Aniline → N-[4-((3aR,4S,7R,7aS)-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl)phenyl]-quinoline-8-carboxamide

HRID 570082Notes

Reaction equation

HRID 570082 reaction equation
[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](Cl)=[O:12])[CH:4]=[CH:3][CH:2]=1.N1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:24]([OH:26])=O)C=CC=1.S(Cl)(Cl)=[O:28].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.[CH3:45][C:46]#[N:47]>>[O:28]=[C:46]1[C@@H:45]2[C@@H:22]([C@H:23]3[CH2:18][C@@H:19]2[CH:20]=[CH:21]3)[C:24](=[O:26])[N:47]1[C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:12])=[CH:33][CH:34]=1

Participants

7

Reactant 6

HCID 6115AnilineHCID 6342AcetonitrileHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 665828-Quinolinecarboxylic acidHCID 14722777Quinoline-8-carbonyl chloride

Product 1

HCID 86689413N-[4-((3aR,4S,7R,7aS)-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl)phenyl]-quinoline-8-carboxamideYield 87%

Procedure

Quinoline-8-carbonyl chloride was freshly prepared by heating 135 mg (0.78 mmol) of quinoline-8-carboxylic acid in an excess of thionyl chloride (622 μL) for three hours at 60-70° C. This mixture was added dropwise to a solution of 100 mg of the aniline precursor from step b (0.39 mmol) and 5 equivalents of triethylamine (1.95 mmol) in 7 mL of dry MeCN. The reaction mixture was stirred at room temperature for three days, concentrated in a vacuum and purified by flash chromatography (toluene/EtOAc/acetone 6/3/1 Rf 0.5). The product was obtained as an off-white solid with 87% yield (140 mg). LC-MS (1000 (+)-5.5-254-80:20): Rt 3.45 min, 412 [M+H]+ >99% at 254 nM; 1H NMR (300 MHz, CDCl3): 1.48-1.75 (m, 6H), 2.88 (me, 2H), 3.25 (me, 2H), 7.27-7.32 (m, 2H), 7.56 (dd, J=4.3, 8.3 Hz, 1H), 7.74 (dd, J=7.45, 7.50 Hz, 1H), 7.98-8.03 (m, 2H), 8.02 (br d, J=1.6 Hz, 1H), 8.34 (dd, J=1.8, 8.4 Hz, 1H), 8.96 (dd, J=1.6, 7.4 Hz, 1H), 9.01 (dd, J=1.8, 4.3 Hz, 1H).

Workup

  1. concentrationconcentrated in a vacuum
  2. custompurified by flash chromatography (toluene/EtOAc/acetone 6/3/1 Rf 0.5)
  3. customThe product was obtained as an off-white solid with 87% yield (140 mg)

Sources & evidence

ORD record
ord-15b66d83b9e34511946b7a0301cc88d2
Source dataset
uspto-grants-2015_05
Patent number
US09023340B2

Reaction notes

Loading…