2-Fluoro-4-nitrophenol → HCID 66691509, compound

HRID 1183150Notes

Reaction equation

HRID 1183150 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:33]>N1C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[O:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 98252-Fluoro-4-nitrophenolHCID 66690365HCID 66690365, compound

Product 1

HCID 66691509HCID 66691509, compoundYield 55,432.102%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of Methyl 1-((4-chloro-6-methoxyquinolin-7-yloxy)methyl)cyclopropane-carboxylate (29.2 g, US12036244) and 2-fluoro-4-nitrophenol (20.5 mg) in pyridine (50 ml) was heated at 110° C. for 4 hours and cooled. The reaction was evaporated and water (300 ml) was added and further sonicated for 20 minutes. The solid was filtered and washed with water followed by acetone to give the product as methyl 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (32 g). This product (3.9 g) was mixed with LiOH (0.82 g) in THF/H2O (40 ml/20 ml) and the mixture was refluxed for 4 hours. The solution was evaporated and acidified with AcOH, the precipitated was filtered and washed with water followed by acetone to give the product as 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclo-propanecarboxylic acid. This acid (1 g) was mixed with DIPEA (0.53 ml) in acetone (50 ml) and cooled at 0° C. To the reaction mixture was added isobutylchloroformate slowly and further stirred for 1 hour at 0° C. To the reaction was added NaN3 (1.52 g) in water (2 ml) and further stirred for 2 hours at 0° C. EtOAc (100 ml) was added to the reaction and washed with brine, dried over Na2SO4. The solution was evaporated to around 10 ml and toluene (70 ml) was added followed by addition of 4-methoxybenzyl alcohol. The solution was refluxed for 4 hours and cooled, EtOAc (50 ml) and water (50 ml) were added and further extracted with EtOAc two times. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified with silica gel column to give 4-methoxybenzyl 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclopropyl-carbamate (850 mg) that was mixed with Fe power (1 g) and NH4Cl (100 mg) in EtOH/H2O (20 ml, 16 ml/4 ml). The solution was refluxed for two hours and filtered through the Celite and washed with MeOH. The filtrate was evaporated and partitioned with water and DCM, the aqueous layer was further extracted with DCM twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated to give 4-methoxybenzyl 1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate (650 mg) for next step without further purification.

Workup

  1. temperaturecooled
  2. customThe reaction was evaporated
  3. additionwater (300 ml) was added
  4. customfurther sonicated for 20 minutes
  5. filtrationThe solid was filtered
  6. washwashed with water

Sources & evidence

ORD record
ord-132acc84494b41e9b3099b3badc38072
Source dataset
uspto-grants-2014_03
Patent number
US08664244B2

Reaction notes

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