Indole-3-Acetic Acid → 3-{2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-1H-indole

HRID 1593121Notes

Reaction equation

HRID 1593121 reaction equation
[F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29](O)=O)=[CH:20]1.C(N(C(C)C)CC)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.O.CCOCC.C1COCC1.CCOC(C)=O.CCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:29][CH2:28][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:19][CH:20]=3)[CH2:10]2)=[CH:5][CH:4]=1

Participants

10

Reactant 4

HCID 802Indole-3-Acetic AcidHCID 81531DiisopropylethylamineHCID 21226445Aluminium lithium hydrideHCID 219019513-(4-Trifluoromethyl-phenoxymethyl)-piperidine

Product 1

HCID 219019863-{2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-1H-indoleYield 69.3%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
0 °C

Procedure

3-(4-Trifluoromethyl-phenoxymethyl)-piperidine (50 mg, 0.19 mmol), (1H-Indol-3-yl)-acetic acid (73 mg, 0.21 mmol), the amide coupling agent BrOP (123 mg, 0.32 mmol), and diisopropylethylamine (75 mg, 0.58 mmol) were dissolved in 2 mL of anhydrous dichloromethane. The mixture was kept at room temperature overnight, diluted with 10 mL of water, and 10 mL of ether. Extractive workup gave in each case, after concentration of the organic layers in vacuo and chromatography on silica gel using a EtOAc-hexane gradient column, the desired amide intermediate (71 mg, 90%). This amide was dissolved in 5 mL of THF at 0° C. and excess lithium aluminum hydride (50 mg, ca. 8 equivalents) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 0.5 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 53 mg of 3-{2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-1H-indole, 180, was obtained (77%). Data for this compound: MS 403 (M++1).

Workup

  1. customExtractive workup gave in each case
  2. temperatureThe solution was heated
  3. temperatureto reflux for 5 minutes
  4. customquenched by dropwise addition of 0.5 mL 1M NaOH
  5. additionAdditional THF (10 mL) was added
  6. filtrationfiltered though a plug of sodium sulfate
  7. customThe solution thus obtained
  8. concentrationwas concentrated in vacuo
  9. customthe residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide

Sources & evidence

ORD record
ord-39052186a5bc4d838c1c366d9dd0a98f
Source dataset
uspto-grants-2007_11
Patent number
US07294637B2

Reaction notes

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