Sulfuric Acid → 7-(2,4-Dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid methyl ester

HRID 500562Notes

Reaction equation

HRID 500562 reaction equation
[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[CH2:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23].OS(O)(=O)=O.[N:30]([O-])=O.[Na+]>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:13]=[N:30][CH:11]=[C:10]2[CH3:12])=[O:24]

Participants

7

Reactant 3

HCID 1118Sulfuric AcidHCID 23668193Sodium NitriteHCID 865986374-Amino-2-(2,4-dichlorophenylamino)-3-fluoro-5-isopropenyl-benzoic acid methyl ester

Product 1

HCID 686371297-(2,4-Dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid methyl esterYield 58.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-amino-2-(2,4-dichlorophenylamino)-3-fluoro-5-isopropenyl-benzoic acid methyl ester (89.9 mg, 0.243 mmol) in THF (2 mL) and conc. H2SO4 (0.050 mL, 0.94 mmol) was added a solution of NaNO2 (24.0 mg, 0.348 mmol) in water (0.5 mL) at 0° C. The reaction temperature was kept below 5° C. during the addition. The reaction mixture was warmed to room temperature, and 2 mL of water was added. After stirring in the dark for 4 days, the reaction mixture was diluted with EtOAc, and washed with water. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) to afford the desired product (54 mg, 58%).

Workup

  1. additionThe reaction temperature was kept below 5° C. during the addition
  2. washwashed with water
  3. customThe organic layer was separated
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give the crude material which
  8. customwas purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-964cfc60ea9f498a9ac79adc27d73213
Source dataset
uspto-grants-2010_08
Patent number
US07772234B2

Reaction notes

Loading…