HCID 178504207, compound → HCID 86651412, compound

HRID 1043740Notes

Reaction equation

HRID 1043740 reaction equation
[Br:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[CH:7]1[NH:12][C:11]([Cl:13])=[N:10][CH:9]=[CH:8]1>CCOC(C)=O.O=[Mn]=O>[Br:1][C:2]1[N:3]=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:8]=[CH:9][N:10]=[C:11]([Cl:13])[N:12]=1

Participants

4

Reactant 1

HCID 178504207HCID 178504207, compound

Product 1

HCID 86651412HCID 86651412, compoundYield 98%

Reagents, catalysts & solvents 2

HCID 14801Manganese dioxideCatalystHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 4,5-dibromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.0 g, 2.0 mmol) in dry THF (10 mL) was cooled to −78° C. under Argon. n-BuLi (1.0 mL, 2.5 M in hexane, 2.5 mmol) was added dropwise, afterwards the reaction was maintained below −70° C. for an additional 45 minutes. A solution of 2-chloropyrimidine (0.29 g, 2.5 mmol) in dry THF (2 mL) was added dropwise at −78° C. After addition, the reaction was allowed to warm to −40° C. over 25 minutes and maintained at −40° C. for 20 minutes. The reaction was then warmed to −5° C. in a brine-ice bath, quenched with water (30 mL), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic phase was separated, dried (Na2SO4), and concentrated. The resulting residue was further purified by flash chromatography (SiO2, 0-20% EtOAc in hexanes) to afford 1.1 g (2.05 mmol, 82%) of 6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine. A solution of 6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine (410 mg, 0.8 mmol) in EtOAc (20 mL) was treated with MnO2 (920 mg, 10.6 mmol) and the resulting reaction mixture was heated to and maintained at reflux for 18 hours. The reaction was allowed to cool to room temperature and was then filtered through Celite. The filter cake was washed with EtOAc (2×20 mL) and the combined filtrates were concentrated to give 400 mg (0.75 mmol, 98%) of 4-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine: 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=5.4 Hz, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 5.77 (s, 2H), 3.49 (t, J=7.5 Hz, 2H), 0.83 (t, J=7.5 Hz, 2H), 0.01 (s, 9H).

Workup

  1. customthe resulting reaction mixture
  2. temperaturewas heated to and
  3. temperaturemaintained
  4. temperatureat reflux for 18 hours
  5. filtrationwas then filtered through Celite
  6. washThe filter cake was washed with EtOAc (2×20 mL)
  7. concentrationthe combined filtrates were concentrated

Sources & evidence

ORD record
ord-35fb66f502bc4fc99f71d02173888b75
Source dataset
uspto-grants-2013_10
Patent number
US08563553B2

Reaction notes

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