Synthesis
The general procedure for the synthesis of 5-bromo-4-fluoro-2-hydroxybenzaldehyde using 4-fluoro-2-hydroxybenzaldehyde as starting material was as follows: a solution of bromine (14.1 g, 88.3 mmol) dissolved in chloroform (25 mL) was added slowly and dropwise over a period of 10 min to a solution of chloroform (68 mL) containing 4-fluoro-2-hydroxybenzaldehyde (13.6 g, 97.1 mmol) in a round bottomed flask. The reaction mixture was stirred at room temperature for 16 hours and then the same amount of bromine (14.1 g) was added. Stirring was continued at room temperature for 24 hours. Upon completion of the reaction, the mixture was washed twice with 30% aqueous sodium thiosulfate to remove the color, followed by washing with water and drying the organic layer with anhydrous sodium sulfate. Finally, the organic phase was concentrated by decompression to afford the target product 5-bromo-4-fluoro-2-hydroxybenzaldehyde (21.3 g, 100% yield).
References
[1] Patent: WO2012/40641, 2012, A2. Location in patent: Page/Page column 135; 136
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 12, p. 3163 - 3179
[3] Patent: US6642222, 2003, B2
[4] Patent: US6593335, 2003, B1
[5] Patent: WO2013/91096, 2013, A1. Location in patent: Page/Page column 37
