1,2-Dimethoxyethane → (R)-4-((R)-1-((3-cyclopropyl-6-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one

HRID 2209154Notes

Reaction equation

HRID 2209154 reaction equation
Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[F:23][CH:24]([F:44])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][C:28]=1[O:42][CH3:43].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.CCOC(C)=O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH:24]([F:44])[F:23])=[C:28]([O:42][CH3:43])[CH:29]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 117843105(R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-onHCID 1317359792-(4-(2,2-Difluoroethoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Product 1

HCID 117843862(R)-4-((R)-1-((3-cyclopropyl-6-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
105 °C

Procedure

In a 50 mL 3-neck flask with a magnetic stir bar and condenser was placed (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-on (125 mg, 0.34 mmol), 2-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (135 mg, 0.43 mmol) and Pd(PPh3)4 (40 mg, 0.027 mmol). Evacuated and filled with nitrogen 3×. Added 2.5 mL DME and 2N sodium carbonate (0.51 ml, 1.03 mmol) via syringe and heated in a 105° C. oil bath for 2 hrs at which time LC-MS indicated a complete reaction. Let cool, added EtOAc and water, separated, washed with brine, dried over Na2SO4, filtered and concentrated. Purified by chromatography: ISCO 50 g C18 reverse phase 0-30% water/acetonitrile/0.1% TFA. Partially concentrated under reduced pressure added EtOAc and sat.aq.bicarb, separated, washed with brine, dried over Na2SO4, filtered and concentrated to give a white solid.

Workup

  1. customIn a 50 mL 3-neck flask with a magnetic stir bar and condenser was placed
  2. customEvacuated
  3. additionfilled with nitrogen 3×
  4. customa complete reaction
  5. temperatureLet cool
  6. customseparated
  7. washwashed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customPurified by chromatography
  12. concentrationPartially concentrated under reduced pressure
  13. additionadded EtOAc and sat.aq.bicarb
  14. customseparated
  15. washwashed with brine
  16. dry with materialdried over Na2SO4
  17. filtrationfiltered
  18. concentrationconcentrated
  19. customto give a white solid

Sources & evidence

ORD record
ord-8f9abc8748824d66a95e253641f7746b
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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