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

HRID 929643Notes

Reaction equation

HRID 929643 reaction equation
[H-].[Na+].[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C@H:7]([CH3:18])[CH2:6][N:5]1[C@H:19]([C:27]1[CH:39]=[CH:38][C:30]([C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1.[CH3:40]I>CCCCC.O1CCCC1>[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C@H:7]([CH3:18])[CH2:6][N:5]1[C@H:19]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[CH:38][CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:40])[CH:21]=1

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 103008024-((alpha-r)-alpha-((2s,5r)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-n,n-diethylbenzamide2×

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 2

HCID 8003PentaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10 mmol)) was washed with pentane (2×7 mL), and tetrahydrofuran (10 mL) was added. The product from Example 11, 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and when effervescence had subsided, methyl iodide (249 δ L, 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 was 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 were 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. additionwas added
  2. customThe reaction mixture was sealed under nitrogen
  3. customThe reaction mixture was evaporated to dryness
  4. customthe residue was partitioned between ethyl acetate (15 mL) and water (5 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous portion extracted with ethyl acetate (2×10 mL)
  7. dry with materialthe combined organic extracts were dried over anhydrous sodium sulfate
  8. customThe organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane
  9. customyielded
  10. 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-71d6954c2d0743678ee9f8820cbb3fe3
Source dataset
uspto-grants-2016_03
Patent number
US09296707B2

Reaction notes

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