Reaktion #73896

Reaktionsgleichung

dimethylamine

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

triethylamine

BOP—Cl

triethylamine

BOP—Cl

bis(2-oxo-3-oxazolidinyl)phosphinic chloride

→

(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

Lösungsmittel

dichloromethane acetonitrile

tetrahydrofuran

dichloromethane acetonitrile

Reaktionsbedingungen

Aufarbeitung

1. 1
   Trocknenabove was dried over P4O10 in vacuo for five hours
2. 2
   Sonstigeto give 0.724 g drier material
3. 3
   Sonstigethe mixture was sonicated for ca. 1 min
4. 4
   Sonstigeto give a gelatinous mass
5. 5
   Sonstigeto give a clear solution
6. 6
   SonstigeThe solvents were removed under reduced pressure
7. 7
   Sonstigethe mixture was partitioned between dichloromethane and 0.1M hydrochloric acid
8. 8
   SonstigeThe organic phase was separated (hydrophobic frit)
9. 9
   Sonstigeevaporated under reduced pressure
10. 10
    SonstigeThe crude product was purified by flash column chromatography (12 g Biotage™ silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1)

Vorschrift

The acid (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoic acid (0.747 g) prepared as described above was dried over P4O10 in vacuo for five hours to give 0.724 g drier material; this was dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated with triethylamine (0.223 ml) and BOP—Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated with triethylamine (0.223 ml) and BOP—Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, 0.450 g) and the mixture was sonicated for ca. 1 min to give a gelatinous mass. After 10 minutes at room temperature a solution of dimethylamine in tetrahydrofuran (10 ml of 2M solution) was added to give a clear solution; this was left for 16 hours at room temperature. The solvents were removed under reduced pressure and the mixture was partitioned between dichloromethane and 0.1M hydrochloric acid. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The crude product was purified by flash column chromatography (12 g Biotage™ silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1) to give the (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 as a colourless solid 0.285 g.

Quelle