Réaction #2075731

Équation de réaction

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

HCl

ethyl acetate

sodium methanthiolate

→

title compound

Rendement 12.7%

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

Rendement 12.7%

Solvants

DMF

water

Conditions de réaction

Traitement

1. 1
   TempératureAfter heating for 4 h
2. 2
   Températurethe mixture was cooled
3. 3
   AutreA small amount of solid was removed by filtration
4. 4
   Extractionthe separated aqueous phase was extracted again with ethyl acetate
5. 5
   LavageThe combined organic phases were washed twice with water
6. 6
   Lavagewashed once with brine
7. 7
   Autredried
8. 8
   Autreevaporated
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
    Autreto destroy excess reagent
13. 13
    TempératureThe reaction solution was heated briefly
14. 14
    Températureto reflux
15. 15
    Concentrationconcentrated
16. 16
    AutreThe product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient with 2% acetic acid)

Mode opératoire

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).

Source