反応 #1898744

反応方程式

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

6-bromo-2-methyl-pyridin-3-ylamine

2-(di-t-butylphosphino) biphenyl

LiN(TMS)2

→

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

収率 44.0%

溶媒

dioxane

反応条件

後処理

1. 1
   温度under reflux
2. 2
   workup.STIRRINGmixture was stirred
3. 3
   温度under reflux for another hour
4. 4
   workup.WAITat room temperature for 3 days
5. 5
   濃縮The mixture was concentrated
6. 6
   抽出residue was extracted with brine and AcOEt
7. 7
   乾燥Organic phases were dried over MgSO4
8. 8
   ろ過filtered
9. 9
   濃縮concentrated
10. 10
    その他The residue was purified by column chromatography (hexane/AcOEt 2:1→1:1)

実験手順

A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (3.3 g, 10.0 mmol), 6-bromo-2-methyl-pyridin-3-ylamine (1.88 g, 10.0 mmol), palladium acetate (118 mg, 0.53 mmol), 2-(di-t-butylphosphino) biphenyl (157 mg, 0.53 mmol) and LiN(TMS)2 (1M in THF, 15 mL, 15 mmol) in 75 mL of dioxane was stirred under reflux. After 4.5 h, more palladium acetate (111 mg, 0.50 mmol) was added and mixture was stirred under reflux for another hour and then at room temperature for 3 days. The mixture was concentrated and residue was extracted with brine and AcOEt. Organic phases were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (hexane/AcOEt 2:1→1:1) to give 4-[6-(6-bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a solid (2.09 g, 44%). 1HNMR (CDCl3, 400 MHz) a 1.27-1.28 (d, 6H), 1.84-1.87 (m, 2H), 2.02-2.08 (m, 2H), 2.58 (s, 3H), 3.40-3.47 (m, 2H), 3.73 (s, 3H), 3.77-3.82 (m, 2H), 4.93-4.97 (m, 1H), 5.41-5.43 (m, 1H), 7.44-7.46 (m, 1H), 7.91-7.93 (m, 1H), 8.24 (s, 1H), 8.70 (s br, 1H). Exact mass calculated for C20H26BrN5O4 479.12. found 482.0 (MH+).

出典