Synthesis
General procedure for the synthesis of 2-hydroxy-5-nitroacetophenone and 2-hydroxy-3-nitroacetophenone from 2'-hydroxyacetophenone: In a four-necked flask, 2'-hydroxyacetophenone (175 g), acetic acid (183 g), and dichloromethane (800 mL) were added sequentially, and the mixture was heated to 40 °C. Subsequently, 63% concentrated nitric acid (165 g) was slowly added dropwise, and the reaction temperature was controlled to be maintained at 40 °C for 4-6 hours. After completion of the dropwise addition, the reaction was continued at 40 °C for 4-6 hours. At the end of the reaction, water (500 g) was added and stirred for 30 minutes for extraction and layering. The organic layer was concentrated to about 200 g of crude product. The above crude product (200 g) was added to a four-necked flask with toluene (900 g), heated to 60-70 °C and reacted at 70-80 °C for 2-4 hours. The reaction mixture was cooled to 30-50 °C and filtered and the filter cake was dried. The dried filter cake was transferred to a four-necked flask, methanol (100 g) and water (800 g) were added and heated to 50-60°C. The reaction mixture was cooled to 30-50°C and filtered. Acetic acid (150 g) was added slowly dropwise and controlled to be added dropwise within 2 hours at 60-70 °C. The reaction mixture was cooled to room temperature and filtered, and the filter cake was dried to give the product A-2 (80 g).
References
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3353 - 3362
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3353 - 3362
[3] Asian Journal of Chemistry, 2015, vol. 27, # 6, p. 2117 - 2124
[4] Patent: WO2009/85256, 2009, A1. Location in patent: Page/Page column 55
[5] Patent: CN103980257, 2016, B. Location in patent: Paragraph 0033; 0034; 0035
