Citric Acid → [3-(2-tert-Butyl-pyrimidin-4-yl)-6-chloro-1H-indol-5-yl]-[4-(4-fluorobenzyl)-piperidin-1-yl]-methanone

HRID 1891020Notes

Reaction equation

HRID 1891020 reaction equation
[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH:13]=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(C1[C:28]2[C:23](=[CH:24][C:25]([Cl:32])=[C:26](C(O)=O)[CH:27]=2)[NH:22][CH:21]=1)(=O)C.[C:33]([N:40]1[CH:44]=[CH:43]N=C1)([N:35]1[CH:39]=[CH:38]N=C1)=O.Cl.FC1C=[CH:58][C:50]([CH2:51]C2CCNCC2)=[CH:49]C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(N(CC)CC)C>[C:50]([C:33]1[N:35]=[C:39]([C:38]2[C:28]3[C:23](=[CH:24][C:25]([Cl:32])=[C:26]([C:13]([N:10]4[CH2:11][CH2:12][CH:7]([CH2:6][C:5]5[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=5)[CH2:8][CH2:9]4)=[O:14])[CH:27]=3)[NH:22][CH:21]=2)[CH:43]=[CH:44][N:40]=1)([CH3:58])([CH3:51])[CH3:49]

Participants

8

Reactant 5

HCID 311Citric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 170394924-[(4-Fluorophenyl)methyl]piperidine hydrochlorideHCID 677727683-acetyl-6-chloro-1H-indole-5-carboxylic acidHCID 86666103[4-(4-Fluorobenzyl)piperidin-1-yl]methanone

Product 1

HCID 57325406[3-(2-tert-Butyl-pyrimidin-4-yl)-6-chloro-1H-indol-5-yl]-[4-(4-fluorobenzyl)-piperidin-1-yl]-methanone

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Procedure

Preparation of 3-acetyl-6-chloro-1H-indol-5-yl)[4-(4-fluorobenzyl)piperidin-1-yl]methanone. A mixture of 3-acetyl-6-chloro-1H-indole-5-carboxylic acid (0,098 g, 0.41 mmol) and carbonyldiimidazole (0.101 g, 0.62 mmol) in dimethylformamide (1.0 mL) was stirred at room temperature for 1.5 h under nitrogen. The reaction mixture was cooled in ice bath, added 4-(4-fluorobenzyl)piperidine hydrochloride (0.1 g, 0.45 mmol), and triethylamine (0.5 g). The resulting mixture was stirred at room temperature for 3 h under nitrogen, added 5% citric acid and extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with water, dried (MgSO4) and concentrated to dryness. The residue was purified by silica gel flash chromatography using 25% ethyl acetate in heptane to afford the title compound as a glassy substance (0.08 g, 47%), m/z 413 (M+H).

Workup

  1. temperatureThe reaction mixture was cooled in ice bath
  2. stirringThe resulting mixture was stirred at room temperature for 3 h under nitrogen
  3. extractionextracted with ethyl acetate (2×10 mL)
  4. washThe combined organic extracts were washed with water
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated to dryness
  7. customThe residue was purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-6268938d990645748d760bbccc2e6afa
Source dataset
uspto-grants-2013_08
Patent number
US08507499B2

Reaction notes

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