1-(2-chloro-4-fluorophenyl)ethanone

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: A mixture of 4'-fluoro-2'-chloroacetophenone (40 g), methylamine (33% w/w solution in industrial methylated spirit, 60 ml), industrial methylated spirit (40 ml) and copper powder (0.5 g) was stirred at 80° in a sealed pressure vessel for 3 hours. After cooling to ambient temperature, the reaction mixture was transferred to a conical flask. The reaction vessel was washed out with industrial methylated spirit (2×30 ml) and the washings added to the reaction mixture. Sodium sulphide nonahydrate (2.3 g) in water (23 ml) was added and the mixture heated at 50° for 10 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name CELITE). Solvent was removed from the filtrate under reduced pressure at 40° and hydrochloric acid (5M, 160 ml) was added to the residue. The mixture was stirred for approximately 2 hours and then extracted with dichloromethane (100 ml, then 2×60 ml). The combined extracts were dried over magnesium sulphate and evaporated to give the novel compound 4'-fluoro-2'-(methylamino)acetophenone as an oil which solidified on storing at ambient temperature. the reaction mixture was transferred to a conical flask The reaction vessel was washed out with industrial methylated spirit (2×30 ml) the washings added to the reaction mixture Sodium sulphide nonahydrate (2.3 g) in water (23 ml) was added the mixture heated at 50° for 10 minutes The mixture was filtered through diatomaceous earth ( Solvent was removed from the filtrate under reduced pressure at 40° hydrochloric acid (5M, 160 ml) was added to the residue The mixture was stirred for approximately 2 hours extracted with dichloromethane (100 ml The combined extracts were dried over magnesium sulphate evaporated

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

実験手順: A reaction vessel was charged with sodium hydride (as a 60% oil dispersion, 5.0 g, 125 mmol), DME (40 ml) and 2-chloro-5-trifluoromethylpyridine (6.93 g, 38.2 mmol). 2-Chloro-4-fluoroacetophenone (6.8 g, 39.4 mmol) in DME (10 ml) was added in portions to the mixture under nitrogen at room temperature. The mixture was stirred at ambient temperature for one hour then at 40-45° C. overnight. Upon the completion of the reaction, the mixture was cooled to 5° C. and 10% aqueous sodium hydroxide solution (20 ml) was slowly added to the reaction mixture. The mixture was partitioned between diethylether (300 ml) and water (300 ml). The layers were separated, the organics dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica eluting with diethylether-cyclohexane (1:3). Concentration of the appropriate fractions afforded 8.10 g (67%) of the title compound. at 40-45° C. overnight Upon the completion of the reaction the mixture was cooled to 5° C. The mixture was partitioned between diethylether (300 ml) and water (300 ml) The layers were separated the organics dried over magnesium sulfate concentrated to dryness The residue was purified by column chromatography on silica eluting with diethylether-cyclohexane (1:3)

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

実験手順: To a solution 4-cyanophenol (CAS Reg. No. 767-00-0, 1.2 g), 2-chloro-4-fluoroacetophenone (CAS Reg. No. 700-35-6, 1.7 g) in DMA (10 ml) was added K2CO3 (1.66 g). The mixture is refluxed for 5 h. TLC (heptane/EtOAc 2:1) showed complete conversion. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2) to give the title compound (1.8 g) as yellow oil. MS (m/e)=272.2 [M+H+]. The mixture is refluxed for 5 h the mixture was extracted with DCM The combined organic layers were dried over Na2SO4 concentrated to an oil The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2)

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

実験手順: A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 315.8 ml), industrial methylated spirit (291.6 ml), 2'-chloro-4'-fluoroacetophenone (203.4 g) and copper powder (2.8 g) was heated to 80° in a glass autoclave over a period of 1 hour. The mixture was stirred at 80° for a further 2 hours and then allowed to cool to 45° over a period of 1 hour. The mixture was transferred to a second vessel and the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel. The mixture was heated to 50°. A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added and the mixture was heated at 50° for a further 15 minutes. The mixture was filtered and the residue washed with industrial methylated spirit (100 ml). The filtrate and washings were combined and evaporated to give a brown oil. The brown oil was stirred with hydrochloric acid (5M; 800 ml) for 2.5 hours and then dichloromethane (600 ml) added. The layers were separated and the aqueous phase further extracted with dichloromethane (2×300 ml). The organic phases were combined and evaporated to give 4'-fluoro-2'-(methylamino)-acetophenone as a brown oil which solidified at ambient temperature. was heated to 80° in a glass autoclave over a period of 1 hour to cool to 45° over a period of 1 hour The mixture was transferred to a second vessel the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel The mixture was heated to 50° A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added the mixture was heated at 50° for a further 15 minutes The mixture was filtered the residue washed with industrial methylated spirit (100 ml) evaporated to give a brown oil The layers were separated the aqueous phase further extracted with dichloromethane (2×300 ml) evaporated

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

実験手順: A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 315.8 ml), industrial methylated spirit (291.6 ml), 2'-chloro-4'-fluoroacetophenone (203.4 g) and copper powder (2.8 g) was heated to 80° in a glass autoclave over a period of 1 hour. The mixture was stirred at 80° for a further 2 hours and then allowed to cool to 45° over a period of 1 hour. The mixture was transferred to a second vessel and the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel. The mixture was heated to 50°. A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added and the mixture was heated at 50° for a further 15 minutes. The mixture was filtered and the residue washed with industrial methylated spirit (100 ml). The filtrate and washings were combined and evaporated to give a brown oil. The brown oil was stirred with hydrochloric acid (5M; 800 ml) for 2.5 hours and then dichloromethane (600 ml) added. The layers were separated and the aqueous phase further extracted with dichloromethane (2×300 ml). The organic phases were combined and evaporated to give 4'-fluoro-2'-(methylamino)-acetophenone as a brown oil which solidified at ambient temperature. was heated to 80° in a glass autoclave over a period of 1 hour to cool to 45° over a period of 1 hour The mixture was transferred to a second vessel the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel The mixture was heated to 50° A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added the mixture was heated at 50° for a further 15 minutes The mixture was filtered the residue washed with industrial methylated spirit (100 ml) evaporated to give a brown oil The layers were separated the aqueous phase further extracted with dichloromethane (2×300 ml) evaporated

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

実験手順: A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 120 ml), industrial methylated spirit (60 ml), 2'-chloro-4'-fluoroacetophenone (51.6 g) and copper powder (0.75 g), was charged to a pressure vessel and heated to 90° for 2 hours. After cooling in an ice bath to 30° the mixture was transferred to a second vessel, heated at 50° and then a solution of sodium sulphide nonahydrate (2.88 g) in water (30 ml) added. The mixture was heated to reflux with stirring for 10 minutes and then filtered. Water (300 ml) was added to the filtrate and the solution heated to reflux. Hydrochloric acid (5M; 90 ml) was added to the hot solution and the mixture heated to reflux for a brief period. The reaction mixture was cooled to ambient temperature and aqueous sodium hydroxide solution (5M; 30 ml) added. The mixture was extracted with dichloromethane (600 ml) and then further extracted with dichloromethane (200 ml). The combined dichloromethane extracts were dried (magnesium sulphate) and evaporated in vacuo to give a crude brown oil. The oil was distilled in vacuo (b.p. 90°, 1 mmHg) to give 4'-fluoro-2'-(methylamino)-acetophenone, m.p. 52°-53°. was charged to a pressure vessel heated to 90° for 2 hours After cooling in an ice bath to 30° the mixture was transferred to a second vessel heated at 50° The mixture was heated to reflux filtered Water (300 ml) was added to the filtrate the solution heated to reflux Hydrochloric acid (5M; 90 ml) was added to the hot solution the mixture heated to reflux for a brief period aqueous sodium hydroxide solution (5M; 30 ml) added The mixture was extracted with dichloromethane (600 ml) further extracted with dichloromethane (200 ml) The combined dichloromethane extracts were dried (magnesium sulphate) evaporated in vacuo to give a crude brown oil The oil was distilled in vacuo (b.p. 90°, 1 mmHg)

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

実験手順: A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 315.8 ml), industrial methylated spirit (291.6 ml), 2'-chloro-4'-fluoroacetophenone (203.4 g) and copper powder (2.8 g) was heated to 80° in a glass autoclave over a period of 1 hour. The mixture was stirred at 80° for a further 2 hours and then allowed to cool to 45° over a period of 1 hour. The mixture was transferred to a second vessel and the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel. The mixture was heated to 50°. A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added and the mixture was heated at 50° for a further 15 minutes. The mixture was filtered and the residue washed with industrial methylated spirit (100 ml). The filtrate and washings were combined and evaporated to give a brown oil. The brown oil was stirred with hydrochloric acid (5M; 800 ml) for 2.5 hours and then dichloromethane (600 ml) added. The layers were separated and the aqueous phase further extracted with dichloromethane (2×300 ml). The organic phases were combined and evaporated to give 4'-fluoro-2'-(methylamino)acetophenone as a brown oil which solidified at ambient temperature. was heated to 80° in a glass autoclave over a period of 1 hour to cool to 45° over a period of 1 hour The mixture was transferred to a second vessel the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel The mixture was heated to 50° A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added the mixture was heated at 50° for a further 15 minutes The mixture was filtered the residue washed with industrial methylated spirit (100 ml) evaporated to give a brown oil The layers were separated the aqueous phase further extracted with dichloromethane (2×300 ml) evaporated

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

実験手順: A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 120 ml), industrial methylated spirit (60 ml), 2'-chloro-4'-fluoroacetophenone (51.6 g) and copper powder (0.75 g), was charged to a pressure vessel and heated to 90° for 2 hours. After cooling in an ice bath to 30° the mixture was transferred to a second vessel, heated at 50° and then a solution of sodium sulphide nonahydrate (2.88 g) in water (30 ml) added. The mixture was heated to reflux with stirring for 10 minutes and then filtered. Water (300 ml) was added to the filtrate and the solution heated to reflux. Hydrochloric acid (5M; 90 ml) was added to the hot solution and the mixture heated to reflux for a brief period. The reaction mixture was cooled to ambient temperature and aqueous sodium hydroxide solution (5M; 30 ml) added. The mixture was extracted with dichloromethane (600 ml) and then further extracted with dichloromethane (200 ml). The combined dichloromethane extracts were dried (magnesium sulphate) and evaporated in vacuo to give a crude brown oil. The oil was distilled in vacuo (b.p. 90°, 1 mmHg) to give 4'-fluoro-2'-(methylamino)acetophenone, m.p. 52°-53°. was charged to a pressure vessel heated to 90° for 2 hours After cooling in an ice bath to 30° the mixture was transferred to a second vessel heated at 50° The mixture was heated to reflux filtered Water (300 ml) was added to the filtrate the solution heated to reflux Hydrochloric acid (5M; 90 ml) was added to the hot solution the mixture heated to reflux for a brief period aqueous sodium hydroxide solution (5M; 30 ml) added The mixture was extracted with dichloromethane (600 ml) further extracted with dichloromethane (200 ml) The combined dichloromethane extracts were dried (magnesium sulphate) evaporated in vacuo to give a crude brown oil The oil was distilled in vacuo (b.p. 90°, 1 mmHg)

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

実験手順: A mixture of 4'-fluoro-2'-chloroacetophenone (40 g), methylamine (33% w/w solution in industrial methylated spirit, 60 ml), industrial methylated spirit (40 ml) and copper powder (0.5 g) was stirred at 80° in a sealed pressure vessel for 3 hours. After cooling to ambient temperature, the reaction mixture was transferred to a conical flask. The reaction vessel was washed out with industrial methylated spirit (2×30 ml) and the washings added to the reaction mixture. Sodium sulphide nonahydrate (2.3 g) in water (23 ml) was added and the mixture heated at 50° for 10 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name CELITE). Solvent was removed from the filtrate under reduced pressure at 40° and hydrochloric acid (5M, 160 ml) was added to the residue. The mixture was stirred for approximately 2 hours and then extracted with dichloromethane (100 ml, then 2×60 ml). The combined extracts were dried over magnesium sulphate and evaporated to give the novel compound 4'-fluoro-2'-(methylamino)acetophenone as an oil which solidified on storing at ambient temperature. the reaction mixture was transferred to a conical flask The reaction vessel was washed out with industrial methylated spirit (2×30 ml) the washings added to the reaction mixture Sodium sulphide nonahydrate (2.3 g) in water (23 ml) was added the mixture heated at 50° for 10 minutes The mixture was filtered through diatomaceous earth ( Solvent was removed from the filtrate under reduced pressure at 40° hydrochloric acid (5M, 160 ml) was added to the residue The mixture was stirred for approximately 2 hours extracted with dichloromethane (100 ml The combined extracts were dried over magnesium sulphate evaporated

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

実験手順: A reaction vessel was charged with sodium hydride (as a 60% oil dispersion, 5.0 g, 125 mmol), DME (40 ml) and 2-chloro-5-trifluoromethylpyridine (6.93 g, 38.2 mmol). 2-Chloro-4-fluoroacetophenone (6.8 g, 39.4 mmol) in DME (10 ml) was added in portions to the mixture under nitrogen at room temperature. The mixture was stirred at ambient temperature for one hour then at 40-45° C. overnight. Upon the completion of the reaction, the mixture was cooled to 5° C. and 10% aqueous sodium hydroxide solution (20 ml) was slowly added to the reaction mixture. The mixture was partitioned between diethylether (300 ml) and water (300 ml). The layers were separated, the organics dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica eluting with diethylether-cyclohexane (1:3). Concentration of the appropriate fractions afforded 8.10 g (67%) of the title compound. at 40-45° C. overnight Upon the completion of the reaction the mixture was cooled to 5° C. The mixture was partitioned between diethylether (300 ml) and water (300 ml) The layers were separated the organics dried over magnesium sulfate concentrated to dryness The residue was purified by column chromatography on silica eluting with diethylether-cyclohexane (1:3)

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

実験手順: A reaction vessel was charged with sodium hydride (as a 60% oil dispersion, 5.0 g, 125 mmol), DME (40 ml) and 2-chloro-5-trifluoromethylpyridine (6.93 g, 38.2 mmol). 2-Chloro-4-fluoroacetophenone (6.8 g, 39.4 mmol) in DME (10 ml) was added in portions to the mixture under nitrogen at room temperature. The mixture was stirred at ambient temperature for one hour then at 40-45° C. overnight. Upon the completion of the reaction, the mixture was cooled to 5° C. and 10% aqueous sodium hydroxide solution (20 ml) was slowly added to the reaction mixture. The mixture was partitioned between diethylether (300 ml) and water (300 ml). The layers were separated, the organics dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica eluting with diethylether-cyclohexane (1:3). Concentration of the appropriate fractions afforded 8.10 g (67%) of the title compound. at 40-45° C. overnight Upon the completion of the reaction the mixture was cooled to 5° C. The mixture was partitioned between diethylether (300 ml) and water (300 ml) The layers were separated the organics dried over magnesium sulfate concentrated to dryness The residue was purified by column chromatography on silica eluting with diethylether-cyclohexane (1:3)