Synthesis
A. Procedure for the synthesis of 5-bromo-2-hydroxybenzamide:
1. In a 100 mL round-bottom flask, 5-bromosalicylic acid (30 g, 135.5 mmol) was dissolved in n-butanol (60 mL) and concentrated sulfuric acid (95.6%, 289 μL, 5.42 mmol) was added. The unit was equipped with a Dean-Stark manifold and reflux condenser and 12 mL of n-butanol was added.
2. Reflow the reaction mixture under heat for 2 days. Upon completion of the reaction, it was cooled to room temperature and concentrated to give a light yellow oil.
3. Methanol (50 mL) was added to the above oil, followed by the slow addition of a methanol solution of ammonia (7 N, 116 mL).
4. The reaction mixture was stirred at room temperature for 2 days and the progress of the reaction was monitored by HPLC. 5.
5. After completion of the reaction, the reaction mixture was concentrated to give a white solid.
6. The crude product was washed with a small amount of ethyl acetate and hexane to give 24 g of white crystalline solid in 82% yield.
References
[1] Patent: WO2005/95326, 2005, A2. Location in patent: Page/Page column 253
[2] Patent: US2018/64726, 2018, A1. Location in patent: Paragraph 0360; 0361
[3] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 4, p. 734 - 745
[4] Patent: US2006/14737, 2006, A1. Location in patent: Page/Page column 25
