DESC:FIELD OF THE INVENTION
The present invention relates to an improved cost-effective process for preparing eltrombopag olamine, its key intermediates and purification process of eltrombopag olamine.

BACKGROUND OF THE INVENTION
Eltrombopag 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 and represented by compound of Formula I.

Formula I
Eltrombopag is marketed as bis-(monoethanolmine) or Olamine salt, represented by compound of Formula Ia, under the trade name PROMACTA®.

Formula Ia
U.S. patent no. 7,160,870, hereinafter referred as US ‘870, disclosed first time eltrombopag and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. US ‘870 patent discloses process for the preparation of eltrombopag by protecting 2-bromo-6-nitrophenol with an alkylating agent such as benzyl bromide or preferably methyl iodide in the presence of a base, solvent such as dimethylformamide, tetrahydrofuran or acetone to give protected nitrophenol (Prot=alkyl or substituted alkyl, e.g. methyl, benzyl). Coupling of the resulting compound with 3-carboxyphenylboronic acid to give substituted aryl compound. Deprotection is done by using a protic or Lewis acid to give the phenol compound. Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal gives the 3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid of Formula II, which is diazotized with sodium nitrite and an appropriate acid to produce a diazonium species which is directly converted to eltrombopag by coupling reaction with 2-(3,4-dimethylphenyl)-5-methyl-1H-pyrazol-3(2H)-one of Formula III. The base patent route of synthesis, wherein protected group is benzyl, can be depicted as below:

The compound of Formula IV or Formula IVa viz. 2-(benzyloxy)-1-halo-3-nitrobenzene an important starting intermediate of eltrombopag of Formula I or eltrombopag olamine of Formula Ia. The compound of Formula IV or Formula IVa are precursor of compound of Formula II, which is key intermediate of eltrombopag or its olamine salt.

Formula II

Formula IVa
wherein X is selected from Cl, Br, I
In the prior art, efforts have been made to optimize process for preparing compound of Formula IV or Formula IVa, an important starting intermediates of eltrombopag having Formula I or eltrombopag olamine having Formula Ia. The relevant prior art references discussed herein below.
European patent application publication no. 2865662 disclosed reaction of 2-bromo-6-nitrophenol with benzyl chloride in presence of potassium carbonate and potassium iodide (KI) in acetone solvent to give 2-(benzyloxy)-1-bromo-3-nitrobenzene and the said conversion is depicted by the below scheme.

From the above process, it is observed that it requires more than 15 hours of time to complete the reaction; hence the said process is industrially not attractive.
Chinese application publication no. 105085276A discloses a process for preparing eltrombopag, wherein 2-bromo-6-nitrophenol is reacted with benzyl bromide in the presence of a potassium carbonate in acetonitrile (ACN) or tetrahydrofuran (THF) to give 2-(benzyloxy)-1-bromo-3-nitrobenzene. The said conversion is depicted below:

Then, the resulting intermediate of Formula IV is converted to eltrombopag.
Indian patent application no. 201841020662 discloses a process for preparing eltrombopag olamine, wherein 2-bromo-6-nitrophenol is reacted with benzyl chloride in the presence of a phase transfer catalyst to give 2-(benzyloxy)-1-bromo-3-nitrobenzene and further, the resulting intermediate is converted to eltrombopag olamine as per the scheme given below:

Finally, the resulting eltrombopag olamine is purified by using dimethyl sulfoxide (DMSO) as solvent and methanol as anti-solvent.
In the above prior art references, the compound of formula IV is prepared by using either benzyl chloride or benzyl bromide. The use of benzyl chloride is preferred over benzyl bromide because benzyl bromide is comparatively highly lachrymatory and difficult to handle. Further, benzyl bromide is more expensive than benzyl chloride.
Further, the prior art processes wherein benzyl chloride is used for preparing compound of Formula IV suffers from several drawback such as use of additional reagent viz. phase transfer catalyst and additional solvent for layer separation. Hence, the said processes are lengthy and uneconomical at industrial level.
Furthermore, the following prior art references focused on the purification of eltrombopag olamine.
U.S. patent no. 7,547,719 discloses eltrombopag olamine (bisethanolamine) salt of Formula Ia and process for the preparation thereof by treating eltrombopag with two or more equivalents of ethanolamine and finally the suspension was filtered and the dark purple solid washed on the filter with Industrial Methylated Spirit (IMS).
U.S. patent no. 8,022,093 discloses amorphous eltrombopag olamine was slurried with cumene solvent to give crystalline eltrombopag olamine.
IPCOM000212582D discloses recrystallization of crude eltrombopag olamine from a mixture of monoethanolamine and one or more solvents like ethanol.
Therefore, in view of the above prior art references there is an urgent need to develop an improved cost-effective process for preparing compound of Formula IV or Formula IVa, which are important starting intermediates of eltrombopag or eltrombopag olamine of Formula Ia .
Further, in view of the above prior art references there is also a need to develop a process for the purification of eltrombopag olamine to get pure eltrombopag olamine of Formula Ia.
OBJECTIVE OF THE INVENTION
The principal object of the present invention is to provide an improved cost-effective process for preparing eltrombopag olamine and its key intermediates.
Another object of the present invention is to provide an improved process for the preparation of compound of Formula IV or Formula IVa, an important starting intermediate of eltrombopag or eltrombopag olamine of Formula Ia.
Another object of the present invention is to provide a purification process of eltrombopag olamine of Formula Ia.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of eltrombopag of Formula I or eltrombopag olamine of Formula Ia,

Formula I
Formula Ia
comprises:
i) reacting 2-halo-6-nitrophenol having following structure,

wherein X is selected from Cl, Br, I
with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture;
ii) adding anti-solvent to the reaction mixture of step i) to obtain compound of Formula IVa; and

Formula IVa
wherein X is selected from Cl, Br, I
iii) converting the compound of Formula IVa to eltrombopag of Formula I or eltrombopag olamine of Formula Ia.

The present invention provides an improved process for the preparation of compound of Formula IVa,

Formula IVa
wherein X is selected from Cl, Br, I
comprises:
i) reacting 2-halo-6-nitrophenol having following structure,

wherein X is selected from Cl, Br, I
with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture;
ii) adding anti-solvent to the reaction mixture of step i) to obtain compound of Formula IVa.

The present invention provides an improved process for the preparation of a compound of Formula IV,

Formula IV
comprises:
i) reacting 2-bromo-6-nitrophenol having following structure,

with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture;
ii) adding anti-solvent to the reaction mixture of step i) to obtain compound of Formula IV.
The present invention provides an improved process for the preparation of eltrombopag of Formula I or eltrombopag olamine of Formula Ia

Formula I
Formula Ia
comprises:
i) reacting 2-bromo-6-nitrophenol having following structure,

with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture;
ii) adding anti-solvent to the reaction mixture of step i) to obtain a compound of Formula IV; and

Formula IV
ii) converting the compound of Formula IV to eltrombopag of Formula I or eltrombopag olamine of Formula Ia.

In one embodiment, the present invention provide a purification process of eltrombopag olamine of Formula Ia comprises:
i) dissolving eltrombopag olamine in ethanolamine at a suitable temperature;
ii) cooling the solution of step i);
iii) adding alcoholic solvent to the solution of step ii) to get a reaction mixture; and
iv) isolating eltrombopag olamine of Formula Ia.

DETAILED DESCRIPTION OF THE INVENTION
The instant invention relates to an improved cost-effective process for preparing eltrombopag olamine, its key intermediates and purification process of eltrombopag olamine.
According to an embodiment, there is provided an improved process for the preparation of eltrombopag of Formula I or eltrombopag olamine of Formula Ia.

Formula I
Formula Ia
In the present invention, the eltrombopag of Formula I or eltrombopag olamine of Formula Ia can be prepared by the method as described herein below.
2-Halo-6-nitrophenol having following structure,

wherein X is selected from Cl, Br, I
is reacted with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture.
The base used for the said reaction may be selected from organic or inorganic base. The organic and inorganic base may be selected from but not limited to ammonia, methylamine, ethylamine, diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and alike or mixture thereof.
The said reaction is carried out at a suitable temperature in the range of 40 °C to 95°C or preferably in the range of 50 °C to 90°C. The said reaction is completed in 1 to 8 hours or preferably 3 to 6 hours. After completion of the reaction, the resulting reaction mixture is cooled to a temperature of 30°C to 70°C or preferably 30 °C to 60°C and then anti-solvent is added to obtain compound of Formula IVa.

Formula IVa
wherein X is selected from Cl, Br, I
In one embodiment, after addition of anti-solvent, the temperature of reaction mixture is lowered to 5-10 °C to obtain the compound of Formula IVa.
In one embodiment, the resulting wet compound of Formula IVa is dried or carried forward as such for further reaction.
The anti-solvent added to the reaction mixture may be selected from the solvents in which compound of Formula IVa is insoluble.
In one preferred embodiment, the anti-solvent added to the reaction mixture is water.
The resulting compound of Formula IVa is converted to eltrombopag of Formula I or eltrombopag olamine of Formula Ia by any method known in prior art or by the method of the present invention. In the present invention compound of Formula IVa is converted to eltrombopag olamine of Formula Ia by using the following route of synthesis (ROS).

The solvent used in the above ROS during reaction may be selected from water; alcoholic solvent comprises ethanol, methanol, propanol, isopropanol and alike or mixture thereof. The base used herein in the above ROS are same as discussed earlier.
In the above scheme, the compound of Formula IVa is reacted with Formula V in the presence of palladium on carbon, base and solvent(s) to obtain compound of Formula VI. After completion of the reaction, the pH of the reaction mixture adjusted and compound of formula VI is isolated.
Optionally, the isolated compound of formula VI is purified by crystallization. In a preferred embodiment, the said crystallization process comprises of suitable solvent and anti-solvent. The suitable solvent used in crystallization can be selected from aprotic solvent. The aprotic solvent is dimethyl sulfoxide (DMSO).
The anti-solvent can be selected from water; alcoholic solvent comprises ethanol, methanol, propanol, isopropanol and alike or mixture thereof.
The compound of Formula VI is converted to Formula II. The compound of Formula II is reacted with compound of Formula III in presence of sodium nitrite and solvent at suitable temperature to give eltrombopag of Formula I.
The solvent used in the said reaction can be selected from water; alcoholic solvent comprises ethanol, methanol, propanol, isopropanol and alike or mixture thereof. The said reaction is carried out at -10°C to 10°C.
Optionally, the eltrombopag of Formula I is isolated after coupling of compounds of Formula II and compound of Formula III. Then, eltrombopag of Formula I is converted to eltrombopag olamine of Formula Ia by using ethanolamine.
In one embodiment, the resulting eltrombopag of Formula I is in-situ converted to eltrombopag olamine of Formula Ia.
In one embodiment, the present invention provide a purification process of eltrombopag olamine of Formula Ia, comprises:
i) dissolving eltrombopag olamine in ethanolamine at a suitable temperature;
ii) cooling the solution of step i);
iii) adding alcoholic solvent to the cooled solution of step ii) to get a reaction mixture; and
iv) isolating eltrombopag olamine of Formula Ia.
The alcoholic solvent used in the purification comprises ethanol, methanol, propanol, isopropanol and alike or mixture thereof.
In one embodiment, the eltrombopag olamine is dissolved in ethanolamine at a temperature in the range of 50°C to 80°C and optionally removal of suspended particles, if formed, by filtration. Thereafter, the solution of step i) is cooled at a temperature in the range of 30°C to 60°C and alcoholic solvent is added to get a reaction mixture.
In one embodiment, the reaction mixture obtained after addition of alcoholic solvent, is further cooled at a suitable temperature of 10°C to 40°C for 5 to 20 hours. Then, the resulting pure eltrombopag olamine of Formula Ia is isolated by filtration followed by washing and drying.
According to another embodiment, the present invention provides an improved process for the preparation of compound of Formula IVa,

Formula IVa
wherein X is selected from Cl, Br, I
In one embodiment, the compound of Formula IVa is prepared by reacting 2-halo-6-nitrophenol having following structure,

with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture.
The base, reaction temperature, time and anti-solvent used herein are the same as discussed above for the said step.
After completion of the reaction, the resulting reaction mixture is cooled to a temperature of 30°C to 70°C or preferably 30 °C to 60°C and then anti-solvent is added to obtain compound of Formula IVa.
In one embodiment, after addition of anti-solvent, the temperature of reaction mixture is lowered to 5-10 °C to obtain the compound of Formula IVa.

The present invention provides an improved process for the preparation of a compound of Formula IV,

Formula IV
The compound of Formula IV is prepared by reacting 2-bromo-6-nitrophenol having following structure,

with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture.
The base, reaction temperature, time and anti-solvent used herein are the same as discussed above for preparing the compound of Formula IVa.
After completion of the reaction, the resulting reaction mixture is cooled to a temperature of 30°C to 70°C or preferably 30 °C to 60°C and then anti-solvent is added to obtain compound of Formula IV.
In one embodiment, after addition of anti-solvent, the temperature of reaction mixture is lowered to 5-10 °C to obtain the compound of Formula IV.
In one embodiment, the compound of Formula IVa or compound of Formula IV are converted to eltrombopag of Formula I or eltrombopag olamine of Formula Ia by using the process known in the prior art or by using the process of the present invention as discussed herein earlier.
The eltrombopag of Formula I or eltrombopag olamine of Formula Ia and/or its intermediate prepared by the present invention may be purified by any technique known in the art such as crystallization, precipitation, filtration, slurry wash and alike or combination of these techniques.

The purity of product/intermediates, reaction completion and monitoring of the reaction of the present invention is checked by any analytical techniques known in the prior art such as high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), gas chromatography (GC) and alike.
The pure eltrombopag olamine of Formula Ia, prepared by the present invention, may be characterized by analytical techniques known in the prior art are selected from but not limited to X-ray crystallography (XRD), differential scanning calorimetry (DSC), infrared spectroscopy (IR) and melting point.

Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by an improved cost-effective process for preparing eltrombopag olamine and its key intermediates.

EXAMPLES
EXAMPLE 1. Preparation of 2-(benzyloxy)-1-bromo-3-nitrobenzene (Formula IV)
2-Bromo-6-nitrophenol (100g) was added in dimethyl sulfoxide (100 mL) at 20- 30oC and stirred to get a clear solution. To the solution potassium carbonate (95g) was added and stirred for 10 minutes and benzyl chloride (64g) was added dropwise to give a reaction mixture. The reaction mixture was heated at 75-80oC under stirring for 4 hours. After completion of the reaction, checked by TLC, the reaction mixture was cooled to 30-35oC and water (1000 mL; 10V) was added slowly to the reaction mixture. The temperature of the reaction mixture was lowered to 5-10oC under stirring for 60 minutes to obtain crude product. The crude product was filtered, washed with water (500 mL; 5V) and dried at 45-50oC for 12 hours to afford, 127g (94%) of titled compound of Formula IV.

EXAMPLE 2. Preparation of 2'-(Benzyloxy)-3'-nitro-1,1'-biphenyl-3-carboxylic acid (Formula VI)
2-(Benzyloxy)-1-bromo-3-nitrobenzene (130g) was added in mixture of methanol (650 mL) and demineralized water (650 mL) at 20-30oC and stirred for 10 minutes to get a reaction mixture. To the reaction mixture 3-boronobenzoic acid (95g), Pd/C (10% w/w, 50% wet) (26g; 0.2T) and sodium bicarbonate (107g) were added at 20-30oC. The resulting reaction mixture was heated at 70-80oC and stirred for 3 hours. After completion of the reaction, monitored on TLC, the reaction mixture was cooled to 20-30oC, filtered through hyflo bed, washed with mixture of methanol (65 mL) and water (65 mL). Then, pH of the reaction mixture was adjusted to 5.0-6.0 with aqueous hydrochloric acid (10% v/v) (450 mL). The reaction mixture was stirred for 90 minutes and filtered, washed with mixture of methanol (65 mL) and water (65 mL) to get a wet material. To the wet material DMSO (130 mL) was added and the resulting reaction mixture was heated to 50-60oC to dissolve the material. To the resulting solution methanol (650 mL) and DM water (130 mL) were added. The reaction mixture was cooled to 20-30oC, stirred for 2 hours then further cooled to 0- 5oC, stirred for 1 hour, filtered and washed with 20% methanolic water (1 V). The wet material was dried at 50-55oC for 16 hours to afford 125g (85%) of titled compound of Formula VI.

EXAMPLE 3. Preparation of 3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid (Formula II)
Palladium on carbon [7 g, 10% w/w (50% wet)] was added to a solution of 2'-(benzyloxy)-3'-nitro-1,1'-biphenyl-3-carboxylic acid (70g) in (1400 mL) and the mixture was stirred under hydrogen pressure of 4-4.5 kg/cm2 at 25-35oC for 4 hours. After completion of the reaction, monitored on TLC, the catalyst was removed by filtration and washed with methanol (140 mL; 2V). The filtrate and washings were combined, and the solvent was distilled off under reduced pressure at 40-50oC to obtain a residue. DM water (1400 ml; 20V) was charged in residue and pH was adjusted to less than 1.0 with concentrated hydrochloric acid (approx. 55 mL),. The resulting reaction mixture stirred for 30-45 minutes at 25-30oC, filtered to remove suspended impurities and washed with demineralized water (140 mL; 2V). To the filtrate 20% aqueous sodium hydroxide solution (approx.110 mL) was added to adjust pH to 4.5-5 to crystalize material and stirred for 2 hours. Then, 38.2g of titled compound of Formula II was isolated by filtration, washed with demineralized water (140 mL; 2V) and dried under vacuum at 45-50°C for 12 hours.

EXAMPLE 4. Preparation of eltrombopag olamine
3'-Amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid (35g) was added in mixture of methanol (875 mL) and water (70ml), stirred and cooled to 0 to -5oC. Aqueous hydrochloric acid (35 mL in 52 mL demineralized water) was slowly added to the reaction mixture at 0 to -5oC and followed by addition of aqueous sodium nitrite solution (11.6g in 35 mL of demineralized water) at 0 to -5oC. The resulting reaction mixture was stirred for 1 hour. After completion of the reaction, monitored on TLC, 2'-(3'4-dimethyl phenyl)-5-methyl-(1H)-pyrazole-3-(2H)-one (Formula III) was added into the reaction mixture at 0 to -5oC and followed by ethanolamine (29.1g; 3 M/eq.) was added at 0-25 oC. Temperature of the reaction mixture was further raised to 25-30oC and stirred for 2 hours and followed by addition of another lot of ethanolamine (17.5g; 2 M/eq.) into the reaction mixture. The reaction mixture was stirred at 25-30oC for 15 hours. Then, the reaction mixture was cooled to 10-15oC and stirred for 1 hour. The resulting wet product is isolated by filtration. The filtered product was washed with the mixture of methanol: water (17.5 mL : 17.5 mL) and dried under vacuum at 50-55°C for 12 hours to yield 80g of titled compound of eltrombopag olamine of Formula Ia.

EXAMPLE 5. Purification process of eltrombopag olamine
To the eltrombopag olamine (35g), ethanolamine (450 mL; 6V), was added at 20-30oC the temperature was raised to 65-70oC, stirred for 30 minutes followed by filtration of reaction mass through micron filter. The reaction mixture was slowly cooled to 40-50oC followed by addition of ethanol (1275 mL: 17V) in the reaction mixture. The reaction mixture was then cooled to 20-30oC under stirring for 15 hours and further, stirred the reaction mixture for 1 hour at 15-20oC to obtain a crude. The crude product is isolated by filtration and washed with ethanol (150 mL: 2V). The isolated product was then dried under vacuum at 50-55°C for 12 hours to yield 66.1g of eltrombopag olamine of Formula Ia.
,CLAIMS:Claim 1. An improved process for the preparation of eltrombopag or eltrombopag olamine comprises:
i) reacting 2-halo-6-nitrophenol having following structure,

wherein X is selected from Cl, Br, I
with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture;
ii) adding anti-solvent to the reaction mixture of step i) to obtain compound of Formula IVa; and

Formula IVa
wherein X is selected from Cl, Br, I
iii) converting the compound of Formula IVa to eltrombopag or eltrombopag olamine.

Claim 2. An improved process for the preparation of compound of Formula IVa,

Formula IVa
wherein X is selected from Cl, Br, I
comprises:
i) reacting 2-halo-6-nitrophenol having following structure,

wherein X is selected from Cl, Br, I
with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture;
ii) adding anti-solvent to the reaction mixture of step i) to obtain compound of Formula IVa.

Claim 3. An improved process for the preparation of a compound of Formula IV,

Formula IV
comprises:
i) reacting 2-bromo-6-nitrophenol having following structure,

with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture;
ii) adding anti-solvent to the reaction mixture of step i) to obtain compound of Formula IV.

Claim 4. An improved process for the preparation of eltrombopag of Formula I or eltrombopag olamine of Formula Ia comprises:
i) reacting 2-bromo-6-nitrophenol having following structure,

with benzyl chloride having following structure,

in the presence of dimethyl sulfoxide and a base to give a reaction mixture;
ii) adding anti-solvent to the reaction mixture of step i) to obtain a compound of Formula IV; and

Formula IV
ii) converting the compound of Formula IV to eltrombopag of Formula I or eltrombopag olamine of Formula Ia via compound of Formula VI.

Formula VI
Claim 5. The process as claimed in claims 1 to 4, wherein the anti-solvent added to the reaction mixture of step ii) is water.

Claim 6. The process as claimed in claim 4, wherein compound of Formula VI is optionally purified with crystallization by using dimethyl sulfoxide (DMSO) as solvent and alcohol-water as anti-solvent.

Claim 7. A purification process of eltrombopag olamine of Formula Ia comprises:
i) dissolving eltrombopag olamine in ethanolamine at a suitable temperature;
ii) cooling the solution of step i);
iii) adding alcoholic solvent to the solution of step ii) to get a reaction mixture; and
iv) isolating eltrombopag olamine of Formula Ia.

Claim 8. The process as claimed in claim 7, wherein in step i) the suitable temperature is in the range of 50°C to 80°C.

Claim 9. The process as claimed in claim 7, wherein the solution of step ii) is cooled to a temperature in the range of 30°C to 60°C.

Claim 10. The process as claimed in claim 7, wherein alcoholic solvent used in the step iii) is selected from ethanol, methanol, propanol, isopropanol and alike or mixture thereof.

Dated this 18th day of August 2022

Kapil
Manager-II, IPR
Ind-Swift Laboratories Limited