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

HRID 1054741
Notes
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Reaction equation

HRID 1054741 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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

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, 1 H), 7.39 (d, 2 H), 7.23 (d, 2 H), 3.70 (s, 2H), 2.39-2.30 (m, 4 H), 2.11-2.09 (m, 1 H), 1.92-1.91 (m, 1 H).

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-ccd9db566ada46a59619d983829fed40
Source dataset
uspto-grants-2016_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09394285B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes