Potassium Iodide → Tert-butyl 4-(2-(methyl(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)amino)ethyl)piperazine-1-carboxylate

HRID 1408085Notes

Reaction equation

HRID 1408085 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]Cl)[CH:30]=2)[CH:10]=1.[CH3:44][NH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.CC(C)=O>[CH3:44][N:45]([CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:28](=[O:37])[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]([C:8](=[O:38])[NH:7][CH2:6][C:5]3[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH:30]=1)[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1

Participants

7

Reactant 4

HCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 23081391tert-Butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylateHCID 665867362-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)-isonicotinamide

Product 1

HCID 66586814Tert-butyl 4-(2-(methyl(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)amino)ethyl)piperazine-1-carboxylateYield 54.6%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 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-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-isonicotinamide (100 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (2.5 mL), acetone (2.5 mL), tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (48 mg, 0.20 mmol, 1.20 equiv), potassium carbonate (68 mg, 0.49 mmol, 3.00 equiv), and potassium iodide (6 mg, 0.04 mmol, 0.20 equiv). The resulting solution was stirred for 2.5 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 75.5 mg (49%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.28 (s, 1H), 9.58-9.54 (m, 1H), 8.94-8.92 (d, J=5.1 Hz, 1H), 8.33-8.27 (m, 2H), 8.04 (s, 1H), 7.96-7.93 (d, J=7.8 Hz, 1H), 7.85-7.84 (d, J=4.2 Hz, 1H), 7.71-7.55 (m, 7H), 7.31-7.28 (d, J=8.1 Hz, 1H), 4.64-4.62 (d, J=5.7 Hz, 2H), 4.29 (s, 2H), 3.44-3.31 (m, 8H), 3.20 (s, 2H), 3.06 (s, 2H), 3.27-3.26 (m, 6H), 1.73 (s, 4H), 1.60 (s, 2H), 1.39 (s, 9H). MS (ES, m/z): 814 [M+H]+.

Workup

  1. customInto a 50-mL round-bottom flask, was placed
  2. concentrationThe resulting mixture was concentrated under vacuum
  3. customThe crude product (100 mg) was purified by reverse phase HPLC
  4. washeluting with a water/CH3CN gradient
  5. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-397378fc1ea94b399079cc7bb2fe9a7f
Source dataset
uspto-grants-2014_12
Patent number
US08916569B2

Reaction notes

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