FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Nitazoxanide (I). It further discloses process for purification of Nitazoxanide (I) to yield Nitazoxanide (I) with more than 99.0 % purity by HPLC (High-performance liquid chromatography)
BACKGROUND OF THE INVENTION
Nitazoxanide is a broad-spectrum antiparasitic and broad-spectrum antiviral drug mostly, used for the treatment of diarrhoea caused by Giardia lamblia or Cryptosporidium parvum. Chemically it is 2-acetyloxy-N-(5-nitro-2-thiazolyl) benzamide and was first approved by the FDA as ALINA on July 21, 2004.
The synthesis of Nitazoxanide (I) was reported in few patents, the contents of which are hereby incorporated as reference in their entirety.
US3950351 patent describes the synthesis of Nitazoxanide by coupling of o-acetylsalicyloyl chloride (III) with 2-amino-5-nitro-thiazole (II) in presence of a base to form Nitazoxanide (I). The compound formed by this process is difficult to isolate and uses high volume of solvents. Also, it does not disclose the purity of the compound. Thus, the process is not suitable at industrial scale as it increases the overall cost of production.

Few prior arts are available which discloses complete synthesis and purification of pure Nitazoxanide (I). Hence, there is a need for improved process for preparing pure Nitazoxanide (I).
OBJECTIVE OF THE INEVNTION
The primary objective of the present invention is to provide an improved process for the preparation of Nitazoxanide (I).
Another objective of the present invention is to provide a suitable method for the purification of Nitazoxanide (I)
Yet, another objective of the invention is to provide pure Nitazoxanide (I) with more than 99.0 % purity by HPLC (High-performance liquid chromatography).
SUMMARY OF THE INVENTION
Accordingly, one aspect of the present invention is to provide an improved process for the preparation of Nitazoxanide (I) comprising:
a) Acetylation of salicylic acid (V) to give 2-acetoxybenzoic acid (IV) using a suitable acetylating agent;
b) chlorinating 2-acetoxybenzoic acid (IV) using a suitable chlorinating agent to form 2-(chlorocarbonyl)phenyl acetate (III); and
c) coupling of 5-nitrothiazol-2-amine (II) with 2-(chlorocarbonyl)phenyl acetate (III) in presence of a suitable base to yield Nitazoxanide (I).
Another aspect of the present invention is to provide a process for the purification of Nitazoxanide (I) comprising:
1. Providing a solution of Nitazoxanide (I) in a mixture of aprotic solvents;
2. heating the reaction mixture at 50-90 °C;

3. cooling the reaction mixture to 0-30 °C; and
4. isolating pure Nitazoxanide (I)
Yet, another aspect of the present invention is to provide pure Nitazoxanide (I) with more than 99.0 (%, w/w) purity by HPLC.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 illustrates X-Ray powder diffraction (XPRD) pattern of Nitazoxanide (I).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for preparation of Nitazoxanide (I) which comprises of the steps as depicted in scheme-
In some embodiment, the present invention provides an improved process for preparation of Nitazoxanide (I), comprising:

a) Acetylation of salicylic acid (V) to give 2-acetoxybenzoic acid (IV) using a suitable acetylating agent;
b) chlorinating 2-acetoxybenzoic acid (IV) using a suitable chlorinating agent to form 2-(chlorocarbonyl)phenyl acetate (III); and
c) coupling of 5-nitrothiazol-2-amine (II) with 2-(chlorocarbonyl)phenyl acetate (III) in presence of a suitable base to yield Nitazoxanide (I).
In some embodiment, step a) proceeds with acetylation of salicylic acid (V) in acidic medium using a suitable acetylating agent to obtain 2-acetoxybenzoic acid (IV) with more than 95.0% purity. The said reaction was carried out at a temperature about at 20-50 °C, preferably 25 to 35 °C. Prior arts do not disclose the purity of the intermediate (IV) formed. Use of pure intennediates increases the purity and reduces the yield loses of the final Active Pharmaceutical Ingredient (API). Hence, the present invention is advantageous over prior art processes.
The suitable acetylating agent used in step a) may be selected from a group comprising of acetic anhydride, acetic acid, acetyl chloride or the like. Preferably, acetic anhydride was used in the present invention.
Suitable acid used in step a) was selected from the group comprising of organic and inorganic acids. The organic acids may be selected from trifluoroacetic acid, trifluoro methane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-touenesulphonic acid or the like. The inorganic acid may be selected from a group comprising of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or the like. Preferably, sulphuric acid was used in the present invention.
In another embodiment, step b) involves chlorination of 2-acetoxybenzoic acid (IV) to form 2-(chlorocarbonyl) phenyl acetate (III) in presence of suitable chlorinating agent and aprotic solvent at a temperature of about at 20-50 °C, preferably 20-25 °C.

The suitable chlorinating agent used in step b) may be selected from the group comprising of oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorous trichloride, phosphorous pentachloride, triphenylphosphine dichloride, N-chlorosuccinimide or the like. Preferably, oxalyl chloride was used in the present invention.
In some embodiment, step c) involves coupling of 5-nitrothiazol-2-amine (II) with 2-(chlorocarbonyl)phenyl acetate (III) in presence of a suitable base to yield Nitazoxanide (I). Intermediate 2-(chlorocarbonyl) phenyl acetate (III) obtained in step b) was reacted with 5-nitrothiazol-2-amine (II) in an aprotic solvent and a suitable base at a temperature about -10 to 5 °C to obtain crude Nitazoxanide (I).
The suitable base employed in step c) may be selected from but not limited to organic and inorganic base. The organic bases may be selected from a group comprising of triethylamine, diethylamine, diethyl aminopyridine, pyridine or the like. The suitable inorganic base may be selected from a group comprising of lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate or the like. Preferably, triethylamine was used in the present invention.
In some embodiment, the suitable protic solvent used in step a) and step c), were selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IP A), n-propanol, n-butanol, or the like, preferably water and ethanol or mixtures thereof were used in the present invention.
The suitable aprotic solvent used in step (b) and step c) may be selected from a group comprising of dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl sulfoxide, acetone or the like. Preferably, dichloromethane, dimethyl formamide and tetrahydrofuran were used in the present invention.
In another embodiment, the present invention provides a suitable method for the purification of Nitazoxanide (I), which comprises of following steps:

1. Providing a solution of Nitazoxanide (I) in a mixture of aprotic solvents;
2. heating the reaction mixture at a suitable temperature;
3. cooling the reaction mixture to at a suitable temperature; and
4. isolating pure Nitazoxanide (I).
In some embodiment, purification process proceeds with addition of suitable aprotic solvent or a mixture of aprotic solvents to crude Nitazoxanide (I) at 25-30 °C. The reaction solution was heated at 50-90 °C, preferably 65-70 °C. A suitable decolorizing agent, preferably neutral charcoal was added to the reaction mixture and filtered through Hyflo in hot condition. The filtrate was then cooled to 0-30 °C, preferably 0-5 °C and pure Nitazoxanide (I) was isolated.
The suitable aprotic solvents or mixtures of aprotic solvents used for the purification of crude Nitazoxanide (I) may be selected from a group comprising of acetone, acetonitrile, dichloromethane, dimethyl formamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran or the like. Preferably, a mixture of ethyl acetate and acetone was used in the present invention.
In another embodiment, Nitazoxanide (I) obtained after purification is having purity greater than 99.0 (%, w/w) purity, preferably more than 99.5 (%, w/w) purity by HPLC.
In another, embodiment Nitazoxanide (I) obtained after purification is having total impurities less than 1.0 (%, w/w), preferably less than 0.5 (%,w/w).
In another embodiment, Nitazoxanide (I) obtained after purification is having Salicylic acid impurity, 2-amino-5-nitrothiazole impurity, 2-acetoxy benzoic acid impurity, tizoxanide impurity and dimer impurity less than 0.5 (%, w/w), preferably less than 0.25 (%, w/w), most preferably less than 0.15 (%, w/w).

In another embodiment, Nitazoxanide (I) obtained in the present invention is having total heavy metals level less than 20 ppm.
In another embodiment, Nitazoxanide (I) obtained in the present invention is having Loss on drying (%, w/w) not more than 0.50 (%, w/w), preferably, not more than 0.25 (%, w/w).
In another embodiment, Nitazoxanide (I) obtained is having X-ray crystallography (XRD) pattern as shown in figure 1 and the 2 theta values ± 0.2 as provided in table 1.

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE 1: Preparation of 2-acetoxybenzoic acid (IV)
100 g of salicylic acid (V) was added to 300mL of acetic anhydride at 25-30 °C. 2mL
of sulfuric acid was added to the reaction mass. On completion of reaction, the reaction
mass was cooled to 5-10 °C and 250 mL of pre-cooled water (15-20 °C) was added to
reaction mixture. The temperature of the reaction mixture was raised to 25-30 °C. The
solid so formed was filtered, washed with water and dried under vacuum below 45 °C
to obtain 2-acetoxybenzoic acid (IV). Yield: 79%; Purity: 99.0%
EXAMPLE 2: Preparation of 2-(chlorocarbonyl)phenyl acetate (III)
lOOg of 2-acetoxybenzoic acid (IV) was added to 1200mL of dichloromethane at 25-
30 °C. The reaction mass was cooled to -5 to 0 °C under nitrogen atmosphere and 4mL
of dimethylformamide was added. 78 g of oxalyl chloride was added to the reaction
mass at -5 to 0 °C and the temperature of the reaction mixture was raised to 20-25 °C.
The product 2-(chlorocarbonyl)phenyl acetate (III), which was formed was directly
used in the next step without purification.
EXAMPLE 3: Preparation of Nitazoxanide (I)
70g of 5-nitrothiazol-2-amine (II) was added to 200mL of tetrahydrofuran at 25-30 °C. The reaction mass was cooled to -5 to 0 °C and 180g of triethylamine was added to the reaction mass. 2-(chlorocarbonyl) phenylacetate (III) obtained in example 2, was then added to the above reaction mass at -5 to 0 °C. On completion of reaction, the temperature of the reaction mixture was raised to 25-30 °C and solvent distilled off below 30 °C. 500mL of water was added to the solid residue and reaction mass cooled to 15-20 °C. The pH of the resulting reaction mass was adjusted to 6.5-6.8 using water:

acetic acid mixture (1:1) and 400 mL of ethanol was added at 15-20 °C. The solid
formed was filtered and washed with 100 mL of water and ethanol mixture (1:1) and
dried. Finally, the solid obtained was dried under vacuum below 40°C to obtain crude
Nitazoxanide (I). Yield: 55%; Purity: 99.5% EXAMPLE 4: Purification of Nitazoxanide (I)
lOOg of crude Nitazoxanide (I) was added to a mixture of ethyl acetate and acetone at 25-30 °C. The reaction mass was heated to 65-70 °C and 25g of neutral charcoal was added to it. The reaction mixture was stirred for lhr and filtered, first through Hyflo, then through 0.2mm micron filter at 65-70 °C. The filtrate so obtained was cooled and stirred at 0-5 °C. The solid so formed was filtered under vacuum to obtain pure Nitazoxanide (I). Yield: 77%; Purity: 99.99%; XRD: Figure 1. EXAMPLE 5: Purification of Nitazoxanide (I)
lOOg of crude Nitazoxanide (I) was added to a mixture of ethyl acetate and acetone at 25-30 °C. The reaction mass was heated to 65-70 °C and 25g of neutral charcoal was added to it. The reaction mixture was stirred for lhr and filtered, first through Hyflo, then through 0.2mm micron filter at 65-70 °C. The filtrate so obtained was cooled and stirred at 0-5 °C. The solid so formed was filtered under vacuum to obtain pure Nitazoxanide (I). Yield: 77%; Purity: 99.99%; XRD: Figure 2.

^e claim:
1. A process for the preparation of Nitazoxanide (I)
w
comprising:
a) acetylation of salicylic acid (V)
(V)
to give 2-acetoxybenzoic acid (IV)
using a suitable acetylating agent; b) chlorinating 2-acetoxybenzoic acid (IV) using a suitable chlorinating agent to form 2-(chlorocarbonyl)phenyl acetate (III);

with 2-(chlorocarbonyl)phenyl acetate (III) in presence of a suitable base to yield Nitazoxanide. (I)
2. The process as claimed in claim 1, wherein suitable acetylating agent used in step a) is selected from a group comprising of acetic anhydride, acetic acid, acetyl chloride or mixtures thereof.
3. The process as claimed in claim 1, wherein the suitable chlorinating agent used in step b) is selected from the group comprising of oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorous trichloride, phosphorous pentachloride, triphenylphosphine dichloride, N-chlorosuccinimide or mixtures thereof.
4. The process as claimed in claim 1, wherein the suitable base used is selected from triethylamine, diethylamine, diethyl aminopyridine, pyridine, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, caesium carbonate and sodium bicarbonate.
5. The process as claimed in claim 1, wherein the suitable solvent is selected from water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, acetone, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl formamide and dimethyl sulfoxide.
6. A process for the purification of Nitazoxanide (I) comprising:
a) providing a solution of Nitazoxanide (I) in a mixture of solvents;
b) heating the reaction mixture to a suitable temperature;
c) cooling the reaction mixture to a suitable temperature; and
d) isolating pure Nitazoxanide (I).

7. The process as claimed in claim 6, wherein the suitable solvents used is selected from a group comprising of acetone, acetonitrile, dichloromethane, dimethyl formamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran or mixtures thereof.
8. The process, as claimed in claim 6, wherein the Nitazoxanide (I) obtained after purification is having purity greater than 99.0 (%, w/w) purity by HPLC.