Water → n-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-4-fluoro-benzamide

HRID 63430Notes

Reaction equation

HRID 63430 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.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.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:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=4)[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 678794-Fluorobenzoyl chlorideHCID 665895253-(5-(aminomethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 44538013n-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-4-fluoro-benzamideYield 53.7%

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 4-fluorobenzoyl chloride (0.19 mL, 1.60 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.45 mL, 3.20 mmol) at room temperature under nitrogen. After 18 h, water (200 mL) was added and the solids were isolated by filtration. The crude product was triturated in 1 N aq. HCl (50 mL) for 2 h then in EtOAc (50 mL) for 18 h. The product was isolated by filtration, washed with EtOAc (25 mL) and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-fluoro-benzamide as a white solid (0.34 g, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.06 min (94.63%); mp: 295-297° C.; 1H NMR (DMSO-d6) δ 1.85-2.12 (m, 1H, CHH), 2.22-2.47 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.79-3.03 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.45 (d, J=17.4 Hz, 1H, CHH), 4.59 (d, J=5.7 Hz, 2H, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.32 (t, J=8.9 Hz, 2H, Ar), 7.47 (d, J=7.7 Hz, 1H, Ar), 7.54 (s, 1H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 7.99 (dd, J=5.6, 8.8 Hz, 2H, Ar), 9.18 (t, J=5.9 Hz, 1H, NH), 10.98 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.78, 47.13, 51.59, 115.26 (d, J=22.0 Hz), 122.08, 122.94, 127.08, 129.93 (d, J=8.8 Hz), 130.39, 130.64 (d, J=2.2 Hz), 142.39, 143.85, 163.93 (d, J=248.7 Hz), 165.22, 167.92, 170.98, 172.85; LCMS: MH=396; Anal Calcd for C21H18N3O4+0.1H2O: C, 63.50; H, 4.62; N, 10.58. Found: C, 63.19; H, 4.54; N, 10.55.

Workup

  1. customthe solids were isolated by filtration
  2. customThe crude product was triturated in 1 N aq. HCl (50 mL) for 2 h
  3. waitin EtOAc (50 mL) for 18 h
  4. customThe product was isolated by filtration
  5. washwashed with EtOAc (25 mL)
  6. customdried in vacuo

Sources & evidence

ORD record
ord-2a69c5066ae64da08792aed3d551808a
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Reaction notes

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