Thionyl Chloride → HCID 178457795, compound

Participants

Reaction Conditions

Reaction Steps

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 at reduced pressure, and the residue was dried in vacuo for 5 minutes. The residue was resuspended in ACN (1 mL) and cooled to 0° C. A suspension of 3,3-difluoropyrrolidine hydrochloride (317 mg, 2.210 mmol) and sodium hydride (88 mg, 2.210 mmol) in ACN (1 mL) was added, and the reaction was stirred overnight at RT. The solvent was removed at reduced pressure, and the residue was redissolved in 2 mL of MeOH. The residual material was purified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/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-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide as a white powder (59 mg, 49.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (s, 1H), 8.32 (s, 2H), 7.63 (brs, 2H), 7.50 (d, J=7.3 Hz, 1H), 7.24 (brs, 2H), 7.15, (d, J=8.0 Hz, 1H), 4.87 (brs, 1H), 4.02-4.05 (m, 1H), 3.69 (s, 2H), 2.89 (t, J=13.1 Hz, 2H), 2.71-2.77 (m, 4H), 2.53 (brs, 1H), 2.27 (m, 2H), 2.12-2.15 (m, 2H), 1.62-1.73 (m, 4H), 1.10 (d, J=5.6 Hz, 6H). MS, m/z (C29H34F3N5O2): calcd, 541.3. found, 541.8 [M+H].

Provenance & Evidence