Lithium Hydroxide → 7-[(5,7-Difluorochroman-4-yl)oxy]-2-methyl-1H-benzo[d]imidazole-5-carboxylic Acid

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Reaction Steps

To a stirred mixture of 1-(1,1-dimethylethyl) 6-methyl 4-hydroxy-2-methyl-1H-benzimidazole-1,6-dicarboxylate (1.33 g, 4.34 mmol, STEP 3 in Example 4), (+)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol (1.82 g, 9.79 mmol, STEP 8 in Example 2) and triphenylphosphine (2.28 g, 8.69 mmol) in toluene (50 mL) was added diisopropyl azodicarboxylate (DIAD) (1.76 g, 8.70 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuum. The residue was dissolved in methanol (20 mL) and tetrahydrofuran (5 mL), and to the mixture was added 4M lithium hydroxide aqueous solution (18.0 mL, 90.0 mmol) at room temperature. After stirring for 1 hour at 80° C., the reaction mixture was concentrated in vacuum. The residue was dissolved with water (200 mL), acidified with 2M hydrochloric acid aqueous solution (50 mL), and extracted with ethyl acetate (200 mL×3). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from ethyl acetate only to ethyl acetate:methanol with 1 wt % of acetic acid=3:1) to afford the title compound as a white solid (1.15 g, 73%, >99% ee).

Provenance & Evidence