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

HRID 2112201Notes

Reaction equation

HRID 2112201 reaction equation
[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]

Participants

7

Reactant 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

Product 1

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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-578d6db22a8e4a6ea09beddb75185c78
Source dataset
uspto-grants-2009_04
Patent number
US07521447B2

Reaction notes

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