methyl N-(2-fluorophenyl)carbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Fluoro-N-methoxycarbonylaniline (3.38 g, 20.0 mmol) prepared as described in Example 1 was dissolved in 77.6% sulfuric acid (20 g) to prepare a solution. 1-Methylcyclohexyl alcohol (2.28 g, 20.0 mol) was added dropwise to the solution under a nitrogen atmosphere over a period of 30 min while stirring and heating the solution at 70° C. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for 5 hr. Subsequently, the reaction solution was cooled to room temperature. n-Hexane (100 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer. n-Hexane (100 mL) was again added to the sulfuric acid layer to carry out extraction for separation of an organic layer. The organic layers thus obtained were combined, and the combined organic layer was washed with water and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 2-fluoro-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline as an oil. The oil was further subjected to separation and purification by column chromatography on silica gel to give 843 mg of 2-fluoro-4-(1-methylcyclohexyl)-N-ethoxycarbonylaniline as a target compound (yield 15.8%, 4-substituted compound: 5-substituted compound=100:0). to prepare a solution After the completion of the dropwise addition the reaction solution was vigorously stirred at the same temperature for 5 hr Subsequently, the reaction solution was cooled to room temperature extraction for separation of the mixture into a sulfuric acid layer n-Hexane (100 mL) was again added to the sulfuric acid layer extraction for separation of an organic layer The organic layers thus obtained the combined organic layer was washed with water and saturated brine in that order The solvent was then removed from the organic layer by distillation

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Fluoro-N-methoxycarbonylaniline (1.00 g, 5.92 mmol) prepared as described in Example 1 was dissolved in 77.6% sulfuric acid (5.00 g) to prepare a solution. Isopropyl alcohol (0.400 g, 6.51 mmol) was added to the solution under a nitrogen atmosphere while stirring and heating the solution at 70° C. The mixture was vigorously stirred for 3 hr. The reaction solution was cooled to room temperature. n-Hexane (10 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer, and this extraction was carried out once again. The organic layers thus obtained were combined, and the combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 666 mg of 2-fluoro-4-isopropyl-N-methoxycarbonylaniline as an oil. The oil was further subjected to separation and purification by column chromatography on silica gel to give 206 mg of 2-fluoro-4-isopropyl-N-methoxycarbonylaniline (yield 17.0%). to prepare a solution The mixture was vigorously stirred for 3 hr The reaction solution was cooled to room temperature extraction for separation of the mixture into a sulfuric acid layer an organic layer, and this extraction The organic layers thus obtained the combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine in that order The solvent was then removed from the organic layer by distillation

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Fluoro-N-methoxycarbonylaniline (150 g, 0.859 mol) was dissolved in 77.6% sulfuric acid (206 g) to prepare a solution. t-Butyl alcohol (72.9 g, 1.07 mol) was added dropwise to the solution under a nitrogen atmosphere over a period of 30 min while stirring and heating the solution at 70° C. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. t-Butyl alcohol (72.9 g, 1.07 mol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. t-Butyl alcohol (72.9 g, 1.07 mol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. The reaction solution was cooled to room temperature. n-Hexane (530 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer. n-Hexane (530 mL) was again added to the sulfuric acid layer to carry out extraction for separation of an organic layer. The organic layers thus obtained were combined, and the combined organic layer was washed with water and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 307 g of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as an oily crude product (yield on weight basis 159%, purity as determined by gas chromatography 65.1%, 4-t-butyl form 5-t-butyl form=100:0). to prepare a solution After the completion of the dropwise addition the reaction solution was vigorously stirred at the same temperature for one hr After the completion of the dropwise addition the reaction solution was vigorously stirred at the same temperature for one hr over a period of 30 min After the completion of the dropwise addition the reaction solution was vigorously stirred at the same temperature for one hr The reaction solution was cooled to room temperature extraction for separation of the mixture into a sulfuric acid layer n-Hexane (530 mL) was again added to the sulfuric acid layer extraction for separation of an organic layer The organic layers thus obtained the combined organic layer was washed with water and saturated brine in that order The solvent was then removed from the organic layer by distillation

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Fluoro-N-methoxycarbonylaniline (500 mg, 3.11 mmol) was dissolved in methylene chloride (20 mL) to prepare a solution. Anhydrous aluminum chloride (986 mg, 7.77 mmol) was added to the solution, and the mixture was stirred at 40° C. for 20 min. Thereafter, the reaction solution was cooled to room temperature. A solution of isobutyl bromide (1.60 mL, 15.5 mmol) in a methylene chloride solution (6 mL) was added dropwise to the cooled reaction mixture while bubbling argon gas over a period of 10 min. The mixture was stirred for one hr. Water was added thereto, followed by separation of an organic layer. The organic layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was then removed from the dried organic layer by distillation to give 779 mg of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as a crude product. The crude product was further subjected to separation and purification by column chromatography on silica gel to give 433 mg of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline (yield 64.0%, 4-t-butyl form: 5-t-butyl form=88:12). to prepare a solution Thereafter, the reaction solution was cooled to room temperature while bubbling argon gas over a period of 10 min The mixture was stirred for one hr Water was added followed by separation of an organic layer The organic layer was washed with water was dried over anhydrous magnesium sulfate The solvent was then removed from the dried organic layer by distillation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Fluoroaniline (10.0 mL, 0.104 mol) was dissolved in ethyl acetate (40 mL) to prepare a solution. Pyridine (10.0 mL, 0.124 mol) was added to the solution, and the mixture was cooled under ice cooling. A solution of methyl chloroformate (8.80 mL, 0.114 mol) in 10 mL of ethyl acetate was added dropwise to the cooled mixture over a period of 30 min. The reaction solution was warmed to room temperature followed by stirring for 3 hr. The disappearance of 2-fluoroaniline from the reaction solution was confirmed by high performance liquid chromatography. Thereafter, 20 mL of water was added thereto under ice cooling to stop the reaction. Next, 50 mL of ethyl acetate and 50 mL of water were added to the reaction mixture to carry out extraction. The organic layer was washed with 40 mL of water and 30 mL of a saturated sodium hydrogencarbonate solution and was then dried over an hydrous magnesium sulfate. The solvent was then removed from the organic layer by distillation to give 16.5 g of 2-fluoro-N-methoxycarbonylaniline as a substantially single product (yield 94.4%). to prepare a solution the mixture was cooled under ice cooling the reaction extraction The organic layer was washed with 40 mL of water and 30 mL of a saturated sodium hydrogencarbonate solution was then dried over an hydrous magnesium sulfate The solvent was then removed from the organic layer by distillation