2-Methyl-2-butene → 5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carboxylic acid

HRID 1054586Notes

Reaction equation

HRID 1054586 reaction equation
[C:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][C:24]=3[Cl:25])[NH:21][CH:20]=[C:19]4[CH:26]=[O:27])=[CH:12][CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2].CC(=CC)C.Cl([O-])=[O:34].[Na+].O.OP([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.O>[C:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][C:24]=3[Cl:25])[NH:21][CH:20]=[C:19]4[C:26]([OH:34])=[O:27])=[CH:14][CH:15]=2)[CH2:5]1)(=[O:3])[CH3:2]

Participants

9

Reactant 5

HCID 105532-Methyl-2-buteneHCID 24437Sodium SulfiteHCID 516949Sodium Phosphate, Monobasic, MonohydrateHCID 23668197Sodium ChloriteHCID 866985875-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde

Product 1

HCID 866985885-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carboxylic acidYield 12.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of 5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde (120 mg, 0.31 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) was added 2-methyl-2-butene (2.17 g, 31 mmol). The mixture was cooled to 0° C., and treated with a solution of sodium chlorite (418 mg, 6.2 mmol) and sodium phosphate monobasic hydrate (856 mg, 6.2 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 16 hours. A solution of sodium sulfite was added slowly to the reaction mixture, and stirred for 1 hour. The reaction mixture was partially evaporated in vacuo. The aqueous residue was extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. The residue was purified by preparative HPLC to give 5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carboxylic acid (15 mg, 12%) as a white solid. MS (ES+) 399.0 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.01 (m, 2H), 7.57 (s, 1H), 7.39 (d, 2H), 7.03 (d, 2H), 4.40 (m, 1H), 4.21 (m, 2H), 4.15 (m, 2H), 3.90 (m, 1H), 3.11 (m, 1H), 1.90 (s, 3H).

Workup

  1. stirringstirred for 1 hour
  2. customThe reaction mixture was partially evaporated in vacuo
  3. extractionThe aqueous residue was extracted with ethyl acetate (10 mL×3)
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give a brown residue
  8. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-8c6f24f27cff421db0d0118ef971d281
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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