Sodium Hydroxide → N-(3-cyclopropyl-1-((5-hydroxy-6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

HRID 79486Notes

Reaction equation

HRID 79486 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]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[Si]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:51][N:52]2[C:60]3[CH:59]=[CH:58][CH:57]=[C:56]([NH2:61])[C:55]=3[C:54]([CH:62]3[CH2:64][CH2:63]3)=[N:53]2)=[N:48][C:49]=1[CH3:50])(C(C)(C)C)(C)C.[OH-].[Na+].[NH4+].[Cl-]>O.CN1C(=O)CCC1>[CH:62]1([C:54]2[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][C:56]=3[NH:61][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:22])[N:52]([CH2:51][C:47]3[CH:46]=[CH:45][C:44]([OH:43])=[C:49]([CH3:50])[N:48]=3)[N:53]=2)[CH2:63][CH2:64]1

Participants

8

Reactant 5

HCID 14798Sodium HydroxideHCID 25517Ammonium ChlorideHCID 27337032,4,6-Trichlorobenzoyl chlorideHCID 67252742Lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylateHCID 672532771-((5-(tert-butyldimethylsilyloxy)-6-methylpyridin-2-yl)methyl)-3-cyclopropyl-1H-indazol-4-amine

Product 1

HCID 67261713N-(3-cyclopropyl-1-((5-hydroxy-6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamideYield 49%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
0 °C

Procedure

To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (101 mg, 0.318 mmol) was added NMP (5 mL, distilled over oven dried MgSO4). A heat gun was used to dissolve the starting material. The reaction was cooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (50.8 μL, 0.318 mmol) was added dropwise. The cold bath was removed once the addition was complete. The reaction mixture was stirred for one hour. 1-((5-(tert-Butyldimethylsilyloxy)-6-methylpyridin-2-yl)methyl)-3-cyclopropyl-1H-indazol-4-amine (100 mg, 0.245 mmol) was then added in one portion to the reaction mixture and the reaction was heated to 88° C. and stirred for 5 hours. NMP was removed by vacuum distillation until the reaction mixture became a thick oil. NaOH (3 equivalents relative to lithium salt starting material) in H2O (5 mL) was added to the thick oil. The mixture was stirred at 80° C. for 30 minutes. The mixture was cooled to ambient temperature and the pH of the dark solution was adjusted to about pH 12-13 with saturated NH4Cl aqueous solution. The mixture was cooled to 0° C. and H2O (10 mL) was added. Stirring was continued for 30 minutes, during which time a solid started to crash out. The mixture was filtered and the solid was washed with a saturated NaHCO3 solution and H2O. The solid was dissolved in DCM and dried (Na2SO4). The solution was filtered, concentrated and triturated with MTBE give the final product (49%). MS (ES+APCI) m/z=581.4 (M+H).

Workup

  1. dissolutionto dissolve the starting material
  2. customThe cold bath was removed once the addition
  3. temperaturethe reaction was heated to 88° C.
  4. stirringstirred for 5 hours
  5. customNMP was removed by vacuum distillation until the reaction mixture
  6. stirringThe mixture was stirred at 80° C. for 30 minutes
  7. temperatureThe mixture was cooled to ambient temperature
  8. temperatureThe mixture was cooled to 0° C.
  9. stirringStirring
  10. waitwas continued for 30 minutes, during which time
  11. filtrationThe mixture was filtered
  12. washthe solid was washed with a saturated NaHCO3 solution and H2O
  13. dissolutionThe solid was dissolved in DCM
  14. dry with materialdried (Na2SO4)
  15. filtrationThe solution was filtered
  16. concentrationconcentrated
  17. customtriturated with MTBE

Sources & evidence

ORD record
ord-049b152309c44266b2990858b3a19a26
Source dataset
uspto-grants-2014_09
Patent number
US08841455B2

Reaction notes

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