Sodium hydride → 1-(5-Methyl-2-(piperidin-4-yloxy)pyridin-3-YL)-N-(thiazol-2-YL)isoquinoline-6-sulfonamide

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Reaction Steps

To a vial charged with 1-(2-fluoro-5-methylpyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Example 377) (50 mg, 0.125 mmol) was added 1-boc-4-hydroxypiperidine (27.6 mg, 0.137 mmol) and DMF (499 μl) and the resulting solution cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (12.48 mg, 0.312 mmol). The mixture was stirred overnight at room temperature (ice melt) affording conversion to desired product as the primary species. To the light brown solution was added IPA (0.5 ml) and AcOH (50 μl). The resulting mixture was dried under reduced pressure affording a yellow oil to which DCM (1 ml) and TFA (0.3 ml) was added. The resulting mixture was stirred at room temperature for 2 hrs affording no Boc cleavage according to LC-MS. Another 0.7 ml of TFA was added and stirring was continued at room temperature for 2 hr affording complete Boc cleavage. The mixture dried under reduced pressure, dissolved in DMSO (1 ml) and purified with RP-HPLC (Gilson) ramping ACN in H2O (5-95%, 0.1% TFA modifier) affording separation of impurities. The product containing eluents were dried under reduced pressure and free-based with a 5 g SCX-2 column washing with MeOH, then 2M NH3 in MeOH. The basic wash was dried under reduced pressure affording a light yellow film which was lyophilized from MeOH/H2O to provide 1-(5-methyl-2-(piperidin-4-yloxy)pyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off-white powder (25 mg, 0.052 mmol, 41.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=5.67 Hz, 1H), 8.43 (d, J=1.66 Hz, 1H), 8.16 (dd, J=0.78, 2.45 Hz, 1H), 8.04 (d, J=5.38 Hz, 1H), 7.88 (dd, J=1.71, 8.85 Hz, 1H), 7.66-7.74 (m, 2H), 7.02 (d, J=4.01 Hz, 1H), 6.59 (d, J=4.11 Hz, 1H), 5.27 (td, J=3.47, 6.94 Hz, 1H), 2.91 (br. s., 2H), 2.61-2.79 (m, 2H), 2.30 (s, 3H), 1.86-2.01 (m, 2H), 1.56 (br. s., 2H). m/z (ESI) 482.1 (M+H)+

Provenance & Evidence