Water → N-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea

HRID 73706ノート

反応式

HRID 73706 の反応式
Br[C:2]1[C:3]([CH3:20])=[C:4]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1)=[O:34].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:11][C:9]1[C:10]2=[C:2]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:23]4[CH:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[CH:26]=[CH:27][C:22]=4[F:21])=[O:34])=[CH:41][CH:40]=3)[C:3]([CH3:20])=[C:4]([CH2:12][N:13]3[CH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1

参加物

7

反応物 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 161252301-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureaHCID 579551855-Bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

生成物 1

HCID 66641326N-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea収率 15%

試薬・触媒・溶媒 2

HCID 11979704Tetrakis(triphenylphosphine)palladium触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
90 °C

実験手順

To a stirred solution of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.29 mmol) and tetrakis(triphenylphosphine)-palladium(0) (101 mg, 0.088 mmol), in degassed 1,4 dioxane (4.0 mL), was added Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea) (248 mg, 0.59 mmol), K2CO3 (162 mg, 1.18 mmol), and H2O (0.4 mL). The mixture was degassed and heated (90° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous Na2CO3 solution (25 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 24 mg (15%) of the desired product. 1H-NMR (DMSO-d6) δ 9.36 (s, 1H), 8.98-8.97 (m, 1H), 8.63 (dd, J=2.4, 7.2 Hz, 1H), 7.85 (s, 1H), 7.60-7.47 (m, 3H), 7.41-7.33 (m, 1H), 7.33 (d, J=8.7 Hz, 2H), 3.95 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 3.59-3.56 (m, 2H), 3.31 (m, 2H), 2.68-2.62 (m, 4H), 2.10 (s, 3H), 1.83-1.75 (m, 2H); MS [M+H]+=558.1; LCMS RT=2.94.

後処理

  1. customThe mixture was degassed
  2. temperaturecooled to rt
  3. customThe mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous Na2CO3 solution (25 mL)
  4. customThe layers were separated
  5. washthe organic phase was washed
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated to dryness
  8. customThe residue was purified by preparative HPLC
  9. washa gradient elution from 10% to 70% acetonitrile

出典と根拠

ORDレコード
ord-a8a08fe6325044eb8540bce5e4fc8638
出典データセット
uspto-grants-2014_09
特許番号
US08829185B2

反応ノート

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