Reaction Steps
A solution of N1-(4-bromobenzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine (63.4 g, 152 mmol) in acetonitrile (400 mL) was added to a mixture of cis-1,2-cyclohexanedicarboxylic anhydride (23.4 g, 152 mmol) in acetonitrile (400 mL). After stirring for 30 min at RT, DIPEA (26.1 mL, 152 mmol) was added followed by a second portion of cis-hexahydroisobenzofuran-1,3-dione (1.55 g, 10 mmol). After stirring for 15 min, HCl (253 mL, 1.52 mol, 6 M) was added and the resulting mixture was heated to 80° Celsius for 2.5 h. The solution was then cooled to 10° Celsius and slowly treated with NaOH (983 mL, 2 M). The resulting mixture was partitioned between water (1150 mL) and toluene (850 mL) and the resulting organic layer was separated. The product containing aqueous layer (pH=12.6) was cooled to 10° Celsius and treated with HCl (69 mL, 6 M) to afford a final pH of 5.9. The resulting mixture was partitioned with ethyl acetate (600 mL) and the organic layer was separated. The organic layer was washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated to dryness to afford a tan solid (73 g, 90%). The initial purification was performed using stationary phase 1000 g of lichroprep silicagel 25-40 um (Merck), 80 mm diameter, 20 cm length, 230 nm detection. A gradient of DCM (95%)/MeOH (5%) was held for 25 min and then ramped over 10 min DCM (90%)/MeOH (10%) and then flushed with 100% ethanol to provide the racemic cis-2-(1-(4-bromobenzyl)-6-((5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid. The racemic material was separated into its constituent enantiomers through chiral stationary phase chromatography (stationary phase 2000 g of Chiralpak AS 1000 Å 20 μm (daicel), 110 mm diameter, 38 cm length, 230 nm detection. Isocratic 100% methanol at 450 mL/min over 36 injections). The first eluting cis isomer was contaminated with a small quantity of trans isomer, which was removed through FCC (95:5 dichloromethane:MeOH ramping to 90:10 dichloromethane:MeOH). After concentration, the title compound was present as a foam (24.8 g, 72% of theoretical for resolution). MS (ESI): mass calcd. for C28H28BrN3O3, 533.10; m/z found, 534.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=2.1, 1H), 7.60 (dd, J=8.2, 2.2, 1H), 7.54 (d, J=8.8, 1H), 7.44-7.39 (m, 2H), 7.38 (d, J=8.0, 1H), 7.02-6.96 (m, 2H), 6.94 (dd, J=8.8, 2.4, 1H), 6.81 (d, J=2.3, 1H), 5.52-5.33 (m, 2H), 5.08 (s, 2H), 3.59-3.52 (m, 1H), 2.86-2.77 (m, 1H), 2.42-2.31 (s, 4H), 2.07-1.68 (m, 5H), 1.52-1.36 (m, 2H). The absolute stereochemistry was determined by single crystal x-ray analysis.
