methyl 3-(3-bromo-4-hydroxyphenyl)propanoate

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:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Intermediate 5 (3.08 g) in anhydrous N-methylpyrrolidone (9.5 ml, WAKO) was successively added with cesium carbonate (3.58 g, WAKO), iodobenzene (1.4 ml, TCI), dipivaloylmethane (0.12 ml, TCI) and copper(I) chloride (275 mg, WAKO), and stirred 120° C. for 16 hours under argon gas atmosphere. The reaction mixture was added with t-butyl methyl ether (25 ml), and insoluble solids were removed by filtration. The filtrate was washed successively with 2 N aqueous hydrochloric acid and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=1:10) to obtain the title compound (Compound No. A-31, 1.00 g). were removed by filtration The filtrate was washed successively with 2 N aqueous hydrochloric acid and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography (hexane:ethyl acetate=1:10)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Intermediate 5 (3.08 g) in anhydrous N-methylpyrrolidone (9.5 ml, WAKO) was successively added with cesium carbonate (3.58 g, WAKO), iodobenzene (1.4 ml, TCI), dipivaloylmethane (0.12 ml, TCI) and copper(I) chloride (275 mg, WAKO), and stirred 120° C. for 16 hours under argon gas atmosphere. The reaction mixture was added with t-butyl methyl ether (25 ml), and insoluble solids were removed by filtration. The filtrate was washed successively with 2 N aqueous hydrochloric acid and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=1:10) to obtain the title compound (Compound No. A-31, 1.00 g). were removed by filtration The filtrate was washed successively with 2 N aqueous hydrochloric acid and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography (hexane:ethyl acetate=1:10)

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

Procedure: A solution of Intermediate 5 (516 mg) in chloroform (5 ml) was added with sulfuryl chloride (177 μl), and stirred at room temperature for 21 hours. The reaction mixture was poured into aqueous saturated sodium hydrogencarbonate (20 ml), and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 6, 290 mg). extracted with ethyl acetate The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1)

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

Procedure: A solution of Intermediate 5 (4.50 g) in DMF (20 ml) was added with 60% sodium hydride (440 mg, KANTO) under ice cooling. The reaction mixture was stirred for 10 minutes, then added with bromocyclopentane (1.61 ml, TCI), warmed to room temperature, stirred for 1.5 hours, then warmed to 60° C., and further stirred for 16 hours. The reaction mixture was added with water (50 ml) and isopropyl ether (300 ml)) for extraction. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:isopropyl ether=7:1) to obtain the title compound (Compound No. A-5, 2.50 g). stirred for 1.5 hours warmed to 60° C. further stirred for 16 hours for extraction The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography (hexane:isopropyl ether=7:1)

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

Procedure: A solution of Intermediate 5 (1.29 g) in DMF (25 ml) was added with potassium carbonate (0.86 g) and bromomethylcyclohexane (1.05 ml, TCI), stirred under argon atmosphere at room temperature for 2 hours, then warmed to 60° C., and stirred for 17 hours. The reaction mixture was poured into ice water, and extracted with isopropyl ether (200 ml). The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:isopropyl ether=9:1) to obtain the title compound (Compound No. A-2, 1.45 g). warmed to 60° C. stirred for 17 hours extracted with isopropyl ether (200 ml) The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography (hexane:isopropyl ether=9:1)

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

Procedure: A solution of Intermediate 5 (1.29 g) in DMF (25 ml) was added with potassium carbonate (0.86 g) and bromomethylcyclohexane (1.05 ml, TCI), stirred under argon atmosphere at room temperature for 2 hours, then warmed to 60° C., and stirred for 17 hours. The reaction mixture was poured into ice water, and extracted with isopropyl ether (200 ml). The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:isopropyl ether=9:1) to obtain the title compound (Compound No. A-2, 1.45 g). warmed to 60° C. stirred for 17 hours extracted with isopropyl ether (200 ml) The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography (hexane:isopropyl ether=9:1)