Reaktion #159081

Reaktionsgleichung

(1-{2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

tributyl(1-ethoxyvinyl)tin

NBS

2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester

DIPEA

→

2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-[2-(7-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-9,10-dihydro-phenanthren-2-yl)-2-oxo-ethyl]ester

Lösungsmittel

ethyl acetate

dioxane

Water

ethyl acetate

acetonitrile

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe reaction mixture was flushed with nitrogen
2. 2
   Temperaturcooled to ambient temperature
3. 3
   WaschenWashed with water and brine
4. 4
   Trocknendried over Na2SO4
5. 5
   Filtrationfiltered
6. 6
   Einengenconcentrated in vacuo
7. 7
   workup.DISSOLUTIONThe obtained residue was dissolved in acetonitrile (3 mL)
8. 8
   workup.STIRRINGThe mixture was stirred at room temperature for 16 hours
9. 9
   WaschenThe organic layer was washed with NaHCO3 solution and water
10. 10
    Trocknendried over Na2SO4
11. 11
    Filtrationfiltered
12. 12
    Einengenconcentrated in vacuo
13. 13
    SonstigeThe obtained residue was purified by flash chromatography

Vorschrift

Pd(Ph3)4 (15 mg, 0.015 mmol) and PdCl2(Ph3)2 (10 mg, 0.015 mmol) were added to a mixture of (1-{2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (200 mg, 0.37 mmol) and tributyl(1-ethoxyvinyl)tin (0.15 mL, 0.44 mL) in 5 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, then cooled to ambient temperature. Water (1.5 mL) and NBS (78 mg, 0.44 mmol) was added and the mixture was stirred at room temperature for 40 minutes, then diluted with ethyl acetate (100 mL). Washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was dissolved in acetonitrile (3 mL). To it was added a solution of 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (167 mg, 0.69 mmol) and DIPEA (0.11 mL, 0.67 mmol) in 2 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO3 solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-[2-(7-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-9,10-dihydro-phenanthren-2-yl)-2-oxo-ethyl]ester as a brown oil (130 mg, 47% over two steps). m/z 754.3 (M+H)+.

Quelle