Lithium Hydroxide → 4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-5-yl]benzonitrile

HRID 929193Notes

Reaction equation

HRID 929193 reaction equation
[Li+].[OH-].[Cl:3][C:4]1[CH:5]=[C:6]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([O:22][C@H:23]3[C@H:27]4[O:28][CH2:29][C@@H:30]([OH:31])[C@H:26]4[O:25][CH2:24]3)=[N:11][C:7]2=[N:8][C:9]=1I.CC1(C)C(C)(C)OB([C:40]2[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=2)O1.CCOC(C)=O.CCCCCC>O1CCOCC1.O>[OH:31][C@@H:30]1[CH2:29][O:28][C@@H:27]2[C@H:23]([O:22][C:12]3[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]4[C:7]([N:11]=3)=[N:8][C:9]([C:40]3[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=3)=[C:4]([Cl:3])[CH:5]=4)[CH2:24][O:25][C@H:26]12

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 27346254-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 21226206Ethyl acetate hexane2×HCID 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 1317350904-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-5-yl]benzonitrile

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

LiOH (0.43 ml, 1.290 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (43.2 mg, 0.053 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-iodo-1-(2-trimethylsilylethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (284.9 mg, 0.514 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (143.1 mg, 0.625 mmol) in dioxane (4.2 ml) and water (0.60 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. for 1.5 hours. Then the reaction mixture was cooled and partitioned between EtOAc (50 ml) and water (50 mL). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×50 ml), dried over Na2SO4′ filtered, and evaporated under reduced pressure to give an amber residue. Flash chromatography of the residue utilizing a 12 g silica RediSep Rf® column and employing a 0-60% EtOAc/hexane gradient followed by 60% EtOAc/hexane afforded the title compound as a yellow residue. LC-MS: calculated for C25H29ClN4O5Si 528.16 observed m/e: 529.22 (M+H)+ (Rt 2.34/4 min).

Workup

  1. customThe reaction mixture was degassed (3×)
  2. temperatureThen the reaction mixture was cooled
  3. custompartitioned between EtOAc (50 ml) and water (50 mL)
  4. extractionThe aqueous layer was extracted with EtOAc (2×50 ml)
  5. washwashed with brine (1×50 ml)
  6. dry with materialdried over Na2SO4′
  7. filtrationfiltered
  8. customevaporated under reduced pressure
  9. customto give an amber residue

Sources & evidence

ORD record
ord-74dde2b4279d43e4b9ca19c36a0d948b
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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