F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: -
NOVEL PROCESS FOR THE PREPARATION OF ELTROMBOPAG AND SALTS AND INTERMEDIATES THEREOF
2. Applicant(s)
(a) NAME: CADILA HEALTHCARE LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: CADILA HEALTHCARE LTD; PLOT NO. 26-29 & 31, DABHASA-UMARAYA ROAD, VILL. DABHASA-391440, TAL. PADRA, DIST. VADODARA, GUJARAT, INDIA
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention

FIELD OF THE INVENTION
The field of the invention relates to a novel process for the preparation of eltrombopag and pharmaceutically acceptable salts thereof. The invention also relates to novel intermediates used for the preparation of eltrombopag. The invention also relates to a novel process for the preparation of intermediates used for the preparation of eltrombopag and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions comprising therapeutically effective amount of eltrombopag and pharmaceutically acceptable salts thereof, for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Eltrombopag is a non-peptide thrombopoietin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes. Eltrombopag is marketed under the trade name PROMACTA® by GlaxosmithKline and Ligand Pharmaceuticals as a bis-ethanolamine salt for the treatment of conditions leading to thrombocytopenia.
Eltrombopag is chemically known as 3’-[(2Z)-[1-(3, 4-dimethylphenyl)-1, 5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] hydrazino]-2’-hydroxy-[1, 1’-biphenyl]-3-carboxylic acid and represented by the following formula (I).

Eltrombopag is disclosed in US patent nos. 7,160,870 B2 and 7,332,481 B2; PCT publication no. WO2001/089457A2 and EP1294378B1.
Eltrombopag bisethanolamine salt is disclosed in US patent nos. 7,547,719 B2 (corresponding to WO2003/098992A2)
Eltrombopag, its certain synthetic intermediates and their syntheses are described in US patent no. 7,160,870 B2. In this patent, 3’-amino-2’-hydroxybiphenyl-3-carboxylic acid is prepared according to the following reaction scheme-I:

US patent no. 7,414,040 B2 discloses another scheme (Scheme-II) for the preparation of 3’-amino-2’-hydroxybiphenyl-3-carboxylic acid, but that does not provide detailed experimental part and data.
The processes described in the literature involve several chemical steps and provide the product in a very low overall yield of about 10%. Moreover 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. Thus, there is a need for a process for preparing the intermediate 3’-amino-2’-hydroxybiphenyl-3-carboxylic acid and the final product eltrombopag and salts thereof in high yield and quality.

It is also desirable to provide an efficient, economical, and eco-friendly process for the preparation of eltrombopag and its pharmaceutically acceptable salts and its intermediates.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a novel process for the preparation of eltrombopag of Formula (I) or its pharmaceutically acceptable salts;
comprising:
(a) reacting 2-bromo-4-chlorophenol of formula (VII) with nitrating agent to
obtain 2-bromo-4-chloro-6-nitrophenol of formula (VI);
(b) reacting 2-bromo-4-chloro-6-nitrophenol of formula (VI) with benzyl halide in the presence of suitable base to obtain benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V);

(c) reacting benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V) with 3-carboxyphenyl boronic acid to obtain 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III);
(d) hydrogenating 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III) to obtain 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II);
(e) reacting 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II) with 3,4-(dimethylphenyl)-3-methyl-3-pyrazolin-5-one of formula (Z) to obtain eltrombopag of Formula (I); and

(f) optionally, converting eltrombopag of Formula (I) into its pharmaceutically acceptable salt.
In an another aspect, there is provided a novel process for the preparation of intermediate 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II), used for the preparation of eltrombopag and pharmaceutically acceptable salts thereof,
comprising:
(a) reacting 2-bromo-4-chlorophenol of formula (VII) with nitrating agent to
obtain 2-bromo-4-chloro-6-nitrophenol of formula (VI);
(b) reacting 2-bromo-4-chloro-6-nitrophenol of formula (VI) with benzyl halide in the presence of suitable base to obtain benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V);

(c) reacting benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V) with 3-carboxyphenyl boronic acid to obtain 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III);
(d) hydrogenating 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III) to obtain 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II);
In another general aspect, there is provided pharmaceutical composition comprising therapeutically effective amount of eltrombopag or its pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION
As used herein the term “obtaining” may include filtration, filtration under
vacuum, centrifugation, and decantation for isolation of the product. The product
may be preceded for further reaction with or without isolation and with or without
drying in case of the product was isolated.
“Suitable solvent” means a single or a combination of two or more solvents.
As used herein, unless indicated otherwise, the term “isolated” or “isolation” refer
to the subject compound as physically separated from the reaction mixture in
which it is formed.
The terms “protection”, “protecting”, “protected” and “protecting group” refer to
the practice of preparing a derivative of a subject compound, wherein one or more
functional groups of the compound are prevented from undergoing undesired
reactions with a “protecting” functional group.
In a general aspect, a novel process for the preparation of eltrombopag of Formula (I) or its pharmaceutically acceptable salts, comprises: (a) reacting 2-bromo-4-chlorophenol of formula (VII) with nitrating agent to obtain 2-bromo-4-chloro-6-nitrophenol of formula (VI);
In general, 2-bromo-4-chloro-6-nitrophenol of formula (VI) can be prepared by reacting 2-bromo-4-chlorophenol of formula (VII) with NaNO3 or nitric acid in the presence of suitable acid, for example, acetic acid, sulfuric acid. Alternatively, the nitration can be carried out using other methods known in the art, can be found

in standard organic synthesis texts such as March, “Advance Organic Chemistry: reactions, mechanisms, and structure,” Wiley, N.Y. (1992). The preferable reagent is NaNO3 in sulfuric acid.
(b) reacting 2-bromo-4-chloro-6-nitrophenol of formula (VI) with benzyl halide in the presence of suitable base to obtain benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V);
The 2-bromo-4-chloro-6-nitrophenol of formula (VI) is then reacted with benzyl halide to obtain benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V). Benzyl halide may be selected from benzyl chloride, benzyl bromide or benzyl iodide. Preferably benzyl chloride may be used.
The protection of hydroxy group can also be carriedout by other alternative groups and methods known and well described in the art for example, in “Protective Groups in Organic Synthesis” by Theodora W. Greene, Wiley-Interscience 1981, New York and references cited therein.
The reaction is carried out in the presence of suitable base, which may be selected from inorganic bases like sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydroxide, potassium tert-butoxide and the like or organic base like triethyl amine, diisopropyl amine, diisopropylethylamine, pyridine and the like. The use of mixture of inorganic and organic base or mixture of two inorganic bases may be considered as the scope of the invention. Preferably, potassium carbonate may be used.

The reaction may be performed in presence of suitable organic solvent selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, acetone and the like. Preferably, dimethylformamide may be used to give protected nitrophenol.
(c) reacting benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V) with 3-carboxyphenyl boronic acid to obtain 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III);
Benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V) may be reacted
with substituted arylboronic acids, such as 3-carboxyphenyl boronic acid.
The reaction is carried out in the presence of catalyst such as [Pd (PPh3)4], [PdCl2
(PPh3)2] or [Pd (Oac) 2/PPh3]. Preferable catalyst is Pd (PPh3)4.
Suitable base for the reaction may be selected from alkali metals or alkali earth
metals carbonates or bicarbonates, organic bases for example triethyl amine,
piperidine, and pyridine. Preferably sodium carbonate may be used.
Suitable solvent for the reaction may be selected form water, C1-C4-alcohols,
dioxane, dimethyl formamide, dimethyl sulfoxide or mixture thereof. Preferably
dimethyl formamide may be used.
(d) hydrogenating 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III) to obtain 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II);

Hydrogenation reaction may be carriedout in the presence of suitable catalyst, selected from raney nickel, palladium, platinum, platinum dioxide and the like with and without carriers. Carrier is selected from barium sulphate, calcium sulphate, carbon and the like. For catalytic hydrogenation, preferably the catalyst is palladium with carbon. Catalytic hydrogenation reaction may be carried out at temperatures from about 20°C to about 100°C, and a pressure of about 1 bar to about 70 bars.
Suitable solvent may be selected from C1-C4-alcohols, for example ethanol, methanol, 2-propanol and butanol. Preferably methanol may be used.
(e) reacting 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II) with 3,4-(dimethylphenyl)-3-methyl-3-pyrazolin-5-one of formula (Z) to obtain eltrombopag of Formula (I); and
The compound 3,4-(dimethylphenyl)-3-methyl-3-pyrazolin-5-one of formula (Z) can be prepared by reacting 3,4-dimethylphenylhydrazine hydrochloride with ethyl acetoacetate in the presence of acetic acid and sodium acetate as shown below:

A solution of 3,4-dimethylphenylhydrazine hydrochloride (17.7 g; 0.1 mol.), ethyl acetoacetate (13.0 g; 0.1 mol.) and sodium acetate (8.2 g; 0.1 mol.) in glacial acetic acid; (250 mL) is stirred and heated under reflux for 24 h.
The mixture is cooled and evaporated and the residue is dissolved in diethyl ether (1 L) and carefully washed with saturated aqueous solution of sodium hydrogen carbonate. Then the ethereal layer is evaporated to afford the 1-(3, 4-Dimethylphenyl)-3-methyl-3-pyrazolin-5-one.
The reaction of 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II) with 3,4-(dimethylphenyl)-3-methyl-3-pyrazolin-5-one can be carriedout, for example, as described in US 7,160,870 B2, which is incorporated herein by reference.
(f) optionally, converting eltrombopag of Formula (I) into its pharmaceutically acceptable salts.
The pharmaceutically acceptable salts may be prepared as well known in the art and described in literature, such as the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference.
In another general aspect, there is provided a novel process for the preparation of eltrombopag of Formula (I) and its pharmaceutically acceptable salts according to the reaction scheme-III substantially as depicted herein after.

In an another aspect, there is provided a novel process for the preparation of intermediate 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II), used for the preparation of eltrombopag and pharmaceutically acceptable salts thereof, comprising:

(a) reacting 2-bromo-4-chlorophenol of formula (VII) with nitrating agent to obtain 2-bromo-4-chloro-6-nitrophenol of formula (VI);
2-Bromo-4-chloro-6-nitrophenol of formula (VI) can be prepared by reacting 2-bromo-4-chlorophenol of formula (VII) with NaNO3 or nitric acid in the presence of suitable acid, or by known methods available in the literature as mentioned herein above. The preferable reagent is NaNO3 in sulfuric acid.
(b) reacting 2-bromo-4-chloro-6-nitrophenol of formula (VI) with benzyl halide in the presence of suitable base to obtain benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V);
Benzyl halide for the reaction may be selected from benzyl chloride, benzyl
bromide or benzyl iodide. Preferably benzyl chloride may be used.
The protection of hydroxy group can also be carriedout by other alternative
groups or by known methods available in the literature as mentioned herein
above.
The reaction is carried out in the presence of suitable base, which may be selected
from the bases as mentioned herein above. Preferable base is potassium carbonate.

The reaction may be performed in presence of suitable organic solvent as mentioned herein above. Preferable solvent is dimethylformamide.
(c) reacting benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V) with 3-carboxyphenyl boronic acid to obtain 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III);
Benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V) may be reacted
with substituted arylboronic acids, such as 3-carboxyphenyl boronic acid.
The reaction is carried out in the presence of catalyst such as [Pd (PPh3)4], [PdCl2
(PPh3)2] or [Pd (Oac) 2/PPh3]. Preferable catalyst is Pd (PPh3)4.
Suitable base for the reaction may be selected from alkali metals or alkali earth
metals carbonates or bicarbonates, organic bases for example triethyl amine,
piperidine, and pyridine. Preferable base is sodium carbonate.
Suitable solvent for the reaction may be selected form water, C1-C4-alcohols,
dioxane, dimethyl formamide, dimethyl sulfoxide or mixture thereof
(d) hydrogenating 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III) to obtain 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II);

Hydrogenation reaction may be carriedout in the presence of suitable catalyst as
mentioned herein above. Preferable catalyst is palladium with carbon.
Catalytic hydrogenation reaction may be carried out at temperatures from about
20°C to about 100°C, and a pressure of about 1 bar to about 70 bars.
Suitable solvent may be selected from C1-C4-alcohols. Preferable solvent is
methanol.
In another general aspect, there is provided pharmaceutical composition comprising therapeutically effective amount of eltrombopag or its pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable excipients.
The invention is explained in its best way by examples herein given below. It will be apparent to those skilled in the art that the various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention.
The examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.
Example-1: Preparation of 2-bromo-4-chloro-6-nitrophenol of formula (VI)

73.7 gm sodium nitrate, 220 ml water were taken in a round bottom flask and cooled to 0°-5°C. 101.5 gm conc. Sulfuric acid was added slowly and stirred for 15-20 minutes at 0°-5°C. 100 gm 2-bromo-4-chloro phenol was added and stirred for 5-6 hours at 5°-10°C.After completion of the reaction, 700ml water was added and stirred at 25°-35°C for 2 hours. The product was filtered and washed with water. This wet cake was taken in 150ml methanol and stirred at 25°-35°C for 1 hour. The product was filtered and washed with methanol and then dried for 8 hours at 45°-55°C to get 2-bromo-4-chloro-6-nitrophenol.
Example-2: Preparation benzyl protected-2-bromo-4-chloro-6-nitrophenol of formula (V)
95 gm 2-bromo-4-chloro-6-nitrophenol, 760 ml DMF were taken in a round bottom flask. 130 gm potassium carbonate and 4.75 gm KI were added into that at 25-35°C. 71.8 gm benzyl chloride then added and the reaction mass was heated to 60-65°C for 3 hours. After completion of the reaction, it was cooled and added into 1900ml chilled water and stirred for 2 hours. The product the obtained was filtered and washed with water. The wet cake was taken in 285 ml IPA and stirred at 50-55°C for one hour and then cooled to 0-5°C. The product thus obtained was filtered and washed with chilled IPA and dried to get benzyl protected-2-bromo-4-chloro-6-nitrophenol.
Example-3: Preparation of 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III)

25 gm benzyl protected-2-bromo-4-chloro-6-nitrophenol, 300ml 1, 4-dioxane were taken in a round bottom flask. 12.17 gm 3-carboxy phenylboronic acid and 9300ml of 1, 4 dioxane were added. Then 15.45 gm sodium carbonate in 115 ml water was added alongwith 3.62 gm of palladium tetrakis triphenylphosphine at 25-35°C. Reaction mass was heated to 85-95°C for 5 hours. After completion of the reaction, the solvent was distilledout under reduced pressure. 250 ml water was added and the reaction mass was stirred for 30 minutes and filtered. The filtrate was washed with toluene and the pH of aqueous layer was adjusted upto 2 using dilute HCl and stirred for 2 hours at 25-35°C. The product was filtered and washed with water. The wet cake was taken in 50 ml methanol and stirred for 30 minutes at 40-45°C and then stirred for one hour at 25-35°C.The product thus obtained was washed with methanol and dried to obtain 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid of Formula (III).
Example-4: Preparation of 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride of Formula (II)
In an autoclave, 4 gm 2’-(benzyloxy)-3’-nitro-5’-chloro-biphenyl-3-carboxylic acid, 200 ml methanol and 0.8 gm of 10% Pd/C were taken. H2 gas was passed at 10 kg pressure at 25-35°C and maintained for 5 to 6 hours. After completion of

the reaction, the reaction mass was filtered through hyflow bad and the solvent was distilledout under vacuum. 20 ml acetone was added into the residue and stirred for one hour. The solid was filtered and washed with acetone and dried to obtained 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride.
Example-5: Preparation of eltrombopag of Formula (I)
10 gm 3’-amino-2’-hydroxy-biphenyl-3-carboxylic acid hydrochloride and 150 ml 0.1 M HCl solution were taken in a round bottom flask and stirred for 15 minutes at 25-35°C. The reaction mass was cooled to 0-5°C. Sodium nitrite solution (3-1 gm NaNO2 dissolved in 50 ml of water) was slowly added at 0-5°C and stirred for 15 minutes then 8.82 gm of 3,4-(dimethylphenyl)-3-methyl-3-pyrazolin-5-one was added at 0-5°C and maintained at this temperature for 30 minutes. Then slowly added 50 gm sodium bicarbonate and 200 ml ethanol at 0-5°C. The reaction mass was stirred at 25-35°C for 12 hours. After completion of the reaction, dilute HCl was added to adjust the pH 1-2 at 10-15°C. Then 100 ml methylene dichloride was added in to the reaction mass and stirred at 10-15°C. The product was filtered and washed with ethanol and dried to obtain eltrombopag.
Example-6: Preparation of eltrombopag olamine.
A solution of 10 gm eltrombopag acid in 180 ml THF was prepared under nitrogen atmosphere. 14 ml ethanolamine and 300 ml ethanol were taken in an

another flask and the above prepared solution of eltrombopag acid in THF was added into that at 75-85°C and maintained for 30 minutes at 75-85°C. The reaction mass was cooled to 20-35°C and maintained at this temperature for 14 hours. The product thus formed was filtered and washed with ethanol and dried under vacuum to obtain eltrombopag olamine.