Ammonium Chloride → 3-(6-Dimethylaminomethyl-imidazo[1,2-a]pyridin-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione

HRID 216669Notes

Reaction equation

HRID 216669 reaction equation
CC(C)([O-])C.[K+].CO[C:9](=[O:21])[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O.[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:35][C:36]([NH2:38])=[O:37])=[CH:33][N:34]=2)[CH:31]=1)[CH3:24].[NH4+].[Cl-].C1CCN2C(=NCCC2)CC1>O1CCCC1.CCOC(C)=O.O>[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:35]3[C:36](=[O:37])[NH:38][C:9](=[O:21])[C:10]=3[C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)=[CH:33][N:34]=2)[CH:31]=1)[CH3:24]

Participants

9

Reactant 5

HCID 25517Ammonium ChlorideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 588944Methyl 3-indoleglyoxylateHCID 23665647Potassium tert-butoxideHCID 591920412-(6-Dimethylaminomethyl-imidazo[1,2-a]pyridin-3-yl)-acetamide

Product 1

HCID 249682363-(6-Dimethylaminomethyl-imidazo[1,2-a]pyridin-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dioneYield 44.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Potassium tert-butoxide (1.0 M in THF, 0.55 ml, 0.55 mmol, 2.7 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-indol-3-yl)-oxo-acetic acid methyl ester (45 mg, 0.22 mmol, 1.1 equiv) and of 2-(6-dimethylaminomethyl-imidazo[1,2-a]pyridin-3-yl)-acetamide (50 mg, 0.20 mmol) in anhydrous tetrahydrofuran (5.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at 0° C. 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 (5 ml), treated with DBU (0.27 ml, 1.8 mmol, 8.9 equiv) and heated to 110° C. for 10 minutes. After cooling, the reaction mixture is diluted with water and extracted three times with CH2Cl2. The combined organic layers are ished with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via preparative HPLC affords the title compound (34 mg, 43%) as its trifluoroacetate salt. 1H NMR (400 MHz, d6-DMSO): δ=12.11 (s, 1H), 11.27 (s, 1H), 9.47 (br s, 1H), 8.21 (d, J=2.9 Hz, 1H), 8.05 (s, 1H), 7.78-7.76 (m, 2H), 7.73 (d, J=8.0 Hz, 1H), 7.29 (dd, J=8.0/4.0 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.49 (t, J=8.0 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 3.48-3.40 (m, 2H), 2.16 (s, 6H). MS (ES+): 386 (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 (5 ml)
  6. temperatureheated to 110° C. for 10 minutes
  7. temperatureAfter cooling
  8. extractionextracted three times with CH2Cl2
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customPurification of the residue via preparative HPLC

Sources & evidence

ORD record
ord-236082662cdf4e70a2c94287ffa5eb2d
Source dataset
uspto-grants-2012_06
Patent number
US08193236B2

Reaction notes

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