1,2-Dichloroethane → 4-Hydroxy-4-methyl-[1,4']bipiperidinyl-1'-carboxylic acid tert-butyl ester

Participants

Reaction Steps

To a suspension of piperidin-4-yl-carbamic acid tert-butyl ester (723 mg, 3.6 mmol) in DCE (20 mL) was added 4-methylpiperidin-4-ol (500 mg, 4.4 mmol). After 30 minutes, sodium triacetoxyborohydride (1.54 g, 7.3 mmol) was added portionwise. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (50 mL) and dichloromethane (75 mL). The organic phase was separated, dried (Na2SO4), filtered and evaporated in-vacuo. The resultant residue was purified by flash chromatography (silica, Biotage 100 g column, 0-10% methanol in dichloromethane) to afford crude 4-hydroxy-4-methyl-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester. This crude material was dissolved in dichloromethane (10 mL) and TFA (2 mL) added. After 30 minutes at ambient temperature, the reaction mixture was concentrated in-vacuo and the resultant residue loaded onto a 20 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo afforded the title compound as a colourless oil (285 mg, 40% over two steps). 1H NMR (300 MHz, CDCl3): 3.15 (d, J=12.3 Hz, 2H), 2.62-2.60 (m, 6H), 2.42-2.39 (m, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.67-1.64 (m, 5H), 1.46-1.44 (m, 2H), 1.24 (s, 3H).

Provenance & Evidence