Cesium carbonate → 1-(2,2-Dimethylpropyl)-5-[2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

HRID 629859Notes

Reaction equation

HRID 629859 reaction equation
FC(F)(F)S(O[C:7]1[CH:8]2[CH2:14][CH2:13][CH:11]([CH:12]=1)[N:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:9]2)(=O)=O.[C:25]([O-])(=O)C.[K+].Cl[C:31]1[N:36]=[C:35]2[N:37]([CH3:45])[C:38](=[O:44])[N:39]([CH2:40][CH:41]3[CH2:43][CH2:42]3)[C:34]2=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O.O1CCOCC1>[CH3:25][C:41]([CH3:42])([CH3:43])[CH2:40][N:39]1[C:34]2[C:35](=[N:36][C:31]([C:7]3[CH:8]4[CH2:14][CH2:13][CH:11]([CH:12]=3)[N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9]4)=[CH:32][CH:33]=2)[N:37]([CH3:45])[C:38]1=[O:44]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 517044Potassium AcetateHCID 772308275-chloro-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneHCID 892876972-(4-Methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl trifluoromethanesulfonate

Product 1

HCID 1177024961-(2,2-Dimethylpropyl)-5-[2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418851HCID 178418851, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

2-(4-Methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl trifluoromethanesulfonate (2-3, 6.2 g, 17.1 mmol, 1.0 equiv), bis(pinocolato)diboron (4.8 g, 18.8 mmol, 1.1 equiv), potassium acetate (5.0 g, 51.2 mmol, 3.0 equiv) and PdCl2(dppf) (0.87 g, 1.2 mmol, 0.07 equiv) were added to anhydrous 1,4-dioxane (22 mL) and heated to 60° C. After 18 h, the reaction contents were cooled to RT, followed by the subsequent addition of water (4.3 mL), 5-chloro-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]-pyridin-2-one (1-4, 4.3 g, 17.1 mmol, 1.0 equiv), Cs2CO3 (11.2 g, 34.3 mmol, 2.01 equiv) and bis(tri-tert-butylphosphine)palladium(0) (1.1 g, 2.22 mmol, 0.13 equiv). The resulting mixture was heated to 60° C. for 4.5 h. Following this duration, LCMS showed consumption of starting material. The contents were then cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through Celite and rinsed with ethyl acetate (3×70 mL) and water (1×30 mL). The filtrate layers were separated and the combined organics were washed with saturated NaHCO3 (120 mL). The combined aqueous layers were then back-extracted with ethyl acetate (2×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a dark red oil. Purification by normal-phase chromatography (0-50% EtOAc:Hex) afforded 2-4 as an off-white solid. MS m/z (M+H): calculated=433.2598; observed=433.2591.

Workup

  1. customthe reaction contents
  2. temperaturewere cooled to RT
  3. temperatureThe resulting mixture was heated to 60° C. for 4.5 h
  4. customconsumption of starting material
  5. temperatureThe contents were then cooled to room temperature
  6. additiondiluted with ethyl acetate (100 mL)
  7. filtrationfiltered through Celite
  8. washrinsed with ethyl acetate (3×70 mL) and water (1×30 mL)
  9. customThe filtrate layers were separated
  10. washthe combined organics were washed with saturated NaHCO3 (120 mL)
  11. extractionThe combined aqueous layers were then back-extracted with ethyl acetate (2×50 mL)
  12. dry with materialThe combined organics were dried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customto give a dark red oil
  16. customPurification by normal-phase chromatography (0-50% EtOAc:Hex)

Sources & evidence

ORD record
ord-a260211d1a13440fb7492c0a5e93d607
Source dataset
uspto-grants-2016_04
Patent number
US09315518B2

Reaction notes

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