Reaktion #2075732

Reaktionsgleichung

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

2,2,2-trifluoroethanol

cesium carbonate

→

title compound

Ausbeute 12.2%

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

Ausbeute 12.2%

Lösungsmittel

water

DMF

Reaktionsbedingungen

Aufarbeitung

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

Vorschrift

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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