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 596002ノート

反応式

HRID 596002 の反応式
[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

参加物

5

反応物 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

生成物 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

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
70 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-5d9a40dbfc5445c8bc76035fc832038e
出典データセット
uspto-grants-2016_01
特許番号
US09242996B2

反応ノート

読み込み中…