Hydrochloric Acid → MK-1903

Participants

Reaction Steps

To a solution of (1R,5S)-bicyclo[3.1.0]hexan-2-one (729 mg, 7.6 mmol) and diethyl oxalate (1030 μL, 7.6 mmol) in EtOH at 0° C. under N2 was added 1 M potassium tert-butoxide (8342 μL, 8.3 mmol). The mixture was warmed to room temperature and stirred for 6 h at which time hydrazine monohydrochloride (779 mg, 11.4 mmol) in H2O (4 mL) was added. The mixture was stirred for 15 h and the ethanol was removed under reduced pressure. The mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in THF (6 mL) and H2O (6 mL). LiOH (363 mg, 15.1 mmol) was added and the mixture was stirred in the microwave at 60° C. for 2 h. The mixture was acidified with 1 N HCl and extracted with EtOAc (twice) and concentrated. The residue was purified by HPLC. The combined HPLC fractions were concentrated to remove CH3CN and the remaining aqueous was extracted with EtOAc (twice). The organics were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound as a white solid (322 mg). LCMS m/z=165.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18 (td, J=4.5 and 3.4 Hz, 1H), 1.10 (td, J=7.8 and 4.5 Hz, 1H), 2.08-2.15 (m, 2H), 2.67 (d, J=16.9 Hz, 1H), 2.80-2.88 (m, 1H), —NH and —CO2H were not observed.

Provenance & Evidence