1,1'-Carbonyldiimidazole → HCID 46198552, compound

HRID 588032Notes

Reaction equation

HRID 588032 reaction equation
CS(O)(=O)=[O:3].[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.C1N=CN([C:31]([N:33]2C=N[CH:35]=[CH:34]2)=[O:32])C=1.[Si](ONC1C=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)(C(C)(C)C)(C)C>CN(C=O)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:31]([NH:33][C:34]4[CH:35]=[CH:51][C:50]([CH3:53])=[C:49]([OH:3])[CH:48]=4)=[O:32])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonateHCID 86644111HCID 86644111, compound

Product 1

HCID 46198552HCID 46198552, compoundYield 46%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate (0.74 g, 2.0 mmol) and CDI (0.32 g, 2.0 mmol) in DMF (30 mL) was stirred at room temperature for 3 h, and then the product from Step 2 (0.47 g, 2.0 mmol) was added. The mixture was heated to 70° C. for 16 h. Then, the mixture was cooled to room temperature and quenched with 1N HCl (30 mL). The resulting mixture was evaporated under vacuum and the residue was purified by preparative HPLC using an acetonitrile-water gradient, and providing 0.38 g of 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(3-hydroxy-4-methylphenyl)urea as a white solid, in 46% yield; HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 4.80 min (100.00%); mp 273-275° C.: 1H NMR (DMSO-d6) δ 2.02 (s, 4H), 2.27-2.47 (m, 1H), 2.63 (m., 1H), 2.80-3.04 (m, 1H), 4.17-4.59 (m, 4H), 5.11 (dd, J=4.7, 13.0 Hz, 1H), 6.47-6.72 (m, 2H), 6.86 (d, J=7.9 Hz, 1H), 7.04 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.51 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 8.39 (s, 1H), 9.13 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 15.35, 22.49, 31.20, 42.74, 47.12, 51.58, 104.76, 108.45, 116.48, 121.86, 122.91, 126.91, 130.19, 130.26, 138.92, 142.36, 144.96, 155.18, 155.29, 167.95, 170.99, 172.85; LCMS MH=423; Anal. Calcd for C22H22N4O5: C, 62.55; H, 5.25; N, 13.26. Found: C, 62.27; H, 5.15; N, 13.18.

Workup

  1. temperatureThe mixture was heated to 70° C. for 16 h
  2. temperatureThen, the mixture was cooled to room temperature
  3. customquenched with 1N HCl (30 mL)
  4. customThe resulting mixture was evaporated under vacuum
  5. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-09cb40ff04844b80bc949ceaa4dce3a0
Source dataset
uspto-grants-2016_01
Patent number
US09227954B2

Reaction notes

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