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Step 2 To a suspension OF 6-TRIFLUOROMETHYLPYRIDINE-2-CARBOXYLIC acid (2.53 g, 13.2 mmol) in THF (50 mL) cooled to-5 C was added triethylamine (1.84 mL, 13.2 mmol) followed by addition of ethyl CHLOROFORMATE (1.26 mL, 13.2 mmol) and the reaction mixture was stirred for 30 min at 0 C. Lithium borohydride (718 mg, 33 mmol) was added in portions, maintaining the temperature BELOW-5 C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 h. Temperature was lowered to-5 C and methanol (10 mL) was added followed by addition of aqueous sodium hydroxide (10 mL, 10 %). After the addition of ethyl acetate (50 mL) and water (40 mL), dilute hydrochloric acid was added to obtain pH = 5.0. After washing aqueous layer thoroughly with ethyl acetate the combined organic extracts were dried over MGS04 and concentrated. Purification by flash column (30% EtOAc-Hexane) gave (6-trifluoromethylpyridin-2-yl) methanol (760 mg) as an oil.
Example 79: 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxynnethyl1-6-trifluoroiotainethyl- pyridine.; Step A: Preparation of (6-Trifluoronnethyl-pyridin-2-yl)-nnethanol.; To a solution of 6-trifluoromethyl-pyhdine-2-carboxylic acid (500 mg, 3 mmol) in dry THF at 0 0C, was added triethylamine (0.36 ml_, 2.6 mmol) followed by ethyl chloroformate (0.25 ml_, 2.6 mmol). After 30 min, LiBH4 (2 M in THF, 3.3 ml_, 6.5 mmol) was added. After an additional 30 min, the ice bath was removed. After 1 h, the reaction was cooled to 0 0C and quenched with MeOH followed by 1 N NaOH and EtOAc. The pH of the solution was adjusted to pH=5 with 1 N HCI and the mixture extracted with EtOAc (2X). The combined organic fractions were dried to provide the title compound that was used without further purification. 1H NMR (CDCI3): 7.89 (dd, J = 7.8, 7.8 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 4.85 (s, 2H).
Step 2; To a suspension of 6-trifluoromethylpyridine-2-carboxylic acid (2.53 g, 13.2 mmol) in THF (50 niL) cooled to -5 0C was added triethylamine (1.84 mL, 13.2 mmol) followed by addition of ethyl chloroformate (1.26 mL, 13.2 mmol) and the reaction mixture was stirred for 30 min at 0 0C. Lithium borohydride (718 mg, 33 mmol) was added in portions, maintaining the temperature below -5 0C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 h. Temperature was lowered to -5 0C and methanol (10 mL) was added followed by addition of aqueous sodium hydroxide (10 mL, 10 %). After the addition of ethyl acetate (50 mL) and water (40 mL), dilute hydrochloric acid was added to obtain pH = 5.0. After washing aqueous layer thoroughly with ethyl acetate the combined organic extracts were dried over MgSO4 and concentrated. Purification by flash column (30% EtOAc-Hexane) gave (6-trifluoromethylpyridin-2-yl)methanol (760 mg) as an oil.
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