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

HRID 1055844Notes

Reaction equation

HRID 1055844 reaction equation
[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C(O)(C(F)(F)F)=O.CS(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH:27]=[CH:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1

Participants

7

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 27342052-Chloro-6-fluoroanilineHCID 897835482-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

Product 2

HCID 897832582-(2-((2-chloro-6-fluorophenyl)amino)quinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-oneYield 4%HCID 897837472-(2-((2-chloro-6-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-oneYield 21%

Reagents, catalysts & solvents 2

HCID 6422Trifluoroacetic acidCatalystHCID 679Dimethyl SulfoxideSolvent

Procedure

To 2-chloro-6-fluoroaniline (0.183 g, 1.259 mmol) and 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 LHMDS (1.0 M solution in THF; 1.259 ml, 1.259 mmol). The reaction was sealed and stirred 1 h at RT, then for 3 h at 70° C. The reaction was subsequently cooled to RT and stirred overnight. 1.5 mL DMSO and 10 drops TFA were added. The mixture was filtered and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA). The product-containing fractions were concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO3 and DCM. The aq. layer was extracted with DCM (3×), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was dissolved in DCM/MeOH, adsorbed onto 0.75 g silica gel, and purified by silica gel chromatography using 0-50% 90/10 MeOH/DCM in DCM. The product-containing fractions were concentrated to separately afford 2-(2-((2-chloro-6-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.022 g, 0.054 mmol, 21% yield) as a light-yellow solid and 2-(2-((2-chloro-6-fluorophenyl)amino)quinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.0037 g, 9.14 μmol, 4% yield) as a yellow solid. 2-(2-((2-Chloro-6-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (7): 1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (1H, br. s), 9.34 (1H, s), 8.16 (1H, d, J=9.0 Hz), 8.01 (1H, dd, J=7.6, 1.6 Hz), 7.55-7.67 (2H, m), 7.41-7.54 (2H, m), 7.28 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=9.0 Hz), 6.83-6.98 (2H, m), 3.32-3.44 (2H, m), 2.43 (2H, t, J=6.8 Hz). m/z (ESI, +ve) 406.9 (M+H)+. 2-(2-((2-Chloro-6-fluorophenyl)amino)quinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (12): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (1H, br. s), 10.68 (1H, d, J=6.1 Hz), 9.41 (1H, s), 8.11-8.26 (2H, m), 7.43-7.76 (4H, m), 7.34 (1H, t, J=7.7 Hz), 7.18-7.25 (1H, m), 7.14 (1H, d, J=9.0 Hz), 6.86-7.00 (1H, m), 5.91 (1H, d, J=6.8 Hz). m/z (ESI, +ve) 405.2 (M+H)+.

Workup

  1. customThe reaction was sealed
  2. waitfor 3 h at 70° C
  3. temperatureThe reaction was subsequently cooled to RT
  4. stirringstirred overnight
  5. filtrationThe mixture was filtered
  6. custompurified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA)
  7. concentrationThe product-containing fractions were concentrated in vacuo
  8. customthe residue was partitioned between saturated aq. NaHCO3 and DCM
  9. extractionThe aq. layer was extracted with DCM (3×)
  10. dry with materialthe combined organic extracts were dried over anhydrous Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. dissolutionThe material was dissolved in DCM/MeOH
  14. custompurified by silica gel chromatography

Sources & evidence

ORD record
ord-337b002f6db045708b6184ccf7a28823
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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