Acetic Acid → tert-butyl N-((2S)-4-chloro-3-oxobutan-2-yl)carbamate

Temperature

0 °C

A solution of chloroacetic acid (23.2 g, 246 mmol) in tetrahydrofuran (100 mL) was added over 35 minutes to a −78° C. solution of lithium diisopropylamide in tetrahydrofuran (2.05 M, 240 mL, 492 mmol), at a rate that kept the internal temperature below −65° C. After 30 minutes, the reaction mixture was quickly transferred into a (dry ice)-jacketed addition funnel and added over 5 minutes to a solution of methyl N-(tert-butoxycarbonyl)-L-alaninate (10.0 g, 49.2 mmol) in tetrahydrofuran (120 mL). Mechanical stirring was used for this reaction. The mixture was stirred for 30 minutes, during which time the reaction mixture warmed to 0° C. It was cooled to −78° C. and treated over 10 minutes with a solution of acetic acid (41 mL, 720 mmol) in tetrahydrofuran (41 mL). At this point, the flask was immersed in an ice bath, and stirring was continued for 1.5 hours, while the reaction warmed to 5° C. Water (250 mL) was added, followed by diethyl ether (400 mL); the organic layer was washed with saturated aqueous sodium bicarbonate solution (150 mL) and with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a waxy, light yellow solid. Yield: 9.47 g, 42.7 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 5.11 (br d, J=6 Hz, 1H), 4.48-4.58 (m, 1H), 4.28 (AB quartet, JAB=15.9 Hz, ΔνAB=8.3 Hz, 2H), 1.44 (s, 9H), 1.38 (d, J=7.1 Hz, 3H).

1. customthe internal temperature below −65° C
2. additionaddition funnel
3. customwas used for this reaction
4. stirringThe mixture was stirred for 30 minutes, during which time the reaction mixture
5. temperatureIt was cooled to −78° C.
6. customAt this point, the flask was immersed in an ice bath
7. stirringstirring
8. waitwas continued for 1.5 hours, while the reaction
9. temperaturewarmed to 5° C
10. washthe organic layer was washed with saturated aqueous sodium bicarbonate solution (150 mL) and with saturated aqueous sodium chloride solution (50 mL)
11. dry with materialdried over magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customto afford the product as a waxy, light yellow solid

ORD record

ord-7bbe0a4508e74628be72fadfe52cea9a

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193726B2