Sodium hydride → HCID 86640216, compound

Temperature

-15 °C

To a solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) at −35° C. under argon was added sodium hydride (39.9 mg, 0.999 mmol). The mixture was stirred for 15 minutes, 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) was added and the reaction mixture was stirred at −35° C. for 30 minutes then slowly warmed to −15° C. After 1 hour the reaction mixture was quenched with water (10 ml), warmed to room temperature and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with sodium hydrogen carbonate saturated solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was then dried (magnesium sulfate), filtered and evaporated. The crude residue was purified by silica gel chromatography eluting with 10-100% of ethyl acetate in isohexane to give 1,1-dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg). LC/MS [M+H]+=265. (ii) 1,1-Dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg, 0.674 mmol) was dissolved in dichloromethane (3.00 ml) and trifluoroacetic acid (1 ml) was added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with dichloromethane and toluene to give a crude 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume 0.674 mmol) which was used for the next reaction. LC/MS [M+H]+=209.

1. customprepared
2. customat −35° C.
3. stirringthe reaction mixture was stirred at −35° C. for 30 minutes
4. customAfter 1 hour the reaction mixture was quenched with water (10 ml)
5. temperaturewarmed to room temperature
6. extractionextracted with ethyl acetate (20 ml×2)
7. washThe combined organic layers were washed with sodium hydrogen carbonate saturated solution (15 ml), water (10 ml×2) and brine (15 ml)
8. dry with materialThe organic layer was then dried (magnesium sulfate)
9. filtrationfiltered
10. customevaporated
11. customThe crude residue was purified by silica gel chromatography
12. washeluting with 10-100% of ethyl acetate in isohexane

ORD record

ord-fc2e6a87aba04a5ab3d72c0bfa9fe6fc

Source dataset

uspto-grants-2011_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07932282B2