Preparation method of 4-fluoro-7-bromobenzofuran_Kain Industrial Additive

Background and overview^[1]

4-Fluoro-7-bromobenzofuran can be used as a pharmaceutical synthesis intermediate. If 4-fluoro-7-bromobenzofuran is inhaled, move the patient to fresh air; if skin contact occurs, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical attention if you feel unwell; if In case of eye contact, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Preparation^[1]

The preparation of 4-fluoro-7-bromobenzofuran is divided into the following two steps:

Step 1: Preparation of 1-bromo-2-(2,2-diethoxyethoxy)-4-fluorobenzene

Combine 2-bromo-5-fluorophenol (0101-2) (1.73g, 9.06mmol, 1.0 equivalent) and 2-bromo-1,1-diethoxyethane (5.45mL, 36.42mmol, 4.0 Equivalent) was dissolved in N,N-dimethylformamide (20 mL), then potassium carbonate (2.50 g, 18.12 mmol, 2.0 Equivalent) was added. Replace the air in the reaction system with nitrogen three times, and then react at 95°C for 8 hours. The reaction solution was diluted with water (100 mL), and then extracted with ethyl acetate (40 mL × 3). The extract was dried with anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 ) to obtain the colorless oily liquid product 1-bromo-2-(2,2-diethoxyethoxy)-4-fluorobenzene (2.78g, yield: 100%). LCMS(ESI): m/z307[M+1]+.

Step 2: Preparation of 4-fluoro-7-bromobenzofuran

Add 1-bromo-2-(2,2-diethoxyethoxy)-4-fluorobenzene (0102-2) (2.75g, 8.95mmol, 1.0 equivalent) into the reaction flask. Phosphoric acid (9.08g, 26.86mmol, 3.0 equivalent) and 1,2-dichloroethane (40mL) were heated to 83°C for 3 hours. The reaction solution was cooled to room temperature and then washed with water (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (petroleum ether) to obtain the light yellow solid product 4-fluoro-7-bromobenzene. and furan (0.992g, yield: 52%). LCMS(ESI): m/z215[M+1]+.

Apply^[1]

4-Fluoro-7-bromobenzofuran can be used as a pharmaceutical synthesis intermediate. For example, prepare 1-(4-fluorobenzofuran-7-yl)ethan-1-one: Dissolve 4-fluoro-7-bromobenzofuran (0103-2) (0.95g, 4.42mmol, 1.0 equivalent) in In anhydrous toluene (15 mL), use a dry ice acetone bath to cool to -78°C, then slowly add n-butyllithium (2.5M, 2.47mL, 6.19mmol, 1.4 equivalent) dropwise, and after the dropwise addition is completed, cool to -78°C. Stir for 1.5 hours. N-methoxy-N-methylacetamide (1.17 mL, 11.05 mmol, 2.5 equivalents) was added dropwise and then slowly warmed to room temperature and stirred for 4 hours. Saturated ammonium chloride solution (50 mL) was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography ( Petroleum ether: ethyl acetate = 30:1) was purified to obtain the light yellow solid product 1-(4-fluorobenzofuran-7-yl)ethan-1-one (0.28g, yield: 36%). LCMS(ESI): m/z179[M+1]⁺.