Sulfuric acid magnesium salt (1:1) → HCID 178519816, compound

Participants

Reaction Steps

To a solution of ethyl 3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (300 mg, 0.897 mmol) in THF (5 mL) at −78° C. under nitrogen was added dropwise, over 10 minutes, diisobutylaluminium hydride (1M in hexanes, 0.9 mL, 0.9 mmol) and the reaction mixture stirred at −78° C. for a further 2.5 hours. The reaction was then allowed to warm slowly to room temperature and stirred under nitrogen for a further 16.5 hours when LCMS indicated the reaction to be incomplete. The reaction was cooled again to −78° C. and more diisobutylaluminium hydride (1M in hexanes, 0.9 mL, 0.9 mmol) was added and stirring continued at −78° C. under nitrogen for a further 2.5 hours when LCMS indicated complete reaction. The mixture was quenched with water (10 mL) and extracted with DCM (50 mL). The organic layer was separated and washed sequentially with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL) and then dried using a hydrophobic frit and evaporated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (50 g) using a 0-25% methanol-dichloromethane gradient over 40 mins. Product containing fractions were combined and evaporated to give impure 3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carbaldehyde as a yellow oil. To a solution of this impure aldehyde (121 mg, 0.417 mmol) in MeOH (3 mL) and DCM (1 mL) was added magnesium sulphate (250 mg, 2.077 mmol), trans-3-[(2,3-dichlorophenyl)oxy]cyclobutanamine hydrochloride (120 mg, 0.447 mmol) and DIPEA (0.08 mL, 0.458 mmol) and the reaction mixture stirred at room temperature for 15 mins under nitrogen. Sodium triacetoxyborohydride (350 mg, 1.651 mmol) was then added and the reaction mixture was stirred under nitrogen for a further 22 hours when LCMS showed the reaction to be incomplete. More sodium triacetoxyborohydride (350 mg, 1.651 mmol) was then added and the mixture stirred under nitrogen at room temperature for 3 hours when LCMS indicated complete reaction. Saturated aqueous sodium bicarbonate solution (10 mL) was then added followed by DCM (15 mL). The organic layer was separated and dried through a hydrophobic frit and the solvent evaporated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (10 g) using a 0-25% methanol-DCM gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give to give the crude TBDMS protected product. This material was dissolved in THF (10 mL) and tetrabutylammonium fluoride in THF (1M, 0.46 mL, 0.46 mmol) was added and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM and purified on a silica cartridge (20 g) using a 0-25% methanol-dichloromethane gradient over 40 min. The product containing fractions were combined and evaporated in vacuo to give still impure material (ca. 200 mg) which was dissolved in 1:1 MeOH:DMSO (2×1 mL) and re-purified by MDAP. Product containing fractions were dried under a stream of nitrogen to give the title compound (16 mg).

Provenance & Evidence