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

温度

0 °C

Trimethylaluminium (0.362 mL, 0.72 mmol) was added to a solution of pyridin-2-amine (68.1 mg, 0.72 mmol) in toluene (8 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 20 mins and then (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate BJ1) (200 mg, 0.36 mmol) in toluene (4 mL) was added. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and the concentrated. The residue was neutralised to pH 7 with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (151 mg, 67.9%).

1. temperatureto warm to room temperature
2. temperatureheated
3. temperatureat reflux under nitrogen for 4 hours
4. temperatureto cool to room temperature
5. customThe organic layer was separated
6. extractionthe aqueous layer re-extracted with DCM (30 mL)
7. dry with materialThe combined organics were dried (MgSO4)
8. filtrationfiltered
9. customevaporated
10. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

ORDレコード

ord-12ee198cf38c436d818851e0e27f7e82

出典データセット

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08143263B2