1,8-Diazabicyclo(5.4.0)undec-7-ene → HCID 58827305, compound

HRID 448482Notes

Reaction equation

HRID 448482 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.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43](O)=[O:44])[CH:38]=[CH:39][C:40]=1[CH3:41].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:43](=[O:44])[CH2:42][C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([F:34])[CH:36]=3)[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 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27746183-Fluoro-4-methylphenylacetic acidHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 58827305HCID 58827305, compoundYield 72.7%

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-hydroxybenzotraiazole (0.4 g, 2.6 mmol) and 3-fluoro-4-methylphenylacetic 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 then 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 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamide (0.7 g, 70%) as a white solid: mp 148-150° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.06 min. (98%); 1H NMR (DMSO-d6) δ 2.04-2.07 (m, 1H), 2.20 (s, 3H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.52 (s, 2H), 4.70 (d, J=5.7 Hz, 2H), 5.12-5.18 (dd, J=5.1 and 12.7 Hz, 1H), 6.99-7.07 (dd, J=11.2 and 14.7 hz, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.63-7.76 (dd, J=3.3 and 7.5 Hz, 1H), 7.77-7.83 (dd, J=7.6 and 11.9 Hz, 2H), 8.65 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 13.74 (13.78), 21.95, 30.90, 37.84, 41.41, 48.83, 115.31, 115.60, 121.89, 124.84 (124.87), 127.12, 131.02 (131.28), 131.51, 133.20, 134.66, 135.87 (135.97), 139.09, 158.77 (161.98), 166.90, 167.42, 169.78, 170.26, 172.73; Anal. Calcd. for C23H20N3O5F: C, 63.15; H, 4.61; N, 9.61; F, 4.34. Found: C, 62.78; H, 4.45; N, 9.32; F, 4.47.

Workup

  1. stirringThe mixture was stirred at room temperature overnight
  2. concentrationthen was 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-9e6261bca2e6473b8cb8e8807356822d
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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