Potassium Carbonate → 6-tert-Butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)phthalazin-1(2H)-one

HRID 1185025ノート

反応式

HRID 1185025 の反応式
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Cl)[C:18]=1[CH2:24][OH:25])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[CH:45][N:44]=2)[C:28]1=[O:56].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[K+].[K+]>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]>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:31]3[CH:30]=[C:29]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([N:49]5[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]5)=[CH:45][N:44]=4)[C:28](=[O:56])[N:27]([CH3:26])[CH:32]=3)[C:18]=1[CH2:24][OH:25])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]

参加物

6

反応物 4

HCID 11430Potassium CarbonateHCID 75806TricyclohexylphosphineHCID 580437641-methyl-3-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 594737806-(tert-butyl)-2-(3-chloro-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one

生成物 1

HCID 469082206-tert-Butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)phthalazin-1(2H)-one収率 47.5%

試薬・触媒・溶媒 1

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium触媒

反応条件

温度
90 °C

実験手順

To a 10 mL flask were added 6-tert-butyl-2-(3-chloro-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one 101j (100 mg, 0.27 mmol), 1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (141 mg, 0.33 mmol), PCy3 (6 mg), Pd(dba)2 (6 mg) and K2CO3 (112 mg, 0.8 mmol) in order. The flask was evacuated and backfilled with nitrogen. This sequence was repeated three times. Then, 20 percent aqueous 1,4-dioxane was added to the reaction mixture. The resulting mixture was heated to 90° C. for gentle reflux and stirred for 1.5 hr under Nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth filtration agent pad (CELITE®) and concentrated to afford a residue which was purified by prep-TLC (10% MeOH in CH2Cl2) to afford 101 (80 mg, 46%) as a yellow solid. MS: [M+H]+ 624. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=2.0 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J=3.2 Hz, 2H), 7.73 (d, J=12.8 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.41 (d, J=3.2 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.35 (dd, J=2.8, 9.2 Hz, 1H), 7.28 (d, J=2. Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 4.58 (t, J=4.8 Hz, 1H), 4.36 (s, 2H), 3.58 (s, 3H), 3.04 (m, 4H), 2.44 (m, 4H), 2.21 (s, 3H), 1.38 (s, 9H).

後処理

  1. customThe flask was evacuated
  2. additionThen, 20 percent aqueous 1,4-dioxane was added to the reaction mixture
  3. temperaturefor gentle reflux
  4. temperatureThe reaction mixture was cooled to room temperature
  5. filtrationfiltered through a diatomaceous earth filtration agent pad (CELITE®)
  6. concentrationconcentrated
  7. customto afford a residue which
  8. customwas purified by prep-TLC (10% MeOH in CH2Cl2)

出典と根拠

ORDレコード
ord-bfc32237078c4e8facf9c4609f483e0b
出典データセット
uspto-grants-2014_03
特許番号
US08669251B2

反応ノート

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