A. 1-Carbethoxymethyl-4-carbethoxypyridinium bromide. A solution of 151 g. (1.00 mole) of ethyl isonicotinate (Note 1) and 167 g. (1.00 mole) of ethyl bromoacetate in 500 ml. of ethanol is allowed to stand overnight at room temperature in a 1-l. round-bottomed flask equipped with a reflux condenser (Note 2). The mixture is then heated at the reflux temperature for 4 hours. The resulting solution of 1-carbethoxymethyl-4-carbethoxypyridinium bromide is used directly for the next step (Note 3).

B. 1-Carbethoxymethyl-4-carbethoxypiperidine. Fifteen grams of 10% palladium on charcoal² is added to the solution of the pyridinium bromide. The mixture is placed in an agitated 2-l. hydrogenation autoclave and hydrogenated at 90° under an initial pressure of 100 atm. (Note 4). Slightly more than the calculated amount of hydrogen (3 moles) is absorbed within 30–60 minutes. The mixture is cooled to 25°, and the catalyst is separated by filtration and washed with 100 ml. of ethanol. The filtrate is evaporated to dryness under water-aspirator vacuum at a bath temperature of 50–60°. The residue, semicrystalline 1-carbethoxymethyl-4-carbethoxypiperidine hydrobromide, is taken up in 500 ml. of ice-cold water. The solution is added to 500 ml. of chloroform in a 5-l. beaker immersed in an ice bath, and an ice-cold solution of 150 g. of potassium carbonate in 250 ml. of water is added gradually with stirring (Note 5). After the carbon dioxide evolution has subsided, the mixture is placed in a 2-l. separatory funnel and thoroughly shaken for some time. The lower, organic layer is drawn off and washed once with 200 ml. of water. The aqueous layers are combined and washed once with 500 ml. of chloroform. The two chloroform extracts are combined and dried over anhydrous sodium sulfate. After 1 hour the sodium sulfate is separated on a Büchner funnel and washed with two 200-ml. portions of chloroform. The chloroform is removed on a steam bath, and the resulting oily residue is distilled under high vacuum through a 20-cm. Vigreux column. A fore-run, weight 4–8 g., is collected below 110° (0.20 mm.). Then 156–190 g. (64–78%) of 1-carbethoxymethyl-4-carbethoxypiperidine is collected as a colorless oil, b.p. 111–113° (0.2 mm.), d15/15 1.057, n²⁰D 1.4585.

C. 3-Quinuclidone hydrochloride. A 2-l. three-necked flask is fitted with a Hershberg stirrer, a pressure-equalizing addition funnel, and a condenser connected to a source of dry nitrogen. Absolute toluene (330 ml.) and 80 g. (2.05 g. atom) of potassium free of oxide crust are added. (Caution! Directions³ for the safe handling of potassium should be consulted.) The air in the flask is replaced by an atmosphere of dry nitrogen that is maintained until the reaction mixture is decomposed. The flask is heated in an oil bath until the toluene begins to reflux gently. As soon as the potassium is molten, it is pulverized by vigorous stirring. One hundred twenty-five milliliters (98.6 g., 2.14 moles) of absolute ethanol (Note 6) is added through the addition funnel within 30 minutes while heating and stirring are continued. After disappearance of the potassium the temperature is raised to 130°, and a solution of 200 g. (0.822 mole) of 1-carbethoxymethyl-4-carbethoxypiperidine in 500 ml. of absolute toluene is added within 2 hours. The mixture is stirred and heated for an additional 3 hours.

The resulting solution is cooled to 0° and decomposed by careful addition of 500 ml. of 10N hydrochloric acid. The mixture is transferred to a separatory funnel, the aqueous phase is separated, and the toluene layer is extracted with two 250-ml. portions of 10N hydrochloric acid. The aqueous extracts are combined and heated under reflux for 15 hours to effect decarboxylation. The hot, dark-colored solution is treated with 10 g. of activated charcoal, filtered, and evaporated to dryness under reduced pressure. The residue is washed into a separatory funnel with 300 ml. of water. The solution is treated with saturated aqueous potassium carbonate solution until it is alkaline to litmus; the carbonate solution must be added very carefully to prevent excessive foaming. Solid potassium carbonate is added until a thin slurry is obtained, and the slurry is extracted with four 400-ml. portions of ether. The combined ether extracts are dried for at least 60 minutes over calcined potassium carbonate and then filtered.

The ether is removed by distillation on a steam bath through a column filled with Raschig rings. The yellowish crystalline residue is treated with 150 g. of ice and 150 g. (130 ml.) of 10N hydrochloric acid, and the solution is evaporated to dryness under reduced pressure (Note 7). The crystalline residue is dissolved in the minimum amount of hot water (about 70 ml.), and boiling isopropyl alcohol (about 1.5 l.) is added until crystalline 3-quinuclidone hydrochloride begins to separate. The mixture is cooled to 0–5°, and the solid is separated by filtration, washed with acetone, and dried. The yield of 3-quinuclidone hydrochloride, m.p. 294–296° (sealed capillary) (Note 8), is 102–109 g. (77–82%).