Lithium Hexamethyldisilazide → (2S,4R)-di-tert-butyl 4-(4-fluoro-2-methylbenzyl)-5-oxopyrrolidine-1,2-dicarboxylate

Temperature

-78 °C

Step (c) (S)-Di-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate (1.15 g, 4.0 mmol) was dissolved in dry THF (20 mL) and the solution was cooled to −78° C. A solution of LiHMDS (1M in hexanes, 4.4 mL, 4.4 mmol) then was added dropwise under nitrogen. The mixture was cooled at −78° C. for 40 minutes and then a solution of 2-methyl-4-fluorobenzyl bromide (975 mg, 4.8 mmol) in THF (5 mL) was added slowly. The mixture was stirred at −78° C. for 2 hours and then quenched with saturated ammonium chloride (20 mL). The mixture was extracted with diethyl ether (3×70 mL) and the combined extract was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Product was purified from the residue by flash column (eluted with a 4:1 hexanes/diethyl ether mixture) to give (2S,4R)-di-tert-butyl 4-(4-fluoro-2-methylbenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (810 mg, 2.0 nmol, 49.7%), clean as a white solid.

1. temperatureThe mixture was cooled at −78° C. for 40 minutes
2. customquenched with saturated ammonium chloride (20 mL)
3. extractionThe mixture was extracted with diethyl ether (3×70 mL)
4. extractionthe combined extract
5. washwas washed with brine (30 mL)
6. dry with materialdried over anhydrous sodium sulfate
7. concentrationconcentrated in vacuo
8. customProduct was purified from the residue by flash column (
9. washeluted with a 4:1 hexanes/diethyl ether mixture)

ORD record

ord-1c5a4263d287456b8ec22013432dd60d

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08791102B2