Citric Acid → (1S,5R)-5-Methoxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid methyl ester

A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (13.4 mL, 13.4 mmol) was added to a solution of (4S)-4-(2-bromoethyl)-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (2.07 g, 6.08 mmol) and methyl chloroformate (0.493 mL, 6.38 mmol) in tetrahydrofuran (20 mL) in a nitrogen atmosphere at −70° C. The mixture was stirred for 14 hours while gradually heating to room temperature. The reaction solution was cooled to 0° C. A 10% citric acid solution (20 mL) was added, and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (100 mL) and water (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→2:1) to give 1.53 g (79%) of the title compound as a pale brown oil.

1. temperatureThe reaction solution was cooled to 0° C
2. stirringthe mixture was stirred for 10 minutes
3. extractionfollowed by extraction with ethyl acetate (200 mL)
4. washThe organic layer was washed with brine (50 mL)
5. dry with materialdried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationThe filtrate was then concentrated under reduced pressure
8. customThe residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→2:1)

ORD record

ord-3031b616034a4c43aec80e313736d4c3

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08618094B2