Tetrahydrofuran → HCID 66685982, compound

HRID 337035Notes

Reaction equation

HRID 337035 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(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])=O.[NH4+:39].O1[CH2:44][CH2:43][CH2:42]C1>O.[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C(O)=O>[CH:42]1([NH:39][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]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:3]3=[O:20])[CH:10]=2)[CH2:43][CH2:44]1

Participants

11

Reactant 5

HCID 8028TetrahydrofuranHCID 10340Sodium CarbonateHCID 66827Phenylboronic Acid2×HCID 2723923Ammonium formateHCID 66688740methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate

Product 1

HCID 66685982HCID 66685982, compound

Reagents, catalysts & solvents 5

HCID 23938PalladiumCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 284Formic AcidSolventHCID 702EthanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
120 °C

Procedure

To a stirred solution of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 0.2 g) in tetrahydrofuran (2 mL) and water (1 mL) was added phenylboronic acid (61 mg), sodium carbonate (105 mg) and tetrakis(triphenylphosphine)palladium(0) (20 mg). The reagents were heated within a microwave at 120° C. for 30 minutes. The reaction was cooled to room temperature, phenylboronic acid (30 mg) added and then heated within a microwave at 80° C. for 40 minutes. The reaction was cooled to room temperature followed by the addition of ammonium formate (0.4 g), 10% palladium on carbon (30 mg), formic acid (0.2 mL) and ethanol (1 mL). The reaction mixture was heated within a microwave for 60 minutes at 100° C. before being cooled to room temperature. Water was added and the mixture extracted with ethyl acetate. The pooled organic were washed with water, dried (Na2SO4), filtered and concentrated. The product was taken up in tetrahydrofuran (4 mL) followed by the addition of cyclopropylamine (0.22 mL) and cyclopentylmagnesium bromide (2M in diethyl ether, 1.5 mL) dropwise. After stirring for 60 minutes, ethanol (2 mL) was added and the mixture was purified by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) to afford the title compound as a solid (20 mg).

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. temperatureheated within a microwave at 80° C. for 40 minutes
  3. temperatureThe reaction was cooled to room temperature
  4. temperatureThe reaction mixture was heated within a microwave for 60 minutes at 100° C.
  5. temperaturebefore being cooled to room temperature
  6. extractionthe mixture extracted with ethyl acetate
  7. washThe pooled organic were washed with water
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. additionfollowed by the addition of cyclopropylamine (0.22 mL) and cyclopentylmagnesium bromide (2M in diethyl ether, 1.5 mL) dropwise
  12. additionethanol (2 mL) was added
  13. customthe mixture was purified by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent)

Sources & evidence

ORD record
ord-cfac09981990447eaecdf006af24408b
Source dataset
uspto-grants-2014_11
Patent number
US08889692B2

Reaction notes

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