1-Hydroxybenzotriazole → Benzo[b]thiophene-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-4-ylmethyl]-amide

HRID 448499Notes

Reaction equation

HRID 448499 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.[S:44]1[C:48]2[CH:49]=[CH:50][C:51]([C:53](O)=[O:54])=[CH:52][C:47]=2[CH:46]=[CH:45]1.Cl.CN(C)CCCN=C=NCC>C(#N)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:53]([C:51]3[CH:50]=[CH:49][C:48]4[S:44][CH:45]=[CH:46][C:47]=4[CH:52]=3)=[O:54])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27954441-Benzothiophene-5-carboxylic acidHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 58827283Benzo[b]thiophene-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-4-ylmethyl]-amideYield 53%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a stirred suspension of 4-aminomethyl-2-(2,6-dioxopiperidin-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 1-benzothiophene-5-carboxylic acid (0.4 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), washed with water (3×40 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 benzo[b]thiophene-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.5 g, 53%) as a white solid: mp 261-263° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.22 min. (99%); 1H NMR (DMSO-d6) δ 2.07-2.11 (m, 1H), 2.55-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.99 (d, J=5.6 Hz, 2H), 5.16-5.22 (dd, J=5.0 and 12.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 7.79-7.92 (m, 5H), 8.11 (d, J=8.4 Hz, 1H), 8.48 (s, 1H), 9.24 (t, J=5.5 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.99, 30.93, 38.44, 48.88, 121.85, 122.50, 122.91, 122.95, 124.39, 127.14, 128.84, 130.39, 131.54, 133.07, 134.79, 139.18, 139.38, 141.92, 166.79, 166.97, 167.55, 169.83, 172.74; Anal. Calcd. for C23H17N3O5S+0.2H2O: C, 61.24; H, 3.89; N, 9.32; S, 7.11. Found: C, 61.04; H, 3.57; N, 8.96; S, 7.19.

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 (3×40 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-c1d77e7ce4074f03b90796e32110ed01
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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