DESC: “IMPROVED PROCESS FOR THE PREPARATION OF ELTROMBOPAG OLAMINE”

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Eltrombopag Olamine and also relates to a process for the purification of Eltrombopag free acid.

BACKGROUND OF THE INVENTION

Eltrombopag is a thrombopoietin receptor agonist, which was approved in US under the brand name of Promacta® and Revolade® in most countries outside the US. It is used for the treatment of thrombocytopenia (abnormally low platelet counts) and severe aplastic anemia and is marketed worldwide by Novartis.

Eltrombopag is commercialized in pharmaceutical compositions comprising this active pharmaceutical ingredient in form of Eltrombopag Olamine or ETP Olamine, i.e. a salt of ETP with ethanolamine in 1:2 ratios, also called Eltrombopag bisethanolamine salt of formula (Ia).

Eltrombopag (I) along with pharmaceutically acceptable salts, hydrates, solvates and esters thereof, disclosed first time in US 7160870. US ‘870 patent discloses a process for the preparation of Eltrombopag (I), which comprises 3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid (III) with 2-(3,4-dimethylphenyl)-5-methyl-1H-pyrazol-3-(2H)-one (II) in presence of sodium nitrite, hydrochloric acid and ethanol/water to produce Eltrombopag (I).
The above process is schematically shown as below:
Scheme 1
IPCOM000212582D reported recrystallization of crude Eltrombopag Olamine from a mixture of monoethanolamine and one or more solvents like ethanol.
U.S. Pat. No. 7,956,048 B2 discloses different crystalline forms of Eltrombopag free acid as well as process for the preparation of crystalline forms.

U.S. Pat. No. 10,336,706 B2 discloses crystalline Form H1 of Eltrombopag free acid and its process for preparation from dimethyl formamide and alcoholic solvents selected from methanol, ethanol, n-butanol, and isopropanol.

WO 2015111085A2 discloses crystalline Form Z of Eltrombopag free acid and its process for preparation from dimethyl formamide and ethanol.

The prior art preparation of Eltrombopag free acid and Eltrombopag Olamine 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 process of Eltrombopag Olamine and purification process of Eltrombopag free acid, which for example, use reagents/solvents 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 Eltrombopag free acid and Eltrombopag Olamine 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 Eltrombopag Olamine with high yield and purity and also relates to a process for the purification of Eltrombopag free acid 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 Eltrombopag Olamine and also relates to a process for the purification of Eltrombopag free acid.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Eltrombopag Olamine and also relates to a process for the purification of Eltrombopag free acid.

One embodiment of the present invention provides, an improved process for the preparation of Eltrombopag Olamine (Ia), comprising the steps of:

a) reacting compound of formula (II) with compound of formula (III) in presence of acid and nitrating agent in a solvent to obtain the compound of formula (I),

b) dissolving the Eltrombopag (I) in a solvent,
c) heating the reaction mixture at suitable temperature,
d) cooling the reaction mixture,
e) adding an anti-solvent to the resulting solution,
f) isolating the pure Eltrombopag (I), and
g) converting Eltrombopag (I) into Eltrombopag Olamine (Ia).

In yet another embodiment of the invention provides, a process for the purification of Eltrombopag free acid, which process comprises the steps of:
i. Eltrombopag (I) is dissolved in a solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adding an anti-solvent to the resulting solution, and
v. isolating the pure Eltrombopag (I).

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

One embodiment of the present invention provides, an improved process for the preparation of Eltrombopag Olamine (Ia), comprising the steps of:
a) reacting compound of formula (II) with compound of formula (III) in presence of acid and nitrating agent in a solvent to obtain the compound of formula (I),

b) dissolving the Eltrombopag (I) in a solvent,
c) heating the reaction mixture at suitable temperature,
d) cooling the reaction mixture,
e) adding an anti-solvent to the resulting solution,
f) isolating the pure Eltrombopag (I), and
g) converting Eltrombopag (I) into Eltrombopag Olamine (Ia).

In yet another embodiment of the invention provides, a process for the purification of Eltrombopag free acid, which process comprises the steps of:
i. Eltrombopag (I) is dissolved in a solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adding an anti-solvent to the resulting solution, and
v. isolating the pure Eltrombopag (I).
In an embodiment of the present invention by reacting compound of formula (II) with compound of formula (III) in presence of acid and nitrating agent in a solvent, the reaction is carried out at 0 to 5°C for 45 to 60 min, followed by add base to the reaction mass and maintained for 18 to 24 hours at 20 to 35ºC to obtain Eltrombopag (I). Eltrombopag (I) is dissolved in a solvent and heating the reaction mixture at suitable temperature, preferably temperature at 70 to 75°C. Cooling the reaction mixture at 25 to 30°C and adding an anti-solvent to the resulting solution. Isolating the pure Eltrombopag (I), and converting Eltrombopag (I) into Eltrombopag Olamine (Ia) from ethanolamine and solvent consisting of methanol, ethanol, isopropyl alcohol, THF and water.

In a specific embodiment of the present invention, a process for the purification of Eltrombopag free acid by Eltrombopag (I) is dissolved in dimethyl sulfoxide (DMSO) as a solvent and heating the reaction mass at 60 to 80ºC. Adding ethanol as an anti-solvent to the resulting solution and isolating the pure Eltrombopag free acid (I).

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

According to an embodiment of the present invention, wherein the suitable acid selected used in the present invention can be 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.

According to an embodiment of the present invention. wherein the nitrating agent is selected from ammonium nitrate (NH4NO3), sodium nitrite (NaNO2), silver nitrate (AgNO3) and isoamyl nitrate.

According to an embodiment of the present invention. wherein the solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; 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 anti-solvent is selected from
methanol, ethanol, isopropyl alcohol, n-butanol and/or mixtures thereof.

According to an embodiment of the present invention, wherein reaction carried out base selected from triethylamine, tert-butylamine, pyridine, diazabicycloundecane (DBU); sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate (sodium bicarbonate), 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 lithium hydroxide, sodium chloride, sodium hydroxide and triethylamine or mixtures thereof or other suitable bases.

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

EXAMPLES
Example-1: Preparation of pure Eltrombopag free acid:
Purified water (45ml), Conc. HCl (22.5ml), 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (25 gm) and tetrahydrofuran (25ml) were added in a round bottom flask at 25-30°C and stir for 30 min. The reaction mass was allowed to cool at 0-5°C, add sodium nitrite solution (7.5gm sodium nitrite dissolved in purified water 25ml) at 0-5°C and stir for 60 min, followed by charged 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (22gm) at below 10°C, further followed by add sodium bicarbonate (45gm) and tetrahydrofuran (25ml) at below 20°C. The reaction mass was maintained at 25-30°C for 20-24 hours. After completion of the reaction add dilute hydrochloric acid (45ml) at 25-30°C, check the reaction mass pH it should be 1.0-2.0 and stir for 30 min. Then product was filtered and washed with purified water (25ml). The obtained wet product was dried at 60-65°C for 8-10 hours to get Eltrombopag crude (55 gm). Crude Eltrombopag was dissolved in dimethyl sulfoxide (200ml) at room temperature. The reaction mass heated to 70-75°C and stir for 20-30 min at same temperature. The reaction mixture was allowed to cool at 25-30°C, followed by added ethanol (400 ml) and stir for 60 min. Thus the obtained product was filtered and washed with ethanol (10ml), unload the material. Wet product was dried at 60-65°C to obtained the orange colour material of pure Eltrombopag free acid.
Yield: 95% (46g),
Purity: 99.8% by HPLC.

Example-2: Purification of pure Eltrombopag free acid:
Crude Eltrombopag (100gm) was dissolved in dimethyl sulfoxide (500ml) at room temperature. The reaction mass heated to 70-75°C and stir for 20-30 min at same temperature. The reaction mixture was allowed to cool at 25-30°C, followed by added ethanol (1000 ml) and stir for 60 min. Thus the obtained product was filtered and washed with ethanol (100ml), unload the material. Wet product was dried at 60-65°C to obtained the orange colour material of pure Eltrombopag free acid.
Yield: 95% (95g),
Purity: 99.8% by HPLC.

Example-3:
Preparation of pure Eltrombopag Olamine (Ia):
Eltrombopag (25gm) was added into ethanolamine (50gm) at 25-30°C and stir for 60min, followed by add methanol (125ml) at 55-60°C and stir for 1 to 2 hours. The reaction mass was allowed to cool at 25-30°C, filter the material wash with methanol (25ml). The obtained product dried at 60-65°C to get the brown color material of pure Eltrombopag Olamine.
Yield: 88% (28g),
Purity: 99.8% by HPLC.

,CLAIMS:WE CLAIM:
1. An improved process for the preparation of Eltrombopag Olamine (Ia), comprising the steps of:
a) reacting compound of formula (II) with compound of formula (III) in presence of acid and nitrating agent in a solvent to obtain the compound of formula (I),

b) dissolving the Eltrombopag (I) in a solvent,
c) heating the reaction mixture at suitable temperature,
d) cooling the reaction mixture,
e) adding an anti-solvent to the resulting solution,
f) isolating the pure Eltrombopag (I), and
g) converting Eltrombopag (I) into Eltrombopag Olamine (Ia).

2. The process as claimed in claim 1, wherein the suitable acid selected from "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.
3. The process as claimed in claim 1, wherein the nitrating agent is selected from ammonium nitrate (NH4NO3), sodium nitrite (NaNO2), silver nitrate (AgNO3) and isoamyl nitrate.

4. A process for the purification of Eltrombopag free acid, which process comprises the steps of:
i. Eltrombopag (I) is dissolved in a solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adding an anti-solvent to the resulting solution, and
v. isolating the pure Eltrombopag (I).

5. The process as claimed in claims 1 and 4, wherein the solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; 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.

6. The process as claimed in claims 1 and 4, wherein the anti-solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol and/or mixtures thereof.

7. The process as claimed in claims 1 and 4, wherein the suitable temperature is carried out at 70 to 75°C.

Dated this fourth (04th) day of August, 2023.