Trifluoroacetic acid → 2-(2-(2-chloro-6-fluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

HRID 1055846Notes

Reaction equation

HRID 1055846 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11].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.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[O:11][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

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 24758Sodium hydrideHCID 27737102-Chloro-6-fluorophenolHCID 897835482-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

Product 1

HCID 897832102-(2-(2-chloro-6-fluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-oneYield 29.4%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 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-chloro-6-fluorophenol (0.258 g, 1.763 mmol). After 10 min, a clear/colorless solution resulted. 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 and the reaction became dark red. The reaction was heated at 70° C. for 1 h, then at 90° C. for 2 h, then at 110° C. for 14 h. The reaction was cooled to 0° C. and quenched with TFA (0.136 ml, 1.763 mmol), diluted with 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo then treated with saturated aq. NaHCO3 and DCM. The organic layer was separated and the aq. layer was extracted 3×DCM. The combined organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(2-chloro-6-fluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.030 g, 0.074 mmol, 29% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (1H, br. s), 8.57 (1H, d, J=8.8 Hz), 8.05-8.15 (1H, m), 7.84 (1H, dt, J=7.7, 0.8 Hz), 7.38-7.69 (5H, m), 6.87-6.91 (1H, m), 6.85 (1H, d, J=2.3 Hz), 3.32-3.38 (2H, m), 2.54-2.50 (2H, m). m/z (ESI, +ve) 408.2 (M+H)+.

Workup

  1. customa clear/colorless solution resulted
  2. waitat 90° C. for 2 h
  3. waitat 110° C. for 14 h
  4. temperatureThe reaction was cooled to 0° C.
  5. filtrationfiltered
  6. custompurified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA)
  7. concentrationproduct-containing fractions were concentrated in vacuo
  8. additionthen treated with saturated aq. NaHCO3 and DCM
  9. customThe organic layer was separated
  10. extractionthe aq. layer was extracted 3×DCM
  11. dry with materialThe combined organic extracts were then dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0560288ddfad4b7d96b47eaf80aa0363
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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