3,3-Dimethylbutanoyl chloride → N-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-3,3-dimethylbutanamide

HRID 331592Notes

Reaction equation

HRID 331592 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]([CH2:27][C:28](Cl)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[CH2:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

5

Reactant 3

HCID 815143,3-Dimethylbutanoyl chlorideHCID 81531DiisopropylethylamineHCID 670197065-(Aminomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride

Product 1

HCID 57730474N-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-3,3-dimethylbutanamideYield 34%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and t-butylacetyl chloride (0.40 g, 3.00 mmol) in CH2Cl2 (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 18 h, solution was washed with dil. aq. HCl (2×50 mL), water (2×50 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2). The product fractions were combined, concentrated and triturated in EtOAc for 18 h. The product was dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3,3-dimethyl-butyramide as a white solid (0.39 g, 34% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.13 min (95.97%); mp: 232-234° C.; 1H NMR (DMSO-d6) δ 0.97 (s, 9H, CH3, CH3, CH3), 1.97-2.17 (m, 3H, CHH, CH2), 2.53-2.69 (m, 2H, CHH, CHH), 2.77-3.01 (m, 1H, CHH), 4.43 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.71-7.83 (m, 2H, Ar), 7.89 (d, J=7.6 Hz, 1H, Ar), 8.46 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 29.68, 30.52, 30.93, 41.87, 48.66, 48.99, 121.91, 123.45, 129.69, 131.57, 133.41, 147.87, 166.97, 167.10, 169.83, 171.11, 172.73; LCMS: MH=386; Anal Calcd for C20H23N3O5: C, 62.33; H, 6.02; N, 10.90. Found: C, 61.96; H, 5.95; N, 10.75.

Workup

  1. washsolution was washed with dil. aq. HCl (2×50 mL), water (2×50 mL)
  2. dry with materialdried (MgSO4)
  3. concentrationconcentrated
  4. customThe crude product was purified by column chromatography (0-5% MeOH/CH2Cl2)
  5. concentrationconcentrated
  6. customtriturated in EtOAc for 18 h
  7. customThe product was dried in vacuo

Sources & evidence

ORD record
ord-366253be566d449e965fd3fb3002ee02
Source dataset
uspto-grants-2014_11
Patent number
US08877780B2

Reaction notes

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