3-(chloromethyl)-1-azabicyclo[2.2.2]octane

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: 0.9 ml of a 65% suspension of sodium amide in xylene and then 25 ml of hexamethylphosphotriamide were added to a suspension of 5.3 g of 2-trifluoromethyl-phenothiazine in 25 ml of xylene. The mixture was agitated and heated to reflux. When the evolution of ammonia ceased (2 hours), 16.3 ml of a 9.8% solution of 3-chloromethyl-quinuclidine in xylene were added to the reaction mixture over a period of 30 minutes and refluxing was continued for 18 hours. After cooling, the xylene was evaporated off under reduced pressure and the residual solution was poured into 250 ml of distilled water. The precipitate obtained was separated on Clarcel filter medium, washed with 50 ml of distilled water, and then suspended in 100 ml of ethyl acetate. The insoluble portion was filtered off and the filtrate was washed with 30 ml of distilled water, and then extracted three times with a total of 150 ml of N.aqueous acetic acid. The combined acid extracts were rendered alkaline on an ice bath with 25 ml of ION aqueous sodium carbonate and the oil which separated was extracted twice with a total of 200 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was recrystallised in acetonitrile; 2-trifluoromethyl-10-(3-quinuclidinyl-methyl)-phenothiazine, m.p. 150° C, was obtained. heated to reflux were added to the reaction mixture over a period of 30 minutes refluxing After cooling the xylene was evaporated off under reduced pressure the residual solution was poured into 250 ml of distilled water The precipitate obtained was separated on Clarcel filter medium washed with 50 ml of distilled water The insoluble portion was filtered off the filtrate was washed with 30 ml of distilled water extracted three times with a total of 150 ml of N.aqueous acetic acid the oil which separated was extracted twice with a total of 200 ml of ethyl acetate The combined organic extracts were dried over magnesium sulphate evaporated The residue was recrystallised in acetonitrile

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

Procedure: 3 ml of a 35% suspension of sodium amide in xylene were added to a suspension of 7 g of 2-chloro-phenothiazine in 100 ml of anhydrous xylene. The mixture was agitated and heated to reflux. When evolution of ammonia ceased (20 hours), a solution of 0.35 g of potassium iodide in 2.3 ml of dimethylformamide was added to the reaction mixture all at once and 34 ml of a 7% solution of 3-chloromethyl-quinuclidine in xylene were then added over a period of an hour. Refluxing of the reaction mixture was continued for 32 hours. After cooling, the reaction mixture was worked up as in Example 2. After recrystallisation of the crude product in in isopropyl oxide, 2-chloro-10-(3-quinuclidinyl-methyl)-phenothiazine, m.p. 122° C, was obtained. heated to reflux (20 hours) were then added over a period of an hour Refluxing of the reaction mixture After cooling After recrystallisation of the crude product in in isopropyl oxide, 2-chloro-10-(3-quinuclidinyl-methyl)-phenothiazine, m.p. 122° C was obtained

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

Procedure: 19.8 ml of a 50% suspension of sodium amide in xylene were added to a suspension of 68.3 g of 2-methoxyphenothiazine in 700 ml of anhydrous xylene. The mixture was agitated and heated to reflux. After 41/2 hours, 272 ml of an 8.5% solution of 3-chloromethyl-quinuclidine in xylene were added over a period of an hour and reflux was maintained for 16 hours. After cooling to room temperature, the reaction mixture was worked up as in Example 2. After recrystallisation of the crude product in a mixture of ether and isopropyl oxide, 2-methoxy-10-(3-quinuclidinylmethyl)-phenothiazine, m.p. 135°-136° C, was obtained. heated to reflux reflux was maintained for 16 hours After recrystallisation of the crude product in a mixture of ether and isopropyl oxide, 2-methoxy-10-(3-quinuclidinylmethyl)-phenothiazine, m.p. 135°-136° C was obtained