8-benzyl-8-azabicyclo[3.2.1]octan-3-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By an analogous method to that described in Example 16, the product from Example 16, compound 3 (185 mg, 0.44 mmol) was combined with 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (97 mg, 0.45 mmol) and Ti(O-i Pr)4 (105 mL, 0.50 mmol) and left stirring for 1 h. To the thick reaction mixture was added NaBH3CN (59.5 mg, 0.95 mmol) and the mixture was stirred overnight. To the reaction mixture was added H2O (1 mL) and it was filtered. The filtrate was washed with EtOH, concentrated and purified by silica gel chromatography, eluting with 30:1:0.1 to 15:1:0.1 CH2Cl2 --MeOH--NH3 aq. to give the title product as a white foam. HRMS (FAB, M+H+); m/e calc'd [C35H41Cl2N4O2 ]+ : 619.2607, found 619.2594. left the mixture was stirred overnight was filtered The filtrate was washed with EtOH concentrated purified by silica gel chromatography eluting with 30:1:0.1 to 15:1:0.1 CH2Cl2

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This was prepared according to the reported method (Chem. Abs., 1958, 53, 432e). A mixture of 2,5-dimethoxytetrahydrofuran (13 ml, 0.1 mol), 2 drops of c-HCl and water (10 ml) was stirred at room temperature for 1 h, then treated with water(10 ml), acetone-1,3-dicarboxylic acid (14.6 g, 0.1 mol), and benzylamine (10.9 ml, 0.1 mol). After the initial foaming had subsided, the pH was adjusted to 5 with 1N HCl, and stirring was continued for 14 h. The reaction mixture was adjusted to pH 1, washed with ethyl acetate, filtered through celite, and then adjusted to pH 12 with NaOH, and extracted with ethyl acetate. The extract was dried over Na2SO4 and concentrated to afford 14.5 g (67% crude) of an oil, which was used for next reaction without further purification. This was prepared stirring was continued for 14 h washed with ethyl acetate filtered through celite extracted with ethyl acetate The extract was dried over Na2SO4 concentrated to afford 14.5 g (67% crude) of an oil, which was used for next reaction without further purification

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of phenylmagnesium bromide in ether (3 M, 2.3 mL) was added dropwise to a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (1.0 g, 4.6 mmol) in THF (20 mL) that had been cooled to 0° C. The mixture was stirred for 3 hours and a solution of saturated aqueous ammonium chloride was added and the products extracted into diethyl ether, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10-30% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.5 g) as an oil. LCMS m/z 294.4 [M+H]+. R.T.=2.59 min (Analytical Method 4). the products extracted into diethyl ether dried over sodium sulphate filtered the solvent removed by evaporation under vacuum The residue was purified by flash chromatography on silica eluting with 10-30% ethyl acetate/hexane The fractions containing the desired product were concentrated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,5-dimethoxytetrahydrofuran (50 g, 378 mmol) in hydrochloric acid (0.025 N, 160 ml) was cooled to 0° C. for 16 hours. Benzylamine hydrochloride (65 g, 453 mmol), ketomalonic acid (55 g, 377 mmol) and an aqueous solution of sodium acetate (300 ml, 0.69 M) were added and the reaction stirred at room temperature for one hour. The mixture was heated to 50° C. for further 90 minutes, then cooled in an ice bath and basified to pH12 with 2N sodium hydroxide solution. The layers were separated and the aqueous phase extracted with ethyl acetate (3×300 ml). The combined organic extracts were washed with water, dried (MgSO4), filtered and evaporated under reduced pressure. The residual brown oil was distilled under reduced pressure (126°/3 mmHg) to afford the title compound as an off-white solid (37.81 g). The mixture was heated to 50° C. for further 90 minutes cooled in an ice bath The layers were separated the aqueous phase extracted with ethyl acetate (3×300 ml) The combined organic extracts were washed with water dried (MgSO4) filtered evaporated under reduced pressure The residual brown oil was distilled under reduced pressure (126°/3 mmHg)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium t-butoxide (2.5 g) was added portionwise to a stirred mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (2.0 g), tosylmethyl isocyanide (2.36 g) and ethanol (2 ml) in dimethoxyethane (50 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.5 hours and then overnight at room ternperature. The mixture was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chromatographed [SiO2 ; hexane:ethyl acetate (80:20)] to give 3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.87 g). overnight The mixture was then filtered the solid residue washed with dimethoxyethane The combined filtrates were evaporated under reduced pressure chromatographed [SiO2 ; hexane:ethyl acetate (80:20)]

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium t-butoxide (2.5 g) was added portionwise to a stirred mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (2.0 g), tosylmethyl isocyanide (2.36 g) and ethanol (2 ml) in dimethoxyethane (50 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.5 hours and then overnight at room ternperature. The mixture was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chromatographed [SiO2 ; hexane:ethyl acetate (80:20)] to give 3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.87 g). overnight The mixture was then filtered the solid residue washed with dimethoxyethane The combined filtrates were evaporated under reduced pressure chromatographed [SiO2 ; hexane:ethyl acetate (80:20)]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Three drops of 5M hydrochloric acid was added to a stirred mixture of 2,5-dimethoxytetrahydrofuran (16.5 g) and water (70 ml). After 10 minutes a mixture of benzylamine (13.6 ml) and 5M hydrochloric acid (30 ml) were added followed by the immediate addition of a mixture of 1,3-acetonedicarboxylic acid (18.2 g) and sodium acetate (10 g) in water (100 ml). After stirring at room temperature for 3 days, during which carbon dioxide was evolved, the mixture was basified to pH8 and extracted with ethyl acetate (×3). The combined extracts were dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2 ; hexane:ethyl acetate] to give 8-benzyl-8-azabicyclo[3.2. 1 ]octan-3-one (11.2 g). were added extracted with ethyl acetate (×3) The combined extracts were dried (MgSO4) evaporated under reduced pressure

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Concentrated hydrochloric acid (30 mL) was added to a heterogeneous solution of 2,5-dimethoxy tetrahydrofuran (82.2 g, 0.622 mol) in water (170 mL) while stirring. In a separate flask cooled to 0° C. (ice bath), concentrated hydrochloric acid (92 mL) was added slowly to a solution of benzyl amine (100 g, 0.933 mol) in water (350 mL). The 2,5-dimethoxytetrahydrofuran solution was stirred for approximately 20 min, diluted with water (250 mL), and then the benzyl amine solution was added, followed by the addition of a solution of 1,3-acetonedicarboxylic acid (100 g, 0.684 mol) in water (400 mL) and then the addition of sodium hydrogen phosphate (44 g, 0.31 mol) in water (200 mL). The pH was adjusted from pH 1 to pH˜4.5 using 40% NaOH. The resulting cloudy and pale yellow solution was stirred overnight. The solution was then acidified to pH 3 from pH 7.5 using 50% hydrochloric acid, heated to 85° C. and stirred for 2 hours. The solution was cooled to room temperature, basified to pH 12 using 40% NaOH, and extracted with DCM (3×500 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate in quantitative yield as a viscous brown oil (˜95% purity based on analytical HPLC). 1H-NMR (CDCl3) δ (ppm) 7.5-7.2 (m, 5H, C6H5), 3.7 (s, 2H, CH2Ph), 3.45 (broad s, 2H, CH—NBn), 2.7-2.6 (dd, 2H, CH2CO), 2.2-2.1 (dd, 2H, CH2CO), 2.1-2.0 (m, 2H, CH2CH2), 1.6 (m, 2H, CH2CH2). (m/z): [M+H]+ calcd for C14H17NO 216.14; found, 216.0. The resulting cloudy and pale yellow solution was stirred overnight stirred for 2 hours The solution was cooled to room temperature extracted with DCM (3×500 mL) The combined organic layers were washed with brine dried (MgSO4) filtered concentrated under reduced pressure