82% |
Stage #1: 2-Fluoroaniline; 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazole-2-carbaldehyde With glacial acetic acid In 1,2-dichloro-ethane at 60 - 70℃; for 3h; Inert atmosphere;
Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at -5 - 45℃; for 20h; Inert atmosphere; |
1.6 Step 6: Synthesize compound 1 with reference to the following reaction formula
Under nitrogen protection, intermediate 1-g (4.56 g, 15 mmol) and 45 mL of dichloroethane were successively added to the reaction flask, and stirred for 10 min. Add raw material 1-h (2.5g, 22.5mmol), glacial acetic acid (1.08g, 18mmol), heat up to 60 - 70°C, and keep reacting for 3h. Cool down to -5 - 5°C, add NaBH(OAc)3 (6.37, 30mmol) in batches, after adding, the temperature is raised to 40 - 45°C for 20h. Adjust pH=7 - 8 with saturated sodium bicarbonate solution, extract twice with dichloromethane (150mL each time), wash the organic phase with water, separate liquids, and dry, the organic phase (40 - 50 °C, -0.08MPa-0.05 MPa) and concentrated to dryness. The concentrate was added with ethanol (concentrate mass: ethanol volume=1 g: 6 mL) and stirred for 0.5 h, after filtration, the filter cake was dried in a vacuum oven (50° C., -0.08-0.07MPa) to obtain compound 1 (4.92 g, 12.3 mmol) with a yield of 82% and a HPLC purity of 97.63%. |
82% |
With glacial acetic acid In 1,2-dichloro-ethane at 60 - 70℃; for 3h; |
1.5 Step 5: Synthesis of Compound 1
Under nitrogen protection, intermediate 1-f (9.12 g, 30 mmol) and 45 mL of dichloroethane were added to the reaction flask successively, stirred for 10 min, and raw material 1-g (5.0 g, 45 mmol), glacial acetic acid (2.16 g, 36 mmol) were added , heat up to 6070, keep the temperature for 3h, the reaction system is cooled to -55, add NaBH(OAc)3 (12.75, 60mmol) in batches, after adding, the temperature is raised to 4045 for 20h. , adjusted pH=78 with saturated sodium bicarbonate solution, extracted with dichloromethane (150.0mL*2), the organic phase was washed with water, separated and dried, the organic phase (4050, -0.08MPa- 0.05MPa) was concentrated to dryness, the product was stirred with 1g:6mL ethanol for 0.5h, filtered, and the filter cake was dried in a vacuum oven (50°C, -0.08MPa) to obtain compound 1 (9.8g, yield 82%). |