4-Methylmorpholine → (R)-benzyl (1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate

HRID 1468885Notes

Reaction equation

HRID 1468885 reaction equation
[C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][CH2:35][CH:36]([O:39][CH3:40])[O:37][CH3:38]>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([CH:13]([CH3:14])[CH3:15])[C:16]([NH:34][CH2:35][CH:36]([O:39][CH3:40])[O:37][CH3:38])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 89728Aminoacetaldehyde dimethyl acetalHCID 712434N-alpha-Benzyloxycarbonyl-D-valine

Product 1

HCID 89827923(R)-benzyl (1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamateYield 99.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-15 °C

Procedure

A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C. and i-butyl chloroformate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxyethane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aq HCl (2×2 L), sat. aq. NaHCO3 (2 L) and sat. aq. Na2CO3 (2 L) and brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+.

Workup

  1. washThe reaction mixture was washed with brine (2 L)
  2. concentrationthe organic phase was concentrated
  3. customto remove the THF
  4. additionThe residue was diluted with EtOAc (4 L)
  5. washwashed with 1N aq HCl (2×2 L), sat. aq. NaHCO3 (2 L) and sat. aq. Na2CO3 (2 L) and brine (1.5 L)
  6. dry with materialAfter drying over Na2SO4
  7. customthe organic solvent was removed

Sources & evidence

ORD record
ord-1115b1d791034d41b7add17c656f232a
Source dataset
uspto-grants-2015_04
Patent number
US09006244B2

Reaction notes

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