1-azabicyclo[2.2.2]octan-3-amine;hydrochloride

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

Procedure: To a stirred solution of quinuclidin-3-amine hydrochloride (324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3 drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol) carefully. The resultant mixture was stirred at 25° C. for 18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283 mg, 55%) was obtained. After HPLC separation

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

Procedure: To a stirred solution of quinuclidin-3-amine hydrochloride (324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3 drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol) carefully. The resultant mixture was stirred at 25° C. for 18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283 mg, 55%) was obtained. After HPLC separation

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

Procedure: To a stirred solution of quinuclidin-3-amine hydrochloride (324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3 drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol) carefully. The resultant mixture was stirred at 25° C. for 18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283 mg, 55%) was obtained. After HPLC separation

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

Procedure: To a stirred solution of quinuclidin-3-amine hydrochloride (324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3 drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol) carefully. The resultant mixture was stirred at 25° C. for 18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283 mg, 55%) was obtained. After HPLC separation

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

Procedure: To a stirred solution of quinuclidin-3-amine hydrochloride (324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3 drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol) carefully. The resultant mixture was stirred at 25° C. for 18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283 mg, 55%) was obtained. After HPLC separation

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of quinuclidin-3-amine hydrochloride (1.06 g, 5.30 mmol) and polymer supported dimethylperhydro-1,3,2-diazaphosphorine (7.0 g, 15.4 mmol) in DMSO (50 mL) was added 5-fluoro-N-methyl-2-nitrobenzamide (Intermediate 3A) (1 g, 5.05 mmol) and reaction heated at 60° C. for 72 hours. The resin was removed by filtration and washed thoroughly with methanol and dichloromethane. The filtrate was purified using a 20 g SCX cartridge followed by trituration with dichloromethane/methanol/diethyl ether to afford N-methyl-2-nitro-5-(quinuclidin-3-ylamino)benzamide (0.41 g, 1.36 mmol). was added The resin was removed by filtration washed thoroughly with methanol and dichloromethane The filtrate was purified

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

Procedure: To a reactor having an agitator were added 11 liters of water, 7.30 kg (36.7 mole) of 3-aminoquinuclidine dihydrochloride and a solution made by mixing 2.93 kg (36.7 mole) of 50% sodium hydroxide and 2.44 kg of crushed ice to give a solution of 3-aminoquinuclidine monohydrochloride. To the cooled reactor solution (30° C.) was added a solution of 45 liters of pyridineand 8.12 kg (40.3 moles, i.e., an excess over the 3-aminoquinuclidine) of 4-amino-5-chloro-2-methoxybenzoic acid, an additional 10 liters of pyridine being used to rinse all the latter solution into the reactor. Cooling was stopped and the reaction mixture was stirred for 1/2 hr. To the reaction mixture was added 8.89 kg (43.0 moles) of warm melted DCC and the mixture was stirred at 25° C. for 6 hr. TLC of a sample, using 15% ammonium hydroxide in methanol on a silica gel plate by the method of P. Haefelfinzer in J. of Chromatography, 48 (184) 1970, showed the presence of unreacted 3-aminoquinuclidine. An additional 3.48 kg (16.8 mole) of DCC was added and the mixture was stirred for 16 hr. A repeat of the TLC test showed no 3-aminoquinuclidine was present. To a reactor having

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

Procedure: 3-(Phenylsulfonyl)aminobenzoic acid as prepared in Example 9 (139 mg, 0.5 mmol), Castro's reagent (benzotriazole-1-yloxytris(dimethylaminophosphonium hexafluorophosphate) (221 mg, 0.5 mmol), 3-aminoquinuclidine hydrochloride (100 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.5 mL) were dissolved in dry DMF (2 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 and extracted with ethyl acetate (3×). The combined ethyl acetate was washed with brine and dried over Na2SO4. After evaporation, the residue was purified by silica gel chromatography using 86% methylene chloride and 14% methanol containing 0.25 mL of acetic acid to give 65 mg (34% yield). 1H-NMR (300 MHz; DMSO-d6): d 1.69-2.14 (m,5H), 3.07-3.35 (m,6H), 3.63 (t, 1H, J=12 Hz), 4.22 (m, 1H), 7.23-7.77 (m, 9H), 8.53 (d, 1H, J=6 Hz). Mass spectrum (MALDI-TOF) calcd. for C20H23N3 O3S: 386.2 (M+H), Found: 386.2. extracted with ethyl acetate (3×) The combined ethyl acetate was washed with brine dried over Na2SO4 After evaporation the residue was purified by silica gel chromatography to give 65 mg (34% yield)