A preparation method of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole

Abstract

The present invention discloses a method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole, and relates to the field of organic synthesis preparative chemistry. The method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole disclosed in the present invention comprises the following steps: adding formamide to an organic solvent, mixing, stirring, then adding an acid binding agent, cooling to 10°C, adding chloroacetyl chloride dropwise, controlling the dropping temperature at 6-15°C for 30-40 minutes, and then maintaining the temperature at 5-25°C for reaction after the dropping is complete to obtain 2-chloro-N-formyl acetamide; and placing 2-chloro-N-formyl acetamide and methylhydrazine in a chlorinated hydrocarbon solvent, adding sulfuric acid for a cyclization reaction, and obtaining the product. The preparation method of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole provided by the present invention is simple, the operating conditions are easy to control, the raw materials are readily available, the production cost is low, and the yield and purity are high, etc., and the method is suitable for mass production.

Description

Technical Field

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

[0002] 3-(Chloromethyl)-1-methyl-1H-[1,2,4]-triazole, a colorless crystalline compound known as 3-(Chloromethyl)-1-methyl-1H-1,2,4-triazole (CAS: 135206-76-7), is a key intermediate in the synthesis of compounds with antifungal activity. Few synthetic methods have been reported for this compound. Triazoles are heterocyclic compounds containing three nitrogen atoms, and their pharmacophores exhibit diverse biological activities, including antifungal, antituberculosis, and antiviral properties. Triazole-containing compounds have become a hot topic and a key area of ​​research and development in drug synthesis in recent years. Numerous triazole-containing antimicrobial drugs are currently in clinical use, exhibiting a variety of effects. Among them, 1,2,4-triazole can inhibit the growth of Mycobacterium tuberculosis by blocking lipid biosynthesis or other mechanisms of action. In addition to its antibacterial activity, 1,2,4-triazole also has multiple biological activities such as anti-tumor, anti-HIV, anti-influenza, anti-inflammatory, anti-malarial, anti-hepatitis C and anti-tuberculosis, and has the advantages of broad spectrum, high efficiency, low toxicity and low drug resistance.

[0003] Currently, there are relatively few reports on the synthesis of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole, which is mainly obtained by chlorination of 1-methyl-1H-[1,2,4]triazol-3-yl-methanol. There are more reports on the synthesis of 1-methyl-1H-[1,2,4]triazol-3-yl-methanol, and the literature Journal of Organic Chemistry, 2022, 67, 9340-9345 synthesizes it by reacting 1,2,4-triazole with methyl bromide. However, the raw material methyl bromide is a toxic gas, and the production safety is not high.

[0004] The method disclosed in the document Chem.Pharm.Bul.42(1)85-94, 1994 is to use 1H-[1,2,4]triazole-3-methanol as a raw material, protect the hydroxyl group with tert-butyldimethylsilyl chloride, react with iodomethane in the presence of sodium hydride, and then remove the protecting group in a methanol solution of sodium hydroxide to obtain the target product 1-methyl-1H-[1,2,4]triazole-3-yl-methanol. This method has low selectivity for the target product.

[0005] Chinese patent CN107879992A discloses (1-methyl-1H-[1,2,4]triazol-3-yl)-methanol, which is prepared from hydroxyacetamide by protecting the hydroxyl group with triphenylmethane, formylation with ethyl formate, condensation with methylhydrazine for deprotection, and chlorination. This preparation process is complex, with high production costs, and is not conducive to industrial production.

[0006] Therefore, it is necessary to conduct in-depth research on the synthesis process of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole, so as to provide a better, more practical and economical reaction route with readily available raw materials to meet the growing market demand. Summary of the Invention

[0007] The main purpose of the present invention is to provide a method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole with low cost, high purity and high yield. The method has readily available raw materials, low price, easy-to-control operating conditions and is suitable for mass production.

[0008] In order to achieve the purpose of the present invention, the present invention provides a method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole, which specifically comprises the following steps:

[0009] (1) Formamide, chloroacetyl chloride and an acid binding agent react in an organic solvent to obtain the intermediate 2-chloro-N-formylacetamide;

[0010] (2) The above-mentioned 2-chloro-N-formylacetamide and methylhydrazine are placed in a chlorinated hydrocarbon solvent, and 98% sulfuric acid is added to carry out a cyclization reaction to obtain the target product 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole.

[0011] Furthermore, in the step (1), the molar ratio of formamide, chloroacetyl chloride and acid binding agent is 1:(1.0-1.2):(1.2-1.5).

[0012] Furthermore, in step (1), the organic solvent is a chlorinated hydrocarbon solvent.

[0013] Furthermore, in the step (1), the reaction temperature is 5-25° C., and the reaction time is 3-4 h.

[0014] Furthermore, in the step (1), the chloroacetyl chloride is added dropwise at a temperature of 6 to 15° C. for 30 to 40 min.

[0015] Furthermore, the acid binding agent is any one of triethylamine and pyridine.

[0016] Furthermore, the chlorinated hydrocarbon solvent is any one of dichloromethane, chloroform or 1,2-dichloroethane.

[0017] Furthermore, in step (2), the molar ratio of 2-chloro-N-formylacetamide, methylhydrazine and sulfuric acid is 1:(1.0-1.5):(0.01-0.05).

[0018] Furthermore, the cyclization reaction temperature is 25-50° C., and the cyclization reaction time is 3-5 h.

[0019] The present invention has achieved the following beneficial effects:

[0020] 1. The 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole of the present invention is prepared by reacting formamide and chloroacetyl chloride as raw materials under the action of an acid binding agent to obtain an intermediate 2-chloro-N-formylacetamide, which is then cyclized with methylhydrazine under the catalysis of an acid. The preparation method is simple, the operating conditions are easy to control, the raw materials are readily available, the production cost is low, and the yield and purity are high.

[0021] 2. The raw materials of the present invention avoid the use of methyl iodide, which is highly toxic, volatile, and expensive. In addition, the reaction temperature in the preparation process is low, the post-treatment process produces less wastewater, and the operation is safe, making it suitable for mass production.

[0022] 3. The method of the present invention has only two steps of reaction, with a total yield of about 80%; the reaction conditions are mild, the post-treatment process produces little wastewater, and the operation is safe; the raw materials used in the reaction are inexpensive, easily available, and the production cost is low; the reaction solvents such as dichloromethane, chloroform, and dichloroethane can be recycled, making it suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The figure is a schematic diagram of the reaction process of one embodiment of the method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole of the present invention. DETAILED DESCRIPTION

[0024] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0025] A method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole, the reaction process diagram of the preparation method is as follows Figure 1 As shown, the specific steps are:

[0026] (1) Add formamide to an organic solvent and mix with stirring. Then add an acid-binding agent, cool to 10°C, and add chloroacetyl chloride dropwise. The temperature is controlled at 6-15°C for 30-40 minutes. After the addition is complete, keep the temperature at 5-25°C for 3-4 hours. Then add water to the intermediate product and allow it to stand for separation. The aqueous layer is extracted, and the organic phases are combined, concentrated under reduced pressure, and dried to obtain the intermediate 2-chloro-N-formylacetamide as a white crystal.

[0027] Preferably, the molar ratio of formamide, chloroacetyl chloride and acid binding agent is 1:(1.0-1.2):(1.2-1.5);

[0028] Preferably, the acid binding agent is triethylamine or pyridine; and the organic solvent is any one of dichloromethane, chloroform or 1,2-dichloroethane.

[0029] (2) The prepared 2-chloro-N-formylacetamide and methylhydrazine are added to a chlorinated hydrocarbon solvent, mixed, stirred, and sulfuric acid is added. The mixture is kept at 25-50°C for 3-5 hours, with the raw material content being controlled to be less than 1%. The pH of the reaction product is then adjusted to 6-7 with a saturated sodium carbonate solution, allowed to stand for separation, the aqueous layer is extracted, and the organic layers are combined, concentrated under reduced pressure, recrystallized, filtered, and dried to obtain colorless needle-shaped crystals of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole.

[0030] Preferably, the molar ratio of the above-mentioned 2-chloro-N-formylacetamide, methylhydrazine and sulfuric acid is 1: (1.0-1.5): (0.01-0.05);

[0031] The chlorinated hydrocarbon solvent is any one of dichloromethane, chloroform or 1,2-dichloroethane.

[0032] The preparation method of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole of the present invention is described below with reference to specific examples.

[0033] Example 1:

[0034] A method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole is as follows:

[0035] The first step is to add formamide 45g (1.0mol) and dichloromethane 300mL into a 1000ml four-necked flask with stirring, thermometer and condenser, turn on stirring, then add triethylamine 121g (1.2mol), cool to 10°C, add chloroacetyl chloride 136g (1.2mol), control the dropping temperature at 10°C, add for 30 minutes, keep at 10°C for 3 hours after dropwise addition, take sampling and control analysis, add 200g water after passing the test, stir for 30 minutes, let stand and delaminate, separate the lower organic layer, extract the aqueous layer with 2×150mL dichloromethane, combine the organic phases, concentrate the organic phase under reduced pressure to obtain a crude product, and dry to obtain 110g of 2-chloro-N-formylacetamide as white crystals with a yield of 88.9% and a purity of 98.2%.

[0036] In the second step, 121.5 g (1.0 mol) of 2-chloro-N-formylacetamide, 55 g (1.2 mol) of methylhydrazine and 400 mL of dichloromethane were added to a 1000 ml four-necked flask equipped with a stirrer, a thermometer and a condenser. The stirring was started and 2 g (0.02 mol) of sulfuric acid was added. The mixture was kept warm at 30°C for 5 hours. The concentration of the raw material was controlled to be less than 1%. The pH value was adjusted to 7 with a saturated sodium carbonate solution. The mixture was allowed to stand and the layers were separated. The aqueous layer was extracted with 2×150 ml of dichloromethane. The organic layers were combined and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol / water (1:3), filtered and dried to obtain 121 g of colorless needle-shaped crystals of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole with a yield of 90.6% and a purity of 98.5%.

[0037] Example 2

[0038] A method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole is as follows:

[0039] The first step is to add formamide 45g (1.0mol) and chloroform 320mL to a 1000ml four-necked flask with stirring, thermometer and condenser, turn on stirring, then add triethylamine 152g (1.5mol), cool to 10℃, add chloroacetyl chloride 124g (1.1mol), control the dropping temperature at 13℃, add time for 35 minutes, keep warm at 16℃ for 3.5 hours after dropwise addition, take sampling and control analysis, add 200g water after passing the test, stir for 30 minutes, let stand and delaminate, separate the lower organic layer, extract the aqueous layer with 2×150mL chloroform, combine the organic phases, concentrate the organic phase solvent under reduced pressure to give a crude product, and dry to give 112g of 2-chloro-N-formylacetamide as white crystals with a yield of 90.6% and a purity of 98.3%.

[0040] In the second step, 121.5 g (1.0 mol) of 2-chloro-N-formylacetamide, 69 g (1.5 mol) of methylhydrazine and 400 mL of chloroform were added to a 1000 ml four-necked flask equipped with a stirrer, a thermometer and a condenser, and stirring was started. 1 g (0.01 mol) of sulfuric acid was added and the mixture was kept warm at 40° C. for 3.5 hours. The concentration of the raw material was controlled to be less than 1%. The pH value was adjusted to 7 with a saturated sodium carbonate solution. The mixture was allowed to stand and the layers were separated. The aqueous layer was extracted with 2×150 ml of chloroform. The organic layers were combined and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol / water (1:3), filtered and dried to obtain 120.5 g of colorless needle-shaped crystals of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole with a yield of 90% and a purity of 98.3%.

[0041] Example 3

[0042] A method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole is as follows:

[0043] The first step is to add 45g (1.0mol) of formamide and 320mL of 1,2-dichloroethane to a 1000ml four-necked flask with stirring, a thermometer, and a condenser, start stirring, then add 131g (1.3mol) of triethylamine, cool to 10°C, add 119g (1.05mol) of chloroacetyl chloride dropwise, control the addition temperature at 15°C, and add for 40 minutes. After the dropwise addition is completed, keep warm at 20°C for 3.5 hours, take samples for central control analysis, add 200g of water after passing the test, stir for 30 minutes, let stand and separate, separate the lower organic layer, extract the aqueous layer with 2×150mL of 1,2-dichloroethane, combine the organic phases, and concentrate the solvent under reduced pressure to obtain a crude product, which is dried to obtain 111g of white crystals of 2-chloro-N-formylacetamide with a yield of 90.2% and a purity of 98.7%.

[0044] In the second step, 121.5 g (1.0 mol) of 2-chloro-N-formylacetamide, 60 g (1.3 mol) of methylhydrazine and 450 mL of 1,2-dichloroethane were added to a 1000 ml four-necked flask equipped with a stirrer, a thermometer and a condenser. Stirring was started, 5 g (0.05 mol) of sulfuric acid was added, and the mixture was kept warm at 45° C. for 3.5 hours. The concentration of the raw material was controlled to be less than 1%. The pH value was adjusted to 7 with a saturated sodium carbonate solution. The mixture was allowed to stand and separate into layers. The aqueous layer was extracted with 2×150 ml of 1,2-dichloroethane. The organic layers were combined and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol / water (1:3), filtered and dried to obtain 121 g of colorless needle-shaped crystals of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole with a yield of 90.7% and a purity of 98.6%.

[0045] Example 4

[0046] A method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole is as follows:

[0047] The first step is to add 45g (1.0mol) of formamide and 350mL of 1,2-dichloroethane to a 1000ml four-necked flask with stirring, a thermometer, and a condenser, start stirring, then add 111g (1.4mol) of pyridine, cool to 10°C, add 124g (1.1mol) of chloroacetyl chloride dropwise, control the addition temperature at 6°C, and add for 35 minutes. After the dropwise addition is completed, keep warm at 5°C for 4 hours, take samples for central control analysis, add 200g of water after passing the test, stir for 30 minutes, let stand and separate, separate the lower organic layer, extract the aqueous layer with 2×150mL1,2-dichloroethane, combine the organic phases, and concentrate the solvent under reduced pressure to obtain a crude product, which is dried to obtain 113g of white crystals of 2-chloro-N-formylacetamide with a yield of 91.6% and a purity of 98.5%.

[0048] In the second step, 121.5 g (1.0 mol) of 2-chloro-N-formylacetamide, 69 g (1.5 mol) of methylhydrazine and 400 mL of 1,2-dichloroethane were added to a 1000 ml four-necked flask equipped with a stirrer, a thermometer and a condenser. Stirring was started, 1 g (0.01 mol) of sulfuric acid was added, and the mixture was kept warm at 25° C. for 5 hours. The concentration of the raw material was controlled to be less than 1%. The pH value was adjusted to 7 with a saturated sodium carbonate solution. The mixture was allowed to stand and separate into layers. The aqueous layer was extracted with 2×150 ml of 1,2-dichloroethane. The organic layers were combined and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol / water (1:3), filtered and dried to obtain 121 g of colorless needle-shaped crystals of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole with a yield of 90.5% and a purity of 98.3%.

[0049] Example 5

[0050] A method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole is as follows:

[0051] The first step is to add formamide 45g (1.0mol) and chloroform 320mL to a 1000ml four-necked flask with stirring, thermometer and condenser, turn on stirring, then add pyridine 95g (1.2mol), cool to 10°C, add chloroacetyl chloride 136g (1.2mol), control the addition temperature at 8°C, add for 40 minutes, keep warm at 25°C for 3 hours after dropwise addition, take samples for central control analysis, add 200g water after passing the test, stir for 30 minutes, let stand for stratification, separate the lower organic layer, extract the aqueous layer with 2×150mL chloroform, combine the organic phases, concentrate the solvent under reduced pressure to give a crude product, and dry to give 111g of 2-chloro-N-formylacetamide as white crystals with a yield of 90% and a purity of 98.5%.

[0052] In the second step, 121.5 g (1.0 mol) of 2-chloro-N-formylacetamide, 69 g (1.5 mol) of methylhydrazine and 450 mL of chloroform were added to a 1000 ml four-necked flask equipped with a stirrer, a thermometer and a condenser. Stirring was started, 3 g (0.03 mol) of sulfuric acid was added, and the mixture was kept warm at 50° C. for 3 hours. The concentration of the raw material was controlled to be <1%. The pH value was adjusted to 7 with a saturated sodium carbonate solution. The mixture was allowed to stand and the layers were separated. The aqueous layer was extracted with 2×150 ml of chloroform. The organic layers were combined and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol / water (1:3), filtered and dried to obtain 122 g of colorless needle-shaped crystals of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole with a yield of 91.3% and a purity of 98.4%.

[0053] Example 6:

[0054] A method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole is as follows:

[0055] The first step is to add formamide 45g (1.0mol) and dichloromethane 300mL to a 1000ml four-necked flask with stirring, thermometer and condenser, turn on stirring, then add pyridine 118.5g (1.5mol), cool to 15°C, add chloroacetyl chloride 133g (1.0mol), control the addition temperature at 15°C, add the solution for 30 minutes, keep the temperature at 15°C for 4 hours after the dropwise addition, take a sample for central control analysis, add 200g of water after passing the test, stir for 30 minutes, let stand for stratification, separate the lower organic layer, extract the aqueous layer with 2×150mL dichloromethane, combine the organic phases, concentrate the solvent under reduced pressure to give a crude product, and dry to give 111g of 2-chloro-N-formylacetamide as white crystals with a yield of 89.6% and a purity of 98.1%.

[0056] In the second step, 121.5 g (1.0 mol) of 2-chloro-N-formylacetamide, 69 g (1.5 mol) of methylhydrazine and 400 mL of dichloromethane were added to a 1000 ml four-necked flask equipped with a stirrer, a thermometer and a condenser. The stirring was started and 3 g (0.03 mol) of sulfuric acid was added. The mixture was kept warm at 35° C. for 4 hours. The concentration of the raw material was controlled to be less than 1%. The pH value was adjusted to 7 with a saturated sodium carbonate solution. The mixture was allowed to stand and the layers were separated. The aqueous layer was extracted with 2×150 ml of dichloromethane. The organic layers were combined and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol / water (1:3), filtered and dried to obtain 120 g of colorless needle-shaped crystals of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole with a yield of 89.5% and a purity of 98.1%.

[0057] Comparative Example 1

[0058] The (1-methyl-1H-[1,2,4]triazol-3-yl)-methanol disclosed in Chinese patent CN107879992A is prepared from hydroxyacetamide as a raw material. After the hydroxyl group is protected by triphenylmethane, the product is formylated with ethyl formate, and then condensed with methylhydrazine for deprotection to obtain the intermediate product (1-methyl-1H-[1,2,4]triazol-3-yl)-methanol, which is then chlorinated to obtain the product.

[0059] The first step is to add 50g (0.666mol, 1.0eq) 2-hydroxyacetamide and 660 grams of dichloromethane in a 1000ml four-necked flask with stirring, thermometer and condenser, stir, then add 204.1g (0.732mol, 1.1eq) triphenylmethane and 87.6g (0.866mol, 1.3eq) triethylamine, be warming up to reflux, be incubated for 2 hours, treat that the raw material reaction is complete, cool, add 100 grams of water, stir 30 minutes, stratify, separate lower floor's organic phase, then use 150 grams of dichloromethane to extract aqueous phase, merge organic phase, organic phase is concentrated under reduced pressure solvent to obtain crude product, crude product is made pulp through ethyl acetate / normal heptane (1:4), suction filtration, dry to give 190.2g of 2-trityloxyacetamide as white solid, yield 90%, purity 98.1%.

[0060] In the second step, 190.2 g (0.6 mol, 1.0 eq) of 2-trityloxyacetamide and 900 g of ethyl formate were added to a 2000 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser. The mixture was stirred and heated to reflux. The mixture was kept warm for 12 hours. Sampling and analysis showed that the remaining raw material was less than 2%. The temperature was lowered and the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from toluene / ethyl acetate (10:1), filtered, and dried to obtain 153.4 g of N-formyl-2-trityloxyacetamide as a white solid with a yield of 74.3% and a purity of 97.5%.

[0061] The third step was to add 153.4 g (0.445 mol, 1.0 eq) of N-formyl-2-trityloxyacetamide, 22.5 g (0.489 mol, 1.0 eq) of methylhydrazine and 1000 g of dichloromethane to a 1000 ml four-necked flask equipped with a stirrer, a thermometer and a condenser. Stirring was started, and 0.76 g (4.5 mmol, 0.01 eq) of p-toluenesulfonic acid was added. The mixture was stirred at room temperature for 4 hours. The remaining raw material was less than 1%. 225 mL of 2 mol / L hydrochloric acid was added dropwise and stirred at room temperature for 2 hours. The pH value was adjusted to 7 with saturated sodium carbonate solution. The layers were separated and the aqueous layer was extracted with dichloromethane (100 ml). X2), the organic layers were combined and the solvent was concentrated under reduced pressure to obtain a crude product, which was recrystallized from ethanol / water (1:2), filtered, and dried to obtain 40.7 g of colorless needle-shaped crystals of (1-methyl-1H-[1,2,4]triazol-3-yl)-methanol, with a yield of 81% and a purity of 97.3%.

[0062] The 4th step, add (1-methyl isophthalic acid H-[1,2,4] triazole-3-yl)-methanol 40.7g (0.36mol, 1.0eq) in the 1000ml four-hole boiling flask with stirring, thermometer, condenser, 500 gram methylene dichloride, open and stir, be cooled to 20 ℃, add sulfur oxychloride 55.3g (0.468mol, 1.3eq), in 20 ℃ of insulations 4 hours, raw material residue<1%, add 200 gram water, it is 7 that saturated sodium carbonate solution is adjusted pH value, layering, dichloromethane extraction (100mlX2) for water layer, the organic layer merges concentrated under reduced pressure solvent and obtains crude product, crude product is through ethanol / water (1:3) recrystallization, suction filtration, dry colorless needle-shaped crystals 3-(chloromethyl)-1-methyl isophthalic acid H-[1,2,4]-triazole 42.5g, yield 88%, purity 98.1% (the 4th step is conventional chlorination process).

[0063] The total yield of 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole obtained in Comparative Example 1 was 48%.

[0064] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by any technician familiar with this technical field within the technical scope disclosed by the present invention should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole, characterized in that: The specific steps include: (1) Formamide, chloroacetyl chloride and an acid-binding agent react in an organic solvent to obtain the intermediate 2-chloro-N-formylacetamide; (2) placing the above-mentioned 2-chloro-N-formylacetamide and methylhydrazine in a chlorinated hydrocarbon solvent, adding sulfuric acid to carry out a cyclization reaction to obtain the target product 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole; The molar ratio of formamide, chloroacetyl chloride and acid binding agent is 1: (1.0-1.2): (1.2-1.5); The organic solvent is a chlorinated hydrocarbon solvent; In the step (1), the reaction temperature is 5-25°C and the reaction time is 3-4h; The acid binding agent is any one of triethylamine and pyridine; The molar ratio of the 2-chloro-N-formylacetamide, methylhydrazine and sulfuric acid is 1: (1.0-1.5): (0.01-0.05).

2. The method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole according to claim 1, wherein In the step (1), chloroacetyl chloride is added dropwise at a temperature of 6 to 15° C. for 30 to 40 minutes.

3. The method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole according to claim 1, characterized in that: The chlorinated hydrocarbon solvent is any one of dichloromethane, chloroform or 1,2-dichloroethane.

4. The method for preparing 3-(chloromethyl)-1-methyl-1H-[1,2,4]-triazole according to claim 1, characterized in that: The cyclization reaction temperature is 25-50° C., and the cyclization reaction time is 3-5 hours.

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