Sodium hydride → 1-[4-[(5-Chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one

HRID 1772228Notes

Reaction equation

HRID 1772228 reaction equation
[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH:35]2[CH2:39][C:38]3[CH:40]=[C:41]([Cl:44])[CH:42]=[CH:43][C:37]=3[O:36]2)[CH2:30][CH2:29]1)=[O:27]>O1CCCC1.CN(C)C=O>[Cl:44][C:41]1[CH:42]=[CH:43][C:37]2[O:36][CH:35]([CH2:34][N:31]3[CH2:30][CH2:29][N:28]([C:26](=[O:27])[CH2:25][O:17][CH:14]4[CH2:15][CH2:16][CH:11]([NH:10][C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:6]=5)[CH2:12][CH2:13]4)[CH2:33][CH2:32]3)[CH2:39][C:38]=2[CH:40]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 433862244-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexanolHCID 867194772-Chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one

Product 1

HCID 867194781-[4-[(5-Chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneYield 38.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexan-1-ol (40 mg, 0.13 mmol) in tetrahydrofuran (1 ml) and N,N-dimethylformamide (0.3 ml) was added sodium hydride (26 mg, 1.08 mmol, 8 eq) with stirring for 30 minutes at 0° C. Then 2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one (90 mg, 0.27 mmol, 2 eq) in tetrahydrofuran (0.5 ml) was added with stirring for 5 hours at room temperature. The reaction mixture was quenched by water (20 ml) and extracted with ethyl acetate (3×30 ml). The organic layers were combined and dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by Pre-TLC using 50% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (29.8 mg, 38%); (ES, m/z): [M+H]+ 597.35; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=7.2 Hz, 1H), 7.04-7.12 (m, 2H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.71 (m, 2H), 5.01 (broad s, 1H), 4.46 (d, J=7.8 Hz, 1H), 4.19 (s, 2H), 3.60-3.73 (m, 3H), 3.40-3.47 (m, 2H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.92-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (m, 1H), 2.62-2.77 (m, 4H), 2.12-2.16 (m, 4H), 1.41-1.52 (m, 3H), 1.22-1.30 (m, 3H).

Workup

  1. stirringwith stirring for 5 hours at room temperature
  2. customThe reaction mixture was quenched by water (20 ml)
  3. extractionextracted with ethyl acetate (3×30 ml)
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe crude material was purified by Pre-TLC
  8. washto elute
  9. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-ff2f7072a79b4dc684aa5cfa90b626b2
Source dataset
uspto-grants-2016_02
Patent number
US09249102B2

Reaction notes

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