Lithium Hexamethyldisilazide → 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

HRID 706692Notes

Reaction equation

HRID 706692 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[N:9]2)[CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][N:41]3[C:44]([C:47](OCC)=[O:48])=[CH:45][N:46]=[C:40]3[CH:39]=2)[CH2:31][CH2:30]1>C1COCC1>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][N:41]3[C:44]([C:47]([NH:17][C:12]4[CH:13]=[CH:14][CH:15]=[C:16]5[C:11]=4[CH:10]=[N:9][N:8]5[CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:48])=[CH:45][N:46]=[C:40]3[CH:39]=2)[CH2:33][CH2:34]1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 67254998Ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylateHCID 679763661-(pyridin-3-ylmethyl)-1H-indazol-4-amine

Product 1

HCID 866993427-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 1-(pyridin-3-ylmethyl)-1H-indazol-4-amine (0.040 g, 0.18 mmol) in THF (1.1 mL) was cooled to −10° C. in an ice/salt bath. LHMDS (0.19 mL, 0.19 mmol, 1.0M THF) was added and the mixture was stirred for 15 minutes. To this dark solution was added a THF (1.1 mL) solution of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.030 g, 0.090 mmol) at 0° C. The mixture was slowly warmed to 0° C. where it stirred for 3 hours. The reaction was quenched with a saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (1 mm, 15% MeOH/CH2Cl2 with NH3) to afford 0.028 g of 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a tan powder. This material was suspended in MeOH (4.0 mL) and HCl (0.90 mL, 1.8 mmol, 2.0M Et2O) was added. The resulting suspension was stirred for 3 hours and then concentrated. The solid was slurried in Et2O and isolated by vacuum filtration. The solid was dried under vacuum overnight to afford 0.035 g of the title compound (62%). MS (ES+APCI) m/z=511 (M+H-3HCl).

Workup

  1. customPreparation A
  2. customat 0° C
  3. stirringstirred for 3 hours
  4. customThe reaction was quenched with a saturated aqueous NaHCO3 solution
  5. extractionextracted with CH2Cl2
  6. washThe combined organic extracts were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude product was purified by preparative TLC (1 mm, 15% MeOH/CH2Cl2 with NH3)

Sources & evidence

ORD record
ord-38e1ad754c974b6b81cf3bc2be4c911f
Source dataset
uspto-grants-2015_11
Patent number
US09174981B2

Reaction notes

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