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

HRID 625365

Reaktionsgleichung

Reaktionsgleichung von HRID 625365
[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:56])([O-])[O-:54].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:43])([F:42])[C:53]([OH:54])=[O:56].[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]

Komponenten

7

Edukt 4

HCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 7016129(3R)-(+)-3-AcetamidopyrrolidineHCID 86705954N-(3-(trifluoromethyl)benzyl)-2-(2-(2-(chloromethyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide

Produkt 1

HCID 86705957(R)-6-((3-Acetamidopyrrolidin-1-yl)methyl)-N-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)picolinamide 2,2,2-trifluoroacetateAusbeute 54,7 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

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), (R)—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 3×20 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 33.4 mg (27%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.90 (d, J=6 Hz, 1H), 8.40 (s, 1H), 8.26 (m, 1H), 8.21-8.09 (m, 2H), 7.98 (d, J=3 Hz, 1H), 7.82 (d, J=6 Hz, 1H), 7.71-7.50 (m, 6H), 4.65 (m, 4H), 4.20 (m, 1H), 3.85 (m, 1H), 3.66-3.63 (m, 4H), 2.50 (m, 1H), 2.00 (m, 4H), 1.80 (m, 3H), 1.68 (m, 3H). MS (ES, m/z): 700 [M+H]+.

Aufarbeitung

  1. customInto a 50-mL round-bottom flask, was placed
  2. washThe resulting mixture was washed with 3×20 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

Quellen und Nachweise

ORD-Eintrag
ord-5d465af115d14562876c73d36188b4b1
Quelldatensatz
uspto-grants-2016_04
Patentnummer
US09301951B2

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