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

HRID 63466Notes

Reaction equation

HRID 63466 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.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][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:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1

Participants

6

Reactant 4

HCID 962WaterHCID 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 6228DimethylformamideSolvent

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 N,N-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-9795cfd6a6d746c6a91d3a088f4d3696
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Reaction notes

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