2-Methyl-2-butene → 6-chloro-5-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-1H-indole-3-carboxylic acid

HRID 338405Notes

Reaction equation

HRID 338405 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([CH2:22][OH:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].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:30])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:22][OH:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1

Participants

8

Reactant 4

HCID 105532-Methyl-2-buteneHCID 23668197Sodium ChloriteHCID 23672064Monosodium phosphateHCID 866987426-Chloro-5-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)-1h-indole-3-carbaldehyde

Product 1

HCID 717678306-chloro-5-[4-[1-(hydroxymethyl)cyclopropyl]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)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde (80 mg, 0.24 mmol) in acetonitrile (3 mL) and tert-butanol (3 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 (650 mg, 4.80 mmol) in water (3 mL) dropwise via addition funnel. The reaction mixture was warmed to room temperature and stirred for 20 hours. The solvent was removed in vacuo to give a residue, which was purified by prep-HPLC (Column: Boston Symmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 36% MeCN in water (0.1% TFA) to 36% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carboxylic acid (25 mg, 32% yield) as a white solid. MS (ES+) 364.0 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 11.96 (s, 1H), 8.07 (d, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 7.38-7.32 (m, 4H), 4.73-4.71 (m, 1H), 3.58-3.57 (m, 2H), 0.88-0.77 (m, 4H).

Workup

  1. temperatureThe reaction mixture was warmed to room temperature
  2. customThe solvent was removed in vacuo
  3. customto give a residue, which
  4. customwas purified by prep-HPLC (Column: Boston Symmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 36% MeCN in water (0.1% TFA) to 36% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min)

Sources & evidence

ORD record
ord-e26c2f46d76a47568b299d3f2b1d25fe
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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