Methyl iodide → 1-(tert-Butyl) 2-methyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate

To a solution of N-BOC-4(R)-hydroxyproline, methyl ester (Bachem, 17 g, 69 mmol) and MeI (276 mmol) in 250 mL of anhydrous THF at −30° C. was added LDA (Aldrich, 1.5 M in cyclohexane, 250 mmol). The reaction was allowed to warm up to rt over 4 h. The reaction was cooled to −30° C., and was quenched with saturated aqueous ammonium chloride (50 mL). The resulting mixture was partitioned between EtOAc and brine, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo. The solvent was removed in vacuo and the residue was purified by repeated flash column chromatography on silica gel eluted with 20:1 to 10:1 hexane/acetone to afford N-BOC-4(R)-hydroxy-2-methyl-(L)-proline, methyl ester (slower eluting and major isomer, 10 g, 58%). The stereochemistry was assigned by NMR comparisons with literature reports (Noe, C R et al Pharmazie 1996, 51, 800).

1. temperatureThe reaction was cooled to −30° C.
2. customwas quenched with saturated aqueous ammonium chloride (50 mL)
3. customThe resulting mixture was partitioned between EtOAc and brine
4. extractionthe product was extracted with EtOAc (3×100 mL)
5. dry with materialThe combined extracts were dried over anhydrous MgSO4
6. concentrationconcentrated in vacuo
7. customThe solvent was removed in vacuo
8. customthe residue was purified by repeated flash column chromatography on silica gel
9. washeluted with 20:1 to 10:1 hexane/acetone

ORD record

ord-53f0d050cda64821b984bfe12cb045ad

Source dataset

uspto-grants-2005_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06855708B2