Water → Pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-amide

HRID 63424Notes

Reaction equation

HRID 63424 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])[CH2:7]2.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Cl)=[O:30].C(N(CC)CC)C.O>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)=[O:30])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

6

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 135033Picolinoyl Chloride HydrochlorideHCID 665895253-(5-(aminomethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 44539607Pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-amideYield 51.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.60 mmol) and picolinoyl chloride hydrochloride (0.29 g, 1.60 mmol) in N,N-dimethylformamide (20 mL), was added triethylamine (0.67 mL, 4.80 mmol) at room temperature under nitrogen. After 18 h, water (100 mL) was added and the product was extracted with CH2Cl2 (3×150 mL). The organic layers were combined, washed with water (3×150 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration, washed with Et2O (25 mL) and dried in vacuo to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.31 g, 51% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 5.52 min (97.80%); mp: 229-231° C.; 1H NMR (DMSO-d6) δ 1.86-2.11 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.59 (d, J=17.0 Hz, 1H, CHH), 2.79-3.06 (m, 1H, CHH), 4.30 (d, J=17.4 Hz, 1H, CHH), 4.44 (d, J=17.4 Hz, 1H, CHH), 4.61 (d, J=6.4 Hz, 2H, CH2), 5.10 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.48 (d, J=7.7 Hz, 1H, Ar), 7.54 (s, 1H, Ar), 7.58-7.65 (m, 1H, Ar), 7.68 (d, J=7.9 Hz, 1H, Ar), 7.89-8.19 (m, 2H, Ar), 8.67 (d, J=4.5 Hz, 1H, Ar), 9.49 (t, J=6.3 Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.51, 47.11, 51.58, 122.02, 122.18, 122.93, 126.62, 127.20, 130.36, 137.81, 142.35, 143.82, 148.47, 149.89, 164.07, 167.92, 170.98, 172.85; LCMS: MH=379; Anal Calcd for C20H18N4O4+0.1H2O: C, 63.18; H, 4.83; N, 14.74. Found: C, 62.80; H, 4.86; N, 14.69.

Workup

  1. extractionthe product was extracted with CH2Cl2 (3×150 mL)
  2. washwashed with water (3×150 mL)
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customThe resulting residue was triturated in Et2O (50 mL) for 18 h
  6. customThe product was isolated by filtration
  7. washwashed with Et2O (25 mL)
  8. customdried in vacuo

Sources & evidence

ORD record
ord-b765031a183149d28385016d3af891ce
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Reaction notes

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