Reaction #49761

Reaction equation

hydrochloric acid

methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate

2-methylcyclopentyl p-toluenesulfonate

potassium hydroxide

→

2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyaniline

Yield 40.0%

Solvents

N,N-dimethylformamide

Conditions

Workup

1. 1
   workup.ADDITIONwas charged into a 50 cc round-bottom flask
2. 2
   Temperaturewhile heating on an oil bath at 80° to 100° C
3. 3
   OtherAfter completion of the reaction
4. 4
   Extractionthe mixture was extracted with ethyl acetate (20 ml×3)
5. 5
   Washwashed with a saturated aqueous solution of sodium chloride
6. 6
   Dryingdried over anhydrous magnesium sulfate
7. 7
   OtherThe drying agent was removed by filtration
8. 8
   workup.DISTILLATIONthe solvent was distilled off under reduced pressure
9. 9
   Otherto obtain a crude product (1.51 g)
10. 10
    OtherThe product was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=17/3)

Procedure

A solution of methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.53 g, 6.98 mmol) synthesized by the process described in Reference Example 3, 2-methylcyclopentyl p-toluenesulfonate (1.78 g, 6.99 mmol) and N,N-dimethylformamide (15 ml) was charged into a 50 cc round-bottom flask, and then potassium hydroxide (400 mg, 7.15 mmol) in a powder form was added thereto, followed by stirring for 7 hours while heating on an oil bath at 80° to 100° C. After completion of the reaction, the reaction solution was cooled to room temperature, 2N hydrochloric acid (50 ml) was added thereto, and the mixture was extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product (1.51 g). The product was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=17/3) to obtain 2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyaniline as a colorless oily substance (666 mg, 2.73 mmol, 40% yield).

Source