Phenol → HCID 66686295, compound

HRID 337036Notes

Reaction equation

HRID 337036 reaction equation
Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6](Br)[N:7]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([N:31](CC)[CH:32]([CH3:34])[CH3:33])(C)C.C1CC=CCC=1>[Pd].O1CCCC1>[CH:32]1([NH:31][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([O:27][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:3]3=[O:20])[CH:10]=2)[CH2:34][CH2:33]1

Participants

7

Reactant 4

HCID 996PhenolHCID 123431,4-CyclohexadieneHCID 81531DiisopropylethylamineHCID 66688740methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate

Product 1

HCID 66686295HCID 66686295, compound

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
140 °C

Procedure

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 204 mg), phenol (206 mg), N,N-diisopropylethylamine (0.3 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 60 minutes at 140° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 38 mg) and tetrahydrofuran (1 mL). 1,4-Cyclohexadiene (1 mL) was added and the mixture was heated under atmosphere of nitrogen within a microwave for 10 minutes at 90° C. before being cooled to room temperature. The mixture was filtered and concentrated. The residue was treated with tetrahydrofuran (10 mL), water (2 mL) and lithium hydroxide (193 mg). The mixture was stirred for 2 h, diluted with ethyl acetate, washed with 2M hydrochloric acid and water. The organic phase was dried (Na2SO4) and concentrated. The solid was washed with small amount of diethyl ether and treated with dichloromethane (3 mL) then N,N-dimethylformamide (1 drop) and oxalyl chloride (0.05 mL) were added. The mixture was stirred till solid disappeared and the solution of acid chloride was transferred to a solution of cyclopropylamine (0.3 mL) in dichloromethane (5 mL). The resulting mixture was stirred for 30 min. then diluted with ethyl acetate (50 mL). The mixture was washed with 2M hydrochloric acid and twice with water. The organic phase was dried (Na2SO4) and concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (70 mg).

Workup

  1. temperaturebefore being cooled to room temperature
  2. temperaturethe mixture was heated under atmosphere of nitrogen within a microwave for 10 minutes at 90° C.
  3. temperaturebefore being cooled to room temperature
  4. filtrationThe mixture was filtered
  5. concentrationconcentrated
  6. additionThe residue was treated with tetrahydrofuran (10 mL), water (2 mL) and lithium hydroxide (193 mg)
  7. additiondiluted with ethyl acetate
  8. washwashed with 2M hydrochloric acid and water
  9. dry with materialThe organic phase was dried (Na2SO4)
  10. concentrationconcentrated
  11. washThe solid was washed with small amount of diethyl ether
  12. additiontreated with dichloromethane (3 mL)
  13. additionN,N-dimethylformamide (1 drop) and oxalyl chloride (0.05 mL) were added
  14. stirringThe mixture was stirred till solid
  15. stirringThe resulting mixture was stirred for 30 min.
  16. additionthen diluted with ethyl acetate (50 mL)
  17. washThe mixture was washed with 2M hydrochloric acid and twice with water
  18. dry with materialThe organic phase was dried (Na2SO4)
  19. concentrationconcentrated in vacuo
  20. customPurification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent)

Sources & evidence

ORD record
ord-370a8168627845e4a96be329f2ed97f3
Source dataset
uspto-grants-2014_11
Patent number
US08889692B2

Reaction notes

Loading…