Water → (S)-N-(2-amino-1-(3-fluoro-5-iodophenyl)ethyl)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamide

HRID 596002Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 596002
[NH2:1][C:2]1[C:3]([C:14]2[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@@H:21]([C:26]3[CH:31]=[C:30]([I:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[CH2:22][N:23]=[N+]=[N-])=[O:19])=[C:16]([F:36])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:23][CH2:22][C@@H:21]([NH:20][C:18](=[O:19])[C:17]1[CH:34]=[CH:35][C:14]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:4]=2)=[CH:15][C:16]=1[F:36])[C:26]1[CH:31]=[C:30]([I:32])[CH:29]=[C:28]([F:33])[CH:27]=1

Komponenten

5

Edukt 3

HCID 962WaterHCID 11776TriphenylphosphineHCID 118045646(S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(2-azido-1-(3-fluoro-5-iodophenyl)ethyl)-2-fluorobenzamide

Produkt 1

HCID 118045684(S)-N-(2-amino-1-(3-fluoro-5-iodophenyl)ethyl)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamide

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

The crude (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(2-azido-1-(3-fluoro-5-iodophenyl)ethyl)-2-fluorobenzamide was dissolved in THF (5 mL), and triphenylphosphine (polymer bound, 3 mmol/g) (0.97 g, 3.70 mmol) was added dropwise. The mixture was heated at 70° C. for 3 h. LCMS indicated absence of starting material (at this stage, the phosphorylimine intermediate is likely present in solid phase). Water (4.5 mL) and THF (5 mL) were added, and the mixture was heated at 80° C. for 3 h and then filtered. The filter cake was washed with DCM and then filtrate was concentrated in vacuo. The residue was dissolved in DCM and washed with water and the organic layer dried over magnesium sulfate, filtered and concentrated in vacuo to afford the residue which was purified by flash chromatography (0-60% DCM/10% MeOH in EtOAc containing 0.5% NH4OH), and the product fractions were collected and concentrated. The residue was dissolved in acetonitrile and water, and lyophillized to obtain 101.2 mg of (S)—N-(2-amino-1-(3-fluoro-5-iodophenyl)ethyl)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamide as the desired product. LCMS (m/z): 580.1 (MH+), 0.70 min. 1H NMR (CD3OD) δ (ppm): 7.92 (s, 1H), 7.85-7.79 (m, 1H), 7.73 (dd, J=8.0, 1.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.50-7.43 (m, 1H), 7.23 (d, J=9.5 Hz, 1H), 5.12 (t, J=6.9 Hz, 1H), 4.07 (dd, J=11.2, 3.3 Hz, 2H), 3.60 (td, J=11.7, 2.0 Hz, 2H), 3.09-2.83 (m, 3H), 2.02-1.76 (m, 4H).

Aufarbeitung

  1. temperaturethe mixture was heated at 80° C. for 3 h
  2. filtrationfiltered
  3. washThe filter cake was washed with DCM
  4. concentrationfiltrate was concentrated in vacuo
  5. dissolutionThe residue was dissolved in DCM
  6. washwashed with water
  7. dry with materialthe organic layer dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto afford the residue which
  11. customwas purified by flash chromatography (0-60% DCM/10% MeOH in EtOAc containing 0.5% NH4OH)
  12. customthe product fractions were collected
  13. concentrationconcentrated
  14. dissolutionThe residue was dissolved in acetonitrile

Quellen und Nachweise

ORD-Eintrag
ord-5d9a40dbfc5445c8bc76035fc832038e
Quelldatensatz
uspto-grants-2016_01
Patentnummer
US09242996B2

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