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

Participants

Reaction Conditions

Reaction Steps

The Pd(Ph3P)4 (61.8 mg, 0.053 mmol) was added to a nitrogen purged and degassed solution of (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (125 mg, 0.27 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (77 mg, 0.29 mmol), and potassium phosphate tribasic (397 mg, 1.9 mmol) in 1,4-dioxane (3.5 mL) and water (0.9 mL). The reaction mixture was stirred in a screw-capped pressure vessel for 4 h at 90° C., cooled, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2CO3). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (2S)-isopropyl 2-(tert-butoxy)-2-(4-(3-cyclopropylpyrrolidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 80 mg (49.6%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.36 (m, 2H), 7.21-7.20 (m, 1H), 7.15-7.12 (m, 2H), 7.03-6.94 (m, 3H), 5.77/5.75 (s, 1H), 4.96-4.91 (m, 1H), 4.21 (t, J=6.6 Hz, 2H) 3.17-3.13/3.01-2.97 (m, 1H), 3.05 (t, J=6.6 Hz, 2H), 2.84-2.74 (m, 2H), 2.70-2.67/2.63-2.60 (m, 1H), 2.42/2.41 (s, 3H), 2.07/2.05 (s, 3H), 1.71-1.64 (m, 1H), 1.42-1.22/1.03-0.097 (m, 2H), 1.19-1.17 (m, 3H), 1.14-1.10 (m, 12H), 0.52-0.47 (m, 1H), 0.32-0.23 (m, 2H), −0.30-0.15 (m, 2H). UPLC (M+H)=603.5.

Provenance & Evidence