2-methyl-2,5-diazabicyclo[2.2.1]heptane

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:

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

Procedure: 15 g (37.36 m Mol) of the mixed anhydride of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and difluoroboronic acid (obtained by heating 7-chloro-6-fluoro-1-(2.4-difluoro- phenyl)-1,4-dihycho-4-oxoquinoline-3-carboxylic acid in 60% aqueous fluoroboronic acid 15.36 g (56 m Mol) of the dihydrobromide of 2-methyl-2,5-diazabicyclo-(2.2.1)heptane and 31 ml (0.224 mol) triethylamine was stirred in 200 ml of dry DMSO at room temperature for 6 days. Then the reaction mixture was poured into 800 ml of cold water and the resultant precipitate collected by filtration washed with water and then heated to reflux with stirring in a mixture of 100 ml dioxane and 150 ml 3N NaOH for 1 hr. After cooling and with stirring, 500 ml of conc. HCl was added. After stirring for 1 hr., the undissolved material was removed by filtration, to give a clear solution which was extracted multiple times with methylene chloride. The aqueous phase was cooled in an ice bath and brought to pH 7.4 by the addition of dilute NaOH. The resultant was extracted with chloroform and the chloroform phase dried over sodium sulfate and the chloroform removed in vacuo, the resulting dark brown oil was recrystallized from 450 ml ethanol to give 3.15 g (18.8%) of the product as a hydrate, mp 215° C.-220° C. dec. the resultant precipitate collected by filtration washed with water heated to reflux After cooling with stirring 500 ml of conc. HCl was added After stirring for 1 hr , the undissolved material was removed by filtration to give a clear solution which was extracted multiple times with methylene chloride The aqueous phase was cooled in an ice bath brought to pH 7.4 by the addition of dilute NaOH The resultant was extracted with chloroform the chloroform phase dried over sodium sulfate the chloroform removed in vacuo the resulting dark brown oil was recrystallized from 450 ml ethanol

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: A solution of 2-methyl-2,5-diaza-bicyclo[2.2.1]heptane (0.4402 g, 1.6 mmol), p-fluoro-nitrobenzene (0.56 mL, 5.4 mmol), N,N-diisopropylethylamine (0.84 mL, 4.82 mmol) in 5 mL of acetonitrile is heated at 100° C. overnight. After the solvent is removed, the residue is treated with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane to yield 0.246 g (65% yield) of 2-methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane. After the solvent is removed the residue is treated with saturated sodium bicarbonate solution extracted with chloroform The organic layer is washed with brine dried over magnesium sulfate filtered evaporated to dryness The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane

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

Procedure: A solution of 2-methyl-2,5-diaza-bicyclo[2.2.1]heptane (0.4402 g, 1.6 mmol), p-fluoro-nitrobenzene (0.56 mL, 5.4 mmol), N,N-diisopropylethylamine (0.84 mL, 4.82 mmol) in 5 mL of acetonitrile is heated at 100° C. overnight. After the solvent is removed, the residue is treated with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane to yield 0.246 g (65% yield) of 2-methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane. After the solvent is removed the residue is treated with saturated sodium bicarbonate solution extracted with chloroform The organic layer is washed with brine dried over magnesium sulfate filtered evaporated to dryness The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane

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

Procedure: A solution of 2-methyl-2,5-diaza-bicyclo[2.2.1]heptane (0.4402 g, 1.6 mmol), p-fluoro-nitrobenzene (0.56 mL, 5.4 mmol), N,N-diisopropylethylamine (0.84 mL, 4.82 mmol) in 5 mL of acetonitrile is heated at 100° C. overnight. After the solvent is removed, the residue is treated with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane to yield 0.246 g (65% yield) of 2-methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane. After the solvent is removed the residue is treated with saturated sodium bicarbonate solution extracted with chloroform The organic layer is washed with brine dried over magnesium sulfate filtered evaporated to dryness The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane