Tetrabutylammonium Fluoride → (2S)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-(2-hydroxyethoxy)propanamide

Tetrabutylammonium fluoride (1M in THF) (0.790 mL, 0.79 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AB4) (576 mg, 0.79 mmol) in THF (2 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (1 mL), diluted with DCM (10 ml) and poured onto a phase separator. The organic layer was collected and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. The resulting product decomposed to an extent during evaporation and so was re-purified by flash silica chromatography, eluting with 0 to 10% MeOH in ethyl acetate to afford the product (82 mg, 21%). 1H NMR (400 MHz, CDCl3) δ 2.49-2.56 (1H, m), 3.69-3.85 (4H, m), 4.14-4.25 (2H, m), 6.08 (1H, t), 7.45-7.50 (1H, m), 7.67-7.72 (1H, m), 7.98-8.04 (1H, m), 8.15-8.28 (2H, m), 8.47 (1H, s), 8.58-8.65 (2H, m), 8.99 (1H, s); m/z (ES+) (M+H)+=490.35; HPLC tR=1.82 min.

1. customThe reaction mixture was quenched with saturated NH4Cl (1 mL)
2. additiondiluted with DCM (10 ml)
3. additionpoured onto a phase separator
4. customThe organic layer was collected
5. customevaporated
6. customThe residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length)
7. customThe resulting product decomposed to an extent during evaporation
8. customso was re-purified by flash silica chromatography
9. washeluting with 0 to 10% MeOH in ethyl acetate

ORD record

ord-f1131b782069418aa0d48a5b14e251e1

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08143263B2