Triethylamine → isoxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide

HRID 448502Notes

Reaction equation

HRID 448502 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].C(N(CC)CC)C.[O:30]1[C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=[N:31]1>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:35]([C:34]3[O:30][N:31]=[CH:32][CH:33]=3)=[O:36])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 2736707Isoxazole-5-carbonyl chlorideHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 58827287isoxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amideYield 50.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (2.7 g, 8.4 mmol) in CH3CN (25 ml), were added triethyl amine (2.9 mL, 8.4 mmol) and isoxazole-5-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL). The solid was dissolved in CH2Cl2 (5 mL) and purified by ISCO silica gel flash chromatography (eluent: 2% MeOH in CH2Cl2) to afford isoxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a light yellow solid (0.87 g, 27%): mp, 257-259° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.62 (99%); 1H NMR (DMSO-d6): δ 2.04-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.93 (d, J=5.6 Hz, 2H), 5.17 (dd, J=6, 12 Hz, 1H), 7.14-8.78 (m, 5H), 9.60 (t, J=5.6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 37.96, 48.87, 106.26, 122.11, 127.25, 131.56, 133.14, 134.89, 138.00, 151.75, 155.95, 162.35, 166.90, 167.44, 169.80, 172.73. Anal Calcd for C18H14N4O6: C, 56.55; H, 3.69; N, 14.65. Found: C, 56.20; H, 3.36; N, 14.47.

Workup

  1. customa suspension was obtained
  2. filtrationThe reaction mixture was filtered
  3. washthe solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL)
  4. dissolutionThe solid was dissolved in CH2Cl2 (5 mL)
  5. custompurified by ISCO silica gel flash chromatography (eluent: 2% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-2665ce8fb3fa48bfa3074a418610ec86
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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