To a solution of 1-[1-(4-bromo-2-chlorophenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (300.0 mg, 0.659 mmol) in tetrahydrofuran (4.0 mL) was added n-butyllithium (1.60 M solution in n-hexane, 0.91 mL, 1.450 mmol) at −78° C., and the mixture was stirred for 30 min. Carbon dioxide gas was bubbled through the mixture for 30 min. The mixture was quenched with aqueous saturated ammonium chloride and added 1N sodium hydroxide solution and extracted with ethyl acetate (×2). The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude compound was subjected to next step without further purification. To a solution of crude material (73.2 mg) in tetrahydrofuran (2.0 mL)/pyridine (0.2 mL) was added acetic anhydride (0.1 mL) at 0° C. The reaction mixture was stirred at room temperature for 14 hrs. The mixture was neutralized with aqueous saturated sodium hydrogen carbonate and concentrated. The residue was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude compound was subjected to next step without further purification. To a solution of crude material (58.9 mg) in N,N-dimethylformamide (1.3 mL) were added 1-hydroxy-1H-benzotriazole ammonium salt (25.2 mg, 0.166 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.8 mg, 0.140 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2), aqueous saturated sodium hydrogen carbonate (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/n-hexane gradient mixture to give the title compound as a mixture. The residue was purified preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an amorphous (16.5 mg, 0.0358 mmol, 5.4% (3 steps)).
