Hydrochloric Acid → 2-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide, dihydrochloride salt

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Reaction Conditions

Reaction Steps

To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.042 g, 0.17 mmol, Compound C of Example 1) and 2-fluoro-N-o-tolylnicotinamide (0.040 g, 0.17 mmol), in anhydrous 1,4-dioxane (0.22 mL) and anhydrous NMP (0.40 mL), was added HCl (4N in 1,4-dioxane, 0.18 mL, 0.72 mmol). The reaction mixture was heated in a sealed tube at 140° C. for 65 hours before being partitioned between chloroform and 10% LiCl (aq). The aqueous layer was extracted with chloroform and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to a tan solid that was dissolved in anhydrous THF (1 mL), cooled to 0° C. and treated with HCl (4N in 1,4-dioxane, 0.5 mL, 2.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.025 g, 29%) as a tan solid. 1H NMR (DMSO-d6) δ 12.74 (s, 1H), 10.89 (s, 1H), 10.26 (s, 1H), 8.10-8.50 (m, 4H), 7.10-7.70 (m, 7H), 6.95-7.05 (m, 1H), 6.65-6.75 (m, 1H), 6.45-6.53 (m, 1H), 2.19 (s, 3H);

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