Preparation background and overview of 2-bromo-5-trifluoromethoxypyridine
2-Bromo-5-trifluoromethoxypyridine is a pharmaceutical intermediate that can be prepared from 2-chloro-5-hydroxypyridine in three steps. There are reports in the literature that it can be used to synthesize BACE inhibitors.
Preparation of 2-bromo-5-trifluoromethoxypyridine
Step 1. Add thiophosgene dropwise to lithium pyridine 2-chloro-5-hydroxycarbonate (10 g, 80 mmol) in 1.5M NaOH (aq) (67 mL) at 0°C. (6.0 mL, 79 mmol)/chloroform (46 mL). After addition, the reaction was stirred for 2 hours. The mixture was then extracted with CHCl3. The combined CHCl3 layers were washed with IN HCl (aq) and water, dried (MgSO4) and filtered. Cl2 gas was bubbled through the solution until the reaction became hot (~1 min). The reaction was stirred at room temperature for 2 hours, then Cl2 gas was bubbled through the mixture again. The reaction was then stirred for 18 hours. Nitrogen gas was then bubbled through the reaction mixture to remove residual Cl2 gas. The reaction was then concentrated in vacuo. The residue was purified by reversed phase chromatography [C18 (800g) 5% (2 column volumes (CV)), 5-100% (10 CV), 100 (2 CV); 0.1% formic acid/water // 0.1% formic acid/acetonitrile ], providing trichloromethyl ether (4.0 g, 21%).
Step 2. At 120°C, add the trichloromethyl ether (2.80 g, 11 mmol) prepared in step 1 to antimony trifluoride (4.05 g, 23 mmol) and antimony pentachloride (0.22 mL, 1.7 mmol). ). The reaction was heated to 165°C and stirred for 14 hours under a nitrogen atmosphere, then to 175°C and stirred for an additional 4 hours. The reaction was cooled to room temperature. The resulting solid was stirred vigorously with saturated NaHCO3 (aq) [gas evolution!] and EtOAc. The mixture was filtered through a plug of celite, washed with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc/hexanes, 30 min) (0.90 g, 40%).
Step 3. Add bromotrimethylsilane (2.8 mL, 21 mmol) to the trifluoromethyl ether (2.0 g, 9.3 mmol) prepared in step 2 (in propionitrile (11 mL)). The reaction was heated to 100°C and stirred for 6.5 hours. Phenanthreneboronic acid The reaction was cooled to room temperature and saturated NaHCO3 was added. The mixture was extracted with EtOAc. The combined organics were washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give the product 2-bromo-5-trifluoromethoxypyridine.
