Piperidine → N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}piperidylcarboxamide

HRID 2103575Notes

Reaction equation

HRID 2103575 reaction equation
C(N(C(C)C)CC)(C)C.Cl.[NH2:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:31])[N:16]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30])[C:17]2=[O:22].ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(#N)C>[O:30]=[C:24]1[CH:23]([N:16]2[C:15](=[O:31])[C:14]3[C:18](=[CH:19][CH:20]=[CH:21][C:13]=3[CH2:12][NH:11][C:36]([N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:42])[C:17]2=[O:22])[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1

Participants

6

Reactant 4

HCID 8082PiperidineHCID 81531Diisopropylethylamine2×HCID 94429TriphosgeneHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 21988619N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}piperidylcarboxamideYield 145.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent3×

Procedure

Diisopropylethylamine (0.88 g, 6.79 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (1.0 g, 3.09 mmol) in acetonitrile (50 mL). After stirring for 20 min, the mixture was slowly added to a stirred solution of triphosgene (0.34 g, 1.14 mmol) in acetonitrile (15 mL) over 30 min. After a further 10 min of stirring, a solution of piperidine (0.26 g, 3.09 mmol) and diisopropylethylamine (0.48 g, 3.71 mmol) in acetonitrile (10 mL) was added in one portion. The mixture was stirred at room temperature for 17 hours. The mixture was concentrated and the residue was dissolved in methylene chloride (80 mL). The methylene chloride solution was washed with 10% KHSO4 (30 mL), H2O (2×30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (CH2Cl2:CH3OH 97.5:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}piperidylcarboxamide (0.66 g, 53%) as a white solid: mp 156-158° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.86-7.75 (m, 2H), 7.69 (d, J=7.4 Hz, 1H), 7.12 (t, J=5.6 Hz, 1H), 5.18-5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.69 (d, J=5.5 Hz, 2H), 3.42-3.32 (m, 4H), 2.96-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.03 (m, 1H), 1.54-1.44 (m, 6H); 13C NMR (DMSO-d6) δ 172.74, 169.83, 167.60, 157.26, 141.46, 134.58, 132.82, 131.38, 126.74, 121.43, 48.82, 44.37, 30.93, 25.37, 24.12, 21.98; Anal. Calcd. For C21H22N4O5+0.22H2O: C, 59.70; H, 5.62; N, 13.92. Found: C, 60.14; H, 5.59; N, 13.47.

Workup

  1. stirringAfter a further 10 min of stirring
  2. stirringThe mixture was stirred at room temperature for 17 hours
  3. concentrationThe mixture was concentrated
  4. dissolutionthe residue was dissolved in methylene chloride (80 mL)
  5. washThe methylene chloride solution was washed with 10% KHSO4 (30 mL), H2O (2×30 mL), brine (30 mL)
  6. dry with materialdried (MgSO4)
  7. customSolvent was removed
  8. customthe residue was purified by chromatography (CH2Cl2:CH3OH 97.5:2.5)

Sources & evidence

ORD record
ord-8d4a398ee6f04f6cb3c9c0981c92b2dd
Source dataset
uspto-grants-2009_08
Patent number
US07576104B2

Reaction notes

Loading…