Réaction #73893

Équation de réaction

isopropylchloroformate

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

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

N-methylmorpholine

→

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

Rendement 27.3%

Solvants

toluene

tetrahydrofuran

tetrahydrofuran

Conditions de réaction

Traitement

1. 1
   workup.WAITAfter 20 hours
2. 2
   Autrethe solvent was removed in vacuo
3. 3
   workup.DISSOLUTIONthe residue was dissolved in 4N hydrochloric acid in dioxan (4 ml)
4. 4
   workup.ADDITIONAfter 4 hours methanol (5 ml) was added
5. 5
   workup.WAITthe reaction was left
6. 6
   workup.WAITto stand for a further 18 hours
7. 7
   AutreThe solvent was then removed in vacuo
8. 8
   workup.DISSOLUTIONthe residue was dissolved in dioxan (5 ml)
9. 9
   workup.ADDITIONto this was added triethylamine (0.5 ml)
10. 10
    workup.WAITAfter 1 hour
11. 11
    Autrethe solvent was removed
12. 12
    LavageThe product was eluted
13. 13
    Autreto further purify the material (2 g, silica)

Mode opératoire

To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (84 mg) in dry tetrahydrofuran (6 ml) at −20° C. under a nitrogen atmosphere was added N-methylmorpholine (32 l) and a solution of isopropylchloroformate in toluene (1.0M, 290 l). After 10 minutes, a solution of N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95 mg) in tetrahydrofuran (10 ml) was added and the reaction was allowed to warm to room temperature. After 20 hours, the solvent was removed in vacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4 ml). After 4 hours methanol (5 ml) was added and the reaction was left to stand for a further 18 hours. The solvent was then removed in vacuo and the residue was dissolved in dioxan (5 ml) and to this was added triethylamine (0.5 ml). After 1 hour, the solvent was removed and the residue was applied to an SPE (10 g, silica). The product was eluted using methanol. A second SPE was used to further purify the material (2 g, silica) using an ethyl acetate:methanol gradient (20:1 to 1:1) to afford (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (38 mg).

Source