Lithium Hexamethyldisilazide → HCID 57384604, compound

HRID 706680Notes

Reaction equation

HRID 706680 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][N:46]3[C:49]([C:52](OCC)=[O:53])=[CH:50][N:51]=[C:45]3[CH:44]=2)[CH2:36][CH2:35]1>C1COCC1>[CH3:18][N:17]([CH3:19])[C:15]([C:14]1[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=1)[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:52]([C:49]3[N:46]4[CH:47]=[CH:48][C:43]([O:42][CH2:41][CH2:40][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[CH:44][C:45]4=[N:51][CH:50]=3)=[O:53])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1)=[O:16]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 67254998Ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylateHCID 67976345HCID 67976345, compound

Product 1

HCID 57384604HCID 57384604, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 3-((4-amino-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide (0.15 g, 0.51 mmol) and THF (1.0 mL) was cooled to −5° C. in an ice/brine bath, then LHMDS (0.48 ml, 0.48 mmol, 1.0M THF) was added drop-wise and the mixture was stirred for 10 minutes, during which a dark emulsion formed. Ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.080 g, 0.24 mmol) was added dropwise as a THF solution (1.0 mL). The reaction was stirred at −5 to 0° C. for 1 hour, then quenched with saturated aqueous NH4Cl (10 mL). The mixture was extracted with CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was slurried in Et2O with vigorous stirring and then filtered through a nylon filter providing crude product with >90% purity (0.083 g). The crude product was purified by column chromatography (5 to 20% MeOH/CH2Cl2 using 5% NH4OH/MeOH). The fractions were concentrated and the product dissolved in CH2Cl2 and then filtered. The filtrate was concentrated to provide N-(1-(3-(dimethylcarbamoyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide as a pale orange solid (0.060 g). This product was dissolved in MeOH (2.4 mL) and then HCl (2.41 mL, 4.81 mmol, 2.0M Et2O) was added. The mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and hexanes and dried under vacuum to provide 0.050 g (31%) of the title product as a pale brown powder. MS (ES+APCI) m/z=581 (M+H-2HCl).

Workup

  1. customformed
  2. stirringThe reaction was stirred at −5 to 0° C. for 1 hour
  3. customquenched with saturated aqueous NH4Cl (10 mL)
  4. extractionThe mixture was extracted with CH2Cl2
  5. washthe combined organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. stirringwith vigorous stirring
  10. filtrationfiltered through a nylon
  11. filtrationfilter
  12. customproviding crude product with >90% purity (0.083 g)
  13. customThe crude product was purified by column chromatography (5 to 20% MeOH/CH2Cl2 using 5% NH4OH/MeOH)
  14. concentrationThe fractions were concentrated
  15. dissolutionthe product dissolved in CH2Cl2
  16. filtrationfiltered
  17. concentrationThe filtrate was concentrated

Sources & evidence

ORD record
ord-37966db6bc3e417d862004a407f5cb0a
Source dataset
uspto-grants-2015_11
Patent number
US09174981B2

Reaction notes

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