Reaktion #1973920

Reaktionsgleichung

2,4,5-trichloropyrimidine

N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide

tri(isopropyl) borate

diisopropylamine

n-BuLi

→

title compound

Ausbeute 32.2%

N-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-(ethoxymethyl)-1H-indole-4-carboxamide

Ausbeute 32.2%

Lösungsmittel

THF

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONAfter the addition
2. 2
   Temperaturcooled to −70° C
3. 3
   workup.STIRRINGThe reaction mixture is stirred at −70° C. for 30 min
4. 4
   TemperaturThe reaction is slowly warmed up to ambient temperature
5. 5
   workup.STIRRINGstirred for 1 h
6. 6
   SonstigeThe crude reaction mixture
7. 7
   Sonstigeis degassed
8. 8
   Sonstigepurged with N2 for three times
9. 9
   workup.STIRRINGstirred under nitrogen
10. 10
    Temperaturat refluxing temperature for 1.5 h
11. 11
    SonstigeThe volatiles are removed in vacuo
12. 12
    ExtraktionThe residue is extracted with dichloromethane (DCM, 3×500 mL)
13. 13
    WaschenThe combined extracts are washed with aqueous saturated sodium chloride (3×100 mL)
14. 14
    Trocknendried over anhydrous Na2SO4
15. 15
    Filtrationfiltered
16. 16
    Einengenconcentrated
17. 17
    SonstigeThe residue is purified by chromatography on silica gel

Vorschrift

To a solution of diisopropylamine (DIPA, 147 mL, 1.04 mol) in anhydrous THF (600 mL) is added n-BuLi (2.5 M in hexane, 420 mL, 1.04 mol) at −50 C. After the addition, the mixture is stirred at −20° C. for 30 minutes and then cooled to −70° C. A solution of N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide (60 g, 0.23 mol) and tri(isopropyl) borate (56.4 mL, 0.25 mol) in anhydrous THF (300 mL) is added. The reaction mixture is stirred at −70° C. for 30 min. The reaction is slowly warmed up to ambient temperature, stirred for 1 h and then quenched with aqueous K3PO4.3H2O (195 g, 0.74 mol, in 700 mL of water). The crude reaction mixture is degassed and purged with N2 for three times. 2,4,5-trichloropyrimidine (51 g, 0.27 mol) and palladium diphenylphosphinoferrocene dichloride (PdCl2(dppf).CH2Cl2, 19.2 g, 0.023 mol) are added and stirred under nitrogen at refluxing temperature for 1.5 h. The volatiles are removed in vacuo. The residue is extracted with dichloromethane (DCM, 3×500 mL). The combined extracts are washed with aqueous saturated sodium chloride (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give the title compound (30 g, 32%). MS (m/z): 405 [(M+1)+, 35Cl, 35Cl], 407 [(M+1)+, 35Cl, 37Cl] and 409 [(M+1)+, 37Cl, 37Cl].

Quelle