Investigational study into the formation of methoxy derivative and other impurities during the optimization of eletriptan hydrobromide

Article abstract of DOI:10.1021/op3002454

During the process development of eletriptan hydrobromide, we have observed formation of an unknown impurity in the final product at enhanced levels which was identified as a methoxy substituted derivative on the side chain of the product. The present work involves detailed optimization studies directed toward the development of an efficient process for the commercial production of eletriptan hydrobromide substantially free from the methoxy impurity and other impurities.

Full text of DOI:10.1021/op3002454

Article
pubs.acs.org/OPRD
Investigational Study into the Formation of Methoxy Derivative and
Other Impurities during the Optimization of Eletriptan
Hydrobromide
U. Sampath Kumar, V. Ravi Sankar, M. Malleswara Rao, T. S. Jaganathan, and R. Buchi Reddy*
Orchid Chemicals and Pharmaceuticals Ltd., Research and Development Center, Plot No.476/14, Old Mahabalipuram Road,
Chennai-600119, India
ABSTRACT: During the process development of eletriptan hydrobromide, we have observed formation of an unknown
impurity in the final product at enhanced levels which was identified as a methoxy substituted derivative on the side chain of the
product. The present work involves detailed optimization studies directed toward the development of an efficient process for the
commercial production of eletriptan hydrobromide substantially free from the methoxy impurity and other impurities.
temperature to afford (R)-5-(phenylsulfonylethenyl)-3-(N-
methylpyrrolidin-2-ylmethyl)-1H-indole (3). Intermediate 3
was subjected to catalytic hydrogenation, followed by the
addition of hydrobromic acid to obtain eletriptan hydro-
bromide (5).
INTRODUCTION
■
Eletriptan Hydrobromide (trade name Relpax) is a selective
agonist of 5-HT1-receptors and particularly of 5-HT1B/1D
receptors and is widely used as an antimigraine agent.1−4 It is
chemically known as (R)-3-[(1-methyl-2-pyrrolidinyl)methyl]-
5-[2-(phenylsulphonyl)ethyl]-1H-indole hydrobromide, which
may be represented by chemical formula 5.
During our preliminary optimization studies, we have
observed four major impurities in the final product, and the
molecular weights of these impurities were identified by LC−
MS analysis as 242, 380, 398, and 412, of which the impurities
with molecular weight 242, 380, and 398 were identified as 5-
ethyl-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (6), unre-
duced intermediate 3, and N-oxide derivative 7, respectively,
with the available literature.9,10 The structure was further
confirmed through synthesis/isolation from mother liquor,
characterization, and HPLC spike studies. The content of 3, 6,
and 7 in the final product varied depending upon the various
process parameters of the reduction and salt formation steps,
and the control of these impurities could be accomplished by
employing appropriate controls in the process and solvents
used in the process. On the other hand, to our surprise, the
content of impurity with the molecular weight 412 remains
unchanged by varying the process parameters in the reduction
step. Detailed investigation and careful mapping of the
impurities at all the stages indicated that the impurity was
formed during the penultimate hydrolysis step due to 1,4
addition of methanol to the α,β-unsaturated sulfone in the
presence of base.11 The structure of the impurity is thus
identified as methoxy derivative 8 and further confirmed by its
synthesis, characterization, and HPLC spike studies. Despite
our sincere investigations on various parameters to remove
impurity 8 during the isolation of intermediate 3, reduction, salt
formation, and subsequent purification of final product, the
content of impurity 8 was the same or marginally reduced and
often resulted in undesirable quality of the product with poor
yield; hence, it is essential to control this impurity at the
hydrolysis stage by optimizing the process conditions.
Although there are several methods reported in the literature
for the synthesis for eletriptan hydrobromide,5−8 we considered
Scheme 1 for the development based on the commercial
availability of raw materials and the scale-up suitability. The
scheme involves reaction of (R)-1-acetyl-5-(phenylsulfonyle-
thenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole 2 by
means of K2CO3 in methanol at ambient temperature, yielding
(R)-5-(phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2-yl-
methyl)-1H-indole (3), reducing the CC double bond in the
presence of Pd/C to give (R)-5-(phenylsulfonylethyl)-3-(N-
methylpyrrolidin-2-ylmethyl)-1H-indole (4), which affords
eletriptan hydrobromide by treating with aqueous hydrobromic
acid. The above process was studied to optimize various
process parameters in the laboratory and finally made suitable
for scale-up in a commercial plant. Herein we report our
investigation on the role of solvent systems, reagents, and
temperature on the rate of reaction and impurity profile of the
final product.
RESULTS AND DISCUSSION
■
Key intermediate 2 was prepared on the basis of a reported
procedure5 by the Heck reaction (Scheme 2) of (R)-1-acetyl-5-
bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (1) and
phenyl vinyl sulfone in the presence of palladium acetate and
tri(o-tolyl) phosphine. Hydrolysis of 2 was performed with
potassium carbonate and methanol as solvent at ambient
Received: September 5, 2012
© XXXX American Chemical Society
A
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Article
a
Scheme 1
a
Reaction conditions: (a) methanol/water, K2CO3; (b) acetone/water, MeSO3H, H2, Pd/C 5%; (c) IPA, aqueous hydrobromic acid (48%).
a
Scheme 2
summarizes the impact of various factors, such as solvent, base,
and temperature, on the content of methoxy impurity 8.
a
Reaction conditions: (a) DMF, Pd(OAc)2/tri-o-tolyl phosphine,
triethylamine, phenyl vinyl sulfone.
During the optimization of the process parameters of the
hydrolysis step, initially we studied various solvents systems
such as, methanol/water, THF/water, and isopropyl alcohol for
the reaction, of which the methanol/water solvent system is
found to be the better choice for this reaction on the basis of
the conversion and operational ease during work up. Temper-
ature and nature of base were observed to be most critical for
the formation of the methoxy impurity; hence, the use of
stronger bases such as sodium hydroxide, potassium carbonate,
and higher temperature was detrimental during the reaction
and led to formation of impurity to the level of more than 25%
(entries 3, 4, and 5, Table 1). Lower temperature and milder
base, such as sodium bicarbonate, are the preferred choice of
conditions, which resulted in a substantially lower level of
impurity formation (entries 9 and 10, Table 1). Table 1
After achieving appropriate controls on the formation of 8,
our attention turned to containing the level of impurities of 3,
7, and 6 in the final product. During the course of our
optimization study on various work up procedures and solvent
purifications of final product to minimize the level of these
impurities, we observed that the content of unreduced
intermediate 3 and impurity 7 is unchanged, akin to the case
of impurity 8, but the level of impurity 6 is reduced to less than
0.1% from 1.0% by HPLC. It was a challenging task to control
the level of unreduced intermediate 3 and impurity 6, since
milder reduction conditions resulted in incomplete conversion
Table 1. Effect of Solvent, Base, and Temperature on the Content of Impurity 8 during Hydrolysis of Intermediate 2
HPLC purity
a
entry
solvent
base
mole
reaction temp (°C)
impurity 8 (%)
intermediate 3 (%)
1
2
isopropyl alcohol
K2CO3
K2CO3
NaOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
NaHCO3
1.0
1.0
2.0
1.0
2.5
1.0
0.5
0.3
1.0
1.0
25−35
25−35
60−65
60−65
60−65
45−50
25−35
25−35
25−35
40−50
no reaction
no reaction
52.65
THF/water (8:2)
methanol
3
42.30
26.36
42.5
9.03
1.13
0.45
ND
4
isopropyl alcohol
53.49
5
methanol/water (5:2)
methanol/water (9:1)
methanol/water (9:1)
methanol/water (9:1)
methanol/water (9:1)
methanol/water (9:1)
53.9
6
90.4
7
96.78
8
97.61
9
99.83
10
ND
99.83
a
As part of our process optimization, we studied the impact of mole ratio of base in a particular solvent system on the formation of methoxy
derivative and observed it to be higher if the amount of base used is higher and vice versa.
B
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Table 2. Effect of Solvent Ratio and Acid Catalyst in the Formation of 6 during Hydrogenation of 3
HPLC purity (%)
entry
solvent
acid catalyst
mol of acid
H2(g) pressure (atm)
time
3
4
6
1
2
3
4
5
6
7
8
7
MeOH (90%) water (10%)
MeOH (90%) water (10%)
acetone
AcOH
MsOH
MsOH
AcOH
MsOH
MsOH
MsOH
MsOH
MsOH
1.2
1.2
1.5
1.2
1.1
1.2
1.5
1.5
2.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
6 h
10 h
9 h
8 h
10 h
3 h
2 h
2 h
2 h
0.04
1.88
7.15
0.04
0.01
0.04
0.01
0.05
0.01
91.54
94.94
90.32
92.57
94.01
96.61
97.02
97.54
97.53
6.68
1.01
0.47
5.14
4.74
1.04
0.91
0.82
0.71
acetone (90%) water (10%)
acetone (90%) water (10%)
acetone (90%) water (10%)
acetone (90%) water (10%)
acetone (90%) water (10%)
acetone (90%) water (10%)
and rigorous conditions resulted in the formation of an
enhanced level of impurity 6. However, by carrying out several
optimizing experiments and the reduction conditions available
in the literature,12,13 we could identify that the nature and mole
ratio of acid used were the most critical parameters; hence, use
of stronger acid and excess moles of acid during the reaction
could complete the reaction in 2.0 h with the desired profile of
impurity 6 and 3 to a level of <1% and <0.1%, respectively
(entries 7, 8, and 9, Table 2). Weaker acids and lower mole
ratio of acid resulted in poor rate of conversion and undesired
impurity profile (entries 4 and 5, Table 2). Although the other
stronger inorganic acids such as hydrochloric acid gave a similar
result to that of methanesulfonic acid during our optimization
studies, inorganic acids were not considered because of the
corrosive nature and operational issues related to handling
during scale up. A combination of acetone (90%), water (10%),
and methanesulfonic acid (1.5 mol), under a hydrogen pressure
of 5 atm, was observed to be the optimal conditions for the
reaction. Table 2 briefly summarizes our efforts in arriving at
the proper combination of process parameters to obtain the
desired levels of 3 and 6 in the final product. Finally, the
formation 7 could be controlled by avoiding oxidizing
conditions during the reaction, work up, and crystallization
and ensured the preparation of eletriptan hydrobromide of
pharmaceutically acceptable quality in good yield.
spectrophotometer. IR spectra were recorded on a Perkin-
Elmer spectrum 65 FT-IR spectrophotometer in KBr pellets.
(R)-1-Acetyl-5-bromo-3-(N-methylpyrrolidin-2ylmeth-
yl)-1H-indole (1). A suspension of (R)-5-bromo-3-(N-
methylpyrrolidin-2ylmethyl)-1H-indole (200 g, 0.68 mol) in
toluene (1000 mL) containing triethylamine (104 g, 1.03 mol)
and 4-dimethylaminopyridine (4.19 g, 0.034 mol) was treated
with acetic anhydride (122 g, 1.20 mol) over 15 min, and then
the mixture was heated to 105−115 °C and maintained for 5−6
h. The mixture was allowed to cool and was quenched with
aqueous bicarbonate solution. The phases were separated, and
the organic phase was washed with water before evaporating
under vacuum to afford 218 g of oil, a 95% yield of 1.
(R)-1-Acetyl-5-(phenylsulfonylethenyl)-3-(N-methyl-
pyrrolidin-2ylmethyl)-1H-indole (2). To the above obtained
oil (218 g, 0.65 mol) was added dimethylformamide (400 mL),
and the reaction mixture was stirred at 25−35 °C to give a clear
solution. This solution was added to a solution of palladium
acetate (2.99 g, 0.0133 mol), tri-o-tolyl phosphine (18.2 g,
0.0597 mol), phenyl vinyl sulfone (126.74 g, 0.7534 mol), and
triethylamine (139 g, 1.38 mol) in dimethylformamide (400
mL) over 15 min, and then the mixture was heated to 100−120
°C. The mixture was maintained for 5−6 h, was allowed to
cool, and was filtered. The filtrate was diluted with water and
acetone to obtain a dark brown slurry. The mixture was filtered,
and the crude solid was washed with water. The crude wet solid
was then purified with aqueous acetone and dried under
vacuum to afford 200 g, 69% yield of 2.
(R)-5-(Phenylsulfonylethenyl)-3-(N-methylpyrrolidin-
2-ylmethyl)-1H-indole (3). A suspension of (R)-1-acetyl-5-
(phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2ylmethyl)-1H-
indole (2) (80.0 g, 0.189 mol) in methanol/water (640 mL/80
mL) was treated with sodium bicarbonate (15.9 g, 0.189 mol)
and heated to 40−50 °C. The reaction mass was maintained at
40−50 °C for 2−3 h and cooled to ambient temperature. The
reaction mixture was stirred for 60 min after the addition of
activated carbon (16.0 g). The reaction mass was filtered, and
the residue was washed with methanol. The filtrate was diluted
with water to obtain a pale brown slurry, and the solid was
filtered. The solid was washed with water before drying under
vacuum to give 62 g, 86% yield of 3.
(R)-5-(Phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-
ylmethyl)-1H-indole (4). A solution of (R)-5-(phenyl-
sulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole
(3) (27 g, 0.071 mol) in acetone (243 mL) and water (27 mL)
was treated with methanesulfonic acid (10.21 g, 0.106 mol) at
25−30 °C over 5 min and then charged to a hydrogenator
vessel. The mixture was hydrogenated at 5−6 atm hydrogen
pressure and 25−35 °C in the presence of Pd/C 5% (50% wet)
CONCLUSION
■
We have demonstrated, through a detailed investigation, the
chemistry of formation of methoxy impurity and other
impurities, which prompted us to identify proper conditions
for reactions, thereby controlling the impurity formation and
avoiding costly purifications at later stages. This allowed us to
develop an optimal process to prepare eletriptan hydrobromide,
which can be scaled up in a commercial plant.
EXPERIMENTAL SECTION
■
General Procedures. Commercially available solvents and
reagents were used without further purification. Reversed
phased HPLC elutions were performed on a stainless steel
column (250 mm length, 4.6 mm internal diameter, and filled
with porous silica particles of 5 μm diameter, which are bonded
to cyanopropyl group) using acetonitrile and buffer (2.72 g of
potassium dihydrogen orthophosphate in 1.0 L of water and
1
adjust pH 3.0 with ortho phosphoric acid) mixtures. H NMR
spectra were recorded on a Bruker Avance 400 MHz
spectrophotometer with a multinuclear BBO probe with TMS
as internal standard in DMSO-d6/CDCl3. Chemical shifts are
reported in δ scale (ppm). Mass spectra were measured on a
PE-SCIEX API-3000 LC/MS/MS with a Turbo ion spray mass
C
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(3) Durham, P. L.; Dong, P. X.; Belasco, K. T.; Kasperski, J.;
Gierasch, L.; Edvinsson, W. W.; Heistad, D. D.; Faraci, F. M.; Russo,
A. F. Brain Res. 2004, 997, 103.
for 2−4 h. The reaction mass was filtered, and then acetone was
removed completely under vacuum to obtain a reddish brown
oil as a residue. The oil was dissolved in ethyl acetate, and water
was added to the solution. The mixture was basified with 14%
aqueous ammonia solution, and the phases were separated. The
organic phase was washed with water, and the solvent was
evaporated under vacuum to afford 25 g of oil, 92% yield of 4.
(R)-5-(Phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-
ylmethyl)-1H-indole Hydrobromide Salt (5). A solution of
(R)-5-(phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmeth-
yl)-1H-indole (4) (25 g, 0.065 mol) in isopropyl alcohol (270
mL) was treated with 47% aqueous hydrobromic acid solution
(11.62 g, 0.067 mol) at 25−35 °C and stirred for 4−5 h to
obtain a pale brown slurry. The solid was filtered and washed
with isopropyl alcohol to give 22 g of crude eletriptan
hydrobromide (5). The crude obtained was purified with
methanol and isopropyl alcohol to afford 20 g of pale brown
solid, 66% of pure 5.
(4) http://www.medicinenet.com/eletriptan/article.htm.
(5) John, E. M.; Martin, J. W. U.S. Patent 5,545,644, 1996.
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Pharm. Biomed. Anal. 2009, 50, 622−629.
(10) Kusumba, V. G.; Sankineni, S. K.; Neela, P. K.; Pradhan, N. S.
WO 2010/097703 A1, 2010.
(11) Prilezhaeva, E. N.; Shapiro, E. S. Bull. Acad. Sci. USSR, Div.
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(12) Patrick, J. F.; Cornelius, J. K.; Ronald, J. O.; Vincent, R. U.S.
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(13) Vinod, K.; Dhirenkumar, N. M.; Rakesh, R. P.; Saurabh, P. U.S.
Patent 2009/0299077 A1, 2009.
5-Ethyl-3-{[1-methylpyrrolidin-2-yl]methyl}-1H-indole
(6). The reaction mass obtained by the reaction conditions
described in entry 6, Table 2 was worked up by following the
procedure described above to isolate eletriptan hydrobromide
(5). The mother liquor obtained was evaporated to obtain a
crude product enriched with 6. The crude product was purified
by preparative HPLC to afford pure 6. 1H NMR (DMSO-d6) δ:
1.2 (t, 3H), 1.46 (m, 1H), 1.58 (m, 2H), 1.70 (m, 1H), 2.16
(m, 1H), 2.38 (s, 3H), 2.41 (m, 1H), 2.45 (m, 1H), 2.64 (q,
2H), 3.02 (m, 2H), 6.91 (d, 1H), 7.09 (s, 1H), 7.22 (d, 1H),
7.29 (s, 1H), 10.6 (br s, 1H). m/z 243 [M + H]+.
5-[1-Methoxy-2-(phenylsulfonyl)ethyl]-3-{[1-methyl-
pyrrolidin-2-yl]methyl}-1H-indole (8). The reaction mixture
obtained by the reaction conditions described in entry 3, Table
1 was evaporated under vacuum to remove the solvent. The
residue obtained was phased between dichloromethane and
water. The organic phase obtained was evaporated under
vacuum to afford the crude product. The crude product was
1
purified by preparative HPLC to obtain pure 8. H NMR
(DMSO-d6) δ: 1.42 (m, 1H), 1.57 (m, 2H), 1.68 (m, 1H), 2.07
(m, 1H), 2.34 (m, 4H), 2.43 (m, 1H), 2.89 (s, 3H), 2.99 (m,
2H), 3.46 (m, 1H), 3.95 (m, 1H), 4.62 (m, 1H), 6.95 (d, 1H),
7.14 (d, 1H), 7.25 (d, 1H), 7.39 (s, 1H), 7.60 (t, 2H), 7.68 (t,
1H), 7.89 (d, 2H), 10.82 (br s, 1H). m/z 413 [M + H]+.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: buchireddyr@orchidpharma.com. Alternate E-mail:
buchireddyr@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank our management and the Analytical Research
Department and IPM groups of Orchid Chemicals and
Pharmaceuticals for their generous support. Finally, it is our
pleasure to acknowledge the reviewers for their suggestions.
REFERENCES
■
(1) The Merck Index, 13th ed.; Merck Research Laboratories, Division
of Merck Co. Ind.: Whitehouse Station, NJ, 2001.
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D
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