Dimethylamine → (s)-5-(2,4-Difluorophenoxy)-1-isobutyl-1h-indazole-6-carboxylic acid (3-dimethylamino-1-dimethylcarbamoylpropyl)-amide

HRID 1897495ノート

反応式

HRID 1897495 の反応式
[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@@H:17]([CH2:21]CN(C)C)[C:18](O)=[O:19])=[O:15])[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:9]=[CH:8]2.[CH3:35][NH:36][CH3:37].C[CH2:39][N:40]=[C:41]=NCCCN(C)C.[CH:49]1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:35][N:36]([CH3:49])[CH2:37][CH2:21][C@H:17]([NH:16][C:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:6][C:5]=1[O:4][C:3]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:2]=1[F:1])=[O:15])[C:18](=[O:19])[N:40]([CH3:41])[CH3:39]

参加物

7

反応物 5

HCID 674DimethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 42611138(S)-2-{[5-(2,4-Difluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-dimethylaminobutyric acid

生成物 1

HCID 67411772(s)-5-(2,4-Difluorophenoxy)-1-isobutyl-1h-indazole-6-carboxylic acid (3-dimethylamino-1-dimethylcarbamoylpropyl)-amide収率 86%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒2 回

実験手順

To a solution of (S)-2-{[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-dimethylaminobutyric acid (33d; Example 123) (0.100 g, 0.21 mmol), dimethylamine (0.095 g, 2.11 mmol), EDCI (0.053 g, 0.27 mmol), HOBt (0.037 g, 0.27 mmol) dissolved in dichloromethane was added drop-wise DIEA (0.082 g, 0.63 mmol). The reaction mixture was stirred at room temperature until complete consumption of the starting material was observed by HPLC analysis. The reaction mixture was then diluted with dichloromethane and washed with saturated NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed on Isolute SPE column flash Si (5 g) eluting with a gradient TEA/dichloromethane (100 mL, 0.3:99.7), TEA/MeOH/dichloromethane (100 mL, 0.3:0.5:99.2), TEA/MeOH/dichloromethane (100 mL, 0.3:2.5:97.2), TEA/MeOH/dichloromethane (100 mL, 0.3:5:94.7). The final product was obtained in 86% yield. MS (ESI+) m/z 502 (M+1) detected; 1H NMR (400 mHz, DMSO-D6) δ 8.63 (d, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.48 (m, 1H), 7.23 (m, 1H), 7.20 (s, 1H), 7.09 (m, 1H), 4.98 (m, 1H), 4.26 (d, 2H), 3.07 (s, 3H), 2.84 (s, 3H), 2.23 (m, 2H), 2.13 (m, 1H), 2.03 (s, 6H), 1.80 (m, 1H), 1.65 (m, 1H), 0.86 (d, 6H).

後処理

  1. washwashed with saturated NaHCO3
  2. dry with materialdried over MgSO4
  3. concentrationconcentrated under reduced pressure
  4. customThe residue was chromatographed on Isolute SPE column flash Si (5 g)
  5. washeluting with a gradient TEA/dichloromethane (100 mL, 0.3:99.7), TEA/MeOH/dichloromethane (100 mL, 0.3:0.5:99.2), TEA/MeOH/dichloromethane (100 mL, 0.3:2.5:97.2), TEA/MeOH/dichloromethane (100 mL, 0.3:5:94.7)

出典と根拠

ORDレコード
ord-fc2cf21093514617a31f96f76186c241
出典データセット
uspto-grants-2013_08
特許番号
US08518983B2

反応ノート

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