3,4-Dichlorobenzoic acid → 3,4-Dichloro-N-[2-(2,6-dioxopiperidin-3-YL)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]benzamide

HRID 448438Notes

Reaction equation

HRID 448438 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[O:45])[N:30]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:31]2=[O:36].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[O:45])[N:30]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:31]2=[O:36])=[O:7]

Participants

6

Reactant 4

HCID 58173,4-Dichlorobenzoic acidHCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 588273453,4-Dichloro-N-[2-(2,6-dioxopiperidin-3-YL)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]benzamideYield 70%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

3,4-Dichlorobenzoic acid (0.30 g, 1.6 mmol) was dissolved in 10 mL DMF and CDI (0.30 g, 1.9 mmol) was added. The mixture was stirred at 40° C. for 1 hour, and then 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol) and triethylamine (0.31 g, 3.1 mmol) were added. After an additional 90 minutes stirring at 40° C., the mixture was cooled. The solvent was evaporated, and the residue was dissolved in 60 mL CH2Cl2, and this solution was washed with water (2×60 mL), dried (MgSO4), and evaporated. The residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.49 g of the product with 98:2 methylene chloride-methanol, in 70% yield: mp 161-163° C.; 1H NMR (DMSO-d6) δ 2.06-2.09 (m, 1H), 2.51-2.58 (m, 2H), 2.84-2.91 (m, 1H), 4.94 (d, J=5.7 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.3 Hz, 1H), 7.74-7.95 (m, 5H), 8.17 (d, J=1.9 Hz, 1H), 9.33 (t, J=5.7 Hz, 1H), 11.10 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.5, 48.9, 122.0, 127.2, 127.7, 129.3, 130.8, 131.3, 131.6, 133.3, 134.3, 134.9, 138.8, 164.4, 167.0, 167.5, 169.8, 172.8; Anal. calcd for C21H15Cl2N3O5: C, 54.80; H, 3.28; N, 9.13. Found: C, 54.85; H, 3.36; N, 8.95.

Workup

  1. stirringAfter an additional 90 minutes stirring at 40° C.
  2. temperaturethe mixture was cooled
  3. customThe solvent was evaporated
  4. dissolutionthe residue was dissolved in 60 mL CH2Cl2
  5. washthis solution was washed with water (2×60 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe residue was chromatographed
  9. washeluting 0.49 g of the product with 98:2 methylene chloride-methanol

Sources & evidence

ORD record
ord-5ae75192400849a883175836d6dacef4
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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