5-Bromo-2,2-difluoro-1,3-benzodioxole → (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoate

To a 25 mL RBF was added zinc powder (1.03 g, 15.8 mmol) and iodine (0.0161 g, 0.0633 mmol). The mixture was heated with a heat gun for 5 minutes and the resulting mixture was then flushed with nitrogen 3 times and allowed to cool to rt. A solution of (R)-methyl2-(tert-butoxycarbonyl)-3-iodopropanoate (3.47 g, 10.5 mmol) in 5 mL of DMF was added dropwise to the mixture over 3 minutes and the resulting grey slurry was stirred at 0° C. for 20 minutes before being warmed to rt. After stirring at rt for 30 minutes, 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (2.50 g, 10.5 mmol), Pd2(dba)3 (0.193 g, 0.211 mmol) and S(Phos) (0.346 g, 0.844 mmol) were added and the reaction mixture was heated to 40° C. for 2 hours. The resulting mixture was cooled to rt and partitioned between ethyl acetate (50 mL) and a solution of ˜9:1 saturated ammonium chloride/ammonium hydroxide pH=9 (250 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with water, brine, and dried over sodium sulfate. Concentration of the filtered solvents and purification of resulting crude material by silica gel chromatography provided (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoate (1.89 g, 49.9% yield) as a slightly brown oil.

1. temperatureThe mixture was heated with a heat gun for 5 minutes
2. customthe resulting mixture was then flushed with nitrogen 3 times
3. temperaturebefore being warmed to rt
4. stirringAfter stirring at rt for 30 minutes
5. temperaturethe reaction mixture was heated to 40° C. for 2 hours
6. temperatureThe resulting mixture was cooled to rt
7. custompartitioned between ethyl acetate (50 mL)
8. extractionThe aqueous layer was extracted with ethyl acetate (3×100 mL)
9. washthe combined organic layers were washed with water, brine
10. dry with materialdried over sodium sulfate
11. customConcentration of the filtered solvents and purification
12. customof resulting crude material by silica gel chromatography

ORD-Eintrag

ord-7187068f522a4995b82cd27bb36d1b99

Quelldatensatz

uspto-grants-2010_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07803809B2