反応 #380
ord-b57d9ea5b2ca4d5c93ac4813f00278f3
溶媒
反応条件
実験手順
N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (7.3 g, 19.10 mmol), 2-amino-5-fluoro-N-methoxybenzamide (5.28 g, 28.66 mmol), diacetoxypalladium (0.214 g, 0.96 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.105 g, 1.91 mmol) and cesium carbonate (12.45 g, 38.21 mmol) were suspended in 1,4-dioxane (76 ml). The reaction was degased, purged with nitrogen and heated to 90°C (internal temperature) overnight _._ Reaction was concentrated to dryness. Residue was diluted with EtOAc (200 mL) and water (200 mL). Aqueous was extracted with EtOAc (100 mL) then with EtOAc/MeOH 9/1 (100 mL) => _aqueous still contained some expected product._ Aqueous was saturated with NaCl and extracted with EtOAc/MeOH 9/1 (100 mL). Combined organic layers were dried over MgSO4 and concentrated to dryness. The crude product (12g) was dissolved in CH2Cl2 (80 mL) for liquid injection but product started to precipitate. Solid was filtered and washed twice with CH2Cl2 to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro- N-methoxybenzamide (7.1 g) as an off-white solid. The filtrate was purified by flash chromatography on silica gel eluting with 10 to 100% ethyl acetate in dichloromethane ( _elution of impurities_ ) then with 5%, 10% and 15% MeOH in ethyl acetate ( _product elutes on TLC plate with 100% EtOAc but n MeOH to elute from the column probably due to poor solubility in EtOAc_ ). The solvent was evaporated to dryness. Residual oil was triturated in CH2Cl2. Resulting solid was filtered nad dried to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (0.9 g) as an off-white solid. Both batches (8g) were combined and recrystallised from EtOH (70 mL) to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (3.6 g) as a white crystalline solid => _less hot EtOH ( <60 mL ?) could have been used to solubilise all._ Filtrate was concentrated to ~half the volume and then stirred at room temperature for 4 hours. The resulting solid was filtered to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (3.2 g) as a white solid. Both batches of solid (6.8 g) were combined and slurried in EtOAc (65 mL) at room temperature for 24 hours. The resulting solid was filtered and dried at 50°C under high vacuum overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro- N-methoxybenzamide (4.52g, 54%, EN03787-13-01) as a white solid. Filtrate was concentrated to ~20 mL and then stirred at room temperature 24 hours. The resulting solid was filtered and dried under high vacuum at 50°C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro- N-methoxybenzamide (1.12g, 13.4%, EN03787-13-02) as a white solid.