Triethylamine → N1-Methyl-5-(2-((4-(2-hydroxy-2-methylpropionyl)piperazino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

HRID 2215511Notes

Reaction equation

HRID 2215511 reaction equation
[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.[C:29](Cl)(=O)[O:30]C1C=CC=CC=1.[OH:39][C:40]([CH3:50])([CH3:49])[C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42]>O1CCCC1.CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:29]([N:46]4[CH2:45][CH2:44][N:43]([C:41](=[O:42])[C:40]([OH:39])([CH3:50])[CH3:49])[CH2:48][CH2:47]4)=[O:30])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 21949141N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamideHCID 219492932-Hydroxy-2-methyl-1-(piperazin-1-yl)propan-1-one

Product 1

HCID 21949211N1-Methyl-5-(2-((4-(2-hydroxy-2-methylpropionyl)piperazino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamideYield 74.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 was dissolved in tetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenyl chlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise at room temperature, and the reaction mixture was stirred for 30 minutes. 1-(2-Hydroxy-2-methylpropionyl)piperazine (412 mg, 2.39 mmol) and N,N-dimethylformamide (3 ml) were added and the reaction mixture was stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). The crystals were precipitated from diethyl ether-hexane (1:2), filtered off, and dried under aeration to yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as white crystals.

Workup

  1. stirringthe reaction mixture was stirred for 3 days
  2. customThe reaction mixture was partitioned between ethyl acetate and water
  3. washThe organic layer was washed with water and brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. distillationThe solvent was distilled off
  6. customthe residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5)
  7. customThe crystals were precipitated from diethyl ether-hexane (1:2)
  8. filtrationfiltered off
  9. customdried under aeration

Sources & evidence

ORD record
ord-fe98dd378e354134bc8e2670c5935e58
Source dataset
uspto-grants-2006_09
Patent number
US07109219B2

Reaction notes

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