DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]

AN IMPROVED PROCESS FOR THE PREPARATION OF
ELTROMBOPAG OLAMINE

PIRAMAL PHARMA LIMITED, a company incorporated under the Companies Act, 2013, of Piramal Ananta, Agastya Corporate Park, Kamani Junction, LBS Marg, Kurla West, Mumbai 400070, State of Maharashtra, India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Eltrombopag olamine (2) and its intermediates.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Eltrombopag (1) is an orally active thrombopoietin receptor agonist with megakaryopoiesis stimulating activity. Eltrombopag (1) binds to and stimulates the platelet thrombopoietin receptor (TPO-R or CD110), a member of the hematopoietin receptor superfamily. Activation of TPO-R leads to the proliferation and differentiation of megakaryocytes, thereby increasing the production of blood platelets.

Eltrombopag (1) is used to treat low blood platelet counts in adults with chronic immune (idiopathic) thrombocytopenia (ITP), when certain other medicines, or surgery to remove the spleen, have not worked well enough. ITP is a condition that may cause unusual bruising or bleeding due to an abnormally low number of platelets in the blood. Eltrombopag (1) has also been recently approved (late 2012) for the treatment of thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy.
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 as Compound of Formula (1). Eltrombopag approved as bisethanolamine or olamine salt is shown below as Compound of Formula (2). Eltrombopag olamine is a biphenyl hydrazone. Eltrombopag olamine is marketed under the brand name PROMACTA®.

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 (Protected group = 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. Removal of the protecting group is accomplished using a protic or Lewis acid; such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to afford the phenol compound. 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 (A), 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 (1) in a coupling reaction with 2-(3,4-dimethylphenyl)-5-methyl-1H-pyrazol-3(2H)-one (Pyrazolone Compound) of a Compound of Formula (B) in the presence of a base, preferably sodium hydrogen carbonate, or an acid, preferably hydrochloric acid.
The process as shown in Scheme-I below:

US9440927B2 reported the preparation of Eltrombopag (1) by treating O-methyl Eltrombopag of formula (C) with 48% aqueous hydrobromic acid (35 mL) and glacial acetic acid (35 mL) with heating under reflux for 60 hours.

The process as shown in Scheme-II below:

The use of HBr necessitates harsh reaction conditions and even under these stringent conditions, the result is often incomplete demethylation, probably due to the poor solubility of the organic substrates. Further, toxic gases that arise during the reaction and work-up greatly diminish their practicability for large-scale synthesis.

Hence, there is always demand for efficient process for the preparation of pharmaceutical active products. Therefore, the inventors of the present invention have developed the process, which avoids the use of HBr and similar reagents and employs thiol-based reagents, which are more user-friendly and are very much suitable to large-scale reactions.

Further, during work-up, these sulfur-containing compounds were extracted into the aqueous phase, thereby almost completely removing odorous compounds from the product. Therefore, present inventors have accordingly developed a simple, cost-effective, production friendly process, which gives Eltrombopag in a desired yield and purity. By means of the process of the instant invention, there is a significant overall advancement in yield, purity and work-up procedure as against prior art methods, is safe and easy to operate at large scale.
SUMMARY OF THE INVENTION
The problem addressed by the present invention is therefore that of providing a better improved process for preparing of Eltrombopag olamine (2), which permits to avoid above reported with reference to the known prior art.
This problem is solved by a process for the preparation of Eltrombopag (1) which involves demethylation of O-methyl Eltrombopag of by using alkyl thiols.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1: X-ray diffraction (XRD) pattern of 3'-{-2-[1-(ethoxycarbonyl)-2-oxopropylidene] - hydrazino}-2'-methoxybiphenyl-3-carboxylic acid of formula (D), prepared according to Example 1
Figure 2: X-ray diffraction (XRD) pattern of O-methyl Eltrombopag of formula (C), prepared according to Example 2
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of Eltrombopag Olamine (2),

comprising;
(a) reacting O-methyl Eltrombopag of formula (C) with alkyl thiol in a solvent, in presence of a base to give Eltrombopag (1), which may or may not be isolated; and

(b) treating Eltrombopag (1) with ethanolamine to give Eltrombopag olamine (2).

The present invention also relates to the process, wherein step (b) can be carried out without isolating the Eltrombopag (1) obtained in of step (a).
The alkyl thiol used in step (a) is selected from methanethiol; ethanethiol; propane thiols such as 1-propanethiol (n-propyl mercaptan) and 2-propanethiol; butane thiols such as 1-butanethiol (n-butyl mercaptan) and 2-methylpropane-2-thiol (t-butyl mercaptan); pentane thiols such as 1-pentanethiol, 2-pentanethiol, 3-pentanethiol, and t-pentane thiol (t-pentyl mercaptan); hexane thiols such as 1-hexanethiol; heptane thiols such as 1-heptanethiol (n-heptyl mercaptan) and 2-heptanethiol; octane thiols such as 1-octanethiol (n-octyl mercaptan), 2-ethylhexanethiol, and 2,4,4-trimethyl-2-pentanethiol (t-octyl mercaptan); nonanethiols such as 1-nonanethiol (n-nonyl mercaptan) and t-nonanethiol (t-nonyl mercaptan); decanethiols such as 1-decanethiol; undecanethiols such as 1-undecanethiol; dodecanethiols such as 1-dodecanethiol and t-dodecanethiol (t-dodecyl mercaptan); tridecanethiols; tetradecanethiols such as 1-tetradecanethiol; pentadecanethiols such as 1-pentadecanethiol; hexadecanethiols such as 1-hexadecanethiol; heptadecanethiols; octadecanethiols such as 1-octadecanethiol; nonadecanthiols; eicosanethiols; triacontanethiols; tetracontanethiols; pentacontanethiols; hexacontanethiols; heptacontanethiols; octacontanethiols; nonacontanethiols; hectanethiols.
The solvent used in step (a) is selected from an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; ketone such as acetone; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene or benzene; water: or a mixture thereof.
The base used in step (a) is selected from an alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

The step (a) is carried out at a temperature in the range of 100° C to 130° C.

The product formed in step (a) can be used in the next stage with or without isolation of the product.

The whole synthetic scheme of preparation of Eltrombopag Olamine (2) according to the present invention can be represented as below:

Accordingly, a specific embodiment of the present invention relates to an improved process for the preparation of Eltrombopag Olamine,

comprising;
(a) reacting O-methyl Eltrombopag of formula (C) with 1-Dodecanethiol in Dimethyl sulfoxide (DMSO), in presence of sodium methoxide to give Eltrombopag (1), which may or may not be isolated; and

(b) treating Eltrombopag (1) with ethanolamine to give Eltrombopag olamine (2).

The step (a) is carried out at a temperature in the range of 110° C to 120° C.

The product formed in step (a) can be used in the next stage with or without isolation of the product.

The whole synthetic scheme of preparation of Eltrombopag Olamine (2) according to the present invention can be represented as below:

Further, the present invention discloses polymorphic form of Eltrombopag (1) intermediates.

In one embodiment the present invention encompasses crystalline 3'-{-2-[1-(ethoxycarbonyl)-2-oxopropylidene]-hydrazino}-2'-methoxybiphenyl-3-carboxylic acid of formula (D) characterized by an XRPD pattern having peaks at 13.6, 15.0, 18.0, 20.5, 23.3, 26.1, 26.8, 27.2±0.2° 2?. The XRPD pattern is as given in Figure 2.

In another embodiment, the crystalline form of O-methyl Eltrombopag of formula (C) is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2? values of 11.8, 13.3, 13.7, 16.2, 17.5, 22.3, 23.4, 23.9, 25.2, 29.5±0.2° 2?. In another embodiment, the crystalline form is further characterized by a powder x-ray diffraction pattern substantially in accordance with Figure 1.

According to the invention, the overall yield of Eltrombopag olamine (2) as obtained by using the process of the present invention is at least about 89-91% yield with purity of at least about 99.9% by HPLC.

Thus, the present invention uses 1-dodacanethiol for demethylation of compound formula (C), which has several advantages over previous methods reported in the literature including:
(i) essentially odorless conditions during the reaction and work-up, which greatly improve the physical environment of the researcher; and
(ii) in-situ generation of the reactive thiolate, thereby simplifying the operation.

Thereby, the practicability of the reaction is greatly enhanced both at the laboratory scale and the industrial scale. The present invention results into yield of at least about 89-91% with purity of at least 99.9 % by HPLC, thereby, making the process ef?cient, economic and industrially viable.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1
Preparation of 3'-{-2-[1-(ethoxycarbonyl)-2-oxopropylidene]-hydrazino}-2'-methoxy biphe- nyl-3-carboxylic acid of formula (D)

Into reactor, methoxy biphenyl amine HCl salt (E) (10 g, 1.0 M), Methanol (50 ml, 5V), conc. HCl (15 ml, 1.5 V) were charged and stirred well at 0-5°C. Sodium nitrite (2.7 g, 1.1 M) was dissolved in Demineralized (DM) water (200 ml, 20 V) and this solution was added to reaction mass at 0-5°C. Reaction mass was stirred for 30-45 min at 0-5°C. Ethyl acetoacetate (F) (4.6 gm, 1.0 M) was added at 0-5°C. Reaction mass was stirred for 30-45 min at 0-5°C. Sodium bicarbonate (~15 gm) was added slowly to get pH of 6-6.1. Reaction mass was stirred for 1.5-2 h at 20-30°C. Reddish brown material was filtered and cake washed by DM water (30 ml, 3 V). Wet material was dried for 10-12 h at 50-60°C. Reddish brown compound of Formula (D) was obtained.
Results:
Yield : 11.5 g
Yield w/w : 1.15
Yield (%) : 82.0 %
The XPRD of above obtained compound of formula (D) is given in Figure 1.

Example 2
Preparation of O-methyl Eltrombopag of formula (C):

Into reactor, Acetic acid (150 ml, 15 V), compound of Formula (D) (10 g, 1.0 M), compound of Formula (G) (4.9 gm, 1.1 M) and sodium acetate anhydrous (2.5 g, 1.2 M) charged and stirred at 100-110°C for 5-6 h. Completion of reaction was checked by HPLC analysis. After completion of reaction, the reaction mass was cooled to 20-30°C and orange material was filtered and cake washed using DM water (3 X 20 ml). Wet material was dried for 10-12 h at 50-60°C. Orange colored O-methyl Eltrombopag of Formula (C) was obtained.
Results:
Yield : 10.0 g
Yield w/w : 1.0
Yield (%) : 85.7 %

The XPRD of above obtained compound of formula (D) is given in Figure 2.

Example 3
Preparation of Eltrombopag olamine

Into reactor DMSO (45 mL, 3 V) and sodium methoxide (7.5 g, 4.2 M) and 1-dodecanethiol (14.6 g, 2.2 M) were charged and stirred well. O-methyl Eltrombopag of Formula (C) (15 g, 1.0 M) and DMSO (30 ml, 2 V) were charged. Reaction mass was stirred for 2 h at 110-120°C. Completion of reaction was checked by HPLC analysis. After completion of reaction, the reaction mass was cooled to 30-40°C and methanol (225 ml, 18 V) and DM water (30 ml, 2 V) were charged into reaction mass. Acetic acid (15 ml, 1 V) was charged and stirred for about 30 minutes. Monoethanolamine (30 ml, 2.0 V, 7.5 M) was charged and stirred at 25-35°C for 10-12 h. Reddish brown material was filtered and cake was washed by methanol (30 ml, 2 V). Wet material was dried for 10-12 h at 50-60°C. Reddish brown Eltrombopag olamine with not less than 99 % purity was obtained.

Results:
Yield : 16.6 g
Yield w/w : 1.10
Yield (%) : 89.8 %
,CLAIMS:We Claim:

1. An improved process for the preparation of Eltrombopag Olamine (2),

comprising;
(a) reacting O-methyl Eltrombopag of formula (C) with alkyl thiol in a solvent, in presence of a base to give Eltrombopag (1), which may optionally be isolated; and

(b) treating Eltrombopag (1) with ethanolamine to give Eltrombopag olamine (2).

2. The process as claimed in claim 1, wherein the alkyl thiol used in step (a) is selected from methanethiol; ethanethiol; propane thiol selected from 1-propanethiol (n-propyl mercaptan) or 2-propanethiol; butane thiol selected from 1-butanethiol (n-butyl mercaptan) or 2-methylpropane-2-thiol (t-butyl mercaptan); pentane thiol selected from 1-pentanethiol, 2-pentanethiol, 3-pentanethiol, or t-pentane thiol (t-pentyl mercaptan); hexane thiol; heptane thiol selected from 1-heptanethiol (n-heptyl mercaptan) or 2-heptanethiol; octane thiol selected from 1-octanethiol (n-octyl mercaptan), 2-ethylhexanethiol, or 2,4,4-trimethyl-2-pentanethiol (t-octyl mercaptan); nonanethiol selected from 1-nonanethiol (n-nonyl mercaptan) or t-nonanethiol (t-nonyl mercaptan); decanethiol; undecanethiol; dodecanethiol selected from 1-dodecanethiol or t-dodecanethiol (t-dodecyl mercaptan); tridecanethiol; tetradecanethiol; pentadecanethiol ; hexadecanethiol; heptadecanethiol; octadecanethiol; nonadecanethiol; eicosanethiol; triacontanethiol; tetracontanethiol; pentacontanethiol; hexacontanethiol; heptacontanethiol; octacontanethiol; nonacontanethiol; hectanethiol.

3. The process as claimed in claim 1, wherein the solvent used in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; ketone selected from acetone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof.

4. The process as claimed in claim 1, wherein the base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide or potassium tert-butoxide; or an organic amine selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

5. The process as claimed in claim 1, wherein step (a) is carried out at a temperature in the range of 100° C to 130° C.

6. The improved process as claimed in claim 1, for the preparation of Eltrombopag Olamine,

comprising;
(a) reacting O-methyl Eltrombopag of formula (C) with 1-Dodecanethiol in Dimethyl sulfoxide (DMSO), in presence of sodium methoxide to give Eltrombopag (1), which may optionally be isolated; and

(b) treating Eltrombopag (1) with ethanolamine to give Eltrombopag olamine (2).

7. The process as claimed in claim 1, wherein the crystalline form of O-methyl Eltrombopag of formula (C) is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2? values of 11.8, 13.3, 13.7, 16.2, 17.5, 22.3, 23.4, 23.9, 25.2, 29.5±0.2° 2?.

8. The process as claimed in claim 1, wherein the Eltrombopag olamine (2) as obtained has a purity of at least about 99.9% by HPLC.