DESC:“IMPROVED PROCESS FOR THE PREPARATION OF OZENOXACIN”

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Ozenoxacin and also relates to a process for the purification of Ozenoxacin.

BACKGROUND OF THE INVENTION

Ozenoxacin (INN; trade names Ozaenex and Xepi) is a quinolone antibiotic being approved for the treatment of impetigo. 1% topical cream is approved for treatment of impetigo in Canada and in the United States. Ozenoxacin is active against some bacteria that have developed resistance to currently used quinolone and fluoroquinolone antibiotics. It is a non-fluorinated quinolone with dual inhibitory activity against bacterial DNA replication enzymes, DNA gyrase A and topoisomerase IV.

Ozenoxacin is chemically known as 1-cyclopropyl-8-methyl-7-(5-methyl-6-methylamino-pyridin-3-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid of formula (I) has the following structure.

Ozenoxacin was first described in example 4 of US 6,335,447 B1, wherein the process is disclosed by compound of formula (IV) is reacted with the compound of formula (VII) in presence of PdCl2(PPh3)2 /toluene to get the compound of formula (V), followed by hydrolysis in presence of NaOH /ethanol/HCl to get the compound of formula (VI). The compound of formula (VI) is deprotecting with Conc. HCl/water to get Ozenoxacin (I). The process is schematically shown as below:

Scheme 1
CN107304198 A discloses a process for the preparation of Ozenoxacin by reacting the compound of formula (X) with compound of formula (IV) in presence of Pd(dppf)2Cl2 / K2CO3 and 1,4-dioxane. The process is schematically shown as below:

Scheme 2
The prior-art preparations of Ozenoxacin with low yield, purity and formation of impurities. The removal of the impurities from the final API requires various techniques to get a purified compound.

The present invention need an alternative preparative routes for improved process of Ozenoxacin and its purification process thereof, which for example, use reactants are less expensive and/or easier to handle, consume smaller amounts of reagents, eco-friendlier to provide a higher yield and good purity of product, further the present invention pure Ozenoxacin substantially free from impurities.

Therefore, it is necessary to design a safer and more environmentally-friendly synthetic route. So, our inventors have developed an improved process for the preparation of Ozenoxacin with high yield and purity and also relates to a process for the purification of Ozenoxacin with high yield and purity, a low-cost, environmentally-friendly, and efficient synthesis method.

OBJECT OF THE INVENTION

The present invention relates to an improved process for the preparation of Ozenoxacin and also relates to a process for the purification of Ozenoxacin.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Ozenoxacin and also relates to a process for the purification of Ozenoxacin.

One embodiment of the present invention provides, an improved process for the preparation of Ozenoxacin (I), which comprises the steps of:

a) compound of formula (IX) is reacting with compound of formula (XI) in presence of base, catalyst and ligand in a suitable solvent to produce the compound of formula (XII),

b) compound of formula (XII) is hydrolysing with acid to produce in-situ compound of formula (XIII),

c) in-situ compound of formula (XIII) is deprotecting with acid to produce Ozenoxacin (I), and

d) isolating Ozenoxacin.

In yet another embodiment of the invention provides, a process for the purification of Ozenoxacin, which comprises the steps of:
i. Ozenoxacin is dissolved in a suitable solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adjusting the pH of the solution obtained in step-(iii) with suitable base,
v. suspending the compound obtained in step-(iv) in suitable solvent,
vi. adjusting the pH of the solution obtained in step-(v) with suitable acid,
vii. suspending the compound obtained in step-(vi) in suitable solvent, and
viii. isolating the pure Ozenoxacin.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Ozenoxacin and also relates to a process for the purification of Ozenoxacin.

One embodiment of the present invention provides, an improved process for the preparation of Ozenoxacin (I), which comprises the steps of:

a) compound of formula (IX) is reacting with compound of formula (XI) in presence of base, catalyst and ligand in a suitable solvent to produce the compound of formula (XII),

b) compound of formula (XII) is hydrolysing with acid to produce in-situ compound of formula (XIII),

c) in-situ compound of formula (XIII) is deprotecting with acid to produce Ozenoxacin (I), and

d) isolating Ozenoxacin.

In an embodiment of the present invention by compound of formula (IX) is reacting with compound of formula (XI) in presence of base, catalyst and ligand in a suitable solvent, the reaction is carried out at 75 to 90ºC for 18 to 20 hrs to produce compound of formula (XII). Compound of formula (XII) is hydrolysing with acid and the reaction carried out at 75 to 100°C for 8-12 hrs to produce the in-situ compound of formula (XIII), followed by add acid and the reaction carried out at 75 to 100°C for 4-6 hrs to produce Ozenoxacin.

In yet another embodiment of the invention provides, a process for the purification of Ozenoxacin, which comprises the steps of:
i. Ozenoxacin is dissolved in a suitable solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adjusting the pH of the solution obtained in step-(iii) with suitable base,
v. suspending the compound obtained in step-(iv) in suitable solvent,
vi. adjusting the pH of the solution obtained in step-(v) with suitable acid,
vii. suspending the compound obtained in step-(vi) in suitable solvent, and
viii. isolating the pure Ozenoxacin.

In an embodiment of the present invention, a process for the purification of Ozenoxacin, which comprises the steps of: Ozenoxacin is dissolved in a suitable solvent and heating the reaction mixture at suitable temperature, preferably heating the reaction mass at 40 to 70ºC for 45-65 min. Cool the reaction mass and adjusting the pH (11.5-13.5) with suitable base, suspending the obtained reaction mixture in suitable solvent, separate the two layers and adjusting the pH (6.5 to 7.5) of the resulting solution with suitable acid. Stir the reaction mass at 15-20°C for 1-2 hours. The obtained solid was dissolved in suitable solvent at ambient temperature. The reaction mass was heated to 70-80°C and stir for 30 min. cool, filtered and isolate the pure Ozenoxacin (I).

According to an embodiment of the present invention provides Ozenoxacin having HPLC purity = 99.8%.

According to an embodiment of the present invention, wherein base is selected from triethylamine, tert-butylamine, pyridine, diazabicycloundecane (DBU); sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium hydride, lithium hydroxide, lithium tert-butoxide, Sodium tert-butoxide, potassium tert-butoxide, Caesium hydroxide, potassium carbonate or potassium hydrogen carbonate. According to a more preferred embodiment the base is potassium carbonate, sodium carbonate, sodium hydroxide and triethylamine or mixtures thereof or other suitable bases.

According to an embodiment of the present invention, wherein catalyst is selected from tetrakis(triphenylphosphine) palladium (0), palladium (II) acetate, tris(dibenzylideneacetone)dipalladium (0), Pd(dppf)Cl2, Dichlorobis (tricyclohexylphosphine) palladium(II); preferably tetrakis (triphenylphosphine) palladium (0).

According to an embodiment of the present invention, wherein ligand is selected from trimethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tolylphosphine, tri-o-tolylphosphine, X-phos, BINAP and bis(diphenylphosphino)methane; preferably tri-o-tolylphosphine.

According to an embodiment of the present invention. wherein the suitable solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and or mixtures thereof.

According to an embodiment of the present invention, wherein the acid selected from but not limited to "inorganic acids" such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, carbonic acid; and "organic acids" such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, succinic acid, citric acid, uric acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, salicylic acid, oleic acid, octanoic acid, stearic acid, mandelic acid, adepic acid, pivalic acid, camphorsulfonic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, naphthalenesulfonic acid and or mixtures thereof.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example-1: Preparation of Ethyl 1-cyclopropyl-8-methyl-7-(5-methyl-6-(N-methylpivalamido) pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Ethyl 7-chloro-1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (50 gr), 1,4-dioxane (500 ml), (5-methyl-6-(N-methylpivalamido) pyridin-3-yl) boronic acid (60 gr), potassium carbonate (25 gr), tris(o-tolyl)phosphine (5gr) and water (100 ml) were charged into around bottom flask and stir for 1 hr at under nitrogen atmosphere, followed by add tetrakis(triphenylphosphine)palladium (0) (0.3 gr) at 25-35°C. The reaction mixture was stir for 20 hr at 80-90°C. The reaction mixture was cooled to 25-35°C, charged with water (250 ml) and dichloromethane (250ml), stir for 30min and separated two layers. Take dichloromethane layer distilled. The obtained reaction mass was charge with mixture of isopropyl alcohol (50ml) and methyl tert-butyl ether (200ml). The obtained product was filtered and washed with isopropyl alcohol (50 ml) to get the wet compound. The obtained wet compound was charged with isopropyl alcohol (250 ml), heated to 70-80°C and stir for 2 hr. The obtained reaction solution was allowed to cool at 25-35° and stirred for 2 hr. The obtained solid was filtered and washed with isopropyl alcohol (50 ml) to get pure title compound.
Yield: 88% (68.5 gr).
Purity: ~ 96% by HPLC
Example-2: Preparation of Ozenoxacin
Ethyl 1-cyclopropyl-8-methyl-7-(5-methyl-6-(N-methylpivalamido) pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (50 gr), hydrochloric acid (50 ml) and water (400 ml) were charged in a round bottom flask. The reaction mixture was heated to 80-l00°C and stir for 10 hr at same temperature. The reaction mixture was allowed to cool at 25-35°C. The obtained solid was filtered and washed with water (50 ml), followed by charged with hydrochloric acid (120 ml) and water (250 ml). The reaction mixture was heated to 80-l00°C and stir for 4-6hr at same temperature. The reaction mixture was allowed to cool at 25-35°C. The obtained solid was filtered and washed with water (50 ml) to get crude Ozenoxacin.
Yield: 98% (37.5 gr).

Purity: ~ 99% by HPLC

Example-3: Purification process of Ozenoxacin

Methanol (240 ml) was charge into crude Ozenoxacin (30.0gr) in RB flask. The reaction mixture was heated at 45-65°C for 50-65 min and then it was allowed to cool at ambient temperature. The obtained solid was filtered and washed with methanol (50 ml), followed by adjust pH:11.5-13.5 with 50% aqueous sodium hydroxide solution (20 mL) and wash with dichloromethane (40 mL). Separate the two layers and added isopropyl alcohol (30ml) to aqueous layer, followed by adjust pH: 6-8 with aqueous hydrochloric acid (~5.0 mL) and stir the reaction mass at 15-20°C for 1-2 hours. The obtained solid was adding in dimethylformamide (400ml) at ambient temperature. The reaction mass was heated to 70-80°C and stir for 30 min at same temperature. The obtain solid was precipitate out and stir the solid for 30 minutes. The obtain filtered cake was washed with methanol (50ml) and water (250ml). The obtained product was dried to give the pure Ozenoxacin as pale yellow colour powder.
Yield: 95% (28.5 gr).
Purity: = 99.8% by HPLC

,CLAIMS:1. An improved process for the preparation of Ozenoxacin (I), which comprises the steps of:
a) compound of formula (IX) is reacting with compound of formula (XI) in presence of base, catalyst and ligand in a suitable solvent to produce the compound of formula (XII),

b) compound of formula (XII) is hydrolysing with acid to produce in-situ compound of formula (XIII),

c) in-situ compound of formula (XIII) is deprotecting with acid to produce Ozenoxacin (I), and

d) isolating Ozenoxacin.

2. A process for the purification of Ozenoxacin, which comprises the steps of:
i. Ozenoxacin is dissolved in a suitable solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adjusting the pH of the solution obtained in step-(iii) with suitable base,
v. suspending the compound obtained in step-(iv) in suitable solvent,
vi. adjusting the pH of the solution obtained in step-(v) with suitable acid,
vii. suspending the compound obtained in step-(vi) in suitable solvent, and
viii. isolating the pure Ozenoxacin.

3. The process as claimed in claims 1 and 2, wherein the base is selected from triethylamine, tert-butylamine, pyridine, diazabicycloundecane (DBU); sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydride, lithium hydroxide, lithium tert-butoxide, Sodium tert-butoxide, potassium tert-butoxide, Caesium hydroxide, potassium carbonate or potassium hydrogen carbonate or mixtures thereof.

4. The process as claimed in claim 1, wherein the catalyst is selected from tetrakis(triphenylphosphine) palladium (0), palladium (II) acetate, tris (dibenzylideneacetone)dipalladium (0), Pd(dppf)Cl2, Dichlorobis (tricyclohexylphosphine) palladium (II).

5. The process as claimed in claim 1, wherein the ligand is selected from trimethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tolylphosphine, tri-o-tolylphosphine, X-phos, BINAP and bis(diphenylphosphino)methane.

6. The process as claimed in claims 1 and 2, wherein the suitable solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and or mixtures thereof.

7. The process as claimed in claims 1 and 2, wherein the acid selected from but not limited to "inorganic acids" such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, carbonic acid; and "organic acids" such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, succinic acid, citric acid, uric acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, salicylic acid, oleic acid, octanoic acid, stearic acid, mandelic acid, adepic acid, pivalic acid, camphorsulfonic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and or mixtures thereof.