Potassium Iodide → 2-(2-(3-((4-Acetamidopiperidin-1-yl)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide

HRID 625353Notes

Reaction equation

HRID 625353 reaction equation
[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[NH:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:51](=[O:53])[CH3:52])[CH2:46][CH2:45]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:51]([NH:50][CH:47]1[CH2:48][CH2:49][N:44]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:45][CH2:46]1)(=[O:53])[CH3:52]

Participants

7

Reactant 4

HCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 14451564-AcetamidopiperidineHCID 665867752-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide

Product 1

HCID 680876702-(2-(3-((4-Acetamidopiperidin-1-yl)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamideYield 75.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), N-(piperidin-4-yl)acetamide (52.5 mg, 0.37 mmol, 2.41 equiv), potassium iodide (12.7 mg, 0.08 mmol, 0.50 equiv), and potassium carbonate (42.4 mg, 0.31 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 80.4 mg (50%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.93-8.92 (d, J=5.2 Hz, 1H), 8.67-8.65 (d, J=8.8 Hz, 1H), 8.44 (s, 1H), 8.13-8.09 (m, 3H), 7.88-7.87 (m, 1H), 7.78-7.67 (m, 5H), 7.62-7.54 (m, 1H), 4.72 (s, 2H), 4.44 (s, 2H), 3.91 (s, 1H), 3.66-3.63 (t, J=5.2 Hz, 4H), 3.57-3.54 (m, 2H), 3.20-3.14 (m, 2H), 2.17-2.13 (m, 2H), 2.05-2.00 (m, 4H), 1.93 (s, 3H), 1.82-1.70 (m, 4H). MS (ES, m/z): 713 [M+H]+.

Workup

  1. customInto a 50-mL round-bottom flask, was placed
  2. extractionThe resulting solution was extracted with 3×20 mL of ethyl acetate
  3. washThe resulting mixture was washed with 3×20 mL of brine
  4. dry with materialThe mixture was dried over anhydrous sodium sulfate
  5. concentrationconcentrated under vacuum
  6. customThe crude product was purified by reverse phase HPLC
  7. washeluting with a water/CH3CN gradient
  8. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-029f86159ca8423fac565e837c32908b
Source dataset
uspto-grants-2016_04
Patent number
US09301951B2

Reaction notes

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