9-Azabicyclo(3.3.1)nonan-3-one Hydrochloride

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

Procedure: 20.9 g of 9-azabicyclo[3.3.1]nonan-3-one hydrochloride was dissolved in 600 mL of DMF. 89.0 g of Cs2CO3 followed by 29 g of 4-chlorobenzenesulfonyl chloride was added and the reaction mixture was stirred overnight at rt. After an additional day of stirring, the reaction mixture was poured into 1.4 L of vigorously stirring EtOAc. The mixture was stirred for 2 h and allowed to stand at rt overnight. The mixture was filtered to remove undissolved solids and the filtrate was washed with H2O (2 L×3) and brine (2 L). The organic layer was dried over MgSO4, filtered and the solvent was removed by rotary evaporation. A granular, tan solid was produced. Trituration with methanol dissolved a tan impurity to afford 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one as a white crystalline solid (25.9 g, 69% yield). was added After an additional day of stirring The mixture was stirred for 2 h to stand at rt overnight The mixture was filtered to remove undissolved solids the filtrate was washed with H2O (2 L×3) and brine (2 L) The organic layer was dried over MgSO4 filtered the solvent was removed by rotary evaporation A granular, tan solid was produced

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

Procedure: In a 30 mL microwave reaction tube were combined 4-(trifluoromethoxy)phenyl-hydrazine hydrochloride (1062 mg, 5.0 mmol; Maybridge), 9-azabicyclo[3.3.1]nonan-3-one hydrochloride (878 mg, 5.0 mmol; Accela ChemBio), and 1 N HCl in acetic acid (15 mL, 15 mmol; Aldrich). The reaction mixture was microwaved at 150° C. (Biotage Personal Chemistry, maximum 300 W) for 15 minutes, then cooled to room temperature. The solvent was removed, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to ˜pH 12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 3:1) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.33-1.52 (m, 2H), 1.64-1.78 (m, 2H), 1.89-2.06 (m, 2H), 2.68 (d, J=17 Hz, 1H), 3.25-3.34 (m, 1H), 3.62 (t, J=5 Hz, 1H), 4.43 (t, J=3 Hz, 1H), 6.93 (ddd, J=9, 2, 1 Hz, 1H), 7.22 (d, J=1 Hz, 1H), 7.31 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 297 (M+H)+. In a 30 mL microwave reaction tube were combined The reaction mixture was microwaved at 150° C. (Biotage Personal Chemistry, maximum 300 W) for 15 minutes The solvent was removed the residue was dissolved in water (20 mL) This solution was extracted with dichloromethane (3×50 mL) the combined organic phases were dried over magnesium sulfate After removing the solvent under vacuum the residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 3:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 100 mL round-bottom flask were combined p-tolylhydrazine hydrochloride (1.80 g, 11.4 mmol; Alfa Aesar), 9-azabicyclo[3.3.1]nonan-3-one hydrochloride (2.0 g, 11.4 mmol; Accela ChemBio), and concentrated sulfuric acid (5 mL) in dioxane (50 mL). The reaction mixture was heated to 80° C. for 2.5 hours, then cooled to room temperature. The solvent was decanted, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to pH ˜12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the residue was purified by silica gel chromatography (CH2Cl2/CH3OH, 3:1) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.39-1.50 (m, 2H), 1.75 (d, J=14 Hz, 2H), 1.91-2.07 (m, 2H), 2.38 (s, 3H), 2.72 (d, J=17 Hz, 1H), 3.27-3.39 (m, 1H), 3.70 (t, J=5 Hz, 1H), 4.55 (t, J=3 Hz, 1H), 6.88 (dd, J=8, 1 Hz, 1H), 7.14 (s, 1H), 7.18 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 227 (M+H)+. In a 100 mL round-bottom flask were combined cooled to room temperature The solvent was decanted the residue was dissolved in water (20 mL) This solution was extracted with dichloromethane (3×50 mL) the combined organic phases were dried over magnesium sulfate After removing the solvent under vacuum the residue was purified by silica gel chromatography (CH2Cl2/CH3OH, 3:1)

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

Procedure: This compound was prepared from 9-azabicyclo[3.3.1]nonan-3-one hydrochloride and 4-fluorophenylhydrazine by the Fischer indole synthesis as described in Example 1, Method A. The product was obtained as yellow crystals (74% yield), mp 200°-201° C. (from methylene chloride).

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

Procedure: This compound was prepared from 9-azabicyclo[3.3.1]nonan-3-one hydrochloride and phenylhydrazine by Fischer indole synthesis as described in Example 1, Method A, to give colorless crystals, mp 198°-203° C. (from methylene chloride; it was also converted to a hydrogen oxalate hemihydrate, mp 68°-72° C. (from ethanol-ether).

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To suspension of zinc (67.2 g, 1.03 g-atom) in glacial acetic acid (40 mL) at 65° C. was slowly added a solution of 9-(2,2,2-trichlorocarbethoxy)-9-azabicyclo[3.3.1]nonan-3-one (80.9 g, 0.26 mol) in glacial acetic acid (120 mL) over 1 hour. An additional 40 mL of glacial acetic acid was used to rinse the addition funnel and the reaction was stirred at 65° C. until no further gas evolution was observed. The reaction was allowed to cool slightly and water (40 mL) was added to dissolve the organic acetate salts. The reaction was filtered and solvent was removed under vacuum. The resultant orange oil was slowly added to concentrated ammonium hydroxide (80 mL) using water (80 mL) to aid in the transfer. An additional 80 mL of concentrated ammonium hdroxide was added, followed by the addition of a solution of 31 g of sodium hydroxide in 155 mL of water. The solution was extracted with methylene chloride (6×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was dissolved in 200 mL of ether and the solution was slowly added to 1N hydrogen chloride in ether (310 mL) while vigorously stirring to give 38.7 g (86% yield) of a colorless hydrochloride, m.p. 216°-219° C. after trituration with ether and drying. Anal. (C8H14ClNO). to rinse the addition funnel to cool slightly water (40 mL) was added to dissolve the organic acetate salts The reaction was filtered solvent was removed under vacuum The resultant orange oil was slowly added to concentrated ammonium hydroxide (80 mL) An additional 80 mL of concentrated ammonium hdroxide was added followed by the addition of a solution of 31 g of sodium hydroxide in 155 mL of water The solution was extracted with methylene chloride (6×300 mL) dried over anhydrous sodium sulfate filtered concentrated to an oil The oil was dissolved in 200 mL of ether the solution was slowly added to 1N hydrogen chloride in ether (310 mL) while vigorously stirring

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

Procedure: 20.9 g of 9-azabicyclo[3.3.1]nonan-3-one hydrochloride was dissolved in 600 mL of DMF. 89.0 g of Cs2CO3 followed by 29 g of 4-chlorobenzenesulfonyl chloride was added and the reaction mixture was stirred overnight at rt. After an additional day of stirring, the reaction mixture was poured into 1.4 L of vigorously stirring EtOAc. The mixture was stirred for 2 h and allowed to stand at rt overnight. The mixture was filtered to remove undissolved solids and the filtrate was washed with H2O (2 L×3) and brine (2 L). The organic layer was dried over MgSO4, filtered and the solvent was removed by rotary evaporation. A granular, tan solid was produced. Trituration with methanol dissolved a tan impurity to afford 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one as a white crystalline solid (25.9 g, 69% yield). was added After an additional day of stirring The mixture was stirred for 2 h to stand at rt overnight The mixture was filtered to remove undissolved solids the filtrate was washed with H2O (2 L×3) and brine (2 L) The organic layer was dried over MgSO4 filtered the solvent was removed by rotary evaporation A granular, tan solid was produced

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

Procedure: 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one hydrochloride (38.8 g) was dissolved in 450 mL of glacial acetic acid. 13.5 Grams of 10% Pd/C (Degussa catalyst E101—containing 50% water) was added. After the appropriate evacuation & purge cycles, the mixture was agitated under 62 psi of H2 at rt overnight. TLC (3% MeOH in CH2Cl2 on silica gel) indicated that the reaction was complete. The reaction mixture was filtered through Celite and concentrated by rotary evaporation under vacuum. The product was redissolved in 0.12 N HCl (250 mL) and the solution was concentrated in vacuo. This was repeated once more with 0.12 N HCl (250 mL). The product was then dissolved in 1 N HCl and concentrated to dryness under vacuum. A sticky brown solid was obtained. The material was recrystallized once from isopropanol and once from EtOH to give 9-azabicyclo[3.3.1]nonan-3-one hydrochloride as a tan granular solid (18.8 g; 73.6% yield) after drying under high vacuum (0.1-1.0 mTorr) overnight. After the appropriate evacuation & purge cycles The reaction mixture was filtered through Celite concentrated by rotary evaporation under vacuum The product was redissolved in 0.12 N HCl (250 mL) the solution was concentrated in vacuo The product was then dissolved in 1 N HCl concentrated to dryness under vacuum A sticky brown solid was obtained The material was recrystallized once from isopropanol and once from EtOH

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

Procedure: 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one hydrochloride (38.8 g) was dissolved in 450 mL of glacial acetic acid. 13.5 Grams of 10% Pd/C (Degussa catalyst E101—containing 50% water) was added. After the appropriate evacuation & purge cycles, the mixture was agitated under 62 psi of H2 at rt overnight. TLC (3% MeOH in CH2Cl2 on silica gel) indicated that the reaction was complete. The reaction mixture was filtered through Celite and concentrated by rotary evaporation under vacuum. The product was redissolved in 0.12 N HCl (250 mL) and the solution was concentrated in vacuo. This was repeated once more with 0.12 N HCl (250 mL). The product was then dissolved in 1 N HCl and concentrated to dryness under vacuum. A sticky brown solid was obtained. The material was recrystallized once from isopropanol and once from EtOH to give 9-azabicyclo[3.3.1]nonan-3-one hydrochloride as a tan granular solid (18.8 g; 73.6% yield) after drying under high vacuum (0.1-1.0 mTorr) overnight. After the appropriate evacuation & purge cycles The reaction mixture was filtered through Celite concentrated by rotary evaporation under vacuum The product was redissolved in 0.12 N HCl (250 mL) the solution was concentrated in vacuo The product was then dissolved in 1 N HCl concentrated to dryness under vacuum A sticky brown solid was obtained The material was recrystallized once from isopropanol and once from EtOH