Phosphorus oxychloride → 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

HRID 706696Notes

Reaction equation

HRID 706696 reaction equation
[Cl-].[Li+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([OH:24])=O)=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1.O=P(Cl)(Cl)Cl.[F:30][C:31]([F:50])([F:49])[C:32]1[CH:33]=[CH:34][C:35]([CH2:38][N:39]2[C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([NH2:48])[C:42]=3[CH:41]=[N:40]2)=[N:36][CH:37]=1>CC(N(C)C)=O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([NH:48][C:43]4[CH:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[CH:41]=[N:40][N:39]5[CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:31]([F:50])([F:49])[F:30])=[CH:37][N:36]=4)=[O:24])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 679758767-(2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid lithium chlorideHCID 679761541-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine

Product 1

HCID 679903867-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideYield 25.7%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid lithium chloride (0.0653 g, 0.188 mmol) in dry DMA (2.0 mL) at 0° C. was added POCl3 (0.0345 mL, 0.376 mmol) and the mixture was stirred at 0° C. for 30 minutes. 1-((5-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine (0.055 g, 0.188 mmol) was added as a DMA solution (1.0 mL) and the mixture was gradually warmed to ambient temperature and stirred overnight. The mixture was concentrated under vacuum and 2M LiOH (2.5 mL) was added. The mixture was stirred for 10 minutes. The mixture was diluted with CHCl3 (20 mL) and with saturated aqueous NaHCO3 and the layers were mixed and separated. The aqueous phase was further extracted with CHCl3 and the combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The product was purified by preparative TLC (15% MeOH/CH2C12 adding 1% 7N NH3/MeOH) to provide 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a tan solid (0.028 g). The solid was dissolved in MeOH (2.0 mL) and HCl (1.88 mL, 3.76 mmol, 2.0M in Et2O) was added. The mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and finally with hexanes and dried under vacuum to provide the title compound (0.032 g, 24%). MS (ES+APCI) m/z=579 (M+H-3HCl).

Workup

  1. temperaturethe mixture was gradually warmed to ambient temperature
  2. stirringstirred overnight
  3. concentrationThe mixture was concentrated under vacuum and 2M LiOH (2.5 mL)
  4. additionwas added
  5. stirringThe mixture was stirred for 10 minutes
  6. additionThe mixture was diluted with CHCl3 (20 mL) and with saturated aqueous NaHCO3
  7. additionthe layers were mixed
  8. customseparated
  9. extractionThe aqueous phase was further extracted with CHCl3
  10. washthe combined organic layers were washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe product was purified by preparative TLC (15% MeOH/CH2C12 adding 1% 7N NH3/MeOH)

Sources & evidence

ORD record
ord-7a139a8b43f24e05b71b58b7c7092765
Source dataset
uspto-grants-2015_11
Patent number
US09174981B2

Reaction notes

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