Réaction #2075732

Équation de réaction

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

2,2,2-trifluoroethanol

cesium carbonate

→

title compound

Rendement 12.2%

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

Rendement 12.2%

Solvants

water

DMF

Conditions de réaction

Traitement

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

Mode opératoire

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).

Source