Potassium Iodide → (S)-6-((3-Acetamidopyrrolidin-1-yl)methyl)-N-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)picolinamide

HRID 1408109Notes

Reaction equation

HRID 1408109 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(CCl)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[NH:44]1[CH2:48][CH2:47][C@H:46]([NH:49][C:50](=[O:52])[CH3:51])[CH2:45]1.[C:53](=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:50]([NH:49][C@H:46]1[CH2:47][CH2:48][N:44]([CH2:53][C:31]2[N:30]=[C:29]([C:28]([NH:27][C:16]3[CH:17]=[CH:18][C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:20][C:15]=3[C:11]3[CH:10]=[C:9]([C:8](=[O:38])[NH:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:4]=4)[CH:14]=[CH:13][N:12]=3)=[O:37])[CH:34]=[CH:33][CH:32]=2)[CH2:45]1)(=[O:52])[CH3:51]

Participants

7

Reactant 4

HCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 7021471(S)-(-)-3-AcetamidopyrrolidineHCID 86705954N-(3-(trifluoromethyl)benzyl)-2-(2-(2-(chloromethyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide

Product 1

HCID 66588137(S)-6-((3-Acetamidopyrrolidin-1-yl)methyl)-N-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)picolinamideYield 45.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(2-(chloromethyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (3 mL), (S)—N-(pyrrolidin-3-yl)acetamide (42 mg, 0.33 mmol, 2.00 equiv), potassium carbonate (45 mg, 0.33 mmol, 2.00 equiv), and potassium iodide (14 mg, 0.08 mmol, 0.50 equiv). The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate, and 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 47.8 mg (39%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.92 (d, J=6 Hz, 1H), 8.42 (s, 1H), 8.19 (m, 1H), 8.15 (m, 1H), 8.10 (m, 1H), 8.04 (m, 1H), 7.83 (d, J=6 Hz, 1H), 7.74 (m, 3H), 7.61 (m, 2H), 7.52 (m, 1H), 4.65 (m, 4H), 4.22 (m, 1H), 3.80 (m, 1H), 3.69-3.54 (m, 5H), 3.44 (m, 1H), 2.49 (m, 1H), 2.05-2.00 (m, 5H), 1.83-1.66 (m, 5H). MS (ES, m/z): 700 [M+H]+.

Workup

  1. customInto a 50-mL round-bottom flask, was placed
  2. washThe resulting mixture was washed with 2×20 mL of brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. concentrationconcentrated under vacuum
  5. customThe crude product (100 mg) was purified by reverse phase HPLC
  6. washeluting with a water/CH3CN gradient
  7. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-60c8212bd9024befa8a342aa58d087c0
Source dataset
uspto-grants-2014_12
Patent number
US08916569B2

Reaction notes

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