2,6-Dimethyl-3-pyridylamine → 4-[6-(2,6-Dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester

HRID 1811565

反応式

HRID 1811565 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]([O:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]([CH3:31])[N:25]=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:30][C:29]3[C:24]([CH3:23])=[N:25][C:26]([CH3:31])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]

参加物

6

反応物 3

HCID 769642,6-Dimethyl-3-pyridylamineHCID 23676156Sodium t-butoxideHCID 51050526Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylate

生成物 1

HCID 115244944-[6-(2,6-Dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester

試薬・触媒・溶媒 2

HCID 167845palladium(II) acetate触媒HCID 312751,4-Dioxane溶媒

実験手順

A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.52 g, 4.60 mmol), 2,6-dimethylpyridin-3-amine (0.562 g, 4.60 mmol), palladium acetate (0.0584 g, 0.260 mmol), and sodium 2-methylpropan-2-olate (0.663 g, 6.90 mmol) in 50 mL dioxane was stirred under reflux for 18 h. Mixture was concentrated and extracted with brine and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was purified by column chromatography (AcOEt/hexane 5:1→AcOEt→AcOEt/MeOH 10:1). Fractions containing pure product were concentrated, residue was treated with 4M HCl in dioxane, and concentrated to give 4-[6-(2,6-dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a white (0.285 g, 15%). Fractions containing product contaminated with 2,6-dimethylpyridin-3-amine was concentrated to give 0.30 g of ca 80% pure product. 1HNMR (CDCl3, 400 MHz) δ 1.24-1.25 (d, J=6.2 Hz, 6H), 1.78-1.84 (m, 2H), 2.00-2.05 (m, 2H), 2.52 (2s, 6H), 3.37-3.44 (m, 2H), 3.76-3.81 (m, 2H), 4.03 (s, 3H), 4.91-4.97 (m, 1H), 5.33-5.38 (m, 1H), 6.81 (s, 1H), 7.04-7.06 (d, J=8.2 Hz, 1H), 8.09 (s, 1H), 8.11-8.13 (d, J=8.2 Hz, 1H). Exact mass calculated for C21H29N5O4 415.22. found 416.5 (MH+).

後処理

  1. temperatureunder reflux for 18 h
  2. concentrationMixture was concentrated
  3. extractionextracted with brine and CH2Cl2
  4. dry with materialOrganic phases were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customResidue was purified by column chromatography (AcOEt/hexane 5:1→AcOEt→AcOEt/MeOH 10:1)
  8. additionFractions containing pure product
  9. concentrationwere concentrated
  10. additionresidue was treated with 4M HCl in dioxane
  11. concentrationconcentrated

出典と根拠

ORDレコード
ord-9239afda501047f092d565914e8cb4cc
出典データセット
uspto-grants-2013_01
特許番号
US08362248B2

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