Tetrahydrofuran → 1-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-2-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yloxy]-ethanone

HRID 511074Notes

Reaction equation

HRID 511074 reaction equation
[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.O1CCCC1.Cl.[N+:37]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[CH:42][C:41]=1[C:53]([F:56])([F:55])[F:54])([O-:39])=[O:38]>CN(C)C=O.ClCCl>[N+:37]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][CH:47]2[CH2:48][CH2:49][N:50]([C:17](=[O:19])[CH2:16][O:15][CH:12]3[CH2:13][CH2:14][N:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:1])[F:20])=[CH:4][CH:5]=4)[CH2:10][CH2:11]3)[CH2:51][CH2:52]2)=[CH:42][C:41]=1[C:53]([F:56])([F:54])[F:55])([O-:39])=[O:38]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 58576204[(4-Trifluoromethyl-phenyl)-piperidin-4-yloxy]-acetic acidHCID 66671805(4-Nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride

Product 1

HCID 469465621-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-2-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yloxy]-ethanoneYield 59%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent

Procedure

[1-(4-Trifluoromethyl-phenyl)-piperidin-4-yloxy]-acetic acid (186 mg; 0.61 mmol, prepared according to Example 11), diisopropylethyl amine (220 μL; 1.22 mmol) and tetramethyl-β-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (232 mg; 0.61 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (18 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (200 mg; 0.61 mmol, prepared in accordance with Example 8) in dimethylformamide (6 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (50 mL), the organic layer is sequentially washed with water (15 mL), aq. sat. sodium hydrogen carbonate (15 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The desired product (209 mg; 0.36 mmol) is isolated in pure form following purification by column chromatography on silica gel (dichloromethane:methanol from 100:0 to 95:5). The structure was confirmed using Protocol II-E. Calculated mass=575; observed mass=576; HPLC retention time=11.52 min.

Workup

  1. stirringthe reaction is then stirred for 3 hours at room temperature
  2. washthe organic layer is sequentially washed with water (15 mL), aq. sat. sodium hydrogen carbonate (15 mL)
  3. dry with materialis dried over magnesium sulfate
  4. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-fe5bd65da3ca45218ee7b0c976867dc5
Source dataset
uspto-grants-2015_08
Patent number
US09096524B2

Reaction notes

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