Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → (S)-(-)-2-(6-chloro-7-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide

HRID 603157ノート

反応式

HRID 603157 の反応式
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][CH:20]=1)[CH3:18].[CH3:30]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([NH:16][C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:28])[CH3:29])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:13])[C:6]=2[C:14]=1[F:15]

参加物

7

反応物 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 582984592-[4-(1-Aminoethyl)phenyl]-2-methylpropanenitrileHCID 58298473(6-chloro-7-fluoro-1H-benzimidazol-1-yl)acetic acid

生成物 1

HCID 66649558(S)-(-)-2-(6-chloro-7-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide収率 159.6%

試薬・触媒・溶媒 3

HCID 142844-(Dimethylamino)pyridine触媒HCID 887Methanol溶媒HCID 6228Dimethylformamide溶媒

実験手順

To a solution of (6-chloro-7-fluoro-1H-benzimidazol-1-yl)acetic acid (100 mg, 0.44 mmol) prepared according to scheme 13, (S) (−)-2-{4-[1-aminoethyl]phenyl}-2-methylpropanenitrile (88.5 mg 0.44 mmol) prepared according to scheme 20 or 21 and DMAP (106 mg, 0.88 mmol) stirred in anhydrous DMF (2.0 mL) is added HATU (166 mg, 0.44 mmol) after 18 hours of stirring, the mixture is diluted with methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4 u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (S)-(−)-2-(6-chloro-7-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (290 mg, 53%) as a clear solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.50 (d, J=7.03 Hz, 3H) 1.69 (s, 6H) 5.03 (q, J=7.01 Hz, 1H) 5.07-5.18 (m, 2H) 7.29 (dd, J=9.37, 6.64 Hz, 3H) 7.39 (d, J=8.59 Hz, 2H) 7.44 (d, J=9.37 Hz, 1H) 7.48 (d, J=8.59 Hz, 2H) 8.14 (s, 1H)MS [M+H], calcd: 399.1, found: 399.2, [α]D=−138° (C=0.5 METHANOL)

後処理

  1. customprepared
  2. customis purified directly on a preparative LCMS system
  3. customequipped with a Synergi Polar (4 u) 21.2×50 mm column, mobile phase
  4. customa short 40 to 60% B 10 min. gradient method
  5. extractionextracted with ethyl acetate which
  6. customis separated
  7. dry with materialdried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure

出典と根拠

ORDレコード
ord-7bc225ff0c344f44a9ce0d74956416b9
出典データセット
uspto-grants-2011_03
特許番号
US07906654B2

反応ノート

読み込み中…