Preparation method of 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole

Abstract

The invention belongs to the field of chemical synthesis, and relates to a preparation method of 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole. Specifically, the invention discloses a preparation method of a compound as shown in a formula II, which comprises the following steps: in the presence of a solvent, reacting a compound as shown in a formula I serving as a raw material with trioxymethylene and HCl to obtain a reaction solution containing the compound as shown in the formula II. According to the method, reaction reagent raw materials are easy to obtain, no extra catalyst is added, route selectivity is good, side reactions are few, the product yield is high, reaction conditions are mild and easy to control, technological operation is simple and easy to industrialize, harmful waste gas is not generated, a solvent obtained through reaction aftertreatment can be directly used mechanically, and the whole reaction process is low in toxicity, efficient, simple, green and easy to industrialize and apply. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a preparation method of 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole, belonging to the field of chemical synthesis. Background Art

[0002] 1-Methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole is an important intermediate in the synthesis of the novel herbicide pyroxasulfone. This intermediate can be prepared via various pathways and is reported in patent applications such as CN117777122A and CN119661438A.

[0003] CN117777122A discloses a synthetic route in which 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole (Intermediate I) undergoes chloromethylation in the presence of sulfuric acid, trioxymethylene, and thionyl chloride to produce 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole (Intermediate II). This reaction requires the addition of sulfuric acid as a catalyst, resulting in low atom economy and not meeting green chemistry requirements.

[0004] The synthetic route disclosed in CN119661438A is as follows, trioxymethylene and 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole are mixed to form solution A, and solution A is mixed with chlorosulfonic acid and then chloromethylated to obtain 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole. This reaction route uses chlorosulfonic acid as a reaction reagent, and chlorosulfonic acid is used to enrich sulfuric acid, which does not meet green chemistry requirements and is also unfavorable for industrial applications. Further, the applicant tested according to the conditions in the embodiment of CN119661438A and found that its reaction yield and product content were not high.

[0005] From the above content, it can be seen that in the existing technology, for the synthesis of 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole, some reactions require the addition of additional catalysts; some reactions require the enrichment of sulfuric acid, which not only brings operational risks but is also environmentally unfriendly. Summary of the Invention

[0006] Problems to be solved by the invention

[0007] In order to solve the existing problems, the present invention intends to provide a method for preparing the sulfonepyrazoline intermediate 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole with low toxicity, high efficiency, simple process, mild conditions and convenient operation, and the method does not require the addition of an additional catalyst.

[0008] Solutions for solving problems

[0009] The present invention provides a method for preparing a compound of formula II, comprising the following steps:

[0010]

[0011] Under solvent conditions, the compound of formula I is used as a raw material to react with triformaldehyde and HCl to obtain a reaction solution containing the compound of formula II.

[0012] The aforementioned HCl is hydrogen chloride gas.

[0013] The aforementioned reaction is carried out in a batch reactor or a continuous reactor. In some specific embodiments, a batch process or a continuous process can be used. For example, process (a): a solvent, a compound of formula I, and trioxymethylene are mixed to form solution A, and hydrogen chloride gas is then introduced into solution A for reaction. The process is carried out in a batch reactor. Process (b): a solvent, a compound of formula I, and trioxymethylene are mixed to form solution B. Solution B and hydrogen chloride gas are pumped into a continuous reactor at a controlled flow rate by a metering pump for reaction. The continuous reactor can be a tubular reactor or a microchannel continuous reactor.

[0014] The molar ratio of the trioxymethylene to the compound of formula I is not less than 0.3:1.0, preferably 0.3:1.0 to 5.0:1.0, more preferably 0.3:1.0 to 1.0:1.0, and most preferably 0.5:1.0. In some specific embodiments, the molar ratio of the trioxymethylene to the compound of formula I is 0.3:1.0, 0.35:1.0, 0.4:1.0, 0.45:1.0, 0.5:1.0, 0.55:1.0, 0.6:1.0, 0.7:1.0, 0.8:1.0, 0.9:1.0, 1.0:1.0, 1.5:1.0, 2.0:1.0, 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0, 4.5:1.0, or 5.0:1.0.

[0015] The aforementioned solvent is one or more of 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole, water, dichloromethane, dichloroethane, toluene, carbon tetrachloride, acetic acid, trifluorotoluene, chloroform, trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid and hexane, preferably water or dichloroethane.

[0016] The mass ratio of the aforementioned solvent to the compound of formula I is not less than 1.0:1.0, preferably 1.0:1.0 to 5.0:1.0, more preferably 1.0:1.0 to 3.0:1.0. In some specific embodiments, the mass ratio of the aforementioned solvent to the compound of formula I is 1.0:1.0, 1.5:1.0, 2.0:1.0, 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0, 4.5:1.0 or 5.0:1.0.

[0017] The molar ratio of the aforementioned HCl to the compound of formula I is not less than 1.0:1.0, preferably 1.0:1.0 to 15.0:1.0, more preferably 2:1.0 to 10:1.0, and most preferably 3.5:1.0 to 7.0:1.0. In some specific embodiments, the molar ratio of HCl to the compound of formula I is 1.0:1.0, 1.5:1.0, 2.0:1.0, 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0, 4.5:1.0, 5.0:1.0, 5.5:1.0, 6.0:1.0, 6.5:1.0, 7.0:1.0, 7.5:1.0, 8.0:1.0, 8.5:1.0, 9.0:1.0, 9.5:1.0, 10.0:1.0, 11.0:1.0, 12.0:1.0, 13.0:1.0, 14.0:1.0, and 15.0:1.0.

[0018] The reaction temperature of the aforementioned reaction is 0° C. to 150° C., preferably 50° C. to 100° C., more preferably 70° C. to 80° C. In some specific embodiments, the reaction temperature of the reaction is 10° C., 20° C., 30° C., 40° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95° C. or 100° C.

[0019] The aforementioned preparation method further comprises the following post-processing steps:

[0020] The reaction solution containing the compound of formula II is separated or distilled to remove the solvent to obtain the compound of formula II.

[0021] The solvent obtained in the above post-treatment step is used for the next batch reaction.

[0022] Effects of the Invention

[0023] The present invention uses 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole, trioxane, and hydrogen chloride as raw materials for a reaction to obtain the sulfonepyrazoline intermediate 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole. The reaction reagents and raw materials of the method are readily available, no additional catalyst is added, the route selectivity is good, side reactions are few, the product yield is high, the reaction conditions are mild and easy to control, the process operation is simple and easy to industrialize, no harmful waste gas is generated, and the solvent obtained by post-reaction treatment can be directly reused. The entire reaction process is low-toxic, efficient, simple, and environmentally friendly, and is easy to industrialize. DETAILED DESCRIPTION

[0024] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior or preferred over other embodiments.

[0025] In addition, numerous specific details are provided in the following detailed description to better illustrate the present invention. Those skilled in the art will appreciate that the present invention can be practiced without certain specific details. In other instances, methods, means, equipment, and steps well known to those skilled in the art are not described in detail in order to highlight the main points of the present invention.

[0026] Unless otherwise stated, the units used in this specification are international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0027] In this specification, the use of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0028] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "embodiments," etc., mean that the specific elements (e.g., features, structures, properties, and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0029] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints A and B.

[0030] Example

[0031] The embodiments of the present invention will be described in detail below with reference to the examples. However, those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. In the examples, where specific conditions are not specified, the conditions were carried out according to conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used, where the manufacturer is not specified, are conventional products that can be obtained commercially. The structures of the compounds were determined by nuclear magnetic resonance (NMR) 1 The purity of the compounds was determined by high performance liquid chromatography (HPLC).

[0032] Example 1

[0033]

[0034] 1-Methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole (71.3 g, 0.33 mol, 1 eq), dichloroethane (213.9 g), and triformaldehyde (14.9 g, 0.165 mol, 0.5 eq) were added sequentially to a 500 mL four-necked flask. The system was temperature-controlled at 70-80°C, and HCl gas (84.3 g, 2.31 mol, 7 eq) was slowly introduced into the system. After the HCl gas was introduced, the system was stirred and reacted at 70-80°C for 10 h. After sampling and HPLC control to detect the complete reaction of the raw materials, the system was directly distilled. The distillation residue was the product 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole (83.4 g), with a yield of 95.7% and a product content of 98.4%.

[0035] The distilled fraction is ethylene dichloride, which can be directly applied to the next batch of reactions.

[0036] Example 2

[0037]

[0038] 1-Methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole (71.3 g, 0.33 mol, 1 eq), dichloroethane (213.9 g), water (22 g), and triformaldehyde (14.9 g, 0.165 mol, 0.5 eq) were added sequentially to a 500 mL four-necked flask. The system was temperature-controlled at 70-80°C, and HCl gas (42.1 g, 1.16 mol, 3.5 eq) was slowly introduced into the system. After the HCl gas was introduced, the system was stirred and reacted at 70-80°C for 6 h. After sampling and HPLC control to determine if the reaction of the raw materials was complete, the system was directly distilled. The distillation residue was 84.8 g of the product, 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole, with a yield of 97.2% and a product content of 98.6%.

[0039] The distillation fraction is a mixture of ethylene dichloride and water, which can be directly applied to the next batch of reactions.

[0040] Example 3

[0041]

[0042] 1-Methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole was mixed with ethylene dichloride and trioxymethylene in a mass ratio of 71.3:213.9:14.9 and stirred uniformly, marking this solution as mixed solution A. The flow rate of the feed metering pump for mixed solution A was set to 37.5 g / min, and the flow rate of the hydrogen chloride gas metering pump was set to 2.26 g / min. Mixed solution A and hydrogen chloride gas were simultaneously introduced into a continuous reaction vessel via metering pumps for reaction. The pressure of the reaction system was controlled at 0.2 MPa, the temperature of the reaction system was controlled at 70-80°C, and the residence time of the reaction system was 1 hour. The reaction solution was continuously transferred to a receiving flask. This reaction solution was directly distilled, and the distillation residue was the product, 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole, with a yield of 98.4% and a product content of 99.2%.

[0043] The distilled fraction is ethylene dichloride, which can be directly applied to the next batch of reactions.

[0044] Example 4

[0045]

[0046] 1-Methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole, ethylene dichloride, trioxymethylene, and water were mixed and stirred uniformly in a mass ratio of 71.3:213.9:14.9:22, labeled as mixed solution A. The feed metering pump for mixed solution A was set to a flow rate of 64 g / min, and the gas metering pump for hydrogen chloride gas was set to a flow rate of 3.59 g / min. Mixed solution A and hydrogen chloride gas were simultaneously introduced into a continuous reaction vessel via metering pumps for reaction. The pressure of the reaction system was controlled at 0.15 MPa, the temperature of the reaction system was controlled at 70-80°C, and the residence time of the reaction system was 25 minutes. The reaction solution was continuously transferred to a receiving flask. This reaction solution was directly distilled, and the distillation residue was the product, 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole, with a yield of 98.7% and a product content of 99.2%.

[0047] The distillation fraction is a mixture of ethylene dichloride and water, which can be directly applied to the next batch of reactions.

[0048] Example 5

[0049]

[0050] 1-Methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole, trioxymethylenediamine, and water were mixed and stirred uniformly in a mass ratio of 71.3:14.9:71.3, labeled as mixed solution A. The feed metering pump for mixed solution A was set to a flow rate of 50 g / min, and the gas metering pump for hydrogen chloride gas was set to a flow rate of 5.74 g / min. Mixed solution A and hydrogen chloride gas were simultaneously introduced into a continuous reaction vessel via metering pumps for reaction. The pressure of the reaction system was controlled at 0.25 MPa, the temperature of the reaction system was controlled at 70-80°C, and the residence time of the reaction system was 10 minutes. The reaction solution was continuously transferred to a receiving flask. This reaction solution was directly phase-separated, and the lower organic phase was the product, 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole, with a yield of 97.6% and a product content of 98.2%.

[0051] The upper aqueous phase is water and can be directly applied to the next batch of reactions.

[0052] It should be noted that, although the technical solutions of the present invention are described with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0053] While various embodiments of the present invention have been described above, the above descriptions are intended to be illustrative, non-exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is selected to best explain the principles of the embodiments, their practical applications, or technological improvements in the marketplace, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A method for preparing a compound of formula II, comprising the following steps: Under solvent conditions, the compound of formula I is used as a raw material to react with triformaldehyde and HCl to obtain a reaction solution containing the compound of formula II.

2. The preparation method according to claim 1, characterized in that The HCl is hydrogen chloride gas.

3. The preparation method according to claim 1 or 2, characterized in that The reaction is carried out in a batch reactor or a continuous reactor.

4. The preparation method according to claims 1 to 3, characterized in that The molar ratio of the trioxymethylene to the compound of formula I is not less than 0.3:1.0, preferably 0.3:1.0 to 5.0:1.0, more preferably 0.3:1.0 to 1.0:1.0, and most preferably 0.5:1.

0.

5. The preparation method according to any one of claims 1 to 4, characterized in that The solvent is one or more of 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole, water, dichloromethane, dichloroethane, toluene, carbon tetrachloride, acetic acid, trifluorotoluene, chloroform, trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid and hexane, preferably water or dichloroethane.

6. The preparation method according to any one of claims 1 to 5, characterized in that The mass ratio of the solvent to the compound of formula I is not less than 1.0:1.0, preferably 1.0:1.0 to 5.0:1.0, more preferably 1.0:1.0 to 3.0:1.

0.

7. The preparation method according to any one of claims 1 to 6, characterized in that The molar ratio of the HCl to the compound of formula I is not less than 1.0:1.0, preferably 1.0:1.0 to 15.0:1.0, more preferably 2:1.0 to 10:1.0, and most preferably 3.5:1.0 to 7.0:1.

0.

8. The preparation method according to any one of claims 1 to 7, characterized in that The reaction temperature of the reaction is 0°C to 150°C, preferably 50°C to 100°C, more preferably 70°C to 80°C.

9. The preparation method according to any one of claims 1 to 8, characterized in that The preparation method further comprises the following post-processing steps: The reaction solution containing the compound of formula II is separated or distilled to remove the solvent to obtain the compound of formula II.

10. The preparation method according to claim 9, characterized in that The solvent obtained in the post-treatment step is used for the next batch reaction.

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