Morpholine → {(S)-1-[1-Cyclopropyl-6-fluoro-7-(morpholine-4-carbonyl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of 2-((S)-1-tert-butoxycarbonylaminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester (441 mg, 1.17 mmol) and LiOH.H2O (196 mg, 4.67 mmol) in MeOH (20 mL) and water (2 mL) was heated at 90° C. for 4 h. Additional LiOH.H2O (196 mg) was added and the mixture heated at 90° C. for 48 h. After cooling to RT, the organic solvent was removed in vacuo and the pH of the mixture adjusted to 3 by addition of 1M HCl(aq). The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. A mixture of this residue (349 mg), HATU (401 mg, 1.06 mmol), morpholine (125 μL, 1.44 mmol) and DIPEA (335 μL, 1.92 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic layer was dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (380 mg, 75% over 2 steps) as a pale yellow oil. LCMS (Method C): RT 2.64 min [M+H]+ 433.25

Provenance & Evidence