Hydrochloric Acid → 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

HRID 1893423Notes

Reaction equation

HRID 1893423 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].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCOCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:21][N:22]=[C:16]2[CH2:15]1)=[O:13]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 72362-BromotolueneHCID 10796Cesium carbonateHCID 11776TriphenylphosphineHCID 497850107-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

Product 1

HCID 497853687-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazineYield 5.92%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
90 °C

Procedure

7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.330 g, 1 mmol, Example 1), 1-bromo-2-methylbenzene (0.132 mL, 1.100 mmol), palladium(II)acetate (0.011 g, 0.050 mmol), triphenylphosphine (0.026 g, 0.100 mmol) and cesium carbonate (0.342 g, 1.050 mmol) were suspended in 1,4-dioxane (5 ml) under argon. The mixture was degassed 3 times and heated at 90° C. for 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml), the combined organic extracts were washed with water (3×50 ml), brine (50 ml) dried over anhydrous sodium sulfate and concentrated to a crude oil. The crude oil was purified by mass-directed automated preparative HPLC to afford the free base that was dissolved in dichloromethane (5 ml) and treated with 4N HCl in dioxane. The solvents were removed in vacuo and the solid tritruated with diethyl ether to afford 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.027 g, 0.059 mmol, 5.92% yield).

Workup

  1. customThe mixture was degassed 3 times
  2. customThe solvent was removed in vacuo
  3. customthe residue partitioned between ethyl acetate (50 ml) and water (50 ml)
  4. extractionThe aqueous phase was extracted with ethyl acetate (2×50 ml)
  5. washthe combined organic extracts were washed with water (3×50 ml), brine (50 ml)
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated to a crude oil
  8. customThe crude oil was purified
  9. customto afford the free base that
  10. customThe solvents were removed in vacuo

Sources & evidence

ORD record
ord-ea37b71eb32d4cd293262fa46067e466
Source dataset
uspto-grants-2013_08
Patent number
US08513248B2

Reaction notes

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