ethyl 3-fluoro-4-hydroxybenzoate

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:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluoro-4-hydroxybenzoic acid (1.2 g), ethanol (20 ml) and concentrated sulfuric acid (1 ml) was refluxed for 13 hours, then concentrated and extracted with chloroform. The extract was washed with aqueous sodium hydrogen carbonate solution, dried and the solvent was distilled off, whereby crystals of ethyl 3-fluoro-4-hydroxybenzoate (1.3 g) was obtained. m.p. 79°-80° C. was refluxed for 13 hours concentrated extracted with chloroform The extract was washed with aqueous sodium hydrogen carbonate solution dried the solvent was distilled off

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

Procedure: 3-Fluoro-4-hydroxybenzoic acid ethyl ester (0.20 g, 1.1 mmol) and N-(2-chloroethyl)morpholine (0.22 g, 1.2 mmol) were dissolved in dry DMF (10 ml). Potassium carbonate (1.88 g, 5 mmol) was added and the turbid reaction mixture was stirred overnight at 40° C. under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue followed by washing with NaHCO3 (½ sat., 3×), water, brine, dried (MgSO4), filtered. The crude oil was purified over silica gel (CH2Cl2/MeOH 39:1): colorless oil 0.16 g (49%); the turbid reaction mixture The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue by washing with NaHCO3 (½ sat., 3×), water, brine dried (MgSO4) filtered The crude oil was purified over silica gel (CH2Cl2/MeOH 39:1)

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

Procedure: 3-Fluoro-4-hydroxybenzoic acid ethyl ester (0.20 g, 1.1 mmol) and N-(2-chloroethyl)morpholine (0.22 g, 1.2 mmol) were dissolved in dry DMF (10 ml). Potassium carbonate (1.88 g, 5 mmol) was added and the turbid reaction mixture was stirred overnight at 40° C. under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue followed by washing with NaHCO3 (½ sat., 3×), water, brine, dried (MgSO4), filtered. The crude oil was purified over silica gel (CH2Cl2/MeOH 39:1): colorless oil 0.16 g (49%); the turbid reaction mixture The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue by washing with NaHCO3 (½ sat., 3×), water, brine dried (MgSO4) filtered The crude oil was purified over silica gel (CH2Cl2/MeOH 39:1)

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

Procedure: 1,4-Dibromobutane (2.34 g, 10.8 mmol), potassium carbon-ate (1.86 g, 13.5 mmol) and potassium iodide (90 mg, 0.5 mmol) were added to a solution of 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (11.0 g, 5.4 mmol) in acetone (25 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane) to yield the title compound (1.38 g, 80%). the mixture was heated at reflux for 20 h The solid was filtered off washed with EtOAc the filtrate was concentrated in vacuo The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane)

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

Procedure: 1,3-Dibromopropane (2.2 g, 11.0 mmol), potassium carbon-ate (1.86 g, 13.6 mmol) and potassium iodide (90 mg, 0.5 mmol) were added to 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (11.0 g, 5.4 mmol) in acetone (25 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% hexane) to yield the title compound (1.18 g, 71%). the mixture was heated at reflux for 20 h The solid was filtered off washed with EtOAc The filtrate was concentrated in vacuo azeotroped with toluene The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% hexane)

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

Procedure: Triphenylphosphine polystyrene (loading 1.0 mmol/g, 11 g, 11.0 mmol) and DEAD (2.45 g, 11.0 mmol) were added to a solution of 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (1.3 g, 7.4 mmol) and 4-(3-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E34 (1.8 g, 7.4 mmol) in tetrahydrofuran (100 ml) at 0° C. The suspension was allowed to warm to room temperature and stirred for 18 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAC) to yield the title compound (1.7 g, 57%). The mixture was filtered the filtrate concentrated in vacuo The residue was purified by flash chromatography on silica gel (eluant; EtOAC)

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

Procedure: A solution of 3-fluoro-4-hydroxy-benzoic acid (5.16 g, 33.1 mmol) in ethanol (100 ml) was treated with conc. sulphuric acid (5 ml), and the mixture heated at reflux for 4 days. The volatiles were removed in vacuo, and the aqueous residue was basified with saturated NaHCO3 and extracted twice with diethyl ether. The combined organic extracts were dried and concentrated in vacuo to yield the title compound (5.16 g, 85%). the mixture heated at reflux for 4 days The volatiles were removed in vacuo extracted twice with diethyl ether The combined organic extracts were dried concentrated in vacuo