Lithium Hexamethyldisilazide → [4-(3-Chloro-pyrazin-2-yloxy)-phenyl]-(6-fluoro-1H-benzoimidazol-2-YL)-methanone

HRID 887385Notes

Reaction equation

HRID 887385 reaction equation
C(O[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.C(OC([N:27]1[C:31]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=2[N:29]=[CH:28]1)=O)(C)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([C:28]3[NH:27][C:31]4[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=4[N:29]=3)=[O:19])=[CH:10][CH:9]=2)=[N:13][CH:14]=[CH:15][N:16]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 45031059Ethyl 4-[(3-chloropyrazin-2-yl)oxy]benzoateHCID 593513726-Fluoro benzoimidazole-1-carboxylic acid tert-butyl ester

Product 1

HCID 46207941[4-(3-Chloro-pyrazin-2-yloxy)-phenyl]-(6-fluoro-1H-benzoimidazol-2-YL)-methanone

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 4-(3-Chloro-pyrazin-2-yloxy)-benzoic acid ethyl ester (20 g, 84.7 mmol) and 6-fluoro benzoimidazole-1-carboxylic acid tert-butyl ester (21.2 g, 76.3 mmol) in freshly dried THF (150 mL) was cooled to −78° C. LiHMDS (106 mL, 106 mmol) was added slowly to it over 1.2 h. The reaction mixture was stirred at the same temperature for 3.5 h. The reaction was brought to −20° C. and slowly quenched with addition of 2N HCl until pH 3-4. The resulting mixture was stirred at RT for 1 h, extracted with ethyl acetate (3×200 mL), and washed with water (2×100 mL). The organic layer was dried (Na2SO4) and concentrated. To the crude product was added methanol (70 mL). After stirring for 1 h, the solid was collected by filtration to give the title compound. MS (ESI, pos. ion) m/z: 369.2 (M+1). IC50 (uM) +.

Workup

  1. customwas brought to −20° C.
  2. customslowly quenched with addition of 2N HCl until pH 3-4
  3. stirringThe resulting mixture was stirred at RT for 1 h
  4. extractionextracted with ethyl acetate (3×200 mL)
  5. washwashed with water (2×100 mL)
  6. dry with materialThe organic layer was dried (Na2SO4)
  7. concentrationconcentrated
  8. additionTo the crude product was added methanol (70 mL)
  9. stirringAfter stirring for 1 h
  10. filtrationthe solid was collected by filtration

Sources & evidence

ORD record
ord-4bb1e61a094e42b6a3464415be1bc3d0
Source dataset
uspto-grants-2012_08
Patent number
US08247418B2

Reaction notes

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