HCID 66729051, compound → HCID 66728686, compound

HRID 1098609Notes

Reaction equation

HRID 1098609 reaction equation
[C:1]([N:5]1[C:9](=O)[CH2:8][CH:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:23]=3)=[CH:17][C:16]=2[F:34])=[O:13])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1>[C:1]([N:5]1[CH2:9][CH2:8][CH:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:23]=3)=[CH:17][C:16]=2[F:34])=[O:13])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]

Participants

4

Reactant 2

HCID 66729051HCID 66729051, compoundHCID 68718528lithium aluminium hydride THF

Product 1

HCID 66728686HCID 66728686, compoundYield 49.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirring solution of 1-(1-tert-butyl-5-oxopyrrolidin-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea from Example 35 (95 mg, 0.20 mmol) in dry THF (3 ml) at RT was added 1.0 M LAH/THF (0.81 ml, 0.82 mmol). The resulting mixture was stirred overnight at RT. It was carefully quenched by the sequential addition of H2O (0.1 ml), 3M NaOH (0.1 ml) and H2O (0.3 ml) and then EtOAc was added. The mixture was stirred at RT for 4 hours. The solution was filtered through a pad of Celite® and washing forward with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo and purified via silica gel column chromatography (CH2Cl2/MeOH), dissolved in CH3CN:H2O (1:1 2 mL) and lyophilized to obtain 1-(1-tert-butylpyrrolidin-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (45 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (brs, 1H), 8.34 (d, J=6.0 Hz, 1H), 8.24 (s, 1H), 8.16 (t, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.16 (m, 2H), 6.93 (m, 2H), 6.63 (dd, J=2.4, and 5.6 Hz, 1H), 4.05 (m, 1H), 3.84 (s, 3H), 2.3-2.8 (m, 4H), 2.03 (m, 1H), 1.48 (m, 1H), 1.01 (s, 9H); MS (ESI) m/z: 453.1 (M+H+).

Workup

  1. customIt was carefully quenched by the sequential addition of H2O (0.1 ml), 3M NaOH (0.1 ml) and H2O (0.3 ml)
  2. additionEtOAc was added
  3. stirringThe mixture was stirred at RT for 4 hours
  4. filtrationThe solution was filtered through a pad of Celite®
  5. washwashing forward with EtOAc
  6. dry with materialThe organic layer was dried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. custompurified via silica gel column chromatography (CH2Cl2/MeOH)
  9. dissolutiondissolved in CH3CN:H2O (1:1 2 mL)

Sources & evidence

ORD record
ord-249feef2e3c348b4b493c514c5934259
Source dataset
uspto-grants-2012_03
Patent number
US08143293B2

Reaction notes

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