1,8-Diazabicyclo(5.4.0)undec-7-ene → 4-Difluoromethoxy-n-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-4-ylmethyl]-benzamide

HRID 448470

反応式

HRID 448470 の反応式
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.[F:34][CH:35]([F:46])[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([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:42])=[CH:44][CH:45]=1

参加物

6

反応物 4

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 7373604-(Difluoromethoxy)benzoic 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

生成物 1

HCID 588273464-Difluoromethoxy-n-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-4-ylmethyl]-benzamide収率 64%

試薬・触媒・溶媒 1

HCID 6342Acetonitrile溶媒

実験手順

To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 4-difluoromethoxy benzoic acid (0.45 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL) and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford 4-difluoromethoxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a yellow solid (0.63 g, 64%): 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=4.2 min. (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.50-2.65 (m, 2H), 2.85-2.92 (m, 1H), 4.95 (d, J=5.8 Hz, 2H), 5.16-5.21 (dd, J=5, 12 Hz, 1H), 7.28-7.30 (m, 2H), 7.36 (t, J=73.5 Hz, 1H), 7.72-7.86 (m, 3H), 7.98-8.02 (m, 2H), 9.18 (t, J=5.8 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.34, 48.86, 112.61, 116.03, 117.97, 119.45, 121.87, 127.13, 129.45, 130.55, 131.52, 133.05, 134.79, 139.22, 153.30, 165.60, 166.95, 167.52, 169.81, 172.74. Anal Calcd for C22H17F2N3O6: C, 57.77; H, 3.75; N, 9.19; F, 8.31. Found: C, 57.67; H, 3.59; N, 9.01; F, 8.22.

後処理

  1. stirringAfter stirring at room temperature overnight
  2. concentrationthe reaction mixture was concentrated in vacuo
  3. dissolutionthe residue was dissolved in CH2Cl2 (50 mL)
  4. washThe CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL)
  5. dry with materialdried over MgSO4
  6. customSolvent was removed in vacuo
  7. customthe resulting oil was purified by ISCO silica gel flash chromatography (eluent
  8. wait0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min

出典と根拠

ORDレコード
ord-0e6340a12bdd496bba14761e98d2641b
出典データセット
uspto-grants-2013_07
特許番号
US08481568B2

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