Potassium Phosphate, Dibasic → (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one

HRID 2209060Notes

Reaction equation

HRID 2209060 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][N:14]([C@@H](C3C=CC(OC)=CC=3)C)[C:13](=[O:26])[CH2:12]2)[CH3:10])[C:5]2[N:27]([CH3:31])[C:28]([CH3:30])=[N:29][C:4]=2[CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].OP([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:26])[CH2:12]3)[CH3:10])[C:5]3[N:27]([CH3:31])[C:28]([CH3:30])=[N:29][C:4]=3[CH:3]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]

Participants

7

Reactant 4

HCID 24450Potassium Phosphate, DibasicHCID 27347023,4-Dimethoxyphenylboronic acidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 117843040(R)-4-((R)-1-(6-chloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one

Product 1

HCID 117843262(R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
100 °C

Procedure

In a microwave vial, (R)-4-((R)-1-(6-chloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.48 (0.1 g, 0.22 mmol), 3,4-dimethoxyphenylboronic acid (43 mg, 0.23 mmol), K2HPO4 (154 mg, 0.67 mmol), X-phos (54 mg, 0.11 mmol) and Pd2(dba)3 (21 mg, 0.023 mmol) were added. Vial was sealed and reagents were taken up in isopropanol (5 mL). After evacuating and backfilling with argon, mixture was heated at 100° C. for one to three hours. After cooling to room temperature, mixture is poured into water and extracted with ethyl acetate. Combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure and resulting residues were used for next step without further purification. Residues were dissolved in trifluoroacetic acid (3 mL), and were heated at 55-60° C. for 6 hr. After cooling to room temperature, mixture was concentrated under reduced pressure, taken up in ethyl acetate, washed with saturated NaHCO3 (aq), and layers separated. Combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to yield residues. Residues were purified via reverse phase chromatography to yield (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.05.

Workup

  1. customVial was sealed
  2. customAfter evacuating
  3. temperatureAfter cooling to room temperature
  4. additionmixture is poured into water
  5. extractionextracted with ethyl acetate
  6. dry with materialCombined organics were dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customresulting residues
  10. customwere used for next step without further purification
  11. dissolutionResidues were dissolved in trifluoroacetic acid (3 mL)
  12. temperaturewere heated at 55-60° C. for 6 hr
  13. temperatureAfter cooling to room temperature
  14. concentrationmixture was concentrated under reduced pressure
  15. washwashed with saturated NaHCO3 (aq), and layers
  16. customseparated
  17. washCombined organic layers were washed with brine
  18. dry with materialdried over MgSO4
  19. filtrationfiltered
  20. concentrationconcentrated under reduced pressure
  21. customto yield residues
  22. customResidues were purified via reverse phase chromatography

Sources & evidence

ORD record
ord-a21dfa1cb82f45f2883e6d1b579305ba
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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