反应 #2075731

反应方程式

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid

HCl

ethyl acetate

sodium methanthiolate

→

title compound

收率 12.7%

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methylsulfanylpyrimidine-4-carboxylic acid methyl ester

收率 12.7%

溶剂

DMF

water

反应条件

后处理

1. 1
   温度After heating for 4 h
2. 2
   温度the mixture was cooled
3. 3
   其他A small amount of solid was removed by filtration
4. 4
   萃取the separated aqueous phase was extracted again with ethyl acetate
5. 5
   洗涤The combined organic phases were washed twice with water
6. 6
   洗涤washed once with brine
7. 7
   其他dried
8. 8
   其他evaporated
9. 9
   workup.DISSOLUTIONThe crude product was dissolved in 7 mL THF
10. 10
    workup.ADDITION5 L methanol and treated with 1.5 mL of 2.0M (trimethylsilyl)diazomethane
11. 11
    workup.ADDITIONA few drops of acetic acid were added
12. 12
    其他to destroy excess reagent
13. 13
    温度The reaction solution was heated briefly
14. 14
    温度to reflux
15. 15
    浓缩concentrated
16. 16
    其他The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient with 2% acetic acid)

实验过程

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid (830 mg, 2.2 mmol; see WO 2007/082076 A1 for preparation) was combined with sodium methanthiolate (470 mg, 6.7 mmol) and cuprous iodide (1.6 g, 8.3 mmol) in 12 mL dry DMF and heated to 50° C. After heating for 4 h, the mixture was cooled, taken up in water and ethyl acetate and acidified with 2M HCl. A small amount of solid was removed by filtration and the separated aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed twice with water, washed once with brine, dried and evaporated. The crude product was dissolved in 7 mL THF and 5 L methanol and treated with 1.5 mL of 2.0M (trimethylsilyl)diazomethane and stirred at room temperature for 30 min. A few drops of acetic acid were added to destroy excess reagent. The reaction solution was heated briefly to reflux and then concentrated. The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient with 2% acetic acid) to yield the title compound (100 mg, 12.7% yield): 1H NMR (CDCl3): δ 7.65 (m, 1H), 7.23 (m, 1H), 5.98 (br s, 2H), 4.00 (s, 3H), 3.99 (d, 3H), 2.35 (s, 3H).

来源