Methyl iodide → Methyl (2s)-2-[(3r)-3-(n-[tert-butyloxycarbonyl]amino)-2-oxo-pyrrolidin-1-yl]propionate

HRID 1263416Notes

Reaction equation

HRID 1263416 reaction equation
CI.[NH:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:4]([C:9]([NH:11][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[O:10])[CH2:5][CH2:6]SC>CN(C=O)C.ClCCl>[C:21]([O:20][C:18]([NH:3][C@@H:4]1[CH2:5][CH2:6][N:11]([C@@H:12]([CH3:13])[C:14]([O:16][CH3:17])=[O:15])[C:9]1=[O:10])=[O:19])([CH3:24])([CH3:23])[CH3:22]

Participants

5

Reactant 2

HCID 6328Methyl iodideHCID 11024115Boc-(D)-Met-(L)-Ala-OMe

Product 1

HCID 9838823Methyl (2s)-2-[(3r)-3-(n-[tert-butyloxycarbonyl]amino)-2-oxo-pyrrolidin-1-yl]propionateYield 61.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
5 °C

Procedure

Note: This sequence must be conducted under dry conditions with dry solvents otherwise epimerisation will occur. Methyl iodide (10 ml) was added to Boc-(D)-Met-(L)-Ala-OMe (8 g) in a mixture of DMF (20 ml) and dichloromethane (20 ml) and the mixture was allowed to stand for 16 hours and then evaporated to dryness. Further dichloromethane (2×50 ml) was added and evaporated to remove residual methyl iodide and the residue was dissolved in a mixture of DMF (300 ml) and dichloromethane (300 ml). The mixture was cooled to ˜5° C. and sodium hydride (0.76 g of an 80% dispersion in mineral oil) was added in one portion and the mixture was stirred at this temperature for 2 hours. Saturated aqueous ammonium chloride (50 ml) was added and the mixture was evaporated to dryness and then partitioned between water and ether. The ether extract was washed with brine and dried and evaporated to give a gum which was purified by flash chromatography on a sinter funnel (25% ethyl acetate:hexane to 100% ethylacetate) to give methyl (2S)-2-[(3R)-3-(N-[tert-butyloxycarbonyl]amino)-2-oxo-pyrrolidin-1-yl]propionate as a gum (4.2 g) which crystallised on standing: NMR (CDCl3): 1.4 (s, 9H), 1.4 (d, 3H), 1.8 (m, 1H), 2.6 (m, 1H), 3.4 (m, 2H), 3.7 (m, 3H), 4.2 (m, 1H), 4.9 (q, 1H), 5.2 (bs, 1H).

Workup

  1. customevaporated to dryness
  2. additionFurther dichloromethane (2×50 ml) was added
  3. customevaporated
  4. customto remove residual methyl iodide
  5. dissolutionthe residue was dissolved in a mixture of DMF (300 ml) and dichloromethane (300 ml)
  6. additionsodium hydride (0.76 g of an 80% dispersion in mineral oil) was added in one portion
  7. additionSaturated aqueous ammonium chloride (50 ml) was added
  8. customthe mixture was evaporated to dryness
  9. custompartitioned between water and ether
  10. extractionThe ether extract
  11. washwas washed with brine
  12. customdried
  13. customevaporated
  14. customto give a gum which
  15. customwas purified by flash chromatography on a sinter funnel (25% ethyl acetate:hexane to 100% ethylacetate)

Sources & evidence

ORD record
ord-ee1020f4106d4342a9f447e38f8e9ace
Source dataset
uspto-grants-2003_04
Patent number
US06541453B2

Reaction notes

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