: performing chlorination reaction of the benzaldehyde oxime compounds II obtained in step 1 with liquid chlorine in a micro-channel reactor to prepare chlorobenzaldehyde oxime compounds III; the feeding speed of the benzaldehyde oxime compounds II is 20-100 g / min, and the feeding molar ratio of the benzaldehyde compounds II to liquid chlorine is 1:(1-1.5).

6. The method for synthesizing phenylisoxazoline compounds according to claim 5, characterized in that, The oil bath control temperature of the micro-channel reactor is-30-10 DEG C, the reaction time is 20 s-10 min, and the reaction pressure is 0-10 bar.

7. The method for synthesizing phenylisoxazoline compounds according to claim 6, characterized in that, The channel of the micro-channel reactor is a heart-shaped structure or a straight structure, and the number of reaction modules used by the micro-channel reactor is 2-6.

8. The method for synthesizing phenylisoxazoline compounds according to claim 7, characterized in that, The step 3 is specifically: mixing the chlorobenzaldehyde oxime compounds III obtained in step 2 with a base and olefin compounds to perform cyclization reaction to prepare phenyl isoxazoline compounds IV; the temperature of the cyclization reaction is-10-15 DEG C, and the reaction time is 2-6 h.

9. The method for synthesizing phenylisoxazoline compounds according to claim 8, characterized in that, The base includes at least one of sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, N,N-diisopropyl ethylamine, and pyridine.

10. The method for synthesizing phenylisoxazoline compounds according to claim 9, characterized in that, The feeding molar ratio of the chlorobenzaldehyde oxime compounds III, the base, and the olefin compounds is 1:(1-3). (1～2)。

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