(3-Bromo-4-fluorophenoxy)(tert-butyl)dimethylsilane → 5-Dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol

Temperatur

-78 °C

Cool a solution of (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane (472 mg, 1.547 mmol) in THF (40 mL) to −78° C. under N2. Then add dropwise a solution of n-BuLi (0.63 mL, 1.547 mmol) in hexane via syringe to the reaction solution. After being stirred at −78° C. for 2 hour, add dropwise a solution of 5-Dimethylaminomethyl-spiro[2.5]octan-6-one (70 mg, 0.387 mmol) in THF (1 mL) to the reaction mixture and stir the mixture at −78° C. for additional 2 hours. Quench the reaction with 20 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 (30 mL×2). 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 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol as white solid (41 mg, yield: 36.3%). MS (m/z): 294 (M+1).

1. stirringstir the mixture at −78° C. for additional 2 hours
2. customQuench
3. customthe reaction with 20 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 (30 mL×2)
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-Eintrag

ord-63d4f0061245490fa7b06819f3082945

Quelldatensatz

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08802728B2