Water → 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methyl-benzamide

HRID 331565Notes

Reaction equation

HRID 331565 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[CH2:30]2.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[CH2:30]2)=[O:7]

Participants

6

Reactant 4

HCID 962WaterHCID 682631,1'-CarbonyldiimidazoleHCID 788403-Chloro-4-methylbenzoic AcidHCID 665895253-(5-(aminomethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 445380113-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methyl-benzamideYield 65.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 3-chloro-4-methylbenzoic acid (0.17 g, 1.0 mmol) and CDI (0.17 g, 1.1 mmol) was stirred in DMF (20 mL) at 40° C. under N2 for 4 hours. 3-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.31 g, 1.0 mmol) was added and stirring continued for 1 h at this temperature. Water (40 mL) was added and the resulting precipitate was filtered, washed with 4% aqueous HCl (40 mL) and dried in vacuo providing 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methyl-benzamide as a white solid (0.28 g, 65% yield); mp 229-231° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min. 240 nm, 40/60 CH3CN/0.1% H3PO4. 4.29 (97.85%); 1H NMR (DMSO-d6) δ 1.97-2.01 (m, 1H), 2.32-2.45 (m, 4H), 2.57-2.62 (m, 1H), 2.85-2.96 (m, 1H), 4.31 (d, 1H, J=17.4), 4.45 (d, 1H, J=17.4), 4.58 (d, 2H, J=6.0), 5.11 (dd, 1H, J=13.2, J=5.1), 7.47-7.49 (m, 2H), 7.54 (s, 1H), 7.70 (d, 1H, J=7.8), 7.79 (dd, 1H, J=7.8, J=1.5), 7.95 (d, 1H, J=1.5), 9.21 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 19.5, 22.5, 31.2, 42.8, 47.1, 51.6, 122.1, 122.9, 126.0, 127.1, 127.5, 130.4, 131.2, 133.3, 133.6, 138.9, 142.4, 143.7, 164.8, 167.9, 171.0, 172.9; LCMS: MH=426, 428; Anal. Calcd for C22H20ClN3O4+0.36 CH2Cl2: C, 58.84; H, 4.58; N, 9.21. Found: C, 58.49; H, 4.45; N, 8.91.

Workup

  1. filtrationthe resulting precipitate was filtered
  2. washwashed with 4% aqueous HCl (40 mL)
  3. customdried in vacuo

Sources & evidence

ORD record
ord-e7adf29adf4e47ffa39bf55d9c79cefb
Source dataset
uspto-grants-2014_11
Patent number
US08877780B2

Reaction notes

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