Potassium Phosphate, Tribasic → (3R,3aR,6R,6aR)-6-((6-chloro-5-(2-fluoro-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

HRID 929239Notes

Reaction equation

HRID 929239 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[N:11](COCC[Si](C)(C)C)[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[F:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][C:32]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CS(C)=O.CC([P+](Cl)(C(C)(C)C)C(C)(C)C)(C)C.C1C=CC(C2C(N)=CC=CC=2)=CC=1.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[C:35]1[CH:34]=[CH:33][C:32]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:31]([F:30])[CH:36]=1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27746982-Fluoro-4-biphenylboronic AcidHCID 90042470(3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

Product 1

HCID 90067395(3R,3aR,6R,6aR)-6-((6-chloro-5-(2-fluoro-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

Reagents, catalysts & solvents 3

HCID 91885323Palladium(2+);2-phenylaniline;tritert-butyl(chloro)phosphaniumCatalystHCID 679Dimethyl SulfoxideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
25 °C

Procedure

A mixture of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (40 mg, 0.072 mmol) and (2-fluoro-[1,1′-biphenyl]-4-yl)boronic acid (18.72 mg, 0.087 mmol) in anhydrous dioxane (0.4 ml) was purged with N2 and then chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (7.4 mg, 0.014 mmol) and tripotassium phosphate (0.217 ml, 0.217 mmol) were added under N2 flow. The mixture was stirred at 25° C. overnight. The crude mixture was extracted with DCM and the combined organic extracts were washed with water and evaporated under reduced pressure. 1 ml of 1:1 CH2Cl2 and TFA was added to the resulting residue and the reaction mixture was stirred for 2 hours. Then the solvent was evaporated under reduced pressure to give an amber residue. The residue was diluted with 1.5 ml DMSO, filtered and purified by mass directed reverse phase column chromatography eluting with acetonitrile/water+0.1% TFA to give the title product. LC-MS: calculated for C24H19ClFN3O4, 467.10, observed m/e: 468.11 (M+H)+ (RT 0.76/2.00 min).

Workup

  1. customwas purged with N2
  2. extractionThe crude mixture was extracted with DCM
  3. washthe combined organic extracts were washed with water
  4. customevaporated under reduced pressure
  5. addition1 ml of 1:1 CH2Cl2 and TFA was added to the resulting residue
  6. stirringthe reaction mixture was stirred for 2 hours
  7. customThen the solvent was evaporated under reduced pressure
  8. customto give an amber residue
  9. filtrationfiltered
  10. custompurified by mass
  11. washeluting with acetonitrile/water+0.1% TFA

Sources & evidence

ORD record
ord-b91a81b20d904096a77743f119e11b84
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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