反应 #742299

反应方程式

citric acid

Sodium hydride

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

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

→

product

收率 57.6%

(S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamide

收率 57.6%

溶剂

tetrahydrofuran

water

ethyl acetate

反应条件

后处理

1. 1
   温度to warm to room temperature
2. 2
   workup.WAITstiffed for 2 hours
3. 3
   其他The organic layer was separated
4. 4
   萃取the aqueous layer re-extracted with ethyl acetate (50 mL)
5. 5
   洗涤The combined organics were washed with saturated brine (75 mL)
6. 6
   干燥dried (MgSO4)
7. 7
   过滤filtered
8. 8
   其他evaporated
9. 9
   其他The crude product was purified by flash silica chromatography
10. 10
    洗涤eluting with 40 to 80% ethyl acetate in isohexane

实验过程

Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyl-oxy)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-(2,6-dichloro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (360 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stiffed for 2 hours. The reaction mixture was neutralised with 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 80% ethyl acetate in isohexane, to afford the product (395 mg, 57.5%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 2.54 (3H, s), 3.09-3.13 (2H, m), 3.16-3.21 (1H, m), 3.29-3.34 (1H, m), 3.87-3.92 (2H, m), 4.51 (1H, qn), 5.92-5.95 (1H, m), 7.43-7.47 (1H, m), 7.52-7.55 (2H, m), 8.14 (1H, d), 8.41 (1H, s), 8.59 (1H, s), 9.42 (1H, d), 9.96 (1H, s); m/z (ES+) (M+H)+=631; HPLC tR=2.94 min.

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