Novel synthesis of gatifloxacin

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.

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.