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Citric Acid → 4,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylic acid

HRID 1054575
Notes
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Reaction equation

HRID 1054575 reaction equation
[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([OH:21])[CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.O.[OH:26]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+].CC(=CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC#N.O.C(O)(C)(C)C>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3([OH:21])[CH2:18][CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:26])=[O:24])=[CH:5][NH:6]2
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 5

HCID 311Citric AcidHCID 105532-Methyl-2-buteneHCID 516949Sodium Phosphate, Monobasic, MonohydrateHCID 23668197Sodium ChloriteHCID 866985794,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carbaldehyde

Product 1

HCID 71767833
4,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylic acid
Yield 24.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolvent

Procedure

To a solution of 4,6-difluoro-5-[4-(1-hydroxy-cyclobutyl)-phenyl]-1H-indole-3-carbaldehyde (37.0 mg, 0.11 mmol) in a mixture of MeCN (2 mL), tert-butanol (1 mL) and water (2 mL) was added sodium phosphate monobasic hydrate (214.0 mg, 1.55 mmol), sodium chlorite (114.0 mg, 1.26 mmol) and 2-methyl-2-butene (1.0 mL, 6.85 mmol). The reaction mixture was stirred at room temperature for 24 hours, acidified with 1 N aqueous citric acid solution (1 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting yellow gum was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 60% H2O/40% MeCN in 8.5 min, 60% H2O/40% MeCN linear to 0% H2O/100% MeCN in 0.5 min, HOLD at 0% H2O/100% MeCN to 10.0 min. Flow: 25 mL/min) to afford the title compound (9.4 mg, 24%).

Workup

  1. extractionextracted with EtOAc
  2. dry with materialThe organic layer was dried over MgSO4
  3. concentrationconcentrated in vacuo
  4. customThe resulting yellow gum was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 60% H2O/40% MeCN in 8.5 min, 60% H2O/40% MeCN linear to 0% H2O/100% MeCN in 0.5 min, HOLD at 0% H2O/100% MeCN to 10.0 min. Flow: 25 mL/min)

Sources & evidence

ORD record
ord-5392d08daf004cdb8d34a43ca3ffc6e9
Source dataset
uspto-grants-2016_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09394285B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes