4-CYANOQUINUCLIDINE

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

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

Procedure: Colourless oil; Rf : 0.3 (trace of tailing; alumina; methylene chloride/methanol=7:3); Mass spectrum: M+=140; Prepared from 4-cyanoquinuclidine (see Example 3 of EP-A-0,213,337).

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

Procedure: Colourless oil; Rf : 0.3 (trace of tailing; alumina; methylene chloride/methanol=7:3); Mass spectrum: M+=140; Prepared from 4-cyanoquinuclidine (see Example 3 of EP-A-0,213,337).

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

Procedure: (Quinuclidin-4-yl)carboxylic acid was prepared from 4-cyanoquinuclidine (Oakwood Products) following the procedure of Grob and Renk, Helv. Chim. Acta, 37, 1681 (1954). To a stirred suspension of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.523 mmol) in 3 mL of anhydrous tetrahydrofuran at 0° C. was added borane methylsulfide complex (42 mg, 0.553 mmol). The mixture was stirred at room temperature for 1 hr and heated to reflux overnight. The reaction was cooled to 0° C. and carefully treated with 1 mL of methanol. The solvent was then removed under reduced pressure to leave the desired alcohol. Yield 36 mg. MS (m/e): 141. was added borane methylsulfide complex (42 mg, 0.553 mmol) heated to reflux overnight The reaction was cooled to 0° C. The solvent was then removed under reduced pressure

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

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

Procedure: (Quinuclidin-4-yl)carboxylic acid was prepared from 4-cyanoquinuclidine (Oakwood Products) following the procedure of Grob and Renk, Helv. Chim. Acta, 37, 1681 (1954). To a stirred suspension of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.523 mmol) in 3 mL of anhydrous tetrahydrofuran at 0° C. was added borane methylsulfide complex (42 mg, 0.553 mmol). The mixture was stirred at room temperature for 1 hr and heated to reflux overnight. The reaction was cooled to 0° C. and carefully treated with 1 mL of methanol. The solvent was then removed under reduced pressure to leave the desired alcohol. Yield 36 mg. MS (m/e): 141. was added borane methylsulfide complex (42 mg, 0.553 mmol) heated to reflux overnight The reaction was cooled to 0° C. The solvent was then removed under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Cyanoquinuclidine (85.0 g) was suspended in ethanol (200 ml), followed by an addition of a solution of p-toluenesulfonic acid monohydrate (119 g) in ethanol (350 ml). The resulting mixture was then stirred at 40° C. for 1 hour. The reaction mixture was cooled with ice and the precipitated crystals were collected by filtration. They were then washed with ethanol and diethylether to obtain 182.9 g of 4-cyanoquinuclidine p-toluenesulfonate as colorless crystals (yield: 95%). The reaction mixture was cooled with ice the precipitated crystals were collected by filtration They were then washed with ethanol and diethylether

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

Procedure: 4- Cyanoquinuclidine (0.31 g, 0.0028 moles) was reduced with lithium aluminium hydride (0.45 g, 0.012 moles) in tetrahydrofuran (20 ml) at ambient temperature for 18 hours. Diethyl ether (20 mls) was added followed by water (1.8 ml) and 10%w/v aqueous sodium hydroxide (0.68 ml) and the mixture stirred for 30 minutes. The mixture was then filtered and the filtrate concentrated in vacuo to give the title compound 0.3 g (94%). The mixture was then filtered the filtrate concentrated in vacuo

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

Procedure: Quinuclidin-4-ylcarbonylchloride hydrochloride (Example 8, Step 4) (3.4 g 0.0016 moles) was dissolved in acetonitrile (150 ml) and treated with 35% ammonia solution (50 ml). The mixture was stirred for 18 hours at ambient temperature then concentrated to dryness in vacuo. 1 g of the residue was then treated with phosphoms oxychloride (8 ml) at reflux for 5 hours. The mixture was then concentrated in vacuo and the residue partitioned between saturated potassium carbonate and diethylether (4×50 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Column chromatography on silica gel elutin with 0-5% methanol/chloroform gave the title compound 0.34 g (75%); 1H NMR (CDCl3) 1.85 (6H t, J 10 Hz), 2.91 (6H, t, J 10 Hz). then concentrated to dryness in vacuo 1 g of the residue was then treated with phosphoms oxychloride (8 ml) at reflux for 5 hours The mixture was then concentrated in vacuo the residue partitioned between saturated potassium carbonate and diethylether (4×50 ml) The combined organic extracts were dried (Na2SO4) filtered concentrated

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

Procedure: 4- Cyanoquinuclidine (0.31 g, 0.0028 moles) was reduced with lithium aluminium hydride (0.45 g, 0.012 moles) in tetrahydrofuran (20 ml) at ambient temperature for 18 hours. Diethyl ether (20 mls) was added followed by water (1.8 ml) and 10%w/v aqueous sodium hydroxide (0.68 ml) and the mixture stirred for 30 minutes. The mixture was then filtered and the filtrate concentrated in vacuo to give the title compound 0.3 g (94%). The mixture was then filtered the filtrate concentrated in vacuo

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

Procedure: Quinuclidin-4-ylcarbonylchloride hydrochloride (Example 8, Step 4) (3.4 g 0.0016 moles) was dissolved in acetonitrile (150 ml) and treated with 35% ammonia solution (50 ml). The mixture was stirred for 18 hours at ambient temperature then concentrated to dryness in vacuo. 1 g of the residue was then treated with phosphoms oxychloride (8 ml) at reflux for 5 hours. The mixture was then concentrated in vacuo and the residue partitioned between saturated potassium carbonate and diethylether (4×50 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Column chromatography on silica gel elutin with 0-5% methanol/chloroform gave the title compound 0.34 g (75%); 1H NMR (CDCl3) 1.85 (6H t, J 10 Hz), 2.91 (6H, t, J 10 Hz). then concentrated to dryness in vacuo 1 g of the residue was then treated with phosphoms oxychloride (8 ml) at reflux for 5 hours The mixture was then concentrated in vacuo the residue partitioned between saturated potassium carbonate and diethylether (4×50 ml) The combined organic extracts were dried (Na2SO4) filtered concentrated

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-cyanoquinuclidine (0.30 g, 2.2 mmol) in diethyl ether (5 mL) was slowly added to a suspension of LAH (0.167 g, 4.41 mmol) in diethyl ether (15 mL) at 0° C. The reaction was stirred at 23° C. for 3 h, then quenched with sodium sulfate decahydrate and stirred for 30 more minutes. Ethyl acetate was then added and, after 30 minutes, celite was added and the suspension was filtered on celite. The filtrate was concentrated to dryness to give an oil (0.310 g, quant.). The compound was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ ppm: 1.31-1.40 (6H, m), 2.43 (2H, s), 2.86-2.94 (6H, m). quenched with sodium sulfate decahydrate stirred for 30 more minutes Ethyl acetate was then added and, after 30 minutes celite was added the suspension was filtered on celite The filtrate was concentrated to dryness to give an oil (0.310 g, quant.) such for the next reaction