Diisopropylethylamine → N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-fluoro-3-trifluoromethyl-benzamide

HRID 448498Notes

Reaction equation

HRID 448498 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].[F:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[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:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:34])([F:35])[F:36])[C:24]=3[F:23])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 27375592-Fluoro-3-(trifluoromethyl)benzoyl chlorideHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 67228871N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-fluoro-3-trifluoromethyl-benzamideYield 76.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

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) and 2-fluoro-3-trifluoromethyl-benzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). The mixture was stirred at room temperature overnight then quenched with methanol (1 mL). The resulting suspension was filtered and the solid was washed with methylene chloride to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-fluoro-3-trifluoromethyl-benzamide (0.8 g, 72%) as a white solid: mp 155-157° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.23 min. (99%); 1H NMR (DMSO-d6) δ 2.04-2.11 (s, 1H), 2.53-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5.3 and 12.6 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.79-8.01 (m, 5H), 9.26 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.96, 30.91, 38.46, 48.87, 117.03 (117.29, 117.45), 120.65 (124.26), 122.03, 125.09 (125.15), 125.45 (125.64), 127.22, 129.24 (129.29), 131.58, 132.97, 134.89, 138.41, 154.37 (157.77), 162.90, 166.91, 167.45, 169.80, 172.73; Anal. Calcd. for C22H15N3O5F4: C, 55.35; H, 3.17; N, 8.80; F, 15.92. Found: C, 55.13; H, 2.95; N, 8.73; F, 15.69.

Workup

  1. customthen quenched with methanol (1 mL)
  2. filtrationThe resulting suspension was filtered
  3. washthe solid was washed with methylene chloride

Sources & evidence

ORD record
ord-1fd61717655443e8b042a6f2573a2b21
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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