(3-Bromo-4-fluorophenoxy)(tert-butyl)dimethylsilane → 2-Dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol

Temperature

-78 °C

Cool a solution of (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane (5.81 g, 19.03 mmol) in THF (100 mL) to −78° C. under N2. Then add dropwise a solution of t-BuLi (14.6 mL, 19.03 mmol) in hexane via syringe to the reaction solution. After being stirred at −78° C. for 1 hour, add dropwise a solution of 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one (2.87 g, 15.86 mmol) in THF (1.5 mL) to the reaction mixture and stir the mixture at −78° C. for additional 1 hour. Quench the reaction with 60 mL of diluted HCl (2N), and stir at ambient temperature for 2 hours. Basify the resultant mixture with K2CO3 to pH=9, and extract with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2 to CH2Cl2:MeOH=10:1) to afford 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol as white solid (2.38 g, yield: 51.2%). MS (m/z): 294 (M+1).

1. stirringstir the mixture at −78° C. for additional 1 hour
2. customQuench
3. customthe reaction with 60 mL of diluted HCl (2N)
4. stirringstir at ambient temperature for 2 hours
5. extractionBasify the resultant mixture with K2CO3 to pH=9, and extract with EtOAc (100 mL×3)
6. washThe combined organic layers are washed with brine
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated under vacuum
10. customPurify the residue by silica gel chromatography (CH2Cl2 to CH2Cl2:MeOH=10:1)

ORD record

ord-1dc5362e93ba4a2caaf92560e3a5fb99

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08802728B2