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

Temperatur

-15 °C

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).

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

ORD-Eintrag

ord-02b7259e8deb4d0587b0cec3f219dd30

Quelldatensatz

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09073931B2