Dimethylformamide → n-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-6-ethoxy-nicotinamide

HRID 331604Notes

Reaction equation

HRID 331604 reaction equation
[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CN(C)C=O.CS(O)(=O)=O.[NH2:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([CH:47]1[CH2:52][CH2:51][C:50](=[O:53])[NH:49][C:48]1=[O:54])[C:40]2=[O:55]>O>[O:54]=[C:48]1[CH:47]([N:41]2[C:40](=[O:55])[C:39]3[C:43](=[CH:44][CH:45]=[C:37]([CH2:36][NH:35][C:8](=[O:10])[C:7]4[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=4)[CH:38]=3)[C:42]2=[O:46])[CH2:52][CH2:51][C:50](=[O:53])[NH:49]1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 682631,1'-CarbonyldiimidazoleHCID 64858176-Ethoxypyridine-3-carboxylic acidHCID 866307665-Aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate

Product 1

HCID 57730485n-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-6-ethoxy-nicotinamideYield 85%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
40 °C

Procedure

A stirred mixture of 6-ethoxy-nicotinic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in NAN-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solvent was removed in vacuo and the crude product was purified by column chromatography (EtOAc/hexanes). The product fractions were combined, concentrated and the residue was triturated in Et2O (20 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-6-ethoxy-nicotinamide as a white solid (1.11 g, 85% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.04 min (98.73%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=7.1 Hz, 3H, CH3), 1.96-2.16 (m, 1H, CHH), 2.41-2.69 (m, 2H, CHH, CHH), 2.79-3.00 (m, 1H, CHH), 4.37 (q, J=7.1 Hz, 2H, CH2), 4.65 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 6.88 (dd, J=0.7, 8.8 Hz, 1H, Ar), 7.77-7.94 (m, 3H, Ar), 8.16 (dd, J=2.6, 8.7 Hz, 1H, Ar), 8.71 (dd, J=0.8, 2.5 Hz, 1H, Ar), 9.21 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.41, 21.99, 30.93, 42.51, 49.01, 61.84, 110.27, 121.99, 123.04, 123.55, 129.82, 131.62, 133.44, 138.18, 147.13, 147.48, 164.79, 165.00, 166.97, 167.12, 169.80, 172.72; LCMS: MH=437; Anal Calcd for C22H20N4O6+0.1H2O: C, 60.30; H, 4.65; N, 12.78. Found: C, 60.08; H, 4.62; N, 12.77.

Workup

  1. temperaturethe mixture was heated at 40° C. for 1.5 h
  2. temperatureThe mixture was cooled to rt
  3. customThe solvent was removed in vacuo
  4. customthe crude product was purified by column chromatography (EtOAc/hexanes)
  5. concentrationconcentrated
  6. customthe residue was triturated in Et2O (20 mL) for 18 h
  7. customThe product was isolated by filtration
  8. customdried in vacuo

Sources & evidence

ORD record
ord-fa1285790ccb47fb99e82c2cf5bda51d
Source dataset
uspto-grants-2014_11
Patent number
US08877780B2

Reaction notes

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