1-Hydroxybenzotriazole → 2-(3,5-difluoro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide

HRID 448476Notes

Reaction equation

HRID 448476 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]1[CH:46]=[C:47]([CH2:52][C:53](O)=[O:54])[CH:48]=[C:49]([F:51])[CH:50]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[F:44][C:45]1[CH:46]=[C:47]([CH2:52][C:53]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:54])[CH:48]=[C:49]([F:51])[CH:50]=1

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 1454243,5-Difluorophenylacetic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 588272922-(3,5-difluoro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamideYield 56%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-difluorophenylacetic acid (0.4 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was filtered, and the solid was reslurried in hot acetone (15 mL) to afford 2-(3,5-difluoro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.5 g, 56%) as a white solid: mp, 238-240° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.63 min. (97%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.60 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.89-7.14 (m, 3H), 7.65-7.84 (m, 3H), 8.70 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.91, 41.41, 48.83, 101.62 (101.95, 102.30), 112.18 (112.28, 112.41, 112.51), 121.95, 127.16, 131.52, 133.29, 134.68, 138.91, 140.24 (140.37, 140.50), 160.39 (160.57, 163.64, 163.82), 166.88, 167.41, 169.53, 169.77, 172.72; Anal. Calcd. for C22H17N3O5F2: C, 59.87; H, 3.88; N, 9.52; F, 8.61. Found: C, 59.66; H, 3.83; N, 9.77; F, 8.47.

Workup

  1. stirringThe mixture was stirred at room temperature overnight
  2. filtrationThe resulting suspension was filtered

Sources & evidence

ORD record
ord-29b41ea4cd284220be50121cc234d748
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

Loading…