Improved, cost-effective process for the production of nitroxoline

Abstract

An improved and cost effective process for the preparation of nitroxoline (5-nitro-8-oxoquinoline) free from process related genotoxic impurities is disclosed herein. The process of the present invention significantly controls the formation of an undesirable by-product, i.e. 7-nitro nitroxoline, during the oxidation of 5-nitroso-8-hydroxyquinoline and results in an improved yield and purity of the product.

Description

Invention Field

[0001] This invention relates to an improved and cost-effective process for preparing nitrohydroxyquinoline (5-nitro-8-hydroxyquinoline) free from process-related genotoxic impurities. The method of this invention significantly controls the formation of the undesirable byproduct 7-nitronitrohydroxyquinoline during the oxidation of 5-nitro-8-hydroxyquinoline, resulting in improved product yield and purity. Background of the Invention

[0002] Nitrohydroxyquinoline, also known as 5-nitro-8-hydroxyquinoline with antibacterial activity, is typically prepared by nitrosation of 8-hydroxyquinoline with sodium nitrite, followed by oxidation with nitric acid to obtain 5-nitroso-8-hydroxyquinoline. However, this traditional oxidation process generates a large amount of the unwanted impurity 7-nitro-nitrohydroxyquinoline, which is difficult to remove and requires numerous purification steps to obtain pure nitrohydroxyquinoline. This purification process is cumbersome and significantly reduces the yield.

[0003]

[0004] RU2702004C2 relates to a method for producing pharmacopoeia-grade 5-nitro-8-hydroxyquinoline using industrial nitroquinoline. The process involves adding activated carbon to industrial nitroquinoline in a first acetone carrier, followed by adding commercial acetone to a second carrier. The ratio of commercial acetone to regenerated acetone in the first carrier is 2:3. The reactants are then heated to 60±5°C and maintained at that temperature for 1.0–2.0 hours. The reactants are then transferred through a filter in a crystallization reactor to a pre-added purified water carrier, and the reactants are cooled to 20±5°C and maintained for 1.5–3.0 hours. The resulting pharmacopoeia-grade nitroquinoline paste is filtered, squeezed, and washed with purified water. The chloride and sulfate content in the paste is then analyzed until the chloride content does not exceed 0.02% and the sulfate content does not exceed 0.02%. The pharmacopoeia-grade nitroquinoline paste is then transferred to a temperature of 60±15°C for drying until the mass loss during drying does not exceed 0.5%.

[0005] SU609284A1 discloses a method for preparing pharmacopoeia-grade nitrohydroxyquinoline, wherein the oxidation of 5-nitroso-8-hydroxyquinoline is carried out under controlled conditions in an organic solvent, namely acetic acid, and purified in acetone at a temperature of 20-50°C. Purification is achieved by transferring the resulting product to hydrochloride and crystallizing it from dilute hydrochloric acid. This process is not advantageous because it cannot control the formation of 5-nitronitrohydroxyquinoline, a process-related genotoxic byproduct of the oxidation of 5-nitroso-8-hydroxyquinoline, even after purification. Nitrohydroxyquinoline and 5-nitronitrohydroxyquinoline have poor solubility in most organic solvents, requiring approximately 40-50 volumes of acetone for single-stage purification, necessitating multiple purifications to achieve the desired quality.

[0006] All reported processes for producing nitroquinoline are inefficient and cumbersome, making them unsuitable for the commercial production of ICH-grade active pharmaceutical ingredients. The inventors have discovered that nitroquinoline obtained by conventional methods is a dull, odorless, and poorly flowable green-brown to yellowish-brown powder, which is not desirable for tablet formulators.

[0007] Therefore, there is a need in the art for an improved process for preparing ICH grade nitrohydroxyquinoline that is cost-effective and commercially viable. The inventors have surprisingly discovered that, during the oxidation and recrystallization steps, a unique solvent system can be used to obtain ICH grade yellow to yellowish-brown shiny powder nitrohydroxyquinoline free of process-related genotoxic impurities. This is also the object of this invention. Summary of the Invention

[0008] Based on the above, the present invention provides an improved and cost-effective method for producing ICH grade nitrohydroxyquinoline, wherein the method includes:

[0009] i. Oxidation of 5-nitroso-8-hydroxyquinoline with an oxidizing agent in a mixture of water and a water-soluble organic solvent to obtain crude nitrohydroxyquinoline; and

[0010] ii. Recrystallize the crude nitrohydroxyquinoline from step (i) from acetone, water, DMF or a mixture thereof to obtain a yellow to yellowish-brown nitrohydroxyquinoline luminescent powder free from process-related genotoxic impurities (e.g., 7-nitronitrohydroxyquinoline and 5-nitroso-8-hydroxyquinoline).

[0011] The water-soluble organic solvent used in the oxidation process in step (i) is selected from lower alcohols, ketones (such as acetone), dialkylamides, dimethyl sulfoxide, or mixtures thereof.

[0012] The oxidizing agent is nitric acid, hydrogen peroxide, or oxygen.

[0013] The crude nitrohydroxyquinoline in step (ii) is recrystallized using acetone, water, DMF, or a mixture thereof to obtain a yellow to yellowish-brown pure nitrohydroxyquinoline powder containing less than 0.005% of unwanted 7-nitro-nitrohydroxyquinoline impurities and 5-nitroso-8-hydroxyquinoline, below the limit of quantitation (BQL).

[0014] In another aspect, 5-nitroso-8-hydroxyquinoline is obtained by nitrification of 8-hydroxyquinoline using methods known in the art. Detailed Implementation

[0015] The invention will now be explained in detail with reference to various preferred and preferred embodiments thereof; however, this should not be construed as limiting the scope of the invention.

[0016] In one embodiment, the present invention relates to an improved, cost-effective method for producing ICH grade nitrohydroxyquinoline, wherein the method comprises:

[0017] i. Oxidation of 5-nitroso-8-hydroxyquinoline with an oxidizing agent in a mixture of water and a water-soluble organic solvent to obtain crude nitrohydroxyquinoline; and

[0018]

[0019] ii. Recrystallize the crude nitrohydroxyquinoline from step (i) from acetone, water, DMF or a mixture thereof to obtain a yellow to yellowish-brown nitrohydroxyquinoline luminescent powder free from process-related genotoxic impurities (e.g., 7-nitronitrohydroxyquinoline and 5-nitroso-8-hydroxyquinoline).

[0020] According to step (i) of the present invention, water and a water-soluble organic solvent are added to 5-nitroso-8-hydroxyquinoline in a reactor, the mixture is stirred and cooled to about 10°C. An oxidant is added to the cooled mixture at a temperature ranging from 10 to 35°C for about 3 to 5 hours. After the reaction is complete, the pH is adjusted with an alkali, and the slurry is filtered, washed, and dried to produce green powdered crude nitrohydroxyquinoline.

[0021] The water-soluble organic solvent is selected from lower alcohols such as methanol, ethanol, and propanol; ketones such as acetone; and dialkylamides such as dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), or mixtures thereof; preferably, the organic solvent is a lower alcohol.

[0022] The oxidant in step (i) includes nitric acid, hydrogen peroxide or oxygen, preferably nitric acid.

[0023] Recrystallization is carried out in the temperature range of 20-100℃.

[0024] Step (ii) involves adding dimethylformamide (DMF) to crude nitrohydroxyquinoline and raising the temperature. The mixture is stirred, then water is slowly added, and the reaction mixture is cooled to room temperature and filtered. The content of 7-nitrohydroxyquinoline in the wet material is checked, and the process is repeated until the content of 7-nitrohydroxyquinoline is 0.5% NMT. ​​The wet material is dried to obtain nitrohydroxyquinoline in the form of a brownish-green powder.

[0025] The purified nitroquinoline obtained above was then recrystallized, including purifying the nitroquinoline with DMF by heating to obtain a clear solution. Activated carbon was then added, stirred, and filtered to remove activated carbon residue. Acetone was slowly added to the filtrate to crystallize the nitroquinoline. The slurry was filtered, and the wet material was dried under reduced pressure to obtain a high-purity yellow powder of nitroquinoline, with genotoxic impurities below the limit of quantitation (BQL).

[0026] In another embodiment, compound 5-nitroso-8-hydroxyquinoline was prepared by nitrifying 8-hydroxyquinoline. Therefore, compound 8-hydroxyquinoline was added to water at ambient temperature. The mixture was cooled and concentrated sulfuric acid was added at 0-40°C. An aqueous solution of sodium nitrite was slowly added, and the mixture was stirred at the same temperature. The pH was adjusted to 5.0 with a sodium hydroxide solution. The slurry was filtered, purified, and dried to obtain the desired product.

[0027] In another embodiment, the present invention discloses an improved, cost-effective method for producing ICH grade nitrohydroxyquinoline, wherein the method comprises:

[0028] i. Nitrate 8-hydroxyquinoline to obtain 5-nitroso-8-hydroxyquinoline by methods known in the art;

[0029] ii. Oxidize the 5-nitroso-8-hydroxyquinoline in step (i) with an oxidant in a mixture of water and a water-soluble organic solvent within a temperature range of 10-35°C;

[0030]

[0031] and

[0032] iii. Recrystallize the crude nitrohydroxyquinoline from step (ii) from acetone, water, DMF or a mixture thereof to obtain ICH grade nitrohydroxyquinoline, which is a yellow to yellowish-brown luminescent powder free from genotoxic impurities such as 7-nitronitrohydroxyquinoline and 5-nitroso-8-hydroxyquinoline.

[0033] The water-soluble organic solvent is selected from lower alcohols such as methanol, ethanol, and propanol; ketones such as acetone; and dialkylamides such as dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), or mixtures thereof; preferably, the organic solvent is a lower alcohol.

[0034] The oxidizing agent in step (i) includes nitric acid, hydrogen peroxide, or oxygen; nitric acid is preferred.

[0035] Recrystallization is carried out in the temperature range of 20-100℃.

[0036] In one embodiment, the pure nitrohydroxyquinoline powder prepared by this method contains less than 0.01% of unwanted 7-nitronitrohydroxyquinoline impurities and 5-nitroso-8-hydroxyquinoline, below the limit of quantitation (BQL).

[0037] In a preferred embodiment, the pure nitrohydroxyquinoline powder prepared by this process contains less than 0.005% of unwanted 7-nitronitrohydroxyquinoline impurities and 5-nitroso-8-hydroxyquinoline, below the limit of quantitation (BQL).

[0038] The advantage of this process is that the use of a solvent mixture of water and organic solvents during the oxidation of 5-nitroso-8-hydroxyquinoline significantly controls the formation of 7-nitro-nitro-hydroxyquinoline, which is considered a genotoxic substance. Using a DMF-acetone mixture or pure acetone can significantly improve the quality of nitro-hydroxyquinoline, changing it from a brownish-green soil-colored substance to a yellow to yellowish-brown luminescent substance.

[0039] Example:

[0040] Example 1: Preparation of 5-nitroso-8-hydroxyquinoline

[0041] At ambient temperature, add water (1000 ml) and 8-hydroxyquinoline (100 gm) to a three-necked round-bottom flask. Then cool and add concentrated sulfuric acid (40 ml) at 15-20°C. Slowly add an aqueous solution of sodium nitrite (20 gm, 200 ml water). Stir the mixture for 80 minutes at the same temperature. Adjust the pH to 5.0 with sodium hydroxide solution. Filter the slurry, purify the wet filter cake with methanol, and dry to obtain the target product. Yield: 95 gm

[0042] Comparative Examples 2 and 3:

[0043] Preparation of crude nitrohydroxyquinoline

[0044] Add water (3 vol) and 5-nitroso-8-hydroxyquinoline (100 gm) to a three-necked round-bottom flask, stir, cool to 10°C, and slowly add nitric acid (2 vol) at 10-35°C over 3-5 hours. After the reaction is complete, adjust the pH to 4-5 with sodium hydroxide aqueous solution. Filter the slurry, wash the wet filter cake with water, and dry to obtain the target product. Yield: 97 gm

[0045]

[0046] Examples 4 and 5: Preparation of crude nitrohydroxyquinoline (this invention)

[0047] Water (3 vol) and methanol (1 vol) were added to a three-necked round-bottom flask at ambient temperature, followed by the addition of 5-nitroso-8-hydroxyquinoline (50 gm). The mixture was stirred and cooled to 10°C. Concentrated nitric acid (2 vol) was slowly added at 10°C-35°C over 3-5 hours. After the reaction was complete, the pH was adjusted to 4-5 with an aqueous sodium hydroxide solution. The slurry was filtered, the wet filter cake was washed with water, and dried to obtain the target product, a green powder. Yield: 53 gm

[0048]

[0049] Note: The percentage of 7-nitronitrohydroxyquinoline impurities has been significantly controlled through this process.

[0050] Example 6(a): Purification of crude nitrohydroxyquinoline

[0051] At ambient temperature, crude nitrohydroxyquinoline (50 gm) and dimethylformamide (4 vol) were added to a three-necked round-bottom flask, and the temperature was raised to 70-80°C. The mixture was stirred, water (8 vol) was slowly added, the mixture was cooled to room temperature, and filtered. The wet material was dried in a hot air furnace to obtain the target product, a brownish-green powder, in a yield of 45 gm.

[0052] The nitrohydroxyquinoline obtained in Example 6(a) was a brownish-green powder with an undesirable blocky texture. This process requires an additional crystallization step to improve the material's properties.

[0053] Example 6(b):

[0054] The purified nitrohydroxyquinoline material from Example 6(a) and DMF (4 vol) were loaded into a three-necked round-bottom flask, and the temperature was raised to 70-80°C to obtain a clear solution. Activated carbon was added, stirred, and the activated carbon residue was filtered off. Acetone (8 vol) was slowly added to the filtrate to crystallize nitrohydroxyquinoline. The slurry was filtered, and the wet material was dried under reduced pressure to obtain the target product as a yellow powder with an HPLC purity of 99.99%. 5-Nitro-8-hydroxyquinoline and 7-nitronitrohydroxyquinoline were below the limit of quantitation (BQL, i.e., 0.005%). Yield: 80%.

[0055] Table 1: Process Comparison

[0056]

[0057] Although the invention has been described in detail above for illustrative purposes, it should be understood that such details are for that purpose only, and those skilled in the art can make changes thereto without departing from the spirit and scope of the invention, unless it may be limited by the claims.

Claims

1. A method for producing ICH grade nitrohydroxyquinoline, characterized in that... The method includes; i. On 10-35 o At temperature C, 5-nitroso-8-hydroxyquinoline was oxidized with nitric acid in a mixture of water and the water-soluble organic solvent methanol to give crude nitrohydroxyquinoline; and ii. Add dimethylformamide (DMF) to crude nitrohydroxyquinoline and raise the temperature; stir the mixture, then slowly add water and cool the reaction mixture to room temperature, then filter; check the 7-nitrohydroxyquinoline content in the wet material, and repeat the process until the 7-nitrohydroxyquinoline content is NMT 0.5%; dry the wet material to obtain brown-green powdered nitrohydroxyquinoline; The purified nitrohydroxyquinoline obtained above was then recrystallized, including purifying nitrohydroxyquinoline with DMF by heating to obtain a clear solution; Then add activated charcoal, stir, and filter to remove any activated charcoal residue; Acetone was slowly added to the filtrate to crystallize nitrohydroxyquinoline; the slurry was filtered and the wet material was dried under reduced pressure to obtain high-purity yellow powdered nitrohydroxyquinoline, wherein 5-nitroso-8-hydroxyquinoline and 7-nitronitrohydroxyquinoline were below the limit of quantitation.

2. The method according to claim 1, wherein the recrystallization in step (ii) is carried out in a temperature range of 20-100°C.

3. The method for producing ICH grade nitrohydroxyquinoline as described in claim 1, comprising: i. Nitrating 8-hydroxyquinoline by methods known in the art to obtain 5-nitroso-8-hydroxyquinoline; ii. Oxidize 5-nitroso-8-hydroxyquinoline in step (i) with nitric acid in a mixture of water and water-soluble organic solvent methanol within a temperature range of 10-35°C; and iii. Add dimethylformamide (DMF) to crude nitrohydroxyquinoline and raise the temperature; stir the mixture, then slowly add water and cool the reaction mixture to room temperature, then filter; check the 7-nitrohydroxyquinoline content in the wet material, and repeat the process until the 7-nitrohydroxyquinoline content is NMT 0.5%; dry the wet material to obtain brown-green powdered nitrohydroxyquinoline; The purified nitrohydroxyquinoline obtained above was then recrystallized, including purifying nitrohydroxyquinoline with DMF by heating to obtain a clear solution; Then, activated carbon is added, stirred, and filtered to remove activated carbon residue; acetone is slowly added to the filtrate to crystallize nitrohydroxyquinoline; the slurry is filtered, and the wet material is dried under reduced pressure to obtain high-purity yellow powdered nitrohydroxyquinoline, free from genotoxic impurities 7-nitrohydroxyquinoline and 5-nitroso-8-hydroxyquinoline.

4. The method according to claim 3, wherein the recrystallization in step (iii) is carried out in a temperature range of 20-100°C.

5. The method according to any one of claims 1-4, wherein the obtained nitrohydroxyquinoline has 7-nitronitrohydroxyquinoline and 5-nitroso-8-hydroxyquinoline impurities, both less than 0.01%.

6. The method according to claim 5, wherein the obtained nitrohydroxyquinoline has 7-nitronitrohydroxyquinoline and 5-nitroso-8-hydroxyquinoline impurities, both of which are less than 0.005%.

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