Field of the Invention
The present invention related to an improved process for the preparation of 3'-amino-2' hydroxy-[l,l'-biphenyl]-3-carboxylic acid (or) 2’-Hydroxy-3’-aminobiphenyl-3 carboxylic acid having the chemical structural Formula I.
Background of the Invention
Eltrombopag is thrombopoietin (TPO) receptor agonist. It interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production. Eltrombopag is indicated for the treatment of thrombocytopenia in patients with chronic ITP, thrombocytopenia in patients with hepatitis C infection and in severe aplastic anemia.

Eltrombopag is known by chemical name 3'-{(2Z)-2-[l-(3, 4-Dimethylphenyl)-3-methyl-5-oxo-l, 5-dihydro-4H-pyrazoM-ylidene]-hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid. It is marketed as its Olamine salt i.e. Bisethanolamine salt, which is formed with two molecules of 2-ami noethanol for one molecule of Eltrombopag. Eltrombopag Olamine is marketed in USA by Novartis Pharms under trade name PROMACTA® in the form of oral tablet of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg acid. Eltrombopag & Eltrombopag Olamine is represented by following structure.
Eltrombopag free base is first time disclosed in US 7,160,870 B2 and EP 1294378 B1 and its salt of Eltrombopag as bisethanolamine salt is disclosed in US 7,547,719 B2.

Several process for the preparation of Eltrombopag Olamine and its intermediates have been disclosed in US 7160870 B2, US 7414040 B2, WO 2013049605A1, WO 2021001044 A1 and WO2019229572A1, WO 2010114943 Al, CN 105085276 A, CN 105085287 A, IN 2018410202662 A, WO 2001089457A2 and US 7,332,481 B2.

In view of the importance of treating and preventing disorders associated with for the treatment of thrombocytopenia in patients with chronic ITP, thrombocytopenia in patients with hepatitis C infection and in severe aplastic anemia, it would be desirable and of paramount importance to have a process for the preparation of Eltrombopag and their intermediates, by employing inexpensive readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require a special purification step, thereby making it more suitable for industrial scale preparation.
Summary of the Invention

The present invention provides a cost effective, novel and an efficient process for the preparation of 3'-amino-2'-hydroxy-[l,l'-biphenyl]-3-carboxylic acid (or) 2’-Hydroxy-3 aminobiphenyl-3-carboxylic acid compound of Formula I with higher yields and better purity.

In one embodiment, the present invention provides an improved process for the preparation of S'-amino^'-hydroxy-ffl’-biphenylJ-S-carboxylic acid having the structural Formula I, in presence of reducing agent, suitable base and suitable solvent or mixture of organic solvents to obtained in-situ compound of 2'-(Benzyloxy)-3'-nitro-[l,r-biphenyl]-3-carboxylic acid.
ii. reduction of 2'-(Benzyloxy)-3'-nitro-[l,l‘-biphenyl]-3-carboxylic acid in presence of hydrogen pressure to obtained 3'-Amino-2'-hydroxy-[l,T-biphenyl]-3-carboxylic acid compound of Formula I.
Detailed description of the invention

Accordingly, the present invention provides an improved process for the preparation of 3'-amino-2'-hydroxy-[l,l'-biphenyl]-3-carboxylic acid (or) 2’-Hydroxy-3’-aminobiphenyl-3-carboxylic acid compound of Formula I.

The main embodiment of the present invention provides an improved process for the preparation of S’-amino^'-hydroxy-fl.r-biphenylJ-S'Carboxylic acid (or) 2’-Hydroxy-3’-aminobiphenyl-3-carboxylic acid compound of Formula I, which is outlined below in Scheme-I.
SCHEME-I
Condensation of 2-(benzyloxy)-l-bromo-3-nitrobenzene with 3-carboxy phenyl boronic acid in presence of reducing agent, suitable base and suitable solvent or mixture of organic solvents to obtained in-situ compound of 2'-(Benzyloxy)-3,-nitro-[l,r-biphenyl]-3-carboxylic acid, which is further reduction of 2'-(Benzyloxy)-3'-nitro-[l,T-biphenyl]-3-carboxylic acid in presence of hydrogen pressure to obtained S'-amino^'-hydroxy-p,!'-biphenyl]-3 -carboxylic acid (or) 2’-Hydroxy-3’-aminobiphenyl-3-carboxylic acid compound of Formula I.

The reaction temperature may range from 40-60 °C and preferably at a temperature in the range from 45-50 °C. The duration of the reaction may range from 5-10 hours, preferably for a period of 6-8 hours.

The reaction hydrogen pressure may range from 3-6 kg and preferably the pressure range from 4-5kg. The duration of the reaction may range from 5-12 hours, preferably for a period of 6-8 hours at a temperature in the range from 45-50 °C.
The reducing agent used in the reaction is selected from the .group .consisting of 10% palladium, Pd(dppf)Ch or tetrakis (triphenylphosphine) -.palladium. Base used in the reaction is selected from the group consisting of sodium carbonate, sodium acetate, Ammonium acetate or Ammonium formate.

Solvent used in the reaction is selected from the group consisting of methanol, ethanol, n-butanol, propanol, isopropanol, ethyl acetate, EDTA, cyclohexane, xylene, hexane, heptanes, water and its mixture thereof.

In yet another embodiment the term “isolating” means isolating by way of solvent crystallization method, partial removal of the solvent from the solution, sonication, solvent/anti sol vent method, slurry, cooling, seeding, filtration, filtration under vacuum, centrifugation, decantation, distillation, evaporation, evaporation under reduced pressure.
EXPERIMENTAL PORTION

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Example 1: Process for the preparation of 3’-amino-2'-hydroxy-[l,l'-biphenylJ-3-carboxylic acid.

A solution of 2-(benzyloxy)-l-bromo-3-nitrobenzene (100 grams), 3-carboxy phenyl boronic acid (65.0grams), sodium carbonate(50.0grams) in isopropanol (1500mL) and water (500 mL) was stirred under nitrogen atmosphere followed by palladium on carbon catalyst at ambient temperature. Then the reaction was refluxed for 3-4 hours, the same reaction mass further applied Hydrogen pressure 4-5 kg and maintained 6-8 hours at 45-50°C. After completion of reaction, filtered the reaction mass and concentrated by vacuum,
dissolved in ethyl acetate (lOOOmL) and water adjusted PH of the reaction mass to 4.0-6.0 with concentrated hydrochloric acid. Organic layer and aqueous layers are separated and organic layer was washed with 5% EDTA solution (500 mL). Organic layer further concentrated by vacuum to get crude product, the crude product was further purified with cyclohexane (500 mL) to obtained 3'-amino-2’-hydroxy-[l,l'-biphenyl]-3-carboxylic acid (77%) with purity).

Yield: 77% Purity: >98%

Example 2: Process for the preparation of 3'-amino-2'-hydroxy-[l,r-biphenyl]-3-carboxylic acid.

A solution of 2-(benzyloxy)-l-bromo-3-nitrobenzene (lO.Ograms), 3-carboxy phenyl boronic acid (6.5grams), sodium carbonate in isopropanol (100 mL) and water (50mL) was stirred under nitrogen atmosphere followed by Pd(dppf)Ch catalyst at ambient temperature. Then the reaction was refluxed for 3-4 hours, the same reaction mass further applied Hydrogen pressure 4-5 kg and maintained 10-12 hours at 45-50°C. After completion of reaction, filtered the reaction mass and concentrated by vacuum, dissolved in ethyl acetate (100 mL) and water adjusted PH of the reaction mass to 4.0-6.0 with concentrated hydrochloric acid. Organic layer and aqueous layers are separated and organic layer was washed with 5% EDTA solution (50 mL). Organic layer further concentrated by vacuum to get crude product, the crude product was further purified with cyclohexane (50mL) to obtained 3'-amino-2'-hydroxy-[l,T-biphenyl]-3-carboxylic acid (77%) with purity).
Yield: 67% Purity: >98%
Example 3: Process for the preparation of S’-amino-Z'-hydroxy-lljl-biphenyll-S-carboxylic acid.

A solution of 2-(benzyloxy)-l-bromo-3-nitrobenzene (lO.Ograms grams), 3-carboxy phenyl boronic acid (6.5grams), sodium carbonate in isopropanol (lOOmL) and water (50mL) was stirred under nitrogen atmosphere followed by tetrakis (triphenylphosphine) palladium (0) catalyst at ambient temperature. Then the reaction was refluxed for 3-4 hours, the same reaction mass further applied Hydrogen pressure 4-5 kg and maintained 10-12 hours at 45-50°C. After completion of reaction, filtered the reaction mass and concentrated by vacuum, dissolved in ethyl acetate (100 mL) and water adjusted PH of the reaction mass to 4.0-6.0 with concentrated hydrochloric acid. Organic layer and aqueous layers are separated and organic layer was washed with 5% EDTA solution (50mL). Organic layer further concentrated by vacuum to get crude product, the crude product was further purified with cyclohexane (50 mL) to obtained S'-amino^'-hydroxy-IT.r-biphenylJ-S-carboxylic acid (77%) with purity).

Yield: 62% Purity: >98%
The present invention has the following advantages:

1. Back ground of invention, the isolated compound synthesized in two steps but our invention is in-situ reaction in single step. Moreover, after completion of reaction in two stages work up, solvent distillation and isolation required more time & energy than compared to present invention.

2. Catalyst consumption is less (half of the quantity) compared to past invention, so it can impact on product costing.
3. Duration the reaction also took more than 24hrs at reflux condition where as in present invention in in-situ reaction time is 10-12hrs at 50-60° C temperature. Because of these conditions decrease the load on utilities during the scale up.

4. Present invention getting good yield (88%) and quality (>98 %) than compared to yield of past invention conditions (79%).

5. Present invention is echo friendly, robust, safe and commercially feasible process.