反応 #1898748

反応方程式

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

2-methyl-6-(methylsulfonyl)pyridin-3-amine

2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane

sodium 2-methylpropan-2-olate

→

HCl

4-[6-(6-methanesulfonyl-2-methyl-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
   その他mixture was purified by HPLC
2. 2
   workup.ADDITIONfractions containing product
3. 3
   その他were collected
4. 4
   濃縮concentrated
5. 5
   抽出Residue was extracted with 1M NaOH and CH2Cl2
6. 6
   乾燥Organic phases were dried over MgSO4
7. 7
   ろ過filtered
8. 8
   濃縮concentrated
9. 9
   その他Residue was re-purified by column chromatography (AcOEt/hexane 5:1)
10. 10
    workup.ADDITIONFractions containing product
11. 11
    濃縮were concentrated
12. 12
    workup.ADDITIONtreated with 4M HCl
13. 13
    濃縮concentrated

実験手順

A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (611 mg, 1.85 mmol), 2-methyl-6-(methylsulfonyl)pyridin-3-amine (345 mg, 1.85 mmol), palladium acetate (37.2 mg, 0.166 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (118 μl, 0.332 mmol), and sodium 2-methylpropan-2-olate (267 mg, 2.78 mmol) in 15 mL dioxane was heated under microwave irradiation at 120° C. After 2 h, mixture was purified by HPLC; fractions containing product were collected and concentrated. Residue was extracted with 1M NaOH and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was re-purified by column chromatography (AcOEt/hexane 5:1). Fractions containing product were concentrated, treated with 4M HCl and concentrated to give 4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a white solid (HCl salt, 326 mg, 34%). 1HNMR (MeOH-d4, 400 MHz) δ 1.23-1.24 (d, J=6.2 Hz, 6H), 1.77-1.85 (m, 2H), 2.01-2.07 (m, 2H), 2.59 (s, 3H), 3.20 (s, 3H), 3.40-3.46 (m, 2H), 3.71-3.77 (m, 2H), 3.98 (s, 3H), 4.83-4.89 (m, 1H), 5.41-5.46 (m, 1H), 7.97-7.99 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 8.29-8.31 (d, J=8.3 Hz, 1H). Exact mass calculated for C21H29N5O6S 479.18 found 480.2 (MH+).

出典