Chloroacetyl chloride → (R)-5-isopropylmorpholin-3-one

Temperatur

90 °C

NaH (6.24 g, 60% wt in mineral oil, 156 mmol, 2.3 equiv) was charged into a 1 L RB flask, followed by addition of 100 mL of toluene. The suspension was stirred in an ice bath. (2R)-2-Amino-3-methyl-1-butanol (7.0 g, 67.9 mmol) in 50 mL of toluene was added portion-wise. Addition took 10 minutes, followed with removal of the cooling bath. The mixture was stirred at ambient temperature for 15 minutes, and cooled in an ice bath. To the cooled mixture was added portion-wise a solution of chloroacetyl chloride (6.25 mL, 78 mmol, 1.15 equiv) in 50 mL of toluene. The mixture began to foam. When the addition neared completion, foaming subsided. The resulting mixture was heated under a reflux condenser to 90° C. (oil bath temp) for 20 hours. The mixture was cooled to room temperature, followed by addition of 22 g of NH4Cl and then water (50 mL). The phases were separated. The aqueous phase was extracted with EtOAc (2×150 mL). The combined organic was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated in 30 mL of hexane. The solids formed were collected by filtration, washing with hexane (2×10 mL). Drying under vacuum at room temperature for 5 hours gave the title compound (6.53 g) as a cream-colored solid. LC-MS (ES) m/z=144

1. additionAddition
2. customfollowed with removal of the cooling bath
3. stirringThe mixture was stirred at ambient temperature for 15 minutes
4. temperaturecooled in an ice bath
5. additionWhen the addition
6. temperatureThe mixture was cooled to room temperature
7. customThe phases were separated
8. extractionThe aqueous phase was extracted with EtOAc (2×150 mL)
9. dry with materialThe combined organic was dried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customThe residue was triturated in 30 mL of hexane
13. customThe solids formed
14. filtrationwere collected by filtration
15. washwashing with hexane (2×10 mL)
16. customDrying under vacuum at room temperature for 5 hours

ORD-Eintrag

ord-01f342b2f2944e4a8f2b4ce922180eaa

Quelldatensatz

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08697685B2