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

HRID 79473Notes

Reaction equation

HRID 79473 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[CH2:28]([C:30]1[C:38]2[C:37]([NH2:39])=[CH:36][CH:35]=[CH:34][C:33]=2[N:32]([CH2:40][C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)[N:31]=1)[CH3:29]>CC(N(C)C)=O>[CH2:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[NH:39][C:20]([C:17]2[N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:12][C:13]3=[N:19][CH:18]=2)=[O:22])[N:32]([CH2:40][C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)[N:31]=1)[CH3:29]

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 672527437-(2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acidHCID 672602643-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-amine

Product 1

HCID 53261959N-(3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamideYield 36%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent2×

Procedure

A solution of 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.346 g, 0.997 mmol) in DMA (5 mL) was cooled to 0° C. and treated with phosphorous oxychloride (0.182 mL, 1.99 mmol). The mixture was warmed up to ambient temperature and after stirring for an hour, the mixture was cooled to 0° C. again and treated with a solution of 3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-amine (0.181 g, 0.665 mmol) in DMA (2 mL). The mixture was allowed to warm up to ambient temperature and stirring continued overnight. The mixture was concentrated and then quenched with saturated aqueous lithium hydroxide, stirred at ambient temperature for 30 minutes and then diluted with DCM. The organic layer was filtered through glass fiber filter paper, concentrated under reduced pressure and purified by silica gel chromatography (2-10% 7N NH3/MeOH in DCM) to provide N-(3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.133 g, 36% yield) as beige solids. MS (APCI) m/z=559 (M+H).

Workup

  1. temperaturethe mixture was cooled to 0° C. again
  2. temperatureto warm up to ambient temperature
  3. stirringstirring continued overnight
  4. concentrationThe mixture was concentrated
  5. customquenched with saturated aqueous lithium hydroxide
  6. stirringstirred at ambient temperature for 30 minutes
  7. additiondiluted with DCM
  8. filtrationThe organic layer was filtered through glass fiber
  9. filtrationfilter paper
  10. concentrationconcentrated under reduced pressure
  11. custompurified by silica gel chromatography (2-10% 7N NH3/MeOH in DCM)

Sources & evidence

ORD record
ord-f519204da40d4add82406f360360a685
Source dataset
uspto-grants-2014_09
Patent number
US08841455B2

Reaction notes

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