Quinuclidone Hydrochloride

l-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 1-1. 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 l-carbethoxymethyl-4-carbethoxypy-ridinium bromide is used directly for the next step (Note 3). 

l-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 2-1. hydrogenation autoclave and hydrogenated at 90° under an initial pressure of 100 atm. (Note 4). Slightly more than the calcu- 

The resulting solution is cooled to 0° and decomposed by careful addition of 500 ml. of 102V 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 102V 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 102V 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 1.) 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%). 

The checkers used ethyl isonicotinate purchased from K and K Laboratories, Inc., Jamaica, New York, or prepared by esterification of isonicotinic acid as described by La Forge 4 for nicotinic acid. 

---

A soln. of ethyl isonicotinate and ethyl bromoacetate in ethanol allowed to stand at room temp, overnight, then refluxed 4 hrs., treated with 10%-Pd-on-charcoal, and hydrogenated 0.5-1 hr. at 90 and 7-100 atm. -> 1-carbethoxy-methyl-4-carbethoxypiperidine (Y 64-78%) dissolved in abs. toluene, added at 130 during 2 hrs. to K-ethoxide in toluene, heating and stirring continued for 3 hrs., cooled to 0 , decomposed by careful addition of 10 N HGl, the aq. phase separated and refluxed 15 hrs. 3-quinuclidone hydrochloride (Y 77-82%). H.U.Daeniker and G. A. Grob, Org. Synth. U, 86 (1964). 

This is the most convenient way to prepare quinuclidone hydrochloride. The second step illustrates the conversion of an N-alkyl-pyridinium salt to an N-alkylpiperidine. The third step illustrates the formation of a bicydic system by the Dieckmann condensation. 

Quinuclidone hydrochloride has been prepared by intramolecular condensation of l-carbethoxymethyl-4-carbethoxypiperidine with potassium 6-8 or, as in the present procedure, with potassium ethoxide.9 l-Carbethoxymethyl-4-carbethoxypiperidine has been prepared by alkylating ethyl hexahydroisonicotinate with ethyl chloroacetate 6-8 or by the present method.7... 

---