Preparation method of clofazimine key intermediate

Abstract

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a clofazimine key intermediate, the structure of the intermediate is as shown in formula I. The preparation method comprises the following steps: S1, carrying out condensation reaction on parachloroaniline and 1, 5-dibromo-2, 4-dinitrobenzene in a solvent I in the presence of an acid-binding agent to obtain a mixed solution; s2, adding N-(4-chlorphenyl)-1, 2-phenylenediamine into the mixed solution to carry out condensation reaction, and carrying out post-treatment to obtain a compound a; and S3, sequentially adding the compound a and a reducing agent into the alkali-containing solution II, heating and stirring, and after the reaction is finished, carrying out post-treatment to obtain a target product b. The preparation method provided by the invention is mild and controllable in reaction condition and high in reaction conversion rate, isomer byproducts are prevented from being generated, high-purity products can be obtained without complicated post-treatment purification, the yield and the product quality are high, and industrialization is easy to realize in the whole process route. And the formula I of the # imgabs0 # is shown in the specification.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a key intermediate of clofazimine. Background Art

[0002] Clofazimine is a drug with antimycobacterial activity that plays an important role in the treatment of leprosy and some other infectious diseases.

[0003] Clofazimine was synthesized by a team of scientists at Trinity College Dublin in 1954. It was originally intended for use against tuberculosis. In 1959, it was found to have a good therapeutic effect on leprosy. In 1969, CibaGeigy launched it as a leprosy treatment drug under the trade name Lamprene. It was approved for marketing by the US FDA in 1986. Its chemical name is 10-(p-chlorophenyl)-2,10-dihydro-3-(p-chloroanilino)-2-isopropyliminophenazine, and its molecular formula is C 29 H 28 F4N4O4, the structural formula is as follows: Its synthesis cannot avoid key intermediates: ; The key intermediate chemical name of clofazimine is N,5-bis(4-chlorophenyl)-3-imino-3,5-dihydrophenazine-2-amine, and its molecular formula is C 24 H 16 Cl2N 4， The structural formula is as follows: There are four main methods for synthesizing key intermediates of clofazimine: Route 1: CN114507189A Route 2: [Journal of the Chemical Society, 1956, p.3347, 3349] [Journal of the Chemical Society, 1958, p.859] The method comprises the following steps: reactants are deprotected under the action of a platinum catalyst and hydrogen to obtain chlorfazimine.

[0004] Route 3: CN117343021A X = Cl or F; Route 4: Clofazimine derivatives as potent broad-spectrum antiviralagents with dual-targetmechanism” European Journal of Medicinal Chemistry 234(2022) 114209. R is Cl, R1 is .

[0005] The above method has the following defects: 1. The intermediates prepared in routes 1 and 3 of the existing methods have low purity and will produce a large amount of isomer impurities during the reaction. The structural formula of the isomer impurities is The generation of this impurity is mainly due to the reaction mechanism. In subsequent reactions, it is extremely difficult to remove this impurity, which has a significant impact on the yield and quality of the subsequent preparation of clofazimine and increases production costs.

[0006] 2. The reactants in Route 2 are not common, and the reaction process uses the precious metal platinum, which has a high production cost. Therefore, this method is not suitable for industrial production.

[0007] 3. Although route 4 can avoid the production of a large number of isomeric impurities, the process conditions of each step in its preparation process are relatively high and the purity is relatively low, making it unsuitable for industrial production of clofazimine.

[0008] In view of this, it is necessary to invent a process route that can reduce by-products, simplify reaction conditions, optimize each step, and be suitable for industrial production. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide a method for preparing a key intermediate of clofazimine.

[0010] In order to solve the above problems, the technical solution adopted by the present invention is: Technical Topic 1 A method for preparing a key intermediate of clofazimine comprises the following steps: S1: condensing p-chloroaniline with 1,5-dibromo-2,4-dinitrobenzene in the presence of an acid-binding agent in solvent I to obtain a mixed solution containing compound a-1; S2: adding N-(4-chlorophenyl)-1,2-phenylenediamine to the mixed solution for condensation reaction, and obtaining compound a through post-treatment; S3: Compound a and a reducing agent are sequentially added to a base-containing solvent II, heated and stirred, and after the reaction is completed, the target product b is obtained through post-treatment.

[0011] As a further improvement of the present invention, the acid binding agent in S1 is selected from one of triethylamine, diethylamine, diisopropylamine and pyridine; The solvent I is selected from one of DMF, DMSO and DMAc; The reducing agent in S3 is selected from one of sodium dithionite, sodium sulfide, and thiourea dioxide; The alkali is selected from one of sodium hydroxide and potassium hydroxide; The solvent II is selected from one of methanol, ethanol, DMSO and DMF.

[0012] As a further improvement of the present invention, the molar ratio of p-chloroaniline, 1,5-dibromo-2,4-dinitrobenzene and N-(4-chlorophenyl)-1,2-phenylenediamine is 1:1-1.2:1-1.2; The molar ratio of p-chloroaniline to the acid binding agent is 1:2.5-4.0; The mass volume ratio of the p-chloroaniline to the solvent I is 1g:30-60ml; The molar ratio of compound a to the reducing agent is 1:5.0-1:7.0; The molar ratio of compound a to base is 1:5-8; The mass volume ratio of the compound a to the solvent II is 1g:6-10ml.

[0013] As a further improvement of the present invention, the S1 is reacted at room temperature for 4-6 hours; The reaction temperature in S2 is 70-100° C. and the reaction time is 4-8 h; The reaction temperature in S3 is 40-70° C., and the reaction time is 6-10 h.

[0014] As a further improvement of the present invention, the molar ratio of p-chloroaniline, 1,5-dibromo-2,4-dinitrobenzene and N-(4-chlorophenyl)-1,2-phenylenediamine is 1:1.1:1.1; The molar ratio of p-chloroaniline to the acid binding agent is 1:3; The mass volume ratio of the p-chloroaniline to the solvent is 1g:40ml; The molar ratio of compound a to the reducing agent is 1:5.5; The molar ratio of compound a to base is 1:6; The mass volume ratio of the compound a to the solvent II is 1 g:8 ml.

[0015] As a further improvement of the present invention, the acid binding agent in S1 is triethylamine; The solvent I is DMF; The reducing agent in S3 is sodium dithionite; The base is sodium hydroxide; The solvent II is methanol.

[0016] As a further improvement of the present invention, the S1 is reacted at room temperature for 4 hours; The reaction temperature in S2 is 80-90°C and the reaction time is 6h; The reaction temperature in S3 is 50-60° C. and the reaction time is 8 h.

[0017] As a further improvement of the present invention, the post-treatment described in S2 is to cool the reaction system to room temperature, add pure water and stir until the solid is completely precipitated, filter, wash and dry; The post-treatment described in S3 is as follows: after the reaction is completed, the reaction system is cooled to room temperature, pure water is added and stirred until the solid is completely precipitated, filtered, the filter cake is washed, and slurried with 95% ethanol to obtain the target product b.

[0018] Technical Topic 2 A use of a clofazimine intermediate prepared by the method described in the first technical subject in the preparation of clofazimine.

[0019] As a further improvement of the present invention, the use is specifically as follows: .

[0020] The beneficial effects of adopting the above technical solution are: 1. The preparation method of the key intermediate of clofazimine provided by the present invention does not produce isomeric impurities that affect the quality, greatly reduces the purification pressure of subsequent steps, and significantly improves the quality and yield of the products in subsequent steps.

[0021] 2. The raw material used in the route of the present invention is 1,5-dibromo-2,4-dinitrobenzene, which is more active than fluoride (1,5-difluoro-2,4-dinitrobenzene), more easily reacted, with higher conversion and recovery rates, and less by-products.

[0022] 3. The preparation method of the present invention is simple to operate, the conditions are mild and controllable, the substrate used is simple and easy to obtain, the process cost is low, and high-purity products can be obtained without complicated post-processing and purification, which is suitable for industrial production. DETAILED DESCRIPTION

[0023] In order to make the objectives, technical solutions and advantages of the present invention more clear, the invention is clearly and completely described below in conjunction with specific embodiments.

[0024] Example 1 S1: Add 12.76 g (0.10 mol) of p-chloroaniline, 35.85 g (0.11 mol) of 1,5-dibromo-2,4-dinitrobenzene, 0.30 mol of triethylamine, and 510 ml of DMF to a reaction flask, and stir at room temperature for 4 h.

[0025] S2: To the above reaction solution, add 24.06 g (0.11 mol) of N-(4-chlorophenyl)-1,2-phenylenediamine. After addition, heat to 80-90°C with stirring for 6 h. After completion of the reaction, cool the reaction system to room temperature and slowly add the reaction solution to 2550 ml of purified water. A large amount of solid precipitates. Stir at room temperature for 2 h, filter, and wash the filter cake with 510 ml of purified water. After filtration, dry the filter cake at 50-60°C for 12 h to obtain Compound a as a brownish-red solid in 86.5% yield and 97.2% purity. LC-MS (m / z) 510 (M+1). 1 H NMR (DMSO-d6) δ6.05(s,1H,Ar-H), 6.83(d,2H,Ar-H), 6.98(m,1H,Ar-H), 7.20(m,5H,Ar-H), 7.26(m ,2H,Ar-H), 7.40(d,2H,Ar-H), 7.83(s,1H,Ar-H), 9.01(s,1H,NH), 9.51(s,1H,NH), 9.69(s,1H,NH).

[0026] S3: To a reaction flask, add 160 mL of methanol, 9.36 g (0.234 mol) of sodium hydroxide, 20.00 g (0.039 mol) of compound a, and 37.46 g (0.215 mol) of sodium dithionite. Stir and heat to 50-60°C. Maintain stirring and react for 8 h. After completion, cool to room temperature. Slowly add 640 mL of purified water to the reaction solution, stir at room temperature for 1 h, filter, and wash the filter cake with 500 mL of purified water. After filtration, add the filter cake to 400 mL of 95% ethanol, stir and heat to 70-80°C to dissolve. Cool to 0-10°C, maintain stirring and crystallize for 2 h, filter, wash the filter cake with 40 mL of 95% ethanol, and dry at 50-60°C for 10 h to obtain a brownish-red solid with a yield of 89.3% and a purity of 98.7%. LC-MS (m / z) 431 (M+1). 1H NMR(DMSO-d6)δ6.08(s,1H,CH), 6.99(t,1H,Ar-H), 7.27(s,1H,CH), 7.53(dd,4H,Ar-H), 7. 67(t,2H,Ar-H), 7.76(d,2H,Ar-H), 7.99(d,2H,Ar-H), 8.11(t,1H,Ar-H), 9.51(s,2H,NH).

[0027] Example 2 S1: Add 12.76 g (0.10 mol) of p-chloroaniline, 39.11 g (0.12 mol) of 1,5-dibromo-2,4-dinitrobenzene, 0.30 mol of triethylamine, and 510 ml of DMF to a reaction flask, and stir at room temperature for 4 h.

[0028] S2: 26.24 g (0.12 mol) of N-(4-chlorophenyl)-1,2-phenylenediamine was added to the above reaction solution. After the addition was completed, the temperature was raised to 80-90°C with stirring and the reaction was carried out for 6 hours. After the reaction was completed, the reaction system was cooled to room temperature and the reaction solution was slowly added to 2550 ml of purified water. A large amount of solid precipitated. The solution was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 510 ml of purified water. After filtration, the filter cake was dried at 50-60°C for 12 hours to obtain a brown-red solid compound a with a yield of 85.4% and a purity of 96.8%.

[0029] S3: 160 ml of methanol was added to the reaction flask, 9.36 g (0.234 mol) of sodium hydroxide was added, and then 20.00 g (0.039 mol) of compound a and 40.74 g (0.234 mol) of sodium dithionite were added, stirred, and heated to 50-60 ° C. The reaction was stirred and maintained at this temperature for 8 hours. After the reaction was completed, the reaction system was cooled to room temperature, and 640 ml of purified water was slowly added to the reaction solution. The mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was washed with 500 ml of purified water. After filtration, the filter cake was added to 100 ml of 400 ml of 95% ethanol, stirred, heated to 70-80 ° C to dissolve, cooled to 0-10 ° C, stirred and crystallized for 2 hours, filtered, and the filter cake was washed with 40 ml of 95% ethanol. After filtration, the filter cake was dried at 50-60 ° C for 10 hours to obtain a brown-red solid with a yield of 88.9% and a purity of 98.4%.

[0030] Example 3 S1: Add 12.76 g (0.10 mol) of p-chloroaniline, 35.85 g (0.11 mol) of 1,5-dibromo-2,4-dinitrobenzene, 30.36 g (0.30 mol) of diisopropylamine, and 510 ml of DMF to a reaction flask, and stir at room temperature for 4 h.

[0031] S2: 24.06 g (0.11 mol) of N-(4-chlorophenyl)-1,2-phenylenediamine was added to the above reaction solution. After the addition was completed, the temperature was raised to 80-90°C with stirring and the reaction was carried out for 6 hours. After the reaction was completed, the reaction system was cooled to room temperature and the reaction solution was slowly added to 2550 ml of purified water. A large amount of solid precipitated. The solution was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 510 ml of purified water. After filtration, the filter cake was dried at 50-60°C for 12 hours to obtain a brown-red solid compound a with a yield of 82.3% and a purity of 95.8%.

[0032] S3: 160 ml of methanol was added to the reaction flask, and 9.36 g (0.234 mol) of sodium hydroxide was added, followed by 20.00 g (0.039 mol) of compound a and 16.78 g (0.215 mol) of sodium sulfide. The mixture was stirred and heated to 50-60°C. The mixture was stirred and reacted for 8 hours. After the reaction was completed, the reaction system was cooled to room temperature. 640 ml of purified water was slowly added to the reaction solution, stirred at room temperature for 1 hour, filtered, and the filter cake was washed with 500 ml of purified water. After filtration, the filter cake was added to 400 ml of 95% ethanol, stirred and heated to 70-80°C for dissolution, cooled to 0-10°C, stirred and crystallized for 2 hours, filtered, and the filter cake was washed with 40 ml of 95% ethanol. After filtration, the filter cake was dried at 50-60°C for 10 hours to obtain a brown-red solid with a yield of 86.5% and a purity of 98.3%.

[0033] Example 4 S1: Add 12.76 g (0.10 mol) of p-chloroaniline, 32.59 g (0.10 mol) of 1,5-dibromo-2,4-dinitrobenzene, 25.30 g (0.25 mol) of triethylamine, and 510 ml of DMF to a reaction flask and react at room temperature for 6 h.

[0034] S2: 21.87 g (0.10 mol) of N-(4-chlorophenyl)-1,2-phenylenediamine was added to the above reaction solution. After the addition was completed, the temperature was raised to 70-80°C with stirring and the reaction was carried out for 8 hours. After the reaction was completed, the reaction system was cooled to room temperature and the reaction solution was slowly added to 2550 ml of purified water. A large amount of solid precipitated. The solution was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 510 ml of purified water. After filtration, the filter cake was dried at 50-60°C for 12 hours to obtain a brown-red solid compound a with a yield of 80.5% and a purity of 95.4%.

[0035] S3: 120 ml of ethanol was added to the reaction flask, and 7.80 g (0.195 mol) of sodium hydroxide was added, followed by 20.00 g (0.039 mol) of compound a and 29.52 g (0.273 mol) of thiourea dioxide. The mixture was stirred and heated to 40-50°C. The mixture was stirred and reacted for 10 h. After the reaction was completed, the reaction system was cooled to room temperature. 640 ml of purified water was slowly added to the reaction solution, stirred at room temperature for 1 h, filtered, and the filter cake was washed with 500 ml of purified water. After filtration, the filter cake was added to 400 ml of 95% ethanol, stirred and heated to 70-80°C for dissolution, cooled to 0-10°C, stirred and crystallized for 2 h, filtered, and the filter cake was washed with 40 ml of 95% ethanol. After filtration, the filter cake was dried at 50-60°C for 10 h to obtain a brownish-red solid with a yield of 82.4% and a purity of 98.2%.

[0036] Example 5 S1: Add 12.76 g (0.10 mol) of p-chloroaniline, 0.12 mol of 1,5-dibromo-2,4-dinitrobenzene, 40.48 g (0.40 mol) of triethylamine, and 510 ml of DMF to a reaction flask and react at room temperature for 6 h.

[0037] S2: 0.12 mol of N-(4-chlorophenyl)-1,2-phenylenediamine was added to the above reaction solution. After the addition was completed, the temperature was raised to 90-100°C with stirring and the reaction was carried out for 4 hours. After the reaction was completed, the reaction system was cooled to room temperature and the reaction solution was slowly added to 2550 ml of purified water. A large amount of solid precipitated. The solution was stirred at room temperature for 2 hours and filtered. The filter cake was washed with 510 ml of purified water. After filtration, the filter cake was dried at 50-60°C for 12 hours to obtain a brown-red solid compound a with a yield of 81.2% and a purity of 95.6%.

[0038] S3: Add 200 ml of DMF to the reaction flask, add 12.48 g (0.312 mol) of sodium hydroxide, then add 20.00 g (0.039 mol) of compound a and 33.95 g (0.195 mol) of sodium dithionite, stir and heat to 50-60 ° C, keep stirring and react for 8 hours. After the reaction is completed, the reaction system is cooled to room temperature, and 640 ml of purified water is slowly added to the reaction solution. Stir at room temperature for 1 hour, filter, wash the filter cake with 500 ml of purified water, and after filtration, add the filter cake to 400 ml of 95% ethanol, stir and heat to 70-80 ° C to dissolve, cool to 0-10 ° C, keep stirring and crystallize for 2 hours, filter, wash the filter cake with 40 ml of 95% ethanol, and after filtration, dry the filter cake at 50-60 ° C for 10 hours to obtain a brown-red solid with a yield of 81.5% and a purity of 98.5%.

[0039] Example 6 160 ml of ethanol was added to the reaction flask, 9.36 g (0.234 mol) of sodium hydroxide was added, and then 20.00 g (0.039 mol) of compound a prepared by the method described in Example 1 and 37.46 g (0.215 mol) of sodium dithionite were added, and the mixture was stirred and heated to 60-70 ° C. The reaction was stirred for 6 hours. After the reaction was completed, the mixture was cooled to room temperature. 640 ml of purified water was slowly added to the reaction solution, stirred at room temperature for 1 hour, filtered, and the filter cake was washed with 500 ml of purified water. After filtration, the filter cake was added to 400 ml of 95% ethanol, stirred and heated to 70-80 ° C to dissolve, cooled to 0-10 ° C, stirred and crystallized for 2 hours, filtered, and the filter cake was washed with 40 ml of 95% ethanol. After filtration, the filter cake was dried at 50-60 ° C for 10 hours to obtain a brown-red solid with a yield of 82.6% and a purity of 98.3%.

[0040] Example 7 S1: Add 12.76 g (0.10 mol) of p-chloroaniline, 35.85 g (0.11 mol) of 1,5-dibromo-2,4-dinitrobenzene, 0.30 mol of diisopropylamine, and 383 ml of DMSO to a reaction flask, and stir at room temperature for 4 h.

[0041] S2: 24.06 g (0.11 mol) of N-(4-chlorophenyl)-1,2-phenylenediamine was added to the above reaction solution. After the addition was completed, the temperature was raised to 80-90°C with stirring and the reaction was carried out for 6 hours. After the reaction was completed, the reaction system was cooled to room temperature and the reaction solution was slowly added to 2550 ml of purified water. A large amount of solid precipitated. The solution was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 510 ml of purified water. After filtration, the filter cake was dried at 50-60°C for 12 hours to obtain a brown-red solid compound a with a yield of 83.9% and a purity of 96.3%.

[0042] S3: 160 ml of DMSO was added to the reaction flask, followed by 9.36 g (0.234 mol) of sodium hydroxide, and then 20.00 g (0.039 mol) of compound a and 37.46 g (0.215 mol) of sodium dithionite. The mixture was stirred and heated to 50-60°C. The mixture was stirred and reacted for 8 hours. After the reaction was completed, the mixture was cooled to room temperature. 640 ml of purified water was slowly added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was washed with 500 ml of purified water. After filtration, the filter cake was added to 400 ml of 95% ethanol, stirred and heated to 70-80°C for dissolution. The mixture was cooled to 0-10°C, stirred and crystallized for 2 hours, filtered, and the filter cake was washed with 40 ml of 95% ethanol. After filtration, the filter cake was dried at 50-60°C for 10 hours to obtain the target product b as a brown-red solid with a yield of 83.4% and a purity of 98.6%.

[0043] Example 8 S1: Add 12.76 g (0.10 mol) of p-chloroaniline, 35.85 g (0.11 mol) of 1,5-dibromo-2,4-dinitrobenzene, 0.30 mol of pyridine, and 766 ml of DMAc to a reaction flask, and stir at room temperature for 4 h.

[0044] S2: 24.06 g (0.11 mol) of N-(4-chlorophenyl)-1,2-phenylenediamine was added to the above reaction solution. After the addition was completed, the temperature was raised to 80-90°C with stirring and the reaction was carried out for 6 hours. After the reaction was completed, the reaction system was cooled to room temperature and the reaction solution was slowly added to 2550 ml of purified water. A large amount of solid precipitated. The solution was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 510 ml of purified water. After filtration, the filter cake was dried at 50-60°C for 12 hours to obtain a brown-red solid compound a with a yield of 82.2% and a purity of 95.5%.

[0045] S3: Add 160 ml of methanol to the reaction flask, add 9.36 g (0.234 mol) of sodium hydroxide, then add 20.00 g (0.039 mol) of compound a and 37.46 g (0.215 mol) of sodium dithionite, stir and heat to 50-60 ° C, keep stirring and react for 8 hours. After the reaction is completed, cool to room temperature, slowly add 640 ml of purified water to the reaction solution, stir at room temperature for 1 hour, filter, wash the filter cake with 500 ml of purified water, and after filtration, add the filter cake to 400 ml of 95% ethanol, stir and heat to 70-80 ° C to dissolve, cool to 0-10 ° C, keep stirring and crystallize for 2 hours, filter 40 ml of 95% ethanol, wash the filter cake, and after filtration, dry the filter cake at 50-60 ° C for 10 hours to obtain the target product b as a brown-red solid with a yield of 80.2% and a purity of 97.8%.

[0046] Comparative Example 1 S1: Add 12.76 g (0.10 mol) of p-chloroaniline, 0.11 mol of 1,5-difluoro-2,4-dinitrobenzene, 0.30 mol of triethylamine, and 510 ml of DMF to a reaction flask, and stir at room temperature for 4 h.

[0047] S2: 24.06 g (0.11 mol) of N-(4-chlorophenyl)-1,2-phenylenediamine was added to the above reaction solution. After the addition was completed, the temperature was raised to 80-90°C with stirring and the reaction was carried out for 6 hours. After the reaction was completed, the reaction system was cooled to room temperature and the reaction solution was slowly added to 2550 ml of purified water. A large amount of solid precipitated. The solution was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 510 ml of purified water. After filtration, the filter cake was dried at 50-60°C for 12 hours to obtain a brown-red solid compound a with a yield of 50.8% and a purity of 85.2%.

[0048] Comparative Example 2 S1: Add 35.85 g (0.11 mol) of 1,5-dibromo-2,4-dinitrobenzene, 24.06 g (0.11 mol) of N-(4-chlorophenyl)-1,2-phenylenediamine, 0.30 mol of triethylamine, and 510 ml of DMF to a reaction flask. Stir and heat to 80-90°C for 6 h. After the reaction is complete, cool the reaction system to room temperature.

[0049] S2: 12.76 g (0.10 mol) of p-chloroaniline was added to the reaction system, and the mixture was stirred at room temperature for 4 h. The reaction solution was slowly added to 2550 ml of purified water, and a large amount of solid precipitated. The mixture was stirred at room temperature for 2 h, filtered, and the filter cake was washed with 510 ml of purified water. After filtration, the filter cake was dried at 50-60°C for 12 h to obtain a brown-red solid compound a with a yield of 56.8% and a purity of 80.4%.

[0050] Comparative Example 3 To the reaction flask, 160 ml of methanol was added, 9.36 g (0.234 mol) of sodium hydroxide was added, and then 20.00 g (0.039 mol) of compound a prepared by the method described in Example 1 and 0.215 mol of sodium bisulfite were added. The mixture was stirred and heated to 50-60 ° C. and stirred for 8 hours. After the reaction was completed, the mixture was cooled to room temperature. 640 ml of purified water was slowly added to the reaction solution, stirred at room temperature for 1 hour, filtered, and the filter cake was washed with 500 ml of purified water. After filtration, the filter cake was added to 400 ml of 95% ethanol, stirred and heated to 70-80 ° C. to dissolve, cooled to 0-10 ° C., stirred and crystallized for 2 hours, filtered, and the filter cake was washed with 40 ml of 95% ethanol. After filtration, the filter cake was dried at 50-60 ° C for 10 hours to obtain a brown-red solid with a yield of 65.5% and a purity of 72.4%.

[0051] Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art may still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a key intermediate of clofazimine, characterized in that: The steps include: S1: condensing p-chloroaniline with 1,5-dibromo-2,4-dinitrobenzene in the presence of an acid-binding agent in solvent I to obtain a mixed solution containing compound a-1; S2: adding N-(4-chlorophenyl)-1,2-phenylenediamine to the mixed solution for condensation reaction, and obtaining compound a through post-treatment; S3: Compound a and a reducing agent are sequentially added to a base-containing solvent II, heated and stirred, and after the reaction is completed, the target product b is obtained through post-treatment.

2. The preparation method according to claim 1, characterized in that The acid binding agent in S1 is selected from one of triethylamine, diethylamine, diisopropylamine and pyridine; The solvent I is selected from one of DMF, DMSO and DMAc; The reducing agent in S3 is selected from one of sodium dithionite, sodium sulfide, and thiourea dioxide; The alkali is selected from one of sodium hydroxide and potassium hydroxide; The solvent II is selected from one of methanol, ethanol, DMSO and DMF.

3. The preparation method according to claim 1, characterized in that The molar ratio of p-chloroaniline, 1,5-dibromo-2,4-dinitrobenzene and N-(4-chlorophenyl)-1,2-phenylenediamine is 1:1-1.2:1-1.2; The molar ratio of p-chloroaniline to the acid binding agent is 1:2.5-4.0; The mass volume ratio of the p-chloroaniline to the solvent I is 1g:30-60ml; The molar ratio of compound a to the reducing agent is 1:5.0-1:7.0; The molar ratio of compound a to base is 1:5-8; The mass volume ratio of the compound a to the solvent II is 1g:6-10ml.

4. The preparation method according to claim 1, characterized in that The S1 is reacted at room temperature for 4-6 hours; The reaction temperature in S2 is 70-100° C. and the reaction time is 4-8 h; The reaction temperature in S3 is 40-70° C., and the reaction time is 6-10 h.

5. The preparation method according to claim 1, characterized in that The molar ratio of p-chloroaniline, 1,5-dibromo-2,4-dinitrobenzene and N-(4-chlorophenyl)-1,2-phenylenediamine is 1:1.1:1.1; The molar ratio of p-chloroaniline to the acid binding agent is 1:3; The mass volume ratio of the p-chloroaniline to the solvent is 1g:40ml; The molar ratio of compound a to the reducing agent is 1:5.5; The molar ratio of compound a to base is 1:6; The mass volume ratio of the compound a to the solvent II is 1 g:8 ml.

6. The preparation method according to claim 1, characterized in that The acid binding agent in S1 is triethylamine; The solvent I is DMF; The reducing agent in S3 is sodium dithionite; The base is sodium hydroxide; The solvent II is methanol.

7. The preparation method according to claim 1, characterized in that Said S1 is reacted at room temperature for 4 hours; The reaction temperature in S2 is 80-90°C and the reaction time is 6h; The reaction temperature in S3 is 50-60° C. and the reaction time is 8 h.

8. The preparation method according to claim 1, characterized in that The post-treatment described in S2 is to cool the reaction system to room temperature, add pure water and stir until the solid is completely precipitated, filter, wash and dry; The post-treatment described in S3 is as follows: after the reaction is completed, the reaction system is cooled to room temperature, pure water is added and stirred until the solid is completely precipitated, filtered, the filter cake is washed, and slurried with 95% ethanol to obtain the target product b.

9. Use of the clofazimine intermediate prepared by the preparation method according to any one of claims 1 to 8 in the preparation of clofazimine.

10. The use according to claim 9, characterized in that The specific method is as follows: 。

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