METHYL BROMO(4-FLUOROPHENYL)ACETATE

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

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

Procedure: Methyl 2-bromo-2-(4-fluorophenyl)acetate (538 mg, 2.18 mmol) was dissolved in CH3CN (6.6 ml) and piperidine (258 μl, 2.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (456 μl, 2.61 mmol) were added sequentially. The solution was stirred at room temperature for 3 hours, then the solvent was evaporated and the crude was purified with flash chromatography (Petroleum ether/EtOAc=9/1) to collect methyl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (320 mg, 58.5% yield) as a colourless oil. the solvent was evaporated the crude was purified with flash chromatography (Petroleum ether/EtOAc=9/1)

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

Procedure: The α-bromo-4-fluorophenylacetic acid from Part 1 was dissolved in methanol (100 ml) and was added Dowex-50X-400® (2.7 g) to the solution. The mixture was refluxed for 6 hours and the resin was removed by filtering through Celite® after cooling. The filtrate was evaporated to give an oily residue, which was purified by column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane to afford methyl α-bromo-4-fluorophenylacetate (87% yield). was added Dowex-50X-400® (2.7 g) to the solution The mixture was refluxed for 6 hours the resin was removed by filtering through Celite® after cooling The filtrate was evaporated to give an oily residue, which was purified by column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane

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

Procedure: Methyl 2-bromo-2-(4-fluorophenyl)acetate (538 mg, 2.18 mmol) was dissolved in CH3CN (6.6 ml) and piperidine (258 μl, 2.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (456 μl, 2.61 mmol) were added sequentially. The solution was stirred at room temperature for 3 hours, then the solvent was evaporated and the crude was purified with flash chromatography (Petroleum ether/EtOAc=9/1) to collect methyl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (320 mg, 58.5% yield) as a colourless oil. the solvent was evaporated the crude was purified with flash chromatography (Petroleum ether/EtOAc=9/1)

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

Procedure: Methyl 2-bromo-2-(4-fluorophenyl)acetate (538 mg, 2.18 mmol) was dissolved in CH3CN (6.6 ml) and piperidine (258 μl, 2.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (456 μl, 2.61 mmol) were added sequentially. The solution was stirred at room temperature for 3 hours, then the solvent was evaporated and the crude was purified with flash chromatography (Petroleum ether/EtOAc=9/1) to collect methyl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (320 mg, 58.5% yield) as a colourless oil. the solvent was evaporated the crude was purified with flash chromatography (Petroleum ether/EtOAc=9/1)

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

Procedure: To a suspension of 2-aminothiophenol (12.6 g) and sodium acetate (23.6 g) in ethanol (150 ml) is added methyl α-bromo-4-fluorophenylacetate (23.6 g), and the mixture is stirred at room temperature overnight. After the solvent is distilled off, water is added to the residue. The resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 2-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (21.7 g) as crystals. M.p. 216°-219° C. After the solvent is distilled off water is added to the residue The resulting precipitate is separated by filtration washed dried recrystallized from tetrahydrofuran-n-hexane

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

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

Procedure: To a suspension of 2-aminothiophenol (12.6 g) and sodium acetate (23.6 g) in ethanol (150 ml) is added methyl α-bromo-4-fluorophenylacetate (23.6 g), and the mixture is stirred at room temperature overnight. After the solvent is distilled off, water is added to the residue. The resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 2-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (21.7 g) as crystals. M.p. 216°-219° C. After the solvent is distilled off water is added to the residue The resulting precipitate is separated by filtration washed dried recrystallized from tetrahydrofuran-n-hexane

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

Procedure: 4-Fluorophenylacetic acid methyl ester (3.0 g, 17.6 mmol) in THF (20 mL) under nitrogen at −78° was treated with 1M lithium hexamethyldisilazide (19.4 mL, 19.4 mmol) and stirred at −78° for fifteen minutes. Trimethyl silyl chloride was added (2.23 mL, 17.6 mmol) and the reaction stirred for a further fifteen minutes. Bromine (0.9 mL, 17.6 mmol) was added and the reaction stirred again for a further fifteen minutes then quenched with water and partitioned between DCM and sodium hydrogen carbonate solution. The organic phase was separated, dried (sodium sulphate) and concentrated in vacuo. Flash chromatography (diethylether-silica) yielded the title compound. the reaction stirred for a further fifteen minutes the reaction stirred again for a further fifteen minutes then quenched with water partitioned between DCM and sodium hydrogen carbonate solution The organic phase was separated dried (sodium sulphate) concentrated in vacuo

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

Procedure: 4-Fluorophenylacetic acid methyl ester (3.0 g, 17.6 mmol) in THF (20 mL) under nitrogen at −78° was treated with 1M lithium hexamethyldisilazide (19.4 mL, 19.4 mmol) and stirred at −78° for fifteen minutes. Trimethyl silyl chloride was added (2.23 mL, 17.6 mmol) and the reaction stirred for a further fifteen minutes. Bromine (0.9 mL, 17.6 mmol) was added and the reaction stirred again for a further fifteen minutes then quenched with water and partitioned between DCM and sodium hydrogen carbonate solution. The organic phase was separated, dried (sodium sulphate) and concentrated in vacuo. Flash chromatography (diethylether-silica) yielded the title compound. the reaction stirred for a further fifteen minutes the reaction stirred again for a further fifteen minutes then quenched with water partitioned between DCM and sodium hydrogen carbonate solution The organic phase was separated dried (sodium sulphate) concentrated in vacuo

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

Procedure: 4-Fluorophenylacetic acid methyl ester (3.0 g, 17.6 mmol) in THF (20 mL) under nitrogen at −78° was treated with 1M lithium hexamethyldisilazide (19.4 mL, 19.4 mmol) and stirred at −78° for fifteen minutes. Trimethyl silyl chloride was added (2.23 mL, 17.6 mmol) and the reaction stirred for a further fifteen minutes. Bromine (0.9 mL, 17.6 mmol) was added and the reaction stirred again for a further fifteen minutes then quenched with water and partitioned between DCM and sodium hydrogen carbonate solution. The organic phase was separated, dried (sodium sulphate) and concentrated in vacuo. Flash chromatography (diethylether-silica) yielded the title compound. the reaction stirred for a further fifteen minutes the reaction stirred again for a further fifteen minutes then quenched with water partitioned between DCM and sodium hydrogen carbonate solution The organic phase was separated dried (sodium sulphate) concentrated in vacuo

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of bromo-(4-fluoro-phenyl)-acetic acid methyl ester (16.0 g) in chloroform (100 mL) was added potassium carbonate (17.9 g, finely ground) followed by 3-amino-1-propanol (4.87 g). The reaction was heated to 45° C. for 18 hours. The reaction was filtered and the filtrate was diluted with water and the phases were separated. The aqueous phase was further extracted with chloroform (3×25 mL) and the combined organics were washed with brine. The chloroform phase was dried over sodium sulfate, filtered and evaporated in vacuo to give the desired (4-fluoro-phenyl)-(3-hydroxy-propylamino)-acetic acid methyl ester (14.85 g, MS (ES+): 242.2 (MH+)) as a yellow oil which was used in the next step without further purification. The reaction was filtered the filtrate was diluted with water the phases were separated The aqueous phase was further extracted with chloroform (3×25 mL) the combined organics were washed with brine The chloroform phase was dried over sodium sulfate filtered evaporated in vacuo