2-Fluorobenzenesulfonyl Fluoride

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a −75° C. solution of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester 2 (500 mg, 1.25 mmol) in THF (25 mL) was slowly added t-BuLi (1.47 mL, 2.5 mmol). The reaction mixture was stirred for 30 minutes at which time 2-fluoro-benzenesulfonyl fluoride 2a (222 mg, 1.5 mmol) was added. The reaction was stirred for 1.5 h at which time the ice bath was removed and the reaction was allowed to warm over 45 min. The reaction mixture was quenched with a saturated solution of ammonium chloride (55 mL). The mixture was then extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (25 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. The oil was chromatographed over silica eluting with hexane:ethyl acetate (17:3) to afford 300 mg (43%) of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-(2-fluoro-benzenesulfonyl)-indole-1-carboxylic acid tert-butyl ester (1-3). To a −75° C. was added was removed to warm over 45 min The reaction mixture was quenched with a saturated solution of ammonium chloride (55 mL) The mixture was then extracted with ethyl acetate (3×20 mL) The combined ethyl acetate layers were washed with brine (25 mL) The organic layer was dried (MgSO4) filtered concentrated to afford a yellow oil The oil was chromatographed over silica eluting with hexane:ethyl acetate (17:3)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Potassium fluoride (99%) (12 g, 216 mmol) was added to a solution of 2-fluoro-benzenesulfonyl chloride (10 g, 51 mmol) in 1, 4 dioxane (35 mL). The reaction mixture was refluxed for 24 hours, then cooled to room temperature and poured into ice water (200 mL). The ice water was extracted with chloroform (3×50 mL). The combined chloroform layers were dried (MgSO4), filtered, and concentrated to afford 2-fluoro-benzenesulfonyl fluoride (2a) as a colorless oil 6.7 g (74%). (M+H)+=177 The reaction mixture was refluxed for 24 hours The ice water was extracted with chloroform (3×50 mL) The combined chloroform layers were dried (MgSO4) filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a −75° C. solution of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester 2 (500 mg, 1.25 mmol) in THF (25 mL) was slowly added t-BuLi (1.47 mL, 2.5 mmol). The reaction mixture was stirred for 30 minutes at which time 2-fluoro-benzenesulfonyl fluoride 2a (222 mg, 1.5 mmol) was added. The reaction was stirred for 1.5 h at which time the ice bath was removed and the reaction was allowed to warm over 45 min. The reaction mixture was quenched with a saturated solution of ammonium chloride (55 mL). The mixture was then extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (25 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. The oil was chromatographed over silica eluting with hexane:ethyl acetate (17:3) to afford 300 mg (43%) of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-(2-fluoro-benzenesulfonyl)-indole-1-carboxylic acid tert-butyl ester (1-3). To a −75° C. was added was removed to warm over 45 min The reaction mixture was quenched with a saturated solution of ammonium chloride (55 mL) The mixture was then extracted with ethyl acetate (3×20 mL) The combined ethyl acetate layers were washed with brine (25 mL) The organic layer was dried (MgSO4) filtered concentrated to afford a yellow oil The oil was chromatographed over silica eluting with hexane:ethyl acetate (17:3)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Potassium fluoride (99%) (12 g, 216 mmol) was added to a solution of 2-fluoro-benzenesulfonyl chloride (10 g, 51 mmol) in 1, 4 dioxane (35 mL). The reaction mixture was refluxed for 24 hours, then cooled to room temperature and poured into ice water (200 mL). The ice water was extracted with chloroform (3×50 mL). The combined chloroform layers were dried (MgSO4), filtered, and concentrated to afford 2-fluoro-benzenesulfonyl fluoride (2a) as a colorless oil 6.7 g (74%). (M+H)+=177 The reaction mixture was refluxed for 24 hours The ice water was extracted with chloroform (3×50 mL) The combined chloroform layers were dried (MgSO4) filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 100-L round bottomed flask fitted with overhead stirrer, nitrogen inlet, temperature probe and ice bath was charged with 2-fluorobenzenesulfonyl chloride (50 g) and tetrahydrofuran (220 g). The solution was cooled down to −5° C. with an ice bath. Tetrabutylammonium fluoride (270 mL of 1M in tetrahydrofuran solution) was added slowly to the reactor. The internal temperature was kept less than 8° C. After the addition was completed, HPLC showed the reaction was completed. The reaction was quenched by slowly adding 250 g of water. Then 430 g of toluene was added to the reaction mixture. The layers were separated. The organic layer was washed with 250 g of water twice. The organic layer was distilled down under vacuum with the bath temperature at 48° C. 1H NMR (400 MHz, CDCl3) δ 8.01-7.96 (m, 1H), 7.76-7.83 (m, 1H), 7.32-7.44 (m, 2H). A 100-L round bottomed flask fitted with overhead stirrer, nitrogen inlet was kept less than 8° C After the addition The reaction was quenched by slowly adding 250 g of water Then 430 g of toluene was added to the reaction mixture The layers were separated The organic layer was washed with 250 g of water twice The organic layer was distilled down under vacuum with the bath temperature at 48° C

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The solution of EXAMPLE 12 (44.3 g) in a solution of 450 ml was added to a round bottomed flask fitted with overhead stirrer, nitrogen inlet, cold-water bath and temperature probe. It was cooled down to 12° C. (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF (6.1 g), was added in one portion. Ruppert's reagent (370 g, CH3SiCF3) was charged slowly to the reaction mixture while maintaining the internal temperature less than 23° C. The reaction was completed after addition. Water (220 g) was added to quench the reaction, the layers were separated, and the organic layer was washed twice with 220 g of water. The organic solution was distilled under vacuum with the bath temperature at 50° C. Heptanes (500 g) were added to the residue, and the mixture was distilled down until the solvent was removed. 1H NMR (400 MHz, CDCl3) δ 8.01-8.05 (m, 1H), 7.84-7.87 (m, 1H), 7.44-7.48 (m, 1H), 7.36-7.39 (m 1H). fitted with overhead stirrer, nitrogen inlet was added in one portion while maintaining the internal temperature less than 23° C after addition to quench the reaction the layers were separated the organic layer was washed twice with 220 g of water The organic solution was distilled under vacuum with the bath temperature at 50° C Heptanes (500 g) were added to the residue the mixture was distilled down until the solvent was removed