Yield:588715-60-0 100%

Reaction Conditions:

with potassium carbonate in N,N-dimethyl-formamide at 20; for 3 h;Inert atmosphere;

Steps:

SI-1.1. 3-{3-[(3,4-Dichlorobenzyl)oxy]phenyl}-3-ethoxypropanoicacid (23)

To a solution of 3-hydroxybenzaldehyde (1.53 g, 12.5 mmol)in DMF (30 mL), 3,4-dichlorobenzyl bromide (3.00 g, 12.5 mmol) and K₂CO₃(3.45 g, 25.0 mmol) were added at room temperature, and stirred under N₂atmosphere for 3 h. Water was added to the reaction mixture, and followed byextraction with AcOEt. The organic layer was washed with brine, and dried over Na₂SO₄and filtered. After the solvent was distilled off under reduced pressure, 3-[(3,4-dichlorobenzyl)oxy]benzaldehydewas obtained as a white solid (3.52 g, 100%).To a solution of AcOEt (1.65 g, 2.34 mol) in THF (30 mL), alithium bis(trimethylsilyl)amide THF solution (1.23 M, 19.0 mL, 2.34 mol) wasadded at -78 ^oC. The reaction mixture was stirred under N₂atmosphere at -78 ^oC for 1 h. To the reaction mixture, 3-[(3,4-dichlorobenzyl)oxy]benzaldehyde(3.52 g, 12.5 mmol) in THF (10 mL) was added, and stirred t -78 ^oC for1 h. To the reaction solution, saturated NH₄Cl aq. was added at -78 ^oC.The organic material was extracted with diehtyl ether. The organic layer waswashed with water and brine, and dried over Na₂SO₄ andfiltered. After the solvent was distilled off under reduced pressure, theresidue was purified by silica gel column chromatography (hexane:AcOEt = 100:0to 80:20 (v/v)), ethyl3-{3-[(3,4-dichlorobenzyl)oxy]phenyl}-3-hydroxypropanoate was obtained ascolorless oil (4.01 g, yield 87 %).To a solution of ethyl3-{3-[(3,4-dichlorobenzyl)oxy]phenyl}-3-hydroxypropanoate (4.01 g, 10.7 mmol)in toluene (100 mL), EtI (2.60 mL, 32.6 mmol) and Ag₂O (7.55 g, 32.6mmol) were added. The reaction mixture was stirred for 2 h at 100 ^oCunder N₂ atmosphere. After cooling to room temperature, the reactionsolution was filtered, and the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (hexane/AcOEt =100:0 to 20:80 (v/v)), ethyl3-{3-[(3,4-dichlorobenzyl)oxy]phenyl}-3-ethoxypropanoate was obtained ascolorless oil (2.76 g, yield 64%).To a solution of 3-{3-[(3,4-dichlorobenzyl)oxy]phenyl}-3-ethoxypropanoate(260 mg, 0.654 mmol) in THF (3.0 mL) and EtOH (3.0 mL), 2 N NaOH aq. (1.0 mL)was added at room temperature, and stirred for 6 h. The solvent was distilledoff under reduced pressure. 2 N HCl aq. (3.0 mL) was added to the reactionmixture, and followed by extraction with AcOEt. The organic layer was washedwith brine and dried over Na₂SO₄ and filtered. Thesolvent was distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/AcOEt=100:0 to 0:100 (v/v)), the titlecompound was obtained as colorless oil (240 mg, 100%).

References:

Takano, Rieko;Yoshida, Masao;Inoue, Masahiro;Honda, Takeshi;Nakashima, Ryutaro;Matsumoto, Koji;Yano, Tatsuya;Ogata, Tsuneaki;Watanabe, Nobuaki;Hirouchi, Masakazu;Kimura, Takako;Toda, Narihiro [Bioorganic and Medicinal Chemistry,2015,vol. 23,# 17,p. 5546 - 5565] Location in patent:supporting information