Danofloxacin (XI) is synthesized by the addition of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X), and further converted to its monomethanesulfonate salt as outlined in Scheme 17912701a: The diazabicycloalkane sidechain (VII) is prepared in one of two ways, both routes starting with trans-4-hydroxy-L-proline (I). In the first sequence, the amino acid (I) is selectively monotosylated on nitrogen by stirring an aqueous solution of (I) in the presence of p-toluenesulfonyl chloride (TsCl) with sodium carbonate as base. The monotosylate (II) is then reduced to the diol (III) with diborane generated in situ. The diol (III) is next converted to either the tritosylate (IV) selectively or to a mixture of (IV) and the monochloride (V) by treatment with excess TsCl in pyridine at either 0 C or room temperature, respectively. Either pure (IV) or a mixture of (IV) and (V) can be cyclized equally well to the bicyclic intermediate (VI) by treatment with methylamine in a sealed container. Finally, (VI) can be deprotected to give the desired (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) in excellent overall yield by treatment with 30% anhydrous hydrogen bromide in acetic acid. By an alternative route, (I) is esterified under Fischer conditions and treated with excess p-toluenesulfonyl chloride in the presence of pyridine and triethylamine. The resulting ester (VIII) is then treated with methylamine to obtain the amide (IX), which is reductively cyclized with lithium aluminum hydride to the bicyclic intermediate (VI). Finally, (VI) is deprotected as described above to give (VII). The reaction of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X) to give danofloxacin free base (XI) is effected by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in pyridine. Conversion of (XI) to danofloxacin mesylate using one equivalent of methanesulfonic acid in ethanol completes the synthesis.

Danofloxacin (XI) is synthesized by the addition of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X), and further converted to its monomethanesulfonate salt as outlined in Scheme 17912701a: The diazabicycloalkane sidechain (VII) is prepared in one of two ways, both routes starting with trans-4-hydroxy-L-proline (I). In the first sequence, the amino acid (I) is selectively monotosylated on nitrogen by stirring an aqueous solution of (I) in the presence of p-toluenesulfonyl chloride (TsCl) with sodium carbonate as base. The monotosylate (II) is then reduced to the diol (III) with diborane generated in situ. The diol (III) is next converted to either the tritosylate (IV) selectively or to a mixture of (IV) and the monochloride (V) by treatment with excess TsCl in pyridine at either 0 C or room temperature, respectively. Either pure (IV) or a mixture of (IV) and (V) can be cyclized equally well to the bicyclic intermediate (VI) by treatment with methylamine in a sealed container. Finally, (VI) can be deprotected to give the desired (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) in excellent overall yield by treatment with 30% anhydrous hydrogen bromide in acetic acid. By an alternative route, (I) is esterified under Fischer conditions and treated with excess p-toluenesulfonyl chloride in the presence of pyridine and triethylamine. The resulting ester (VIII) is then treated with methylamine to obtain the amide (IX), which is reductively cyclized with lithium aluminum hydride to the bicyclic intermediate (VI). Finally, (VI) is deprotected as described above to give (VII). The reaction of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X) to give danofloxacin free base (XI) is effected by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in pyridine. Conversion of (XI) to danofloxacin mesylate using one equivalent of methanesulfonic acid in ethanol completes the synthesis.

Danofloxacin (XI) is synthesized by the addition of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X), and further converted to its monomethanesulfonate salt as outlined in Scheme 17912701a: The diazabicycloalkane sidechain (VII) is prepared in one of two ways, both routes starting with trans-4-hydroxy-L-proline (I). In the first sequence, the amino acid (I) is selectively monotosylated on nitrogen by stirring an aqueous solution of (I) in the presence of p-toluenesulfonyl chloride (TsCl) with sodium carbonate as base. The monotosylate (II) is then reduced to the diol (III) with diborane generated in situ. The diol (III) is next converted to either the tritosylate (IV) selectively or to a mixture of (IV) and the monochloride (V) by treatment with excess TsCl in pyridine at either 0 C or room temperature, respectively. Either pure (IV) or a mixture of (IV) and (V) can be cyclized equally well to the bicyclic intermediate (VI) by treatment with methylamine in a sealed container. Finally, (VI) can be deprotected to give the desired (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) in excellent overall yield by treatment with 30% anhydrous hydrogen bromide in acetic acid. By an alternative route, (I) is esterified under Fischer conditions and treated with excess p-toluenesulfonyl chloride in the presence of pyridine and triethylamine. The resulting ester (VIII) is then treated with methylamine to obtain the amide (IX), which is reductively cyclized with lithium aluminum hydride to the bicyclic intermediate (VI). Finally, (VI) is deprotected as described above to give (VII). The reaction of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X) to give danofloxacin free base (XI) is effected by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in pyridine. Conversion of (XI) to danofloxacin mesylate using one equivalent of methanesulfonic acid in ethanol completes the synthesis.

Danofloxacin (XI) is synthesized by the addition of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X), and further converted to its monomethanesulfonate salt as outlined in Scheme 17912701a: The diazabicycloalkane sidechain (VII) is prepared in one of two ways, both routes starting with trans-4-hydroxy-L-proline (I). In the first sequence, the amino acid (I) is selectively monotosylated on nitrogen by stirring an aqueous solution of (I) in the presence of p-toluenesulfonyl chloride (TsCl) with sodium carbonate as base. The monotosylate (II) is then reduced to the diol (III) with diborane generated in situ. The diol (III) is next converted to either the tritosylate (IV) selectively or to a mixture of (IV) and the monochloride (V) by treatment with excess TsCl in pyridine at either 0 C or room temperature, respectively. Either pure (IV) or a mixture of (IV) and (V) can be cyclized equally well to the bicyclic intermediate (VI) by treatment with methylamine in a sealed container. Finally, (VI) can be deprotected to give the desired (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) in excellent overall yield by treatment with 30% anhydrous hydrogen bromide in acetic acid. By an alternative route, (I) is esterified under Fischer conditions and treated with excess p-toluenesulfonyl chloride in the presence of pyridine and triethylamine. The resulting ester (VIII) is then treated with methylamine to obtain the amide (IX), which is reductively cyclized with lithium aluminum hydride to the bicyclic intermediate (VI). Finally, (VI) is deprotected as described above to give (VII). The reaction of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X) to give danofloxacin free base (XI) is effected by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in pyridine. Conversion of (XI) to danofloxacin mesylate using one equivalent of methanesulfonic acid in ethanol completes the synthesis.

Danofloxacin (XI) is synthesized by the addition of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X), and further converted to its monomethanesulfonate salt as outlined in Scheme 17912701a: The diazabicycloalkane sidechain (VII) is prepared in one of two ways, both routes starting with trans-4-hydroxy-L-proline (I). In the first sequence, the amino acid (I) is selectively monotosylated on nitrogen by stirring an aqueous solution of (I) in the presence of p-toluenesulfonyl chloride (TsCl) with sodium carbonate as base. The monotosylate (II) is then reduced to the diol (III) with diborane generated in situ. The diol (III) is next converted to either the tritosylate (IV) selectively or to a mixture of (IV) and the monochloride (V) by treatment with excess TsCl in pyridine at either 0 C or room temperature, respectively. Either pure (IV) or a mixture of (IV) and (V) can be cyclized equally well to the bicyclic intermediate (VI) by treatment with methylamine in a sealed container. Finally, (VI) can be deprotected to give the desired (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) in excellent overall yield by treatment with 30% anhydrous hydrogen bromide in acetic acid. By an alternative route, (I) is esterified under Fischer conditions and treated with excess p-toluenesulfonyl chloride in the presence of pyridine and triethylamine. The resulting ester (VIII) is then treated with methylamine to obtain the amide (IX), which is reductively cyclized with lithium aluminum hydride to the bicyclic intermediate (VI). Finally, (VI) is deprotected as described above to give (VII). The reaction of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X) to give danofloxacin free base (XI) is effected by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in pyridine. Conversion of (XI) to danofloxacin mesylate using one equivalent of methanesulfonic acid in ethanol completes the synthesis.