Potassium Phosphate, Tribasic → (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

HRID 929243Notes

Reaction equation

HRID 929243 reaction equation
P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:28][C@H:29]3[C@H:33]4[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]4[O:31][CH2:30]3)=[N:17][C:13]2=[N:14][C:15]=1I.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:56][CH2:55][N:54]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH2:53]3)=[CH:48][CH:47]=2)O1>O1CCOCC1.C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:28][C@H:29]3[C@H:33]4[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]4[O:31][CH2:30]3)=[N:17][C:13]2=[N:14][C:15]=1[C:46]1[CH:47]=[CH:48][C:49]([CH:52]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]([F:60])([F:59])[F:61])[CH2:53]2)=[CH:50][CH:51]=1

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 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-olHCID 900426383-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoroethyl)pyrrolidine

Product 1

HCID 131735111(3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Tripotassium phosphate 2.0 M aqueous solution (0.6 ml, 1.200 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (25.2 mg, 0.031 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-iodo-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (147.1 mg, 0.266 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoroethyl)pyrrolidine (94.6 mg, 0.266 mmol) in dioxane (2.1 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. After 18 hours, the reaction mixture was cooled to room temperature before being partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was separated and extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow residue. The residue was dissolved in DCM, loaded onto a 5 g silica solid load cartridge, and purified using an ISCO Rf and a 12 g silica column (CV=16.8 ml) by eluting as follows: 100% Hex (5 CV), 0-70% EtOAc/Hex gradient (50 CV), 70% EtOAc/Hex (35 CV) at 30 ml/min. The product fractions were combined and evaporated under reduced pressure to give the desired product as a yellow residue. LC-MS: calculated for C30H38ClF3N4O5Si 654.23 observed m/e: 655.32 (M+H)+ (Rt 1.37/2 min)

Workup

  1. customThe reaction mixture was degassed (3×)
  2. temperaturethe reaction mixture was cooled to room temperature
  3. custombefore being partitioned between EtOAc (50 ml) and water (50 ml)
  4. customThe aqueous layer was separated
  5. extractionextracted with EtOAc (2×50 ml)
  6. washwashed with brine (1×30 ml)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customevaporated under reduced pressure
  10. customto give a yellow residue
  11. custompurified
  12. washa 12 g silica column (CV=16.8 ml) by eluting
  13. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-ee56a64fb94d425f8ba21f88494c6ace
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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