(4-amino-5-chloro-2-methoxyphenyl)methanol

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

Procedure: Obtained as a light brown solid (76%) starting from commercially available methyl 4-amino-3-chlorobenzoate (4 g; 0.021 mol) and lithium aluminium hydride (1.09 g; 0.028 mol) in 144 ml tetrahydrofuran following the experimental procedure as described for intermediate 38.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-amino-5-chloro-2-methoxyphenyl)methanol (intermediate 38; 1.5 g, 0.008 mol) in dimethylformamide (35 mL) was added imidazole (1.7 g, 0.02 mol). The mixture was cooled to 0° C. and chloro(isopropyl)dimethylsilane (2.5 g, 0.01 mol) was added dropwise. The reaction was stirred overnight at room temperature. The solvent was removed and the crude was partitioned between water and hexane, the organic layer was washed with water, sodium bicarbonate 4% and brine, dried, filtered and evaporated to dryness. The crude obtained was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 8/1 to 4/1). The title compound was obtained as a yellow solid (58%). The solvent was removed the crude was partitioned between water and hexane the organic layer was washed with water, sodium bicarbonate 4% and brine dried filtered evaporated to dryness The crude obtained was purified by column chromatography with silica gel eluting with hexane/ethyl acetate (from 8/1 to 4/1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of lithium aluminium hydride (0.96 g, 0.025 mol) in tetrahydrofuran (100 mL) was added dropwise at room temperature a solution of ethyl 4-amino-5-chloro-2-methoxybenzoate (intermediate 37; 4.4 g, 0.019 mol) in tetrahydrofuran (25 mL). Then the mixture was refluxed for 2 hours. The excess of hydride was destroyed by successive addition of 1 ml of water, 1 ml of 4N NaOH solution and 2 ml of water, filtered through celite and washed with ethyl acetate. The organic solvent was reduced and hexane was added. The mixture was cooled at 0° C. during 1 hour and then the precipitate was filtrated and washed with hexane. The title compound was obtained as a pale yellow solid (80%) which was used in the next step without further purification. Then the mixture was refluxed for 2 hours The excess of hydride was destroyed by successive addition of 1 ml of water, 1 ml of 4N NaOH solution and 2 ml of water filtered through celite washed with ethyl acetate hexane was added the precipitate was filtrated washed with hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of lithium aluminium hydride (0.96 g, 0.025 mol) in tetrahydrofuran (100 mL) was added dropwise at room temperature a solution of ethyl 4-amino-5-chloro-2-methoxybenzoate (intermediate 37; 4.4 g, 0.019 mol) in tetrahydrofuran (25 mL). Then the mixture was refluxed for 2 hours. The excess of hydride was destroyed by successive addition of 1 ml of water, 1 ml of 4N NaOH solution and 2 ml of water, filtered through celite and washed with ethyl acetate. The organic solvent was reduced and hexane was added. The mixture was cooled at 0° C. during 1 hour and then the precipitate was filtrated and washed with hexane. The title compound was obtained as a pale yellow solid (80%) which was used in the next step without further purification. Then the mixture was refluxed for 2 hours The excess of hydride was destroyed by successive addition of 1 ml of water, 1 ml of 4N NaOH solution and 2 ml of water filtered through celite washed with ethyl acetate hexane was added the precipitate was filtrated washed with hexane

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

Procedure: To a suspension of lithium aluminum hydride (25.0 g, 116 mmol) in tetrahydrofuran (150 mL), 4-amino-5-chloro-2-methoxybenzoic acid (5 g, 28.0 mmol) was added in portions under ice-water cooling and the mixture was heated under reflux for 5 hours. Under ice-water cooling, a saturated aqueous solution of Rochelle salt was added to stop the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of Rochelle salt and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The solid obtained was washed with a mixed solvent of hexane-ethyl acetate (4:1), collected by filtration, and dried under reduced pressure to obtain 4-amino-5-chloro-2-methoxybenzyl alcohol (11.8 g) was added in portions under ice-water cooling the mixture was heated under reflux for 5 hours the reaction the reaction mixture was extracted with ethyl acetate The organic layer was washed with a saturated aqueous solution of Rochelle salt a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate concentrated under reduced pressure The solid obtained was washed with a mixed solvent of hexane-ethyl acetate (4:1) collected by filtration dried under reduced pressure

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

Procedure: Obtained as a light brown solid (76%) starting from commercially available methyl 4-amino-3-chlorobenzoate (4 g; 0.021 mol) and lithium aluminium hydride (1.09 g; 0.028 mol) in 144 ml tetrahydrofuran following the experimental procedure as described for intermediate 38.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-amino-5-chloro-2-methoxyphenyl)methanol (intermediate 38; 1.5 g, 0.008 mol) in dimethylformamide (35 mL) was added imidazole (1.7 g, 0.02 mol). The mixture was cooled to 0° C. and chloro(isopropyl)dimethylsilane (2.5 g, 0.01 mol) was added dropwise. The reaction was stirred overnight at room temperature. The solvent was removed and the crude was partitioned between water and hexane, the organic layer was washed with water, sodium bicarbonate 4% and brine, dried, filtered and evaporated to dryness. The crude obtained was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 8/1 to 4/1). The title compound was obtained as a yellow solid (58%). The solvent was removed the crude was partitioned between water and hexane the organic layer was washed with water, sodium bicarbonate 4% and brine dried filtered evaporated to dryness The crude obtained was purified by column chromatography with silica gel eluting with hexane/ethyl acetate (from 8/1 to 4/1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of lithium aluminium hydride (0.96 g, 0.025 mol) in tetrahydrofuran (100 mL) was added dropwise at room temperature a solution of ethyl 4-amino-5-chloro-2-methoxybenzoate (intermediate 37; 4.4 g, 0.019 mol) in tetrahydrofuran (25 mL). Then the mixture was refluxed for 2 hours. The excess of hydride was destroyed by successive addition of 1 ml of water, 1 ml of 4N NaOH solution and 2 ml of water, filtered through celite and washed with ethyl acetate. The organic solvent was reduced and hexane was added. The mixture was cooled at 0° C. during 1 hour and then the precipitate was filtrated and washed with hexane. The title compound was obtained as a pale yellow solid (80%) which was used in the next step without further purification. Then the mixture was refluxed for 2 hours The excess of hydride was destroyed by successive addition of 1 ml of water, 1 ml of 4N NaOH solution and 2 ml of water filtered through celite washed with ethyl acetate hexane was added the precipitate was filtrated washed with hexane