Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide

Article abstract of DOI:10.3762/bjoc.8.162

Eletriptan hydrobromide (1) is a selective serotonin (5-HT1) agonist, used for the acute treatment of the headache phase of migraine attacks. During the manufacture of eletriptan hydrobromide the formation of various impurities were observed and identified by LC-MS. To control the formation of these impurities during the preparation of active pharmaceutical ingredients, the structure of the impurities must be known. Major impurities of the eletriptan hydrobromide synthesis were prepared and characterized by using various spectroscopic techniques, i.e., mass spectroscopy, FTIR , ¹H NMR, ¹³C NMR/DEPT, and further confirmed by co-injection in HPLC. The present study will be of great help in the synthesis of highly pure eletriptan hydrobromide related compounds.

Full text of DOI:10.3762/bjoc.8.162

Synthesis of compounds related to the anti-migraine
drug eletriptan hydrobromide
Suri Babu Madasu1,2, Nagaji Ambabhai Vekariya*1, M. N. V. D. Hari Kiran1,
Badarinadh Gupta1, Aminul Islam1, Paul S. Douglas2
and Korupolu Raghu Babu2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1400–1405.
1Chemical Research and Development, Aurobindo Pharma Ltd.,
Survey No. 71 & 72, Indrakaran (V), Sangareddy (M), Medak
Dist-502329, Andhra Pradesh, India and 2Engineering Chemistry
Department, AU College of Engineering, Andhra University,
Visakhapatnam-530003, Andhra Pradesh, India
doi:10.3762/bjoc.8.162
Received: 23 April 2012
Accepted: 27 July 2012
Published: 30 August 2012
Email:
Associate Editor: J. Aube
Nagaji Ambabhai Vekariya* - navekariya1@rediffmail.com
© 2012 Madasu et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
characterization; control; eletriptan; origin; related substances
Abstract
Eletriptan hydrobromide (1) is a selective serotonin (5-HT1) agonist, used for the acute treatment of the headache phase of migraine
attacks. During the manufacture of eletriptan hydrobromide the formation of various impurities were observed and identified by
LC–MS. To control the formation of these impurities during the preparation of active pharmaceutical ingredients, the structure of
the impurities must be known. Major impurities of the eletriptan hydrobromide synthesis were prepared and characterized by using
various spectroscopic techniques, i.e., mass spectroscopy, FTIR , 1H NMR, 13C NMR/DEPT, and further confirmed by co-injec-
tion in HPLC. The present study will be of great help in the synthesis of highly pure eletriptan hydrobromide related compounds.
Introduction
Eletriptan hydrobromide was first disclosed in U.S. patent been cited anywhere, except for in the case of some metabolites
5,545,644 (1996), assigned to Pfizer, New York, claiming the [3]. Eletriptan hydrobromide (1, Figure 1) is a second-genera-
product “eletriptan” and its pharmaceutically acceptable salts tion drug serotonin (5-HT1) agonist [4,5] used in the manage-
thereof. An optimization of the eletriptan hydrobromide syn- ment of sensations of tightness, pain, pressure and heaviness in
thesis to prepare chemically pure eletriptan hydrobromide was the precordium, throat and jaws. Eletriptan is more lipophilic
reported in the literature [1,2]. However, a detailed study on the than other triptans and absorbed more quickly than sumatriptan
profile of the impurities present and their synthesis has not yet in the intestinal absorption. Eletriptan is more effective than
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Figure 1: Related compounds of eletriptan hydrobromide.
sumatriptan in reducing the blood vessels surrounding the brain, Deacetylation of (12) by using potassium carbonate affords
which cause the swelling that is associated with the headache (R)-5-[(2-phenylsulfonyl)ethenyl]-3-(N-methylpyrrolidine-2-
pain of a migraine attack, by blocking the release of substances ylmethyl)-1H-indole (13). Reduction of 13 in the presence of
from the nerve endings that causes more pain.
palladium on carbon yields the free base of eletriptan, which on
further treatment with hydrobromic acid gives eletriptan hydro-
Eletriptan is metabolized by the enzyme CYP3A4 and desig- bromide (1).
nated chemically as (R)-5-[2(phenylsulfonyl)ethyl]-3-(N-
methylpyrrolidin-2-ylmethyl)-1H-indole. Various procedures Eletriptan is used as monohydrobromide salt and has molecular
for the synthesis of eletriptan hydrobromide are known [6-8], formula C22H27BrN2O2S and molecular weight 463.43 amu.
but the one generally used is the synthesis shown in Scheme 1. The maximum daily dose of eletriptan hydrobromide is 97 mg
Acetylation of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)- per day, which is equivalent to 80 mg of eletriptan base [10].
1H-indole (9) by using acetic anhydride and triethylamine in During the manufacture of eletriptan hydrobromide (1), many
N,N-dimethylformamide affords (R)-1-acetyl-5-bromo-3-(N- process-related impurities have been identified. As per ICH
methylpyrrolidin-2-ylmethyl)-1H-indole (10). When coupled in guide lines the acceptable level for known and unknown related
situ with phenyl vinyl sulfone (11) in the presence of a catalytic impurities in the drug substance should be not more than 0.15%
amount of palladium acetate [9] this affords (R)-1-acetyl-5- and 0.10%, respectively [11], depending on the maximum daily
[2(phenylsulfonyl)ethyenyl]-3-(N-methylpyrrolidin-2- dose. To meet the meticulous regulatory requirements, the
ylmethyl)-1H-indole (12), under Heck reaction conditions. impurities present in the drug substance must be identified and
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Scheme 1: Synthetic route of eletriptan hydrobromide. Reagents and conditions: (i) Acetic anhydride, TEA, DMF, 90–100 °C; (ii) palladium acetate,
tri-(o-tolyl)phosphine, TEA, DMF, 90–100 °C; (iii) methanol, K2CO3, acetonitrile, H2O, 5–10 °C; (iv) palladium on carbon, acetone, H2O, aqueous
hydrobromic acid, IPA, 25–30 °C.
characterized. By knowing the chemical structure of these low. Impurity 2 was prepared by the dimerization of desacetyl-
impurities, control may be possible. The related compounds ensulfone derivative 13 using a strong base, such as sodium
(impurities) of eletriptan hydrobromide were synthesized and hydride, under Michael addition reaction conditions in an anhy-
characterized by using various spectroscopic techniques, and drous medium (Scheme 2). This impurity can be controlled by
further confirmed by co-injection in HPLC.
using hydrous conditions during the deacetylation reaction.
Results and Discussion
Eletriptan N-oxide isomers 3 and 4 are possible contaminants
The eletriptan dimer impurity 2 is observed at 0.3–0.5% during that can be formed by oxidation in air. These compounds were
the basic hydrolysis of enesulfone derivative 12 and the impu- prepared by oxidation of eletriptan (14) with aqueous hydrogen
rity level is reduced to less than 0.20% during the isolation and peroxide (~50%, w/w) in the presence of catalytic amounts of
purification process [12]. It is necessary to remove the impurity ammonium molybdate. The isomers 3 and 4 were separated by
at this stage or control the formation during basic hydrolysis. preparative HPLC and confirmed by 1H NMR spectroscopy
Otherwise, the reduction rate of this impurity in later stages is [13,14] (Scheme 3). The combined contamination by 3 and 4
Scheme 2: Dimerization of 13. Reagents and conditions: (i) NaH, THF, 30–35 °C, 2 h; 11.6% yield after column chromatography.
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Scheme 3: Formation of the isomers 3 and 4. Reagents and conditions: (i) Aqueous hydrogen peroxide, methanol, ammonium molybdate, 25–30 °C,
ethyl acetate; 71% yield.
was 0.05–0.25% in eletriptan hydrobromide. Formation of this can carry forward up to eletriptan hydrobromide (1). Indolyl
impurity can be controlled by using peroxide-free solvents pyrrolidine 6 was prepared by catalytic hydrogenation of
during the final stage of synthesis.
bromoindolyl pyrrolidine (9) with palladium on carbon
(Scheme 5). The contamination of this impurity in eletriptan
Impurity 5 is formed at 1.0–1.5% during hydrogenation due to hydrobromide (1) was 0.10–0.20%. This impurity can be
hydrolytic cleavage. This impurity is reduced down to controlled by tightening up the in-process control of the
0.25–0.50% during isolation and in further stages. Impurity 5 N-acetyl bromoindole pyrrolidine during the Heck reaction.
was prepared by alkylation of N-acetyl bromoindolyl pyrroli-
dine 10 with triethylborane [15-17] in the presence of a catalytic
amount of palladium acetate in tetrahydrofuran, as in the
following reaction scheme (Scheme 4).
Scheme 5: Debromination of 9 to 6. Reagents and conditions: Palla-
dium on carbon, ethanol, ca. 7 bar, 25–30 °C, ethyl acetate; 94.5%
yield.
During the initial process development of eletriptan, the
deacetylation of enesulfone derivative 12 was performed in an-
hydrous methanol at ambient temperature with potassium
carbonate. The reaction was completed within 30 min, but the
formation of eletriptan methoxy impurity 7 was high
(0.20–0.70%). Moreover, after isolation and the subsequent
stage, it was still about 0.25%. To control the formation of 7,
the deacetylation reaction should be carried out in aqueous
Scheme 4: Synthesis of impurity 5. Reagents and conditions: (i) Acetic
anhydride, TEA, DMF, 90–100 °C; (ii) palladium acetate, tri-(o-
methanol instead of anhydrous methanol. Thus, a content of 7
below 0.05% is observed. Compound 7 was prepared by
treating desacetyl-ensulfone 13 with potassium carbonate in an-
hydrous methanol (Scheme 6). This impurity can be controlled
by using the hydrous conditions during the deacetylation reac-
tolyl)phosphine, K2CO3, triethyl borane in THF (1 M), THF, 64–66 °C;
(iii) methanol, K2CO3, methylene chloride, H2O, 5–10 °C and 85%
yield.
The content of indole pyrrolidine 6 in bromoindolyl pyrrolidine tion.
9 is controlled by its specification to not more than 0.5%.
However, during basic hydrolysis of enesulfone derivative 12, Surprisingly, we found that one unknown impurity (40–60%, by
unreacted N-acetyl bromoindolyl pyrrolidine 10 is converted to HPLC area normalization) was formed during the force degrad-
bromoindolyl pyrrolidine 9. Further, 9 will convert into 6 due to ation study of eletriptan hydrobromide (1) at higher tempera-
debromination during the hydrogenation reaction of 13 and it tures (80–85 °C) in the presence of peroxide in aqueous acetoni-
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Scheme 6: Formation of 7. Reagents, conditions: (i) (a) K2CO3, methanol, reflux, 2 days; 40% yield after column chromatography.
trile. It was also observed that only 4.5% of this impurity was
formed when 10% (w/w) hydrogen peroxide was used.
However, this impurity was formed at 40–60%, when 30%
(w/w) hydrogen peroxide used. This impurity was identified by
LC–MS and characterized by 1H NMR, 13C NMR, LC–MS and
FTIR. Based on the spectral data, the impurity was named as,
4-methyl-8-[2-(phenylsulfonyl)ethyl]-1,2,3,5,10,10a-hexahy-
dropyrrolizino[3,2-b]indole-4-ium (tetracyclic eletriptan impu-
rity, 8). A similar tetracyclic impurity (UK-373,236) is also
reported in literature [18]. This impurity is forming only in
aprotic solvents, e.g., acetonitrile in the presence of peroxides at
higher temperature. It was prepared by treating eletriptan hydro-
bromide (1) with aqueous hydrogen peroxide (30% w/w) in
aqueous acetonitrile at 80–85 °C (Scheme 7). Formation of this
impurity can be controlled by using peroxide-free aprotic
solvents at lower temperature.
Supporting Information
Experimental data, IR, 1H NMR and 13C NMR, LC-MS,
HPLC chromatograms for compounds 2 to 8 and HPLC
chromatogram of eletriptan spiked with related compounds
of eletriptan are included in the supporting information
files.
Supporting Information File 1
Experimental data of compounds 2 to 8.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-162-S1.pdf]
Supporting Information File 2
Characterization data of compounds 2 to 8.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-162-S2.pdf]
Conclusion
We have demonstrated the synthesis and complete characteriza-
tion of some of the critical impurities of eletriptan hydrobro- Acknowledgements
mide (1). This investigation helped us to establish the impurity The authors are grateful to colleagues in the Analytical
profile of 1.
Research Department of APL Research Centre, a division of
Scheme 7: Synthesis of the tetracyclic compound 7. Reagents and conditions: (i) aqueous hydrogen peroxide, water, acetonitrile, 80–85 °C, meth-
ylene chloride; 60% yield.
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Beilstein J. Org. Chem. 2012, 8, 1400–1405.
Aurobindo Pharma Limited, Hyderabad for their valuable
contribution to this work. The authors also thank the manage-
ment for giving permission to publish this work.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
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