2-Methyl-2-butene → 4,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carboxylic acid

HRID 1054623Notes

Reaction equation

HRID 1054623 reaction equation
[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:31])=[O:24])=[CH:5][NH:6]2

Participants

8

Reactant 4

HCID 105532-Methyl-2-buteneHCID 516949Sodium Phosphate, Monobasic, MonohydrateHCID 23668197Sodium ChloriteHCID 866986254,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carbaldehyde

Product 1

HCID 866986264,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carboxylic acidYield 10.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 4,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carbaldehyde (38 mg, 0.12 mmol) was dissolved in acetonitrile (1 mL) and warm tert-butanol (0.3 mL). The reaction mixture was treated with 2-methyl-2-butene (0.3 ml), cooled to 0° C., and treated with a solution of sodium chlorite (199 mg, 2.36 mmol) and sodium phosphate monobasic hydrate (332 mg, 2.41 mmol) in water (1 mL) via addition funnel. The ice bath was removed, and the reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was diluted with water (2 mL) and NH4Cl (2 mL). The product was extracted with EtOAc (3×20 mL). The organic layer was concentrated in vacuo to give the crude product, which was purified using prep-HPLC to give the title compound (4.3 mg). MS (ES+) 346.0 (M+H)+. Retention time: 2.04 min. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. Flow: 2.0 mL/min.

Workup

  1. customThe ice bath was removed
  2. temperaturethe reaction mixture was warmed to room temperature
  3. additionThe reaction mixture was diluted with water (2 mL) and NH4Cl (2 mL)
  4. extractionThe product was extracted with EtOAc (3×20 mL)
  5. concentrationThe organic layer was concentrated in vacuo
  6. customto give the crude product, which
  7. customwas purified

Sources & evidence

ORD record
ord-fda5f484053f471992a9378c37655770
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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