(2,6-difluorophenyl)-piperazin-1-ylmethanone

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

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

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

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

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

Procedure: Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.

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

Procedure: Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.

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

Procedure: Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.

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

Procedure: Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.

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

Procedure: Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.

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

Procedure: Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.

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

Procedure: Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.

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

Procedure: Charge (2,6-difluoro-phenyl)-piperazin-1-yl-methanone (1.07 equiv, 1.55 moles, 350.00 g), methanol (37.06 moles, 1.50 L, 1.19 kg), triethylamine (1.79 moles, 250.00 mL, 181.50 g), 6-chloro-2-methyl-3-nitro-pyridine (1.00 equiv, 1.45 moles, 250.00 g) to a 5 L flask with over head stirrer. Stir the reaction mixture at room temperature for 0.5 hours. Slowly heat to 60° C., and continue to stir at 60° C. overnight. Add water (750 mL) drop wise while maintaining the temperature at 60° C. Allow mixture to cool to room temperature. Filter and wash cake with 2:1 methanol/water 150 mL, then twice with MTBE. Dry under reduced pressure at 45° C. to obtain (2,6-difluoro-phenyl)-[4-(6-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone as a yellow solid (535 g). Slowly heat to 60° C. to stir at 60° C. overnight to cool to room temperature Filter wash cake with 2:1 methanol/water 150 mL Dry under reduced pressure at 45° C.