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

HRID 63443Notes

Reaction equation

HRID 63443 reaction equation
[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=[O:19])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])[CH2:35]2.CCOC(C)=O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:19])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[CH:6]=[CH:5][C:4]([S:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 682631,1'-CarbonyldiimidazoleHCID 670196615-(Ethylthio)picolinic acidHCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate

Product 1

HCID 247883745-ethylsulfanyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amideYield 60%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A stirred mixture of 5-ethylsulfanyl-pyridine-2-carboxylic acid (0.48 g, 2.60 mmol) and CDI (0.44 g, 2.70 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (1.0 g, 2.60 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 (hexanes EtOAc, gradient, product eluted at ˜85% EtOAc). The product fractions were combined and concentrated to give 5-ethylsulfanyl-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 (0.65 g, 60% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 7.53 min (97.70%); mp: 198-200° C.; 1H NMR (DMSO-d6) δ 1.28 (t, J=7.4 Hz, 3H), 2.00-2.16 (m, 1H), 2.53-2.67 (m, 2H), 2.79-3.02 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 4.65 (d, J=6.4 Hz, 2H), 5.14 (dd, J=5.4, 12.9 Hz, 1H), 7.72-8.06 (m, 5H), 8.54 (d, J=1.5 Hz, 1H), 9.53 (t, J=6.3 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 13.84, 21.99, 25.27, 30.93, 42.36, 48.99, 122.08, 122.18, 123.51, 129.78, 131.56, 133.56, 135.42, 137.99, 146.30, 146.37, 147.54, 164.07, 166.99, 167.13, 169.80, 172.72; LCMS: MH=453; Anal Calcd for C22H20N4O5S: C, 58.40; H, 4.46; N, 12.38. Found: C, 58.27; H, 4.35; N, 12.30.

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 (hexanes EtOAc, gradient, product eluted at ˜85% EtOAc)
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-5d75873461414d6cadd47b45ba2be059
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Reaction notes

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