Acetic Acid → (4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone

HRID 1025882Notes

Reaction equation

HRID 1025882 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.C([O:35]B(OC(C)C)OC(C)C)(C)C.C([Li])CCC.C(=O)=O.C(O)(=O)C.OO>O1CCCC1>[CH:25]1([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([C:13]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[C:29]([Cl:30])[C:2]([OH:35])=[CH:3][C:4]=3[Cl:31])=[O:14])[CH2:16][CH2:17]2)[CH2:27][CH2:26]1

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 280Carbon DioxideHCID 784Hydrogen PeroxideHCID 21531Triisopropyl borateHCID 53312111[4-(4-Bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanoneHCID 178418339Butyllithium

Product 1

HCID 53311358(4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanoneYield 65.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-75 °C

Procedure

To a solution of 1.0 g (1.93 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 26) in 20 mL dry tetrahydrofuran was added 0.85 mL (3.72 mmol) triisopropylborate (commercially available, CAS RN 5419-55-6). The solution was cooled to −75° C. using a dry ice bath and 1.50 mL (2.4 mmol) n-butyllithium solution (1.6M in n-hexane) was added over 3 min. to the reaction mixture. Stirring was continued for another 1.5 hours. The dry-ice bath was replaced by an ice bath and 0.98 g (8.17 mmol) acetic acid (50% solution in water) and 0.28 g (2.89 mmol) hydrogen peroxide (35% solution in water) were added. The reaction mixture was stirred at 0° C. for 1 hour, the cooling batch was removed and stirring was continued at room temperature for 20 hours. The solution was poured on 10% aqueous sodium thiosulfate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 0.575 g (65%) of the title compound as a light brown solid. MS (ESI): m/z=456.2 [M+H]+.

Workup

  1. stirringThe reaction mixture was stirred at 0° C. for 1 hour
  2. customthe cooling batch was removed
  3. stirringstirring
  4. waitwas continued at room temperature for 20 hours
  5. additionThe solution was poured on 10% aqueous sodium thiosulfate solution
  6. extractionextracted three times with ethyl acetate
  7. washThe combined organic layers were washed with brine
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. additiontreated with silica gel
  11. customevaporated to dryness
  12. customThe resulting powder was purified by silica gel chromatography

Sources & evidence

ORD record
ord-7faccb82e4d74b0e8f6aec490df7cadd
Source dataset
uspto-grants-2014_05
Patent number
US08729091B2

Reaction notes

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