Preparation method of 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole

Abstract

The invention provides a preparation method of 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole, which comprises the following steps: firstly reacting 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid with a chlorinating agent to generate a trichloromethyl group, and then reacting the trichloromethyl group with a fluorinating agent to convert the trifluoromethyl group. Furthermore, 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid is prepared using 2-bromo-4-chloroaniline as a raw material. The preparation method provided by the invention has the advantages of more economical raw materials, high reaction conversion rate, easy purification, and the like, and has good industrialization prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole. Background Art

[0002] Asundexian, English name Asundexian, has the following structural formula:

[0003]

[0004] Ashoksen is a new type of coagulation factor Xla (Factor XIa, FXIa for short) inhibitor, or a dual inhibitor of factor Xla and plasma kallikrein, launched by Bayer in WO2017005725A1. It can therefore be used to treat, inhibit or improve one or more disease states that can benefit from factor Xla or plasma kallikrein inhibitors, including thrombosis, embolism, hypercoagulability or fibrotic changes.

[0005] Further research into its chemical structure has been conducted by domestic and international companies and institutions, including Merck's WO2017074832A1, Jiangxi Jimin's CN112028877A, Shanghai Meiyue Bio's WO222222960A1, and Chengdu Taihe Weiye Bio's CN116283750A. Bayer's original research route and the aforementioned patented synthesis routes all involve the use of Compound V, a key intermediate.

[0006]

[0007] There are two main synthetic routes for compound V reported so far:

[0008] WO2017005725A1 discloses a two-step reaction using 2-bromo-4-chloroaniline as the starting material to obtain compound V. The final step of this route uses trifluoropropyne, which is not a commonly available commercial reagent and requires customization. This is very expensive, resulting in extremely high production costs, making it unsuitable for industrialization.

[0009]

[0010] The method disclosed in CN112028877A uses 2-bromo-4-chloroaniline as a raw material, first converting the amino group to formamide, then to isocyanide, which is then reacted with trifluoroethyldiazonium under the catalysis of silver carbonate to obtain Compound V. However, isocyanide compounds are unstable, toxic, and have a foul odor; trifluoroethyldiazonium is a toxic gas that easily decomposes and is inconvenient to use; and silver carbonate, as a catalyst, requires large quantities and is expensive. Most importantly, the triazole cyclization reaction has difficult-to-control side reactions, resulting in an extremely low yield (37% reported in the patent). Furthermore, two post-processing steps in this route require normal-phase column purification, making it unsuitable for industrialization.

[0011]

[0012] In addition, the method of converting triazolecarboxylic acid into trifluoromethyl has also been reported in the literature (J.Org.Chem.2020,85,3110-3124 and Synthesis 2010,No.7,pp 1075-1077). The reagent used in the reaction is mainly sulfur tetrafluoride, which is a low-boiling (boiling point below -40°C) toxic and corrosive gas with high operating requirements; the autoclave used in the reaction needs to be heated to above 120°C, and high temperature and high pressure have high requirements on equipment. This method is difficult to apply to industrial production.

[0013]

[0014] Similarly, numerous literature and patents report methods for converting trichloromethyl to trifluoromethyl, primarily using hydrogen fluoride as the fluorination reagent. For example, CN107400052A and CN106316933A employ direct hydrogen fluoride at 70-90°C and 1-2 MPa to obtain trifluoromethyl compounds, simultaneously converting the chlorine on the aromatic ring to fluorine. Journal of Fluorine Chemistry, 2010, vol. 131, 1241-1246 and CN104557683A achieve the conversion at 50°C and 7500 Torr. CN106397309 achieves the conversion at 170-180°C and 1500 Torr. WO2014 / 198278 and CN109988101A both require high temperature and high pressure to complete the conversion. These conditions involve high temperature and high pressure, requiring stringent equipment, making them difficult to commercialize. Furthermore, the bromine and chlorine on the benzene ring structure of compound V are easily fluorinated under such conditions to generate impurities, which makes purification difficult and reduces the yield.

[0015]

[0016] In summary, existing synthetic routes for Compound V suffer from drawbacks such as limited availability of raw materials, high cost, low yield, difficulty in purification, high toxicity of related reagents, inconvenience in use, and demanding production process conditions. Therefore, it is imperative to develop a process route that is lower in cost, more operational, and with higher yields that is amenable to industrial production. Summary of the Invention

[0017] In view of the shortcomings of the prior art described above, the object of the present invention is to provide a method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole, so as to obtain a preparation method with better operability, low cost, high yield, easy purification, and suitable for large-scale industrial production.

[0018] To achieve the above-mentioned and other related purposes, the present invention provides a method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole, comprising the following steps:

[0019] 1) reacting compound III with a chlorinating agent to obtain compound IV;

[0020] 2) reacting compound IV with a fluorinating agent to obtain compound V, i.e., 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole;

[0021]

[0022] Preferably, the compound III in step 1) is prepared by the following method:

[0023] A) using a one-pot method to react compound I or a salt thereof stepwise with a diazotizing agent and an azide reagent to obtain compound II;

[0024] B) performing a cyclization reaction of compound II with propiolic acid in the presence of a catalyst to obtain compound III; or performing a cyclization reaction of compound II with a propiolic acid derivative in the presence or absence of a catalyst, followed by hydrolysis to obtain compound III;

[0025]

[0026] As described above, the preparation method of 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole of the present invention has the following beneficial effects:

[0027] The reagents used in the preparation method of the present invention are all conventional commercially available reagents, which are low in price and easily available. The preparation method of the present invention has a high conversion rate, especially in the fluorination step, with few by-products and easy purification, thereby greatly reducing the cost.

[0028] The entire production process of the preparation method of the present invention is simple to operate and has low risk, thereby minimizing harm to the environment and injury to operators. Moreover, the reaction can be carried out at normal pressure and low temperature, thus meeting the requirements of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Shown is a synthetic route for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole using 2-bromo-4-chloroaniline as the starting material. DETAILED DESCRIPTION

[0030] The following describes the embodiments of the present invention through specific examples. Those skilled in the art will readily understand the other advantages and benefits of the present invention from the disclosure herein. The present invention may also be implemented or applied through various other specific embodiments, and the details in this specification may be modified or altered based on different viewpoints and applications without departing from the spirit of the present invention.

[0031] Please refer to the accompanying drawings. It should be noted that the illustrations provided in this embodiment are merely schematic illustrations of the basic concept of the present invention. Therefore, the drawings only show components relevant to the present invention and are not drawn according to the number, shape, and size of components in actual implementation. In actual implementation, the type, quantity, and proportion of each component may be varied arbitrarily, and the component layout may also be more complex.

[0032] The present invention provides a method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole, comprising the following steps:

[0033] 1) reacting compound III with a chlorinating agent to obtain compound IV;

[0034] 2) reacting compound IV with a fluorinating agent to obtain compound V, i.e., 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole;

[0035]

[0036] In some embodiments of the present invention, the chlorination agent in step 1) is selected from one or more of phosphorus oxychloride, phosphorus pentachloride, and dichlorophenylphosphine. In a preferred embodiment of the present invention, the chlorination agent in step 1) is selected from one or more of phosphorus oxychloride, phosphorus pentachloride, and dichlorophenylphosphine.

[0037] In some embodiments of the present invention, the molar ratio of compound III to the chlorination reagent in step 1) is 1:0.5-4. For example, 1:0.5-1, 1:1-1.5, 1:1.5-2, 1:2-2.5, 1:2.5-3, 1:3-3.5 or 1:3.5-4.

[0038] In some embodiments of the present invention, the reaction temperature of the compound III and the chlorination reagent in step 1) is 80-130° C., for example, 80-85° C., 85-90° C., 90-95° C., 95-100° C., 100-105° C., 105-110° C., 110-115° C., 115-120° C., 120-125° C., or 125-130° C.

[0039] In some embodiments of the present invention, the reaction time of the compound III and the chlorination reagent in step 1) is 12 to 24 hours, for example, 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 20 hours, 20 to 22 hours, or 22 to 24 hours.

[0040] In some embodiments of the present invention, the reaction in step 1) is carried out in a solvent selected from one or more of dichloroethane, chlorobenzene, and dichlorobenzene. In a preferred embodiment of the present invention, the solvent is selected from one or more of dichloroethane, chlorobenzene, and dichlorobenzene.

[0041] In some embodiments of the present invention, the fluorination agent in step 2) is selected from one or more of hydrogen fluoride, triethylamine salt of hydrogen fluoride, and pyridinium salt of hydrogen fluoride. In a preferred embodiment of the present invention, the fluorination agent in step 2) is selected from one or more of triethylamine salt of hydrogen fluoride and pyridinium salt of hydrogen fluoride.

[0042] In some embodiments of the present invention, the reaction in step 2) is carried out with or without a catalyst, and the catalyst is selected from one or more of ferric chloride, zinc chloride, nickel chloride, antimony pentachloride, molybdenum hexachloride, and molybdenum pentachloride.

[0043] Wherein, the molar ratio of compound IV to the fluorination agent and catalyst in step 2) is 1:3-6:0-0.05, for example, 1:3-4:0-0.05, 1:4-5:0-0.05, 1:5-6:0-0.05, 1:3-6:0-0.01, 1:3-6:0.01-0.02, 1:3-6:0.02-0.03, 1:3-6:0.03-0.04, or 1:3-6:0.04-0.05.

[0044] The reaction temperature of the reaction of compound IV with the fluorinating agent in step 2) is 20-80° C., for example, 20-25° C., 25-30° C., 30-35° C., 35-40° C., 40-45° C., 45-50° C., 50-55° C., 55-60° C., 60-65° C., 65-70° C., 70-75° C., or 75-80° C. In general, increasing the reaction temperature is beneficial to accelerating the reaction rate, but it should be considered that increasing the reaction temperature may lead to the occurrence of side reactions.

[0045] When the fluorinating agent is triethylamine hydrogen fluoride or pyridinium hydrogen fluoride, the reaction temperature with the fluorinating agent in step 2) is 20-65° C., for example, 20-25° C., 25-30° C., 30-35° C., 35-40° C., 40-45° C., 45-50° C., 50-55° C., 55-60° C., or 60-65° C.

[0046] When the fluorinating agent is hydrogen fluoride, the reaction temperature with the fluorinating agent in step 2) is 60-80°C, for example, 60-65°C, 65-70°C, 70-75°C or 75-80°C.

[0047] It is known that at temperatures higher than these, the fluorination reaction will produce more complex side reactions, one of which is the replacement of chlorine and bromine in the compound IV molecule by fluorine, thereby generating 1-(2-fluoro-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole and 1-(2,4-difluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole. Since these impurities are structurally similar to the target compound V, purification and separation are difficult, seriously affecting the quality and yield of the target substance.

[0048] The reaction time of the compound IV and the fluorination reagent in step 2) is 8 to 48 hours, for example, 8 to 12 hours, 12 to 16 hours, 16 to 20 hours, 20 to 24 hours, 24 to 28 hours, 28 to 32 hours, 32 to 36 hours, 36 to 40 hours, 40 to 44 hours, or 44 to 48 hours.

[0049] The reaction in step 2) is carried out in a solvent selected from one or more of dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, xylene, benzonitrile, dichlorobenzene, and difluorotrifluoromethylbenzene. In a preferred embodiment of the present invention, the solvent is selected from one or more of dichloroethane, dichloromethane, dimethyl sulfoxide, benzonitrile, dichlorobenzene, and difluorotrifluoromethylbenzene.

[0050] In some embodiments of the present invention, Figure 1 As shown, the compound III in step 1) is prepared by the following method:

[0051] A) using a one-pot method to react compound I or a salt thereof stepwise with a diazotizing agent and an azide reagent to obtain compound II;

[0052] B) performing a cyclization reaction of compound II with propiolic acid in the presence of a catalyst to obtain compound III; or performing a cyclization reaction of compound II with a propiolic acid derivative in the presence or absence of a catalyst, followed by hydrolysis to obtain compound III;

[0053]

[0054] Wherein, the diazotization reagent in step A) is selected from one of sodium nitrite / hydrochloric acid, sodium nitrite / sulfuric acid, isopropyl nitrite, tert-butyl nitrite, and isoamyl nitrite. In a preferred embodiment of the present invention, the diazotization reagent in step A) is selected from one of sodium nitrite / hydrochloric acid, isopropyl nitrite, and tert-butyl nitrite.

[0055] The azide reagent in step A) is selected from one or more of sodium azide, azidotrimethylsilane, and p-toluenesulfonyl azide. In a preferred embodiment of the present invention, the azide reagent in step A) is selected from one or more of sodium azide and azidotrimethylsilane.

[0056] The molar ratio of compound I or its salt to the diazotizing agent and the azide agent in step A) is 1:1-2:1-2. For example, 1:1-1.2:1-2, 1:1.2-1.4:1-2, 1:1.4-1.6:1-2, 1:1.6-1.8:1-2, 1:1.8-2:1-2, 1:1-2:1-1.2, 1:1-2:1.2-1.4, 1:1-2:1.4-1.6, 1:1-2:1.6-1.8, or 1:1-2:1.8-2.

[0057] The one-pot reaction temperature in step A) is 0-30°C, for example, 0-5°C, 5-10°C, 10-15°C, 15-20°C, 20-25°C or 25-30°C.

[0058] The one-pot reaction time in step A) is 2 to 6 hours, for example, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours or 5 to 6 hours.

[0059] The one-pot reaction solvent in step A) is selected from one or more of water, dichloromethane, ethyl acetate, methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, and toluene. In a preferred embodiment of the present invention, the one-pot reaction solvent in step A) is selected from one or more of water, methanol, ethanol, acetonitrile, acetone, and tetrahydrofuran.

[0060] The propiolic acid derivative in step B) is selected from one or more of methyl propiolate, ethyl propiolate, and tert-butyl propiolate. In a preferred embodiment of the present invention, the propiolic acid derivative in step B) is selected from one or more of methyl propiolate and tert-butyl propiolate.

[0061] The catalyst in step B) is selected from one or more of cuprous oxide and cuprous bromide. In a preferred embodiment of the present invention, the catalyst in step B) is cuprous oxide.

[0062] The molar ratio of compound II, propiolic acid or a propiolic acid derivative, and catalyst in step B) is 1:1-1.5:0-0.1, for example, 1:1-1.1:0-0.1, 1:1.1-1.2:0-0.1, 1:1.2-1.3:0-0.1, 1:1.3-1.4:0-0.1, 1:1.4-1.5:0-0.1, 1:1-1.5:0-0.02, 1:1-1.5:0.02-0.04, 1:1-1.5:0.04-0.06, 1:1-1.5:0.06-0.08, or 1:1-1.5:0.08-0.1.

[0063] The cyclization reaction time in step B) is 2 to 24 hours, for example, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, 10 to 12 hours, 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 20 hours, 20 to 22 hours, or 22 to 24 hours.

[0064] The cyclization reaction temperature in step B) is 60-110°C, for example, 60-65°C, 65-70°C, 70-75°C, 75-80°C, 80-85°C, 85-90°C, 90-95°C, 95-100°C, 100-105°C or 105-110°C.

[0065] The ring-closure reaction in step B) is carried out in the presence of a solvent selected from one or more of methanol, ethanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, or toluene. In a preferred embodiment of the present invention, the solvent is selected from one or more of methanol, ethanol, acetonitrile, ethyl acetate, tetrahydrofuran, and toluene. If the ring-closure reaction does not use a catalyst, a higher temperature and a longer reaction time are required.

[0066] The hydrolysis in step B) is acidic hydrolysis or alkaline hydrolysis; the acid used in the acidic hydrolysis is selected from one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, or methanesulfonic acid; the base used in the alkaline hydrolysis is selected from one or more of sodium bicarbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, sodium methoxide, and potassium tert-butoxide. In a preferred embodiment of the present invention, the base used in the alkaline hydrolysis is selected from one or more of potassium carbonate, lithium hydroxide, and sodium hydroxide.

[0067] The molar ratio of the compound II to the acid in step B) is 1:3-10, for example 1:3-5, 1:5-7, 1:7-9 or 1:9-10.

[0068] In step B), the molar ratio of the compound II to the base is 1:2-5, for example, 1:2-3, 1:3-4 or 1:4-5.

[0069] The reaction temperature of the hydrolysis in step B) is 20-80° C., for example, 20-25° C., 25-30° C., 30-35° C., 35-40° C., 40-45° C., 45-50° C., 50-55° C., 55-60° C., 60-65° C., 65-70° C., 70-75° C., or 75-80° C.

[0070] The reaction time of the hydrolysis in step B) is 4 to 12 hours, for example, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, 10 to 12 hours or 12 to 14 hours.

[0071] The reaction solvent for the hydrolysis in step B) is selected from one or more of water, dichloromethane, methanol, ethanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, or toluene. In a preferred embodiment of the present invention, the reaction solvent for the hydrolysis in step B) is selected from one or more of water, dichloromethane, methanol, ethanol, and toluene. When acidic hydrolysis is employed, no organic solvent may even be used.

[0072] The raw materials used in the following examples are conventional raw materials in the art and are commercially available. The purity specifications used are analytically pure or chemically pure.

[0073] The analytical methods and instruments used in the following examples are as follows:

[0074] Instrument: LC-2050C high performance liquid chromatograph, supplier: Shimadzu.

[0075] Reagents: acetonitrile (HPLC grade), water (HPLC grade), phosphoric acid (AR grade).

[0076] Chromatographic conditions: chromatographic column, XDB-C18, 4.6×150 mm, 5 um; flow rate: 1.0 mL / min; column temperature: 40°C; detection wavelength: 210 nm.

[0077] Mobile phase: A, 0.1% phosphoric acid aqueous solution; B, acetonitrile;

[0078] Elution gradient:

[0079] Time (min) A(％) B(％) 0.0 90 10 5.0 90 10 15.0 5 95 20.0 5 95 21.0 90 10 25.0 90 10

[0080] Example 1 Compound II: Preparation of 1-azido-2-bromo-4-chlorobenzene

[0081] At 0-10°C, an aqueous solution (60g) of sodium nitrite (11.0g, 160mmol) was slowly added dropwise to a mixture of an aqueous solution (300g) of compound I (30.0g, 145mmol) and concentrated hydrochloric acid (16.2g, 160mmol). After stirring for 1 hour, an aqueous solution (60g) of sodium azide (10.4g, 160mmol) was slowly added to the reaction solution, and stirring was continued for 1 hour. After liquid phase control, ethyl acetate (300g) was added for extraction after the reaction was completed, and the organic phase was washed with saturated sodium bicarbonate aqueous solution (150g) and saturated brine (150g) in sequence. The obtained organic phase was concentrated under reduced pressure and dried to give an off-white solid compound II (31g, yield 91.8%, HPLC: 99.7%). 1 H NMR (400MHz, DMSO): δ7.71 (d, J=2.4Hz, 1H), 7.50 (dd, J=8.8Hz, 2Hz, 1H), 7.39 (d, J=8.8Hz, 1H). 13 C NMR (400MHz, DMSO): 137.80, 133.00, 129.88, 129.43, 121.97, 113.86.

[0082] Example 2 Compound II: Preparation of 1-azido-2-bromo-4-chlorobenzene

[0083] Isopropyl nitrite (4.3 g, 48 mmol) was slowly added to a solution of Compound I (5 g, 24 mmol) in tetrahydrofuran (50 g) at 0-10°C. After stirring for 1 hour, trimethylsilylazide (5.6 g, 48 mmol) was slowly added to the reaction solution. The temperature was naturally increased and stirred for 4 hours. Liquid phase control was used. After the reaction was completed, water (50 g) was added dropwise to crystallize. After filtration and drying, an off-white solid, Compound II (5.3 g, 94.3% yield, HPLC: 99.4%), was obtained.

[0084] Example 3 Compound III: Preparation of 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0085] A mixed solution of compound II (5.1 g, 22 mmol), propiolic acid (2.3 g, 33 mmol) and cuprous oxide (320 mg, 2.2 mmol) in ethyl acetate (50 g) and ethanol (25 g) was heated to reflux (80 ° C) and stirred for 12 hours. Liquid phase central control was used. After the reaction was completed, the mixture was filtered while hot and the filtrate was concentrated under reduced pressure to obtain an off-white crude product. The crude product was slurried with methanol, filtered and dried to obtain compound III as a white solid (4.3 g, yield 64.8%, HPLC: 98.1%). 1H NMR (400MHz, DMSO): δ13.40 (s, 1H), 9.16 (s, 1H), 8.15 (d, J=2Hz, 1H), 7.80-7.74 (m, 2H). 13 C NMR (400MHz, DMSO): 161.89, 140.32, 136.57, 135.20, 133.37, 131.72, 130.46, 129.49, 120.86.

[0086] Example 4 Compound III: Preparation of 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0087] A solution of compound II (40.0 g, 172 mmol), methyl propiolate (17.4 g, 206 mmol) and cuprous bromide (2.5 g, 17 mmol) in acetonitrile (600 g) was heated to reflux (80 ° C) and stirred for 4 hours. Liquid phase control was used. After the reaction was completed, the mixture was filtered while hot and the filtrate was concentrated under reduced pressure to obtain a light yellow crude product. The crude product was slurried with hexane (200 g), filtered and dried to obtain an off-white solid 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (48.8 g, HPLC: 99.6%).

[0088] A mixture of the above solid (48.8 g, 154 mmol) and sodium hydroxide (18.5 g, 462 mmol) in methanol (490 g) and water (245 g) was stirred at room temperature for 3 hours. Liquid phase control was used. After the reaction was completed, concentrated hydrochloric acid (approximately 47 g) was added dropwise to adjust the pH of the reaction solution to 1-2. After filtration and drying, Compound III (42.1 g, 80.9% yield, HPLC: 99.2%) was obtained as a white solid.

[0089] Example 5 Compound III: Preparation of 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0090] A solution of compound II (5.1 g, 22 mmol) and methyl propiolate (2.8 g, 33 mmol) in toluene (50 g) was heated to reflux (110°C) and stirred for 24 hours. Liquid phase control was used. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a yellowish-brown crude product. The crude product was slurried with methanol, filtered, and dried to obtain a yellow solid compound, methyl 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylate (5.8 g, HPLC: 98.8%).

[0091] A mixture of the above solid (5.8 g, 18 mmol) and lithium hydroxide (2.2 g, 91 mmol) in tetrahydrofuran (30 g) and water (30 g) was stirred at room temperature for 6 hours. Liquid phase chromatography was used. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the tetrahydrofuran. Concentrated hydrochloric acid (approximately 7.5 g) was added dropwise to the remaining reaction solution to adjust the pH to 1-2. After filtration and drying, Compound III (5.2 g, yield 78.3%, HPLC: 98.8%) was obtained as a white solid.

[0092] Example 6 Compound III: Preparation of 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0093] A solution of compound II (5.1 g, 22 mmol), tert-butyl propiolate (3.3 g, 26 mmol), and cuprous oxide (320 mg, 2.2 mmol) in methanol (50 g) was heated to reflux (60°C) and stirred for 2 hours. Liquid phase chromatography was used. After the reaction was completed, the mixture was filtered while hot and the filtrate was concentrated under reduced pressure to obtain a reddish-brown crude product. The crude product was recrystallized from ethyl acetate and hexane, filtered, and dried to obtain tert-butyl 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylate (7.3 g, HPLC: 99.1%) as a light brown solid.

[0094] A mixture of the above solid (7.3 g, 20 mmol) in concentrated hydrochloric acid (7 g) and dichloromethane (21 g) was stirred at room temperature for 12 hours. Liquid phase chromatography was used. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove dichloromethane, filtered, and dried to obtain Compound III (5.9 g, 88.9% yield, HPLC: 98.6%) as a white solid.

[0095] Example 7 Compound III: Preparation of 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0096] A solution of compound II (5.1 g, 22 mmol), tert-butyl propiolate (3.3 g, 26 mmol) and cuprous bromide (310 mg, 2.2 mmol) in methanol (50 g) was heated to reflux (60 ° C) and stirred for 2 hours. Liquid phase control was used. After the reaction was completed, the mixture was filtered while hot and the filtrate was concentrated under reduced pressure to obtain a reddish-brown crude product. The crude product was recrystallized from ethyl acetate and hexane, filtered and dried to obtain a light brown solid compound 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid tert-butyl ester (7.1 g, HPLC: 98.7%).

[0097] A solution of the above solid (7.1 g, 20 mmol) in methanesulfonic acid (21 g) was stirred at room temperature for 4 hours. Liquid phase chromatography was used. After the reaction was complete, water (80 g) was added dropwise to the reaction solution and stirred for 10 minutes. After filtration and drying, a white solid, Compound III (5.1 g, 76.8% yield, HPLC: 97.9%), was obtained.

[0098] Example 8 Compound IV: Preparation of 1-(2-bromo-4-chlorophenyl)-4-(trichloromethyl)-1H-1,2,3-triazole

[0099] A solution of compound III (29.6 g, 98 mmol) and phosphorus oxychloride (60.0 g, 391 mmol) in dichloroethane (120 g) was heated to reflux (80 ° C) and stirred for 24 hours. Liquid phase control was used. After the reaction was completed, 40 ° C hot water (120 g) was added dropwise to the reaction solution to quench the reaction and stirred for 30 minutes. After separation, the organic phase was washed with saturated sodium carbonate aqueous solution (120 g) and saturated brine (120 g) in sequence. After reduced pressure concentration, the resulting oil-solid mixture was slurried with hexane (150 g) and filtered and dried to obtain an off-white solid compound IV (28.4 g, yield 77.2%, HPLC: 98.4%). 1 H NMR (400MHz, DMSO): δ9.21 (d, J=5.2Hz, 1H), 8.17 (d, J=2Hz, 1H), 8.87 (d, J=8.8Hz, 1H), 7.78-7.75 (m, 1H). 13 C NMR (400MHz, DMSO): 150.99, 136.83, 134.98, 133.41, 130.66, 129.53, 126.25, 121.05, 87.96.

[0100] Example 9 Compound IV: Preparation of 1-(2-bromo-4-chlorophenyl)-4-(trichloromethyl)-1H-1,2,3-triazole

[0101] A solution of compound III (13.5 g, 45 mmol) in chlorobenzene (55 g) was heated to an internal temperature of 60-70°C, and phosphorus pentachloride (37.2 g, 178 mmol) was added to the reaction solution in batches. The temperature was continued to rise to reflux (130°C) and stirred for 18 hours. Before reaching the reflux temperature, the low-boiling fraction of the system was collected with a water separator. Liquid phase control was used. After the reaction was completed, 40°C hot water (55 g) was added dropwise to the reaction solution to quench the reaction and stirred for 30 minutes. After separation, the organic phase was washed with saturated sodium carbonate aqueous solution (55 g) and saturated brine (55 g) in sequence. After reduced pressure concentration, the resulting oil-solid mixture was slurried with hexane (40 g), filtered and dried to obtain a light yellow solid compound IV (13.1 g, yield 78.1%, HPLC: 98.1%).

[0102] Example 10 Compound IV: Preparation of 1-(2-bromo-4-chlorophenyl)-4-(trichloromethyl)-1H-1,2,3-triazole

[0103] A solution of compound III (4.8 g, 16 mmol) and phosphorus oxychloride (6.1 g, 40 mmol) in dichlorobenzene (20 g) was heated to an internal temperature of 60-70 ° C, and dichlorophenylphosphine (1.4 g, 8 mmol) was added dropwise to the reaction solution. The temperature was continued to rise to a slight reflux (80 ° C), and the mixture was stirred for 12 hours. The reaction was quenched by adding 40 ° C hot water (20 g) to the reaction solution after the reaction was completed, and the mixture was stirred for 30 minutes. After separation, the organic phase was washed with saturated sodium carbonate aqueous solution (55 g) and saturated brine (55 g) in sequence, and dried over anhydrous sodium sulfate. The obtained organic phase was directly used for the next fluorination after the content was calculated by external standard method.

[0104] Example 11 Preparation of Compound V: 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole

[0105] A solution of compound IV (25.2 g, 67 mmol) and triethylamine hydrogen fluoride (M = 161, 32.4 g, 201 mmol) in dichloroethane (100 g) was heated to 40°C and stirred for 18 hours. Liquid phase control was used. After the reaction was completed, the reaction system was purged with nitrogen for 1 hour. The reaction solution was washed with water (100 g) and concentrated under reduced pressure. The resulting oil-solid mixture was recrystallized from ethyl acetate and hexane, filtered, and dried to obtain compound V (20.4 g, yield 93.2%, HPLC: 98.8%) as a yellow solid. 1 H NMR (400MHz, DMSO): δ9.43 (s, 1H), 8.17 (d, J = 2Hz, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.78 (dd, J = 8.4Hz, 2Hz, 1H). 13 C NMR (400MHz, DMSO): 137.95-136.79 (q, J C-F =39Hz, 1C), 137.03, 134.80, 133.47, 130.64, 129.62, 128.65, 125.09-117.12 (q, J C-F =266Hz,1C)120.96. 19 F NMR (400MHz, DMSO): -59.62.

[0106] Example 12: Preparation of Compound V: 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole

[0107] A solution of compound IV (11.3 g, 30 mmol) and pyridine hydrofluoride (M = 99, 9.8 g, 99 mmol) in dichloromethane (60 g) was heated to reflux (40°C) and stirred for 20 hours. Liquid phase control was used. After the reaction was completed, the reaction system was purged with nitrogen for 1 hour. The reaction solution was washed with water (100 g), concentrated under reduced pressure, and the resulting oil-solid mixture was recrystallized from ethyl acetate and hexane. After filtration and drying, compound V (8.9 g, yield 90.7%, HPLC: 98.4%) was obtained as a yellow solid.

[0108] Example 13 Compound V: Preparation of 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole

[0109] At 60-70°C, hydrogen fluoride gas was slowly introduced into a benzonitrile (100g) solution of compound IV (4.9g, 13mmol), ferric chloride (105mg, 0.65mmol), and antimony pentachloride (39mg, 0.13mmol). The mixture was stirred and maintained at this temperature for 36 hours. Liquid phase control was used. After the reaction was completed, nitrogen was purged into the reaction system for 1 hour. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (50g) and water (50g) in sequence. The organic phase was concentrated under reduced pressure to obtain an oil-solid mixture that was recrystallized with ethyl acetate and hexane. After filtration and drying, compound V (3.6g, yield 84.8%, HPLC: 98.9%) was obtained as a yellow solid.

[0110] Comparative Example 1: Preparation of Compound V: 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole

[0111] A solution of compound IV (4.9 g, 13 mmol) and potassium fluoride (4.5 g, 78 mmol) in dimethyl sulfoxide (25 g) was heated to reflux (180 ° C) and stirred for 16 hours. After the reaction was completed, water (100 g) was added to the reaction solution and stirred for 10 minutes. The filter cake was recrystallized with ethyl acetate and hexane, filtered and dried to obtain a yellow solid compound V (3.6 g, yield 84.8%, HPLC: 93.6%). The mixture was recrystallized again with ethyl acetate and hexane, filtered and dried to obtain a yellow solid compound V (3.5 g, yield 82.5%, HPLC: 94.9%).

[0112] Comparative Example 2: Preparation of Compound V: 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole

[0113] At 100-110°C, hydrogen fluoride gas was slowly introduced into a benzonitrile (100g) solution of compound IV (4.9g, 13mmol), ferric chloride (105mg, 0.65mmol), and antimony pentachloride (39mg, 0.13mmol). The mixture was stirred and maintained at this temperature for 21 hours. Liquid phase control was used. After the reaction was completed, the temperature was lowered to room temperature and the reaction system was purged with nitrogen for 1 hour. The reaction solution was washed sequentially with saturated sodium bicarbonate aqueous solution (50g) and water (50g). The organic phase was concentrated under reduced pressure to obtain an oil-solid mixture that was recrystallized with ethyl acetate and hexane. After filtration and drying, compound V (3.5g, yield 82.5%, HPLC: 92.9%) was obtained as a yellow solid.

[0114] In summary, the method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole of the present invention is a process in which triazolecarboxylic acid (specifically 1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid) is reacted with a chlorinating agent to first generate a trichloromethyl group, and then reacted with a fluorinating agent to convert the trifluoromethyl group, wherein the triazolecarboxylic acid is prepared using 2-bromo-4-chloroaniline as a raw material. The preparation method of the present invention starts from 2-bromo-4-chloroaniline and undergoes multiple steps to prepare 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole in a high yield; the preparation method provided by the present invention has the advantages of more economical raw materials, high reaction conversion rate, few by-products in the fluorination step, and easy purification, and has good industrialization prospects. Therefore, the present invention effectively overcomes the various shortcomings of the prior art and has high industrial utilization value.

[0115] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Anyone skilled in the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by one of ordinary skill in the art without departing from the spirit and technical principles disclosed herein are intended to be covered by the claims of the present invention.

Claims

1. A method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole, characterized in that: The following steps are involved: 1) reacting compound III with a chlorinating agent to obtain compound IV; 2) reacting compound IV with a fluorinating agent to obtain compound V, i.e., 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole; 2. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 1, characterized in that: The chlorination agent in step 1) is selected from one or more of phosphorus oxychloride, phosphorus pentachloride, and dichlorophenylphosphine; and / or, in step 1), the molar ratio of compound III to the chlorination reagent is 1:0.5-4; And / or, the reaction temperature of the reaction of compound III with the chlorination reagent in step 1) is 80-130° C.; and / or, the reaction time of the compound III and the chlorination reagent in step 1) is 12 to 24 hours; And / or, the reaction in step 1) is carried out in a solvent, and the solvent is selected from one or more of dichloroethane, chlorobenzene, and dichlorobenzene.

3. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 1, characterized in that: The fluorination agent in step 2) is selected from one or more of hydrogen fluoride, triethylamine hydrogen fluoride, and pyridinium hydrogen fluoride.

4. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 3, characterized in that: The reaction in step 2) is carried out with or without a catalyst, and the catalyst is selected from one or more of ferric chloride, zinc chloride, nickel chloride, antimony pentachloride, molybdenum hexachloride, and molybdenum pentachloride.

5. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 4, characterized in that: In step 2), the molar ratio of compound IV to the fluorination agent and catalyst is 1:3-6:0-0.05; and / or, the reaction temperature of the compound IV and the fluorination agent in step 2) is 20-80° C.; and / or, the reaction time of the compound IV and the fluorination reagent in step 2) is 8 to 48 hours; And / or, the reaction in step 2) is carried out in a solvent, and the solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, xylene, benzonitrile, dichlorobenzene, and difluorotrifluoromethylbenzene.

6. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 1, characterized in that: The compound III in step 1) is prepared by the following method: A) using a one-pot method to react compound I or a salt thereof stepwise with a diazotizing agent and an azide reagent to obtain compound II; B) performing a cyclization reaction of compound II with propiolic acid in the presence of a catalyst to obtain compound III; or performing a cyclization reaction of compound II with a propiolic acid derivative in the presence or absence of a catalyst, followed by hydrolysis to obtain compound III; 7. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 6, characterized in that: The diazotizing agent in step A) is selected from one or more of sodium nitrite / hydrochloric acid, sodium nitrite / sulfuric acid, isopropyl nitrite, tert-butyl nitrite, and isoamyl nitrite; And / or, the azide reagent in step A) is selected from one or more of sodium azide, trimethylsilyl azide, and p-toluenesulfonyl azide; And / or, in step A), the molar ratio of compound I or its salt to the diazotizing agent and the azide agent is 1:1-2:1-2; and / or, the one-pot reaction temperature in step A) is 0-30° C.; and / or, the one-pot reaction time in step A) is 2 to 6 hours; And / or, the one-pot reaction solvent in step A) is selected from one or more of water, dichloromethane, ethyl acetate, methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, and toluene.

8. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 6, characterized in that: The propiolic acid derivative in step B) is selected from one or more of methyl propiolate, ethyl propiolate, and tert-butyl propiolate; And / or, the catalyst in step B) is selected from one or more of cuprous oxide and cuprous bromide; and / or, in step B), the molar ratio of compound II, propiolic acid or a propiolic acid derivative, and the catalyst is 1:1-1.5:0-0.1; and / or, the cyclization reaction temperature in step B) is 60-110° C.; and / or, the cyclization reaction time in step B) is 2 to 24 hours; And / or, the cyclization reaction in step B) is carried out in the presence of a solvent, and the solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or toluene.

9. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 6, characterized in that: The hydrolysis in step B) is acidic hydrolysis or alkaline hydrolysis; the acid used in the acidic hydrolysis is selected from one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid or methanesulfonic acid; the base used in the alkaline hydrolysis is selected from one or more of sodium bicarbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, sodium methoxide and potassium tert-butoxide.

10. The method for preparing 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole according to claim 9, characterized in that: In step B), the molar ratio of compound II to the acid is 1:3 to 10; and / or, in step B), the molar ratio of the compound II to the base is 1:2-5; and / or, the reaction temperature of the hydrolysis in step B) is 20-80° C.; and / or, the reaction time of the hydrolysis in step B) is 4 to 12 hours; And / or, the reaction solvent for the hydrolysis in step B) is selected from one or more of water, dichloromethane, methanol, ethanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or toluene.

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