Preparation method of 7-bromobenzofuran-2-carboxylic acid_Kain Industrial Additive

Background and overview^[1]

7-Bromobenzofuran-2-carboxylic acid can be used as a pharmaceutical synthesis intermediate.

Preparation^[1]

Method 1: The preparation of 7-bromobenzofuran-2-carboxylic acid is divided into the following two steps:

1) 3-Bromo-2-hydroxybenzaldehyde. Add 20.0g (115.6mmol) of 2-bromophenol to 500ml of anhydrous acetonitrile. Add 16.84g (176.87mmol) anhydrous magnesium chloride, 23.4g paraformaldehyde particles and 41.9ml (300.6mmol) triethylamine. The reaction mixture was heated to reflux for 4 hours, and after cooling to 0°C, 300 ml of 2N hydrochloric acid was added. The aqueous phase was extracted three times with 200 ml of diethyl ether each time. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The title compound was isolated and reacted further without further purification. 24g (64% of theory, 62% purity according to HPLC). HPLC (Method 1): Rt=4.25 minutes. MS (ESIpos): m/z=202(M+H)+.

2) 7-bromobenzofuran-2-carboxylic acid. 13.5g (40.3mmol) 3-bromo-2-hydroxybenzaldehyde (Example 28A, 62% purity) was mixed with 9.18g (84.62mmol) methyl chloroacetate, 1.49g (4.03mmol) tetra-n-butylammonium iodide Heat with 22.28. g (161.18mmol) potassium carbonate maintained at 130°C for 6 hours. After cooling to room temperature, 100 ml of water, 100 ml of THF, and 13.57 g (241.77 mmol) of potassium hydroxide were added, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was dissolved in 400 ml of water and washed four times with a total of 400 ml of diethyl ether. While cooling with ice, the pH was adjusted to 0 with concentrated hydrochloric acid, and extracted 5 times with a total of 700 ml of ethyl acetate. The organic phase was washed with 100 ml of saturated sodium chloride solution and dried over magnesium sulfate. The crude product was completely freed of residual solvent under high vacuum and stirred with 80 ml of diethyl ether. The product 7-bromobenzofuran-2-carboxylic acid was filtered off and washed with a small amount of ice-cold ether. Yield: 4.8 g (47% of theory). 1H-NMR (200MHz, DMSO-d6): δ=13.5 (br.s, 1H), 7.86-7.72 (m, 2H), 7.79 (s, 1H), 7.31 (t, 1H). MS (DCI/NH3): m/z=258 (M+NH4)+.

Method 1: The preparation of 7-bromobenzofuran-2-carboxylic acid is divided into the following two steps:

1) 3-Bromo-2-hydroxybenzaldehyde. Add 20g (115.6mmol) 4-bromo-2-hydroxybenzaldehyde and 16.84g (176.9mmol) magnesium chloride into 500ml anhydrous acetonitrile. 41.9 ml (300.6 mmol) triethylamine was added, and the mixture was heated to reflux for 3 hours. The mixture was cooled to 0°C and 300 ml of 2N hydrochloric acid was added. The aqueous phase was extracted three times with a total of 600 ml of diethyl ether. The organic phase was washed with 200 ml of saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure. Finally any last solvent residues are removed under high vacuum. 24 grams (64% of theoretical value). HPLC: Rt=4.25 min (Method H) MS (ESIpos): m/z=201(M)+.

2) 7-bromobenzofuran-2-carboxylic acid. 10 g (49.75 mmol) of 3-bromo-2-hydroxybenzaldehyde and 1.84 g (4.97 mmol) of tetra-n-butylammonium iodide were added together with 27.5 g (199.0 mmol) of anhydrous potassium carbonate. Add 24.3g (223.86mmol) methyl chloroacetate. The reaction mixture was heated to 130°C for 4 hours and then cooled to 0°C using an ice bath. 100 ml THF and a solution of 16.75 g (298.5 mmol) potassium hydroxide in 100 ml water were added, and the mixture was stirred at 40°C for 4 hours. The solvent was removed under reduced pressure. The residue was diluted with water and acidified with concentrated hydrochloric acid. hydrochloric acid. The product was purified on silica gel 60 (eluent: toluene/ethyl acetate/acetic acid 40:10:1). The solvent was removed under reduced pressure. Finally any last solvent residues are removed under high vacuum. Polishing was performed by preparative HPLC. 7-Bromobenzofuran-2-carboxylic acid yield: 303 mg (2.5% of theory). HPLC: Rt=4.16min (Method H). MS (ESIpos): m/z=258 (M+NH4)+.