Reacción #73889

Ecuación de reacción

(2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid

N-methylmorpholine

N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine

isopropylchloroformate

→

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide

Disolventes

tetrahydrofuran

N,N-dimethylformamide tetrahydrofuran

toluene

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroThe solvent was then removed in vacuo
2. 2
   workup.ADDITIONthe residue was treated with 4N hydrochloric acid in dioxane (2 ml)
3. 3
   workup.WAITAfter 4 hours
4. 4
   workup.ADDITIONmethanol (5 ml) was added to the reaction mixture
5. 5
   workup.WAITthis was left
6. 6
   workup.WAITto stand for 18 hours
7. 7
   OtroThe solvent was then removed in vacuo
8. 8
   Otrothe residue was purified on an SPE cartridge (50 g, silica)
9. 9
   Lavadoeluting with cyclohexane/ethyl acetate (gradient from 4:1 to neat ethyl acetate), which

Procedimiento

To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (291 mg) in dry tetrahydrofuran (5 ml) under a nitrogen atmosphere at −20° C. was added N-methylmorpholine (101 mg) and a solution of isopropylchloroformate in toluene (1.0M, 1 ml). After 10 minutes, a solution of N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine (342 mg) in N,N-dimethylformamide/tetrahydrofuran (5 ml/10 ml) was added and the resultant mixture was stirred at room temperature for 4 hours. The solvent was then removed in vacuo and the residue was treated with 4N hydrochloric acid in dioxane (2 ml). After 4 hours, methanol (5 ml) was added to the reaction mixture and this was left to stand for 18 hours. The solvent was then removed in vacuo and the residue was purified on an SPE cartridge (50 g, silica) eluting with cyclohexane/ethyl acetate (gradient from 4:1 to neat ethyl acetate), which furnished the two diastereomers as white solids (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide; (0.137 g)

Fuente