반응 #2075732

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

2,2,2-trifluoroethanol

cesium carbonate

→

title compound

수율 12.2%

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

수율 12.2%

용매

water

DMF

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후처리

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

실험 절차

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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