Water → 1,1-Dimethylethyl 4-{[5'-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-2'-(methyloxy)-3-biphenylyl]methyl}-1-piperidinecarboxylate

Participants

Reaction Conditions

Reaction Steps

To N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (6.75 g, 11.00 mmol) in 1,4-dioxane (120 mL) was added 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (4.42 g, 11.00 mmol). Then potassium carbonate (4.56 g, 33.0 mmol), water (40.0 mL) and tetrakis(triphenylphosphine)palladium(0) (0.636 g, 0.550 mmol) was added and the reaction was heated at 100° C. for 1 h. HPLC showed a small amount of starting material present therefore the reaction was left for a further hour. HPLC showed no change so the reaction was worked up. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was washed with EtOAc and the combined organic layers were rinsed with brine, dried over MgSO4, filtered and evaporated to give a light brown foam (˜11 g). The foam was dissolved in DCM and passed through a celite column before combining with a batch from a similar preparation (0.85 g). The combined brown solutions were concentrated and applied to a 330 g silica column using 15-100% EtOAc-DCM over 10 column volumes as the gradient. Product fractions were combined and evaporated to yield a white foam 7.42 g (83%). A second peak containing the product was combined and evaporated to yield as a pale yellow oil, 0.69 g (7%) HPLC 2.61 min (ret time) 96.6%; LC-MS m/z 808 (M+H)+, 3.78 min (ret time).

Provenance & Evidence