2,3-dihydro-1,4-benzodioxin-3-ylmethanamine;hydrochloride

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

Procedure: 5-methoxyindole-3-butyric acid (1.5 g, 6.4 mmole), 1-hydroxybenzotriazole hydrate (1.0 g, 7.7 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.3 g, 6.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of TBF to remove a by-product and to give 1.8 g (74%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-1H-indole-3-yl)-butanamide, as an oil. the mixture was further stirred for 24 hours The solvent was removed the residue partitioned between dichloromethane and water The separated dichloromethane layer was dried over anhydrous sodium sulfate filtered concentrated in vacuum The residue was chromatographed on a silica gel column Fractions containing product were concentrated washed with a minimum amount of TBF to remove a by-product

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

Procedure: 5-Fluoroindole-3-butyric acid (1.5 g, 6.8 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 8.2 mmole) and 1,3-diisopropylcarbodiimide (2.6 ml, 16.3 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.8 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions of the products were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.5 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3yl)-butanamide, as an oil. the mixture was further stirred for 24 hours The solvent was removed the residue partitioned between dichloromethane and water The separated dichloromethane layer was dried over anhydrous sodium sulfate filtered concentrated in vacuum The residue was chromatographed on a silica gel column Fractions of the products were concentrated washed with a minimum amount of THF to remove a by-product

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

Procedure: 3-Indolepropionic acid (1.1 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.2 g, 6.0 mmole) in 50 ml of DMF, and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as an oily solid. the mixture was further stirred for 24 hours The solvent was removed the residue partitioned between dichloromethane and water The separated dichloromethane layer was dried over anhydrous sodium sulfate filtered concentrated in vacuum The residue was chromatographed on a silica gel column Fractions containing product were concentrated washed with a minimum amount of THF to remove a by-product

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

Procedure: 3-Indolebutyric acid (1.2 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2methanamine hydrochloride (1.2 g, 6.0 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (57%) of the desired product, (2,3-dihydro-benzo [1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as an oil. the mixture was further stirred for 24 hours The solvent was removed the residue partitioned between dichloromethane and water The separated dichloromethane layer was dried over anhydrous sodium sulfate filtered concentrated in vacuum The residue was chromatographed on a silica gel column Fractions were concentrated washed with a minimum amount of THF to remove a by-product

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,3-Dihydro-1,4-benzodioxin-2-methanamine hydrochloride (2.0 g, 10.0 mmole) in DMF (100 ml) was slowly added to the mixture of 5-fluoro-3-(3-bromopropyl)indole (2.6 g, 10.0 mmole) and diisopropylethylamine (8.7 ml, 50 mmole) in 100 ml of DMF with stirring and the mixture was heated at 80° C. for 24 hours. Most of DMF was removed and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and column chromatographed on silica gel using ethyl acetate as the eluant. The combined fractions of free base of the expected product (0.5 g, 1.6 mmole, 15%) were concentrated, dissolved in 50 ml of ethanol-diethyl ether (1:1). To this was added 0.25M of fumaric acid in ethanol (3.4 ml, 0.85 mmole) and then a minimum amount of hexane to precipitate the title compound as a light tan solid, (2:1) fumarate salt, m.p. 186°-188° C. Most of DMF was removed the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate The dichloromethane solution was dried over anhydrous sodium sulfate filtered concentrated in vacuum and column chromatographed on silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,3-Dihydro-1,4-benzodioxin-2-methanamine hydrochloride (2.3 g, 11.0 mmole) in DMF (100 ml) was slowly added to a mixture of 5-methoxy-3-(3-bromopropyl)indole (3.0 g, 11.0 mmole) and diisopropylethylamine (9.7 ml, 55 mmole) in 100 ml of DMF with stirring and the mixture was heated at 80° C. for 24 hours. Most of DMF was removed in vacuum and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and chromatographed on silica gel using ethyl acetate as the eluant. The combined fractions of free base of the expected product (1.3 g, 3.7 mmole, 34%) were concentrated, treated with 0.25M of fumaric acid in ethanol (8.1 ml, 2.0 mmole) and diluted first with 50 ml of ethanol-diethyl ether (1:1) and then with a minimum amount of hexane to precipitate the title compound as a white solid, (2:1) fumarate salt, m.p. 135°-136° C. Most of DMF was removed in vacuum the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate The dichloromethane solution was dried over anhydrous sodium sulfate filtered concentrated in vacuum chromatographed on silica gel

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

Procedure: 5-Benzyloxyindole-3-propionic acid (2.7 g, 9.1 mmole), 1-hydroxybenzotriazole hydrate (1.5 g, 10.9 mmole) and 1,3-diisopropylcarbodiimide (3.4 ml, 21.8 mmole) were combined in 200 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.8 g, 9.1 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on silica gel using first dichloromethane and then 2.5% methanol in dichloromethane as eluants to give 3.2 g (79%) of the desired product, (2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-(5-benzyloxy-1H-indol-3-yl)-propanamide, as a light tan solid. the mixture was further stirred for 24 hours The solvent was removed The mixture was then washed with H2O The separated organic layer was dried over anhydrous sodium sulfate filtered concentrated in vacuum The residue was chromatographed on silica gel using first dichloromethane