Sodium Hydroxide → 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methylester

Temperature

-78 °C

To a solution of LDA (1.5 M in cyclohexane, 33 mL, 49.5 mmole) in THF (40 mL), at −78° C., is added dropwise a solution of 2-(2-fluoro-phenoxy)-propionic acid ethyl ester (7.70 g, 36.3 mmole) in THF (100 mL). After stirring for 30 minutes at −78° C., a solution of toluene-4-sulfonic acid 4-iodomethyl-phenyl ester (12.8 g, 33.0 mmole) is injected to the reaction mixture. The reaction is stirred at −78° C. for one hour, then warmed up to room temperature and stirred overnight. The reaction is treated with 5.0N NaOH (50 mL) in presence of methanol (200 mL). After evaporating methanol, the aqueous solution is acidified with concentrated HCl to pH=1 and is extracted with ethyl acetate (2×300 mL). The combined organic layers are dried, filtered and concentrated in vacuo. The residue is dissolved in MeOH (200 mL) and treated with concentrated sulfuric acid (2 mL) at 80° C. overnight. The reaction mixture is partitioned between ethyl acetate (500 mL) and water (500 mL), the organic layer is washed by brine (3×500 mL), dried, filtered and concentrated in vacuo. The compound is purified by chromatography (silica gel, gradient elution 0-20% ethyl acetate in hexane) to provide an oil (6.02 g, 60%), which is then resolved by chiral HPLC to generate the enantiomer as an oil (2.30 g). Mass [EI+] 322 (M+NH4)+, [EI−] 303 (M−H)−.

1. stirringThe reaction is stirred at −78° C. for one hour
2. temperaturewarmed up to room temperature
3. stirringstirred overnight
4. customAfter evaporating methanol
5. extractionis extracted with ethyl acetate (2×300 mL)
6. customThe combined organic layers are dried
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. dissolutionThe residue is dissolved in MeOH (200 mL)
10. additiontreated with concentrated sulfuric acid (2 mL) at 80° C. overnight
11. customThe reaction mixture is partitioned between ethyl acetate (500 mL) and water (500 mL)
12. washthe organic layer is washed by brine (3×500 mL)
13. customdried
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customThe compound is purified by chromatography (silica gel, gradient elution 0-20% ethyl acetate in hexane)

ORD record

ord-4fa916bf465a40a28cfcff50fff5a305

Source dataset

uspto-grants-2009_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07544812B2