반응 #2075731

반응 방정식

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

HCl

ethyl acetate

sodium methanthiolate

→

title compound

수율 12.7%

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

수율 12.7%

용매

DMF

water

반응 조건

후처리

1. 1
   온도After heating for 4 h
2. 2
   온도the mixture was cooled
3. 3
   기타A small amount of solid was removed by filtration
4. 4
   추출the separated aqueous phase was extracted again with ethyl acetate
5. 5
   세척The combined organic phases were washed twice with water
6. 6
   세척washed once with brine
7. 7
   기타dried
8. 8
   기타evaporated
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
    기타to destroy excess reagent
13. 13
    온도The reaction solution was heated briefly
14. 14
    온도to reflux
15. 15
    농축concentrated
16. 16
    기타The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient with 2% acetic acid)

실험 절차

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).

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