Claims:1) An improved process for the preparation of Eltrombopag or its olamine salts comprising:

a) reacting 1-Bromo-2-methoxy-3-nitrobenzene(II) with 3-Carboxyphenyl boronic acid(III) in presence of a coupling agent to form 3-nitro-2-methoxybiphenyl-3-carboxylic acid(IV);

b) hydrolyzing 3-nitro-2-methoxybiphenyl-3-carboxylic acid (IV) in presence of acid to yield 3-nitro-2-hydroxybiphenyl-3-carboxylic acid (V);

c) reducing 3-nitro-2-hydroxybiphenyl-3-carboxylic acid (V) in presence of reducing agent to yield 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI);

d) purification of 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI), wherein the purification process involves:
• dissolving 3-amino-2-hydroxybiphenyl-3-carboxylic acid in presence of solvent;
• heating the reaction mixture to reflux temperature;
• slowly adding acid solution and then followed by isolation of acid salt;
• dissolving acid salt in a solvent and then followed by basification using a base;
• isolating pure 3-amino-2-hydroxybiphenyl-3-carboxylic acid;
e) cyclizing 3,4-(dimethylphenyl)hydrazine(VII) with ethylacetoacetate to form 1-(3,4-(dimethylphenyl)-3-methyl-1,2-dihydro pyrazyl-5-one (VIII);

f) condensing 1-(3,4-(dimethylphenyl)-3-methyl-1,2-dihydro pyrazyl-5-one(VIII) with 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) in presence of base to yield Eltrombopag(I); and

g) optionally converting Eltrombopag to its olamine salt.

2) An improved process for the preparation of Eltrombopag or its olamine salts according to claim 1, wherein coupling agent is selected from palladium acetate, Tetrakis(triphenyl phosphene)palladium(0), palladium(II)trifluoroacetate, ammonium tetrachloropalladate, palladium(II)acetate, Bis (dibenzylidene acetone) palladium(0), Bis(acetonitrile) dichloro palladium(II) more preferably palladium acetate.

3) An improved process for the preparation of Eltrombopag or its olamine salts according to claim 1, wherein acid hydrolysis is performed in presence of acid selected from hyrobromic acid, hydrochloric acid, acetic acid, sulphuric acid, nitric acid, formic acid, benzoic acid.
4) An improved process for the preparation of Eltrombopag or its olamine salts according to claim 1, wherein acid reducing agents selected from Palladium on carbon, palladium, Platinum, Raney nickel, Hydrazine solution with Raney nickel, Nickel(II) bis(acetylacetonate) in presence of Hydrogen or Iron, Tin and Zinc in presence of acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid.

5) An improved process for the preparation of Eltrombopag or its olamine salts according to claim 1, wherein solvent in step (d) is selected from acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; from methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, t-butyl alcohol, water and mixtures there of more preferably isopropyl alcohol; acid solution is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, acetic acid; base is selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate the organic base selected from triethyl amine, Dimethyl amine, t-butylamine, pyridine.

6) An improved process for the preparation of Eltrombopag or its olamine salts according to claim 1, wherein base is selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate the organic base selected from triethyl amine, methyl amine, t-butylamine, pyridine.

7) An improved process for the preparation of olamine salt of Eltrombopag (I) comprising reacting Eltrombopag free acid with ethanolamine without using any solvent to produce bis-ethanolamine salt of Eltrombopag.

8) An improved process for the preparation of Eltrombopag or its olamine salts, wherein purification of 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) involves:
• dissolving 3-amino-2-hydroxybiphenyl-3-carboxylic acid in presence of solvent;
• adding anti solvent;
• isolating pure 3-amino-2-hydroxybiphenyl-3-carboxylic acid.

9) An improved process for the preparation of Eltrombopag or its olamine salts according to claim 8, wherein solvent is selected from acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone.

10) An improved process for the preparation of Eltrombopag or its olamine salts according to claim 8, wherein anti-solvent is selected from methanol, ethanol, isopropyl alcohol n-butanol, ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of compound of formula (I) and its pharmaceutical acceptable salts thereof.

The present invention relates to a process for the preparation of highly pure Eltrombopag (I).

BACKGROUND OF THE INVENTION
Eltrombopag Olamine is a biphenyl hydrazine chemically known as 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid -2-aminoethanol (1:2). Eltrombopag is used for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have an insufficient response to corticosteroids, immunoglobulins, or splenectomy. (1.1) and thrombocytopenia in patients with chronic hepatitis-C to allow the initiation and maintenance of interferon-based therapy and patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy and it is approved by USFDA November 20, 2008 under the brand name Promacta®.

Eltrombopag is marketed in the form of crystalline Olamine salt, which is a crystalline solid, red/brown, sparingly soluble in water. It is thermally stable up to about 125°C. The empirical formula of Eltrombopag Olamine is C25H22N4O4 • 2(C2H7NO) and molecular weight is 564.65 for Eltrombopag Olamine and 442.5 for eltrombopag free acid.

Eltrombopag and its pharmaceutical acceptable salts are first disclosed in US 7,160, 870 B2. This patent disclosed a process for the preparation of Eltrombopag monohydrate, which is shown schematically in below scheme:

The free acid is poorly soluble in water (approximately 5 micrograms per milliliter). This poor solubility adversely affects the ability of the free acid to be formulated into pharmaceutical dosage forms and reduces the bioavailability of the compound in vivo. The processes disclosed in the literature involve several chemical steps and provide the product in a very low overall yield. The given processes involve use of methyl iodide which is expensive and exhibits moderate to high acute toxicity for inhalation and ingestion and result into an expensive process for the preparation of the intermediate and the final Eltrombopag API.

Pliva in et al US 7,547,719 B2 discloses the process for the preparation of Eltrombopag mono and bis-ethanolamine salt. This is schematically represented as below

The process proposed involves the preparation of Eltrombopag olamine from Eltrombopag free acid. It is always advantageous to prepare Eltrombopag Olamine without isolation of Eltrombopag. Direct preparation of Eltrombopag olamine from Eltrombopag free acid reduces one isolation and drying operation which helps in enhancing throughput of the product during commercialization. However, this process involves the use of additional solvent in the last stage of the chemical reaction, which in turn results in Eltrombopag olamine with residual solvents exceeds the ICH guidelines.

Nasir et al in WO20170042839 discloses Eltrombopag tromethamine salt and its process for the preparation thereof.

Krishnaji et al in WO2013072921A2 discloses ammonium salt of Eltrombopag and its preparation. IP.com journal, volume 9, issue 12A, 2009 discloses t-butylamine salt and meglumine salt of Eltrombopag.

Shashi et al in WO 2019229572A1 discloses purification process of Eltrombopag Olamine salt by the using of anti-solvent. Further this patent also discloses process for the preparation of 2-(benzyloxy)-l-bromo-3-nitrobenzene in the presence of phase transfer catalyst.

Further review of the available literature regarding Eltrombopag Olamine discloses various other processes for its preparation. However, due to one or more drawbacks with respect to the production of side products, the use of expensive coupling reagents, less than desirable yields, and the need for multiple reaction steps, most of them are not particularly convenient and economical for industrial scale up.

Hence, there is an unmet need to develop improved, cost effective and industrially amenable processes for the preparation of Eltrombopag Olamine involving lesser number of steps and providing higher yield of end product with better purity.

Therefore, inventors of the present application provide a simple high yielding process for preparation of highly pure Eltrombopag which overcomes the disadvantages associated with prior disclosed literature methods.

OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide an improved process for the preparation of Eltrombopag and its olamine salts.

Yet another object of the present invention is to provide an improved process for the preparation of Eltrombopag intermediates.

Yet another object of the invention is to provide an improved process for the preparation of highly pure Eltrombopag and its olamine salts.

SUMMARY OF THE INVENTION
The main aspect of the present invention relates to an improved process for the preparation of Eltrombopag or its olamine salts comprising:

a) reacting 1-Bromo-2-methoxy-3-nitrobenzene(II) with 3-Carboxyphenyl boronic acid(III) in presence of a coupling agent to form 3-nitro-2-methoxybiphenyl-3-carboxylic acid(IV);

b) hydrolyzing 3-nitro-2-methoxybiphenyl-3-carboxylic acid (IV) in presence of acid to yield 3-nitro-2-hydroxybiphenyl-3-carboxylic acid (V);

c) reducing 3-nitro-2-hydroxybiphenyl-3-carboxylic acid (V) in presence of reducing agent to yield 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI);

d) purification of 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI), wherein the purification process involves:
• dissolving 3-amino-2-hydroxybiphenyl-3-carboxylic acid in presence of solvent;
• heating the reaction mixture to reflux temperature;
• slowly adding acid solution and then followed by isolation of acid salt;
• dissolving acid salt in a solvent and then followed by basification using a base;
• isolating pure 3-amino-2-hydroxybiphenyl-3-carboxylic acid;
e) cyclizing 3,4-(dimethylphenyl)hydrazine(VII) with ethylacetoacetate to form 1-(3,4-(dimethylphenyl)-3-methyl-1,2-dihydro pyrazyl-5-one (VIII);

f) condensing 1-(3,4-(dimethylphenyl)-3-methyl-1,2-dihydro pyrazyl-5-one(VIII) with 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) in presence of base to yield Eltrombopag(I); and

g) optionally converting Eltrombopag to its olamine salt.

Another aspect of the present invention relates to an improved process for the preparation of olamine salt of Eltrombopag (I) comprising reacting Eltrombopag free acid with ethanolamine without using any solvent to produce bis-ethanolamine salt of Eltrombopag.

In another aspect of the present invention relates to an improved process for the preparation of Eltrombopag or its olamine salts, wherein purification of 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) involves:
• dissolving 3-amino-2-hydroxybiphenyl-3-carboxylic acid in presence of solvent;
• adding anti solvent;
• isolating pure 3-amino-2-hydroxybiphenyl-3-carboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved, commercially viable and industrially –advantageous process for the preparation of Eltrombopag and its pharmaceutically acceptable salts thereof.
The present invention relates to an improved process for the preparation of Eltrombopag and its olamine salt having a purity of greater than 99.5%.

The main embodiment of the present invention relates to an improved process for the preparation of Eltrombopag or its olamine salts comprising reacting 1-Bromo-2-methoxy-3-nitrobenzene(II) with 3-Carboxyphenyl boronic acid(III) in presence of a coupling agent selected from palladium acetate, Tetrakis(triphenyl phosphene)palladium(0), palladium(II)trifluoroacetate, ammonium tetrachloropalladate, palladium(II)acetate, Bis (dibenzylidene acetone) palladium(0), Bis(acetonitrile) dichloro palladium(II) more preferably palladium acetate; wherein the process involves dissolving coupling agent in a solvent selected from alcohol such as methanol, ethanol, isopropyl alcohol n-butanol and thereof, stir the reaction mass for 10 to 30 minutes at 25-35°C; followed by addition of base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide and lithium carbonate under nitrogen atmosphere, followed by addition of 1-Bromo-2-methoxy-3-nitrobenzene (II) and 3-Carboxyphenyl boronic acid (III) and maintaining the reaction at 40-70°C for a period of 4 to 5 hours. Filtered the reaction mass through hyflow bed and then washed with water. Adjust the pH of the reaction mass with Concentrated hydrochloric acid and continued stirring for 30 minutes to 1 hour 30 minutes at 80-85°C. Cool the reaction mass to 10-15°C and maintain the reaction mass for 2-3 hours at 10-15°C. Filtered the product and wash the wet cake with water. Dry the material for 12 to 14 hours at 55-60°C to yield highly pure to form 3-nitro-2-methoxybiphenyl-3-carboxylic acid (IV).

The above obtained pure 3-nitro-2-methoxybiphenyl-3-carboxylic acid (IV) undergo hydrolysis; wherein the process involves dissolving 3-nitro-2-methoxybiphenyl-3-carboxylic acid in an acid selected from hyrobromic acid, hydrochloric acid, acetic acid, sulphuric acid, nitric acid, formic acid, benzoic acid or mixtures thereof preferably HBr in acetic acid; followed by addition of water and maintain the reaction mass for 10-11 hours at 80-130°C; cool the reaction mass to 25-35°C and then slowly added water for 1 hour to 2 hours, filter the reaction mass and wash the wet cake with water. Dry the material at 50-60°C for a period of 10 hours to 15 hours to yield 3-nitro-2-hydroxybiphenyl-3-carboxylic acid (V).

The obtained 3-nitro-2-hydroxybiphenyl-3-carboxylic acid (V) undergo reduction; wherein the process involves dissolving 3-nitro-2-hydroxybiphenyl-3-carboxylic acid (V) in a solvent selected from ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate, acetic acid or mixtures there of; adding reducing agents selected from Palladium on carbon, palladium, Platinum, Raney nickel, Hydrazine solution with Raney nickel, Nickel(II) bis(acetylacetonate) in presence of Hydrogen or Iron, Tin and Zinc in presence of acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid in to reaction mass. The reaction is continued under reduction chamber under hydrogen atmosphere for a period of 5 hours to 8 hours; after completion of the reaction the reaction mass was heated to 50- 70°C and dimethyl formamide was added slowly in to the reaction mass; distill off the aqueous layer and adjusted the pH of the reaction mass to 3.5-4.5 using sodium bicarbonate solution; followed by cooling the reaction mass to 5-10°C. filter the product and dry the material at 50-70°C for a period of 10 hours to 15 hours to yield 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI).

The above obtained 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) had a purity of 97 to 98% with formation of major unknown impurity at around 2 % at RRT -3.02.

To overcome the issues, the present invention involves the purification of 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) by dissolving 3-amino-2-hydroxybiphenyl-3-carboxylic acid in a solvent selected from acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; from methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, t-butyl alcohol, water and mixtures there of; heating the reaction mixture to reflux temperature and then slowly adding acid solution selected from hydrochloric acid, hydrobromic acid, sulphuric acid, acetic acid; maintain the reaction mass for 1 hour to 3 hours at 25-35°C to yield; filter the product and isolate of acid salt of 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI).

The obtained acid salt of 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) was basified using a base; wherein the process involves dissolving the obtained acid salt in a water and adjusting the pH of the reaction mass using a base selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate the organic base selected from triethyl amine, Dimethyl amine, t-butylamine, pyridine; cooling the obtained reaction mass to 5-10°C; followed by filtration and drying at 55-60°C for a period of 10- 15 hours to yield highly pure 3-amino-2-hydroxybiphenyl-3-carboxylic acid having a purity of greater than 99.5% by HPLC.

In another aspect of the present invention relates an improved process for the preparation of Eltrombopag or its olamine salts, wherein purification of 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) involves dissolving 3-amino-2-hydroxybiphenyl-3-carboxylic acid in presence of solvent selected from selected from acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone at a temperature ranging from 25- 35°C and maintaining the reaction mass for 1 hours to 3 hours, followed by addition of anti-solvent selected from methanol, ethanol, isopropyl alcohol n-butanol, ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate. Followed by filtration and drying for a period for a period of 10- 15 hours to yield highly pure 3-amino-2-hydroxybiphenyl-3-carboxylic acid having a purity of greater than 99.5% by HPLC.

The other intermediate 1-(3,4-(dimethylphenyl)-3-methyl-1,2-dihydro pyrazyl-5-one (VIII) is obtained by cyclizing 3,4-(dimethylphenyl)hydrazine(VII) with ethylacetoacetate; wherein the process involves dissolving 3,4-(dimethylphenyl)hydrazine(VII) in a solvent selected from such as Dichloro methane, n-hexane, n-heptane, cyclohexane, cycloheptane; aromatic hydrocarbons such as toluene, xylene; alcohols like ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, t-butyl alcohol or mixture thereof; followed by addition of ethylacetoacetate at room temperature; maintain the reaction mass at 40-45°C for 4 hours to 6 hours; distill of solvent and then charge toluene and water; separate the organic layer and the pH of the reaction mass was adjusted with acid between 6.5 and 7; cooled the reaction mass to 10-15°C; filter the material and wash with water; dry the material at 55-60°C for 10- 15 hours to yield 1-(3,4-(dimethylphenyl)-3-methyl-1,2-dihydro pyrazyl-5-one (VIII);

The above obtained 1-(3,4-(dimethylphenyl)-3-methyl-1,2-dihydro pyrazyl-5-one(VIII) is condensed with 3-amino-2-hydroxybiphenyl-3-carboxylic acid (VI) in presence of base to yield Eltrombopag(I); wherein the process involves dissolving the reactants in solvent selected from ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, 2-methyl tetrahydrofuran; in the presence of sodium nitrate at 0-5 °C. maintain the reaction mass for 30 minutes to 1 hour at 0-5°C. Adjust the pH of the reaction mass with base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, triethylamine, diisopropyl amine, diisopropylethylamine and pyridine; maintain the reaction ass for 3hours to 4 hours at 15-20°C; Adjust the pH of the reaction mass between 1.0 to 2.0 at 0-5°C; filter the material and dry the material at 40-60°C for 10 hours to 15 hours to produce Eltrombopag free acid of formula (I).

In an another embodiment of the present invention relates to an improved process for the preparation of olamine salt of Eltrombopag (I) comprising reacting Eltrombopag free acid with ethanolamine without using any solvent to produce bis-ethanolamine salt of Eltrombopag; where in the process involves dissolving Eltrombopag in ethanolamine and heating the reaction mass to 60-65°C. maintain the reaction mass for 30 minutes to 1 hour 30 minutes at 60-65°C. cool the reaction mass 25-30°C and main the reaction mass for 12 hours. After completion of the reaction, acetone was added for free flow and filter the reaction mass, followed by drying for 20- 25 hours at 80-90°C under vacuum to yield highly pure Eltrombopag olamine.

According to the present invention, the said methods should in particular be more industrially scalable, allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle and industrial applicable.

On the other hand, the prior art process does not suggest the particular process for the preparation of Eltrombopag. Further, the prior art processes involve the use of excess solvents and reagents, further involves distillation of solvent and purifications, which leads in the decomposition of product and lowering the quantity of yield.

The merit of the process according to the present invention resides in this process, after formation of Eltrombopag Olamine salt does not involve the any further purifications, prior art process is involving the use of excess of solvents for the purification which is impact on product yield and quality. The Eltrombopag or its pharmaceutically acceptable salts obtained by the process of the present invention results in the final API purity by HPLC of more than 99.7% w/w and found to be stable at different ICH conditions.

To overcome the above disadvantage the inventors of the present invention developed a process, which is industrially liable, viable and environmentally friendly.

The obtained pure Eltrombopag or its pharmaceutically acceptable salts having purity greater than 99.7% and substantially free from process related impurities:

The process related impurities that appear in the impurity profile of the Eltrombopag may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Eltrombopag or its pharmaceutically acceptable salts (I) obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from Eltrombopag or its pharmaceutically acceptable salts (I) of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
Example-1:
Preparation of 1-(3, 4-dimethylphenyl)-3-methyl-1, 2-dihydro pyrazol-5-one:
3,4-dimethylphenylhydrazine or its hydrochloride salt (50 gm, 0.2896 mol), ethyl acetoacetate (45.2 gm, 0.3475 mol) and dichloromethane (250 ml) were charged into a round bottom flask at 25-30° C. The obtained reaction mass was stirred for 10-15 minutes. Raise the temperature to 40-45°C and continued stirring for 5-6 hours. Distilled off the solvent from the reaction mass under vacuum at below 60° C to get to get brown color solid. Toluene (2 × 150 ml) was added to solid and distilled out the solvent under vacuum to get brown color solid. pH of the reaction mass was adjusted to 6.5 to 7.0 using 20% hydrochloric acid. Cool the reaction mass to 10-15°C and continued the stirring for 1 hour to 2 hours. Filter the reaction mass and dried under vacuum to obtain title compound.
Purity: 99.85%
Yield: 90.0 gm

Example-2:
Preparation of 3'-nitro-2'-methoxybiphenyl-3-carboxylic acid:
1-bromo-2-methoxy-3-nitrobenzene (100 g, 0.0431 mol), 3-carboxyphenyl boronic acid (92.9g, 0.0560 mol) were charged in to a reaction flask containing isopropyl alcohol (2000 ml), purified water (500 ml), sodium carbonate (96 gm, 0.086 mol) and stir for one hour at 25-35°C. Slowly add palladium acetate (0.5g, 0.00022 mol) to the reaction mixture under nitrogen atmosphere at 25-35°C. Stir the reaction mass to 15 minutes at same temperature. Raise the temperature of reaction mass 60-65° C under nitrogen atmosphere and maintain for 4-5 hours. The reaction mass was treated with activated carbon and washed with purified water. pH of the reaction mass was adjusted with con HCl and stir for 30 minutes at room temperature. Raise the reaction mass temperature 80-85°C and maintain for 30 minutes. After completion the reaction the reaction mixture was allowed to 25-30 °C and filtered to solid. The solid was filtered and dried to yield 3'-nitro-2'-methoxybiphenyl-3-carboxylic acid.
Purity: 99.60%
Yield: 94.5 gm

Example-3:
Preparation of 3'-nitro-2'-hydroxybiphenyl-3-carboxylic acid:
3'-nitro-2'-methoxybiphenyl-3-carboxylic acid (85.0 gm, 0.3111 mol) was dissolved in HBr in acetic acid (1020 ml) and stir for 10-15 minutes at 25-35°C. water (225 ml) was added to the reaction mixture at same temperature and stir for 15 minutes. The temperature of the reaction mass was raised to 110°-120°C and continued stirring for 10-12 hours, after completion of the reaction, the reaction mass was cooled to 25-35°C. Slowly add water (850 ml) to the reaction mass and stir for 1-2 hours at room temperature to get wet solid. The solid was filtered and dried to get 3'-nitro-2'-hydroxybiphenyl-3-carboxylic acid.
Purity: 99.48%
Yield: 83.0-gm

Example-4
Preparation of Preparation of 3'-Amino-2'-hydroxy-[1, 1'-biphenyl]-3-carboxylic acid:
3'-nitro-2'-hydroxybiphenyl-3-carboxylic acid (65.0 gm, 0.2507mol) was added to a mixture of ethylacetate (1625 ml) and acetic acid (65.0 ml) and stir the reaction mass at 25-35°C for a period of 10 minutes to 20 minutes. To the reaction mass Pd on carbon (3.25 gm )was added to the reaction mixture at room temperature under hydrogen atmosphere. Maintain the reaction mass at 9-10 kg/cm2 pressure of hydrogen gas for 5-6hrs at 25-35°C. Raise the temperature 60-65° C and maintain for 1 hour. After completion of the reaction, dimethyl formamide (325 ml) and activated carbon was added to the reaction mass and stir for 45 minutes at 60-65° C. Cool the reaction mass to 25-35°C and washed with ethyl acetate and dimethylformamide. Charge water (650 ml) in to reaction mass at 25-35°C and stir for 15 minutes. Adjust the reaction mass pH to 4.0-5.0 with 40 ml of 8% sodium bicarbonate solution at 25-35°C and stir for 20 minutes. Cool the reaction mass to 5-10° C and maintain for one hour to get a wet solid. The solid was filtered and dried to get 3'-amino-2'-hydroxy-[1, 1'-biphenyl]-3-carboxylic acid.
Purity: 97.59%
Yield: 64.0gm

Example-5
Purification of 3'-Amino-2'-hydroxy-[1, 1'-biphenyl]-3-carboxylic acid
3'-amino-2'-hydroxy-[1, 1'-biphenyl]-3-carboxylic acid (45 gm) was dissolved in acetone (900 ml) and stir for 15 minutes at 25-35°C. Raise the temperature 55-60° C and maintain for 30 minutes. Slow addition of IPA.HCl (225 ml) to the above reaction mass for 30-45 minutes at 25-35°C and stir for one hour at 55-60°C. Cool the reaction mass to 25-35°C. Filtered the product and washed with acetone and suck dried for 2 hours. The obtained wet material (acid salt) was dissolved in water (225 ml) and stir for 15 minutes at room temperature. pH of the obtained reaction mass was adjusted to 4-5 with 160 ml 8% Sodium bicarbonate solution at 25-35°C and stir for 20 minutes at same temperature. Cool the reaction mass to 5-10° C and maintain for one hour at same temperature. Filtered the product and washed with water and dried for for12-14 hours at 55-60°C under vacuum to get pure 3'-Amino-2'-hydroxy-[1, 1'-biphenyl]-3-carboxylic acid.
Purity: 99.50%
Yield: 43.0-gm

Example-6
Preparation of Eltrombopag Free acid
3'-amino-2'-hydroxy-[1, 1'-biphenyl]-3-carboxylic acid (30 gm, 0.1309 mol) was added in to a reaction flask containing 1N HCl (450.0 mL) and tetrahydrofuran (300.0 mL) and the reaction mass was stirred for 15 minutes at 25-35°C. Cool the reaction mass 0-5° C, charge chilled sodium nitrite solution (8.5 gm sodium nitrite+150 ml water) over a period of 30-45 minutes at 0-5° C. Stir the reaction mass and maintain for 30 minutes at 0-5° C. pH of the reaction mass adjusted to 9 to 10 using TEA (70 ml) at 0-5°C. 1-(3, 4-dimethylphenyl)-3-methyl-1, 2-dihydro pyrazol-5-one (27 gm, 0.133 mol) was added to reaction mixture at 0-5° C and stir for 30 minutes. Heat the reaction mass 15-20° C and maintain for 3 hours. After completion of the reaction, the reaction mass was cooled to 0-5° C and adjust the pH 1.0-2.0 with 6N HCl (60 ml) and stir for 2 hours at 0-5° C. The wet material was filtered and suck dried for 2 hours.
Purification of Eltrombopag free acid:
The wet material obtained was dissolved in ethanol (750 ml) and stir 10 minutes at 25-35°C. Raise the reaction mass to 70-72°C and maintain for 2 hours. Cool the reaction mass to 25-35°C to get solid. Filter the wet solid and washed with ethanol. The obtained wet solid was dissolved in tetrahydrofuran and stir for 10 minutes at room temperature. Heat the reaction mass to 60-65° C and maintain for one hour. Filter the reaction mass and washed with tetrahydrofuran. The filtrate was taken in to round bottom flask and stir for 10 minutes at room temperature. Raise the reaction mass temperature to 60-65°C and water (810 ml) was added to the reaction mass over the period of 45-60 minutes at 60-65°and maintain for one hour. Cool the reaction mass to 25-35°C and stir for one hour to obtain the solid. Filtered the product, washed with water and dried for 14-16 hours at 55-60° C under vacuum to yield pure Eltrombopag.
Purity: 99.25%
Yield: 14.0-gm

Example-7
Preparation of Eltrombopag Olamine
100 gm of Eltrombopag was added to the 250 ml of ethanolamine at room temperature and stir for 10-15 minutes. Raise the reaction mass temperature to 60-65°C and maintain for one hour. Cool the reaction mass to room temperature and maintain for 12 hours. Add acetone (1000 ml) to the reaction mass and stir for one hour at 25-35°C. Filtered the solid and washed with acetone and dried for 24 hours at 85-90°C under vacuum.
Purity: 99.75%
Yield: 110.0-gm