Preparation method of 5-bromine-2-trifluoromethylpyrimidine

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 5-bromine-2-trifluoromethylpyrimidine. The preparation method of the 5-bromine-2-trifluoromethylpyrimidine comprises the following steps: step 1, carrying out a dechlorination reaction on 4, 6-dichloro-2-trifluoromethylpyrimidine under the action of a catalyst, a reducing agent and an alkaline reagent, so as to obtain 2-trifluoromethylpyrimidine; and 2, carrying out a bromination reaction on the 2-(trifluoromethyl) pyrimidine and a bromination reagent to obtain the 5-bromine-2-(trifluoromethyl) pyrimidine. The preparation process of the 5-bromine-2-trifluoromethylpyrimidine provided by the invention is relatively low in cost, mild in reaction condition, simple in post-treatment and more suitable for industrial production, and the obtained product is higher in yield and purity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 5-bromo-2-trifluoromethylpyrimidine. Background Art

[0002] 5-Bromo-2-trifluoromethylpyrimidine is an important pharmaceutical intermediate and is widely used in the development of new drugs. For example, it can be used to synthesize Lp-PLA2 inhibitors, TRPA1 modulators, P2X7 receptor antagonists, anticoagulant agents, GRP119 modulators and histamine H3 antagonists, etc., which are used to treat diabetes, Alzheimer's disease and other diseases.

[0003] Chinese patent CN106588783A discloses a method for synthesizing 2-trifluoromethyl-5-bromopyrimidine, specifically disclosing: 2-amino-5-bromopyrimidine is subjected to a diazotization reaction with sodium nitrite in the presence of an acid, followed by the addition of trifluoromethyl boride and a base to obtain 2-trifluoromethyl-5-bromopyrimidine. The preparation process of this patent adopts a diazotization reaction, and the diazonium salt produced by the reaction is extremely dangerous. The diazonium salt is very easy to decompose in a dry state, and can decompose or even explode under the action of heat, friction, impact, etc., which poses a safety hazard and is difficult to be applied industrially. Summary of the invention

[0004] Technical problem solved by the present invention: In the prior art, the synthesis process of 5-bromo-2-trifluoromethylpyrimidine has technical problems such as high raw material cost, low yield, high operation difficulty and difficulty in industrialization.

[0005] In view of the above technical problems, the object of the present invention is to provide a method for preparing 5-bromo-2-trifluoromethylpyrimidine. The synthetic route adopted by the present invention can obtain a product with higher purity and higher yield.

[0006] Specifically, the present invention provides the following technical solutions:

[0007] In one aspect, the present invention provides a method for preparing 5-bromo-2-trifluoromethylpyrimidine, comprising the following steps:

[0008] Step 1: dechlorinating 4,6-dichloro-2-trifluoromethylpyrimidine in the presence of a catalyst, a reducing agent and an alkaline reagent to obtain 2-trifluoromethylpyrimidine;

[0009] Step 2: 2-trifluoromethylpyrimidine is subjected to bromination reaction with a brominating agent to obtain 5-bromo-2-trifluoromethylpyrimidine.

[0010] Preferably, in step 1, the catalyst comprises one or more selected from the group consisting of palladium-containing catalysts, platinum-containing catalysts, rhodium-containing catalysts, ruthenium-containing catalysts and nickel-containing catalysts; more preferably, the catalyst is a palladium-containing catalyst; further preferably, the palladium-containing catalyst comprises one or more selected from the group consisting of Pd / C, bis(triphenylphosphine)palladium dichloride and palladium chloride; further preferably, in the Pd / C catalyst, Pd accounts for 3% to 10% of the total mass of the Pd / C catalyst. And / or

[0011] Preferably, the catalyst accounts for 0.5% to 3.5% of the mass of 4,6-dichloro-2-trifluoromethylpyrimidine; more preferably, the catalyst accounts for 0.5% to 3% of the mass of 4,6-dichloro-2-trifluoromethylpyrimidine; further preferably, the catalyst accounts for 0.5% to 1.5% of the mass of 4,6-dichloro-2-trifluoromethylpyrimidine. And / or

[0012] Preferably, in step 1, the reducing agent is H2; more preferably, the pressure of H2 is 0.5-3.5 MPa; further preferably, the pressure of H2 is 0.5-3 MPa; further preferably, the pressure of H2 is 0.5-1.5 MPa. And / or

[0013] Preferably, in step 1, the alkaline agent includes one or more selected from the group consisting of triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate and potassium carbonate; more preferably, the alkaline agent includes triethylamine. And / or

[0014] Preferably, the molar ratio of the alkaline agent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2 to 3.5:1; more preferably, the molar ratio of the alkaline agent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.2 to 2.8:1; further preferably, the molar ratio of the alkaline agent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.4 to 2.6:1. And / or

[0015] Preferably, in step 1, the solvent used includes one or more selected from toluene, n-hexane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether, isopropyl ether and water; preferably, the solvent includes one or more selected from toluene, isopropyl ether, methyl tert-butyl ether and water; more preferably, the solvent is a mixed solution of toluene and water. And / or

[0016] And / or, the mass ratio of the solvent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.5-5:1; preferably, the mass ratio of the solvent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.5-3.5:1.

[0017] Preferably, in step 1, the temperature of the dechlorination reaction is 30 to 55° C.; more preferably, the temperature of the dechlorination reaction is 35 to 45° C.; further preferably, the temperature of the dechlorination reaction is 38 to 42° C. And / or preferably, the time of the dechlorination reaction is 5 to 10 hours; more preferably, the time of the dechlorination reaction is 6 to 8 hours.

[0018] and / or

[0019] Preferably, the reaction is continued for 0.5 to 1.5 h after the H2 pressure remains constant.

[0020] Preferably, in step 1, after the dechlorination reaction is completed, the temperature is first lowered, and then salt is added to the reaction solution, and then separation, extraction and distillation are performed to obtain 2-trifluoromethylpyrimidine.

[0021] More preferably, the temperature is first lowered to 17-33°C; further preferably, the temperature is first lowered to 20-30°C. And / or

[0022] More preferably, the salt is added until the solution is saturated. And / or

[0023] More preferably, the separation is solid-liquid separation; further preferably, the solid-liquid separation is performed by filtering. And / or

[0024] More preferably, the extraction solvent comprises one or more selected from the group consisting of toluene, n-hexane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether and isopropyl ether. And / or

[0025] Preferably, in step 2, the bromination reagent comprises N-bromosuccinimide and / or dibromohydantoin; more preferably, the bromination reagent comprises N-bromosuccinimide. And / or

[0026] Preferably, the molar ratio of the bromination reagent to 2-trifluoromethylpyrimidine is 0.9 to 1.8:1; preferably, the molar ratio of the bromination reagent to 2-trifluoromethylpyrimidine is 1 to 1.5:1; further preferably, the molar ratio of the bromination reagent to 2-trifluoromethylpyrimidine is 1.25 to 1.35:1. And / or

[0027] Preferably, the bromination reagent is added in batches; more preferably, the bromination reagent is added in 10 to 20 batches; further preferably, the bromination reagent is added in 13 to 17 batches; further preferably, the interval between adding two batches of bromination reagent is 5 to 15 minutes; most preferably, the interval between adding two batches of bromination reagent is 8 to 12 minutes. And / or

[0028] Preferably, in step 2, the solvent used includes one or more selected from the group consisting of phosphoric acid, acetic acid, sulfuric acid, methanesulfonic acid and trifluoromethanesulfonic acid; more preferably, the solvent includes sulfuric acid and / or methanesulfonic acid. And / or

[0029] Preferably, the mass ratio of the solvent used to 2-trifluoromethylpyrimidine is 2 to 9:1; more preferably, the mass ratio of the solvent used to 2-trifluoromethylpyrimidine is 5 to 6:1. And / or

[0030] Preferably, in step 2, the temperature of the bromination reaction is 0 to 40°C; more preferably, the temperature of the bromination reaction is 30 to 40°C. And / or

[0031] Preferably, the bromination reaction time is 7 to 15 h; more preferably, the bromination reaction time is 7 to 9 h.

[0032] Preferably, in step 2, after the bromination reaction is completed, the reaction is quenched, and then separated and dried to obtain 5-bromo-2-trifluoromethylpyrimidine.

[0033] More preferably, an aqueous sodium bisulfite solution is added to quench the reaction. And / or

[0034] More preferably, the separation is solid-liquid separation; further preferably, the solid-liquid separation is performed by filtration.

[0035] Beneficial Effects of the Invention

[0036] (1) The 5-bromo-2-trifluoromethylpyrimidine preparation process provided by the present invention has low cost, mild reaction conditions, simple post-treatment, and is more suitable for industrial production.

[0037] (2) In the preparation method of 5-bromo-2-trifluoromethylpyrimidine of the present invention, the yield of the obtained product is relatively high, up to 76.5%, and the purity of the product is above 98.0%.

[0038] (3) In the preparation method of 5-bromo-2-trifluoromethylpyrimidine of the present invention, an alkaline reagent is added during the dechlorination process, which can significantly reduce the content of the catalyst, thereby saving the cost of raw materials. In addition, the dechlorinated product of the present invention is obtained by distillation and purification, and then a product with higher purity can be obtained through a simple post-treatment through a bromination reaction, which is easier to realize industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the hydrogen spectrum of 2-trifluoromethylpyrimidine prepared in Example 1-2.

[0040] Figure 2 This is a partially enlarged view of the hydrogen spectrum of 2-trifluoromethylpyrimidine prepared in Example 1-2.

[0041] Figure 3 This is the hydrogen spectrum of 5-bromo-2-trifluoromethylpyrimidine prepared in Example 2-4.

[0042] Figure 4This is a partially enlarged view of the hydrogen spectrum of 5-bromo-2-trifluoromethylpyrimidine prepared in Example 2-4. DETAILED DESCRIPTION

[0043] As described above, the object of the present invention is to provide a method for preparing 5-bromo-2-trifluoromethylpyrimidine.

[0044] In the present invention, the first object is to provide a method for preparing 5-bromo-2-trifluoromethylpyrimidine, comprising the following steps:

[0045] Step 1: Dechlorination reaction of 4,6-dichloro-2-trifluoromethylpyrimidine in the presence of a catalyst, a reducing agent and an alkaline reagent to obtain 2-trifluoromethylpyrimidine;

[0046] Step 2: 2-trifluoromethylpyrimidine is subjected to bromination reaction with a brominating agent to obtain 5-bromo-2-trifluoromethylpyrimidine.

[0047] In the present invention, the reaction route of 5-bromo-2-trifluoromethylpyrimidine is as follows:

[0048]

[0049] Preferably, in a specific embodiment of the present invention, the specific steps are as follows:

[0050] Step 1: dechlorination reaction of 4,6-dichloro-2-trifluoromethylpyrimidine in the presence of a catalyst, a reducing agent and an alkaline reagent, wherein the temperature of the dechlorination reaction is 30-55° C., the reaction time is 5-10 hours, and the reaction is continued for 0.5-1.5 hours after the H2 pressure remains unchanged to obtain 2-trifluoromethylpyrimidine; wherein the catalyst is a palladium-containing catalyst; the catalyst accounts for 0.5% to 3.5% of the mass of 4,6-dichloro-2-trifluoromethylpyrimidine; the reducing agent is H2; the pressure of H2 is 0.5 to 3.5 MPa; the alkaline reagent is selected from triethylamine, diisopropylethylamine, sodium carbonate, carbonate One or more of the substance group consisting of sodium bicarbonate and potassium carbonate; preferably, the alkaline agent includes triethylamine; the molar ratio of the alkaline agent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2-3.5:1; the solvent used includes one or more selected from toluene, n-hexane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether, isopropyl ether and water; the mass ratio of the solvent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.5-5:1; after the dechlorination reaction is completed, the temperature is first lowered, and then salt is added to the reaction solution, and then separation, extraction and distillation are performed respectively to obtain 2-trifluoromethylpyrimidine.

[0051] Step 2: 2-trifluoromethylpyrimidine is subjected to bromination reaction with a bromination reagent, the bromination reaction temperature is 0-40°C, the bromination reaction time is 7-15h, and 5-bromo-2-trifluoromethylpyrimidine is obtained; the bromination reagent comprises N-bromosuccinimide and / or dibromohydantoin; the molar ratio of the bromination reagent to 2-trifluoromethylpyrimidine is 0.9-1.8:1; the temperature is controlled at 0-10°C, and the bromination reagent is added in 10-20 batches; the interval time between the addition of two batches of bromination reagent is 5-15min; the solvent used comprises one or more selected from the group consisting of phosphoric acid, acetic acid, sulfuric acid, methanesulfonic acid and trifluoromethanesulfonic acid; preferably, the solvent comprises sulfuric acid and / or methanesulfonic acid; the mass ratio of the solvent used to 2-trifluoromethylpyrimidine is 2-9:1; after the bromination reaction is completed, the reaction is quenched, and then separation and drying are performed to obtain 5-bromo-2-trifluoromethylpyrimidine.

[0052] Unless otherwise specified, the raw materials used in the present invention are generally chemically pure reagents commonly sold on the market. The experimental material information used in the present invention is shown in the following table:

[0053] Table 1 Experimental materials and vendors

[0054]

[0055] In order to better understand the technical solution of the present invention, the technical solution of the present invention is described in detail below in conjunction with specific embodiments.

[0056] Example 1: Preparation of 2-trifluoromethylpyrimidine

[0057] Example 1-1

[0058] At a temperature of 10-30°C, toluene (542.5g), water (217.0g), 4,6-dichloro-2-trifluoromethylpyrimidine (217.0g), triethylamine (253.0g) and 2.2g palladium carbon catalyst (Pd accounts for 5wt% of the catalyst) were added to the reactor, and then N2 was passed to 1.0MPa to replace the gas in the reactor, and the replacement was 3 times, and H2 was passed to 1.0MPa to replace the gas in the reactor, and the replacement was 3 times. The temperature was raised to 40°C, and H2 was maintained at 1.0MPa. The reaction was stirred for 6-8h, and the pressure was kept constant, and then stirred for 1h. After the reaction was completed, the temperature was lowered to 20-30°C, sodium chloride was added to the reaction solution until saturated, stirred for 1h, filtered, and the filter cake was rinsed with toluene (217.0g). The eluent and the filtrate were combined, and the layers were allowed to stand for stratification. The water layer was extracted with 200g toluene, extracted twice, and the organic layers were combined. The organic layer was distilled at normal pressure using a 20 cm glass fiber column to remove toluene, and then the product was distilled at reduced pressure to obtain a colorless liquid (133.3 g) with a yield of 90%. The purity was ≥98.0% based on 4,6-dichloro-2-trifluoromethylpyrimidine.

[0059] Example 1-2

[0060] At a temperature of 10-30°C, add isopropyl ether (650.9g), water (217.0g), 4,6-dichloro-2-trifluoromethylpyrimidine (217.0g), triethylamine (303.5g) and 6.5g of palladium carbon catalyst (Pd accounts for 5wt% of the catalyst) into the reactor, then pass N2 to 1.0MPa to replace the gas in the reactor, replace 3 times, then pass H2 to 1.0MPa to replace the gas in the reactor, replace 3 times. Raise the temperature to 50°C, maintain H2 1.0MPa, stir the reaction for 6-8h, and continue stirring for 1h after the pressure remains unchanged. After the reaction is finished, the temperature is lowered to 20-30°C, sodium chloride is added to the reaction solution until saturated, stirred for 1 hour, and filtered; the filter cake is rinsed with isopropyl ether (217.0g), the eluent and the filtrate are combined, and the layers are separated by standing. The aqueous layer is extracted with 200g of isopropyl ether, extracted twice, and the organic layers are combined; the organic layer is distilled at normal pressure using a 20cm glass fiber packing column to remove the isopropyl ether, and then the product is distilled under reduced pressure to obtain a colorless liquid (118.4g) with a yield of 80%. The purity is ≥98.0% based on 4,6-dichloro-2-trifluoromethylpyrimidine. The hydrogen spectrum of the obtained 2-trifluoromethylpyrimidine is as follows Figure 1 and Figure 2 As shown, 1 HNMR (400MHz, DMSO) δ: 8.94 (s, 2H), 7.55 (t, 1H).

[0061] Examples 1-3

[0062] At a temperature of 10-30°C, add methyl tert-butyl ether MTBE (434.0g), water (217.0g), 4,6-dichloro-2-trifluoromethylpyrimidine (217.0g), triethylamine (303.5g) and Re-Ni catalyst (6.5g) into the reactor, then pass N2 to 1.0MPa to replace the gas in the reactor for 3 times, then pass H2 to 1.0MPa to replace the gas in the reactor for 3 times. Raise the temperature to 50°C, stir and react for 6-8h, maintain H2 at 2.0MPa, and continue stirring for 1h after the pressure remains unchanged. After the reaction was completed, the temperature was lowered to 20-30° C., sodium chloride was added to the reaction solution until saturated, and the mixture was stirred for 1 h and filtered; the filter cake was rinsed with MTBE (217.0 g), the eluate and the filtrate were combined, and the layers were separated by standing. The aqueous layer was extracted with 200 g of MTBE, and the extraction was repeated twice. The organic layers were combined; the organic layer was distilled at normal pressure using a 20 cm glass fiber column to remove MTBE, and then the product was distilled off under reduced pressure to obtain a colorless liquid (74.1 g) with a yield of 50%. The purity was ≥98.0% based on 4,6-dichloro-2-trifluoromethylpyrimidine.

[0063] Examples 1-4

[0064] At a temperature of 10-30°C, add isopropyl ether (650.9g), water (217.0g), 4,6-dichloro-2-trifluoromethylpyrimidine (217.0g), triethylamine (253g) and 6.5g of palladium carbon catalyst (Pd accounts for 3wt% of the catalyst) into the reactor, then pass N2 to 1.0MPa to replace the gas in the reactor, replace 3 times, then pass H2 to 1.0MPa to replace the gas in the reactor, replace 3 times. Raise the temperature to 50°C, stir the reaction for 6-8h, maintain H2 at 3.0MPa, and continue stirring for 1h after the pressure remains unchanged. After the reaction was completed, the temperature was lowered to 20-30°C, sodium chloride was added to the reaction solution until saturated, and the mixture was stirred for 1 hour and filtered; the filter cake was rinsed with isopropyl ether (217.0 g), the eluate and the filtrate were combined, and the layers were separated by standing. The aqueous layer was extracted with 200 g of isopropyl ether, and the extraction was repeated twice. The organic layers were combined; the organic layer was distilled at normal pressure using a 20 cm glass fiber column to remove the isopropyl ether, and then the product was distilled off under reduced pressure to obtain a colorless liquid (123.0 g) with a yield of 83%. The purity was ≥98.0% based on 4,6-dichloro-2-trifluoromethylpyrimidine.

[0065] Examples 1-5

[0066] At a temperature of 10-30°C, toluene (542.5g), water (217.0g), 4,6-dichloro-2-trifluoromethylpyrimidine (217.0g), triethylamine (253g) and 6.5g of palladium carbon catalyst (Pd accounts for 5wt% of the catalyst) were added to the reactor, and then N2 was passed to 1.0MPa to replace the gas in the reactor, and the replacement was performed 3 times, and then H2 was passed to 1.0MPa to replace the gas in the reactor, and the replacement was performed 3 times. The temperature was raised to 50°C, H2 was maintained at 2.0MPa, and the reaction was stirred for 6-8h. After the pressure remained constant, stirring was continued for 1h. After the reaction was completed, the temperature was lowered to 20-30°C, sodium chloride was added to the reaction solution until saturated, and the mixture was stirred for 1 hour and filtered; the filter cake was rinsed with toluene (217.0 g), the eluate and the filtrate were combined, and the layers were separated by standing. The aqueous layer was extracted with 200 g of toluene, and the extraction was repeated twice. The organic layers were combined; the organic layer was distilled at normal pressure using a 20 cm glass fiber packed column to remove toluene, and then the product was distilled off under reduced pressure to obtain a colorless liquid (125.9 g) with a yield of 85%. The purity was ≥98.0% based on 4,6-dichloro-2-trifluoromethylpyrimidine.

[0067] Example 2: Preparation of 5-bromo-2-trifluoromethylpyrimidine

[0068] Example 2-1

[0069] At a temperature of 0-10°C, add materials to the reactor, first add methanesulfonic acid (444g), then take 148g of 2-trifluoromethylpyrimidine prepared by repeating the steps of Example 1-1; then weigh NBS (231.4g) and divide it into 15 parts, add it in 15 times, and the time interval between two additions is 10min. After the addition, continue to react at 0-10°C for 12h. After the reaction is completed, add the reaction solution dropwise to an aqueous solution containing 2% sodium bisulfite, stir for 1h, filter, rinse the filter cake with water once, then mix and rinse the filter cake with water twice, and dry the obtained solid product in a sealed environment at a temperature of 10-20°C. A white to off-white solid is obtained, with a purity of ≥98% and a yield of 71%.

[0070] Example 2-2

[0071] At a temperature of 0-10°C, add materials to the reactor, first add sulfuric acid (740g), then take 148g of 2-trifluoromethylpyrimidine prepared by repeating the steps of Example 1-1; then weigh NBS (231.4g) and divide it into 15 parts, add it in 15 times, and the time interval between two additions is 10min. After the addition, heat it to 30-40°C and continue to react for 8h. After the reaction is completed, add the reaction solution dropwise to an aqueous solution containing 2% sodium bisulfite, stir for 1h, filter, rinse the filter cake with water once, then mix and rinse the filter cake with water twice, and dry the obtained solid product in a sealed environment at a temperature of 10-20°C. A white to off-white solid is obtained, with a purity of ≥98% and a yield of 85%.

[0072] Example 2-3

[0073] At a temperature of 0-10°C, add materials to the reactor, first add sulfuric acid (1184g), then take 148g of 2-trifluoromethylpyrimidine prepared by repeating the steps of Example 1-1; then weigh dibromohydantoin (371.8g) and divide it into 15 parts, add it in 15 times, and the time interval between two additions is 10min. After the addition, heat it to 30-40°C and continue to react for 8h. After the reaction is completed, add the reaction liquid dropwise to an aqueous solution containing 2% sodium bisulfite, stir for 1h, filter, rinse the filter cake with water once, then mix and rinse the filter cake with water twice, and dry the obtained solid product in a sealed environment at a temperature of 10-20°C. A white to off-white solid is obtained, with a purity of ≥98% and a yield of 73%.

[0074] Embodiment 2-4

[0075] At a temperature of 0-10°C, add materials to the reactor, first add sulfuric acid (890g), then take 148g of 2-trifluoromethylpyrimidine prepared by repeating the steps of Example 1-1; then weigh NBS (196g) and divide it into 15 parts, add it in 15 times, and the time interval between two additions is 10min. After the addition, heat the temperature to 30-40°C and continue to react for 14h. After the reaction is completed, add the reaction solution dropwise to an aqueous solution containing 2% sodium bisulfite, stir for 1h, filter, rinse the filter cake with water once, then wash it with water and rinse the filter cake twice, and dry the obtained solid product in a sealed environment at a temperature of 10-20°C. A white to off-white solid is obtained with a purity of ≥98% and a yield of 82%. The hydrogen spectrum of the obtained 5-bromo-2-trifluoromethylpyrimidine is as follows Figure 3 and Figure 4 As shown, 1 H NMR (400MHz, DMSO) δ: 9.30 (s, 2H).

[0076] Embodiment 2-5

[0077] At a temperature of 0-10°C, add materials to the reactor, first add sulfuric acid (444g), then take 148g of 2-trifluoromethylpyrimidine prepared by repeating the steps of Example 1-1; then weigh NBS (267g) and divide it into 15 parts, add it in 15 times, and the time interval between two additions is 10min. After the addition, heat it to 30-40°C and continue to react for 8h. After the reaction is completed, add the reaction solution dropwise to an aqueous solution containing 2% sodium bisulfite, stir for 1h, filter, rinse the filter cake with water once, then mix and rinse the filter cake with water twice, and dry the obtained solid product in a sealed environment at a temperature of 10-20°C. A white to off-white solid is obtained, with a purity of ≥98% and a yield of 80%.

[0078] Comparative Example 1

[0079] Relative to Example 1, triethylamine was not added, and the remaining preparation steps were the same as those in Example 1. The specific steps are as follows:

[0080] At a temperature of 10-30°C, toluene (542.5g), water (217.0g), 4,6-dichloro-2-trifluoromethylpyrimidine (217.0g) and 2.2g palladium carbon catalyst (Pd accounts for 5wt% of the catalyst) were added to the reactor, and then N2 was passed to 1.0MPa to replace the gas in the reactor, and the replacement was performed 3 times, and H2 was passed to 1.0MPa to replace the gas in the reactor, and the replacement was performed 3 times. The temperature was raised to 40°C, and H2 was maintained at 1.0MPa. The reaction was stirred for 6-8h, and the pressure was kept constant, and then stirred for 1h. After the reaction was completed, the temperature was lowered to 20-30°C, sodium chloride was added to the reaction solution until saturated, stirred for 1h, filtered, and the filter cake was rinsed with toluene (217.0g). The eluent and the filtrate were combined, and the layers were allowed to stand for stratification. The water layer was extracted with 200g toluene, extracted twice, and the organic layers were combined. The organic layer was distilled at normal pressure using a 20 cm glass wool column to remove toluene, and then distilled at reduced pressure to obtain the product.

[0081] The above is a specific description of a feasible embodiment of the present invention, but the embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the technical spirit of the present invention should be included in the patent scope of the present invention.

Claims

1. A method for preparing 5-bromo-2-trifluoromethylpyrimidine, characterized in that: The following steps are involved: Step 1: dechlorinating 4,6-dichloro-2-trifluoromethylpyrimidine in the presence of a catalyst, a reducing agent and an alkaline reagent to obtain 2-trifluoromethylpyrimidine; Step 2: 2-trifluoromethylpyrimidine is subjected to bromination reaction with a brominating agent to obtain 5-bromo-2-trifluoromethylpyrimidine.

2. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to claim 1, wherein: In step 1, the catalyst comprises one or more selected from the group consisting of a palladium-containing catalyst, a platinum-containing catalyst, a rhodium-containing catalyst, a ruthenium-containing catalyst and a nickel-containing catalyst; Preferably, the catalyst is a palladium-containing catalyst; More preferably, the palladium-containing catalyst comprises one or more selected from the group consisting of Pd / C, bis(triphenylphosphine)palladium dichloride and palladium chloride; More preferably, in the Pd / C catalyst, Pd accounts for 3% to 10% of the total mass of the Pd / C catalyst; And / or, the catalyst accounts for 0.5% to 3.5% of the mass of 4,6-dichloro-2-trifluoromethylpyrimidine; preferably, the catalyst accounts for 0.5% to 3% of the mass of 4,6-dichloro-2-trifluoromethylpyrimidine; more preferably, the catalyst accounts for 0.5% to 1.5% of the mass of 4,6-dichloro-2-trifluoromethylpyrimidine.

3. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to claim 1 or 2, wherein: In step 1, the reducing agent is H2; Preferably, the pressure of H2 is 0.5 to 3.5 MPa; More preferably, the pressure of H2 is 0.5 to 3 MPa; More preferably, the pressure of H2 is 0.5-1.5 MPa.

4. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to any one of claims 1 to 3, wherein: In step 1, the alkaline reagent includes one or more selected from the group consisting of triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate and potassium carbonate; preferably, the alkaline reagent includes triethylamine; And / or, the molar ratio of the alkaline reagent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2-3.5:1; preferably, the molar ratio of the alkaline reagent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.2-2.8:1; more preferably, the molar ratio of the alkaline reagent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.4-2.6:

1.

5. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to any one of claims 1 to 4, wherein: In step 1, the solvent used includes one or more selected from the group consisting of toluene, n-hexane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether, isopropyl ether and water; preferably, the solvent includes one or more selected from the group consisting of toluene, isopropyl ether, methyl tert-butyl ether and water; more preferably, the solvent is a mixed solution of toluene and water; And / or, the mass ratio of the solvent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.5-5:1; preferably, the mass ratio of the solvent to 4,6-dichloro-2-trifluoromethylpyrimidine is 2.5-3.5:

1.

6. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to any one of claims 1 to 5, wherein: In step 1, the temperature of the dechlorination reaction is 30 to 55° C.; preferably, the temperature of the dechlorination reaction is 35 to 45° C.; more preferably, the temperature of the dechlorination reaction is 38 to 42° C.; And / or, the dechlorination reaction time is 5 to 10 hours; preferably, the dechlorination reaction time is 6 to 8 hours; More preferably, the reaction is continued for 0.5 to 1.5 h after the H2 pressure remains constant.

7. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to any one of claims 1 to 6, wherein: In step 1, after the dechlorination reaction is completed, the temperature is first lowered, and then salt is added to the reaction solution, and then separation, extraction and distillation are performed to obtain 2-trifluoromethylpyrimidine; Preferably, the temperature is first lowered to 17-33°C; more preferably, the temperature is first lowered to 20-30°C; and / or, preferably, adding salt until the solution is saturated; And / or, preferably, the separation is solid-liquid separation; more preferably, the solid-liquid separation is performed by filtration; And / or, preferably, the extraction solvent includes one or more selected from the group consisting of toluene, n-hexane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether and isopropyl ether.

8. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to any one of claims 1 to 7, wherein: In step 2, the bromination reagent comprises N-bromosuccinimide and / or dibromohydantoin; preferably, the bromination reagent comprises N-bromosuccinimide; and / or, the molar ratio of the bromination reagent to 2-trifluoromethylpyrimidine is 0.9 to 1.8:1; preferably, the molar ratio of the bromination reagent to 2-trifluoromethylpyrimidine is 1 to 1.5:1; more preferably, the molar ratio of the bromination reagent to 2-trifluoromethylpyrimidine is 1.25 to 1.35:1; And / or, the brominating reagent is added in batches; preferably, when the brominating reagent is added, the temperature is controlled to be 0-10°C; more preferably, the brominating reagent is added in 10-20 batches; further preferably, the brominating reagent is added in 13-17 batches; further preferably, the interval time between adding two batches of brominating reagent is 5-15 minutes; most preferably, the interval time between adding two batches of brominating reagent is 8-12 minutes.

9. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to any one of claims 1 to 8, wherein: In step 2, the solvent used includes one or more selected from the group consisting of phosphoric acid, acetic acid, sulfuric acid, methanesulfonic acid and trifluoromethanesulfonic acid; preferably, the solvent includes sulfuric acid and / or methanesulfonic acid; And / or, the mass ratio of the solvent used to 2-trifluoromethylpyrimidine is 2 to 9:1; preferably, the mass ratio of the solvent used to 2-trifluoromethylpyrimidine is 5 to 6:

1.

10. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to any one of claims 1 to 9, wherein: In step 2, the temperature of the bromination reaction is 0 to 40°C; preferably, the temperature of the bromination reaction is 30 to 40°C; And / or, the bromination reaction time is 7 to 15 hours; preferably, the bromination reaction time is 7 to 9 hours.

11. The method for preparing 5-bromo-2-trifluoromethylpyrimidine according to any one of claims 1 to 10, wherein: In step 2, after the bromination reaction is completed, the reaction is quenched, and then separated and dried to obtain 5-bromo-2-trifluoromethylpyrimidine; Preferably, an aqueous solution of sodium bisulfite is added to quench the reaction; And / or, preferably, the separation is solid-liquid separation; more preferably, the solid-liquid separation is performed by filtration.

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