Methyl chloroformate → (R)-2-[[2-[2,6-Difluoro-4-(methylcarbamoyl)phenyl]-5-methyl-1H-benzimidazol-1-yl]methyl]morpholine-4-carboxylic acid methyl ester

Participants

Reaction Steps

A mixture of (S)-3,5-difluoro-N-methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide trifluoroacetic acid salt (150 mg, 0.37 mmol), methyl chloroformate (0.058 mL, 0.75 mmol), and N,N-diisopropylethylamine (0.072 mL, 0.41 mmol) in DCM (10.00 mL) was stirred at room temperature for 30 min. The mixture was then concentrated under reduced pressure, and the residue was purified on preparative HPLC MS using the short high pH shallow gradient method (mobile phase: 30-50% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 10 min run; XBridge Prep C18 OBD, Waters reverse phase column; column size: 30×50 mm; particle size: 5 μm). This produced to afford (R)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate (41.7 mg, 24% yield) as a solid. The solid was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; and particle size: 5 μm). MS m/z 459.3 [M+H]+ (ESI), Rt 1.58 min. 1H NMR (400 MHz, methanol-d4) δ ppm 2.50 (s, 3H) 2.54 (dd, J=4.49, 3.71 Hz, 1H) 2.69-2.84 (m, 1H) 2.96 (s, 3H) 3.25 (td, J=11.91, 2.73 Hz, 1H), 3.55-3.64 (m, 2H), 3.66 (s, 3H), 3.74 (d, J=12.89 Hz, 1H), 3.96 (d, J=12.89 Hz, 1H), 4.16 (dd, J=15.23, 7.42 Hz, 1H), 4.37 (dd, J=15.23, 3.12 Hz, 1H), 7.26 (dd, J=8.59, 1.17 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=8.59 Hz, 1H), 7.64 (d, J=8.59 Hz, 2H). HRMS m/z calcd for C23H25F2N4O4 459.1838 [M+H]+. found 459.1849.

Provenance & Evidence