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

HRID 69348Notes

Reaction equation

HRID 69348 reaction equation
Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:30][C:13]2=[CH:14][C:15]3[C:16](=[O:29])[N:17]([C:22]4[CH:23]=[N:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl.[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[C:35]([F:41])[C:34]=1[CH2:42][C@@H:43]([NH2:45])[CH3:44].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(O)CCC>[F:28][C:25]1[N:24]=[CH:23][C:22]([N:17]2[C:16](=[O:29])[C:15]3[CH:14]=[C:13]4[NH:30][C:10]([C:3]5[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=5[NH:45][C@@H:43]([CH3:44])[CH2:42][C:34]5[C:35]([F:41])=[C:36]([F:40])[CH:37]=[C:38]([F:39])[C:33]=5[F:32])=[N:11][C:12]4=[CH:20][C:19]=3[C:18]2=[O:21])=[CH:27][CH:26]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 666867222-(4-Chloro-2-methoxypyridin-3-yl)-6-(6-fluoropyridine-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 136353590(S)-6-(6-Fluoropyridin-3-yl)-2-(2-oxo-4-((1-(2,3,5,6-tetrafluorophenyl)propan-2-yl)amino)-1,2-dihydropyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dioneYield 63%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 312751,4-DioxaneSolvent

Procedure

2-(4-Chloro-2-methoxypyridin-3-yl)-6-(6-fluoropyridine-3-yl)imidazo[4,5-f]isoindole-5,7(1H, 6H)-dione (0.15 g, 0.35 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 (55 mg, 0.26 mmol), N,N-diisopropylethylamine (1 mL) and n-butanol (20 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, 80 mg, 63.0% yield. MS: 578.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.48 (s, 1H), 11.35 (d, 1H, J=6.0 Hz), 10.91 (d, 1H, J=8.5 Hz), 8.40 (d, 1H, J=2.0 Hz), 8.26 (s, 1H), 8.18-8.14 (m, 1H), 8.04 (s, 1H), 7.77-7.70 (m, 1H), 7.42-7.39 (m, 2H), 6.19 (d, 1H, J=7.5 Hz), 4.27-4.24 (m, 1H), 3.18-3.10 (m, 2H), 1.39 (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, 80 mg, 63.0% yield

Sources & evidence

ORD record
ord-38066c0e196c4c9f9792bfe1bac13512
Source dataset
uspto-grants-2014_09
Patent number
US08822500B2

Reaction notes

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