2,4-Difluoroaniline → 2-(2-((2,4-difluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

HRID 1055845Notes

Reaction equation

HRID 1055845 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C=O)C>[F:3][C:4]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1

Participants

5

Reactant 3

HCID 97092,4-DifluoroanilineHCID 24758Sodium hydrideHCID 897835482-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

Product 1

HCID 897835532-(2-((2,4-difluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-oneYield 21.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2,4-difluoroaniline (0.178 ml, 1.763 mmol). After 10 min, 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added as a solid and the reaction became dark red. The reaction was heated at 70° C. for 4 h, and then cooled to RT and partitioned between saturated aq. NH4Cl and EtOAc. The organic layer was separated and sequentially washed with saturated aq. NH4Cl and saturated aq. NaCl, and the organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 2-(2-((2,4-difluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.021 g, 0.054 mmol, 21% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (1H, br. s), 9.27 (1H, s), 8.13 (1H, d, J=9.0 Hz), 7.83-8.00 (2H, m), 7.59 (1H, dt, J=7.6, 0.9 Hz), 7.46 (1H, ddd, J=11.2, 8.8, 2.9 Hz), 7.28 (1H, t, J=7.6 Hz), 7.17-7.24 (1H, m), 7.14 (1H, d, J=9.0 Hz), 6.89-6.96 (2H, m), 3.35-3.41 (2H, m), 2.57 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 391.2 (M+H)+.

Workup

  1. temperaturecooled to RT
  2. custompartitioned between saturated aq. NH4Cl and EtOAc
  3. customThe organic layer was separated
  4. washsequentially washed with saturated aq. NH4Cl and saturated aq. NaCl
  5. dry with materialthe organic layers were dried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. additionThe material was treated with DCM
  9. custompurified by silica gel chromatography
  10. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-35b363e6ca964ade8cbbd8d5399ee65e
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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