Water → (R)-5'-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-6'-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

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Reaction Conditions

Reaction Steps

(R)-6′-Chloro-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Example 53, 139 mg, 0.28 mmol) and trimethyl-boroxine (34.4 mg, 0.274 mmol) were dissolved in dioxane (1.5 mL). K2CO3 (104 mg, 0.756 mmol) was added, the RM was flushed with argon and Pd(PPh3)4 (32.4 mg, 0.028 mmol) was added. The RM was heated overnight at 110° C. After cooling to RT, the RM was dissolved in EtOAc treated with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH). Further purification by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10 to 41% MeCN+0.1% formic acid). The combined pure fractions were neutralized with NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH and evaporated under reduced pressure to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=5.16 min, UPLC-MS (Condition 7) m/z=477.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 1H) 1.78-1.88 (m, 1H) 2.42-2.56 (m, 3H) 2.87 (d, J=11.73 Hz, 1H) 3.14-3.28 (m, 2H) 3.33-3.43 (m, 1H) 4.18 (br. s, 1H) 4.84 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.71 (dd, J=10.17, 1.56 Hz, 1H) 7.79-7.90 (m, 2H) 8.02 (d, J=2.35 Hz, 1H) 8.34 (s, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.15 (s, 1H).

Provenance & Evidence