Hydrochloric Acid → 4-{[Cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methyl]amino}benzoic acid

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Reaction Steps

To a mixture of cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methanone (628 mg) synthesized above, methyl 4-aminobenzoate (402 mg), triethylamine (2.70 mL) and methylene chloride (10 mL) was added titanium (IV) chloride (318 μL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (30 mL) of the obtained oil in tetrahydrofuran were added acetic acid (277 μL) and sodium cyanoborohydride (304 mg), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, the organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give an orange solid. To a mixture of the obtained solid, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred with heating under reflux for 4 hr. 1N Hydrochloric acid (5.00 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-100% ethyl acetate/hexane) to give the title object compound (202 mg, 22%) as a yellow solid.

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