Hydrochloric Acid → 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate

Participants

Reaction Conditions

Reaction Steps

N2 was bubbled for 5 min through a suspension of tert-butyl 4-(3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridine-1(2 H)-carboxylate (Intermediate D14, 735 mg, 1.197 mmol), 3-fluoro-5-hydroxyphenylboronic acid (0.28 g, 1.795 mmol), S-Phos-Pd-G2 (0.130 g, 0.179 mmol) and potassium phosphate (572 mg, 2.695 mmol) in THF/water 3:1 (8 ml). The mixture was heated at 85° C. for 1 hr by MW irradiation. A second run was performed in the same conditions on a mixture of reagents in the exact same amounts. The two reaction mixtures were combined and cone HCl (20 ml) was slowly added while stirring. Stirring went on at rt for 3 h, then volatiles were removed under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, 60 g C18 column, gradient elution from 100:0 to 70:30 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate (0.990 g, 1.818 mmol, 76% yield) as a pale yellow powder.

Provenance & Evidence