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

HRID 929238Notes

Reaction equation

HRID 929238 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[N:25](COCC[Si](C)(C)C)[C:24]([O:34][C@H:35]3[C@H:39]4[O:40][CH2:41][C@@H:42]([OH:43])[C@H:38]4[O:37][CH2:36]3)=[N:23][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[CH:46]=1.N#N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CS(C)=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:25][C:24]([O:34][C@H:35]3[C@H:39]4[O:40][CH2:41][C@@H:42]([OH:43])[C@H:38]4[O:37][CH2:36]3)=[N:23][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:45]2[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[CH:46]=2)=[CH:10][CH:9]=1

Participants

8

Reactant 4

HCID 947NitrogenHCID 62657Potassium Phosphate, TribasicHCID 108220943-Bromo-5-fluoroanisoleHCID 89558876(3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

Product 1

HCID 90067406(3R,3aR,6R,6aR)-6-((6-chloro-5-(3'-fluoro-5'-methoxy-[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 105144Allyl(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)chloropalladium(II)CatalystHCID 679Dimethyl SulfoxideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

(3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (40 mg, 0.063 mmol) and 1-bromo-3-fluoro-5-methoxybenzene (15.62 mg, 0.076 mmol) in anhydrous dioxane (0.4 ml) was purged with N2 and then chloro[tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6.5 mg, 0.013 mmol) and tripotassium phosphate (0.191 ml, 0.191 mmol) were added under N2 flow. The mixture was heated to 60° C. overnight. Then the crude mixture was extracted with DCM. 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 solution was stirred for 2 h. 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 C25H21ClFN3O5, 497.12, observed m/e: 498.11 (M+H)+ (RT 1.03/2.00 min)

Workup

  1. extractionThen the crude mixture was extracted with DCM
  2. washThe combined organic extracts were washed with water
  3. customevaporated under reduced pressure
  4. addition1 mL of 1:1 CH2Cl2 and TFA was added to the resulting residue
  5. customThen the solvent was evaporated under reduced pressure
  6. customto give an amber residue
  7. filtrationfiltered
  8. custompurified by mass
  9. washeluting with acetonitrile/water+0.1% TFA

Sources & evidence

ORD record
ord-46c9da3292ac487ebb793ea7f5a3b4aa
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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