Reaction #1185447

Reaction equation

citric acid

Sodium hydride

(S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide

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

→

product

Yield 82.0%

(2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamide

Yield 82.0%

Solvents

tetrahydrofuran

water

ethyl acetate

Conditions

Workup

1. 1
   Temperatureto warm to room temperature
2. 2
   workup.STIRRINGstirred for 2 hours
3. 3
   OtherThe organic layer was separated
4. 4
   Extractionthe aqueous layer re-extracted with ethyl acetate (50 mL)
5. 5
   WashThe combined organics were washed with saturated brine (75 mL)
6. 6
   Dryingdried (MgSO4)
7. 7
   Filtrationfiltered
8. 8
   Otherevaporated
9. 9
   OtherThe crude product was purified by flash silica chromatography
10. 10
    Washeluting with 40 to 100% ethyl acetate in isohexane

Procedure

Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB2) (400 mg, 1.09 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (318 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and then diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 40 to 100% ethyl acetate in isohexane followed by 0-20% methanol in ethyl acetate to afford the product (532 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.83 (9H, s), 2.45 (3H, s), 3.61-3.90 (4H, m), 4.47-4.60 (2H, m), 4.69 (1H, m), 6.22 (1H, m), 7.36-7.48 (3H, m), 7.51-7.57 (1H, m), 8.03 (1H, s), 8.38 (1H, s), 8.50 (1H, s), 9.27 (1H, s), 10.31 (1H, s); m/z (ES+) (M+H)+=595; HPLC tR=2.63 min.

Source