Pretreatment method of 3-(chloromethyl)-1-methyl-1H-1, 2, 4-triazole hydrochloride and compound preparation method

Abstract

The invention relates to the technical field of organic synthesis, in particular to a pretreatment method of 3-(chloromethyl)-1-methyl-1H-1, 2, 4-triazole hydrochloride, which comprises the following steps: dissolving the 3-(chloromethyl)-1-methyl-1H-1, 2, 4-triazole hydrochloride in a solvent, then adding carbonate or an aqueous solution thereof for reaction, and separating and purifying to obtain 3-(chloromethyl)-1-methyl-1H-1, 2, 4-triazole hydrochloride. According to the method, high-purity 3-(chloromethyl)-1-methyl-1H-1, 2, 4-triazole can be efficiently prepared, the purity of the 3-(chloromethyl)-1-methyl-1H-1, 2, 4-triazole is 97% or above, the yield is basically 90% or above, the total impurity content is smaller than 3%, and the 3-(chloromethyl)-1-methyl-1H-1, 2, 4-triazole can be conveniently used in subsequent actual production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a pretreatment method of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride and a preparation method of the compound. Background Art

[0002] 3-(Chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride is an important pharmaceutical intermediate with huge market potential, and it can also be used as an intermediate in other pharmaceutical synthesis processes. The prior art discloses that the yield of 6-ethylthio-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione compound is less than 50%, and the purity does not meet the requirements. The post-processing operation is complicated and is not suitable for large-scale industrial production. There is no method for preparing the compound with high yield in the prior art.

[0003] At present, many patents have reported the production and preparation of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride. In the prior art, the hydrochloride is often used directly in production, which may cause the following problems: 1) Alkali must be added during the reaction, and the hydrochloride will react with the alkali. The neutralization reaction is exothermic, making it difficult to control the temperature; 2) The reaction of hydrochloride with the alkali will generate water. In the presence of water, the ethylthio group of 6-(ethylthio)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione will hydrolyze to produce a large amount of impurities, affecting production.

[0004] Therefore, there is an urgent need to provide an efficient 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride pretreatment method to ensure the purity and yield of the subsequent target compound. Summary of the invention

[0005] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, the present invention provides a pretreatment method for 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride. The method can obtain 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole with high purity and yield, and basically does not produce hydrolysis impurities. Compared with the prior art directly using 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride for subsequent reactions, the use of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole obtained by pretreatment is more conducive to the preparation of subsequent compounds.

[0006] To this end, the first aspect of the present invention provides a pretreatment method for 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, the pretreatment method comprising: dissolving 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride in a solvent, adding a carbonate or an aqueous solution thereof to react, and obtaining 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole;

[0007] Wherein, the solvent includes at least one selected from ethyl acetate, dichloromethane, isopropyl acetate, methanol, ethanol, and acetonitrile.

[0008] The inventors have found that by dissolving 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride in the above solvent and then adding carbonate or its aqueous solution for reaction, high-purity 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole can be efficiently prepared, and its use in subsequent production can significantly improve the purity and yield of the target compound. The pretreatment method is efficient and simple, and after the reaction is completed, the yield of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole is basically above 90%, the purity is above 97%, and the total impurity content is less than 3%.

[0009] According to an embodiment of the present invention, the carbonate comprises an alkali metal carbonate.

[0010] According to an embodiment of the present invention, the alkali metal carbonate is selected from potassium carbonate and / or sodium carbonate.

[0011] According to an embodiment of the present invention, the amount of the carbonate is 0.6-4.0 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0012] According to an embodiment of the present invention, the amount of the carbonate is 1.2-1.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0013] According to an embodiment of the present invention, the amount of the carbonate is 1.2 or 1.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0014] According to an embodiment of the present invention, the amount of the carbonate is 1.5-3.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0015] According to an embodiment of the present invention, the concentration of the potassium carbonate aqueous solution is 0.1-1.0 g / ml, preferably 0.3-0.8 g / ml, and more preferably 0.4-0.7 g / ml. This concentration range has a preferred alkalization efficiency, can reduce subsequent purification costs, and has a higher yield.

[0016] According to an embodiment of the present invention, the volume ratio of the solvent to the carbonate aqueous solution is (6:1)-(1:2).

[0017] According to an embodiment of the present invention, the volume ratio of the solvent to the carbonate aqueous solution is (6:1)-(3:1).

[0018] According to an embodiment of the present invention, the reaction temperature is 0-30°C.

[0019] According to an embodiment of the present invention, the reaction temperature is 0-10°C.

[0020] According to an embodiment of the present invention, the reaction time is 25-60 minutes.

[0021] According to an embodiment of the present invention, the reaction time is 25-35 minutes.

[0022] According to some embodiments of the present invention, carbonate is added to react, and the reaction product contains a solid-liquid mixture; according to some embodiments of the present invention, a carbonate aqueous solution is added to react, and the reaction product contains an organic-aqueous phase mixed solution.

[0023] According to an embodiment of the present invention, the pretreatment method further includes: obtaining a reaction product after the reaction is completed, purifying the reaction product to obtain the 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole, and the purification method includes one or more of filtration, extraction, and washing.

[0024] According to an embodiment of the present invention, the extraction method includes, for an organic-aqueous phase mixed solution, extracting the aqueous phase using an extractant after standing and stratifying, and combining the organic phases; the extractant includes at least one of ethyl acetate and dichloromethane;

[0025] The filtering method comprises performing separation treatment on the solid-liquid mixture and collecting the filtrate;

[0026] The washing method includes washing the organic phase with a saturated sodium chloride solution, or washing the filter cake with a detergent, wherein the detergent includes at least one of methanol, ethanol, dichloromethane and acetonitrile.

[0027] According to an embodiment of the present invention, the purification method comprises:

[0028] (1) The reaction product is a mixed solution, the mixed solution is allowed to stand for stratification, the aqueous phase is extracted with ethyl acetate solution, and the organic phases are combined;

[0029] (2) Wash the organic phase with a saturated sodium chloride solution.

[0030] According to an embodiment of the present invention, the volume ratio of the ethyl acetate solution in step (1) to the saturated sodium chloride solution in step (2) is (3:1)-(6:1).

[0031] According to an embodiment of the present invention, the purification process further comprises the step of subjecting the organic phase of the target product to reduced pressure distillation.

[0032] According to an embodiment of the present invention, the purification treatment further comprises washing the organic phase with a saturated sodium chloride solution and then performing a reduced pressure distillation operation.

[0033] According to another aspect of the present invention, there is also provided a method for preparing 6-(ethylthio)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione, the preparation method comprising reacting 6-(ethylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione with 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole in the presence of a catalyst.

[0034] With respect to the reaction of 6-(ethylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride in the prior art, the preparation method of the present invention has higher overall yield and efficiency.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] (1) The method is more efficient. In the prior art, 6-(ethylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione, 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride and potassium carbonate are added to DMF, and the mixture is stirred sufficiently for direct reaction. However, in the present invention, 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride is pretreated, and the pretreatment reaction is convenient and efficient. The obtained free base reacts with 6-(ethylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione, and the purity is higher, which greatly reduces the difficulty of subsequent purification and is more efficient overall.

[0037] (2) The product purity is higher and is conducive to the preparation of subsequent target compounds. The 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride pretreatment method provided by the present invention can achieve a purity of more than 97%, a yield of more than 90%, and a total impurity content of less than 3%. Using it in the preparation of subsequent target compounds can significantly improve the purity and yield of the target compound.

[0038] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0040] Figure 1 The structural formula of the product 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole in Example 1 of the present invention is shown;

[0041] Figure 2 The NMR spectrum of the product 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole in Example 1 of the present invention is shown;

[0042] Figure 3 The liquid phase spectrum of the product 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole in Example 2 of the present invention is shown;

[0043] Figure 4 The liquid phase spectrum of the product 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole in Example 5 of the present invention is shown;

[0044] Figure 5 The liquid phase spectrum of the product 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole in Example 8 of the present invention is shown. DETAILED DESCRIPTION

[0045] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0046] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0047] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0048] In order to make the present invention more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present invention belongs.

[0049] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0050] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0051] The term "largest single impurity" is to be understood as the largest known impurity, ie the hydrolysis impurity.

[0052] According to an embodiment of the present invention, a first aspect of the present invention provides a pretreatment method for 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, the pretreatment method comprising: dissolving 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride in a solvent, adding a carbonate aqueous solution to react, and obtaining 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole;

[0053] Wherein, the solvent includes at least one selected from ethyl acetate, dichloromethane, isopropyl acetate, methanol, ethanol, and acetonitrile.

[0054] The preparation method of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride does not affect the pretreatment of the present invention, that is, the 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride used in the present invention can be a pre-synthesized product or a commercially available product.

[0055] According to an embodiment of the present invention, the carbonate comprises an alkali metal carbonate, preferably selected from potassium carbonate and / or sodium carbonate. Compared with a strong base containing hydroxide, the present invention selects carbonates with weaker alkalinity, thereby avoiding the hydrolysis of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole in a strong alkaline solution, improving the purity and yield of the product, and avoiding the generation of hydrolysis impurities.

[0056] According to an embodiment of the present invention, the amount of the carbonate is 0.6-4.0 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride. Compared with the use amount of 4eq of carbonate in the conventional pretreatment method, the present invention can select a smaller amount of raw materials, and can also avoid the problem of subsequent solvent replacement due to excessive potassium salt dissolved in the solution.

[0057] According to a preferred embodiment of the present invention, the amount of the carbonate is 0.6-3.8 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0058] According to some embodiments of the present invention, the amount of the carbonate is 1.5-3.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0059] According to some embodiments of the present invention, the amount of the carbonate is 1.2-1.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0060] According to a preferred embodiment of the present invention, the amount of the carbonate is 1.2 or 1.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0061] According to an embodiment of the present invention, the volume ratio of the solvent to the carbonate aqueous solution is (6:1)-(1:2), thereby ensuring the purity and yield of the product.

[0062] According to a preferred embodiment of the present invention, the volume ratio of the solvent to the carbonate aqueous solution is (6:1)-(3:1).

[0063] According to an embodiment of the present invention, the reaction temperature is 0-30°C.

[0064] According to an embodiment of the present invention, the reaction temperature is 0-10°C.

[0065] According to an embodiment of the present invention, the reaction time is 25-60 minutes.

[0066] According to an embodiment of the present invention, the reaction time is 25-35 minutes.

[0067] According to an embodiment of the present invention, the pretreatment method further comprises: obtaining a reaction product after the reaction is completed, purifying the reaction product to obtain the 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole, and the purification method comprises one or more of filtration, extraction, and washing.

[0068] According to an embodiment of the present invention, the extraction method includes, for an organic-aqueous phase mixed solution, extracting the aqueous phase with an extractant after layering, and combining the organic phases; the extractant includes at least one of ethyl acetate and dichloromethane.

[0069] The extraction method according to the embodiment of the present invention includes performing separation treatment on the solid-liquid mixture and collecting the filtrate.

[0070] According to an embodiment of the present invention, the extraction method includes washing the organic phase with a saturated sodium chloride solution, or washing the filter cake with a detergent, wherein the detergent includes at least one of methanol, ethanol, dichloromethane, and acetonitrile.

[0071] According to an embodiment of the present invention, a potassium carbonate aqueous solution is used for the reaction, and the reaction product is a mixed solution. The extraction method comprises:

[0072] (1) allowing the mixed solution to stand for stratification, extracting the aqueous phase with ethyl acetate solution, and combining the organic phases;

[0073] (2) Wash the organic phase with a saturated sodium chloride solution.

[0074] According to an embodiment of the present invention, the volume ratio of the ethyl acetate solution in step (1) to the saturated sodium chloride solution in step (2) is (3:1)-(6:1).

[0075] According to an embodiment of the present invention, the purification treatment further comprises washing the organic phase with a saturated sodium chloride solution and then performing a reduced pressure distillation operation.

[0076] According to a specific embodiment of the present invention, the pretreatment method of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride is specifically:

[0077] (1) Dissolve 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride in ethyl acetate, stir at 0-10°C, add potassium carbonate solution dropwise and stir for 30 minutes, and when the pH of the system is alkaline, stop the reaction and allow to stand for stratification;

[0078] (2) collecting the organic phase, extracting the aqueous phase with ethyl acetate, and then combining the organic phases;

[0079] (3) The obtained organic phase was washed twice with a saturated sodium chloride solution and then distilled under reduced pressure to obtain high-purity 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole.

[0080] The scheme of the present disclosure will be explained below in conjunction with the examples. Those skilled in the art will appreciate that the following examples are only used to illustrate the present disclosure and should not be considered to limit the scope of the present disclosure. Where specific techniques or conditions are not indicated in the examples, the techniques or conditions described in the literature in this area or the product instructions are used. Where the manufacturers of reagents or instruments are not indicated, they are all conventional products that can be obtained commercially.

[0081] Example 1 Pretreatment of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride

[0082] (1) Dissolve 50.0 g of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride in methanol solution and stir thoroughly at 0-10°C;

[0083] (2) Add 136.7 g potassium carbonate in batches to the system of step (1), stir and detect the pH value of the system. If the system is alkaline, stop the reaction;

[0084] (3) Filtering, washing the filter cake with methanol and dichloromethane in turn; combining the filtrates; and concentrating the mixture by distillation under reduced pressure until the water content is ≤ 0.2%. After the concentration, 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole is obtained with a yield of 97.9%, an impurity content of 1.51%, and a maximum single impurity content of 1.02%.

[0085] Its structural formula and corresponding NMR spectrum are shown in Figure 1 and Figure 2 .

[0086] Example 2 Pretreatment of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride

[0087] (1) Dissolve 50.0 g of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride in 300 mL of ethyl acetate solution and stir thoroughly at 0-10°C;

[0088] (2) Dissolve 61.7 g of potassium carbonate in 100 mL of water to obtain a potassium carbonate solution, and add the potassium carbonate aqueous solution dropwise to the solution obtained in step (1), keeping the temperature constant during the addition process. After the addition is complete, stir for 5 minutes and measure the pH value of the system. If the system is alkaline, stop the reaction and let stand for stratification;

[0089] (3) The organic phase was collected, and the aqueous phase was extracted with 300 ml of ethyl acetate. The organic phases were combined, and then washed twice with 100 ml of saturated sodium chloride solution. The organic phases were collected again and distilled under reduced pressure to obtain 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole.

[0090] Example 3 Selection of solvent system

[0091] According to Example 2, five groups of solvent systems were set up, namely dichloromethane, ethyl acetate, isopropyl acetate, methanol, and ethanol for corresponding pretreatment.

[0092] The results of the pretreatment of each group are shown in Table 1. The results show that when methanol or ethanol is used as the solvent, the purity and yield of the obtained product are lower than the purity and yield when ethyl acetate, dichloromethane and isopropyl acetate are used as the solvent of the present invention, and the impurity content is also higher than the impurity content when ethyl acetate, dichloromethane and isopropyl acetate are used as the solvent.

[0093] Table 1 Screening results of solvent systems for pretreatment with 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole

[0094] Solvents HPLC / % Yield / % Impurities / % Maximum single impurity / % Ethyl acetate 100％ 100％ none none Dichloromethane 99.85％ 97.8％ 0.15％ 0.06％ Isopropyl acetate 99.88％ 99.1％ 0.12％ 0.06％ Methanol 97.82％ 89.67％ 2.18％ 1.62％ Ethanol 98.12％ 93.4％ 1.88％ 1.04％

[0095] Example 4 Selection of carbonate

[0096] Compared with Example 2, this embodiment differs only in that the carbonate type is changed, and the purpose is to investigate the effect of the carbonate type on the product, and the results are shown in Table 2. From the results in the table, it can be seen that the final results of potassium carbonate and sodium carbonate are not much different, but since potassium carbonate has better solubility in water than sodium carbonate, and considering the cost of treating wastewater, potassium carbonate is preferred.

[0097] Table 2 Carbonate screening results

[0098] Carbonate Type HPLC / % Yield / % Impurities / % Maximum single impurity / % Potassium carbonate 100％ 100％ none none Sodium carbonate 99.82％ 98.2％ 0.18％ 0.07％

[0099] Example 5 Selection of potassium carbonate dosage

[0100] Compared with Example 2, the difference between this embodiment is only that the amount of potassium carbonate is changed, the purpose is to investigate the effect of the amount of potassium carbonate on the product. The results are shown in Table 3. The results show that when the amount of potassium carbonate is 1.2eq and 1.5eq, the purity and yield of the obtained product are higher than the pretreatment result when 4.0eq is used in the prior art. At the same time, when the amount of potassium carbonate is 1.5eq, its purity and yield can reach 100%, which not only saves the raw material cost, but also ensures the pretreatment effect.

[0101] Table 3 Selection results of potassium carbonate dosage

[0102]

[0103] Example 6 Selection of volume ratio of ethyl acetate solution to potassium carbonate solution

[0104] Compared with Example 2, the difference between this example is that the volume ratio of the ethyl acetate solution to the potassium carbonate solution is changed, and the purpose is to investigate the effect of the volume ratio of the two on the product. The results are shown in Table 4. The results show that when the volume ratio of the ethyl acetate solution to the potassium carbonate solution is 6:1, 5:1, 4:1, 3:1, 2:1, and 1:1, the purity and yield of the obtained product can reach 98% or more, and when the volume ratio of the ethyl acetate solution to the potassium carbonate solution is 6:1-3:1, its purity and yield can reach 100%.

[0105] Table 4 Selection results of ethyl acetate solution and potassium carbonate solution volume ratio

[0106] <![CDATA[EA(ml) / K2CO3(ml)]]> HPLC / % Yield / % Impurities / % Maximum single impurity / % 6:1 100％ 100％ none none 5:1 100％ 100％ none none 4:1 100％ 100％ none none 3:1 100％ 100％ none none 2:1 99.8％ 99.8％ 0.2％ 0.09％ 1:1 99.7％ 98％ 0.3％ 0.15％ 1:2 99.79％ 97.5％ 0.21％ 0.11％

[0107] Example 7 Selection of reaction temperature

[0108] The difference between this example and Example 2 is only that the reaction temperature is changed, the purpose is to investigate the effect of the reaction temperature on the product, the results are shown in Table 5. The results show that when the reaction temperature is 0-10°C, the purity and yield of the obtained product can reach 100%.

[0109] Table 5 Results of reaction temperature selection

[0110] Reaction temperature HPLC / % Yield / % Impurities / % Maximum single impurity / % 0～10℃ 100％ 100％ none none 10～20℃ 98.12％ 95.0％ 1.88％ 1％ 20～30℃ 97.21％ 90.1％ 2.79％ 1.7％

[0111] Example 8 Selection of reaction time

[0112] The difference between this example and Example 2 is only that the reaction time is changed, the purpose is to investigate the effect of the reaction time on the product, and the results are shown in Table 6. The results show that when the reaction time is 30 minutes, the purity and yield of the obtained product can reach 100%.

[0113] Table 6 Selection results of reaction time

[0114] Reaction time HPLC / % Yield / % Impurities / % Maximum single impurity / % 25min 100％ 99.2％ none none 30min 100％ 100％ none none 35min 99.8％ 99.5％ 0.2％ 0.15％ 45min 99.0％ 97.8％ 1.0％ 0.50％ 60min 98.1％ 96.0％ 1.9％ 1.5％

[0115] Example 9 Selection of the volume ratio of ethyl acetate solution to saturated sodium chloride solution

[0116] Compared with Example 2, this example is different only in that the volume ratio of ethyl acetate solution to saturated sodium chloride solution is changed, the purpose is to investigate the effect of volume ratio on the product, and the results are shown in Table 7. The results show that when the volume ratio of ethyl acetate solution to saturated sodium chloride solution is 3:1, 4:1, 5:1 and 6:1, the purity of the obtained product is higher than 99%, and the yield is higher than 98%. Among them, when the volume ratio of ethyl acetate solution to saturated sodium chloride solution is 3:1, the purity and yield of the obtained product both reach 100%.

[0117] Table 7 Selection results of volume ratio of ethyl acetate solution to saturated sodium chloride solution

[0118] EA(ml) / NaCl(ml) HPLC / % Yield / % Impurities / % Maximum single impurity / % 3:1 100％ 100％ none none 4:1 99.86％ 99.1％ 0.14％ 0.08％ 5:1 99.78％ 99.4％ 0.22％ 0.11％ 6:1 99.75％ 99.8％ 0.25％ 0.15％

[0119] Example 10 Destructive Test

[0120] To investigate the stability of the obtained 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole, after the reaction is completed, an extraction operation is performed, and the organic phase is first heated to reflux for 5 hours to collect the organic phase, and the product purity is detected by HPLC. The organic phase is then desolventized, and after one-third of the solvent is removed by distillation, the organic phase is heated to reflux for 5 hours, and the product purity is detected by HPLC; then the remaining half of the solvent is removed by distillation, heated to reflux for 5 hours, and the product purity is detected by HPLC; finally, the solvent is spin-dried, and after heating to reflux for 5 hours, the product purity is detected by HPLC. The experimental results are shown in Table 8, and the results show that the 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole obtained by the pretreatment method provided by the present invention still has good stability as the time of reduced pressure distillation increases, and can be better adapted to industrial production.

[0121] Table 8 Destructive test results

[0122]

[0123] Example 11 Preparation of 6-(ethylthio)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione

[0124] (1) 50.0 g of 6-(ethylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (IM-2), 24.9 g of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole (SM3) obtained by different pretreatment methods in Example 3, and 26.01 g of potassium carbonate were added to 750 mL of DMF and stirred thoroughly;

[0125] (2) After heating to 60° C. for 1 hour, 12.39 g of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole (SM3) and 26.01 g of potassium carbonate were added, and the temperature was maintained constant and the reaction was continued for 7 hours. The reaction solution was monitored by HPLC and IM-2 was less than 10%, which was the end point of the reaction;

[0126] (3) After the reaction is completed, filter and wash the filter cake with DMF; combine the filtrates and drop saturated ammonium chloride solution into the system. Filter and wash the filter cake twice with purified water; add dichloromethane to dissolve the filter cake and wash it twice with purified water, separate the liquids, and collect the lower organic phase; concentrate the organic phase under reduced pressure at 30-40°C to obtain a white solid, which is the product 6-(ethylthio)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione.

[0127] Comparative Example 1

[0128] This comparative example is compared with Example 11, the difference is that 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole is replaced with 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride for reaction. The experimental results are shown in Table 9, wherein "direct reaction" corresponds to directly using 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride for subsequent reaction, and "pretreatment" corresponds to 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride for corresponding pretreatment to obtain 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole for subsequent reaction. As shown in Table 9, the purity, yield, etc. of subsequent compounds can be significantly improved using the pretreatment method provided by the present invention.

[0129] Table 9 Comparative experimental results

[0130]

[0131] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", "some implementation schemes" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, unless they are contradictory.

[0132] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for pretreating 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, characterized in that: The pretreatment method comprises: Dissolving the 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride in a solvent, adding a carbonate or an aqueous solution thereof to react, and obtaining 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole; Wherein, the solvent includes at least one selected from ethyl acetate, dichloromethane, isopropyl acetate, methanol, ethanol, and acetonitrile.

2. The pretreatment method according to claim 1, characterized in that The carbonate comprises an alkali metal carbonate, preferably selected from potassium carbonate and / or sodium carbonate.

3. The pretreatment method according to claim 1, characterized in that: The amount of the carbonate is 0.6-4.0 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride; Optionally, the amount of the carbonate is 1.2-1.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride; Optionally, the amount of the carbonate is 1.5-3.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride; Optionally, the amount of carbonate is 1.2 or 1.5 molar equivalents of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

4. The pretreatment method according to claim 1, characterized in that: The volume ratio of the solvent to the carbonate aqueous solution is (6:1)-(1:2); Optionally, the volume ratio of the solvent to the carbonate aqueous solution is (6:1)-(3:1).

5. The pretreatment method according to claim 1, characterized in that: The reaction temperature is 0-30°C; Optionally, the reaction temperature is 0-10°C.

6. The pretreatment method according to claim 1, characterized in that: The reaction time is 25-60min; Optionally, the reaction time is 25-35 min.

7. The pretreatment method according to claim 1, characterized in that: The pretreatment method further includes: obtaining a reaction product after the reaction is completed, purifying the reaction product to obtain the 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole, and the purification method includes one or more of filtration, extraction, and washing.

8. The pretreatment method according to claim 7, characterized in that: The extraction method comprises: for an organic-aqueous phase mixed solution, extracting the aqueous phase with an extractant after layering, and combining the organic phases; the extractant comprises at least one of ethyl acetate and dichloromethane; The filtering method comprises performing separation treatment on the solid-liquid mixture and collecting the filtrate; The washing method includes washing the organic phase with a saturated sodium chloride solution, or washing the filter cake with a detergent, wherein the detergent includes at least one of methanol, ethanol, dichloromethane and acetonitrile.

9. The pretreatment method according to claim 8, characterized in that: The purification method comprises: (1) The reaction product is a mixed solution, the mixed solution is allowed to stand for stratification, the aqueous phase is extracted with ethyl acetate solution, and the organic phases are combined; (2) washing the organic phase with a saturated sodium chloride solution; Optionally, the volume ratio of the ethyl acetate solution in step (1) to the saturated sodium chloride solution in step (2) is (3:1)-(6:1).

10. A method for preparing 6-(ethylthio)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione, characterized in that: The method comprises reacting 6-(ethylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione with 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole obtained by the pretreatment method according to any one of claims 1 to 9.

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