Bicarbonate Ion → 1-(5-{2-[3-(methylsulfonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1,3-thiazol-2-yl)cyclobutanol

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Reaction Conditions

Reaction Steps

To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107C) (150 mg, 0.272 mmol) and 3-methylsulfonyl phenylboronic acid (54.4 mg, 0.272 mmol) in N,N-dimethylformamide (2.04 mL) was added saturated aqueous bicarbonate solution (680 μL) followed by bis(triphenylphosphine) palladium dichloride (13.37 mg, 0.019 mmol). The mixture was heated to 70° C. for 3 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. A solution of the residue in methanol (2.0 mL) and 2N sodium hydroxide solution (700 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.60 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.37 (d, J=7.93 Hz, 1H), 8.28 (d, J=5.04 Hz, 1H), 7.88 (d, J=6.71 Hz, 1H), 7.75 (t, J=7.78 Hz, 3H), 7.51 (s, 1H), 7.32 (d, J=5.04 Hz, 1H), 3.32 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 426.7 [M+H]+.

Provenance & Evidence