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

Participants

Reaction Steps

A sealed tube was charged with a stir bar, 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (75 mg, 0.27 mmol), Pd2(dba)3 (7.4 mg, 8.1 μmol), X-PHOS (19.3 mg, 0.04 mmol), and potassium carbonate (41 mg, 0.30 mmol). The tube was evacuated and backfilled with argon 3×. 2-(6-Bromopyridin-2-yl)-2-(1,1-dioxidothiomorpholin-4-yl)ethanol (92 mg, 0.28 mmol) was placed in a separate vial which was also evacuated and backfilled with argon 3×. Fully degassed tert-amyl alcohol (700 μl) was added to the vial containing 2-(6-bromopyridin-2-yl)-2-(1,1-dioxidothiomorpholin-4-yl)ethanol and the resulting solution was transferred to the sealed tube containing the rest of the reactants. This tube was then sealed, placed in an oil bath at 100° C., and stirred overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate (2×) and brine (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed using reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier, monitoring at 230 nM). Desired fractions were poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was extracted, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was taken up in a 1:1 mixture of methanol:ethyl acetate, 0.6 g of silica gel was added, and the solvent was removed in vacuo. The compound on silica was purified via flash chromatography (silica, 0-8% methanol/ethyl acetate) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 11.28 (s, 1H), 7.85 (d, 2H), 7.72 (s, 1H), 7.70 (t, 1H), 7.60 (s, 1H), 7.55 (d, 2H), 7.08 (d, 1H), 7.99 (d, 1H), 5.09 (s, 1H), 4.64 (t, 1H), 3.99 (m, 3H), 3.07 (m, 4H), 3.04 (m, 2H), 2.95 (m, 2H), 1.42 (s, 6H). LRMS (APCI) calcd for C24H30N5O5S2 [M+H]+: 532.2, found 532.0

Provenance & Evidence