DESC: “IMPROVED PROCESS FOR THE PREPARATION OF ELTROMBOPAG OLAMINE BY USING AMINE SALTS”

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Eltrombopag Olamine by using amine salts and also relates to a process for the purification of Eltrombopag amine salts.

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
US 20180273490A1 discloses process for the preparation of Eltrombopag Olamine, which involves Eltrombopag is reacted with diisopropylethylamine in THF to produce Eltrombopag diisopropylethylamine salt (Ib), and it is followed by reacted with bis-ethanolamine to produce Eltrombopag Olamine (Ia). The above process is schematically shown as below:

The process disclosed in US ‘490 is isolating the Eltrombopag free acid, further treated with diisopropylethylamine (amine) and followed by treated with ethanolamine. The main disadvantage of this process is formation of amine impurities, hence this leads to the multiple purification steps required to isolate the pure compound of final API.
The prior art preparation of Eltrombopag Olamine with low yield, purity and formation of amine impurities. The removal of the impurities from the final API, which take multiple purification techniques required.

The present invention improved process for the preparation of Eltrombopag Olamine and also purification process of Eltrombopag amine salts. The present invention eco-friendlier to provide a higher yield and good purity of Eltrombopag Olamine substantially free from impurities.

OBJECT OF THE INVENTION
The present invention relates to an improved process for the preparation of Eltrombopag Olamine by using amine salts and also relates to a process for the purification of Eltrombopag amine salts.

BRIEF DESCRIPTION OF THE FIGURES
1. Figure 1 shows a powder XRD pattern of crystalline Eltrombopag diisopropylethyl amine salt.
2. Figure 2 shows a powder XRD pattern of crystalline Eltrombopag diisopropylamine salt.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Eltrombopag Olamine by using amine salts and also relates to a process for the purification of Eltrombopag amine salts.

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, nitrating agent in a solvent and diisopropylethyl amine to obtain the compound of di- isopropyl ethyl amine salt of formula (Ib), and

b) converting diisopropyl ethyl amine salt of formula (Ib) into Eltrombopag Olamine (Ia).

Second 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, nitrating agent in a solvent and diisopropyl amine to obtain the compound of diisopropyl amine salt of formula (Ic), and

b) converting diisopropyl amine salt of formula (Ic) into Eltrombopag Olamine (Ia).

Third embodiment of the invention provides, a process for the purification of diisopropyl ethyl amine salt of Eltrombopag (Ib), which process comprises the steps of:
i. diisopropyl ethyl amine salt of Eltrombopag (Ib) 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 diisopropyl ethyl amine salt of Eltrombopag (Ib).

Fourth embodiment of the invention provides, a process for the purification of diisopropyl amine salt of Eltrombopag (Ic), which process comprises the steps of:
i. diisopropyl amine salt of Eltrombopag (Ic) 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 isopropyl amine salt of Eltrombopag (Ic)

DETAILED DESCRIPTION OF THE INVENTION

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, nitrating agent in a solvent and diisopropylethyl amine to obtain the compound of di- isopropyl ethyl amine salt of formula (Ib), and

b) converting diisopropyl ethyl amine salt of formula (Ib) into Eltrombopag Olamine (Ia).

According to 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, followed by add diisopropylethyl amine, maintained the reaction mass for 1 to 4 hours at 20 to 35ºC to obtain Eltrombopag diisopropyl ethyl amine salt of formula (Ib). Eltrombopag diisopropyl ethyl amine salt of formula (Ib) and charge solvent in round bottom flask at 25-30°C, then heat the reaction mass temperature to 60-70°C, filter the mass through watmann filter paper, distil out the filtrations mass below 60°C, cool the mass to 25-30°C, to charge ethanolamine in to reaction mass at 25-30°C and stir for 1-3 hours, heat the mass temperature to 50-75°C to add solvent 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 solvent. The obtained product dried at 60-65°C to get the brown color material of pure Eltrombopag Olamine..

Second 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, nitrating agent in a solvent and diisopropyl amine to obtain the compound of diisopropyl amine salt of formula (Ic), and

b) converting diisopropyl amine salt of formula (Ic) into Eltrombopag Olamine (Ia).

According to 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 diisopropylamine to the reaction mass and maintained for 2 to 4 hours at 20 to 35ºC to obtain Eltrombopag diisopropyl amine salt of formula (Ic). Eltrombopag diisopropyl amine salt of formula (Ic) and charge solvent in round bottom flask at 25-30°C, then heat the reaction mass temperature to 60-70°C, filter the mass through watmann filter paper, distil out the filtrations mass below 60°C, cool the mass to 25-30°C, to charge ethanolamine in to reaction mass at 25-30°C and stir for 1-3 hours, heat the mass temperature to 50-75°C to add solvent 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 solvent. The obtained product dried at 60-65°C to get the brown color material of pure Eltrombopag Olamine.

Third embodiment of the invention provides, a process for the purification of diisopropyl ethyl amine salt of Eltrombopag (Ib), which process comprises the steps of:
i. diisopropyl ethyl amine salt of Eltrombopag (Ib) 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 diisopropyl ethyl amine salt of Eltrombopag (Ib).

Fourth embodiment of the invention provides, a process for the purification of diisopropyl amine salt of Eltrombopag (Ic), which process comprises the steps of:
i. diisopropyl amine salt of Eltrombopag (Ic) 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 isopropyl amine salt of Eltrombopag (Ic).

According to an embodiment of the present invention, a process for the purification of Eltrombopag diisopropyl ethyl amine salt (Ib) or diisopropyl amine salt of formula (Ic) by Eltrombopag diisopropyl ethyl amine salt or diisopropyl amine salt is dissolved in dimethyl sulfoxide (DMSO) as solvent and heat the reaction mass at 60 to 80ºC, followed by adding ethanol as an anti-solvent. The resultant product was isolated to get pure Eltrombopag diisopropyl ethyl amine salt or diisopropyl amine salt.

According to an embodiment of the present invention provides Eltrombopag amine salts or Eltrombopag Olamine having HPLC purity = 99.98%.

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, a crystalline form of Eltrombopag diisopropylethyl amine salt characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 9.50, 9.61, 12.89, 17.48, 18.38, 19.28, 24.96 and 27.85 ±0.2 degrees 2?. A crystalline form of Eltrombopag diisopropylethyl amine salt characterized by a powder x-ray diffraction pattern substantially in accordance with figure 1.

According to an embodiment of the present invention, a crystalline form of Eltrombopag diisopropyl amine salt characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 8.62, 11.52, 12.33, 12.95, 17.25 and 25.37 ±0.2 degrees 2?. A crystalline form of Eltrombopag diisopropyl amine salt characterized by a powder x-ray diffraction pattern substantially in accordance with figure 2.

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

EXAMPLES
Example-1: Preparation of Eltrombopag diisopropyl ethylamine salt:
Purified water (75ml), Conc. HCl (22.5ml), 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (III) (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 lot-2-25ml) at 0-5°C and stir for 60 min, then charged 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (22gm) at below 10°C. Diisopropyl ethyl amine (50ml) and tetrahydrofuran (25ml) were adding to the obtain reaction mixture at below 20°C and the reaction mixture was maintained for 2-3 hours at 25-30°C. The obtained product was filtered and washed with purified water-3 (50ml) and followed by methanol (25ml), unload the material. Wet product was dried at 60-65°C to obtained the red colour material of Eltrombopag diisopropyl ethylamine salt.
Yield: 80% (50g),
Purity: = 99.98 % by HPLC.

Example-2: Purification of Eltrombopag diisopropyl ethylamine salt:
Crude Eltrombopag diisopropyl ethylamine salt (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 diisopropyl ethylamine salt.
Yield: 95% (95g),
Purity: = 99.0 % by HPLC.

Example-3:
Preparation of Eltrombopag Olamine (Ia) from Eltrombopag diisopropyl ethylamine salt:
Eltrombopag diisopropyl ethylamine salt (25gm) and charge methanol lot-1(375ml) in round bottom flask at 25-30°C, then heat the reaction mass temperature to 60-70°C, filter the mass through watmann filter paper, distil out the filtrations mass below 60°C, cool the mass to 25-30°C, to charge ethanolamine in to reaction mass (50gm) at 25-30°C and stir for 60min, heat the mass temperature to 55-60°C to add methanol lot-2 (125ml) at 55-60°C and stir for 1 to 2 hours. Mass was cool to 25-30°C, filter the material wash with methanol lot-3 (25ml). The obtained product dried at 60-65°C to get the brown color material of pure Eltrombopag Olamine.
Yield: 93% (23 g),
Purity: = 99.99% by HPLC.

Example-4: Preparation of Eltrombopag diisopropyl amine salt:
Purified water (75ml), Conc. HCl (22.5ml), 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (III) (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 lot-2-25ml) at 0-5°C and stir for 60 min, then charged 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (22gm) at below 10°C. Diisopropyl amine (50ml) and tetrahydrofuran (25ml) were adding to the obtain reaction mixture at below 20°C and the reaction mixture was maintained for 2-3 hours at 25-30°C. The obtained product was filtered and washed with purified water (25ml), unload the material. Wet product was dried at 60-65°C to obtained the brown colour material of crude Eltrombopag diisopropyl amine salt.
Yield: 85% (50g),
Purity: = 99.0 % by HPLC.

Example-5: Purification of Eltrombopag diisopropyl amine salt:
Crude Eltrombopag diisopropyl amine salt (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 Diisopropyl amine salt.
Yield: 90% (90g),
Purity: = 99.0 % by HPLC.

Example-6:
Preparation of Eltrombopag Olamine (Ia) from Eltrombopag diisopropyl amine salt:
Eltrombopag diisopropyl amine salt (25gm) and charge methanol lot-1(375ml) in round bottom flask at 25-30°C, then heat the reaction mass temperature to 60-70°C, filter the mass through watmann filter paper, distil out the filtrations mass below 60°C, cool the mass to 25-30°C, to charge ethanolamine in to reaction mass (50gm) at 25-30°C and stir for 60min, heat the mass temperature to 55-60°C to add methanol lot-2 (125ml) at 55-60°C and stir for 1 to 2 hours. Mass was cool to 25-30°C, filter the material wash with methanol lot-3 (25ml). The obtained product dried at 60-65°C to get the brown color material of pure Eltrombopag Olamine.
Yield: 92.3% (24 g),
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, nitrating agent in a solvent and diisopropylethyl amine to obtain the compound of di- isopropyl ethyl amine salt of formula (Ib), and

b) converting diisopropyl ethyl amine salt of formula (Ib) into Eltrombopag Olamine (Ia).

2. 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, nitrating agent in a solvent and diisopropyl amine to obtain the compound of diisopropyl amine salt of formula (Ic), and

b) converting diisopropyl amine salt of formula (Ic) into Eltrombopag Olamine (Ia).

3. A process for the purification of diisopropyl ethyl amine salt of Eltrombopag (Ib), which process comprises the steps of:
i. diisopropyl ethyl amine salt of Eltrombopag (Ib) 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 diisopropyl ethyl amine salt of Eltrombopag (Ib).

4. A process for the purification of diisopropyl amine salt of Eltrombopag (Ic), which process comprises the steps of:
i. diisopropyl amine salt of Eltrombopag (Ic) 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 isopropyl amine salt of Eltrombopag (Ic).

5. The process as claimed in claims 1 & 2, wherein the nitrating agent is selected from ammonium nitrate (NH4NO3), sodium nitrite (NaNO2), silver nitrate (AgNO3) and isoamyl nitrate.

6. The process as claimed in claims 1 & 2, wherein the acid selected "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.

7. The process as claimed in claims 1-4, wherein the solvent is selected from 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.

8. The process as claimed in claims 3 and 4, wherein the anti-solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol and/or mixtures thereof.