Methyl iodide → 4-((alpha-r)-alpha-((2s,5r)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-n,n-diethylbenzamide

HRID 1795901Notes

Reaction equation

HRID 1795901 reaction equation
[H-].[Na+].O1CCC[CH2:4]1.[CH3:8][C@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C@H:12]([CH3:23])[CH2:11][N:10]1[C@H:24]([C:32]1[CH:44]=[CH:43][C:35]([C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1.CI>CCCCC>[CH3:8][C@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C@H:12]([CH3:23])[CH2:11][N:10]1[C@H:24]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37])=[CH:43][CH:44]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:4])[CH:26]=1

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 8028TetrahydrofuranHCID 24758Sodium hydrideHCID 103008024-((alpha-r)-alpha-((2s,5r)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-n,n-diethylbenzamide

Product 1

HCID 101862094-((alpha-r)-alpha-((2s,5r)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-n,n-diethylbenzamide

Reagents, catalysts & solvents 1

HCID 8003PentaneSolvent

Procedure

Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10 mmol)) was washed with pentane (2×7 mL), then tetrahydrofuran (10 mL) added as supernatant. 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (Example 1, 1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and when effervescence had subsided, methyl iodide (249 μL, 568 mg, 4 mmol) was added. The reaction mixture was sealed under nitrogen and stirred for 6 h at ambient temperature. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, the aqueous portion extracted with ethyl acetate (2×10 mL) and the combined organic extracts dried over anhydrous sodium sulfate. The organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane yielded 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid (0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc. for C32H40FN3O2 0.25 H2O: C, 73.60; H, 7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84%. 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J=6.2 Hz, 6H, superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H); 6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26 (m, 5H); 7.46 (d, J=7.8 Hz, 2H).

Workup

  1. customThe reaction mixture was sealed under nitrogen
  2. customThe reaction mixture was evaporated to dryness
  3. customthe residue partitioned between ethyl acetate (15 mL) and water (5 mL)
  4. customThe organic layer was separated
  5. extractionthe aqueous portion extracted with ethyl acetate (2×10 mL)
  6. dry with materialthe combined organic extracts dried over anhydrous sodium sulfate
  7. customThe organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane
  8. customyielded
  9. dry with material4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid (0.798 g, 77% after drying at room temperature and 5 mm Hg)

Sources & evidence

ORD record
ord-701f69c90f734423bd591f66cc9c2b92
Source dataset
uspto-grants-2006_04
Patent number
US07030124B2

Reaction notes

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