2,2-Difluoro-2-(fluorosulfonyl)acetic acid → (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate

Temperature

45 °C

A 100 mL round-bottom flask was charged with (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.33 g, 12.84 mmol), Cul (0.489 g, 2.56 mmol), and anhydrous acetonitrile (57.1 mL). The reaction was heated to 45° C. (ext. oil bath). 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.655 mL, 25.68 mmol) was added at 45° C. over 30 minutes via syringe pump. The reaction was heated for 30 minutes. Upon completion as monitored by TLC, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was diluted in EtOAc and washed with sodium bicarbonate (aq). The bicarbonate layer was back extracted with ethyl acetate twice. Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated. The resulting residue was further purified via silica gel chromatography (10 to 40% EtOAc/Hexanes) to afford (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 61%). MS (ESI) m/z 210.21 [M+H−Boc]+.

1. temperatureThe reaction was heated for 30 minutes
2. temperaturethe reaction mixture was cooled to room temperature
3. concentrationconcentrated in vacuo
4. additionThe crude residue was diluted in EtOAc
5. washwashed with sodium bicarbonate (aq)
6. extractionThe bicarbonate layer was back extracted with ethyl acetate twice
7. washCombined organic layers were washed with brine
8. dry with materialdried over sodium sulphate
9. filtrationfiltered
10. concentrationconcentrated
11. customThe resulting residue was further purified via silica gel chromatography (10 to 40% EtOAc/Hexanes)

ORD record

ord-f9dae356f81948979736f0d15a49e3bc

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09221833B2