(S)-TERT-BUTYL 4-AMINOAZEPANE-1-CARBOXYLATE

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl cyclopent-3-ene-1-carboxylate (4.42 g, 35 mmol) was dissolved in DCM/MeOH (160 mL, 3:1) and cooled to −78° C. Ozone was passed through the solution until a blue colour persisted. Excess ozone was purged from the reaction mixture with dry N2. Dimethylsulfide (10 mL) was added and the reaction mixture was warmed to rt, the solvent was removed in vacuo. The residue was added to a solution of tert-butyl (4S)-4-aminoazepane-1-carboxylate (7.5 g, 35 mmol), STAB (18.57 g, 87.6 mmol), NEt3 (4.26 g, 42.1 mmol) and acetic acid (1.8 mL) in DCE (200 mL). The mixture was stirred for 3 hours at rt and was then poured into aqueous Na2CO3 solution. The mixture was extracted with EtOAc (3×200 mL), the organic phase were washed with water (100 mL) and brine (100 mL), dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by column chromatography (gradient 0% to 25% EtOAc in Petroleum ether) to give tert-butyl (4S)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (7.7 g, 64.6% yield) as a yellow oil. Excess ozone was purged from the reaction mixture with dry N2 Dimethylsulfide (10 mL) was added the reaction mixture was warmed to rt the solvent was removed in vacuo The mixture was extracted with EtOAc (3×200 mL) the organic phase were washed with water (100 mL) and brine (100 mL) dried over Na2SO4 The solvent was removed in vacuo the residue was purified by column chromatography (gradient 0% to 25% EtOAc in Petroleum ether)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl cyclopent-3-ene-1-carboxylate (4.42 g, 35 mmol) was dissolved in DCM/MeOH (160 mL, 3:1) and cooled to −78° C. Ozone was passed through the solution until a blue colour persisted. Excess ozone was purged from the reaction mixture with dry N2. Dimethylsulfide (10 mL) was added and the reaction mixture was warmed to rt, the solvent was removed in vacuo. The residue was added to a solution of tert-butyl (4S)-4-aminoazepane-1-carboxylate (7.5 g, 35 mmol), STAB (18.57 g, 87.6 mmol), NEt3 (4.26 g, 42.1 mmol) and acetic acid (1.8 mL) in DCE (200 mL). The mixture was stirred for 3 hours at rt and was then poured into aqueous Na2CO3 solution. The mixture was extracted with EtOAc (3×200 mL), the organic phase were washed with water (100 mL) and brine (100 mL), dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by column chromatography (gradient 0% to 25% EtOAc in Petroleum ether) to give tert-butyl (4S)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (7.7 g, 64.6% yield) as a yellow oil. Excess ozone was purged from the reaction mixture with dry N2 Dimethylsulfide (10 mL) was added the reaction mixture was warmed to rt the solvent was removed in vacuo The mixture was extracted with EtOAc (3×200 mL) the organic phase were washed with water (100 mL) and brine (100 mL) dried over Na2SO4 The solvent was removed in vacuo the residue was purified by column chromatography (gradient 0% to 25% EtOAc in Petroleum ether)

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

Procedure: A suspension of Pd(OH)2/C (10%, 550 mg), tert-butyl (4S)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (5.5 g, 17.3 mmol) and HCOONH4 (3.3 g, 51.9 mmol) in MeOH (80 mL) was heated at reflux for 1.5 h. The reaction mixture was cooled to rt and filtered, the solvents of the filtrate were removed in vacuo. The residue was purified by column chromatography (gradient 0% to 10% MeOH in DCM) to give tert-butyl (4S)-4-aminoazepane-1-carboxylate (3.2 g, 87.3%). was heated at reflux for 1.5 h filtered the solvents of the filtrate were removed in vacuo The residue was purified by column chromatography (gradient 0% to 10% MeOH in DCM)

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

Procedure: To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51.7 mg, 0.187 mmol) in dry dichloromethane (2 mL) was added a solution of tert-butyl (4S)-4-aminoazepane-1-carboxylate (69 mg, 0.275 mmol), triethylamine (0.090 mL, 0.646 mmol), HOBT (42.5 mg, 0.278 mmol), and EDC (54.7 mg, 0.285 mmol) sequentially at room temperature under nitrogen. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound as a white solid after lyophilization. The reaction mixture was concentrated under vacuum the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl cyclopent-3-ene-1-carboxylate (4.42 g, 35 mmol) was dissolved in DCM/MeOH (160 mL, 3:1) and cooled to −78° C. Ozone was passed through the solution until a blue colour persisted. Excess ozone was purged from the reaction mixture with dry N2. Dimethylsulfide (10 mL) was added and the reaction mixture was warmed to rt, the solvent was removed in vacuo. The residue was added to a solution of tert-butyl (4S)-4-aminoazepane-1-carboxylate (7.5 g, 35 mmol), STAB (18.57 g, 87.6 mmol), NEt3 (4.26 g, 42.1 mmol) and acetic acid (1.8 mL) in DCE (200 mL). The mixture was stirred for 3 hours at rt and was then poured into aqueous Na2CO3 solution. The mixture was extracted with EtOAc (3×200 mL), the organic phase were washed with water (100 mL) and brine (100 mL), dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by column chromatography (gradient 0% to 25% EtOAc in Petroleum ether) to give tert-butyl (4S)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (7.7 g, 64.6% yield) as a yellow oil. Excess ozone was purged from the reaction mixture with dry N2 Dimethylsulfide (10 mL) was added the reaction mixture was warmed to rt the solvent was removed in vacuo The mixture was extracted with EtOAc (3×200 mL) the organic phase were washed with water (100 mL) and brine (100 mL) dried over Na2SO4 The solvent was removed in vacuo the residue was purified by column chromatography (gradient 0% to 25% EtOAc in Petroleum ether)

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

Procedure: A suspension of Pd(OH)2/C (10%, 550 mg), tert-butyl (4S)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (5.5 g, 17.3 mmol) and HCOONH4 (3.3 g, 51.9 mmol) in MeOH (80 mL) was heated at reflux for 1.5 h. The reaction mixture was cooled to rt and filtered, the solvents of the filtrate were removed in vacuo. The residue was purified by column chromatography (gradient 0% to 10% MeOH in DCM) to give tert-butyl (4S)-4-aminoazepane-1-carboxylate (3.2 g, 87.3%). was heated at reflux for 1.5 h filtered the solvents of the filtrate were removed in vacuo The residue was purified by column chromatography (gradient 0% to 10% MeOH in DCM)

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

Procedure: To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51.7 mg, 0.187 mmol) in dry dichloromethane (2 mL) was added a solution of tert-butyl (4S)-4-aminoazepane-1-carboxylate (69 mg, 0.275 mmol), triethylamine (0.090 mL, 0.646 mmol), HOBT (42.5 mg, 0.278 mmol), and EDC (54.7 mg, 0.285 mmol) sequentially at room temperature under nitrogen. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound as a white solid after lyophilization. The reaction mixture was concentrated under vacuum the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes