2-Bromopyridine → [6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-pyridin-2-yl-methanol

HRID 1925855Notes

Reaction equation

HRID 1925855 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]=[O:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1

Participants

5

Reactant 3

HCID 79732-BromopyridineHCID 211142076-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehydeHCID 178418339Butyllithium

Product 1

HCID 11442581[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-pyridin-2-yl-methanolYield 62%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 2-bromopyridine (0.10 mL, 1.04 mmol) in THF (3 mL) at −78° C. is added n-BuLi (0.39 mL, 0.98 mmol, 2.5 M solution in hexane). After stirring for 10 minutes at −78° C., a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehyde 10h (25 mg, 0.064 mmol) in THF (1 mL) is added. The resulting reaction mixture is stirred for 1.5 hours at −78° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (2.5% MeOH in CH2Cl2) to afford the desired product (18 mg, 62%): MS APCI (+) m/z 461, 463 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.31 (d, 1H), 8.16 (s, 1H), 7.65 (m, 3H), 7.38 (d, 1H), 7.10 (m, 1H), 7.00 (dd, 1H), 6.11 (dd, 1H), 6.05 (s, 1H), 3.94 (s, 3H); 19F NMR (376 MHz, CD3OD)-135.79 (s).

Workup

  1. customThe resulting reaction mixture
  2. stirringis stirred for 1.5 hours at −78° C.
  3. customquenched with saturated aqueous NH4Cl
  4. extractionextracted with EtOAc
  5. dry with materialThe organic layer is dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. custompurified by flash chromatography (2.5% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-842c0cd42d4047c1984b9812c21e837b
Source dataset
uspto-grants-2012_05
Patent number
US08178693B2

Reaction notes

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