Back to results
US 2008/0176834 A1Published application
Quinolone Carboxylic Acids, Derivatives Thereof, and Methods of Making and Using Same
AssigneeBausch & Lomb Incorporated
InventorArthur E. Harms
Life of this patent
Estimating the term…
Abstract
A process of preparing a quinolone carboxylic acid or its derivatives having Formula I, Ia, or IV, as shown herein, comprises using a starting quinolone that already has one or more desired substituents at one or more particular positions on the quinolone ring and preserving the orientation of such substituents throughout the synthesis. The present process comprises fewer steps than prior-art processes. The present process also can include a simple separation of a desired enantiomer of the quinolone carboxylic acid or its derivatives from the enantiomeric mixture. Pharmaceutical compositions comprising fluoroquinolones prepared by the present process can be used effectively against a variety of microbial pathogens.
Claims47
A process of preparing a fluoroquinolone having Formula I or salts thereof, the process comprising contacting a first compound having Formula II with a second compound having Formula III to produce a fluoroquinolone having Formula I, wherein the fluoroquinolone, the first compound, and the second compound are represented by
- wherein R1 is selected from the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, cycloalkyl groups, unsubstituted C5-C24 aryl groups, substituted C5-C24 and groups, unsubstituted C5-C24 heteroaryl groups, substituted C5-C24 heteroaryl groups, and groups that can be hydrolyzed in living bodies, R2 is selected from the group consisting, of hydrogen, unsubstituted amino group, and amino groups substituted with one or two lower alkyl groups;
- R3 is selected from the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, cycloalkyl groups, unsubstituted lower alkoxy groups, substituted lower alkoxy groups, unsubstituted C5-C24 aryl groups, substituted C5-C24 and groups, unsubstituted C5-C24 heteroaryl groups, substituted C5-C24 heteroaryl groups, unsubstituted C5-C24 aryloxy groups, substituted C5-C24 aryloxy groups, unsubstituted C5-C24 heteroaryloxy groups, substituted C5-C24 heteroaryloxy groups, and groups that can be hydrolyzed in living bodies;
- X is selected from the group consisting of halogen atoms;
- Y is selected from the group consisting of CH2, O, S, SO, SO2, and NR4, wherein R4 is selected from the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, and cycloalkyl groups;
- and Z is selected from the group consisting of oxygen and two hydrogen atoms.
2 more elements
A process of preparing a fluoroquinolone having Formula IV or salts thereof, the method comprising:
- (a) contacting a first compound having Formula II with a third compound having Formula V to produce a fourth compound having Formula VI, wherein the fluoroquinolone having Formula IV, the first compound, the third compound, and the fourth compound are represented by
- wherein R3 is selected from the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, cycloalkyl groups, unsubstituted C5-C24 aryl groups, substituted C5-C24 aryl groups, unsubstituted C5-C24 heteroaryl groups, substituted C5-C24 heteroaryl groups, and groups that can be hydrolyzed in living bodies;
- R3 is selected from, the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, cycloalkyl groups, unsubstituted lower alkoxy groups, substituted lower alkoxy groups, unsubstituted C5-C24 aryl groups, substituted C5-C24 and groups, unsubstituted C5-C24 heteroaryl groups, substituted C5-C24 heteroaryl groups, unsubstituted C5-C24 aryloxy groups, substituted C5-C24 aryloxy groups, unsubstituted C5-C24 heteroaryloxy groups, substituted C5-C24 heteroaryloxy groups, and groups that can be hydrolyzed in living bodies;
- X is selected from the group consisting of halogen atoms;
- Y is selected from the group consisting of CH2, O, S, SO, SO2, and NR4, wherein R4 is selected from the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, and cycloalkyl groups;
- Z is selected from the group consisting of oxygen and two hydrogen atoms;
- and R5 comprises a protected amino group having a formula of
- —NR6, wherein R6 comprises a protecting group that is capable of leaving the protected amino group —NR6;
- and
- (b) contacting the fourth compound with a sufficient amount of a catalyst and at a condition sufficient to effect a cleavage of the protecting group R6 from the —NR6 group, to produce a fluoroquinolone having Formula IV.
7 more elements
A process for preparing a fluoroquinolone carboxylic acid having Formula Ia or salts thereof, the process comprising:
- (a) contacting a compound having Formula IIa with a compound having Formula VIIa at a temperature in the range from about room temperature to about 100° C. for a time from about 10 minutes to about 7 days, to produce a compound having Formula VIa, wherein the fluoroquinolone having Formula Ia and the compounds having Formulae IIa, VIa, and VIIa are represent by
- (b) contacting the compound having Formula VIa with an amount of HCl equal to about 0.1 to about 5 moles per mole of the compound having Formula VIIa at a temperature in the range from about room temperature to about 100° C., in a presence of methanol to produce the fluoroquinolone carboxylic acid having Formula Ia;
- and
- (c) recovering the fluoroquinolone carboxylic acid having Formula Ia.
1 more element
A process of preparing a fluoroquinolone having Formula I, the process comprising:
- (a) contacting a compound having Formula XIII with a compound having Formula III to produce a compound having Formula XIV;
- and (b) halogenating the compound having Formula XIV with a halogenating agent to produce the fluoroquinolones having Formula I,
- wherein R1 is selected from the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, cycloalkyl groups, unsubstituted C5-C24 aryl groups, substituted C5-C24 aryl groups, unsubstituted C5-C24 heteroaryl groups, substituted C5-C24 heteroaryl groups, and groups that can be hydrolyzed in living bodies;
- R2 is selected from the group consisting of hydrogen, unsubstituted amino group, and amino groups substituted with one or two lower alkyl groups;
- R3 is selected from the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, cycloalkyl groups, unsubstituted lower alkoxy groups, substituted lower alkoxy groups, unsubstituted C5-C24 aryl groups, substituted C5-C24 and groups, unsubstituted C5-C24 heteroaryl groups, substituted C5-C24 heteroaryl groups, unsubstituted C5-C24 aryloxy groups, substituted C5-C24 aryloxy groups, unsubstituted C5-C24 heteroaryloxy groups, substituted C5-C24 heteroaryloxy groups, and groups that can be hydrolyzed in living bodies;
- X is selected from the group consisting of halogen atoms;
- Y is selected from the group consisting of CH2, O, S, SO, SO2, and NR4, wherein R4 is selected from the group consisting of hydrogen, unsubstituted lower alkyl groups, substituted lower alkyl groups, and cycloalkyl groups, and Z is selected from the group consisting of oxygen and two hydrogen atoms.
4 more elements
A process for preparing a fluoroquinolone carboxylic acid having Formula Ia, the process comprising:
- (a) contacting a compound having Formula XV with a compound having Formula VIIa at a temperature in the range from about room temperature to about 100° C. for a time from about 10 minutes to about 7 days, to produce a compound having Formula XVI;
- (b) chlorinating the compound having Formula XVI with a chlorinating agent to produce the fluoroquinolones having Formula XVII;
- (c) contacting the compound having Formula XVII with an amount of HCl equal to about 0.1 to about 5 moles per mole of the compound having Formula VIIa, at a temperature in the range from about room temperature to about 100° C., in a presence of methanol, to produce the fluoroquinolone carboxylic acid having Formula Ia;
- and (d) recovering the fluoroquinolone carboxylic acid having Formula Ia;
- wherein
2 more elements
Dependencies are inferred from the claim text.