Preparation method of pyroxasulfone intermediate

Abstract

The invention discloses a preparation method of a pyroxasulfone intermediate shown as a formula I. The method comprises the following steps: 1) reacting a compound shown as a formula III with 1, 3-dimethylimidazolidine-2-thioketone in a solvent to generate a compound shown as a formula III '; 2) reacting the compound shown as the formula III'with a compound shown as a formula II in the presence of alkali to prepare a compound shown as a formula I; the synthetic route is as follows: # imgabs0 #, wherein X1 and X are respectively and independently halogen. According to the preparation method disclosed by the invention, the generation of a large amount of waste salt in the prior art can be avoided, the byproduct 1, 3-dimethylimidazolidine-2-thioketone generated from the raw material 1, 3-dimethylimidazolidine-2-thioketone can be used as a common organic solvent, and the production cost is greatly reduced. The method can greatly save the reaction time in production, is simple to operate and convenient to implement, and has great application value in industrial production.

Description

Technical Field

[0001] The invention relates to the field of pesticide chemical synthesis, and in particular to a method for preparing a sulfonepyraclostrobin intermediate 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole. Background Art

[0002] 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is an important intermediate for the preparation of the highly effective herbicide sulfonepyraclostrobin. It is reported that the herbicidal activity of sulfonepyraclostrobin is 8-12 times that of sethoxydim and isopropylamine. Therefore, this product has considerable market prospects.

[0003] 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is prepared by the following steps to obtain sulfonepyrazoline technical drug;

[0004]

[0005] According to patents CN112969697A, CN111574511A, and WO2020 / 240392Al, 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is mainly prepared by reacting 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole and [5,5-dimethyl-(4,5-dihydroisoxazol-3-yl)]thiocarboxamidine hydrochloride or hydrobromide;

[0006]

[0007] Wherein, [5,5-dimethyl-(4,5-dihydroisoxazol-3-yl)]thiocarboxamidine hydrochloride or hydrobromide is prepared by reacting 3-halogenated 5,5-dimethyl-4,5-dihydroisoxazole with thiourea;

[0008]

[0009] This method will produce a large amount of waste salts and high-content nitrogen salts during the production process, and the use of thiourea has high production costs and low atomic utilization, and has certain limitations.

[0010] Patent CN113135867A reports that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol and formaldehyde undergo condensation reaction in an alkaline water environment, and then react with S-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl))ethyl ethyl sulfate to obtain an intermediate, and then pass freon to obtain 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole (compound of formula I);

[0011]

[0012] Although this method avoids the generation of a large amount of ammonia nitrogen wastewater, it will produce sodium acetate waste salt, which is difficult to handle and has high raw material production costs. In addition, because a large amount of alkali is required in the early stage of the reaction and acidic conditions are required in the later stage, a large amount of waste salt will be produced.

[0013] Patent WO2021 / 019537Al uses the following steps:

[0014]

[0015] This method is similar to the method reported in patent CN113135867A, which produces sodium acetate waste salt, which is difficult to handle, and has high raw material production costs.

[0016] Patent WO2021 / 176456Al also reports some synthesis methods of thioisoxazoles, but they all require some good leaving groups, and industrial production is not realistic. For example:

[0017] Summary of the invention

[0018] In view of the various defects existing in the prior art, the present invention provides a new method for preparing 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole (Formula I).

[0019] The specific technical scheme of the present invention is to react 3-halo-5,5-dimethyl-4,5-dihydroisoxazole or 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole with 1,3-dimethylimidazolidine-2-thione, and then react with the corresponding halide to prepare 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole (Formula I).

[0020] Specifically, the present invention provides a method for preparing a 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole (Formula I) compound, the method comprising the following steps:

[0021] Step 1): the compound of formula III is reacted with 1,3-dimethylimidazolidine-2-thione in a solvent to generate a compound of formula III';

[0022] Step 2): The compound of formula III' reacts with the compound of formula II in the presence of a base to obtain the compound of formula I;

[0023] Its synthetic route is as follows:

[0024]

[0025] Wherein, X1 and X are independently halogen, preferably Cl or Br.

[0026] The present invention also provides another method for preparing 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole (Formula I) compound, which comprises the following steps:

[0027] Step a): the compound of formula II is reacted with 1,3-dimethylimidazolidine-2-thione in an organic solvent to generate a compound of formula II';

[0028] Step b): reacting a compound of formula II' with a compound of formula III in the presence of a base to obtain a compound of formula I;

[0029] Its synthetic route is as follows:

[0030]

[0031] Wherein, X1 and X are independently halogen, preferably Cl or Br.

[0032] Beneficial Effects

[0033] 1. The preparation method of the present invention has mild reaction conditions, high reaction efficiency and short reaction time.

[0034] 2. The preparation method of the present invention can avoid the generation of a large amount of waste salts in the prior art.

[0035] 3. The byproduct 1,3-dimethylimidazolidinone generated from the raw material 1,3-dimethylimidazolidine-2-thione used in the present invention can be used as a commonly used organic solvent, which greatly reduces the production cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 13-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole 1 H NMR spectra DETAILED DESCRIPTION

[0037] The specific implementation methods of the present invention are further described in detail below in conjunction with the examples and drawings. In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "including" or its variations such as "comprising" or "including" will be understood to include the stated components and steps, without excluding the presence of other material components or steps.

[0038] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0039] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0040] Hereinafter, embodiments of the present invention are described in detail. However, these embodiments are exemplary, the present invention is not limited thereto, and the present invention is defined by the scope of the claims.

[0041] In the present invention, halogen means fluorine, chlorine, bromine and iodine.

[0042] In the present invention, the percentage content refers to the mass percentage content unless otherwise specified.

[0043] The present invention first provides a method for preparing a 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole (Formula I) compound, which comprises the following steps:

[0044] Step 1): the compound of formula III is reacted with 1,3-dimethylimidazolidine-2-thione in a solvent to generate a compound of formula III';

[0045] Step 2): The compound of formula III' reacts with the compound of formula II in the presence of a base to obtain the compound of formula I;

[0046] Its synthetic route is as follows:

[0047]

[0048] Wherein, X1 and X are independently halogen, preferably Cl or Br.

[0049] Preferably, the solvent described in step 1) of the above preparation method is an organic solvent or water, preferably one or more of water, DMSO, tetrahydrofuran, DMF, methanol, ethanol and acetonitrile, more preferably one or more of water, acetonitrile and methanol; the molar ratio of the amount of 1,3-dimethylimidazolidine-2-thione to the compound of formula III is 1-4:1, preferably 1.05-1.5:1.

[0050] Preferably, the reaction temperature in step 1) of the above preparation method is 0-60°C, preferably 10-30°C;

[0051] Preferably, the solvent described in step 2) of the above preparation method is an organic solvent or water, preferably one or more of water, DMSO, tetrahydrofuran, DMF, methanol, ethanol and acetonitrile, more preferably one or more of water, tetrahydrofuran, acetonitrile and methanol.

[0052] Preferably, the base in step 2) of the above preparation method is an organic base or an inorganic base, and the organic base is preferably triethylamine or pyridine; the inorganic base is preferably one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

[0053] The present invention also provides another method for preparing the compound of formula I, which comprises the following steps:

[0054] Step a): reacting the compound of formula II with 1,3-dimethylimidazolidine-2-thione in a solvent to generate a compound of formula II';

[0055] Step b): reacting a compound of formula II' with a compound of formula III in the presence of a base to obtain a compound of formula I;

[0056] Its synthetic route is as follows:

[0057]

[0058] Wherein, X1 and X are independently halogen, preferably Cl or Br.

[0059] Preferably, the solvent described in step a) of the above preparation method is an organic solvent or water, preferably one or more of water, DMSO, tetrahydrofuran, DMF, methanol, ethanol and acetonitrile, more preferably one or more of water, acetonitrile and methanol; the molar ratio of the amount of the 1,3-dimethylimidazolidine-2-thione to the compound of formula III is 1-4:1, preferably 1.05-1.5:1.

[0060] Preferably, the reaction temperature in step a) of the above preparation method is 0-60°C, preferably 10-30°C;

[0061] Preferably, the solvent in step b) of the preparation method is an organic solvent or water, preferably one or more of water, DMSO, tetrahydrofuran, DMF, methanol, ethanol and acetonitrile, more preferably one or more of water, acetonitrile and methanol.

[0062] Preferably, the base in step b) of the preparation method is an organic base or an inorganic base, and the organic base is preferably triethylamine or pyridine; the inorganic base is preferably one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

[0063] The present invention can prepare the compound of formula I by using the compound of formula II' or formula III' to overcome the generation of a large amount of waste salts in the prior art. At the same time, the by-product 1,3-dimethylimidazolidinone generated during the reaction can be used as a common organic solvent, greatly reducing the production cost.

[0064] The present invention will be described in detail below by way of examples. The raw materials in the examples can be prepared by conventional test methods.

[0065] The amounts of reactants and products in the following examples were measured by liquid chromatography (Agilent HPLC 1260). In the following examples, the conversion rate and selectivity of the reaction were calculated by the following formula:

[0066] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%

[0067] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%

[0068] Example 1 Synthesis of 2-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium

[0069]

[0070] 13.3 g (0.1 mol) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was dissolved in 50 g of acetonitrile, and 13.65 g (0.105 mol) of 1,3-dimethylimidazolidine-2-thione was added. The temperature was controlled at 20° C. and the reaction was completed under liquid phase monitoring. The conversion rate was 99% and the quantitative yield was 98%.

[0071] Example 2 Synthesis of 2-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium

[0072]

[0073] 13.3 g (0.1 mol) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was dissolved in 50 g of methanol, and 13.65 g (0.105 mol) of 1,3-dimethylimidazolidine-2-thione was added. The temperature was controlled at 20° C. and the reaction was completed under liquid phase monitoring. The conversion rate was 95% and the quantitative yield was 93%.

[0074] Example 3 Synthesis of 2-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium

[0075]

[0076] 13.3 g (0.1 mol) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was dissolved in 50 g of acetonitrile, and 19.5 g (0.15 mol) of 1,3-dimethylimidazolidine-2-thione was added. The temperature was controlled at 20° C. and the reaction was completed by liquid phase monitoring. The conversion rate was 99% and the quantitative yield was 97%.

[0077] Example 4 Synthesis of 2-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium

[0078]

[0079] 13.3 g (0.1 mol) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was dissolved in 50 g of acetonitrile, and 13.65 g (0.105 mol) of 1,3-dimethylimidazolidine-2-thione was added. The temperature was controlled at 40° C. and the reaction was completed by liquid phase monitoring. The conversion rate was 99% and the quantitative yield was 93%.

[0080] Example 5 Synthesis of 2-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium

[0081]

[0082] 26.4 g (0.1 mol) of 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole was dissolved in 50 g of acetonitrile, and 13.65 g (0.105 mol) of 1,3-dimethylimidazolidine-2-thione was added. The temperature was controlled at 20°C for reaction. The liquid phase was monitored for reaction until completion, with a conversion rate of 95% and a quantitative yield of 90%.

[0083] Example 6 Synthesis of 2-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium

[0084]

[0085] 26.4 g (0.1 mol) of 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole was dissolved in 50 g of methanol, and 13.65 g (0.105 mol) of 1,3-dimethylimidazolidine-2-thione was added. The temperature was controlled at 20°C for reaction. The reaction was monitored by liquid phase until completion, with a conversion rate of 93% and a quantitative yield of 89%.

[0086] Example 7 Synthesis of 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole

[0087]

[0088] Then, 48 g (0.12 mol) of 10% aqueous sodium hydroxide solution was slowly added dropwise to an acetonitrile solution of 35.9 g (0.1 mol) of 2-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazole-3-ium at 10-20° C., and then 13.3 g (0.1 mol) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was slowly added dropwise. After the reaction was completed, the mixture was allowed to stand for separation, and the organic phase was concentrated to obtain the target product. The conversion rate of the reaction was measured to be 98%, and the yield was 97%. 1 H NMR (500MHz, CDCl3) δ6.73 (t, J = 71.9Hz, 1H), 4.18 (s, 2H), 3.82 (s, 3H), 2.79 (s, 2H), 1.42 (s, 6H).

[0089] Example 8 Synthesis of 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole

[0090]

[0091] At 10-20°C, 48 g (0.12 mol) of 10% aqueous sodium hydroxide solution was slowly added dropwise to an acetonitrile solution of 22.8 g (0.1 mol) of 2-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium. After the addition was complete, 26.4 g (0.1 mol) of 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole was slowly added dropwise. After the reaction was completed, the mixture was allowed to stand for separation and the organic phase was concentrated to obtain the target product. The conversion rate of the reaction was measured to be 98% and the yield was 95%.

[0092] Example 9 Synthesis of 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole

[0093]

[0094] At 10-20° C., 48 g (0.12 mol) of 10% aqueous sodium hydroxide solution was slowly added dropwise to a methanol solution of 35.9 g (0.1 mol) of 2-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-1,3-dimethyl-4,5-dihydro-1H-imidazole-3-ium. After the addition, 13.3 g (0.1 mol) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was slowly added dropwise. After the reaction was completed, the mixture was allowed to stand for separation and the organic phase was concentrated to obtain the target product. The conversion rate of the reaction was measured to be 95% and the yield was 93%.

[0095] According to the method for preparing 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole of the present invention, a higher reaction conversion rate and selectivity can be obtained, and the cost is greatly reduced.

[0096] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula I, characterized in that: The following steps are involved: Step 1): the compound of formula III is reacted with 1,3-dimethylimidazolidine-2-thione in a solvent to generate a compound of formula III'; Step 2): The compound of formula III' reacts with the compound of formula II in the presence of a base to obtain the compound of formula I; Its synthetic route is as follows: Wherein, X1 and X are independently halogen, preferably Cl or Br.

2. The method according to claim 1, characterized in that The solvent in step 1) is an organic solvent or water, preferably one or more of water, DMSO, tetrahydrofuran, DMF, methanol, ethanol and acetonitrile, more preferably one or more of water, acetonitrile and methanol; the molar ratio of the amount of 1,3-dimethylimidazolidine-2-thione to the compound of formula III is 1-4:1, preferably 1.05-1.5:

1.

3. The method according to claim 1, characterized in that The reaction temperature in step 1) is 0-60°C, preferably 10-30°C.

4. The method according to claim 1, characterized in that: The step 2) is reacted in a solvent, wherein the solvent is an organic solvent or water, preferably one or more of water, DMSO, tetrahydrofuran, DMF, methanol, ethanol and acetonitrile, more preferably one or more of water, tetrahydrofuran, acetonitrile and methanol.

5. The method according to claim 1, characterized in that The base in step 2) is an organic base or an inorganic base, and the organic base is preferably triethylamine or pyridine; the inorganic base is preferably one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

6. A method for preparing a compound of formula I, characterized in that: The following steps are involved: Step a): the compound of formula II is reacted with 1,3-dimethylimidazolidine-2-thione in a solvent at a certain temperature to generate a compound of formula II'; Step b): reacting a compound of formula II' with a compound of formula III in the presence of a base to obtain a compound of formula I; Its synthetic route is as follows: Wherein, X1 and X are independently halogen, preferably Cl or Br.

7. The method according to claim 6, characterized in that The solvent in step a) is an organic solvent or water, preferably one or more of water, DMSO, tetrahydrofuran, DMF, methanol, ethanol and acetonitrile, more preferably one or more of water, acetonitrile and methanol; the molar ratio of the amount of 1,3-dimethylimidazolidine-2-thione to the compound of formula III is 1-4:1, preferably 1.05-1.5:

1.

8. The method according to claim 6, characterized in that The reaction temperature in step a) is 0-60°C, preferably 10-30°C.

9. The method according to claim 6, characterized in that The step b) is reacted in a solvent, and the solvent is an organic solvent or water, preferably one or more of water, DMSO, tetrahydrofuran, DMF, methanol, ethanol and acetonitrile, more preferably one or more of water, acetonitrile and methanol.

10. The method according to claim 6, characterized in that The base in step b) is an organic base or an inorganic base, and the organic base is preferably triethylamine or pyridine; the inorganic base is preferably one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

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