Potassium Phosphate, Tribasic → (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate

Participants

Reaction Conditions

Reaction Steps

Pd(Ph3P)4 (144 mg, 0.125 mmol) was added to an argon-degassed solution (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (300 mg, 0.624 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (179 mg, 0.687 mmol), potassium phosphate tribasic (994 mg, 4.68 mmol) in dioxane (4 ml) and water (0.8 ml) stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-70% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 291 mg (76%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.3 (m, 2H), 7.19 (br. s, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.08-7.06 (m, 1H), 7.02-7.00 (m, 2H), 5.91 (br. s, 1H), 4.94 (br. s, 1H), 4.28-4.23 (m, 1H), 4.19-4.15 (m, 1H), 3.44-3.40 (m, 4H), 3.05 (t, J=6.2 Hz, 2H), 2.45 (s, 3H), 2.06 (s, 3H), 1.80 (br. s, 1H), 1.69 (br. s, 1H), 1.55 (br. s, 1H), 1.34-1.32 (m, 1H), 1.29 (s, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.15-1.1 (m, 12H). UPLC (M+H)=616.6.

Provenance & Evidence