N-bromobutanimide → 3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

HRID 1893419Notes

Reaction equation

HRID 1893419 reaction equation
[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][N:22]=[C:16]2[CH2:15]1)=[O:13].C1C(=O)N([Br:30])C(=O)C1>C1(C)C=CC=CC=1.CN(C)C=O.[Cl-].[Na+].O>[Br:30][C:20]1[N:17]2[CH2:18][CH2:19][N:14]([C:12]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=3[Cl:1])=[O:13])[CH2:15][C:16]2=[N:22][CH:21]=1

Participants

6

Reactant 2

HCID 67184N-bromobutanimideHCID 497850107-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

Product 1

HCID 497852023-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazineYield 76%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (3.30 g, 10 mmol, Example 1) and NBS (1.869 g, 10.50 mmol) were heated at 110° C. for 2 hr in Toluene (50 ml) and N,N-dimethylformamide (DMF) (10 ml). The mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml). Very bad emulsions were obtained that did not clear using brine, filteration or saturation with salt. Repeated extractions with ethyl acetate (×10) and treatment of the organic extracts with anhydrous sodium sulfate removed the water. The solvents were concentrated in vacuo, and the residue dissolved in chloroform (500 mL), dried over anhydrous sodium sulfate and concentrated to an oil. The crude oil was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100% gradient of [10% 2M NH3/MeOH in DCM]/DCM) to afford product 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (3.1 g, 7.59 mmol, 76% yield), as a beige foam. A 0.180 g sample of this material was further purified by mass-directed automated preparative HPLC and then dissolved in dichloromethane (5 ml) and treated with 4N HCl in dioxane (0.5 ml). The solvents were removed in vacuo and the resulting solid tritruated in diethyl ether to afford 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (0.095 g, 0.213 mmol, 2.135% yield).

Workup

  1. temperatureThe mixture was cooled
  2. concentrationconcentrated in vacuo
  3. customThe residue was partitioned between ethyl acetate (100 ml) and water (100 ml)
  4. extractionThe aqueous phase was extracted with ethyl acetate (100 ml)
  5. customVery bad emulsions were obtained
  6. extractionextractions with ethyl acetate (×10) and treatment of the organic extracts with anhydrous sodium sulfate
  7. customremoved the water
  8. concentrationThe solvents were concentrated in vacuo
  9. dissolutionthe residue dissolved in chloroform (500 mL)
  10. dry with materialdried over anhydrous sodium sulfate
  11. concentrationconcentrated to an oil
  12. customThe crude oil was purified by flash chromatography (Biotage SP4, 40+M
  13. washeluting with a 0-100% gradient of [10% 2M NH3/MeOH in DCM]/DCM)

Sources & evidence

ORD record
ord-900cad469c9247be8b911885152551eb
Source dataset
uspto-grants-2013_08
Patent number
US08513248B2

Reaction notes

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