Chloroiodomethane → 3(S)-[N-(t-butoxycarbonyl)-N-benzylamino]-1,2-(S)-epoxy-4-phenylbutane

Temperature

-72.5 °C

A solution of 2.5 g (7.37 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal and 0.72 mL of chloroiodomethane in 35 mL of THF was cooled to −78° C. A 4.64 mL of a solution of n-butyllithium (1.6 M in hexane, 7.42 mmoles) was added slowly, keeping the temperature below −70° C. The mixture was stirred for 10 minutes between −70 to −75° C. Two additional portions of 0.22 mL of chloroiodomethane and 1.4 mL of n-butyllithium was added sequentially and the mixture was stirred for 10 minutes between −70 to −75° C. after each addition. Four additional portions of 0.11 mL of chloroiodomethane and 0.7 mL of n-butyllithium was added sequentially and the mixture was stirred for 10 minutes between −70 to −75° C. after each addition. The mixture was warmed to room temperature for 3.5 hours. The product was quenched at below 5° C. with 24 mL of ice-cold water. The biphasic layers were separated and the aqueous layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers was washed three times with 10 mL water, then with 10 mL brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2.8 g of a yellow crude oil. This crude oil (>100% yield) is a mixture of the diastereomeric epoxides N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine and N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine. The crude mixture is used directly in the next step without purification.

1. customthe temperature below −70° C
2. stirringthe mixture was stirred for 10 minutes between −70 to −75° C.
3. additionafter each addition
4. stirringthe mixture was stirred for 10 minutes between −70 to −75° C.
5. additionafter each addition
6. temperatureThe mixture was warmed to room temperature for 3.5 hours
7. customThe product was quenched at below 5° C. with 24 mL of ice-cold water
8. customThe biphasic layers were separated
9. extractionthe aqueous layer was extracted twice with 30 mL of ethyl acetate
10. washThe combined organic layers was washed three times with 10 mL water
11. dry with materialwith 10 mL brine, dried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure

ORD record

ord-03a60cc5823549108aabe087505ce691

Source dataset

uspto-grants-2005_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06861539B1