반응 #742299

반응 방정식

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

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product

수율 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

수율 57.6%

용매

tetrahydrofuran

water

ethyl acetate

반응 조건

후처리

1. 1
   온도to warm to room temperature
2. 2
   workup.WAITstiffed for 2 hours
3. 3
   기타The organic layer was separated
4. 4
   추출the aqueous layer re-extracted with ethyl acetate (50 mL)
5. 5
   세척The combined organics were washed with saturated brine (75 mL)
6. 6
   건조dried (MgSO4)
7. 7
   여과filtered
8. 8
   기타evaporated
9. 9
   기타The crude product was purified by flash silica chromatography
10. 10
    세척eluting with 40 to 80% ethyl acetate in isohexane

실험 절차

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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