2-(5-bromo-1H-indol-3-yl)-N,N-dimethylethanamine

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: A solution of 5-bromo-N,N-dimethyl-α-oxo-1H-indole-3-acetamide (from step (a), 19.85 g, 67.3 mmol) in tetrahydrofuran (100 ml) was added dropwise to a slurry of lithium aluminium hydride (7.66 g, 0.2 mol) in tetrahydrofuran (20 ml) under a nitrogen atmosphere, maintaining the temperature below 5° C. The yellow green slurry was then warmed to ambient temperature and then brought to gentle reflux. Reflux was maintained for 5 hr after which time the reaction mixture was cooled to 0° C. and isopropyl alcohol (150 ml) and IMS (150 ml) were added sequentially. The grey slurry was then warmed to ambient temperature, before 1N NaOH (100 ml) was added. The reaction mixture was then filtered through a celite (trade mark) pad and the pad washed consecutively with demineralised water (100 ml) and IMS (100 ml). The filtrate was then concentrated under reduced pressure until all alcohol had been removed and then the aqueous residue was extracted with ethyl acetate (2×200 ml). The combined organic extracts were then evaporated in vacuo to give a brown oil. This was triturated with a mixture of hexane and ethyl acetate (1:1) (30 ml) to give the subtitle compound (13.4 g, 75%) as a cream solid. m.p. 82-85° C. maintaining the temperature below 5° C Reflux was maintained for 5 hr after which time the reaction mixture was cooled to 0° C. was added The reaction mixture was then filtered through a celite (trade mark) pad the pad washed consecutively with demineralised water (100 ml) and IMS (100 ml) The filtrate was then concentrated under reduced pressure until all alcohol had been removed the aqueous residue was extracted with ethyl acetate (2×200 ml) The combined organic extracts were then evaporated in vacuo to give a brown oil This was triturated with a mixture of hexane and ethyl acetate (1:1) (30 ml)

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

Procedure: Benzoyl chloride (1.7 mL, 14.6 mmol) was added to a solution of 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1H-indole (Example 3a, 9.5 mmol) in dichloromethane (70 mL) containing triethylamine (4 mL, 28.7 mmol) and DMAP (206 mg, 1.7 mmol). The resulting solution was stirred at room temperature for 20 h. Dilution with dichloromethane (500 mL) was followed by sequential washing with water (200 mL) and brine (150 mL), drying over sodium sulfate and removal of the solvent in vacuo. Flash chromatography (silica gel, 3-5% 2M methanolic ammonia in dichloromethane) yielded 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (2.95 g, 84%). by sequential washing with water (200 mL) and brine (150 mL) drying over sodium sulfate and removal of the solvent in vacuo

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

Procedure: (R)-5-Bromo-3-[(N-methylpyrrolidin-2-yl)methyl]-1H-indole: (63%) from (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl5-bromo-1H-indole (Example 2a).

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

Procedure: (R)-5-Bromo-3-[(N-methylpyrrolidin-2-yl)methyl]-1H-indole: (63%) from (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl5-bromo-1H-indole (Example 2a).

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

Procedure: [2-(5-Bromo-1H-indol-3-yl)-ethyl]-dimethylamine (16) (500.0 mg, 1.872 mmol) (U.S. Pat. No. 5,998,438) was placed in an argon purged oven dried flask fitted with a stirbar. Zinc cyanide (395.0 mg, 3.368 mmol, 1.8 equivalents); Zinc powder (14.7 mg. 0.225 mmol, 0.12 equivalents) and tris(dibenzylideneacetone)dipalladium(0) (42.9 mg, 0.0468 mmol, 0.025 equivalents) were added sequentially followed by anhydrous N,N-dimethylformamide (15 mL). A solution of tri-t-butylphosphine in hexanes (10 wt %, 189.0 mg, 280 μl, 0.05 equivalents) was added and the mixture was stirred for 15 minutes at room temperature and then heated in an oil bath at 60° C. for 30 minutes. After cooling to room temperature the mixture was transferred into a separatory funnel and diluted with distilled water (15 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel column chromatography (10% 2M NH3 in methanol/90% dichloromethane) to provide 3-(2-(dimethylamino)ethyl)-1H-indole-5-carbonitrile (57) as a yellow residue (150 mg, 37.6% yield). 1H NMR (DMSO) δ: 2.21 (s, 6H), 2.54 (m, 2 H), 2.84 (t, 2H), 7.36-7.41 (m, 2H), 7.49 (d, 1H), 8.07 (s, 1H), 11.38 (br s, 1H). 5,998,438) was placed in an argon purged oven dried flask fitted with a stirbar heated in an oil bath at 60° C. for 30 minutes After cooling to room temperature the mixture was transferred into a separatory funnel The aqueous phase was extracted with ethyl acetate (3×30 mL) The combined organic extracts were dried over magnesium sulfate filtered concentrated The residue was purified via silica gel column chromatography (10% 2M NH3 in methanol/90% dichloromethane)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask is charged with 5-bromo-dimethyltryptamin (5.34 g, 20 mmol), copper (I)cyanide (2.69 g, 30 mmol), and N-Methylpyrrolidone (20 ml). The mixture is heated at 200° C. for 9 hours under a nitrogen atmosphere and then left stirring over night. The brown mixture is poured on water to give a brown precipitate. This is suspended in ammonia (100 ml 25% solution in water), and the mixture is stirred over night. Extraction with TBME (3*100 ml), and removal of the solvent from the dried (sodium sulfate) organic layer gives the title product as a yellow solid (properties as in Reference Example 3). left The brown mixture is poured on water to give a brown precipitate the mixture is stirred over night Extraction with TBME (3*100 ml), and removal of the solvent from the dried (sodium sulfate) organic layer

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask is charged with 5-bromo-dimethyltryptamin (5.34 g, 20 mmol), copper (I)cyanide (2.69 g, 30 mmol), and N-Methylpyrrolidone (20 ml). The mixture is heated at 200° C. for 9 hours under a nitrogen atmosphere and then left stirring over night. The brown mixture is poured on water to give a brown precipitate. This is suspended in ammonia (100 ml 25% solution in water), and the mixture is stirred over night. Extraction with TBME (3*100 ml), and removal of the solvent from the dried (sodium sulfate) organic layer gives the title product as a yellow solid (properties as in Reference Example 3). left The brown mixture is poured on water to give a brown precipitate the mixture is stirred over night Extraction with TBME (3*100 ml), and removal of the solvent from the dried (sodium sulfate) organic layer

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Reference Example 2) (15 g, 56.1 mmol) in ether (450 mL), at −75° C. a solution of tert-butyl lithium (99 ml of 1.7 N solution in hexanes, 168 mmol) is added. The mixture is stirred for 50 minutes at −75° C., and then for 30 minutes at −30° C. To the obtained beige suspension, DMF (22.5 ml) is added during 15 minutes, and then the mixture is allowed to warm to ambient temperature. The mixture is poured on water and extracted with diethyl ether (500 mL). After washing the organic layer with brine (3 times 500 mL), and drying (sodium sulfate), removal of the solvent leaves the crude aldehyde, which is recrystallized, from toluene/hexane. Yield of the title compound: 9.9 g (81.8%) yellowish plates, mp=103° C. for 30 minutes at −30° C to warm to ambient temperature The mixture is poured on water extracted with diethyl ether (500 mL) After washing the organic layer with brine (3 times 500 mL) drying (sodium sulfate), removal of the solvent

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere a flask is charged with [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (1.0 g, 3.74 mmol), zinc cyanide (0.235 g, 2 mmol), Pd2(dba)3xCHCl3 (0.194 mg, 5 mol %), dppf (bis-diphenylphosphino ferrocene) (0.207 g, 0.374 mmol, 10 mol %), and DMF (12 mL). The orange slurry is heated to 110° C. and stirred for 21 hours. To the black suspension, which has formed, THF (100 mL) is added, and this is extracted with 1 N NaOH (100 mL). The organic layer is washed with water twice (50 mL each), dried and removal of the solvent gives the title product (0.67 g, 84%) as brown solid. To the black suspension, which has formed this is extracted with 1 N NaOH (100 mL) The organic layer is washed with water twice (50 mL each) dried removal of the solvent

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere a flask is charged with [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (1.0 g, 3.74 mmol), zinc cyanide (0.235 g, 2 mmol), Pd2(dba)3xCHCl3 (0.194 mg, 5 mol %), dppf (bis-diphenylphosphino ferrocene) (0.207 g, 0.374 mmol, 10 mol %), and DMF (12 mL). The orange slurry is heated to 110° C. and stirred for 21 hours. To the black suspension, which has formed, THF (100 mL) is added, and this is extracted with 1 N NaOH (100 mL). The organic layer is washed with water twice (50 mL each), dried and removal of the solvent gives the title product (0.67 g, 84%) as brown solid. To the black suspension, which has formed this is extracted with 1 N NaOH (100 mL) The organic layer is washed with water twice (50 mL each) dried removal of the solvent