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

HRID 1160369ノート

反応式

HRID 1160369 の反応式
[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

参加物

10

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 5

HCID 962Water溶媒HCID 3283Diethyl Ether溶媒HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒HCID 21226206Ethyl acetate hexane溶媒

反応条件

温度
0 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-a25efb17669f469e9fa85aca460f8da2
出典データセット
uspto-grants-2010_10
特許番号
US07816375B2

反応ノート

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