反応 #1898747

反応方程式

4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester

2,6-dimethylpyridin-3-amine

sodium 2-methylpropan-2-olate

→

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

溶媒

dioxane

反応条件

後処理

1. 1
   温度under reflux for 18 h
2. 2
   濃縮Mixture was concentrated
3. 3
   抽出extracted with brine and CH2Cl2
4. 4
   乾燥Organic phases were dried over MgSO4
5. 5
   ろ過filtered
6. 6
   濃縮concentrated
7. 7
   その他Residue was purified by column chromatography (AcOEt/hexane 5:1→AcOEt→AcOEt/MeOH 10:1)
8. 8
   workup.ADDITIONFractions containing pure product
9. 9
   濃縮were concentrated
10. 10
    workup.ADDITIONresidue was treated with 4M HCl in dioxane
11. 11
    濃縮concentrated

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+).

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