Sodium Iodide → 4-((alpha-r)-alpha-((2s,5r)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-n,n-diethylbenzamide

HRID 237897Notes

Reaction equation

HRID 237897 reaction equation
[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:36]=[CH:35][C:27]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:11]=1.[I-].[Na+].C(N(CC)CC)C.[F:46][C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49]Br>C(#N)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:49][C:48]2[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=2[F:46])[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:35][CH:36]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])[CH:11]=1

Participants

6

Reactant 4

HCID 5238Sodium IodideHCID 8471TriethylamineHCID 67968alpha-Bromo-o-fluorotolueneHCID 589265384-((alpha-R)-alpha-((2 S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,N-diethylbenzamide

Product 1

HCID 876966604-((alpha-r)-alpha-((2s,5r)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-n,n-diethylbenzamideYield 96%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,N-diethylbenzamide (from Example 1, Method A, 527.6 mg, 1.0 mmol) was dissolved in acetonitrile (4.0 mL) and sodium iodide (15 mg, 0.1 mmol) added. The suspension was stirred during the addition of triethylamine (500 μL (363 mg), 3.59 mmol), followed by 2-fluorobenzyl bromide (241 μL (378 mg), 2.0 mmol). The reaction mixture was sealed under nitrogen and stirred overnight at room temperature. The reaction mixture was evaporated to dryness and partitioned between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (2.5 mL). The supernatant organic layer was removed, and the aqueous portion washed with ethyl acetate (3×10 mL). The combined organic extract and washings were dried over anhydrous sodium sulfate and evaporated to a golden oil. The residue was dissolved in ethyl acetate (7 mL), applied to a pre-packed intermediate (4×15 cm, Biotage) column and eluted with ethyl acetate. Pure fractions containing desired product, as evidenced by t.l.c. (silica gel, EM60F264, 100% ethyl acetate, Rf=0.77) were evaporated to dryness to yield the intermediate 4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide (610 mg), as a yellow oil, which was used without further purification. The oil was dissolved in ethanol (7 mL) and aqueous 2.5 M (10%) sodium hydroxide solution (5 mL, 12.5 mmol) was added. The reaction mixture was set aside at room temperature for 5 h, then the ethanol removed by evaporation. The oily suspension of the sodium salt was clarified by the addition of water (5 mL), and the pH of the solution adjusted to 9-10 by the passage of gaseous carbon dioxide (from dry ice). The copious white precipitate was washed well with water and dried under vacuum (2 mm Hg) at room temperature overnight to yield the title compound as a white solid (431 mg, 85.6%). Calc. for C31H38FN3O2: C, 73.93; H, 7.61; N, 8.34; F, 3.77. Found C, 73.96; H, 7.67; N, 8.29; F, 3.75%. 1H NMR (CDCl3, 300 MHz); δ 1.05 (d, J=6.1 Hz, 3H); 1.09 (d, J=6 Hz, 3H); 1.12 (br m, 3H); 1.24 (br m, 3H); 1.96 (t, J=10 Hz, 1H); 2.07 (t, J=10 Hz, 1H); 2.56 (br m, 2H); 2.60 (d, J=11 Hz, 1H); 2.72 (d, J=11 Hz, 1H); 3.29 (br m, 2H); 3.36 (d, J=14 Hz, 1H); 3.55 (br m, 2H); 3.89 (d, J=14 Hz, 1H); 5.13 (s, 1H); 6.57 (s, 1H); 6.66 (d, J=10 Hz, 2H); 7.00 (t, J=9 Hz, 1H); 7.07 (t, J=7.5 Hz, 1H); 7.10 (t, J=8 Hz, 1H); 7.20 (m, 1H); 7.27 (d, J=8 Hz, 2H); 7.38 (t, J=7 Hz, 1H); 7.43 (d, J=7 Hz, 2H).

Workup

  1. customThe reaction mixture was sealed under nitrogen
  2. customThe reaction mixture was evaporated to dryness
  3. custompartitioned between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (2.5 mL)
  4. customThe supernatant organic layer was removed
  5. washthe aqueous portion washed with ethyl acetate (3×10 mL)
  6. extractionThe combined organic extract
  7. dry with materialwashings were dried over anhydrous sodium sulfate
  8. customevaporated to a golden oil
  9. dissolutionThe residue was dissolved in ethyl acetate (7 mL)
  10. washeluted with ethyl acetate
  11. additionPure fractions containing desired product
  12. custom(silica gel, EM60F264, 100% ethyl acetate, Rf=0.77) were evaporated to dryness

Sources & evidence

ORD record
ord-b8162c8dc66e427bbe394ef8c523307a
Source dataset
uspto-grants-2014_02
Patent number
US08642599B2

Reaction notes

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