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

HRID 1897495노트

반응식

HRID 1897495 반응식
[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]

참가 물질

7

반응물 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

생성물 1

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

시약·촉매·용매 1

HCID 6344Dichloromethane용매2회

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-fc2cf21093514617a31f96f76186c241
출처 데이터셋
uspto-grants-2013_08
특허 번호
US08518983B2

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