Ethyl Acetate → 5-methylsulfanyl-pyridine-2-carboxylic acid 4-ethanesulfonyl-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide

HRID 63449

Reaction equation

HRID 63449 reaction equation
[CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C1N=C[N:17](C(N2C=NC=C2)=O)C=1.Cl.[NH2:28][CH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([C:40]1([CH3:48])[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[C:33]2=[O:49].CCOC(C)=O>CN(C)C=O>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:28][CH2:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[C:35](=[O:39])[N:34]([C:40]2([CH3:48])[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]2=[O:47])[C:33]3=[O:49])=[O:12])=[CH:13][CH:14]=1)(=[O:4])=[O:5])[CH3:2].[CH3:1][S:3][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[N:17][CH:7]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 682631,1'-CarbonyldiimidazoleHCID 1793674-Ethylsulfonylbenzoic acidHCID 670232045-Aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)isoindole-1,3-dione hydrochloride

Product 1

HCID 670231705-methylsulfanyl-pyridine-2-carboxylic acid 4-ethanesulfonyl-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamideYield 46.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A stirred mixture of 4-ethylsulfonylbenzoic acid (0.43 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 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 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient). The product fractions were combined and concentrated to give 5-methylsulfanyl-pyridine-2-carboxylic acid 4-ethanesulfonyl-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.31 g, 32% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.40 min (98.51%); mp: 178-180° C.; 1H NMR (DMSO-d6) δ 1.10 (t, J=7.2, 7.4 Hz, 3H), 1.89 (s, 3H), 2.00-2.15 (m, 1H), 2.54-2.77 (m, 3H), 3.35 (q, J=7.4 Hz, 2H), 4.66 (d, J=5.9 Hz, 2H), 7.73-7.86 (m, 3H), 7.97-8.07 (m, 2H), 8.07-8.21 (m, 2H), 9.48 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 7.06, 21.00, 28.57, 29.09, 42.75, 49.04, 58.78, 121.70, 123.22, 128.02, 128.29, 129.71, 131.41, 133.47, 138.51, 140.85, 146.97, 165.21, 167.72, 167.85, 172.13, 172.19; LCMS: MH=498; Anal Calcd for C24H23N3O7S+0.15 CH2Cl2: C, 56.85; H, 4.60; N, 8.23. Found: C, 57.11; H, 4.87; N, 7.85.

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 (3×100 mL)
  4. concentrationthen concentrated in vacuo
  5. customThe crude residue was purified by column chromatography (EtOAc/hexanes, gradient)
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-ee62464b6a27498ba2d315265cbe9c10
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Linked notes

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