9-Benzyl-3-oxo-9-azabicyc...

Benzylamine (5.0 g, 47 mmol) and Na2HPO4 · 12H2O (5.0 g) were dissolved in 50 ml of water and acetone dicarboxylic acid(8 g, 20 mmol, 1.0 eq) at a concentration of 25percent in an ice-water bath was added dropwise over 60 minutes and allowed to warm to room temperature for 24 hours and then concentrated Hydrochloric acid to adjust the pH to 3, After stirring for 2 hours in an oil bath at 50 ° C, Cooled to room temperature, adjusted to pH 10 with 20percent NaOH solution, Then extracted twice with dichloromethane, the organic phase was combined and the organic phase was washed once with saturated brine, Concentrated under reduced pressure to give 9-benzyl-9-azabicyclo- [3, 3, 1] non-3-one soil as a yellow solid, With a volume ratio of 1: 5 by volume of ethyl acetate and petroleum ether for crystallization purification, filtration, To give 9 g of 9-benzyl-9-azabicyclo- [3, 3, 1] non-3-one as a yellowish solid. Yield 91percentPreparation of 3-amino-ABNO (12) was envisioned from the known ketone 21, which was easily accessible in one step from acetonedicarboxylic acid and glutaraldehyde (Scheme 1). Conversion of 21 to oxime 22, followed by reduction to the amine with nickel boride and N-Boc protection provided carbamate 23 in high yield. Removal of the benzyl group by catalytic hydrogenolysis and oxidation of the free secondary amine in the presence of urea-hydrogen peroxide complex (UHP) furnished the Boc -protected nitroxide 24. However, once the Boc group was removed, the resulting 3-amino-ABNO (12) was found to be unstable, thus preventing its use in the coupling step with 15a, the carboxylic acid derived from 15.(a) Synthesis of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one acetonedicarboxylic acid (16.1 g, 109.9 mmol) in a mixture of acetic acid (46 ml) and water (92 ml) was successively added dropwise with 50percent aqueous glutaraldehyde (26.5 ml, 146.5 mmol), and benzylamine (10 ml, 91.6 mmol) at room temperature, and then the mixture was stirred at the same temperature for 9 hours. The reaction mixture was added with dichloromethane (50 ml), and made basic by addition of 5 M aqueous sodium hydroxide (180 ml), and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, and then dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain crude crystals (17.2 g). The crude crystals were added with ethyl acetate (5 ml) and hexane (50 ml), and the slurry was stirred for 24 hours. The crystals were collected by filtration, washed with a mixed solution of ethyl acetate and hexane (10:1), and then dried under reduced pressure to obtain the objective compound (12.7 g, 60.6percent).A. EXAMPLE 6 To a solution in water (400 ml) of pentandial (84.5 g) and benzylamine hydrochloride (36.3 g), cooled at 0° C., 30.8 g of 1, 3-acetonedicarboxylic acid are added. 70 ml of an aqueous solution of sodium acetate at 10percent are then added. The obtained mixture is kept under stirring at room temperature for one hour and then heated for 4 hours to 50° C. The mixture is then acidified at pH 2 with a 10percent w. HCl aqueous solution and then washed with diethyl ether. The pH is then brought to 6 with sodium bicarbonate and the aqueous phase extracted with dichloromethane. The organic extracts are anhydrified on sodium sulphate and the solvent evaporated to obtain 38.5 g of the compound 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (6a) as a light coloured solid. Yield: 78percent; B.p.: 165-169° C./0.2 mmHg; To a solution in water (400 ml) of pentandial (84.5 g) and benzylamine hydrochloride (36.3 g), cooled at 0°C, 30.8 g of 1, 3-acetonedicarboxylic acid are added. 70 ml of an aqueous solution of sodium acetate at 10percent are then added. The obtained mixture is kept under stirring at room temperature for one hour and then heated for 4 hours to 50°C. The mixture is then acidified at pH 2 with a 10percent w. HCl aqueous solution and then washed with diethyl ether. The pH is then brought to 6 with sodium bicarbonate and the aqueous phase extracted with dichloromethane. The organic extracts are anhydrified on sodium sulphate and the solvent evaporated to obtain 38.5 g of the compound 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (6a) as a light coloured solid. [Show Image] Yield: 78percent; B.p.: 165-169°C/0.2 mmHg; A two-liter, 2-neck flask, an overhead stirrer and an addition funnel were used. Glutaraldehyde (100 ml_, 50percent aq. solution) was placed in the flask. Water (63 mL) was added. 36.5 grams of 1 , 3-acetonedicarboxylic acid were added. Some bubbling was observed. NaOAc (14.25 g) was added and the mixture was stirred vigorously. A solution of benzylamine hydrochloride (35.6 g) in 112 mL of water was placed in the addition funnel. Alternatively it may be advantageous to dissolve the benzylamine hydrochloride in 80 mL of water and 30 mL of 0.12 N aqueous HCI, instead of 112 mL of H200 ml of water, 130 ml of dimethylsulfoxide (DMSO) and 212 g of the crude product of the formula (I) obtained in were heated and stirred at 100 C. for 3 hours, After cooling, the pH was adjusted to weakly acidic with NaOH aqueous solution and then heated and stirred at 100 C. for 12 hours. After cooling, methanol and water were added and an aqueous NaOH solution was further added to adjust the pH to 12 or more, and seed crystals of

Molecular Weight:229.32
XLogP3:2.2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:229.146664230
Monoisotopic Mass:229.146664230
Topological Polar Surface Area:20.3
Heavy Atom Count:17
Complexity:267
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes