Dichloromethane → 4,6-Dichloro-2-(pyrazin-2-yl)-5-(2,4,6-trifluorophenyl)pyrimidine

HRID 1783445Notes

Reaction equation

HRID 1783445 reaction equation
[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:12]=C(O)[C:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[C:9](O)[N:8]=1.P(Cl)(Cl)([Cl:26])=O.C(N(CC)C(C)C)(C)C.Cl[CH2:39][Cl:40]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:26][C:9]1[C:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[C:39]([Cl:40])[N:12]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 24813Phosphorus oxychloride2×HCID 81531DiisopropylethylamineHCID 178517557HCID 178517557, compound

Product 1

HCID 589101014,6-Dichloro-2-(pyrazin-2-yl)-5-(2,4,6-trifluorophenyl)pyrimidine

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
10 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-752c3064797e4b33b13060c6aef298ec
Source dataset
uspto-grants-2009_03
Patent number
US07501423B2

Reaction notes

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