Thionyl Chloride → HCID 178457796, Verbindung

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed, and the residue was resuspended in 2 mL DMSO, cooled to 0° C., and 4,4-difluoropiperidine hydrochloride (348 mg, 2.210 mmol) and TEA (0.308 mL, 2.210 mmol) were added. The reaction was stirred for 30 minutes at 0° C. and then at RT for 16 hours. The reaction was concentrated, and the residue was purified by reverse-phase preparative HPLC, using 0.1% TFA in AC/water (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-N-(6-((4,4-difluoropiperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide as a white powder (71 mg, 57.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (s, 6H), 1.54-1.83 (m, 5H), 1.94-2.18 (m, 7H), 2.53 (br. s., 3H), 2.67-2.86 (m, 2H), 3.64 (s, 2H), 3.94-4.09 (m, 1H), 4.91 (br. s., 1H), 7.13 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.60-7.82 (m, 2H), 8.20-8.43 (m, 2H), 12.75 (br. s., 1H). MS, m/z (C30H36F3N5O2): calcd, 555.3. found, 555.9 [M+H].

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