Aniline → HCID 89783256, compound

HRID 1055861Notes

Reaction equation

HRID 1055861 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([C:29]3[NH:37][C:36]4[CH:35]([CH3:38])[CH2:34][NH:33][C:32](=[O:39])[C:31]=4[CH:30]=3)[CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[CH3:38][CH:35]1[CH2:34][NH:33][C:32](=[O:39])[C:31]2[CH:30]=[C:29]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:21]=3[N:20]=[C:19]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:28]=[CH:27]4)[NH:37][C:36]1=2

Participants

6

Reactant 4

HCID 6115AnilineHCID 6422Trifluoroacetic acidHCID 2733832Lithium Hexamethyldisilazide2×HCID 89783271HCID 89783271, compound

Product 1

HCID 89783256HCID 89783256, compoundYield 40.1%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

A solution of LHMDS (1.0 M in THF; 2.197 ml, 2.197 mmol), aniline (0.200 ml, 2.197 mmol), and 2-(2-chloroquinolin-8-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 27; 0.137 g, 0.439 mmol) was stirred at RT for 1.5 h. An additional 2 equiv LHMDS (1.0 M in THF) was added, and the reaction was stirred overnight. The reaction was concentrated under N2, treated with DMSO and TFA (0.474 ml, 6.15 mmol), filtered, and 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-7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.065 g, 0.176 mmol, 40% yield, Example 238) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.11 (1H, br. s), 9.53 (1H, s), 8.12 (1H, d, J=9.0 Hz), 7.93 (1H, dt, J=7.4, 0.8 Hz), 7.56-7.71 (3H, m), 7.34-7.45 (2H, m), 7.29 (1H, t, J=7.6 Hz), 6.99-7.14 (2H, m), 6.85-6.98 (2H, m), 3.38-3.52 (1H, m), 2.86-3.08 (2H, m), 0.84 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 369.1 (M+H)+. A portion of this material was resolved by chiral SFC (ChiralPak AS-H (21×250, 5 μm); additive in supercritical fluid CO2 was 40% MeOH with 20 mM NH3; 60 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers 7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 29, first eluting enantiomer) and 7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 30, second eluting anantiomer).

Workup

  1. concentrationThe reaction was concentrated under N2
  2. filtrationfiltered
  3. custompurified 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-09f72e4e3aef42018907caa90592e155
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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