Claims:1. An improved, cost effective process for producing ICH grade nitroxoline characterized in that said process comprising;
i. Oxidizing 5-Nitroso-8-hydroxy quinoline with nitric acid in mixture of water and water miscible organic solvents at a temperature in the range of 10-35oC to obtain crude nitroxoline;

and
ii. Recrystallizing the crude nitroxoline of step (i) from acetone, water, DMF or mixture thereof to obtain ICH grade nitroxoline as yellow to yellowish brown shinning powder free from genotoxic impurities such as 7-Nitro nitroxoline, 5-Nitroso-8-hydroxyquinoline and 5,7-Dinitro-8-hydroxyquinoline.

2. The improved process as claimed in claim 1, wherein the water miscible organic solvent for step (i) is selected from lower alcohol such as methanol, ethanol, propanol, dialkyl amides such as dimethyl formamide (DMF), N,N dimethyl acetamide (DMAc), dimethyl sulfoxide (DMSO) and the like or mixtures thereof.

3. The improved process as claimed in claim 1, wherein re-crystallization of step (ii) is carried out at a temperature in the range of 20-100oC.

4. The improved and cost effective process for producing ICH grade nitroxoline as claimed in claim 1, comprising;
i. Nitrating 8-hydroxyquinoline to obtain 5-Nitroso-8-hydroxy quinoline by a process known in art;
ii. Oxidizing 5-Nitroso-8-hydroxy quinoline of step (i) with nitric acid in mixture of water and water miscible organic solvent at a temperature in the range of 10-35oC to obtain crude nitroxoline;

and
iii. Recrystallizing the crude nitroxoline of step (ii) from acetone, water, DMF or mixture thereof to obtain ICH grade nitroxoline as yellow to yellowish brown shinning powder free from genotoxic impurities such as 7-Nitro nitroxoline, 5-Nitroso-8-hydroxyquinoline

5. The improved process as claimed in claim 4, wherein the water miscible organic solvent for step (i) is selected from lower alcohol such as methanol, ethanol, propanol, dialkyl amides such as dimethyl formamide (DMF), N,N dimethyl acetamide (DMAc), dimethyl sulfoxide (DMSO) and the like or mixtures thereof.

6. The improved process as claimed in claim 4, wherein the re-crystallization of step (iii) is carried out at a temperature in the range of 20-100oC.

7. The improved process as claimed in any of the preceding claims, wherein Nitroxoline obtained is having 7-nitro nitroxoline and 5-Nitroso-8-hydroxy quinoline impurity both less than 0.01%.

8. The improved process as claimed in claim 7, wherein Nitroxoline obtained is having 7-nitro Nitroxoline and 5-Nitroso-8-hydroxy quinoline impurity both less than 0.005%.

, Description:

FIELD OF INVENTION
The present invention relates to an improved and cost effective process for preparation of Nitroxoline (5-nitro-8-oxyquinoline) free from process related genotoxic impurities. The process of the present invention significantly controls the formation of the undesired side-product i.e. 7-Nitro nitroxoline during oxidation of 5-nitroso-8-oxyquinoline and results in improved yield and purity of the product.

BACKGROUND OF THE INVENTION
Nitroxoline i.e. 5-nitro-8-hydroxyquinoline with antibacterial activity is conventionally prepared by nitrosating 8-oxyquinoline with sodium nitrite, followed by oxidizing the resulting 5-nitroso-8-hydroxyquinoline with nitric acid. In the conventional oxidation process there is substantial formation of the undesired impurity 7-Nitro nitroxoline which is very difficult to remove and requires extensive purification stages to obtain pure nitroxoline. The purification steps are tedious and reduce the yield significantly.

RU2702004C2 relates to a process of producing pharmacopoeial 5-nitro-8-hydroxyquinoline using technical nitroxoline. The process includes adding in the first load acetone, activated carbon to technical nitroxoline followed by adding commodity acetone in the second load. The ratio of the commodity acetone to the regenerated acetone of the first load is 2:3. This is followed by heating the reaction mass to a temperature of 60 ± 5°C for 1.0-2.0 hours. The reaction mass is then transferred through a filter in the crystallizer reactor into which purified water is pre-loaded, after which the reaction mass is cooled to a temperature of 20 ± 5° C and held for 1.5-3.0 hours. The resulting pharmacopoeial nitroxoline paste is filtered, squeezed and washed with purified water, then the content of chlorides and sulfates in the paste are analyzed, until the content of chlorides in it is not more than 0.02% and sulfates not more than 0.02%, after that the pharmacopoeial nitroxoline paste is transferred to drying, which is carried out at a temperature of 60±15°C until a mass loss upon drying of not more than 0.5% is achieved.

SU609284A1 discloses a process for preparation of pharmacopoeial nitroxoline, wherein the oxidation of 5-nitroso-8-hydroxyquinoline is carried under controlled conditions in organic solvent i.e. acetic acid, and purified in acetone at a temperature of 20-50° C. The purification of the resulting product is carried out by transferring it to the hydrochloric acid salt and crystallizing it from dilute hydrochloric acid. The process is not advantageous as it cannot control the formation of 5-nitro nitroxoline, which is a process related genotoxic byproduct during oxidation of 5-nitroso-8-hydroxyquinoline, even after purification.. The nitroxoline and 5-nitro nitroxoline are poorly soluble in most of the organic solvents, it requires about 40-50 volume acetone for single purification stage and it needs multiple purifications to meet the desired quality.

All the reported processes of nitroxoline are less productive, cumbersome and not suitable for commercial manufacturing for ICH grade API. The present inventors found that nitroxoline obtained by the conventional methods is greenish brown to soil color powder without gloss which is unpleasant, has poor flow property, not desired by the formulators for tableting.

Therefore, there is a need in the art to provide an improved process for preparation of ICH grade nitroxoline which is cost effective and practical for commercial manufacturing. The present inventors surprisingly found that ICH grade nitroxoline as yellow to yellowish brown shinning powder free from process related genotoxic impurities can be obtained using a unique solvent system both during the oxidation step and during re-crystallization. This remains the objective of the invention.

SUMMARY OF THE INVENTION
In accordance with the above, the present invention provides an improved, cost effective process for producing ICH grade nitroxoline, wherein said process comprising;
i. Oxidizing 5-Nitroso-8-hydroxy quinoline with a oxidizing agent in water and water miscible organic solvent mixture to obtain crude nitroxoline; and
ii. Recrystallizing the crude nitroxoline of step (i) from acetone, water, DMF or mixture thereof to obtain nitroxoline as yellow to yellowish brown shinning powder free from process related genotoxic impurities such as 7-Nitro nitroxoline and 5-Nitroso-8-hydroxyquinoline.
The water miscible organic solvent during oxidation in step (i) is selected from lower alcohols, ketones such as acetone; dialkyl amides, dimethylsulphoxide or mixtures thereof.

The oxidizing reagents are nitric acid, hydrogen peroxide, or oxygen gas.
The recrystallization of crude nitroxoline in step (ii) is carried out using acetone, water, DMF or mixtures thereof to obtain pure nitroxoline as yellow to yellowish brown powder containing less than 0.005% of undesired 7-Nitro Nitroxoline impurity and 5-Nitroso-8-hydroxyquinoline, which is below quantification limit (BQL).

In another aspect, the 5-Nitroso-8-hydroxy quinoline is obtained by nitration of 8-hydroxyquinoline by a process known in the art.

DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be explained in detail with reference to its various preferred as well as optional embodiment, which, however should not be construed to limit the scope of the invention.

In an embodiment, the present invention relates to an improved, cost effective process for producing ICH grade nitroxoline wherein said process comprising;
i. Oxidizing 5-Nitroso-8-hydroxy quinoline with a oxidizing agent in mixture of water and water miscible organic solvent to obtain crude nitroxoline;
and
ii. Recrystallizing the crude nitroxoline of step (i) from acetone, water, DMF or mixtures thereof to obtain nitroxoline as yellow to yellowish brown shinning powder free from genotoxic impurities such as 7-Nitro nitroxoline and 5-Nitroso-8-hydroxyquinoline.

According to the present process step (i) water and water miscible organic solvent were charged to 5-Nitroso-8-hydroxy quinoline in a reactor and the mixture was stirred and cooled to about 10oC. To the cooled mixture was added oxidizing agent at a temperature in the range of 10-35oC over a period of about 3-5hrs. After completion of the reaction the pH was adjusted with a base, the slurry was filtered, washed and dried to yield crude nitroxoline as greenish powder.

The water miscible organic solvent is selected from lower alcohols such as methanol, ethanol, propanol; ketones such as acetone; dialkyl amides such as dimethyl formamide (DMF), N,N dimethyl acetamide (DMAc), dimethyl sulfoxide (DMSO) and the like or mixtures thereof; preferably the organic solvent is lower alcohol.
The oxidizing reagents for step (i) include nitric acid, hydrogen peroxide or oxygen gas, preferably nitric acid.

The re-crystallization is carried out at a temperature in the range of 20-100oC.
The process step (ii) comprises adding dimethyl formamide (DMF) to crude nitroxoline and raising the temperature. Stirring the mixture followed by adding water slowly and cooling the reaction mixture to room temperature, filtering. Checked the 7-Nitro nitroxoline content in the wet material and the process was repeated until the 7-nitro nitroxoline content is NMT 0.5%. Dried the wet material to obtain Nitroxoline as brownish green color powder.

This was followed by re-crystallization of the above obtained purified nitroxoline which comprises heating the purified nitroxoline with DMF to obtain clear solution. Activated carbon was then added, stirred and filtered to remove the activated carbon residue. Acetone was added slowly to the filtrate to crystallize Nitroxoline. Filtered the slurry, dried the wet material under reduced pressure to get the Nitroxoline as yellow color powder of high purity wherein the genotoxic impurities are below quantification limit (BQL).

In another embodiment, the compound 5-Nitroso-8-hydroxy quinoline is prepared by nitration of 8-hydroxyquinoline. Accordingly, the compound 8-hydroxyquinoline was charged in water at ambient temperature. The mixture was cooled and added conc. sulphuric acid at 0-40oC. Slowly added aqueous solution of sodium nitrite and the mixture was stirred at the same temperature. Adjusted the pH to 5.0 with sodium hydroxide solution. The slurry was filtered, purified and dried to obtain the desired product.

In another embodiment, the present invention discloses an improved, cost effective process for producing ICH grade nitroxoline wherein said process comprising;
i. Nitrating 8-hydroxyquinoline to obtain 5-Nitroso-8-hydroxy quinoline by a process known in art;
ii. Oxidizing 5-Nitroso-8-hydroxy quinoline of step (i) with a oxidizing agent in a mixture of water and water miscible organic solvent at a temperature in the range of 10-35oC;

and
iii. Recrystallizing the crude nitroxoline of step (ii) from acetone, water, DMF or mixture thereof to obtain ICH grade nitroxoline as yellow to yellowish brown shinning powder free from genotoxic impurities such as 7-Nitro nitroxoline and 5-Nitroso-8-hydroxyquinoline.

The water miscible organic solvent is selected from lower alcohols such as methanol, ethanol, propanol; ketones such as acetone; dialkyl amides such as dimethyl formamide (DMF), N,N dimethyl acetamide (DMAc), dimethyl sulfoxide (DMSO) and the like or mixtures thereof; preferably the organic solvent is lower alcohol.

The oxidizing reagents for step (i) include nitric acid, hydrogen peroxide or oxygen gas; preferably nitric acid.

The re-crystallization is carried out at a temperature in the range of 20-100oC.
In an embodiment, pure Nitroxoline prepared by the present process as yellow to yellowish brown powder contain less than 0.01% of undesired 7-nitro nitroxoline impurity and 5-Nitroso-8-hydroxy quinoline which is below quantification Limit (BQL).
In a preferred embodiment, pure Nitroxoline prepared by the present process as yellow to yellowish brown powder contain less than 0.005% of undesired 7-Nitro Nitroxoline impurity and 5-Nitroso-8-hydroxyquinoline which is below quantification Limit (BQL).

The advantage of the present process is that the use of solvent mixture of water and organic solvent during the oxidation of 5-Nitroso-8-hydroxy Quinoline significantly controls the formation of 7-Nitro nitroxoline which is considered as genotoxic material. The use of DMF- acetone mixture or pure acetone improves the quality of nitroxoline evident from its change from brownish green soil color material to yellow to yellowish brown shining material.

Experimental:
Example 1: Preparation of 5-Nitroso-8-hydroxyquinoline
To a 3 neck round bottom flask was charged water (1000 ml) and 8-hydroxyquinoline (100gm) at ambient temperature. It was then cooled and added concentrated sulfuric acid (40ml) at 15-20oC. Slowly added the aqueous solution of sodium nitrite (20gm, 200ml water). The mixture was stirred for 80min at the same temperature. Adjusted the pH to 5.0 with sodium hydroxide solution. The slurry was filtered and the wet cake was purified with methanol, dried to yield the title product. Yield: 95gm
Comparative Example 2&3:
Preparation of Nitroxoline crude
To a 3 neck round bottom flask was charged water (3vol) and 5-Nitroso-8-hydroxyquinoline (100gm), stirred, cooled to 10 ºC and added nitric acid (2 vol) slowly at 10-35ºC over a period of 3-5hr. After completion of reaction adjusted the pH to 4-5 with aqueous sodium hydroxide. The slurry was filtered and the wet cake was washed with water, dried to obtain the title product. Yield: 97gm

Example Batch No. HPLC purity
Nitroxoline 7-Nitro nitroxoline impurity
2 RD/NTX/II/19/104 93.55% 6.23%
3 RD/NTX/II/19/109 93.88% 5.78%

Example 4& 5: Preparation of Nitroxoline crude (present invention)
To a 3 neck round bottom flask was charged water (3 vol) and methanol (1vol) at ambient temperature and added 5-Nitroso-8-hydroxyquinoline (50gm) material, stirred and cooled to 10ºC. The concentrated nitric acid (2 vol) was slowly added at 10-35ºC over a period of 3-5hr. After completion of reaction adjusted pH 4-5 with aqueous sodium hydroxide. The slurry was filtered and the wet cake was washed with water, dried to obtain the title product as greenish powder. Yield: 53gm

Example Batch No. HPLC purity
5-Nitro Nitroxoline 5-Nitro Nitroxoline
4 RD/NTX/II/20/073 99.05% 0.67%
5 RD/NTX/II/20/076 98.80% 0.94%

Note: 7-Nitro Nitroxoline percentage impurity has been significantly controlled by the present process.

Example 6 (a): Purification of Nitroxoline Crude
To a 3 neck round bottom flask was charged crude nitroxoline (50gm) and dimethyl formamide (4 vol) at ambient temperature and raised the temperature to 70-80?. Stirred the mixture and added water (8vol) slowly, cooled to room temperature and filtered. The wet material was dried under hot air oven to obtain the title product as brownish green color powder, yield 45gm.
The nitroxoline obtained in example 6 (a) was brownish green color powder with improper lumpy poor texture the process required an additional crystallization step to improve the description of the material.

Example 6(b):
To a 3 neck round bottom flask was charged the purified nitroxoline material of example 6(a) and DMF (4 vol) and raised the temperature to 70-80? to get the clear solution. Activated carbon was added, stirred and filtered out the activated carbon residue. Acetone (8 vol) was added slowly into filtrate to crystallize Nitroxoline. Filtered the slurry, the wet material was dried under reduced pressure to get the title product as yellow color powder with HPLC purity 99.99%, 5-Nitroso-8-hydroxyquinoline and 7-Nitro nitroxoline are below quantification Limit, (BQL, i.e. 0.005%) Yield: 80%.

Table 1: Process Comparison
Attributes Prior Art Process Present Process
7-Nitro Nitroxoline impurity formation during reaction 2.5 to 10% Less than 1.0%
Description Brownish green powder Yellow to yellowish brown powder
Yield (w/w from 8-Hydroxy Quinoline) 0.40 - 0.50 0.70 – 0.85
Number of Purification required to meet the HPLC limit test for 7-Nitro Nitroxoline i.e. <0.15% w/w 2-3 purification cycle is required Only one purification cycle

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.