WO2013049605A1

WO2013049605A1 - Processes for the preparation of an intermediate in the synthesis of eltrombopag

Info

Publication number: WO2013049605A1
Application number: PCT/US2012/057973
Authority: WO
Inventors: Amir Avdagic; Phil S. Baran
Original assignee: Assia Chemical Industries Ltd.; Teva Pharmaceutical Usa, Inc.
Priority date: 2011-09-28
Filing date: 2012-09-28
Publication date: 2013-04-04

Abstract

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid (BPCA) and related compounds have been prepared using compounds such as: wherein R¹ is -H, -Cl or -F; R² is -Br or -I; and R³ is -H or -N0₂. BPCA is useful, for example, in the preparation of Eltrombopag.

Description

PROCESSES FOR THE PREPARATION OF AN INTERMEDIATE IN THE

SYNTHESIS OF ELTROMBOPAG

Field of the Invention

[0001] The present invention relates to novel processes for preparing 3'-amino-2 hydroxybiphenyl-3-carboxylic acid (referred to as BPCA), a synthetic intermediate for preparation of Eltrombopag.

Background of the Invention

[0002] Eltrombopag, (Z)-3'-(2-(l-(3, 4-dimethylphenyl)-3-methyl-5-oxo-lH-pyrazol-

4(5H)-ylidene)hydrazinyl)-2'-hydroxybiphenyl-3 -carboxylic acid has the following chemical structure:

[0003] Eltrombopag is a small-molecule, non-peptide thrombopoitin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes. Eltrombopag is marketed under the trade name PROMACTA® by GlaxoSniithKline and Ligand

Pharmaceuticals as a bis-ethanolamine salt for the treatment of conditions leading to thrombocytopenia.

[0004] Eltrombopag, certain synthetic intermediates thereof, and their syntheses are described in US patent No. 7,160,870. In this patent, 3'-amino-2'-hydroxybiphenyl-3- carboxylic acid (referred to as BPCA) is prepared according to the following Scheme I: Scheme I

1. Pd/C, H₂, EtOH, aq. NaOH

2. 3M HCI

[0005] US patent No. 7,414,040 discloses another scheme for the preparation of

BPCA, providing no experimental data. This scheme is presented in the following Scheme II.

Scheme II

[0006] The processes described in the literature involve several chemical steps and provide the product, BPCA, in a very low overall yield of about 10%.

[0007] Thus, there is a need for a process for preparing the intermediate BPCA and the final product Eltrombopag and salts thereof in high yield and quality.

Summary of the Invention

[0008] The present invention provides novel processes for preparing 3'-amino-2'- hydroxybiphenyl-3-carboxylic acid (referred to as BPCA).

[0009] In one embodiment the present invention encompasses a process for preparing a compound of formula 2:

Formula 2

[0010] The process comprises re f formula 1 :

Formula 1

and the arylboronic acid, referred to as compound 3 :

Compound 3

wherein R¹ is -H, -CI or -F; R² is -Br or -I; and R³ is -H or -N0₂.

[001 1] In another embodiment the present invention encompasses a process for preparing BPCA of the followi

BPCA

comprising preparing the compound of formula 2 by the above described process and converting it to BPCA.

[0012] In another embodiment the present invention encompasses a process for preparing Eltrombopag or a salt thereof, comprising preparing a compound of formula 2 by the above described process and converting it to Eltrombopag or a salt thereof. Detailed Description of the Invention

[0013] The present invention relates to novel processes for preparing 3'-amino-2'- hydroxybiphenyl-3-carboxylic acid (referred to as BPCA), a synthetic intermediate for preparation of Eltrombopag.

[0014] The processes known in the literature for preparing BPCA require five chemical steps and at least one chromatographic purification step. In these processes, the BPCA product is obtained as a hydrochloride salt in a poor overall yield of less than 10%.

[0015] The present invention provides a simple and economically viable process, which provides BPCA, a key intermediate in the synthesis of Eltrombopag, in very high yield and purity. In this novel process the reaction between the arylboronic acid and the halo-phenol derivative is done with surprising success, without requiring protection of the hydroxyl group.

[0016] As used herein, unless indicated otherwise, the term "Room temperature" or

"RT" refers to a temperature from about 20 °C to about 30 °C. Usually, room temperature ranges from about 20°C to about 25 °C.

[0017] As used herein, unless indicated otherwise, the term "Overnight" refers to a period from about 15 to about 20 hours, typically from about 16 to about 20 hours.

[0018] As used herein, the term "reference standard" refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. For example, the HPLC retention time of the reference standard compound allows a relative retention time with respect to the active pharmaceutical ingredient to be determined, thus making qualitative analysis possible. Furthermore, the concentration of the compound in solution before injection into an HPLC column allows the areas under the HPLC peaks to be compared, thus making quantitative analysis possible.

[0019] A "reference marker" is used in qualitative analysis to identify components of a mixture based upon their position, e.g., in a chromatogram or on a Thin Layer

Chromatography (TLC) plate (Strobel pp. 921, 922, 953). For this purpose, it is not necessary to add the reference marker to the mixture if it is present in the mixture. A "reference marker" is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

[0020] The process of the present invention can be illustrated by the following

Schemes III and IV: Scheme III;

Scheme (IV):

[0021] In one embodiment the present invention encompasses a process for preparing a compound of formula 2 of the following structure:

Formula 2

comprising reacting the compound of the following formula 1 :

Formula 1

and the arylboronic acid, referred to as Compound 3 of the following formula:

Compound 3

wherein R¹, R², and R³ are as defined above.

[0022] The above reaction is preferably done in the presence of a suitable catalyst and a suitable base. The catalyst is preferably a palladium catalyst, such as Pd(OAc)₂,

tetrakis(triphenylphosphine)palladium(0), trans-benzyl(chloro)bis(triphenyl- phosphine)palladium(II), or other suitable catalyst. The reaction is preferably carried out in the presence of a suitable solvent. Suitable solvents include, for example THF, dioxane, DMF, polyethylene glycol (PEG)-2000, PEG-400, acetone, mixtures thereof and mixtures thereof with water.

[0023] Suitable bases include organic bases, like Hunig's base (diisopropylethyl amine), triethylamine and diazabicycloundecane (DBU); or inorganic bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate or cesium carbonate. According to some embodiments the base is triethyl amine, sodium carbonate or cesium carbonate, preferably sodium carbonate or cesium carbonate.

1

[0024] According to one embodiment, R is -CI and R is -Br.

[0025] When R₃ is H, the compound of formula la of the following structure:

Formula la

is reacted with the compound 3 to obtain the compound of formula 2a of the following structure:

Formula 2a

[0026] In this process, BPCA can be obtained in overall yield of at least about 60%.

[0027] When R₃ is -N0₂, the compound of formula lb of the following structure:

Formula lb

is reacted with the compound 3 to obtain the compound of formula 2b of the following structure:

Formula 2b

[0028] The compound of formula lb can be typically prepared by halogenating the 2- position of the compound of formula 4 of the following structure:

Formula 4

[0029] In this process, BPCA can be obtained in overall yield of at least about 40%.

[0030] In another embodiment the present invention encompasses process for preparing 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (BPCA) of the following structure:

comprising preparing the compound of formula 2 by the above described process and converting it to BPCA. The conversion of the compound of formula 2 to BPCA comprises hydrogenating the compound of formula 2, particularly the compound 2b. If necessary, the compound 2a is first converted to Compound 2b before hydrogenation. Typically, when R is -H and the compound of formula 2a is obtained, it is converted to the compound of formula 2b before the hydrogenation step. The conversion from 2a to 2b, can be done by reacting the compound of formula 2a with NaN0₃ or nitric acid, for example in the presence of a suitable acid. Suitable acids for this reaction include, for example, acetic acid.

[0031] The hydrogenation is typically done with a suitable catalyst, such as Pd/C in the presence of a suitable base and a suitable solvent. Suitable bases include organic bases, like Hunig's base (diisopropylethyl amine), triethylamine, pyridine and diazabicycloundecane (DBU); or inorganic bases, such as sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate or potassium hydrogencarbonate. According to some embodiments the base is triethyl amine, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide. Suitable solvents include, for example, alcohol solvents, such as Cj-C₄ alcohols, for example ethanol, methanol, 2-propanol and butanol. According to some embodiments the solvent is methanol or ethanol.

[0032] The obtained BPCA can be recovered from the reaction mixture, for example by extraction, using a suitable solvent such as methylene chloride, ethyl acetate, toluene or n- butanol, and subsequently isolated by removing the solvent, for example by evaporation.

[0033] Alternatively, BPCA can be isolated by acidification of the reaction mixture to pH 2-4 with a suitable acid, e.g., aqueous HCl and subsequent addition of a suitable base, e.g., aqueous NaOH to adjust the pH to 5-7. According to some embodiments, the aqueous HCl and NaOH are used at molarities of about 0.5 M to about 6 M. [0034] The processes of the present invention provide BPCA in high overall yield, for example from about 40% to about 60%. The obtained BPCA also has high purity, for example of at least about 98% as assessed by a suitable analysis, e.g., HPLC. In particular, the above chemically pure BPCA can be purified from the following impurities:

• 3'-amino-5'-chloro-2'-hydroxy-[l,l '-biphenyl]-3-carboxylic acid of the following formula:

• 2'-hydroxy-[l, -biphenyl]-3-carboxylic acid of the following formula:

biphenyl]-3,3 '-dicarboxylic acid of the following formula:

[0035] In preferred embodiments, each of the above impurities in the purified BPCA can be present in an amount from about 0 wt % to about 1 wt %, from about 0.01 wt % to about 0.1 wt %, from about 0.01 wt % to about 0.07 wt %, or from about 0.01 wt % to about 0.05 wt %, as measured by HPLC.

[0036] In one embodiment the present invention encompasses a composition comprising BPCA and the above described impurities in the above described amounts.

[0037] In some embodiments, the present invention provides 3'-amino-5'-chloro-2'- hydroxy-[l,r-biphenyl]-3-carboxylic acid of the following formula:

[0038] Preferably, the above compound is isolated. According to some embodiments it can be in a crystalline form.

[0039] As used herein, unless indicated otherwise, the term "isolated" in reference to the Eltrombopag intermediates and potential impurities which are disclosed herein, such as 3'-amino-5'-chloro-2'-hydroxy-[l, -biphenyl]-3-carboxylic acid, corresponds to the subject compound as physically separated from the reaction mixture in which it is formed.

[0040] The terms "protection," "protecting" and "protecting group" in the context of synthetic organic chemistry refer to the practice of preparing a derivative of a subject compound, wherein one or more functional groups of the compound are prevented from undergoing undesired reactions with a "protecting" functional group. A "hydroxyl-protecting group," e.g., a benzyl or carbobenzyloxy group, is a protecting group that is suitable for preventing undesirable reactions at a hydroxyl group. The practice of "protecting" a functional group such as a hydroxyl group, during a synthesis is well-known to those skilled in the art and is described in detail in the art, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

[0041] According to one embodiment, the present invention encompasses the above

3'-amino-5'-chloro-2'-hydroxy-[l, -biphenyl]-3-carboxylic acid for use as a reference marker and/or reference standard in the analysis and/or quantification of the purity of BPCA.

[0042] In another embodiment the present invention encompasses a process for preparing Eltrombopag or a salt thereof comprising preparing the compound of formula 2, particularly 2a or 2b, especially 2b, by the above described process and converting it to Eltrombopag or a salt thereof. [0043] The conversion can be done, for example, by converting the compound of formula 2 to BPCA and converting the obtained BPCA to Eltrombopag.

[0044] The conversion to eltrombopag can be done, for example, as described in example 1 of US 7,956,048, herein example 13.

[0045] For example, the conversion can be done by reacting the obtained BPCA and

2-(3,4-dimethylphenyl)-5-methyl-lH-pyrazol-3(2H)-one (referred to herein as the pyrazole) of the following structure:

to produce eltrombopag and, if desired, reacting with a suitable base, such as ethanolamine, to obtain an Eltrombopag salt, such as Eltrombopag ethanolamine.

[0046] The reaction of BPCA and the pyrazole to obtain Eltrombopag can be done, for example, as described in US 7,160,870, which is incorporated herein by reference. For example, the process can comprise suspending BPCA in aqueous HCl, adding a solution of sodium nitrite in water and reacting with a mixture of the pyrazole, sodium hydrogen carbonate and ethanol. Typically the final pH of the reaction mixture is from 7 to 8.

[0047] Having described the invention with reference to certain preferred

embodiments, other embodiments 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 the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. HPLC Methods

" NUCLEOSIL® 100-5 CI 8 - Octadecyl modified silica phases for HPLC

Nonpolar. 5 μη particles, 100 A pores, 15 % C endcapped.

Nuclear Magnetic Resonance (NMR) method

[0048] 1H and ¹³C (APT) NMR spectra were recorded on Bruker AVANCE 600 NMR spectrometer operating at 600.133 MHz for the Ή nucleus and 150.917 MHz for ¹³C nucleus. DSMO-c¾was used as a solvent. Chemical shifts, in ppm, are referred to TMS as internal standard.

Examples

Example 1 : Synthesis of 5'-chloro-2'-hvdroxybiphenyl-3-carboxylic acid (Compound 2a):

[0049] A mixture of Na₂C0₃ (2.12 g, 20 mmol), Pd(OAc)₂ (112 mg, 5 mol %), PEG

2000 (35 g) and water (30 mL) was heated to 50 °C under an inert atmosphere with stirring. Afterward, 2-bromo-4-chlorophenol (Compound la, 2.07 g, 10 mmol) and 3-carboxyphenyl- boronic acid (Compound 3, 2.49 g, 15 mmol) were added to the solution, and the mixture was heated at 50 °C under inert atmosphere. After 4 hrs the reaction mixture was cooled to room temperature, diluted with water (60 mL), and treated with 5% aq. HC1 to adjust to pH = 2. The mixture was then extracted with ethyl acetate (3x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂S0₄ and concentrated in vacuo to provide the crude (2a) as an off-white solid (2.31 g, 86%, purity 93% HPLC Method B). This crude product was used in the next reaction without further purification.

1H-NMR (DMSO-d₆) & 6.99 (d, J=8.6 Hz, 1H), 7.25 (dd, J;=2.6, J₂=8.6, 1H), 7.32 ((d, J=2.6 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 8.13 (s, 1H), 9.98 (s, 1H), 13.02 (s, lH) ppm; ¹³C-NMR (150 MHz, DMSO-d₆) δ: 118.18, 123.44, 128.45, 128.93, 128.97, 129.00, 129.95, 130.40, 131.06, 133.85, 137.83, 153.77, 167.75 ppm; MS m/z [M-H]^': 247.1.

Example 2: Synthesis of 5'-chloro-2'-hydroxybiphenyl-3-carboxylic acid (Compound 2a):

[0050] A mixture of Na₂C03 (4.24 g, 40 mmol), Pd(0 Ac)₂ (224 mg, 5 mol %), PEG

2000 (70 g) and water (60 mL) was heated to 50 °C under inert atmosphere with stirring. Afterward, 2-bromo-4-chlorophenol (Compound la, 4.15 g, 20 mmol) and 3-carboxyphenyl- boronic acid (Compound 3, 4.98 g, 30 mmol) were added to the solution, and the mixture was heated at 50 °C under inert atmosphere for 4 hrs. The reaction mixture was then cooled to room temperature, diluted with water (150 mL), and treated with 5 % aq. HC1 to adjust to pH = 2. The mixture was then extracted with ethyl acetate (3x 80 mL). The combined organic extracts were washed with water, then brine (50 mL), dried over anhydrous Na₂S0₄ and concentrated in vacuo. Crystallization from 50% methanol/water gave the product (2a) (4.75 g, yield 95%) as an off-white solid (purity, 96 %, HPLC Method B).

Example 3: Synthesis of 5'-chloro-2'-hydrobiphenyl-3-carboxylic acid (Compound 2a):

[0051] 2-Bromo-4-chlorophenol (la) (50.0 g, 0.24 mol), 3-carboxyphenylboronic acid

(Compound 3) (47.0 g, 0.28 mol) and Na₂C0₃ (57.6 g, 0.54 mol) were added to a mixture of water (1.9 L) and acetone (1.4 L). The resulting suspension was heated with stirring at 50 °C resulting in dissolution. Pd(OAc)₂ (0.27 g, 1.20 mmol) in acetone (0.5 L) was slowly added into the solution. The reaction mixture was stirred for 30 min at 50 °C at which time active carbon (0.6 g) was added. The stirring was continued for 15 min at 50 °C. The reaction mixture was then cooled to 20 °C and filtered through diatomaceous earth (Celite). The filtrate was acidified to pH 2 with 2M HC1 and the solvent was removed by distillation under vacuum at 35-40 °C while crystallization occurred. The solid was filtered, washed with a mixture of water/acetone (10/1, 1.2 L) and then with water (2 x 0.6 L). The obtained solid (2a) was dried at 50 °C/50 mbar to provide the desired product (55.1 g, 91%, HPLC purity 98.9%).

Example 4: Synthesis of 5'-chloro-2'-hvdroxy-3'-nitrobiphenyl-3-carboxylic acid (Compound 2b according to Scheme III:

[0052] To a suspension of 5'-chloro-2'-hydroxybiphenyl-3-carboxylic acid

(Compound 2a, 2.31 g, 9.3 mmol) in 50 % H₂S0₄ (15 mL) and acetic acid (120 mL) was added a solution of NaN0₃ (1.70 g, 20 mmol) in 25 % H₂S0 (6.5 mL). This mixture was stirred for 1 hour at room temperature, and then diluted with water (150 mL). A precipitate formed and was collected by filtration, washed with water and dried to yield compound (2b) as a greenish yellow solid (2.53 g, 92%, purity 97%, HPLC Method B).

Ή-NMR (DMSO-d₆) δ: 7.58 (t, J=7.7 Hz, 1H), 7.75-7.78 (m, 2H), 7.97 (td, J_/=1.4, J₂=7.7, 1H), 8.05 (d, J=2.7 Hz, 1H), 8.09 (t, J=1.5 Hz, 1H), 10.73 (s, 1H), 12.98 (s, 1H) ppm; ¹³C- NMR (150 MHz, DMSO-d₆) δ: 123.75, 124.23, 129.22, 129.48, 130.75, 131.28, 134.21, 134.24, 135.91, 136.48, 137.80, 149.17, 167.50 ppm; MS m/z [M-H]^': 292.0.

Example 5: Synthesis of 5'-chloro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (Compound 2b):

[0053] 5'-Chloro-2'-hydroxybiphenyl-3-carboxylic acid (Compound 2a, 41.8 g, 0.168 mol) was suspended in acetic acid (2.2 L) at 25 °C and 50% H₂S0₄ (0.25 L) was added. The suspension was stirred for 30 min and then a nitrate solution (prepared by dissolving NaN0₃ (28.6 g) in water (75 mL) and 50% H₂S0₄ (75 mL)) was added dropwise to the suspension over 30 min. The resulting reaction mixture was stirred for 1 h at 25 °C. During this time, a precipitate formed. The precipitate was collected by filtration, washed with a mixture of AcOH/water = 1/1 (0.6 L) and then with water (3 x 0.6 L) and then dried at 50°C/50 mbar to provide 42.0 g (83%, HPLC purity 98.4%) of the compound (2b).

Example 6: Synthesis of 2-bromo-4-chloro-6-nitiOphenol (Compound lb):

[0054] A solution of 4-chloro-2-nitrophenol (4) (3.12 g, 18.0 mmol) in acetic acid (25 mL) was cooled to 5-10 °C, and bromine (1.0 mL, 19.7 mmol) was added dropwise. The reaction mixture was stirred for half an hour at 10 °C and then for 3 hours at room

temperature. The mixture was then diluted with ice- water and extracted with

dichloromethane (DCM) (3x30 mL). The combined organic extracts were washed with brine (30 mL) and dried over anhydrous Na₂S0₄. The solvent was then evaporated to give the crude product which was recrystallized from 96 % ethanol to afford a yellow crystalline product (lb) (3.80 g, 84%, purity 99%, HPLC Method B).

1H NMR (600 MHz, DMSO-d₆) δ: 8.02 (d, J= 2.6 Hz, 1H), 8.09 (d, J= 2.6 Hz, 1H) ppm; 1H NMR (300 MHz, CDC1₃) δ: 7.86 (d, J= 2.6 Hz, 1H), 8.11 (d, J= 2.6 Hz, 1H), 11.03 (1H, s, OH);¹³C NMR (150 MHz, DMSO-d₆) δ: 114.90, 123,38, 123.97, 137.67, 137.77, 148.12 ppm; MS m/z [M-H]^" 252.1.

Example 7: Synthesis of 5'-chloro-2'-hvdroxy-3'-nitrobiphenyl-3-carboxylic acid (Compound 2b according to Scheme (IV):

[0055] A mixture of Na₂C0₃ (424 mg, 4 mmol), Pd(OAc)₂ (22.4 mg, 5 mol %), PEG

2000 (7 g) and water (6 mL) was heated to 50 °C under an inert atmosphere with stirring. Afterward, 2-bromo-4-chloro-6-nitrophenol (Compound lb, 508 mg, 2 mmol) and 3- carboxyphenylboronic acid (Compound 3) (494 mg, 3 mmol) were added to the solution, and the mixture was heated at 50 °C under an inert atmosphere. After 3.5 hrs the reaction mixture was cooled to room temperature, diluted with water (50 mL), treated with 5% aq. HC1 to adjust to pH = 2 and extracted with ethyl acetate (3x 20 mL). The combined ethyl acetate extracts were washed with water and brine (50 mL), dried over anhydrous Na₂S0₄ and concentrated in vacuo. The crude product was obtained as a brown solid and was

recrystallized from 60 % acetic acid/water to afford compound (2b) (340 mg, 58%, purity 92%, HPLC Method B).

Example 8: Synthesis of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (BPCA):

[0056] 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid_(Compound 2b, 0.2 g,

0.68 mmol) was dissolved in a solution of NaOH (0.06 g, 1.5 mmol) in methanol (30 mL) and hydrogenated over 10 % Pd/C (50 mg, w/w 10 %) at room temperature in an autoclave at 10 bar for 6.5 hours. The reaction mixture was then filtered and the filtrate was concentrated. The resulting dark residue was dissolved in water and acidified with 0.5 M HC1 to pH = 6.5-7. A precipitate formed and was separated by filtration and purified through a short silica gel column (eluent DCM/MeOH/Et₃N = 9/1/0.1) to give the product as a yellow solid. The crude product was dissolved in 0.5 M NaOH (2mL) and acidified to pH = 6.5-7 at room

temperature. The resulting suspension was filtered, and the collected solid was washed with water and dried to yield BPCA (1 19 mg, yield 76 %, purity 98.1%, HPLC method A). Mp. 220-221 °C (dec). 1H NMR (600 MHz, DMSO-d₆) δ: 8.08 (1H, s), 7.86 (1H, d, J= 7.7 Hz), 7.71 (1H, d, J= 7.7 Hz), 7.51 (1H, t, J= 7.7 Hz), 6.71 (1H, t, J- 7.6 Hz), 6.67 (1H, dd, J= 1.8, 7.7 Hz), 6.49 (1H, dd, J= 1.8, 7.6 Hz); ¹³C NMR (150 MHz, DMSO-d₆) δ: 167.48, 140.32, 139.68, 138.45, 133.48, 130.48, 130.09, 128.86, 128.27, 127.29, 120.80, 118.05, 1 14.63; MS m/z [M-H]^" 228.3; Mol.Wt. (Ci₃H_uN0₃): 229.23.

Example 9: Synthesis of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (BPCA):

[0057] 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (Compound 2b) (1.25 g, 4.3 mmol) was dissolved in a solution of NaOH (0.35 g, 8.7 mmol) in methanol (75 mL) and hydrogenated over 10 % Pd/C (125 mg, w/w 10 %; Merck, oxidic form) at room temperature in an autoclave at 10 bar for 18 hours. The reaction mixture was then filtered through diatomaceous earth (Celite) and concentrated. The resulting residue was dissolved in water (10 mL), acidified with 0.5 M HC1 to pH = 2. Charcoal (10 mg; w/w 1%) was added and the resulting suspension was filtered. The resulting clear solution was adjusted to pH = 5. A precipitate formed and was filtered to give 596 mg BPCA. The filtrate was extracted with n-butanol. The extract was concentrated in vacuo and the resulting residue was washed with water, filtered and dried to give an additional 205 mg of BPCA. Combining the solids of the same purity, obtained from precipitate and the filtrate gave a total of 801 mg (82 %, purity 98%, HPLC Method B) of BPCA.

Example 10: Synthesis of 3'-amino-2^,-hvdroxybiphenyl-3-carboxylic acid (BPCA):

[0058] 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (Compound 2b) (5.0 g) was dissolved in a mixture of MeOH (300 mL) and Et₃N (4.75 mL). Pd/C (0.5 g) was added to the solution and the mixture was hydrogenated for 21 h at room temperature and 10 bars pressure. The catalyst was then removed by filtration, the filtrate was concentrated to dryness, and the residue was dissolved in water (40 mL). The pH was adjusted to 5.5 by dropwise addition of 0.5 M HC1 and the resulting suspension was stirred at RT for 30 min. The suspension was filtered, and the collected solid was washed with water (2 x 10 mL) and dried at 50 °C/50 mbar to provide BPCA (3.4 g; 86.7%; HPLC purity 97.9%).

Example 1 1 : Synthesis of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (BPCA):

[0059] 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (Compound 2b) (5.0 g) was dissolved in a mixture of MeOH (300 mL) and Et₃N (4.75 mL). Pd/C (0.5 g) was added to the solution and the mixture was hydrogenated for 21 h at room temperature and 10 bars pressure. The catalyst was removed by filtration. The filtrate was evaporated and the resulting residue was dissolved in mixture of water (40 mL) and MeOH (15 mL). The pH of the solution was adjusted to 5.5 by dropwise addition of 0.5 M HC1 and the resulting suspension was stirred at RT for 30 min. The suspension was filtered, and the collected solid was washed with water (2 x 10 mL) and dried at 50 °C/50 mbar to provide BPCA (3.3 g; 82.1%; HPLC purity 96.8%).

Example 12: Preparation of 3'-amino-5-chloro-2'-hydroxy-[l J'-biphenyll-3-carboxylic acid:

3'-amino-5ⁱ-c i orc-2'-?iydi'oxy--[1 ,1'-bipiienyl;^;-3-ciirboxylic acid

[0060] 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (Compound 2b) (1.0 g) was dissolved in a mixture of n-BuOH (40 mL) and NaOH (133 mg). Pd/C (0.1 g) was added to the solution and the mixture was hydrogenated for 30 min at room temperature and 10 bars H₂ pressure. Methanol (40 mL) was added and the catalyst was then removed by filtration, the filtrate was cooled to 0 °C. A precipitate formed and was separated by was filtration and dried at 50 °C to obtain the title compound.

Ή NMR (DSMO-d6) δ 6.48 (d, J = 2.5 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 8.08 (s, 1H).

¹³C NMR (DSMO-d6) δ 1 13.2, 1 16.4, 124.4, 127.8, 128.4, 129.9, 130.0, 130.6, 133.3, 138.3, 139.1, 140.5, 167.3.

Example 13: Preparation of Crude Eltrombopag

[0061] 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid ("BPCA") Form I (90 g, 392.6 mmol), was added slowly with stirring at room temperature to a solvent mixture of tech. methanol (1.8 L) and 4 M hydrochloric acid (0.245 L, 981.5 mmol) in a 3 L reactor. The resulting red solution was stirred for thirty minutes. The solution was then cooled to 0-5 °C and a cold solution of sodium nitrite (27 g, 391.3 mmol) in 90 mL of water was added over twenty minutes such that the reaction mixture temperature did not rise above 10 °C. The reaction mixture was stirred for one hour at 5-10 °C. Sulfamic acid (4 g, 41.2 mmol) in 90 mL of water was added at 5 °C, and the resulting mixture was stirred for an additional one hour at the same temperature. The reaction mixture was warmed to room temperature and triethylamine (ca 104 mL) was added to adjust to pH 7-8. l-(3,4-Dimethylphenyl)-3-methyl- lH-pyrazol-5-ol ("pyrazole") form I (72 g, 357.8 mmol), was added in one portion to the reaction mixture and the resulting mixture was stirred for an additional two hours at room temperature. Hydrochloric acid (4M, ca 140 mL) was slowly added with stirring over twenty minutes to adjust the pH to 1.8. A solid precipitated and was collected by filtration, washed with MeOH: water (1 :1 , 100 mL) and dried at 40 °C/0 bar in vacuum oven for about 18 hours giving 151 g of crude orange to brown crystals of Eltrombopag crude (HPLC: 98.5%, Yield=95.4%).

Claims

What is claimed is:

1. A process for preparing a compound of formula 2 :

Formula 2

comprising reacting a compound of formula 1 :

Formula 1

and the arylboronic acid ("Compound 3"):

Compound 3

wherein R¹ is -H, -CI or -F; R² is -Br or -I; and R³ is -H or -N0₂.

2. The process of claim 1, wherein R³ is -H, and the product is a compound of formula 2a of the following structure:

3. The process of claim 1, wherein R³ is -N0₂, and the product is a compound of formula 2b of the following structure:

Formula 2b

4. The process of any one of claims 1 to 3, wherein R¹ is -CI and R² is -Br.

5. The process of any one of claims 1 to 4, wherein the process is done in the presence of a catalyst and a base.

6. A process for preparing a compound of formula 2:

Formula 2

comprising reacting a compound of formula 1 :

Formula 1

and the arylboronic acid ("Compound 3"):

Compound 3

wherein R¹ is -H, -CI or -F; R² is -Br or -I; and R³ is -H or -N0₂;

wherein the process is done in the presence of a catalyst and a base.

7. The process of claim 6, wherein R³ is -H, and the product is a compound of formula 2a of the following structure:

Formula 2a

8. The process of claim 6, wherein R³ is -N0₂, and the product is a compound of formula 2b of the following structure:

1 * 2

9. The process of any one of claims 6 to 8, wherein R is -CI and R is -Br.

10. Use of a compound of formula 1 :

Formula 1

in a process of preparing BPCA wherein said process does not include any hydj group protection of the compound of formula 1.

A process for preparing BPCA:

comprising use of a compound of formula 1 :

Formula 1 wherein the process does not include protection of the hydroxyl-group on the formula 1 compound.

12. In a process for preparing BPCA:

the step of reacting a compound of formula 1 :

Formula 1

and the arylboronic acid ("Compound 3"):

(HO)₂B^ ^rffe^ ^CO,H

Compound 3

wherein R¹ is -H, -CI or -F; R^z is -Br or -I; and is -H or -N0₂.

13. A process for preparing BPCA of the following structure:

comprising preparing a compound of formula 2:

by the process of any one of claims 1-5 and converting it to BPCA.

14. The process of claim 13, wherein the conversion of a compound of formula 2 to BPCA comprises hydrogenating said compound of formula 2.

15. The process of claim 14, wherein R³ is -N0₂.

16. Use of a compound of formula 1 :

Formula 1

in a process of preparing Eltrombopag or a salt thereof, wherein said process does not include any hydroxyl-group protection of the compound of formula 1.

17. A process for preparing Eltrombopag or a salt thereof comprising use of a compound of formula 1 :

Formula 1

wherein the process does not include protection of the hydroxyl-group on the formula 1 compound.

18. In a process for preparing Eltrombopag or a salt thereof, the step of reacting a compound of formula 1 :

Formula 1

and the arylboronic acid ("Compound 3")

Compound 3

wherein R¹ is -H, -CI or -F; R² is -Br or -I; and R³ is -H or -N0₂.

19. A process for preparing Eltrombopag or a salt thereof, comprising preparing a compound of formula 2:

by the process of any one of claims 1-9, and converting it to Eltrombopag or a salt thereof.

20. The process of claim 19, wherein the conversion of a compound of formula 2 to Eltrombopag or a salt thereof comprises:

a) converting the compound of formula 2 to BPCA:

b) reacting the obtained BPCA and 2-(3,4-dimethylphenyl)-5-methyl-lH-pyrazol- 3(2H)-one of the following structure:

to produce Eltrombopag; and

c) optionally, reacting the Eltrombopag with a base, to obtain an Eltrombopag salt.

21. The process of claim 20, wherein the Eltrombopag is reacted with ethanolamine to obtain an Eltrombopag salt.

22. The compound 3'-amino-5'-chloro-2'-hydroxy-[l,l '-biphenyl]-3-carboxylic acid of the following formula:

The compound of claim 22, wherein the compound is in isolated form.

The compound of claim 23, wherein the compound is in crystalline form.

25. The compound of any one of claims 22-24, for use as a reference marker and/or a reference standard in the analysis and/or quantification of the purity of BPCA.

26. A composition comprisi

and one or more of the following BPCA impurities:

• 3 ' -amino-5 ' -chloro-2 ' -hydro - [ 1 , 1 ' -biphenyl] -3 -carboxylic acid:

3,3'-(2-amino-3-oxo-3H-phenoxazine-4,6-diyl)dibenzoic acid:

2 ' -hydroxy-[ 1 , 1 ' -biphenyl] -3 -carboxylic acid:

[1,1 '-biphenyl] -3 -dicarboxylic acid:

wherein each of said impurities can be present in an amount from about 0 wt % to about 1 wt %, as measured by HPLC.