Potassium Carbonate → 2-(2-(3-((4-Methyl-1,4-diazepan-1-yl)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide

HRID 625352Notes

Reaction equation

HRID 625352 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.[CH3:44][N:45]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:44][N:45]1[CH2:51][CH2:50][CH2:49][N:48]([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])[CH2:47][CH2:46]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 2283491-MethylhomopiperazineHCID 665867752-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide

Product 1

HCID 665882222-(2-(3-((4-Methyl-1,4-diazepan-1-yl)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamideYield 38.9%

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), 1-methyl-1,4-diazepane (65.4 mg, 0.57 mmol, 3.74 equiv), KI (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, 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 40 mg (23%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.95-8.93 (d, J=4.2 Hz, 1H), 8.75-8.73 (d, J=6.6 Hz, 1H), 8.46 (s, 1H), 8.18-8.17 (d, J=4.2 Hz, 1H), 8.09 (s, 1H), 8.02-8.00 (d, J=8 Hz, 1H), 7.90-7.88 (m, 1H), 7.75-7.55 (m, 1H), 4.72 (s, 2H), 4.19 (s, 2H), 3.70-3.67 (t, J=5.6 Hz, 4H), 3.55-3.49 (m, 4H), 3.18-3.16 (t, J=5.6 Hz, 2H), 2.95 (s, 3H), 2.22-2.18 (m, 2H), 2.07-2.05 (t, J=5.2 Hz, 4H), 1.84-1.83 (d, J=5.2 Hz, 1H). MS (ES, m/z): 685 [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 materialdried 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-6d3b698448954835ac255f87e2b28f26
Source dataset
uspto-grants-2016_04
Patent number
US09301951B2

Reaction notes

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