1142194-24-8

Example 15: Synthesis of 3-methoxy-1-(2-(4-(4-[4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl)pyrrolidine-2-carboxylic acid [3-(2-isopropoxypyridin-4-yl)-1H-indazol-5-yl]amide Step 1: Preparation of 4-bromo-2-isopropoxypyridine Anhydrous isopropanol (50 mL) solution of 4-bromo-2-fluoropyridine (4.12 g, 23.41 mmol) followed by potassium tert-butoxide (2.627 g, 23.41 mmol) was added to a 150 mL pressure vessel under nitrogen protection. The pressure vessel was sealed and the reaction was heated at 80 °C for 3 hours. After completion of the reaction, the pressure vessel was cooled to 0 °C in an ice bath. The reaction mixture was transferred to a 250 mL round bottom flask and concentrated to a small volume. The concentrated mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a clarified oil. Purification by RediSep 80 g silica gel column chromatography with 20:1 hexane/ethyl acetate as eluent gave the clarified oily product 4-bromo-2-isopropoxypyridine (4.2 g, 83%).

[1] Patent: WO2009/105500, 2009, A1. Location in patent: Page/Page column 274
[2] Patent: WO2015/42397, 2015, A1. Location in patent: Paragraph 000652