Nordihydroguaretic acid → 1,4-bis{3,4-bis(2-methyl-thiazol-4-yl-methoxy)phenyl}-2,3-dimethyl-(2R,3S)-butane

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Reaction Conditions

Reaction Steps

To an ice-cooled solution of NDGA (1.50 g, 4.96 mol) in DMF (50 mL) was added 60% suspension of sodium hydride in paraffin (1.98 g=1.19 g NaH, 49.6 mmol, 10 mole equiv.). The mixture was stirred at 0° C. for 30 min. and at room temperature for 30 min. Then a solution of 4-chloromethyl-2-methylthiazole (5.86 g, 39.69 mmol, 8.0 mole equiv.) in DMF (20 mL) was added and the reaction mixture was allowed to stir for 16 h at room temperature. The reaction mixture was added to the saturated aqueous ammonium chloride (300 mL) and ether (600 mL). After shaking, the organic layer was separated, and the aqueous layer was extracted with ether (2×200 mL). The combined organic layer and extracts were washed with water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate and concentrated to dryness under reduced vacuum (30-40 mm Hg) at 25° C. The residue was dissolved in a minimum amount of dichloromethane and purified by silica gel flash chromatographic column using hexane:ethyl acetate (50:50 to 0:100) as eluant to give expected product as white solid (1.56 g, 42.09% yield). It was further purified by crystallization from acetate-hexane.

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