1,8-Diazabicyclo(5.4.0)undec-7-ene → 3-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-propyl-carbamic acid t-butyl ester

HRID 448302

Reaction equation

HRID 448302 reaction equation
N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33]([NH:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:36]([O:35][C:33](=[O:34])[NH:40][CH2:41][CH2:42][CH2:43][C:44](=[O:45])[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])([CH3:39])([CH3:37])[CH3:38]

Participants

6

Reactant 4

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 2948944-(((Tert-butoxy)carbonyl)amino)butanoic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 219885683-(4-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 161174773-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-propyl-carbamic acid t-butyl esterYield 77.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

1,8-Diazabicyclo[5,4,0]-undec-7-ene (1.8 g, 11.8 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.4 g, 4.5 mmol) in DMF (50 mL). After stirring for 10 minutes, 1-hydroxbenzotriazole (0.7 g, 5.4 mmol) and N—BOC-γ-aminobutyric acid (1.1 g, 5.4 mmol) were added. The reaction was initiated by addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.3 g, 6.8 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with EtOAc (50 mL) and H2O (40 mL) for 30 minutes. The mixture was filtered, and dried to give (3-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-propyl-carbamic acid t-butyl ester (1.6 g, 77%) as a white solid: mp 199-201° C.; 1H NMR (DMSO-d6) δ 1.37 (s, 9H, 3CH3), 1.58-1.66 (m, 2H, CH2), 1.99-2.16 (m, 3H), 2.36-2.49 (m, 1H), 2.58-2.64 (m, 1H), 2.86-2.94 (m, 3H), 4.31 (d, J=5.6 Hz, 2H, CH2), 4.38 (d, J=17.3 Hz, 1H), 4.46 (d, J=17.3 Hz, 1H), 5.10-5.18 (dd, J=5.0 and 13.1 Hz, 1H, CH), 6.81 (t, J=5.4 Hz, 1H, NH), 7.48-7.64 (m, 3H, Ar), 8.37 (t, J=5.7 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.56, 25.72, 28.23, 31.18, 32.63, 38.95, 46.15, 51.56, 77.04, 121.60, 128.27, 130.55, 131.61, 134.70, 140.06, 155.55, 168.04, 170.97, 171.90, 172.82; Anal. calcd. for C23H30N4O6: C, 60.25; H, 6.59; N, 12.22. Found: C, 60.12; H, 6.55; N, 12.15.

Workup

  1. stirringThe mixture was stirred at room temperature overnight
  2. concentrationThe mixture was concentrated
  3. stirringthe residue was stirred with EtOAc (50 mL) and H2O (40 mL) for 30 minutes
  4. filtrationThe mixture was filtered
  5. customdried

Sources & evidence

ORD record
ord-028d9c88c000478393c16547cc33c50f
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Linked notes

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