Title of the invention:

Improved process for the preparation of Ciprofloxacin and its acid addition salts.

Cross reference to related applications:

[0001 ] This application claims priority from the Provisional specification No. 505/CHE/201 1 filed on 21.02.201 1 which is post-dated to 21.03.201 1. Field of the invention:

[0002] The present invention relates to an improved process for the preparation of Fluoroquinolones more particularly Ciprofloxacin and its acid addition salts.

Background of the invention:

[0003] Fluoroquinolones are antibiotics obtained by chemical synthesis exhibiting a wide antibacterial spectrum. These compounds inhibit topoisomerase II or DNA gyrase, the enzyme that is necessary for the replication and the transcription of the DNA of bacteria. [0004] Ciprofloxacin is chemically known as l -cyclopropyl-6-fluoro-l,4-dihydro-4- oxo-7-(l -piperazinyl)-3-quinolinecarboxylic acid and belonging to a class of compounds fluoroquinolones. The hydrochloride salt of ciprofloxacin, shown as structure (I) below, is a broad spectrum synthetic antibiotic effective against gram- positive organisms, such as methicillin-sensitive S. aureus, and gram-negative bacteria that include Enterobacteriaceae, Acinetobacter, Aeromonas, H. influenzae, M. catarrhalis, N. gonorrhoeae, N. meningitides, P. aeruginosa and P. multocida. Ciprofloxacin hydrochloride also exhibits in vitro activity against other pathogens such as L. pneumophila, M. pneumoniae and B. anthracis.

[0005] Ciprofloxacin hydrochloride exhibits its antibacterial activity by inhibiting topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), enzymes that are necessary for bacterial DNA replication, transcription, repair, and recombination. Topoisomerases prevent "overwinding" or excessive positive supercoiling of the DNA which can occur during and after replication. By blocking topoisomerase activity, ciprofloxacin hydrochloride inhibits DNA replication thereby resulting in cell death. Ciprofloxacin hydrochloride has been shown to be effective for the treatment of various infections including urinary tract infections, respiratory tract infections, acute sinusitis, acute uncomplicated cystitis, chronic bacterial prostates, skin and soft tissue infections, infectious diarrhea, typhoid fever, uncomplicated gonorrhea, and septicemia.

[0006] U S 4,670,444 discloses this antibiotic as the monohydrate hydrochloride salt, the form available commercially. US4670444B 1 mentions the preparation of Ciprofloxacin hydrochloride mono hydrate by reacting 6-fluoro-7-chloro-l- cyclopropyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid (Q-acid) with anhydrous piperazine in Dimethyl Sulphoxide (DMSO).

[0007] This process not only produces desired Ciprofloxacin but also the positional isomer namely (7-chloro- 1 -cyclopropyl-4-oxo-6-(piperazin- 1 -yl)- 1 ,4-dihydro quinoline-3-carboxylicacid) as a major impurity. Since it is a positional isomer it is very difficult to remove it. Formation of other positional isomers, decarboxylated compound and ethylene diamine adduct leads to lower yield and inferior quality which may not be suitable for pharmaceutical approach without purification. Purification of Ciprofloxacin in removing these impurities results in lower yields thereby increasing the product cost.

[0008] U S 5,091,530 describes a new invention for the process for preparing Ciprofloxacin with simple manner, high yields and short reaction time. According to this invention, ((l -cyclopropyl-6-fluoro-7-chloro-l ,4-dihydro-4-oxo-quinoline-3- carboxylate-O ³ , 0 ⁴ )-bis(aceto-0)-boron is reacted with piperazine in the presence of

[0009] This process involves more number of steps and use of toxic chemicals. So this process is not cost effective and industrially viable.

[0010] An improved method has now been developed for the preparation of Ciprofloxacin in a limited number of steps with high yields and high level of purity. Summary of the invention:

[001 1] The present invention is an improved process for the synthesis of 1- cyclopropyl -6-fluoro -1 ,4-dihydro 4-oxo -7-(l-piperazinyl) -3-quinolinecarboxylic acid (Ciprofloxacin) and its acid addition salts preferably hydrochloride salt with high yield and high purity. The process comprising of reacting 6-fluoro-7-chloro-l- cyclopropyl-4-oxo-l,4-dihydro-quinoline-3 -carboxylic acid with piperazine in presence of a catalyst in an organic solvent to form Ciprofloxacin which then reacts with hydrochloric acid to form Ciprofloxacin hydrochloride.

[0012] The main object of the invention is to provide an improved cost effective process for the preparation of Ciprofloxacin using Lewis acids like Aluminum chloride, Ferric chloride. [0013] Another object of the invention is to provide a process for the preparation of Ciprofloxacin that leads to high yield and high purity.

Description of the invention:

[0014] In accordance with the present invention, l -cyclopropyl-6-fluoro-l ,4- dihydro-4-oxo-7-(l-piperazinyl)-3 - quinolinecarboxylic acid (Formula - III) and its acid addition salts preferably hydrochloride salt (Formula - IV) is obtained by the reaction of 6-fluoro-7-chloro-l-cyclopropyl-4-oxo-l ,4-dihydro-quinoline-3- carboxylic acid (Formula - 1) with piperazine (Formula - II) in presence of aluminum chloride and n-butanol. The process of the invention is depicted in following scheme.

Acetic acid HCl

Methanol

[0015] The 6-fluoro-7-chloro-l -cyclopropyl-4-oxo-l , 4-dihydro-quinoline-3- carboxylic acid which is the starting material of present invention is commercially available or can be synthesized by the teachings of the prior art. Further process comprises reacting the 6-fluoro-7-chloro-l-cyclopropyl-4-oxo-l ,4-dihydro- quinoline-3-carboxylic acid with piperazine in the presence of a catalyst selected from ferric chloride, aluminium chloride, zinc chloride or boron trifluoride but preferably ferric chloride or aluminium chloride and solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, pentanol, sulfoxide, ketones, ethers and esters but preferably butanol or pyridine to get the 1 -cyclopropyl-6- fluoro-l ,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinoline carboxylic acid. The obtained Ciprofloxacin base taken into an organic solvent selected from the group consisting of methanol, ethanol, propanol and the like but preferably methanol heated to 45-50 °C added commercial HCl (44 gm) and maintained for sufficient period of time to give Ciprofloxacin hydrochloride.

[0016] The advantage of the present process is that there is very less formation of positional isomer (7-chloro- 1 -cyclopropyl-4-oxo-6-(piperazin- 1 -yl)- 1 ,4-dihydro quinoline-3-carboxylicacid) of Formula -V, in comparison to the prior art process and formation of decarboxylic and ethylene diamine adduct impurity is also less. According to the present invention, the formation of compound of formula - V in reaction mass of the formation of Ciprofloxacin is less than 5% and in Ciprofloxacin hydrochloride it is less than 0.10%.

[0017] The process is effectively carried out at the catalytically amount of aluminum chloride in between 1% and 3% and volume of n-butanol in between 0.5 vol - 3 vol at 1 10-130 ^° C.

The invention is further illustrated with the following non-limiting examples.

Examples: Example 1: Preparation of l -cyclopropyl-6-fluoro- 4-oxo-7-piperazin-l -yl- quinoline-3-carboxylic acid (Ciprofloxacin base).

[0018] The mixture of 7-chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo- quinoline-3-carboxylic acid (100 gm), piperazine (81 gm), anhydrous aluminium chloride (5 gm) and n-butanol (175 ml) was heated to reflux temperature i.e. 1 18-122 C and maintained for 10-14 hours. After the completion of the reaction, reaction mass was cooled to 70-80 C, n-butanol was distilled out completely under vacuum, added water and adjusted the reaction mass pH 6.5-6.6 with hydrochloric acid, heated the contents to 50-55 C and adjusted the reaction mass pH 4.0-4.5 with acetic acid, stirred the mass for 1.0 hour at the same conditions, activated carbon (6.8 gm) and EDTA (0.046gm) were charged and stirred for 1.0 hour at 55-60 C, filtered the carbon the filtrate pH adjusted 6.8 to 7.2 with 20% aqueous sodium hydroxide solution and stirred for 1.0 hour and filtered the isolated compound, washed with water (Wet weight of Ciprofloxacin base is 200-250 gm).

Example 2: Preparation of l-cyclopropyl-6-fluoro- 4-oxo-7-piperazin-l-yl- quinoline-3-carboxylic acid hydrochloride mono hydrate (Ciprofloxacin.HCl.H ₂ O). [0019] The wet cake (From example- 1) taken in to aqueous Methanol( methanol contains 30-40% moisture content) heated to 45-50 °C added Hydrochloric acid (44 gm), stirred for 2.0 hrs at same temperature and slowly cooled the mass to 5-8 °C filtered the isolated compound and washed with fresh methanol. The wet compound taken in to aqueous Methanol heated the contents to reflux temperature, added activated carbon (4.8 g) to the clear solution stirred for 30 minutes, filtered the carbon, slowly cooled the filtrate to 5-8 °C and the isolated compound was filtered, washed with chilled methanol and dried.

Dry weight: 100 gm

Yield: 72.4%

HPLC purity: 99.85% ( Any single impurity less than 0.10%)

Example 3: Preparation of l-cyclopropyl-6-fluoro- 4-oxo-7-piperazin-l-yl- quinoline-3-carboxylic acid (Ciprofloxacin base).

[0020] The mixture of 7-chloro-l -cyclopropyl-6-fluoro-l , 4-dihydro-4-oxo- quinoline-3-carboxylic acid (100 gm), piperazine (81 gm), Ferric chloride (5 gm) and

Pyridine (175 ml) was heated to reflux temperature i.e. 1 10-120 C and maintained for 8-12 hours. After completion of the reaction, reaction mass was cooled to 70-80 C, pyridine was distilled out completely under vacuum at below 80 °C and co- distilled with water to remove the pyridine traces and added water cooled the mass to 50-55 °C, adjusted the pH 1 1.5-12.0 with 20% sodium hydroxide solution at the same temperature, added EDTA stirred for 1-2 hours at 50-55 °C filtered, the filtrate pH was adjusted to 6.8-7.2, maintained for 2.0 hrs at the same temperature and filtered the isolated compound, washed with water. Wet compound taken in to water heated to 50-55 °C and adjusted pH 4.0-4.5 with acetic acid, stirred the mass for 1.0 hour at the same conditions, activated carbon (6.8 gm) and EDTA (0.046gm) were charged to mass and maintained for 1 hour at 50-55 ^° C stirred for 1.0 hour filtered the carbon, the filtrate pH adjusted 6.8 to 7.2 with 20% aqueous sodium hydroxide solution and stirred for one hour, filtered the isolated compound and washed with water (Wet weight of Ciprofloxacin base is 200-250 gm).

Example 4: Preparation of l-cyclopropyl-6-fluoro-4-oxo-7-piperazin-l -yl- quinoline-3-carboxylic acid hydrochloride mono hydrate (Ciprofloxacin. HC1.H ₂ 0).

[0021] The wet cake (From example-3) taken in to aqueous Methanol( methanol contains 30-40% moisture content) heated to 45-50 °C added Hydrochloric acid (44 gm), stirred for 2.0 hrs at same temperature and slowly cooled the mass to 5-8 °C filtered the isolated compound and washed with fresh methanol. The wet compound taken in to aqueous Methanol heated the contents to reflux temperature, added activated carbon (4.8 g) to the clear solution stirred for 30 minutes, filtered the carbon, slowly cooled the filtrate to 5-8 °C and the isolated compound was filtered, washed with chilled methanol and dried.

Dry weight: 105 gm.

Yield: 76.0%

HPLC Purity: 99.82% (Any single individual impurity is less than 0.10%)