3-Pyridinecarbonyl chloride, hydrochloride (1:1) → N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)nicotinamide

HRID 906705

Reaction equation

HRID 906705 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>O1CCCC1.O.CCOCC>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:29])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1

Participants

6

Reactant 2

HCID 884383-Pyridinecarbonyl chloride, hydrochloride (1:1)HCID 134780Pomalidomide

Product 1

HCID 10270982N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)nicotinamideYield 79.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

A stirred mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.09 g, 4.0 mmol) and nicotinoyl chloride hydrochloride (1.42 g, 8.0 mmol) in tetrahydrofuran (60 ml) was heated to reflux for 22 h. The suspension was filtered and washed with tetrahydrofuran (20 ml) and ether (10 ml) to yield a white solid. The solid was slurried in pH 7 buffer (40 ml) and ether (30 ml) for 1 h. The suspension was filtered and washed with water (20 ml) and ether (20 ml) to N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-3-pyridylcarboxamide as a white solid (1.2 g, 79% yield): mp, 176-178° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.3, 12.5 Hz, 1H, NCH), 7.64 (dd, J=4.9, 7.9 Hz, 1H, Ar), 7.71 (d, J=7.3 Hz, 1H, Ar), 7.92 (t, J=7.8 Hz, 1H, Ar), 8.29-8.34 (m, 1H, Ar), 8.45 (d, J=8.2 Hz, 1H, Ar), 8.83 (dd, J=1.2, 4.8 Hz, 1H, Ar), 9.15 (d, J=1.7 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 49.00, 119.06, 119.34, 123.91, 127.36, 129.17, 131.55, 135.24, 135.94, 136.20, 148.47, 152.95, 163.85, 166.59, 167.54, 169.69, 172.72; Anal Calcd for C19H14N4O5±0.13H2O: C, 59.95; H, 3.78; N, 14.72; H2O, 0.62. Found: C, 59.83; H, 3.66; N, 14.68; H2O, 0.64.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 22 h
  3. filtrationThe suspension was filtered
  4. washwashed with tetrahydrofuran (20 ml) and ether (10 ml)
  5. customto yield a white solid
  6. filtrationThe suspension was filtered

Sources & evidence

ORD record
ord-df7663400e9644a2a6cee6f1a8ac7904
Source dataset
uspto-grants-2011_09
Patent number
US08012997B2

Linked notes

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