tert-butyl N-(4-oxocyclohexyl)carbamate → HCID 178498037, compound

Participants

Reaction Steps

To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (500 mg, 2.505 mmol) and 4-N-Boc-aminocyclohexanone (2.0 g, 9.38 mmol) in methanol (20 mL) was added zinc chloride (1.0 g, 7.34 mmol). The reaction was stirred for 2 h at room temperature, then sodium cyanoborohydride (700 mg, 11.14 mmol) was added portionwise over 2 h. The reaction was then heated to 40° C. and stirred for 24 h. LCMS showed that the reaction was mostly complete (11% starting amine remained with two product peaks 40% and 49% corresponding to the trans and cis products). The reaction was evaporated to dryness, taken up in EtOAc, washed with aq. NH4Cl, 1 N Na2CO3, brine, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, SF25-80 g, 10 to 30% EtOAc in hexanes). The cis-diastereomer was contaminated with 27% of the methyl 3-amino-5-chloro-2-methylbenzoate starting material. Trituration and filtration from a small volume of 10% EtOAc in hexanes gave the pure cis-diastereomer methyl 3-(((cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (305 mg, 0.730 mmol, 29.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=6.85 (d, J=2.3 Hz, 1 H), 6.74 (d, J=2.0 Hz, 1 H), 6.62 (d, J=7.1Hz, 1 H), 4.66 (d, J=6.8 Hz, 1 H), 3.81 (s, 3 H), 3.47 (br. s., 2 H), 2.19 (s, 3 H), 1.75-1.51 (m, 8 H), 1.39 (s, 9 H). MS(ES) [M+H]+ 397.2.

Provenance & Evidence