Dicyclohexylcarbodiimide → benzyl [(S)-p-t-butoxy-alpha-[[4-[(t-butoxycarbonyl)methoxy]-piperidino]carbonyl]phenethyl]carbamate

Participants

Reaction Steps

11.14 g (30 mmol) of N-(benzyloxycarbonyl)-O-(1,1-dimethylethyl)-L-tyrosine were dissolved in 65 ml of ethyl acetate while warming to 40°. The solution was treated at 20° with 0.1 g (0.9 mmol) of N-hydroxysuccinimide. Subsequently, a solution of 7.5 g (36 mmol) of dicyclohexylcarbodiimide in 40 ml of ethyl acetate was added dropwise at 22° within 25 minutes. A white suspension formed during the addition and this was stirred for 30 minutes. A solution of 7.8 g (36 mmol) of t-butyl (4-piperidinyloxy)acetate in 100 ml of ethyl acetate was then added dropwise to the suspension within 30 minutes. A suspension formed and this was stirred at 22° for 3 hours. The precipitated dicyclohexylurea was filtered off and the filtrate was washed with 2N hydrochloric acid, water and semi-saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and, after removing the drying agent, evaporated. The residue was a viscous oil and weighed 18.5 g. The oil was diluted with a mixture of 10 ml of ethyl acetate and 60 ml of hexane and warmed to 50°. The insoluble solid was filtered off under suction and the filtrate was treated with 20 ml of hexane and seeded with a small amount of crystalline product at 30°. The mixture was cooled to 0° within one hour and stirred at this temperature for 30 minutes. The crystals were then filtered off under suction and washed on the filter with 20 ml of hexane. 14.5 g (85%) of benzyl [(S)-p-t-butoxy-α-[[4-[(t-butoxycarbonyl)methoxy]-piperidino]carbonyl]phenethyl]carbamate were obtained in this manner. Its content was 96% according to HPLC.

Provenance & Evidence