1,8-Diazabicyclo(5.4.0)undec-7-ene → benzo[c]isoxazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide

HRID 448504Notes

Reaction equation

HRID 448504 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[N:34]1[O:35][C:36]([C:43](O)=[O:44])=[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43]([C:36]3[O:35][N:34]=[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=34)=[O:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

6

Reactant 4

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 258162Anthroxanic acidHCID 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 58827282benzo[c]isoxazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amideYield 78.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.8 g, 5.7 mmol) in DMF (20 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 g, 6.8 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.9 g, 6.8 mmol) and benzo[c]isoxazole-3-carboxylic acid (1.0 g, 6.3 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.5 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford benzo[c]isoxazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a yellow solid (1.93 g, 78%): mp, 253-255° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=6.6 min (96%); 1H NMR (DMSO-d6): δ 2.08-2.13 (m, 1H), 2.53-2.65 (m, 2H), 2.86-2.94 (m, 1H), 5.02 (d, J=6.0 Hz, 2H), 5.19 (dd, J=6, 12 Hz, 1H), 7.27-7.97 (m, 5H), 9.90 (t, J=6 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 21.98, 30.93, 40.33, 48.89, 115.15, 118.27, 120.74, 122.07, 127.24, 131.54, 131.96, 133.20, 134.88, 138.13, 156.43, 156.52, 156.97, 160.91, 166.93, 167.49, 169.82, 172.75. Anal Calcd for C22H16N4O6+0.2H2O: C, 60.61; H, 3.79; N, 12.85. Found: C, 60.38; H, 3.50; N, 12.80.

Workup

  1. stirringThe mixture was stirred at room temperature overnight
  2. concentrationwas concentrated in vacuo
  3. dissolutionThe residue was dissolved in CH2Cl2 (50 mL)
  4. washwashed with water (2×30 mL) and brine (30 mL)
  5. dry with materialdried over MgSO4
  6. customSolvent was removed in vacuo
  7. customthe resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-1b23ee030e4643a1b2236d324f4a8158
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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