methyl 5-(bromomethyl)-2-methoxybenzoate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension containing 0.5 g (2.2 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole, 0.8 g (2.7 mmol) of 5-bromomethyl-2-methoxy-benzoic acid methyl ester and 0.6 g (4.3 mmol) of potassium carbonate in 10 ml of ethyl isobutylketone was heated at 90° C. for 16 hours. The inorganic solid was filtrated and the solvent was removed under reduced pressure. 0.91 g (97% of yield) of the expected product was obtained. The inorganic solid was filtrated the solvent was removed under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.9 g (0.0071 mol) of 5-bromomethyl-2-methoxy-benzoic acid methyl ester in 5 ml of methyl isobutylketone was added to a suspension of 1.8 g (0.065 mol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-indole and 1.8 g (0.013 mol) of potassium carbonate in 45 ml of methyl isobutylketone. The reaction mixture was heated at 60° C. for 20 h. The crude mixture was filtered to remove inorganic salts and the solvent was removed under reduced pressure affording 3.5 g of a crude oil. The crude mixture was purified by flash chromatography over silica gel affording 1.8 g (48% of yield) of 5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidin-1-ylmethy}-2-methoxy-benzoic acid ethyl ester. This ester was dissolved in 18 ml of ethanol and hydrolysed with 2N NaOH at room temperature for 20 hours. The crude mixture was neutralised with 2N HCl aqueous solution and the solvent was removed under reduced pressure. The crude residue was extracted between dichloromethane and water. After drying, filtering and removing the solvent under reduced pressure, the residue obtained was recrystallised with ethanol affording 0.77 g (27% of overall yield) of the expected acid. The crude mixture was filtered to remove inorganic salts the solvent was removed under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension containing 0.5 g (2.2 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole, 0.8 g (2.7 mmol) of 5-bromomethyl-2-methoxy-benzoic acid methyl ester and 0.6 g (4.3 mmol) of potassium carbonate in 10 ml of ethyl isobutylketone was heated at 90° C. for 16 hours. The inorganic solid was filtrated and the solvent was removed under reduced pressure. 0.91 g (97% of yield) of the expected product was obtained. The inorganic solid was filtrated the solvent was removed under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.9 g (0.0071 mol) of 5-bromomethyl-2-methoxy-benzoic acid methyl ester in 5 ml of methyl isobutylketone was added to a suspension of 1.8 g (0.065 mol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-indole and 1.8 g (0.013 mol) of potassium carbonate in 45 ml of methyl isobutylketone. The reaction mixture was heated at 60° C. for 20 h. The crude mixture was filtered to remove inorganic salts and the solvent was removed under reduced pressure affording 3.5 g of a crude oil. The crude mixture was purified by flash chromatography over silica gel affording 1.8 g (48% of yield) of 5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidin-1-ylmethy}-2-methoxy-benzoic acid ethyl ester. This ester was dissolved in 18 ml of ethanol and hydrolysed with 2N NaOH at room temperature for 20 hours. The crude mixture was neutralised with 2N HCl aqueous solution and the solvent was removed under reduced pressure. The crude residue was extracted between dichloromethane and water. After drying, filtering and removing the solvent under reduced pressure, the residue obtained was recrystallised with ethanol affording 0.77 g (27% of overall yield) of the expected acid. The crude mixture was filtered to remove inorganic salts the solvent was removed under reduced pressure

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

Procedure: Under a nitrogen atmosphere, methyl 2-methoxy-5-methylbenzoate (901 mg, 5 mmol) was dissolved in acetonitrile, and N-bromosuccinimide (890 mg, 5 mmol) and benzoyl peroxide (24 mg, 0.1 mmol) were added thereto. The mixture was refluxed for one hour. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature, and the solvent was distilled off. Thereafter, the residue was dissolved in ethyl acetate. The organic layer was washed with water 3 times and then with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, and then the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate (volume ratio)=10:1) to give the title compound (570 mg, 44.0%) as an oily substance. The mixture was refluxed for one hour the solvent was distilled off Thereafter, the residue was dissolved in ethyl acetate The organic layer was washed with water 3 times with a saturated saline solution, and dried over magnesium sulfate The solvent was distilled off the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate (volume ratio)=10:1)

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

Procedure: Under a nitrogen atmosphere, methyl 2-methoxy-5-methylbenzoate (901 mg, 5 mmol) was dissolved in acetonitrile, and N-bromosuccinimide (890 mg, 5 mmol) and benzoyl peroxide (24 mg, 0.1 mmol) were added thereto. The mixture was refluxed for one hour. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature, and the solvent was distilled off. Thereafter, the residue was dissolved in ethyl acetate. The organic layer was washed with water 3 times and then with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, and then the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate (volume ratio)=10:1) to give the title compound (570 mg, 44.0%) as an oily substance. The mixture was refluxed for one hour the solvent was distilled off Thereafter, the residue was dissolved in ethyl acetate The organic layer was washed with water 3 times with a saturated saline solution, and dried over magnesium sulfate The solvent was distilled off the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate (volume ratio)=10:1)

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

Procedure: A mixture of 2-methoxy-5-methylbenzoic acid methyl ester (J.Chem.Soc.Perkin Trans.1, 1994, 1125) (1.47 g) and N-bromosuccinimide (1.45 g) in benzene (15 ml) was irradiated under a 500 W halogen lamp for 3 hours. The solvent was evaporated and the residue triturated with diethyl ether. The succinimide was filtered off and the filtrate evaporated. The solvent was evaporated the residue triturated with diethyl ether The succinimide was filtered off the filtrate evaporated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension containing 0.5 g (2.2 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole, 0.8 g (2.7 mmol) of 5-bromomethyl-2-methoxy-benzoic acid methyl ester and 0.6 g (4.3 mmol) of potassium carbonate in 10 ml of ethyl isobutylketone was heated at 90° C. for 16 hours. The inorganic solid was filtrated and the solvent was removed under reduced pressure. 0.91 g (97% of yield) of the expected product was obtained. The inorganic solid was filtrated the solvent was removed under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.9 g (0.0071 mol) of 5-bromomethyl-2-methoxy-benzoic acid methyl ester in 5 ml of methyl isobutylketone was added to a suspension of 1.8 g (0.065 mol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-indole and 1.8 g (0.013 mol) of potassium carbonate in 45 ml of methyl isobutylketone. The reaction mixture was heated at 60° C. for 20 h. The crude mixture was filtered to remove inorganic salts and the solvent was removed under reduced pressure affording 3.5 g of a crude oil. The crude mixture was purified by flash chromatography over silica gel affording 1.8 g (48% of yield) of 5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidin-1-ylmethy}-2-methoxy-benzoic acid ethyl ester. This ester was dissolved in 18 ml of ethanol and hydrolysed with 2N NaOH at room temperature for 20 hours. The crude mixture was neutralised with 2N HCl aqueous solution and the solvent was removed under reduced pressure. The crude residue was extracted between dichloromethane and water. After drying, filtering and removing the solvent under reduced pressure, the residue obtained was recrystallised with ethanol affording 0.77 g (27% of overall yield) of the expected acid. The crude mixture was filtered to remove inorganic salts the solvent was removed under reduced pressure