Acetone → racemic cis-1-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidine-3,4-diol

HRID 1529388Notes

Reaction equation

HRID 1529388 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[CH:29]=[N:28]C=C(N2CCC=CC2)[N:25]=1.[CH3:36][N+:37]1([O-])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.OS([O-])=O.[Na+].[CH3:49][C:50](C)=[O:51]>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[N:25]=[C:42]([N:37]2[CH2:36][CH2:49][C@H:50]([OH:51])[C@H:39]([OH:40])[CH2:38]2)[CH:41]=[N:28][CH:29]=1

Participants

7

Reactant 4

HCID 180AcetoneHCID 82029Methyl morpholine oxide3×HCID 23665763Sodium BisulfiteHCID 679596105-(2,6-difluorophenyl)-3-(6-(5,6-dihydropyridin-1(2H)-yl)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Product 1

HCID 67959584racemic cis-1-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidine-3,4-diolYield 41.5%

Reagents, catalysts & solvents 2

HCID 30318Osmium TetroxideCatalyst3×HCID 962WaterSolvent4×

Procedure

To a bright yellow slurry of 5-(2,6-difluorophenyl)-3-(6-(5,6-dihydropyridin-1(2H)-yl)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.225 g, 0.475 mmol) and NMO (aldrich) (0.083 g, 0.713 mmol) in 3 mL acetone and 1 mL water was added osmium tetroxide 4% solution in water (aldrich) (0.151 mL, 0.024 mmol). The reaction was sealed and stirred rapidly over the weekend. The heterogeneous reaction was refreshed with NMO (aldrich) (0.083 g, 0.713 mmol) and osmium tetroxide 4% solution in water (aldrich) (0.151 mL, 0.024 mmol) and stirred rapidly for 36 h. The heterogeneous reaction was refreshed with NMO (aldrich) (0.083 g, 0.713 mmol) and osmium tetroxide 4% solution in water (Aldrich) (0.151 mL, 0.024 mmol) and stirred rapidly 48 h. The reaction was treated with 2 mL sat'd aqueous NaHSO3, and partitioned between water and DCM. The aqueous layer was extracted with DCM 4 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with 10% MeOH in DCM and adsorbed onto 2 g silica gel, then purified by silica gel chromatography (40 g column) using 0-75% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford racemic cis-1-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidine-3,4-diol (0.10 g, 0.197 mmol, 41.5% yield) as a yellow solid: MS (ESI, pos. ion) m/z: 508 (M+1).

Workup

  1. customThe reaction was sealed
  2. customThe heterogeneous reaction
  3. stirringstirred rapidly for 36 h
  4. customThe heterogeneous reaction
  5. stirringstirred rapidly 48 h
  6. additionThe reaction was treated with 2 mL
  7. custompartitioned between water and DCM
  8. extractionThe aqueous layer was extracted with DCM 4 times
  9. dry with materialthe combined organics were dried over anhydrous Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. additionThe material was treated with 10% MeOH in DCM
  13. custompurified by silica gel chromatography (40 g column)
  14. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-a98339c3408546d9a31da5dd57cb9906
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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