Hydrochloric Acid → (S)-2-(2-oxo-4-((1-(2,3,5,6-tetrafluorophenyl)propan-2-yl)amino)-1,2-dihydropyridin-3-yl)-6-(pyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione

HRID 920472Notes

Reaction equation

HRID 920472 reaction equation
Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:29][C:13]2=[CH:14][C:15]3[C:16](=[O:28])[N:17]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl.[F:31][C:32]1[C:37]([F:38])=[CH:36][C:35]([F:39])=[C:34]([F:40])[C:33]=1[CH2:41][C@@H:42]([NH2:44])[CH3:43].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(O)CCC>[O:8]=[C:4]1[C:3]([C:10]2[NH:11][C:12]3=[CH:20][C:19]4[C:18](=[O:21])[N:17]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)[C:16](=[O:28])[C:15]=4[CH:14]=[C:13]3[N:29]=2)=[C:2]([NH:44][C@@H:42]([CH3:43])[CH2:41][C:33]2[C:34]([F:40])=[C:35]([F:39])[CH:36]=[C:37]([F:38])[C:32]=2[F:31])[CH:7]=[CH:6][NH:5]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 666872822-(4-Chloro-2-methoxypyridin-3-yl)-6-(pyridine-3-yl)imidazo[4,5-f]isoindole-5,7(1H, 6H)-dioneHCID 86663212(2S)-1-(2,3,5,6-Tetrafluorophenyl)propan-2-amine

Product 1

HCID 136353563(S)-2-(2-oxo-4-((1-(2,3,5,6-tetrafluorophenyl)propan-2-yl)amino)-1,2-dihydropyridin-3-yl)-6-(pyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dioneYield 78.3%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 312751,4-DioxaneSolvent

Procedure

2-(4-Chloro-2-methoxypyridin-3-yl)-6-(pyridine-3-yl)imidazo[4,5-f]isoindole-5,7(1H, 6H)-dione (0.60 g, 1.48 mmol) was dissolved in 10 mL of 1,4-dioxane and 5 mL of concentrated HCl at rt. The reaction mixture was stirred at rt overnight. Then, the volatile was removed to give a yellow-brown solid. This solid was mixed with (S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.46 g, 2.22 mmol), N,N-diisopropylethylamine (1.32 mL, 7.40 mmol) and n-butanol (30 mL) in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Then, volatiles were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow-brown solid product, 0.65 g, 78.3% yield. MS: 560.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.48 (s, 1H), 11.35 (d, 1H, J=4.5 Hz), 10.91 (d, 1H, J=8.0 Hz), 8.73-8.72 (m, 1H), 8.63-8.61 (m, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.95 (dd, 1H, J1=8.0 Hz, J2=2.0 Hz), 7.77-7.70 (m, 1H), 7.62-7.58 (m, 1H), 7.41 (t, 1H, J=4.5 Hz), 6.18 (d, 1H, J=7.5 Hz), 4.25 (m, 1H), 3.18-3.10 (m, 2H), 1.93 (d, 3H, J=6.0 Hz).

Workup

  1. customat rt
  2. customThen, the volatile was removed
  3. customto give a yellow-brown solid
  4. stirringThe reaction mixture was stirred
  5. temperatureheated
  6. temperatureto reflux overnight under argon
  7. customThen, volatiles were removed under reduced pressure
  8. customThe residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v)
  9. customto give a yellow-brown solid product, 0.65 g, 78.3% yield

Sources & evidence

ORD record
ord-95e858b2ddec4cb2bfb1ae5172c23bd5
Source dataset
uspto-grants-2016_03
Patent number
US09273055B2

Reaction notes

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