Acetic Acid → (3R,5S)-1-(tert-butoxycarbonyl)piperidine-3,5-dicarboxylic acid

Participants

Reaction Conditions

Reaction Steps

Dimethylpyridine-3,5-dicarboxylate (50 g) was dissolved in acetic acid (300 ml), 5% rhodium carbon (5 g) was added, and the mixture was stirred under pressurized hydrogen atmosphere (5 atm) at 50° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, the rhodium catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (300 ml) and, under ice-cooling, triethylamine (107 ml) and di-tert-butyl dicarbonate (67 g) were successively added. The reaction mixture was stirred at room temperature for 15 hr, and concentrated under reduced pressure. The residue was dissolved in water, and the mixture was adjusted to pH 3 with 6 M hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate extract layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (250 ml), and 8 N aqueous sodium hydroxide solution (128 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 24 hr, and methanol was evaporated under reduced pressure. The concentrated solution was diluted with saturated aqueous sodium hydrogen carbonate solution (100 ml) and washed twice with diethyl ether. The basic aqueous layer was acidified (pH 3) with 6 M hydrochloric acid. The precipitated powder was collected by filtration, washed with water, and air-dried. The obtained powder (55 g) was dissolved in methanol (200 ml) by heating and the mixture was concentrated under reduced pressure until the amount of methanol became half. Water (50 ml) was added, and the mixture was stood at room temperature overnight. The precipitated white powder was collected by filtration, washed with cold methanol/water=2/1 (200 ml) and air-dried to give the object compound (38 g) as a powder.

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