Pentane → 6-(4-hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester

HRID 2390924Notes

Reaction equation

HRID 2390924 reaction equation
C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Na+].[H-].[Na+].[Br:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:26][NH:27]2)=[CH:23][CH:22]=1.C([Li])(C)(C)C.CCCCC.[O:47]1[CH2:52][CH2:51][C:50](=[O:53])[CH2:49][CH2:48]1>O1CCCC1>[Br:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:26][NH:27]2)=[CH:23][CH:22]=1.[C:33]([O:32][C:30]([C:25]1[C:24]2[C:28](=[CH:29][C:21]([C:50]3([OH:53])[CH2:51][CH2:52][O:47][CH2:48][CH2:49]3)=[CH:22][CH:23]=2)[NH:27][N:26]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]

Participants

10

Reactant 7

HCID 8003PentaneHCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 90495Di-tert-butyl dicarbonateHCID 121599Tetrahydro-4H-pyran-4-oneHCID 66702912tert-Butyl 6-bromo-1H-indazole-3-carboxylateHCID 178418306HCID 178418306, compound

Product 2

HCID 667025586-(4-hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl esterYield 68%HCID 66702912tert-Butyl 6-bromo-1H-indazole-3-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

tert-Butyl 6-bromoindazole-3-carboxylate was prepared from the acid by reaction with a 2-fold excess of di-tert-butyldicarbonate followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% mineral oil dispersion) (4.8 mmol) in tetrahydrofuran (40 mL) at 0° C. was slowly added a solution of tert-butyl 6-bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL). After stifling for 0.5 h at 0° C., the mixture was cooled to −78° C. and a 1.7 M solution of tert-butyllithium in pentane (5.1 mmol) was added. After 0.5 h at −78° C., a solution of tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h and warmed to 0° C. The reaction mixture was quenched with saturated aqueous ammonium chloride and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine (50 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (70/30 ethyl acetate/hexanes) to yield 6-(4-hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (68%) as a colorless solid.

Workup

  1. waitAfter 0.5 h at −78° C.
  2. temperaturewarmed to 0° C
  3. customThe reaction mixture was quenched with saturated aqueous ammonium chloride
  4. customthe mixture was partitioned between ethyl acetate (100 mL) and water (100 mL)
  5. customThe organic layer was separated
  6. washwashed with brine (50 mL)
  7. dry with materialdried (magnesium sulfate)
  8. concentrationconcentrated
  9. customThe residue was purified by chromatography (70/30 ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-0f3e3bfd5a4c47c5b538db696176091b
Source dataset
uspto-grants-2012_09
Patent number
US08273891B2

Reaction notes

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