Réaction #1973920

Équation de réaction

2,4,5-trichloropyrimidine

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

tri(isopropyl) borate

diisopropylamine

n-BuLi

→

title compound

Rendement 32.2%

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

Rendement 32.2%

Solvants

THF

THF

Conditions de réaction

Traitement

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

Mode opératoire

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].

Source