Water → 2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzonitrile

HRID 1967035Notes

Reaction equation

HRID 1967035 reaction equation
Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([Cl:31])[CH:3]=1.[NH:32]1CCC[C@H:33]1C(O)=O.[Cu]C#N.O>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:29]1[CH:28]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])[C:4]([Cl:31])=[CH:3][C:2]=1[C:33]#[N:32]

Participants

7

Reactant 4

HCID 962WaterHCID 145742L-ProlineHCID 53312111[4-(4-Bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanoneHCID 178418546HCID 178418546, compound

Product 1

HCID 533112742,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzonitrileYield 25.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

To a suspension of 0.20 g (0.43 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 26) in 0.2 mL N,N-dimethylformamide was added 0.044 g (0.38 mmol) L-proline (commercially available, CAS RN 147-85-3) followed by the addition of 0.068 g (0.76 mmol) copper(I) cyanide. The resulting dark brown suspension was stirred at 120° C. for 17 hours. Then another 0.2 mL N,N-dimethylformamide were added and stirring was continued for another 7 hours at 120° C. The reaction was allowed to cool to room temperature, stirred for another 64 hours and then partioned between water and ethyl acetate. The resulting turbid mixture was filtered and washed with ethyl acetate. The layers of the filtrate were separated and the water layer extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The remaining light brown oil was dissolved in dichloromethane, treated with silica gel and then evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to afford 0.045 g (25%) of the title compound as a brown solid. MS (ESI): m/z=465.1 [M+H]+.

Workup

  1. stirringstirring
  2. waitwas continued for another 7 hours at 120° C
  3. temperatureto cool to room temperature
  4. stirringstirred for another 64 hours
  5. filtrationThe resulting turbid mixture was filtered
  6. washwashed with ethyl acetate
  7. customThe layers of the filtrate were separated
  8. extractionthe water layer extracted twice with ethyl acetate
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried over magnesium sulfate
  11. filtrationfiltered
  12. customevaporated to dryness
  13. dissolutionThe remaining light brown oil was dissolved in dichloromethane
  14. additiontreated with silica gel
  15. customevaporated
  16. customThe resulting powder was purified by silica gel chromatography

Sources & evidence

ORD record
ord-4a86084415f44c7a86febe6d893e3ff5
Source dataset
uspto-grants-2013_04
Patent number
US08420647B2

Reaction notes

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