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

HRID 1886738Notes

Reaction equation

HRID 1886738 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1([NH:16][C:17]([C:19]2[C:20]3[CH:21]=[CH:22][N:23]([CH2:28][O:29][CH2:30][CH3:31])[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[O:18])[CH2:15][CH2:14]1.B(OC(C)C)(OC(C)C)OC(C)C.[Cl:45][C:46]1[N:51]=[C:50](Cl)[C:49]([Cl:53])=[CH:48][N:47]=1>C1COCC1.[Cl-].[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Pd+2]>[CH:13]1([NH:16][C:17]([C:19]2[C:20]3[CH:21]=[C:22]([C:48]4[C:49]([Cl:53])=[CH:50][N:51]=[C:46]([Cl:45])[N:47]=4)[N:23]([CH2:28][O:29][CH2:30][CH3:31])[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[O:18])[CH2:15][CH2:14]1

Participants

8

Reactant 5

HCID 7912DiisopropylamineHCID 21531Triisopropyl borateHCID 2372592,4,5-TrichloropyrimidineHCID 67466461N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamideHCID 178418339Butyllithium

Product 1

HCID 86677431N-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-(ethoxymethyl)-1H-indole-4-carboxamideYield 32.2%

Reagents, catalysts & solvents 2

HCID 178478644HCID 178478644, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

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].

Workup

  1. additionAfter the addition
  2. temperaturecooled to −70° C
  3. stirringThe reaction mixture is stirred at −70° C. for 30 min
  4. temperatureThe reaction is slowly warmed up to ambient temperature
  5. stirringstirred for 1 h
  6. customThe crude reaction mixture
  7. customis degassed
  8. custompurged with N2 for three times
  9. stirringstirred under nitrogen
  10. temperatureat refluxing temperature for 1.5 h
  11. customThe volatiles are removed in vacuo
  12. extractionThe residue is extracted with dichloromethane (DCM, 3×500 mL)
  13. washThe combined extracts are washed with aqueous saturated sodium chloride (3×100 mL)
  14. dry with materialdried over anhydrous Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customThe residue is purified by chromatography on silica gel

Sources & evidence

ORD record
ord-26a1af052672469497fc09fb7ead38ad
Source dataset
uspto-grants-2013_08
Patent number
US08501166B2

Reaction notes

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