3-(2-Isopropoxyethoxy)-1H-indazole-5-carbaldehyde → 2,6-Bis(difluoromethyl)-4-{3-[2-(propan-2-yloxy)ethoxy]-1H-indazol-5-yl}-1,4-dihydropyridine-3,5-dicarbonitrile

HRID 1038414Notes

Reaction equation

HRID 1038414 reaction equation
[CH:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[NH:10][N:9]=1)([CH3:3])[CH3:2].[NH2:19][C:20]([CH:24]([F:26])[F:25])=[CH:21][C:22]#[N:23]>C(O)(=O)C.C1COCC1>[F:25][CH:24]([F:26])[C:20]1[NH:19][C:20]([CH:24]([F:26])[F:25])=[C:21]([C:22]#[N:23])[CH:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[C:21]=1[C:22]#[N:23]

Participants

5

Reactant 2

HCID 584076443-(2-Isopropoxyethoxy)-1H-indazole-5-carbaldehydeHCID 762236343-Amino-4,4-difluorobut-2-enenitrile

Product 1

HCID 670238222,6-Bis(difluoromethyl)-4-{3-[2-(propan-2-yloxy)ethoxy]-1H-indazol-5-yl}-1,4-dihydropyridine-3,5-dicarbonitrile

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8028TetrahydrofuranSolvent

Procedure

80 mg (0.32 mmol) 3-(2-isopropoxyethoxy)-1H-indazole-5-carbaldehyde (Example 32A), 84 mg (0.71 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)] and a small amount of powdered 4 Å molecular sieve in acetic acid (310 μl) were heated to 115° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to give 85 mg (59% of th.) of the title compound.

Workup

  1. filtrationfiltered
  2. customThe filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient)

Sources & evidence

ORD record
ord-139225bee4f34f8181ab90bb2381559b
Source dataset
uspto-grants-2013_10
Patent number
US08551989B2

Reaction notes

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