Acetic Acid → (S)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide

Participants

Reaction Steps

Saturated aq. sodium hydrogencarbonate solution (0.13 ml) was added to a solution of (S)-4-(3-hydroxy-propyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (intermediate 21; 95 mg, 0.26 mmol), potassium bromide (3 mg, 0.03 mmol), and 2,2,6,6-tetramethylpiperidin-1-oxyl (0.4 mg, 0.003 mmol) in dichloromethane (5 ml). Sodium hypochlorite solution (10% in water, 0.16 ml, 0.26 mmol) was added portionwise at 0° C., and the course of the oxidation was monitored by thin layer chromatography. After all starting material had reacted, the reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution, and the aqueous layer was extracted twice with dichloromethane. The organic phases were pooled, dried (MgSO4), filtered, and evaporated, thus affoding (S)-2-methyl-3-oxo-4-(3-oxo-propyl)-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (75 mg). This was dissolved in dichloromethane (2 ml) and added over 20 min to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 39 mg, 0.24 mmol) triethylamine (25 mg, 0.25 mmol), acetic acid (29 mg, 0.48 mmol) and sodium triacetoxyborohydride (58 mg, 0.26 mmol) in dichloromethane (2 ml). After 16 h the reaction mixture was treated with 25% aq. ammonia solution (70 μL, 0.48 mmol) and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (43 mg, 35%). White solid, MS (ISP)=469.3 (M+H)+.

Provenance & Evidence