Novel synthesis of gatifloxacin

Abstract

Provided is a method for making (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolenecarboxylic acid, commonly known as gatifloxacin, in high purity, in a suspension in a dipolar aprotic solvent.

1 . A process for making gatifloxacin comprising the steps of:
 (a) heating a reaction mixture comprising 2-methylpiperazine and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid in a dipolar aprotic solvent to a reaction temperature between about 40° C. and about 70° C. in a atmosphere of inert gas for a period of time sufficient to obtain gatifloxacin,   (b) maintaining the reaction mixture at a holding temperature of about 40° C. or less to precipitate the gatifloxacin from the reaction mixture, and   (c) isolating the precipitated gatifloxacin from the reaction mixture,   wherein the reaction mixture is maintained in step (b) for a holding time sufficiently long so that there is no further increase in percent precipitate for a period of about one-half hour.   
     
     
         2 . The process of  claim 1 , wherein the dipolar aprotic solvent is selected from the group consisting of: N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrolidone, or mixtures of these. 
     
     
         3 . The process of  claim 1 , wherein the inert gas is nitrogen or argon. 
     
     
         4 . The process of  claim 1 , further comprising the step of, prior to step (b), concentrating the reaction mixture to about 75% to about 33% of its initial volume. 
     
     
         5 . The process of  claim 4 , wherein the reaction mixture is concentrated to about 50% of its initial volume. 
     
     
         6 . The process of  claim 1 , wherein a cosolvent is added prior to or simultaneously with step (b). 
     
     
         7 . The process of  claim 6 , wherein the cosolvent is selected from benzene, toluene, dimethylcarbonate, and water. 
     
     
         8 . The process of  claim 7 , wherein the dipolar aprotic solvent is N,N-dimethylformamide, the cosolvent is dimethylcarbonate, and the holding temperature is about 5° C. or less. 
     
     
         9 . The process of  claim 1 , wherein the holding temperature is about 25° C. or less and the holding time is at least about 12 hours. 
     
     
         10 . The process of  claim 1 , wherein the dipolar aprotic solvent is DMSO and the reaction temperature is about 50° C. to 60° C. 
     
     
         11 . The process of  claim 10 , wherein the reaction temperature is about 53° C. to about 57° C. 
     
     
         12 . The process of  claim 1 , wherein the reaction mixture is agitated while maintained at the holding temperature. 
     
     
         13 . The process of  claim 1 , further comprising the step of slurrying the isolated gatifloxacin with water or a mixture of water and acetonitrile at about 20° C. to about 30° C. for a slurry time. 
     
     
         14 . The process of  claim 13 , wherein the slurry time is about 30 minutes to about 3 hours. 
     
     
         15 . The process of  claim 13 , wherein the isolated gatifloxacin is slurried with water in an amount of about 3 mL to about 10 mL of water per gram of isolated gatifloxacin. 
     
     
         16 . The process of  claim 13 , further comprising the step of isolating gatifloxacin from the slurry, wherein the gatifloxacin isolated from the slurry has about 0.07 area-% or less desmethyl gatifloxacin and about 0.06 area-% or less 2′-methyl gatifloxacin. 
     
     
         17 . In a process for making gatifloxacin, the steps of:
 (a) heating a reaction mixture comprising a suspension of 2-methylpiperazine and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid in a dipolar aprotic solvent to a reaction temperature between about 50° C. and about 60° C. in a atmosphere of nitrogen or argon for a period of time sufficient to obtain gatifloxacin, and   (b) maintaining the reaction mixture at a holding temperature of about 40° C. or less to precipitate the gatifloxacin from the reaction mixture, and   wherein the dipolar aprotic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrolidone, and mixtures thereof, and   the reaction mixture is maintained in step (b) for a holding time sufficiently long so that there is no further increase in percent precipitate for a period of about one-half hour.   
     
     
         18 . In a method of making gatifloxacin having about 0.07 area-% or less desmethyl gatifloxacin and about 0.06 area-% or less 2′-methyl gatifloxacin, the steps of:
 (a) heating a reaction mixture comprising 2-methylpiperazine and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid in a dipolar aprotic solvent to a reaction temperature between about 53° C. and about 57° C. in a atmosphere of nitrogen or argon for a period of time sufficient to obtain gatifloxacin, and   (b) maintaining the reaction mixture at a holding temperature of about 25° C. or less for a holding time of about 12 to about 24 hours to precipitate the gatifloxacin from the reaction mixture,   (c) isolating the precipitated gatifloxacin from the reaction mixture,   (d) slurrying the isolated gatiflaoxacin with water or a mixture of water and acetonitrile at a temperature of about 20° C. to about 30° C. for a slurry time, and   (e) isolating gatifloxacin having about 0.07 area-% or less desmethyl gatifloxacin and about 0.06 area-% or less 2′-methyl gatifloxacin from the slurry,   wherein the dipolar aprotic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrolidone, and mixtures thereof.   
     
     
         19 . The method of  claim 18 , wherein the reaction mixture is formed by portionwise addition of the 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid to a mixture of dipolar aprotic solvent and 2-methylpiperazine. 
     
     
         20 . The method of  claim 18 , wherein the reaction mixture is maintained at a temperature of about 5° C. or less, further comprising the step of, prior to or simultaneous with step (b), the step of adding to the reaction mixture a cosolvent selected from benzene, toluene, dimethylcarbonate, and water. 
     
     
         21 . The method of  claim 18 , further comprising the step of, prior to step (b), concentrating the reaction mixture to about 40% to about 60% of its initial volume by distilling-off dipolar aprotic solvent.