Claims:1) A process for the preparation of Eltrombopag olamine of Formula (I)

I
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in a suitable solvent with sodium nitrite in water to get a diazocompound of formula IVa in solution

IV IVa
b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III) to afford Eltrombopag acid in solution form

III
c. optionally adjusting pH up to 1-2 of the solution of step b. with an acid followed by extracting with an organic solvent.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II)

II
e. treating novel salt of eltrombopag (II) with ethanolamine in an organic solvent to afford Eltrombopag olamine of formula (I).
2) The process for the preparation of Eltrombopag olamine of formula (I), according to claim 1, wherein organic amine (X) used is selected from dicyclohexylamine or N-methyl morpholine to afford compound of formula IIa or IIb

IIa IIb
3) The process for the preparation of Eltrombopag olamine of formula (I), according to claim 1, wherein the acid used in the step c. is selected from hydrochloric acid, sulphuric acid and phosphoric acid.

4) The process for the preparation of Eltrombopag olamine of formula (I), according to claim 1, wherein the suitable solvent used in step a. is selected from water or tetrahydrofuran (THF) or 1,4-dioxane.

5) The process for the preparation of Eltrombopag olamine of formula (I), according to claim 1, wherein the organic solvent used in step c. or step e. is selected from acetonitrile or ketone solvents selected from acetone, methyl ethyl ketone (MEK) or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or alcoholic solvent selected from methanol, ethanol, isopropanol, propanol, butanol or ether solvents selected from methyl tertiary butyl ether or THF or mixtures thereof.

6) A process for the preparation of Eltrombopag Olamine of formula (I)

I
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in tetrahydrofuran cooled at temperature -5°C to +5°C and treating with sodium nitrite in water for 1 hour to get a diazocompound of formula IVa in solution

IV IVa

b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III) at temperature 10-20°C for time duration ranging between 1- 3 hours to afford Eltrombopag acid in solution form

III

c. optionally adjusting pH up to 1-2 of the solution of step b. with hydrochloric acid followed by extracting with ethyl acetate.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II).

II

e. treating novel salt of eltrombopag (II) with ethanolamine in methyl tertiary butylether (MTBE) solvent to afford Eltrombopag olamine of formula (I).

7) A process for the preparation of commercially useful novel Eltrombopag amine salts of Formula (II)

II
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in tetrahydrofuran with aqueous sodium nitrite solution to get a diazocompound of formula IVa in solution

IV IVa

b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III)
III
to afford Eltrombopag acid in solution form
c. optionally adjusting pH up to 1-2 of the solution of step b. with hydrochloric acid followed by extracting with ethyl acetate.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II)

II

8) Commercially useful novel Eltrombopag amine salts of Formula (IIa and IIb)

IIa IIb

9) Commercially useful novel Eltrombopag amine salts according to claim 8, wherein-
i. A crystalline Eltrombopag dicyclohexyl amine salt compound of formula (IIa)

IIa
characterized by x-ray diffraction pattern comprising characteristic diffraction angle peaks at 2?: 5.6, 7.3, 8.3, 8.7, 11.4, 12.1, 12.2, 12.9, 14.8, 15.7, 15.9, 16.2, 16.8, 17.4, 18.2, 19.1, 20.0, 23.9 and 24.6 ± 0.2° 2?.
ii. A crystalline Eltrombopag N-methyl morpholine salt compound of formula (IIb)

IIb

characterized by x-ray diffraction pattern comprising characteristic diffraction angle peaks at 2?: 3.4, 7.0, 10.5, 13.5 14.1and 17.7 ± 0.2° 2?.
, Description:FIELD OF THE INVENTION
The present invention relates to improved and commercially viable process for the preparation of Eltrombopag Olamine of formula (I) using novel commercially useful eltrombopag amine salts of formula (II).

Eltrombopag Olamine of formula (I) is useful as a thrombopoietin (TPO) receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic ITP, thrombocytopenia in patients with hepatitis C infection and in severe aplastic anemia.

BACKGROUND OF THE INVENTION
Eltrombopag (Ia) is non-peptide thrombopoietin (TPO) receptor agonist indicated for treatment of thrombocytopenia in patients with chronic immune thrombocytopenia purpura, thrombocytopenia in patients with hepatitis C infection and in severe aplastic anemia.
Eltrombopag (Ia) chemically known as (Z)-3'-(2-(l-(3, 4-dimethylphenyl)-3-methyl-5-oxo- lH-pyrazol-4(5H)-ylidene)hydrazinyl)-2'-hydroxybiphenyl-3-carboxylic acid having the following chemical structure:

Eltrombopag (Ia)
Eltrombopag is marketed as bis-(monoethanolmine) or Olamine salt under the trade name PROMACTA® by GlaxoSmithKline, which is shown as formula (I):

I
Duffy, et al. in US Patent No. 7,160,870 (the US '870 patent) discloses Eltrombopag and its salts.
Moore in US Patent No. 7,547,719 discloses, bisethanolamine salt of Eltrombopag, which is also known as olamine salt of Eltrombopag. US '870 patent discloses a process for the preparation of Eltrombopag free acid, which is shown schematically by Scheme I:

Process for the preparation of mono and bis-ethanolamine salt of eltrombopag disclosed in US Patent No. 7,547,719, which is shown schematically by Scheme II:

Eltrombopag olamine (I) obtained using the process disclosed in most of the references resulted in various drawbacks e.g. high level of residual solvents and this is a major concern to meet the ICH guidelines, besides unknown impurities. Thus, the present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of Eltrombopag olamine (I), which provides eltrombopag olamine (I) having pharmaceutical grade purity. The present invention provides a process for preparation of pure eltrombopag olamine (II) via formation of novel salts.

SUMMARY OF INVENTION
Particular aspect of the present invention relates to an efficient process for the preparation of Eltrombopag olamine of Formula (I)

I
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in a suitable solvent with sodium nitrite in water to get a diazocompound of formula IVa in solution

IV IVa
b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III) to afford Eltrombopag acid in solution form

III
c. optionally adjusting pH up to 1-2 of the solution of step b. with an acid followed by extracting with an organic solvent.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II)

II
e. treating novel salt of eltrombopag (II) with ethanolamine in an organic solvent to afford Eltrombopag olamine of formula (I).

In another aspect of the present invention, it relates to process for the preparation of Eltrombopag Olamine of formula (I)

I
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in tetrahydrofuran cooled at temperature -5°C to +5°C and treating with sodium nitrite in water for 1 hour to get a diazocompound of formula IVa in solution

IV IVa

b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III) at temperature 10-20°C for time duration ranging between 1- 3 hours to afford Eltrombopag acid in solution form

III
c. optionally adjusting pH up to 1-2 of the solution of step b. with hydrochloric acid followed by extracting with ethyl acetate.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II).

II
e. treating novel salt of eltrombopag (II) with ethanolamine in methyl tertiary butylether (MTBE) solvent to afford Eltrombopag olamine of formula (I).

In yet another aspect of the present invention, it relates to process for the preparation of commercially useful novel Eltrombopag amine salts of Formula (II)

II
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in tetrahydrofuran with aqueous sodium nitrite solution to get a diazocompound of formula IVa in solution

IV IVa

b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III)
III
to afford Eltrombopag acid in solution form
c. optionally adjusting pH up to 1-2 of the solution of step b. with hydrochloric acid followed by extracting with ethyl acetate.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II)

II
In yet further another aspect of the present invention, it relates to novel Eltrombopag amine salts of Formula (IIa and IIb)

IIa IIb

wherein-
i. Crystalline Eltrombopag dicyclohexyl amine salt compound of formula (IIa)


IIa
characterized by
a. x-ray diffraction pattern comprising characteristic diffraction angle peaks at 2?: 5.6, 7.3, 8.3, 8.7, 11.4, 12.1, 12.2, 12.9, 14.8, 15.7, 15.9, 16.2, 16.8, 17.4, 18.2, 19.1, 20.0, 23.9 and 24.6 ± 0.2° 2?.
b. DSC isothermal peaks at 233°C.
ii. Crystalline Eltrombopag N-methyl morpholine salt compound of formula (IIb)

IIb
characterized by
a. x-ray diffraction pattern comprising characteristic diffraction angle peaks at 2?: 3.4, 7.0, 10.5, 13.5 14.1and 17.7 ± 0.2° 2?.
b. DSC isothermal peaks at 210°C.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline form of Eltrombopag dicyclohexylamine salt.
Fig. 2 is an example of Differential Scanning Calorimetry (“DSC”) crystalline form of Eltrombopag dicyclohexylamine salt.
Fig. 3 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline form of Eltrombopag N-methyl morpholine salt.
Fig. 4 is an example of Differential Scanning Calorimetry (“DSC”) crystalline form of Eltrombopag N-methyl morpholine salt.
DETAILED DESCRIPTION
In one embodiment, the present invention provides an efficient process for the preparation of Eltrombopag olamine of Formula (I)

I
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in a suitable solvent with sodium nitrite in water to get a diazocompound of formula IVa in solution

IV IVa
b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III) to afford Eltrombopag acid in solution form

III
c. optionally adjusting pH up to 1-2 of the solution of step b. with an acid followed by extracting with an organic solvent.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II)

II
e. treating novel salt of eltrombopag (II) with ethanolamine in an organic solvent to afford Eltrombopag olamine of formula (I).
The process of step a. according to present invention, wherein organic amine (X) used is selected from dicyclohexylamine and N-methyl morpholine to afford compound of formula IIa or IIb.
In one of the particular embodiment of the present invention, organic amine (X) used in step a is dicyclohexylamine.
The suitable solvent used in the reaction are selected from water or ether solvents selected from methyl tertbutyl ether (MTBE), tetrahydrofuran (THF) or nitrile solvents selected from acetonitrile or aromatic hydrocarbon selected from toluene or ketone solvents selected from acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK) or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or alcoholic solvent selected from methanol, ethanol, isopropanol, propanol, butanol or mixtures thereof.
In one of the particular embodiment of the present invention, suitable solvents used were water, tetrahydrofuran (THF) or mixtures thereof.
Step a. is performed a by reacting mixture of 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in tetrahydrofuran cooled at temperature -5°C to +5°C and treating with sodium nitrite in water for 1 hour to get a diazo compound of formula IVa and then condensing with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III) at temperature 10-20°C for time duration ranging between 1- 3 hours and optionally adjusting the pH with hydrochloric acid followed by treating with dicyclohexylamine in tetrahydrofuran (THF) to get dicyclohexylamine salt of eltrombopag compound of formula (IIa).
In a particular embodiment of the present invention, it provides process for the preparation of Eltrombopag Olamine of formula (I)

I
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in tetrahydrofuran cooled at temperature -5°C to +5°C and treating with sodium nitrite in water for 1 hour to get a diazocompound of formula IVa in solution

IV IVa

b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III) at temperature 10-20°C for time duration ranging between 1- 3 hours to afford Eltrombopag acid in solution form

III

c. optionally adjusting pH up to 1-2 of the solution of step b. with hydrochloric acid followed by extracting with ethyl acetate.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II).

II

e. treating novel salt of eltrombopag (II) with ethanolamine in methyl tertiary butylether (MTBE) solvent to afford Eltrombopag olamine of formula (I).
In yet another particular embodiment according to present invention, it provides process for the preparation of commercially useful novel Eltrombopag amine salts of Formula (II)

II
comprising the steps of:
a. reacting the 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid of formula (IV) in hydrochloric acid in tetrahydrofuran with aqueous sodium nitrite solution to get a diazocompound of formula IVa in solution

IV IVa

b. reacting the step a. solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (III)
III
to afford Eltrombopag acid in solution form
c. optionally adjusting pH up to 1-2 of the solution of step b. with hydrochloric acid followed by extracting with ethyl acetate.
d. reacting step c. solution with organic amine (X) selected from dicyclohexylamine or N-methyl morpholine to get their novel salt of eltrombopag (II) or directly reacting the step b. solution with organic amine (X) to get novel salt of eltrombopag (II)

II

In yet another particular embodiment of the present invention, it provides commercially useful novel Eltrombopag amine salts of Formula (IIa and IIb)

IIa IIb

i. Crystalline Eltrombopag dicyclohexyl amine salt compound of formula (IIa)


IIa
characterized by
a. x-ray diffraction pattern comprising characteristic diffraction angle peaks at 2?: 5.6, 7.3, 8.3, 8.7, 11.4, 12.1, 12.2, 12.9, 14.8, 15.7, 15.9, 16.2, 16.8, 17.4, 18.2, 19.1, 20.0, 23.9 and 24.6 ± 0.2° 2?.
b. DSC isothermal peaks at 233°C.

ii. Crystalline Eltrombopag N-methyl morpholine salt compound of formula (IIb)

IIb
characterized by
a. x-ray diffraction pattern comprising characteristic diffraction angle peaks at 2?: 3.4, 7.0, 10.5, 13.5 14.1and 17.7 ± 0.2° 2?.
b. DSC isothermal peaks at 210°C.
In view of the few reported amine salts like diethyl amine or triethyl amine or diisopropylamine and converting them into Eltrombopag Olamine salt, inventors of the present invention observed the serious concerns of impurities and solvent retention in APIs. This led to explore most suitable and more economically viable solution, which is amenable to scale with no apparent handling concerns. Eltrombopag dicyclohexyl amine salt compound of formula (IIa) and Eltrombopag N-methyl morpholine salt compound of formula (IIb) were the result of such difficulties to make API process affordable and economically viable.
The purity of the samples of compounds was measured using HPLC Chromatography. HPLC Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 Photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.
Eltrombopag Olamine (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.5% w/w.
The crystalline form of novel salts [i.e. Eltrombopag dicyclohexyl amine salt compound of formula (IIa) and Eltrombopag N-methyl morpholine salt compound of formula (IIb)] described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of Eltrombopag novel salts (IIa & IIb) were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source--Cu K a radiation using the wavelength 1.5418 A and lynx Eye detector. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of analytical data for the Eltrombopag novel salts (IIa & IIb) obtained in the Examples are set forth in the FIGS. 1-4.
In a further embodiment according to the specification, the invention also relates to a composition containing crystalline Eltrombopag Olamine (I) of which at least 95%, by total weight of Eltrombopag Olamine (I) in the composition is the crystalline form.
The Eltrombopag Olamine (I) obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with crystalline form of Eltrombopag Olamine (I), while retaining the crystalline nature of the premix.
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 Olamine(I) of the present application include, but are 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 of Eltrombopag Olamine(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.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES:
Example 1: Preparation of 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid compound of formula (V)
100 g (0.37 mol) of 2’-methoxy-3’-nitrobiphenyl-3- carboxylic acid was charged in to a mixture of 1L of glacial acetic acid and 1L of 48% HBr in water at 25-30°C. Reaction mixture was heated to 110-115 °C (reflux) and maintained for 6h. After completion of the reaction, cool the reaction mass to 25-30°C, charged 2000 ml of water and stirred at room temperature for 2h. The product was isolated by filtration and purified in isopropyl alcohol yielded 80g (84 %) of the product as yellow colour solid.
HPLC purity: 99.5 %

Example 2: Preparation of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (IV)
50 g (0.19 mol) of 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (IV), 250 mL of THF and 500 ml of water were charged in to a round bottomed flask .The reaction mixture was cooled to 5 – 10°C and 200 g of sodium dithionite was added lot wise. Temperature was raised to 30-35°C and maintained at the same temperature for 2 h. After completing the reaction, the product was extracted with ethyl acetate and isolated by adding n-Hexane afforded 35 g (80 %) of the product as a brown colour solid.
HPLC purity: 97 %

Example 2A: Preparation of Eltrombopag free acid (Ia)
10 g (0.043 mol) of stage 2 was dissolved in 150 mL of 1M Aq.HCl and 100 mL of THF under nitrogen atmosphere. Cool the reaction mass to -5-+5° C and added 2.8 g of sodium nitrite solution in to the reaction mixture. After completion of the diazotization reaction, the pH of the reaction mixture was adjusted to 9-10 with triethyl amine. 8.8 g (0.04 mol) of 1-(3,4-Dimethylphenyl)-3-methyl-3-pyrazolin-5-one was added in to the reaction mixture and maintained the reaction at 10-20°C for 2 h. After completing the reaction, pH of the reaction mass was adjusted to 1.5-2.0 with Aq.HCl. Reaction mixture was stirred for 1h and the crude product was isolated by filtration. The product was purified in ethanol yielded 12.8 g (67 %) of Eltrombopag free acid (Ia) as reddish brown coloured solid.
HPLC Purity: 99.4 %.

Example 3: Preparation of Eltrombopag Dicyclohexylamine (IIa)
2 g (0.0087 mol) of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (IV) was dissolved in 30 mL of 1M Aq.HCl and 20 mL of THF under nitrogen atmosphere. Reaction mixture was cooled to -5 to +5°C and added a solution of sodium nitrite in water. Maintained the reaction mixture for another 1h at the same temperature and adjusted the pH of the reaction mixture to 9-10 with triethyl amine. 1.75 g (0.0087 mol) of 3, 4-Dimethylphenyl-3-methyl-3-pyrazolin-5-one was added to the reaction mixture and stirred the reaction mixture at 10-20°C for 2h. pH of the reaction mixture was adjusted to 1-1.5 with con.HCl and extracted the product in to ethyl acetate. 2.36g (0.013 mol) Dicyclohexyl amine was added to the ethyl acetate layer and stirred the mixture for another 3h. The product was isolated by filtration and drying under vacuum yielded 3.2 g (59 % ) of the Eltrombopag Dicyclohexyl amine salt (IIa) as reddish coloured solid.
HPLC purity: 99.50%

Example 4: Preparation of Eltrombopag Dicyclohexylamine (IIa)
1g (0.0043 mol) of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (IV) was dissolved in 15 mL of 1M Aq.HCl and 10 mL of THF under nitrogen atmosphere. Reaction mixture was cooled to -5 to +5°C and added a solution of sodium nitrite in water. Maintained the reaction mixture for another 1h at the same temperature and adjusted the pH of the reaction mixture to 9-10 with Dicyclohexyl amine. 0.875 g (0.0043 mol) of 3, 4-Dimethylphenyl-3-methyl-3-pyrazolin-5-one was added to the reaction mixture and stirred the reaction mixture at 10-20°C for 2h. The product was isolated by filtration and drying under vacuum yielded 2.2 g (80.8 % ) of Eltrombopag Dicyclohexyl amine salt (IIa) as reddish coloured solid.
HPLC purity: 96.7 %.

Example 5: Preparation of Eltrombopag N-methyl morpholine salt (IIb)
1 g (0.0043 mol) of stage 2 was dissolved in 30 mL of 1M Aq.HCl and 20 mL of THF under nitrogen atmosphere. Reaction mixture was cooled to -5 to +5°C and added a solution of sodium nitrite in water. Maintained the reaction mixture for another 1h at the same temperature and adjusted the pH of the reaction mixture to 9-10 with triethyl amine. 1.75 g (0.0087 mol) of 3, 4-Dimethylphenyl-3-methyl-3-pyrazolin-5-one was added to the reaction mixture and stirred the reaction mixture at 10-20°C for 2h. pH of the reaction mixture was adjusted to 1-1.5 with con.HCl and extracted the product in to ethyl acetate. 1.67 g (0.0165 mol) N-methyl morpholin was added to the ethyl acetate layer and stirred the mixture for another 3h. The product was isolated by filtration and drying under vacuum yielded 1.8 g (77 %) of Eltrombopag: N-methyl morpholine salt (IIb) as reddish colour solid.
HPLC purity: 88.95 %.

Example 6: Eltrombopag olamine (I) using Eltrombopag Dicyclohexyl amine salt (IIa)
1.5 g (0.0025 mol) of Eltrombopag Dicyclohexyl amine salt (II) was added to a solution of 0.85 g (0.014 mol) of ethanol amine in 15 mL of acetonitrile and stirred the mixture at 25-30° C for 3h. The product was isolated by filtration followed by acetonitrile slurry afforded 1.2 g (85 %) of Eltrombopag Olamine (I) as a dark brown colour solid.
HPLC purity: 99.81%.

Example 7: Eltrombopag olamine (I) using Eltrombopag Dicyclohexyl amine salt (IIa)
2gm (0.0032 mol) of Eltrombopag dicyclo hexyl amine salt (IIa) was suspended in 20 mL of MTBE and heated to 65° C. 0.45 g (0.0073 mol) of ethanol amine was added to the suspension and continued the reflux for another 1h. The reaction mixture was cooled to 25-35° C and stirred for 1 h at 25-35° C. Product was isolated by filtration and dried under vacuum afforded 1.7 (94%) of Eltrombopag Olamine (I) as a dark brown colour solid.
HPLC purity: 99.63%.

Example 8: Eltrombopag olamine (I) using Eltrombopag N-methyl morpholine salt (IIb)
1.2gm (0.0022 mol) of Eltrombopag N-methyl morpholine salt was suspended in 12 mL of MTBE and heated to 65° C. 0.655 g (0.01072 mol) of ethanol amine was added to the suspension and continued the reflux for another 1h. The reaction mixture was cooled to 25-35° C and stirred for 1 h at 25-35° C. Product was isolated by filtration and dried under vacuum afforded 1.2gm (97 %) of Eltrombopag Olamine as a dark brown colour solid.

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein may be interpreted as mere illustrative of the invention and not in a limiting sense.