Sodium Chloride → 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbonitrile

HRID 389517Notes

Reaction equation

HRID 389517 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=O.C([N:21](CC)CC)C.Cl.NO.ClC(Cl)(Cl)C(Cl)=O.[Cl-].[Na+]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]#[N:21]

Participants

7

Reactant 5

HCID 5234Sodium ChlorideHCID 6420Trichloroacetyl chlorideHCID 8471Triethylamine2×HCID 443297Hydroxyamine hydrochlorideHCID 866624125-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

Product 1

HCID 667602805-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbonitrileYield 86.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (353 mg, 1.14 mmol) in MeCN (11.4 mL) was added triethylamine (223 uL, 1.60 mmol) and hydroxylamine hydrochloride (95.2 mg, 1.37 mmol). The reaction was heated to 60° C. for 16 h. The reaction mixture was then cooled to room temperature and additional triethylamine (541 uL, 3.88 mmol) was added, followed by trichloroacetyl chloride (306 uL, 2.74 mmol) dropwise. After stirring 30 min at room temperature, the reaction was heated to 65° C. for 20 h. The reaction mixture was then cooled to room temperature and poured into saturated aqueous sodium chloride (100 mL). The aqueous fraction was extracted with ethyl acetate (3×75 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated onto silica gel. Purification by ISCO chromatography (10 to 40% ethyl acetate:hexanes) afforded 301 mg (86%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J=1.8 Hz, 1 H), 7.97 (d, J=8.3 Hz, 1 H), 7.75 (dd, J=1.9, 9.0 Hz, 1 H), 6.07 (dd, J=2.5, 9.1 Hz, 1 H), 3.97-3.60 (m, 2 H), 2.40-2.17 (m, 1 H), 2.12-1.91 (m, 2 H), 1.84-1.64 (m, 1 H), 1.66-1.47 (m, 2 H); HPLC tR=3.73 min.

Workup

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. temperaturethe reaction was heated to 65° C. for 20 h
  3. temperatureThe reaction mixture was then cooled to room temperature
  4. extractionThe aqueous fraction was extracted with ethyl acetate (3×75 mL)
  5. dry with materialThe combined organic fractions were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated onto silica gel
  8. customPurification by ISCO chromatography (10 to 40% ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-c3e1eee3f1f249a6addac6cb948b66af
Source dataset
uspto-grants-2013_02
Patent number
US08378104B2

Reaction notes

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