Potassium Carbonate → 2-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-({6-[(2-hydroxy-2-methylpropoxy)methyl]pyridin-2-yl}amino)-1,3-thiazole-4-carboxamide

Participants

Reaction Conditions

Reaction Steps

A sealed tube was charged with a stir bar, 5-amino-2-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 15, Step 5) (150 mg, 0.48 mmol), 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (125 mg, 0.48 mmol), Pd2(dba)3 (44 mg, 0.048 mmol), X-PHOS (114 mg, 0.24 mmol), and potassium carbonate (66 mg, 0.48 mmol) were added. The tube was evacuated and backfilled with argon 3×. Fully degassed tert-amyl alcohol (0.95 ml) was added and the reaction vessel was sealed and left to stir at 100° C. overnight. The reaction vessel was removed from the heat and allowed to cool to room temperature. The reaction mixture was taken up in ethyl acetate and washed with 100 mL water. The water layer was treated with concentrated ammonium hydroxide and extracted with ethyl acetate. The organic fractions were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The compound on silica was purified by reverse phase chromatography (10-100% acetonitrile/water+0.05% TFA modifier). Desired fractions were poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduce pressure to afford the title compound as a yellow solid. 1H NMR (500 MHz, d6-DMSO) δ 11.37 (s, 1H), 7.76 (t, 1H), 7.66 (s, 1H), 7.53 (s, 1H), 7.32 (d, 2H), 7.16 (d, 1H), 7.05 (d, 1H), 4.59 (s, 2H), 3.29 (s, 2H), 1.44 (s, 6H), 1.09 (s, 6H). Hydroxyl protons were not observed. LRMS (APCI) calc'd for C23H27F2N4O4S [M+H]+: 493.2, found 493.2.

Provenance & Evidence