tert-butyl N-[(3S,4R)-4-methylpyrrolidin-3-yl]carbamate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.11 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.082 g), DBU (0.054 g) and anhydrous acetonitrile (5 ml) was refluxed for 1.5 hours and then concentrated. The resulting residue was dissolved in chloroform (50 ml) and washed with 10% aqueous citric acid solution and water successively. The organic layer was concentrated under reduced pressure and to the oily residue was added methanol to crystallize. The resulting precipitate was collected by filtration, washed with chilled methanol and this was added to concentrated hydrochloric acid-methanol (1:1, 2 ml) and stirred for an hour at room temperature. The reacting mixture was neutralized with concentrated aqueous ammonia, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:concentrated aqueous ammonia=20:6:1) and then recrystallized from dichloromethanemethanol (1:1) to give the title compound (0.04 g) as pale yellow powder, mp 186°-190° C. (decompd.). was refluxed for 1.5 hours concentrated The resulting residue was dissolved in chloroform (50 ml) washed with 10% aqueous citric acid solution and water successively The organic layer was concentrated under reduced pressure and to the oily residue was added methanol to crystallize The resulting precipitate was collected by filtration washed with chilled methanol this was added to concentrated hydrochloric acid-methanol (1:1, 2 ml) concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography (chloroform:methanol:concentrated aqueous ammonia=20:6:1) recrystallized from dichloromethanemethanol (1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.4 g), anhydrous acetonitrile (4 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.43 g) and DBU (0.22 g) was refluxed for an hour. After cooling, the resulting precipitate was collected by filtration and washed with acetonitrile and ethanol successively to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.34 g) as white yellowish powder, mp 237°-240° C. (decompd.). was refluxed for an hour After cooling the resulting precipitate was collected by filtration washed with acetonitrile and ethanol successively

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.4 g), anhydrous acetonitrile (4 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.43 g) and DBU (0.22 g) was refluxed for an hour. After cooling, the resulting precipitate was collected by filtration and washed with acetonitrile and ethanol successively to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.34 g) as white yellowish powder, mp 237°-240° C. (decompd.). was refluxed for an hour After cooling the resulting precipitate was collected by filtration washed with acetonitrile and ethanol successively

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (2.2 g), anhydrous acetonitrile (22 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (reference example 5; 2.4 g) and DBU (1.22 g) was refluxed for 5 hours. The reacting mixture was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with 10% aqueous citric acid solution. The chloroform layer was further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot methanol (20 ml) and, after cooling, the resulting precipitate was collected by filtration to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (3.62 g) as yellow needle, mp 210°-213° C. (decompd.). was refluxed for 5 hours The reacting mixture was concentrated under reduced pressure the resulting residue was dissolved in chloroform washed with 10% aqueous citric acid solution The chloroform layer was further washed with saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was dissolved in hot methanol (20 ml) after cooling the resulting precipitate was collected by filtration

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 1-benzyl-trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (4.8 g) and 10% palladium-on-charcoal (1.8 g) in ethanol (40 ml) was shaken with hydrogen were absorbed under elevated pressure (100 kg/cm2) at 50°-70° C. for 6.5 hours. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (3.09 g) as brown oil. This oil was gradually solidified at room temperature. were absorbed under elevated pressure (100 kg/cm2) at 50°-70° C. for 6.5 hours The catalyst was removed by filtration the filtrate was evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the presence of triethylamine, 59 g of benzoyl chloride was reacted at room temperature with 81.4 g of trans-3-tert-butoxycarbonylamino-4-methylpyrrolidine in methylene chloride, whereby 120 g of trans-3-tert-butoxycarbonylamino-4-methyl-1-benzoylpyrrolidine (a) was obtained. Hydrochloric acid was then reacted at room temperature with 123 g of the compound (a) in ethanol, so that 83 g of trans-3-amino-4-methyl-1-benzoylpyrrolidine (b) was obtained. In methylene chloride, 68.4 g of (R)-(-)mandelic acid was then reacted at room temperature with 83 g of the compound (b) in the presence of 87.3 g o 1-hydroxybenzotriazole, 87.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 46.5 g of triethylamine. 34 g of trans-3-(2-(R)-2-phenyl-2-hydroxyacetylamino)-4-methyl-1-benzoylpyrrolidine diastereomer (A), (c) was obtained. Acetic acid and hydrochloric acid were then reacted with the compound (c) under reflux, whereby 16.8 g of (-)-trans-3-amino-4-methylpyrrolidine dihydrochloride was obtained as a colorless solid.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the presence of triethylamine, 59 g of benzoyl chloride was reacted at room temperature with 81.4 g of trans-3-tert-butoxycarbonylamino-4-methylpyrrolidine in methylene chloride, whereby 120 g of trans-3-tert-butoxycarbonylamino-4-methyl-1-benzoylpyrrolidine (a) was obtained. Hydrochloric acid was then reacted at room temperature with 123 g of the compound (a) in ethanol, so that 83 g of trans-3-amino-4-methyl-1-benzoylpyrrolidine (b) was obtained. In methylene chloride, 68.4 g of (R)-(-)mandelic acid was then reacted at room temperature with 83 g of the compound (b) in the presence of 87.3 g o 1-hydroxybenzotriazole, 87.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 46.5 g of triethylamine. 34 g of trans-3-(2-(R)-2-phenyl-2-hydroxyacetylamino)-4-methyl-1-benzoylpyrrolidine diastereomer (A), (c) was obtained. Acetic acid and hydrochloric acid were then reacted with the compound (c) under reflux, whereby 16.8 g of (-)-trans-3-amino-4-methylpyrrolidine dihydrochloride was obtained as a colorless solid.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (0.40 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.41 g), DBU (0.21 g) and anhydrous acetonitrile (5 ml) was refluxed for 2.5 hours and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform (40 ml) and washed with 10% aqueous citric acid solution (20 ml) and with saturated saline (20 ml) successively. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was crystallized from ethanol to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. To a suspension of these crystals in methanol (5 ml) was added concentrated hydrochloric acid (5 ml) dropwise. After stirring for 1.5 hours at room temperature, the reaction mixture was neutralized with concentrated aqueous ammonia, the resulting crystals were collected by filtration and washed with water sufficiently to give the title compound (0.29 g) as colorless powder, mp 214°-215° C. was refluxed for 2.5 hours the reaction mixture was concentrated under reduced pressure The residue was dissolved in chloroform (40 ml) washed with 10% aqueous citric acid solution (20 ml) and with saturated saline (20 ml) successively The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was crystallized from ethanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.11 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.082 g), DBU (0.054 g) and anhydrous acetonitrile (5 ml) was refluxed for 1.5 hours and then concentrated. The resulting residue was dissolved in chloroform (50 ml) and washed with 10% aqueous citric acid solution and water successively. The organic layer was concentrated under reduced pressure and to the oily residue was added methanol to crystallize. The resulting precipitate was collected by filtration, washed with chilled methanol and this was added to concentrated hydrochloric acid-methanol (1:1, 2 ml) and stirred for an hour at room temperature. The reacting mixture was neutralized with concentrated aqueous ammonia, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:concentrated aqueous ammonia=20:6:1) and then recrystallized from dichloromethanemethanol (1:1) to give the title compound (0.04 g) as pale yellow powder, mp 186°-190° C. (decompd.). was refluxed for 1.5 hours concentrated The resulting residue was dissolved in chloroform (50 ml) washed with 10% aqueous citric acid solution and water successively The organic layer was concentrated under reduced pressure and to the oily residue was added methanol to crystallize The resulting precipitate was collected by filtration washed with chilled methanol this was added to concentrated hydrochloric acid-methanol (1:1, 2 ml) concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography (chloroform:methanol:concentrated aqueous ammonia=20:6:1) recrystallized from dichloromethanemethanol (1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.4 g), anhydrous acetonitrile (4 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.43 g) and DBU (0.22 g) was refluxed for an hour. After cooling, the resulting precipitate was collected by filtration and washed with acetonitrile and ethanol successively to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.34 g) as white yellowish powder, mp 237°-240° C. (decompd.). was refluxed for an hour After cooling the resulting precipitate was collected by filtration washed with acetonitrile and ethanol successively

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (2.2 g), anhydrous acetonitrile (22 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (reference example 5; 2.4 g) and DBU (1.22 g) was refluxed for 5 hours. The reacting mixture was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with 10% aqueous citric acid solution. The chloroform layer was further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot methanol (20 ml) and, after cooling, the resulting precipitate was collected by filtration to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (3.62 g) as yellow needle, mp 210°-213° C. (decompd.). was refluxed for 5 hours The reacting mixture was concentrated under reduced pressure the resulting residue was dissolved in chloroform washed with 10% aqueous citric acid solution The chloroform layer was further washed with saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was dissolved in hot methanol (20 ml) after cooling the resulting precipitate was collected by filtration

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 1-benzyl-trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (4.8 g) and 10% palladium-on-charcoal (1.8 g) in ethanol (40 ml) was shaken with hydrogen were absorbed under elevated pressure (100 kg/cm2) at 50°-70° C. for 6.5 hours. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (3.09 g) as brown oil. This oil was gradually solidified at room temperature. were absorbed under elevated pressure (100 kg/cm2) at 50°-70° C. for 6.5 hours The catalyst was removed by filtration the filtrate was evaporated