Preparation method of N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide

Abstract

The present invention discloses a preparation method of N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide, belonging to the technical field of pharmaceutical synthesis. The preparation method of N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide is as follows: 4-bromo-2-fluorobenzonitrile, 2-aminophenylboronic acid, a catalyst, a base, and an aqueous Brij-30 solution are sequentially added to a reaction vessel and reacted at a certain temperature; after the reaction is completed, p-methoxybenzenesulfonyl chloride is directly added and reacted at a certain temperature. After the reaction is completed, post-treatment is carried out to obtain the N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide. The present invention completes the reaction by a one-pot two-step method, with mild reaction conditions and a green and environmentally friendly reaction process, so it is beneficial to scale-up production and can be widely applied.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide. Background Art

[0002] A series of N-sulfonyl-amino diaryl derivatives are generally considered to be novel anti-tuberculosis drugs. And the compound [N-(4-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide] simultaneously exhibits significant anti-proliferative activity against four cancer cell lines (pancreatic AsPC1, lung A549, liver Hep3B, and prostate PC-3) (J. Med. Chem. 2015, 58, 6549-6558, Chem. Sci. 2019, 10, 8825-8831). The current method for synthesizing the compound [N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide] is as follows: First, 2-nitrobromobenzene and 3-fluoro-4-cyanophenylboronic acid are added, and then Pd(PPh3)4 and K2CO3 are added, and reflux reaction is carried out in a mixed system of toluene and ethanol. Subsequently, the nitro group in the product of the previous step is reduced to an amino group with iron powder, ammonium chloride, and isopropanol in water. Subsequently, 4-methoxybenzenesulfonyl chloride and pyridine are added, and the reaction is carried out at 50 °C for a certain time. After the reaction is completed, the compound N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide is obtained (J. Med. Chem. 2015, 58, 6549-6558). The synthetic route is as follows:

[0003]

[0004] This method requires three-step reactions, and the steps are complex and cumbersome. In the first Suzuki reaction, toluene needs to be used as a solvent. The use of organic solvents is likely to cause damage to the environment, and reflux is required, and the reaction temperature is relatively high, resulting in waste of energy. And when using a micelle system, relatively high temperature and long reaction time are often required. For example, when Bruce uses 4-bromo-2-fluorobenzonitrile and 2-aminophenylboronic acid to react in a TPGS-750-M / H2O micelle system, the reaction temperature needs to be 55 °C and the reaction time is 24 h (Chem. Sci., 2019, 10, 8825-8831). And in the amidation process, organic solvents such as dichloromethane (Angew. Chem. Int. Ed. 2022, 61, e202206420) and pyridine (Bioorg. Med. Chem. 2007, 15, 1014-1021) are usually used, which are likely to cause environmental pollution. Summary of the Invention

[0005] The object of the present invention is to overcome the deficiencies of the prior art and provide a preparation method of N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide. The present invention completes the reaction by a one-pot two-step method, with mild reaction conditions and a green and environmentally friendly reaction process. Therefore, it is beneficial for scale-up production and can be widely applied.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] A preparation method of N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide, comprising the following steps:

[0008] Step 1: Add 4-bromo-2-fluorobenzonitrile, 2-aminophenylboronic acid, a catalyst, a base, and an aqueous Brij-30 solution into a reaction vessel in sequence, and react at a certain temperature;

[0009] Step 2: After the reaction is completed, directly add p-methoxybenzenesulfonyl chloride and react at a certain temperature. After the reaction is completed, perform post-treatment to obtain the N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide.

[0010] Further, the molar ratio of 4-bromo-2-fluorobenzonitrile, 2-aminophenylboronic acid, the catalyst, the base, and p-methoxybenzenesulfonyl chloride is: 1:1.2~2:0.01~0.02:3~5:2~4.

[0011] Further, the catalyst in Step 1 is Pd(Amphos)Cl2, Pd(dppf)Cl2, or Pd(dtbpf)2Cl2.

[0012] Further, the base in Step 1 is triethylamine or pyridine.

[0013] Even further, the aqueous Brij-30 solution is a 1~3 wt.% aqueous Brij-30 solution.

[0014] Even further, the temperature during the reaction in Step 1 is 30~50 °C, and the reaction time is 4~6 h.

[0015] Even further, the temperature during the reaction in Step 2 is 40~50 °C, and the reaction time is 24~48 h.

[0016] Compared with the prior art, the beneficial effects of the present invention are:

[0017] First: The reaction of the present invention is carried out in a micelle system, which is more environmentally friendly than organic solvents, friendly to the environment, and has a lower reaction temperature, reducing energy consumption.

[0018] Second: The present invention directly performs the Suzuki reaction between 4-bromo-2-fluorobenzonitrile and boric acid, reducing the oxidation step and streamlining the reaction steps.

[0019] In summary, the present invention completes the reaction by a one-pot two-step method, with mild reaction conditions and a green and environmentally friendly reaction process. Therefore, it is conducive to scale-up production and can be widely applied. Description of the Drawings

[0020] Figure 1 It is the 1 H NMR spectrum of N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide of the present invention;

[0021] Figure 2 It is the 13 C NMR spectrum of N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide of the present invention;

[0022] 1 H NMR (500 MHz, Chloroform-d) δ 7.74 (d, J = 2.1 Hz, 3H), 7.59 -7.53(m, 2H), 7.46 (td, J = 7.7, 1.7 Hz, 1H), 7.38 -7.30 (m, 1H), 7.24 (d, J =10.0 Hz, 1H), 7.13 -7.06 (m, 1H), 6.96 -6.93 (m, 3H), 3.97 (s, 3H).

[0023] 13 C NMR (126 MHz, Chloroform-d) δ164.40, 162.33, 147.64, 143.39,133.79, 130.16, 130.14, 125.60, 125.58, 124.24, 119.11, 117.05, 116.90,116.40, 114.08, 99.77, 55.62. Detailed Description of the Invention

[0024] The present invention will be further described in detail below in conjunction with the embodiments.

[0025] Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. For those without specific technical or conditions noted in the examples, the techniques or conditions described in the literature in this field or according to the product specifications are followed. For reagents or instruments without the manufacturer noted, they are all conventional products that can be obtained by purchase.

[0026] The reaction formula for preparing N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide of the present invention is as follows:

[0027]

[0028] Example 1:

[0029] 0.2 mmol of 4-bromo-2-fluorobenzonitrile (40 mg), 0.24 mmol of 2-aminophenylboronic acid (32.9 mg), 3.0 mg of PdCl2(dtbpf) (2 mol%), 1.0 mmol of triethylamine, and 2 mL of 2 wt.% Brij-30 aqueous solution were successively added to a reaction vessel and reacted at 40 °C for 6 h. After the reaction was completed, without post-treatment, 0.8 mmol of p-methoxybenzenesulfonyl chloride was added, and then the reaction was continued at 50 °C for 48 h. After the reaction was completed, the temperature was lowered to room temperature, and the product was extracted with ethyl acetate. The compound N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide was obtained by column chromatography, and 71 mg of the product was obtained with a separation yield of 93%.

[0030] Example 2:

[0031] 0.2 mmol of 4-bromo-2-fluorobenzonitrile (40 mg), 0.24 mmol of 2-aminophenylboronic acid (32.9 mg), 1.5 mg of PdCl2(dtbpf) (1 mol%), 0.6 mmol of triethylamine, and 2 mL of 2 wt.% Brij-30 aqueous solution were successively added to a reaction vessel and reacted at 40 °C for 6 h. After the reaction was completed, without post-treatment, 0.4 mmol of p-methoxybenzenesulfonyl chloride was added, and then 0.4 mmol of triethylamine was added. Then the reaction was continued at 50 °C for 24 h. After the reaction was completed, the temperature was lowered to room temperature, and the product was extracted with ethyl acetate. The compound N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide was obtained by column chromatography, and 68 mg of the product was obtained with a separation yield of 89%.

[0032] Example 3:

[0033] 0.2 mmol of 4-bromo-2-fluorobenzonitrile (40 mg), 0.24 mmol of 2-aminophenylboronic acid (32.9 mg), 1.5 mg of PdCl2(dtbpf) (1 mol%), 0.6 mmol of triethylamine, and 2 mL of 2 wt.% Brij-30 aqueous solution were successively added to a reaction vessel, and the reaction was carried out at 30 °C for 4 h. After the reaction was completed, 0.4 mmol of p-methoxybenzenesulfonyl chloride was added without post-treatment, and then 0.4 mmol of triethylamine was added, and then the reaction was carried out at 50 °C for 24 h. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was extracted with ethyl acetate. Compound N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide was obtained by column chromatography, and 55 mg of the product was obtained with a separation yield of 72%.

[0034] Example 4:

[0035] 0.2 mmol of 4-bromo-2-fluorobenzonitrile (40 mg), 0.24 mmol of 2-aminophenylboronic acid (32.9 mg), 1.5 mg of PdCl2(dtbpf) (1 mol%), 0.6 mmol of triethylamine, and 2 mL of 2 wt.% Brij-30 aqueous solution were successively added to a reaction vessel, and the reaction was carried out at 40 °C for 4 h. After the reaction was completed, 0.4 mmol of p-methoxybenzenesulfonyl chloride was added without post-treatment, and then 0.4 mmol of pyridine was added, and then the reaction was carried out at 50 °C for 24 h. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was extracted with ethyl acetate. Compound N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide was obtained by column chromatography, and 65 mg of the product was obtained with a separation yield of 85%.

[0036] Example 5:

[0037] 0.2 mmol of 4-bromo-2-fluorobenzonitrile (40 mg), 0.24 mmol of 2-aminophenylboronic acid (32.9 mg), 0.75 mg of PdCl2(dtbpf) (0.5 mol%), 0.6 mmol of triethylamine, and 2 mL of 2 wt.% Brij-30 aqueous solution were successively added to a reaction vessel, and the reaction was carried out at 40 °C for 4 h. After the reaction was completed, 0.4 mmol of p-methoxybenzenesulfonyl chloride was added without post-treatment, and then 0.4 mmol of triethylamine was added, and then the reaction was carried out at 50 °C for 24 h. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was extracted with ethyl acetate. Compound N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide was obtained by column chromatography, and 41 mg of the product was obtained with a separation yield of 54%.

[0038] Comparative Example 1:

[0039] 0.2 mmol of 4-bromo-2-fluorobenzonitrile (40 mg), 0.24 mmol of 2-aminophenylboronic acid (32.9 mg), 1.0 mg of PdCl2(dppf) (1 mol%), 0.6 mmol of triethylamine, and 2 mL of 2 wt.% Brij-30 aqueous solution were successively added to a reaction vessel, and the reaction was carried out at 40 °C for 4 h. After the reaction was completed, 0.4 mmol of p-methoxybenzenesulfonyl chloride was added without post-treatment, and then the reaction was carried out at 50 °C for 24 h. After the reaction was completed, the temperature was lowered to room temperature, and the product was extracted with ethyl acetate. Compound N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide was obtained by column chromatography, and 54 mg of the product was obtained with a separation yield of 21%.

[0040] Comparative Example 2:

[0041] 0.2 mmol of 4-bromo-2-fluorobenzonitrile (40 mg), 0.24 mmol of 2-aminophenylboronic acid (32.9 mg), 1.5 mg of PdCl2(dtbpf), 0.6 mmol of pyridine, and 2 mL of 2 wt.% Brij-30 aqueous solution were successively added to a reaction vessel, and the reaction was carried out at 40 °C for 4 h. After the reaction was completed, 0.4 mmol of p-methoxybenzenesulfonyl chloride was added without post-treatment, and then 0.4 mmol of pyridine was added, and the reaction was carried out at 50 °C for 24 h. After the reaction was completed, the temperature was lowered to room temperature, and the product was extracted with ethyl acetate. Compound N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide was obtained by column chromatography, and 26 mg of the product was obtained with a separation yield of 34%.

[0042] Summary table of reaction conditions for examples and comparative examples (Table 1):

[0043] Table 1 Summary table of reaction conditions for examples and comparative examples

[0044]

[0045] Reaction conditions: 0.2 mmol of 4-bromo-2-fluorobenzonitrile, 0.24 mmol of 2-aminophenylboronic acid, the catalyst was 1.5 mg of PdCl2(dtbpf) (1 mol%), the amount of the first base was 0.6 mmol, the amount of the second base was 0.4 mmol, and the second reaction temperature was 50 °C. a The mass of PdCl2(dtbpf) was 3.0 mg, b The amount of triethylamine was 1.0 mmol, c PdCl2(dtbpf) was 0.75 mg.

[0046] The above embodiments have described the implementation manners of the present invention in detail. However, the present invention is not limited to the above implementation manners. Within the scope of knowledge possessed by those of ordinary skill in the art, various changes can be made without departing from the gist of the present invention. The above are only preferred and feasible embodiments of the present invention, and thus do not limit the scope of rights of the present invention. Any equivalent structural changes made by using the content of the specification of the present invention are included within the scope of rights of the present invention.

Claims

1. A method for preparing N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide, characterized in that, It includes the following steps: Step 1: Add 4-bromo-2-fluorobenzonitrile, 2-aminophenylboronic acid, a catalyst, a base, and an aqueous Brij-30 solution into a reaction vessel in sequence, and react at a certain temperature; the catalyst is PdCl2(dtbpf); the base is triethylamine or pyridine; the reaction temperature is 30-50 °C, and the reaction time is 4-6 h; Step 2: After the reaction is completed, directly add p-methoxybenzenesulfonyl chloride and react at a certain temperature. The reaction temperature is 40-50 °C, and the reaction time is 24-48 h. After the reaction is completed, perform post-treatment to obtain N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide.

2. The preparation method of N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide according to claim 1, characterized in that, The molar ratio of 4-bromo-2-fluorobenzonitrile, 2-aminophenylboronic acid, the catalyst, the base, and p-methoxybenzenesulfonyl chloride is: 1:1.2-2:0.01-0.02:3-5:2-4.

3. The preparation method of N-(4′-cyano-3′-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide according to any one of claims 1 to 2, characterized in that, The aqueous Brij-30 solution is a 1-3 wt.% aqueous Brij-30 solution.

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