DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATE USED IN THE PREPARATION OF ELTROMBOPAG

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATERMARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the nature of this invention and the manner in which is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Eltrombopag olamine and its intermediates, which are substantially free of N-methyl impurity.

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, as shown below a Compound of Formula (1). Eltrombopag approved as bisethanolamine or olamine salt as shown below a Compound of Formula (2). Eltrombopag olamine is a biphenyl hydrazone. Eltrombopag olamine is marketed under the brand name PROMACTA®. PROMACTA (Eltrombopag) tablets contain Eltrombopag olamine, a small molecule Thrombopoeitin (TPO) receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production.

Formula 1

Formula 2

FDA approved Promacta® (Eltrombopag) Tablets for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. FDA also approved, Promacta® (Eltrombopag) for Oral Suspension and for the treatment of thrombocytopenia in adult and pediatric patients one year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.

Eltrombopag (1) along with pharmaceutically acceptable salts, hydrates, solvates and esters thereof, disclosed first time in US 7160870, which is hereby incorporated by reference. US ‘870 patent discloses 2-bromo-6-nitrophenol is protected by reaction with an alkylating agent such as benzyl bromide or preferably methyl iodide in the presence of a base such as sodium hydride or potassium carbonate in a suitable solvent such as dimethylformamide, tetrahydrofuran or acetone to give protected nitrophenol (Prot=alkyl or substituted alkyl, e.g. methyl, benzyl). Coupling of this compound with 3-carboxyphenylboronic acid, in the presence of a catalyst tetrakistriphenylphosphino palladium and a base such as sodium carbonate to triethylamine in a suitable solvent such as aqueous 1,4-dioxane or dimethylformamide afforded substituted aryl compound (3). Removal of the protecting group (Prot) is accomplished using a protic or Lewis acid; such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to afford the phenol compound (4). Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as iron of tin dichloride in a suitable solvent such as ethanol, acetic acid; or water gives the 3'-Amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid (Amine Compound) of a Compound of Formula (5), which is diazotized by reaction with sodium nitrite and an appropriate acid, such as nitric acid, sulfuric acid or, preferably, hydrochloric acid, in an appropriate aqueous solvent, such as water or, preferably, an ethanol-water mixture to produce a diazonium species which is directly converted to Eltrombopag in a coupling reaction with 2-(3,4-dimethylphenyl)-5-methyl-1H-pyrazol-3(2H)-one (Pyrazolone Compound) of a Compound of Formula (6) in the presence of a base, preferably sodium hydrogen carbonate, or an acid, preferably hydrochloric acid.
The process as shown in Scheme-I below:

Scheme-I
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. The given Benzyl bromide is lachrymatory compound and expensive in comparison to other compounds.

Further, the inventors of the present invention have found that the deprotection reaction of the phenolic hydroxyl in a compound of formula (3) under the conditions reported above is carried out under particularly drastic conditions (i.e. in 48% HBr in acetic acid at reflux temperature), and leads to the formation of various impurities in the compound of formula (4). Due to its lachrymatory property commercial use of it is less preferred.

WO 2014177517 reported, a process of Eltrombopag (1), wherein hydrogenation of compound (3) using Pd-C/H2 in methanol to produce Compound (5), which is treated with sodium nitrite in ethylacetoacetate to produce Compound (7), which is further treated with Compound (8) to produce Eltrombopag (1).
The process as shown in Scheme-II below:

Scheme-II

From the above process, it is observed that it requires more than 15 hours of time to complete the reaction; hence it is industrially not feasible. This process gives N-Methyl impurity in the preparation of compound (5). N-Methyl impurity is having structural alert for genotoxicity.

CN 105085287 reported, a process of Eltrombopag (1), wherein hydrogenation of compound (3) using Pd-C/H2 in ethyl acetate solvent to produce Compound (5), which is further converted to Eltrombopag (1).
The process as shown in Scheme-III below:
Scheme-III

From the above process, it is observed that it requires higher volume (30 volume) of ethyl acetate to dissolve compound-3, due to which process is not commercially feasible.

WO 2013049605 reported, a process of Eltrombopag (1), wherein hydrogenation of compound (9) using Pd-C/H2 in methanol and triethylamine base to produce Compound (5), which is further converted to Eltrombopag (1).
The process as shown in Scheme-IV below:

Scheme-IV

Eltrombopag obtained by the processes described in the prior art are often associated with various impurities especially N-Methyl impurity of a compound of formula (10). Unacceptable amounts of impurities are generally formed along with Eltrombopag.

Formula 10

Considering the above there is consequently a need for an alternative, improved preparation method, which is simpler and more advantageous, to prepare Eltrombopag of the compound of formula (1) and consequently Eltrombopag olamine of formula (2). Said new method should in particular comprise a smaller number of synthesis steps, and the use of intermediates that can be synthesized and purified more easily on an industrial scale. Said process should also be cheap, safe for humans and the environment, and use mild reaction conditions to obtain Eltrombopag of formula (1) with high yields and efficiency.

In view of this, inventers have developed the present invention; it has now surprisingly been found that the pure Eltrombopag olamine have numerous advantages over the reported processes.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to produce a process for the preparation of Eltrombopag olamine and its intermediates with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of Eltrombopag olamine salt of a Compound of Formula (2), which is substantially free of N-methyl impurity;

Formula 2
which comprises:
(i) reducing a Compound of Formula (3A);

Formula 3A
wherein R is a hydrogen or a protecting group comprises substituted or unsubstituted alkyl or aryl group;
in the presence of monoethanolamine or diethanolamine or triethanolamine to produce a Compound of Formula (5);

Formula 5
(ii) converting a Compound of Formula (5) to Eltrombopag of a Compound of Formula (1); and

Formula 1
(iii) optionally further converted to Eltrombopag olamine salt of a Compound of Formula (2).

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention provides an improved process for the preparation of Eltrombopag olamine salt of a Compound of Formula (2);

Formula 2
which comprises;
(i) reducing a Compound of Formula (3A);

Formula 3A
wherein R is a hydrogen or a protecting group comprises substituted or unsubstituted alkyl or aryl group;
in the presence of monoethanolamine or diethanolamine or triethanolamine to produce a Compound of Formula (5);

Formula 5
(ii) reacting a Compound of Formula (5) with a Compound of Formula (6)

Formula 6
to produce Eltrombopag of a Compound of Formula (1);

Formula 1
(iii) treating Eltrombopag of a Compound of Formula (1) with or without isolation with ethanolamine to produce Eltrombopag olamine salt of a Compound of Formula (2).

In another embodiment, wherein R is a hydrogen or a hydroxyl protecting group comprises substituted or unsubstituted alkyl or aryl group.

In another embodiment, substituted or unsubstituted alkyl or aryl group comprises methyl or ethyl or propyl or isopropyl or Benzyl.

In still another embodiment, step (i) is carried out using a reducing agent and a solvent.

In still another embodiment, reducing agent comprises Palladium-Carbon (Pd-C), Fe, Sn, Zn in acidic media, sodium borohydride (NaBH4), Lithium borohydride (LiBH4), diborane, Sodium aluminium hydride (NaAlH4), hydrazine hydrate, sodium dithionate (Na2S2O4), sodium sulfide, ammonium sulfide, sodium cyanoborohydride (NaBH3CN), hydrogenation catalysts comprises rhodium, raney cobalt, raney iron, lithium aluminum hydride (LiAlH4), sodium amalgam, borane-tetrahydrofuran complex, and in combination with hydrogen.

In still another embodiment, the solvent used in the reaction step comprises polar protic solvent or polar aprotic solvent or non-polar solvent and/or mixtures thereof.

In another embodiment, polar protic solvent comprises water, methanol, ethanol, isopropyl alcohol, n-butanol, and/or mixtures thereof; polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidoneand/or mixtures thereof; and non-polar solvents comprises hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH2Cl2) and/or mixtures thereof.

In one more embodiment, the reaction is carried out at room temperature depending upon the solvent used in the reaction for a time period of 2-5 hours.

In another embodiment, hydrogenation and removal of protecting group step (i) is accomplished by catalytic hydrogenation using 10% palladium on carbon in a suitable solvent such as methanol or water in presence of monoethanolamine or diethanolamine or triethanolamine, followed by acidified with aq. hydrochloric acid to adjust pH 0.5-1 at 25-30°C. Thereafter adjust pH to 4.5-5° by adding 10% aqueous sodium hydroxide to gives Amine Compound of a Formula (5).
The advantage of using ethanolamine in the reaction, it will produce a Compound of Formula (5) with substantially free of N-Methyl impurity of formula (10) and higher yield is obtained after isolation.

Formula 10

In another embodiment, in step (ii) Amine Compound of a Formula (5) is diazotized by reaction with aq. sodium nitrite and an appropriate acid, such as nitric acid, sulfuric acid or, preferably, hydrochloric acid, in an appropriate aqueous solvent, such as methanol-water mixture to produce a diazonium species, aqueous solution of sulfamic acid was added, which is directly converted to Eltrombopag in a coupling reaction with 2-(3,4-dimethylphenyl)-5-methyl-1H-pyrazol-3(2H)-one (Pyrazolone Compound) of a Compound of Formula (6), which in-situ further converted to Eltrombopag olamine salt of a Compound of Formula (2) by treatment with ethanolamine in step (iii).
In another embodiment, in step (f) purification of Eltrombopag olamine salt of a Compound of Formula (2) by conventional methods.
In another embodiment, purification is carried out by crystallization using a solvent and anti-solvent system.
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 3’-AMINO-2’-HYDROXY-1,1’-BIPHENYL-3-CARBOXYLIC ACID [BIPHENYL AMINO COMPOUND (5)]
In a 2 Lt. autoclave 2’-(benzyloxy)-3’-nitro-1,1’-biphenyl-3-carboxylic acid (3) (100 g), methanol (1 Lt.) and Monoethanolamine (52.4 g) were charged at 25-30 °C. Thereafter, 10% w/w Palladium on carbon was added (5 g) to the solution under nitrogen atmosphere while stirring. Autoclave was evacuated with vacuum and then applied hydrogen pressure. Reaction mass was hydrogenated at 20-30 °C by maintaining the hydrogen pressure at 70-80 psi for ~4 h. Thereafter, hydrogen in autoclave was replaced with nitrogen and mass filtered through hyflo bed to remove catalyst. The contents were stirred, filtered and concentrated at below 40 °C under reduced pressure to get residue. This residue was diluted with water at 25-30 °C and acidified with conc. hydrochloric acid (~130 mL) to the pH 0.5-1.0 at 25-30 °C. Thus, obtained solution was filtered to remove any un-dissolved material and filtrate was washed with methylene chloride. Thereafter, adjusted the pH of the aqueous layer to 4.5-5 by adding 10% aqueous solution of sodium hydroxide (~480 mL) at 25-30 °C. Product precipitated out, which was further stirred for ~30 minutes and filtered at 25-30 °C. Obtained wet solid was dried at 45-50 °C under vacuum (~ 50 mm Hg) for 8-10 h to get product as a brown powder (59 g; 90 % yield) with >99 % HPLC purity.
EXAMPLE 2: PREPARATION OF ELTROMBOPAG OLAMINE (2)
In a round bottom flask, dilute hydrochloric acid (~270 mL, prepared by mixing 114 g of ~35% w/w hydrochloric acid and 156 g of water) was added to a pre-cooled (0-5 °C) suspension of biphenyl amino compound (5) (100 g; 0.44 mole) in 2.5 Lt of methanol slowly by maintaining temperature of the reaction mass at 0-5 °C. Solution of sodium nitrite (~120 mL, prepared by dissolving 33.15 g; 0.48 mole, of sodium nitrite in 100 mL of water) was added to the reaction mass at 0-5 °C. Reaction mass was stirred at 0-5 °C for 1 h to complete diazotization. Then aqueous solution of sulfamic acid (~105 mL, prepared by dissolving 8.5 g; 0.9 mole, in 100 mL of water) was added at 0-5 °C to the mass and stirred at this temperature for another 1h.
2’-(3,4-Dimethylphenyl)-5-methyl-(1H)-pyrazole-3-(2H)-one (Compound 6) (88.2 g; 0.44 mole) was added to the resulting reaction mass, in one portion at 0-5 °C and then the temperature of reaction mixture was allowed to 20-30 °C. Thereafter, monoethanolamine (133 g) was added to the reaction mass at 25-30 °C (pH=8.5-9.5) and further stirred for 2 h, solid product precipitated out. The product was filtered under suction, washed the solid with mixture of methanol:water (~100 mL; 1:1 ratio) and dried at 65-70 °C under vacuum (~50 mmHg) for 10 h to get Eltrombopag olamine crude (226 g; 92 % yield) with >99% purity.
EXAMPLE 3: PURIFICATION OF ELTROMBOPAG OLAMINE
In a round bottom flask, Eltrombopag olamine, crude (200 g) was dissolved in DMSO (1 Lt) at 65-70 °C and stirred for ~20 minutes at this temperature. Thus the obtained solution was filtered through micron filter at 40-45 °C and washed with 400 mL of DMSO at 40-45 °C. Ethanol (3 Lt) was added to the obtained solution, and reaction mass was stirred for ~1h at 40-45 °C. Then reaction mass was slowly cooled to 25-30 °C and stirred at this temperature for ~12 h to complete precipitation of product. Thereafter, product was filtered and washed with 400 mL of ethanol at 25-30 °C. Wet product was dried at 65-70 °C under reduced pressure (~ 50 mm Hg) to obtain 152 g (76 % yield) as a brick red colored crystalline powder with >99.9 % purity. ,CLAIMS:WE CLAIM:
1. A process for the preparation of Eltrombopag (1),

1
which is substantially free of N-methyl impurity of a Compound of Formula (10);

Formula 10
which comprises:
(i) reducing a Compound of Formula (3A);

Formula 3A
wherein R is a hydrogen or a protecting group comprises substituted or unsubstituted alkyl or aryl group;
in the presence of monoethanolamine or diethanolamine or triethanolamine to produce a Compound of Formula (5);

Formula 5
(ii) further comprises, condensation of a Compound of Formula (5) with a Compound of Formula (6):

Formula 6
to produce Eltrombopag (1).

2. The process as claimed in claim 1, wherein substituted or unsubstituted alkyl or aryl group comprises methyl or ethyl or propyl or isopropyl or Benzyl.
3. The process as claimed in claim 1, step (i) is carried out using a reducing agent and a solvent.
4. The process as claimed in claim 1 and claim 3, reducing agent comprises Palladium-Carbon (Pd-C), Fe, Sn, Zn in acidic media, sodium borohydride (NaBH4), Lithium borohydride (LiBH4), diborane, Sodium aluminium hydride (NaAlH4), hydrazine hydrate, sodium dithionate (Na2S2O4), sodium sulfide, ammonium sulfide, sodium cyanoborohydride (NaBH3CN), hydrogenation catalysts comprises rhodium, raney cobalt, raney iron, lithium aluminum hydride (LiAlH4), sodium amalgam, borane-tetrahydrofuran complex, and/or in combination with hydrogen.
5. The process as claimed in claim 1 and claim 3, solvent comprises water, methanol, ethanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidone, hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH2Cl2) and/or mixtures thereof.
6. The process as claimed in claim 1, in step (ii), Compound of a Formula (5) is diazotized by reaction with sodium nitrite to produce a diazonium species and then condensation with a Compound of Formula (6) to produce Eltrombopag (1).