N-[[(3R,4S)-4-fluoropyrrolidin-3-yl]methyl]cyclopropanamine

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

Procedure: Using ethyl 6,7,8-trifluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylate (50.0 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (29.0 mg), the same procedure was followed as in Example 40 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylic acid as a pale yellow powder (25.1 mg).

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

Procedure: Using ethyl 6,7-difluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylate (309 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 40 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (91.3 mg).

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

Procedure: Ethyl 7-chloro-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylate (327 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (160 mg) and acetonitrile (5 mL) were mixed together. The reaction mixture was stirred at 80° C. for 1 hour and was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (30 ml), washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:acetone=2:1->1:1->dichloromethane:methanol=10:1). The eluted pale yellow solid was dissolved in ethanol (4 mL), followed by addition of a 10% aqueous solution of sodium hydroxide (4 mL), stirring at 60° C. for 70 min, and concentration under reduced pressure. The resulting residue was diluted with water (10 mL), neutralized with 1 mol/L hydrochloric acid (pH 7.5), and extracted with dichloromethane (2×30 mL). The dichloromethane extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:methanol=10:1) to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid as white crystals (141 mg). was concentrated under reduced pressure The resulting residue was dissolved in dichloromethane (30 ml) washed sequentially with water and saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:acetone=2:1->1:1->dichloromethane:methanol=10:1) The eluted pale yellow solid was dissolved in ethanol (4 mL) followed by addition of a 10% aqueous solution of sodium hydroxide (4 mL) stirring at 60° C. for 70 min concentration under reduced pressure The resulting residue was diluted with water (10 mL) extracted with dichloromethane (2×30 mL) washed with saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:methanol=10:1)

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

Procedure: Using 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (20.0 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (15.2 mg), the same procedure was followed as in Example 36 to give 5-amino-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid as a yellow solid (9.6 mg).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (250 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), triethylamine (0.17 mL) and dimethylsulfoxide (4 mL) were mixed together. The mixture was stirred at 100° C. for 9 hours and was subsequently concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=40:1). The eluted yellow solid was recrystallized from ethanol to give 5-amino-1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid as yellow crystals (248 mg). was subsequently concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=40:1) The eluted yellow solid was recrystallized from ethanol

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

Procedure: Using 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (318 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 8-chloro-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a yellow solid (93.6 mg).

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

Procedure: Using 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (301 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (231 mg).

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

Procedure: Using 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (283 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (203 mg).

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

Procedure: Using 7-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (200 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (116 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid as pale yellow crystals (101 mg).

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

Procedure: Using 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (300 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 8-chloro-1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow solid (218 mg).

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

Procedure: Using 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (212 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (142 mg), the same procedure was followed as in Example 23 to give 1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow crystals (157 mg).

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

Procedure: Using 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (199 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (131 mg), the same procedure was followed as in Example 23 to give 1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (148 mg).