(3S)-1-azabicyclo[2.2.2]octan-3-ol

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

Procedure: The product of Example 6C (7.0 g, 18.4 mmol) was treated with NaOH (aqueous) according to the procedure of Example 1B. The title product was obtained as white a solid (2.0 g, yield, 86%). MS (DCl/NH3) m/z 128 (M+H)+.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,7-dibromodibenzothiophene-5,5-dioxide (0.60 g, 1.75 mmol; see J. Med. Chem. 1978, 21, 1084), (S)-(−)-quinuclidin-3-ol (280 mg, 2.2 mmol; Acros), copper(I) iodide (33 mg, 0.17 mmol; Aldrich), 1,10-phenanthroline (63 mg, 0.35 mol; Aldrich) and powdered cesium carbonate (0.86 g, 2.64 mmol; Aldrich) in toluene (2 mL) was heated to 110° C. with vigorous stirring for 30 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate and dichloromethane, and the residue purified by flash chromatography (80 g silica gel, 1:10:89 NH4OH-MeOH-CH2Cl2) to afford the title compound (0.37 g, 1.08 mmol; 63% yield): MS (DCl/NH3): m/z 342 (M+1)+. After cooling to room temperature the reaction mixture was filtered through diatomaceous earth rinsing with ethyl acetate and dichloromethane the residue purified by flash chromatography (80 g silica gel, 1:10:89 NH4OH-MeOH-CH2Cl2)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,7-dibromodibenzothiophene-5,5-dioxide (0.60 g, 1.75 mmol; see J. Med. Chem. 1978, 21, 1084), (S)-(−)-quinuclidin-3-ol (280 mg, 2.2 mmol; Acros), copper(I) iodide (33 mg, 0.17 mmol; Aldrich), 1,10-phenanthroline (63 mg, 0.35 mol; Aldrich) and powdered cesium carbonate (0.86 g, 2.64 mmol; Aldrich) in toluene (2 mL) was heated to 110° C. with vigorous stirring for 30 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate and dichloromethane, and the residue purified by flash chromatography (80 g silica gel, 1:10:89 NH4OH-MeOH-CH2Cl2) to afford the title compound (0.37 g, 1.08 mmol; 63% yield): MS (DCl/NH3): m/z 342 (M+1)+. After cooling to room temperature the reaction mixture was filtered through diatomaceous earth rinsing with ethyl acetate and dichloromethane the residue purified by flash chromatography (80 g silica gel, 1:10:89 NH4OH-MeOH-CH2Cl2)

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

Procedure: A solution of (3S)-(+)-quinuclidin-3-ol (0.50 g, 3.93 mmol) [M. Langlois, C. Meyer, and J. L. Soulier, Synth. Comm., 23, 1895-1911 (1992)], phenyl isocyanate (0.47 mL, 4.32 mmol, 1.1 equivalents), and dibutyltin dilaurate (0.013 mL, 0.08 mmol) in anhydrous toluene (20 mL) was heated at reflux under nitrogen for 1 hour. The resulting reaction mixture was evaporated under reduced pressure, and the resulting solid was placed in 1N HCl (25 mL). The resulting aqueous mixture was extracted with ethyl acetate (2×25 mL), basified to pH 10 with Na2CO3, and extracted with chloroform (3×50 mL). The chloroform extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The resulting solid was recrystallized using toluene (5 mL) to afford the title compound (0.875 g, 90%) as a white solid: mp 129.0-130.0° C.; FAB LRMS m /z (relative intensity, %) 247 (MH+, 39), 110 (100); [α]22D =-7.5° (c=1.0, MeOH). at reflux under nitrogen for 1 hour The resulting reaction mixture was evaporated under reduced pressure The resulting aqueous mixture was extracted with ethyl acetate (2×25 mL) extracted with chloroform (3×50 mL) dried (MgSO4) evaporated under reduced pressure The resulting solid was recrystallized

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

Procedure: A solution of (3S)-(+)-quinuclidin-3-ol (0.50 g, 3.93 mmol) [M. Langlois, C. Meyer, and J. L. Soulier, Synth. Comm., 23, 1895-1911 (1992)], phenyl isocyanate (0.47 mL, 4.32 mmol, 1.1 equivalents), and dibutyltin dilaurate (0.013 mL, 0.08 mmol) in anhydrous toluene (20 mL) was heated at reflux under nitrogen for 1 hour. The resulting reaction mixture was evaporated under reduced pressure, and the resulting solid was placed in 1N HCl (25 mL). The resulting aqueous mixture was extracted with ethyl acetate (2×25 mL), basified to pH 10 with Na2CO3, and extracted with chloroform (3×50 mL). The chloroform extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The resulting solid was recrystallized using toluene (5 mL) to afford the title compound (0.875 g, 90%) as a white solid: mp 129.0-130.0° C.; FAB LRMS m /z (relative intensity, %) 247 (MH+, 39), 110 (100); [α]22D =-7.5° (c=1.0, MeOH). at reflux under nitrogen for 1 hour The resulting reaction mixture was evaporated under reduced pressure The resulting aqueous mixture was extracted with ethyl acetate (2×25 mL) extracted with chloroform (3×50 mL) dried (MgSO4) evaporated under reduced pressure The resulting solid was recrystallized

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,7-dibromodibenzothiophene-5,5-dioxide (0.60 g, 1.75 mmol; see J. Med. Chem. 1978, 21, 1084), (S)-(−)-quinuclidin-3-ol (280 mg, 2.2 mmol; Acros), copper (I) iodide (33 mg, 0.17 mmol; Aldrich), 1,10-phenanthroline (63 mg, 0.35 mol; Aldrich) and powdered cesium carbonate (0.86 g, 2.64 mmol; Aldrich) in toluene (2 mL) was heated to 110° C. with vigorous stirring for 30 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate and dichloromethane, and the residue purified by flash chromatography (80 g silica gel, 1:10:89 NH4OH-MeOH—CH2Cl2) to afford the title compound (0.37 g, 1.08 mmol; 63% yield): MS (DCI/NH3): m/z 342 (M+1)+. After cooling to room temperature the reaction mixture was filtered through diatomaceous earth rinsing with ethyl acetate and dichloromethane the residue purified by flash chromatography (80 g silica gel, 1:10:89 NH4OH-MeOH—CH2Cl2)

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

Procedure: To a refluxing solution of methyl 3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.36 mmol) and (S)-3-quinuclidinol (0.184 g, 1.44 mmol) in toluene (2 mL), was added titanium(IV)-i-propoxide (0.105 mL, 0.36 mmol, d=0.97). After refluxing for 18 h, the reaction mixture was diluted with 5% methanol/dichloromethane, washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.08 g, 34%); 1H NMR (DMSO-d6): δ 1.32-1.36 (m, 1H), 1.51-1.54 (m, 4H), 1.79-1.84 (m, 3H), 1.99-2.01 (m, 1H), 2.35 (t, 2H, J=6.8 Hz), 2.52-2.72 (m, 11H), 3.15-3.21 (m, 1H), 3.85 (t, 2H, J=6.8 Hz), 4.61 (d, 4H, J=13.2 Hz), 4.90-4.92 (m, 1H), 6.76 (t, 1H, J=6.8 Hz), 6.84 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.24 (m, 3H), 7.52-7.59 (m, 2H), 7.87-7.92 (m, 2H), 10.80 (br, 1H); MS for C38H44N6O4 m/z 649.11(M+H)+. After refluxing for 18 h washed with water and brine The organic phase was dried over MgSO4 filtered concentrated isolated by reverse phase HPLC

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

Procedure: To a refluxing solution of methyl 3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.36 mmol) and (S)-3-quinuclidinol (0.184 g, 1.44 mmol) in toluene (2 mL), was added titanium(IV)-i-propoxide (0.105 mL, 0.36 mmol, d=0.97). After refluxing for 18 h, the reaction mixture was diluted with 5% methanol/dichloromethane, washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.08 g, 34%); 1H NMR (DMSO-d6): δ 1.32-1.36 (m, 1H), 1.51-1.54 (m, 4H), 1.79-1.84 (m, 3H), 1.99-2.01 (m, 1H), 2.35 (t, 2H, J=6.8 Hz), 2.52-2.72 (m, 11H), 3.15-3.21 (m, 1H), 3.85 (t, 2H, J=6.8 Hz), 4.61 (d, 4H, J=13.2 Hz), 4.90-4.92 (m, 1H), 6.76 (t, 1H, J=6.8 Hz), 6.84 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.24 (m, 3H), 7.52-7.59 (m, 2H), 7.87-7.92 (m, 2H), 10.80 (br, 1H); MS for C38H44N6O4 m/z 649.11(M+H)+. After refluxing for 18 h washed with water and brine The organic phase was dried over MgSO4 filtered concentrated isolated by reverse phase HPLC

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

Procedure: To stirred and cooled (0° C.) solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid (0.784 g, 2.96 mmol) in THF (25 mL) was added triethylamine (0.82 mL, 5.9 mmol) followed by isobutyl chloroformate (0.58 mL, 4.4 mmol). The reaction was stirred cold for another 1 hour before adding a solution of sodium azide (0.385 g, 5.92 mmol) in water (7 mL). The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×60 mL). The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL), dried (Na2SO4) and concentrated. After coevaporating with toluene (2×30 mL), the resulting off-white solid was taken up in toluene (25 mL) and refluxed for 4 hours. (S)-3-quinuclidinol (0.753 g, 5.92 mmol) was then added and reflux was continued for 3 hours. The reaction was concentrated and the residue was purified by flash chromatography using a chloroform/methanol/ammonia gradient to afford the title compound as a white solid (0.793 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.90-7.81 (m, 2H), 7.32 (s, 1H), 7.14-7.05 (m, 2H), 5.76 (br s, 1H), 4.72-4.65 (m, 1H), 3.26-3.10 (m, 1H), 3.03-2.37 (m, 5H), 2.05-1.23 (m, 1H) ppm. 13C NMR (400 MHz, CDCl3) δ 177.6, 162.6 (d, J=248.4 Hz), 154.8, 153.6, 130.8 (d, J=3.2 Hz), 128.1 (d, J=8.1 Hz), 115.9 (d, J=21.7 Hz), 112.2, 71.6, 55.7, 47.4, 46.5, 29.1, 25.4, 24.7, 19.6 ppm. Purity: 100% UPLCMS (210 nm & 254 nm): retention time 0.82 min: (M+1) 390. The reaction was stirred cold for another 1 hour The reaction was stirred overnight extracted with ethyl acetate (2×60 mL) The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL) dried (Na2SO4) concentrated refluxed for 4 hours reflux The reaction was concentrated the residue was purified by flash chromatography

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

Procedure: To stirred and cooled (0° C.) solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid (0.784 g, 2.96 mmol) in THF (25 mL) was added triethylamine (0.82 mL, 5.9 mmol) followed by isobutyl chloroformate (0.58 mL, 4.4 mmol). The reaction was stirred cold for another 1 hour before adding a solution of sodium azide (0.385 g, 5.92 mmol) in water (7 mL). The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×60 mL). The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL), dried (Na2SO4) and concentrated. After coevaporating with toluene (2×30 mL), the resulting off-white solid was taken up in toluene (25 mL) and refluxed for 4 hours. (S)-3-quinuclidinol (0.753 g, 5.92 mmol) was then added and reflux was continued for 3 hours. The reaction was concentrated and the residue was purified by flash chromatography using a chloroform/methanol/ammonia gradient to afford the title compound as a white solid (0.793 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.90-7.81 (m, 2H), 7.32 (s, 1H), 7.14-7.05 (m, 2H), 5.76 (br s, 1H), 4.72-4.65 (m, 1H), 3.26-3.10 (m, 1H), 3.03-2.37 (m, 5H), 2.05-1.23 (m, 1H) ppm. 13C NMR (400 MHz, CDCl3) δ 177.6, 162.6 (d, J=248.4 Hz), 154.8, 153.6, 130.8 (d, J=3.2 Hz), 128.1 (d, J=8.1 Hz), 115.9 (d, J=21.7 Hz), 112.2, 71.6, 55.7, 47.4, 46.5, 29.1, 25.4, 24.7, 19.6 ppm. Purity: 100% UPLCMS (210 nm & 254 nm): retention time 0.82 min: (M+1) 390. The reaction was stirred cold for another 1 hour The reaction was stirred overnight extracted with ethyl acetate (2×60 mL) The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL) dried (Na2SO4) concentrated refluxed for 4 hours reflux The reaction was concentrated the residue was purified by flash chromatography

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

Procedure: To a stirred and cooled (0° C.) solution of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid (4.02 g, 15.2 mmol) in THF (100 mL) was added triethylamine (4.2 mL, 30 mmol) followed by isobutyl chloroformate (3.0 mL, 23 mmol). The reaction was stirred cold for another 1 hour before adding a solution of sodium azide (1.98 g, 30.5 mmol) in water (20 mL). The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×60 mL). The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL), dried (Na2SO4) and concentrated. After coevaporating with toluene (2×50 mL), the resulting white solid was taken up in toluene (100 mL) and refluxed for 4 hours. (S)-3-quinuclidinol (3.87 g, 30.4 mmol) was then added and reflux was continued overnight. The reaction was concentrated and the residue partitioned between ethyl acetate (100 mL) and aqueous NaHCO3 (150 mL). The organic layer was washed with water (1×150 mL), dried (Na2SO4) and concentrated. The resulting off-white solid was purified by flash chromatography using a chloroform/methanol/ammonia gradient to afford the title compound as a white solid (4.34 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.96-7.88 (m, 2H), 7.16-7.04 (m, 3H), 5.55 (br s, 1H), 4.69-4.62 (m, 1H), 3.24-3.11 (m, 1H), 3.00-2.50 (m, 5H), 2.01-1.26 (m, 11H) ppm. 13C NMR (400 MHz, CDCl3) δ 166.4, 165.1, 163.8 (d, J=250.3 Hz), 162.9, 155.0, 130.1 (d, J=3.3 Hz), 128.4 (d, J=8.5 Hz), 115.9 (d, J=22.3 Hz), 112.5, 71.2, 55.7, 54.2, 47.5, 46.5, 28.0, 25.5, 24.7, 19.6 ppm. Purity: 100% UPLCMS (210 nm & 254 nm): retention time 0.83 min: (M+1) 390. The reaction was stirred cold for another 1 hour The reaction was stirred overnight extracted with ethyl acetate (2×60 mL) The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL) dried (Na2SO4) concentrated refluxed for 4 hours reflux The reaction was concentrated the residue partitioned between ethyl acetate (100 mL) and aqueous NaHCO3 (150 mL) The organic layer was washed with water (1×150 mL) dried (Na2SO4) concentrated The resulting off-white solid was purified by flash chromatography

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

Procedure: To stirred and cooled (0° C.) solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid (0.784 g, 2.96 mmol) in THF (25 mL) was added triethylamine (0.82 mL, 5.9 mmol) followed by isobutyl chloroformate (0.58 mL, 4.4 mmol). The reaction was stirred cold for another 1 hour before adding a solution of sodium azide (0.385 g, 5.92 mmol) in water (7 mL). The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×60 mL). The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL), dried (Na2SO4) and concentrated. After coevaporating with toluene (2×30 mL), the resulting off-white solid was taken up in toluene (25 mL) and refluxed for 4 hours. (S)-3-quinuclidinol (0.753 g, 5.92 mmol) was then added and reflux was continued for 3 hours. The reaction was concentrated and the residue was purified by flash chromatography using a chloloform/methanol/ammonia gradient to afford the title compound as a white solid (0.793 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.90-7.81 (m, 2H), 7.32 (s, 1H), 7.14-7.05 (m, 2H), 5.76 (br s, 1H), 4.72-4.65 (m, 1H), 3.26-3.10 (m, 1H), 3.03-2.37 (m, 5H), 2.05-1.23 (m, 11H) ppm. 13C NMR (400 MHz, CDCl3) δ 177.6, 162.6 (d, J=248.4 Hz), 154.8, 153.6, 130.8 (d, J=3.2 Hz), 128.1 (d, J=8.1 Hz), 115.9 (d, J=21.7 Hz), 112.2, 71.6, 55.7, 47.4, 46.5, 29.1, 25.4, 24.7, 19.6 ppm. Purity: 100% UPLCMS (210 nm & 254 nm); retention time 0.82 min; (M+1) 390. The reaction was stirred cold for another 1 hour The reaction was stirred overnight extracted with ethyl acetate (2×60 mL) The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL) dried (Na2SO4) concentrated refluxed for 4 hours reflux The reaction was concentrated the residue was purified by flash chromatography