Phthaloyl chloride → 2-(6-(Bis(4-methoxybenzyl)amino)-2,7-naphthyridin-1-yl)isoindoline-1,3-dione

HRID 874691Notes

Reaction equation

HRID 874691 reaction equation
[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([NH2:19])=[N:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:48])[C:39]1[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:41](Cl)=[O:42]>ClCCl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([N:19]2[C:41](=[O:42])[C:40]4[C:39](=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:38]2=[O:48])=[N:14][CH:13]=[CH:12]3)=[CH:22][CH:23]=1

Participants

5

Reactant 3

HCID 6955Phthaloyl chlorideHCID 8471TriethylamineHCID 117672701N6,N6-bis(4-methoxybenzyl)-2,7-naphthyridine-1,6-diamine

Product 1

HCID 1176661932-(6-(Bis(4-methoxybenzyl)amino)-2,7-naphthyridin-1-yl)isoindoline-1,3-dione

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred mixture of crude 4-5 (10.9 g, <19.3 mmol), triethylamine (8.05 mL, 57.8 mmol), and dichloromethane (75.0 mL) at 0° C. under an atmosphere of nitrogen gas was added phthaloyl dichloride (90%; 3.75 mL, 23.4 mmol). The resulting mixture was stirred at ambient temperature for 15 hours under an atmosphere of nitrogen gas. The reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) and the resulting mixture was extracted with dichloromethane (1000 mL, 500 mL×2). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 200 g, step gradient eluting with 50:1, 40:1, 30:1, 20:1, 10:1, and 5:1 dichloromethane/ethyl acetate) followed by recrystallization from dichloromethane to give 3.94 g (39% in 3 steps) of 4-6 as yellow crystals: 1H NMR (400 MHz, CDCl3) δ 8.94 (1H, br s), 8.33 (1H, d, J=6.0 Hz), 8.02 (2H, m), 7.84 (2H, m), 7.31 (1H, dd, J=6.0, 0.8 Hz), 7.15 (4H, m), 6.85 (4H, m), 6.52 (1H, br s), 4.81 (4H, br s), 3.79 (6H, s); ESI-MS m/z 531 [C32H26N4O4+H]+.

Workup

  1. customThe reaction mixture was quenched with saturated aqueous NH4Cl (200 mL)
  2. extractionthe resulting mixture was extracted with dichloromethane (1000 mL, 500 mL×2)
  3. washThe combined organic extracts were washed with brine (200 mL)
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting residue was purified by column chromatography (silica gel 200 g, step gradient eluting with 50:1, 40:1, 30:1, 20:1, 10:1, and 5:1 dichloromethane/ethyl acetate)
  7. customfollowed by recrystallization from dichloromethane

Sources & evidence

ORD record
ord-49b79df79f9d448794bf2484fdc1e453
Source dataset
uspto-grants-2015_03
Patent number
US08980916B2

Reaction notes

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