Acetic Acid → 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride

To a suspension of (3S,4S)-4-methyl-piperidin-3-ol hydrochloride (intermediate 26; 0.04 g, 0.3 mmol) in dichloromethane (1 ml) was added triethylamine (0.04 ml, 0.3 mmol) and acetic acid (0.03 ml, 0.5 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.08 g, 0.3 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.07 g, 0.4 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=468.1 (M+H)+.

1. washafter which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution
2. dry with materialdried (Na2SO4)
3. concentrationconcentrated
4. additionThe crude residue was then treated with HCl in dioxane (2 ml, 4N)
5. stirringstirred for 30 minutes after which time the reaction
6. concentrationwas concentrated

ORD record

ord-6bb42396d1a348b0b64b41f36cb0fa1c

Source dataset

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08063042B2