Tetrabutylammonium Fluoride → (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)-3-(2-hydroxyethoxy)propanamide

Tetrabutylammonium fluoride (1M in THF) (0.611 mL, 0.61 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)propanamide (Intermediate AH1) in THF (5 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (2 mL), diluted with DCM (25 mL) and poured through a phase separator. The organic phase was reduced to give a gum. This 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 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)-3-(2-hydroxyethoxy)propanamide (194 mg, 61.7%, 84% ee). 1H NMR (400 MHz, DMSO) δ 3.53 (2H, m), 3.70-3.58 (2H, m), 4.05 (1H, m), 4.13 (1H, m), 4.62 (1H, t), 5.95 (1H, s), 7.92-7.86 (2H, m), 8.06-8.00 (1H, m), 8.17 (1H, m), 8.19 (1H, m), 8.42-8.38 (1H, m), 8.61 (1H, s), 8.79 (1H, d), 11.21 (1H, s). m/z (ES+) (M+H)+=514; HPLC tR=2.10 min.

1. customThe reaction mixture was quenched with saturated NH4Cl (2 mL)
2. additiondiluted with DCM (25 mL)
3. additionpoured through a phase separator
4. customto give a gum
5. customThis was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length)
6. additionFractions containing the desired compound
7. customwere evaporated to dryness

ORD record

ord-07ce8ac91af8420ebf7aa45e7ade326b

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08143263B2