Diisopropylethylamine → (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide

HRID 19135

反応式

HRID 19135 の反応式
[F:1][C:2]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.Cl.[OH:25][C@@H:26]([CH2:56]O)[CH2:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:68]=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[OH:25][C:26]([CH3:56])([CH3:68])[CH2:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:29]1

参加物

6

反応物 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 66894967HCID 66894967、化合物HCID 66899094HMS5552 HCl

生成物 1

HCID 44252755(S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide収率 67.9%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

反応条件

温度
0 °C

実験手順

To a solution of (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.100 g, 0.31 mmol) in dichloromethane (3 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.100 g, 0.64 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.137 g, 0.31 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.04 g, 0.31 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was extracted with ethyl acetate and washed with a citric acid solution. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by reverse phase HPLC (C18, 20% to 100% acetonitrile/water) which afforded (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.097 g, 57%) as an off-white solid: HR-ES-MS m/z calculated for C23H29FN4O5 [M+H]+ 461.2195, observed 461.2194, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.05 (s, 3H), 1.07 (s, 3H), 1.37-1.51 (m, 1H), 1.57 (ddd, J=13.6, 9.1, 4.8 Hz, 1H), 1.68-1.84 (m, 1H), 3.90 (s, 2H), 4.20 (d, J=18.5 Hz, 1H), 4.59 (d, J=18.5 Hz, 1H), 4.67 (s, 1H), 4.85-4.92 (m, 1H), 4.88 (s, 1H), 6.45 (d, J=1.9 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H), 6.91 (t, J=7.9 Hz, 1H), 6.98-7.10 (m, 1H), 7.54 (d, J=1.9 Hz, 1H), 10.36 (br. s., 1H), 10.79 (s, 1H).

後処理

  1. stirringThe mixture was stirred at room temperature for 4 h
  2. customthe solvents were evaporated
  3. extractionThe residue was extracted with ethyl acetate
  4. washwashed with a citric acid solution
  5. washThe organic layer was washed with brine
  6. dry with materialdried over sodium sulfate
  7. customThe solvents were evaporated
  8. customthe residue was purified by reverse phase HPLC (C18, 20% to 100% acetonitrile/water) which

出典と根拠

ORDレコード
ord-0f6c8e1835264a3d93eb35bc68eba742
出典データセット
uspto-grants-2010_06
特許番号
US07741327B2

関連ノート

読み込み中…