Diisopropylethylamine → (S)-2-[4-(3-ethoxy-2,6-difluoro-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 19420ノート

反応式

HRID 19420 の反応式
Cl.[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:53][C:52]([O:54][C:55]4[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=4[F:65])=[CH:51][C:50]3=[O:66])CC(C)C)=N2)CO1>C(#N)C>[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([N:17]2[CH2:53][C:52]([O:54][C:55]3[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=3[F:65])=[CH:51][C:50]2=[O:66])[CH2:13][CH:14]([CH3:15])[CH3:16])=[N:6]1

参加物

5

反応物 3

HCID 81531Diisopropylethylamine2 回HCID 44252606HCID 44252606、化合物HCID 66899584(S)-2-amino-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]amide hydrochloride

生成物 1

HCID 57920135(S)-2-[4-(3-ethoxy-2,6-difluoro-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 16%

試薬・触媒・溶媒 1

HCID 6342Acetonitrile溶媒2 回

反応条件

温度
60 °C

実験手順

A suspension of (S)-2-amino-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]amide hydrochloride salt (2.0 g, 5.8 mmol) in acetonitrile (25 mL) was treated with N,N-diisopropylethylamine (4.0 mL) and stirred at 60° C. for 15 min. At this time N,N-diisopropylethylamine (2.5 mL) and a solution of (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 116, 1.37 g, 3.75 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 48 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (295 mg, 16%): HR-ES-MS (m/z) calculated for C25H32F2N4O5 [M+H]+ 507.2414, observed 507.2414; 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (br. s., 6H), 1.13 (br. s., 6H), 1.42 (br. s., 3H), 1.48-1.64 (m, 1H), 1.66-1.95 (m, 2H), 3.73 (br. s., 1H), 3.91 (br. s., 2H), 4.01-4.24 (m, 3H), 4.38 (d, J=17.8 Hz, 1H), 4.88 (br. s., 1H), 4.99 (br. s., 1H), 6.66 (br. s., 1H), 6.73-7.00 (m, 2H), 7.27 (br. s., 1H), 8.79 (br. s., 1H).

後処理

  1. temperaturethe resulting solution refluxed for 48 h
  2. concentrationThe mixture was concentrated in vacuo
  3. customthe residue partitioned between ethyl acetate and water
  4. customThe layers were separated
  5. dry with materialthe organic layer was dried over sodium sulfate
  6. filtrationThe mixture was filtered
  7. concentrationconcentrated in vacuo
  8. customthe residue purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which

出典と根拠

ORDレコード
ord-31ae88a5ba674494b06d73350f5f46b1
出典データセット
uspto-grants-2010_06
特許番号
US07741327B2

反応ノート

読み込み中…