(2-aminophenyl)-(4-fluorophenyl)methanone

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

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

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

Procedure: A solution of 4-bromofluorobenzene (1 eq.) in THF was cooled to −78° C. under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The internal temperature did not rise above −74° C. The orange solution was stirred at −78° C. for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as a solution in THF. The reaction was warmed to 0° C. and stirred for 2 hours. 3N HCl was added to the mixture and stirring continued for 30 minutes. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted thrice with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 93:7 hexanes/ethyl acetate. did not rise above −74° C The reaction was warmed to 0° C. stirred for 2 hours stirring continued for 30 minutes the layers were separated The aqueous layer was back-extracted thrice with ethyl acetate The combined extracts were washed with brine dried over Na2SO4 filtered concentrated The residue was purified via HPLC eluting with 93:7 hexanes/ethyl acetate

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

Procedure: A stirred mixture of 35 g (0.163 mole) of 2-amino-4'-fluorobenzophenone and 27 g (0.21 mole) of 3-amino-2-chloropyridine was heated at 175°-180° C. for 2.5 hr. The mixture was allowed to cool to 110° C., after which 100 ml of hot toluene was added. On cooling to 50° C., 50 ml of methylene chloride was added. The solvent layer was decanted, leaving a black solid mass which was dissolved in hot methanol. The solution volume was reduced by one half and allowed to stand overnight at room temperature. The mixture was filtered and the filter cake washed twice by suspending in methylene chloride. The weight of crude solid produced was 22.5 g. The solid was dissolved in methanol and basified with 50% aqueous sodium hydroxide. The mixture was extracted with methylene chloride and the extract dried and concentrated. The residue was twice crystallized from isopropyl alcohol, decolorizing by boiling with charcoal the second time, to give 14 g (28%) solid which was red-orange in color; m.p. 121.5°-122.5° C. was heated at 175°-180° C. for 2.5 hr On cooling to 50° C. The solvent layer was decanted leaving a black solid mass which The mixture was filtered the filter cake washed twice The weight of crude solid produced The mixture was extracted with methylene chloride the extract dried concentrated The residue was twice crystallized from isopropyl alcohol

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

Procedure: A stirred mixture of 35 g (0.163 mole) of 2-amino-4'-fluorobenzophenone and 27 g (0.21 mole) of 3-amino-2-chloropyridine was heated at 175°-180° C. for 2.5 hr. The mixture was allowed to cool to 110° C., after which 100 ml of hot toluene was added. On cooling to 50° C., 50 ml of methylene chloride was added. The solvent layer was decanted, leaving a black solid mass which was dissolved in hot methanol. The solution volume was reduced by one half and allowed to stand overnight at room temperature. The mixture was filtered and the filter cake washed twice by suspending in methylene chloride. The weight of crude solid produced was 22.5 g. The solid was dissolved in methanol and basified with 50% aqueous sodium hydroxide. The mixture was extracted with methylene chloride and the extract dried and concentrated. The residue was twice crystallized from isopropyl alcohol, decolorizing by boiling with charcoal the second time, to give 14 g (28%) solid which was red-orange in color; m.p. 121.5°-122.5° C. was heated at 175°-180° C. for 2.5 hr On cooling to 50° C. The solvent layer was decanted leaving a black solid mass which The mixture was filtered the filter cake washed twice The weight of crude solid produced The mixture was extracted with methylene chloride the extract dried concentrated The residue was twice crystallized from isopropyl alcohol

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

Procedure: A stirred mixture of 35 g (0.163 mole) of 2-amino-4'-fluorobenzophenone and 27 g (0.21 mole) of 3-amino-2-chloropyridine was heated at 175°-180° C. for 2.5 hr. The mixture was allowed to cool to 110° C., after which 100 ml of hot toluene was added. On cooling to 50° C., 50 ml of methylene chloride was added. The solvent layer was decanted, leaving a black solid mass which was dissolved in hot methanol. The solution volume was reduced by one half and allowed to stand overnight at room temperature. The mixture was filtered and the filter cake washed twice by suspending in methylene chloride. The weight of crude solid produced was 22.5 g. The solid was dissolved in methanol and basified with 50% aqueous sodium hydroxide. The mixture was extracted with methylene chloride and the extract dried and concentrated. The residue was twice crystallized from isopropyl alcohol, decolorizing by boiling with charcoal the second time, to give 14 g (28%) solid which was red-orange in color; m.p. 121.5°-122.5° C. was heated at 175°-180° C. for 2.5 hr On cooling to 50° C. The solvent layer was decanted leaving a black solid mass which The mixture was filtered the filter cake washed twice The weight of crude solid produced The mixture was extracted with methylene chloride the extract dried concentrated The residue was twice crystallized from isopropyl alcohol

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

Procedure: A stirred mixture of 35 g (0.163 mole) of 2-amino-4'-fluorobenzophenone and 27 g (0.21 mole) of 3-amino-2-chloropyridine was heated at 175°-180° C. for 2.5 hr. The mixture was allowed to cool to 110° C., after which 100 ml of hot toluene was added. On cooling to 50° C., 50 ml of methylene chloride was added. The solvent layer was decanted, leaving a black solid mass which was dissolved in hot methanol. The solution volume was reduced by one half and allowed to stand overnight at room temperature. The mixture was filtered and the filter cake washed twice by suspending in methylene chloride. The weight of crude solid produced was 22.5 g. The solid was dissolved in methanol and basified with 50% aqueous sodium hydroxide. The mixture was extracted with methylene chloride and the extract dried and concentrated. The residue was twice crystallized from isopropyl alcohol, decolorizing by boiling with charcoal the second time, to give 14 g (28%) solid which was red-orange in color; m.p. 121.5°-122.5° C. was heated at 175°-180° C. for 2.5 hr On cooling to 50° C. The solvent layer was decanted leaving a black solid mass which The mixture was filtered the filter cake washed twice The weight of crude solid produced The mixture was extracted with methylene chloride the extract dried concentrated The residue was twice crystallized from isopropyl alcohol

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of 2-amino-4′-fluorobenzophenone (100 g) in acetic acid (500 ml) added methyl 3-cyclopropyl-3-oxopropanoate (132 g), sulfuric acid (5 ml) and stirred for 15 minutes at 25° C. Heated the reaction mixture to 100° C. for 10 hrs. Cooled the reaction mixture to 0-5° C. and pH adjusted to neutral conditions with 40% sodium hydroxide solution. Filtered the solid formed and washed with water. The wet solid was dissolved in methylene chloride and separated the water from it. Silica slurry was given to the reaction mixture and filtered it. Methylene chloride was distilled off and the compound was co-distilled with methanol. To the compound added methanol (150 ml) and stirred for 1 hr at 25° C. Filtered the solid and washed with methanol (50 ml). Dried the obtained solid to get the title compound. Heated the reaction mixture to 100° C. for 10 hrs Cooled the reaction mixture to 0-5° C. Filtered the solid formed washed with water The wet solid was dissolved in methylene chloride separated the water from it filtered it Methylene chloride was distilled off To the compound added methanol (150 ml) stirred for 1 hr at 25° C Filtered the solid washed with methanol (50 ml) Dried the obtained solid

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of 2-amino-4′-fluorobenzophenone (100 g) in acetic acid (500 ml) added methyl 3-cyclopropyl-3-oxopropanoate (132 g), sulfuric acid (5 ml) and stirred for 15 minutes at 25° C. Heated the reaction mixture to 100° C. for 10 hrs. Cooled the reaction mixture to 0-5° C. and pH adjusted to neutral conditions with 40% sodium hydroxide solution. Filtered the solid formed and washed with water. The wet solid was dissolved in methylene chloride and separated the water from it. Silica slurry was given to the reaction mixture and filtered it. Methylene chloride was distilled off and the compound was co-distilled with methanol. To the compound added methanol (150 ml) and stirred for 1 hr at 25° C. Filtered the solid and washed with methanol (50 ml). Dried the obtained solid to get the title compound. Heated the reaction mixture to 100° C. for 10 hrs Cooled the reaction mixture to 0-5° C. Filtered the solid formed washed with water The wet solid was dissolved in methylene chloride separated the water from it filtered it Methylene chloride was distilled off To the compound added methanol (150 ml) stirred for 1 hr at 25° C Filtered the solid washed with methanol (50 ml) Dried the obtained solid

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of 2-amino-4′-fluorobenzophenone (100 g) in methanol (500 ml) added Methyl 3-cyclopropyl-3-oxopropanoate (132 g), sulfuric acid (5 ml) and stirred for 15 minutes at 25° C. Heated the reaction mixture to 65° C. for 22 hrs. Distilled off the methanol completely under reduced pressure. Cooled the reaction mixture to 25° C., added water (500 ml) and stirred for 30 minutes. Cooled the reaction mixture to 0° C. and pH adjusted to 6.0 with sodium carbonate solution. Stirred the reaction mixture for 45 minutes at 25° C. Filtered the cake and washed with water. Spin dry the compound for 60 minutes. To this compound added methanol (150 ml) and stirred for 1 hr at 25° C. Filtered the solid and washed with methanol (50 ml). Dried the obtained solid to get the title compound. Heated the reaction mixture to 65° C. for 22 hrs Distilled off the methanol completely under reduced pressure Cooled the reaction mixture to 25° C. added water (500 ml) stirred for 30 minutes Cooled the reaction mixture to 0° C. Stirred the reaction mixture for 45 minutes at 25° C Filtered the cake washed with water Spin dry the compound for 60 minutes To this compound added methanol (150 ml) stirred for 1 hr at 25° C Filtered the solid washed with methanol (50 ml) Dried the obtained solid

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

Procedure: A solution of 4-bromofluorobenzene (1 eq.) in THF was cooled to −78° C. under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The internal temperature did not rise above −74° C. The orange solution was stirred at −78° C. for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as a solution in THF. The reaction was warmed to 0° C. and stirred for 2 hours. 3N HCl was added to the mixture and stirring continued for 30 minutes. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted thrice with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 93:7 hexanes/ethyl acetate. did not rise above −74° C The reaction was warmed to 0° C. stirred for 2 hours stirring continued for 30 minutes the layers were separated The aqueous layer was back-extracted thrice with ethyl acetate The combined extracts were washed with brine dried over Na2SO4 filtered concentrated The residue was purified via HPLC eluting with 93:7 hexanes/ethyl acetate

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

Procedure: 47.9 g of methyl 3-cyclopropyl-3-oxopropionate and 100 g of 2-amino-4′-fluorobenzophenone methanesulfonate were added to 584 g of toluene, and the mixture was dehydrated and refluxed at an internal temperature of 79 to 81° C. under a reduced pressure of 40 kPa. The reaction mixture was analyzed with HPLC during the reaction, and methyl 3-cyclopropyl-3-oxopropionate was added thereto by dividing it into several parts until the residual amount of 2-amino-4′-fluorobenzophenone was less than 2%. An additional amount of methyl 3-cyclopropyl-3-oxopropionate was 13.8 g. After 40 hours of reaction time, the residual amount of 2-amino-4′-fluorobenzophenone was 1.7%. The reaction solution was washed with 320 g of 4% aqueous solution of sodium hydroxide and then 140 g of 2% aqueous solution of sodium hydroxide. The reaction solution was further washed with 100 g of 5% brine solution, and then dried over 10 g of anhydrous magnesium sulfate. Toluene was removed under a reduced pressure, and crystallization was carried out in 740 g of cyclohexane to obtain 88.4 g of methyl 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carboxylate. was added After 40 hours of reaction time The reaction solution was washed with 320 g of 4% aqueous solution of sodium hydroxide The reaction solution was further washed with 100 g of 5% brine solution dried over 10 g of anhydrous magnesium sulfate Toluene was removed under a reduced pressure, and crystallization