(R)-benzyl (1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate synthesis

Yield:1456693-00-7 99.5%

Reaction Conditions:

Stage #1: N-[(benzyloxy)carbonyl]-D-valinewith 4-methyl-morpholine;isobutyl chlorocarbonate in tetrahydrofuran at -15; for 0.5 h;
Stage #2: 2,2-dimethoxyethylamine in tetrahydrofuran at -15; for 2 h;

Steps:

2.1

Step 1: 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 /-butyl chlorofomate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of l-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 IN aq HC1 (2 X 2 L), sat. aq. NaHC0₃ (2 L) and sat. aq. Na₂C0₃ (2 L) and brine (1.5 L). After drying over Na₂S0₄, the organic solvent was removed under reduce pressure to afford (R)-benzyl (l-((2,2-dimethoxyethyl)amino)-3-methyl-l-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]^{+ X}H NMR (CD₃OD 300MHz): 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).

References:

WO2013/138565,2013,A1 Location in patent:Page/Page column 38; 39