Acetic Acid → HCID 178434235, compound

HRID 1474452Notes

Reaction equation

HRID 1474452 reaction equation
[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[F:13][C:14]([F:21])([F:20])[C:15](=O)[CH2:16][C:17]#[N:18].[NH2:22][C:23]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=1)=[CH:24][C:25]#[N:26].C(O)(=O)C>C(O)CCCC.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([C:14]([F:21])([F:20])[F:13])[NH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[N:28]=4)=[C:24]3[C:25]#[N:26])[CH:9]=2)[NH:4][N:3]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 138435404,4,4-Trifluoro-3-oxobutanenitrileHCID 67235870HCID 67235870, compoundHCID 178434286HCID 178434286, compound

Product 1

HCID 178434235HCID 178434235, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 62761-PentanolSolvent

Conditions

Temperature
130 °C

Procedure

A solution of 150 mg (0.936 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A) in n-pentanol (4 ml) containing powdered 4 Å molecular sieve was treated with 128 mg (0.936 mmol) 4,4,4-trifluoro-3-oxobutanenitrile (Example 8A) and stirred at 130° C. for 1 h. Then, 94 mg (0.44 mmol) 3-amino-3-[6-(trifluoromethyl)pyridin-2-yl]prop-2-enenitrile (Example 7A) and acetic acid (1.2 ml) were added, and the mixture was stirred at 130° C. for further 15 min. Upon cooling, water (6 ml) was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), and the solution was washed several times with brine, then with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (1 ml) containing 4 Å molecular sieve. A solution of tetra-n-butylammonium fluoride (TBAF, 1 N in THF, 1.5 ml) was added, and the mixture was stirred at 70° C. for 5 h. Upon cooling, the mixture was concentrated under reduced pressure, and the crude product was finally purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 15 mg (7% of th.) of the racemic title compound.

Workup

  1. stirringthe mixture was stirred at 130° C. for further 15 min
  2. temperatureUpon cooling
  3. filtrationthe mixture was filtered
  4. concentrationthe filtrate was concentrated under reduced pressure
  5. dissolutionThe residue was dissolved in ethyl acetate (30 ml)
  6. washthe solution was washed several times with brine
  7. dry with materialwith water, dried over sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. dissolutionThe residue was dissolved in THF (1 ml)
  10. additioncontaining 4 Å molecular sieve
  11. additionA solution of tetra-n-butylammonium fluoride (TBAF, 1 N in THF, 1.5 ml) was added
  12. stirringthe mixture was stirred at 70° C. for 5 h
  13. temperatureUpon cooling
  14. concentrationthe mixture was concentrated under reduced pressure
  15. customthe crude product was finally purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient)

Sources & evidence

ORD record
ord-3be47f386fc2463aa572a3e97efc3a04
Source dataset
uspto-grants-2015_04
Patent number
US09018234B2

Reaction notes

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