Synthesis and characterization of potential impurities of eltrombopag olamine

Article abstract of DOI:10.14233/ajchem.2021.22951

This work reports the feasibility of recently developed industrial viable process for eltrombopag olamine starting from 2-bromo-6-nitro phenol and reports the identification of four potential impurities related to eltrombopag olamine, namely eltrombopag o

Full text of DOI:10.14233/ajchem.2021.22951

Asian Journal of Chemistry; Vol. 33, No. 1 (2021), 97-102
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2021.22951
Synthesis and Characterization of Potential Impurities of Eltrombopag Olamine
1,*,
1
1
1
1
KATUROJU SRINIVASACHARY
, CHENNURI RAJESH , SHASHIKANT TIWARI , Y.S. SOMANNAVAR , SAILENDRA KUMAR NADAKUDITY ,
1
1
2
KRISHNA MURTHY V.R. MOTURU , SAMALA BHANUCHADAR and BHOOMIREDDY RAMADEVI
1Chemical Research and Development, APL Research Centre-II, Aurobindo Pharma Ltd., Survey No.71 & 72, Indrakaran Village, Kandi
Mandal, Sangareddy District-502329, India
2Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Hyderabad-500072, India
*Corresponding author: E-mail: kathrojusrinivasachary@gmail.com
Received: 17 August 2020;
Accepted: 25 September 2020;
Published online: 10 December 2020;
AJC-20183
This work reports the feasibility of recently developed industrial viable process for eltrombopag olamine starting from 2-bromo-6-nitro
phenol and reports the identification of four potential impurities related to eltrombopag olamine, namely eltrombopag olamine ester (1),
2-aminophenol analogue of eltrombopag (2), 3,3′-(2-amino-3-oxo-3H-phenoxazine-4,6-diyl dibenzoic acid (3), 2′-hydroxy[1,1-biphenyl]-
3-carboxylic acid (4). These impurities are the crucial components in determining the quality of the drug substance, eltrombopag olamine
during its manufacturing. These impurities have impact on the quality of eltrombopag olamine and controlled these impurities results
excellent yields of active pharma ingredient of eltrombopag olamine
Keywords: Eltrombopag olamine, 2-Amino phenol, Impurities.
meters such as specificity, linearity, accuracy, limit of detection
(LOD), limit of quantification (LOQ) and relative retention [7].
Due to the stringent impurity profiling of API from the drug
regulatory authorities and their importance we herein report
the synthesis and characterization of four potential impurities
related to eltrombopag olamine, an anti-thrombocytopenic drug
viz. eltrombopag olamine ester (1), 2-amino-phenol analogue
of eltrombopag (2), 3,3′-(2-amino-3-oxo-3H-phenoxazine-4,6-
diyl dibenzoic acid (3), 2′-hydroxy[1,1-biphenyl]-3-carboxylic
acid (4) are reported. In the above mentioned impurities 2 and
3 are the process related impurities from the key intermediate
3′-amino-2′-hydroxy biphenyl-3-carboxylic acid, while impu-
rities 1 and 4 are the process degradant products from eltrom-
bopag olamine.
INTRODUCTION
Eltrombopag olamine is an anti-thrombocytopenic drug
and chemically known as 3′-{(2Z)-2-[1(3,4-dimethyl phenyl)-
3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-
2′-hydroxy-3-biphenyl carboxylic acid, bisethanol amine [1,2].
This drug is a small thromboprotein receptor agonist for oral
administration [3-5] and interacts with the transmembrane
domain of the thromboprotein receptor leading to increase the
platelet production.
The major challenge for the organic chemist is to produce
a quality, safe, reproducible synthetic schemes within the devel-
opmental space. Furthermore, it is extremely challenging to
identify the impurities or related substances which are important
components arise in trace level during the synthesis of drug
substance. Besides, the presence of impurities in an active pharm-
aceutical ingredient (API) has a significant impact on the quality
and safety of the drug. Therefore , it is always recommended
by ICH guidelines to study the origin and control of such imp-
urities which are present in the API at a level ≤ 0.05% w/w
[6,7] and also important to identify, synthesize and characterize
such impurities in a pure form to check the analytical para-
EXPERIMENTAL
Melting points were determined using Reichert Thermopan
apparatus. 1H & 13C NMR spectra were recorded with a Bruker
Avance 300MHz and Varian 500 MHz spectrometers,
respectively using TMS as internal standard in DMSO-d6. IR
spectra were recorded using Perkin-Elmer Spectrum One Fourier
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98 Srinivasachary et al.
Asian J. Chem.
O
OH
O
OH
O
O
NH2
OH
OH
OH
NH
NH
NH
OH
N
Methane sulfonic acid
Aluminum oxide
N
aq.HCl
N
H2N
CH3
2
H3C
O
H3C
O
H3C
O
N
N
N
N
N
N
CH3
CH3
CH3
CH3
CH3
1
5a
5
Scheme-I: Synthesis of eltrombopag olamine ester (1)
Transform (FT) IR spectrophotometer. High-resolution mass
spectral (HRMS) analyses were performed using the electro-
spray ionization (ESI) method on Xevo G2 QTOF mass spectro-
meter. HPLC measurements were run on Inertsil ODS-4 (250
mm × 4.6 mm, 5 µm; make: GL Sciences) with a flow rate of
1.0 mL/min having a column oven temperature of 25 ºC. UV
detection occurred at λ = 240 nm. Reagents and solvents were
procured from the commercial sources.
OH
(i) aq. NaNO2/
aq. HCl/methanol
NH
N
H3C
O
OH
O
N
(ii)
NH2
N
N
11
CH3
CH3
H3C
N
CH3
H
7
Preparation of eltrombopag olamine ester (1):Suspended
aluminium oxide (14 g, 135.7 mmol) in methane sulfonic acid
( 65.15 g, 678 mmol) was mixed with eltrombopag free base
(20 g, 45 mmol), monoethanol amine (3 g, 41.5 mmol) at 25-
30 ºC. Heated the reaction mass to 75-80 ºC and stirred the
reaction mass for 24 h and poured the reaction mass in to ice
cold demineralized water resulted in a solid crude, which was
precipitated out. Purified the solid crude by column chromato-
graphy with tetrahydrofuran:methylene chloride to yield eltrom-
bopag olamine ester (1) as a orange colour solid [8] (Scheme-I).
Yield: 15 g (68%); Purity: 96.28%, m.p.: 182 ºC; 1H NMR (300
MHz, DMSO-d6) δ ppm: 2.085-2.188 (t, 1H), 2.225-2.513 (m,
9H ), 2.730-2.732 (s, 1H), 2.890 (s,1H), 3.168-3.546 (t, 2H),
4.467 (s, 2H), 7.057-8.338 (m, 10H), 14.923 (brs, 1H);13C NMR
(100 MHz, DMSO-d6) δ ppm: 11.562, 18.865, 19.673, 38.053,
41.199, 57.443, 61.644, 114.058, 115.368, 118.929, 121.990,
127.210, 128.416, 128.701, 128.923, 129.535, 129.807, 130.184,
130.656, 132.249, 132.857, 134.150, 135.756, 136.811, 137.810,
142.540, 147.838, 150.826, 156.895, 165.599; HRMS (ESI,
QTOF) for C27H27N5O4[M+H]+: m/z calcd. (found): 486.2141
(486.2158).
Synthesis of 2-amino phenol analogue of eltrombopag
olamine (2): Added aqueous 4 M HCl (24 mL) to suspension
of 2-amino phenol (5 g, 46 mmol) in methanol (150 mL)
followed by the addition of 35% w/w aqueous sodium nitrite
solution (10 g, 50 mmol) at 0-5 ºC and stirred the reaction
mixture at the same temperature for 2 h. Now added compound
7 (50 mmol), triethylamine (13.95 g, 137.85 mmol) at 0-5 ºC
and stirred the reaction mixture for 30 min, then slowly raised
the reaction mixture to 20-25 ºC, again stirred the reaction
mixture at the same temperature for 2 h, filtered, washed with
methanol (10 mL) and dried under reduced pressure at 55 ºC
to obtained compound 2 as orange colour solid (Scheme-II).
CH3
2
(iii) Triethyl amine
Scheme-II: Synthesis of 2-aminophenol analogue of eltrombopag (2)
Yield: 10 g (68%); Purity: 99.61%; m.p.: 195 ºC. IR (KBr, νmax
,
cm-1): 3402 (phenolic-OH), 3048 (mononuclear arom. 1,3,4-
substituted), 1704 (C=O, amide); 1H NMR (300 MHz, DMSO-
d6) δ ppm: 2.226-2.488 (s, 6H), 2.494-2.512 (s, 3H), 6.918-
7.211 (m, 4H), 7.608-7.712 (m, 3H), 10.623 (brs, 1H), 13.625
(brs, 1H); 13C NMR (75 MHz, DMSO-d6) δ ppm: 11.508,
18.845, 19.626, 41.163, 57.429, 114.320, 115.312, 115.816,
118.856, 120.170, 126.295, 127.931, 128.904, 129.744, 132.724,
135.789, 136.752, 146.289, 147.670, 156.946; HRMS (ESI,
QTOF) for C18H18N4O2[M+H]+: m/z calcd. (found): 323.1508
(323.1478).
Synthesis of 3,3′-(2-amino-3-oxo-3H-phenoxazine-4,6-
diyl)dibenzoic acid (3): Cupric nitrate (2.65 g, 100 mmoL) was
added to a solution of compound 6 (25 g, 109 mmol) in DMF
(150 mL) at 25-30 ºC. Stirred the reaction mass at 60-65 ºC for
24 h and thereafter it was concentrated under vacuum at 55-
60 ºC. Purified the crude product by column chromatography
[9] (Scheme-III). Yield: 22 g (45%); Purity: 95.47%; m.p.:
175 ºC; IR (KBr, νmax, cm-1 ): 3329 (arom. NH2 ), 2955 (OH), 1266
(C-O). 1HNMR (300 MHz, DMSO-d6) δppm: 7.2-7.9 (m, 12H),
1.15-1.20 (brs, 2H); 13C NMR (75 MHz, DMSO-d6) δ ppm:
38.661, 38.939, 39.218, 39.774, 40.330, 98.155, 114.797,
125.120, 127.398, 127.786, 128.094, 128.310, 129.396,
129.945, 130.315, 130.845, 131.048, 131.667, 133.511, 133.951,
134.851, 135.198, 139.028, 144.531, 147.061, 147.815, 166.889,
167.100, 178.660; HRMS (ESI, QTOF) for C26H16N2O6[M+H]+:
m/z calcd. (found): 453.1087 (453.1091).
Synthesis of 2′-hydroxy[1,1-biphenyl]-3-carboxylic
acid (4): Compound 6 (5 g, 21.8 mmol) was added to mixture

Vol. 33, No. 1 (2021)
Synthesis and Characterization of Potential Impurities of Eltrombopag Olamine 99
O
OH
While searching the literature [17], it is observed that 2′-
benzyloxy-3′-nitro biphenyl-3-carboxylic acid (10) undergoes
COOH
N
O
a hydrogenation with PdC in methanol to afford [18] 3′-amino-
2′-hydroxy biphenyl-3-carboxylic acid (6) during these process
leads to a formation of impurities namely 3,3′-(2-amino-3-
oxo-3H-phenoxazine-4,6-diyl)-dibenzoic acid (3) and surpri-
Cu(NO3)2 / DMF
O
COOH
H2N
OH
NH2
singly another identified the process degradant impurity 2-
3
6
Scheme-III: Synthesis of 3,3′-(2-amino-3-oxo-3H-phenoxazine-4,6-diyl)-
dibenzoic acid (3)
amino phenol (11). Impurity 3 did not participate in the reaction
of 5 but it appeared as a contaminant in crude eltrombopag
olamine (5) and 2-amino phenol (11) was identified by HPLC.
It is further participated in eltrombopag olamine (5) reaction,
which involves in the diazotization with aqueous HCl and
NaNO2 followed by condensation with 2′-(3,4-dimethyl phenyl)-
5-methyl-(1H)-pyrazole-3-(2H)-one (7) in the presence of
base mono ethanolamine (8) to afforded 2-amino phenol analo-
gue of eltrombopag (2) with crude eltrombopag olamine (5)
[19].
Impurity 1 was formed in trace level during the conden-
sation of biphenyl-3-carboxy-2′-hydroxy-3′-diazonium chloride
(9) with 2′-(3,4-dimethyl phenyl)-5-methyl-(1H)-pyrazole-3-
(2H)-one (7) in the presence of base mono ethanol amine (8)
at 60-65 ºC for longer time (48 h). Impurity 4 was formed in
trace during the condensation of compound 9 with compound
7, where a loss of azo group of compound 9 leads to afford
impurity 4 [14,15].
The formation of impurity 1 is due to the thermal degrad-
ation of eltrombopag olamine, results in the esterification of
eltrombopag with monoethanol amine. It is difficult to synthe-
size impurity 1 in pure form because every time amide impurity
was obtained since the carboxylic group of eltrombopag having
high vicinity to react with amine group of mono ethanol amine.
However, we succeeded to prepare impurity 1 using an alter-
native route, acidified compound 5 with aqueous HCl results
in the formation of a free acid compound 5a. Coupling of free
acid compound 5a with mono ethanolamine (8) in the presence
of methane sulfonic acid, aluminium oxide to afford a crude
compound [8], which was purified by column chromatography.
For controlling of this impurity, attempted several experiments
and finally achieved the suitable procedure for the synthesis of
compound 5 and performed the reaction at 5-30 ºC.
of methanol (100 mL) and 4 M aqueous HCl (8 mL) at 0-5 ºC
and followed by the addition of sodium nitrite (1.65 g, 7 mmol).
Now added demineralized water (5 mL) and stirred the reaction
for 1 h at 0-5 ºC. Added 50% w/w aqueous hypophosphorous
acid solution (4.3 g, 32 mmol) and raised the reaction mixture
to 25-30 ºC. Thereafter, slowly raised the reaction mass temper-
ature to 65-70 ºC and reaction was completed in 6 h, by checking
TLC and concentrated the reaction mass under reduced pressure.
Dissolved the residue in methylene chloride (100 mL) and then
added demineralized water (50 mL). Now separated the organic
layer and evaporated under vacuum and purified the crude
compound by colum chromatography with using ethyl acetate
and hexane (Scheme-IV).Yield: 3.74 g (80%); Purity: 92.24%;
m.p.: 143 ºC. IR (KBr, νmax, cm-1 ): 3329 (arom. NH2), 2955 (OH),
1266 (C-O);1H NMR (300 MHz, DMSO-d6) δppm: 6.873-8.137
(m, 8H), 9.620 (s, 1H), 12.896 (brs, 1H);13C NMR (75 MHz,
DMSO-d6) δppm: 116.146, 119.606, 126.759, 127.441, 128.301,
128.988, 129.991, 130.284, 130.510, 133.416, 138.836, 154.317,
167.456; HRMS (ESI, QTOF) for C26H16N2O6[M-H]−: m/z calcd.
(found): 213.0552 (213.0557).
O
OH
COOH
aq. NaNO2 / aq. HCl/Methanol
aq. H3PO2
OH
OH
4
NH2
6
Scheme-IV: Synthesis of 2′-hydroxy[1,1-biphenyl]-3-carboxylic acid (4)
RESULTS AND DISCUSSION
It is very interesting to study of the formation of 2-amino
phenol analogue of eltrombopag olamine (2). A Suzuki reaction
of compound 13 was condensed with 3-carboxy phenyl boranic
acid with Pd/C and Na2CO3 in methanol medium leads to the
formation of compound 14 along with compound 10, which
undergoes hydrogenation with Pd/C with H2 gas results in the
formation of compounds 6 and 11. Compound 11 also partici-
pates in the final reaction of compound 5 to form trace level
of impurity 2 (Scheme-III).Alternatively, synthesis of impurity
2 can also be obtained by treating 2-aminophenol with aqueous
sodium nitrite and aqueous HCl and followed by condensation
with 2′-(3,4-dimethyl phenyl)-5-methyl-(1H)-pyrazole-3-
(2H)-one (7) in the presence of triethylamine leads to the
formation of impurity 2
Various synthetic routes are available in literature for the
preparation of eltrombopag olamine [10,11]. Duffy et al. [4]
reported the synthesis of eltrombopag, which is poorly soluble
in water. However, this compound has adverse effects and
further developed as pharmaceutically acceptable salt namely
eltrombopag olamine [12,13]. The process involves usage of
expensive reagents and very low isolation yield. Currently, a
developed method [14-16] involving inexpensive reagents is
shown in Scheme-V.According to Scheme-V, the synthesis of
eltrombopag olamine (5) involves the protection of 2-bromo-6-
nitro phenol (12) with benzyl chloride in the presence of K2CO3
and catalytic amount of tetrabutylammonium iodide in
acetonitrile to afford benzyl protected-2-bromo-6-nitro phenol
(13). Compound 13 was condensed with 3-carboxy phenyl
boranic acid with using 10% PdC (50% wet), Na2CO3 in methanol
to afford 2′-benzyloxy-3′-nitro biphenyl-3-carboxylic acid (10).
To control this impurity in compound 5, 2-aminophenol
content is limited to not more than 0.1% (w/w) in the specifi-
cation of 3′-amino-2′-hydroxy biphenyl-3-carboxylic acid (6)

100 Srinivasachary et al.
Asian J. Chem.
COOH
O
OH
Cl
B
Br
Br
O
HO OH
Tetrabutyl ammonium
ioedide
Pd / C
Sodium carbonate
Methanol
OH
O
NO2
NO2
NO2
12
10
13
O
NO2
14
O
OH
O
OH
COOH
H2 / Pd - C
Methanol
N
O
O
O
OH
OH
COOH
14
H2N
NO2
NH2
NH2
6
11
10
3
O
OH
O
OH
O
OH
OH
OH
H2N
NH
O
8
aq HCl
OH
2
N
H2N
aq NaNO2
Methanol
O
OH
OH
H3C
N
N
NH2
Cl
N N
N
11
3
H3C
N
H
6
CH3
CH3
9
CH3
CH3
7
5
Scheme-V: Synthetic scheme of eltrombopag olamine (5)
controls 2-aminophenol analogue of eltrombopag. Further, the
above specification limit of 2-aminophenol in compound 6
also controls 2-aminophenol less than 31.3 µg (30% of accept-
able limit ) in eltrombopag olamine drug substance as per ICH
M7.
and ethanol. This impurity is controlled to the limit less than
0.1% in eltrombopag olamine drug substance as per ICH Q3A.
2′-Hydroxy[1,1′-biphenyl]-3-carboxylic acid (4)is a degrad-
ation impurity. It was believed that this impurity originates
due to elimination of diazonium group from biphenyl-3-
carboxy-2-hydroxy-3′-diazonium chloride (9), during the syn-
thesis of eltrombopag olamine crude and can carry over to
eltrombopag olamine drug substance, and also further the
hydrolytic degradation of Eltrombopag results in impurity 4.
To control the impurity 4 during the isolation of eltrombopag
olamine crude implemented aqueous methanol followed by
purification from a mixture of DMSO and ethanol this impurity
is controlled to the limit (< 0.15%) in eltrombopag olamine
drug substance as per ICH Q3A. Synthesis of this impurity
(Scheme-VII) involves by treating of compound 6 with aqu-
eous sodium nitrite, aqueous HCl, aqueous hypo phosphorous
acid solution leads to form impurity 4 and isolated in form by
using column chromatography.
It is quite interesting to know the formation of impurity
3, during the preparation of compound 6. This can be under-
stood from the plausible mechanism of the formation of
compound 3. Preparation of impurity 3 involves (Scheme-VI)
by treating of compound 6 with cupric nitrate in DMF medium
leads to the formation of compound 3 and further purified by
column chromatography. This impurity was carry forward from
compound 6 to compound 5 but it not participated in the final
reaction of compound 5. The plausible mechanism of impurity
3 reveals the route that is during the synthesis of compound 6
from compound 10, the oxidative degradation leads to to form
impurity 3. In order to control this impurity, this impurity was
washed out during purification of compound 5 with DMSO

Vol. 33, No. 1 (2021)
Synthesis and Characterization of Potential Impurities of Eltrombopag Olamine 101
O
OH
O
OH
O
OH
OH
OH
O
HN
H
OH
NH2
NH
O
O
6
NH2
O
OH
O
OH
O
O
OH
OH
OH
H
N
OH
N
OH
H
N
OH
O
H
O
O
O
O
OH
OH
NH2
NH2
NH2
O
OH
O
COOH
N
O
O
[O]
(or)
O
COOH
O
H2N
N
OH
-2H
N
OH
H
O
O
O
H
O
NH2
NH2
3
Scheme-VI: Plausible mechanism of 3,3′-(2-amino-3-oxo-3H-phenoxazine-4,6-diyl)dibenzoic acid (3)
NH
O
OH
N
OH
H3C
O
N N
OH
CH3
CH3
OH2
NH
N
COOH
H3C
O
H2O
OH
N N
CH3
CH3
4
5
Scheme-VII: Plausible mechanism of 2′-hydroxy[1,1-biphenyl]-3-carboxylic acid (4)

102 Srinivasachary et al.
Asian J. Chem.
7. International Conference on Harmonization (ICH) Guidelines Q3A(R):
Impurities in New Drug substances; ICH Guidelines: Geneva, Switzerland
(2002).
8. H. Sharghi and M.H. Sarvari, Tetrahedron, 59, 3627 (2003);
https://doi.org/10.1016/S0040-4020(03)00518-0
Conclusion
In this work, a successful effort was made to synthesize
the four potential impurities related to eltrombopag olamine
viz. eltrombopag olamine ester (1), 2-amino phenol analogue
of eltrombopag (2), 3,3′-(2-amino-3-oxo-3H-phenoxazine-4,6-
diyl dibenzoic acid (3), 2′-hydroxy[1,1-biphenyl]-3-carboxylic
acid (4). These potential impurities will allow to understand
the actual cause for its generation and control in future.
9. S. Mukherjee, S. Roy, S. Mukherjee and B. Biswas, J. Mol. Struct.,
1217, 128348 (2020);
https://doi.org/10.1016/j.molstruc.2020.128348
10. S. Tingting,A Kind of Preparation Method for the Medicine Eltrombopag
Olamine for being used to Treat Idiopathic Thrombocytopenic Purpura,
Chinese Patent CN 107915678A (2017).
11. V.K. Agarwal, L.K. Katariya, G.B. Patel and H.S. Patel, Process for
the Preparation of Eltrombopag Olamine, Patent WO 2017081014A1
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12. S.J. Desai, S.P.D. Dwivedi, M.L. Rupapara and D.M. Keshavala,
Processes for the Preparation of Eltrombopag and Pharmaceutically
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ACKNOWLEDGEMENTS
The authors thank the management ofAurobindo Pharma
Ltd. and Chemical and Analytical Research Department,
Aurobindo Pharma Ltd. for their support and cooperation.
13. V.R.M. Moturu, S. Tiwari, S.K. Nadakudity, B. Samala, C. Rajesh, K.S.
Chary and M. Sivakumaran, An Improved Process for the Preparation
of Eltrombopag Olamine and its Intermediates, Indian Patent IN
201841020662A (2019).
14. B.P. Reddy, K.R. Reddy, J.S. Reddy and B.V. Krishna, Crystalline form
of Eltrombopag Free Acid, Patent WO 2016/035018A1 (2015).
15. V.R.M. Moturu, S. Tiwari, S.K. Nadakudity, B. Samala, C. Rajesh, K.S.
Chary and M. Sivakumaran, Novel Salts of Eltrombopag and Process
for the Preparation Thereof, Indian Patent IN 201841008924A (2019).
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Method of Eltrombopag Olamine, Chinese Patent CN 109096195A
(2018).
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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