Diisopropylethylamine → 6-[2-[4-(2,6-Difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-nicotinic acid methyl ester

HRID 18979ノート

反応式

HRID 18979 の反応式
[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:60][O:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[N:65][CH:64]=1>ClCCl>[CH3:60][O:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:11](=[O:12])[CH:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[CH:6][C:7]2=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:65][CH:64]=1

参加物

6

反応物 4

HCID 81531DiisopropylethylamineHCID 737487Methyl 6-aminonicotinateHCID 2733179PyBroPHCID 668950782-[4-(2,6-Difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid

生成物 1

HCID 442537566-[2-[4-(2,6-Difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-nicotinic acid methyl ester収率 55%

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 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (155 mg, 0.42 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (240 mg, 0.051 mmol), N,N-diisopropylethylamine (165 mg, 0.127 mmol) and 6-aminonicotinic acid methyl ester (80 mg, 0.51 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-[2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-nicotinic acid methyl ester (110 mg, 55%), as an off-white solid: LR-ES-MS m/z calculated for C25H25F2N3O6 [M]+ 501, observed [M+H]+ 502; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20-1.95 (m, 7H) 3.11-3.32 (m, 2H) 3.70-3.92 (m, 2H) 3.86 (s, 3H) 4.37 (d, J=18.1 Hz, 1H) 4.64 (d, J=18.1 Hz, 1H) 4.98-5.12 (m, 2H) 7.30-7.51 (m, 3H) 8.13-8.20 (m, 1H) 8.28 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.33 (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-1a44fa3ba5084f518e870f89759fe773
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…