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Trifluoroacetic acid → 9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-[4,6-dimethyl-2-(1-methylethyl)pyrimidin-5-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

HRID 1399129
Notes
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Reaction equation

HRID 1399129 reaction equation
[CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([CH3:28])=[N:22][C:23](Cl)=[N:24][C:25]=4[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([O:34][CH:35]([F:37])[F:36])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=1.FC(F)(F)C(O)=O>O1CCCC1.[Cl-].[NH4+].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:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[N:24][C:23]([CH:1]([CH3:3])[CH3:2])=[N:22][C:21]=4[CH3:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([O:34][CH:35]([F:36])[F:37])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 6422Trifluoroacetic acidHCID 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 178418918HCID 178418918, compound

Product 1

HCID 577860649-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-[4,6-dimethyl-2-(1-methylethyl)pyrimidin-5-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

Reagents, catalysts & solvents

3
HCID 178418745HCID 178418745, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 25517Ammonium ChlorideSolvent

Procedure

i-Propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.76 mL, 0.760 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 (189 mg, 0.381 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (20.7 mg, 0.0381 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with aqueous ammonium chloride 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 50-100% 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 containing 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 (19.1 mg, 0.0379 mmol, 10%).

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 50-100% 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-efc98c5d38f94ec3809b9e82622679ec
Source dataset
uspto-grants-2014_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08901141B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes