Aniline → HCID 89783663, compound

HRID 1055863Notes

Reaction equation

HRID 1055863 reaction equation
Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH:17]([CH3:21])[NH:16][C:15](=[O:22])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(C(F)(F)F)=O>CS(C)=O>[CH3:21][CH:17]1[NH:16][C:15](=[O:22])[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:11]=[CH:10]4)[NH:20][C:19]=2[CH2:18]1

Participants

6

Reactant 4

HCID 6115AnilineHCID 6422Trifluoroacetic acidHCID 2733832Lithium HexamethyldisilazideHCID 89783654HCID 89783654, compound

Product 1

HCID 89783663HCID 89783663, compoundYield 31.3%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

2-(2-Chloroquinolin-8-yl)-6-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 31; 0.050 g, 0.160 mmol) and aniline (0.073 ml, 0.802 mmol) were treated with LHMDS (1.0 M solution in THF; 1.203 ml, 1.203 mmol). The dark red reaction was stirred for 3 h, at which point it was concentrated then treated with DMSO and TFA (0.185 ml, 2.406 mmol). This material was purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.018 g, 0.050 mmol, 31% yield, Example 237) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (1H, br. s), 9.52 (1H, s), 8.11 (1H, d, J=9.0 Hz), 7.93 (1H, dt, J=7.4, 0.9 Hz), 7.65 (2H, d, J=7.6 Hz), 7.58 (1H, dt, J=7.7, 1.0 Hz), 7.40 (2H, t, J=7.9 Hz), 7.28 (1H, t, J=7.7 Hz), 7.02-7.15 (2H, m), 6.82-6.97 (2H, m), 3.75 (1H, dt, J=11.3, 5.8 Hz), 2.65 (1H, dd, J=15.6, 5.3 Hz), 2.36-2.47 (1H, m), 1.23 (3H, d, J=6.3 Hz). m/z (ESI, +ve) 369.2 (M+H)+. A portion of this material was resolved by chiral SFC (Chiralcel IC-H (150×21 mm, 5 μm); additive in supercritical fluid CO2 was 40% EtOH with 40 mM NH3; 70 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers 6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 33, first eluting enantiomer) and 6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 34, second eluting enantiomer).

Workup

  1. customThe dark red reaction
  2. concentrationwas concentrated
  3. customThis material was purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA)
  4. additionproduct-containing fractions were treated with saturated aq. NaHCO3 and DCM
  5. customThe organic layer was separated
  6. extractionthe aq. layer was extracted 3×DCM
  7. dry with materialThe combined organic layers were then dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-56791fb457aa4487b81414aa3c51f79b
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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