5-methoxy-3-piperidin-4-yl-1H-indole

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.6 g of 4-(5-methoxy-[1H]-indol-3-yl)-piperidine, 4.3 g of α-(chloromethyl)-1,4-benzodioxin-2-methanol, 4.4 g of sodium carbonate, 3.3 g of potassium iodide and 25 ml of dimethylformamide was heated with stirring at 100° C for 24 hours under a nitrogen atmosphere and then the mixture was cooled and filtered. The filter was washed with dimethylformamide and the filtrate was evaported under reduced pressure to dryness. The residue was taken up in a 1--1 mixture of water and methylene chloride and the organic phase was recovered by decantation, was washed, dried and evaporated to dryness under reduced pressure to obtain 9.1 g of α-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-(5-methoxyl-[1H]-indol-3-yl)-1-piperidine-ethanol in the form of a mixture of 2 diastereoisomeric racemates in the form of a brown oil which was used as is for the next step. was heated the mixture was cooled filtered The filter was washed with dimethylformamide The residue was taken up in a 1--1 mixture of water and methylene chloride the organic phase was recovered by decantation was washed dried evaporated to dryness under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.6 g of 4-(5-methoxy-[1H]-indol-3-yl)-piperidine, 4.3 g of α-(chloromethyl)-1,4-benzodioxin-2-methanol, 4.4 g of sodium carbonate, 3.3 g of potassium iodide and 25 ml of dimethylformamide was heated with stirring at 100° C for 24 hours under a nitrogen atmosphere and then the mixture was cooled and filtered. The filter was washed with dimethylformamide and the filtrate was evaported under reduced pressure to dryness. The residue was taken up in a 1--1 mixture of water and methylene chloride and the organic phase was recovered by decantation, was washed, dried and evaporated to dryness under reduced pressure to obtain 9.1 g of α-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-(5-methoxyl-[1H]-indol-3-yl)-1-piperidine-ethanol in the form of a mixture of 2 diastereoisomeric racemates in the form of a brown oil which was used as is for the next step. was heated the mixture was cooled filtered The filter was washed with dimethylformamide The residue was taken up in a 1--1 mixture of water and methylene chloride the organic phase was recovered by decantation was washed dried evaporated to dryness under reduced pressure

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

Procedure: This compound was prepared following the procedure described in example 1 (parts A and B) starting with 5.9 g (40 mmol) of 5-methoxyindol and 15.5 g (100 mmol) of 4-piperidone. In this case the hydrogenation took place for 24 hours at 30 psi and the catalyst used was platinum (IV) oxide. 6.8 g (74% of yield) of 5-methoxy-3-piperidin-4-yl-1H-indole were obtained. This compound was prepared for 24 hours

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

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

Procedure: In each case 5-methoxy-3-piperidine-4-yl-1H-indole (169.3 mg, 0.735 mmole) in dioxane (4.5 ml) and the diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (259.0 mg, 0.735 mmole) were dissolved in two microwave reaction vessels. The reaction mixture was treated with microwave radiation as follows: experiment 1 (150° C., 52 minutes) and experiment 2 (200° C., 2 minutes). In each experiment the reaction mixture was worked up by distilling off the solvent in vacuo. The respective residue contained, apart from phenol, also the two diastereomers of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (30 g and 40 g). Methanol/EE (1:1, ca. 600 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide [experiment 1 (116 mg, m.p. 106°-107° C., 32%) and experiment 2 (89 mg, m.p. 110°-112° C., 25%)], and the polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide [experiment 1 (108 mg, m.p. 98°-100° C., 30%) and experiment 2 (92 mg, m.p. 92°-97° C., 26%)] were thereby obtained in pure form. were dissolved in two microwave reaction vessels The reaction mixture was treated with microwave radiation experiment 1 (150° C., 52 minutes) and experiment 2 (200° C., 2 minutes) by distilling off the solvent in vacuo The diastereoisomers were separated purified by flash chromatography on silica gel (30 g and 40 g)

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

Procedure: In each case 5-methoxy-3-piperidine-4-yl-1H-indole (169.3 mg, 0.735 mmole) in dioxane (4.5 ml) and the diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (259.0 mg, 0.735 mmole) were dissolved in two microwave reaction vessels. The reaction mixture was treated with microwave radiation as follows: experiment 1 (150° C., 52 minutes) and experiment 2 (200° C., 2 minutes). In each experiment the reaction mixture was worked up by distilling off the solvent in vacuo. The respective residue contained, apart from phenol, also the two diastereomers of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (30 g and 40 g). Methanol/EE (1:1, ca. 600 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide [experiment 1 (116 mg, m.p. 106°-107° C., 32%) and experiment 2 (89 mg, m.p. 110°-112° C., 25%)], and the polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide [experiment 1 (108 mg, m.p. 98°-100° C., 30%) and experiment 2 (92 mg, m.p. 92°-97° C., 26%)] were thereby obtained in pure form. were dissolved in two microwave reaction vessels The reaction mixture was treated with microwave radiation experiment 1 (150° C., 52 minutes) and experiment 2 (200° C., 2 minutes) by distilling off the solvent in vacuo The diastereoisomers were separated purified by flash chromatography on silica gel (30 g and 40 g)

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

Procedure: The non-polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (338 mg, 1.0 mmole) was added to a solution of 5-methoxy-3-piperidine-4-yl-1H-indole (230 mg, 1.0 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained in a yield of 170 mg (36%) as a colourless solid. under reflux for 32 hours by distilling off dioxane diluting with water (10 ml) extracted with EE (3×20 ml) The organic phase was dried with Na2SO4 concentrated by evaporation The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml) It was obtained in a yield of 170 mg (36%) as a colourless solid

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

Procedure: The non-polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (338 mg, 1.0 mmole) was added to a solution of 5-methoxy-3-piperidine-4-yl-1H-indole (230 mg, 1.0 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained in a yield of 170 mg (36%) as a colourless solid. under reflux for 32 hours by distilling off dioxane diluting with water (10 ml) extracted with EE (3×20 ml) The organic phase was dried with Na2SO4 concentrated by evaporation The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml) It was obtained in a yield of 170 mg (36%) as a colourless solid

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

Procedure: 5-methoxy-3-piperidine-4-yl-1H-indole (461 mg, 2 mmole) and 4-dimethylamino-4-phenylcyclohexane (435 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (40 ml). Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg, 2.8 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (20 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The non-polar diastereoisomer was obtained as a colourless oil in a yield of 590 mg (68%) and the polar diastereoisomer was obtained as a colourless oil in a yield of 170 mg (20%). by distilling off the 1,2-dichloroethane diluting with water (20 ml) extracted with EE (3×20 ml) The organic phase was dried with Na2SO4 concentrated by evaporation a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol The non-polar diastereoisomer was obtained as a colourless oil in a yield of 590 mg (68%) the polar diastereoisomer was obtained as a colourless oil in a yield of 170 mg (20%)

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

Procedure: This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 5 g (33.9 mmol) of 5-methoxyindol and 13.2 g (86.2 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 6.5 g (83% of yield) of the desired product were obtained. This compound was prepared