Hydrochloric Acid → (S)-Benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate

Temperature

5 °C

CBZ-L-Alanine (6.5 kg, 28.5 mol), HOBT-hydrate (4.8 kg, 34.8 mol), Me(MeO)NH2Cl (3.4 kg, 36.2 mol) and THF (32 L) were charged to a clean flask under nitrogen. The mixture was cooled to 0-10° C. and diisopropylethylamine (12.4 L) was slowly added at a temperature less than 20° C. EDC-HCl (7 kg, 36.2 mol) was added slowly with slight cooling at 15°-25° C. The slurry was aged overnight at 20°-25° C. The mixture was cooled to 0°-10° C. and 3N HCl (13 L) is added slowly. Isopropyl acetate (45.5 L) was added and the layers were separated. The organic layer was washed once with HCl (13 L) and twice with 8% NaHCO3 (13 L). The organic layer was concentrated under vacuum to <20 L at 50° C. The clear solution was cooled slowly to room temperature, allowing the product to crystallize. Heptane (˜70 L) was added slowly. The slurry was filtered, washed with heptane (18 L), and dried at room temperature on the filter pot. Benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate was obtained with >99.9% ee measured by chiral HPLC.

1. temperaturewith slight cooling at 15°-25° C
2. temperatureThe mixture was cooled to 0°-10° C.
3. customthe layers were separated
4. washThe organic layer was washed once with HCl (13 L) and twice with 8% NaHCO3 (13 L)
5. concentrationThe organic layer was concentrated under vacuum to <20 L at 50° C
6. temperatureThe clear solution was cooled slowly to room temperature
7. customto crystallize
8. additionHeptane (˜70 L) was added slowly
9. filtrationThe slurry was filtered
10. washwashed with heptane (18 L)
11. customdried at room temperature on the filter pot

ORD record

ord-b74005a2927742d9890ccf6075744762

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08440702B2