Acetic Acid → 2-(4-Chlorophenyl)-6-(difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile

HRID 1474450Notes

Reaction equation

HRID 1474450 reaction equation
[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6](/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[F:21])[NH:17][N:16]=[C:15]3[CH3:22])/[C:9]#[N:10])=O)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH:30]([F:32])[F:31])=[CH:27][C:28]#[N:29].C(O)(=O)C>CC(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[NH:25][C:26]([CH:30]([F:32])[F:31])=[C:27]([C:28]#[N:29])[CH:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[NH:17][N:16]=[C:15]4[CH3:22])[C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 762236343-Amino-4,4-difluorobut-2-enenitrileHCID 178434323HCID 178434323, compound

Product 1

HCID 1784343182-(4-Chlorophenyl)-6-(difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

A mixture of 200 mg (0.542 mmol) (2E)-2-(4-chlorobenzoyl)-3-(6-fluoro-3-methyl-1H-indazol-5-yl)prop-2-enenitrile (Example 6A) and 66 mg (0.542 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Then, acetic acid (1.5 ml) was added, and stirring at reflux was continued for 6 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 80:20 v/v) to yield 33 mg (14% of th.) of the racemic title compound.

Workup

  1. temperatureat reflux for 12 h
  2. stirringstirring
  3. temperatureat reflux
  4. temperatureUpon cooling
  5. concentrationthe mixture was concentrated under reduced pressure
  6. customthe residue was directly purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 80:20 v/v)

Sources & evidence

ORD record
ord-0e62059f98934cc8b43ac0101c6ebb73
Source dataset
uspto-grants-2015_04
Patent number
US09018234B2

Reaction notes

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