tert-butyl 2,4-dioxo-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

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

Procedure: A suspension of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester (1 g, 3.6 mmol) in acetic anhydride (20 mL) is heated at reflux for 2 h. The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid. MS (LC-MS): 278 [M+Na]+. is heated at reflux for 2 h The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid

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

Procedure: A suspension of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester (1 g, 3.6 mmol) in acetic anhydride (20 mL) is heated at reflux for 2 h. The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid. MS (LC-MS): 278 [M+Na]+. is heated at reflux for 2 h The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid

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

Procedure: A suspension of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester (1 g, 3.6 mmol) in acetic anhydride (20 mL) is heated at reflux for 2 h. The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid. MS (LC-MS): 278 [M+Na]+. is heated at reflux for 2 h The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid

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

Procedure: The title compound is prepared analogously as described in Example 152A using cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amine and 2,4-Dioxo-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester. MS: 485 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.09 min. 3.09 min.

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

Procedure: A suspension of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester (1 g, 3.6 mmol) in acetic anhydride (20 mL) is heated at reflux for 2 h. The reaction mixture is evaporated 3× times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid. MS (LC-MS): 278 [M+Na]+. is heated at reflux for 2 h The reaction mixture is evaporated 3× times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid

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

Procedure: To a solution of Cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-amine (1.18 g, 4.45 mmol) and triethylamine (0.68 mL, 4.90 mmol) in THF (20 mL) at room temperature is added 2,4-Dioxo-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (1.07 g, 4.19 mmol). After stirred for 2 h, bulk of the solvent is concentrated. The residue is diluted with EtOAc, and washed with aq. KHSO4, water, and brine, dried over Na2SO4, filtered, and concentrated. To a solution of a part of the residue (673 mg, 1.29 mmol) in toluene (5 mL) at room temperature are added triethylamine (0.2 mL, 1.44 mmol) and DPPA (0.31 mL, 1.43 mmol). After stirred for 40 min, TMSCH2CH2OH (0.9 mL, 6.31 mmol) is added. The reaction mixture is refluxed for 2 h. After dilution with EtOAc, the mixture is washed with aq. KHSO4, water, aq. sat. NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to afford the desired carbamate (332 mg, 0.522 mmol), which is treated with TBAF (410 mg, 1.57 mmol) in THF (5 mL) at 50° C. for 2.5 h. After dilution with EtOAc, the mixture is washed with water (×2) and brine, dried over Na2SO4, filtered, and concentrated to afford the title compound as a pale yellow oil. MS: 491 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 2 min then 100% CH3CN+0.1% TFA for 1 min, flow 0.5 ml/min): 1.67 min. bulk of the solvent is concentrated The residue is diluted with EtOAc washed with aq. KHSO4, water, and brine dried over Na2SO4 filtered concentrated After stirred for 40 min The reaction mixture is refluxed for 2 h After dilution with EtOAc, the mixture is washed with aq. KHSO4, water, aq. sat. NaHCO3, and brine dried over Na2SO4 filtered concentrated The residue is purified by silica gel column chromatography

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

Procedure: Under a nitrogen stream, quinidine (69.9 g, 0.215 mol) and tetrahydrofuran (200 mL) were charged and the mixture was cooled to −5 to 5° C. tert-Butyl 2,4-dioxo-3-oxa-7-azabicyclo[3,3,1]nonane-7-carboxylate (50.0 g, 0.196 mol) was added at the same temperature, and the used container was washed with tetrahydrofuran (50.0 mL). Methanol (9.41 g, 0.29 4 mol) was added dropwise at −5 to 5° C., and the mixture was stirred at −5 to 5° C. for 2 hr. To the reaction mixture were added ethyl acetate (350 mL) and 20 w/v % aqueous citric acid solution (250 mL), and the mixture was partitioned. The aqueous layer was extracted again with ethyl acetate (125 mL×2). The organic layers were combined and washed successively with 20 w/v % aqueous citric acid solution (250 mL) and water (250 mL×2). The organic layer was concentrated under reduced pressure. To the residue were added ethanol (100 mL) and ethyl acetate (450 mL), the mixture was heated to 60-70° C., and (R)-phenethylamine (23.7 g, 0.196 mol) was added. The mixture was stirred at 50-60° C. for 1 hr, at 20-30° C. for 1 hr and at −5 to 5° C. for 1 hr. The precipitated crystals were collected by filtration, washed with ethanol-ethyl acetate (2:9, 100 mL), and dried under reduced pressure at 50° C. to give (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (1R)-1-phenylethylamine salt as a white crystalline powder (55.7 g, yield 69.6%). was added at the same temperature the used container was washed with tetrahydrofuran (50.0 mL) the mixture was partitioned The aqueous layer was extracted again with ethyl acetate (125 mL×2) washed successively with 20 w/v % aqueous citric acid solution (250 mL) and water (250 mL×2) The organic layer was concentrated under reduced pressure To the residue were added ethanol (100 mL) and ethyl acetate (450 mL) the mixture was heated to 60-70° C. The mixture was stirred at 50-60° C. for 1 hr, at 20-30° C. for 1 hr and at −5 to 5° C. for 1 hr The precipitated crystals were collected by filtration washed with ethanol-ethyl acetate (2:9, 100 mL) dried under reduced pressure at 50° C.

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen stream, 1-(tert-butoxycarbonyl)piperidine-3,5-dicarboxylic acid (5.00 g, 18.3 mmol) was suspended in tetrahydrofuran (10.0 mL), and trifluoroacetic anhydride (3.80 mL, 27.5 mmol) was added dropwise at 20-30° C. After completion of the dropwise addition, the mixture was stirred at 20-30° C. for 1 hr. To the reaction mixture was added dropwise heptane (20.0 mL) at 20-30° C., and the mixture was cooled to 0-10° C. and stirred for 3 hr. The precipitated crystals were collected by filtration, washed with heptane (3.00 mL), and dried under reduced pressure at 40° C. to give tert-butyl 2,4-dioxo-3-oxa-7-azabicyclo[3,3,1]nonane-7-carboxylate as a white crystalline powder (4.03 g, yield 86.1%). After completion of the dropwise addition the mixture was cooled to 0-10° C. stirred for 3 hr The precipitated crystals were collected by filtration washed with heptane (3.00 mL) dried under reduced pressure at 40° C.

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

Procedure: A suspension of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester (1 g, 3.6 mmol) in acetic anhydride (20 mL) is heated at reflux for 2 h. The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid. MS (LC-MS): 278 [M+Na]+. is heated at reflux for 2 h The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid