تفاعل #1999489

معادلة التفاعل

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

HCl

ethyl acetate

sodium methanthiolate

→

title compound

المردود 12.7%

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

المردود 12.7%

المذيبات

DMF

water

ظروف التفاعل

المعالجة

1. 1
   درجة الحرارةAfter heating for 4 h
2. 2
   درجة الحرارةthe mixture was cooled
3. 3
   أخرىA small amount of solid was removed by filtration
4. 4
   استخلاصthe separated aqueous phase was extracted again with ethyl acetate
5. 5
   غسيلThe combined organic phases were washed twice with water
6. 6
   غسيلwashed once with brine
7. 7
   أخرىdried
8. 8
   أخرىevaporated
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
    أخرىto destroy excess reagent
13. 13
    درجة الحرارةThe reaction solution was heated briefly
14. 14
    درجة الحرارةto reflux
15. 15
    تركيزconcentrated
16. 16
    أخرىThe product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient with 2% acetic acid)

الإجراء التجريبي

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).

المصدر