1,8-Diazabicyclo(5.4.0)undec-7-ene → 3-Difluoromethoxy-n-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-4-ylmethyl]-benzamide

HRID 448471Notes

Reaction equation

HRID 448471 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][CH:35]([F:46])[O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41].Cl.CN(C)CCCN=C=NCC>CC#N>[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([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:41]

Participants

6

Reactant 4

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 8426143-(Difluoromethoxy)benzoic 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 588273503-Difluoromethoxy-n-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-4-ylmethyl]-benzamideYield 65%

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 (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-difluoromethoxy benzoic acid (0.45 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was then 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: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford 3-difluoromethoxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a white solid (0.64 g, 65%): mp, 164-166° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.6 min (99%); 1H NMR (DMSO-d6): δ 2.04-2.09 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.93 (m, 1H), 4.92 (d, J=6.0 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 6.97-7.86 (m, 8H), 8.97 (t, J=6.0 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.91, 38.29, 48.86, 113.18, 116.60, 119.08, 120.02, 121.91, 125.34, 127.12, 128.74, 129.58, 131.48, 131.54, 113.18, 116.60, 119.08, 120.02, 121.91, 125.34, 127.12, 127.74, 128.58, 131.48, 131.54, 132.96, 134.64, 138.89, 147.66, 165.60, 166.94, 167.51, 169.81, 172.73. Anal Calcd for C22H17F2N3O6: C, 57.77; H, 3.75; N, 9.19; F, 8.31. Found: C, 57.62; H, 3.60; N, 8.99; F, 8.32.

Workup

  1. stirringAfter stirring at room temperature overnight
  2. concentrationthe reaction mixture was concentrated in vacuo
  3. dissolutionthe residue was dissolved in CH2Cl2 (50 mL)
  4. washThe CH2Cl2 solution was then washed 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
  8. wait0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min

Sources & evidence

ORD record
ord-3d3acde325844d70b962e80c605972b1
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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