反应详情

温度

10 °C

According to scheme 1, step c, to a mixture of 2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine-4,6-diol 4 in an aprotic solvent preferably toluene (g/ml) preferably 5-15 parts, more preferably in 5-10 parts, most preferable in 7 parts, is slowly added at about 10-15° C., phosphorus oxychloride. Following complete addition of the phosphorus oxychloride, N,N-diisopropylethyl amine in a molar ratio of about 1:1 to 1:5, preferably in the range of 1:4 is slowly added at about 10-15° C. and the mixture heated to reflux for about 6 to 24 h, preferably about 6 h. The volatiles are removed by distillation to a residue which is further distilled with toluene preferably two times to afford a further residue. The further residue is dissolved in a solvent selected from ethyl acetate, dichloromethane and toluene, preferably ethyl acetate then partitioned by pouring into water while maintaining the temperature between about 5-15° C. The solvent layer is separated, washed with water, dried over sodium sulfate and filtered through a pad of filter aid such as diatomaceous earth or through hydrous magnesium silicate and most of the volatiles removed to a residue to which is added heptane forming a precipitated product. The precipitated product 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 is collected and having a purity of >95% as shown by high pressure liquid chromatography (HPLC). Further, the 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 is formed and isolated without chromatography.

1. additionis slowly added at about 10-15° C.
2. additionpreferably in the range of 1:4 is slowly added at about 10-15° C.
3. temperaturethe mixture heated
4. temperatureto reflux for about 6 to 24 h, preferably about 6 h
5. customThe volatiles are removed by distillation to a residue which
6. distillationis further distilled with toluene preferably two times
7. customto afford a further residue
8. dissolutionThe further residue is dissolved in a solvent
9. customthen partitioned
10. additionby pouring into water
11. customThe solvent layer is separated
12. washwashed with water
13. dry with materialdried over sodium sulfate
14. filtrationfiltered through a pad of filter aid such as diatomaceous earth or through hydrous magnesium silicate and most of the volatiles
15. customremoved to a residue to which
16. additionis added heptane forming a precipitated product
17. customThe precipitated product 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 is collected