1-bromo-4-fluorobutane

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:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-4-fluorobutane (3.57 g, 23.1 mmol) was added dropwise to a mixture of 2-fluoro-4-hydroxybenzoic acid (3.00 g, 19.2 mmol), ethanol (11.5 ml) and water (2.3 ml), potassium hydroxide (2.37 g, 42.3 mmol) at 80° C., and the mixture was stirred at 80° C. for 17 hrs. The solvent was evaporated under reduced pressure. The residue was dissolved in water and the solution was acidified by adding 1N hydrochloric acid. The insoluble materials were filtered off and dried to give the title compound (1.73 g) as a pale-brown powder. The solvent was evaporated under reduced pressure The residue was dissolved in water by adding 1N hydrochloric acid The insoluble materials were filtered off dried

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 150 mg of the compound obtained in Step A of Example 1 are dissolved in 8 ml of acetonitrile, to which 300 mg of K2CO3 and 0.15 ml of 1-bromo-4-fluorobutane are added. The reaction mixture is introduced into a sealed autoclave and is heated at 100° C. for 3 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in a minimum of water. The insoluble material is collected by filtration, washed with water and dried. The precipitate is then recrystallised from a minimum of ethyl acetate with the aid of heat. After cooling, the title compound is collected by filtration, washed with a minimum of ethyl acetate and dried. are added The reaction mixture is introduced into a sealed autoclave After cooling the solvent is evaporated off under reduced pressure The insoluble material is collected by filtration washed with water dried The precipitate is then recrystallised from a minimum of ethyl acetate with the aid of heat After cooling the title compound is collected by filtration washed with a minimum of ethyl acetate dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 150 mg of the compound obtained in Step A of Example 1 are dissolved in 8 ml of acetonitrile, to which 300 mg of K2CO3 and 0.15 ml of 1-bromo-4-fluorobutane are added. The reaction mixture is introduced into a sealed autoclave and is heated at 100° C. for 3 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in a minimum of water. The insoluble material is collected by filtration, washed with water and dried. The precipitate is then recrystallised from a minimum of ethyl acetate with the aid of heat. After cooling, the title compound is collected by filtration, washed with a minimum of ethyl acetate and dried. are added The reaction mixture is introduced into a sealed autoclave After cooling the solvent is evaporated off under reduced pressure The insoluble material is collected by filtration washed with water dried The precipitate is then recrystallised from a minimum of ethyl acetate with the aid of heat After cooling the title compound is collected by filtration washed with a minimum of ethyl acetate dried

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

Procedure: To a suspension of 1 g (2.74 mmol) of [(4-hydroxy-benzenesulfonyl)-(4-methoxy-benzyl)-amino]-acetic acid methyl ester and 1.14 g (8.22 mmol) of K2CO3 in 8 ml of DMF, 0.59 ml (5.47 mmol) of 1-bromo-4-fluorobutane is added dropwise at r.t. After stirring for 18 h at r.t., the reaction mixture is diluted with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (AcOEt:n-hexane=3:1) to give {[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)-amino}-acetic acid methyl ester; NMR (CDCl3): 1.86–1.96 (m, 4H), 3.57 (s, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.08 (t, 2H, J=6.04 Hz), 4.39 (s, 2H), 4.46 (t, 1H, J=6.04 Hz), 4.55–4.65 (m, 1H), 6.83 (d, 2H, J=8.56 Hz), 6.97 (d, 2H, J=9.08 Hz), 7.15 (d, 2H, J=8.56 Hz), 7.82 (d, 2H, J=9.08 Hz). is added dropwise at r.t extracted with AcOEt The combined extracts are washed with brine dried over MgSO4 concentrated under reduced pressure The residue is purified by column chromatography on silica gel (AcOEt:n-hexane=3:1)