HCID 57798921, compound → HCID 11562577, compound

HRID 2100409Notes

Reaction equation

HRID 2100409 reaction equation
[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.[CH3:38][Li]>C1COCC1>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][C:34]([OH:37])([CH3:38])[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1

Participants

4

Reactant 2

HCID 57798921HCID 57798921, compoundHCID 178418348HCID 178418348, compound

Product 1

HCID 11562577HCID 11562577, compoundYield 23.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

4-oxo-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (50 mg, 0.1 mmol) in dry THF under argon, at −78° C. was treated dropwise with methyllithium (1.5M in diethylether, 0.2 mL, 0.3 mmol). The reaction was stirred for 30 minutes at −78° C. before warming to rt. The reaction was stirred overnight before partitioning between EtOAc and saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:2) to give 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (12 mg, 23%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.13 (1H, s), 9.02 (1H, s), 8.25 (1H, s), 8.13 (1H, d), 8.10 (1H, s), 7.94 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.64 (1H, d), 7.23-7.32 (2H, m), 6.92 (1H, d), 6.66 (1H, t), 6.54 (1H, d), 4.43 (2H, d), 4.31 (1H, s), 4.13 (3H, s), 3.68-3.74 (2H, m), 3.16-3.25 (2H, m), 1.35-1.46 (4H, m), 1.12 (3H, s); m/z (ES+) 514 [M+H]+.

Workup

  1. temperaturebefore warming to rt
  2. stirringThe reaction was stirred overnight
  3. custombefore partitioning between EtOAc and saturated aqueous ammonium chloride solution
  4. washThe organic phase was washed with brine
  5. customdried
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:2)

Sources & evidence

ORD record
ord-7b3f3b7ec37840fc9144537911ff3546
Source dataset
uspto-grants-2009_08
Patent number
US07572794B2

Reaction notes

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