Реакция #2075732

Уравнение реакции

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

2,2,2-trifluoroethanol

cesium carbonate

→

title compound

Выход 12.2%

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

Выход 12.2%

Растворители

water

DMF

Условия реакции

Обработка

1. 1
   ТемператураAfter cooling
2. 2
   Экстракцияextracted twice with ethyl acetate
3. 3
   ПромывкаThe combined extracts were washed twice with water
4. 4
   Другоеdried
5. 5
   Другоеevaporated
6. 6
   ДругоеThe residue was purified by flash chromatography on silica gel (5 to 20% ethyl acetate in hexane)
7. 7
   Другоеrepurified by preparative HPLC (55% acetonitrile
8. 8
   workup.ADDITIONtreated with a 2 M solution of (trimethylsilyl)diazomethane in hexanes (1 mL)
9. 9
   ДругоеThe excess reagent was destroyed by addition of 0.5 mL acetic acid
10. 10
    Другоеthe volatiles were removed by evaporation
11. 11
    Промывкаwashed with saturated sodium bicarbonate
12. 12
    Промывкаwashed with brine
13. 13
    Другоеdried
14. 14
    Другоеevaporated
15. 15
    Другоеthe product was precipitated as a solid by slow addition of hexane

Методика

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid (240 mg, 0.64 mmol), 2,2,2-trifluoroethanol (1.4 mL, 1.9 g, 1.9 mmol), cesium carbonate (1.0 g, 3.2 mmol) and cuprous bromide (92 mg, 0.64 mmol) were combined in 7 mL dry DMF and heated to 80° C. for 3 h. After cooling, the mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were washed twice with water, dried and evaporated. The residue was purified by flash chromatography on silica gel (5 to 20% ethyl acetate in hexane) and then repurified by preparative HPLC (55% acetonitrile buffered with 0.1% v/v acetic acid). The purified acid was taken up in 5 mL methanol, treated with a 2 M solution of (trimethylsilyl)diazomethane in hexanes (1 mL) and stirred for 30 m at 25° C. The excess reagent was destroyed by addition of 0.5 mL acetic acid and the volatiles were removed by evaporation. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate, washed with brine, dried and evaporated. The residue was taken up in a small amount of dichloromethane and the product was precipitated as a solid by slow addition of hexane to give 32 mg of the title compound as a white solid: mp 123-125° C.: 1H NMR (CDCl3) δ 7.61 (dd, 1H), 7.20 (dd, 1H), 5.51 (br s, 2H), 4.51 (q, 1H), 4.01 (s, 3H), 3.99 (s, 3H).

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