Indole-3-acetamide → 3-[6-[tert-butylsilyloxy(diphenyl)methyl]-2-methylimidazo[1,2-a]pyrazin-3-yl]-4-(1H-indol-3-yl)pyrrole-2,5-dione

HRID 216660

Reaction equation

HRID 216660 reaction equation
CC(C)([O-])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([NH2:19])=[O:18])=[CH:8]1.C([O:22][C:23](=O)[C:24]([C:26]1[N:30]2[CH:31]=[C:32]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:36][SiH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=[CH:34][C:29]2=[N:28][C:27]=1[CH3:54])=O)C.[NH4+].[Cl-].C1CCN2C(=NCCC2)CC1>O1CCCC1.CCOC(C)=O.O>[C:38]([SiH2:37][O:36][C:35]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:32]1[N:33]=[CH:34][C:29]2[N:30]([C:26]([C:24]3[C:23](=[O:22])[NH:19][C:17](=[O:18])[C:16]=3[C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:7][CH:8]=3)=[C:27]([CH3:54])[N:28]=2)[CH:31]=1)([CH3:41])([CH3:39])[CH3:40]

Participants

9

Reactant 5

HCID 397Indole-3-acetamideHCID 25517Ammonium ChlorideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 23665647Potassium tert-butoxideHCID 131729752[6-(Tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyrazin-3-yl]-oxo-acetic acid ethyl ester

Product 1

HCID 1540901423-[6-[tert-butylsilyloxy(diphenyl)methyl]-2-methylimidazo[1,2-a]pyrazin-3-yl]-4-(1H-indol-3-yl)pyrrole-2,5-dioneYield 34%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Potassium tert-butoxide (1.0 M in THF, 0.86 ml, 0.86 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of 2-(1H-indol-3-yl)-acetamide (50 mg, 0.29 mmol, 1.0 equiv) and of [6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyrazin-3-yl]-oxo-acetic acid ethyl ester (158 mg, 0.32 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (1.0 ml, dried over molecular sieves). The reaction mixture is stirred for 15 minutes at room temperature. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (1.0 ml), treated with DBU (0.43 ml, 2.9 mmol, 10 equiv) and stirred under an atmosphere of argon for 5 minutes at 110° C. After cooling, the reaction mixture is diluted with water and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of hexane/EtOAc 100:0 to 50:50) afford the title compound (60 mg, 34%). 1H NMR (400 MHz, d6-DMSO): δ=12.05 (br s, 1H), 11.25 (br s, 1H), 8.85 (d, J=1.2 Hz, 1H), 8.04 (s, 1H), 7.76 (s, 1H), 7.51-7.45 (m, 4H), 7.41-7.30 (m, 6H); 6.95 (t, J=7.1 Hz, 1H), 6.47 (t, J=7.4Hz, 1H), 5.76 (d, J=8.0 Hz, 1H), 4.59-4.47 (m, 2H), 2.82 (s, 3H), 0.92 (s, 9H). MS (ES+): 612 (M+H)+.

Workup

  1. extractionAfter three extractions with EtOAc
  2. dry with materialthe combined organic layers are dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue is dissolved in N,N-dimethylformamide (1.0 ml)
  6. stirringstirred under an atmosphere of argon for 5 minutes at 110° C
  7. temperatureAfter cooling
  8. extractionextracted three times with EtOAc
  9. washThe combined organic layers are washed with brine
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customPurification of the residue via flash chromatography (gradient of hexane/EtOAc 100:0 to 50:50)

Sources & evidence

ORD record
ord-dd4687598be14d368ed70832dc3fb52b
Source dataset
uspto-grants-2012_06
Patent number
US08193236B2

Linked notes

Loading…