3-hydroxy-1-azabicyclo[2.2.2]octane-3-carbonitrile

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 solution of potassium cyanide (10.15 g, 0.156 mol) in water (31.25 ml) was added dropwise to a solution of 1-azabicyclo[2.2.2]-octan-3-one hydrochloride (25.0 g, 0.155 mol) in water (31.25 ml) at 0°-5°. Following the addition, the reaction mixture was stirred for 3 h and then filtered. The solid was washed with ice-cold water (2×15 ml) and was then dried over phosphorus pentoxide overnight, m.p. 155°-156°. Recrystallisation of a 1 g sample from dioxane gave pure 3-cyano-3-hydroxy-1-azabicyclo[2.2.2]octane, m.p. 172°-173°. the addition filtered The solid was washed with ice-cold water (2×15 ml) was then dried over phosphorus pentoxide overnight, m.p. 155°-156° Recrystallisation of a 1 g sample from dioxane

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

Procedure: A solution of potassium cyanide (10.15 g, 0.156 mol) in water (31.25 ml) was added dropwise to a solution of 1-azabicyclo[2.2.2]-octan-3-one hydrochloride (25.0 g, 0.155 mol) in water (31.25 ml) at 0°-5°. Following the addition, the reaction mixture was stirred for 3 h and then filtered. The solid was washed with ice-cold water (2×15 ml) and was then dried over phosphorus pentoxide overnight, m.p. 155°-156°. Recrystallisation of a 1 g sample from dioxane gave pure 3-cyano-3-hydroxy-1-azabicyclo[2.2.2]octane, m.p. 172°-173°. the addition filtered The solid was washed with ice-cold water (2×15 ml) was then dried over phosphorus pentoxide overnight, m.p. 155°-156° Recrystallisation of a 1 g sample from dioxane

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 3-hydroxyquinuclidine-3-carbonitrile (38 mg, 0.25 mmol) in acetonitrile/dioxane (3 mL) at room temperature was added triethylamine (7.0 uL, 0.05 mmol). The reaction mixture was stirred for 15 min and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (49.0 uL, 0.248 mmol) was added dropwise. The reaction was stirred for a period of 18 h at 65° C. and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding carbamate as a clear oil (57 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.42-7.20 (s, 5H), 6.61 (s, 1H), 5.11 (s, 1H), 3.29 (d, J=12.0 Hz, 1H), 3.09 (d, J=12.0 Hz, 1H), 2.93 (d, J=4.0 Hz, 2H), 2.79-2.68 (m, 2H), 2.13 (s, 6H) 2.05-2.00 (m, 2H), 1.91 (s, 3H), 1.87 (s, 2H), 1.50-1.37 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 135.4, 128.7, 125.2, 124.5, 124.0, 122.0, 112.9, 61.2, 47.0, 46.2, 32.4, 31.8, 29.9, 29.4, 29.2, 26.6, 25.7, 23.7, 22.8, 22.2, 19.2 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.81 min; (M+1) 354. The reaction was stirred for a period of 18 h at 65° C. concentrated The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH)

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

Procedure: To a cooled (ice bath), stirred solution of 3-quinuclidinone hydrochloride (300 g) in water (400 ml) was added dropwise a solution of sodium cyanide (90.97 g) in water (400 ml). After stirring at ice bath temperature for three hours the precipitate was collected by filtration, washed with water and dried under vacuum to afford the title compound (282 g); m.p. 153°-157° C. (lit m.p. 152°-155° C.; Helv. Chim. Acta., 1954, 37, 1689). To a cooled (ice bath) was collected by filtration washed with water dried under vacuum

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

Procedure: A process for the preparation of quinuclidine-3-methanol comprising reacting quinuclidine-3-one acid addition salt with an alkali metal cyanide in an aqueous media to obtain 3-cyano-3-hydroxy-quinuclidine, reacting the latter with anhydrous methanol in the presence of hydrogen chloride gas followed by treatment with aqueous alkali to obtain methyl 3-hydroxy-quinuclidine-3-carboxylate, reacting the latter with thionyl chloride to form methyl 1-azabicyclo(2,2,2)oct-2-ene-3-carboxylate, hydrogenating the latter with Raney nickel to obtain methyl 1-azabicyclo(2,2,2)octane-3-carboxylate and reducing the latter to obtain quinuclidine-3-methanol.

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

Procedure: 1,420 g (8.78 mole) of quinuclidine-3-one-hydrochloride were dissolved in 1800 ml of cold water and at 15° C., 432 g (8.81 mole) of sodium cyanide and 1600 of ml water were added dropwise over one hour followed by stirring for another hour at this temperature. The mixture was filtered, washed with cold water, and dried at 60° C. to obtain 1,290 g (8.48 mole) of 3-cyano-3-hydroxy-quinuclidine (97% yield), in the form of white crystals having a melting point of 157° to 159° C. The mixture was filtered washed with cold water dried at 60° C.

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

Procedure: The novel process of the invention for the preparation of quinuclidine-3-methanol comprises reacting quinuclidine-3-one acid addition salt with an alkali metal cyanide in an aqueous meda to obtain 3-cyano-3-hydroxy-quinuclidine, reacting the latter with anhydrous methanol in the presence of hydrogen chloride gas followed by treatment with aqueous alkali to obtain methyl 3-hydroxy-quinuclidine-3-carboxylate, reacting the latter with thionyl chloride to form methyl 1-azabicyclo(2,2,2)oct-2-ene-3-carboxylate, hydrogenating the latter with Raney nickel to obtain methyl 1-azabicyclo(2,2,2)octane-3-carboxylate and reducing the latter to obtain quinuclidine-3-methanol.

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

Procedure: A solution of potassium cyanide (10.15 g, 0.156 mol) in water (31.25 ml) was added dropwise to a solution of 1-azabicyclo[2.2.2]octan-3-one hydrochloride (25.0 g, 0.155 mol) in water (31.25 ml) at 0°-5°. Following the addition, the reaction mixture was stirred for 3 h and then filtered. The solid was washed with ice-cold water (2×15 ml) and was then dried over phosphorus pentoxide overnight, m.p. 155°-156°. Recrystallisation of a 1 g sample from dioxane gave pure 3-cyano-3-hydroxy-1-azabicyclo[2.2.2]octane, m.p. 172°-173°. the addition filtered The solid was washed with ice-cold water (2×15 ml) was then dried over phosphorus pentoxide overnight, m.p. 155°-156° Recrystallisation of a 1 g sample from dioxane