9-Chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole → 9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2,4,6-trimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

HRID 1399127Notes

Reaction equation

HRID 1399127 reaction equation
[CH3:1][Mg]Br.[Cl:4][C:5]1[C:13]2[N:12]=[C:11]3[N:14]([C:18]4[C:19]([CH3:26])=[N:20][C:21](Cl)=[N:22][C:23]=4[CH3:24])[CH2:15][CH2:16][CH2:17][N:10]3[C:9]=2[C:8]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])=[CH:7][CH:6]=1>O1CCCC1.O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:4][C:5]1[C:13]2[N:12]=[C:11]3[N:14]([C:18]4[C:23]([CH3:24])=[N:22][C:21]([CH3:1])=[N:20][C:19]=4[CH3:26])[CH2:15][CH2:16][CH2:17][N:10]3[C:9]=2[C:8]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:30])([F:31])[F:29])=[CH:7][CH:6]=1

Participants

6

Reactant 2

HCID 577862249-Chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoleHCID 178418573HCID 178418573, compound

Product 1

HCID 577860969-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2,4,6-trimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

Reagents, catalysts & solvents 3

HCID 178418745HCID 178418745, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Methylmagnesium bromide (1.0 M solution in tetrahydrofuran, 0.49 mL, 0.490 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (163 mg, 0.328 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (17.8 mg, 0.0328 mmol) in tetrahydrofuran (1.3 mL) at 0° C., and the mixture was stirred at room temperature for 7 hr. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (49.8 mg, 0.105 mmol, 32%)

Workup

  1. extractionextracted with ethyl acetate
  2. washThe combined organic layer was washed with brine
  3. dry with materialdried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture
  7. concentrationThe filtrate was concentrated in vacuo
  8. customto give the solid, which
  9. customwas purified by preparative HPLC
  10. customto give a mixture

Sources & evidence

ORD record
ord-7b2d1847bb4a468788f76fe0dc97b9f5
Source dataset
uspto-grants-2014_12
Patent number
US08901141B2

Reaction notes

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