2-Bromo-6-chloropyridine → (6-chloropyridin-2-yl)(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol

HRID 1773739Notes

Reaction equation

HRID 1773739 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Li]CCCC.[CH3:14][C:15]1[C:19]([C:20]2[CH:21]=[C:22]([C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:33])[C:23]3[N:27]=[C:26]([O:28][CH2:29][CH3:30])[NH:25][C:24]=3[CH:31]=2)=[C:18]([CH3:40])[O:17][N:16]=1>CC1OCCC1>[Cl:8][C:4]1[N:3]=[C:2]([C:32]([C:22]2[C:23]3[N:27]=[C:26]([O:28][CH2:29][CH3:30])[NH:25][C:24]=3[CH:31]=[C:20]([C:19]3[C:15]([CH3:14])=[N:16][O:17][C:18]=3[CH3:40])[CH:21]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[OH:33])[CH:7]=[CH:6][CH:5]=1

Participants

5

Reactant 3

HCID 788202-Bromo-6-chloropyridineHCID 117601753(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin 2-yl)methanoneHCID 178418339Butyllithium

Product 1

HCID 117601743(6-chloropyridin-2-yl)(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanolYield 48.7%

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent2×

Procedure

To a solution of 2-bromo-6-chloropyridine (83 mg, 0.43 mmol) in 2-MeTHF (1.5 mL) cooled to −78° C. was added n-BuLi (1.6 M, 0.27 mL, 0.43 mmol) dropwise and the reaction was allowed to stir for 40 mins. A solution of (6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (100 mg, 0.22 mmol) in 2-MeTHF (0.5 mL) was added to the reaction and the reaction was allowed to stir for an additional 10 mins at −78° C. and then quenched with water. The reaction mixture was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by silica gel chromatography to yield (6-chloropyridin-2-yl)(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol (51 mg, 41%) as a white solid. The solid (26.5 mg, 0.055 mmol) was taken up in EtOH (1 mL) and 4M HCl/dioxane (0.5 mL) and heated for two hours at 65° C. and then concentrated to afford the desired product as a pale yellow powder.

Workup

  1. stirringto stir for an additional 10 mins at −78° C.
  2. customquenched with water
  3. extractionThe reaction mixture was extracted three times with EtOAc
  4. washwere washed once with water
  5. concentrationconcentrated
  6. custompurified by silica gel chromatography

Sources & evidence

ORD record
ord-3d10d41ed17f4263a33cd103904dc877
Source dataset
uspto-grants-2016_02
Patent number
US09255089B2

Reaction notes

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