Pyrazine → 4-((2,6-difluorophenyl)(hydroxy)(pyrazin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

HRID 1773684Notes

Reaction equation

HRID 1773684 reaction equation
[Li]CCCC.CC1(C)CCCC(C)(C)N1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[F:22][C:23]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:24]=1[C:25]([C:27]1[C:35]2[N:34]=[C:33]([O:36]CC)[N:32](C(OC(C)(C)C)=O)[C:31]=2[CH:30]=[C:29]([C:46]2[C:47]([CH3:52])=[N:48][O:49][C:50]=2[CH3:51])[CH:28]=1)=[O:26]>C1COCC1>[F:22][C:23]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:24]=1[C:25]([OH:26])([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][N:16]=1)[C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[C:29]([C:46]2[C:47]([CH3:52])=[N:48][O:49][C:50]=2[CH3:51])[CH:28]=1

Participants

6

Reactant 4

HCID 9261PyrazineHCID 130352,2,6,6-TetramethylpiperidineHCID 117601789tert-butyl 4-(2,6-difluorobenzoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 862967744-((2,6-difluorophenyl)(hydroxy)(pyrazin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
65 °C

Procedure

n-BuLi (0.21 mL, 0.33 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (0.06 mL, 0.33 mmol) in THF (0.7 mL) at 0° C. and was allowed to stir for 5 minutes. Pyrazine (24 mg, 0.3 mmol) in THF (0.4 mL) was added and the reaction was stirred for an additional 5 minutes and then cooled to −78° C. tert-butyl 4-(2,6-difluorobenzoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in THF (0.4 mL) was added, the solution was allowed to stir for 5 minutes and then quenched with water. Solution was extracted three times with EtOAc, washed once with brine and concentrated. Crude was purified by reverse-phase HPLC and then taken up in EtOH (3 mL) and HCl (0.1 mL) and heated to 65° C. for 2 hours. Reaction was cooled and concentrated to afford desired product as a pale brown powder.

Workup

  1. stirringthe reaction was stirred for an additional 5 minutes
  2. additionwas added
  3. stirringto stir for 5 minutes
  4. customquenched with water
  5. extractionSolution was extracted three times with EtOAc
  6. washwashed once with brine
  7. concentrationconcentrated
  8. customCrude was purified by reverse-phase HPLC
  9. customReaction
  10. temperaturewas cooled
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-dd6feeb2e2484b83b025b13f00f9673c
Source dataset
uspto-grants-2016_02
Patent number
US09255089B2

Reaction notes

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