Triethylamine → 1-[4-(5-Fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

HRID 1772241Notes

Reaction equation

HRID 1772241 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[O:11])[CH2:7][C:6]=2[CH:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:63][CH2:62][CH:61]([O:64][CH2:65][C:66](O)=[O:67])[CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:69]([F:72])([F:71])[F:70])([O-:50])=[O:49]>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:66](=[O:67])[CH2:65][O:64][CH:61]4[CH2:62][CH2:63][CH:58]([NH:57][C:54]5[CH:55]=[CH:56][C:51]([N+:48]([O-:50])=[O:49])=[C:52]([C:69]([F:71])([F:70])[F:72])[CH:53]=5)[CH2:59][CH2:60]4)[CH2:16][CH2:17]3)=[O:11])[CH2:7][C:6]=2[CH:18]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 672837722-(4-(4-Nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acidHCID 90149847(5-Fluoro-2,3-dihydro-benzofuran-2-yl)-piperazin-1-yl-methanone

Product 1

HCID 901499311-[4-(5-Fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanoneYield 44%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

In a 50 ml round-bottomed flask containing a solution of (5-fluoro-2,3-dihydro-benzofuran-2-yl)-piperazin-1-yl-methanone (76 mg, 0.30 mmol, 1.1 eq) in 30 ml of dichloromethane was added EDAC.HCl (76 mg, 0.40 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (56 mg, 0.55 mmol, 2.0 eq), and [4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid (100 mg, 0.28 mmol). The solution was stirred overnight at room temperature before diluting with 30 ml of water. The crude product was then extracted from the mixture using 3×30 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using ethyl acetate/dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 72 mg of the desired amide as a yellow solid (44%); 1H NMR (300 MHz, CDCl3): δ 8.04 (d, J=6.6 Hz, 1H), 6.95 (d, J=5.4, 1H), 6.83 (m, 2H), 6.66 (m, 2H), 5.43 (m, 1H), 4.25 (s, 1H), 3.75-3.95 (m, 4H), 3.27-3.80 (m, 8H), 2.12-2.22 (m, 4H), 1.50 (dd, J=7.8 Hz, 16.8 Hz, 2H), 1.31 (dd, J=7.8 Hz, 16.8 Hz, 2H).

Workup

  1. extractionThe crude product was then extracted from the mixture
  2. dry with materialdried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated under vacuum
  5. customThe crude residue was purified by silica gel chromatography
  6. washto elute
  7. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-c623144ca8034d41811b687c4d703089
Source dataset
uspto-grants-2016_02
Patent number
US09249102B2

Reaction notes

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