Method for preparing 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1h-pyrazole

Abstract

The present invention belongs to the field of chemical synthesis, and relates to a method for preparing 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole. Specifically, disclosed is a method for preparing a compound of formula II, comprising the following steps: using a compound of formula I as a raw material to react with reagent A and reagent B, to obtain a reaction solution containing the compound of formula II, the reagent A being an aldehyde reagent and the reagent B being an acyl chloride reagent. The method uses reaction reagents that are inexpensive and readily available, does not require addition of an additional catalyst, has good route selectivity with few side reactions, high product yield, mild and easily controllable reaction conditions, has simple process operation suitable for industrialization, does not generate harmful exhaust gases, and is a low-toxicity, efficient, simple and green synthesis route.

Description

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

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

[0002] 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole is an important intermediate for synthesizing a new herbicide pyroxasulfone. The preparation of this intermediate can be synthesized by various routes, which are reported in patent applications such as CN117777122A and CN118221663A.

[0003] CN117777122A discloses the following synthesis route: in the presence of sulfuric acid, trioxane and thionyl chloride, 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole (intermediate I) undergoes chloromethylation to form 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole (intermediate II). This reaction requires the additional addition of a catalyst, sulfuric acid, which is not high in atomic economic efficiency and does not meet the requirements of green chemistry. Moreover, the inventors of the present application have repeated the synthesis process of intermediate II in Example 1, and the mother liquor obtained was analyzed and detected, but no intermediate II was detected.

[0004] CN118221663A discloses the following synthesis route: 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole, formaldehyde solution and / or polyformaldehyde, concentrated hydrochloric acid and a third catalyst (including any one or more of sulfuric acid, acetic acid, ferric chloride, magnesium chloride, aluminum chloride and zinc chloride) are continuously fed into a reactor to undergo continuous chloromethylation to obtain 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole. This reaction route uses concentrated hydrochloric acid as a reaction reagent, which not only has a high amount, but also requires the additional addition of a catalyst during the reaction process. After the reaction, there is a large amount of waste water, which is not conducive to process scaling and does not meet the requirements of green chemistry.

[0005] From the above, it can be seen that: in the prior art, for the synthesis of 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole, some reactions require additional addition of catalyst; some reactions require the use of a large amount of corrosive, environmentally unfriendly raw materials or reagents, and sulfuric acid enrichment not only brings operation risk, but also produces a large amount of three wastes, which is not environmentally friendly. SUMMARY

[0006] Problems to be solved by the invention

[0007] In order to solve the existing problems, the present application aims to provide a preparation method of the sulfenazole intermediate 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole, which is low-toxic, high-efficiency, simple process, mild condition and easy operation, and the method does not require additional addition of catalyst.

[0008] Solution for solving the problem

[0009] [1] A preparation method of a compound of formula II, comprising the following steps:

[0010] The compound of formula I is used as a raw material, and is reacted with reagent A and reagent B to obtain a reaction liquid containing the compound of formula II.

[0011] Among them, the reagent A is one or more of formaldehyde and its polymers;

[0012] The reagent B is one or more of sulfenyl chloride, chlorosulfonic acid, p-benzenedisulfonyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or hydrogen chloride.

[0013] [2] The preparation method according to [1], characterized in that,

[0014] The reagent B is sulfenyl chloride, chlorosulfonic acid, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride or hydrogen chloride.

[0015] [3] The preparation method according to [1] or [2], characterized in that,

[0016] The molar ratio of the compound of formula I to the formaldehyde or the formaldehyde monomer in the polymer is 1.0:1.0 to 1.0:3.0, preferably 1.0:1.5 to 1.0:2.5.

[0017] [4] The preparation method according to any one of [1] to [3], characterized in that,

[0018] The reaction is carried out in the presence of a solvent or water.

[0019] [5] A preparation method of a compound of formula II, comprising the following steps:

[0020] reacting a compound of formula I with reagent A and reagent B in the presence of water to obtain a reaction solution comprising a compound of formula II;

[0021] wherein the reagent A is one or more of formaldehyde and polymers thereof;

[0022] the reagent B is one or more of sulfuryl dichloride, chlorosulfonic acid, p- benzenedisulfonyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or hydrogen chloride.

[0023] [6] The preparation method according to [5], characterized in that,

[0024] the molar ratio of the water to the compound of formula I is not less than 1.0:1.0, preferably 3.0:1.0 to 5.0:1.0.

[0025] [7] The preparation method according to any one of [1] to [6], characterized in that,

[0026] when the reagent B is sulfuryl dichloride, the molar ratio of the compound of formula I to the sulfuryl dichloride is 1.0:1.0 to 1.0:3.5, preferably 1.0:1.2 to 1.0:2.0;

[0027] when the reagent B is hydrogen chloride, the molar ratio of the compound of formula I to the hydrogen chloride is 1.0:1.0 to 1.0:3.0, preferably 1.0:1.5 to 1.0:2.0.

[0028] [8] The preparation method according to any one of [1] to [7], characterized in that,

[0029] when the reagent B is chlorosulfonic acid, phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride, the molar ratio of the compound of formula I to the reagent B is 1.0:1.0 to 1.0:3.0, preferably 1.0:1.1 to 1.0:1.5.

[0030] [9] The preparation method according to any one of [1] to [8], characterized in that,

[0031] the reaction is carried out in a solvent, which is one or more of protic solvents and aprotic solvents;

[0032] preferably, the solvent is one or more of halogenated alkanes, ethers, aromatic hydrocarbons, nitriles and water;

[0033] more preferably, the solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, toluene, water and acetonitrile;

[0034] Further preferably, the solvent is acetonitrile, tetrahydrofuran or water.

[0035]

[0010] The preparation method according to any one of [1] to [9], characterized in that,

[0036] The feeding temperature of the reaction is 0-60°C, preferably 5-40°C, more preferably 10-20°C.

[0037]

[0011] The preparation method according to any one of [1] to

[0010] , characterized in that,

[0038] The reaction temperature of the reaction is 60-80°C, preferably 60-70°C or 70-80°C.

[0039]

[0012] The preparation method according to any one of [1] to

[0011] , characterized in that,

[0040] The preparation method further comprises the following steps:

[0041] The reaction solution comprising the compound of formula II is optionally separated, and the solvent is distilled off to obtain the compound of formula II.

[0042]

[0013] A preparation method of a compound of formula II, comprising the following steps:

[0043] The compound of formula I is used as raw material to react with paraformaldehyde and HCl under solvent or solvent-free conditions to obtain a reaction solution comprising the compound of formula II.

[0044]

[0014] The preparation method according to

[0013] , characterized in that the HCl is hydrogen chloride gas.

[0045]

[0015] The preparation method according to

[0013] or

[0014] , characterized in that the method is carried out without adding a Lewis acid catalyst, preferably without additional catalyst.

[0046]

[0016] The preparation method according to any one of

[0013] to

[0015] , characterized in that the molar ratio of the paraformaldehyde 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 1.1:1.0 to 2.0:1.0, and most preferably 1.5:1.0.

[0047]

[0017] The preparation method according to any one of

[0013] to

[0016] , wherein the molar ratio of the paraformaldehyde to the compound of Formula I is 1.0:1.0, 1.1:1.0, 1.2:1.0, 1.3:1.0, 1.4:1.0, 1.5:1.0, 1.6:1.0, 1.7:1.0, 1.8:1.0, 1.9:1.0, 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.

[0048]

[0018] The preparation method according to any one of

[0013] to

[0017] , wherein the solvent under the solvent condition is selected from a solvent that is inert to the hydrogen chloride and has a certain solubility.

[0049]

[0019] The preparation method according to any one of

[0013] to

[0018] , wherein 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.

[0050]

[0020] The preparation method according to any one of

[0013] to

[0019] , wherein the mass ratio of the solvent to the compound of Formula I under the solvent condition 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.

[0051]

[0021] The preparation method according to any one of

[0013] to

[0020] , wherein the mass ratio of the 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.

[0052]

[0022] The preparation method according to any one of

[0013] to

[0021] , wherein the molar ratio of the hydrogen chloride 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 1.1:1.0 to 12.0:1.0, most preferably 1.5:1.0 to 7.0:1.0.

[0053]

[0023] The preparation method according to any one of

[0013] to

[0022] , characterized in that the molar ratio of the HCI 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, 11.5:1.0, 12.0:1.0.

[0054]

[0024] The preparation method according to any one of

[0013] to

[0023] , characterized in that the feeding temperature of the reaction is 0-60°C, preferably 5-40°C, more preferably 10-20°C.

[0055]

[0025] The preparation method according to any one of

[0013] to

[0024] , characterized in that the feeding temperature of the reaction is 10°C, 20°C, 30°C, 40°C, 50°C or 60°C.

[0056]

[0026] The preparation method according to any one of

[0013] to

[0025] , characterized in that the reaction temperature of the reaction is 0-150°C, preferably 50-100°C, more preferably 60-80°C.

[0057]

[0027] The preparation method according to any one of

[0013] to

[0026] , characterized in that 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.

[0058]

[0028] The preparation method according to any one of

[0013] to

[0027] , characterized in that the preparation method further comprises the following post-treatment step: separating or distilling off the solvent from the reaction solution containing the compound of formula II to obtain the compound of formula II.

[0059]

[0029] The preparation method according to any one of

[0013] to

[0028] , characterized in that the solvent obtained in the post-treatment step is used for the next batch reaction.

[0060]

[0030] A preparation method of a compound of formula II, comprising the following steps:

[0061] In a solvent condition, a compound of formula I is used as a raw material to react with trioxane and HCl to obtain a reaction solution containing a compound of formula II.

[0062]

[0031] The preparation method according to

[0030] , characterized in that the HCl is hydrogen chloride gas.

[0063]

[0032] The preparation method according to

[0030] or

[0031] , characterized in that the aforementioned reaction is carried out in a batch reactor or a continuous reactor.

[0064]

[0033] The preparation method according to any one of

[0030] to

[0032] , characterized in that it can be carried out in a batch mode or a continuous mode.

[0065]

[0034] The preparation method according to

[0033] , characterized in that mode (a): the solvent, the compound of formula I and trioxane are mixed to prepare solution A, and then hydrogen chloride gas is introduced into solution A to react, and the process is carried out in a batch kettle.

[0066]

[0035] The preparation method according to

[0033] , characterized in that mode (b): the solvent, the compound of formula I and trioxane are mixed to prepare solution B, and then solution B and hydrogen chloride gas are pumped into a continuous reactor through a metering pump to control the flow rate to react, and the continuous reactor can be a tubular reactor or a micro-channel continuous reactor.

[0067]

[0036] The preparation method according to any one of

[0030] to

[0035] , characterized in that the molar ratio of the aforementioned trioxane 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.

[0068]

[0037] The preparation method according to any one of

[0030] to

[0036] , characterized in that the molar ratio of the trioxane 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.

[0069]

[0038] The production method according to any one of

[0030] to

[0037] , wherein 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.

[0070]

[0039] The production method according to any one of

[0030] to

[0038] , wherein 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.

[0071]

[0040] The production method according to any one of

[0030] to

[0039] , wherein the mass ratio of the 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.

[0072]

[0041] The production method according to any one of

[0030] to

[0040] , wherein the molar ratio of the aforementioned HC1 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, most preferably 3.5:1.0 to 7.0:1.0.

[0073]

[0042] The production method according to any one of

[0030] to

[0041] , wherein the molar ratio of the HC1 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.

[0074]

[0043] The production method according to any one of

[0030] to

[0042] , wherein 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.

[0075]

[0044] The preparation method according to any one of

[0030] to

[0043] , characterized in that 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.

[0076]

[0045] The preparation method according to any one of

[0030] to

[0044] , characterized in that the aforementioned preparation method further comprises the following post-processing step:

[0077] The reaction solution containing the compound of formula II is separated or distilled to remove the solvent to obtain the compound of formula II.

[0078]

[0046] The preparation method according to any one of

[0030] to

[0045] , characterized in that the solvent obtained in the aforementioned post-processing step is used for the next batch of reaction.

[0079] Effects of the invention

[0080] In the present specification, the term "formaldehyde and its polymers" includes formaldehyde, formaldehyde aqueous solution, trioxane and polyoxymethylene. It is known to those skilled in the art that formaldehyde is a gas with irritating odor at normal temperature and pressure, and the common commercially available forms of formaldehyde raw materials include formaldehyde aqueous solution, and solid forms of trioxane and polyoxymethylene.

[0081] According to embodiments [1] to

[0046] , the present application uses 1-methyl-3- (trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole as the raw material to react with the innovative chloromethylation reagent to obtain the sulfonyl pyrazole intermediate 1-methyl-3- (trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole. The raw material of the reaction reagent is cheap and easy to obtain, no additional catalyst is added, the route selection is good, the side reaction is less, the product yield is high, the reaction condition is mild and easy to control, the process operation is simple and easy to industrialization, and no harmful waste gas is produced. It is a low-toxicity, high-efficiency, simple and green synthesis route.

[0082] According to the embodiments

[0013] to

[0029] , the present application reacts 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole, paraformaldehyde and hydrogen chloride (optionally) and aqueous solution thereof to obtain the intermediate 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole of the sulfenyl pyroxasulfon. The raw materials of the reaction reagent are easy to obtain, no additional catalyst is added, the route has good selectivity, less side reactions, high product yield, mild reaction conditions, simple process operation, no harmful waste gas is produced, the water phase of the reaction can be directly reused or reused after continuing to pass in HCl gas, after the water phase cannot continue to be reused for the next batch, the water phase can be distilled and recovered for reuse in the next batch reaction, and almost no waste water is produced in the whole reaction process, which is a low-toxicity, high-efficiency, simple and green synthesis route.

[0083] According to the embodiments

[0030] to

[0046] , the present application reacts 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole, paraformaldehyde and hydrogen chloride to obtain the intermediate 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole of the sulfenyl pyroxasulfon. The raw materials of the reaction reagent are easy to obtain, no additional catalyst is added, the route has good selectivity, less side reactions, high product yield, mild reaction conditions, simple process operation, no harmful waste gas is produced, the water phase of the reaction can be directly reused, the whole reaction process is low-toxicity, high-efficiency, simple and green, and easy to be applied in industrialization. DETAILED DESCRIPTION

[0084] Various exemplary embodiments, features, and aspects of the present application will be described in detail below. The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0085] In addition, in order to better illustrate the present application, numerous specific details are given in the following detailed description. Those skilled in the art will understand that the present application can also be implemented without certain specific details. In some examples, methods, means, apparatus and steps that are well known to those skilled in the art are not described in detail in order to highlight the main idea of the present application.

[0086] Unless otherwise specified, the units used in the specification are international standard units, and the numerical values and numerical ranges appearing in the present application should be understood to include the systematic errors that are inevitable in industrial production.

[0087] In the specification, the meaning of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0088] In this specification, "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", and the like mean that a particular feature (e.g., characteristic, structure, property, and / or characteristic) described is included in at least one embodiment described herein, and can or can not be present in other embodiments. In addition, it is to be understood that the described features can be combined in various ways without departing from the scope of the present application.

[0089] In this specification, a numerical range expressed using "numerical value A ~ numerical value B" means a range including the end point numerical values A, B.

[0090] Examples

[0091] The embodiments of the present application will be described in detail below with reference to Examples, but those skilled in the art will appreciate that the following Examples are for illustrative purposes only and should not be construed as limiting the scope of the present application. When specific conditions are not mentioned in the Examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. When the manufacturers of reagents or instruments are not mentioned, they are all conventional products that can be obtained commercially. The structures of the compounds are determined by nuclear magnetic resonance (H NMR) or mass spectrometry (MS). The purity of the compounds is determined by high performance liquid chromatography (HPLC). 1 H NMR) or mass spectrometry (MS). The purity of the compounds is determined by high performance liquid chromatography (HPLC).

[0092] Example 1

[0093] In a 500 mL four-necked flask, 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole (71.3 g, 0.33 mol, 1 eq) and acetonitrile (213 g, 5.18 mol) were sequentially added. 37% aqueous formaldehyde solution (40.1 g, 0.495 mol, 1.5 eq) was added to the system under the condition of 10-20°C and stirred. The system was controlled at 10-20°C, and sulfuryl dichloride (53.4 g, 0.396 mol, 1.2 eq) was added dropwise. After the addition of sulfuryl dichloride was completed, the system was incubated at 10-20°C and stirred for 30 min. Then the system was warmed to 60-70°C and stirred for 4-6 h. After the completion of the reaction was detected by sampling HPLC, the system was directly separated, and the upper organic phase was collected. The organic phase was concentrated under reduced pressure to obtain the product 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole 83.4 g, yield 95.3%, product content 96.1%.

[0094] Examples 2-15 were investigated for the reaction solvent, the amount of 37 wt% aqueous formaldehyde solution, the amount of sulfuryl dichloride (or alternative chlorinating reagent B), and the reaction temperature, respectively, and the synthesis step was referred to Example 1.

[0095] Example 16

[0096] Into a 500 mL four-necked flask, 1 -methyl-3-(trifluoromethyl)-5-(difluoromethoxy)- 1 H-pyrazole (100 g, 0.46 mol, 1 eq) and acetonitrile (300 g) were added. The system was stirred at 10-20 °C, and 37% formaldehyde aqueous solution (55.9 g, 0.69 mol, 1.5 eq) was added dropwise. The system was controlled at 10-20 °C, and chlorosulfonic acid (58.9 g, 0.51 mol, 1.1 eq) was added dropwise. After the addition of chlorosulfonic acid was completed, the system was incubated at 10-20 °C and stirred for 30 min. Then the system was warmed to 60-70 °C and stirred for 4-6 h. After the sample was detected by HPLC to confirm that the raw material was completely reacted, the system was directly separated into two phases, and the upper organic phase was collected. The product, 1 -methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)- 1 H-pyrazole, was concentrated under reduced pressure to obtain 116.9 g, with a yield of 96.1% and a product content of 97.2%.

[0097] Example 17 is investigated by replacing chlorosulfonic acid with phosphorus oxychloride in the synthesis steps in Example 16.

[0098] Example 18 is investigated by replacing chlorosulfonic acid with phosphorus trichloride in the synthesis steps in Example 16.

[0099] Example 19 is investigated by replacing acetonitrile with water in the synthesis steps in Example 16.

[0100] Example 20 is investigated by replacing acetonitrile with water and replacing chlorosulfonic acid with phosphorus oxychloride in the synthesis steps in Example 16.

[0101] Example 21 is investigated by replacing acetonitrile with water and replacing chlorosulfonic acid with phosphorus trichloride in the synthesis steps in Example 16.

[0102] Example 22 is investigated by removing acetonitrile and replacing chlorosulfonic acid with hydrogen chloride in the synthesis steps in Example 16, wherein the hydrogen chloride is directly introduced into the reaction system in the form of hydrogen chloride gas.

[0103] Example 23 is investigated by replacing acetonitrile with water and replacing chlorosulfonic acid with phosphorus pentachloride in the synthesis steps in Example 16, wherein the phosphorus pentachloride is a solid and is added in batches during the addition.

[0104] In addition, the inventors found in early experiments that when the feeding temperature is 10-20 °C, the yield is about 95%, and as the feeding temperature increases, the yield gradually decreases. For example, when the feeding temperature is increased to 30 °C, the yield is about 90%; when the feeding temperature is increased to 40 °C, the yield is about 80%; and when the feeding temperature is increased to 50 °C, the yield is about 70%.

[0105] The reaction raw materials, reaction conditions, contents and yields in Examples 1-23 above are summarized in Table 1.

[0106] Table 1

[0107] As can be seen from Table 1, when the reaction solvent is acetonitrile, water or tetrahydrofuran, the product yield and purity are relatively high; when the 37 wt% formaldehyde aqueous solution is 1.5-2.5 eq., the product yield and purity are excellent; when the reagent B is sulfuryl dichloride, chlorosulfonic acid, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride or hydrogen chloride, the product yield and purity are relatively excellent; when the reagent B is sulfuryl dichloride, the product yield and purity are excellent when it is 1.2-2.0 eq.; when the reagent B is chlorosulfonic acid, phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride, the product yield and purity are excellent when it is 1.1-1.5 eq.; when the reagent B is hydrogen chloride, the product yield and purity are excellent when it is 1.5-2.0 eq.; for the reaction temperature, the product yield and purity are excellent when it is 60-80 °C, preferably 60-70 °C or 70-80 °C.

[0108] Example 24

[0109] In a 500 mL four-necked flask, 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H-pyrazole (71.3 g, 0.33 mol, 1 eq) and water (214 g) were sequentially added. Under the condition of 10-20 °C, polyformaldehyde (14.9 g, 0.495 mol, 1.5 eq) was added to the system and stirred. The system was controlled at 10-20 °C, and HCl gas (144.5 g, 3.96 mol, 12 eq) was introduced into the system. After the introduction of HCl gas was completed, the system was sealed and heated to 70-80 °C and stirred for 4 h. After the complete reaction of the raw material was detected by HPLC, the system was directly separated, and the lower organic phase was collected, which was the product 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole 84.7 g, with a yield of 97.1% and a product content of 98.7%.

[0110] The aqueous phase was directly used in the next batch of reaction, and the specific conditions and results are shown in the following table:

[0111] Example 25

[0112] Into a 500 mL four-necked flask, 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H- pyrazole (71.3 g, 0.33 mol, 1 eq), water 214 g were added in sequence. The system was stirred at 10-20 °C after the addition of paraformaldehyde (14.9 g, 0.495 mol, 1.5 eq). The system was controlled at 10-20 °C, and HCl gas (84.3 g, 2.31 mol, 7 eq) was introduced into the system. After the introduction of HCl gas was completed, the system was sealed and heated to 70-80 °C for stirring for 5 h. After the complete reaction of the raw material was detected by HPLC, the system was directly separated into two phases, and the lower organic phase was collected. The organic phase was the product 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole 85.9 g, with a yield of 98.4% and a product content of 99.2%.

[0113] The aqueous phase was introduced into the next batch of reaction after the introduction of HCl gas (12.0 g, 1 eq). The specific conditions and results are listed in the following table:

[0114] Example 26

[0115] Into a four-necked flask, 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole (71.3 g, 0.33 mol, 1 eq), water 142.6 g and dichloroethane 71.3 g were added in sequence. The system was stirred at 10-20 °C after the addition of paraformaldehyde (14.9 g, 0.495 mol, 1.5 eq). The system was controlled at 10-20 °C, and HCl gas (18 g, 0.495 mol, 1.5 eq) was introduced into the system. After the introduction of HCl gas was completed, the system was heated to 70-80 °C for stirring for 6 h under normal pressure. After the complete reaction of the raw material was detected by HPLC, the system was directly separated into two phases, and the lower organic phase was collected. The dichloroethane was recovered by distillation of the organic phase, and the distillation residue was the product 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole 84.9 g, with a yield of 97.2% and a product content of 99.5%.

[0116] The aqueous phase was introduced into the next batch of reaction after the introduction of HCl gas (12.0 g, 1 eq). The recovered dichloroethane was directly used in the next batch of reaction.

[0117] According to the foregoing method, the type of solvent was changed, and dichloroethane was continuously used, or toluene or chlorobenzene was used to replace dichloroethane. The specific results are listed in the following table:

[0118] Example 27

[0119] In a four-necked flask, 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole (71.3 g, 0.33 mol, 1 eq), 30 wt% hydrochloric acid (120.4 g, 0.99 mol, 3 eq) were added in sequence. To the system, paraformaldehyde (14.9 g, 0.495 mol, 1.5 eq) was added at room temperature with stirring. The system was heated to 70-80 °C and stirred for 12 h. After the reaction was completed, the system was directly separated into two phases, and the lower organic phase was collected. The organic phase was the product 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole 84.1 g, yield 96.3%, product content 98.2%.

[0120] The water phase was purged with HCl gas (12.0 g, 1 eq) and used in the next batch of reaction.

[0121] Example 28

[0122] In a high-pressure autoclave Hastelloy reactor, 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole (71.3 g, 0.33 mol, 1 eq), dichloroethane 71.3 g, and paraformaldehyde (14.9 g, 0.495 mol, 1.5 eq) were added in sequence with stirring. The system was heated to 70-80 °C, and HCl gas (36.1 g, 0.99 mol) was purged into the reactor with stirring. After the HCl gas was purged, the system was heated to 70-80 °C and stirred for 2 h. After the reaction was completed (the HCl gas released was recovered and used in the next batch of reaction), the reaction solution was distilled to recover the dichloroethane. The distillation residue was the product 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole 84.2 g, yield 96.5%, product content 97.4%. The recovered dichloroethane was directly used in the next batch of reaction.

[0123] Example 29 sealed system

[0124] In a four-necked flask, 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole (71.3 g, 0.33 mol, 1 eq), water 71.3 g were added in sequence. Under the condition of 10-20 °C, polyformaldehyde (14.9 g, 0.495 mol, 1.5 eq) was added into the system with stirring. The system was controlled at 10-20 °C, and HCl gas (18 g, 0.495 mol, 1.5 eq) was introduced into the system. After the introduction of HCl gas was completed, the system was sealed and heated to 70-80 °C for stirring for 6 h. The system was sealed by using a sealed tube or a high-pressure reactor. After the complete reaction of the raw material was detected by HPLC control, the system was directly separated into two phases, and the lower organic phase was collected. The organic phase was the product 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole 85.4 g, with a yield of 97.9% and a product content of 98.9%.

[0125] After the water phase was introduced into HCl gas (12.0 g, 1 eq), it was used for the next batch reaction.

[0126] The reaction conditions were changed, and the specific results are shown in the following table:

[0127] Example 30 atmospheric pressure system

[0128] In a four-necked flask equipped with a condenser, 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole (71.3 g, 0.33 mol, 1 eq), water 71.3 g were added in sequence. Under the condition of 10-20 °C, polyformaldehyde (14.9 g, 0.495 mol, 1.5 eq) was added into the system with stirring. The system was controlled at 10-20 °C, and HCl gas (18 g, 0.495 mol, 1.5 eq) was introduced into the system. After the introduction of HCl gas was completed, the system was heated to 70-80 °C for stirring, and the reaction was carried out for 8 h. After the complete reaction of the raw material was detected by HPLC control, the system was directly separated into two phases, and the lower organic phase was collected. The organic phase was the product 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole 84.6 g, with a yield of 96.9% and a product content of 98.1%.

[0129] After the water phase was introduced into HCl gas (12.0 g, 1 eq), it was used for the next batch reaction.

[0130] Example 31 solvent-free system

[0131] In a 500 mL four-necked flask, 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H- pyrazole (71.3 g, 0.33 mol, 1 eq), dichloroethane (213.9 g), water (22 g) and trioxane (14.9 g, 0.165 mol, 0.5 eq) were added in sequence. The system was 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 introduction of HCl gas was completed, the system was kept at 70-80 °C and stirred for 6 h. After the sample was detected by HPLC, the system was directly distilled, and the distillation residue was the product 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole 84.8 g, with a yield of 97.2% and a product content of 98.6%.

[0132] Example 32

[0133] In a 500 mL four-necked flask, 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H- pyrazole (71.3 g, 0.33 mol, 1 eq), dichloroethane (213.9 g), water (22 g) and trioxane (14.9 g, 0.165 mol, 0.5 eq) were added in sequence. The system was 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 introduction of HCl gas was completed, the system was kept at 70-80 °C and stirred for 6 h. After the sample was detected by HPLC, the system was directly distilled, and the distillation residue was the product 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole 84.8 g, with a yield of 97.2% and a product content of 98.6%.

[0134] The distillation fraction was dichloroethane, which could be directly used in the next batch of reaction.

[0135] Example 33

[0136] In a 500 mL four-necked flask, 1-methyl-3-(trifluoromethyl)-5-(difluoromethoxy)-1H- pyrazole (71.3 g, 0.33 mol, 1 eq), dichloroethane (213.9 g), water (22 g) and trioxane (14.9 g, 0.165 mol, 0.5 eq) were added in sequence. The system was 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 introduction of HCl gas was completed, the system was kept at 70-80 °C and stirred for 6 h. After the sample was detected by HPLC, the system was directly distilled, and the distillation residue was the product 1-methyl-3-(trifluoromethyl)-4-(chloromethyl)-5-(difluoromethoxy)-1H-pyrazole 84.8 g, with a yield of 97.2% and a product content of 98.6%.

[0137] The distillate is a mixture of dichloroethane and water, which can be directly used for the next batch reaction.

[0138] Example 34

[0139] 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole, dichloroethane, trioxane and water were mixed in the ratio of 71.3:213.9:14.9:22, and stirred uniformly, labeled as mixed solution A. The flow rate of the feed metering pump of the mixed solution A was set to 64 g / min, and the flow rate of the gas metering pump of the hydrogen chloride gas was set to 3.59 g / min. The mixed solution A and the hydrogen chloride gas were simultaneously fed into the continuous reaction vessel (a tubular reactor) by the metering pumps to carry out the reaction, the pressure of the reaction system was controlled to 0.15 MPa, the temperature of the reaction system was controlled to 70-80°C, and the residence time of the reaction system was 25 min. The reaction liquid was continuously fed into a receiving bottle. The reaction liquid 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%.

[0140] The distillate is dichloroethane, which can be directly used for the next batch reaction.

[0141] Example 35

[0142] 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole, dichloroethane, trioxane and water were mixed in the ratio of 71.3:213.9:14.9:22, and stirred uniformly, labeled as mixed solution A. The flow rate of the feed metering pump of the mixed solution A was set to 64 g / min, and the flow rate of the gas metering pump of the hydrogen chloride gas was set to 3.59 g / min. The mixed solution A and the hydrogen chloride gas were simultaneously fed into the continuous reaction vessel (a tubular reactor) by the metering pumps to carry out the reaction, the pressure of the reaction system was controlled to 0.15 MPa, the temperature of the reaction system was controlled to 70-80°C, and the residence time of the reaction system was 25 min. The reaction liquid was continuously fed into a receiving bottle. The reaction liquid 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%.

[0143] The distillate is a mixture of dichloroethane and water, which can be directly used for the next batch reaction.

[0144] Example 36

[0145] Mix 1-methyl-3-trifluoromethyl-5-difluoromethoxy-1-H-pyrazole, paraformaldehyde and water with the mass ratio of 71.3:14.9:71.3, and stir until uniform, labeled as mixed solution A. Set the flow rate of the feed metering pump of mixed solution A to 50 g / min, and set the flow rate of the gas metering pump of hydrogen chloride gas to 5.74 g / min. Pass mixed solution A and hydrogen chloride gas through the metering pumps simultaneously into a continuous reaction vessel (a tubular reactor) to react, control the pressure of the reaction system to be 0.25 MPa, control the temperature of the reaction system to be 70-80°C, and control the residence time of the reaction system to be 10 min. The reaction liquid continuously enters a receiving bottle. The reaction liquid is directly phase separated, and the lower organic phase is 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%.

[0146] The upper aqueous phase is water, which can be directly used in the next batch of reaction. It should be noted that although the technical solutions of the present application are described in specific examples, those skilled in the art can understand that the present application should not be limited thereto.

[0147] The above has described various embodiments of the present application, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes are obvious to those skilled in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles, practical applications, or technical improvements in the market of the embodiments, or to enable other ordinary skilled persons in the art to understand the embodiments disclosed herein.

Claims

1. A process for the preparation of a compound of formula II comprising the steps of: reacting a compound of formula I with reagent A and reagent B to obtain a reaction solution comprising a compound of formula II; wherein the reagent A is one or more of formaldehyde and polymers thereof; the reagent B is one or more of sulfuryl dichloride, chlorosulfonic acid, p-phenylenedisulfonyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride or hydrogen chloride.

2. The preparation method according to claim 1, wherein the reagent B is sulfuryl dichloride, chlorosulfonic acid, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride or hydrogen chloride.

3. The preparation method according to claim 1 or 2, wherein the molar ratio of the compound of formula I to the formaldehyde or formaldehyde monomer in the polymer is 1.0:1.0 to 1.0:3.0, preferably 1.0:1.5 to 1.0:2.

5.

4. The preparation method according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of a solvent or water; preferably, the molar ratio of the water to the compound of formula I is not less than 1.0:1.

0.

5. The preparation method according to any one of claims 1 to 4, wherein when the reagent B is sulfuryl dichloride, the molar ratio of the compound of formula I to the sulfuryl dichloride is 1.0:1.0 to 1.0:3.5, preferably 1.0:1.2 to 1.0:2.0; when the reagent B is hydrogen chloride, the molar ratio of the compound of formula I to the hydrogen chloride is 1.0:1.0 to 1.0:3.0, preferably 1.0:1.5 to 1.0:2.

0.

6. The preparation method according to any one of claims 1 to 4, wherein when the reagent B is chlorosulfonic acid, phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride, the molar ratio of the compound of formula I to the reagent B is 1.0:1.0 to 1.0:3.0, preferably 1.0:1.1 to 1.0:1.

5.

7. The preparation method according to any one of claims 1 to 6, wherein the reaction is carried out in a solvent, which is one or more of protic solvents and aprotic solvents; preferably, the solvent is one or more of halogenated alkanes, ethers, aromatic hydrocarbons, nitriles and water; more preferably, the solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, toluene, water and acetonitrile; further preferably, the solvent is acetonitrile, tetrahydrofuran or water.

8. The preparation method according to any one of claims 1 to 7, wherein the feeding temperature of the reaction is 0-60°C, preferably 5-40°C, more preferably 10-20°C.

9. The preparation method according to any one of claims 1 to 8, wherein the reaction temperature of the reaction is 60-80°C, preferably 60-70°C or 70-80°C.

10. The preparation method according to any one of claims 1 to 9, further comprising the following step: optionally separating the reaction solution comprising the compound of formula II, and distilling off the solvent to obtain the compound of formula II. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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