DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Eltrombopag Olamine of formula (I).

(I)
BACKGROUND OF THE INVENTION
Eltrombopag is 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 having following formula.

Eltrombopag is marketed as bis-(monoethanolmine) or Olamine salt under trade name PROMACTA® by GlaxoSmithKline having following formula.

Eltrombopag 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.

US Patent No. 7,160,870 (the US '870 patent) discloses Eltrombopag and its salts.
US '870 patent discloses a process for the preparation of Eltrombopag free acid, which is shown schematically by below Scheme.

US Patent No. 7,547,719 discloses bisethanolamine salt of Eltrombopag, which is also known as olamine salt of Eltrombopag. Process for the preparation of Eltrombopag Olamine, as disclosed in US’719 is shown schematically by below Scheme.

WO2013072921 discloses a process for the preparation of Eltrombopag Olamine, which is shown schematically by below Scheme.

WO2015111085 discloses a process for the preparation of Eltrombopag Olamine, which is shown schematically by below Scheme.

WO2017081014 discloses a process for the preparation of Eltrombopag Olamine, which is shown schematically by below Scheme.

Eltrombopag olamine obtained using the process disclosed in prior art references involve reaction of compound 3'-Amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid in hydrochloric acid in a suitable solvent with sodium nitrite in water to get a diazocompound in solution and then in-situ reaction with 2-(3,4-dimethylphenyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one to obtain Eltrombopag.

Eltrombopag olamine obtained using the process disclosed in prior art references resulted in various drawbacks e.g. high level of residual solvents and 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, which provides eltrombopag olamine having pharmaceutical grade purity.

None of the prior art process involve isolation of novel intermediate 3-(Benzo[d][1,2,3]oxadiazol-7-yl)benzoic acid of formula (IV).

The present invention provides a process for preparation of pure eltrombopag olamine via isolation of intermediate 3-(Benzo[d][1,2,3]oxadiazol-7-yl)benzoic acid of formula (IV) as crystalline solid in good yield. Therefore, nitroso amine impurity as well as other impurities removed in mother liquor and in next stage Eltrombopag olamine obtained with high purity.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of eltrombopag olamine of formula I which comprises;

(a) Reacting compound of formula (V) with hydrochloric acid in suitable solvent and sodium nitrite in water to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of triethylamine in suitable solvent to obtain triethylamine salt of eltrombopag of formula (II).

(c) Treating triethylamine salt of eltrombopag of formula (II) with ethanolamine in suitable solvent to obtain eltrombopag olamine of formula (I).

Another object of the present invention is to provide an improved process for the preparation of eltrombopag olamine of formula (I) which comprises;

(a) Reacting compound of formula (V) with hydrochloric acid in suitable solvent and sodium nitrite in water to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of ethanolamine in suitable solvent to obtain eltrombopag olamine of formula (I).

In yet another object of the present invention is to provide compound of formula (IV).

Yet another object of the present invention is to provide use of compound of formula (IV) for the preparation of eltrombopag olamine of formula (I).

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of eltrombopag olamine of formula (I) which comprises;

(a) Reacting compound of formula (V) with hydrochloric acid in suitable solvent and sodium nitrite in water to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of triethylamine in suitable solvent to obtain triethylamine salt of eltrombopag of formula (II).

(c) Treating triethylamine salt of eltrombopag of formula (II) with ethanolamine in suitable solvent to obtain eltrombopag olamine of formula (I).

Another aspect of the present invention is to provide an improved process for the preparation of eltrombopag olamine of formula (I) which comprises;

(a) Reacting compound of formula (V) with hydrochloric acid in suitable solvent and sodium nitrite in water to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of ethanolamine in suitable solvent to obtain eltrombopag olamine of formula (I).

In yet another aspect of the present invention is to provide compound of formula (IV).

In yet another aspect of the present invention is to provide use of compound of formula (IV) for the preparation of eltrombopag olamine of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide an improved process for the preparation of eltrombopag olamine of formula (I) which comprises;

(a) Reacting compound of formula (V) with hydrochloric acid in suitable solvent and sodium nitrite in water to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of triethylamine in suitable solvent to obtain triethylamine salt of eltrombopag of formula (II).

(c) Treating triethylamine salt of eltrombopag of formula (II) with ethanolamine in suitable solvent to obtain eltrombopag olamine of formula (I).

Step (a) is carried out with sodium nitrite solution in water and Conc. hydrochloric acid. Addition of sodium nitrite solution and Conc. hydrochloride dropwise at a temperature of about 0-10°C.

Stir the reaction mass for 60 to 90 min at 0-10°C and add purified water at 0-10°C and stir the reaction mass for 30 to 40 min. Filter the product and isolate compound of formula (IV) as crystalline solid in good yield. Therefore, nitroso amine impurity as well as other impurities removed in mother liquor.

Step (b) is carried out with triethylamine. Adjust the pH of reaction mass to 7.5 to 8.0 by using triethylamine at a temperature of about 25-35°C and stir the reaction mass for 30 to 40 min. Filter the product and isolate triethylamine salt of eltrombopag of formula (II).

Step (c) is carried out with ethanolamine. Addition of ethanolamine dropwise at a temperature of about 25-35°C and stir the reaction mass for 3 hr. Filter the product and isolate eltrombopag olamine of formula (I).

Another embodiment of the present invention is to provide an improved process for the preparation of eltrombopag olamine of formula I which comprises;

(a) Reacting compound of formula (V) with hydrochloric acid in suitable solvent and sodium nitrite in water to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of ethanolamine in suitable solvent to obtain eltrombopag olamine of formula (I).

Step (a) is carried out with sodium nitrite solution in water and Conc. hydrochloric acid. Addition of sodium nitrite solution and Conc. hydrochloride dropwise at a temperature of about 0-10°C.

Stir the reaction mass for 60 to 90 min at 0-10°C and add purified water at 0-10°C and stir the reaction mass for 30 to 40 min. Filter the product and isolate compound of formula (IV) as crystalline solid in good yield. Therefore, nitroso amine impurity as well as other impurities removed in mother liquor.

Step (b) is carried out with ethanolamine. Adjust the pH of reaction mass to 7.5 to 8.0 by using ethanolamine at a temperature of about 25-35°C and stir the reaction mass for 30 to 40 min. Filter the product and isolate eltrombopag olamine of formula (I).

Wherein the suitable solvents which could be employed in step (a), (b) and (c) may be selected from group comprising of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate, isopropyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethyl ether, 1,2-dimethoxyethane, aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, aliphatic hydrocarbons hexane, heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dialkylformamides selected from dimethyl formamide, dialkylsulfoxides selected from dimethyl sulfoxide, dialkylacetamides selected from N,N,-dimethyl acetamide; nitriles selected from acetonitrile and propionitrile; water or mixtures thereof.
Yet another embodiment of the present invention is to provide compound of formula (IV).

Yet another embodiment of the present invention is to provide use of compound of formula (IV) for the preparation of eltrombopag olamine of formula I.

In step (a) after the completion of reaction isolation of intermediate 3-(Benzo[d][1,2,3]oxadiazol-7-yl)benzoic acid of formula (IV) is carried out by addition of purified water in reaction mass at 0-10°C and stir for 30-40 min.

In step (a) intermediate 3-(Benzo[d][1,2,3]oxadiazol-7-yl)benzoic acid of formula (IV) isolated as crystalline solid in good yield.

The following examples illustrate the present invention and as such are not being considered as limiting the invention set forth in the claims appended hereto.
EXAMPLES
Example 1: Preparation of 3-(Benzo[d][1,2,3]oxadiazol-7-yl)benzoic acid (Formula IV)
To a solution of methanol (2000 ml) add 3'-Amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (Formula V) (100 gm), stir the reaction mass for 5 to 10 min and cool to 0-5°C. Add Conc.Hydrochloric acid (400 ml) dropwise at 0-10°C and stir the reaction mass for 10 to 15 min. Add sodium nitrite solution [sodium nitrite (36 gm) in purified water (400 ml)] at 0-10°C and stir the reaction mass for 60 to 90 min. Add purified water (400 ml) at 0-10°C and stir the reaction mass for 30 to 40 min. Filter the product and wash with purified water (100 ml). Dry the wet material in hot air oven at 50-55°C for 10 to 12 hrs. (Formula IV)
Dry Weight: 70 gm to 85 gm.
Example 2: Preparation of Eltrombopag Triethylamine (Formula II)
To a solution of methanol (1500 ml) add 3-(Benzo[d][1,2,3]oxadiazol-7-yl)benzoic acid (Formula IV) (100 gm), stir the reaction mass for 5 to 10 min. Add triethylamine (~100 ml) at 25-30°C to adjust the pH of reaction mass to 7.5 to 8.0. Add 2-(3,4-dimethylphenyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one (Formula III) at 25-35°C and stir the reaction mass for 30 to 40 min. Distill out the reaction mass under vacuum at 50-55°C and degas it for 30 min. Add methanol (1000 ml) at 25-35°C and stir the reaction mass for 60-90 min. Filter the product and wash with methanol (100 ml). Dry the wet material in vacuum tray dryer at 50-55°C for 10 to 12 hrs. (Formula II)
Dry Weight: 120 gm to 150 gm.

Example 3: Preparation of Eltrombopag Olamine (Formula I)
To a solution of methanol (1000 ml) add eltrombopag triethylamine (Formula II) (100 gm), stir the reaction mass for 5 to 10 min. Add ethanolamine (196.55 gm) dropwise at 25-35°C and stir the reaction mass for 3 hrs. Heat the reaction mass at 55-60°C and stir for 60-90 min. Cool the reaction mass at 25-30°C and stir for 60-90 min. Filter the product and wash with methanol (100 ml). Dry the wet material in vacuum tray dryer at 50-55°C for 10 to 12 hrs. (Formula I)
Dry Weight: 80 gm to 100 gm.

Example 4: Preparation of Eltrombopag Olamine (Formula I)
To a solution of methanol (1500 ml) add 3-(Benzo[d][1,2,3]oxadiazol-7-yl)benzoic acid (Formula IV) (100 gm), stir the reaction mass for 5 to 10 min. Add ethanolamine (~100 ml) at 25-30°C to adjust the pH of reaction mass to 7.5 to 8.0. Add 2-(3,4-dimethylphenyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one (Formula III) at 25-35°C and stir the reaction mass for 30 to 40 min. Distill out the reaction mass under vacuum at 50-55°C and degas it for 30 min. Add methanol (1000 ml) at 25-35°C and stir the reaction mass for 60-90 min. Filter the product and wash with methanol (100 ml). Dry the wet material in vacuum tray dryer at 50-55°C for 10 to 12 hrs. (Formula I). Dry Weight: 80 to100 gm.
The process of present invention is depicted in following schemes.
SCHEME – I

SCHEME - II

,CLAIMS:We claim:

1. An improved process for the preparation of eltrombopag olamine of formula (I) which comprises;

(a) Reacting compound of formula (V) with hydrochloric acid in suitable solvent and sodium nitrite in water to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of triethylamine in suitable solvent to obtain triethylamine salt of eltrombopag of formula (II).

(c) Treating triethylamine salt of eltrombopag of formula (II) with ethanolamine in suitable solvent to obtain eltrombopag olamine of formula (I).

2. The process as claimed in claim 1, wherein suitable solvent for step (a), (b) and (c) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, isopropyl acetate or mixtures thereof.

3. An improved process for the preparation of eltrombopag olamine of formula I which comprises;

(a) Reacting compound of formula (V) with hydrochloric acid in suitable solvent and sodium nitrite in water to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of ethanolamine in suitable solvent to obtain eltrombopag olamine of formula (I).

4. The process as claimed in claim 2, wherein suitable solvent for step (a) and (b) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, isopropyl acetate or mixtures thereof.

5. A compound of formula (IV).

6. Use of compound of formula (IV) for the preparation of eltrombopag olamine of formula I.