1-methylpiperidine;hydrochloride

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

Procedure: Finely ground sodium azide (325 mg., 5 mmole) is added to a solution of 7 -acetoxy-6-(2-cyanoethyl)-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline (506 mg., 1 mmole) in 5 ml. of ethanol-free chloroform containing 271 mg. (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmole of N-methylpiperidine hydrochloride is added, refluxing continued for another hour and allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution. The aqueous layer is adjusted to pH 5, extracted again with chloroform and the combined organic layers washed with water and the chloroform is dried (MgSO4). Evaporation of solvent under reduced pressure affords the title compound. The mixture is heated at reflux for one hour refluxing continued for another hour The mixture is partitioned between chloroform and aqueous sodium carbonate solution extracted again with chloroform the combined organic layers washed with water the chloroform is dried (MgSO4) Evaporation of solvent under reduced pressure

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

Procedure: Finely ground sodium azide (325 mg., 5 mmole) is added to a solution of 7 -acetoxy-6-(2-cyanoethyl)-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline (506 mg., 1 mmole) in 5 ml. of ethanol-free chloroform containing 271 mg. (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmole of N-methylpiperidine hydrochloride is added, refluxing continued for another hour and allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution. The aqueous layer is adjusted to pH 5, extracted again with chloroform and the combined organic layers washed with water and the chloroform is dried (MgSO4). Evaporation of solvent under reduced pressure affords the title compound. The mixture is heated at reflux for one hour refluxing continued for another hour The mixture is partitioned between chloroform and aqueous sodium carbonate solution extracted again with chloroform the combined organic layers washed with water the chloroform is dried (MgSO4) Evaporation of solvent under reduced pressure

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

Procedure: A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (10 g. 0.0193mole) sodium azide (7.41 g., 0.114 mole), N-methylpiperidine hydrochloride (3.39 g., 0.025 mole) and chloroform (100 ml.) is refluxed for four hours in a round-bottomed flask equipped with stirrer, condenser, and drying tube. The reaction mixture is then cooled and water (300 ml.) and chloroform (100 ml.) added. The mixture is thoroughly mixed, the chloroform layer separated and washed successively with 1N hydrochloric acid (100 ml.) and saturated brine (100 ml.). It is then filtered quickly through anhydrous sodium sulfate and concentrated under reduced pressure to about 75 ml. Hexane (20 ml.) is added to the concentrate to precipitatethe product as white crystals. The crystals are recovered by filtration, washed with 20% hexane-methylene chloride (50 ml.) and dried in vacuo at room temperature. Yield = 2.7 g. (29.6%) m.p. 133=136° C. is refluxed for four hours in a round-bottomed flask equipped with stirrer, condenser drying tube The reaction mixture is then cooled water (300 ml.) and chloroform (100 ml.) added The mixture is thoroughly mixed the chloroform layer separated washed successively with 1N hydrochloric acid (100 ml.) and saturated brine (100 ml.) It is then filtered quickly through anhydrous sodium sulfate concentrated under reduced pressure to about 75 ml Hexane (20 ml.) is added to the concentrate to precipitatethe product as white crystals The crystals are recovered by filtration washed with 20% hexane-methylene chloride (50 ml.) dried in vacuo at room temperature 133=136° C.

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

Procedure: A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (4.39 g. 0.01mole), anhydrous ethanol-free chloroform (20 ml.), powdered sodium azide (650 mg., 0.01 mole) and dry N-methylpiperidine (2.98 g., 0.03 mole) is heated to 58°-60° C. (internal temperature). To the mixture is added with stirring 5 ml. of a solution of dry N-methylpiperidine hydrochloride (1.5 g., 0.011 mole) in ethanol-free chloroform (20 ml.) every 15 minutes over a period of one hour. The mixture is stirred and heated for 1.5 hours at 58°-60° C. following the additions of N-methylpiperidine and is then charged with finely powdered sodium azide (650 mg.) and N-methylpiperidine hydrochloride (1.5 g., 0.011 mole) in ethanol-free chloroform (20 ml.). The reaction mixture is heated for anadditional hour and is then cooled to room temperature and diluted with water (150 ml.) and ethanol-free chloroform (250 ml.). The mixture is thoroughly shaken and the chloroform phase then separated and washed with successively with 1N HCl (1 × 250 ml.) and water (1 × 150 ml.). is heated to 58°-60° C. (internal temperature) To the mixture is added The mixture is stirred heated for 1.5 hours at 58°-60° C. The reaction mixture is heated for anadditional hour The mixture is thoroughly shaken the chloroform phase then separated washed with successively with 1N HCl (1 × 250 ml.) and water (1 × 150 ml.)

Conditions: temp:53.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dry N-methylpiperidine hydrochloride (8.14 g., 0.06 mole) anhydrous ethanol free chloroform (180 ml.), 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (13.2g, 0.03 mole), finely powdered sodium azide (3.9 g., 0.06 mole) and N-methylpiperidine (8.9 g., 0.09 mole) is heated to 53° C. (internal temperature) for 80 minutes. It is then cooled to room temperature and diluted with ethanolfree chloroform (750 ml.) and water (800 ml.). It is thoroughly shaken, thechloroform phase separated and washed successively with 1.5N HCl (1 ×1000 ml.) and water (1 × 800 ml.). The chloroform solution is filtered through anhydrous sodium sulfate and then concentrated under reduced pressure to about 300 ml. White crystals separate. The concentrateis diluted with hexane (350 ml.) and filtered after 15 minutes. The crystalline product is washed with hexane and dried in air for 15 minutes followed by drying under vacuum at 56° C. for 1 hour. Yield = 7.66 g. (52.9%). It is then cooled to room temperature thechloroform phase separated washed successively with 1.5N HCl (1 ×1000 ml.) and water (1 × 800 ml.) The chloroform solution is filtered through anhydrous sodium sulfate concentrated under reduced pressure to about 300 ml White crystals separate The concentrateis diluted with hexane (350 ml.) filtered after 15 minutes The crystalline product is washed with hexane dried in air for 15 minutes by drying under vacuum at 56° C. for 1 hour

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

Procedure: Finely ground sodium azide (325 mg, 5 mmole) is added to a solution of 5-acetoxy-4-cyano-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran (1.855 g, 5 mmole) in 10 ml ethanol-free chloroform containing 271 mg (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmoles of N-methylpiperidine hydrochloride is added, refluxing is continued for one hour and the mixture is allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution, the aqueous phase is adjusted to pH 5 and extracted again with chloroform. The combined organic layers are washed with water, dried (MgSO4) and the solvent evaporated in vacuo to afford the title compound. The mixture is heated at reflux for one hour refluxing to stand overnight at room temperature The mixture is partitioned between chloroform and aqueous sodium carbonate solution extracted again with chloroform The combined organic layers are washed with water dried (MgSO4) the solvent evaporated in vacuo

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

Procedure: Finely ground sodium azide (325 mg, 5 mmole) is added to a solution of 5-acetoxy-4-cyano-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran (1.855 g, 5 mmole) in 10 ml ethanol-free chloroform containing 271 mg (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmoles of N-methylpiperidine hydrochloride is added, refluxing is continued for one hour and the mixture is allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution, the aqueous phase is adjusted to pH 5 and extracted again with chloroform. The combined organic layers are washed with water, dried (MgSO4) and the solvent evaporated in vacuo to afford the title compound. The mixture is heated at reflux for one hour refluxing to stand overnight at room temperature The mixture is partitioned between chloroform and aqueous sodium carbonate solution extracted again with chloroform The combined organic layers are washed with water dried (MgSO4) the solvent evaporated in vacuo

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

Procedure: A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (10 g. 0.0193 mole) sodium azide (7.41 g., 0.114 mole), N-methylpiperidine hydrochloride (3.39 g., 0.025 mole) and chloroform (100 ml.) is refluxed for four hours in a round-bottomed flask equipped with stirrer, condenser, and drying tube. The reaction mixture is then cooled and water (300 ml.) and chloroform (100 ml.) added. The mixture is thoroughly mixed, the chloroform layer separated and washed successively with 1N hydrochloric acid (100 ml.) and saturated brine (100 ml.). It is then filtered quickly through anhydrous sodium sulfate and concentrated under reduced pressure to about 75 ml. Hexane (20 ml.) is added to the concentrate to precipitate the product as white crystals. The crystals are recovered by filtration, washed with 20% hexane-methylene chloride (50 ml.) and dried in vacuo at room temperature. Yield = 2.7 g. (29.6%) m.p. 133°-136° C. is refluxed for four hours in a round-bottomed flask equipped with stirrer, condenser drying tube The reaction mixture is then cooled water (300 ml.) and chloroform (100 ml.) added The mixture is thoroughly mixed the chloroform layer separated washed successively with 1N hydrochloric acid (100 ml.) and saturated brine (100 ml.) It is then filtered quickly through anhydrous sodium sulfate concentrated under reduced pressure to about 75 ml Hexane (20 ml.) is added to the concentrate to precipitate the product as white crystals The crystals are recovered by filtration washed with 20% hexane-methylene chloride (50 ml.) dried in vacuo at room temperature

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

Procedure: A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (4.39 g. 0.01 mole), anhydrous ethanol-free chloroform (20 ml.), powdered sodium azide (650 mg., 0.01 mole) and dry N-methylpiperidine (2.98 g., 0.03 mole) is heated to 58°-60° C. (internal temperature). To the mixture is added with stirring 5 ml. of a solution of dry N-methylpiperidine hydrochloride (1.5 g., 0.011 mole) in ethanol-free chloroform (20 ml.) every 15 minutes over a period of one hour. The mixture is stirred and heated for 1.5 hours at 58°-60° C. following the additions of N-methylpiperidine and is then charged with finely powdered sodium azide (650 mg.) and N-methylpiperidine hydrochloride (1.5 g., 0.011 mole) in ethanol-free chloroform (20 ml.). The reaction mixture is heated for an additional hour and is then cooled to room temperature and diluted with water (150 ml.) and ethanol-free chloroform (250 ml.). The mixture is thoroughly shaken and the chloroform phase then separated and washed with successively with 1N HCl (1 × 250 ml.) and water (1 × 150 ml.). is heated to 58°-60° C. (internal temperature) To the mixture is added The mixture is stirred heated for 1.5 hours at 58°-60° C. The reaction mixture is heated for an additional hour The mixture is thoroughly shaken the chloroform phase then separated washed with successively with 1N HCl (1 × 250 ml.) and water (1 × 150 ml.)

Conditions: temp:53.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dry N-methylpiperidine hydrochloride (8.14 g., 0.06 mole) anhydrous ethanol free chloroform (180 ml.), 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (13.2g., 0.03 mole), finely powdered sodium azide (3.9 g., 0.06 mole) and N-methylpiperidine (8.9 g., 0.09 mole) is heated to 53° C. (internal temperature) for 80 minutes. It is then cooled to room temperature and diluted with ethanol free chloroform (750 ml.) and water (800 ml.). It is thoroughly shaken, the chloroform phase separated and washed successively with 1.5N HCl (1 × 1000 ml.) and water (1 × 800 ml.). The chloroform solution is filtered through anhydrous sodium sulfate and then concentrated under reduced pressure to about 300 ml. White crystals separate. The concentrate is diluted with hexane (350 ml.) and filtered after 15 minutes. The crystalline product is washed with hexane and dried in air for 15 minutes followed by drying under vacuum at 56° C. for one hour. Yield = 7.66 g. (52.9%). It is then cooled to room temperature the chloroform phase separated washed successively with 1.5N HCl (1 × 1000 ml.) and water (1 × 800 ml.) The chloroform solution is filtered through anhydrous sodium sulfate concentrated under reduced pressure to about 300 ml White crystals separate The concentrate is diluted with hexane (350 ml.) filtered after 15 minutes The crystalline product is washed with hexane dried in air for 15 minutes by drying under vacuum at 56° C. for one hour

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

Procedure: Finely ground sodium azide (325 mg, 5 mmole) is added to a solution of 5-acetoxy-4-cyano-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran (1.855 g, 5 mmole) in 10 ml ethanol-free chloroform containing 271 mg (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmoles of N-methylpiperidine hydrochloride is added, refluxing is continued for one hour and the mixture is allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution, the aqueous phase is adjusted to pH 5 and extracted again with chloroform. The combined organic layers are washed with water, dried (MgSO4) and the solvent evaporated in vacuo to afford the title compound. The mixture is heated at reflux for one hour refluxing to stand overnight at room temperature The mixture is partitioned between chloroform and aqueous sodium carbonate solution extracted again with chloroform The combined organic layers are washed with water dried (MgSO4) the solvent evaporated in vacuo

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

Procedure: Finely ground sodium azide (325 mg, 5 mmole) is added to a solution of 5-acetoxy-4-cyano-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran (1.855 g, 5 mmole) in 10 ml ethanol-free chloroform containing 271 mg (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmoles of N-methylpiperidine hydrochloride is added, refluxing is continued for one hour and the mixture is allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution, the aqueous phase is adjusted to pH 5 and extracted again with chloroform. The combined organic layers are washed with water, dried (MgSO4) and the solvent evaporated in vacuo to afford the title compound. The mixture is heated at reflux for one hour refluxing to stand overnight at room temperature The mixture is partitioned between chloroform and aqueous sodium carbonate solution extracted again with chloroform The combined organic layers are washed with water dried (MgSO4) the solvent evaporated in vacuo