Ethyl Bromide → 2-(2-(2-(2-((4-(1-Ethylpiperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide

HRID 1473176Notes

Reaction equation

HRID 1473176 reaction equation
[CH:1](N(CC)C(C)C)(C)[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31]4[C:36]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:35][CH:34]=[CH:33][N:32]=4)[C:26]([C:41]([F:44])([F:43])[F:42])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:11]1.BrCC>CN(C=O)C>[CH2:1]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31]4[C:36]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:35][CH:34]=[CH:33][N:32]=4)[C:26]([C:41]([F:42])([F:44])[F:43])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:11]1)[CH3:2]

Participants

5

Reactant 3

HCID 6332Ethyl Bromide2×HCID 81531DiisopropylethylamineHCID 601649122-(2-(2-(2-((4-(Piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide

Product 1

HCID 712090182-(2-(2-(2-((4-(1-Ethylpiperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamideYield 36%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

N,N-Diisopropylethylamine (18.0 μL, 0.103 mmol) was added to a solution of 2-(2-(2-(2-((4-(Piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (39) (17 mg, 0.034 mmol) in DMF (5 mL). The mixture was stirred for 5 min then bromoethane (4.0 μL, 0.051 mmol) was added and stirring was continued for 24 h at room temperature. A further portion of bromoethane (4.0 μL, 0.051 mmol) was added and the reaction mixture was stirred for an additional 16 hours at room temperature. The volatiles were evaporated in vacuo and the residue partitioned between ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over Na2SO4. Filtration then removal of the solvent under reduced pressure afforded a beige solid which was purified by mass-directed preparative HPLC to afford the title compound (40) (6.2 mg, 36%) as a white solid; 1H NMR (400 MHz, d4-MeOH) δ 8.54 (s, 1H), 8.38 (dd, J=4.8, 1.5 Hz, 1H), 7.69-7.66 (m, 3H), 7.28-7.19 (m, 3H), 3.68 (s, 2H), 3.59-3.46 (m, 2H), 3.38-3.22 (m, partially obscured by d4-MeOH), 3.19-3.08 (m, 2H), 3.04-2.80 (m, 3H), 2.12-1.99 (m, 2H), 1.99-1.70 (m, 2H), 1.34 (t, J=7.3 Hz, 3H). LCMS Method C: rt=4.20 min, m/z=513.2 [M+H]+, 511.2 [M−H]−.

Workup

  1. stirringstirring
  2. waitwas continued for 24 h at room temperature
  3. stirringthe reaction mixture was stirred for an additional 16 hours at room temperature
  4. customThe volatiles were evaporated in vacuo
  5. customthe residue partitioned between ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL)
  6. customThe layers were separated
  7. extractionthe aqueous layer extracted with ethyl acetate (2×10 mL)
  8. washThe combined organic layers were washed with water (10 mL), brine (10 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationFiltration
  11. customremoval of the solvent under reduced pressure
  12. customafforded a beige solid which
  13. customwas purified by mass-directed preparative HPLC

Sources & evidence

ORD record
ord-ec9c01ae73224850ae96e2f53d7fb2bc
Source dataset
uspto-grants-2015_04
Patent number
US09012461B2

Reaction notes

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