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1-Hydroxybenzotriazole → 3-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide

HRID 9971
Notes
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Reaction equation

HRID 9971 reaction equation
N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[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].ON1C2C=CC=CC=2N=N1.[C:44]([NH:51][CH2:52][CH2:53][C:54](O)=[O:55])([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].Cl.CN(C)CCCN=C=NCC>CC#N>[C:47]([O:46][C:44]([NH:51][CH2:52][CH2:53][C:54]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[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])=[O:55])=[O:45])([CH3:50])([CH3:49])[CH3:48]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 76809N-((1,1-dimethylethoxy)carbonyl)-beta-alanineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 10276197
3-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide
Yield 67.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.62 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 1-hydroxybenzotriazole (0.3 g, 2.22 mmol), N-BOC-b-alanine (0.42 g, 2.22 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride 0.53 g, 2.78 mmol) were added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N citric acid (30 ml), H2O (2×30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 100:2) to give 3-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.57 g, 67%) as a white solid: mp 96–98° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.50 (t, J=5.8 Hz, 1H), 7.82–7.67 (m, 3H), 6.81 (t, J=5.1 Hz, 1H), 5.19–5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 3.21–3.13 (dd, J=6.8 and 13.1 Hz, 2H), 2.92–2.85 (m, 1H), 2.64–2.33 (m, 4H), 2.08–2.04 (m, 1H), 1.37 (s, 9H); 13C NMR (DMSO-d6) δ d 172.71, 170.87, 169.77, 167.46, 166.93, 155.45, 139.27, 134.67, 133.17, 131.47, 127.03, 121.80, 77.57, 48.84, 37.63, 36.69, 35.62, 30.91, 28.21, 21.96; Anal. Calcd. For C22H26N4O7+0.28 H2O: C, 57.01; H, 5.78; N, 12.09. Found: C, 56.99; H, 5.89; N, 11.79.

Workup

  1. stirringThe mixture was stirred at room temperature for 17 hours
  2. customThe solvent was removed in vacuo
  3. dissolutionthe residue was dissolved in CH2Cl2 (70 ml)
  4. washThe CH2Cl2 solution was washed with 1N citric acid (30 ml), H2O (2×30 ml), brine (30 ml)
  5. dry with materialdried (MgSO4)
  6. customThe solvent was removed in vacuo
  7. customthe residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 100:2)

Sources & evidence

ORD record
ord-9e53191210c54c80a7a976acd132a28e
Source dataset
uspto-grants-2006_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07091353B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes