4-Methylmorpholine → tert-Butyl [(3S)-1-chloro-4-methyl-2-oxopentan-3-yl]carbamate

HRID 236459Notes

Reaction equation

HRID 236459 reaction equation
[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.[Cl:23][C:24](OCC(C)C)=O>C1COCC1.C(OCC)(=O)C>[NH2:1][C@H:2]([C:6]([CH2:24][Cl:23])=[O:8])[CH:3]([CH3:4])[CH3:5].[ClH:23].[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([CH2:24][Cl:23])=[O:8])[CH:3]([CH3:4])[CH3:5]

Participants

7

Reactant 3

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 83693Boc-L-Valine

Product 2

HCID 13919082tert-Butyl [(3S)-1-chloro-4-methyl-2-oxopentan-3-yl]carbamateYield 108.1%HCID 13919089HCID 13919089, compound

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

First, precursor H-ValCH2Cl.HCl was prepared by dissolving Boc-Val-OH (6.5 g, 30 mmol) in 10 mL of THF and treating it with N-methylmorpholine (3.3 mL, 30 mmol) and isobutyl chloroformate (3.9 mL, 30 mmol) for 10 minutes at -20°. The resulting mixture was filtered and the retained material was washed with 40 mL of cold THF. The combined filtrates were added to 200 mL of diazomethane:ether. The resulting solution was stirred for 2 hours at 0°, and then solvent was removed by evaporation to yield an oil. The oil was dissolved in ethyl acetate, washed with 5% sodium bicarbonate followed by saturated aqueous sodium chloride, and then dried over sodium sulfate. Evaporation of solvent left 6.4 g of an oil. The oil was dissolved in 100 mL of ether, and the resulting solution was treated with a 5% excess of ethanolic HCl for 15 minutes at 0°. This solution was washed with cold water followed by saturated aqueous sodium chloride, and then dried over sodium sulfate. After evaporation of solvent, product was washed with hexane to yield 2.7 g of Boc-ValCH2Cl (m.p. 70°-73°). Boc-ValCH2Cl (1.0 g) was deblocked by stirring with 5 mL of 3N ethanolic HCl for 30 minutes at about 23°. Solvent was evaporated and the resulting residue was triturated with ether to yield 0.69 g of H-ValCH2Cl.HCl.

Workup

  1. filtrationThe resulting mixture was filtered
  2. washthe retained material was washed with 40 mL of cold THF
  3. additionThe combined filtrates were added to 200 mL of diazomethane
  4. customsolvent was removed by evaporation
  5. customto yield an oil
  6. washwashed with 5% sodium bicarbonate
  7. dry with materialdried over sodium sulfate
  8. customEvaporation of solvent
  9. waitleft 6.4 g of an oil
  10. dissolutionThe oil was dissolved in 100 mL of ether
  11. additionthe resulting solution was treated with a 5% excess of ethanolic HCl for 15 minutes at 0°
  12. washThis solution was washed with cold water
  13. dry with materialdried over sodium sulfate
  14. customAfter evaporation of solvent, product
  15. washwas washed with hexane

Sources & evidence

ORD record
ord-ed6c82accc9947e6babd71ca0c7eb926
Source dataset
uspto-grants-1987_02
Patent number
US04644055

Reaction notes

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