(S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate → (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate

Participants

Reaction Steps

The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (670 mg, 1.58 mmol) and 0.15 mL of 70% HClO4 in DCM (15 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel. The reaction was then diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 651 mg (86%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 6.06 (br. s, 1H), 4.93-4.89 (m, 1H), 4.03 (br. s, 1H), 3.43-3.41 (m, 2H), 3.00 (br. s, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.05 (br. s, 1H), 1.93 (br. s, 1H), 1.80-1.71 (m, 1H), 1.58 (br. s, 1H), 1.42 (s, 3H), 1.15-1.13 (m, 12H), 1.05 (d, J=6.2 Hz, 3H). UPLC (M+H)=482.4.

Provenance & Evidence