Ammonium Chloride → 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carboxylic acid amide

HRID 1025614Notes

Reaction equation

HRID 1025614 reaction equation
Br[C:2]1[C:3]([CH:15]=[O:16])=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]([C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([F:31])[CH:30]=1)[C:27](=[O:32])[NH:26][N:25]=[CH:24]2)([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-:34].[Na+].[NH4+].[Cl-]>[Cu]I.CS(C)=O>[C:17]([C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([F:31])[CH:30]=1)[C:27](=[O:32])[N:26]([C:2]1[C:3]([CH2:15][OH:16])=[C:4]([N:8]3[CH:12]=[C:11]([C:13]([NH2:14])=[O:34])[CH:10]=[N:9]3)[CH:5]=[CH:6][CH:7]=1)[N:25]=[CH:24]2)([CH3:20])([CH3:18])[CH3:19]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 516892Sodium BicarbonateHCID 594737656-(tert-Butyl)-8-fluorophthalazin-1(2H)-oneHCID 866737221-(3-bromo-2-formylphenyl)-1H-pyrazole-4-carbonitrile

Product 1

HCID 710082901-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carboxylic acid amide

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
120 °C

Procedure

In a 25 mL container, 1-(3-bromo-2-formylphenyl)-1H-pyrazole-4-carbonitrile (100 mg, 362 μmol, Eq: 1.00), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (160 mg, 724 μmol, Eq: 2) and copper (I) iodide (138 mg, 724 μmol, Eq: 2.00) were combined with DMSO (2.00 ml) to give a yellow suspension. Sodium bicarbonate (76.1 mg, 906 μmol, Eq: 2.5) was added to it. The mixture was heated in a microwave at 120° C. for 1 hr. The reaction mixture was poured into 25 mL sat NH4Cl and extracted with EtOAc (3×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The organic layer was concentrated and purified through ISCO flash column chromatography using ethyl acetate (containing 5% methanol) in hexanes (5% to 80% linear gradient in 15 minutes, 24 g silica gel) to give the pure desired product which was triturated with ether in hexanes and filtered to obtain 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-1H-pyrazole-4-carbonitrile (110 mg, 73%). Step 3. The aldehyde is reduced to the alcohol as in Example 22. Step 4. In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-4-carbonitrile (89 mg, 213 μmol, Eq: 1.00) and hydrido(dimethylyphosphinous acid-kP) (4.58 mg, 10.7 μmol, Eq: 0.05) were combined with Ethanol (1 ml) and Water (1.00 ml) to give a colorless solution. The reaction mixture was heated to 85° C. and stirred for 45 min. Mixture was allowed to come to room temperature and the solvent was removed under vacuum. Purification by reverse phase HPLC gave 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carboxylic acid amide (51 mg, 56%, [M+H]+ 436)

Workup

  1. customto give a yellow suspension
  2. additionThe reaction mixture was poured into 25 mL
  3. extractionextracted with EtOAc (3×25 mL)
  4. dry with materialThe organic layers were dried over MgSO4
  5. concentrationconcentrated in vacuo
  6. concentrationThe organic layer was concentrated
  7. custompurified through ISCO flash column chromatography
  8. customethyl acetate (containing 5% methanol) in hexanes (5% to 80% linear gradient in 15 minutes, 24 g silica gel)

Sources & evidence

ORD record
ord-6adfdc7cdbc549039ecc7ba055134b8d
Source dataset
uspto-grants-2014_05
Patent number
US08729078B2

Reaction notes

Loading…