Lithium propan-2-olate → 9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-[4,6-dimethyl-2-(1-methylethoxy)pyrimidin-5-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

HRID 1399126Notes

Reaction equation

HRID 1399126 reaction equation
[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18](Cl)=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[CH3:33][CH:34]([CH3:36])[O-:35].[Li+]>CC(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:35][CH:34]([CH3:36])[CH3:33])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:27])([F:28])[F:26])=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 23673350Lithium propan-2-olateHCID 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]benzimidazole

Product 1

HCID 577860899-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-[4,6-dimethyl-2-(1-methylethoxy)pyrimidin-5-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
70 °C

Procedure

A mixture 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 (161 mg, 0.324 mmol) and lithium isopropoxide (64.3 mg, 0.973 mmol) in 2-propanol (2.2 mL) was stirred at 70° C. for 17 hr. The mixture was concentrated in vacuo, 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 30-70% 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 (71.0 mg, 0.137 mmol, 42%).

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. additiondiluted with water
  3. extractionextracted with ethyl acetate
  4. washThe combined organic layer was washed with brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture
  9. concentrationThe filtrate was concentrated in vacuo
  10. customto give the solid, which
  11. customwas purified by preparative HPLC
  12. customto give a mixture

Sources & evidence

ORD record
ord-780a185f516441a8acecd4c8c28e148e
Source dataset
uspto-grants-2014_12
Patent number
US08901141B2

Reaction notes

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