2-Methyl-2-butene → 4,6-difluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylic acid

HRID 1054882Notes

Reaction equation

HRID 1054882 reaction equation
[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:23])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:24]=[O:25])=[CH:5][NH:6]2.CC(=CC)C.Cl([O-])=[O:32].[Na+].P([O-])(O)(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:21][OH:22])[CH2:18][CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[C:9]([F:23])[CH:8]=[C:7]2[C:3]=1[C:4]([C:24]([OH:32])=[O:25])=[CH:5][NH:6]2

Participants

9

Reactant 5

HCID 105532-Methyl-2-buteneHCID 24437Sodium SulfiteHCID 23668197Sodium ChloriteHCID 23672064Monosodium phosphateHCID 866988454,6-difluoro-5-(4-(1-(hydroxymethyl)cyclobutyl)phenyl)-1H-indole-3-carbaldehyde

Product 1

HCID 717679884,6-difluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylic acidYield 42%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 4,6-difluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde (34 mg, 0.10 mmol) in acetonitrile (5 mL) and tert butanol (5 mL) was added 2-methyl-2-butene (700 g, 10.0 mmol). The mixture was cooled to 0° C. with ice bath. The sodium chlorite (273 mg, 3.00 mmol) and sodium dihydrogenphosphate (360 mg, 3.00 mmol) were dissolved in water (5 mL). The aqueous was added to the organic solution and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 48 hours. TLC (petroleum ether/ethyl acetate=1:1) showed the reaction was complete. A solution of sodium sulfite was added slowly to the stirring mixture. The reaction mixture was allowed to stir 1 hour. Then the organics were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. The residue was purified by preparative reverse phase HPLC to give the title compound (15 mg, 42%) as a white solid. MS (ES+) 380.0 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.41 (d, 1H), 7.28 (d, 2H), 7.14 (d, 2H), 3.76 (s, 2H), 2.36 (m, 4H), 2.13 (m, 1H), 1.93 (m, 1H).

Workup

  1. additionThe aqueous was added to the organic solution
  2. temperatureto warm to room temperature
  3. stirringto stir 1 hour
  4. customThen the organics were removed under reduced pressure
  5. extractionThe aqueous layer was extracted with ethyl acetate (20 mL×3)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give a brown residue
  10. customThe residue was purified by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-9369b1743d1445e894562f609ba082c7
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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