Description:FIELD OF THE INVENTION
The present invention relates to a cost effective, environmental friendly process for synthesis of Ciprofloxacin hydrochloride. Particularly the present invention relates to a cost effective, environmental friendly process for synthesis of Ciprofloxacin hydrochloride utilizing 68% Piperazine as both the solvent and reagent thereby eliminating the need for solvent recovery systems for use of conventional organic solvents. The 68% Piperazine used in the present process can be recovered and reused making the process industrially feasible and economical over the conventional methods of preparing Ciprofloxacin hydrochloride.

BACKGROUND OF THE INVENTION
Ciprofloxacin, chemically known as 1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid belong to a class of compounds fluoroquinolones.

Ciprofloxacin is a broad-spectrum antibiotic and is active against some Gram-positive and many Gram-negative bacteria. It functions by inhibiting a type II topoisomerase (DNA gyrase) and topoisomerase IV, necessary to separate bacterial DNA, thereby inhibiting cell division.
Ciprofloxacin has been known to treat a wide variety of infections, including infections of bones and joints, endocarditis, bacterial gastroenteritis, malignant otitis externa, bubonic plague, respiratory tract infections, cellulitis, urinary tract infections, prostatitis, anthrax, and chancroid.
IN324037 discloses process for the preparation of Fluoroquinolones more particularly Ciprofloxacin and its acid addition salts. The process is depicted in Scheme 1 below:

According to the process 6-fluoro-7-chloro-1 -cyc1opropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with Piperazine in the presence of a catalyst 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 yield 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperaziny1)-3-quinoline carboxylic acid. The obtained Ciprofloxacin is further converted to its hydrochloride salt monohydrate in presence of methanol.

WO03/010144A2 discloses a process for obtaining antibiotics, fluoroquinolonic derivatives, of general formula I;

(wherein the variables are as disclosed therein)
by reacting Piperazine, or Piperazine derivatives, of general formula V

(wherein the variables are as disclosed therein)
with the compound of general formula VI

(wherein the variables are as disclosed therein)
in presence of an inert solvent at atmospheric pressure and at a temperature range of 20 to 200ᵒC and using an inorganic acid. The fluoroquinolonic derivative of general formula I then undergoes hydro chlorination by the addition of hydrochloric acid, followed by extraction into an organic solvent such as methanol, absolute ethanol, or isopropanol, resulting in the formation of the compound of general formula III as a pharmaceutically acceptable salt and/or hydrate of pharmacological purity.

CN101851198A discloses the preparation of Ciprofloxacin HCl comprising reacting cyclopropyl carboxylic acid in the organic solvent with Piperazine at 60～120 ℃. The organic solvent comprises 2-Pyrrolidone, dimethylacetamide, dinethylformamide, propylene carbonate, diethyl carbonate, 1-Methyl-2-Pyrrolidone, N-ethyl pyrrolidone, ethylene carbonate, propyl carbinol or n-hexyl alcohol or combinations thereof.

The processes described in the art are carried out in solvent and requires an additional step of recovery of the solvent which makes the process cumbersome and tedious. Researches therefore focused their attention to provide a solvent free process for preparation of ciprofloxacin.
CN101481381B discloses a process for preparation of Ciprofloxacin comprising reacting cyclopropane carboxylic acid of formula (ii) with Piperazine of formula (iii) in a molar ratio 1-10:1 in presence of metal Lewis acid catalyst and performing the reaction in a water-containing system at 80-150℃. This is followed by adding inorganic base into the reaction solution at the temperature of 20-100 ℃ to adjust the pH value of the reaction system to 9-12, filtering and adding inorganic acid into the filtrate to adjust the pH value to 7-8, and crystallizing to obtain the product. The process discloses the use of an auxiliary agent after the initial step, the auxiliary agent is selected from one or more of benzoic acid, tartaric acid, citric acid, oxalic acid, EDTA, commercially available soluble salts of EDTA, phosphate, hydrogen phosphate, dihydrogen phosphate, halide, fluoride, and hydrates of the above salts. CN’381 discloses the use of anhydrous piperazine, pentapiperazine, hexapentapiperazine.

One of the challenges in a chemical process is optimum use of the reagents, solvents and optimizing the process parameters to make the chemical process more cost effective and industrially feasible.

The present inventors observed that there is a scope to provide an improved process for synthesis of Ciprofloxacin hydrochloride over the process disclosed in CN101481381B. The present inventors felt that an improved process for synthesis of Ciprofloxacin hydrochloride may be provided using 68% Piperzaine which could act both as a reagent and solvent and which can be recovered and reused thus making the process more cost efficient and industrially feasible. This remains the object of the invention.

SUMMARY OF THE INVENTION
In accordance with the above objective, the present invention provides a cost effective, environmental friendly process for synthesis of Ciprofloxacin and its addition salt comprising;
(i) Reacting 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with 68% Piperazine in the presence of a catalyst to obtain Ciprofloxacin
(ii) Isolating Ciprofloxacin and recycling the Piperazine in the next batch;
(iii) Converting the Ciprofloxacin to its hydrochloride salt.

In an aspect, the catalyst for the process is selected from Lewis acid catalyst such as Ferric chloride (FeCl3), Aluminium chloride (AlCl3) and the like.
In another aspect, the reaction is carried out at a temperature ranging between 100-130ᵒC.

In yet another aspect, 68% Piperazine used in the reaction is recovered and reused.

In another aspect, the content of 6 -substituted compound (isomer) of formula given below in Ciprofloxacin HCl is less than 0.1%.

DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. However, any skilled person will appreciate the extent to which such embodiments could be extrapolated in practice.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention.

Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.
The present invention provides a ground breaking approach to chemical synthesis, showcasing remarkable and substantial advancements over previous methodologies in the synthesis of Ciprofloxacin and its acid addition salt. A key feature of the present process is the utilization of 68% Piperazine as both the solvent and reagent. This choice eliminates the use of traditional organic solvents, thereby eliminating the need for solvent recovery systems. As a result, the production costs are significantly reduced, and the method contributes to a decrease in environmental pollution a critical consideration in contemporary industrial processes.

In addition to its environmentally friendly profile, the preparation method is designed to optimize efficiency. The reaction time is notably shortened, allowing for quicker production cycles without compromising the quality of the output. This efficiency is enhanced through the incorporation of Lewis acid metal chlorides as catalysts. These catalysts not only facilitate the reaction but also operate at low proportions of 6-position fluorine-substituted by-products, which is crucial for maintaining the desired product integrity and yield.

Moreover, the present process involves the pH adjustment of the crude product. By neutralizing the pH, using HCl instead of acetic acid and caustic Lye solution, the Piperazine reagent efficiently dissolves into the mother liquor, enabling its recovery and reuse within the process. The major breakthrough involves eliminating the purification of Ciprofloxacin from the process which previously required the use of Caustic lye. This significant improvement further supports cost-effectiveness and sustainability, as it minimizes waste, effluent and maximizes the utility of the reagent.

In an embodiment, the present invention relates to a cost effective, environmental friendly process for synthesis of Ciprofloxacin and its addition salt comprising;
(i) Reacting 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with 68% Piperazine in the presence of a catalyst to obtain Ciprofloxacin
(ii) Isolating Ciprofloxacin and recovering the Piperazine. and
(iii) Converting Ciprofloxacin to its hydrochloride salt.
The process of the present invention is disclosed in Scheme 2 below:
According to the process, to the mixture of anhydrous 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid was added 68% Piperazine and the catalyst selected is Aluminium chloride. The reaction mixture was heated to reflux at a temperature ranging between 100-130ᵒC and maintained for about 4-6 hours. After completion of the reaction, reaction mass was cooled to a temperature ranging between 85-90ᵒC. Added water and adjusted the reaction mass to 7.0-7.2 pH using hydrochloric acid. Then stirred the reaction mass at a temperature of 55-65°C, filtered and washed with hot water to obtain Ciprofloxacin. The filtrate was concentrated and the Piperazine recovered is used in the subsequent batch.

The wet cake i.e. Ciprofloxacin isolated was then dissolved in water, heated and adjusted the reaction mass to 4.0-4.5 pH with Hydrochloric acid. The reaction mass was stirred for about an hour at 55-65°C, added activated carbon and EDTA, stirred and filtered. The filtrate was concentrated to maximum, added Methanolic HCl until the reaction mass pH is 2.0-2.5, cooled to 15-20°C, filtered the obtained solid, washed with chilled methanol and dried.

In an embodiment of the present process, the filtrate containing the Piperazine is concentrated and said concentrate is used in the next batch.

In another embodiment, the present invention discloses a cost effective, environmental friendly process for synthesis of Ciprofloxacin and its addition salt comprising;
(i) Reacting anhydrous 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with 68% Piperazine in the presence of AlCl3;
(ii) Heating the reaction mixture to reflux temperature, cooling to 85-90°C and adjusting the pH to 7.0-7.2 with Hydrochloric acid, stirring, washing and filtering to obtain Ciprofloxacin base;
(iii) Concentrating the filtrate and recycling the Piperazine for use in the subsequent batch;
(iv) Dissolving Ciprofloxacin base of step (ii) in water, heating and adjusting the reaction mass to 4.0-4.5 pH with Hydrochloric acid, stirring;
(v) Adding activated charcoal and EDTA to the above mixture, stirring, filtering and concentrating the filtrate to maximum, followed by adding Methanolic HCl to adjust the pH in the range 2.0-2.5 washing and drying to obtain Ciprofloxacin hydrochloride.
In an embodiment, the content of 6 substituted compound (isomer) of formula given below in Ciprofloxacin HCl is less than 0.1%.

In an embodiment, the output of Ciprofloxacin HCl using Aluminium Chloride as a catalyst is greater than 80%.
In an embodiment, the obtained yield is greater than 80%, the purity is greater than 99.8% and any single impurity is less than 0.1%.

In an embodiment, the present invention which provides a process for synthesis of Ciprofloxacin and its acid addition salt offers a multitude of advantages: it ensures high yield rates, significantly shortens reaction times, eliminates the need for solvent and Piperazine recovery, and does not rely on caustic substances or lye solution. These elements collectively contribute to a substantial reduction in industrial costs while simultaneously prioritizing environmental responsibility. The process of the present invention results in the desired product in high yield and purity in a more efficient, cost-effective, eco-friendly manner and the quality of the Ciprofloxacin HCl accords with the standard of EP,USP,BP and IP.

Experimental:
Example 1: Preparation of l-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl- quinoline-3- carboxylic acid (Ciprofloxacin )
A mixture of 200 g (0.710 mol) 7-chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo- quinoline-3-carboxylic acid, 324g (1.878 mol) 68% Piperazine, Aluminium chloride (catalyst) 6g (0.065mol) was heated to 115-125°C temperature and maintained for 4-6 hours. After completion of the reaction, the reaction mass was cooled to 85-90°C. added water, heated the contents and adjusted the PH of the reaction mass to 7.0-7.2 with Hydrochloric acid. Then stirred the reaction mass at 55-65°C, filtered and washed with hot water to obtain Ciprofloxacin (Wet weight of Ciprofloxacin is 500-600 gm). The filtrate was concentrated and the Piperazine recovered is used in the subsequent batch (i.e. Exampel-4).

Examples 2: Preparation of l-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-quinoline-3- carboxylic acid hydrochloride monohydrate (Ciprofloxacin HCl. H2O)
The wet cake (Example -1) i.e. Ciprofloxacin was dissolved in water, heated the contents and adjusted the reaction mass to 4.0-4.5 pH with Hydrochloric acid. Stirred the mass for 1.0 hour at 55-65°C, activated carbon and EDTA were charged into the reaction mass, stirred and filtered. The filtrate was concentrated to maximum and Methanolic HCl was added until the reaction mass pH is 2.0-2.5. The reaction mass was cooled to 15-20°C, filtered the obtained solid washed with chilled Methanol and dried.
Dry weight: 230 g

Yield: 84.5%

HPLC purity: 99.86 % (Total impurities: 0.14%)

Piperazine recovery and Re-use process:

Examples 3: Preparation of l-cyclopropyl-7- ( (4-ethoxycarbonyl) - 1-piperazinyl) -6-fluoro-l, 4-dihydro-4-oxo-quinoline-3- carboxylic acid hydrochloride mono hydrate (Ciprofloxacin HCl.H2O)

To a mixture of 100 g (0.355 mol) of 7-chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo- quinoline-3-carboxylic acid was added 45 g (0.518 mol) 68% Piperazine and the filtrate containing Piperazine from example-1. This was followed by addition of Aluminium chloride (catalyst) and the mixture was heated to reflux temperature and maintained for 4-6 hours. After the completion of the reaction, the reaction mass was cooled to 85-90°C. Added water and adjusted the reaction mass to 7.0-7.2 pH using Hydrochloric acid. Then stirred the mass at 55-65°C filtered and washed with hot water to obtain Ciprofloxacin. The filtrate was concentrated and the Piperazine recovered was used in the subsequent batch. The wet cake i.e. Ciprofloxacin was dissolved in water, heated the contents and adjusted the reaction mass to 4.0-4.5 pH with hydrochloric acid. Stirred the mass for 1.0 hour at 55-65°C, activated carbon and EDTA were charged, stirred and filtered. The filtrate was concentrated and Methanolic HCl was added until the reaction mass pH is 2.0-2.5. Cooled the solution to 15-20°C, filtered the obtained solid washed with chilled Methanol and dried.
Dry weight: 117.5 gm

Yield: 86.3%

HPLC purity: 99.85 % (Total impurities: 0.15%)

Note:
Example 4: Experiment is repeated using the recovered Piperazine by 4 turn over cycles.

Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
, Claims:1. A cost effective, environmental friendly process for synthesis of Ciprofloxacin and its addition salt comprising;
(i) Reacting 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with 68% Piperazine in the presence of a catalyst to obtain Ciprofloxacin;
(ii) Isolating Ciprofloxacin and recovering the Piperazine in the subsequent batch; and
(iii) Converting the Ciprofloxacin to its hydrochloride salt.

2. The cost effective process as claimed in claim 1, wherein the starting reagent is 68% Piperazine.

3. The cost effective process as claimed in claim 1, wherein the catalyst is selected from Lewis acid catalyst such as Aluminium chloride (AlCl3).

4. The cost effective process as claimed in claim 1, wherein the temperature of the reaction step (i) is between 100-130ᵒC.

5. The cost effective process as claimed in claim 1, wherein 68% Piperazine used in the reaction is recovered and used in the subsequent batch.

6. The cost effective process as claimed in any one of the preceding claims comprising;
(i) Reacting 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with 68% Piperazine;
(ii) Heating the reaction mixture to reflux temperature, cooling to 85-90°C and adjusting the pH to 7.0-7.2 with hydrochloric acid, stirring, washing and filtering to obtain Ciprofloxacin ;
(iii) Concentrating the filtrate and recovering the Piperazine for use in the subsequent batch;
(iv) Dissolving Ciprofloxacin of step (ii) in water, heating and adjusting the reaction mass to 4.0-4.5 pH with Hydrochloric acid;
(v) Adding activated charcoal and EDTA to the above mixture, stirring, filtering and concentrating the filtrate followed by adding Methanolic HCl to adjust the pH in the range 2.0-2.5 washing and drying to obtain Ciprofloxacin hydrochloride.

7. The cost effective process as claimed in claim 6, wherein the content of 6 substituted compound (isomer) in Ciprofloxacin HCl is less than 0.1%.