4-Methylmorpholine → 3-(2,6-Difluorophenyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1-(4-methylphenyl)-1H indazole-6-carboxamide

HRID 1047632ノート

反応式

HRID 1047632 の反応式
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:10]=1.Cl.Cl.[CH3:30][C:31]1[N:35]=[C:34]([C@H:36]([NH2:38])[CH3:37])[O:33][N:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([NH:38][C@@H:36]([C:34]3[O:33][N:32]=[C:31]([CH3:30])[N:35]=3)[CH3:37])=[O:20])=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:10]=1

参加物

7

反応物 5

HCID 79724-MethylmorpholineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 66661491(R)-1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethanamine dihydrochlorideHCID 666616413-(2,6-Difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid

生成物 1

HCID 469459763-(2,6-Difluorophenyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1-(4-methylphenyl)-1H indazole-6-carboxamide収率 58.2%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

反応条件

温度
50 °C

実験手順

3-(2,6-Difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid (30.0 mg, 0.040 mmol, with 6 equivalents of sodium chloride), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (12.5 mg, 0.062 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.2 mg, 0.085 mmol), 1-hydroxy-7-azabenzotriazole (3.4 mg, 0.025 mmol), and N-methylmorpholine (20 μl, 0.182 mmol) were dissolved in N,N-dimethylformamide (500 μl) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 30 min. The reaction was stopped and quenched by addition of water (ca 0.1 mL) and trifluoroacetic acid (ca 0.1 mL). The crude reaction mixture was purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water+0.1% trifluoroacetic acid (5-95%), to afford the title compound (16.3 mg, 0.023 mmol, 58.2% yield) as a white solid. HRMS [M+1]=474.1739. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H); 7.77 (d, J=8.6 Hz, 1H); 7.66 (d, J=8.2 Hz, 2H); 7.61 (dd, J=8.5, 1.4 Hz, 1H); 7.48-7.40 (m, 1H); 7.38 (d, J=8.1 Hz, 2H); 7.10 (m, 2H); 6.79 (d, J=7.7 Hz, 1H); 5.62 (m, 1H); 2.46 (s, 3H); 2.41 (s, 3H); 1.73 (d, J=7.1 Hz, 3H).

後処理

  1. customquenched by addition of water (ca 0.1 mL) and trifluoroacetic acid (ca 0.1 mL)
  2. customThe crude reaction mixture
  3. customwas purified directly by preparative HPLC (Reverse phase (C-18))
  4. washeluting with acetonitrile/water+0.1% trifluoroacetic acid (5-95%)

出典と根拠

ORDレコード
ord-148c8c748a18493d917594c2559098b2
出典データセット
uspto-grants-2013_10
特許番号
US08569512B2

反応ノート

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