2,5-Dimethyl-3-furoic acid → 2-(2,5-dimethyl-furan-3-yl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide

HRID 448489

Reaction equation

HRID 448489 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.ON1C2C=CC=CC=2N=N1.CC1[O:46][C:47]([CH3:53])=[CH:48][C:49]=1[C:50](O)=[O:51].Cl.CN(C)[CH2:57][CH2:58][CH2:59]N=C=NCC>C(#N)C>[CH3:53][C:47]1[O:46][C:58]([CH3:57])=[CH:59][C:48]=1[CH2:49][C:50]([NH: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])=[O:51]

Participants

7

Reactant 5

HCID 694652,5-Dimethyl-3-furoic acidHCID 757711-HydroxybenzotriazoleHCID 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 672289192-(2,5-dimethyl-furan-3-yl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamideYield 73%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2,5-dimethyl-3-furoic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford 2-(2,5-dimethyl-furan-3-yl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.65 g, 73%) as a white solid: mp 193-195° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.45 min. (99%); 1H NMR (DMSO-d6) δ 2.06-2.11 (m, 1H), 2.23 (s, 3H), 2.46 (s, 3H), 2.54-2.63 (m, 2H), 2.85-2.97 (m, 1H), 4.85 (d, J=5.9 Hz, 2H), 5.14-5.20 (dd, J=5.3 and 12.6 Hz, 1H), 6.49 (s, 1H), 7.67-7.86 (m, 3H), 8.54 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 12.98, 13.08, 21.96, 30.92, 37.53, 48.85, 104.86, 115.84, 121.77, 126.99, 131.48, 132.99, 134.76, 139.69, 149.11, 154.47, 163.32, 166.96, 167.54, 169.81, 172.74; Anal. Calcd. for C21H19N3O6: C, 61.61; H, 4.68; N, 10.26. Found: C, 61.66; H, 4.37; N, 9.99.

Workup

  1. stirringThe mixture was stirred at room temperature overnight
  2. concentrationwas concentrated in vacuo
  3. dissolutionThe residue was dissolved in CH2Cl2 (80 mL)
  4. washwashed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL)
  5. dry with materialdried over MgSO4
  6. customSolvent was removed in vacuo
  7. customthe residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7)

Sources & evidence

ORD record
ord-9c6eb2a8fb8f4166aa08a21742d2e165
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Linked notes

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