2-Methyl-2-butene → 6-fluoro-5-[4-(1-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indole-3-carboxylic acid

HRID 338290Notes

Reaction equation

HRID 338290 reaction equation
[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:22]O[CH2:20]2)=[C:15]([O:24][CH3:25])[CH:14]=1.[CH3:26]C(=CC)C.Cl([O-])=O.[Na+].[OH2:35].[OH2:36].P([O-])(O)(O)=O.[Na+]>CC#N.O.C(O)(C)(C)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:36])=[O:35])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:20][CH2:26][CH2:22]2)=[C:15]([O:24][CH3:25])[CH:14]=1

Participants

8

Reactant 4

HCID 105532-Methyl-2-buteneHCID 23668197Sodium ChloriteHCID 23673460Sodium Phosphate, Monobasic, DihydrateHCID 866986366-fluoro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carbaldehyde

Product 1

HCID 866986386-fluoro-5-[4-(1-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indole-3-carboxylic acidYield 8.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
0 °C

Procedure

6-fluoro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carbaldehyde (86 mg, 0.2534 mmol) was dissolved in MeCN (6 mL) and warm t-butanol (6 mL). 2-methyl-2-butene (4 mL) was then added and cooled to 0° C. Sodium chlorite (342 mg, 5.07 mmol) and sodium dihydrogen phosphate dihydrate (791 mg, 5.07 mmol) were dissolved in water (3 mL). The aqueous solution was added to the organic solution dropwise via addition funnel and the ice bath was removed and the mixture was allowed to warm to room temperature. The reaction was quenched with saturated aqueous sodium sulfite, concentrated to remove the organics and extracted with EtOAc (20 mL×3). The combined organics were washed with brine (20 mL), dried and concentrated to give a crude residue, which was purified by prep HPLC to afford the title compound (7.3 mg, 8.1%) as an off-white solid.

Workup

  1. additionThe aqueous solution was added to the organic solution dropwise via addition funnel
  2. customthe ice bath was removed
  3. temperatureto warm to room temperature
  4. customThe reaction was quenched with saturated aqueous sodium sulfite
  5. concentrationconcentrated
  6. customto remove the organics and
  7. extractionextracted with EtOAc (20 mL×3)
  8. washThe combined organics were washed with brine (20 mL)
  9. customdried
  10. concentrationconcentrated
  11. customto give a crude residue, which
  12. customwas purified by prep HPLC

Sources & evidence

ORD record
ord-8e4ee619e53347b19a6b055ddb7436ac
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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