4-Bromo-2,5-difluoroaniline → 4-[6-(4-Bromo-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic Acid Isopropyl Ester

HRID 1036774ノート

反応式

HRID 1036774 の反応式
[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[Br:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH2:36])=[C:31]([F:37])[CH:30]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=C(P(C(C)(C)C)C(C)(C)C)C=1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:36][C:32]3[CH:33]=[C:34]([F:35])[C:29]([Br:28])=[CH:30][C:31]=3[F:37])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]

参加物

7

反応物 3

HCID 27732854-Bromo-2,5-difluoroanilineHCID 114933574-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl esterHCID 23676156Sodium t-butoxide

生成物 1

HCID 598566844-[6-(4-Bromo-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic Acid Isopropyl Ester収率 41%

試薬・触媒・溶媒 3

HCID 167845palladium(II) acetate触媒HCID 67201513Biphenyl-3-yl-di-tert-butyl-phosphane触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
120 °C

実験手順

A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.03 g, 3.28 mmol), palladium acetate (74 mg, 0.33 mmol), biphenyl-3-yl-di-tert-butyl-phosphane (9.7 mg, 0.033 mmol), sodium tert-butoxide (708 mg, 7.36 mmol), and 4-bromo-2,5-difluoro-phenylamine (706 mg, 3.39 mmol) in 15 mL dioxane was heated in microwave for 1 hour at 120° C. Solids were filtered off and mixture was purified by column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give compound A86 as a tanned solid (652 mg, 41%). 1H NMR (CDCl3, 400 MHz) δ 1.04-1.05 (d, 6H), 1.50-1.61 (m, 2H), 1.74-1.82 (m, 2H), 1.89 (s, 3H), 3.16-3.22 (m, 2H), 3.51-3.60 (m, 2H), 4.69-4.76 (m, 1H), 5.09-5.15 (m, 1H), 6.34-6.36 (m, 1H), 7.07-7.11 (m, 1H), 8.15 (s, 1H), 8.34-8.38 (m, 1H). Exact mass calculated for C20H23BrF2N4O3 484.09, found 485.2 (MH+).

後処理

  1. filtrationSolids were filtered off
  2. custommixture was purified by column chromatography (hexane/AcOEt)
  3. customcrystallized from hexane/AcOEt

出典と根拠

ORDレコード
ord-d17d5b5b08864bb1a143ed7d0cc3f00b
出典データセット
uspto-grants-2013_10
特許番号
US08546429B2

反応ノート

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