Preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline

Abstract

The invention discloses a preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline, the reaction route is as follows: # imgabs0 #, and the preparation method comprises the following steps: step 1, carrying out nitration reaction on a compound II to obtain a compound III; 2, carrying out a fluorination reaction on the compound III to obtain a compound IV; 3, carrying out a reduction reaction on the compound IV to obtain a compound V; step 4, carrying out diazotization bromination reaction on the compound V to obtain a compound VI; 5, carrying out nitration reaction on the compound VI to obtain a compound VII; 6, the compound VII is subjected to a reduction reaction, a compound I is obtained, and the compound I is 3-bromine-4-fluoro-5-trifluoromethylaniline. O-chlorobenzotrifluoride serves as a raw material, a target product is obtained through the six steps of nitration, fluorination, reduction, bromination, nitration and reduction, the blank in the prior art is filled, conventional chemical reagents are used in the reaction, operation is easy and feasible, and the method is suitable for industrial production. The product quality is high, and the process has industrial amplification prospects.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and specifically to a preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline. Background Art

[0002] 3-Bromo-4-fluoro-5-trifluoromethylaniline is a high-grade pharmaceutical intermediate and a key fragment of various anti-cancer targeted drugs. The patents with publication numbers CN116041344A disclose SOS1 inhibitors, the patent with publication number CN11691728A6 discloses A 6-carbamate-substituted heteroaromatic ring derivatives, and the patent with publication number WO2022199635A1 discloses benzylaminoquinazoline derivatives, etc. The structures of these small molecule drugs all involve this compound fragment, and its chemical structural formula is as follows in Formula I.

[0003]

[0004] Currently, there is no literature report on the synthesis route of 3-bromo-4-fluoro-5-trifluoromethylaniline, which makes it difficult to obtain the required raw materials during the development of related drugs. Usually, it can only be custom-synthesized at a high price to meet the research and development needs. To address this problem, it is necessary to develop a synthesis route of 3-bromo-4-fluoro-5-trifluoromethylaniline, using simple and commonly used reagents with commercial sources as raw materials, while ensuring high product purity and simple and feasible process operation conditions, and having certain industrial feasibility to meet different market demands.

[0005] Application Content

[0006] The purpose of this application is to provide a preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline to solve the problems in the above background art.

[0007] To achieve the above purpose, this application provides the following technical solution: A preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline, the reaction route is as follows,

[0008]

[0009] , and the steps are as follows:

[0010] Step 1: Nitrate compound II to obtain compound III;

[0011] Step 2: Fluorinate compound III to obtain compound IV;

[0012] Step 3: Reduce compound IV to obtain compound V;

[0013] Step 4: Diazotize and brominate compound V to obtain compound VI;

[0014] Step 5: Obtain compound VII by subjecting compound VI to a nitration reaction;

[0015] Step 6: Obtain compound I by subjecting compound VII to a reduction reaction. Compound I is 3-bromo-4-fluoro-5-trifluoromethylaniline.

[0016] This method uses o-chlorobenzotrifluoride as a raw material and obtains the target product 3-bromo-4-fluoro-5-trifluoromethylaniline through six steps: nitration, fluorination, reduction, bromination, nitration, and reduction. In the reaction, simple and commonly used commercially available reagents are used as raw materials. The process operation is simple and feasible, the product quality is high, and it has the feasibility of industrial scale-up.

[0017] Preferably, Step 1 includes: adding compound II to a mixed acid solution of nitric acid and another strong acid, controlling the temperature for the nitration reaction. After the reaction is completed, separate the layers. The organic layer is washed with alkali and water, and then the crude product of compound III is obtained. The crude product of compound III is added to a solvent for purification, filtered, and dried to obtain compound III.

[0018] Preferably, the other strong acid in Step 1 is sulfuric acid.

[0019] Preferably, Step 2 includes: carrying out a fluorination reaction on compound III by adding a solvent and a fluorination reagent and maintaining the temperature to obtain compound IV.

[0020] Preferably, Step 3 includes: adding a reducing reagent to the solution of compound IV and carrying out a heat preservation reaction to obtain compound V.

[0021] Preferably, Step 4 includes: adding hydrobromic acid to compound V for reaction, then adding an aqueous solution of sodium nitrite for reaction. After the reaction is completed, quench with water, add an extraction solvent for extraction. After separating the layers, the organic layer is evaporated to dryness under reduced pressure to obtain compound VI.

[0022] Preferably, Step 5 includes: dropping a mixed acid of sulfuric acid and nitric acid into compound VI, controlling the temperature for the nitration reaction. After the reaction is completed, add the material liquid to water for quenching, carry out solvent extraction and separation. The organic layer is evaporated to dryness under reduced pressure to obtain compound VII.

[0023] Preferably, Step 6 includes: adding a reducing reagent to compound VII, carrying out a reduction reaction while maintaining the temperature. After the reaction is completed, obtain the crude product of compound VII. Add a solvent to the crude product for recrystallization, filter, and dry to obtain 3-bromo-4-fluoro-5-trifluoromethylaniline.

[0024] Preferably, the reducing reagent in Step 3 is hydrogen.

[0025] Compared with the prior art, the beneficial effects of this application are:

[0026] 1. The preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline fills the gap in the prior art and discloses a synthesis method of 3-bromo-4-fluoro-5-trifluoromethylaniline;

[0027] 2. The raw materials used in the preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline are simple and easily available, with sufficient market sources and low process costs, making it suitable for laboratory or production use;

[0028] 3. The reactions in the preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline are all classical organic chemical reactions, with a clear mechanism for the synthesis route, simple operation, and industrial feasibility;

[0029] 4. The final product 3-bromo-4-fluoro-5-trifluoromethylaniline obtained by the preparation method of 3-bromo-4-fluoro-5-trifluoromethylaniline has a high purity, reaching over 98.0%. Description of the Drawings

[0030] Figure 1 It is the liquid-phase detection spectrum of 3-bromo-4-fluoro-5-trifluoromethylaniline shown in Formula I in Example 1 of the present invention;

[0031] Figure 2 It is the liquid-phase detection spectrum of 3-bromo-4-fluoro-5-trifluoromethylaniline shown in Formula I in Example 2 of the present invention. Detailed Embodiments

[0032] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application without creative efforts shall fall within the protection scope of the present application.

[0033] Example 1

[0034] Step 1: Add 100 g (1.51 mol, 1.1 eq) of 95% fuming nitric acid to a 1000 mL glass reaction flask, start stirring, and then slowly add 300 g (2.99 mol, 2.2 eq) of 98% sulfuric acid to the reaction flask. Control the temperature of the feed liquid at 45 °C, and slowly dropwise add 250 g (1.38 mol) of o-chlorobenzotrifluoride to the reaction flask. After the addition is complete, keep the reaction at 45 °C for 2 hours, then raise the temperature to 65 °C and react for 2 hours. After the reaction is complete, cool the feed liquid to 30 °C, let it stand for separation. The lower layer of waste acid enters the waste acid treatment container, and the upper organic layer is washed once with 200 ml of saturated sodium bicarbonate aqueous solution and 200 mL of drinking water each. The organic layer is the crude product of Compound II. Add 600 g of absolute ethanol to the crude product, heat it to 45 °C and stir until dissolved clearly, then cool it to 25 °C for crystallization, and then cool it to -10 °C for heat preservation crystallization. Filter, and vacuum dry the filter cake to obtain 272.8 g of Compound III (2-chloro-3-nitrobenzotrifluoride), with a yield of 87.3%.

[0035] Step 2: Add 270 g (1.20 mol) of Compound III prepared in Step 1 and 600 g of DMSO to a 1000 mL glass reaction flask, start stirring, and then add 279 g (4.80 mol, 4.0 eq) of anhydrous potassium fluoride to the reaction flask. Heat the feed liquid to 160 °C and keep the reaction for 6 hours. After the reaction is complete, cool the feed liquid to room temperature. After cooling, add the feed liquid to 2000 g of drinking water for quenching. After quenching, extract twice with 500 g of ethyl acetate and once with 200 g of ethyl acetate. Combine the organic layers and evaporate to dryness under reduced pressure to obtain 234.4 g of Compound IV (2-fluoro-3-nitrobenzotrifluoride), with a yield of 93.6%.

[0036] Step 3: Add 230 g (1.1 mol) of 2-fluoro-3-nitrobenzotrifluoride prepared in Step 2 to a 500 mL hydrogenation autoclave, heat the material to 75 °C to melt it, add 11.5 g of 5% palladium on carbon to the autoclave, raise the temperature in the autoclave to 90 °C, and introduce hydrogen into the autoclave. Keep the pressure in the autoclave at 0.3 - 0.4 MPa until hydrogen absorption stops, then stop introducing hydrogen. Cool the feed liquid to 20 - 30 °C, filter the feed liquid, recover the palladium on carbon catalyst, and the filtrate is the feed liquid of Compound V (2-fluoro-3-aminobenzotrifluoride).

[0037] Step 4: Add 380 g of 48% hydrobromic acid (2.25 mol, 2.05 eq), 200 g of drinking water and the feed liquid obtained finally in Step 3 into a 1000 mL reaction flask. Dropwise add 180 g of 50% sodium nitrite solution (91 g of sodium nitrite, 1.32 mol, 1.20 eq) at -5 - 0°C. After the addition, keep the temperature at 0°C and react for 2 hours. Add 79.3 g of cuprous bromide (0.55 mol, 0.50 eq), keep the temperature at 40°C and react for 4 hours. After the reaction is completed, cool down to 20°C. Add 400 g of ethyl acetate and extract twice. Combine the organic layers. Wash the organic layers twice with 200 g of saturated brine and 100 g of drinking water. After washing, perform vacuum distillation to obtain 221.5 g of compound VI (2-fluoro-3-bromobenzotrifluoride). The overall yield of Steps 3 and 4 is 82.9%.

[0038] Step 5: Add 75 g of 95% fuming nitric acid (1.25 mol, 1.1 eq) into a 1000 mL glass reaction flask. Start stirring, and then slowly add 250 g of 98% concentrated sulfuric acid (2.21 mol, 2.5 eq) into the reaction flask. Control the temperature of the feed liquid at 20°C. Slowly add 220 g (0.91 mol) of 2-fluoro-3-bromobenzotrifluoride obtained in Step 4 into the reaction flask. After the addition, keep the temperature at 30°C and react for 2 hours. After the reaction is completed, slowly add the feed liquid into 800 g of ice water. After the addition, extract three times with 300 g of ethyl acetate. Combine the organic layers, and perform vacuum concentration and evaporation to dryness at 40°C to obtain the crude product of compound VII. Add 500 g of absolute ethanol to the crude product, heat up to 30°C to dissolve it clearly, and then slowly cool down to -30°C. Keep the temperature for crystallization for 6 hours. After crystallization is completed, filter at -30°C. The filter cake is dried by vacuum distillation at 40°C to obtain 116.6 g of the refined product of oil-like compound VII (2-fluoro-3-bromo-5-nitrobenzotrifluoride), with a yield of 44.7%.

[0039] Step 6: Add 100 g (0.347 mol) of 2-fluoro-3-bromo-5-nitrobenzotrifluoride obtained in Step 5 and 10 g of 5% palladium on carbon into a 500 mL hydrogenation autoclave. Heat up the temperature in the autoclave to 80°C, introduce hydrogen gas into the autoclave, and keep the pressure in the autoclave at 0.3 - 0.4 MPa until hydrogen absorption stops. Filter the feed liquid to recover the palladium on carbon catalyst. Add 300 g of ethanol to the filtrate, stir to dissolve it clearly, cool down to -15°C and keep the temperature for crystallization for 4 hours. After keeping the temperature, filter at low temperature. The filter cake is dried by vacuum distillation at 40°C. As Figure 1 shown, 75.2 g of compound I (3-bromo-4-fluoro-5-trifluoromethylaniline) is obtained, with a yield of 83.9% and a purity of 98.4%.

[0040] Example 2

[0041] Step 1: Add 80 g (0.83 mol, 1.2 eq) of 65% concentrated nitric acid to a 500 mL glass reaction flask, start stirring, and then slowly add 150 g (1.50 mol, 2.2 eq) of 98% concentrated sulfuric acid to the reaction flask. Control the temperature of the feed liquid at 45 °C, and slowly dropwise add 125 g (0.69 mol) of o-chlorobenzotrifluoride to the reaction flask. After the addition is complete, keep the temperature at 60 °C for 4 hours for the reaction. After the reaction is complete, cool the feed liquid to 30 °C, let it stand for liquid separation. The lower layer of waste acid enters the waste acid treatment container, and the upper organic layer is washed once with 120 ml of saturated sodium bicarbonate aqueous solution and 100 mL of saturated brine respectively. The organic layer is the crude product of compound II. Add 240 g of methanol to the crude product, heat up to 40 °C and stir until dissolved clearly, then cool down to -15 °C and keep the temperature for crystallization, filter, and vacuum dry the filter cake to obtain 111.6 g of compound III (2-chloro-3-nitrobenzotrifluoride), with a yield of 71.5%.

[0042] Step 2: Add 100 g (0.44 mol) of compound III prepared in Step 1 and 350 g of sulfolane to a 500 mL glass reaction flask, start stirring, and then add 98 g (1.67 mol, 3.8 eq) of anhydrous potassium fluoride to the reaction flask. Heat up the feed liquid to 150 °C and keep the temperature for 8 hours for the reaction. After the reaction is complete, cool the feed liquid to 25 °C. After cooling, add the feed liquid to 1000 g of ice water for quenching. After quenching, extract three times with 300 g of dichloromethane, combine the organic layers, and evaporate to dryness under reduced pressure to obtain 85.5 g of compound IV (2-fluoro-3-nitrobenzotrifluoride), with a yield of 92.2%.

[0043] Step 3: Add 80 g (0.38 mol) of 2-fluoro-3-nitrobenzotrifluoride obtained in Step 2, 120 g (1.15 mol, 3 eq) of concentrated hydrochloric acid, 400 g of water, and 218.2 g (1.15 mol, 3 eq) of stannous chloride to a 500 mL reaction flask. Heat up the temperature of the feed liquid to 80 °C and stir for 6 hours for the reaction. After the reaction is complete, add sodium hydroxide aqueous solution dropwise to adjust the pH of the feed liquid to 8. After adjustment, extract three times with 200 g of ethyl acetate, combine the organic layers, and concentrate to dryness under reduced pressure to obtain 51.4 g of compound V (2-fluoro-3-aminobenzotrifluoride), with a yield of 75.0%.

[0044] Step 4: Add 81 g of 48% hydrobromic acid (0.57 mol, 2.05 eq) to a 500 mL reaction flask, cool down to -5°C, add 50 g (0.28 mol) of the compound V obtained in Step 3, and dropwise add 48 g (0.3 mol, 1.07 eq) of bromine at -5°C. After the addition is complete, keep the reaction at -5°C for 2 hours. After the reaction is complete, dropwise add 60 g of 50% sodium nitrite solution (30 g of sodium nitrite, 0.43 mol, 1.56 eq) at -5 - 0°C. After the addition is complete, keep the reaction at 0°C for 1 hour. After the reaction is complete, adjust the pH of the material liquid to 8 by dropwise adding 50% aqueous sodium hydroxide solution. After the adjustment is complete, extract with 200 g of dichloromethane three times, combine the organic layers, wash twice with 100 g of drinking water. After the washing is complete, perform vacuum distillation to obtain 75.6 g of compound VI (2-fluoro-3-bromobenzotrifluoride), with a yield of 81.39%.

[0045] Step 5: Add 75 g (0.77 mol, 2.5 eq) of 65% fuming nitric acid to a 500 mL glass reaction flask, start stirring, and then slowly add 200 g (2.0 mol, 2.6 eq) of 98% concentrated sulfuric acid to the reaction flask. Control the temperature of the material liquid at 30°C, and slowly add 75 g (0.31 mol) of 2-fluoro-3-bromobenzotrifluoride obtained in Step 4 to the reaction flask. After the addition is complete, keep the reaction at 30°C for 4 hours. After the reaction is complete, slowly add the material liquid to 600 g of ice water. After the addition is complete, extract with 150 g of ethyl acetate three times, combine the organic layers, and concentrate and evaporate to dryness under reduced pressure at 40°C to obtain the crude product of compound VII. Add 200 g of isopropanol to the crude product, heat up to 40°C to dissolve it clearly, and then slowly cool down to -30°C, keep the temperature for 6 hours for crystallization. After the crystallization is complete, filter at low temperature, and evaporate the filter cake to dryness under reduced pressure at 50°C to obtain 38.2 g of the refined product of the oily compound VII (2-fluoro-3-bromo-5-nitrobenzotrifluoride), with a yield of 43.0%.

[0046] Step 6: Add 35 g (0.12 mol) of 2-fluoro-3-bromo-5-nitrobenzotrifluoride obtained in Step 5 and 5 g of 5% palladium-carbon to a 200 mL hydrogenation autoclave. Heat up the temperature in the autoclave to 80°C, introduce hydrogen into the autoclave, and keep the pressure in the autoclave at 0.3 - 0.4 MPa until hydrogen absorption stops. Filter the material liquid, recover the palladium-carbon catalyst, add 100 g of ethanol to the filtrate, stir to dissolve it clearly, cool down to -15°C, and keep the temperature for 4 hours for crystallization. After the insulation is complete, filter at low temperature, and evaporate the filter cake to dryness under reduced pressure at 50°C. As Figure 2 shown, 22.5 g of compound I (3-bromo-4-fluoro-5-trifluoromethylaniline) is obtained, with a yield of 71.8% and a purity of 97.2%.

[0047] The methods used in the present invention are all conventional methods in the art unless otherwise specified.

[0048] The above are only the preferred embodiments of the present invention and do not impose any limitations on the present invention. Any simple modifications, changes, and equivalent transformations made to the above embodiments based on the technical essence of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline, characterized in that: The reaction route is as follows, Here are the steps: Step 1: subjecting compound II to nitration reaction to obtain compound III; Step 2: subjecting compound III to fluorination reaction to obtain compound IV; Step 3: Compound IV is subjected to reduction reaction to obtain compound V; Step 4: subjecting compound V to diazotization and bromination reaction to obtain compound VI; Step 5: subjecting compound VI to nitration reaction to obtain compound VII; Step 6: Compound VII is subjected to a reduction reaction to obtain compound I, which is 3-bromo-4-fluoro-5-trifluoromethylaniline.

2. The method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline according to claim 1, characterized in that: Step 1 comprises: adding compound II to a mixed acid solution of nitric acid and another strong acid and controlling the temperature to carry out a nitration reaction, separating the layers after the reaction is completed, washing the organic layer with alkali and water to obtain a crude compound III, adding the crude compound III to a solvent for refining, filtering, and drying to obtain compound III.

3. The method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline according to claim 2, characterized in that: The other strong acid described in step 1 is sulfuric acid.

4. The method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline according to claim 1 or 2, characterized in that: Step 2 comprises: adding a solvent and a fluorination agent to compound III and keeping the mixture warm to carry out a fluorination reaction to obtain compound IV.

5. The method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline according to claim 1 or 2, characterized in that: Step three includes: adding a reducing agent to the solution of compound IV and carrying out a heat-insulating reaction to obtain compound V.

6. The method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline according to claim 1 or 2, characterized in that: Step 4 comprises: adding hydrobromic acid to compound V for reaction, then adding sodium nitrite aqueous solution for reaction, adding water for quenching after the reaction is completed, adding extraction solvent for extraction, and after layering, evaporating the organic layer under reduced pressure to obtain compound VI.

7. The method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline according to claim 1 or 2, characterized in that: Step five comprises: adding a mixed acid of sulfuric acid and nitric acid dropwise to compound VI, controlling the temperature to carry out nitration reaction, and after the reaction is completed, adding the feed solution into water to quench, extracting the layers with a solvent, and evaporating the organic layer under reduced pressure to obtain compound VII.

8. The method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline according to claim 1 or 2, characterized in that: Step six comprises: adding a reducing agent to compound VII, keeping warm for reduction reaction, obtaining a crude compound VII after the reaction is completed, adding a solvent to the crude compound for recrystallization, filtering, and drying to obtain 3-bromo-4-fluoro-5-trifluoromethylaniline.

9. The method for preparing 3-bromo-4-fluoro-5-trifluoromethylaniline according to claim 2, characterized in that: In step 3, hydrogen is used as the reducing agent.

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