DESC:AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTITUTED BI-PHENYL CARBOXYLIC ACID COMPOUND AND IT’S USE IN THE PREPARATION OF ELTROMBOPAG

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of substituted Bi-Phenyl Carboxylic Acid Compound. More specifically it relates to a process for preparation of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid compound of Formula (I) substantially free of impurities and further conversion to Eltrombopag or pharmaceutically acceptable salts thereof.

(I)
BACKGROUND OF THE INVENTION:
Eltrombopag, also known as 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-
dihydro-pyrazol-4-ylidene]-hydrazino)-2'-hydroxybiphenyl-3-carboxylic acid is represented
by the structure of formula (Ia):

Eltrombopag
(Ia)
Eltrombopag approved as bisethanolamine or olamine salt and it 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.
Eltrombopag, certain synthetic intermediates thereof, and their synthesizes are described in United States Patent No. 7,160,870. In this patent, 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid is prepared according to the following Scheme I:

Scheme I
The processes known in the art for the preparation of biphenyl compound of formula (I) has various drawbacks like high level of unwanted positional isomers and residual solvents besides unknown impurities, which leads to less yield of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid.
More specifically the overall molar yield of the process to convert 2-bromophenol to 2-bromo-6-nitrophenol is quite low to 25% and impurities formed are undesired isomer and dibromo substituted impurity, which ultimately reduced the yield of desired compound 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid to 47%.
Moreover, the starting material used in the above reaction 2-bromophenol and its nitration reaction are more hazardous nature. It causes skin and eye irritation and inhalation problems. It is environmentally toxic also. Further, 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.
There is always a need for alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, more selective and provide a higher yield of product, have smaller and/or eco-friendlier waste products, and/or provide a product of higher purity.
In view of this, our scientists have developed the present invention; it has now surprisingly been found that the improved method for the synthesis of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid have numerous advantages over the reported processes with respect to higher yields & purity, cost effectiveness and environment friendly.

OBJECTIVE OF INVENTION:
The main objective of the present invention is to improve the process for the preparation of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid with high purity and good yield on commercial scale and further conversion it into Eltrombopag or pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION In one aspect, the present invention provides a process for the preparation of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid compound of formula (I) and further converts it into Eltrombopag or pharmaceutically acceptable salts thereof.
Accordingly, the present invention provides a process for the preparation of 2-bromo-6-nitrophenol compound of formula (III) from 2-nitrophenol compound of formula (II) in presence of brominating agent.
In another aspect, the present invention provides Methylation of 2-bromo-6-nitrophenol compound of formula (III) in the presence of Dimethyl sulphate to obtain 1-bromo-2-methoxy-3-nitrobenzene compound of formula (IV).
In another aspect, the present invention provides Palladium catalyzed coupling of 3-carboxyphenylboronic acid with compound of formula (IV) to obtain 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid compound of formula (I).
In another aspect, the present invention provides a process for the preparation of Eltrombopag of formula (Ia) or pharmaceutically acceptable salt thereof from 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid.

DETAILED DESCRIPTION:
In one embodiment, the present invention provides an improved process for the preparation of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid compound of formula(I)

Formula I

which comprises the steps of:
(i) Brominating the 2-nitrophenol compound of formula (II)

Formula II
in presence of brominating agent, organic base and suitable solvent to obtain 2-bromo-6-nitrophenol compound of formula III:

Formula III
(ii) methylation of 2-bromo-6-nitrophenol compound of formula (III) with Dimethyl sulphate in presence of base to obtain 1-bromo-2-methoxy-3-nitrobenzene compound of formula (IV):

Formula IV
(iii) palladium catalyzed coupling reaction of 3-carboxyphenylboronic acid with compound of formula IV to obtain 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid compound of formula (I).

Formula I

In still another embodiment, the aforesaid improved process comprises selection of brominating agent, molar ratio of brominating agent, mode of addition and rate of addition are critical parameters to achieve desired purity and yield of the final compound.
Accordingly, the brominating agent used in step i) is selected from N-bromo succinimide (NBS), bromine, dibromoisocyanuric acid (DBI), phosphorus tribromide, bromine chloride, and aluminum tribromide,1,3-Dibromo-5,5-dimethylhy-dantoin (DBDMH), 2,4,4,6-Tetrabromo-2,5-cyclohex-adien one (TBCHD). More preferably, the brominating agent selected from N-bromo succinimide (NBS) and 1,3-Dibromo-5,5-dimethylhy-dantoin (DBDMH).
The molar equivalents of brominating agent being used can be from about 0.5 to 1 mole to the 2- nitrophenol. Further, the reaction mass containing brominating agent is slowly added to the reaction mass of 2- nitrophenol at least for 0.5 hours to 2 hours.

The advantage of adding reaction mass of brominating agent to reaction mass of 2-nitrophenol is to reduce the undesired positional isomers and dibromo impurity, which ultimately gives better yield of desired compound 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid.

The organic base used in step i) is selected from, but not limited to organic amines such as primary amine include methylamine, aniline; secondary amines include dimethylamine, diphenylamine; tertiary amines include tert-Butylamine, trimethylamine, quaternary ammonium salt includes tetrabutyl ammonium bromide (TBAB), preferably tert-butylamine.

The suitable solvent used in step i), ii, or iii) selected from but not limited to water, acetic acid, alcohols such as methanol, ethanol, isopropanol or their mixtures thereof; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile and the like; ketonic solvents such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK) and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as ?,?-dimethylformamide (DMF), ?,?-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof. .
The reaction of step i) can be carried out at a temperature range from about -10°C to about 150°C or the boiling point of the solvent(s).

After completion of the reaction, the resultant 2-bromo-6-nitrophenol compound of formula (III) thus formed may be isolated as a solid or proceed further without isolating the compound of Formula III into subsequent reactions.
In still another embodiment, the base used in step ii) selected from organic or inorganic base. The inorganic base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. The organic base comprises alkali metal acetate such as potassium acetate, sodium acetate; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof.
In still another embodiment, the reaction step iii) carried out in the presence of palladium catalyst, preferably 10% palladium on carbon and a base such as sodium carbonate in a suitable solvent such as aqueous methanol followed by acidified with dilute hydrochloric acid to adjust pH 4-5.

In another embodiment of the present invention provides an improved process for the preparation of 2-bromo-6-nitrophenol compound of formula (III):

Formula III
comprises reacting a compound of formula (II):

Formula II
with brominating agent, in presence of organic base and suitable solvent.
In still another embodiment, the brominating agent is selected from N-bromo succinimide (NBS), bromine, dibromoisocyanuric acid (DBI), phosphorus tribromide, bromine chloride, and aluminum tribromide, 1,3-Dibromo-5,5-dimethylhy-dantoin (DBDMH), 2,4,4,6-Tetrabromo-2,5-cyclohex-adien one (TBCHD). More preferably, the brominating agent selected from N-bromo succinimide (NBS) and 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH).

In still another embodiment, organic base used in the above reaction selected from, but not limited to organic amines such as primary amine include methylamine, aniline; secondary amines include dimethylamine, diphenylamine; tertiary amines include tert-Butylamine, trimethylamine, quaternary ammonium salt includes tetrabutyl ammonium bromide (TBAB), preferably tert-butylamine.
Organic solvent used in the above reaction selected from but not limited to water, acetic acid, alcohols such as methanol, ethanol, isopropanol or their mixtures thereof; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile and the like; ketonic solvents such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK) and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as ?,?-dimethylformamide (DMF), ?,?-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof.

In still another embodiment, the molar equivalents of brominating agent being used can be from about 0.5 to 1 mole to the 2- nitrophenol. Further, the reaction mass containing brominating agent is slowly added to the reaction mass of 2- nitrophenol at least for 0.5 hours to 2 hours. In another embodiment, the present invention provides a process for the preparation of 1-bromo-2-methoxy-3-nitrobenzene compound of formula (IV)

Formula IV
comprising methylation of compound of formula (III) in the presence of dimethyl sulfate, base and suitable solvent.

In still another embodiment, the base used in above reaction selected from organic or inorganic base. The inorganic base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. The organic base comprises alkali metal acetate such as potassium acetate, sodium acetate; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof.
The suitable solvent selected from but not limited to water, acetic acid, alcohols such as methanol, ethanol, isopropanol or their mixtures thereof; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile and the like; ketonic solvents such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK) and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as ?,?-dimethylformamide (DMF), ?,?-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof. .

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

In another embodiment, the present invention provides a process for the preparation of Eltrombopag or pharmaceutically acceptable salts thereof from 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid (I) obtained according to the aforesaid improved process comprises:

(i) O-demethylation of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid of Compound of Formula I;

Formula I
in the presence of Glacial acetic acid and HBr to produce a compound of formula (V)

Formula V
(ii) Reducing the compound of formula (V) to amino compound to produce the compound od formula VI

Formula VI
(iii) reacting the 3'-Amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid of formula (VI) in hydrochloric acid in a suitable solvent with sodium nitrite in water to get a diazocompound of formula (VIIa) in solution


Formula VIIa
(iv) reacting the step (iii) solution with 2-(3,4-Dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one of formula (VIIb) to afford Eltrombopag acid in solution form

Formula VIIb
(v) optionally adjusting pH up to 1-2 of the solution of step b. with an acid followed by extracting with an organic solvent.
(vi) reacting step (v) solution with organic amine (X) to get their novel salt of eltrombopag (I) or directly reacting the step (iv) solution with organic amine (X) to get novel salt of eltrombopag (Ia)

Formula Ia
(vii) treating novel salt of eltrombopag (Ia) with ethanolamine in an organic solvent to afford Eltrombopag olamine.
The reduction step ii) can be carried out in the presence of suitable reducing agent known in the art; preferably, sodium dithionate.
The process of step vi) according to present invention, wherein organic amine (X) used is selected from dicyclohexylamine and N-methyl morpholine.
The suitable solvent used in the above reaction steps selected from water or ether solvents selected from methyl tertbutyl ether (MTBE), tetrahydrofuran (THF) or nitrile solvents selected from acetonitrile or aromatic hydrocarbon selected from toluene or ketone solvents selected from acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK) or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or alcoholic solvent selected from methanol, ethanol, isopropanol, propanol, butanol or mixtures thereof.

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 2-bromo-6nitrophenol (III)
Dichloromethane (1 L) and 28.91 g of ter-butylamine (1.0 mol) were charged into a clean round bottom flask at room temperature; followed by 63.91 g of N-bromo succinimide (1.0 mole) was added and maintained. the reaction mixture at room temperature for 60-90 minutes (First reaction mass). In another round bottom flask 2-nitro phenol (50g; 1.0 mol) and dichloromethane (250 ml) were charged and cooled the reaction mass to -10 to 0°C (second reaction mass). Then, the first reaction mass was slowly added to the second reaction mass for 1-2 hours at temperature -10 to 0°C and stirred the reaction mass for 4-5 hours -10 to 0°C. After completion of the reaction, con. HCl and water were added to the reaction mass and stirred the reaction mass at 25-35°C for 10-15 minutes. The organic, aqueous layers were separated, and the aqueous layer was extracted with dichloromethane (100 ml). Both DCM layers combined and washed with water followed by DCM layer was distilled out U/vacuum and degas for 30 min and yielded 78 g (100%) of 2-bromo-6nitrophenol as light yellow colored solid.
HPLC Purity: ?80%

Example 1A: Preparation of 2-bromo-6nitrophenol (III)
Dichloromethane (1 L) and 28.91 g of ter-butylamine (1.0 mole) were charged into a clean round bottom flask at room temperature; followed by 51.38 g of 1,3-dibromo-5,5-dimetylhydantoin (0.5 mole) was added and maintained. The reaction mixture at room temperature for 60-90 minutes (First reaction mass). In another round bottom flask 2-nitro phenol (50g; 1.0 mol) and dichloromethane (250 ml) were charged and cooled the reaction mass to -10 to 0°C (second reaction mass). Then, the first reaction mass was slowly added to the second reaction mass for 1-2 hours at temperature -10 to 0°C and stirred the reaction mass for 4-5 hours -10 to 0°C. After completion of the reaction, aqueous HCl was added to the reaction mass and stirred the reaction mass at 25-35°C for 10-15 minutes. The organic, aqueous layers were separated, and the aqueous layer was extracted with dichloromethane (100 ml). Both DCM layers combined and washed with water followed by DCM layer was distilled out U/vacuum and degas for 30 min and yielded 75 g (96%) of 2-bromo-6nitrophenol as light yellow colored solid.
HPLC Purity: ? 80%

Example 2: Preparation 1-bromo-2-methoxy-3nitrobenzene (IV)
800 mL of Acetone was charged to a round bottomed flask containing reaction mass of 2-bromo-6-nitrophenol (obtained in example 1) at 25-35°C, followed by dimethyl sulfate (49.86g; 1.1 mole) was added and the resulting reaction mixture heated to reflux and maintained 2-3 hours. After completion of reaction, Acetone was distilled out and residue was obtained. Added the residue with 500 mL of dichloromethane and water and stirred at 25-35°C for 10-15 min. The organic, aqueous layers were separated, and the aqueous layer was extracted with dichloromethane (100 ml); the dichloromethane layer was distilled completely and charged 250 ml of Isopropyl alcohol and heated the reaction mass to 45-50 °C for 60-90 minutes then gradually cooled the reaction mass to 0- 5 °C and maintained at same temperature for 60-90 minutes. The reaction mass was filtered and washed with 50 mL of pre-cooled IPA and dried for 6-8h under vacuum yielded 23 g (46%) of the 1-bromo-2-methoxy-3nitrobenzene as off white colored solid.
HPLC Purity:99%

Example 3: Preparation of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid (V) (Suzuki Coupling)
100 g (1.0 mol) of 1-Bromo-2-methoxy-3-nitrobenzene and 1.0 L of Methanol were charged into round bottomed flask followed by 92.97 g (1.3 mol) of 3-Carboxyphenylboronic acid was added and followed by addition of aqueous Na2CO3 solution (137.03 g in 550ml) and stirred at 25oC-35oC.To this 4.0 g of 5% Pd\C was added and raised the temperature to reflux for 5-6 h. After completion of reaction, reaction mixture was cooled, filtered the Pd\C residue and wash with a mixture of water (50 ml) and methanol (50 ml). Keep the wet Pd\C residue aside and collect the filtrate. The filtrate was filtered through hyflo bed then washed with 400ml methanol followed by addition of 500 mL to filtrate. pH was adjusted to 5.0 to 6.0 by adding 5% aqueous HCl solution and stirred the reaction mass at 25oC-35oC for 2-3 h and filtered the reaction mass and washed with water. The resulting we material was purified with IPA and dried at 50-55°C for 6-8 h U/vacuum yielded 93 g (79%) of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid as off white coloured solid. HPLC Purity- 99%. The above wet Pd\C residue was used as such for further next 3 cycles of convertion of the reaction followed by isolation as the above said process and obtained with yield 78-80%. HPLC Purity- 99%.

Example 4: Preparation of 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid compound of formula (VI)

100 g (0.37 mol) of 2'-methoxy-3'-nitrobiphenyl-3- carboxylic acid was charged in to a mixture of 1L of glacial acetic acid and 1L of 48% HBr in water at 25-30°C. Reaction mixture was heated to 110-115 °C (reflux) and maintained for 6h. After completion of the reaction, cool the reaction mass to 25-30°C, charged 2000 ml of water and stirred at room temperature for 2h. The product was isolated by filtration and purified in isopropyl alcohol yielded 80g (84 %) of the product as yellow coloured solid.
HPLC purity: 99.5 %

Example 5: Preparation of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (VII)

50 g (0.19 mol) of 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (VI), 250 mL of THF and 500 ml of water were charged in to a round bottomed flask. The reaction mixture was cooled to 5 – 10°C and 200 g of sodium dithionite was added lot wise. Temperature was raised to 30-35°C and maintained at the same temperature for 2 h. After completing the reaction, the product was extracted with ethyl acetate and isolated by adding n-Hexane afforded 35 g (80 %) of the product as a brown coloured solid.
HPLC purity: 97 %

Example 6: Preparation of Eltrombopag free acid (Ia)

10 g (0.043 mol) of example 5 was dissolved in 150 mL of 1M Aq.HCl and 100 mL of THF under nitrogen atmosphere. Cool the reaction mass to -5-+5° C and added 2.8 g of sodium nitrite solution in to the reaction mixture. After completion of the diazotization reaction, the pH of the reaction mixture was adjusted to 9-10 with triethyl amine. 8.8 g (0.04 mol) of 1-(3,4-Dimethylphenyl)-3-methyl-3-pyrazolin-5-one was added in to the reaction mixture and maintained the reaction at 10-20°C for 2 h. After completing the reaction, pH of the reaction mass was adjusted to 1.5-2.0 with Aq. HCl. Reaction mixture was stirred for 1 h and the crude product was isolated by filtration. The product was purified in ethanol yielded 12.8 g (67 %) of Eltrombopag free acid (Ia) as reddish brown coloured solid.
HPLC Purity: 99.4 %.

Example 7: Preparation of Eltrombopag Dicyclohexylamine (VIII)

2 g (0.0087 mol) of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (VII) was dissolved in 30 mL of 1M Aq. HCl and 20 mL of THF under nitrogen atmosphere. Reaction mixture was cooled to -5 to +5°C and added a solution of sodium nitrite in water. Maintained the reaction mixture for another 1h at the same temperature and adjusted the pH of the reaction mixture to 9-10 with triethyl amine. 1.75 g (0.0087 mol) of 3, 4-Dimethylphenyl-3-methyl-3-pyrazolin-5-one was added to the reaction mixture and stirred the reaction mixture at 10-20°C for 2h. pH of the reaction mixture was adjusted to 1-1.5 with con.HCl and extracted the product in to ethyl acetate. 2.36g (0.013 mol) Dicyclohexyl amine was added to the ethyl acetate layer and stirred the mixture for another 3h. The product was isolated by filtration and drying under vacuum yielded 3.2 g (59 %) of the Eltrombopag Dicyclohexyl amine salt (IIa) as reddish coloured solid.
HPLC purity: 99.50%
Example 8: Preparation of Eltrombopag olamine (I) using Eltrombopag Dicyclohexyl amine salt (IIa)
2gm (0.0032 mol) of Eltrombopag dicyclo hexyl amine salt (IIa) was suspended in 20 mL of MTBE and heated to 65° C. 0.45 g (0.0073 mol) of ethanol amine was added to the suspension and continued the reflux for another 1h. The reaction mixture was cooled to 25-35° C and stirred for 1 h at 25-35° C. Product was isolated by filtration and dried under vacuum afforded 1.7 (94%) of Eltrombopag Olamine (I) as a dark brown colour solid.
HPLC purity: 99.63%.

Dated this: 03rd day of July 2023.

Signature:
Name: Mr. Srinivasa Reddy Madduri
Patent Agent Reg. No.: IN/PA-1268
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana,
INDIA-500 081

,CLAIMS:We Claim:
1. A process for the preparation of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid compound of formula (I):

Formula I
which comprises the steps of:
(iv) Brominating the 2-nitrophenol compound of formula (II)

Formula II
in presence of brominating agent, organic base and suitable solvent to obtain 2-bromo-6-nitrophenol compound of formula III:

Formula III
(v) methylation of 2-bromo-6-nitrophenol compound of formula (III) with Dimethyl sulphate in presence of base to obtain 1-bromo-2-methoxy-3-nitrobenzene compound of formula (IV):

Formula IV
(vi) palladium catalyzed coupling reaction of 3-carboxyphenylboronic acid with compound of formula IV to obtain 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid compound of formula (I).

Formula I
2. The process as claimed in claim 1, the brominating agent used in step (i) is selected from N-bromo succinimide, bromine, dibromoisocyanuric acid, phosphorus tribromide, bromine chloride, aluminum tribromide, 1,3-Dibromo-5,5-dimethylhy-dantoin, and 2,4,4,6-Tetrabromo-2,5-cyclohex-adien one.
3. The process as claimed in claim 1, the organic base used in step (i) is selected from organic amines such as primary amine include methylamine, aniline; secondary amines include dimethylamine, diphenylamine; tertiary amines include tert-Butylamine, trimethylamine, quaternary ammonium salt includes tetrabutyl ammonium bromide.
4. The process as claimed in claim 1, the base used in step (ii) is selected from organic or inorganic base such as potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, potassium acetate, sodium acetate; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene.
5. The process as claimed in claim 1, wherein the step-iii is carried out in the presence of palladium catalyst selected from palladium on carbon and a base selected from sodium carbonate in a suitable solvent selected from aqueous methanol.
6. A process for the preparation of 1-bromo-2-methoxy- 3-nitrobenzene compound of formula (IV)

Formula IV
comprising methylation of compound of formula (III)

Formula III
in the presence of dimethyl sulfate, base and suitable solvent.

7. The process as claimed in claim 6, wherein step-ii the base is selected from organic or inorganic base such as potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, potassium acetate, sodium acetate; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene.
8. The use of 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid compound of formula (I) obtained according to claim 1 in the preparation of eltrombopag olamine.
9. An improved process for the preparation of 2-bromo-6-nitrophenol compound of formula III:

Formula III
comprising specific sequence of addition that is adding brominating agent to the reaction mixture contain 2-nitrophenol compound of formula (II).

Formula II
10. The process as claimed in claim 9, wherein the molar ratio of brominating agent to 2- nitrophenol compound is about 0.5 to 1 mole.

Dated this: 03rd day of July 2023.

Signature:
Name: Mr. Srinivasa Reddy Madduri
Patent Agent Reg. No.: IN/PA-1268
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana,
INDIA-500 081