2-amino-N,6-dimethoxybenzamide → 2-[[2-[(2,5-dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)pyridin-4-yl]amino]-N,6-dimethoxybenzamide

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N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (22.8 g, 59.67 mmol), 2-amino-N,6-dimethoxybenzamide (19.90 g, 101.43 mmol), diacetoxypalladium (0.670 g, 2.98 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.45 g, 5.97 mmol) and cesium carbonate (23.33 g, 71.60 mmol) were suspended in 1,4-dioxane (199 ml). The reaction was degased, purged with nitrogen and heated to 90 °C => _reaction turned to dark brown and solidified after ~15 minutes._ 1,4-dioxane (50 mL) was added and reaction was stirred at 90°C (internal temperature) overnight => _stirring became easier and mixture turned to beige/yellow then to dark green/grey during the night._ Reaction was concentrated to dryness. Residue was diluted with CH2Cl2 (300 mL) and water (300 mL). Aqueous was extracted with CH2Cl2 (100 mL) then with CH2Cl2/MeOH 9/1 (100 mL) => _aqueous still contained expected product._ Aqueous was saturated with NaCl and extracted with CH2Cl2/MeOH 9/1 (100 mL). Combined organic layers were dried over MgSO4 and concentrated to dryness. The crude product (38.5g) was dissolved in CH2Cl2 (100 mL) for liquid injection but some product started to precipitate. Solid was filtered and washed twice with CH2Cl2 to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (5.2 g) as a white solid. The filtrate was purified by flash chromatography on silica gel eluting with 0 to 7% methanol in ethyl acetate. The solvent was evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (20.6 g) as a beige solid. Both batches of product (25.8 g) were combined and triturated in tBuOMe (50 mL) / CH2Cl2 (20 mL). The resulting solid was filtered, washed with tBuOMe (50 mL) to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (23 g) as a white solid. It was suspended in H2O (350 mL) and stirred at room temperature overnight => _mixture solidified._ It was filtered and dried over P2O5 under high vacuum for 6 hours. The resulting solid was suspended in acetonitrile (460 mL) and stirred at room temperature over the weekend. It was filtered, washed with cold acetonitrile and dried under high vacuum at 50°C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (8.4 g, 31.3%, EN03787-12-01) as a white solid => _product is quite soluble in acetonitrile, volume of solvent was too important (ref from PARD : 50mg in 1mL)_ Filtrate was concentrated to ~100 mL (= until preciptation occured on the rotavapor) and then stirred at room temperature for 4 hours. The resulting solid was filtered and dried under high vacuum at 50°C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (9.3 g, 34.6%, EN03787-12-02) as a white solid. Filtrate was concentrated to dryness to afford another batch of impure product (2.8g) which was slurried in CH3CN (28 mL) at room temperature overnight. The resulting solid was filtered and dried under high vacuum at 50°C to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (1.54 g, 5.73%, EN03787-12-03) as a white solid => _this batch is less pure than the 2 others_

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