Preparation of 5-bromobenzo[1,3]dioxole-4-carboxylic acid_Kain Industrial Additive

Background and overview^[1]

5-Bromobenzo[1,3]dioxole-4-carboxylic acid can be used as a pharmaceutical synthesis intermediate. It can be prepared from 6-bromo-2,3-dihydroxybenzaldehyde in three steps.

Preparation^[1]

Step 1: 6-bromo-2,3-dihydroxybenzaldehyde

Dissolve 6-bromo-2-hydroxy-3-methoxybenzaldehyde (2.00g, 8.65mmol) in dichloromethane (10mL) and cool to 0°C. Boron tribromide (17.0 mL of a 1.0 M solution, 17.00 mmol) was added via syringe and the solution was stirred at 0 °C for 1 h. The reaction was then warmed to ambient temperature and stirred for 15 h, at which time TLC analysis indicated completion of the reaction. The reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated by rotary evaporation to afford 1.82 g of 6-bromo-2,3-dihydroxybenzaldehyde as a yellow solid (8.39 mmol, 97% yield).

Step 2: 5-bromo-1,3-benzobisoxazole-4-carbaldehyde

Dissolve 6-bromo-2,3-dihydroxybenzaldehyde (1.82g, 8.39mmol) in DMF (20mL) and dibromomethane (1.57g, 9.00mmol) and add potassium fluoride (2.44g, 42.00 mmol). The reaction mixture was heated to 100°C for 2 hours, at which time TLC analysis indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature and partitioned between water and dichloromethane. The organic layer was washed 4 times with water, dried over magnesium sulfate, and concentrated by rotary evaporation to afford 0.60 g of oily product (2.62 mmol, 31% yield). ¹HNMR (CDC1₃) δ10.24 (s, IH), 7.09 (d, /=8.3Hz, IH), 6.79 (d, /=8.3Hz, IH), 6.10(s, 2H).

Step 3: 5-bromobenzo[1,3]dioxole-4-carboxylic acid

Dissolve potassium permanganate (1.03g, 6.55mmol) in water (25mL). 5-Bromo-1,3-benzobisoxazole-4-carbaldehyde (0.60 g, 2.62 mmol) was dissolved in acetone (25 mL), then slowly added to the permanganate solution, and the reaction mixture was allowed to stand at ambient temperature The mixture was stirred for 24 hours, at which time TLC analysis showed that the reaction was complete. Quench the reaction mixture with 5% sodium sulfite (100 mL). Concentrated HCl (10 mL) was added and the mixture turned light yellow. The solution was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate and concentrated by rotary evaporation to obtain 0.34g of the off-white solid product 5-bromobenzo[1,3]dioxole-4-carboxylic acid ( 1.39mmol, 53% yield).

Main reference materials

[1] WO1998038991 – POLYCYCLIC ETHYL ALKYLAMIDE MELATONERGIC AGENTS