Sodium Bicarbonate → tert-butyl methyl 2-{(S)-amino[3-(benzyloxy)phenyl]methyl}propanedioate

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Reaction Steps

To tert-butyl methyl 2-{(1S)-[3-(benzyloxy)phenyl][(tert-butoxycarbonyl)amino]methyl}propanedioate (600 mg, 1.24 mmol) was added 0° C. cold formic acid (13.8 mL) and the solution was stored at 5° C. for 20 hours. Ice was added and pH was adjusted to 8 by addition of aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with ethyl acetate. The combined extracts were washed with aqueous sodium hydrogen carbonate solution and brine and dried over sodium sulfate. Concentration under reduced pressure yields 390 mg of raw tert-butyl methyl 2-{(1S)-amino[3-(benzyloxy)phenyl]methyl}propanedioate. (3R)-1-{3-[1-(Tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (447 mg, 1.21 mmol) were suspended in N,N-dimethylformamide (14 mL) and cooled to 0° C. HATU (646 mg, 1.7 mmol), a solution of the raw tert-butyl methyl 2-{(1S)-amino[3-(benzyloxy)phenyl]methyl}propanedioate (780 mg, 1.21 mmol) in N,N-dimethylformamide (14 mL) and N-ethyl-diisopropylamine (350 μL, 3.64 mmol) were added. The mixture was stirred at 0° C. for 2 hours. Ice water and saturated ammonium chloride solution was added, the mixture extracted with ethyl acetate and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on an amino phase column (Separtis® Flash-NH2, ethyl acetate in hexane 0 to 100%) to yield 700 mg of tert-butyl methyl-[(S)-[3-(benzyloxy)phenyl]({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)methyl]propanedioate.

Provenance & Evidence