Diisopropylethylamine → 6-{(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-nicotinic acid methyl ester

HRID 18982ノート

反応式

HRID 18982 の反応式
[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[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.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:57][O:58][C:59](=[O:67])[C:60]1[CH:65]=[CH:64][C:63]([NH2:66])=[N:62][CH:61]=1>ClCCl>[CH3:57][O:58][C:59](=[O:67])[C:60]1[CH:65]=[CH:64][C:63]([NH:66][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:62][CH:61]=1

参加物

6

反応物 4

HCID 81531DiisopropylethylamineHCID 737487Methyl 6-aminonicotinateHCID 2733179PyBroPHCID 66894519(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

生成物 1

HCID 442517336-{(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-nicotinic acid methyl ester収率 20%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒2 回

反応条件

温度
25 °C

実験手順

A solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (as prepared in Example 45, 200 mg, 0.62 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (345 mg, 0.74 mmol), N,N-diisopropylethylamine (240 mg, 1.85 mmol) and 6-aminonicotinic acid methyl ester (115 mg, 0.74 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-nicotinic acid methyl ester (57 mg, 20%) as a light yellow solid: LR-ES-MS m/z calculated for C23H23F2N3O5 [M]+ 459, observed [M+H]+ 460; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.9 Hz, 3H) 0.94 (d, J=6.9 Hz, 3H) 1.39-1.74 (m, 2H) 1.73-1.92 (m, 1H) 3.86 (s, 3H) 4.32 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.95-5.05 (m, 1H) 5.06 (s, 1H) 7.25-7.53 (m, 3H) 8.17 (d, J=8.8 Hz, 1H) 8.29 (dd, J=8.8, 2.1 Hz, 1H) 8.87 (d, J=2.1 Hz, 1H) 11.34 (s, 1H).

後処理

  1. washwashed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
  2. dry with materiala saturated sodium chloride solution and dried over magnesium sulfate
  3. concentrationThe organic layer was concentrated
  4. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes)

出典と根拠

ORDレコード
ord-250938e950cb405f80818e488952d7eb
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…