1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone

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

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

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: To a solution of 11.5 g (46.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 ml N,N-dimethylformamide were slowly added 6.25 g (55.7 mmol) potassium tert-butylate. The temperature was kept below 32° C. The reaction mixture was allowed to cool to room temperature and stirred for 20 min. To the resulting brown suspension were added slowly 12.4 g (55.7 mmol) 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. The reaction mixture was stirred at room temperature until complete consumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was monitored by thin layer chromatography. Dilution with 300 ml tert-butyl methyl ether was followed by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid. The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give 11.1 g (61%) of the title compound as an off-white solid. The filtrate was concentrated to dryness. The residue was triturated with 50 ml warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give another 3.5 g (19%) of the title compound as an off-white solid. was kept below 32° C by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether The combined organic layers were washed with water and brine dried over sodium sulfate concentrated in vacuo The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether After cooling to room temperature the precipitate was collected by filtration washed with cold tert-butyl methyl ether dried in vacuo

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

Procedure: To a solution of 11.5 g (46.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 ml N,N-dimethylformamide were slowly added 6.25 g (55.7 mmol) potassium tert-butylate. The temperature was kept below 32° C. The reaction mixture was allowed to cool to room temperature and stirred for 20 min. To the resulting brown suspension were added slowly 12.4 g (55.7 mmol) 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. The reaction mixture was stirred at room temperature until complete consumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was monitored by thin layer chromatography. Dilution with 300 ml tert-butyl methyl ether was followed by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid. The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give 11.1 g (61%) of the title compound as an off-white solid. The filtrate was concentrated to dryness. The residue was triturated with 50 ml warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give another 3.5 g (19%) of the title compound as an off-white solid. was kept below 32° C by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether The combined organic layers were washed with water and brine dried over sodium sulfate concentrated in vacuo The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether After cooling to room temperature the precipitate was collected by filtration washed with cold tert-butyl methyl ether dried in vacuo

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

Procedure: To a stirred solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.75 g) in 20 ml of DMF at 0° C., were added 128 mg (1.1 eq.) of NaH (60% in oil). The mixture was stirred for 30 min. and then 0.32 ml (1.1 eq.) of dimethylamino-acetyl chloride were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 598 mg (61%) of 2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide as a white solid. The mixture was stirred an additional hour poured onto water extracted with ethyl acetate The combined organic phases were dried over Na2SO4 concentrated in vacuo

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

Procedure: To a stirred solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.75 g) in 20 ml of DMF at 0° C., were added 128 mg (1.1 eq.) of NaH (60% in oil). The mixture was stirred for 30 min. and then 0.32 ml (1.1 eq.) of dimethylamino-acetyl chloride were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 598 mg (61%) of 2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide as a white solid. The mixture was stirred an additional hour poured onto water extracted with ethyl acetate The combined organic phases were dried over Na2SO4 concentrated in vacuo

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

Procedure: A mixture of 2.0 g (9.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, 4.59 g (14.1 mmol) cesium carbonate and 2.14 g (10.4 mmol) 3,5-difluorobenzyl bromide in 90 ml acetonitrile was heated at 80° C. for 3 h. After cooling to room temperature addition of 150 ml water was followed by extraction with three 150-ml portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in 30 ml hot cyclohexane. Filtration gave 2.2 g (64%) of the crude title compound as light brown solid. After cooling to room temperature was followed by extraction with three 150-ml portions of tert-butyl methyl ether The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo The residue was triturated in 30 ml hot cyclohexane Filtration

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

Procedure: A mixture of 1.3 g (5.3 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone and 26.5 ml of a 4 M aqueous solution of sodium hydroxide was heated at reflux for 4.5 h. The mixture was cooled to room temperature and washed with two 100-ml portions of tert-butyl methyl ether. The aqueous layer was acidified to pH 2-3 by addition of concentrated hydrochloric acid solution at 0° C. Extraction with three 100-ml portions of tert-butyl methyl ether, drying over sodium sulfate, filtration and concentration in vacuo gave 0.80 g (78%) of the crude title compound as a brown solid. was heated at reflux for 4.5 h washed with two 100-ml portions of tert-butyl methyl ether The aqueous layer was acidified to pH 2-3 by addition of concentrated hydrochloric acid solution at 0° C Extraction with three 100-ml portions of tert-butyl methyl ether drying over sodium sulfate, filtration and concentration in vacuo

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

Procedure: A mixture of 1.3 g (5.3 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone and 26.5 ml of a 4 M aqueous solution of sodium hydroxide was heated at reflux for 4.5 h. The mixture was cooled to room temperature and washed with two 100-ml portions of tert-butyl methyl ether. The aqueous layer was acidified to pH 2-3 by addition of concentrated hydrochloric acid solution at 0° C. Extraction with three 100-ml portions of tert-butyl methyl ether, drying over sodium sulfate, filtration and concentration in vacuo gave 0.80 g (78%) of the crude title compound as a brown solid. was heated at reflux for 4.5 h washed with two 100-ml portions of tert-butyl methyl ether The aqueous layer was acidified to pH 2-3 by addition of concentrated hydrochloric acid solution at 0° C Extraction with three 100-ml portions of tert-butyl methyl ether drying over sodium sulfate, filtration and concentration in vacuo

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

Procedure: To a stirred solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (described previously in U.S. 2004067939) in DMF were added 2.1 eq. NaH (60% in oil). The mixture was stirred at RT for 30 min. and then the (commercially available) 2-chloro-N-methyl-acetamide (1.1 eq.) was added. The mixture was stirred an additional 14 hours at 60° C. and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Purification by preparative HPLC gave the title compound. The mixture was stirred an additional 14 hours at 60° C. poured onto water extracted with ethyl acetate The combined organic phases were dried over Na2SO4 concentrated in vacuo Purification by preparative HPLC