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

4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,N-diethylbenzamide (Example 10, 527.6 mg, 1.0 mmol) was dissolved in acetonitrile (4.0 mL) with sodium iodide (30 mg, 0.2 mmol). The suspension was stirred during the addition of triethylamine (800 μL, 580.8 mg, 5.74 mmol), followed by 4-fluorobenzyl bromide (249 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 the residue dissolved in ethyl acetate (10 mL). The organic solution was washed with saturated aqueous sodium bicarbonate solution (2×5 mL) and saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate and evaporated to a golden oil (a single spot on silica gel, EM60F264, 2% NH4OH in ethyl acetate, Rf=0.86). This intermediate 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide (608.9 mg) was used without further purification. The oil was dissolved in ethanol (8 mL) and aqueous 2.5 M (10%) sodium hydroxide solution (5 mL, 12.5 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 h and the ethanol was removed by evaporation. The oily suspension of the sodium salt was clarified by the addition of water (7.5 mL), and the pH of the solution was adjusted to 8.5-9 by the passage of gaseous carbon dioxide (from dry ice). The copious white precipitate was collected by filtration, washed well with water, and dried under vacuum (2 mm Hg) at room temperature overnight to yield 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide as a white solid (423.6 mg, 84%). Calc. for C31H38FN3O2 C, 73.93; H, 7.61; N, 8.34. Found C, 73.91; H, 7.65; N, 8.21% 1H NMR (CDCl3, 600 MHz); δ 1.05 (d, J=6.3 Hz, 3H); 1.07 (d, J=6.3 Hz, 3H); 1.11 (br m, 3H); 1.25 (br m, 3H); 1.97 (m, 2H); 2.53 (br m, 1H); 2.57 (br m, 1H); 2.61 (dd, J=9, 2.6 Hz, 1H); 2.65 (dd, J=9, 2.4 Hz, 1H); 3.14 (d, J=13 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.87 (d, J=13 Hz, 1H); 5.13 (s, 1H); 6.62 (s, 1H); 6.70 (m, 2H); 6.96 (t, J=8.5 Hz, 2H); 7.13 (t, J=7.8 Hz, 1H); 7.24 (m, 2H); 7.28 (d, J=8.2 Hz, 2H); 7.43 (d, J=8.1 Hz, 2H).

1. customThe reaction mixture was sealed under nitrogen
2. customThe reaction mixture was evaporated to dryness
3. dissolutionthe residue dissolved in ethyl acetate (10 mL)
4. washThe organic solution was washed with saturated aqueous sodium bicarbonate solution (2×5 mL) and saturated sodium chloride solution (5 mL)
5. dry with materialdried over anhydrous sodium sulfate
6. customevaporated to a golden oil (a single spot on silica gel, EM60F264, 2% NH4OH in ethyl acetate, Rf=0.86)
7. customThis intermediate 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide (608.9 mg) was used without further purification
8. dissolutionThe oil was dissolved in ethanol (8 mL)
9. stirringThe reaction mixture was stirred at room temperature for 3.5 h
10. customthe ethanol was removed by evaporation
11. additionThe oily suspension of the sodium salt
12. additionwas clarified by the addition of water (7.5 mL)
13. filtrationThe copious white precipitate was collected by filtration
14. washwashed well with water
15. customdried under vacuum (2 mm Hg) at room temperature overnight

ORD record

ord-411e7eec33bc4540a257bb9db8bc6b32

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296707B2