Ethyl Acetate → 5-Ethanesulfonyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-amide

HRID 331583Notes

Reaction equation

HRID 331583 reaction equation
[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[C:37]2=[O:52].CCOC(C)=O>CN(C)C=O>[O:51]=[C:45]1[CH:44]([N:38]2[C:37](=[O:52])[C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:11][N:10]=4)=[O:14])[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 682631,1'-CarbonyldiimidazoleHCID 67019684HCID 67019684, compoundHCID 866307665-Aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate

Product 1

HCID 577304755-Ethanesulfonyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-amideYield 32.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A stirred mixture of 5-ethanesulfonyl-pyridine-2-carboxylic acid (0.34 g, 1.60 mmol) and CDI (0.27 g, 1.70 mmol) in N,N-dimethylformamide (15 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.61 g, 1.60 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 80-90% EtOAc). The product fractions were combined and concentrated to give 5-ethanesulfonyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.25 g, 32% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.15 min (96.20%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.15 (t, J=7.4 Hz, 3H), 2.00-2.20 (m, 1H), 2.52-2.67 (m, 2H), 2.77-3.01 (m, 1H), 3.48 (q, J=7.4 Hz, 2H), 4.69 (d, J=6.2 Hz, 2H), 5.14 (dd, J=5.4, 12.7 Hz, 1H), 7.73-8.04 (m, 3H), 8.29 (d, J=8.3 Hz, 1H), 8.49 (dd, J=2.3, 8.1 Hz, 1H), 9.10 (d, J=1.7 Hz, 1H), 9.86 (t, J=6.3 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 6.83, 21.99, 30.93, 42.58, 49.01, 49.34, 122.17, 122.68, 123.54, 129.87, 131.59, 133.63, 137.04, 138.13, 147.09, 147.60, 153.38, 163.02, 166.97, 167.12, 169.80, 172.72; LCMS: MH=485; Anal Calcd for C22H20N4O7S: C, 54.54; H, 4.16; N, 11.56. Found: C, 54.82; H, 3.92; N, 11.57.

Workup

  1. temperaturethe mixture was heated at 40° C. for 2 h
  2. temperatureThe mixture was cooled to rt
  3. washThe organic layer was washed with sat. aq. NaHCO3 (3×75 mL)
  4. concentrationthen concentrated in vacuo
  5. customThe crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 80-90% EtOAc)
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-dc2f77bd9d324ec5ac29b4ca1f2ea8b6
Source dataset
uspto-grants-2014_11
Patent number
US08877780B2

Reaction notes

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