(2-fluorophenyl)-piperazin-1-ylmethanone

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

Procedure: A mixture of 4.5 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 6 parts of 1-(2-fluorobenzoyl)piperazine, 2-phenylhydrazine, 5.04 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred overnight at reflux temperature. The inorganic salts were filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.5 parts (25.8) of 3-[2-[4-[(2-fluorophenyl)(2-phenylhydrazono)methyl]-1-piperazinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 180° C. (int. 10). at reflux temperature The inorganic salts were filtered off the filtrate was evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions were collected the eluent was evaporated The residue was crystallized from 2-propanol The product was filtered off dried

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

Procedure: A mixture of 4.5 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 6 parts of 1-(2-fluorobenzoyl)piperazine, 2-phenylhydrazine, 5.04 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred overnight at reflux temperature. The inorganic salts were filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.5 parts (25.8) of 3-[2-[4-[(2-fluorophenyl)(2-phenylhydrazono)methyl]-1-piperazinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 180° C. (int. 10). at reflux temperature The inorganic salts were filtered off the filtrate was evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions were collected the eluent was evaporated The residue was crystallized from 2-propanol The product was filtered off dried

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

Procedure: To a stirred mixture of 12.5 parts of piperazine, 3.6 parts of N,N-diethylethanamine and 75 parts of trichloromethane was added a solution of 9 parts of 2-fluoro-N-phenyl-benzenecarbohydrazonoyl chloride in 75 parts of trichloromethane. The whole was stirred for 2 hours at room temperature. After the addition of 5 parts of potassium carbonate, the reaction mixture was stirred for 30 minutes at reflux temperature. The mixture was cooled, washed with 100 parts of water and the layers were separated. The organic layer was dried, filtered and evaporated, yielding 6 parts (55.8%) of 1-(2-fluorobenzoyl)-piperazine, 2-phenylhydrazine as a residue (int. 9). the reaction mixture was stirred for 30 minutes at reflux temperature The mixture was cooled washed with 100 parts of water the layers were separated The organic layer was dried filtered evaporated

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

Procedure: Add (2-fluoro-phenyl)-piperazin-1-yl-methanone (3.16 g, 12.9 mmol) and K2CO3 (8.9 g, 64.5 mmol) to 1-chloro-4-nitroisoquinoline (2.85 g, 13.7 mmol) in acetonitrile (100 mL) and stir for 24 hours. Filter the insoluble solid and wash the cake with AcOEt. Evaporate the solvent under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexane:AcOEt 20-90% to give 3.72 g of (2-fluoro-phenyl)-[4-(4-nitro-isoquinolin-1-yl)-piperazin-1-yl]-methanone as a solid. LCMS ES+(m/z) 381.2 [M+H]. Filter the insoluble solid wash the cake with AcOEt Evaporate the solvent under reduced pressure to give a residue Subject residue to silica gel chromatography eluting with hexane

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

Procedure: A mixture of 4.5 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 6 parts of 1-(2-fluorobenzoyl)piperazine, 2-phenylhydrazine, 5.04 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred overnight at reflux temperature. The inorganic salts were filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.5 parts (25.8) of 3-[2-[4-[(2-fluorophenyl)(2-phenylhydrazono)methyl]-1-piperazinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 180° C. (int. 10). at reflux temperature The inorganic salts were filtered off the filtrate was evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions were collected the eluent was evaporated The residue was crystallized from 2-propanol The product was filtered off dried

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

Procedure: To a stirred mixture of 12.5 parts of piperazine, 3.6 parts of N,N-diethylethanamine and 75 parts of trichloromethane was added a solution of 9 parts of 2-fluoro-N-phenylbenzenecarbohydrazonoyl chloride in 75 parts of trichloromethane. The whole was stirred for 2 hours at room temperature. After the addition of 5 parts of potassium carbonate, the reaction mixture was stirred for 30 minutes at reflux temperature. The mixture was cooled, washed with 100 parts of water and the layers were separated. The organic layer was dried, filtered and evaporated, yielding 6 parts (55.8%) of 1-(2-fluorobenzoyl)-piperazine, 2-phenylhydrazine as a residue (int. 9). the reaction mixture was stirred for 30 minutes at reflux temperature The mixture was cooled washed with 100 parts of water the layers were separated The organic layer was dried filtered evaporated

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

Procedure: A mixture of 4.5 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 6 parts of 1-(2-fluorobenzoyl)piperazine, 2-phenylhydrazine, 5.04 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred overnight at reflux temperature. The inorganic salts were filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.5 parts (25.8) of 3-[2-[4-[(2-fluorophenyl)(2-phenylhydrazono)methyl]-1-piperazinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 180° C. (int. 10). at reflux temperature The inorganic salts were filtered off the filtrate was evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions were collected the eluent was evaporated The residue was crystallized from 2-propanol The product was filtered off dried

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

Procedure: To a stirred mixture of 12.5 parts of piperazine, 3.6 parts of N,N-diethylethanamine and 75 parts of trichloromethane was added a solution of 9 parts of 2-fluoro-N-phenyl-benzenecarbohydrazonoyl chloride in 75 parts of trichloromethane. The whole was stirred for 2 hours at room temperature. After the addition of 5 parts of potassium carbonate, the reaction mixture was stirred for 30 minutes at reflux temperature. The mixture was cooled, washed with 100 parts of water and the layers were separated. The organic layer was dried, filtered and evaporated, yielding 6 parts (55.8%) of 1-(2-fluorobenzoyl)-piperazine, 2-phenylhydrazine as a residue (int. 9). the reaction mixture was stirred for 30 minutes at reflux temperature The mixture was cooled washed with 100 parts of water the layers were separated The organic layer was dried filtered evaporated

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

Procedure: Add (2-fluoro-phenyl)-piperazin-1-yl-methanone (3.16 g, 12.9 mmol) and K2CO3 (8.9 g, 64.5 mmol) to 1-chloro-4-nitroisoquinoline (2.85 g, 13.7 mmol) in acetonitrile (100 mL) and stir for 24 hours. Filter the insoluble solid and wash the cake with AcOEt. Evaporate the solvent under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexane:AcOEt 20-90% to give 3.72 g of (2-fluoro-phenyl)-[4-(4-nitro-isoquinolin-1-yl)-piperazin-1-yl]-methanone as a solid. LCMS ES+(m/z) 381.2 [M+H]. Filter the insoluble solid wash the cake with AcOEt Evaporate the solvent under reduced pressure to give a residue Subject residue to silica gel chromatography eluting with hexane