# US 2008/0188658 A1 · Novel synthesis of gatifloxacin

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- Number: US 2008/0188658 A1
- Document ID: US20080188658A1
- Status: Published application
- Kind: A1
- Application number: 12/080,470
- Filed: 2008-04-02
- Published: 2008-08-07
- Earliest claimed: 2002-08-14
- Assignees: Teva Pharmaceuticals USA, Inc.
- Inventors: Valerie Niddam-Hildesheim; Ben-Zion Dolitzky; Gideon Pilarski; Greta Sterimbaum
- Web page: https://patentgrep.com/patent/US20080188658A1

## CPC

- C07D 215/56: with oxygen atoms in position 4
- A61P 31/04: Antibacterial agents
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

The process of claim 1, wherein the inert gas is nitrogen or argon.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 4)

The process of claim 4, wherein the reaction mixture is concentrated to about 50% of its initial volume.

### Claim 6 (depends on 1)

The process of claim 1, wherein a cosolvent is added prior to or simultaneously with step (b).

### Claim 7 (depends on 6)

The process of claim 6, wherein the cosolvent is selected from benzene, toluene, dimethylcarbonate, and water.

### Claim 8 (depends on 7)

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.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 1)

The process of claim 1, wherein the dipolar aprotic solvent is DMSO and the reaction temperature is about 50° C. to 60° C.

### Claim 11 (depends on 10)

The process of claim 10, wherein the reaction temperature is about 53° C. to about 57° C.

### Claim 12 (depends on 1)

The process of claim 1, wherein the reaction mixture is agitated while maintained at the holding temperature.

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 13)

The process of claim 13, wherein the slurry time is about 30 minutes to about 3 hours.

### Claim 15 (depends on 13)

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.

### Claim 16 (depends on 13)

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.

### Claim 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.

### Claim 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.

### Claim 19 (depends on 18)

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.

### Claim 20 (depends on 18)

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.

### Claim 21 (depends on 18)

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.