(4-Formylphenyl)-acetic acid ethyl ester (Example 16, step a, 0.44 g) was added to a solution of acetic acid (0.14 mL), trimethylorthoformate (2.53 g) and 2-(2,6-dichlorophenyl)ethylamine (0.54 mL) in dimethylformamide (10 mL) and stirred at room temperature, under nitrogen. After 1 hour, sodium triacetoxyborohydride (0.79 g) was added and the resulting mixture stirred for 18 hours, then concentrated. The residue was dissolved in methanol (5 mL) and loaded onto conditioned Tosic-65A resin (5 g, Argonaut). The resin was washed with methanol (3×20 mL) and then eluted with 3M methanolic ammonia solution (2×15 mL). The combined elution fractions were evaporated. The residue was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.42 g) was added. The mixture was stirred at room temperature, under nitrogen, for 18 hours. Purification on silica, eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil. The oil was dissolved in tetrahydrofuran (4 mL) and a solution of lithium hydroxide (21 mg) in water (2 mL) was added and stirred for 18 hours, under nitrogen. The pH was adjusted to pH˜4 with acetic acid and the mixture concentrated to ˜2 mL. The aqueous residue was extracted with ethyl acetate (3×10 mL), the organics combined, washed with brine (10 mL), dried (magnesium sulfate) and evaporated, to give the subtitle compound as a gum (350 mg).
