Reaction #1185443

Reaction equation

citric acid

Sodium hydride

(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-fluoropyridin-2-yl)-2-hydroxypropanamide

4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine

→

product

Yield 82.1%

(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide

Yield 82.1%

Solvents

THF

water

EtOAc

Conditions

Workup

1. 1
   Temperatureto warm to room temperature
2. 2
   workup.STIRRINGstirred overnight
3. 3
   OtherThe organic layer was separated
4. 4
   Extractionthe aqueous layer re-extracted with EtOAc (2×50 mL)
5. 5
   WashThe combined organics were washed with saturated brine (75 mL)
6. 6
   Dryingdried (MgSO4)
7. 7
   Filtrationfiltered
8. 8
   Concentrationconcentrated in vacuo
9. 9
   OtherThe crude product was purified by flash silica chromatography, elution gradient 25 to 100% EtOAc in isohexane

Procedure

Sodium hydride (60% dispersion in mineral oil) (83 mg, 2.07 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-fluoropyridin-2-yl)-2-hydroxypropanamide (Intermediate BA2) (500 mg, 1.04 mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (310 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and the reaction mixture diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 25 to 100% EtOAc in isohexane to afford the product (637 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 0.99 (9H, t), 3.69-3.72 (2H, m), 3.82 (2H, t), 4.16-4.24 (2H, m), 6.06 (1H, t), 7.31-7.47 (8H, m), 7.52-7.55 (2H, m), 7.63-7.66 (4H, m), 8.12 (1H, d), 8.26-8.29 (1H, m), 8.42 (1H, s), 8.58 (1H, s), 8.79 (1H, s).

Source