2-(fluoromethyl)piperazine

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

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

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 530.4 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 590.7 mg of 2-(fluoromethyl)piperazine and 2 ml of pyridine was heated at 115° C. for 30 minutes, then filtered and the filtrate refrigerated overnight. The resulting crystals were collected, washed with water, ether and dried, giving 262 mg of the desired compound as light yellow crystals, mp 202°-203° C. filtered the filtrate refrigerated overnight The resulting crystals were collected washed with water, ether dried

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

Procedure: A mixture of 650 mg of 2-(fluoromethyl)piperazine, 500 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was stirred under nitrogen in a capped bottle at for 2.5 hours. The solvent was removed and the residue triturated with methanol. The solid was collected, washed twice with methanol and dried, giving 376 mg of racemic 1-ethyl-6,8-difluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxlic acid. The solvent was removed the residue triturated with methanol The solid was collected washed twice with methanol dried

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

Procedure: A mixture of 650 mg of 2-(fluoromethyl)piperazine, 500 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was stirred under nitrogen in a capped bottle at for 2.5 hours. The solvent was removed and the residue triturated with methanol. The solid was collected, washed twice with methanol and dried, giving 376 mg of racemic 1-ethyl-6,8-difluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxlic acid. The solvent was removed the residue triturated with methanol The solid was collected washed twice with methanol dried

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

Procedure: A mixture of 500 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, 650 mg of racemic 3-fluoromethylpiperazine and 5 ml of pyridine was stirred at 80° C. in a sealed bottle under nitrogen for 2.5 hours. The solvents were removed and the residue triturated with methanol. The solid was collected, washed with methanol and dried, giving 376 mg of the desired product, mp 230°-235° C. (dec.). The solvents were removed the residue triturated with methanol The solid was collected washed with methanol dried

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

Procedure: A mixture of 500 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, 650 mg of racemic 3-fluoromethylpiperazine and 5 ml of pyridine was stirred at 80° C. in a sealed bottle under nitrogen for 2.5 hours. The solvents were removed and the residue triturated with methanol. The solid was collected, washed with methanol and dried, giving 376 mg of the desired product, mp 230°-235° C. (dec.). The solvents were removed the residue triturated with methanol The solid was collected washed with methanol dried

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

Procedure: To a solution of 1-(cyclohexyl)methyl-7-methoxy-indole-3-carboxylic acid (0.59 g, 2.04 mmol, prepared following the method in Example 1) and 2-(fluoromethyl) piperazine (0.37 g, 3.15 mmol) in dichloromethane (15 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.47 g, 2.45 mmol) and 1-hydroxy benzotriazole (0.07 g, 0.51 mmol). The mixture was stirred at room temperature for 18 h and evaporated. The residue was purified by flash chromatography eluting with 0-10% (v/v) methanol in dichloromethane to afford the title compound (free base) as a colourless oil (0.47 g). The free base (0.05 g) was dissolved in diethyl ether (3 ml) and treated dropwise with 2 M hydrochloric acid in diethyl ether (1 ml). The resulting precipitate was collected by filtration, washed with diethyl ether (10 ml) and dried under reduced pressure to afford the title compound (1:1 hydrochloric acid salt) as a colourless solid (0.05 g, 0.12 mmol). 1H NMR (400 MHz, CD3OD) δH 0.98-1.27 (5H, m), 1.57 (2H, br d, J 12.9), 1.63-1.90 (4H, m), 3.21-3.53 (4H, m), 3.68-3.79 (1H, m) 3.95 (3H, s), 4.26 (2H, d, J 7.1), 4.43-4.82 (4H, m), 6.77 (1H, d, J 7.7), 7.11 (1H, t, J 7.5), 7.27 (1H, d, J 8.0), 7.57 (1H, s); EIMS: m/z 270.2 [Fragment+H]+. evaporated The residue was purified by flash chromatography eluting with 0-10% (v/v) methanol in dichloromethane

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

Procedure: In the same manner as described in Example 1, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro4-oxoquinoline-3-carboxylic acid, 2-fluoromethylpiperazine, and dioxane was refluxed for 5 hours to give 1-cyclopropyl-5,6,8-trifluoro-7-(3-fluoromethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, which was recrystallized from chloroform, m.p. 219°-220° C. was refluxed for 5 hours

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 530.4 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 590.7 mg of 2-(fluoromethyl)piperazine and 2 ml of pyridine was heated at 115° C. for 30 minutes, then filtered and the filtrate refrigerated overnight. The resulting crystals were collected, washed with water, ether and dried, giving 262 mg of the desired compound as light yellow crystals, mp 202°-203° C. filtered the filtrate refrigerated overnight The resulting crystals were collected washed with water, ether dried

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

Procedure: A mixture of 650 mg of 2-(fluoromethyl)piperazine, 500 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was stirred under nitrogen in a capped bottle at for 2.5 hours. The solvent was removed and the residue triturated with methanol. The solid was collected, washed twice with methanol and dried, giving 376 mg of racemic 1-ethyl-6,8-difluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxlic acid. The solvent was removed the residue triturated with methanol The solid was collected washed twice with methanol dried

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

Procedure: A mixture of 500 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, 650 mg of racemic 3-fluoromethylpiperazine and 5 ml of pyridine was stirred at 80° C. in a sealed bottle under nitrogen for 2.5 hours. The solvents were removed and the residue triturated with methanol. The solid was collected, washed with methanol and dried, giving 376 mg of the desired product, mp 230°-235° C. (dec.). The solvents were removed the residue triturated with methanol The solid was collected washed with methanol dried