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

HRID 1521481Notes

Reaction equation

HRID 1521481 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.[NH2:26][CH2:27][C:28]([O:32][CH3:33])([O:30][CH3:31])C>C1COCC1>[CH3:31][O:30][CH:28]([O:32][CH3:33])[CH2:27][NH:26][C:16](=[O:18])[C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:13]([CH3:14])[CH3:15]

Participants

5

Reactant 3

HCID 79724-MethylmorpholineHCID 712434N-alpha-Benzyloxycarbonyl-D-valineHCID 149002072,2-Dimethoxypropan-1-amine

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., i-butylchlorofomate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxypropane (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 aqueous HCl (2×2 L), washed with sat. NaHCO3 (2 L) and Na2CO3 (2 L), and washed with 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]+. 1H NMR (CD3OD 300 MHz): δ 7.35-7.30 (m, 5H), 5.08 (s, 2H), 4.45-4.35 (m, 1H), 3.95-3.85 (m, 1H), 3.34-3.25 (m, 8H), 2.10-1.90 (m, 1H), 0.94-0.91 (m, 6H).

Workup

  1. additioni-butylchlorofomate (299 g, 2.19 mol) was added dropwise
  2. washThe reaction mixture was washed with brine (2 L)
  3. concentrationthe organic phase was concentrated
  4. customto remove the THF
  5. additionThe residue was diluted with EtOAc (4 L)
  6. washwashed with 1N aqueous HCl (2×2 L)
  7. washwashed with sat. NaHCO3 (2 L) and Na2CO3 (2 L)
  8. washwashed with brine (1.5 L)
  9. dry with materialAfter drying over Na2SO4
  10. customthe organic solvent was removed

Sources & evidence

ORD record
ord-02b7259e8deb4d0587b0cec3f219dd30
Source dataset
uspto-grants-2015_07
Patent number
US09073931B2

Reaction notes

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