Cesium carbonate → 4-methyl-piperazine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide

HRID 2100413ノート

反応式

HRID 2100413 の反応式
Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:77][N:78]1[CH2:83][CH2:82][N:81]([C:84]([NH2:86])=[O:85])[CH2:80][CH2:79]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:24][N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([NH:14][C:12]([C:11]3[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=3[NH:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:86][C:84]([N:81]4[CH2:82][CH2:83][N:78]([CH3:77])[CH2:79][CH2:80]4)=[O:85])[CH:7]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1

参加物

8

反応物 4

HCID 10796Cesium carbonateHCID 4102614-Methylpiperazine-1-carboxamideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 231189722-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide

生成物 1

HCID 115333714-methyl-piperazine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide収率 22.5%

試薬・触媒・溶媒 3

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 6228Dimethylformamide溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
110 °C

実験手順

2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (110 mg, 0.25 mmol) was suspended in dioxane (3 mL) and treated consecutively with DMF (1 mL), Pd2dba3 (5 mg, 0.005 mmol), Xantphos (9 mg, 0.015 mmol), cesium carbonate (98 mg, 0.3 mmol) and 4-methyl-piperazine-1-carboxylic acid amide (184 mg, 1.3 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 3 hours at 110° C. (bath temperature). On cooling the volatiles were removed in vacuo and the residue was partitioned between CH2Cl2 and water. The organic phase was washed with brine, dried, filtered and concentrated. The residue was purified by chromatography using Isolute® Flash NH2 (Separtis) as stationary phase (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 95:5) to give 4-methyl-piperazine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (28 mg, 22%) as a foam; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.11 (1H, s), 8.25 (1H, S), 8.14 (1H, d), 8.10 (1H, s), 7.95 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.23-7.32 (2H, m), 6.94 (1H, d), 6.66 (1H, t), 6.53 (1H, d), 4.43 (2H, d), 4.13 (3H, s), 3.41-3.44 (4H, m), 2.25-2.28 (4H, m), 2.17 (3H, s); m/z (ES+) 499.

後処理

  1. temperatureOn cooling the volatiles
  2. customwere removed in vacuo
  3. customthe residue was partitioned between CH2Cl2 and water
  4. washThe organic phase was washed with brine
  5. customdried
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by chromatography
  9. washas stationary phase (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 95:5)

出典と根拠

ORDレコード
ord-09e260b53c2246e8a702493a489a471b
出典データセット
uspto-grants-2009_08
特許番号
US07572794B2

反応ノート

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