Synthesis
The general procedure for the synthesis of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2) from 5-bromo-2-hydroxybenzaldehyde (1) by nitration reaction is as follows:
Step 1a: 1.0 mole of 5-bromo-2-hydroxybenzaldehyde (1) was dissolved in 3.75 liters of 98% acetic acid and heated to about 60°C. 1.5 moles of concentrated nitric acid (137 g, 97 mL) was added slowly over about 1 hour. After addition, stirring was continued at 65°C for 10 minutes. The reaction solution was then cooled to 45°C and 4 liters of water was added to precipitate the product. After stirring for at least 3 hours, the product was collected by filtration and washed with water until the pH of the mother liquor was about 6. As much water as possible was removed by centrifugation.
Step 1b: The crude product was dissolved in 800 ml of acetone under reflux and stirring. 400 ml of acetone was removed by distillation. After cooling to 20°C, stirring was continued for 3 hours. The precipitate was collected by filtration and washed with petroleum ether (boiling point 40-65°C). The solid was dried overnight at 40°C in a stream of air.
Step 1c: The crude product (2) was recrystallized from acetone to give a final product of 98% purity as shown by NMR analysis.The characteristic chemical shift of 5-bromo-2-hydroxybenzaldehyde (1) was δ 9.84 ppm; and the characteristic chemical shift of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2) was δ 10.4 ppm.The overall yield for this step was about 60% (based on the crude product).
References
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 35, p. 6460 - 6469
[2] Tetrahedron, 2003, vol. 59, # 46, p. 9239 - 9247
[3] Patent: WO2015/42397, 2015, A1. Location in patent: Paragraph 000244
[4] Patent: WO2005/92340, 2005, A1. Location in patent: Page/Page column 17-18
[5] Patent: WO2005/92339, 2005, A1. Location in patent: Page/Page column 16-17
