tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

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:

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

Procedure: A suspension of zinc powder (5.59 g, 85.5 mmol) in tetrahydrofuran (THF, 100 mL) at 0° C., was treated with titanium(IV)chloride (4.69 mL, 42.8 mmol) by dropwise addition. The resultant mixture was heated at reflux for 2 h. The resultant solution was cooled to 0° C. 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.4 g, 10.7 mmol) and 5-bromo-9-oxo-9H-xanthene-3-carboxylic acid diethylamide (4.0 g, 10.7 mmol) were added and the solution was heated at reflux for 4 h. Potassium sodium tartrate tetrahydrate (30 g, 106 mmol) was added to the reaction mixture and allowed to stir at ambient temperature overnight. The inorganic solids were removed by filtration and washed successively with THF, EtOAc and dichloromethane. The solvent was evaporated in vacuo. Purification by flash chromatography using a gradient 1% to 10% methanol (with ammonia, 2 N) in dichloromethane as the eluent gave Compound 7j (3.65 g). Crude product was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%), to give the trifluoroacetic acid salt of compound 7j. MS: m/z 467.0 (MH+). 1H NMR (DMSO-d6): δ 1.0-1.2 (br m, 6H), 1.32 (d, 2H, J=7.9 Hz), 1.75-1.85 (br m, 2H), 2.85-3.10 (m, 4H), 3.15-3.50 (br m, 4H), 4.01 br s, 2H), 7.15-7.26 (m, 3H), 7.42 (d, 1H, J=6.7 Hz), 7.49 (d, 1H, J=7.9 Hz), 7.66 (d, 1H, J=7.9 Hz), 8.81 (br s, 1H) and 9.12 br d, 1H). at reflux for 2 h the solution was heated at reflux for 4 h The inorganic solids were removed by filtration washed successively with THF, EtOAc and dichloromethane The solvent was evaporated in vacuo Purification by flash chromatography

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

Procedure: NaBH4 (8.8 g, 0.23 mol) was added to a 0° C. solution of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35 g, 0.16 mol) in ethanol (200 ml). The reaction mixture was stirred for 45 min at 0° C., whereupon it was allowed to reach 20° C. After stirring overnigth the suspension was evaporated to dryness. EtOAc (350 ml) was added, and the precipitate was filtered off. Water (200 ml) was added to the filtrate, and the layers were separated. The aqueous layer was extracted with EtOAc (100 ml), and the combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 29.5 g of an oil, which crystallised on standing. The two isomers were separated by flash chromatography (EtOAc/heptane 1:5 □ 1:1), affording 5 g of the title compound. LC-MS (m/z): 250 (M+23(Na)). to reach 20° C After stirring overnigth the suspension was evaporated to dryness EtOAc (350 ml) was added the precipitate was filtered off Water (200 ml) was added to the filtrate the layers were separated The aqueous layer was extracted with EtOAc (100 ml) the combined organic layers were dried (Na2SO4) concentrated in vacuo

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

Procedure: To 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 1.33 mmol) was added DME (9 mL) and EtOH (0.2 mL). The mixture was cooled to 0 C when TOSMIC (530 mg, 2.65 mmol) and potassium tert-butoxide (609 mg, 5.2 mmol) were added. The mixture was stirred to room temperature and then heated at 50 C for 18 h. After this time the reaction was evaporated and loaded onto a silica column and eluted with heptane-10% to 30% ethyl actetate to give the title compound (216 mg, 69%). Method B HPLC-MS: MH+ requires m/z=237. Found: m/z=237, Rt=1.35 min (86%). were added heated at 50 C for 18 h After this time the reaction was evaporated eluted with heptane-10% to 30% ethyl actetate

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

Procedure: 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester (8 g, 35.5 mmol) was dissolved in 100 mL of ethanol. Sodium borohydride (2 g, 53.5 mmol) was added to the solution portionwise at room temperature. After stirring for 3 hours, the reaction was evaporated in vacuo to give clear viscous oil. The oil was dissolved in dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford 7.55 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester as a white crystalline solid; 1H NMR (300 MHz, DMSO-d6): 4.23 (dd, J=2.7, 4.6 Hz, 1H), 4.18-4.06 (m, 2H), 2.17-2.06 (m, 1H), 1.99-1.91 (m, 3H), 1.72-1.50 (m, 5H), 1.47 (s, 9H). the reaction was evaporated in vacuo to give clear viscous oil washed with water and brine dried over anhydrous sodium sulfate filtered evaporated

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

Procedure: 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester (8 g, 35.5 mmol) was dissolved in 100 mL of ethanol. Sodium borohydride (2 g, 53.5 mmol) was added to the solution portionwise at room temperature. After stirring for 3 hours, the reaction was evaporated in vacuo to give clear viscous oil. The oil was dissolved in dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford 7.55 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester as a white crystalline solid; 1H NMR (300 MHz, DMSO-d6): 4.23 (dd, J=2.7, 4.6 Hz, 1H), 4.18-4.06 (m, 2H), 2.17-2.06 (m, 1H), 1.99-1.91 (m, 3H), 1.72-1.50 (m, 5H), 1.47 (s, 9H). the reaction was evaporated in vacuo to give clear viscous oil washed with water and brine dried over anhydrous sodium sulfate filtered evaporated

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

Procedure: A suspension of zinc powder (5.59 g, 85.5 mmol) in tetrahydrofuran (THF, 100 mL) at 0° C., was treated with titanium(IV) chloride (4.69 mL, 42.8 mmol) by dropwise addition. The resultant mixture was heated at reflux for 2 h. The resultant solution was cooled to 0° C. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.4 g, 10.7 mmol) and 5-bromo-9-oxo-9H-xanthene-3-carboxylic acid diethylamide (4.0 g, 10.7 mmol) were added and the solution was heated at reflux for 4 h. Potassium sodium tartrate tetrahydrate (30 g, 106 mmol) was added to the reaction mixture and allowed to stir at ambient temperature overnight. The inorganic solids were removed by filtration and washed successively with THF, EtOAc and dichloromethane. The solvent was evaporated in vacuo. Purification by flash chromatography using a gradient 1% to 10% methanol (with ammonia, 2 N) in dichloromethane as the eluent gave Compound 7j (3.65 g). Crude product was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%), to give the trifluoroacetic acid salt of compound 7j. MS: m/z 467.0 (MH+). 1H NMR (DMSO-d6): δ 1.0-1.2 (br m, 6 H), 1.32 (d, 2 H, J=7.9 Hz), 1.75-1.85 (br m, 2 H), 2.85-3.10 (m, 4 H), 3.15-3.50 (br m, 4 H), 4.01 br s, 2H), 7.15-7.26 (m, 3 H), 7.42 (d, 1 H, J=6.7 Hz), 7.49 (d, 1 H, J=7.9 Hz), 7.66 (d, 1 H, J=7.9 Hz), 8.81 (br s, 1 H) and 9.12 br d, 1 H). at reflux for 2 h the solution was heated at reflux for 4 h The inorganic solids were removed by filtration washed successively with THF, EtOAc and dichloromethane The solvent was evaporated in vacuo Purification by flash chromatography

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

Procedure: A suspension of zinc powder (5.59 g, 85.5 mmol) in tetrahydrofuran (THF, 100 mL) at 0° C., was treated with titanium(IV) chloride (4.69 mL, 42.8 mmol) by dropwise addition. The resultant mixture was heated at reflux for 2 h. The resultant solution was cooled to 0° C. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.4 g, 10.7 mmol) and 5-bromo-9-oxo-9H-xanthene-3-carboxylic acid diethylamide (4.0 g, 10.7 mmol) were added and the solution was heated at reflux for 4 h. Potassium sodium tartrate tetrahydrate (30 g, 106 mmol) was added to the reaction mixture and allowed to stir at ambient temperature overnight. The inorganic solids were removed by filtration and washed successively with THF, EtOAc and dichloromethane. The solvent was evaporated in vacuo. Purification by flash chromatography using a gradient 1% to 10% methanol (with ammonia, 2 N) in dichloromethane as the eluent gave Compound 7j (3.65 g). Crude product was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%), to give the trifluoroacetic acid salt of compound 7j. MS: m/z 467.0 (MH+). 1H NMR (DMSO-d6): δ 1.0-1.2 (br m, 6 H), 1.32 (d, 2 H, J=7.9 Hz), 1.75-1.85 (br m, 2 H), 2.85-3.10 (m, 4 H), 3.15-3.50 (br m, 4 H), 4.01 br s, 2H), 7.15-7.26 (m, 3 H), 7.42 (d, 1 H, J=6.7 Hz), 7.49 (d, 1 H, J=7.9 Hz), 7.66 (d, 1 H, J=7.9 Hz), 8.81 (br s, 1 H) and 9.12 br d, 1 H). at reflux for 2 h the solution was heated at reflux for 4 h The inorganic solids were removed by filtration washed successively with THF, EtOAc and dichloromethane The solvent was evaporated in vacuo Purification by flash chromatography