Sodium Chlorite → 6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylic acid

HRID 338403Notes

Reaction equation

HRID 338403 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[CH:15][CH:14]=1.Cl([O-])=[O:26].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:26])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[CH:17][CH:18]=1

Participants

8

Reactant 3

HCID 23668197Sodium Chlorite2×HCID 23673460Sodium Phosphate, Monobasic, Dihydrate2×HCID 866987406-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carbaldehyde

Product 1

HCID 866987416-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylic acidYield 4.1%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolventHCID 105532-Methyl-2-buteneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carbaldehyde (crude, 0.23 g, 0.68 mmol) in acetonitrile (8 mL) and tert-butanol (8 mL) was added 2-methyl-2-butene (8 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (683 mg, 7.50 mmol) and sodium phosphate monobasic dihydrate (1.59 g, 10.2 mmol) in water (4 mL) dropwise. The reaction mixture was stirred at room temperature for two hours and treated with additional sodium chlorite (911 mg, 10.0 mmol) and sodium phosphate monobasic dihydrate (2.12 g, 13.6 mmol) in H2O (4 mL) and 2-methyl-2-butene (2 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified via prep-HPLC to give 6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylic acid (10 mg) as a solid. MS (ES+) 354.9 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.01 (m, 2H), 7.59 (s, 1H), 7.3-7.5 (m, 4H), 3.40-4.00 (m, 5H), 3.06 (s, 3H), 2.1-2.7 (m, 2H).

Workup

  1. stirringThe resulting mixture was stirred at room temperature for 16 h
  2. customThe reaction mixture was evaporated in vacuo
  3. extractionthe aqueous residue was extracted with EtOAc (3×30 mL)
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified via prep-HPLC

Sources & evidence

ORD record
ord-a814e18d086b48ef83f36cfd838bb6de
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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