(4-fluorophenyl)-phenylmethanone

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: o-Allylphenol (52.2 g), 4,4'-difluorobenzophenone (35 g), 4-fluorobenzophenone (13.8 g), potassium carbonate (37.75 g), dry N-methylpyrrolidone (200 ml) and toluene (75 ml) are placed in a 3-necked 1500 ml flask fitted with a stirrer, reflex condensor and thermometer and the mixture is heated under nitrogen to a temperature between 155°-160° C. and stirred for 3 hours. Water and toluene are separated via a Dean Stark trap and finally after 3 hours the reaction mixture reaches a temperature of 160° C. The mixture is cooled to 100° C. and a 1:1 mixture of toluene/water (400 ml) is added while stirring. After phase separation the aqueous layer is washed with toluene (100 ml) and the combined toluene layers are washed 4 times with water (150 ml). The toluene phase is dried over sodium sulphate and toluene distilled off by use of a rotary evaporator finally in vacuum leaving a 4,4'-bis[o-(1-propenyl)phenoxy]benzophenone/4-[o-(1-propenyl)phenoxy]benzophenone mixture as a light yellow melt. The yield is 89 g. fitted with a stirrer reflex condensor and thermometer and the mixture is heated under nitrogen to a temperature between 155°-160° C. Water and toluene are separated via a Dean Stark trap and finally after 3 hours the reaction mixture a temperature of 160° C a 1:1 mixture of toluene/water (400 ml) is added while stirring After phase separation the aqueous layer is washed with toluene (100 ml) the combined toluene layers are washed 4 times with water (150 ml) The toluene phase is dried over sodium sulphate and toluene distilled off by use of a rotary evaporator finally in vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: o-Allylphenol (33.5 g), 4-fluorobenzophenone (50.05 g), potassium carbonate (24.20 g), dry N-methylpyrrolidone (160 ml) and toluene (60 ml) are placed in a 3-necked 500 ml flask fitted with a stirrer, reflex condensor and thermometer and the mixture is heated under nitrogen to a temperature between 155°-160° C. and stirred for 3 hours. Water and toluene are separated via a Dean Stark trap and finally after 3 hours the reaction mixture reaches a temperature of 160° C. The mixture is cooled to 100° C. and a 1:1 mixture of toluene/water (400 ml) is added while stirring. After phase separation the aqueous layer is washed with toluene (50 ml) and the combined toluene layers are washed 4 times with water (150 ml). The toluene phase is dried over sodium sulphate and toluene distilled off by use of a rotary evaporator finally in vacuum leaving 4-[o-(1-propenyl)phenoxy]benzophenone as a light yellow melt. The yield is 73 g. fitted with a stirrer reflex condensor and thermometer and the mixture is heated under nitrogen to a temperature between 155°-160° C. Water and toluene are separated via a Dean Stark trap and finally after 3 hours the reaction mixture a temperature of 160° C a 1:1 mixture of toluene/water (400 ml) is added while stirring After phase separation the aqueous layer is washed with toluene (50 ml) the combined toluene layers are washed 4 times with water (150 ml) The toluene phase is dried over sodium sulphate and toluene distilled off by use of a rotary evaporator finally in vacuum

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,5-dimethyltetrazole (29.25 g; 0.298 mole) in dry THF (400 mL) was cooled to -78° C. and treated with n-butyllithium (133 mL of a 2.5M solution in hexane; 0.3325 mole) over 30 minutes. The mixture was stirred at -78° C. for 30 minutes and treated with 4-fluorobenzophenone (50 g; 0.25 mole). The mixture was stirred at -78° C. for 30 minutes and allowed to warm up to 23° C. over 2 hours. The reaction was quenched with 2N HCl (100 mL) and the organic solvent was removed by evaporation. The residue was extracted with CHCl3 (2×100 mL) and the combined organic layers were dried (Na2SO4) and evaporated to afford a brown oil. Purification by chromatography using 20% EtOAc-hexane as eluent afforded the title compound as a white solid (46.3 g; 62%). m.p.=113°-114° C. (crystallized from EtOAc-hexane). MS (CI): m/e=299 for (M+H)+ ; The mixture was stirred at -78° C. for 30 minutes to warm up to 23° C. over 2 hours The reaction was quenched with 2N HCl (100 mL) the organic solvent was removed by evaporation The residue was extracted with CHCl3 (2×100 mL) the combined organic layers were dried (Na2SO4) evaporated to afford a brown oil Purification by chromatography

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

Procedure: 180 mg of the title compound were prepared as described for [3,5-difluoro-4-((R)-octahydropyrido[1,2-a]pyrazin-2-yl)phenyl]-[phenyl]methanone, using 4-fluorobenzophenone instead of 3,4,5-trifluorobenzophenone.

Conditions: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100 mL two-neck flask was charged with 4-fluorobenzophenone (15.0 g; 74.9 mmol) and diethanolamine (55.1 g; 524 mmol). The flask was flushed with nitrogen, fitted with a reflux condenser and heated to 155° C. for 48 h under a gentle stream of nitrogen. Complete conversion of the starting 4-fluorobenzophenone was confirmed by TLC. After cooling to ambient temperature, the dark viscous reaction mixture was poured into water (2000 mL). The resulting suspension was thoroughly extracted with diethyl ether (6×250 mL). The aqueous phase was discarded and the organic phase was extracted with hydrochloric acid (2M, 5×200 mL). The pH of the strongly acidic aqueous phase was adjusted to 12-13 by slow addition of 35% aq. ammonia to reprecipitate the product. The aqueous phase was then reextracted with dichloromethane (3×300 mL). The crude organic extract was purified by passing through a short silica gel column (eluent: ethyl acetate). The eluted yellow solution was evaporated and the oily residue dried in vacuo to provide {4-[bis(2-hydroxyethyl)amino]phenyl}(phenyl)methanone (yellow-brown solid; 13.176 g; 62% yield). The flask was flushed with nitrogen fitted with a reflux condenser After cooling to ambient temperature the dark viscous reaction mixture was poured into water (2000 mL) The resulting suspension was thoroughly extracted with diethyl ether (6×250 mL) the organic phase was extracted with hydrochloric acid (2M, 5×200 mL) The pH of the strongly acidic aqueous phase was adjusted to 12-13 by slow addition of 35% aq. ammonia The crude organic extract was purified The eluted yellow solution was evaporated the oily residue dried in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,5-dimethyltetrazole (29.25 g; 0.298 mole) in dry THF (400 mL) was cooled to -78° C. and treated with n-butyllithium (133 mL of a 2.5M solution in hexane; 0.3325 mole) over 30 minutes. The mixture was stirred at -78° C. for 30 minutes and treated with 4-fluorobenzophenone (50 g, 0.25 mole. The mixture was stirred at -78° C. for 30 minutes and allowed to warm up to 23° C. over 2 hours. The reaction was quenched with 2N HCl (100 mL) and the organic solvent was removed by evaporation. The residue was extracted with CHCl3 (2×100 mL) and the combined organic layers were dried (Na2SO4) and evaporated to afford a brown oil. Purification by chromatography using 20% EtOAc-hexane as eluent afforded the title compound as a white solid (46.3 g; 62%). m.p.=113°-114° C. (crystallized from EtOAc-hexane). MS (CI): m/e=299 for (M+H)+ ; The mixture was stirred at -78° C. for 30 minutes to warm up to 23° C. over 2 hours The reaction was quenched with 2N HCl (100 mL) the organic solvent was removed by evaporation The residue was extracted with CHCl3 (2×100 mL) the combined organic layers were dried (Na2SO4) evaporated to afford a brown oil Purification by chromatography

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

Procedure: A solution of commercially available 4-fluorobenzophenone (42 g., 0.21 mole), diethyl succinate (43.6 g., 0.25 mole) and potassium t-butoxide (23.7 g., 0.21 mole) in t-butanol (250 ml.) was stirred at reflux for 6 hours and then stirred at room temperature for an additional 16 hours. The reaction mixture was then acidified with 6N hydrochloric acid (200 ml.), evaporated under vacuum to remove the t-butanol and extracted with ether (2×250 ml.). The combined ether extract was extracted with 10% aqueous ammonium hydroxide (2×350 ml.). The combined aqueous extract was washed with ether (2×200 ml.), re-acidified with 6N hydrochloric acid and extracted again with ether (2×400 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated under vacuum to an oil, which was crystallized by dissolution in hexane (100 ml.) followed by scratching the flask to initiate crystallization (48 g., 70% yield, m.p. 98°-99° C., elemental analysis calculated: 69.50% C; 5.22% H; 5.78% F; found: 69.34% C; 5.36% H; 6.09% F). at reflux for 6 hours evaporated under vacuum to remove the t-butanol extracted with ether (2×250 ml.) The combined ether extract was extracted with 10% aqueous ammonium hydroxide (2×350 ml.) The combined aqueous extract was washed with ether (2×200 ml.), re-acidified with 6N hydrochloric acid extracted again with ether (2×400 ml.) The combined ether extract was dried (MgSO4) filtered evaporated under vacuum to an oil, which was crystallized by dissolution in hexane (100 ml.) crystallization (48 g., 70% yield, m.p. 98°-99° C., elemental analysis calculated: 69.50% C; 5.22% H; 5.78% F; found: 69.34% C; 5.36% H; 6.09% F)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1000 mL 3-necked round-bottomed flask fitted with a Dean-Stark trap, condenser, stir-bar and nitrogen gas adaptor was charged with 4-iodophenol (19.0 g, 0.086 mol), 4-fluorobenzophenone (15.72 g, 0.079 mol), potassium carbonate (7.16 g, 0.0518 mol), DMF (157 mL) and toluene (16 mL). The resulting mixture was stirred and refluxed for 2 hours (solution temperature ˜160° C.) under nitrogen atmosphere. Water was collected at the trap during this period of time. After 2 hours, the reaction was cooled to room temperature, and water (400 mL) was added to the reaction mixture and the desired product precipitated out of solution as a cream white solid. The product was further purified by re-crystallization isopropanol (400 mL) to give the desired product as a white crystalline solid (25 g, 87% yield). A 1000 mL 3-necked round-bottomed flask fitted with a Dean-Stark trap, condenser, stir-bar and nitrogen gas adaptor Water was collected at the trap during this period of time the reaction was cooled to room temperature water (400 mL) was added to the reaction mixture the desired product precipitated out of solution as a cream white solid The product was further purified by re-crystallization isopropanol (400 mL)

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

Procedure: A solution of commercially available 4-fluorobenzophenone (42 g., 0.21 mole), diethyl succinate (43.6 g., 0.25 mole) and potassium t-butoxide (23.7 g., 0.21 mole) in t-butanol (250 ml.) was stirred at reflux for 6 hours and then stirred at room temperature for an additional 16 hours. The reaction mixture was then acidified with 6N hydrochloric acid (200 ml.), evaporated under vacuum to remove the t-butanol and extracted with ether (2×250 ml.). The combined ether extract was extracted with 10% aqueous ammonium hydroxide (2×350 ml.). The combined aqueous extract was washed with ether (2×200 ml.), re-acidified with 6N hydrochloric acid and extracted again with ether (2×400 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated under vacuum to an oil, which was crystallized by dissolution in hexane (100 ml.) followed by scratching the flask to initiate crystallization (48 g., 70% yield, m.p. 98°-99° C., elemental analysis calculated: 69.50% C; 5.22% H; 5.78% F; found: 69.34% C; 5.36% H; 6.09% F). at reflux for 6 hours evaporated under vacuum to remove the t-butanol extracted with ether (2×250 ml.) The combined ether extract was extracted with 10% aqueous ammonium hydroxide (2×350 ml.) The combined aqueous extract was washed with ether (2×200 ml.), re-acidified with 6N hydrochloric acid extracted again with ether (2×400 ml.) The combined ether extract was dried (MgSO4) filtered evaporated under vacuum to an oil, which was crystallized by dissolution in hexane (100 ml.) crystallization (48 g., 70% yield, m.p. 98°-99° C., elemental analysis calculated: 69.50% C; 5.22% H; 5.78% F; found: 69.34% C; 5.36% H; 6.09% F)

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

Procedure: 180 mg of the title compound were prepared as described for [3,5-difluoro-4-((R)-octahydropyrido[1,2-a]pyrazin-2-yl)phenyl]-[phenyl]methanone, using 4-fluorobenzophenone instead of 3,4,5-trifluorobenzophenone.