Preparation method of 4-chloro-3-trifluoromethylaniline

Abstract

The invention discloses a preparation method of 4-chloro-3-trifluoromethylaniline, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: brominating 4-chlorophenylboronic acid serving as a raw material, protecting boric acid by adopting MIDA, and then carrying out trifluoromethylation reaction in the presence of a palladium catalyst, or directly carrying out trifluoromethylation reaction on a brominated product; and finally, carrying out ammonolysis reaction to generate the 4-chloro-3-trifluoromethylaniline. According to the method, all the raw materials can be conveniently purchased on the market, the bromination reaction and the trifluoromethylation reaction are high in selectivity and good in yield, and the route operability is high.

Description

Technical Field

[0001] This invention relates to a method for preparing 4-chloro-3-trifluoromethylaniline, belonging to the field of pharmaceutical intermediate preparation technology. Background Technology

[0002] 4-Chloro-3-trifluoromethylaniline (CAS No: 320-51-4) is an important organic synthetic intermediate with a wide range of applications. It is the main raw material for the synthesis of sorafenib. Sorafenib, as the world's first multi-target anticancer drug, belongs to the small-molecule multi-kinase inhibitor class. It exerts a dual antitumor effect by simultaneously inhibiting tumor cell proliferation and tumor angiogenesis. Initially used for advanced renal cell carcinoma, it has since been extended to hepatocellular carcinoma and radioactive iodine-resistant thyroid cancer.

[0003] For this product, after reviewing existing literature, there are currently many reported synthesis methods.

[0004] Literature and patents [Green Chemistry, 2018, 20, 130; Angew. Chem., 2016, 128, 9125; WO2017106426A] report the production of 4-chloro-3-trifluoromethylaniline by reduction with 4-chloro-3-trifluoromethylnitro; literature and patents [Organic Letters, 2015, 17, 5934; CN107915676A] report the production of 4-chloro-3-trifluoromethylaniline by reacting 1,4-dichloro-2-trifluoromethylbenzene with ammonia or hydrazine hydrate; literature [Nature Chemistry, 2017, 9, 681; ACS Catalysis, 2022, 12, 15590; Organic Letters, 2013, 15,

[3734] reported that 4-chloro-3-trifluoromethylaniline was generated by reacting 5-bromo-2-chlorotrifluoromethylbenzene with ammonium chloride or ammonium carbonate; literature and patents [Mendeleev Communications, 2006, 16, 192; Carbohydrate Research, 2018, 457, 32; CN110885298A; New Journal of Chemistry, 2020, 44, 19723] reported that 4-chloro-3-trifluoromethylaniline was generated by using 1-chloro-2-trifluoromethylbenzene as a raw material through nitration and reduction reactions.

[0005] To address the shortcomings of the above routes, it is necessary to develop new methods for synthesizing 4-chloro-3-trifluoromethylaniline, in order to provide a better, simpler, safer, more stable, and more economical process route that meets the growing market demand. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing 4-chloro-3-trifluoromethylaniline. The method provided by the present invention uses 4-chlorophenylboronic acid as raw material and brominates it; then uses MIDA to protect the boric acid; then a trifluoromethylation reaction occurs under the action of palladium catalyst; and finally an ammoniation reaction is carried out to generate 4-chloro-3-trifluoromethylaniline.

[0007] The preparation method of 4-chloro-3-trifluoromethylaniline according to the present invention is achieved through the following technical solution, and the reaction equation is expressed as follows:

[0008] Includes the following steps: A. 4-Chlorophenylboronic acid and NBS are reacted in the presence of a catalytic amount of triphenylphosphine to generate intermediate 1; B. Mix intermediate 1 and MIDA in DMF, heat and react to generate intermediate 2; C. React intermediate 2, potassium trifluoromethyltrifluoroborate, palladium catalyst and base in a polar aprotic solvent by heating to generate intermediate 3; D. Intermediate 3 is reacted with ammonia in the presence of cuprous oxide and potassium hydroxide to produce 4-chloro-3-trifluoromethylaniline.

[0009] Further, in a preferred embodiment, in step A above, the molar ratio of 4-chlorophenylboronic acid, NBS and triphenylphosphine is 1:1.1-1.3:0.03-0.06.

[0010] Further, in a preferred embodiment, in step B above, the molar ratio of intermediate 1 to MIDA is 1:1-1.1.

[0011] Furthermore, in a preferred embodiment, in step B above, the heating reaction is at 80-120°C.

[0012] Further, in a preferred embodiment, in step C above, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; the base is potassium acetate; and the polar aprotic solvent is DMSO, DMF, or dioxane.

[0013] Further, in a preferred embodiment, in step C above, the molar ratio of intermediate 2, CF3BF3K, palladium catalyst and base is 1:1.1-1.3:0.01-0.05:1.5-2.5.

[0014] Furthermore, in a preferred embodiment, in step C above, the heating reaction is 60-120°C.

[0015] Further, in a preferred embodiment, in step D above, the ammonia water is a 15-25% ammonia solution.

[0016] Further, in a preferred embodiment, in step D above, the molar ratio of intermediate 3, cuprous oxide, ammonia and potassium hydroxide is 1:0.05-0.1:1.1-1.5:2-3.

[0017] This invention also improves upon the above-mentioned synthesis process, and research has found that:

[0018] When using trifluoromethyl (1,10-phenanthroline) copper reagent, the trifluoromethylation reaction can be carried out directly using intermediate 1, without the need for boric acid protection via MIDA ester, making the reaction route simpler and more efficient.

[0019] Further, in a preferred embodiment, during the second step of the trifluoromethylation reaction, the reaction is carried out in a sulfolane solvent at 100-140°C, and the molar ratio of intermediate 1 to trifluoromethyl(1,10-phenanthroline) copper is 1:1-1.5.

[0020] Beneficial effects of this invention: A. This invention develops a simple and practical synthetic route with readily available raw materials and good operability, providing a useful reference for the preparation of this type of compound.

[0021] B. Using 4-chlorophenylboronic acid as a raw material, the bromination reaction yield is high under the combined action of NBS and triphenylphosphine.

[0022] C. In this invention, MIDA is used to protect boric acid before trifluoromethylation or trifluoromethylation is performed directly. Both methods can react effectively. In particular, the latter method uses copper catalysis in the steps, which does not require the participation of precious metals. Specific Implementation Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be determined by the scope of the claims.

[0024] Example 1

[0025] Under nitrogen protection, 4-chlorophenylboronic acid (15.6 g, 0.1 mol), NBS (21.4 g, 0.12 mol), and triphenylphosphine (1.3 g, 5 mmol) were mixed in 300 mL of ethyl acetate and reacted at room temperature for 4 hours. The mixture was washed with 100 mL of saturated sodium thiosulfate solution and saturated brine. The organic layer was concentrated to give 22.4 g of intermediate 1, with a yield of 95% and an HPLC yield of 98.8%. 1 HNMR (400 MHz, DMSO-d6): 8.12 (s, 2H), 7.63 (m, 1H), 7.44 (m, 1H), 7.30 (m, 1H).

[0026] Example 2

[0027] Under nitrogen protection, intermediate 1 (23.5 g, 0.1 mol), MIDA (15.5 g, 0.105 mol), and 4A molecular sieve (40 g) were mixed in 400 mL of LDM, heated to 100 °C, and the reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, filtered, and concentrated to obtain 33.9 g of intermediate 2, with a yield of 98% and an HPLC yield of 98.5%. 1 HNMR (400 MHz, DMSO-d6): 7.68(m, 1H), 7.49 (m, 1H), 7.34 (m, 1H), 4.20 (d, 2H), 3.76 (d, 2H), 2.61 (s,3H).

[0028] Example 3

[0029] Under nitrogen protection, intermediate 2 (17.3 g, 0.05 mol), potassium trifluoromethyl trifluoroborate (10.6 g, 0.06 mol), PdCl2 (dppf) (1.1 g, 1.5 mmol), and potassium acetate (7.4 g, 0.075 mol) were mixed in 250 mL of LDM, heated to 80-85 °C, and reacted for 10 hours. The mixture was then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to about 50 mL. 350 mL of ethyl acetate was added, followed by washing twice with 200 mL of water. The organic layer was concentrated, and the crude product was recrystallized using a mixture of methanol and dichloromethane. After filtration and drying, 13.1 g of intermediate 3 was obtained, with a yield of 78% and an HPLC yield of 98.6%. 1HNMR (400 MHz, DMSO-d6): 7.73(d, 1H), 7.52 (d, 1H), 7.38 (d, 1H), 4.26 (d, 2H), 3.83 (d, 2H), 2.62 (s,3H).

[0030] Example 4

[0031] Intermediate 3 (16.8 g, 0.05 mol), cuprous oxide (0.5 g, 3.5 mmol), 11.4 g of 20% ammonia and potassium hydroxide (7 g, 0.125 mol) were mixed in 150 mL of acetonitrile and reacted at room temperature for 3 hours. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure to about 50 mL, and 200 mL of dichloromethane was added. The mixture was then washed three times with 50 mL of water. The organic layer was concentrated, and the crude product was purified by column chromatography using ethyl acetate / n-hexane (v / v = 2 / 8) as the eluent to give 9.1 g of 4-chloro-3-trifluoromethylaniline, with a yield of 93% and an HPLC yield of 99.4%. 1 HNMR (400 MHz, CDCl3): 7.21 (d, 1 H), 6.94 (d, 1 H), 6.73 (m, 1 H), 3.82 (s, 2 H).

[0032] Example 5

[0033] Under nitrogen protection, intermediate 1 (11.8 g, 0.05 mol), potassium tert-butoxide (6.2 g, 0.055 mol), copper trifluoromethyl (1,10-phenanthroline) (21.9 g, 0.07 mol), and 180 mL of sulfolane were mixed, heated to 120-125 °C, and reacted for 6 hours. The mixture was then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. 500 mL of ethyl acetate was added, followed by washing twice with water. The organic layer was concentrated, and the crude product was dissolved in 15 mL of methanol. Then, 110 mL of water was added (with 3-5 drops of concentrated hydrochloric acid added), and the product precipitated after stirring. The mixture was filtered, dried, and yielded 9.8 g of intermediate 4, with a yield of 87% and an HPLC yield of 99.1%. 1 HNMR (400 MHz, DMSO-d6): 8.30 (s, 2H), 7.79 (m, 1H), 7.58 (m, 1H), 7.36 (m, 1H).

[0034] Example 6

[0035] Intermediate 4 (11.2 g, 0.05 mol), cuprous oxide (0.5 g, 3.5 mmol), and 11.4 g of 20% ammonia were mixed in 150 mL of acetonitrile and reacted at room temperature for 4 hours. The mixture was filtered, concentrated under reduced pressure to approximately 50 mL, and then 200 mL of dichloromethane was added. The mixture was washed three times with 50 mL of water. The organic layer was concentrated, and the crude product was purified by column chromatography using ethyl acetate / n-hexane (v / v = 2 / 8) as the eluent to give 8.9 g of 4-chloro-3-trifluoromethylaniline, yield 91%, HPLC 99.2%.

[0036] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A process for the preparation of 4-chloro-3-trifluoromethylaniline, characterized in that, Comprising the following steps: ， A. reacting 4-chlorophenylboronic acid and NBS in the presence of catalytic amount of triphenylphosphine to form intermediate 1; B. mixing intermediate 1 and MIDA in DMF and reacting at elevated temperature to form intermediate 2; C. reacting intermediate 2, potassium trifluoromethyltrifluoroborate, palladium catalyst and base in polar aprotic solvent at elevated temperature to form intermediate 3; D. reacting intermediate 3 with ammonia in the presence of cuprous oxide and potassium hydroxide to form 4-chloro-3-trifluoromethylphenylamine.

2. The process for the preparation of 4-chloro-3-trifluoromethylaniline according to claim 1, characterized in that: In step A, the molar ratio of 4-chlorophenylboronic acid, NBS and triphenylphosphine is 1:1.1-1.3:0.03-0.

06.

3. The process for the preparation of 4-chloro-3-trifluoromethylaniline according to claim 1, characterized in that: In step B, the molar ratio of intermediate 1 and MIDA is 1:1-1.

1.

4. The process for the preparation of 4-chloro-3-trifluoromethylaniline according to claim 1, characterized in that: In step B, the elevated temperature is 80-120°C.

5. The process for the preparation of 4-chloro-3-trifluoromethylaniline according to claim 1, characterized in that: In step C, the catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; the base is potassium acetate; the polar aprotic solvent is selected from DMSO, DMF or dioxane.

6. The process for the preparation of 4-chloro-3-trifluoromethylaniline according to claim 1, characterized in that: In step C, the molar ratio of intermediate 2, CF3BF3K, palladium catalyst and base is 1:1.1-1.3:0.01-0.05:1.5-2.5; the elevated temperature is 60-120°C.

7. The process for the preparation of 4-chloro-3-trifluoromethylaniline according to claim 1, characterized by the fact that: In step D, the molar ratio of intermediate 3, cuprous oxide, ammonia and potassium hydroxide is 1:0.05-0.1:1.1-1.5:2-3; the ammonia is 15-25% ammonia solution.

8. A process for the preparation of 4-chloro-3-trifluoromethylaniline, characterized in that, Comprising the following steps: 。 9. The process for the preparation of 4-chloro-3-trifluoromethylaniline according to claim 8, characterized in that: In the trifluoromethylation reaction of the second step, the reaction is carried out in sulfolane solvent at 100-140°C, and the molar ratio of intermediate 1 and copper trifluoromethyl(1,10-phenanthroline) is 1:1-1.5.

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