2-Methyl-2-butene → 6-Chloro-5-(4-(1-(hydroxymethyl)cyclobutyl)phenyl)-1h-indole-3-carboxylic acid

HRID 338398Notes

Reaction equation

HRID 338398 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]([C:19]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1

Participants

8

Reactant 4

HCID 105532-Methyl-2-buteneHCID 516949Sodium Phosphate, Monobasic, MonohydrateHCID 23668197Sodium ChloriteHCID 866987376-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde

Product 1

HCID 717659566-Chloro-5-(4-(1-(hydroxymethyl)cyclobutyl)phenyl)-1h-indole-3-carboxylic acidYield 32%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of 6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde (80 mg, 0.24 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (420 mg, 4.80 mmol) and sodium phosphate monobasic hydrate (650 mg, 4.80 mmol) in water (3 mL) dropwise via additional funnel. The ice bath was removed, and the reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo to give a residue, which was purified by prep-HPLC (Kromasil Eternity-5-C18 150*30 mm*5 μm Mobile phase: from 35% MeCN in water (0.1% TFA) to 50% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylic acid (25 mg, 32% yield) as a white solid. MS (ES+) 377.9 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.97 (s, 1H), 7.57 (s, 1H), 7.39 (d, 2H), 7.23 (d, 2H), 3.70 (s, 2H), 2.39-2.30 (m, 4H), 2.11-2.09 (m, 1H), 1.92-1.91 (m, 1H).

Workup

  1. customThe ice bath was removed
  2. customThe solvent was removed in vacuo
  3. customto give a residue, which
  4. customwas purified by prep-HPLC (Kromasil Eternity-5-C18 150*30 mm*5 μm Mobile phase: from 35% MeCN in water (0.1% TFA) to 50% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min)

Sources & evidence

ORD record
ord-3967a5d3be5949e6b3bb17d058d7aa9f
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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